Fishman's Pulmonary Diseases and Disorders - PART 15

PART

XV Neoplasms of the Lungs

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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SECTION FIFTEEN

Cancer of the Lungs

102 CHAPTER

Genetic and Molecular Changes of Human Lung Cancer Jeffrey A. Kern

Geoffrey McLennan

I. GENETIC SUSCEPTIBILITY TO LUNG CANCER Acquired Genetic Changes II. MOLECULAR CHANGES Cytogenetic Changes Dominant Oncogenes Tumor Suppressor Genes Other Proto-Oncogenes and Oncoproteins

Lung cancer is the phenotypic consequence of an accumulation of genetic changes in airway epithelial cells that result in unrestrained cellular proliferation. The genetic and molecular changes that typify lung cancer are complex and not yet fully understood. There continue to be advances in knowledge and, with this, a better understanding of how the changes might contribute to the cancer phenotype, with possible diagnostic and therapeutic measures arising from this understanding.

Initial studies in the 1960s were performed using cytogenetics, and they allowed for developments in molecular biology to unravel some of the mystery of oncogenes. Although oncogenes were very much at the leading edge in the 1980s, in the early 1990s tumor suppressor genes (recessive oncogenes or antioncogenes) added immensely to our understanding This chapter has been slightly modified from the version that appeared in the third edition of Fishman’s Pulmonary Diseases and Disorders.

III. THE PROGRESSION OF NORMAL AIRWAY EPITHELIUM TO MALIGNANT EPITHELIUM Colorectal Carcinogenesis IV. THE IMPACT OF MOLECULAR GENETIC CHANGES ON THE CELL CYCLE

of tumorigenesis. Currently much interest is focused on the influence of these genetic factors on the cell cycle and on programmed cell death, or apoptosis. Underlying all this is the influence of environmental factors, especially cigarette smoke exposure, on any genetic susceptibility to lung cancer.

What is to be gained from understanding molecular and genetic changes in the development of lung cancer? We firmly believe that analysis of these factors will have a profound effect on diagnosis, histologic typing, the development of novel treatment strategies and therapeutic agents, prediction of response to therapy, and assessment of risk of relapse and long-term survival. Because of this, much effort has been expended translating newly discovered molecular and genetic changes into clinically useful information. Indeed, recent studies have begun to achieve this goal, with the realization that some genetic changes can identify patient subsets with differing prognoses and therapeutic responses, and with the

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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design of novel therapeutic agents targeting the defect. In this chapter we review recent knowledge in molecular genetics as it relates to small cell lung cancer (SCLC) and non–small-cell lung cancer (NSCLC).

percent of the population appear to be genetically susceptible to smoking-associated lung cancers. Though mathematically compelling, the physical existence of such a lung cancer susceptibility gene has not yet been demonstrated.

Acquired Genetic Changes GENETIC SUSCEPTIBILITY TO LUNG CANCER Many epidemiologic studies have demonstrated that some cancers are clustered in families, suggesting that susceptibility to the cancer may be inherited. Lung cancer, however, is most commonly thought of as a cancer that is determined solely by the environment. Certainly, the risks of lung cancer associated with cigarette smoking and in certain occupations, such as uranium mining and shipbuilding, are well established. On the basis of clinical findings, however, differing susceptibilities for tumor formation due to these environmental agents have often been postulated. Demonstrated epidemiologic differences between NSCLC in never-smokers and smokers, as well as differing survival outcomes, for instance, suggest that the pathogenesis and behavior of NSCLC progression may be different for the two groups.

Epidemiologic evidence for an increased familial risk of lung cancer was first noted in the early 1960s. In the largest study to date, a 2.4-fold increased risk of lung cancer was identified in relatives of lung cancer patients. This familial risk is supported by data from the Utah Population Database. More than one-third of all cancer cases in Utah were examined for a relationship with their genealogic record. These data also identified a familial clustering of lung cancer. Other studies have identified a gender disparity, with women at greater risk of developing lung cancer through familial factors than men.

Epidemiologically, this is most likely to occur in women who do not have a history of heavy smoking, who have a younger age at onset of the disease, and who have squamous cell carcinoma.

More recent studies of familial risks or genetic susceptibility to lung cancer have demonstrated a chromosomal linkage between lung cancer and lung function, as well as overlap in candidate genes for these outcomes and a fivefold increase in breast cancer risk for first-degree relatives of women with a positive family history of early-onset lung cancer. Specific genetic polymorphisms have also been associated with lung cancer risk.

Modeling of the familial clustering data suggests a mendelian pattern of codominant inheritance, the result of a rare autosomal gene. This model suggests that carriers of this gene have a young age at lung cancer onset, with a risk 2245fold greater in nonsmoking individuals homozygous for the affected gene. In this model, the putative lung cancer gene accounts for 69 and 47 percent of the cumulative incidence of lung cancer in patients up to 50 and 60 years old, respectively, and is involved in 22 percent of all lung cancers in persons up to age 70. Significantly, random environmental factors do not explain this familial clustering. Further segregation analysis of smoking-associated malignancies has demonstrated that 62

Not all lung cancers have a heritable basis. Thus, other explanations must exist for cancers that arise as sporadic or nonfamilial cases. These tumors are not due to germ line mutations or a cancer susceptibility gene that would result in a heritable cancer, but must be due to acquired somatic genetic alterations. The first persuasive evidence that cancer could be attributed to discrete, noninherited, genetic elements was the observation by Rous in 1911 that a cell-free filtrate from a chicken sarcoma could induce sarcomas in other chickens. The cancer-causing element was ultimately found to be a virus, the Rous sarcoma virus, and its oncogenic potential was demonstrated to result from a specific gene called v-src, which was identified as a mutated cellular gene. Since the discovery of this oncogene, more than 50 different cellular oncogenes have been discovered and found to have critical roles in human cancer development.

There are two classes of oncogenes, dominant oncogenes and recessive oncogenes, or tumor suppressor genes. Oncogenes are derived from normal cellular genes called protooncogenes. The encoded protein product of a proto-oncogene often plays an important role in cell signaling, or cell growth regulation. These genes can become activated by mutation, chromosomal translocation, amplification (gene duplication manyfold in the genome), or transcriptional dysregulation, resulting in the production of an abnormal protein or an overabundance of the normal protein. These activated protooncogenes are now called oncogenes, and their protein products are oncoproteins. Proto-oncogenes and oncogenes are named with a three-letter designation (e.g., myc). The same three-letter code, nonitalicized and starting with a capital letter, denotes the protein product (e.g., Myc). The prefix v, as in v-src, refers to an oncogene of viral origin. The corresponding cellular proto-oncogene is given the prefix c (c-src). In their activated form, the oncogenes provide a growth advantage for the expressing cell. Laboratory, clinical, and epidemiologic observations suggest that more than one genetic or biochemical event is needed to transform normal cells into malignant cells. Thus, the further accumulation of critical events in a cell population with a growth advantage results in tumorigenesis. Once a cell becomes transformed into a malignant cell (i.e., no growth restraint), other events are required for malignant cells to proliferate successfully, especially the provision of new blood vessels (angiogenesis) to create a favorable environment for growth. The interactions between the genetic changes in the cell nucleus and the changes necessary in the cell environment such as blood supply, nutrition, and extracellular matrix are only just beginning to be studied. However, these interactions are likely to be critical to conferring the various degrees of malignancy.

In practical terms, proto-oncogenes fall into five categories: growth factors, receptors for growth factors or hormones,

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Genetic and Molecular Changes of Human Lung Cancer

Receptor Overexpression Unregulated Intracellular Signal Transduction ras family

Normal Protein from Normal Allele

Oncoprotein from Mutant Allele

No Functional Effect One allele Affected

Proto Once Gene

Mutation of one allele [Oncogene]

Loss of Protein Function p53 Both Alleles Rb Affected

Nuclear Effects

Abnormal Transcription Factors [fos, jun, myc family] Loss of programmed celldeath [bcl-2]

A

B

Figure 102-1 The role of dominant oncogenes and recessive oncogenes in human lung cancer. A. Dominant oncogenes require activation of only one allele. The resultant oncoprotein functions abnormally or is overproduced. Shown here are oncogenes and oncoproteins known to be active in lung cancer. B. Recessive oncogenes require two mutations, resulting in the actual loss or loss of function of the encoded protein. Shown here are recessive oncogenes known to be associated with lung cancer.

intracellular signal transducers, nuclear transcription factors, and cell cycle control proteins. Thus, it is understandable that an oncogene, through the action of its corresponding oncoprotein, can have a profound effect on cell growth.

Dominant oncogenes are relatively easily identified, since they have a genetically dominant role in converting a nontransformed cell to a transformed (malignant) cell. In this instance, only one of the two alleles carrying a specific gene needs to be affected. The concept of dominant oncogenes and the resulting oncoproteins is illustrated in Fig. 102-1 A. This figure also highlights oncogenes that have been noted so far in lung cancer.

Evidence for a second class of genes active in tumor formation—recessive oncogenes or tumor suppressor genes—has been much more difficult to establish. The earliest evidence for the existence of tumor suppressor genes in cancer genesis was from somatic cell genetic studies in which normal and tumor cells were fused. Surprisingly, the resultant hybrid cells were often not tumorigenic, an unexpected finding if a dominant oncogene was involved. If transformation was due to a dominant oncogene supplied by one member of the hybrid, the presence of normal genetic information supplied by the other member should have no effect on transformation.

This led to the notion that the tumor cell had lost genetic information from both the maternal and paternal alleles of a critical genetic locus, which was replaced by the normal cell in the hybrid.

A second line of evidence for the existence of tumor suppressor genes was provided by studies of the genetics and natural history of pediatric tumors—in particular, retinoblastoma. It was proposed by Knudson that the development of retinoblastoma could be explained by the acquisition of two mutations (i.e., one mutation in both alleles of the same genetic locus). For each gene locus, the human genome has two gene copies, one maternal and one paternal. One mutation was proposed to be present in a parent’s germ line and therefore abnormal in all somatic cells of the affected subject at birth. With the acquisition of a second mutation in the remaining normal allele, the protein product encoded by the affected gene became functionally inactive, and the retinoblast cell underwent malignant transformation. After elegant cytogenetic and molecular genetic analysis, it was determined that one allele of the retinoblastoma gene (Rb) was inactivated in the inherited form of retinoblastoma as hypothesized. On inactivation of the other retinoblastoma allele, a retinoblastoma developed. In the nonfamilial form of retinoblastoma, somatic mutations in both alleles of the retinoblastoma gene are acquired after birth. The acquisition of two events in the correct alleles is, of course, much less likely than the single event required for the heritable form of the disease, making sporadic retinoblastoma much rarer. Thus, for tumors to develop as a result of tumor suppressor oncogene abnormalities, both maternal and paternal alleles must be mutated/inactivated before the malignant phenotype is evident. Therefore, the

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name recessive oncogenes or tumor suppressor genes was developed. The concept of recessive oncogenes is shown in Fig. 102-1B, which also highlights recessive oncogenes found in lung cancer.

Many genetic regions containing suspected tumor suppressor genes have been discovered by examination of DNA obtained from malignant and normal cells from the same patient for loss of alleles, i.e., loss of heterozygosity (LOH). The two alleles of a gene locus, one maternal and one paternal, are often polymorphic and thus distinguishable through genetic techniques. However, the heterozygous pattern often found in normal tissue, due to alleles inherited from two parents, is not seen if one allele is lost or mutated. If a mutation is present in the remaining allele, the loss of the other allele unmasks the mutation, resulting in the outgrowth of cells that have lost the function of the affected gene, as in the example of retinoblastoma. In lung cancer, many such allelic losses in specific chromosomal regions have been identified.

However, outside of the retinoblastoma and the p53 gene, the presumed target of the losses (i.e., specific putative tumor suppressor genes) has not been identified.

MOLECULAR CHANGES Cytogenetic Changes Chromosomal changes are informative in tumors, as they point to a discrete area in the genome to examine for mutated or lost growth regulatory genetic information. Initially, chromosomal changes were discovered by examination of chromosomes in a dividing cell with microscopy. This tedious task, known as cytogenetics, began our genetic understanding of many malignant changes, beginning with the Philadelphia chromosome in 1960. In lung cancer, karyotypic or cytogenetic changes in SCLC have been repeatedly demonstrated, with consistent deletions of the short arm (p) of chromosome 3 (3p), especially 3p21-25, suggesting a tumor suppressor gene at that site. Also, losses cytogenetically of the long arm (q) of chromosomes 5, (5q21), 13 (13q14), and 17 (17q13) have been described cytogenetically. The last two sites contain the Rb and p53 suppressor loci. In addition, in NSCLC numerous chromosomal abnormalities are seen on cytogenetic study, most frequently (in descending order) in 3p14, 3q21, 19q13, 11p15, 1q11, 7q11, 1q21, 3p23, and 3p21.

A recent meta-analysis of chromosomal imbalances reports identification of affected genes that may contribute to SCLC and NSCLC development and progression. Other findings point out the many chromosomal defects in NSCLC that are likely to contribute to the pathogenesis of the disease, and new dominant and recessive oncogenes are likely to be discovered.

Dominant Oncogenes Myc Family The myc family of proto-oncogenes encode nuclear proteins that have DNA-binding properties and are thought to

be active in the regulation of transcription. There are three members of this family, c-myc (chromosome 8q24), N-myc (chromosome 2p23-24), and L-myc (chromosome 1p32). Activation of this family of proto-oncogenes in lung cancer occurs by gene amplification and overproduction of the normal protein product. Amplification of all members of this family has been found in SCLC. In any single tumor, however, only one member of the family has been reported amplified at a time. Amplification of two or all three members simultaneously has not been found. The myc genes encode three related cell cycle–specific nuclear phosphoproteins. It is likely that the myc genes, which are highly conserved over large phylogenic distances, are important in normal cell growth and differentiation, embryo genesis, and apoptosis. Clinically, c-myc gene amplification has been related to a more malignant course in SCLC. N-myc gene overexpression in SCLC has been correlated with a poor response to chemotherapy and a more aggressive clinical course. L-myc is also overexpressed in some patients with SCLC, but without apparent clinically significant effects. However, the L-myc EcoR1 polymorphism has been shown to be a marker of tumor prognosis in lung cancer.

Understanding this abnormality has led to the possibility of targeting c-myc as a new form of therapy. Exposure of an SCLC cell line expressing L-myc to L-myc antisense DNA inhibited cell growth in a dose-dependent manner, perhaps suggesting a therapeutic opportunity as well as providing insight into function. Myc gene amplification also occurs in NSCLC. In a recent study, c-myc amplification was found in 48 percent of NSCLC, but amplification of L-myc and N-myc was uncommon. Unfortunately, the presence of c-myc amplification in NSCLC does not appear to have any clinical significance. It is emerging that there is clearly complex regulation of myc expression, and myc appears to regulate the expression of other proto-oncogenes. For example, c-kit expression may be regulated by c-myc when cells expressing c-myc do not express c-kit.

Ras There are three ras proto-oncogenes, H-ras, K-ras, and N-ras. These genes code for closely related 21-kD guanosine triphosphate (GTP)–binding proteins, called p21ras, which are functionally related and have structural similarities to G proteins. These proteins are localized to the inner side of the cell membrane and participate in signal transduction. Specific K-ras point mutations are relatively common in NSCLC, especially in adenocarcinomas. These mutations result in a single amino acid change in the protein, causing a marked reduction in its intrinsic GTPase activity, and the protein remains in an active GTP-bound state. Thus the protein is fixed in the “on” position and cannot turn off. Once acquired, these mutations appear stable, being present both in the primary tumor and in metastases, as is the case with most of the genetic mutations, although the ras abnormalities have been best studied in this regard. H-ras and N-ras mutations appear to be rare in human lung cancers. As the sensitivity of assays increases, the incidence of K-ras mutations continues

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to increase, occurring in up to 56 percent of lung cancers. It is interesting that K-ras mutations have been noted in bronchial biopsies from smokers with no evidence of lung cancer, and they can be found in sputum samples up to 1 year before the clinical diagnosis of lung cancer, raising the question of their use as premalignant markers. Indeed, examination of the distribution of K-ras mutations in established tumors suggests that these changes occur at an early stage in the development of the malignancy.

The carcinogen causing the K-ras mutation is not known, but K-ras mutations are closely associated with cigarette smoke exposure. Whether this is a causative factor or only an association is unclear. Clinically, the presence of a K-ras mutation in an adenocarcinoma is an independent portent of poor survival, which two recent meta-analyses have confirmed. However, one study indicates that for patients with completely resected NSCLC, K-ras mutations in combination with p53 mutations may only be a weak prognostic marker. Nonetheless, the presence of this discrete molecular change has led to the design of a new treatment strategy.

Tumor growth in cell lines containing a K-ras mutation is markedly reduced by a K-ras antisense RNA construct introduced by a retroviral vector. Thus, a better understanding of this molecular change in lung cancer has led to the recognition of an important negative prognostic factor, possible premalignant marker, and novel therapeutic approach.

Ras Protein The protein product of the ras gene (p21ras) has been demonstrated also to be an independent prognostic factor in defining survival in NSCLC. Subjects whose tumors had a high level of p21ras expression had shorter survival than those whose tumors were p21ras negative. How this finding relates, if at all, to the known ras gene mutations in lung cancer and whether it provides information independent from them are unclear.

Of great interest is the recent observation that inhibition of p21ras activity may be a viable treatment strategy by interfering with a posttranslational lipid modification of the molecule necessary for its function. With use of the farnesyltransferase inhibitor (FTI276), growth of a human lung cancer characterized by a K-ras mutation was inhibited in an animal host in a dose-dependent manner.

Tumor Suppressor Genes Retinoblastoma Gene The retinoblastoma gene, located on 13q, was the first tumor suppressor gene to be identified, owing to its importance in the genesis of hereditary retinoblastoma. It encodes a 105,000-Da nuclear phosphoprotein (pRB) that is a regulator of cell division. pRB’s phosphorylation status is key to a cell’s progression through the cell cycle. pRB is underphosphorylated in G1, is heavily phosphorylated in late G1 just before S phase, but reverts to an unphosphorylated state just before G0. pRB in its unphosphorylated state binds to the E2F family of transcription factors, not allowing the E2F-induced

Genetic and Molecular Changes of Human Lung Cancer

transcription of genes important to cell cycle progression.

This results in a block of S phase entry, ultimately causing cell division to stop. pRB isolated from tumors is often mutated, resulting in a functionally inactive protein unable to bind E2F or to be regulated by phosphorylation. Thus, cellular proliferation becomes unregulated. Rb gene inactivation may promote cell division by other measures as well, such as shortening telomere length. In addition, differential regulation of the pRB protein may occur in SCLC versus NSCLC; pRB may be inhibited by p16 (a cyclin-dependent kinase inhibitor) in SCLC, but not in NSCLC, indicating the complex relationships that exist in genetic abnormalities and are increasingly being demonstrated. However, the relationships between various common gene abnormalities have been assessed in lung cancer, and generally there is no clear or regular association of one gene defect with another. Although resectable NSCLS may show distinct patterns of TSG inactivation, no clear correlate has been established with respect to pRB, among other abnormalities.

Defects in the Rb gene or in pRB are almost universal in SCLC but are seen in only 30 percent of NSCLC. No relationship to clinical survival has been found. The central importance of pRB in growth regulation has been shown by reconstitution of the Rb gene into SCLC lines. This suppresses their growth, without the requirement for correction of other genetic abnormalities. This finding perhaps points to another potential therapeutic strategy. p53 Gene Initially, p53 was thought to be a dominant oncogene, as the p53 protein was detected at very high levels in cancers. However, it is now realized that wild-type p53 is a regulator of cell growth, and mutations in the p53 gene produce either a dysfunctional or no p53 protein. The mutant protein has a much longer half-life than the wild type, resulting in the high levels that are seen in transformed cells. The p53 gene is located on chromosome 17p. p53 Gene abnormalities are common in lung cancer, usually as a point mutation, which has been detected in exhaled breath condensate. The encoded protein (p53) is probably a nuclear transcription factor, and it is a tumor suppressor factor by mechanisms that are not yet fully elucidated. p53 Regulates cell growth at the G1-S phase interface of the cell cycle and plays a role in inducing apoptosis, or programmed cell death, in cells with damaged DNA. Mutations in p53 appear to be associated with exposures to environmental substances such as cigarette smoke but are not correlated to resectable NSCLCs. Abnormalities in p53 expression do not appear to be associated with prognosis in mixed lung tumors, but they may confer a worse prognosis in patients with stage I adenocarcinomas. A meta-analysis of published studies shows that p53 alteration is more likely as overexpression (protein) than mutation (DNA), and less likely in adenocarcinoma than in squamous cell carcinoma; and confirms that it is a significant marker of poor prognosis.

It has been demonstrated in an animal model that wild-type p53 can be transduced into lung cancer tumor spheroids with

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a retroviral vector. If the tumor cells were homozygous for a mutant p53, there was significant growth inhibition after transduction and expression of wild-type p53, with apoptosis induced in the cellular spheroids. This raises the possibility of a novel therapeutic approach to lung cancers that have a p53 gene mutation. A recent study has shown that intratumoral injections of Ad5CMV-p53 have been linked to clinical benefits for advanced NSCLC patients, including specific p53 transgene expressions.

9p LOH on the short arm of chromosome 9 (9p) occurs in more than 50 percent of NSCLC, and in SCLC there are abnormalities in the same region (9p21-22) in approximately 58 percent of cases. Of interest is that 9p contains the interferon and the methylthioadenosine phosphorylase genes. These genes are deleted or rearranged in 36 to 43 percent of all lung tumor types and, while not themselves tumor suppressor genes, are probably adjacent to a putative tumor suppressor gene.

This gene has recently been identified as the multiple tumor suppressor 1/cyclin-dependent kinase-4 inhibitor (MTS 1/CDK4I) gene and is inactivated in NSCLC. When the MTS1 gene encoding p16INK4 is introduced into human lung cancer cell lines not expressing the gene, tumor proliferation is inhibited in vivo and in vitro. These tumor cells are growth arrested in G1 just before S phase. This also raises the notion that such a gene may be a suitable gene therapy candidate in selected lung tumors. Similarities between mutations in HER2 and EFR genes with respect to tumor type, mutation type, and patient subpopulations (smokers versus never smokers) suggest similar etiologic factors. The mutual exclusivity shown between EGFR, HER2, and K-ras mutations suggests different pathways to lung cancer in smokers and never smokers.

5q There have been further observations on the LOH involving 5q, which has been observed in 29 percent of NSCLC. 5q LOH correlates with tumor progression and poor survival.

In SCLC, 5q LOH is even more frequent, being found in more than 80 percent of cases. This locus is in the region of the adenomatous polyposis coli (APC) gene associated with colorectal cancers, suggesting that a lung cancer tumor suppressor gene is present at this site and is associated with these lung carcinomas.

Other Proto-Oncogenes and Oncoproteins Several other oncogenes in lung cancer appear to exert their effects through the overproduction of the normally encoded protein, not through a mutant gene or the production of an abnormal protein. The overproduction suggests a regulatory defect in transcription of the gene or gene amplification. The genes and protein products commonly affected in this manner are c-erbB-1 and c-erbB-2, both receptor tyrosine kinases; c-src, a nonreceptor tyrosine kinase; c-kit, c-met, and c-fms, also receptor tyrosine kinases; c-fos and c-jun, nuclear transcription factors; p40TAK, a protein kinase; and RAF1,

a serine kinase. At least two of these oncoproteins—namely, c-kit in SCLC and c-erbB-2 in NSCLC—are increased without detectable gene amplification. c-erbB-1 This membrane-bound proto-oncogene encodes a 170,000Da tyrosine kinase growth receptor that is the epidermal growth factor receptor (EGFR). The proto-oncogene, through its protein product, functions in the normal lung to stimulate epithelial cell proliferation and promote airway maturation during development. Overexpression of the proto-oncogene has been found in NSCLC, especially the squamous cell subtype, in 65 to 90 percent of reported cases.

The mechanism for this is complex, as overexpression of c-erbB-1 alone does not result in transformation of cultured NIH3T3 cells. However, transformation of these cells does occur in the presence of the c-erbB-1 ligand (epidermal growth factor, transforming growth factor-α). Analysis of c-erbB-1’s ability to transform airway epithelial cells has not been performed, so it is not clear whether c-erbB-1 overexpression is causative or simply associated with human lung cancer. The use of c-erbB-1 overexpression as a clinical prognostic marker is controversial, with some studies showing an association with poor survival, while others do not. c-erbB-2 This proto-oncogene is in the c-erbB-1 family of membranebound tyrosine kinase receptors; thus it is related to c-erbB-1 structurally and in amino acid sequence. The encoded protein, called p185c-erbB-2 or HER2, also is expressed in normal lung respiratory airway epithelial cells and may play a role in normal lung epithelium growth and differentiation. HER2 is coproduced with EGFR in many lung adenocarcinomas and almost certainly contributes to sustained cell growth. This oncoprotein also co-localizes with integrin alpha 6 beta 4 at cell-cell junctions in a lung cancer cell line, suggesting one mechanism of action—namely, control of the tyrosine phosphorylation at these sites. Overexpression of HER2 has been demonstrated in 34 percent of adenocarcinomas, and its presence is associated independently with a poor prognosis in this cell type. This association of HER2 with prognosis has been independently confirmed, together with the finding that EGFR expression does not show any survival effect. Of further interest is the demonstration of measurable serum levels of HER2 in 27 percent of adenocarcinomas, with an increased level in subjects with more advanced disease, suggesting a possible role as a systemic tumor marker. Both of these c-erbB proteins have extracellular domains, making them attractive targets for specific antibodies, either for diagnosis or therapy.

However, therapeutic agents directed against this target may also interfere with normal epithelial turnover. Overexpression of c-erbB-2 in normal airway epithelial cells in vitro does not result in their transformation, suggesting that overexpression of c-erbB-2 alone does not result in tumor formation.

The prognostic value of p53 and c-erbB-2 immunostaining and preoperative serum levels of CEA and CA125 has also been evaluated in NSCLC patients with resectable tumors,

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indicating poor prognosis and likelihood of relapse. With the identification that the receptor complex actually consists of a heterodimer consisting of HER2 and another member of the erbB family, HER3, transformation may require both to be present to form the correct heterodimeric receptor for the specific activating ligand, Heregulin. fos The c-fos gene encodes a transcription factor active in cell proliferation and differentiation. Increased expression of c-fos is seen in NSCLC, especially the squamous cell subtype.

In this study, c-Fos proteins were found in 41 percent of squamous cell lung tumors. c-Fos immunoreactivity has also been demonstrated in mucosal biopsies of the airways from asthmatic subjects, suggesting a role in normal inflammation. Its role in lung cancer remains indeterminate. jun c-jun Encodes an oncoprotein that functions as a transcriptional regulator. This product (c-Jun) associates with the c-fos product (c-Fos) to form a nucleoprotein transcription complex that interacts with AP-1 control elements. c-Jun is another oncogene product that is overexpressed in squamous cell lung cancer. In this study, expression of c-jun, c-erbB-1, and c-fos were all associated with a poor prognosis. C-myc and c-erbB-2 overexpression did not have any survival effect. This study is one of the few studies that has examined the coexpression of a variety of oncogenes; it is a demonstration that, in the future, clinical studies might be necessary to define the interaction of the various oncogenes and protein products, rather than just examining these aspects in isolation. The role of c-jun in the development of lung cancer is largely unclear.

However, a recent study has shown that when c-jun was inducted into a bronchial epithelial cell line, in contrast to c-fos and c-myc, its disregulated expression may be involved in anchorage independence in the process of lunch carcinogenesis. src The c-src protein (pp60) was identified as the Rous sarcoma virus transforming region (src); it is expressed in both SCLC and NSCLC but not in histologically uninvolved lung tissue.

The importance of this remains uncertain.

THE PROGRESSION OF NORMAL AIRWAY EPITHELIUM TO MALIGNANT EPITHELIUM As described thus far, many genetic alterations can be found in lung cancers. The current evidence suggests that many events, both genetic and epigenetic, are necessary for the transformation of normal cells to neoplastic cells. It is logical to postulate that with the accumulation of these events, the involved cell(s) would have characteristic genetic, biochemical, and morphologic changes. How many events are necessary for the malignant transformation of a lung epithelial cell and in what order they occur in lung cancer constitute an area of intense research. Colorectal carcinogenesis provides a useful paradigm

Genetic and Molecular Changes of Human Lung Cancer

for understanding this process. Further, it may be directly relevant to lung cancer, since embryologically the lung develops from the foregut, and both organs are constantly exposed to external carcinogens. In addition, the emerging association of lung cancer with known colorectal cancer genes is of great interest.

Colorectal Carcinogenesis Morphologically, colorectal carcinomas arise from preexisting adenomas, which in turn arise from areas of hyperproliferative mucosa or mucosa with abnormal tissue architecture.

Thus, normal mucosa undergoes changes that result in proliferative or structural changes and forms microadenomas.

With progression, the microadenoma becomes an early adenoma, an intermediate adenoma, a late adenoma, and finally a carcinoma. Through molecular genetic analysis of colorectal tissue at these defined morphologic stages, certain genetic alterations have been found to occur at a high frequency.

These studies have become the basis for assigning a multistep pathway of genetic alterations that correspond to the mucosal phenotypic changes, summarized in Fig. 102-2.

Many studies have been performed on patients with familial adenomatous polyposis. These patients suffer from an autosomal dominant disorder resulting in diffuse colon polyp formation, and they are at increased risk for developing colorectal carcinoma. In this syndrome, germ line mutations (thus inherited) in the APC gene are believed to be responsible for the epithelial hyperproliferation found in the initial stage. In patients who do not have this inherited defect, LOH on chromosome 5q and/or somatic mutations of the APC gene may play a role in the early stages. LOH involving chromosomes 18q and 17p and mutations in the DCC (deleted in colorectal carcinoma) and p53 genes occur more frequently at later stages of tumorigenesis and are infrequent in early-stage tumors. Mutations in the K-ras gene occur during the transition of early adenomas to intermediate adenomas. It should be made clear that the order of genetic changes is probably not invariant. It is the composite of changes rather than the specific sequence that is of importance. In addition, changes are likely to be carcinogen dependent; therefore, changes found in colorectal carcinomas may not be directly associated with pulmonary tumorigenesis. Finally, not all alterations may exist within a tumor. Thus the accumulation and interaction of numerous genetic events determine the histology and clinical phenotype of the tumor.

This paradigm, while attractive, is a working model; it does not take into account quantitative alterations in levels of oncogene expression or the effect of growth factors, the surrounding connective tissue, tissue oxygenation, or angiogenesis factors. Although the model is logical and is supported by histologic and genetic studies, it is likely to be incomplete and perhaps simplistic.

Can this model be applied to the development of lung cancer? It probably can, with some similarities and many important differences. Lung cancer is also thought to develop through many stages of histologically defined epithelial

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INTERMEDIATE ADENOMA

MILD DYSPLASIA

LATE ADENOMA

SEVERE DYSPLASIA

Figure 102-2 The multistage carcinogenesis model for colorectal cancer is shown in the top panel. This model has been reasonably validated for colorectal cancer and demonstrates a progressive series of genetic events. In contrast, the evolution of lung cancer (shown in the bottom panel) using the same multistage carcinogenesis approach is less well studied. Lung cancer, as indicated in the text, is more complex because of the different cell types and because peripheral lung tumors are not easily studied. Nevertheless, it is emerging that lung cancer also is likely to exhibit a series of defined genetic events that confer specific phenotype expression.

changes. The earliest changes include squamous metaplasia, followed by dysplasia, carcinoma in situ, and microinvasive and invasive cancer. While no longitudinal studies have definitely implicated the metaplastic and dysplastic lesions as premalignant, there is strong circumstantial evidence to support the notion that epithelial dysplasia represents an early stage in the development of bronchogenic carcinoma. In a study of 14,414 male smokers, the presence of atypical squamous metaplasia on cytologic examination of the sputum was considered an indicator of a modest elevation in the risk of bronchogenic carcinoma. And the development and application of an 80-gene biomarker distinguishing smokers with lunch cancer from those without lung cancer has demonstrated that gene expression in cytologically normal epithelial cells can serve as a biomarker for the disease. Perhaps the strongest factor making this link is the dose-response relationship between the number of cigarettes smoked per day and the frequency of dysplastic lesions in the bronchial epithelium. These changes are most evident in pulmonary squamous cell carcinomas, as has been assessed using serial sections around minute squamous cell carcinomas; but they are not as clear in lung adenocarcinomas, owing to the inability to readily access, screen, and study areas of the peripheral lung from which these tumors usually arise. There is reasonable evidence, however, that a sequence of morphologic changes occur in the bronchial mucosa, consistent

with a multistage model of carcinogenesis for lung cancer development.

It is of great interest, therefore, to examine whether genetic changes occur in a stepwise fashion in the bronchial epithelium to correlate with the morphologic changes. This area is currently being defined, and extensive information is not yet available. However, the limited information that is available leads to the conclusion that stepwise accumulation of genetic changes also occurs in lung cancer. Not surprisingly, the events and their timing differ from the colorectal carcinoma paradigm, undoubtedly reflecting differences in the epithelium, microenvironment, and carcinogen exposure. The most studied molecular change has been in p53 expression. In several analyses of preneoplastic lung lesions and lung neoplasms, alterations in the immunohistochemically defined levels of p53 expression (which implies a mutation in p53) occur early, with p53 abnormalities found in metaplastic and mild to moderate dysplastic lesions (10–30 percent of cases). The frequency of p53 alterations jumps to more than 60 percent in severe dysplasia and as high as 80 percent in carcinomas. Further molecular changes have been the LOH of 3p and the LOH of chromosome 9p, described at the severe-dysplasia stage. Hyperproliferation is evident during early dysplasia, when proliferating cell nuclear antigen (PCNA), a marker of cell proliferation, is found in 33 percent of samples, as opposed to 25 percent of normal airway

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epithelium samples. This increases to 40 percent in severe dysplasia and to more than 85 percent at the carcinoma in situ stage. This study suggests that hyperproliferation is quickly followed by DNA aneuploidy and then p53 immunoreactivity. Genetic instability is evident early in the natural history of bronchogenic cancer, with DNA aneuploidy found in 8 percent of samples with mild dysplasia, 33 percent with severe dysplasia, and 100 percent of samples with carcinoma in situ.

K-ras mutations have not been studied as completely as p53, but they have been shown to occur early in the course of lung tumorigenesis, at least in adenocarcinomas.

The information necessary to construct as complete a paradigm for pulmonary tumorigenesis as has been done for colorectal carcinogenesis is not available, although it is clearly being derived. Fig. 102-2 provides a summary of our current understanding. It is clear that changes in specific oncogenes can be associated with specific phenotypes, giving credence to this paradigm. The ability to identify dysplastic airway lesions at bronchoscopy will create the opportunity to obtain a better collection of samples for analysis. However, there is evidence of hyperproliferation in preneoplastic pulmonary epithelium, p53 mutations, and genetic instability. The molecular paradigm for lung cancer is very complex because of the unclear familial genetics of the disease, the large number of carcinogens that may play a role in pulmonary tumorigenesis, and the variability in the malignant phenotypes that can be expressed (small cell vs. large cell vs. squamous cell). And unlike the situation with colon carcinoma, early events in the airway have not been as easily detected macroscopically, reducing the possibility of obtaining tissue. Also, surveillance bronchoscopies for early detection of lung cancer are not recommended, even in known at-risk patient groups.

THE IMPACT OF MOLECULAR GENETIC CHANGES ON THE CELL CYCLE We have identified a number of genetic changes that have been found in lung cancer and proposed a multistep paradigm of lung cancer development. It is not clear, however, whether these molecular-genetic events are causative or simply associated with lung cancer. Are these events directly responsible for the genesis of lung cancer? The answer to this question is unknown, but there is evidence to suggest that some of these events may have a direct role in pulmonary tumorigenesis. At the simplest level, malignant transformation represents either the loss of regulated growth or the loss of programmed cell death (apoptosis). Therefore, if the genetic changes that occur in lung cancer affect growth regulation or apoptosis, a causative role may be implied.

Recently, much has been learned about events that regulate cell growth. In addition, all oncogenes and the genetic changes described in this chapter have an impact on cellular growth regulation. Within this framework, many of the genetic changes we have discussed affect the cell cycle. EGFR and HER2 are membrane-bound receptors that can initiate

Genetic and Molecular Changes of Human Lung Cancer

signaling and transmit a growth signal; p21 ras is also active in intracellular signaling pathways related to cell proliferation.

Fos, Jun, and Myc are nuclear transcription factors that could control growth regulatory genes. The tumor suppressor genes provide the best examples of the effect of genetic changes on the cell cycle.

The cell cycle is divided into distinct periods—the G1 period (preparing for DNA synthesis), S phase (DNA synthesis), G2 period (postsynthesis), and M (mitosis). At various points in the cell cycle, there are checkpoints at which the cell has the ability to assess itself and determine whether it is ready to progress to the next phase of the cell cycle. These checkpoints are under the influence of both positive and negative regulators. If the function of a negative regulator is lost, or if a positive regulator is overexpressed, the cell may progress to the next portion of the cell cycle at an inappropriate time. Perhaps the most important checkpoint is the G1-to-S transition.

At this time the cell must determine the integrity of its DNA before replication, so as not to replicate any DNA defects into the genetic code. If regulation of this checkpoint is lost, or a mutation inadvertently replicates in an important growth regulatory gene before it can be repaired, uncontrolled cell growth may result.

The Rb protein is a key regulator of the passage of cells through the G1 period. pRB function is regulated by its phosphorylation status. During the G1 period, pRB is primarily hypophosphorylated. Thus, the growth suppressive form of pRB is thought to be the hypophosphorylated form. In late G1, pRB goes through successive phosphorylations that inactivate its ability to suppress cell proliferation. The phosphorylation of pRB is regulated by a complex consisting of two subunits—a cyclin and a cyclin-dependent kinase (cdk).

Specifically, the D type cyclins (D1, D2, D3) complex with and activate cdk4 and cdk6, which mediate the phosphorylation of pRB. The cyclin/cdk complexes themselves are under regulation by a series of small protein inhibitors (p15, p16, p21, and p27). How is the phosphorylation of pRB important in regulation of the cell cycle? While this is still currently being defined, it appears that in its unphosphorylated state, pRB binds and sequesters specific proteins necessary for cell cycle progression. The bound proteins include members of the E2F family of transcription factors, which are necessary for the expression of many genes active in DNA replication (DNA polymerase-α, PCNA). Thus, pRB binding to E2F prevents transcription from promoters containing E2F sites. Upon pRB phosphorylation, E2F is released, activating transcription. E2F DNA binding sites have been noted in a number of genes critical for cell entry into S phase. Thus, mutations of pRB that interfere with E2F binding, or affect pRB phosphorylation by cdk4 or cdk6, may result in unrestrained entry into S phase.

The G1-to-S transition is also a p53-regulated checkpoint. Structurally, p53 has hallmarks of a transcription factor; it has a sequence-specific DNA binding domain, and its amino terminus has a transcriptional activation domain. p53 Has a role in DNA repair through one of its transcriptional targets, Gadd45. In response to DNA damage, p53 levels rise,

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Figure 102-3 Tumor suppressor genes are thought to act on the cell cycle. Several different pathways of activity have been identified. The retinoblastoma protein (pRb) undergoes phosphorylation, allowing E2F to interact with its promoter, leading to transcriptional activation and the production of cell cycle regulatory proteins. p53 Can act by inhibiting S phase entry through the induction of p21, by inhibition of DNA synthesis or repair through interaction with p21 and PCNA, or by inducing apoptosis.

resulting in the transcriptional induction of the cdk inhibitor p21. p21 Causes an accumulation of unphosphorylated pRB, which in turn causes G1 arrest; p53 levels also rise in response to hypoxia. The p53 rise consequent on DNA damage not only seems to arrest the growth of the cell, thereby preventing transmission of the abnormal DNA, but under hypoxic conditions, it appears that the rise in p53 triggers apoptosis. In tumors that have a mutant p53 gene, resulting in a functional loss of p53, control of cell cycle progression or apoptosis may be lost, leading to unrestrained cell growth.

Apoptosis is probably regulated by p53 through a further mechanism. In the face of pRB inactivation or ectopic expression of E2F, entry into S phase is uncontrolled. In such cells, if there is a wild-type p53 background, apoptosis ensues.

In a mutant p53 background, apoptosis does not occur; uncontrolled cell proliferation ensues, with the ultimate result being neoplastic transformation. Thus, p53 regulates both cell

cycle progression and apoptosis with a key role in protecting cells from duplicating damaged DNA. These interactions are summarized in Fig. 102-3.

These two genes and the effects their mutations have on cell growth regulation illustrate how genetic events may play a direct role in tumor formation through deregulating cell growth. p53 And Rb have a clear impact on cell cycle regulation; however, many other genetic events found in lung cancer potentially have an impact on cell growth. p21 Ras plays a role in signaling and in its mutant form may provide an unregulated growth stimulus signal; the myc family of oncogenes are believed to be transcriptional activators and in a mutated form perhaps provide unregulated transcription of genes important in the cell cycle; mutant or high-level expression of growth factor receptors or their ligands may result in a continuous growth stimulatory signal. Clearly, when more is understood about the function of these genetic events

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in lung cancer, it is likely that they will be found to have an effect on the cell cycle. In addition, many currently undescribed changes will be identified in known cell cycle genes and their encoded proteins, leading to a further understanding of genetic events occurring in pulmonary tumorigenesis.

These changes provide discrete therapeutic targets for the development of new treatments of this devastating disease. Many of these therapeutic targets have already been the subject of in vivo and in vitro experiments to assess the effects on tumor growth and differentiation. For instance, a recent study of the role of p53 in growth inhibition and apoptosis has shown that it may be a factor in determining sensitivity to treatment by gefitinib, by regulating Fas expression in NSCLC. Morover, restoration of p53 by a Cre-loxP-based strategy, controlling the tumor suppression gene in vivo, has led to apoptosis in lymphoma and suppression of cell growth in sarcomas. Other studies have shown similar promise. Other experiments that have been described in association with the description of the particular oncogene or oncoprotein are summarized in Fig. 102-4. In all instances so far reported, there has been a measurable effect on tumor growth. It is therefore possible that major changes in the therapy of lung cancer will occur in the future with the use of these approaches either as single agents or, more likely, as part of a combined-

GENE TRANSFER OF WILD-TYPE Rb p53, MTSI GENE

Figure 102-4 The potential sites for therapeutic targets are shown. Opportunities exist to target the extra cellular domain of EGFR and HER2, by either proteins or specific antibodies. Antisense RNA and DNA are currently being directed against K-ras and L-myc in cell culture studies, and specific oncoprotein inhibitors are also being tested for antitumor activity. Finally, gene transfer of several tumor suppressor genes is undergoing laboratory study, especially the transfer of the wild-type Rb and p53 gene.

Genetic and Molecular Changes of Human Lung Cancer

modality therapy. This molecular approach to therapy will probably be combined with a molecular evaluation of the population most at risk, so that effective screening programs can be established. This, together with increasing efforts to reduce environmental exposures such as those from tobacco smoke, should help to bring the epidemic of deaths from lung cancer under control.

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103 The Solitary Pulmonary Nodule: A Systematic Approach David Ost

Alan M. Fein

I. DEFINITION II. INCIDENCE AND PREVALENCE III. MALIGNANT SOLITARY PULMONARY NODULES IV. BENIGN SOLITARY PULMONARY NODULES V. IMAGING TECHNIQUES Plain Chest Radiography Standard and Computed Tomography Positron Emission Tomography

Assessment of Nodule Growth Rate and Frequency of Follow-up Imaging Estimating Probability of Malignancy VII. BIOPSY TECHNIQUES Bronch oscopy Percutaneous Needle Aspiration VIII. THORACOTOMY AND THORACOSCOPY IX. DIAGNOSTIC APPROACH

VI. DISTINGUISHING BETWEEN BENIGN AND MALIGNANT NODULES Nodule Shape and Calcification Patterns

The radiographic finding of a solitary pulmonary nodule, formerly known as a coin lesion, has long challenged the clinician.

At the heart of the dilemma, the question remains unchanged: “Is it malignant or benign?” Bronchogenic carcinoma is the most common malignancy found in solitary pulmonary nodules, and it remains the leading cause of cancer death in the United States. When faced with a solitary pulmonary nodule, the clinician and the patient usually have one of three choices: (1) observe it with serial chest computed tomography (CT); (2) perform additional diagnostic tests (imaging and/or a biopsy); or (3) remove it surgically.

The proper choice depends on radiographic appearance, epidemiology, assessment of surgical risk, and patient preferences. Surgical resection of an early solitary malignant lesion still represents the best chance for cure. On the other hand, unnecessary resection of benign nodules exposes patients to the morbidity and mortality of a surgical procedure.

The aim of this chapter is to review what we know about the solitary pulmonary nodule to formulate a diagnostic approach to this often controversial problem. The goal is to

arrive at a systematic approach that will promptly identify and bring to surgery all patients with operable malignant nodules while avoiding thoracotomy in patients with benign nodules.

DEFINITION A solitary pulmonary nodule is defined as a single discrete pulmonary opacity that is surrounded by normal lung tissue that is not associated with adenopathy or atelectasis. Previously there was controversy as to what constituted the upper size limit for defining a solitary pulmonary nodule. Some early series included lesions up to 6 cm in size. However, it is now recognized that lesions larger than 3 cm are almost always malignant, so current convention is that solitary pulmonary nodules must be 3 cm or less in diameter. Larger lesions should be referred to as pulmonary masses and should be managed with the understanding that they are most likely malignant; prompt diagnosis and resection are usually advisable.

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INCIDENCE AND PREVALENCE The frequency with which a solitary pulmonary nodule is identified on chest radiography is on the order of 1 to 2 per thousand chest radiographs. Most of these are clinically silent, and about 90 percent are noted as an incidental finding on radiographic examination. The prevalence of malignancy in nodules varies widely, depending on the patient population; thus, many case series may not be directly comparable. Surgical series in the era before computed tomography (CT), including both calcified and noncalcified nodules, reported an overall malignancy rate of 10 to 68 percent. A Veterans Administration Armed Forces Cooperative Study in 1963 reported an overall 35 percent malignancy rate in a cohort that included a significant number of young military recruits (about half of them under age 50). Infectious granulomas were found in 53 percent. When those over the age of 50 were studied, a 56 percent malignancy rate was noted, with a 30 percent incidence of granulomas. Of those under the age of 35, only three patients had a malignancy, one of which was a primary lung carcinoma. Series that have used chest CT to screen out benign-appearing calcified nodules show much higher overall malignancy rates: 56 to 100 percent. A series of 360 patients from the Minneapolis Veterans Administration Medical Center, which used CT scan to exclude benign nodules, showed an overall malignancy rate of 79 percent, with an increase from about 60 percent in the early 1980s to 100 percent from 1990 to 1994. This population included mostly male smokers aged about 65. A smaller series (40 patients), referred to the outpatient practice of a pulmonologist in an urban university hospital from 1990 to 1993, had a 53 percent malignancy rate. The mean age was 65, 83 percent were smokers, and sex distribution was almost equal.

Younger patients from areas where granulomatous diseases such as tuberculosis, histoplasmosis, and coccidioidomycosis are endemic can be expected to have a lower malignancy rate. In an Air Force Medical Center study from Illinois of 137 patients, only 22 (16 percent) had a malignancy. Granulomas were diagnosed in 103 patients (75 percent); 53 of them were attributable to histoplasmosis endemic to the area. Most of these patients (77 percent) were under age 45, and no malignant nodules were diagnosed in patients less than 35 years of age. This series predated the use of chest CT.

MALIGNANT SOLITARY PULMONARY NODULES Risk factors for malignancy have been identified from studies of large series of solitary pulmonary nodules and include patient age, smoking history, nodule size, and prior history of malignancy. Age is one of the most consistent risk factors.

In a series of 370 indeterminate solitary pulmonary nodules, the incidence of malignancy increased from 63 percent for

patients aged 45 to 54, to 74 percent for those aged 54 to 64, and continued to rise with age to 96 percent for those above the age of 75. These findings correlate with those of previous studies, which also show that malignancy is very rarely found in patients under the age of 35.

Smoking is closely correlated with the development of lung cancer, particularly squamous and small cell carcinoma.

The Surgeon General’s report of 1964 and subsequent studies have demonstrated that the risk of lung cancer increases with the duration of smoking and the number of cigarettes smoked. Average smokers have about a 10-fold risk and heavy smokers a 20-fold risk of developing lung cancer when compared with nonsmokers. Smoking is responsible for about 85 percent of the cases of bronchogenic carcinoma. Cessation of smoking reduces this risk after 10 to 20 years, but it now appears that former smokers have a slightly higher risk of cancer throughout their lifetimes.

Nodule size is closely correlated to risk of malignancy.

Several series have demonstrated an increased incidence of malignancy with increasing nodule size. Nodules larger than 3 cm are malignant 80 to 99 percent of the time, whereas those under 2 cm in size are malignant in 20 to 66 percent of cases.

A history of current or prior extrapulmonary malignancy greatly increases the probability that a nodule is malignant. Depending on the series, 33 to 95 percent of such nodules have proved to be malignant—most represent metastases but some second primaries. The most common histologic types of metastatic nodules are adenocarcinomas of colon, breast, kidney, head and neck tumors, sarcoma, and melanoma.

Primary bronchogenic carcinoma is the most common malignant tumor that presents as a solitary pulmonary nodule. Histologically, adenocarcinoma and squamous cell carcinoma make up the majority; of the two, adenocarcinoma is the more common. Less frequent as a solitary pulmonary nodule is the bronchioloalveolar cell carcinoma. Small cell carcinoma that presents as a solitary pulmonary nodule is rare. Other rare primary lung tumors that may present as solitary pulmonary nodules are bronchial carcinoids (1–5 percent), which are usually peripherally located; lymphomas; hemangioendotheliomas; and sarcomas.

Metastases may present as solitary pulmonary nodules in patients who have known primary malignancies or in whom the presence of primary malignancy is unknown. In up to 40 percent of such patients, who manifest only a single nodule on chest radiograph, CT scan may show other nodules that are not disclosed by plain chest radiograph. Even though the lesion is solitary, in patients with an established diagnosis of cancer, up to 95 percent of these nodules are malignant upon resection. Because of this high likelihood of malignancy, a nodule in a patient with an established diagnosis of cancer should be treated differently from other solitary nodules.

Assuming no other obvious metastatic spread, one should consider proceeding directly to biopsy. Even in the presence of a known malignancy, some of these nodules may represent a second primary pulmonary malignancy that is similar

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in histologic appearance. Immunohistochemistry and other confirmatory marker studies may be indicated to determine the nature of the nodule. A solitary pulmonary nodule in a patient with a history of malignant disease should be removed so long as there is no other evidence of recurrent or metastatic disease.

BENIGN SOLITARY PULMONARY NODULES Benign solitary pulmonary nodules are more common in the young and in nonsmokers. They include both infectious and noninfectious granulomas, benign tumors such as hamartomas, vascular lesions, and rare miscellaneous conditions (Table 103-1).

Hamartomas are the most common benign tumors presenting as solitary pulmonary nodules. They are believed to be developmental malformations composed mainly of cartilage, fibromyxoid stroma, and adipose tissue. Our review of six series of resected solitary pulmonary nodules since 1974 shows that 192 of 3802 nodules (5 percent) were histologically proved hamartomas. In a series of 215 hamartomas resected at the Mayo Clinic, the peak incidence was in the seventh decade of life; male-to-female ratio was 1:1; and the average size was 1.5 cm, although some were as big as 6 cm. Most hamartomas were asymptomatic (97 percent), and 17 percent were noted to grow slowly on serial radiographic examination. They may be identified radiographically by a pattern of “popcorn” calcification, which is often intermixed with areas of low attenuation on CT scan representing fat deposits within the nodule. CT appearance is diagnostic in about 50 percent of hamartomas.

Infectious granulomas make up more than 90 percent of all benign nodules. They arise as a result of healing after infection from a variety of organisms. The offending agents vary, depending on geographic location. Among the most common causes are histoplasmosis, coccidioidomycosis, and tuberculosis. Other, less common causes are dirofilariasis (dog heartworm), mycetoma, echinococcal cyst, and ascariasis. A history of exposure is important in establishing a possible infectious origin. Clues such as prior travel history, places of residence, occupation, and pets may be invaluable in some instances.

Noninfectious granulomas sometimes occur as solitary pulmonary nodules in systemic diseases such as sarcoidosis, in which nodules are not invariably accompanied by hilar adenopathy; rheumatoid arthritis, usually in patients with active disease who often have subcutaneous nodules; and Wegener’s granulomatosis.

Miscellaneous causes of solitary pulmonary nodules have been described. Some of the more common conditions are lung abscess; rounded or spherical pneumonia; pseudotumor (Fig. 103-1), which represents fluid in an intralobar fissure; hematomas after thoracic trauma or surgery; and fibrosis or scars resulting from the resolution of infectious or inflammatory process. Rarer conditions presenting as solitary

The Solitary Pulmonary Nodule

Table 103-1 Differential Diagnosis of Solitary Pulmonary Nodules Malignant tumors Bronchogenic carcinoma (adenocarcinoma, large cell, squamous, small cell) Carcinoid Pulmonary lymphoma Pulmonary sarcoma Plasmocytoma Solitary metastases (colon, breast, kidney, head and neck, germ cell, sarcoma, thyroid, melanoma, others) Benign tumors Hamartoma Adenoma Lipoma Infectious granulomas Tuberculosis Histoplasmosis Coccidioidomycosis Mycetoma Ascaris Echinococcal cyst Dirofilariasis (dog heartworm) Noninfectious granulomas Rheumatoid arthritis Wegener’s granulomatosis Sarcoidosis Paraffinoma Others Miscellaneous BOOP Abscess Silicosis Fibrosis/scar Hematoma Pseudotumor Spherical pneumonia Pulmonary infarction Arteriovenous malformation Bronchogenic cyst Amyloidoma

pulmonary nodules include silicosis, bronchogenic cyst, amyloidosis, pulmonary infarct, and vascular anomalies. Arteriovenous malformations may present as solitary pulmonary nodules. They may grow slowly and have a characteristic appearance on contrast-enhanced CT scan.

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Figure 103-1 Pseudotumor. Fluid in a fissure, the result of both pleural disease and fluid overload, has the appearance of a pulmonary mass.

IMAGING TECHNIQUES Imaging techniques are often helpful in distinguishing benign from malignant causes of solitary pulmonary nodules, and as such they play a key role in their evaluation and management. During the last decade, rapid advances in both CT and positron emission tomography (PET) have dramatically changed the diagnostic approach to the solitary pulmonary nodules. However, this does not mean that these techniques should be used indiscriminately. Cost-effective strategies to manage solitary pulmonary nodules require that we understand the performance characteristics (sensitivity, specificity), strengths, and weaknesses of each of these technologies, so that they can be applied properly. The primary technologies that need to be considered are plain chest radiography, CT, and PET.

Plain Chest Radiography Most solitary pulmonary nodules are discovered on routine plain chest radiograph while asymptomatic. Malignant nodules are usually identifiable on chest radiograph by the time they are 0.8 to 1 cm in diameter, although nodules 0.5 to 0.6 cm are seen occasionally. Most are identified on posteroanterior (PA) projection, but some are seen only on lateral projection, so standard PA and lateral chest radiography should be obtained whenever possible. When a nodule can be seen only on one projection, the clinician should question whether it is truly in the lung parenchyma. Structures overlying the skin of the chest wall—such as leads used for cardiac monitoring, nipple shadows, skin lesions, bone lesions, and pulmonary

vessels on end—can all mimic pulmonary nodules. Once it has been ascertained that a true nodule exists, the first step is to make every effort to obtain previous radiographs for comparison. A nodule that has remained stable, with no increase in size, for 2 years, is very probably benign and warrants no further investigation. Conversely, a nodule that was not present on a comparable radiograph within the past 2 months is unlikely, having grown so rapidly, to be a malignancy. On rare occasions, small cell carcinoma may present as a solitary pulmonary nodule with a doubling time of less than 30 days.

Newer techniques, such as digital chest radiography, which uses computerized postprocessing to enhance radiographic images, can improve the detection of nodules over normally radiopaque areas of the thorax, such as the mediastinum and the diaphragm. This is accomplished by means of computerized algorithms (e.g., adaptive spatial filtering) that selectively change enhancement patterns over the areas of interest, making previously unseen nodules visible.

Standard and Computed Tomography Standard tomography was once used extensively in the evaluation of solitary pulmonary nodules, and it can be very useful in determining their exact location and characteristics. With the advent of CT, however, this technique is now seldom used, and few radiologists are being trained to use the technique.

CT has replaced plain tomography as a more sensitive tool in the evaluation of solitary pulmonary nodules.

CT is indicated when one is assessing indeterminate nodules less than 3 cm in diameter or in staging of larger lesions. It

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The Solitary Pulmonary Nodule

Figure 103-2 Noncontrast CT shows a round 1-cm nodule, with relatively high radiographic density, proven on resection to be a granuloma.

can pinpoint the exact location of the nodule and provide three-dimensional images of the lesion. Thin-section highresolution CT (HRCT) can better define the borders and the nodule’s relation to adjacent structures, such as vessels and the pleura. It is more sensitive than standard tomography in detecting calcification patterns, and it can detect fat within a nodule—which, when coupled with calcification, is highly suggestive of a benign hamartoma. In up to 40 percent of cases, previously unseen synchronous lesions can be seen. CT may be useful in looking for hilar or mediastinal adenopathy, and in evaluating accessibility of nodules for biopsy or resection.

HRCT can quantify calcification in nodules even when they are not readily visible to the naked eye. Nodules with higher radiographic density are more likely to be benign (Fig. 103-2). This technique has been suggested for indeterminate nodules smaller than 3 cm in diameter. Nodules that are bigger than 3 cm or that have suspect characteristics in the right clinical setting (e.g., an older smoker, spiculated borders) should be considered for biopsy or resection. Because it is difficult to standardize radiographic density on CT when a nodule is being examined for occult calcification, a phantom model is constructed to mimic the patient’s chest, nodule size, and location. Benign nodules usually have a density greater than 164 Hounsfield units. Therefore, the reference nodule is created with a known density greater than this—at about 185 Hounsfield units. The patient’s nodule density is measured with HRCT and is compared with the reference phantom. If the patient’s nodule is denser than the phantom, it is very probably benign and can be observed with sequential conventional radiographs. If it is less dense than the reference phantom, it remains indeterminate and further workup is

indicated. It should be noted that in a study of 85 nodules that were classified as having a high probability of benignity by the means of the 185 Hounsfield units cutoff, eight of them (9 percent) proved to be malignant on biopsy or resection. The CT reference phantom technique can be a helpful adjunct in the evaluation of the solitary pulmonary nodule, but it is helpful in only about 30 percent of cases, with 70 percent of nodules evaluated remaining indeterminate. CT densitometry has not achieved widespread clinical use.

Another CT technique that may be helpful is incremental dynamic CT, which uses serially increasing doses of iodinated IV contrast to look for enhancement of nodules. Although malignant nodules enhance more than benign ones, benign lesions, such as hamartomas and tuberculomas, may also enhance. In centers with expertise with this methodology, the sensitivity and specificity of the test are good. However, few centers at the present time are using this approach. The development of faster multidetector scanners has also had a great impact on the evaluation of pulmonary nodules. The ability to scan a large area with a single breath hold, thereby eliminating respiratory artifact, has increased the ability of radiologists to reconstruct images at different intervals and thicknesses. This also has increased the ability detect smaller subcentimeter nodules, down to 1 to 2 mm in size.

Positron Emission Tomography Newer imaging methods, such as PET, can be used to differentiate noninvasively between malignant and benign nodules. PET takes advantage of the fact that tumor cells have an increased glucose uptake and metabolism. A d-glucose analog labeled with a positron-emitting fluorine-18 radioisotope

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Figure 103-3 Characteristic appearance of nodule IV is edges. Type I is sharp and smooth, type II is lobulated, type III has irregular undulations, and type IV is grossly irregular with many spiculations. (Based on data of Siegelman SS, Khouri NF, Leo FP, et al: Solitary pulmonary nodules: CT assessment. Radiology 160:307–312, 1986.)

(FDG) is injected into the patient, and uptake by the nodule is then measured. Malignant nodules have a higher uptake of FDG. A meta-analysis of 13 studies involving 450 patients estimated the sensitivity of PET to be 94.3 percent with a specificity of 83.3 percent.

However, PET appears to be less sensitive for lesions less than 1 cm in size, so its use should be limited to those lesions 1 cm or greater in size. Although there is limited preliminary evidence that PET may be useful for lesions as small as 8 to 10 mm in size, there are still too many false-negatives reported to make PET useful for these types of lesions outside of a clinical trial at the current time. False-negative findings have also been seen in patients with bronchioloalveolar cell carcinoma, carcinoids, and mucinous adenocarcinomas. False-positives have been seen in patients with granulomatous infections, such as tuberculosis or endemic fungi, as well as in patients with inflammatory conditions, such as rheumatoid arthritis and sarcoidosis. Theoretically, false-positive results can also be caused by uncontrolled hyperglycemia.

DISTINGUISHING BETWEEN BENIGN AND MALIGNANT NODULES The goal of management algorithms for solitary pulmonary nodules is to bring to surgery all patients with potentially curable disease while avoiding unnecessary surgery in those who do not need it. As such, distinguishing between benign and malignant nodules is critical. Assessing image characteristics from a PET scan at a given moment in time is one method to help distinguish benign from malignant pulmonary nodules.

However, there are other methods that can help the physician with this critical step. These include assessment of a nodule’s shape and calcification pattern, the nodule’s growth rate, and assessment of the probability of malignancy based on epidemiologic risk factors.

Nodule Shape and Calcification Patterns Certain shapes make a nodule more likely to be malignant.

Although nodules may appear to be spherical on plain chest

radiograph, further study by CT may disclose irregular borders and shapes. The borders of benign nodules are often well circumscribed, with a rounded appearance. On the other hand, malignant nodules tend to have irregular, lobulated, or spiculated borders (Fig. 103-3). A malignant nodule may have pleural tags or tails extending from its body (Fig. 103-4), or a notch may be present in the border of the nodule (Rigler’s sign). None of these radiographic signs is entirely specific for malignancy.

Calcification is generally an indication of benignity in a solitary pulmonary nodule. Infectious granulomas tend to calcify with central, diffuse, or stippled patterns (Fig. 103-5).

Laminar or concentric calcification is characteristic of granulomas caused by histoplasmosis. Popcorn calcification, when present, is suggestive of a hamartoma. Eccentric calcification patterns should make one suspicious for malignancy.

It should be noted that, in general, 6 to 14 percent of malignant nodules exhibit calcification. When present, calcifications are usually eccentric and few. Benign patterns of calcification (central, diffuse, laminar, or popcorn) are very rare in malignant nodules. In one study of 1267 solitary pulmonary nodules, only seven malignant nodules (0.6 percent) had a benign calcification pattern. Most nodules with a benign calcification pattern can be observed with serial CT scans.

Rapid advances in CT technology have also led to more precise characterization of the morphology of lung nodules. Small nodules can be visualized by high resolution CT (HRCT) with thin (approximately 1 mm) slices through the target nodule, allowing for a higher degree of resolution and more precise description of their morphology. It is now appreciated that nodules may be characterized as solid, partly solid, or pure ground-glass opacities (defined as focal densities in which underlying lung morphology is preserved). This is particularly useful for categorizing small nodules (less than 1 cm) since these categories can help to distinguish benign from malignant nodules. The percentage of pure ground-glass opacities that are malignant varies significantly in the literature, from 18 percent to almost 60 percent. For subcentimeter nodules, the likelihood of malignancy was similarly high in partly solid lesions, but much lower (less than 10 percent) in solid nodules.

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Figure 103-4 Three-centimeter mass with irregular borders and pleural tag highly suggestive of malignancy–proven adenocarcinoma.

A

B

C

D

E

F

Figure 103-5 Patterns of calcification in nodules. A. Central. B . Laminated. C . Diffuse. D . Popcorn. E . Eccentric.

Patterns A, B, C, and D generally indicate a benign process; E and F suggest malignancy. (Based on data of Lillington GA: Management of solitary pulmonary nodules. Dis Mon 37:271–318, 1991.)

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Ground-glass nodules may represent either atypical adenomatous hyperplasia (AAH) or true bronchioloalveolar cell carcinoma. In contrast, partly solid or solid nodules usually represent adenocarcinoma, but can also be caused by squamous cell carcinoma or small cell carcinoma. When a pure ground-glass opacity starts to grow and becomes more solid, demonstrating a replacement growth pattern, this is highly suspicious for adenocarcinoma. Of note, observed growth rates are often very slow for malignant ground-glass opacities, intermediate for partly solid nodules, and relatively fast for solid nodules.

Assessment of Nodule Growth Rate and Frequency of Follow-up Imaging Assessing a nodule’s growth rate can further assist in distinguishing between benign and malignant nodules, provided serial images over time are available for comparison. Determination of nodule growth is based on the assumption that nodules are more or less spherical. Growth of a sphere must be considered in three-dimensional volume, not in twodimensional diameter. The formula for volume of a sphere is 4/3(π )r3 , or 1/6(π )D3 , where r = radius and D = diameter.

A nodule originally 1 cm in diameter whose diameter is now 1.3 cm has actually more than doubled in volume. Similarly, a 2-cm nodule has doubled in volume by the time its diameter reaches 2.5 cm. A nodule that has doubled in diameter has undergone an eightfold increase in volume. When old radiographs are available, growth rate and nodule doubling time (i.e., the time for a nodule to double in volume) can be estimated. Accepting the assumption that a tumor arises from serial doublings of a single cancerous cell, we can estimate that it will take 27 doublings for it to reach 0.5 cm, the smallest lesion detectable on chest radiography. By the time a nodule is 1 cm in diameter, it represents 30 doubling times and about 1 billion tumor cells. Depending on the exact growth rate, this theoretical 1-cm nodule has probably existed for years before it is detected, as malignant bronchogenic tumors have doubling times estimated at between 20 and 400 days. The natural history of a tumor usually spans about 40 doublings, whereupon the tumor is 10 cm in diameter and the patient has usually died. Squamous and large cell tumors have an average doubling time of 60 to 80 days. Adenocarcinomas double at about 120 days, and the rare small cell carcinoma that presents as a solitary pulmonary nodule can have a doubling time of less than 30 days. A nodule that has doubled in weeks to months is probably malignant and should be removed when possible.

Benign nodules have doubling times of less than 20 days or more than 400 days. A nodule that doubles in size in less than 20 days is usually the result of an acute infectious or inflammatory process, whereas those that grow very slowly are usually chronic granulomatous reactions or hamartomas.

Such nodules can be observed with serial radiographs.

Nodule growth rate and doubling times become clinically relevant when we have to decide how often to order follow-up imaging when observing a solitary pulmonary

nodule. The question often arises whether observing a solitary pulmonary nodule for an extra 3 to 6 months increases the likelihood of metastatic disease, since that nodule has probably been growing for years. There is no convincing empiric evidence to support this hypothesis. Whether delays longer than 3 to 6 months are safe is unknown. However, estimating this hazard of delay is clinically relevant, since the optimal frequency of serial CT follow-up imaging to monitor nodules for growth is predicated on limiting this hazard of delay. The question is, how frequently do follow-up scans need to be done to minimize the hazard of delay while containing costs and avoiding excessive radiation exposure?

Traditional practice, based on little empiric evidence, recommended that when a careful observation strategy was warranted, repeat CT scans be done at 3, 6, 12, and 24 months.

However, more recent data from lung cancer screening trials using CT imaging suggest that a less aggressive practice may be reasonable in some patients with very small nodules. Therefore, decisions about the frequency and duration of follow-up for patients with solitary pulmonary nodules need to consider multiple dimensions of the problem, including clinical risk factors, nodule size, the probable growth rate as reflected by CT morphology, the limits of imaging technology resolution and volume measurement (especially at sizes less than 5 mm), radiation dose, surgical risks, patient preferences, and cost.

All of these can affect the optimal frequency of CT follow-up significantly. For example, in patients who are not considered to be surgical candidates due to other comorbidities, such as severe emphysema, the utility of follow-up CT imaging is questionable and less aggressive approaches, such as no imaging at all, are reasonable.

Given this framework, it is reasonable to apply more recent expert consensus-based guidelines to help guide the frequency of follow-up CT imaging for the solitary pulmonary nodule. For follow-up studies, imaging should be performed with the lowest possible radiation dose that provides adequate imaging (with current technology between 40 and 100mA).

The key variables that determine optimal imaging frequency are surgical risk, size, and lung cancer risk. For patients who are potential surgical candidates with no lung cancer risk factors, the frequency of repeat CT imaging is: Nodule size ≤ 4 mm: No follow-up needed.

Nodule size > 4 mm but less then 6 mm: Re-evaluate in 12 months. If there is no change, then no additional follow-up is warranted.

Nodule size ≥ 6 to 8 mm: Follow in 6 to 12 months and then again at 18 to 24 months if there is no change.

Nodule size > 8 mm: Traditional schedule with serial CT imaging at 3, 6, 12, and 24 months if there is no change.

For patients who are potential surgical candidates with one or more lung cancer risk factors, the frequency of repeat CT imaging is:

Nodule size ≤ 4 mm: Once at 12 months, no additional imaging if there is no change.

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Nodule size > 4 mm but < 6 mm: Initially at 6 to 12 months, and if no growth repeat again at 18 to 24 months if there is no change.

Nodule size â&#x2030;Ľ 6 to 8 mm: Initially at 3 to 6 months and then again at 9 to 12 months, and then again at 24 months if there is no change.

Nodules size > 8 mm: Traditional schedule with serial CT imaging at 3, 6, 12, and 24 months if there is no change.

It should also be noted that controversy remains regarding how long follow-up should be continued. Although traditional teaching has recommended observing lesions for a maximum of 2 years, it is now recognized that for some lesions longer follow-up may be warranted. Long doubling times have been observed in malignant lesions that presented as ground-glass nodules or as partially solid nodules. As a consequence, longer follow-up extending over years may be appropriate in some special instances, especially if there is an antecedent history of lung cancer. For most nodules, 2 years of follow-up without evidence of growth is sufficiently long to warrant discontinuation of CT imaging.

Estimating Probability of Malignancy Several authors have attempted to develop mathematical models to estimate the probability of malignancy of indeterminate solitary pulmonary nodules. Using clinical and radiographic characteristics of malignancy derived from the literature, these authors have analyzed some combination of the following malignant risk factors by Bayesian, neural network, and other methods to obtain a mathematical estimate of the probability of malignancy: nodule size, location, growth rate, margin characteristics, age of the patient, smoking history, prevalence of malignancy in the community, and occult calcification on CT densitometry.

For example, in the Bayesian approach, each risk factor for a particular patient and nodule is assigned a likelihood ratio of malignancy derived from published data. In one model, overall prevalence of malignancy, diameter of the nodule, patientâ&#x20AC;&#x2122;s age, and smoking history were considered. The likelihood ratios for malignancy of each of these factors were then multiplied to provide odds of malignancy, which are then converted into a percent probability of cancer (pCa). Three different management strategies are followed, depending on the calculated pCa. If the pCa is under 5 percent, careful observation with follow-up imaging is recommended; if the pCa is more than 60 percent, immediate resection of the nodule is warranted; if the pCa is between 5 and 60 percent, percutaneous needle aspiration biopsy is equal to or slightly preferable to resection. In a computerized neural network model that uses nonlinear mathematics to analyze input data, risk factors for malignancy were used and compared with the results of Bayesian analysis. The authors found that their neural network was not as accurate as Bayesian analysis in predicting malignancy.

The Solitary Pulmonary Nodule

One of the problems with these and other methods is the quality of the input data (i.e., the likelihood ratios), which may not be representative of all patient populations. In addition, Bayesian analysis presupposes that the likelihood ratios for a particular risk factor are not affected by the presence or absence of any other factor. It is not clear that this is true of the likelihood ratios. Therefore, although mathematical models to predict probability of malignancy may seem attractive, the complexity of the issue once again leaves us with an uncertain answer. This may explain why the described methods are not in widespread clinical use.

However, assessment of the pretest probability of malignancy is central to optimal strategy selection making when managing solitary pulmonary nodules. Although these formulas and neural networks may lack precision on an individual patient level, they can serve to inform decision making as to what risk factors to pay attention to and how important they are relative to each other. Risk factors associated with a low probability of malignancy include diameter less than 1.5 cm, age less than 45 years, absence of tobacco use, having quit for 7 or more years, and a smooth appearance on radiography. Risk factors associated with a moderately increased risk of malignancy include diameter 1.5 to 2.2 cm, age 45 to 59, smoking up to 20 cigarettes per day, being a former smoker within the last 7 years, or a scalloped edge appearance on radiography. Risk factors associated with a high risk of malignancy include a diameter of 2.3 cm or greater, age greater than 60 years, being a current smoker of more than 20 cigarettes per day, a history of prior cancer, and a corona radiate or spiculated appearance on radiography.

BIOPSY TECHNIQUES The issue of whether it is useful to biopsy an indeterminate solitary pulmonary nodule and, if so, how to do it remains controversial. Most experts agree that in certain clinical circumstances, a biopsy procedure is warranted. For example, in a patient who is at high surgical risk, it may be useful in establishing a diagnosis and guiding decision making. If the biopsy reveals malignancy, it may convince a patient who is wary of surgery to undergo thoracotomy or thoracoscopic resection of a potentially curable lesion. Another indication for biopsy may be anxiety to establish a specific diagnosis in a patient in whom the nodule seems to be benign. Some chest physicians argue that all indeterminate nodules should be resected if the results of history, physical examination, and laboratory and radiographic staging methods are negative for metastases. Others argue that this last approach exposes patients with benign nodules to the risks of needless surgery. In such cases, a biopsy procedure sometimes provides a specific diagnosis of a benign lesion and obviates surgery.

Once it has been decided to biopsy a solitary pulmonary nodule, the choice of procedure is a matter of debate, but includes fiberoptic bronchoscopy, percutaneous needle

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aspiration, thoracoscopic biopsy (usually with video assistance), and open thoracotomy.

BRONCHOSCOPY Traditionally, bronchoscopy has been regarded as a procedure of limited usefulness in the evaluation of solitary pulmonary nodules. Studies have shown variable success rates, with an overall diagnostic yield of 36 to 68 percent, in nodules greater than 2 cm with bronchoscopic biopsy, brushings, and washings. In general, the yield for specific benign diagnoses has ranged from 12 to 41 percent.

For smaller nodules, the sensitivity of bronchoscopy is significantly worse. For example, for nodules larger than 2 cm in diameter, a sensitivity as high as 68 percent (average 55 percent) can be obtained. However, this dropped to 11 percent for nodules smaller than 2 cm. Location also matters: nodules located in the inner or middle one-third of the lung fields have the best diagnostic yield; nodules in the outer one-third have a much lower diagnostic yield and as such are probably best approached with percutaneous needle aspiration if biopsy is needed.

Another characteristic of solitary pulmonary nodules to consider when deciding on the role of bronchoscopy is the nodule’s relation to neighboring bronchi (Fig. 103-6). Tsuboi and colleagues described four types of tumor–bronchus relationships: (1) the bronchial lumen is patent up to the tumor; (2) the bronchus is contained in the tumor mass; (3) the bronchus is compressed and narrowed by the tumor, but the bronchial mucosa is intact; and (4) the proximal bronchial tree is narrowed by peribronchial or submucosal spread of the tumor or by enlarged lymph nodes. The presence of types I and II, a bronchus leading to or contained within the body of a nodule or mass on HRCT, has subsequently been termed

a positive bronchus sign. When a bronchus sign is present on HRCT, the diagnostic yield of fiberoptic bronchoscopy can be as high as 60 to 90 percent. With a negative bronchus sign, the yield drops to 14 to 30 percent. Signs and symptoms of airway involvement (cough, hemoptysis, localized wheezing), although rare in solitary pulmonary nodules, increases diagnostic yield when present.

After an extensive evidence based review of the various studies, it was concluded that bronchoscopy can play a role in the evaluation of the solitary pulmonary nodule under rare circumstances but that most of the time bronchoscopy is not the best choice. In those cases in which there is an airbronchus sign, or in cases in which there are very central lesions abutting the large airways, bronchoscopy may be of use.

Similarly, if there is a suspicion for unusual infections, such as tuberculosis or fungal infections, then bronchoscopy may be warranted. However, for most patients bronchoscopy does not play a major role. It should also be mentioned that routine preoperative staging bronchoscopy is of no value in asymptomatic patients with a solitary pulmonary nodule smaller than 3 cm because it has not been shown to alter management decisions.

Percutaneous Needle Aspiration Percutaneous needle aspiration can be performed under fluoroscopic or CT guidance, the choice often depending on the availability and experience of the operator. It is most useful as the initial procedure in peripheral lesions, in the outer third of the lung, and in lesions under 2 cm in diameter. It can establish the diagnosis of malignancy in up to 95 percent of cases and can establish specific benign diagnosis (granuloma, hamartoma, infarct) in up to 68 percent of patients. The use of larger-bore biopsy needles—such as a 19 gauge, which provides a core specimen in addition to cytology—improves the yield for both malignant and benign lesions. The major limitation of percutaneous needle aspiration is its high rate of pneumothorax (10–35 percent overall); pneumothorax is more likely when lung parenchyma lies in the path of the needle (Fig. 103-7). Of these pneumothoraxes, 5 to 10 percent require drainage with a chest tube. Because of the high rate of pneumothorax and its possible complications, the following patients should not undergo percutaneous needle aspiration: those with limited pulmonary reserve (e.g., FEV1 under 1 L); those with bullous emphysema or blebs in the needle path; and postpneumonectomy patients. Other general contraindications are: bleeding diathesis, inability to hold breath, and severe pulmonary hypertension. Bronchoscopy can sometimes be used when percutaneous needle aspiration is contraindicated. The two procedures can be used successfully in a complementary fashion.

THORACOTOMY AND THORACOSCOPY Figure 103-6 Schematic illustration of tumor–bronchus relationships (see text). (Based on data of Tsuboi E, Ikeda S, Tajima M, et al: Transbronchial biopsy smear for diagnosis of peripheral pulmonary carcinomas. Cancer 20:687–698, 1967.)

Lobectomy using either open thoracotomy or video-assisted thoracoscopic surgery with lymph node resection and staging remain the standard of care for stage I bronchogenic

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Figure 103-7 Malignant nodule during CT-guided aspiration showing development of pneumothorax.

carcinoma, the most common malignancy among solitary pulmonary nodules. Nodules greater than 3 cm in diameter have a more than 90 percent chance of being malignant, and in the face of a negative metastatic workup and adequate pulmonary reserve, indeterminate nodules of this size should be resected. Smaller nodules that remain indeterminate after appropriate radiographic evaluation and possibly biopsy (bronchoscopic and/or percutaneous needle aspiration where indicated) either can be resected or observed with close serial CT follow-up. The decision depends on the patient and physician, who must educate the patient on the alternatives and possible consequences.

Thoracotomy has a reported mortality of 3 to 7 percent. It is higher in patients over age 70 and those with malignancy. These patients usually have other coexisting illnesses, such as chronic obstructive pulmonary disease (COPD), and coronary artery disease. The mortality risk increases with the extent of the procedure. In one series by Ginsberg and coworkers, the mortality was 1.4 percent for wedge resection, 2.9 percent for lobectomy, and 6.2 percent for pneumonectomy.

More recent observational studies of lung cancer surgery reported similar 30-day mortality rates. Of note, this study indicated that there may be a relationship between volume of surgeries performed and outcome. Hospitals that performed the highest volume of lung cancer surgeries had lower 30day mortality than those that had the lowest volume (3 vs.

6 percent).

VATS uses fiberoptic telescopes and miniaturized video cameras to facilitate biopsies and resection. VATS represents a complementary approach to traditional thoracotomy and can be very useful in some patients. This approach still requires

general anesthesia but does not require a full thoracotomy incision or spreading of the ribs. VATS allows the experienced surgeon to identify and wedge out peripheral nodules in many cases with minimal morbidity and mortality. In a series by Mack and colleagues, 242 nodules were resected with no mortality and minimal morbidity. Average hospital stay was 2.4 days. Video-assisted thoracic surgery can spare some patients with benign nodules the risks of open thoracotomy and can be useful for wedging out nodules in patients who have limited pulmonary reserve who cannot otherwise tolerate a lobectomy. However, in a significant percentage of cases conversion from VATS to a mini-thoracotomy is still required.

However resection is performed, whether by VATS or thoracotomy, lobectomy remains the procedure of choice for malignant solitary pulmonary nodules. Wedge excisions or segmental resections for smaller cancers have been evaluated, but the role of these limited pulmonary resections in the management of lung cancer remains controversial. The Lung Cancer Study Group evaluated this in a study of 276 patients with T1 N0 lesions that were strictly staged to prove N0 status. Patients were randomized to lobectomy or limited resection. In patients undergoing limited resection, there was an observed 75 percent increase in recurrence rates ( p = 0.02, one-sided) attributable to an observed tripling of the local recurrence rate ( p = 0.008 two-sided), an observed 30 percent increase in overall death rate ( p = 0.08, one-sided), and an observed 50 percent increase in death with cancer rate ( p = 0.09, one-sided) compared with patients undergoing lobectomy ( p = 0.10, one-sided was the predefined threshold for statistical significance for this equivalency study). Because of the higher death rate and locoregional recurrence rate

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associated with limited resection, lobectomy has been recommended as the surgical procedure of choice for patients with peripheral T1 N0 non-small cell lung cancer.

For patients with insufficient pulmonary reserve to tolerate a lobectomy, segmentectomy or wedge resection remains a viable alternative. In addition, whether or not very small malignant lesions, less than 2 cm in size, can be managed with segmentectomy, radiation, or some combination thereof, remains controversial and is the subject of ongoing research. At the present time, it is reasonable to recommend lobectomy for all patients with malignant solitary pulmonary nodules who have sufficient pulmonary reserve to tolerate the procedure, with consideration of segmentectomy for those patients with inadequate pulmonary function to tolerate a lobectomy.

DIAGNOSTIC APPROACH As is often the case in medicine, it is unwise to presume that an infallible algorithm can be provided for the evaluation of all solitary pulmonary nodules. Since no consensus can be reached on the basis of available data, the best that can be done is to offer recommendations. The pathway to be taken and final decision rest on the individual physician and patient. Individual patient preferences also play a key role. A 30-year-old nonsmoker, the mother of two children, with an indeterminate lesion, may not be willing to “observe with serial CT scans” and demand a resection; in contrast, a 75-year-old smoker with mild COPD and a lesion that seems to be malignant may decide to leave well enough alone and ignore it. The following recommendations represent one possible approach to this complex clinical problem (Fig. 103-8).

1. On discovering a solitary pulmonary nodule, the clinician should determine whether it is a true solitary nodule, spherical, and located within the lung fields. CT imaging should be part of the initial evaluation.

2. A thorough history and physical may provide clues about the nodule’s possible cause. (A history of tuberculosis in an asymptomatic patient suggests granuloma, whereas weight loss and adenopathy point toward malignancy.) Most of the time, solitary pulmonary nodules are asymptomatic. The history should include an assessment of risk factors for cancer, including smoking history, occupational exposures, exposure to endemic fungi, and any history of prior malignancy. Patient risk preferences should be obtained as part of the discussion.

3. If it is established that the nodule is truly solitary, and a benign pattern of calcification is present, the nodule is considered benign and no further workup is necessary. Follow-up with serial CT imaging may be warranted based on the size of the lesion and risk factors for cancer as described.

4. All prior chest radiographs and CT images should be obtained and compared with the present images.

If prior chest radiographs are available, and the nodule has remained unchanged for 2 years or longer, no further workup is necessary. Follow-up with serial CT imaging may be warranted if there is a concern for a slow-growing bronchioloalveolar cell carcinoma or there are other risk factors for cancer, as described.

If the nodule has grown and the doubling time is more than 20 days but less than 18 months, it is considered malignant and should be resected. If the doubling time is more than 18 months, consideration of a slow-growing bronchioloalveolar cell carcinoma or a carcinoid is warranted and, depending on the patient’s preferences and surgical risk, a biopsy procedure may be useful to provide further reassurance to the patient. Alternatively, the nodule may be benign and close serial CT follow-up is also reasonable, perhaps every 2 to 3 months for the first year and every 6 months for the next year.

If old chest images are available but the nodule was not present on prior radiographs, an upperlimit doubling time is calculated. The assumption is made that a 0.8-cm nodule was present but not yet detectable in the last available radiograph, and the doubling time is then calculated. If the doubling time is again less than 18 months, it is considered to be malignant and resected. If the doubling time is more than 18 months, the nodule remains indeterminate. Nodules for which previous radiographs are unavailable are also indeterminate.

5. The physician should arrive at an estimate of the probability of malignancy based on the history, physical, and CT imaging characteristics.

Those with a low probability (less than 10 percent) of malignant disease, such as those that have been demonstrated to be stable on serial CXR for 2 years or more, have a characteristic benign calcification pattern, or are present in patients less than 35 years of age in the absence of other risk factors, can be observed with serial CT scans depending on their size. The follow-up would be as described, with surgery for those with evidence of progression.

Those with a high probability of malignant disease who are surgical candidates should be considered for staging followed by VATS/thoracotomy. Examples are a new nodule of large size in an older patient with a heavy smoking history and a spiculated pattern on CXR. Staging would include a PET scan plus investigation of any other symptoms.

PET scanning in these instances is primarily to look for mediastinal and extrapulmonary disease, since 4 to 20 percent of patients without evidence of lymph node enlargement on CT have nodal or extrapulmonary disease. When the probability of

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Figure 103-8 An approach to the solitary pulmonary nodule.

malignant disease is this high, even if the PET scan is completely negative, biopsy or resection is warranted. Note that PET in this instance is more of a staging tool (determine extent and respectability of cancer), rather than a diagnostic tool (determine whether or not there is cancer present).

The third category, which many patients fall into, consists of those patients who are surgical candidates with nodules with a moderate probability (10–60 percent) of cancer. These nodules are considered indeterminate. After a standard evaluation including chest radiographs and CT scanning, 70 to 75 percent of nodules that remain indeterminate are malignant. The management of these nodules remains controversial. PET scanning for those with nodules measuring 1 cm or greater in

size is warranted. Transthoracic fine-needle aspiration, bronchoscopy if there is an air-bronchus sign, or a contrast-enhanced CT are reasonable options. If the results are positive, then surgery is clearly warranted whereas a specific benign diagnostic result (example: core biopsy demonstrates hamartoma or bronchoscopy demonstrates tuberculosis) is usually sufficient to guide management. However, a nonspecific nondiagnostic result should be interpreted with caution. Depending on the patient’s preferences, surgical risk, and probability of cancer, VATS/thoracotomy or careful follow-up CT imaging may be warranted.

6. The probability thresholds that define “low,” “moderate,” and “high” probability are not arbitrary but rather are determined by multiple factors, including

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the patient’s preferences, estimates of the effectiveness of surgery, the risks of surgery in those with and without disease, the long-term consequences of surgery, estimates of the hazard of delay, the patient’s comorbidities, the range of alternative diagnostic tests and their performance characteristics (sensitivity and specificity), and the range of alternative treatments.

“Low” probability in this case means that after considering all these factors, the probability of cancer is sufficiently low that the best strategy is careful observation with serial CT follow-up.

“High” means that after consideration of all these factors, the best strategy is VATS/thoracotomy.

“Moderate” means that one of the available diagnostic studies has sufficient discriminatory power to change what would be done in the absence of that test, either toward careful observation if the result is negative or surgery if the result is positive.

Many decision analysis studies of solitary pulmonary nodules have been published over time, and the probability thresholds that define the low, moderate, and high probability groups vary among studies. In part, this is because the available technologies and treatments have changed over time, so these probability thresholds also vary over time. As new diagnostic and treatment alternatives become available, these thresholds need to be periodically reassessed. However, even if technology were unchanging, patient preferences vary significantly, so defining a single “optimal” answer is not feasible.

Given these constraints, all of the decision analyses published are fairly consistent, with low probability being approximately 10 to 12 percent or less, and high probability being approximately 60 to 72 percent. However, these recommendations are just estimates. Their value lies not in their precision, but in the systematic approach that they promote and the recognition that careful assessment of the probability of cancer is critical to determining optimal strategy.

7. Noncalcified nodules greater than 3 cm and of indeterminate stability are likely to be malignant and should be resected if the patient has adequate pulmonary reserve and staging CT and PET imaging do not suggest mediastinal or distant metastatic disease.

If there is no evidence of extrapulmonary disease but CT or PET suggest mediastinal nodal disease, bronchoscopy with transbronchial needle aspiration (with or without endobronchial ultrasound) is probably the most cost-effective initial approach. In select patients when the anatomic location makes it feasible, endoscopic ultrasound–guided aspiration is an alternative. If bronchoscopic transbronchial needle aspiration is non-diagnostic, mediastinoscopy

is warranted. Importantly, enlarged lymph nodes (greater than 1 cm) on CT or a PET scan that shows nodal involvement is not sufficient to rule out surgery as an option; a biopsy should still be obtained in such instances to determine whether the patient does indeed have metastatic disease.

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104 The Pathology of Non–Small Cell Lung Carcinoma Leslie A. Litzky

I. THE 1999 AND 2004 WORLD HEALTH ORGANIZATION CLASSIFICATION OF LUNG TUMORS---MAJOR REVISIONS II. GENERAL CONSIDERATIONS IN HISTOLOGICAL CLASSIFICATION III. SQUAMOUS CELL CARCINOMA IV. ADENOCARCINOMA, INCLUDING BRONCHIOLOALVEOLAR CARCINOMA V. ADENOSQUAMOUS CARCINOMA VI. LARGE CELL CARCINOMA Large Cell Neuroendocrine Carcinoma of the Lung Basaloid Carcinoma of the Lung Other Variants of Large Cell Carcinoma

As a broad diagnostic category, non–small-cell lung carcinoma (NSCLC) comprises about 80 percent of all lung cancers. The World Health Organization (WHO) classification of lung tumors is the most frequently used system for categorizing these lung tumors. There have been two significant revisions of this classification in the intervening years since the 1981 revision and the previous edition of this book. Within the modified 2004 WHO classification, there are seven major categories of malignant non–small cell epithelial lung tumors (Table 104-1). Squamous cell carcinoma, adenocarcinoma and large cell carcinoma have traditionally been grouped as non–small cell lung carcinoma (NSCLC) in research studies and for treatment purposes. This practice is becoming less common as details about the biologic behavior and/or response to different therapeutic drugs emerge. This chapter focuses on these major histological subtypes, as well as carcinoid tumors, sarcomatoid carcinoma, and salivary gland

VII. SARCOMATOID CARCINOMA VIII. CARCINOID TUMORS Typical Carcinoid Atypical Carcinoid IX. SALIVARY GLAND TUMORS Adenoid Cystic Carcinoma Mucoepidermoid Carcinoma X. ANCILLARY STUDIES XI. HISTOCHEMICAL STAINS Immunohistochemistry XII. CONCLUSION

tumors. Small cell carcinomas, as well as other unusual tumors, both benign and malignant, are covered in separate chapters.

THE 1999 AND 2004 WORLD HEALTH ORGANIZATION CLASSIFICATION OF LUNG TUMORS---MAJOR REVISIONS Pathologic assessments are continually refined to reflect changes in surgical and medical management, as well as to incorporate an improved understanding of basic tumor biology. Once the diagnosis of malignancy has been made, the pathologic evaluation of non–small cell carcinoma has typically focused on histological subtyping and determining the extent of disease. Histological classification is essentially

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 104-1 WHO Classification of Malignant Epithelial Non–Small-Cell Lung Tumors Major Subtype

Variants

Squamous cell carcinoma

Papillary Clear cell Small cell Basaloid

Adenocarcinoma

Adenocarcinoma, mixed type Acinar adenocarcinoma Papillary adenocarcinoma Bronchioloalveolar carcinoma Solid adenocarcinoma with mucin production

Adenosquamous carcinoma Large cell carcinoma

Large cell neuroendocrine carcinoma Basaloid carcinoma Lymphoepithelioma-like carcinoma Clear cell carcinoma Large cell carcinoma with rhabdoid phenotype

Sarcomatoid carcinoma

Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma

Carcinoid tumor

Typical carcinoid Atypical carcinoid

Salivary gland tumors

Adenoid cystic carcinoma Mucoepidermoid carcinoma Epithelial-myoepithelial carcinoma

source: Data from Travis WD, Brambilla E, Muller-Hermelink, HK, et al: Tumours of the Lung, in Travis WD, Brambilla E, Muller-Hermelink HK, et al (eds), Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. WHO Health Organization Classification of Tumours, vol 10. Lyon, France, IARC Press, 2004.

predicated on the assumption that the quantitative predominance of a particular histological pattern reflects distinctive biologic characteristics. There remains great expectation that developments in other disciplines such as molecular biology may have a profound impact on tumor categorization, as well as on prognosis and treatment. Whether basic research in molecular biology and other fields will substantiate or modify the currently accepted histological classification is an actively debated question. The 1999 revisions introduced significant changes in the classification and nomencla-

ture of malignant epithelial lung tumors from the previous 1981 WHO classification. These changes reflected the substantial amount of pathologic observation and translational research that had ensued in the intervening eighteen years.

The 2004 revision made some minor changes in nomenclature but preserved the overall classification scheme that had been established in 1999. Major changes in the 1999 revision included the introduction of new variants of squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, as well as new or refined definitions for bronchioloalveolar carcinoma and solid adenocarcinoma. The 1999 revisions also incorporated the long anticipated consensus on neuroendocrine tumor nomenclature and classification criteria as well as consensus on biphasic and pleomorphic tumor nomenclature and classification criteria. Although it is beyond the scope of this chapter, it is worth noting that 1999 WHO revisions also added and defined two other preneoplastic processes— atypical adenomatous hyperplasia (AAH) and diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH)—to the previously recognized squamous dysplasia/carcinoma in situ. Finally, it should be recognized that in some circumstances, notably bronchioloalveolar carcinoma and carcinoid tumors, the 1999/2004 revisions require a very detailed histological examination of a resected specimen for definitive diagnosis.

The 2004 WHO classification of lung tumors was the first edition to extensively summarize the molecular biology of different tumor subtypes. Nevertheless, the main purpose of the current 2004 WHO classification, as in previous editions, is to provide reproducible criteria to pathologists worldwide by using recognizable architectural patterns and individual cellular features that can be appreciated by routine light microscopy and standard hematoxylin and eosin stained slides. The use of ancillary techniques, such as immunohistochemistry or molecular biology, is not required in most instances, thereby making the classification accessible to all pathologists for diagnosis and for fostering consistency in treatment and research protocols. Although this approach might be open to some criticism, it should be noted that the incorporation of data from ancillary studies such as immunohistochemistry or molecular has broad implications, not the least of which is the expense of the laboratory tests, which would require additional time, special equipment, and technical expertise. Criteria for the interpretation of some of these tests have yet to be well defined and it will only be possible to address definitively the clinical significance of these markers within the confines of prospectively designed, large clinical studies with standardized laboratory analysis and rigorous follow-up.

GENERAL CONSIDERATIONS IN HISTOLOGICAL CLASSIFICATION Tumor classification and associated generalizations pertaining to tumor type are often made to seem relatively

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straightforward but, in practice, it is always a challenge for any proposed scheme of histopathological classification to ensure the reproducible recognition of tumor subtypes. In order to understand some of these difficulties in lung tumor subclassification, it is worth recalling that all of the epithelial tissues in the lung are derived from an endodermal outpouching lined by a single layer of cuboidal cells that in turn differentiate to form the many different epithelial lining cell types and secretory cells. It is therefore not surprising that many epithelial tumors show a mixture of different cell types at both the light microscopic and ultrastructural level. This overlap extends to the presentation of antigens and cell products. As is often true of any classification scheme, distinctions can be somewhat arbitrary and before proceeding to a general discussion of histological subtypes, it is also appropriate to consider the factors that led to variability or lack of specificity in the classification of lung tumors. Roggli outlines two different aspects of variability in his analysis. As mentioned, one component is that of histopathological variability within a particular tumor due to divergent pathways of differentiation. It is well recognized that lung cancers frequently show histologic heterogeneity and that almost 50 percent of lung carcinomas exhibit more than one of the major histological types. A second component is that of interobserver or intraobserver variation in the application of a particular histopathological classification scheme. Factors that affect interobserver/intraobserver variability, in both published studies and in general practice, include the extent of tumor sampling and the field-to-field variation, the source of the material (i.e., biopsy vs. surgical vs. autopsy), the number of observers, the number of cases studied, and the manner in which the cases are evaluated. In an older study that looked at diagnostic consensus, overall interobserver agreement was obtained in 76 percent of cases.

Consensus was best for small cell carcinomas (72.5 percent), intermediate for adenocarcinomas and squamous cell carcinomas (56 and 48 percent, respectively), and very poor for large cell carcinomas (about 5 percent). Agreement was also quite poor for further tumor subtyping within a specific tumor type such as bronchioloalveolar carcinoma within adenocarcinoma. It should be noted that this study was published prior to the major criteria revisions in the 1999 WHO classification, some of which were specifically aimed at improving consensus in subtype diagnoses such as bronchioloalveolar carcinoma.

The practical impact of this variability is the resultant discrepancy that occurs occasionally between the cytologic and surgical pathological diagnosis or the final findings at autopsy. Recognition of histological heterogeneity depends to a great extent on sampling techniques that may, in turn, have implications for protocol design and prognosis. Similarly, interpretative disagreements following a second review do arise and should be viewed with appropriate circumspection as to clinical significance. In one study of lung cancer heterogeneity, there was no significant difference in survival between patients with homogeneous, as compared with heterogeneous tumors, when differences in stage were considered. The interobserver agreement for small cell carcinoma is

The Pathology of Non–Small Cell Lung Carcinoma

also worth noting and underscores the fact that lung tumor heterogeneity may confound a clear-cut pathologic distinction between non–small cell and small cell carcinoma. From a therapeutic point of view, the recognition of any small cell component has significant clinical relevance, but interpretative disagreements as to whether the tumor is a combined small cell carcinoma or a pure small cell carcinoma may not.

Lung carcinomas are classified according to the best differentiated component, and pathologists assign a degree of differentiation to tumors that show differentiation, such as squamous cell carcinoma and adenocarcinoma. This is also known as histological grading and it is an assessment as to how much the tumor cells phenotypically resemble a normal cell type, such as a squamous cell or a glandular cell. Histological grading should not be viewed as a histogenetic determination, i.e., that a tumor is derived from a specific cell of origin, such as a squamous cell, or that the tumor cell has “dedifferentiated” from a cell of origin. There are three histological degrees of differentiation: well differentiated, moderately differentiated, and poorly differentiated. As a group, lung cancers tend to be poorly differentiated, but many lung tumors show a wide variation in differentiation. Even if a tumor is largely undifferentiated but contains focal squamous cell carcinoma or adenocarcinoma, it would be classified as a poorly differentiated squamous cell carcinoma or adenocarcinoma. It is not clear that reporting precise percentages in terms of areas of well, moderate, and poor differentiation improves prognostic accuracy. Some tumors, such as small cell carcinoma or sarcomatoid carcinoma, are poorly differentiated by definition.

SQUAMOUS CELL CARCINOMA Adenocarcinoma replaced squamous cell carcinoma as the leading lung cancer cell type among both men and women in the United States by the 1990s. Nevertheless, this histological subtype of squamous cell carcinoma is still very strongly correlated with cigarette smoking and is seen more commonly in men. About two-thirds of squamous cell carcinomas occur centrally, where involvement of a mainstem, lobar, or segmental bronchus may be demonstrated (Fig. 104-1A).

As would be expected from an endobronchial growth pattern, squamous cell carcinomas frequently are associated with bronchial obstruction and postobstructive pneumonia. Cavitation is seen more frequently in squamous cell carcinoma than in the other histological subtypes (Fig. 104-1B). Squamous cell carcinomas may also present as a peripheral nodule and there is some recent evidence to suggest that the proportion of peripheral squamous cell carcinomas is increasing in at least some populations (Fig. 104-1C ).

By the 1999/2004 WHO classification, squamous cell carcinoma is defined as a malignant epithelial tumor showing keratinization and/or intercellular bridges. Keratinization may be in the form of squamous pearls or individual cells with

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dense eosinophilic cytoplasm. Intercellular â&#x20AC;&#x153;bridgesâ&#x20AC;? are seen in paraffin sections due to cell shrinkage caused by fixation and correspond to the desmosomal attachments that can be appreciated ultrastructurally (Fig. 104-2B and C ). A desmoplastic (i.e., fibrotic) response is often associated with the invasive nests of tumor cells (Fig. 104-2 A). As noted with the other histological types, squamous cell carcinomas often show significant areas of histological heterogeneity. There are four histological variants with the 1999/2004 WHO classification of squamous cell carcinoma: papillary, clear cell, small cell, and basaloid patterns. On occasion, a tumor may consist entirely of one of these variants, but it is more common for these patterns to be focal. A familiarity with these variant patterns is useful for the practicing pathologist, but at the current time there is no evidence that these variant patterns have any clinical significance. The papillary variant is characterized by an exophytic growth pattern and papillary cores. The classic tumor cells of a squamous cell carcinoma are large and polygonal with eosinophilic cytoplasm, but in the clear cell variant, as the name suggests, cells with clear cell cytoplasm can be seen (Fig. 104-2D). In the basaloid variant, the nests of tumor cells have prominent peripheral palisading and have less cytoplasm toward the periphery, but the

Figure 104-1 A. Large endobronchial squamous cell carcinoma with atelectasis and obstructive pneumonitis. B. Cavitation within a squamous cell carcinoma. C. Right upper lobectomy with chest wall resection for squamous cell carcinoma.

more centrally located cells have more obvious keratinization. In the small cell variant of squamous cell carcinoma, the tumor cells are relatively smaller and can have granular nuclear chromatin, but there is some chromatin variation with more coarse or vesicular chromatin and prominent nucleoli.

A careful search shows cytoplasmic evidence of squamous differentiation in the form of focal keratinization or intracellular bridges.

Although not invariably demonstrated, it is easiest to identify a trend in tumor progression with this histological subtype. Sampling of a resected specimen typically shows changes in the adjacent bronchial mucosa ranging from squamous metaplasia to dysplasia to carcinoma in situ. If identified, the presence of an in situ component helps to differentiate a primary squamous cell carcinoma from a metastatic lesion. At the present time, there is no other conclusive means of differentiating a primary pulmonary squamous cell carcinoma from a metastasis, but there is a tendency for metastatic tumors from the head and neck to be better differentiated (i.e., show more extensive keratinization) than their primary pulmonary counterparts.

Electron microscopy demonstrates the presence of tonofilaments and desmosomes in squamous cell carcinomas.

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Figure 104-2 A. Desmoplastic response with nests of infiltrating squamous cell carcinoma (H&E, 200×).

B. Squamous cell carcinoma with keratinization and intracellular bridges (H&E, 200×). C. High power view of keratinization and intercellular bridges (H&E, 400×). D. Tumor cells with clear cytoplasm from a squamous cell carcinoma (H&E, 400×).

However, these findings are non-specific and may also be present in adenocarcinomas. There continues to be a considerable amount of active research focused on an immunohistochemical panel or a molecular profiling technique that would reliably distinguish a primary squamous cell carcinoma of the lung from other primary sites.

ADENOCARCINOMA, INCLUDING BRONCHIOLOALVEOLAR CARCINOMA Within the United States, epidemiologic studies have now demonstrated that adenocarcinoma is the most frequently diagnosed histological type of lung cancer. Adenocarcinoma is also the most frequently diagnosed subtype in women, as well as in non-smokers, although most patients with adeno-

carcinoma are smokers. It is generally believed that most likely explanation for the increased proportion of adenocarcinoma among smokers relates to the shift to low-tar filter cigarettes during the 1960s and 1970s.

A majority of adenocarcinomas arise in the periphery of the lung and are typically associated with puckering of the overlying pleura or parenchymal scarring (Fig. 104-3). It was initially assumed that all these lesions represented a tumor arising in an area of preexisting fibrosis. A number of studies subsequently challenged this view and presented various lines of evidence to support the hypothesis that the scarring represents a desmoplastic response to the tumor. It is likely that both observations are correct and that the etiology of the tumor-associated fibrosis depends on the clinical circumstances. There are well-documented cases of adenocarcinoma occurring in patients with diffuse pulmonary fibrosis, remote infarcts, tuberculomas, and within emphysematous bullae.

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Figure 104-3 Peripheral adenocarcinoma of the lung with pleural puckering.

The histological appearance of adenocarcinomas is extremely diverse and this histological heterogeneity presents a significant problem when the differential diagnosis includes metastasis or malignant mesothelioma. In addition, this histological heterogeneity has always made reproducible subclassification with primary pulmonary adenocarcinomas extremely difficult. Small adenocarcinomas (typically less than 2 cm) are more likely to consist of one histological pattern, but even small adenocarcinomas can contain more than one histological subtype. This practical problem was to a great extent resolved by the 1999 WHO revision, which introduced, for the first time, a mixed subtype, to the four previously recognized subtypes of acinar, papillary, bronchioloalveolar, and solid. The 1999/2004 WHO classifications also recognize five relatively uncommon variants: fetal adenocarcinoma, mucinous (“colloid”) carcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell adenocarcinoma.

Acinar adenocarcinomas consist of irregularly contoured but nonetheless recognizable glandular structures and are often associated with a desmoplastic stroma (Fig. 1044A and B). The papillary variant is illustrated in Fig. 1044C . The presence of cytoplasmic vacuoles suggests the solid variant of adenocarcinoma, which then may be confirmed by a special stain for mucin (Fig. 104-4D). The 1999/2004 WHO classification requires that be there five or more mucinpositive cells in at least two high-power fields for the diagnosis of solid adenocarcinoma with mucin production. This criterion was adopted because it is not uncommon for squamous cell or large cell carcinomas to have focal mucin droplets. By definition, given the solid pattern of the tumor, solid adenocarcinomas are poorly differentiated. Some of the other rare variants such as signet ring carcinomas and cystic mucinous tumors resemble other solid organ malignancies and may be very difficult to distinguish as primary lung cancers.

The distinction between peripheral adenocarcinomas with extensive pleural involvement, diffuse carcinomatous in-

volvement of the pleura by metastatic tumor, and malignant mesothelioma may be problematic. Some carcinomas grow in a manner virtually identical to malignant mesothelioma, with extensive pleural involvement and limited parenchymal invasion. Clinically, radiographically, and macroscopically, these tumors are indistinguishable from malignant pleural mesothelioma. The histological appearance may be equally confusing, requiring the use of immunohistochemical stains.

A strict definition for bronchioloalveolar carcinoma (BAC) was adopted in the 1999 revision and retained in the 2004 revision. The definition requires that the tumor have a pure lepidic growth pattern without evidence of stromal, vascular, or pleural invasion. The term “lepidic” means that the proliferation of tumor cells should line the alveolar walls in a uniform manner, using the alveolar walls as a supporting stroma. It should be noted that prior to the 1999 revision, pathologists widely varied in their assessments, with some allowing for more histological variability in the definition.

Adenocarcinomas with a minor, usually central, and often more poorly differentiated glandular component along with a peripheral bronchioloalveolar pattern are frequently encountered. In instances in which the peripheral BAC component predominated, it had been a common practice to designate the tumor either as a BAC or an “adenocarcinoma with a BAC pattern.” This term of “adenocarcinoma with a BAC pattern” should be avoided and the current WHO nomenclature should be adhered to, whatever its shortcomings. The stricter definition prevailed in the revisions because of studies that demonstrated that small (less than 2.0 cm) solitary tumors with a pure lepidic growth pattern had a 100 percent 5-year survival. Although it is true that this strict definition has improved the reproducibility of the diagnosis, application of the criteria, specifically defining stromal invasion, are still somewhat problematic in practice. Many adenocarcinomas have areas of fibrosis due to alveolar wall collapse or septal fibrosis. This is not considered to be true invasion, but this assessment can be difficult. Histological criteria for true invasion include single cell infiltration, a fibromyxoid stromal response, high-grade cytology, and a cribriform or acinar growth pattern. Some experts have suggested the use of elastic or trichrome stains to help highlight parenchymal disruption but consensus protocols for finding and defining invasion—other than submitting the entire lesion for histological examination—have not yet been published. A second issue is what to do about tumors with areas of focal or “minimal” invasion, which are now subsumed under the “mixed” subtype of pulmonary adenocarcinomas. There are a number of studies that have argued for a quantitation of the lepidic growth pattern and the area of invasion within these mixed adenocarcinomas. Some of these studies have focused on a cutoff of less than 5 mm of invasion as a way of defining a “minimally invasive adenocarcinoma.” However, a consensus on the clinical meaning of this type of minimal invasion, how to accurately and reproducibly measure it, how significantly it affects an individual patient’s prognosis, and whether there

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Figure 104-4 A. Moderately differentiated adenocarcinoma, acinar pattern, with recognizable gland formation (H&E, 200×). B. Poorly differentiated adenocarcinoma, acinar pattern. Within the desmoplastic stroma, the tumor forms occasional small, irregularly shaped glands with mucin vacuoles (H&E, 400×). C. Adenocarcinoma, papillary pattern. Malignant cells are arranged on the surface of fibrovascular cores (H&E, 400×). D. Adenocarcinoma, solid growth pattern with mucin production (H&E, 400×).

is any geographic variability in these outcomes has not been clearly established. Another issue is how to classify patients for treatment purposes when they have had a very small sampling of their tumor—either by bronchial washings, transbronchial biopsy, or fine needle procedures. It is clear that the final diagnosis of BAC can only be rendered on a full histological examination of the resection specimen. For smaller samplings, it is recommended that the diagnosis be stated as “adenocarcinoma, possible bronchioloalveolar carcinoma,” but this leaves opens the issue of clinical management in patients who will not undergo resection. This uncertainty may be problematic as more specific treatment protocols for specific tumor subtypes are introduced, unless some compromise, possibly using radiographic correlation, is made.

Histologically, BACs are divided into two major subtypes: nonmucinous and mucinous. A rare mixed nonmucinous and mucinous or indeterminate subtype is also recog-

nized in the 1999/2004 revisions. The more common nonmucinous type consists of cuboidal, columnar, or so-called “hobnail” cells with apical nuclei (Fig. 104-5A). The mucinous type shows goblet cell differentiation, i.e., tall columnar cells with abundant apical pale mucinous cytoplasm and basally located nuclei (Fig. 104-5B). Other mucinous carcinomas, particularly of pancreatic ovarian origin, may metastasize to the lung and grow in a bronchioloalveolar pattern.

It has become increasing apparent that the two cell types do have some distinctive clinical and radiographic correlations.

The pure ground-glass opacities without a solid component that are now commonly detected on high resolution CT scans and that prove to be a tumor on resection are strongly correlated with the non-mucinous subtype. Most solitary BACs are also of the non-mucinous type. A diffuse pneumonic infiltrate has a significantly worse survival when compared with unifocal and multifocal patterns. The mucinous subtype

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Figure 104-5 A. Bronchioloalveolar carcinoma, non-mucinous type. Malignant cells uniformly line thickened alveolar septa. B. Bronchioloalveolar carcinoma, mucinous type. Tall columnar cells with abundant mucinous cytoplasm line the alveolar septa (H&E, 400×).

is more frequently associated with this diffuse pneumonic pattern.

The ultrastructural appearance of adenocarcinomas can be quite heterogeneous but electron microscopy can still be useful in some problematic cases. In contrast to malignant mesotheliomas, which have long microvilli, these cells have short, uniform microvilli and prominent rootlets with a fuzzy glycocalyx. As discussed in the general section on immunohistochemistry, there are multiple antibodies that will stain adenocarcinomas of the lung. Many of these antibodies (CEA, MOC31, B72.3, LeuM1, and BerEP4) recognize glycoproteins and are not specific for the lung. Clara cell antigen and surfactant apoprotein antibodies are commercially available but have limited diagnostic utility. Until relatively recently, it was believed that TTF-1 was specific for lung and thyroid, but there is now evidence that this antibody stains a wider variety of tumors. The sensitivity of TTF-1 staining is also quite variable depending on the adenocarcinoma subtype. For example, TTF-1 stains a much lower percentage of mucinous bronchioloalveolar carcinomas.

LARGE CELL CARCINOMA Large cell carcinomas account for a little less than 10 percent of all lung cancers. Large cell undifferentiated carcinoma (LCC) is defined in the 1999/2004 WHO classification as “an undifferentiated malignant epithelial tumor that lacks the cytologic features of small cell carcinoma and glandular or squamous differentiation”. The cells typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm (Fig. 104-6). As is evident from this description, this tumor is defined more by what it is not than what it is; therefore, for all practical purposes, it is a diagnosis of exclusion. The practical implication of this definition is that the diagnosis of LCC, as with BAC, requires examination of the entire tumor to rule out areas of squamous or glandular differentiation. The

ADENOSQUAMOUS CARCINOMA This tumor consists of well-defined squamous carcinoma and adenocarcinoma components, with each component comprising at least 10 percent of the whole tumor. The areas of glandular and squamous differentiation may be located in different areas of the tumor or may be intimately admixed.

In the past, different criteria had been used for this histological subtype and these differences in definition, in addition to its low incidence, have made it extremely difficult to compare survival rates with other non–small cell carcinomas. The SEER data show an overall 21 percent 5-year survival rate. The current 1999/2004 WHO criteria of 10 percent should foster more uniformity in future studies.

Figure 104-6 Large cell carcinoma of the lung. There is no obvious squamous differentiation in the form of keratinization or intercellular bridges and a mucin stain was negative (H&E, 400×).

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WHO criteria are based on conventional microscopy, the occasional use of mucin stains, and the required use of immunohistochemistry for one variant (large cell neuroendocrine carcinoma). On electron microscopy, many large cell carcinomas show focal ultrastructural features consistent with adenocarcinoma or a poorly differentiated squamous cell carcinoma. Melanoma and malignant large cell lymphomas also can mimic large cell carcinoma, typically requiring the use of immunohistochemistry to exclude these diagnoses. The major change in the 1999/2004 revisions was to expand the number of variants included within the category of large cell carcinoma and transfer others, namely giant cell carcinoma and spindle cell carcinoma, into the sarcomatoid carcinoma category. The large cell carcinoma variants include large cell neuroendocrine carcinoma, combined large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype.

Large Cell Neuroendocrine Carcinoma of the Lung Large cell neuroendocrine carcinoma (LCNEC) is defined as “a large cell carcinoma showing histological features such as organoid nesting, trabecular, rosette-like and palisading patterns that suggest neuroendocrine differentiation and in which the latter can be confirmed by immunohistochemistry or electron microscopy” (Fig. 104-7A). The cells are relatively large in size, often polygonal in shape, with moderate to abundant cytoplasm. The nuclear chromatin ranges from vesicular to finely granular. Nucleoli are frequent and often prominent (Fig. 104-7A). The presence of nucleoli tends to be a critical feature in the separation from small cell carcinoma (Fig. 104-7B) but some LCNECs lack this criterion.

Mitoses should be greater than 10 mitoses/10 high power

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fields. As mentioned previously, neuroendocrine differentiation must be demonstrated by ancillary techniques such as immunohistochemistry. Chromogranin and synaptophysin are the two stains that are most frequently used and are considered to be more specific that neuron-specific enolase (NSE). In order for a tumor to be designated as an LCNEC, the tumor must have both neuroendocrine morphology and positive staining. Tumors that otherwise look like squamous cell carcinomas, adenocarcinomas, or large cell carcinomas but have focal neuroendocrine staining have been termed “non–small cell lung carcinoma with neuroendocrine differentiation” (NSCLC-ND). Although this designation appears in the literature, particularly in studies that have sought to determine whether NSCLC-ND has a worse prognosis or differs in its response to chemotherapy, it is actually not formally part of the WHO classification. In 1991, Travis and coworkers first proposed criteria for this entity, which was considered to be histologically distinct from other tumors with neuroendocrine differentiation such as atypical carcinoids or small cell carcinoma. A great deal of controversy ensued over the following decade and continues to some extent. One controversy, which centered around the reproducibility of the diagnosis of LCNEC as well as other neuroendocrine tumors, was addressed by a study that demonstrated substantial agreement, at least among experienced lung pathologists. In this study, a majority consensus diagnosis was achieved for 50 percent of the cases of LCNEC, which is no worse than other categories of lung tumors. The second controversy focused on the clinical significance of the diagnosis, particularly in relationship to small cell carcinoma. It has been very clear from multiple studies that both tumors are aggressive and have a very poor prognosis. From an epidemiologic perspective, both tumors are associated with heavy tobacco use, both tumors share a loss of Rb and both tumors can occur in combination with other non–small cell lung cancers. Combined large

B

Figure 104-7 A. Large cell neuroendocrine carcinoma. The tumor cells are arranged in large organoid nests with numerous mitoses and necrosis (H&E, 200×). B. Comparison of large cell neuroendocrine carcinoma (left) with small cell carcinoma (right) at same magnification. The large cell neuroendocrine cells are larger, with a lower nuclearcytoplasmic ratio, and the chromatin is coarsely granular (H&E, 400×).

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cell neuroendocrine carcinoma refers to a large cell neuroendocrine carcinoma with components of another non–small cell carcinoma such as, for example, squamous cell carcinoma or adenocarcinoma.

Basaloid Carcinoma of the Lung In the 1999/2204 WHO revisions, pure primary basaloid carcinoma of the lung is considered to be a variant of large cell carcinoma. The basaloid histological features in lung carcinomas are similar to those also seen in other extrapulmonary sites such as the head and neck or cervix. Basaloid cells are typically described as relatively small monomorphic cuboidal to fusiform cells with moderately hyperchromatic nuclei, finely granular chromatin, absent or focal nucleoli, scant cytoplasm, and a high mitotic rate. Intercellular bridges and/or individual cell keratinization should not be present. The tumor cells are usually arranged in lobular, trabecular or palisading growth patterns (Fig. 104-8). Since these types of histological patterns can also be seen in neuroendocrine tumors, immunohistochemical stains for neuroendocrine markers should be negative or extremely focal. These tumors are reported to be consistently positive for cytokeratin 903 as well as negative for TTF-1. Unlike the other variants of large cell carcinoma that are more likely to occur as peripheral tumors, basaloid carcinomas usually develop in proximal bronchi and have a central endobronchial component. About 50 percent of cases have associated carcinoma in situ. If the basaloid component is less than 50 percent and combined with a non–small carcinoma such as squamous cell carcinoma, the tumor is classified as squamous cell carcinoma (basaloid variant).

Other Variants of Large Cell Carcinoma Lymphoepithelial-like carcinomas are extremely rare in the United States but represent 1 percent of all lung cancers in China. The histological features in lung carcinomas are sim-

Figure 104-8 Basaloid carcinoma of the lung. The tumor cells are relatively small with hyperchromatic nuclei and scant cytoplasm. Note the tendency of the tumor cells to palisade at the periphery of the tumor nest (H&E, 400×).

ilar to those also seen in other extrapulmonary sites such as the head and neck. Large malignant cells with prominent nucleoli are arranged in nests within a lymphoid-rich stroma.

Epstein-Barr virus EBER-1 RNA has been demonstrated to be present in the large tumor cells. The clear cell carcinoma variant consists of a pure clear cell carcinoma without evidence of squamous or glandular differentiation. Pure large cell carcinoma with rhabdoid phenotype, i.e., a large cell carcinoma with cells showing prominent eosinophilic cytoplasmic globules, is extremely rare.

SARCOMATOID CARCINOMA Tumors that have sarcoma-like elements such as malignant spindle or giant cells or have a sarcomatous component that consists of a neoplastic but differentiated connective tissue phenotype such as neoplastic bone, cartilage, and striated muscle have been described in many primary organ sites, including the lung. The proliferation of terms in past literature and even the variations in nomenclature that have characterized revisions in the WHO classification have generated a disproportionate degree of confusion when compared with the actual incidence of these relatively rare lung tumors. Various terms in the literature have included spindle cell carcinoma, sarcomatoid carcinoma, carcinosarcoma, pleomorphic carcinoma, giant cell carcinoma, and pulmonary blastoma. The 1999 revision established a minimum requirement of 10 percent for certain elements, such as spindle cells or giant cells, for a tumor to be appropriately classified. The most recent 2004 WHO revision has settled on the term sarcomatoid carcinoma to categorize these tumors, which are by definition poorly differentiated non–small cell carcinomas that have a histological appearance that suggests mesenchymal differentiation. The current variants of sarcomatoid carcinoma include pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma. It is now accepted that these variants are merely the phenotypic variations that can occur within the spectrum of epithelial-derived lung tumors. Careful sampling of these tumors usually demonstrates an identifiable component of squamous cell carcinoma, adenocarcinoma, or large cell carcinoma. The rarity of these tumors and previous confusion in terminology have made it difficult to characterize clinical characteristics and outcome. These tumors have no distinguishing radiologic features and have been reported in both central and peripheral locations. With the exception of pulmonary blastoma, which appears to be most frequent in the fourth decade and occurs equally in women and men, the other variants occur primarily in men in the sixth and seventh decade and have the same general association with tobacco use as other more common lung tumors. In a large series that was based on current WHO criteria and was analyzed according to stage, sarcomatoid carcinomas had a worse prognosis than conventional non–small cell carcinomas at surgically curable stage I.

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well-differentiated fetal adenocarcinoma and a primitive mesenchymal stroma, which occasionally has foci of osteosarcoma, chondrosarcoma, or rhabdomyosarcoma. The term pulmonary blastoma had been used historically to describe tumors that have been reported in all age groups. Manivel et al. argued that the childhood intrathoracic tumor was a distinct clinicopathologic entity that differed from the adult type, particularly in the absence of a carcinomatous component and its variable anatomic location. They proposed the alternate nomenclature of pleuropulmonary blastoma for these pediatric tumors, which occur almost exclusively in children of 6 years of age or younger, and this has been preserved in the 1999/2004 WHO revisions as a distinctly separate entity in the classification of soft tissue tumors. Pulmonary blastoma mainly occurs in adults. Although uncommon, pulmonary blastomas composed exclusively of embryonal-like epithelial and mesenchymal elements do occur. Adult tumors consisting entirely of malignant primitive glandular epithelium have also been described and are termed fetal adenocarcinomas, a variant of adenocarcinoma. Pulmonary blastomas have a histologically distinct, more embryonic appearance resembling fetal lung, with primitive cellular stroma and distinctive “endometrioid”-type glands (Fig. 104-11A and B).

Figure 104-9 Pleomorphic carcinoma of the lung. The spindle cell and giant cell component in this large cell carcinoma comprise at least 10 percent of the tumor (H&E, 400×).

Pleomorphic carcinoma is defined as a poorly differentiated non–small cell carcinoma containing spindle cells and/or giant cells. As mentioned, the spindle cell and/or giant cell component should comprise at least 10 percent of the tumor (Fig. 104-9). Spindle cell carcinoma and giant cell carcinoma are terms that are reserved for the extremely rare instance in which the tumor is shown to consist entirely of spindle cells or giant cells, respectively. In the pathology literature, tumors that contain cells with a neoplastic but differentiated connective tissue phenotype are said to have “heterologous elements.” Carcinosarcoma refers to a lung tumor that has recognizable heterologous elements such as rhabdomyosarcoma, osteosarcoma, or chondrosarcoma (Fig. 104-10A and B). Rather than terminology, the more significant issues confronting the pathologist are exclusion of metastasis from another site and avoiding the misdiagnosis of a primary pulmonary sarcoma.

Pulmonary blastoma is a biphasic tumor that contains a primitive epithelial component that resembles

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CARCINOID TUMORS Pulmonary carcinoid tumors represent about 1 to 5 percent of all lung malignancies. The 1999/2004 WHO revisions recognize two distinct subtypes of well-differentiated neuroendocrine tumors, typical carcinoid tumor and atypical carcinoid tumor. Both tumors are recognized by their low-power architectural pattern and characteristic cytologic features that are familiar to pathologists and are similar in appearance to carcinoid tumors that occur in other primary sites such as the gastrointestinal tract. However, in contrast to the term “welldifferentiated neuroendocrine carcinoma” that is gaining in

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Figure 104-10 A. Carcinosarcoma showing a mixture of sarcoma (center) and carcinoma (periphery) (H&E stain, 100×). B. Same tumor with focus of histologically malignant cartilage (H&E stain, 200×).

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Typical Carcinoid

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Figure 104-11 A. Pulmonary blastoma, showing a characteristic endometrioid-type gland, composed of cells with clear cytoplasm and basally oriented nuclei (H&E, 200×). B. Malignant stroma in a pulmonary blastoma (H&E, 400×).

popularity in extrapulmonary sites, carcinoid tumor has been retained in lung tumor classification because of its familiarity to clinicians and because of the well-established clinical behavior associated with the terminology. In the intervening years between the 1981 WHO revisions and the 1999/2004 revisions, there was a significant amount of debate regarding the diagnostic criteria for these lesions, the most appropriate nomenclature, and their clinical behavior within the broader context of pulmonary neuroendocrine tumors. It has been intellectually appealing to try to view neuroendocrine tumors as a continuous spectrum, with carcinoid tumors at one end and small cell carcinoma, as an aggressive tumor with neuroendocrine differentiation, at the other end. Numerous research studies have suggested that this is likely not the case and it is best to regard each tumor as a unique entity with set diagnostic criteria and a generally predictable clinical course.

As will become clear in the discussion of these tumors that follows, it may be impossible to separate an atypical carcinoid from a typical carcinoid tumor on the basis of a small biopsy specimen. This distinction should not affect initial surgical management but it may significantly impact on subsequent prognosis.

Typical carcinoid tumors can be divided into central and peripheral variants. Both variants can be asymptomatic but central carcinoids, which characteristically grow as an endobronchial mass, may present clinically with recurrent pneumonias or hemoptysis. There is a roughly equal incidence among males and females, with a wide age range at presentation. Typical carcinoid tumors are not associated with tobacco use, but there is a rare association with MEN1 syndrome. The association of bronchial carcinoid tumors with carcinoid syndrome is extremely unusual and typically occurs in the presence of widespread metastatic disease. Cushing’s syndrome due to ectopic production of ACTH is similarly rare.

Central carcinoids grossly appear as yellow or fleshy, polypoid masses (Fig. 104-12). The tumor usually has a significant exophytic endobronchial component but the tumor can infiltrate between cartilaginous rings to extensively involve the bronchial submucosa. The tumor cells form diverse patterns such as organoid nests, trabeculae, insular islands, ribbon, or rosette-like arrangements. Carcinoids can also have papillary, sclerosing, follicular, and glandular patterns. The tumor cells are generally uniform in appearance and have a low nuclear:cytoplasmic ratio with round to oval nuclei and eosinophilic cytoplasm (Fig. 104-13). The tumor cells have characteristic neuroendocrine tumor chromatin that is finely granular or classically described as “salt and pepper.”

Peripheral carcinoids are frequently subpleural and can be associated with a scar (Fig. 104-14A). Unlike the cells of central tumors, which are usually round or polygonal in shape, the tumor cells of peripheral carcinoids tend to have prominent spindle cell features (Fig. 104-14B). These fusiform cells have less cytoplasm than central tumors, but this feature should not be considered a sign of atypia. There is a subset of patients with one or more peripheral carcinoid tumors who have multiple tumorlets (small neuroendocrine cell proliferations less than 0.5 cm) and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). In these patients, it is believed that the neuroendocrine cell hyperplasia represents a preneoplastic condition. The most significant complication for this subset of patients is airway fibrosis, which can progress to severe obstructive lung disease and require lung transplantation.

The pathologic attributes of these tumors have been examined in numerous histological, immunohistochemical, and molecular studies. The only consistent prognostic indicators have proved to be mitotic rate and necrosis. The current 1999/2004 WHO criteria for the diagnosis of carcinoid tumor require fewer than 2 mitoses per 10 high-power fields of viable tumor and no necrosis. Cytologic atypia, increased cellularity, and lymphovascular invasion are not predictive features. Although carcinoid tumors have an excellent prognosis with reported 5-year survival rates of 87 to 100 percent, it is critical to understand that typical carcinoids are lowgrade but malignant tumors. Hilar and mediastinal lymph

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node metastases occur in 5 to 10 percent of cases, but do not necessarily indicate a poor prognosis. There are currently no histological characteristics that reliably predict which typical carcinoid tumors will behave more aggressively and go on to develop systemic disease.

Atypical Carcinoid The term “atypical carcinoid” was first introduced by Arrigoni et al. in 1972. Twenty-three tumors were described that appeared to have a general resemblance to carcinoid tumors but that also had a focally disorganized growth pattern, areas of tumor necrosis, increased mitoses, and cellular pleomorphism. Dissension was immediately generated by the use of the word “atypical,” given the aggressive biologic behavior in their series with 30 percent dead of disease at 3 years, a 70 percent incidence of metastases, and a mean survival of 27 months. Many other terms were introduced into the literature in the 1980s as more published reports detailing this entity appeared. Other terms used include malignant carcinoid, well-differentiated neuroendocrine carcinoma, peripheral small cell carcinoma of lung resembling carci-

Figure 104-12 A. Large endobronchial carcinoid. B. Endobronchial carcinoid. Grossly, the tumor is yellow, fleshy, and vascular.

noid tumor, and Kulchitsky cell carcinoma II. The tumors described in these papers have been a heterogeneous group.

This is in, in part, due to the subjective interpretation of features such as “architectural distortion.” In defending atypical carcinoids as a distinct clinicopathologic entity, Travis et al. emphasized that the overall architecture should be that of a recognizable carcinoid tumor with a predominantly organoid growth pattern. Following numerous studies, the most reliable criteria for the reproducible diagnosis of these tumors and separation of typical carcinoid from atypical carcinoid proved to be mitotic rate and necrosis. In the 1999/2004 WHO revisions, an atypical carcinoid tumor is defined as a carcinoid tumor with between two and 10 mitoses per 10 high-power fields and/or with foci of necrosis. The necrosis in these tumors is usually punctate (Fig. 104-15) and one should be careful to exclude the possibility of a large area of necrosis that is secondary to a previous needle biopsy. Although cytologic atypia, lymphovascular invasion, nucleoli, increased cellularity, and disorganized architecture may be seen, these features are not a part of the classification system. In published reports of this entity, the gender distribution and age at presentation overlap with that of typical carcinoids. Like

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Figure 104-13 A. Cytologic features of carcinoid tumor with small, uniform cells. The nuclei are round to oval with a ‘‘salt and pepper” chromatin pattern (H&E, 400×). B. Carcinoid tumor, nested pattern of carcinoid tumor (H&E, 200×). C. Carcinoid tumor, ribboned pattern in carcinoid tumor (H&E, 200×).

typical carcinoid tumors, atypical carcinoid tumors can occur centrally as well as in the periphery. It is appropriate to consider atypical carcinoid tumors as an intermediate grade malignant tumor with an increased capacity for progression.

Atypical carcinoids have a higher incidence of lymph node

metastases at presentation and, in contrast to typical carcinoids, nodal disease is a negative predictor of survival. A tumor size of 3.5 cm or greater and a higher mitotic rate are also poor prognostic indicators. The overall 5- and 10-year survival rates for atypical carcinoid are reported as 61 to 73

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Figure 104-14 A. Peripheral carcinoid. B. Peripheral carcinoid with prominent spindle cell features (H&E, 200×).

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Figure 104-15 Central necrosis in an atypical carcinoid tumor (H&E, 200×).

percent and 35 to 59 percent, respectively. Chemotherapy and radiation have not been demonstrated to be efficacious.

SALIVARY GLAND TUMORS Mixed seromucinous glands are found in the tracheal and large bronchial submucosa and are believed to give rise to a variety of salivary gland-like tumors, histologically indistinguishable from their major salivary gland counterparts. The 2004 WHO revision recognizes three major subtypes of malignant salivary gland tumors: mucoepidermoid carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma. There is also a category of other rare malignant salivary gland tumors that includes malignant mixed tumors and acinic cell carcinoma. It is considered quite likely that some tumors diagnosed as adenocarcinomas (usually of acinar subtype) are actually of bronchial gland origin because their histological features are not sufficiently distinctive to confirm bronchial gland origin. Salivary gland carcinomas represent less than 1 percent of all lung carcinomas, with mucoepidermoid carcinoma and adenoid cystic carcinoma being the most common subtypes. Although relatively uncommon, their distinctive morphology, growth pattern, and clinical presentation make these two salivary gland-type tumors of the lung an important subgroup of non–small cell lung carcinoma.

Adenoid Cystic Carcinoma Adenoid cystic carcinoma is the most common of the tracheobronchial gland tumors. Patients range in age from 18 to 82 at presentation and the incidence is equal among men and women. The vast majority of cases originate intraluminally and the typical presenting symptoms such as wheezing, progressive dyspnea, stridor, cough, and hemoptysis reflect this intraluminal tumor growth. Unlike carcinoid tumors and mucoepidermoid carcinomas, which usually present as intra-

The Pathology of Non–Small Cell Lung Carcinoma

luminal endophytic masses, adenoid cystic carcinomas have a more variable growth pattern. Some tumors are grossly nodular with minimal invasion of the bronchus, whereas others have a mixed nodular/infiltrative or predominantly infiltrative growth pattern (Fig. 104-16A andB). More infiltrative tumors appear as small nodules within the airway or cause a generalized constriction of the airway. There may be lymph node involvement, usually by direct extension, and highergrade tumors have a tendency to radially spread into the adjacent parenchyma rather than along the airways.

The microscopic level of invasion nearly always exceeds that which is grossly apparent. Negative resection margins often are difficult to achieve. Complete resection may be quite difficult and can require multiple frozen sections to confirm clear surgical margins. The tumor cells are small with a relatively high nuclear/cytoplasmic ratio but nuclear pleomorphism and mitoses are rare. Characteristic mucinous cysts of varying size are present within the tubular and cribriform patterns (Fig. 104-16C ). Poorly differentiated tumors have a significant component of solid tumor nests. As is characteristic of their salivary gland counterparts, adenoid cystic carcinomas are notorious for perineural spread. Long-term survival can be achieved with adequate resection but local recurrence may occur even late (greater than 10 years) following resection. The most common site of disseminated disease is the lung parenchyma, but extrathoracic metastases have been reported.

Mucoepidermoid Carcinoma Mucoepidermoid carcinomas account for approximately 0.1 to 0.2 percent of lung cancers. Patients with this tumor may be asymptomatic, but it is common for patients to present with symptoms of bronchial obstruction due to the tumor’s characteristic endobronchial location. These symptoms include wheezing, cough, and hemoptysis, and patients may present with postobstructive pneumonia. The age at presentation varies, but almost half of patients with mucoepidermoid carcinoma occur in patients under 30 years of age.

There is no significant association with tobacco use. A chest radiograph often reveals a solitary, centrally located mass with distal pneumonia or atelectasis.

Mucoepidermoid carcinomas usually arise from segmental and subsegmental bronchi, but can involve the trachea as well. They range in size from a few millimeters to up to 6 cm and grow as polypoid masses with a tan or gray surface (Fig. 104-17A and B). On cross-section, the tumor may appear more mucoid or cystic than the more common non–small cell carcinomas of the lung.

Histologically, mucoepidermoid tumors are separated into low- and high-grade tumors. The tumors are composed of a mixture of mucin-secreting cells, squamous cells, and what are termed “intermediate cells.” The intermediate cells have a polygonal shape and eosinophilic cytoplasm, but lack obvious squamous or glandular differentiation. The mucinous component consists of well-differentiated glands, with both intracellular and extracellular mucin (Fig. 104-17C ).

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In low-grade tumors, the cells have minimal pleomorphism, rare mitoses, and minimal necrosis. Suggested criteria for high grade tumors include an increased mitotic rate (average of 4 per 10 high-power fields), necrosis, and nuclear pleomorphism. High-grade mucoepidermoid carcinomas may be difficult to distinguish from adenosquamous carcinomas.

High-grade mucoepidermoid carcinomas still retain a characteristic admixture of mucin-containing cells, squamoid cells, a central endobronchial location, and transitional areas from low-grade mucoepidermoid carcinoma. There should be no keratinization, squamous pearl formation, or in situ squamous cell carcinoma: features, which if present, are consistent with a diagnosis of squamous or adenosquamous carcinoma.

The clinical behavior of these neoplasms had been controversial, mainly due to past ambiguities regarding the definition of high-grade mucoepidermoid carcinomas and their distinction from adenosquamous carcinomas. In an analysis of 58 cases, Yousem and Hochholzer separated mucoepidermoid tumors into low- and high-grade tumors using cri-

Figure 104-16 A. Carinal resection for adenoid cystic carcinoma with a mixed infiltrative and nodular pattern of growth within the submucosa. B. Same adenoid cystic carcinoma in cross-section, illustrating the extensive diffuse involvement of the submucosa with infiltration beyond the cartilage. C. Cribriform growth pattern of adenoid cystic carcinoma (H&E, 200Ă&#x2014;).

teria formulated for mucoepidermoid tumors of the salivary glands. In this study, there was no evidence of disease following complete surgical excision for 41 patients with low-grade tumors and an average follow-up of 4 years.

Of 13 patients with high-grade mucoepidermoid carcinomas, 3/13 patients died of metastatic disease, but 8/13 were alive without evidence of disease at a median follow-up of 31 months. Almost all of the tumors reported in patients younger than 30 years have been low-grade tumors, which are mostly endobronchial and have an excellent prognosis. There is a low reported incidence of lymph node metastases (about 2 percent). Local recurrence has been reported with incomplete excision and adequate excision may require a lobectomy, bronchoplastic procedure (sleeve lobectomy), or pneumonectomy. High-grade tumors, which tend to invade the adjacent lung parenchyma, are associated with an older population and carry a worse prognosis. High-grade mucoepidermoid carcinomas tend to behave in a manner similar to the more common nonâ&#x20AC;&#x201C;small cell carcinomas.

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Figure 104-17 A. Left main-stem bronchus resection for endobronchial mucoepidermoid carcinoma. B. Same mucoepidermoid carcinoma tumor in cross-section, demonstrating an attachment to the bronchus but invasion is limited to the superficial portion of the submucosa. C. Mucoepidermoid carcinoma. There are both welldifferentiated mucinous glands (left) and intermediate cells (right) that have a polygonal shape and abundant eosinophilic cytoplasm (H&E, 200×).

ANCILLARY STUDIES The lung is a common site for both primary tumors and metastases and the pathologist must consider a broad differential diagnosis when analyzing a cytologic or tissue preparation. Ancillary studies typically are used to narrow the differential diagnosis or demonstrate differentiation. It is a general principle of laboratory diagnosis that the sensitivity and specificity of any test depends on the pretest prevalence of the disease. The appropriate use of ancillary studies is grounded in a well-formulated differential diagnosis based on the tumor’s histological appearance. The clinician contributes greatly by providing a complete clinical history, which helps direct the diagnostic work-up and avoid unnecessary tests.

HISTOCHEMICAL STAINS The most commonly used histochemical stains are those that demonstrate intracellular mucins—periodic acid-Schiff (PAS) after diastase and mucicarmine—and are characteris-

tic of adenocarcinomas. As discussed in the chapter on the pleura, stains for neutral mucins are often used to distinguish adenocarcinoma from epithelial mesothelioma. Alcian blue staining with hyaluronidase treatment had been used to distinguish the acid mucin of mesothelial cells from the epithelial mucin associated with adenocarcinomas, but its use has largely been supplanted by immunohistochemistry.

Mucin stains are also typically performed on poorly differentiated carcinomas, which appear as solid carcinomas lacking glandular differentiation but prove to have numerous mucinpositive tumor cells and therefore would be best classified as adenocarcinomas, solid type.

Immunohistochemistry Immunohistochemistry is based on a primary antigenantibody reaction and a secondary antibody-enzyme complex that interacts with a chromogen for a microscopically visible color reaction. Since its introduction into diagnostic pathology in the early 1980s, immunohistochemistry has become an integral part of tumor diagnosis. Unfortunately, there are very few antibodies that approach 100 percent sensitivity and specificity. As experts on immunohistochemistry have emphasized, it is diagnostically irrelevant to speak of overall

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sensitivity and specificity for a particular antibody. Rather it is more appropriate to speak of relative sensitivity and specificity within a particular differential diagnosis. This requires clinical interaction and morphologic expertise in generating a differential diagnosis in addition to critical assessment of the immunohistochemical results with appropriate controls.

Immunohistochemistry is often used in the work-up of an undifferentiated large cell carcinoma, usually to exclude melanoma and lymphoma, which can mimic a highly pleomorphic epithelial tumor. Within this differential diagnosis of an undifferentiated tumor comprised of large cells, cytokeratin antibodies such as AE1/3, CAM 5.2, and pancytokeratin are used to support the diagnosis of carcinoma. Cytokeratin antibodies least focally stain most non–small cell carcinomas of all histological subtypes, in addition to a wide variety of carcinomas from other primary sites. There are, however, potential pitfalls. Cytokeratin antibodies stain benign bronchial and alveolar epithelia, which can be entrapped within tumors and lead to a false-positive interpretation. Reactive mesothelial cells and malignant mesotheliomas are cytokeratin positive as well. Cytokeratin positivity, usually focal, also has been demonstrated in sarcomas and melanomas. S100, HMB45, and melanA are markers of melanocytic differentiation. Although sensitive, S100 is less specific for melanoma and stains other tumors, including those of neural origin and some adenocarcinomas of both primary pulmonary and extrapulmonary origin, such as the breast. Leukocyte common antigen (LCA), CD30 (for Ki-1 positive large cell lymphomas), and B and T cell markers are the immunohistochemical stains most frequently used to exclude lymphoma.

As discussed in the section on malignant mesothelioma, there are antibodies to glycoproteins such as CEA, MOC31, B72.3, LeuM1, Bg8, and BerEP4, which stain a high percentage of adenocarcinomas, including adenocarcinomas of the lung.

Different staining patterns of epithelial membrane antigen (EMA) immunoreactivity have been reported as a means of distinguishing malignant mesothelioma from adenocarcinoma, but others have disputed the utility of EMA for this purpose.

The biggest challenge within immunohistochemistry remains the differential diagnosis of pulmonary primary from metastatic disease. There are only a limited number of instances in which immunohistochemical stains are useful in differentiating a pulmonary primary from a metastatic tumor. Outside of thyroglobulin for the majority of thyroid tumors and prostate-specific antigen for the majority of prostatic adenocarcinomas, most other antibodies have too much overlap in specificity to be conclusive. There has been some more qualified success in some instances when the differential diagnosis includes other common solid organ malignancies such as breast or gastrointestinal carcinomas. Staining with a panel of antibodies to bolster one’s diagnostic certainty in the differential diagnosis of primary lung carcinoma versus metastasis can certainly enhance diagnostic accuracy. Fundamentally, however, this type of immunohistochemical analysis remains an exercise in probabilities and may not be suf-

ficient for certain clinical circumstances. It is most often the case that new markers are introduced into the literature with initial reports of high sensitivity and specificity. After a time, with additional studies and incorporation into daily practice, more exceptions appear. A good example is thyroid transcription factor (TTF-1). On average, TTF-1 stains about 75 percent of primary pulmonary adenocarcinomas, although the percentage is lower in more poorly differentiated tumors, some subtypes of adenocarcinoma, better differentiated neuroendocrine tumors, and squamous cell carcinomas. It was initially believed that the only extrapulmonary tumor that was as frequently positive for TTF-1 was thyroid carcinoma.

Now there are reports of TTF-1 positivity in extrathoracic tumors that would not be expected—such as ovarian epithelial tumors—making the marker less specific than was initially asserted. Whether “molecular profiles” will be able to improve diagnostic accuracy remains to be seen. For the present, the fundamental lesson is that there is no substitute for a good clinical history, thorough physical examination, and highquality radiographic studies.

CONCLUSION In addition to the clinicopathologic features and histological subtyping of non–small cell carcinoma, recent changes and current controversies in tumor classification have been reviewed. The pathologist makes a critical contribution to the management and treatment of lung carcinoma, but the final pathologic interpretation should not be rendered in a clinical vacuum. It is incumbent upon the clinician caring for the patient to be sure that the pathologist has the benefit of complete clinical information. This should include symptoms at presentation, radiographic findings, and past medical history, particularly as it relates to prior malignancies.

The inclusion of the pathologist as an integral part of what is now commonly a multidisciplinary evaluation for a thoracic malignancy enhances the quality of care for the individual patient, as well as refining the general practice of thoracic oncology.

SUGGESTED READING Attanoos RL, Gibbs AR: ‘Pseudomesotheliomatous’ carcinomas of the pleura: A 10-year analysis of cases from the Environmental Lung disease Research Group, Cardiff.

Histopathology 43, 2003.

Beasley MB, Thunnissen FB, Brambilla E, et al: Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 31:1255, 2000.

Ebright MI, Zakowski MF, Martin J, et al: Clinical pattern and pathological stage but not histological features predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg 74:1640, 2002.

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Fraire AE, Roggli VL, Vollmer RT, et al: Lung cancer heterogeneity: Prognostic implications. Cancer 60:370, 1987.

Funai K, Yokose T, Ishii G, et al: Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung.

Am J Surg Pathol 27:978, 2003.

Graham AD, Williams ARW, Salter DM: TTF-1 expression in primary ovarian epithelial neoplasia. Histopathology 48:764, 2006.

Janssen-Heijnen ML, Coebergh JW: Trends in incidence and prognosis of the histological subtypes of lung cancer in North America, Australia, New Zealand and Europe. Lung Cancer 31:123, 2001.

Keehn R, Auerbach O, Nambu S, et al: Reproducibility of major diagnoses in a binational study of lung cancer in uranium miners and atomic bomb survivors. Am J Clin Pathol 101:478, 1994.

Manivel JC, Priest JR, Watterson J, et al: Pleuropulmonary blastoma. The so-called pulmonary blastoma of childhood. Cancer 62:1516, 1988.

Moran CA: Primary salivary gland-type tumors of the lung.

Semin Diagn Pathol 12:106, 1995.

Noguchi M, Morikawa A, Kawasaki M, et al: Small adenocarcinomas of the lung. Histological characteristics and prognosis. Cancer 15:2844, 1995.

Noguchi M, Yokose T, Suzuki K, et al: Favorable and unfavorable morphological prognostic factors in peripheral adenocarcinoma of the lung 3 cm or less in diameter. Lung Cancer 29:179, 2000.

Roggli VL: Histological classification of lung cancers. Factors affecting its variability. Am J Clin Pathol 101:411, 1994.

Rossi G, Cavazza A, Sturm N, et al: Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

A clinicopathologic and immunohistochemical study of 75 cases. Am J Surg Pathol 27:311, 2003.

Sturm N, Lantuejoul S, Laverriere M, et al: Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34β E12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung. Hum Pathol 32:918, 2001.

The Pathology of Nonâ&#x20AC;&#x201C;Small Cell Lung Carcinoma

Suzuki K, Yokose T, Yoshida J, et al: Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung. Ann Thorac Surg 69:893, 2000.

Travis WD, Brambilla E, Muller-Hermelink HK, et al: Tumours of the lung, in Travis WD, Brambilla E, MullerHermelink HK, et al (eds), Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. WHO Health Organization Classification of Tumours, vol 10. Lyon, France, IARC Press, 2004, p 10.

Travis WD, Colby TV, Corrin B, et al: WHO Histological Classification of Tumours. Histological Typing of Lung and Pleural Tumours, 3rd ed. Berlin, Springer-Verlag, 1999.

Travis WD, Gal AA, Colby TV, et al: Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 29:272, 1998.

Travis WD, Linnoila RI, Tsokos MG, et al: Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 15:529, 1991.

Travis WD, Lubin J, Ries L, et al: United States lung carcinoma incidence trends: declining for most histological types among males, increasing among females. Cancer 77:2464, 1996.

Travis WD, Rush W, Flieder DB, et al: Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 22:934, 1998.

Yim J, Zhu LC, Chiriboga L, et al: Histological features are important prognostic indicators in early stages lung adenocarcinoma. Mod Pathol 20:233, 2007.

Yousem SA, Hochholzer L: Mucoepidermoid tumors of the lung. Cancer 60:1346, 1987.

Zamecnik J, Kodet R: Value of thyroid transcription factor-1 and surfactant apoprotein A in the differential diagnosis of pulmonary carcinomas. A study of 109 cases. Virchows Arch 440:353, 2002.

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105 Part I: Treatment of Non--Small-Cell Lung Cancer Surgical Larry R. Kaiser

I. DIAGNOSIS The Symptomatic Patient The Asymptomatic Patient with Abnormal Chest Radiograph II. STAGING III. SURGICAL TREATMENT OF LUNG CANCER N2 Disease

V. RESULTS OF TREATMENT Postoperative Complications Postoperative Mortality Postoperative Morbidity Prognosis Following Resection Sites of Recurrence Postsurgical Follow-up VI. FUTURE DIRECTIONS

IV. CHEST WALL RESECTION Tumors Involving the Mediastinum by Direct Extension Palliative Resections

Lung cancer is a clinical problem of the twentieth century, having been virtually unrecognized until the early part of this century. It is a disease for which the cause is known in the majority of cases yet despite that knowledge the incidence in women continues to rise, while it has leveled off for men. Thus it is both a travesty and an indictment against us as a society that lung cancer is the leading cause of death from cancer in both men and women despite our knowledge that cigarette smoking causes the disease. The treatment of lung cancer has evolved from a single modality, surgery, to a multimodality approach that calls upon the skills of numerous specialists.

Not many years ago an operation was all that could be offered to a patient, and it has taken a considerable amount of time to recognize that not only is an operation not for everyone but may be contraindicated in many situations. It has remained for students of the disease—surgeons, and medical and ra-

This chapter has been slightly modified from the version that appeared in the third edition of Fishman’s Pulmonary Diseases and Disorders.

diation oncologists—to define the role that surgery should play in the modern management of lung cancer. Surgery was and is the cornerstone of management in this disease, and surgeons continue to assume a leading role in the diagnosis and treatment of patients with lung cancer.

DIAGNOSIS It is illustrative to consider the route taken by most patients prior to being referred to a surgeon and the qualifications that the surgeon should ideally possess to contribute optimally to the management of the patient with lung cancer. Patients with lung cancer either present with symptoms or are found inadvertently to have an abnormal chest radiograph when the film has been done for some other reason. The symptomatic patient sees his or her primary care physician, who may initiate further evaluation or more likely refer the patient to a pulmonary physician. Rarely is a patient referred

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directly to the surgical specialist for evaluation of an abnormal chest radiograph, although this does occur with greater frequency in certain communities. From the surgeonâ&#x20AC;&#x2122;s viewpoint how should a patient with a presumed lung cancer be evaluated? How likely is it for a given patient to have a lung cancer? We look at smokers differently than we look at nonsmokers when evaluating an abnormal chest radiograph. Certainly lung cancer is seen in nonsmokers, but we are much less suspicious in this group than in smokers, in whom an abnormal chest radiograph is lung cancer until proved otherwise. If a previous chest radiograph is available, the first move should be to compare it with the current film. A lesion present on a previous film markedly diminishes, but does not eliminate, the probability that the current finding represents a lung cancer.

The Symptomatic Patient Patients present with symptoms either referable to the chest or related to the presence of metastatic disease. The initial evaluation should be directed toward an explanation of the symptoms. A complete discussion of the clinical presentation is available in Chapter 104. Patients with evidence of metastatic disease still require a tissue diagnosis. The method employed to obtain the tissue diagnosis should have the highest probability of success. Whereas bronchoscopy has a high likelihood of yielding a diagnosis in the patient who presents with cough or hemoptysis, it is less likely to be successful when the lung findings are confined to multiple small nodules. Often transthoracic needle biopsy may have the highest yield, and bronchoscopy is not required. When a patient presents with presumed metastatic disease that is accessible, such as a palpable supraclavicular lymph node, a needle aspirate, done in the office, likely will be all that is required both to diagnose and stage the patient. Again, there is no need to bronchoscope such a patient unless specifically indicated. A percutaneous biopsy of an adrenal lesion may also provide both a diagnosis and stage. Too often extra procedures are performed that add no useful information to the subsequent management of the patient. Unfortunately the only question of significance in the patient with metastatic disease is the differentiation between small cell and nonâ&#x20AC;&#x201C;small-cell lung cancer (NSCLC), and this difference, although intuitively of great importance, is actually of minimal significance, since the chemotherapy, if indicated, is quite similar for both diseases. Yet it seems important to know the histology if for no other reason than to be able to discuss the prognosis with the patient. What is important in this early phase of the management of a patient with presumed metastatic lung cancer is to select a procedure that is likely to yield the most information with regard to both histologic type and stage and avoid unnecessary procedures in these individuals who have a limited life expectancy.

Rarely is it necessary in the patient with metastatic disease to subject them to a procedure any more invasive than a needle biopsy or bronchoscopy. Occasionally mediastinoscopy may be required to obtain enough tissue and very rarely video thoracoscopic excision of a lung nodule, but a so-called ex-

ploratory thoracotomy really has no place in the management of these patients.

The Asymptomatic Patient with Abnormal Chest Radiograph Usually patients who are asymptomatic present with a solitary pulmonary nodule since those with an infiltrate or consolidation of a lobe rarely are without some symptom or sign of disease. The real question in this situation comes down to whether the nodule is malignant. A chest computed tomographic (CT) scan should be performed to determine if the nodule is solitary as well as to assess the status of the mediastinum, liver, and adrenals. The role of percutaneous needle biopsy of the solitary pulmonary nodule remains controversial. Bronchoscopy in this situation adds little and is probably not indicated. One approach in certain patients, namely nonsmokers with a small nodule, is to follow the lesion over a period of time. A repeat chest radiograph in 4 to 6 weeks to assess a change in size of the nodule is a reasonable alternative as long as the patient can tolerate the uncertainty that the nodule may prove to be a carcinoma. If the lesion has increased in size, then excision is carried out. No change in size warrants continued observation with repeated chest radiographs. Conversely, in a smoker in whom there is a high probability that the nodule is malignant, excision is justified in most cases no matter the result of a needle biopsy. A negative biopsy does not negate the fact that a suspicious nodule remains; if the biopsy is positive it only confirms what we already suspected, but the patient has been exposed to the risk of the needle biopsy, namely, a 30 percent incidence of pneumothorax with a need for a chest tube in one-half of cases.

The problem remains that a negative needle biopsy is of little help. Some positive information has to be obtained, such as cartilage or fungal elements, for the biopsy to be definitive in order to prevent an operation. To really understand and use a negative needle biopsy to guide therapy we need to know not just what percentage of patients with negative needle biopsies prove to have cancers, but also what percentage of needle biopsies are negative when performed in patients in whom there is a high suspicion of cancer. A recent study from the University of Toronto, where essentially all patients with pulmonary nodules undergo needle biopsy, shows that 6 percent of patients with a negative needle biopsy ultimately prove to have a cancer (T. Todd, personal communication).

The role of needle biopsy has been further diminished by the development of video thoracoscopy, which in a relatively minimally invasive fashion, allows for the excision of a pulmonary nodule and a definitive diagnosis. If the nodule proves to be benign, video thoracoscopic excision both makes the diagnosis and treats the problem. If the nodule is malignant, the procedure may be immediately converted to the appropriate anatomic pulmonary resection, most commonly lobectomy. Needle biopsy is useful for the patient who insists on having a diagnosis of malignancy prior to going to the operating room. The argument that needle biopsy should be performed to rule out small-cell carcinoma is weak, since

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in the absence of mediastinal adenopathy, extremely rare for a small cell, a solitary nodule should be excised even if the needle biopsy suggests the diagnosis of small cell carcinoma by histology. All the preceding notwithstanding, needle biopsies continue to be performed almost routinely despite the current concern regarding costs.

STAGING A discussion of noninvasive staging is beyond the scope of this chapter and is dealt with elsewhere in this volume; however, the role of invasive staging and specific procedures utilized deserve mention. In discussing stage, distinction must be made between clinical and pathologic stage. The former is based solely on noninvasive imaging studies, whereas the latter depends on actual histologic material obtained either by invasive staging studies or at the time of the surgical resection.

A clinical stage is no more or less than an assumption, which is only as good as the noninvasive studies employed. A chest CT scan provides excellent visualization of the contents of the superior mediastinum. However, size of the lymph nodes remains the only criterion on which to base a judgment as to whether tumor is present in these nodes. There are no other specific criteria either on CT or magnetic resonance imaging (MRI) by which to make such a judgment. The sensitivity and specificity of CT depends on the size cutoff arbitrarily determined to separate a positive finding from a negative one.

The smaller the size chosen, the greater the specificity, but at the expense of the sensitivity. A larger size increases the sensitivity but decreases the specificity. In the authorâ&#x20AC;&#x2122;s clinic, 1.5 cm is used as the threshold for determining whether a patient should have a mediastinoscopy performed. It has to be realized, however, that even though a size criterion has

Part I: Treatment of NSCLC: Surgical

been determined, problems remain both in the subjectivity in measuring 1.5 cm on CT and the thickness of the slices utilized in performing the scan.

Mediastinoscopy provides a great deal of information about the lymph node status of the superior mediastinum and is the gold standard for the assessment of the mediastinal lymph nodes. The procedure has a false-negative rate of less than 10 percent, far better than CT, but has the disadvantage of being an invasive procedure. As the resolution of CT scans has improved, performing routine mediastinoscopy on all patients with lung cancer must be questioned when the procedure may be applied selectively based on the size of the lymph nodes seen on the CT. This avoids a needless operation in over 80 percent of patients. There are nodal stations that cannot be accessed by standard cervical mediastinoscopy. These include the aortopulmonary window (level 5), a common site for lymph node involvement in left upper lobe tumors, and the posterior subcarinal space (level 7). However, the anterior subcarinal space, usually representative of the contents of the posterior subcarinal space, is accessible to mediastinoscopic biopsy, and involved lymph nodes in the aortopulmonary window in the absence of other lymph node disease carries a prognosis equivalent to N1 (hilar) disease.

Mediastinoscopy is performed through a small (2-cm) incision made in the neck 1 cm above the sternal notch. The area explored by mediastinoscopy, the superior mediastinum, is palpated first by inserting a finger along the anterior aspect of the trachea which also serves to develop the space and facilitate insertion of the mediastinoscope (Fig. 110 I-1).

Obviously involved lymph nodes often may be palpated, but palpation alone is insufficient, since intranodal disease may be present that can only be identified if representative biopsies of the important nodal stations are taken following insertion of the mediastinoscope. Of major importance are the ipsilateral nodes, but just as important is the status of the contralateral

Figure 105 I-1 Mediastinoscope in place demonstrating the superior mediastinal plane.

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Neoplasms of the Lungs

left upper paratracheal (level 2)

innominate a.

innominate v.

superior vena cava

right upper paratracheal (level 2) left lower paratracheal (level 4)

right lower paratracheal (level 4, 10)

subcarinal (level 7)

aortic arch azygous v.

right main pulmonary a.

Figure 105 I-2 Lymph node stations accessible by cervical mediastinoscopy. For consistency the levels should be labeled with the appropriate number when submitted to surgical pathology.

Figure 105 I-3 The relationship of major vascular structures potentially encountered during mediastinoscopy to the trachea and main bronchi.

lymph nodes, especially in left lower lobe lesions, in which right paratracheal lymph nodes are commonly involved. Despite notions to the contrary, left-sided lymph nodes are readily accessible at mediastinoscopy but are somewhat more difficult to identify. In fact the left paratracheal lymph nodes are much more easily sampled at mediastinoscopy than at left thoracotomy because of the location of the aortic arch relative to the left mainstem bronchus. Because of this we have a much lower threshold for performing mediastinoscopy for left-sided lesions.

Nodal stations most frequently sampled include levels 2 (upper paratracheal) and 4 (lower paratracheal) on the right, level 3 (pretracheal), level 7 (subcarinal), and level 4 on the left (Fig. 110 I-2). Because the left level-4 lymph nodes occur at a slightly higher location, it is identifying separate level 2 nodes on the left can be difficult. It is not necessary always to sample all nodal stations; if there are nodes obviously involved, these, along with contralateral nodes, are all that are necessary to adequately stage the patient. This makes it sound very simple to carry out the procedure, but in fact mediastinoscopy is a technically demanding procedure that is performed correctly and thoroughly only by those who have been well-grounded in the techniques. It is a difficult procedure to teach, and the close proximity of a number of major vascular structures makes it daunting even to the experienced practitioner. The vessels include the inominate artery, aortic arch, superior vena cava, azygous vein, and right main pulmonary artery. Unfortunately none of these structures is easily seen, and success requires that the operator know where they are located to avoid injury (Fig. 110 I-3). The left recurrent laryngeal nerve and esophagus are also subject to injury. Many surgeons have had disastrous experiences with mediastinoscopy and have great hesitation about performing it despite the wealth of information obtained when it is performed properly. These are usually the same clinicians who downplay the importance of the procedure in staging lung cancer and seek to avoid it. A surgeon attempting to practice thoracic surgery without the ability to perform a complete and thorough mediastinoscopy

is at a great disadvantage, which unfortunately is passed on to patients. This inability usually results in the performance of many thoracotomies that otherwise could be avoided.

Although mediastinoscopy is the mainstay of invasive staging for lung cancer, other procedures provide additional information that often complements that obtained at mediastinoscopy. The aortopulmonary window, a common site of nodal spread from tumors of the left upper lobe, may be reached with a parasternal mediastinotomy, or so-called Chamberlain procedure. An incision is made over the left second costal cartilage, the cartilage is excised, and the pleural reflection is swept laterally to access the aortopulmonary window in an extrapleural plane. The involvement of lymph nodes at this level (level 5) in the absence of other nodal disease is associated with a 5-year survival that approaches 50 percent if the disease can be completely resected at thoracotomy, a survival that is almost identical to that seen with N1 (hilar) disease. The rationale, then, behind performing parasternal mediastinotomy either is to assess resectability or document mediastinal nodal disease to justify placing the patient into an experimental protocol of neoadjuvant chemotherapy, radiation therapy, or both.

Similarly, video thoracoscopy aids in the staging of lung cancer, although not in lieu of mediastinoscopy, which offers an opportunity to sample nodes on the right and left through one incision, but as an adjunct. Nodes inaccessible by mediastinoscopy, including the aortopulmonary window (level 5), subcarinal (level 7), and inferior pulmonary ligament (level 9) are easily sampled utilizing video thoracoscopy. This technique also visualizes the pleural space, especially useful in the patient with a pleural effusion and negative fluid cytology, so as to rule out diffuse pleural involvement and prevent an unnecessary thoracotomy. Other nodules seen on CT scan that may have an impact on treatment planning also may be excised and defined histologically prior to formal thoracotomy.

Video thoracoscopic examination has not proved particularly useful in assessing resectability of a tumor when there is a question because of presumed invasion of an adjacent

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mediastinal structure. Usually the ultimate decision regarding resectability of a locally invasive lesion must be made at the time of thoracotomy when the lesion itself may be palpated and the dissection conducted under greater control. A logical progression from the less invasive to the more invasive procedures guided by the imaging studies often results in the patient being spared a procedure from which there will be no significant benefit.

Any discussion of staging presupposes that the information obtained will be used in the decision regarding therapy. It is of no use obtaining information and subjecting the patient to the risk of an additional procedure unless the information obtained is utilized. Discovering at mediastinoscopy that there is N2 disease and still proceeding on to thoracotomy makes little sense. Why bother with the mediastinoscopy?

This introduces the concepts of operability and resectability, two terms that are not synonymous, although mistakenly used as such. Any staging study or procedure, invasive or noninvasive, contributes to the decision regarding operability but usually has no bearing whatsoever on resectability. A patient who has bone metastases is inoperable, by definition, since the local control achieved by removing the primary tumor has no effect at all on the fact that the patient already has disseminated disease. Removing the primary tumor, although an extremely difficult concept to convey to the patient and family, offers nothing in terms of survival and only subjects the patient to the morbidity of the operation. This same patient, although inoperable, may have an eminently resectable lesion.

Resectability is a surgical determination made by the surgeon at the time of the operation. Staging studies have little to do with determining resectability, the exception being the finding of gross extranodal disease at mediastinoscopy that both defines operability and, for the most part, precludes resection.

Finding diffuse pleural studding at video thoracoscopy does not define resectability, since the primary tumor easily may be resected, but it does prove inoperability, since removing the tumor will add nothing to the overall outcome. Operability may also be determined by coexisting medical problems such as heart disease, although the patient may have a resectable primary tumor. The two terms refer to decidedly different concepts; resectability is a surgical term whose use should be confined to surgeons. Unless you are the one doing the resecting, how can you know what is resectable and what is not?

The recognition of this concept would go a long way toward allowing patients to obtain a complete assessment of their disease followed by the institution of appropriate treatment.

For a nonsurgeon to decide, based on imaging studies, what is resectable and then institute treatment without referring the patient to a thoracic surgeon at least for consultation does a disservice to the patient.

SURGICAL TREATMENT OF LUNG CANCER Many patients undergo very little in the way of a staging evaluation prior to operation. The type and extent of the staging

Part I: Treatment of NSCLC: Surgical

evaluation depends on a number of clinical factors. At a minimum patients should have a recent chest radiograph and CT scan of the chest. Most, but not all, should have a recent set of pulmonary function studies. The decision to search for disseminated disease with a bone scan and brain CT or MRI is a difficult one, and precise criteria to define when they should be obtained do not exist. A complete discussion of this issue may be found in Chapter 104. The practice in this clinic is to obtain a complete evaluation of the extent of disease if there is any reason at all to do so. This includes any organ-specific or nonspecific signs or symptoms. Nonspecific signs include weight loss, easy fatigueability, or anemia; organ-specific signs include bone pain, elevated liver enzymes, or localizing neurologic findings. If any of these findings are present, a complete evaluation is obtained, not just the study pointed to by the organ-specific complaint. Any patient with a history of malignancy should have a complete extent of disease workup, as should the patient who is at a higher risk for operation, such as an individual with multiple medical problems or borderline pulmonary function. As well, any patient with locally advanced disease in whom the indications for operation are being extended (i.e., N2 disease) or the nonsmoker with a lung mass should have disseminated disease ruled out. The aim is to avoid operating on a patient who proceeds to manifest disseminated disease within 1 year of operation, a finding that ideally should have been identified preoperatively.

Recognizing that operation is the best treatment for early-stage disease, it is important that the appropriate procedure be performed. Lobectomy remains the definitive resection for most lung cancers, since it is an anatomic resection that removes the regional lymph nodes located along the lobar bronchus. Doing less than a lobectomy must be considered a compromise, although a non-anatomic wedge excision is tempting for small primary tumors. Not only does a wedge excision not include the lobar bronchus, precluding evaluation of lobar lymph nodes, but it provides only a minimal parenchymal margin. The Lung Cancer Study Group (LCSG) addressed the question of lobectomy versus limited resection for T1N0 lesions (tumor lass than 3 cm, negative lymph nodes) in a prospective randomized trial. The early analysis of the data demonstrated an increased incidence of local recurrence in the limited resection group but no difference in survival. The final analysis revealed superior survival for patients in the lobectomy group. Other studies have looked retrospectively at patients undergoing limited resection, which includes segmental resection, and have demonstrated longterm survivors, but the LCSG study stands alone as the only randomized trial.

For patients in whom lobectomy is not feasible, a lesser resection offers the best alternative, although admittedly it is a compromise. Patients in this category are those with borderline pulmonary function or those who have had previous pulmonary resections. Whenever possible the lesser resection should be an anatomic segmental resection, which takes the segmental artery and vein as well as the segmental bronchus with its accompanying lymph nodes (Fig. 110 I-4).

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Neoplasms of the Lungs

parenchyma ligated segmental art. apical post. ant. bronchus left upper lobe

Figure 105 I-4 Segmental resection. The example shown here is the resection of the apical-posterior segment of the left upper lobe. The segmental pulmonary arterial branch is shown ligated and divided. The segmental bronchus has been dissected out and is the next structure to be divided.

A classic segmental resection is a relatively difficult operation, and many surgeons do not possess a significant amount of experience in performing this procedure. The prototype segmental resections include the lingular resection and resection of the superior segment of the lower lobe, but any lung segment may be removed anatomically. The key to segmental resection is the identification of the segmental artery, which, once ligated and divided, reveals the location of the segmental bronchus that is taken next. The segmental vein is divided last, and the parenchyma is divided with a stapler or “stripped” as described.

With the development of video thoracoscopic techniques and the simplicity of wedge resection via this approach, there has been renewed interest in utilizing this technique for T1N0 lung cancers. Based on the LCSG data this should be avoided, and patients who are found to have a cancer should be offered the best possible procedure, which, to the best of present knowledge, is a lobectomy. Wedge resection is, at best, a compromise, and patients who otherwise could tolerate an anatomic resection are not well served by having less done.

There have also been several reports of tumor growing in thoracoscopic incision sites when lung cancers have been pulled through these small incisions.

Depending mainly on the location of the tumor, more extensive and complex resections than lobectomy may be required. The determination as to when to perform pneumonectomy is made at the time of operation, rarely preoperatively. Recognizing that even today pneumonectomy carries a perioperative mortality of at least 5 percent, we do everything possible to avoid removing an entire lung. There are only a few absolute indications for performing pneumonectomy for the experienced surgeon. These include such proximal in-

volvement of the main pulmonary artery that it is difficult to place a clamp on the artery, endobronchial tumor so extensive as to preclude sleeve resection, and involvement of the confluence of the pulmonary veins or of the left atrium. There is reason for concern if a surgeon is performing an abundance of pneumonectomies. A “difficult” fissure, unless tumor involves the artery in the fissure, is not an indication for pneumonectomy, nor is tumor crossing a fissure an absolute indication. Pneumonectomy, technically, is an easier operation to perform than lobectomy, requiring very little dissection and only several applications of the stapler. Sleeve resections, or bronchoplastic procedures, are technically more demanding procedures that result in the same bronchial resection as a pneumonectomy, yet preserve lung tissue. The prototypical bronchoplastic procedure is the right upper lobe sleeve resection, in which the main bronchus is divided just proximal to the right upper lobe takeoff and the bronchus intermedius is divided just distal to the upper lobe bronchus (Fig. 110 I-5).

The right upper lobe, with tumor present at the lobar orifice, is thus removed with a portion of the mainstem bronchus, and the bronchus intermedius is anastamosed to the mainstem bronchus. Thus the proximal bronchial division occurs essentially at the same site as if a pneumonectomy had been performed. Other sleeve resections are possible on both the right and left side, all result in lung conservation and are associated with long-term survival equivalent to pneumonectomy, depending on the indications.

Even with proximal involvement of the pulmonary artery, partial resection or sleeve resection of the artery is possible to avoid removal of the entire lung. A patch angioplasty with pericardium may be utilized if a significant enough portion of the anterior wall of the artery is taken so as to narrow it. Alternatively a segment of the artery may be removed

anastomosis of right wall bronchus to bronchus intermedius right upper lobe

right upper lobe bronchus with tumor

tumor bronchus intermedius right main bronchus

azygous vein

Figure 105 I-5 Right upper lobe sleeve resection. The right main bronchus has been divided just proximal to the right upper lobe takeoff where the tumor is located. The bronchus intermedius has been divided just distal to the right upper lobe bronchus. The bronchus intermedius is anastamosed to the right main bronchus (inset).

1857 Chapter 105

and an end-to-end anastamosis completed. Sometimes a pneumonectomy must be done, but the complete thoracic surgeon always looks to see if alternatives exist while preserving the principles of the cancer operation and not compromising margins. With any lung-conserving procedure, the margins of the resection should be sent for frozen section confirmation that no tumor is present.

A complete pulmonary resection requires more than simply excision of the tumor and the surrounding lung parenchyma, whether lobe or entire lung. The operation is incomplete without excision of lymph nodes to complete the staging assessment. We perform a mediastinal lymph node dissection even if mediastinoscopy has been performed. This procedureâ&#x20AC;&#x201D;when, at least on the right side, the entire contents of the superior mediastinum are removedâ&#x20AC;&#x201D;is the only one that assures complete lymph nodes staging. The hilar and peribronchial lymph nodes are removed with the lobectomy or pneumonectomy specimen but must be specifically searched for by the pathologist. Any sampling procedure of mediastinal lymph nodes depends on how the nodes to be sampled are chosen. The failure to include mediastinal lymph nodes as part of a resection results in incomplete information.

Not only must the mediastinal lymph nodes be removed as part of the resection, but also they should be labeled according to their location in the mediastinum.

Having removed the mediastinal lymph nodes, it is not uncommon to find microscopic disease in a node that grossly appears normal. Finding tumor in mediastinal lymph nodes portends a significantly worse prognosis and at least prompts thought regarding postoperative treatment. Postoperative adjuvant therapy, usually radiation therapy, has not improved survival. Currently patients with disease found in mediastinal lymph nodes (25â&#x20AC;&#x201C;30 percent, 5-year survival) following a complete resection may be entered into a national randomized protocol that compares postoperative radiation therapy alone with concurrent chemotherapy and radiation therapy (ECOG 3509).The drugs employed, cis-platinum and VP-16, are both active agents in NSCLC and are reasonably well tolerated. Patients with N1 disease (hilar, peribronchial, and segmental nodes) are also eligible for treatment on this adjuvant protocol.

The designation locally advanced includes a wide variety of lesions that extend outside of the lung parenchyma, whether by direct extension or nodal involvement to involve other structures within the hemithorax. Certain criteria need to be fulfilled before considering extending the indications for resection, since the intent is to maximize survival. The most obvious criterion is the exclusion of disseminated disease; thus, it is vital to complete an extentof-disease evaluation before embarking upon a complex resection in which the indications for resection have been extended.

N2 Disease Classically the involvement of mediastinal lymph nodes with tumor precluded any attempt at surgical resection, since most

Part I: Treatment of NSCLC: Surgical

of these patients died within 2 years due to the development of disseminated disease. Utilizing mediastinoscopy, mediastinal lymph node involvement may be detected prior to thoracotomy, saving the patient a needless operation. Contralateral nodal disease, which carries a significantly worse prognosis than ipsilateral disease, may also be detected at mediastinoscopy and if found usually takes the patient out of the realm of operative intervention even if combined with neoadjuvant therapy. Perhaps the first recognition that a subset of patients with mediastinal lymph node involvement could benefit from surgery came from the work of Martini, who was able to completely resect 151 patients out of approximately 500 with N2 disease. Many of these patients were treated with postoperative radiation therapy. For the group of completely resected patients he found a 28 percent 5-year actuarial survival and subsequently a 26 percent absolute survival. All the patients with N2 disease, resected or not, were identified at the time of thoracotomy, as mediastinoscopy was not performed. Breaking the patients down into two groups yields those staged as N0 or N1 preoperatively, and those with bulky disease, so-called clinical N2, noted either on preoperative chest radiograph or at bronchoscopy when carinal splaying was noted. Those patients thought to have N0 or N1 disease preoperatively had a 35 percent 5-year survival, and those with clinical N2 disease had 0 percent 5-year survival. Fewer than 10 percent of patients with clinical N2 disease could be completely resected.

In recognition that patients with bulky N2 disease not only had a low rate of resectability but also a poor long-term outlook, an attempt was made to improve the resectability rate and, it was hoped, survival in this patient group by employing preoperative chemotherapy. There was a 77 percent response rate to the chemotherapy regimen of velban and cis-platinum with 10 percent complete responders. Sixty-five percent of patients who underwent operation were able to have a complete resection, a significant improvement over the rate able to be resected when no preoperative therapy was employed. Keep in mind that patients entered into this trial were those with bulky mediastinal disease. The overall survival was 28 percent at 3 years and 17 percent at 5 years, with a median survival of 19 months. Patients who were able to undergo a complete resection had a mean survival of 27 months and 3- and 5-year survival of 44 and 26 percent, respectively.

Multiple other nonrandomized phase II trials of preoperative therapy have been carried out in patients with N2 disease utilizing chemotherapy alone or chemotherapy combined with radiation therapy.

Resections following preoperative therapy can be extremely difficult and hazardous because of the fibrosis that often results as a response to the therapy. This is especially significant when there has been a response in involved lymph nodes, since the nodes are intimately associated with the pulmonary artery and its branches, often making resection quite tricky. It is particularly important to have proximal control of the pulmonary artery prior to undertaking a resection in a patient with N2 disease who has received preoperative therapy, and resections of this type ideally should only be undertaken

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Table 105 I-1 Summary from Randomized Trial of Chemotherapy plus Surgery versus Surgery Alone for Stage IIIa Disease Chemo + Surgery

Surgery Alone

Median survival (est)

64 months

11 months ( p < 0.008)

2-Year survival (est)

60%

25%

3-Year survival (est)

56%

15%

Source: From Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemo therapy and surgery with surgery alone in resectable stage III A nonâ&#x20AC;&#x201C;small-cell lung cancer. J Natl Cancer Inst 86: 673â&#x20AC;&#x201C;680, 1994.

by a surgeon with experience in dealing with complex resections.

Two prospective, randomized trials have been completed demonstrating the superiority of preoperative neoadjuvant therapy followed by operation compared with operation alone in patients with N2 disease. Unfortunately neither of these trials dealt solely with a population of patients with N2 disease, as they both included patients with T3 disease. Roth and colleagues randomized 28 patients to a combined therapy group who received three cycles of preoperative chemotherapy with cyclophosphamide, etoposide, and cis-platinum followed by operation, and 32 patients underwent operation without preoperative therapy. Results of the trial are summarized in Table 110 I-1. Significant survival advantage was conferred upon those who received preoperative therapy (Fig. 110 I-6). Median survival in the surgeryonly group was 11 months versus 64 months in the combined therapy group ( p > 0.008). This is all the more interesting considering that fewer than 40 percent of the patients in each group were able to have a complete resection. (39 vs. 31 percent, combined vs. surgery alone). This trial is notable for several reasons. It clearly demonstrates an advantage to neoadjuvant therapy in a group of patients with locally advanced disease. Survival in the surgery-only group was significantly shorter than expected, making the survival difference between the groups more striking. Excluded from the trial were patients with left lung tumors and left paratracheal disease, as these patients were felt to be unresectable, so there is some selection bias to the study population. However, one must be impressed by the significant difference in survival observed in this randomized trial.

Likewise, Rosell randomized 60 patients with stage IIIa disease, 25 of whom had N2 disease who received chemotherapy followed by an operation. Nineteen patients with N2 disease underwent operation as their only therapy. As in the

Figure 105 I-6 Time to death for all patients by treatment group, surgery alone versus chemotherapy plus surgery from the Roth trial. (From Roth JA, Fossella F, Komaki R, et al.: A randomized trial comparing perioperative chemotherapy and surgery with surgery along in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 86:673â&#x20AC;&#x201C;680, 1994, with permission.)

Roth trial there was a significant survival benefit in the group that received combination therapy (median, 26 vs. 8 months, p<0.001).

There is a suggestion that a preoperative regimen incorporating radiation therapy and chemotherapy may be more efficacious than either modality alone. In a phase II trial the Southwest Oncology Group studied concurrent induction chemotherapy with cis-platinum and etoposide in both stage IIIa and IIIb patients. Complete resection was accomplished in 74 percent of patients. Although there was an 8 percent incidence of postoperative death, no tumor was found in 22 percent of the resections. Median survival was 13 months, and 2- and 3-year survival was 37 and 27 percent, respectively. Patients with a pathologic complete response in the lymph nodes had a 30-month median survival compared with 10 months for those with persistent lymph node disease ( p < 0.0005).

Despite the numerous studies addressing preoperative therapy, whether chemotherapy alone or combined with radiation therapy, the question as to what role surgical resection plays in the outcome of patients with N2 disease remains unanswered. To date no conclusive studies have proved that operation is superior to radiation therapy in controlling local disease in these patients. One reason for this is the difficulty in accruing patients on a study in which the randomization chooses between a surgical and nonsurgical arm. A study addressing this question, Radiation Therapy Oncology Group (RTOG) 89-01, accrued fewer than 80 patients in the 4 years it was open. Currently there is an ongoing intergroup phase III randomized trial (RTOG 9309) for patients with N2 disease comparing concurrent chemotherapy (cis-platinum, vinblastine) and radiation therapy followed by surgical excision or additional radiation (total 61 Gy over 6 weeks).

Thus, although there is a suggestion that neoadjuvant therapy results in improved survival when compared with surgery alone, this has not been confirmed in a phase III

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randomized, large multi-institutional trial. There is evidence, however, that 60 to 75 percent of patients with lymph node disease as the only site of spread respond to the preoperative regimens, a significantly greater response than when the same regimens are used in patients with disseminated disease, and over half of these patients go on to resection. Between 10 and 20 percent of patients resected have no evidence of disease found on histologic examination of the resected material. The activity of the neoadjuvant regimen in this patient population cannot be denied. Whether surgical excision is required or radiation is an acceptable modality for local control remains to be determined. Of great importance is the consideration of quality of life in patients undergoing these combined regimens, an area that has not been adequately addressed. The quality of life measurement tools are available to incorporate into future studies so that additional information should be forthcoming. Toxicity from these preoperative regimens can be substantial, especially if there is an element of postobstructive pneumonia. In the SWOG trial, two deaths resulted from the preoperative regimen, and 13 percent of patients experienced grade 4 or greater acute toxicity. The overall treatment-related mortality was 15 percent in the neoadjuvant study from Toronto. This further underscores the importance of confining multimodality therapy for N2 disease to controlled trials as opposed to routine community use, despite the current enthusiasm.

CHEST WALL RESECTION Approximately 5 percent of lung cancers involve the chest wall by direct extension. This involvement may be limited to the parietal pleura or may invade the endothoracic fascia, intercostal muscle, or ribs. Chest wall involvement by direct extension is not a contraindication to resection unless vertebral bodies are invaded, and even then, under some circumstances, resection may still be completed. Chest wall pain is the most sensitive predictor of chest wall involvement in a patient with a peripheral lung lesion in which there is a question of chest wall invasion. Neither CT scan nor MRI can distinguish between abuttment and invasion unless there is gross invasion of bone. The radionuclide bone scan may be negative with chest wall involvement, especially if only the parietal pleura and muscle are involved. Lesions involving parietal pleura or other chest wall structures are staged as T3 primary tumors, but often definitive staging cannot be accomplished until the time of operation.

As with any lung cancer it is important to rule out disseminated disease prior to considering operation in a patient with chest wall involvement. It is particularly important to assess the mediastinum in these patients, since mediastinal lymph node involvement is the single best prognostic indicator. Three-year survival approaches zero in patients with chest wall and mediastinal lymph node involvement, underscoring the importance of invasive mediastinal lymph node staging, usually with mediastinoscopy, prior to considering

Part I: Treatment of NSCLC: Surgical

thoracotomy in this patient group. Conversely, greater than 50 percent 5-year survival can be expected in patients with chest wall involvement with negative mediastinal lymph nodes as long as the resection margins are negative.

The operation performed in a patient with suspected chest wall involvement begins by assessing the pleural space to rule out diffuse pleural disease and then defining whether the chest wall is invaded. Prior to beginning the chest wall resection it is important to assess the hilum of the lung to ensure that the findings do not preclude resection. It is disconcerting to resect a large chunk of chest wall only to find that there is such extensive disease at the pulmonary hilum as to preclude parenchymal resection. Often one finds only adherence with no evidence of invasion, and this is established by beginning the resection in the extrapleural plane, thus separating the parietal pleura from the endothoracic fascia in the area of the lesion. If this plane is easily developed, something that is very clear to the experienced surgeon, it may be that the parietal pleura are not invaded. If there is any question at all about invasion when attempting to develop the extrapleural plane, then chest wall resection is performed (Fig. 110 I-7). Ideally the chest wall resection is performed in continuity with the parenchymal resection, that is the portion of chest wall resected remains attached to the underlying lung. The chest wall resection should include at least one rib and preferably two above and below the area of chest wall invaded. Three- to five-cm margins should also be taken anteriorly and posteriorly. The intent is to achieve negative margins, so the resection should be wide; there is little if any additional morbidity to taking a somewhat larger piece of chest wall.

Once the chest wall block is totally mobilized, the lobectomy and mediastinal lymph node dissection are completed.

A mediastinoscopy should have been performed earlier, but a lymph node dissection should be done for complete staging.

A posterior chest wall defect is reconstructed with polypropylene mesh, and a defect in the anterior chest wall should be reconstructed with a sandwich of methylmethacrylate cement and polypropylene mesh. Posteriorly the defect is covered additionally by the scapula, but anteriorly the rigid fixation provided by the methyl methacrylate and mesh eliminates any paradoxical motion that might interfere with mechanics of breathing. Interference with the mechanics of breathing is much less likely to occur with posterior defects.

Chest wall resection adds little if any additional morbidity to a pulmonary resection. Patients tend to have the chest tubes in a few days longer following chest wall resection because of increased fluid drainage. Pain in the early postoperative period is best controlled with a thoracic epidural catheter, which allows patients to be comfortable enough to maintain a good cough for clearance of secretions. There is no evidence that patients undergoing chest wall resection are subject to more pain than those who have a simple lobectomy. If the cough is ineffective, then secretion retention is aggressively managed with periodic bronchoscopies.

Postoperative treatment for patients who have undergone chest wall resection with pulmonary resection remains controversial. The most important consideration is

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Figure 105 I-7 Operative photograph showing the defect left after resection of the left upper lobe in continuity with the anterior chest wall. This anterior defect requires reconstruction with prosthetic mesh and methylmethacrylate cement.

the attainment of negative resection margins at the time of operation. The surgeon should never think that a few close margins or even a small amount of gross disease left behind can be â&#x20AC;&#x153;cleaned upâ&#x20AC;? by the radiation oncologist.

Anything less than a complete resection is associated with poor long-term survival. With negative surgical margins is there a role for radiation therapy? Currently no evidence exists that postoperative radiation therapy prolongs survival in this patient group, but local recurrence may be problematic.

Thus there may be a role for radiation therapy in some of these patientsâ&#x20AC;&#x201D;in particular those with disease close to the spine, in whom local recurrence presents major management problems.

Tumors Involving the Mediastinum by Direct Extension Some centrally located primary tumors may involve structures in the mediastinum by direct extension (Fig. 110 I-8).

The assessment of this involvement, whether there is true invasion or just abuttment and adherence, cannot be determined until the findings are seen intraoperatively and then often only as the dissection proceeds. The presence of a central

tumor that appears on CT scan to be close to the mediastinum is not justification for making a judgment of unresectability, especially if the judgment is being made by someone other than a surgeon. This is a judgment that can only be made intraoperatively, since no imaging modality readily distinguishes abuttment from invasion. There may be other reasons why the patient should not be operated on, but it is dangerous to simply assume that a lesion is unresectable. The distinction between a T3 tumor involving the mediastinum and a T4 tumor depends on the mediastinal structure invaded. Tumors invading structures such as the phrenic nerve, mediastinal pleura or fat, the pericardium, or the diaphragm that may be readily removed are classified as T3 primary tumors and as such are in the stage IIIa group, which also includes mediastinal lymph node involvement and tumors involving chest wall. T4 primary tumors involve those structures that usually are not considered to be resectable, such as aorta, left atrium, superior vena cava, trachea esophagus, or vertebral bodies.

There are occasions when tumors involving these structures are resected, most commonly with lesions involving the vena cava or left atrium. Rarely, if ever, is a portion of aorta resected for excision of a lung tumor, but a lesion may involve only the muscular coat of the esophagus and thus may be amenable to

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Part I: Treatment of NSCLC: Surgical

Figure 105 I-8 MRI scan showing a primary lung tumor involving the aorta by direct extension (T4 primary). The distinction between abuttment and invasion often cannot be made until the findings are seen at operation. MRI is no better at delineating invasion than CT.

resection. What is important to recognize, however, is despite the seeming ability to remove some of these invasive lesions, the prognosis for long-term survival is dismal. For T4 lesions, fewer than 10 percent of patients are alive at 5 years. From the viewpoint of the surgeon, although certainly recognizing the poor long-term survival with these tumors, in the absence of mediastinal lymph node involvement it is difficult to simply back out and leave the tumor in place when it is possible to resect the lesion with minimal morbidity, such as when a portion of vena cava or piece of left atrium is all that is necessary to complete a resection. Extensive involvement of one of these structures is an absolute contraindication to resection.

It is illustrative to discuss the situation of a patient who presents with the new onset of hoarseness and is found to have a paralysis of the left vocal cord. Almost always a tumor will be found in the left chest, usually the left upper lobe. In fact the acute onset of left vocal cord paralysis should be assumed to be from a cancer of the lung until proved otherwise.

A benign problem causing a left vocal cord paralysis is distinctly unusual. Rarely, if ever, is hoarseness due to right vocal cord paralysis because of the position of the right recurrent laryngeal nerve, which â&#x20AC;&#x153;recursâ&#x20AC;? around the right subclavian artery above the apex of the chest. Conversely, the left recurrent nerve is in a position of great vulnerability, since it arises after the vagus nerve crosses the aortic arch and recurs around the ligamentum arteriosum (Fig. 110 I-9). The left recurrent nerve may be involved either by a primary tumor, which encases the vagus nerve as it crosses the aortic arch, or more commonly by lymph node disease in the aortopulmonary window. Because of the depth of the aortopulmonary window, there can be gross mediastinal lymph node involvement and a sheet of tumor with minimal plain radiographic

evidence, since tumor underneath the aortic arch is not easily seen. CT scan usually confirms extensive involvement. Involvement of the left recurrent laryngeal nerve represents a contraindication to operation, since rarely are these lesions able to be completely resected. Left recurrent laryngeal nerve involvement should exclude patients from participating in neoadjuvant trials as well. The only exception is the occasional situation in which the primary tumor involves the vagus nerve as it crosses the aortic arch, a situation that may prove to be resectable and justifies exploration.

vagus n. aortic arch

left recurrent laryngeal n. ligamentum arteriosum

left main bronchus

left main pulmonary art.

Figure 105 I-9 The anatomy of the aortopulmonary window showing the relationship of the left recurrent laryngeal nerve to the aortic arch and ligamentum arteriosum. The nerve is easily damaged in this location. Hoarseness may result from tumor involvement of the nerve in this location or from involvement of the vagus nerve at the level of the aortic arch proximal to the location where the recurrent laryngeal nerve originates.

1862 Part XV

Neoplasms of the Lungs

Palliative Resections There is essentially no role for palliative resections in the modern management of NSCLC. Morbidity resulting from the primary tumor usually may be managed using modalities other than operation. There probably is no justification for operation if less than a complete resection is anticipated.

At the present time there is no role for surgical “debulking” in the management of the patient with unresectable disease.

With the newer treatment planning modalities available, radiation therapy can be given accurately and in high doses to patients who are inoperable or unresectable. Patients with hemoptysis or postobstructive pneumonia may benefit from laser excision of the endobronchial disease combined with external beam radiation therapy and endobronchial placement of radioactive sources. Laser excision may be combined with stent placement to maintain open an obstructed bronchus or trachea. Chest wall pain usually is readily controlled by a course of radiation therapy.

fine their practice to general thoracic surgery, as distinct from cardiac surgery, have come dedicated inpatient units to care for patients undergoing pulmonary resections.

Postoperative Mortality Recent analyses identify that modern 30-day operative mortality from pulmonary resections should be less than 4 percent. Lobectomies and lesser resections should have a mortality between 1 and 2 percent, and pneumonectomies still carry a mortality of 6 to 7 percent. The mortality rate is directly proportional to increased age, associated diseases, and the extent of resection. Respiratory complications, not surprisingly, are the most common cause of postoperative mortality in patients undergoing pulmonary resection. Cardiac complications also account for a significant percentage of mortality, and technical problems such as hemorrhage, bronchopleural fistula, and empyema account for a small but significant percentage of complications leading to death.

Postoperative Morbidity RESULTS OF TREATMENT Postoperative Complications Major improvements in perioperative care of patients undergoing thoracic surgical procedures have led to decreased morbidity and mortality when compared with only 10 to 20 years ago. Improved preoperative evaluation of patients has allowed us to identify risk factors associated with morbidity and address these early on. Experience with lung transplantation has shown that deconditioned patients benefit from at least a 6-week period of pulmonary rehabilitation, and selected patients with otherwise operable disease may be placed in a rehabilitation program prior to undergoing operation.

Quantitative perfusion lung scans have allowed us to better select borderline patients for pulmonary resection, especially when pneumonectomy is a possibility. This information has all but eliminated the “pulmonary cripple” as a result of a lung resection. Recent experience with bilateral lung volume reduction surgery demonstrates that patients with severe emphysema and hyperinflation actually benefit from the resection of nonfunctional pulmonary parenchyma and has fueled the realization that no matter how poor the pulmonary function studies, many of these patients may be candidates for resection. The further refinement of lung-conserving procedures and the use of minimally invasive techniques such as video thoracoscopy along with better perioperative pain management provided by continuous epidural administration of narcotic have provided the incentive for us to operate on many patients previously thought not to be candidates because of poor pulmonary function. A greater recognition of the importance of preoperative teaching of postoperative maneuvers such as coughing and the use of chest physiotherapy given by expertly trained individuals also has contributed to decreasing respiratory complications. With the ascent of a class of formally trained cardiothoracic surgeons who con-

Approximately 30 percent of patients undergoing pulmonary resection sustain a postoperative complication, of which approximately two-thirds are minor and the other one-third nonfatal major complications. The most common complication is supraventricular arrhythmia, which occurs in up to 20 percent of patients, depending on how closely patients are monitored. Most of these respond to simple pharmacologic manipulation and rarely are hemodynamically significant at onset. With appropriate treatment the rhythm reverts to sinus rhythm quickly, and patients may be taken off the antiarrhythmic drugs usually after 1 month. Other minor complications include postoperative air leaks lasting greater than 7 days and atelectasis. Major nonfatal events most commonly are respiratory related, with patients developing significant infiltrates and pneumonitis. A small percentage of patients require reintubation in the postoperative period for respiratory failure usually related to the development of an infiltrate. There are no definitive predictors for postoperative pulmonary complications, although significant risk factors for major complications include age greater than 60 years, FEV1 less than 2 L, weight loss greater than 10 percent, associated systemic disease, and extent of disease. Pulmonary complications can be minimized with meticulous attention to postoperative respiratory maneuvers, including chest physiotherapy and preoperative teaching.

Other complications of pulmonary resection include wound infections and disturbances in mental status, especially in older patients. Fortunately, Postpneumonectomy complications are unusual, but the most common one is empyema with or without a bronchial stump leak.

Prognosis Following Resection Prognosis following pulmonary resection has been well analyzed, and results are summarized in Table 110 I-2.Prognosis

1863 Chapter 105

Table 105 I-2 5-Year Postoperative Survival by TNM Stage Based on Data from Lung Cancer Study Group Trials Squamous Cell Adenocarcinoma Stage

(n = 549),%

(n = 572)%

Stage I T1NO T2NO

83 64

69 ( p = 0.02) 57

Stage II T1N1 T2N1

75 53

52 ( p = 0.04) 25 ( p < 0.01)

Stage IIIa T1-2N2 T3N0

46 37

35 21

depends mainly on TNM stage, a classification that was revised as recently as 1986. Short of disseminated disease, prognosis mainly depends on the status of the regional lymph nodes. Prognostic data are only as good as the sampling done at the time of operation, and lymph node dissection is the only sure way to ascertain definitively the status of the lymph nodes. Histologic type also has some prognostic significance but to a lesser extent, and histologic grade, according to present knowledge, has little prognostic significance. The presence of neuroendocrine features in what is otherwise an NSCLC, however, may have prognostic significance.

Sites of Recurrence Patients with lung cancer die of disseminated disease, and it is a distant site that most commonly is the first site of recurrent disease. Over 30 percent of patients with adenocarcinomas develop brain metastases, a percentage significantly higher than for patients with squamous carcinoma. Other common sites of metastatic disease include bone, lung, liver, and adrenals. Patients with higher-stage disease have a significantly greater likelihood of developing disseminated disease.

This recognition has led to the neoadjuvant treatment regimens in patients with N2 disease. Local recurrence occurs, most commonly associated with distant disease. Isolated local recurrence is a rare phenomenon but sometimes is amenable to resection. This underscores the importance of a complete resection at the time of the initial operative procedure. Sites of local recurrence that may cause problems include the chest wall (pain), superior vena cava (SVC syndrome), and involvement of the left recurrent laryngeal nerve (hoarseness and swallowing problems). Symptomatic local recurrence is of-

Part I: Treatment of NSCLC: Surgical

ten treated with radiation therapy, and chemotherapy is employed for some patients who develop disseminated disease, while recognizing that cure is usually not possible in patients who have developed distant disease.

Postsurgical Follow-up Recognizing that essentially no patient is cured once distant disease is present might raise the question of why patients should be followed at all after pulmonary resection. Is there an advantage to recognizing the development of distant disease early rather than late? Actually there may be some advantage, especially when it comes to preventing some of the morbidity that may accompany disseminated disease if treatment begins early. Also the occasional patient presents with an isolated local recurrence that may be amenable to surgery. Perhaps most important is the sense of comfort patients derive from knowing that they are being closely followed by their physician or surgeon, especially if the follow-up is done in a cost-efficient manner it is difficult to fault.

Since most local recurrences occur within the first 2 years following resection, patients should be seen every 3 months, with a chest radiograph as the only diagnostic study.

There is absolutely no need to obtain a CT scan as a followup study, and no blood tests are of any use in following these patients. Further studies are ordered based on patient complaints or findings elicited by a careful history and physical examination in addition to the chest radiograph. Between years 2 and 5, patients are seen every 6 months, and after 5 years on a yearly basis. Usually the development of disseminated disease is obvious as patients relate the history of problems since their last visit. Imaging studies tend only to confirm the clinical impression, and then a decision regarding further treatment needs to be made.

FUTURE DIRECTIONS The role of surgery in the management of NSCLC has been well defined and remains the standard therapy for patients with localized disease. The challenge for all who deal with lung cancer is the problem of disseminated disease. Perhaps the better way to deal with the problem is to identify causes of the disease in addition to the already well-defined risk of cigarette smoking. Thus far a â&#x20AC;&#x153;lung cancer susceptibilityâ&#x20AC;? gene has not been demonstrated; however, based on the recent explosion of knowledge related to breast cancer, the identification of one or more genes involved in the genesis of certain lung cancers is at hand. Cigarette smoking has been identified as a major risk factor, yet only a small percentage of patients who smoke develop lung cancers. Efforts to identify such susceptibility genes have been hampered by the relative lack of families with a genetic predisposition. The issue of smoking as a risk factor only serves to confound the search.

Molecular markers to identify patients at increased risk of developing recurrent disease are also desperately needed.

1864 Part XV

Neoplasms of the Lungs

Once identified, these patients would begin adjuvant therapy designed to prevent recurrence in this high-risk group, sparing those patients who are at lower risk. This further underscores the need for better adjuvant therapy, since none exists at present. Targeting specific factors that control lung cancer development or specific receptors on lung cancer cells seems a more sensible strategy than that utilized by currently available antineoplastic agents. Major strides have been and continue to be made in the molecular biology and genetics of tumors, and we can expect lung cancer to be the beneficiary of some of these developments.

In the meantime refinements in surgical techniques and perioperative management of patients with lung cancer have allowed greater numbers of patients with localized and locally advanced disease to benefit from operative intervention.

Many patients with mediastinal lymph node disease previously thought not to be operative candidates now are able to be operated upon with improved survival after a course of neoadjuvant therapy. Other patients with pulmonary function so compromised that it precluded resection now are often considered for resection using the minimally invasive techniques developed within the previous few years aided by better pain management and postoperative chest physiotherapy. It’s safe to say that surgery will continue to play a major role in the management of patients with NSCLC.

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Part I: Treatment of NSCLC: Surgical

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105 Part II: Treatment of Non--Small-Cell Lung Cancer Chemotherapy Ranee Mehra Joseph Treat

I. CRITERIA FOR REPORTING RESULTS II. LOCALIZED NON--SMALL-CELL LUNG CANCER Early Stage Disease III. LOCALLY ADVANCED NSCLC Radiation Therapy Alone Chemotherapy Followed by Radiation Therapy: Randomized Trials Concurrent Chemotherapy and Radiation Therapy

Approximately 45 percent of patients with non–small-cell lung cancer (NSCLC) have evidence of advanced stage disease when first seen by a physician. Such data have led to the assumption that NSCLC is generally a systemic disease and that relatively few patients have localized disease that is amenable to a surgical approach alone. Unfortunately, patients with disseminated disease are rarely cured despite our best efforts. In the most favorable prognostic group, those with T1N0 disease (i.e., up to 25 percent) are destined to fail within 5 years after surgery. Therefore, since even patients with localized disease are likely to develop disseminated disease, systemic therapy is an important component of therapy.

Historically, single cytotoxic chemotherapeutic agents have achieved only minimal response rates in NSCLC, so regimens that entail combinations of drugs have evolved as firstline standard therapy—if any therapy can be designated as “standard” in this disease. Definition of the role of chemotherapy in the treatment of this disease continues to evolve. In addition, the development and study of molecular targeting agents have added more treatment options for NSCLC, especially in the advanced stage setting.

Chemotherapy Followed by Surgery Chemotherapy and Radiation Followed by Surgery Future Directions IV. ADVANCED-STAGE NSCLC First-Line Chemotherapy Second-Line Therapy Future Directions V. CONCLUSION

CRITERIA FOR REPORTING RESULTS Several criteria are used in assessing the efficacy of chemotherapy. One of these is response rate based on radiographic criteria. Response is measured as the percent of decreasing tumor size; the decrease is qualified in terms of being complete (total disappearance by radiologic or physical examination) or partial. A partial response is defined as either a 50 percent reduction in the product of the largest dimensions of the lesion without any new lesions (WHO criteria), or as a 50 percent reduction in the sum of the largest dimension of all target lesions without any new lesions (RECIST criteria).

Responses are almost always partial in NSCLC. Although response rates are important in the assessment of new agents or combinations, response rates that are reported by a single institution on the basis of a nonrandomized trial (without a “standard” comparison arm) should be interpreted with caution. A high response rate determined in this way may call attention to an active new agent or combination, but in the last analysis, efficacy can be demonstrated

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only by larger randomized trials. Many factors influence the response rate in single-arm phase II trials. These include patient selection in terms of performance status, extent of disease, weight loss, and symptoms. Sicker patients, with extensive disease and a worse performance status, tend to be left out of these trials.

Once a new active drug or combination has been identified, a larger randomized trial is necessary to determine whether it offers advantages over a previously established regimen. Although response rates are still being reported, survival is the major end point in treating NSCLC by chemotherapy.

Small improvements in survival (e.g., additional 10 weeks), although statistically significant, are of dubious biologic and clinical significance. In addition, quality-of-life indices that are standardized and reproducible are now available as part of the evaluation of clinical benefit. It seems likely that future clinical trials will include quality of life and cost analysis as measurable end points.

It is also important at this point to distinguish between efficacy and effectiveness. A particular regimen may demonstrate efficacy within the confines of a limited clinical trial conducted at academic institutions by interested and committed investigators who have a large cohort of patients from which to choose for the study. The extent to which the results of such a trial, based on a selected group of patients, is applicable to the general population is often unpredictable. An efficacious regimen administered within the confines of a limited clinical trial by dedicated investigators may prove not to be effective when applied to a larger population and administered by a multitude of clinicians.

This dichotomy between efficacy and effectiveness needs to be kept in mind when one is evaluating results of any clinical trial. It is especially important, however, when one is looking at results of trials of therapeutic methods in advanced malignant disease, in which the response rates are modest at best.

Figure 105 II-1 Chest radiograph of a 60-year-old female smoker who presented with increasing cough. The film shows a large right upper-lobe mass with obvious mediastinal and hilar adenopathy. Ipsilateral mediastinal lymph node involvement was confirmed by mediastinoscopy. An extent-of-disease evaluation failed to demonstrate any evidence of disseminated disease.

The patient was treated in a protocol setting with preoperative chemotherapy.

Role of Adjuvant Chemotherapy It is well recognized that despite complete resection, most patients with locally advanced NSCLC will, at some time, develop disseminated disease. As noted, the risk of developing disseminated disease can be predicted, with some accuracy,

LOCALIZED NON--SMALL-CELL LUNG CANCER Early Stage Disease Surgery remains the best option for patients with localized disease who do not have overwhelming medical contraindications to a lobectomy or pneumonectomy. Staging is central to the therapeutic approach to NSCLC. This entails determination of the extent of invasion of the mediastinal lymph nodes. Mediastinoscopy is the procedure of choice for sampling mediastinal lymph nodes before a thoracotomy. As for all surgical interventions for thoracic malignancy, complete nodal sampling or lymph node dissection is an integral part of the procedure. Staging of a patient with localized lung cancer is feasible only if the status of the mediastinal lymph nodes is ascertained. Reliance on noninvasive imaging alone may be inadequate for accurate assessment of the mediastinum (Figs. 105 II-1 and 105 II-2).

Figure 105 II-2 Chest radiograph of the same patient as in Fig. 105 II-1 following two cycles of chemotherapy. Note the minimal effect on the primary tumor, but the considerable decrease in size of the nodal metastatic disease. The patient subsequently went to surgery and was able to have a complete resection.

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Table 105 II-1 Randomized Trials for Adjuvant Chemotherapy Overall Number of Patients

Stage

Therapy

1867

IA, IB, II, III

Observation Chemo

Survival (months)

344

IB–T2N0

Obs Chemo

78 95

482

IB, II (no T3N0)

Obs Chemo

73 94

840

IB-IIIA

Obs Chemo

43.7 65.7∗

∗ Statistically

Survival (%) 1 Yr

94 94

2 Yr

3 Yr

66.7 70.3∗

44.5∗

84 90

71 79∗

5 Yr

Reference

40.4

IALT Arriagada R, Bergman B, et al., 2004

57 59

CALGB 9633 Strauss GM, Maddaus MA, Johnstone DW, Johnson EA, et al., 2004; Strauss GM, Maddaus MA, Johnstone DW, et al., 2006

54 69∗

NCIC JBR10 Winton T, Livingston, R, et al., 2005 ANITA Douillard JY, Rosell R, et al., 2006

insignificant.

on the basis of the stage of the disease determined at the time of the initial resection. However, the value of the staging information depends on the completeness of the staging procedures carried out at the time of resection. Even with stage I disease, as many as 20 percent of patients die of disseminated disease within 5 years. With stage II disease, less than 50 percent of patients are alive at 5 years; with stage IIIA N2 disease, at best 30 percent of patients are alive at 5 years. These numbers make clear the need for some additional therapy to improve on the overall survival achieved by surgery.

To this end, there has been an emergence of a body of data to better define the role of chemotherapy in the adjuvant setting. The rationale behind this approach is to treat patients who are deemed to be at high risk for recurrence and dissemination of disease in the hope of eliminating micrometastatic disease. Early trials to study adjuvant chemotherapy have been negative, possibly either due to the use of less effective chemotherapy regimens, the increased morbidity of treatment with fewer supportive care options, or the lack of statistical power. However, interest in studying adjuvant chemotherapy reemerged with presentation of a meta-analysis in 1995 in which 52 randomized trials were reviewed. The authors concluded that the trials that compared cisplatin–based chemotherapy to no chemotherapy favored the used of chemotherapy with an absolute benefit at 5 years

of 5 percent. Since then, more homogeneous trials randomizing patients to surgery versus surgery followed by platinumbased chemotherapy have been conducted. These studies are outlined in Table 105 II-1.

International Adjuvant Lung Cancer Trial

The International Adjuvant Lung Cancer Trial (IALT) randomized 1867 patients with stage I, II, or III NSCLC to observation or chemotherapy after they had undergone a surgical resection of their tumor. The two groups were evenly matched with regard to age, sex, stage, performance status, type of surgery, and histologic subtype. The chemotherapy regimen used consisted of cisplatin 80, 100, or 120 mg/m2 offered on one of four different schedules with vindesine, vinblastine, vinorelbine, or etoposide. Patients were treated with three or four cycles. Of the various choices, the combination of cisplatin and etoposide was used to treat nearly 50 percent of the patients. Due to the lack of consensus regarding the used of adjuvant radiotherapy, this was allowed with the choice being left available to individual practitioners.

When offered, radiation was given after chemotherapy in the group randomized to postoperative treatment. Radiation was planned for about 30 percent of the patients of the trial, with two-thirds of these having N2 disease. It was actually delivered to slightly more patients in the control group compared with the chemotherapy group (28 vs. 23 percent). Overall,

1870 Part XV

Neoplasms of the Lungs

the results favored the use of adjuvant chemotherapy, with a hazard ratio (HR) for death of 0.86 (0.76â&#x20AC;&#x201C;0.98). At five years, the group that received chemotherapy had a statistically significant improvement in survival of 44.5 versus 40.4 percent.

The toxicities associated with chemotherapy included the expected risks of neutropenia and nausea/vomiting. However, seven patients died due to chemotherapy-related acute toxicities. In general though, this positive trial provided an absolute benefit in 5 years that was consistent with the meta-analysis and provided support for the use of a cisplatin doublet in the adjuvant setting.

Retrospectively, tissue samples collected from patients on IALT have been analyzed by immunohistochemistry (IHC) to assess which biomarkers may predict for a response to cisplatin therapy. Specifically, investigators have assayed for the enzyme excision repair cross-complementation group 1 (ERCC1). Cisplatin acts by directly binding to DNA and forming platinum-DNA adducts, which prevents DNA replication. It is known that the presence of ERCC1 is associated with cisplatin resistance due to the activation of DNA repair mechanisms. To study this in the context of the IALT results, 761 tumor samples from that trial were assayed for ERCC1 expression by IHC; half of these patients received chemotherapy and the remainder were in the control group.

Of the tumors analyzed, 44 percent were ERCC1 positive. Expression was more common in patients over the age of 55 and those with squamous cell histology. Interestingly, there was a benefit from adjuvant chemotherapy in patients with ERCC1-negative tumors, with a statistically significant improvement in overall survival and disease-free survival due to chemotherapy (HR 0.65). In contrast, patients with ERCC1positive tumors did not achieve a survival benefit from adjuvant chemotherapy compared with the control group. Among patients in the control group, those with ERCC1-positive tumors had an increased survival compared with patients with ERCC1-negative tumors. Although these results are intriguing, ERCC1 is currently not routinely tested in the clinical setting, and its use as a predictive marker for cisplatin-based adjuvant therapy needs to be validated in a prospective clinical trial.

the study to be terminated early, and the NCCN practice guidelines adopted the use of adjuvant chemotherapy in stage IB patients. Since then, when the results were updated after longer follow-up in 2006, the difference in 5-year survival between the chemotherapy and observation arms (59 vs. 57 percent) was no longer statistically significant. However, the 3-year survival difference still remains statistically significant, and there is a trend favoring a benefit in overall survival in the patients who received chemotherapy. Despite this, the routine practice of treating patients with stage IB disease can no longer be endorsed. In a subset analysis of the updated results, there was a statistically significant benefit in overall and disease free survival in patients with tumors over 4 cm in size who received chemotherapy. This benefit was not shared in those with tumors less than 4 cm in size.

Therefore, in practice, many oncologists choose to treat patients with larger tumors, based on this subset analysis. The analysis of this study is still preliminary, as it has not met its planned target of 150 events for a final statistical analysis. Therefore, there will be much interest as the follow-up and data further mature. Currently, the reason why the results are negative to date is an active area of debate, and it is not known if this is due to the population of patients being treated, the choice of a carboplatin-based regimen rather than cisplatin, or the abridged number of patients who were treated.

NCIC JBR 10

In this intergroup study, 482 patients with stage IB or II (excluding T3N0) NSCLC were randomized to either surgery or surgery followed by four cycles of chemotherapy. Again, the treatment studied included cisplatin (50 mg/m2 days 1 and 8) and vinorelbine (25 mg/m2 weekly); one cycle was 4 weeks.

This also was a positive study, with the 5-year survival favoring the chemotherapy group (69 vs. 54 percent), as well as a statistically significant improvement in disease-free and overall survival. Toxicity was associated with this regimen with two treatment-related deaths and over 70 percent of patients experiencing either grade 3 or 4 neutropenia. Other toxicities included fatigue, anorexia, and vomiting.

CALGB 9633

The Cancer and Leukemia Group B (CALGB) conducted a trial to test the benefit of adjuvant chemotherapy in only stage IB (T2N0) patients. Other studies have included these patients along with those with more advanced disease, and in subset analyses the true benefit of chemotherapy after surgery in this population has been questioned. Originally, this study was intended to enroll 500 patients. However, due to poor accrual, this number was modified and in the final analysis 344 patients were treated. Patients randomized to the chemotherapy arm received carboplatin AUC 6 and paclitaxel 200 mg/m2 every 3 weeks for four cycles. This study has been provocative in that it was initially reported to be a positive trial with a statistically significant survival advantage in 2004, after a median follow-up of 34 months. This prompted

ANITA

The most recent study of interest is the Adjuvant Navelbine International Trialist Association study (ANITA), in which 799 patients with stage IB, II, or IIIA NSCLC were randomized to four cycles of chemotherapy or observation after surgery. Similar to the other trials, the chemotherapy regimen consisted of cisplatin (100 mg/m2 , day 1) and vinorelbine (30 mg/m2 , weekly) for a 4-week cycle. The choice of radiotherapy was left to the discretion of the treating physicians, and in the final analysis 24 percent of patients in the chemotherapy arm and 33 percent of patients in the observation arm received radiation. Patients who were randomized to chemotherapy had a significant improvement in overall survival to 66 months, compared with 44 months in the

1871 Chapter 105

control group. At 5 years, the absolute benefit in survival was 8.6 percent, and in a subset analysis this benefit seemed to be mainly noted in stage II and IIIA patients. This result is tempered by the occurrence of seven chemotherapy-related deaths.

Future Directions

Adjuvant cisplatin doublet chemotherapy is currently the standard of care for stage II and IIIA patients. The role of adjuvant treatment of stage IB patients has yet to be defined more clearly, but based on subset analyses it is possible that patients with tumors greater than 4 cm will benefit from chemotherapy. Given the now-negative results of the CALGB 9633 study, carboplatin cannot be recommended as a standard choice for adjuvant treatment. Hopefully future studies will provide further data to guide the therapy of stage IB patients. Also, although molecularly targeted agents have been studied in the advanced disease stage (as detailed in the following), the utility of these agents in the early stage setting is unknown.

To begin to answer this question, the current large intergroup effort that is underway will randomize patients with stage IB (greater than 4 cm), II, and IIIA NSCLC to a cisplatin–based doublet either with or without the anti-angiogenesis agent bevacizumab.

Role of Adjuvant Radiotherapy Research conducted by the Lung Cancer Study Group on patients with either stage II or IIIA disease who had undergone resection of a squamous cell carcinoma showed that those who received postoperative radiation therapy (without chemotherapy) had a significantly lower incidence of local recurrence to the ipsilateral lung or mediastinum than those receiving no postoperative radiation. There was especially a benefit in patients with N2 disease. However, the decreased incidence of local recurrence with radiation has not been shown to translate into a survival benefit. This result should not be surprising, since patients with lung cancer die of disseminated disease and one would not expect treatment with postoperative radiation therapy—like surgery, a local modality—to prevent the development of disseminated disease. With trials that support the use of adjuvant chemotherapy in stage II and IIIA disease, adjuvant radiotherapy alone is not considered to be the standard of care. The Eastern Cooperative Oncology Group (ECOG) conducted a trial in which patients were randomized to postoperative radiotherapy or radiotherapy (RT) and chemotherapy (cisplatin/etoposide). However, there was no benefit in overall survival or local control with the addition of chemotherapy to RT. Thus, concurrent postoperative chemoradiotherapy is also not considered to be a standard treatment approach. Sequential RT after adjuvant chemotherapy in patients with N2 disease is currently an area of controversy. Although this approach is recommended by some practitioners, it has not been validated in a prospective, randomized study.

Treatment of NSCLC: Chemotherapy

LOCALLY ADVANCED NSCLC The term locally advanced includes several different presentations of primary lung cancer, but all have in common the absence of disease outside of the chest. Some of these lesions are eminently resectable, others marginally resectable, and others out of the realm of resectability. Included in this group of lesions are those with mediastinal lymph node involvement (N2 disease), direct extension into certain mediastinal structures (T3), direct extension into the chest wall (T3), and certain endobronchial lesions.

Lesions that directly invade the mediastinum but affect structures that are not usually considered resectable (e.g., aorta, esophagus, and vertebral bodies) are classified as T4 and are considered to be stage IIIB. The distinction between IIIA and IIIB lesions is important, since prognosis is significantly worse for the latter lesions. The distinction between a T3 and T4 primary often cannot be made on the basis of preoperative imaging and depends on a determination made at thoracotomy. As indicated, mediastinal lymph node invasion can be determined before thoracotomy by way of mediastinoscopy, which also allows contralateral mediastinal lymph nodes to be sampled. Contralateral nodal invasion indicates N3 disease, which also falls within the unresectable stage IIIB classification.

Many studies in which patients with locally advanced disease were treated with chemotherapy, radiotherapy, or a combination of the two have relied on noninvasive determination of the extent of the disease. Thus, on the basis of enlarged mediastinal lymph nodes seen on a computed tomographic (CT) scan, patients were assumed to have N2 disease and were treated without histologic documentation of mediastinal lymph node impairment. Such studies are seriously flawed. For meaningful interpretation, accurate histologic staging has to be included as an entry criterion for any study of locally advanced disease.

About 40,000 cases of stage IIIA and IIIB disease occur per year in the United States. The best treatment approach to locally advanced disease has not yet been determined. A wide array of combined modality approaches have been used in stage IIIA patients (particularly those with N2 nodes). These include varying combinations of chemotherapy, radiation, and surgery. Unfortunately, some T3 patients have been included in many of these trials—again complicating interpretation of the results (Fig. 105 II-3).

Radiation Therapy Alone Prior to the development of regimens with chemotherapy and chemoradiotherapy, radiation therapy alone was the standard treatment for patients with N2 disease. This practice resulted in a 5-year survival of about 5 percent. This form of treatment was based largely on a clinical trial begun in 1973 by the Radiation Therapy Oncology Group (RTOG 73-01). This study looked at different doses of radiation (4000, 5000, or

1872 Part XV

Neoplasms of the Lungs

Figure 105 II-3 MRI scan of a patient with locally advanced disease invading the chest wall and at least abutting the mediastinum. At exploration, the lesion was found not to be invading the mediastinum and was completely removed with a lobectomy and chest wall resection.

6000 cGy), as well as split-course versus continuous therapy at 4000 cGy. Interpretation of this study is difficult because of the relatively poor quality of the CT scan images available at that time and the lack of histologic evidence of N2 disease before entry into the study. Nonetheless, this trial did demonstrate responsiveness at the higher doses of radiation and improved survival at 3 years for the 6000-cGy arm. At 5 years, all treatment arms were associated with a 5 percent survival. Today, after accurate staging, many of these patients would be eligible for combined modality treatment that consists of chemotherapy and radiation therapy, with or without surgery.

Another historic study, conducted by the Southwestern Oncology Group, randomized patients to radiation alone (6000 cGy), single-agent chemotherapy with vindesine, or concurrent vindesine and radiation therapy. The median survival and percentage of patients alive at 5 years were 8.6 (3 percent), 10.1 (1 percent), and 9.4 months (3 percent), respectively. This study underscore the lack of effect of radiation as a single modality as well as the lack of improvement when a single drug is added to radiation therapy. Since combination chemotherapy that includes cisplatin provided longer survival than did any single agent, in subsequent studies combination chemotherapy was added to radiation therapy in the attempt to improve results.

Chemotherapy Followed by Radiation Therapy: Randomized Trials Several prospective, randomized studies have compared radiation therapy alone and radiation therapy in sequence with

chemotherapy. Mattsonâ&#x20AC;&#x2122;s team reported a series of â&#x20AC;&#x153;inoperableâ&#x20AC;? patients randomized to receive either radiation alone (5500 cGy) or chemotherapy (cyclophosphamide [Cytoxan], doxorubicin [Adriamycin], and cisplatin) followed by radiation. Patients were entered in this trial if they had disease confined to the hemithorax or mediastinal lymph nodes. Thus, patients with N1 disease and presumed T3 disease were included and analyzed together. There was no statistically significant difference in median survival times (10.2 vs. 10.9 months) or in long-term survival for the study groups as a whole. The study was flawed because of the inclusion of patients with different disease stages, a lack of histologic documentation of the stage of disease, and the use of a smaller than usual dose of cisplatin.

The North Central Cancer Treatment Group randomized patients to radiation alone (6000 cGy) versus chemotherapy (intravenous methotrexate, intravenous doxorubicin, intravenous cyclophosphamide, and oral lomustine) followed by radiation and additional chemotherapy. Again, no difference in median survival or long-term outcome could be demonstrated between the two treatment groups. Failure to obtain a benefit from chemotherapy may be due to the absence of cisplatin from this chemotherapy regimen.

In contrast, reports of cisplatin-based regimens do indicate an advantage for combined chemotherapy and radiation.

Le Chevalier and associates randomized 353 patients to radiation alone (6500 cGy) or to cisplatin-based chemotherapy followed by radiation. One-, 2-, and 3-year survival rates all favored the combined therapy arm (51, 21, and 12 percent versus 41, 14, and 4 percent, respectively). However, using repeat biopsies, the study found only a 17 percent incidence of

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local control in the radiation arm and a 15 percent incidence of local control in the chemotherapy and radiation arm.

In a trial conducted by the Cancer and Leukemia Group B (CALGB), 155 patients were randomized to either radiation alone (6000 cGy) or a cisplatin-based regimen followed by radiation. The median survival favored the combination therapy arm (13.8 vs. 9.7 months). The results at 1 and 2 years were so striking for the combined therapy group that the study was terminated early—a decision that subsequently prompted considerable criticism. The 3- and 5-year survival rates also favored the combination therapy (25 and 19 percent) over radiation therapy alone (11 and 7 percent). However, the intrathoracic failure rate was very high. Unfortunately, the study was limited to patients with a high performance status and less than 5 percent weight loss in the 6 months before enrollment in the trial. Limiting a study to the most favorable patients begs the question of the applicability of the results to the general group of patients with locally advanced lung cancer, many of whom have a decrease in their performance status and have lost considerable weight.

A study seeking to confirm the CALGB report was initiated by the RTOG, which randomized patients to the same two arms, in addition to a third arm using hyperfractionation radiation (69.6 cGy twice daily) as the only treatment modality. This study, RTOG-88-08, demonstrated that chemotherapy combined with radiation was indeed superior in the patients with good performance status (i.e., loss of weight of less than 5 percent in the previous 3 months). Analysis at 1 year showed the median survival to be statistically longer for those in the combined chemotherapy and radiation arm.

At 3 years’ follow-up, however, no difference in survival (14 percent) was found between the chemotherapy and radiation arm and the hyperfractionated arm. Both of these treatment regimens were better than standard radiation alone.

Concurrent Chemotherapy and Radiation Therapy The rationale for concurrent therapy (i.e., chemotherapy given during a course of radiation therapy) is based on the concept that some drugs or drug combinations (notably cisplatin) may act synergistically with radiation. The trade-off, however, is an increase in toxicity and a regimen that is not well tolerated by all potentially eligible patients.

Several studies have tested the concept of concurrent therapy by combining frequent dosing of cisplatin with radiation. One such study, conducted by the European Organization for Research and Treatment of Cancer (EORTC), randomized 331 patients to radiation alone or to radiation with cisplatin given on either a daily or weekly schedule. At 2 years, 26 percent of patients treated with concurrent radiation and daily cisplatin were alive, in contrast to only 13 percent survival in the group receiving radiation alone. When given on a weekly basis with radiation, the cisplatin did not confer any advantage over radiation alone. In contrast, several older studies have failed to demonstrate an advantage for concurrent therapy in locally advanced disease (Table 105

Treatment of NSCLC: Chemotherapy

II-2). It seems though, that the greatest advantage with concurrent chemotherapy and radiation therapy is seen at the 2and 3-year marks.

Currently, with more experience with combined modality therapy, concurrent platinum chemotherapy and radiation therapy is the treatment of choice for patients with locally advanced, inoperable disease, provided their performance status and co-morbidities do not limit their ability to withstand the toxicities associated with this approach. This is based on data using platinum based chemotherapy regimens in conjunction with radiation. The RTOG conducted a three-arm trial (9410) in which 610 patients with unresectable NSCLC were randomized to sequential chemotherapy (cisplatin/vinblastine) followed by conventional RT, concurrent chemoradiotherapy with the same regimen, and concurrent chemotherapy with hyperfractionated RT. Median and 4-year survival were improved in the concurrent chemoradiotherapy arm with conventional RT, compared to sequential therapy and concurrent therapy with hyperfractionated RT (14.6, 17, 15.2 months, and 12, 21, 17%, respectively). Based on small phase II trials conducted by the Southwest Oncology Group (SWOG), a favored regimen for concurrent therapy utilizes cisplatin (day 1, 8, 29, 36) and etoposide (days 1–5, 29–33) with conventional RT. In one of these trials, this was followed by two cycles of consolidation cisplatin and etoposide with results of a median survival of 15 months and a 5-year survival of 15 percent. A subsequent trial used the same combined treatment regimen, but then used docetaxel for consolidation. This yielded a median survival of 26 months and a 3year survival of 37 percent. However, a recent randomized study in which patients received cisplatin, etopiside, and radiation, either with or without consolidation docetaxel, failed to show a benefit from consolidation treatment. This is the first and only study of consolidation therapy after concurrent therapy and radiation. Another favored regimen utilizes low dose carboplatin and paclitaxel with radiation, followed by consolidation therapy with the same agents, resulting a median survival of 16 months, but again, this has only been studied in non-comparative phase II studies. As is described, it is unclear how combined chemoradiotherapy compares to induction chemotherapy followed by surgery or chemoradiotherapy followed by surgery. At the present time, this is a matter of institutional preference as well as based on the characteristics of individual patients.

Chemotherapy Followed by Surgery Neoadjuvant therapy, also referred to as induction therapy, has been applied to the treatment of NSCLC as well as to treatment of many other solid tumors. It entails treating patients with chemotherapy even though there is no clinical evidence that the primary cancer has spread. Lung cancers are particularly attractive targets for neoadjuvant therapy because even though many present as locally advanced disease confined to the chest, patients run a considerable risk of developing distant disease within a short time. Neoadjuvant therapy affords a unique opportunity to assess the sensitivity of the cancer

1874 Part XV

Neoplasms of the Lungs

Table 105 II-2 Randomized Trials in Stage III Disease: Radiation Alone vs. Radiation and Chemotherapy Number of Patients

Median Survival Therapy

Survival

1 Yr

2 Yr

3 Yr

Reference

155

RT RT/CT

9.6 13.8

40 55

13 26

11 23

Dillman RO, Seagren SL, et al., 1990

353

RT RT/CT

10 12

41 51

14 21

4 12

Le Chevalier T, Arriagada R, et al., 1991.

238

RT

10.2 RT/CT

41 10.9

17 42

19

46 54 44

13 26 19

2 16 13

331

RT RT/CT

95

RT RT/CT

11 16

240

RT RT/CT

46 43

Mattson K, Holsti, L.R., et al., 1988 Schaake-Koning C, van den Bogaert W, et al., 1992.

Soresi E, Clerici M, et al., 1988

45 43

to the drug regimen. This information may be useful in the postoperative period when the possibility of adjuvant therapy is under consideration. Moreover, preoperative neoadjuvant therapy may render resectable a tumor that would otherwise be regarded as unresectable. Another consideration is that the required dose-intensive regimens are apt to be tolerated better before than after surgery. Finally, neoadjuvant therapy may allow for improved drug delivery to the preserved vasculature of the tumor, and thus decrease the prospect of developing drug resistance. However, the possibility exists that delaying surgery may be disadvantageous. In patients with locally advanced disease who are at high risk for developing disseminated disease, the delay imposed by the administration of chemotherapy provides an additional period of observation during which a nonresponder may manifest distant disease, thereby precluding surgery.

There have been two phase III randomized trials of neoadjuvant chemotherapy in patients with locally advanced lung cancer (stage IIIA). Some patients had N2 disease alone; while others had T3N0 disease. In contrast to results in patients with disseminated NSCLC in whom the response to chemotherapy at best approaches 30 percent, 60 to 70 percent of patients with locally advanced disease responded favorably.

Also, in both trials, the median survival was improved in the group of patients who received neoadjuvant treatment. The explanation for this difference in responsive may be the better overall status of patients who are regarded as candidates

13 18

2 5

Blanke C, Ansari R, et al., 1995

for surgery and the smaller tumor burden that these patients bear. Alternatively, qualities inherent in the primary tumor that differ from those in tumor that has metastasized may contribute to a better response to chemotherapy. Currently, there is no way of assessing the response of micrometastatic disease other than the disease-free interval after resection and survival.

Another experience with neoadjuvant chemotherapy for NSCLC was reported from the Memorial Sloan-Kettering Cancer Center. The study was prospective but nonrandomized. It included 41 patients with â&#x20AC;&#x153;clinical N2â&#x20AC;? disease defined as bulky mediastinal adenopathy that could be seen on the conventional chest radiograph or was manifested at bronchoscopy by widening of the carina. Patients received a cisplatin-based regimen plus mitomycin. The overall response rate was 77 percent; 19 of the patients achieved a complete response that was confirmed by histologic examination. Seventy-five percent of patients were able to undergo resection, even though resectability based on previous experience would have been anticipated to be about 10 percent. It must be emphasized that these patients had bulky mediastinal lymph node disease, not lymph nodes that appeared grossly normal but in whom disease was subsequently detected. The authors concluded that the results obtained paralleled those noted in neoadjuvant studies with other solid tumors in that response rates to chemotherapy were high, and complete resection rates were high after response to chemotherapy. They

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identified response to chemotherapy as a significant prognostic indicator for survival; complete response was associated with prolonged survival.

Chemotherapy and Radiation Followed

by Surgery Various theoretical considerations have led to trials of chemotherapy and radiation followed by surgery (trimodality therapy): (1) tumor cell subpopulations in locally advanced NSCLC may respond differently to radiation and chemotherapy, and cells resistant to one treatment method may be sensitive to the other; (2) chemotherapy may promote the emergence of radiosensitive cells, thereby increasing the total number of cells killed by continued radiation treatments; and (3) induction of cell cycle synchronization by certain drugs may increase cell killing by radiation and induce recruitment of tumor cells in G0 .

The Southwest Oncology Group conducted a trial (8805) using the cisplatin/etoposide regimen that they had developed with concurrent radiotherapy; the trial included both stage IIIA and IIIB patients. All 126 patients underwent mediastinoscopy for histologic evaluation of mediastinal lymph nodes. The response rate to the preoperative therapy was 59 percent, with 29 percent having stable disease. The resection rate was 85 percent in the stage IIIA patients, and 80 percent in the stage IIIB patients. The 3-year survival was similar in both stage IIIA and IIIB patients at 27 and 24 percent, respectively.

The absence of tumor in the mediastinal nodes at the time of surgery was associated with improved survival. Failure was more common in distant, rather than locoregional sites, with the occurrence of brain relapses in 26 patients.

It remains to be proved that surgery is a necessary part of the treatment of these patients. The high response rate to chemoradiotherapy in the high-performance patients entered into these clinical trials raises the question of whether chemotherapy and radiation (RT) might be able to achieve a similar end point with regard to local control. A large intergroup study (0139) addressed this question. In this trial, 396 patients with stage IIIA, pathologic N2 disease were randomized to either concurrent chemotherapy with cisplatin/etoposide and RT to 4500 cGY followed by surgery or the same chemotherapy regimen with RT to higher doses of 6100 cGy. The patients who were randomized to surgery had a statistically significant improvement in progression free survival (12.8 vs. 10.5 months), but while there was a trend toward an improvement in overall survival in the surgery group, this was not statistically significant. Patients who seemed to do better were those who had a lobectomy rather than a pneumonectomy, as well as those who had obtained a pathologic response in the mediastinal nodes. Although there was no significant benefit in overall survival, surgery is still often offered to medically fit patients after induction chemoradiotherapy.

In summary, major issues remain concerning the sequence and number of treatment methods for locally advanced disease. Although some permutation of combined

Treatment of NSCLC: Chemotherapy

modality treatment is clearly needed in patients with locally advanced disease, we currently do not have data in the form of randomized control studies that compare the efficacy of the varying combinations of chemotherapy, radiation and surgery. In patients who can tolerate the added toxicity, combined concurrent chemoradiotherapy is more effective than sequential therapy. Although it has not been proven that surgery after induction chemoradiotherapy confers a survival benefit compared to definitive chemoradiotherapy, surgery is still a preferred approach in many institutions if patients can tolerate tri-modality treatment. As far as whether induction treatment should consist of chemotherapy alone or combined with radiation, this is an unanswered question at this time.

Future Directions The next large intergroup effort plans to determine if increasing the dose of radiation in combination with chemotherapy will decrease the rate of local failure. In order to answer this question, patients will be randomized to either 6400 cGy or 7400 cGy. Also, trials are underway to determine if prophylactic cranial irradiation after definitive treatment of a locally advanced tumor will decrease the occurrence of brain metastases. Finally, the integration of biologic molecular targeting agents into combined modality treatment of locally advanced disease will certainly be studied in the future. Currently, the CALGB is sponsoring a randomized phase II study in which patients with unresectable disease are randomized to chemoradiotherapy with or without the epidermal growth factor receptor (EGFR) targeting monoclonal antibody, cetuximab.

ADVANCED-STAGE NSCLC The goal of chemotherapy in advanced-stage disease is palliation, since with few exceptions, disseminated lung cancer, like most other solid tumors, is essentially impossible to cure.

Among the issues that have been raised with respect to the relative value of chemotherapy in patients with disseminated disease are the response rate, survival data, cost-effectiveness, and the quality of life.

Prognostic criteria play an important role in analyzing and constructing clinical trials. For example, patients with a poor performance status (spending more than 50 percent of time in bed, significant weight loss) are much less likely to respond to chemotherapy than those with a better performance status. Especially in patients with a poor prognosis, it is important to assess the effect of treatment-related toxicity on overall quality of life and the cost effectiveness of therapy.

Several of the older studies that randomized patients with disseminated disease to receive either best supportive care or systemic chemotherapy had mixed results. In addition,

1876 Part XV

Neoplasms of the Lungs

several meta-analyses have reviewed studies that randomized patients to best supportive care or chemotherapy. One of these meta-analyses that did detect a significant benefit in survival from chemotherapy reviewed 52 randomized trials comparing chemotherapy with best supportive care. There was a 10 percent absolute improvement in survival in 1 year, and a median survival improvement of 2 months. Another more recent review indicated a similar benefit. These data can be used to make the case for or against systemic chemotherapy (i.e., that the patients did live longer when treated or that the 2 to 3 additional months of survival had little biologic significance).

An issue of great concern in this setting is the balance between obtaining a survival benefit with palliation of cancer related symptoms and the toxicity associated with systemic chemotherapy. Most of the studies have included only the higher performance status patients—which calls into question the general applicability of the results. Whether to treat a patient with disseminated disease using chemotherapy or to treat symptoms as they arise often comes down to the judgment of the medical oncologist balanced against the wishes of the patient. Patients with a poor performance status can be expected to have a worse response to chemotherapy than those with relatively good performance status; therefore, they are often not offered chemotherapy.

First-Line Chemotherapy For patients of adequate performance status, the standard first-line chemotherapy recommendations currently consist of a platinum or non-platinum–based doublet. Numerous randomized studies have been conducted that compare the benefits of single agent versus doublet regimens. A metaanalysis that reviewed 65 of these trials found a significant benefit in response and median survival with a cytotoxic doublet. There was no survival benefit with the addition of a third cytotoxic agent at the time of this analysis. Although there are several cisplatin or carboplatin backbone doublets to consider, carboplatin tends to be favored in the palliative setting due to its better toxicity profile. A large study that was conducted by ECOG randomized 1207 patients with advanced disease to either cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, or carboplatin/paclitaxel. The median survival among all four treatment groups was 7.9 months, with a 1-year survival of 33 percent and a 2-year survival of 11 percent. There was no clear survival benefit with any one regimen compared with the others. Those with an ECOG performance status of 2 tended to do worse. Carboplatin/paclitaxel did seem to have a slightly better toxicity profile. Hence, this is a common regimen in use, but the other doublets are acceptable as well.

Two randomized phase III studies have addressed the use of non-platinum–based regimens in first line treatment.

The first, by Kosmidis et al., randomized patients to paclitaxel and gemcitabine versus paclitaxel and carboplatin.

The study showed similar efficacy with respect to median survival, 1-year survival and response rate. Both regimens

were well tolerated. The largest study to address the role of non-platinum doublets randomly allocated 929 patients to carboplatin/paclitaxel (CP), carboplatin/gemcitabine (CG), or gemcitabine/paclitaxel (GP). Again, the results indicated similar efficacy in all three arms. There were differences in toxicities in that anemia and thrombocytopenia were more common in the CG arm, although peripheral neuropathy and alopecia were more common in the paclitaxel containing groups. For chemotherapy na¨ıve patients, treatment choices tend to be heavily dependent on a patient’s co-morbidities and the toxicity profile of each regimen.

The issue of how to treat the elderly and those with a poor performance status is an issue of ongoing debate. There are data to suggest that single agent chemotherapy, such as vinorelbine or docetaxel, does palliate symptoms and result in a modest survival benefit. However, there are situations when it is reasonable to defer chemotherapy.

Anti-angiogenesis Therapy The generation of new vasculature from existing vessels has an important role in tumor pathogenesis. Tumor growth beyond a certain size depends on the development of new blood vessels at the growing edge, a process that depends on the vascular endothelial growth factor receptors (VEGFR1/2) and the ligand vascular endothelial growth factor (VEGF).

Anti-angiogenic agents are thought to inhibit tumor growth by several mechanisms: (1) blocking the formation of new blood vessels needed to sustain growth; (2) blocking tumor metastasis; and (3) enhancing drug delivery to tumors by normalizing tumor blood flow and reducing tumor interstitial pressure.

Bevacizumab is a monoclonal antibody that targets VEGF. It has demonstrated efficacy in the treatment of colorectal cancer, among others. In a pivotal trial conducted by ECOG, 878 patients with stage IIIB or IV NSCLC were randomized to carboplatin/paclitaxel or carboplatin/paclitaxel/ bevacizumab in the first-line setting. In the group that was randomized to bevacizumab (BV), after the chemotherapy had been completed, the BV was continued until progression.

Given the risk of potentially fatal bleeding that has been noted with this agent, patients with brain metastases, a history of hemoptysis, on therapeutic anticoagulation, and with squamous cell tumors were excluded from this trial. Also, given the known toxicities of hypertension and thromboembolic events with BV, those with uncontrolled hypertension and active cardiovascular disease were also excluded. There was a 2-month improvement in median survival with the addition of BV (12.3 vs. 10.3 months), which was statistically significant. Although this is a modest benefit, this trial did generate excitement in that a biologically targeting agent yielded a statistically significant survival benefit in this disease. Despite the entry criteria, there were 15 treatment related deaths in the chemotherapy plus BV group, with 5 being from pulmonary hemorrhage. Thus, it is important to consider the risks of this agent in determining if a patient is eligible for BV therapy.

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Treatment of NSCLC: Chemotherapy

Table 105 II-3 Advanced NSCLC Second-Line Randomized Trials Number of Patients

Therapy

104

D BSC

373

Median Survival

1 Yr

Reference

7.5 4.6

37 11

Shepherd FA, Dancey J, et al., 2000

D 75 I/V

5.6 5.6

32 19

Fossella FV, De Vore R, et al., 2000

571

D Pem

10.2 8.3

30 30

Hanna N, Shepherd FA, et al., 2004

731

Placebo E

4.7 6.7

Shepherd FA, Rodrigues Pereira J, et al., 2005

D = docetaxel; E = erlotinib; I = Ifosfamide; Pem = pemetrexed; V = vinorelbine.

Second-Line Therapy Ultimately, patients with advanced disease will progress after receiving first-line therapy. There are several options to consider in the second-line setting. Docetaxel was one of the first agents approved for this indication. In the first trial of interest, 104 previously treated patients were randomized to docetaxel every 3 weeks at 100 mg/m2 , 75 mg/m2 or to supportive care. Docetaxel therapy resulted in an improvement in median survival (7.5 vs. 4.6 months) and 1-year survival (37 vs. 11 percent). The lower dose of docetaxel was better tolerated. In another study, 373 patients who progressed after platinum therapy were randomized to docetaxel at one of two schedules, ifosfamide or vinorelbine. Treatment with docetaxel at 75 mg/m2 was associated with a higher response rate as well as an improvement in 1-year survival. Interestingly, there was no difference in overall survival between the four groups (Table 105 II-3).

Pemetrexed, an antifolate, is a relatively new addition to the available agents in the second line setting. In the phase III registration trial, 571 patients were randomized to docetaxel or pemetrexed. The survival data was similar in each arm with a median survival of 8.3 and 7.9 months for pemetrexed and docetaxel, respectively. The 1-year survival was 29.7 percent in both groups. Although the survival data with pemetrexed were not improved compared to docetaxel, it was better tolerated with a significant decrease in the incidence of grade 3 or 4 neutropenia and febrile neutropenic events.

EGFR Inhibitor Therapy Another biological target of considerable interest is the epidermal growth factor receptor (EGFR). The EGFR is a transmembrane tyrosine kinase receptor with an extracellular, transmembrane and intracellular domain. Following ligand

binding, the EGFR is activated by either homodimerization with another EGFR, or via heterodimerization with another member of this type 1 receptor tyrosine kinase (RTK) family.

EGFR stimulation results in activation of signal transduction pathways for PI3-Akt and Ras-Raf-MEK-MAPK. There are several EGFR inhibiting agents in varying stages of development. To date, the small molecule agents, such as gefitinib (Iressa) and erlotinib (Tarceva), have played a greater role in the treatment of NSCLC than the EGFR targeting antibodies. Gefitinib initially obtained provisional FDA approval based on encouraging results from a phase II study. However, when it was studied in the larger phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial, in which 1692 patients were randomized to gefitinib versus placebo, the results were negative with no detected survival benefit. In subset analyses, patients who never smoked and were of Asian origin seemed to have a greater benefit to therapy. There are several theories as to why this trial was negative.

For one, it is possible that a subtherapeutic dose of gefitinib was used. Also, this was a large study with a heterogeneous population and did not enrich its entry criteria to include the subsets of patients who may benefit from this type of treatment. Subsequent analyses of tumor samples from this trial indicate that high EGFR gene copy number, increased EGFR expression, and EGFR mutations are related to higher response rates. Although Asian patients seemed to respond in the original study, a recent trial in Japan in which patients were randomized to gefitinib or docetaxel failed to show a benefit with gefitinib.

As data to support the use of gefitinib in NSCLC were diminishing, erlotinib emerged as the small molecule tyrosine kinase inhibitor of EGFR of choice. In a large multicenter trial, 731 patients with stage IIIB or IV disease who were previously treated with first or second-line therapy were randomized to

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either erlotinib or placebo, in a 2:1 randomization favoring erlotinib. Patients with an ECOG performance status of 0, 1, 2, and 3 were eligible. The response rate to erlotinib was 8.9 percent, with an overall survival of 6.7 versus 4.7 months in the placebo arm. In addition, there was an improvement in cancer-related symptoms in patients who received erlotinib.

This was a significant survival benefit, and based on this study, erlotinib obtained FDA approval in the second-line setting. A small percentage of patients required dose reductions or were taken off of therapy due to drug-related toxicity. Although overall erlotinib is well tolerated, it can cause a characteristic rash, which seems to be a class effect. Other side effects are diarrhea and a low risk of pneumonitis. In a subset analysis of this study, patients who had an increased likelihood of a response included those who were never smokers, of Asian origin, female, or who had the adenocarcinoma histology.

This is a consistent finding with this class of agents. Currently, the small benefit seen with EGFR inhibitors is limited to their use as a single agent. Several trials in which either gefitinib or erlotinib were combined with platinum-based chemotherapy have all been negative, with no improvement in survival.

Although data are emerging that EGFR copy number and expression levels can predict for a response to erlotinib, currently these are not tested routinely in the clinical setting.

Similarly, in analyzing tumors from patients who have had a remarkable response to EGFR inhibitors, investigators have detected the presence of EGFR somatic mutations. The more common ones characterized are in exon 19 or 21, but there are likely others as well. These mutations may be involved in the pathogenesis of lung cancer in never-smokers, and can predict for sensitivity for EGFR inhibitor therapy. Again, assays for mutations are still in the realm of research and are not routine clinical tests.

Future Directions The integration of agents that target signal transduction and other biologically relevant pathways are beginning to make an impact in the care of patients and in the design of future trials for NSCLC. Although responses and survival benefits are currently modest, one avenue of research is to combine multiple agents with nonoverlapping mechanisms of action and toxicity profiles to have obtain a greater clinical benefit. Also, the early investigations of multikinase targeting small molecule agents, such as sorafenib, sunitinib, and ZD6474 indicate that these agents may have activity in NSCLC. There are also currently trials underway to study the safety and effectiveness of bevacizumab in patients with treated brain metastases, and squamous cell cancers that have already initiated treatment with the hope that this would serve to reduce the risk of bleeding in these patients. Finally, now that the number of biologic agents in development is increasing at a faster pace, future research will focus heavily on learning more about patterns of resistance and determining which biomarkers will predict for responsiveness to each agent and regimen.

CONCLUSION Chemotherapy has an established role in the adjuvant therapy of stage II and IIIA NSCLC. Randomized clinical trial data demonstrate improved median and long-term survival when antineoplastic agents are used as part of a multimodality approach. The next step in the development of adjuvant regimens will be to add molecular targeting agents; these trials are already underway.

Response rates to chemotherapy are higher in patients with localized disease than in those with disseminated disease. Some of these differences may be related to tumor burden or overall performance status. Questions that need to be addressed in future and ongoing trials include the optimal sequence for various modalities and the best modalities for each situation in locally advanced disease.

For advanced-stage NSCLC, there is now a growing list of active agents. However, especially for heavily pretreated patients and those with a poor performance status, response rates and overall prognosis are still limited. There are data to suggest though that cytotoxic and now biologic agents can modestly increase survival and improve a patient’s quality of life. However, even in the most recent phase III trial with bevacizumab in the advanced setting, the median survival barely increased over the 1-year mark. Thus, there is still considerable room for improvement. Cost analyses will have to continue to be a matter of consideration, as the newer agents are especially expensive. However, with the development of molecular agents and the future potential to select treatment options based on genomic and protenomic profiles, there is cautious optimism that the treatment of this disease will take a new direction with more hope in the future.

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105 Part III: Treatment of Nonâ&#x20AC;&#x201C;Small-Cell Lung Cancer Radiation Therapy Mitchell Machtay

I. MANAGEMENT OF NON--SMALL-CELL LUNG CANCER Neoadjuvant Therapy Adjuvant Therapy Definitive Therapy (Locally Advanced, Nonoperative NSCLC) Palliative Therapy II. LIMITED-STAGE SMALL-CELL LUNG CARCINOMA Thoracic Radiation Prophylactic Cranial Irradiation

Most patients with lung cancer receive radiotherapy as part of their treatment, either as initial management or later in the course of their disease. This may include thoracic radiotherapy and/or irradiation of sites of metastatic disease. Thoracic radiotherapy (RT) for non-small cell lung carcinoma is usually categorized as follows: Neoadjuvant = preoperative Adjuvant = postoperative Definitive = cure without surgery as treatment goal; with or without chemotherapy Palliative = directed at relief of thoracic symptoms

There is some overlap in these categories with respect to the goals of treatment. For example, most patients treated with definitive intent are not cured but do achieve palliation of intrathoracic symptoms. Similarly, a few patients originally considered to be technically unresectable may have a dramatic response to irradiation and/or chemotherapy, and the goal of treatment may then change from palliative to neoadjuvant or

III. TOXICITY OF THORACIC RADIOTHERAPY Lungs: Acute Complications Lungs: Late Complications Esophagus Heart IV. ADVANCES IN RADIOTHERAPY Radiation Dose-Fractionation Modulation Technical Planning and Delivery of Radiation Combined Modality Therapy/Radiosensitizers V. SUMMARY

definitive intent. The size of the primary lesion, stage, and total dose of radiation are important factors in determining local control. A summary of radiotherapy for lung cancer is provided in Table 105 III-1.

Utilization of thoracic radiotherapy as part of the therapeutic regimen and the therapeutic goal of the therapy depends not only on tumor related-factors such as stage but also on patient-related factors such as pulmonary reserve and performance status. All these factors need to be considered when deciding whether to irradiate. Although radiotherapy might be appropriate for a patient with a postoperative forced expiratory volume (FEV1 ) of 2.0 l and pathologic stage T2N2M0 disease with a close margin, the same treatment would be problematic in a patient with pathologic stage T1N1 disease and a postlobectomy FEV1 of 1.1 l who has had a series of postoperative complications. Of course, such clearcut cases usually are the exception rather than the rule in clinical oncology. Table 105 III-2 lists the relative contraindications to thoracic radiation for lung cancer.

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 105 III-1 Summary of Radiotherapy for Lung Cancer: Indications and Treatment Type

Indication(s)

Dose∗

Preoperative (with chemotherapy)

Pancoast tumor; clinical N2

45–50 Gy

Postoperative

N2 disease; T4 tumors; selected T3 and/or N1 disease; Incomplete resection

50–66 Gy (depends on surg-path findings)

Definitive medically inoperable

T1-2NO-1 not surgical candidate or refuses surgery

60–74 Gy (conventional fractionation) or 40–60 Gy (accelerated hypofractionation with stereotactic techniques)

Definitive unresectable (with chemotherapy)

Selected stage III patients; performance status high

56–74 Gy

Palliative unresectable

Other stage III and IV patients with local symptoms

20–50 Gy with accelerated hypofractionation (2.5–4 Gy fraction size)

Small cell (with chemotherapy)

Limited stage with good performance status

45–55 Gy or Gy in 1.5 Gy bid fractionation

∗ (1.8–2

Gy once daily fractionation unless otherwise indicated.)

Finally, it must be remembered that the prognosis for most patients with non–small-cell lung carcinoma (NSCLC) is poor with standard therapy, and a concerted effort should be made to enter patients into clinical trials that are investigating new treatments or combinations of treatments for this disease.

Table 105 III-2 Relative Contraindications to Thoracic Radiotherapy (RT) for Lung Cancer Prior high-dose thoracic radiotherapy Connective tissue disease FEV1 < 800 cc

MANAGEMENT OF NON--SMALL-CELL LUNG CANCER Surgery, irradiation, and chemotherapy are all used in the treatment of lung cancer. Surgical resection remains the primary curative modality and may be the only treatment required in early stage disease if all the cancer is removed. The local failure rate in stage I patients after lobectomy or pneumonectomy is less than 10 percent. With such a low incidence of local failure the addition of postoperative irradiation is unnecessary if resection margins are negative. Unfortunately, most patients present with unresectable or marginally resectable disease. The addition of radiation and chemotherapy is aimed at decreasing the unacceptably high frequency of failure due to local and distant spread that occur with surgery alone. However, progress has been slow, and the overall survival of patients with locally advanced lung cancer has only risen modestly over the past 20 years.

Tracheobronchial-esophangeal fistula Projected RT fields to include >35% of normal lung volume (i.e., >40% of normal lung volume is projected by 3-D treatment plan to receive > 20 Gy).

Projected RT fields to include >50% of heart volume Patient expected to be noncompliant with treatment or follow-up visits

Neoadjuvant Therapy The current use of preoperative radiotherapy in the management of NSCLC falls into two categories: (1) as part of neoadjuvant chemoradiotherapy for N2 (IIIA) disease; and (2) as part of neoadjuvant chemoradiotherapy for superior sulcus (Pancoast) tumors (T3-4NxM0). For patients who are otherwise surgical candidates but are found at mediastinoscopy to have positive mediastinal lymph nodes (N2 disease), it is not

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clear whether neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy; either is an acceptable option.

In most institutions, preoperative chemoradiotherapy is standard management for Pancoast tumors. However, based on the surgical-pathologic findings, modern imaging techniques, including magnetic resonance imaging (MRI) of the spine and brachial plexus, have made it possible for selected patients to undergo surgery first followed by adjuvant treatment.

Conceptually, it has become attractive to attempt to convert patients with bulky mediastinal nodal disease to patients with microscopic mediastinal nodal disease, thereby rendering them candidates for surgical resection. A large number of phase II clinical trials have been conducted utilizing induction chemotherapy or induction chemoradiotherapy in patients with bulky mediastinal adenopathy (“clinical” stage N2 disease). These include both single-institution studies (e.g., from Memorial Sloan-Kettering Cancer Center) and multi-institutional cooperative group studies (e.g., from the Southwest Oncology Group [SWOG]). These studies clearly show significantly improved outcomes with neoadjuvant treatment as opposed to historical controls treated with local therapy alone. Several randomized trials have confirmed a benefit to induction chemotherapy prior to surgery. It is far less clear, however, what the optimal local therapy is for these patients, despite several large and well publicized phase III randomized trials. Options include chemotherapy followed by surgery; chemoradiotherapy followed by surgery; and definitive chemoradiotherapy alone.

The median and 5-year survival rates for all of these three options appear to be similar. There is the suggestion that induction chemotherapy followed by pneumonectomy (particularly right pneumonectomy) may be excessively toxic, with some studies reporting treatment-related mortality rates above 20 percent. In contrast, induction therapy (chemotherapy or chemoradiotherapy) followed by lobectomy appears to be well tolerated, and retrospective studies show encouraging outcomes.

Chemoradiotherapy followed by thoracotomy is an intensive treatment with considerable morbidity and mortality.

Its use should be limited to patients with excellent cardiac and pulmonary reserve and a high performance status. Preferably this combination should be used in the context of a prospective clinical trial. Only patients with reasonable expectation of benefit should receive this form of aggressive management; thorough staging workups for metastatic disease (CT scans of the chest, abdomen, and brain, and bone scan) should be performed prior to the start of preoperative treatment and in the “window” period (i.e., after this therapy has been administered and before surgery). Lesions that are suspected of being distant metastases should be investigated by tissue biopsy. The radiotherapy dose should be moderate, approximately 45 to 50 Gy, with standard fractionation (1.8–2 Gy once daily). An interval of approximately 3 to 8 weeks between completion of irradiation and surgery is advised to minimize the risk of difficulties in wound healing. Bronchial stump reinforcement at the time of surgery is strongly encouraged. As noted, right

Treatment of NSCLC: Radiation Therapy

pneumonectomy after neodjuvant chemoradiotherapy has a high mortality rate and should be avoided.

Preoperative radiotherapy carries with it the potential disadvantage of limiting the ability to give additional radiotherapy if tumor proves to be unresectable or if residual disease remains after resection. After 45 Gy preoperatively, only about 30 Gy of additional irradiation can be safely administered postoperatively. Thus, it may be preferable to defer additional radiotherapy (reirradiation) unless or until there is clear evidence of local progression. Chemotherapy may be offered, although in general, the patient left with residual or unresectable disease after preoperative chemoradiotherapy has a poor chance for long-term disease-free survival.

Adjuvant Therapy The primary tumor-related factors in considering postoperative radiotherapy (PORT) are the pathologic stage and the completeness of the surgery. Based on its proven and very dramatic efficacy in decreasing the risk of local-regional recurrences, PORT is generally considered to be the standard of care for patients with resected mediastinal node-positive (N2) NSCLC. Based on the Lung Cancer Study Group Trial in patients with N2 disease, which suggested a longer relapsefree survival in this subgroup, the presence of N2 disease would seem to favor PORT. There is no role for PORT for T1-2N0 tumors completely resected by lobectomy or pneumonectomy and a dubious role for PORT for T1-2N1 tumors.

In fact, there is the suggestion of a slight detrimental effect of postoperative radiotherapy on overall survival. It is less clear whether radiotherapy should be administered after a wedge resection, although in selected patients, the high local failure rate after this procedure suggests a possible role for adjuvant radiotherapy, particularly the placement of intraoperative brachytherapy sources via a catheter-based mesh.

Phase II data suggest that the combination of wedge resection + brachytherapy results in local failure rates below 5 percent, comparable to that of lobectomy.

Whether postoperative irradiation has any impact on survival is debatable. Although many retrospective studies have shown a survival benefit to PORT, randomized trials have not. In fact, a highly publicizied meta-analysis of randomized trials of surgery alone vs. surgery + PORT showed a detrimental effect of PORT on survival. This negative effect of PORT was very strong for stage I disease and modest for stage II disease; there was no evidence of any detrimental effect of PORT in stage III disease. The reason for excess deaths in the PORT arm were not explained, though likely attributable to radiation-induced cardiopulmonary toxicity. It should be noted that the randomized trials included in the PORT meta-analysis all used radiotherapy techniques that would be considered grossly outdated by modern standards.

Future studies of PORT should foucs on stage III disease and selected stage II disease. The majority of patients with node-positive resected NSCLC probably harbor micrometastatic disease outside of the thorax and thus adjuvant

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Neoplasms of the lungs

chemotherapy is appropriate. However, the risk for potentially very morbid local-regional recurrence also exists in these patients. Further research is needed to better identify which patients are at very high risk for local-regional recurrence and thus most likely to benefit from PORT. If more effective therapy to prevent distant disease is developed, then the improvement in local control may lead to consistent significant increases in survival.

If PORT is going to be used, meticulous radiotherapy treatment planning is essential in order to minimize risks of toxicity. Radiotherapy fields should be relatively modest in size, yet include the high risk regions of the bronchial stump, ipsilateral hilum and the portion(s) of the mediastinum considered high risk for regional recurrence. If resection margins are negative and if there is no chest wall invasion, there is no reason to irradiate the “tumor bed”; doing so would only increase toxicity by irradiating that portion of remaining lung that has filled into the space left by the lobectomy. A radiation dose of 50 to 55 Gy using a standard fractionation schedule (1.8–2 Gy per day) should provide excellent local and regional control. Higher doses may be reasonable if resection margins are compromised and the patient has excellent underlying cardiopulmonary function.

Patients who undergo incomplete resection (gross residual disease) or suffer local recurrence after surgery alone have a poor prognosis, although radiation is usually used in an attempt to maximize local control. These patients should be considered to have the equivalent of locally advanced, nonoperative NSCLC and treated accordingly, potentially with definitive intent (see the following).

Definitive Therapy (Locally Advanced, Nonoperative NSCLC) Patients who do not have demonstrable distant metastases but are not candidates for surgery because of locally advanced stage and/or medical inoperability are often referred for radiation therapy, with or without chemotherapy. Patients with malignant pleural or pericardial effusions, although technically still having stage IIIB disease, should not be considered candidates for curative treatment and should be offered appropriate palliative measures, which may include surgical intervention (pericardial window or thoracoscopic sclerosis), chemotherapy, or moderate-dose palliative radiotherapy to bulky central disease. Combined chemotherapy and radiotherapy has not been well studied in patients with medically inoperable stage I disease. Definitive radiotherapy alone remains the standard treatment for these patients.

Patients with “medically inoperable” stage I NSCLC treated with radiotherapy have a significantly improved prognosis compared with locally advanced “technically unresectable” stage II/III NSCLC. This is one major argument in favor of intervention with radiotherapy prior to disease progression to stage III. Relatively small radiotherapy fields can be safely used for most patients with stage I disease, and high doses can be administered. A traditional radiotherapy course consists of 60 to 70 Gy in conventional fractionation

Figure 105 III-1 Pre-radiotherapy chest radiograph of a patient with a medically inoperable T2N0M0 non–small cell lung carcinoma of the left hilar region.

(1.8–2 Gy once daily). However, there is recent interest in more aggressive radiation fractionation schedules (which are also usually more convenient for these patients), given via high-technology radiation treatments often referred to as stereotactic radiotherapy (SRT). This may consist of three sessions of 20 Gy each (60 Gy total), a dose of radiation that is generally considered uniformly ablative of malignant cells.

A recent report suggests that SRT offers extremely high local control rates approaching those achievable with lobectomy.

However, long-term data are still pending, and at this time relatively few centers carry great expertise in this highly complex treatment.

For other nonoperable (stage IIIA and IIIB) patients, combined chemotherapy and radiation therapy is often considered an alternative to radiotherapy or supportive care alone. The most important factor to consider in selecting patients for combined modality therapy, which has considerable toxicity and a high level of patient time, commitment, and expense, is their performance status. In general, intensive chemoradiotherapy should be limited to patients whose Karnofsky scores are 70 percent or greater. Significant weight loss, defined in most cooperative group trials as greater than 5 percent, is also a relative contraindication to aggressive combined modality therapy. Although age itself is not a contraindication to combination therapy, intensive regimens should be applied cautiously in patients more than 70 years old. Of note is that in most of the trials utilizing chemoradiotherapy, the median age averaged 60 years. Although large tumor size is not a contraindication to definitive treatment, larger tumors generally result in a larger portion of normal

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Treatment of NSCLC: Radiation Therapy

Figure 105 III-2 Chest radiograph 1 month after definitive radiotherapy for the patient shown in Fig. 105 III-1.

tissue (lung, heart, and esophagus) being included in a radiotherapy portal, and the resultant high-dose irradiation may carry an unacceptable risk of complications. The location of the tumor (e.g., proximity to the heart and/or extensive involvement of the right lower lobe of the lung) and the patient’s pulmonary reserve may also influence the decision regarding definitive irradiation. Supraclavicular adenopathy (N3 disease) is not an absolute contraindication for definitive therapy, although its presence is a poor prognostic indicator.

In recent years, there has been increasingly strong evidence that concurrent chemoradiotherapy is better than sequential induction chemotherapy followed by radiotherapy.

A sizeable number of randomized trials have addressed this topic, and most show a clear benefit in local-regional control, median survival, and 2- and 3-year survival in favor of concurrent therapy. Long-term toxicity rates appear similar between sequential versus concurrent chemoradiotherapy; however acute toxicity (especially esophagitis) is markedly increased with concurrent therapy. The conventional dose fractionation schedule used for definitive irradiation is 60 to 66 Gy in standard fractionation (1.8–2 Gy once daily). The maximum tolerated dose of irradiation is probably higher than that for small to medium-sized tumors in which the amount of normal tissue in the field is low. Several institutional and cooperative group prospective phase I/II studies suggest that in combination with concurrent chemotherapy, the highest “safe” dose of thoracic radiotherapy is 74 Gy. A randomized trial comparing 60 Gy vs. 74 Gy is under development.

For many years, the fields to be treated in the definitive therapy of NSCLC have followed the Halsted principle

Figure 105 III-3 Simulation (radiation planning) film for ‘‘radical en bloc” radiotherapy for a patient with T4N2M0 non–small-cell lung carcinoma of the right hilar region. The actual area being irradiated is inside the yellow boundaries. All other areas are shielded via primary collimation, secondary multileaf collimation and/or lead alloy blocks.

Figure 105 III-4 Radiotherapy simulation film (highly magnified, compared with Fig. 105 III-3) for the patient with medically inoperable NSCLC shown in Figs. 105 III-1 and 105 III-2. The area being irradiated is inside the yellow boundaries. CT-assisted radiation dosimetry revealed the amount of normal lung tissue in the treated field to be under 15 percent.

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of “radical en bloc” loco-regional therapy. The typical radiotherapy field, encompassed the primary tumor (with approximately 2-cm margin), both the ipsilateral and contralateral hila, and the entire mediastinum from the thoracic inlet to a point at least 5 cm below the carina. Elective supraclavicular nodal irradiation was also typically used for upper lobe cancers. This usually results in a field size measuring approximately 16 by 20 cm, which incidentally irradiates a large amount of normal tissue. With this technique, it has been estimated that greater than 30 percent of a patient’s normal lung tissue is exposed to a dose of irradiation expected to cause permanent fibrosis and nonfunction.

Because of these issues, in recent years, there has been a trend toward smaller field size in definitive radiotherapy, encompassing gross disease with an appropriate margin and fewer areas of “prophylactic” nodal stations. This evolution has been accelerated by improvements in pre-radiotherapy imaging (e.g., PET scan–based treatment planning) and the addition of chemotherapy to control microscopic disease. The use of smaller field sizes does appear to make radiotherapy better tolerated and offers the possibility for higher doses of radiotherapy in combination with chemotherapy. A concern about local failure just outside of the irradiated volume (also known as “marginal miss”) with these newer techniques exists; however, the risk of this kind of failure appears to be relatively low compared with central local or distant failure.

Most studies show that the risk for a marginal miss recurrence is between 5 and 10 percent, compared with 30 to 60 percent risk for central local recurrence and/or distant metastases.

Through advances in chemoradiotherapy over the past 20 years, there have been improvements in the prognosis for locally advanced, unresectable NSCLC, as reviewed in Table 105 III-3. With supportive care alone (i.e., antibiotics, expectorants, oxygen, etc.) it has been shown that only about

5 percent of patients are alive at 2 years, with an expected survival less than 6 months. Single agent radiotherapy improves the median survival to about 9 months, with approximately 20 percent 2-year survivors. Sequential induction chemotherapy followed by radiotherapy further improves these values to approximately 14 months and 33 percent, whereas concurrent chemoradiotherapy increases these values to 17 months and 40 percent. Several phase II studies incorporating newer chemotherapy agents/schedules with modern radiotherapy have reported median survivals of about 2 years, with approximately 20 percent chance for 5-year survival. Clearly a portion of these gains are related to patients selection and stage migration, particularly with the widespread use of PET scan–based staging.

Improvements in supportive care are also likely valuable contributors. However, the improvements in the prognosis for stage III nonoperative NSCLC are well documented by large, prospective randomized trials and should be considered valid. It must be stressed that the trials in which the outcomes were positive involved patients with good performance status, absence of malignant effusion(s), and minimal weight loss.

Not all patients with presumed unresectable disease would benefit from highly aggressive concurrent chemoradiotherapy.

Current and future research consists primarily of optimizing radiation techniques and integrating new molecularly targeted therapies into the treatment of locally advanced NSCLC. As noted, there has been a paradigm shift away from large-field/medium-dose radiotherapy toward smallfield/high-dose radiotherapy. This will hopefully continue to improve the therapeutic ratio of radiotherapy while making it more feasible to introduce new agents with less worry about excessive overlapping toxicities. Preclinical data suggest a benefit from combining radiotherapy with agents that target

Table 105 III-3 Review of Relative Efficacy of Various Treatments for Locally Advanced Nonoperative but Non-metastatic Non–Small-Cell Lung Carcinoma Treatment

Approximate Local Response Rate (%)

Approximate Median Survival (mo)

RT alone—40 Gy

45

8

8

RT alone—50–60 Gy

60

9

10

RT alone—70 Gy

70

11

15

Sequential chemo followed

by RT (60 Gy)

70

14

25

Concurrent Chemo–RT (60 Gy)

80

17

35

Adapted from data from multiple prospective trials of the Radiation Therapy Oncology Group (RTOG) and other clinical trials.

Approximate 3-Y Survival Rate (%)

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signal transduction and/or angiogenesis pathways. Clinically, while this approach has been validated in some extrathoracic tumor sites (e.g., head and neck cancer), it is still investigational in lung cancer.

Palliative Therapy The goal of treatment in patients with advanced malignancies is to preserve the quality of life. This may require intervention with a potentially morbid treatment in order to relieve the patient of an unpleasant complication of the disease.

Palliative radiation therapy is most often used in situations in which the patient’s quality of life is, or could be, substantially compromised. Situations in which treatment is commonly applied include locally advanced disease with hemoptysis, dyspnea, or obstructive pneumonia and metastatic disease.

Although response rates to chemotherapy have improved, radiotherapy remains the mainstay of palliative therapy for distressing local symptoms of lung cancer. The selection of patients for palliative radiotherapy is often more difficult than is the selection for adjuvant or definitive treatment, since the goals may be less well defined. The presence of a large lung cancer in and of itself is not an indication for palliative radiotherapy, particularly when a patient has been shown to have distant metastases with minimal, or no, local symptoms. Fairly clear situations that call for palliative thoracic radiotherapy include the superior vena caval syndrome, hemoptysis, and significant pain.

Cough, often due to partial bronchial obstruction, is frequently palliated by radiotherapy. Atelectasis is rarely reversed by radiotherapy, although consideration should be given to irradiation in order to prevent refractory postobstructive atelectasis and pneumonia when impending obstruction of a mainstem or lobar bronchus is identified by bronchoscopy. A summary of the response rate (partial relief) of symptoms is shown in Table 105 III-4.

The palliative role of external irradiation in endobronchial disease has been evaluated in patients with inoperable NSCLC. Hemoptysis was relieved in 76 percent of patients, obstructive pneumonia in 59 percent, cough in 55 percent, chest pain in 50 percent, and dyspnea in 37 percent. Significant toxicity occurred in less than 6 percent of patients; radiation pneumonitis was the most common adverse reaction.

Palliative radiotherapy generally involves lower total doses and smaller fields than does definitive radiotherapy.

Larger daily fraction size is used (2.5–4 Gy once daily) in the attempt to achieve relatively rapid palliation and minimize the number of trips to the radiotherapy department. In addition, late radiotherapy complications (which are related to larger fraction size) are less relevant in this patient population. There is no standard palliation regimen, and treatments have ranged from a single fraction of 10 Gy (a very popular European regimen) to a full course of 60 Gy in standard 2 Gy once daily fractions. A typical compromise palliative radiotherapy schema in the United States is to deliver 3 Gy times 10 fractions (30 Gy total), which may be followed by a second

Treatment of NSCLC: Radiation Therapy

Table 105 III-4 Response Rate to Palliative Radiotherapy (RT) Symptom

Response Rate (%)

Atelectasis

20

Cough

35–65

Dyspnea

35–50

Hemoptysis

75–85

Pain

50–75

SVC syndrome

60–80

Weight loss/anorexia

30–50

Vocal cord paralysis Overall symptomatic response

5 60–75

SVC = superior vena cava.

similar course of treatment, either after a 1- to 2-week break or later, at the time of further local progression.

After full-course external beam irradiation, patients commonly develop symptoms associated with recurrent disease. In this situation, additional external radiotherapy may not be possible. If the primary cause of the distressing symptom(s) is endobronchial disease, the patient may be a candidate for endobronchial irradiation. This treatment can be given over a short period of time and because of its highly localized nature, it rarely causes radiation esophagits or pneumonitis. Endobronchial irradiation typically uses an Iridium-192 source, with a depth penetration that is superior to current laser or photodynamic treatments. However, it does carry the risk of massive hemoptysis (presumably the result of tumor lysis with bronchovascular fistula); this risk is between 5 and 10 percent.

Finally, radiotherapy plays an important role in the palliation of metastatic sites, including brain and bone metastases. Whole-brain irradiation, to a dose of 30 Gy in 10 fractions, is appropriate therapy for multiple brain metastases. In addition to palliating neurologic symptoms in many patients, it marginally improves survival compared with steroids alone.

In addition, patients with solitary brain metastases appear to benefit from a combination of whole-brain irradiation plus either surgical resection or stereotactic radiosurgery boost.

For bony metastases, most patients achieve at least partial pain relief from a typical palliative dose of 30 Gy in 10 fractions. The appearance caused by disfiguring metastases to the skin, subcutaneous tissues, and/or lymph nodes can be

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improved by similar modest dosages of irradiation. Occasionally, pain from adrenal metastases can be palliated with radiotherapy in patients in whom the radiotherapy field would not include an excessive amount of liver, kidney, or bowel.

LIMITED-STAGE SMALL-CELL LUNG CARCINOMA Thoracic Radiation It is now generally accepted, based on the results of two metaanalyses, that combined chemotherapy and thoracic radiotherapy is superior to chemotherapy alone in the treatment of limited-stage small-cell lung carcinoma. However, the best way to combine these treatments remains controversial. Concurrent chemoradiation at the start of therapy appears to be superior to â&#x20AC;&#x153;consolidativeâ&#x20AC;? radiotherapy at the end of all chemotherapy, although this comes at the expense of increased toxicity. A possible advantage of delayed radiotherapy is that chemotherapy usually shrinks bulky hilar/mediastinal tumor, allowing smaller and potentially less toxic radiotherapy portals to be used.

In general, for patients with high performance status and good cardiopulmonary function, concurrent chemoradiotherapy (with etoposide and cisplatin) at the start of treatment represents the standard of care in the United States at this time. Although low doses of radiotherapy (less than 40 Gy) appear to be less effective in local control, it is unclear whether increasing the dose above 45 to 50 Gy improves outcome. Radiotherapy fractionation appears to be more important in small cell lung cancer than in NSCLC; a large randomized trial showed that 1.5 Gy bid (to 45 Gy total) was superior to 1.8 Gy qd (also to 45 Gy total). Both local control and overall survival were improved with bid radiotherapy, although esophageal toxicity was significantly increased. The increased toxicity of bid radiotherapy, as well as its inconvenience to patients, has limited its widespread acceptance and alternative radiotherapy fractionation schedules are under study. For example, an RTOG trial showed that a new regimen of 61.2 Gy over 5 weeks had an 18-month survival rate of 82 percent.

Prophylactic Cranial Irradiation The role of prophylactic cranial irradiation (PCI) remains controversial. Its use should be considered only for patients thought to be in complete remission after chemoradiotherapy. PCI dramatically reduces the risk of brain metastases and offers a modest but real improvement in survival (approximately 5 percent absolute gain). The primary argument against the use of PCI is the high incidence of neurocognitive deficits in long-term survivors after PCI. These deficits may range from subtle abnormalities that are demonstrable only by sophisticated neuropsychologic testing and/or highresolution imaging all the way up to progressive dementia.

Many studies critical of PCI have included patients who received relatively high doses of PCI and/or received PCI with

concurrent chemotherapy. Moreover, recent neurocognitive studies of patients with newly diagnosed small cell lung cancer have shown deficits before any treatment was administered, suggesting that at least some of the problem with neurocognitive deficits is due to a paraneoplastic syndrome.

When given, PCI should be delivered at least 2 to 3 weeks after all chemotherapy has been completed. In order to minimize the risk and severity of late sequelae, a whole-brain dose of 2.5 Gy in 10 fractions (25 Gy) or 2 Gy in 15 fractions (30 Gy) is recommended. Aside from alopecia and fatigue, acute toxicity from this treatment is minimal. Steroids are not usually needed for PCI (in contrast to their use when treating brain metastases). If steroids are required, however, extreme care must be taken in tapering them, since rebound radiation pneumonitis may develop (from the patientâ&#x20AC;&#x2122;s prior thoracic radiotherapy).

TOXICITY OF THORACIC RADIOTHERAPY Toxicity from radiotherapy occurs both as acute side effects, generally defined as those occurring during or within 90 days after the completion of a course of irradiation, and late effects, which do not develop until at least 90 days after the completion of irradiation. Although some of the same factors that predict acute effects also increase the likelihood of late effects, the acute effects themselves do not necessarily lead to the late, long-term complications. In general, most injuries from irradiation are a consequence of localized damage to tissue within the irradiated portal. However, some effects are more generalized (e.g., fatigue, immunosuppression, and the rare complication of diffuse adult respiratory distress syndrome [ARDS]). The grade of radiation toxicity is generally reported on a 1 to 5 scale, with grade 1 toxicity representing mild effects (e.g., dyspnea on exertion) and grade 5 representing fatal toxicity.

In the treatment of thoracic malignancies, where high irradiation doses and large fields are often used, the organs of greatest concern for both acute and late complications are the lung, esophagus, and heart. Significant dermatologic toxicity has been virtually eliminated by the use of megavoltage equipment. Likewise, with modern treatment planning techniques, spinal cord complications should be extremely rare. Other structures at risk for injury by thoracic irradiation include the brachial plexus, the tracheobronchial tree, the great vessels, the ribs, and the sternum. Although many complications of thoracic irradiation are manageable, the most important prospect is prevention through sophisticated treatment planning and appropriate selection of patients for treatment.

Lungs: Acute Complications Radiation pneumonitis and pulmonary fibrosis are the most common serious complications of thoracic irradiation. Radiation pneumonitis represents acute/subacute lung injury. It

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Treatment of NSCLC: Radiation Therapy

Figure 105 III-5 Preradiotherapy chest radiograph of a patient with limited-stage small cell carcinoma of the right lower lobe.

usually occurs from 1 to 4 months after irradiation, although it may occur during a course of particularly intensive radiotherapy, often when combined with chemotherapy. Dyspnea is the most characteristic symptom, although cough, lowgrade fever, and pleuritic chest pain often are also present (Figs. 105 III-5 to 105 III-7).

Although infiltrates outside of the radiation portal do not completely rule out radiation pneumonitis, they make the diagnosis less likely. Regardless of the radiographic appearance, community-acquired pneumonia and opportunistic infections as well as progressive malignancy can mimic radiation pneumonitis. Therefore, appropriate testing and

Figure 105 III-6 Chest radiograph 1 month after definitive radiotherapy and chemotherapy for the patient shown in Fig. 105 III-5.

Figure 105 III-7 Chest radiograph 4 months after completion of radiotherapy for the patient shown in Figs. 105 III-5 and 110 III6. He presented with severe dyspnea on exertion. Radiographic infiltrates conform to the shape of his radiation portal. He responded promptly to steroids but soon developed fatal brain metastases.

consultation with the patientâ&#x20AC;&#x2122;s radiation oncologist are indicated before empiric corticosteroids are begun. Mild cases should be treated supportively, reserving steroids for more severe symptoms. For severe radiation pneumonitis, prednisone 20 mg, three times per day, for approximately 2 weeks is used; tapering is done slowly (i.e., during the subsequent 2 to 4 weeks). Whether antibiotics should be used in addition to corticosteroids is controversial.

The incidence of serious (greater than or equal to grade 3) radiation pneumonitis ranges from 5 to 15 percent, and the risk depends on several variables. The most important factor appears to be the amount of normal lung tissue irradiated (see Advances in Radiation Therapy: Technical Planning and Delivery of Radiation). The total radiotherapy dose prescribed for the tumor appears to be somewhat less important, since virtually any dose used for the definitive or palliative treatment of lung cancer devitalizes the lung tissue within the treated portal. Other factors that appear to increase the risk of radiation pneumonitis include radiation dose per fraction (i.e., larger fraction size increases the risk) and tumor location (i.e., lower lobe lesions have a higher risk). The use of chemotherapy (particularly the anthracyclines, methotrexate, bleomycin, and mitomycin) and poor pulmonary function before treatment also increase the risks of serious damage to the lungs by radiation.

On rare occasion, a patient develops an adult respiratory distress syndrome shortly after irradiation. The chest radiographs reveal diffuse infiltrates both within and outside of the radiotherapy portal. It has been hypothesized that a severe autoimmune response may be involved: Whereas mild

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Neoplasms of the lungs

after radiation therapy. With standard radiotherapy (60 Gy in standard fractionation) this mucositis is almost always self-limited and usually responds to topical agents, such as sucralfate slurry or “magic mouthwash” combinations (e.g., antacid, viscous lidocaine, and diphenhydramine) with or without non-opiod and/or mild opioid pain medications.

However, with more intensive radiotherapy or with concurrent chemotherapy, the incidence of grade 3 esophagitis is higher, the recovery period is longer, and the need for aggressive pain management is greater.

Esophageal stricture is a late complication and its incidence is likely to increase as there are more long-term survivors following thoracic radiotherapy. The risk of esophageal stricture is strongly related to the dose to the esophagus, approximately 1 percent with 50 Gy, 10 percent with 60 Gy and may be as high as 50 percent with 70 Gy. It is likely that the concurrent use of chemotherapy potentiates this effect.

Most cases of radiation esophageal stricture respond well to endoscopic dilatation although the procedure may have to be repeated. More severe complications, such as esophageal fistula or perforation, fortunately, are rare.

Figure 105 III-8 Chest radiograph of a patient 6 years after definitive radiotherapy for stage III unresectable non–small-cell lung carcinoma. radiation fibrosis in the right upper lobe with mediastinal shift to the treated side and an ipsilateral pleural effusion and thickening is evident. Patient remained asymptomatic.

and moderate radiation injury becomes manifest only in the irradiated portion of lung, a severe autoimmune response results in generalized bilateral lung injury.

Lungs: Late Complications The late complication of radiation fibrosis develops from 3 to 18 months after radiotherapy. Essentially 100 percent of patients irradiated for lung carcinoma with high doses of radiation develop radiologic evidence of radiation fibrosis in the portion of the lung that was heavily irradiated (Fig. 105-III8). The major difficulty is in distinguishing between fibrosis and residual, or recurrent, tumor. In clinically significant radiation fibrosis, there is usually a progressive decrease in the DlCO , which may be combined with a more modest decrease in the FEV1, reflecting the restrictive nature of radiation fibrosis.

Severe symptoms from radiation fibrosis are uncommon in patients who were irradiated to modest-sized radiation fields. However, established fibrosis does not respond to corticosteroids or any other therapy. Longitudinal studies in Hodgkin’s disease patients suggest some recovery of lung function at approximately 3 years, after treatment. It is less clear if lung cancer patients, who are far older and more chronically ill than most lymphoma patients, can expect appreciable recovery.

Esophagus Most patients receiving moderate- to high-dose radiotherapy for lung cancer experience an acute mucositis of the esophagus that is similar to that seen on other epithelial surfaces

Heart Acute effects of radiotherapy on the heart during treatment are extremely uncommon, although effects related to the tumor itself (e.g., atrial fibrillation due to lung cancer invading the pericardium) are relatively common. Radiation pericarditis may occasionally occur during a course of treatment but, in general this is a subacute or late complication, developing several months to years after irradiation. The presentation is similar to that for other causes of pericarditis, and as in the case of radiation pneumonitis, distinguishing between radiation pericarditis and tumor progression can be difficult.

Most cases are self-limited and are treated supportively with antipyretics, analgesics, and occasionally with antiarrhythmic agents. Pericardiocentesis for tamponade is rarely required.

Occasionally, severe constrictive changes may develop, leading to signs and symptoms of heart failure and necessitating pericardiectomy.

The risk of symptomatic radiation pericarditis is about 5 percent when doses of 60 Gy are administered to one-third of the heart. However, considerably lower doses (35–40 Gy) can induce this disorder when a large part of the heart is in the treatment field (e.g., radiation therapy for Hodgkin’s disease or for tumors in the left lower lobe). In addition to the risk of radiation pericarditis, irradiation has increased longterm morbidity and mortality from heart disease in patients cured of Hodgkin’s disease, seminoma, and breast cancer, presumably due to accelerated coronary artery disease.

Long-term cardiac complications of radiotherapy are rarely encountered in patients with lung cancer, since few patients survive long enough to manifest these effects. Furthermore, it can be difficult or impossible to distinguish between a cardiac event due to prior mediastinal irradiation and a cardiac event that is unrelated to radiation, since the risk of coronary artery disease is high in the older, heavy smoker who develops lung cancer.

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ation (e.g., 1.5 Gy bid) or as hypofractionation (e.g., 4 Gy qd). It is designed to reduce the amount of tumor repair and repopulation that occurs during treatment of rapidly dividing tumors and, therefore, improve local control. Much of the data on modified patterns of fractionation come from patients treated for cancers of the head and neck. In patients with epithelial neoplasms, both accelerated fractionation and hyperfractionation increase local-regional control.

As noted, acclerated hyperfractionation was superior to standard treatment for limited stage small cell lung cancer. Data for NSCLC are less clear; although as noted, extreme accelerated hypofractionation (stereotactic irradiation) appears to be beneficial for medically inoperable stage I disease.

ADVANCES IN RADIOTHERAPY Radiation Dose-Fractionation Modulation As the understanding of the relationship between radiation and cellular kinetics has grown, mathematical models have been developed that allow us to predict the responses of both normal tissue and tumor to radiation. This capability has led to many creative new fractionation schemes designed to maximize the destruction of tumor while minimizing damage to normal tissue. The difference in cellular kinetics between tumor cells and normal cells makes these new schemes possible and attractive. Both tumor cells and normal cells are injured by radiation; however, normal cells usually have a greater ability to repair this damage than do the tumor cells and can repopulate more between fractions. Hyperfractionation utilizes multiple daily fractions in an effort to reduce the late effects in normal tissue without decreasing tumor control. The overall treatment time is the same as conventional schedules, but multiple smaller fractions are given each day, and total doses are increased. By giving multiple smaller fractions, the normal tissues are able to repair a greater percentage of the damage during the course of treatment; this may allow higher total cumulative doses of radiotherapy to be safely administered.

Accelerated treatment administers a larger total dose of radiation per day and also decreases the overall treatment time. The nominal final dose of radiotherapy may be similar to (or even somewhat less than) that of conventional treatment. Accelerated treatment may be given via hyperfraction-

A

Treatment of NSCLC: Radiation Therapy

Technical Planning and Delivery of Radiation Complementing the advances in dose-fractionation schedules in radiotherapy are the advances in technical planning and delivery of radiotherapy. Specifically, three-dimensional (3D) conformal radiation therapy, which includes newer techniques such as intensity modulated radiation therapy (IMRT), proton beam radiotherapy, and stereotactic radiotherapy (SRT), is used in efforts to improve local control while minimizing toxicity. Utilizing three-dimensional planning of both the tumor and surrounding normal tissue, the radiation beam(s) can be precisely conformed and modulated to the shape and size of the tumor volume (Fig. 105 III-9). Powerful computer software allows for detailed analysis of anticipated radiation dose/volume distributions, so that adjustments in the treatment plan can be made if necessary (Fig. 105 III-10).

B

Figure 105 III-9 High technology radiation therapy involves the design of multiple conformal radiation beams directed in 3-dimensional space from various angles and using variable field shapes and intensities. These slides illustrate the radiation dosimetry for a patient with a pancoast tumor (T4N2M0) of the right upper lobe (A = axial view of radiation treatment planning CT scan; B = coronal view). The spinal cord is (relatively) spared from maximal radiation doses.

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Figure 105 III-10 This figure illustrates the cumulative radiation dose volume histogram plots for the patient from Fig. 105 III-9. This graph includes the DVH curves for multiple normal organs (lung, heart, esophagus, spinal cord) as well as DVH curves for the tumor itself and electively irradiated targets adjacent to the gross tumor. The degree of radiation exposure to the normal lung tissue is expressed as The lung V20, the percent of the patient’s total lung volume that receives a dose of at least 20 Gy, which is expected to devitalize that portion of lung. In this case the V20 is approximately 20 percent, which is generally considered a ‘‘safe” amount of radiation lung exposure and low risk for clinical radiation pneumonitis.

This information includes comprehensive dose volume histograms (DVHs), which quantitatively plot the volume of a given organ (or tumor/target) receiving a given dose of radiation. DVH analysis has demonstrated a powerful relationship between the risk of radiation pneumonopathy and the amount of lung tissue irradiated to a certain threshold dose, usually considered to be 20 Gy in most studies.

In the future, these techniques may simultaneously allow a higher dose to the tumor and lower dose to normal tissues such as the spinal cord, esophagus, and normal lung tissue, offering an improved therapeutic ratio. As noted, dose escalation studies have determined maximum tolerated doses of radiotherapy for standard 3-D conformal radiotherapy. It is likely that higher doses will be achievable with IMRT, proton beam radiotherapy, and SRT, particularly as better technology is developed to account for intratreatment tumor motion due to respiration.

Combined Modality Therapy/Radiosensitizers The rationale for combining radiotherapy with other anticancer treatments is twofold: first is the hope that the non-radiotherapy treatment can sterilize tumor cells located outside of the radiation field (this is also known as spatial cooperation). Second and more intriguing to radiation oncologists is the hypothesis that these other treatments act as radiosensitizers, turning a sublethal dose of radiation into a lethal dose of radiation. Both concepts apply to standard

cisplatin-based polychemotherapy. However, the toxicity of combined chemoradiotherapy appears to be at the limites of acceptability. Thus newer and better drugs and drug schedules are needed. Regarding standard chemotherapy, one modern technique is to combine the benefits of both sequential and concurrent chemoradiotherapy. Specifically this involves several cycles of very intense chemotherapy alone before or after concurrent chemoradiotherapy, in an effort to eradicate distant metastases; this may allow the use of less toxic dose schedules of chemotherapy during radiotherapy.

As noted, conventional chemoradiotherapy is suboptimal against lung cancer, so newer, better targeted agents are needed to complement current treatment. As of the writing of this chapter, two molecularly targeted agents are approved for systemic therapy for stage IV NSCLC, specifically the antiEGFR small molecule drug erlotinib and the anti-angiogenic humanized antibody bevacizumab. These and other compounds are currently undergoing testing in phase I and II studies in combination with radiotherapy for stage III disease.

SUMMARY External beam radiotherapy plays a major role in the treatment of lung cancer. It improves local control and enhances curability in patients with marginally resectable NSCLC. Patients with medically inoperable NSCLC have a good

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chance for durable local control with high-dose radiotherapy, particularly with modern technology. In patients with unresectable NSCLC, radiotherapy (combined with chemotherapy) maximizes the median survival and offers occasional cure. Aggressive thoracic radiotherapy with chemotherapy and prophylactic cranial irradiation offers potentially curative treatment for limited stage small-cell lung cancer, once considered a universally fatal disease. Finally, radiotherapy often provides good palliation for patients with incurable and/or metastatic lung cancer.

APPENDIX Glossary of Terms Related to Radiation Therapy Adjuvant: Generally refers to postoperative therapy. However, chemotherapy given after definitive radiotherapy would also be considered adjuvant.

Blocks: Thick shields made of a leadlike alloy that can be shaped for each patient to block portions of their anatomy that would otherwise fall into the radiation field. These heavy physical devices have been largely replaced by mutlileaf collimators installed directly into the gantry of modern linear accelerators.

Brachytherapy: Radiotherapy given in the form of radioactive sources placed directly into or around a patient’s tumor.

This may be given interstitially (sources imbedded directly into tissue) or intracavitary (sources laid into a cavity such as a bronchus). cGy (centigray): A modern basic unit of radiotherapy dose.

One Gy (Gray) = 100 cGy. Conedown: Shrinking the field size sometime during the course of radiotherapy, to take advantage of the decreasing size of tumor during treatment and minimize the amount of toxicity of treatment. For example, a patient may begin radiotherapy with a large treatment plan/field irradiating half of his or her hemithorax, and then have a conedown midway through treatment to a small field only irradiating the gross tumor itself.

Conformal radiotherapy: The use of extremely sophisticated imaging studies and dosimetry to design radiation fields that conform precisely to the shape of a patient’s tumor. Conformal radiotherapy usually uses smaller safety margins around a patient’s tumor, a larger number of fields, and less prophylactic radiotherapy of clinically uninvolved lymph node areas.

Consolidative: Refers to radiotherapy given after a maximal or complete response to chemotherapy.

Course: A series or program of radiation treatments or fractions with a specific goal in mind for a patient (e.g., a 7-week course of daily radiotherapy to the lung for attempted cure).

Definitive: Refers to radiotherapy given with the intention of cure without surgery. May be given with other nonsurgical treatment such as chemotherapy.

Dosimetry: The process of optimizing the radiotherapy fields and dose by calculating the radiation dose to be received by

Treatment of NSCLC: Radiation Therapy

a tumor and/or normal tissues in a radiation field. Physicists and “dosimetrists” work with the radiation oncologist in comparing possible radiation treatment plans with the goal of maximizing the radiation dose to the tumor while minimizing dose to normal tissue, often requiring sophisticated computer programs.

Endobronchial irradiation: A form of brachytherapy in which radioactive sources are placed directly into a bronchus using a hollow catheter threaded into the diseased area via bronchoscopy.

External beam radiotherapy (x-ray therapy): Radiotherapy given from a machine (usually a linear accelerator) which produces a high-energy x-ray beam that is then aimed at a patient’s tumor and/or suspected tumor areas.

Field: An area at which a radiotherapy beam is directed, usually described as a rectangular shape, in cm (e.g., 10 × 14 cm). Blocks are often used to further customize the shape of a field. A single fraction of radiotherapy may include multiple fields, typically two to four, although extremely high-technology conformal radiotherapy may include 6 to 20 fields.

Fraction: A single radiation therapy session, usually given over 1 to 5 min. A fraction may consist of one or multiple fields, and any dose, as prescribed by the radiation oncologist. Most courses of radiotherapy involve one fraction per day, Monday through Friday, over 1 to 7 weeks, although an infinite number of possible fractionation schedules are possible.

Gy (Gray): The SI modern basic unit of radiotherapy dose; 1 Gy = 100 cGy = 100 rad. One Gy = 1 joule per kilogram of absorbed energy.

Hyperfractionation (see also fraction: The delivery of two or more radiation fractions per day, generally given with a 4or more hour interval between fractions.

Intensity Modulated Radiation therapy (IMRT): An advanced form of 3-D conformal radiotherapy in a very large number of small radiation beams of variable intensity are used instead of a small number of larger radiation beams.

This offers potentially better conformal dosimetry than standard 3-D XRT. However, it may result in a larger volume of normal lung tissue receiving small to medium doses of irradiation; this is of unknown clinical significance.

Karnofsky score: A performance status scale commonly used in oncology to measure a patient’s level of independent function. Scores range from 10 (moribund) to 100 (asymptomatic, able to work full-time). Karnofsky score has been shown to be highly predictive of survival in lung cancer.

Neoadjuvant: Generally refers to preoperative therapy. However, chemotherapy prior to definitive radiotherapy would also be considered neoadjuvant.

Palliative: Refers to therapy given with the goal of relieving distressing symptoms, without any anticipated effect on survival.

Prophylactic: Refers to radiotherapy given to a site at which there is no known tumor but which is considered to be at high risk for harboring occult “microscopic” disease, such as lymph node areas.

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Proton beam radiotherapy: Proton beam radiotherapy uses all of the same principles as standard x-ray (photon beam) radiotherapy, but requires a far more sophisticated accelerator to produce radiation. Proton beam radiotherapy may offer significantly more conformal radiotherapy dosimetry than standard XRT. Rad: Basic unit of radiotherapy dose; terminology not changed to the SI units (cGy and Gy).

Radiation Therapy Oncology Group (RTOG): A National Cancer Institute–sponsored multicenter clinical trials cooperative group which performs studies related to radiation therapy, including many lung cancer studies.

Radiosensitizers: Drugs or other treatments which increase the cellular response to radiotherapy. Many chemotherapy drugs and molecularly taregeted agents have radiosensitizing properties.

Safety margin: A margin of “normal-appearing” tissue which is added onto the visible tumor area for the purposes of radiation planning. Typically 1.5 to 2 cm in all dimensions is added, to account for microscopic extension of tumor cells and the possibility of slight patient motion during treatment.

The most significant motion variable in the treatment of lung cancer is tumor motion due to normal breathing (particularly in the superior-inferior direction due to diaphragmantic motion).

Simulation: A detailed planning session for radiation therapy that simulates but does not actually deliver a radiation treatment. Simulation consists of immobilization of the patient in an appropriate position for radiation therapy, marking the patient’s skin, localizing the area to be treated under fluoroscopy, taking radiographs of the area to be treated, and taking measurements of the patient’s contour for dosimetry purposes.

SUGGESTED READING Auperin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. PCI Overview Collaborative Group.

N Engl J Med 341:476–484, 1999.

Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15).

Int J Radiat Oncol Biol Phys 54:719, 2002.

Emami B, Lyman J, Brown A, et al.: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109–122, 1991.

Furuse K, Fukuoka M, Kawahara M: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small cell lung cancer. J Clin Oncol 17:2692–2699, 1999.

Gandara DR, Chansky K, Albain KS, et al.: Long-term survival with concurrent chemoradiation therapy followed by consolidation docetaxel in stage IIIB non-small-cell

lung cancer: A phase II Southwest Oncology Group Study (S9504). Clin Lung Cancer 8:116–121, 2006.

Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy vs. limited resection for T1N0 non-small cell lung cancer.

Ann Thorac Surg 60:615–623, 1995.

Kelsey CR, Werner-Wasik M, Marks LB: Stage III lung cancer: two or three modalities? The continued role of thoracic radiotherapy. Oncology (Williston Park) 20:1210–1219; discussion 1219, 1223, 1225, 2006.

Lung Cancer Study Group: Effects of post-operative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 315:1377– 1381, 1986.

Machtay M, Hsu C, Komaki R, et al.: Effect of overall treatment time on outcome after concurrent chemoradiation for locaclly advnced non-small cell lung carcinoma: Analysis of the Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys 63:667–671, 2005.

Machtay M: Pulmonary complications of anti-cancer treatment, in Abeloff M, ed. Clinical Oncology, 3rd ed. Churchill Livingston, 2003.

Marino P, Preatoni A, Cantoni A: Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb nonsmall cell lung cancer: A meta-analysis. Cancer 76:593–601, 1995.

Murray N, Coy P, Pater JL, et al.: The importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The NCIC Clinical Trials Group. J Clin Oncol 11:336–344, 1993.

Patchell RA, Tibbs PA, Walsh JW, et al.: A randomized trial of surgery in the treatment of single metastases to the brain.

N Engl J Med 322:494–500, 1990.

Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable nonsmall-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330–353, 2004.

Pignon J, Arriagada R, Ihde D, et al.: A meta-analysis of thoracic radiotherapy for small cell lung cancer. N Engl J Med 327:1618–1624, 1992.

PORT Meta-Analysis Group: Postoperative radiotherapy in non-small cell lung cancer: Systematic review and metaanalysis of individual patient data from nine randomised controlled trials. Lancet 352:257–263, 1998.

Roach MR, Gandara DR, Yuo HS, et al.: Radiation pneumonitis following combined modality therapy for lung cancer: Analysis of prognostic factors. J Clin Oncol 13:2606–2612, 1995.

Rodrigues G, Lock M, D’Souza D, et al.: Prediction of radiation pneumonitis by dose-volume histogram parameters in lung cancer. A systematic review. Radiother Oncol 71:127–138, 2004.

Rojas AM, Lyn BE, Wilson EM, et al.: Toxicity and outcome of a phase II trial of taxane-based neoadjuvant chemotherapy and 3-dimensional, conformal, accelerated radiotherapy in locally advanced nonsmall cell lung cancer. Cancer 107:1321–1330, 2006.

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Ryu JS, Choi NC, Fischman AJ, et al.: FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: Correlation with histopathology. Lung Cancer 35:179–187, 2002.

Simpson JR, Farncis ME, Perez-Tamayo R, et al.: Palliative radiotherapy for inoperable carcinoma of the lung: Final report of a RTOG multi-institutional trial. Int J Radiat Oncol Biol Phys 11:751–758, 1985.

Timmerman RD, Kavanagh BD, Cho LC, et al.: Stereotactic body radiation therapy in multiple organ sites. J Clin Oncol 25:947–952, 2007.

Ung YC, Yu E, Falkson C, et al.: The role of high-doserate brachytherapy in the palliation of symptoms in pa-

Treatment of NSCLC: Radiation Therapy

tients with non-small-cell lung cancer: a systematic review.

Brachytherapy 5:189–202, 2006. van Meerbeeck JP, Kramer GW, Van Schil PE, et al.: Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99:442–450, 2007.

Wakelee HA, Stephenson P, Keller SM, et al.: Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590. Lung Cancer 48:389–397, 2005.

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106 Small Cell Lung Cancer: Diagnosis, Treatment, and Natural History Kevin Palka

David H. Johnson

I. EPIDEMIOLOGY

X. PROGNOSTIC FACTORS

II. HISTOPATHOLOGIC CLASSIFICATION

VII. CLINICAL PRESENTATION

XI. TREATMENT Surgery Chemotherapy Thoracic Radiotherapy Prophylactic Cranial Irradiation Second-Line Chemotherapy Treatment in Patients with Poor Performance Status

VIII. PARANEOPLASTIC PHENOMENA

XII. LATE COMPLICATIONS

III. TUMOR BIOLOGY IV. NATURAL HISTORY V. DIAGNOSIS VI. STAGING

IX. EXTRAPULMONARY SMALL CELL CARCINOMA

Small cell lung cancer (SCLC) is a tumor of extremes. Untreated, it is one of the most highly virulent malignancies known, with a life expectancy best measured in days to weeks.

On the other hand, it displays exquisite chemosensitivity, resulting in partial or complete responses in the vast majority of cases. Unfortunately, although many patients can be rendered free of clinical evidence of disease, most quickly relapse and die from this malignancy. Over the past 20 years, little progress has been made in prolonging survival in this disease, despite trials using newer chemotherapeutic agents. This chapter reviews several aspects of the diagnosis, natural history, and best current therapies for SCLC.

EPIDEMIOLOGY Lung cancer remains the leading cause of neoplastic death in American men and women. In 2006 estimates called for 174,470 cases of newly diagnosed lung cancer (92,700 men and 81,770 women) and 162,460 deaths (90,330 in men and 72,130 in women) from this disease. However, for the first

XIII. CONCLUSION

time in 50 years, the incidence rate in men is declining, whereas the incidence rate in women has reached a plateau after a long period of increase. The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) suggest that small cell lung cancer (SCLC) currently represents approximately 14 percent (roughly 24,000 cases) of lung cancers in the United States, a decline from the peak of approximately 17 to 20 percent in 1986. In the United States and Europe, SCLC constituted about 77,000 of the 550,000 lung cancers diagnosed in 2004. Between 1985 and 2000 there was a significant increase in the percentage of women and patients over 70 years of age who were diagnosed with SCLC. Of note, national health surveillance studies have demonstrated that non–African Americans have improved survival rates compared with African Americans.

Like all other lung cancers, SCLC is linked to a variety of environmental risk factors. By far the strongest association is with the use of tobacco: Up to 98 percent of SCLC patients have a history of smoking. In most populations the incidence of SCLC rises with increasing tobacco exposure in a dose-dependent fashion, making the overall risk for smokers

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approximately 15-fold higher than for nonsmokers. Occupational risks for SCLC include exposure to bischloromethyl ethers, nickel, vinyl chloride, asbestos, cadmium, and radon daughters (in uranium miners). Other types of radiation exposure also appear to be significant risk factors, with an increased incidence of SCLC in atomic bomb survivors and patients (typically those with breast cancer or Hodgkin’s lymphoma) exposed to therapeutic irradiation. Industrial nations in general have an increased incidence of SCLC, possibly secondary to higher levels of air pollutants.

HISTOPATHOLOGIC CLASSIFICATION A number of different histologic classification schemes have been proposed for SCLC over the past 80 years beginning with Bernard’s initial report published in 1926 in which he described the epithelial nature of this “mediastinal tumor.”

Bernard’s “The Nature of the ‘Oat Cell Sarcoma,”’ was a four-subtype morphologic classification. Although the first World Health Organization (WHO) small cell classification included only two subtypes (oat cell and polygonal), the categorization published by WHO in 1967 returned to the original four: fusiform, polygonal, lymphocyte-like, and “other.” Subsequent modifications were suggested by pathologists in the Working Party for Therapy of Lung Cancer, and in 1981 WHO changed the lymphocyte-like subtype to the oat cell classification, and combined fusiform and polygonal cell types into the intermediate cell type classification. In 1988, citing lack of differences in biologic behavior among the various subtypes within the WHO classification scheme, the Pathology Committee of the International Association for the Study of Lung

Cancer (IASLC) recommended discarding the terms “oat cell” and “intermediate” and substituting the terms “pure small cell carcinoma” (more than 90 percent of small cell cancers) and “variant” histology. The latter contains large cell elements (including mixed, a combination of small and large cells, and combined, an admixture of small cells with defined non–small cell adenocarcinoma or squamous cell carcinoma elements).

More recently, the WHO joined with the IASLC pathology panel to develop a revised classification of lung and pleural tumors. In the updated classification schema neuroendocrine tumors are viewed as a spectrum extending from low-grade typical carcinoid to intermediate-grade atypical carcinoid to high-grade neuroendocrine tumors, including large cell neuroendocrine carcinoma (LCNEC) and SCLC. Because of differences in clinical behavior, therapeutic implications, and epidemiologic context, these tumors have been presented separately in the WHO revised classification. Using only very objective criteria (mitosis and necrosis), there is substantial inter-observer reproducibility for subclassification of pulmonary neuroendocrine tumors, with the most common disagreement involving LCNEC vs. SCLC. Although, IASLC had proposed to recognize a variant form of SCLC called mixed small cell-large cell carcinoma, this variant was not retained in revised WHO classification. Instead, SCLC is now described with only one variant: “SCLC combined,” when at least 10 percent of the tumor bulk is made of an associated non–small cell component. SCLC presents a proliferation of small cells (less than 4 lymphocytes in diameter) with unique and strict morphologic features, scant cytoplasm, ill-defined borders, finely granular “salt and pepper” chromatin, absent or inconspicuous nucleoli, frequent nuclear molding, and a high mitotic count (Fig. 106-1). The category of combined

Figure 106-1 Photomicrograph of pure small cell carcinoma, demonstrating a homogeneous cell population with salt and pepper chromatin and moderately prominent nucleoli (H&E, 250×; inset 400×). (Courtesy of Dr. Michael T. Lomis, Vanderbilt University.)

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small cell carcinoma includes cases with a mixture of small cell and large cell or any other non–small cell component. Importantly for the clinical significance of the diagnostic signature, any case showing at least 10 percent of SCLC is diagnosed as SCLC combined, even if the tumor has a heterogeneous sarcomatous component. SCLC alone is reserved to tumors with pure SCLC histology. SCLC associated with LCNEC is diagnosed as SCLC combined with LCNEC. Thus, there are currently three histologic categories: classical small cell cancer, large cell neuroendocrine cancer, and combined small cell cancer. The clinical significance of dividing small cell cancer into these histologic subtypes is controversial as there appears to be no significant survival difference between LCNEC and SCLC when stratified by stage (see Prognosis ). Regardless, pathologists must be cautious in making a diagnosis, since poor fixation can make small cell components appear to be large cells, and crush artifact can give large cells a small cell appearance.

TUMOR BIOLOGY Most cancers arise as a consequence of genetic abnormalities caused by exposure to environmental carcinogens. Activation of a dominant oncogene or inactivation of a tumor suppressor gene can both lead to the development of a malignant phenotype. In SCLC the most common genetic abnormalities include loss of chromosomal material associated with

Small Cell Lung Cancer

inactivation of specific tumor suppressor genes. This frees the cells from the normal growth constraint imposed by the gene products, resulting in unrestrained growth of the cancer cell.

The chromosomal abnormalities most commonly associated with SCLC include loss of a portion of the short arm of chromosomes 3, 9, 11, and 17. Deletions in 3p are found in nearly all (90 percent) SCLC tumors and cell lines. Three tumor suppressor genes of particular interest are located in this region: the fragile histidine triad gene (FHIT) at 3p14.3 encoding the enzyme diadenosine triphosphate hydrolase, the RAS effector homologe (RASSF1A) at 3p21.3 encoding a microtubule-binding protein, and the RARB gene at 3p24 encoding the retinoic acid receptor β. All three gene products are important in cell cycle control or induction of apoptosis; the detailed mechanisms of which are outside the scope of this chapter. The retinoblastoma gene (RB1) at 13q14.11 encodes a nuclear protein involved in cell-cycle progression, and inactivating mutations of this gene are found in more than 90 percent of SCLC. Transfection of a normal Rb gene into tumor cell lines with defective retinoblastoma genes causes normal Rb protein production in the tumor cells and reverses malignant phenotype. Mutations of the TP53 gene at 17p13.1, the most common gene abnormality in all human cancers, are found in 75–80 percent of SCLC (Table 106-1).

Dominant oncogene abnormalities are less common in SCLC. For example, overexpression of myc oncogene through gene amplification is seen in approximately 25 percent of SCLC patients. The myc oncogenes c-myc, n-myc, and l-myc

Table 106-1 Genetic Abnormalities in SCLC Gene

Chromosome

Protein

Frequency

Fragile histidine triad (FHIT)

3p14.3

Diadenosine triphosphate hydrolase

∼90%

RAS effector homologue (RASSF1A)

3p21.3

Microtubule binding protein

∼90%

Retinoic acid receptor β (RARB)

3p24

Retinoic acid receptor β

∼90%

Retinoblastoma (RB1)

13q14.11

Nuclear protein involved in cell-cycle progression

∼90%

TP53

17p13.1

p53: multifunctional transcription factor

c-myc/N-myc/L-myc (amplification)

8q24/2p24-25/1p34-35

Nuclear DNA-binding phosphioproteins

∼25%

K-ras (point mutation)

12p11-12

G-protein regulator of cellular signal transduction

Rare

c-kit receptor

4q12

Transmembrane receptor tyrosine kinase

75%–80%

70%

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are closely related nuclear DNA-binding phosphoproteins involved in gene regulation. In two retrospective studies, the presence of myc DNA amplification in tumor cell lines and myc family DNA amplification was associated with shortened survival in SCLC patients. In laboratory studies, transfection of myc into a SCLC cell line was found to be associated with faster growth, a greater cloning efficiency in soft agarose, altered cell structure, and altered histology in athymic nude mice. These findings connote a more aggressive form of SCLC in association with myc amplification. Mutations in ras are mainly observed in NSCLC and rarely in SCLC. It is interesting to note that the mutation is most commonly seen in adenocarcinomas and primarily in subjects with a smoking history. Like myc amplification, ras mutation in NSCLC is associated with a worse prognosis.

SCLC has long been associated with the production of numerous peptides, including ADH, ACTH, and calcitonin.

The autocrine growth promotion potential of these peptides was first proposed almost 25 years ago. The classic autocrine agent in SCLC is gastrin-releasing peptide (GRP), a mammalian analog of the amphibian hormone bombesin. SCLC cells produce GRP, as well as neuromedin B, which bind to one of three receptors (GRP receptor, neuromedin B receptor, and bombesin receptor subtype 3) to active the autocrinesimulated growth loop. A murine anti-bombesin monoclonal antibody directed against GRP has been shown to inhibit the growth of SCLC in vitro and in a mouse model. Unfortunately, no clinically usable antibody is currently available.

A second autocrine growth loop involves the c-kit receptor, which is found in the majority of gastrointestinal stromal tumors (GIST), as well as up to 70 percent of SCLC tumors.

The ligand stem-cell factor is produced by small cell cancers, which in turn binds to the c-kit receptor to stimulate cell growth. The tyrosine kinase inhibitor imatinib, although effective in GIST, was not shown to have any antitumor activity in two phase II trials, and is not an option for treatment at present. Elevated levels of IGF-1 have been detected in more than 90 percent of SCLC tumors and cell lines, and receptors for IGF-1 are found on SCLC cell lines, suggesting autocrine growth activity.

NATURAL HISTORY The natural history of untreated SCLC is early dissemination and death. Unlike NSCLC, it is always considered a systemic disease at diagnosis, even if it appears clinically confined to the chest. Postmortem exams performed on patients who died from other causes shortly after the “complete” surgical resection of their SCLC have demonstrated identifiable metastases in up to 70 percent of cases. Evidence of distant spread can be found in virtually any organ system. The most common sites of involvement, however, are the liver, bone and bone marrow, and central nervous system (Table 106-2). This pattern of spread dictates how the search for metastatic disease is made (see Staging).

Table 106-2 Extent of Disease at Presentation Limited stage disease

25%–30%

Extensive stage disease

70%–75%

Metastatic sites: Liver Bone Bone marrow Adrenal Brain Extrathoracic lymph nodes Subcutaneous masses

25%–30% 25%–40% 20% 5%–30% 10% 5% 5%

Patients with SCLC have a short lifespan if therapy is not instigated in a timely fashion. The median survival for untreated patients is 4 to 6 months if they have disease that is apparently confined to the chest, and 5 to 9 weeks if they present with metastatic disease. With therapy, survival improves significantly (see Treatment). Chemotherapy with or without irradiation can extend median survival to an average of 14 to 20 months for those with thorax-confined disease and 7 to 10 months for those with more extensive spread. At 2 to 3 years, a consistent 10 to 25 percent of limited-stage patients will still be alive, although cure is not guaranteed even in these relatively long-term survivors (see Late Complications). Recent trials indicate that 2-year survival may be as high as 40 percent for aggressively treated limited-stage patients. Twoto three-year survival remains a dismal 1 to 2 percent for those with metastatic disease.

DIAGNOSIS The diagnosis of SCLC is usually not difficult (see also Histopathologic Classification). The gross specimen often reflects a central lesion arising from a major bronchus and extending into the nearby pulmonary parenchyma. Necrosis and hemorrhage are often present. The classic oat cell form of small cell cancer consists of sheets of heavily staining “blue” cells with scant cytoplasm, hyperchromatic nuclei, and non-prominent nucleoli. In general, any subtype of description of “small cell carcinoma” includes cells double the size of a small lymphocyte, with salt-and-pepper chromatin, nuclear molding, and areas of necrosis (Fig. 106-1). Inflammatory response and desmoplastic reactions are usually absent. Although biopsy specimens are ideal, cytologic specimens alone are often sufficient for diagnosis, with a sensitivity of 60 to 90 percent and a specificity of greater than 95 percent.

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Difficulty occasionally arises in distinguishing small cell carcinomas from lymphomas, other neuroendocrine tumors (e.g., atypical carcinoids), and poorly differentiated non– small cell cancers. The presence of “crush artifact” is more common in SCLC than NSCLC, but it can be present in lymphomas. If additional review fails to reveal subtle glandular or epidermoid differentiation, tests beyond light microscopy may be necessary to establish the diagnosis. Electron microscopy can be useful in this setting, particularly with large cell neuroendocrine cancers, revealing dense neurosecretory granules.

Immunohistochemistry plays an important role in the diagnosis of SCLC. Nearly all small cell cancers are positive for the epithelial markers keratin, epithelial membrane antigen, and BER-EP4. (Non-Hodgkin’s lymphoma is suggested by antibodies against the common leukocyte antigen, with negative epithelial markers.) Given their neuroendocrine derivation, many of the tumors will stain positively for one of a variety of neuroendocrine markers, with neuron-specific enolase and chromogranin A being the two most common. Other neuroendocrine markers that can be found include dopa decarboxylase, calcitonin, Leu-7, CD56 (neural cell adhesion molecule [NCAM]), gastrin releasing peptide (GRP), and insulin-like growth factor-I (IGF-I). One or more of these markers can be found in approximately 75 percent of SCLCs. However, negative neuroendocrine markers should not deter one from diagnosing SCLC.

STAGING Staging a cancer defines the anatomic extent of the tumor, helps determine prognosis, and guides treatment options. Although the TNM staging system can be used for SCLC, most authorities prefer a simpler two-stage system, which reflects not only the systemic nature of the disease at diagnosis, but also the beneficial role of radiotherapy in early-stage cancer. This two-stage system has been found to have independent prognostic implications for patients with SCLC. As originally proposed by the Veterans Administration Lung Cancer Study Group, the staging system places patients with disease that can be confined to a single, tolerable radiation portal in the limited stage category (25–30 percent of all patients with SCLC): all others are defined as extensive stage (70–75 percent) (Table 106-2). Unlike pulmonary adenocarcinoma, isolated pleural effusions are uncommon in SCLC. Controversy exists over the staging of an ipsilateral pleural effusion, which technically could be confined to a single radiation portal, although most authorities consider this to be extensive disease. Similar controversy exists for supraclavicular and contralateral hilar adenopathy.

Clinical conditions, such as the superior vena cava (SVC) syndrome, are not strictly encompassed by this twostage system. Many authorities do not believe SVC syndrome automatically places the patient into the extensive-stage cate-

Small Cell Lung Cancer

gory, because it does not significantly change the prognosis of those treated with combination chemotherapy. Some authors have even proposed a “very limited” stage, which purports to define a group of patients without any mediastinal adenopathy (18.5 percent of limited-stage patients, and approximately 6 percent of all SCLC patients) who have long-term survival much beyond that normally seen for those who are “conventionally limited.”

A full history and physical examination, complete blood count with platelet analysis, and blood chemistries (including liver function tests, lactate dehydrogenase, and alkaline phosphatase) should be performed after diagnosis. Tests such as mediastinoscopy, which may or may not be necessary for diagnosis, are not required for staging once the diagnosis has been made. Current guidelines call for computed tomography (CT) scans of the chest to assess for adenopathy, contralateral parenchymal disease, and pleural effusion. Liver metastases occur in roughly 25 percent of SCLC patients, and adrenal metastases in 5 to 30 percent; therefore, the initial CT of the chest should be extended caudally to include the liver and both adrenal glands.

Patients with any neurological abnormality should immediately undergo MRI or CT of the brain and MRI of the spinal cord, as 80 to 90 percent of these SCLC patients have disease in the central nervous system. Radionuclide bone scans are called for in any patient with bony pain. As 25 to 40 percent of patients have bony metastases on presentation, and most of these patients are asymptomatic with normal serum alkaline phosphatases, a bone scan can be considered an integral part of the staging workup.

Positron emission tomography (PET) scans have recently been show to have utility in SCLC. SCLC is fluorodeoxy-d-glucose (FDG) avid at both primary and metastatic sites. PET appears to be more sensitive and specific than CT scans in detecting non–brain distant metastases, but less sensitive than MRI or CT in detecting brain metastases.

Approximately 10 percent of limited stage patients can be upstaged to extensive stage disease through the use of PET scans, and therein lies the best defined clinical utility for this modality. Nonetheless, the U.S. Centers for Medicare & Medicaid Services (CMS) does not consider SCLC an appropriate indication for PET scanning.

Histologic bone marrow examination has historically been deemed to be of value in the initial evaluation of otherwise limited SCLC. Unless significantly low, hematologic variables do not reliably predict bone marrow metastases, and leukoerythroblastic changes on peripheral smear are usually seen only with extensive marrow involvement. However, fewer than 5 percent of patients have bone marrow involvement as their only metastatic disease, and stage is rarely altered (less than 2 percent) on the basis of bone marrow biopsy alone. Thus this test is not routinely performed if other blood parameters are normal. Although the true incidence of marrow metastases is probably much higher than that reported from series using histologic examination alone, there is no proof that immunostaining with monoclonal antibodies or doing cell cultures to detect microscopic bone

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marrow involvement will meaningfully change treatment planning.

CLINICAL PRESENTATION No aspect of the clinical presentation of SCLC distinguishes it from NSCLC or even from neoplasms metastatic to the lungs.

However, the duration of symptoms of small cell cancer tends to be very short, due to the rapid dissemination of the disease. The typical patient is a middle-aged or elderly smoker who presents with symptoms attributable to their pulmonary and mediastinal disease: cough, dyspnea, chest pain, hoarseness, and/or hemoptysis. Because of the usual endobronchial location of the tumor, patients often have accompanying postobstructive pneumonia.

Constitutional symptoms may include weakness, anorexia, weight loss, and, rarely, fever. Symptoms may also arise from distant metastases, including headache or seizures in patients with central nervous system (CNS) disease, and abdominal or bone pain with hepatic and osseous metastases, or from regional disease with attendant superior vena cava obstruction, manifesting as facial fullness, upper extremity swelling, headache, and dysphagia. In rare instances, patients present with symptoms from a paraneoplastic syndrome. The more common of these rare presentations are inappropriate secretion of antidiuretic hormone (SIADH) and other causes of hyponatremia, Cushingâ&#x20AC;&#x2122;s syndrome, Lambert Eaton syndrome, and other paraneoplastic neuropathies or neurologic disorders.

Physical exam may yield only the stigmata of chronic obstructive pulmonary disease, or it may demonstrate lymphadenopathy, hepatomegaly, bone tenderness, or neurologic findings. Signs of the superior vena cava syndrome include venous distention of the neck and chest wall, cyanosis, facial plethora, and upper extremity edema.

A chest radiograph typically demonstrates a central mass (75 percent of patients) with or without hilar nodal involvement (Fig. 106-2). Postobstructive atelectasis and pneumonia are very common with small cell lung cancer, but cavitation on chest radiograph suggests the alternative diagnosis of squamous cell lung cancer.

Laboratory evaluation reveals mild abnormalities of liver function (usually elevated alkaline phosphatase, and less commonly SGOT, SGPT, or bilirubin) and/or elevated lactate dehydrogenase in about 50 percent of patients. Leukopenia and thrombocytopenia are unusual and hardly ever seen in the absence of widespread disease at a number of sites beside the bone marrow.

Two special situations warrant brief discussion. Organ involvement from SCLC obviously can lead directly to failure of that organ, but this neoplasm can also cause problems in an indirect fashion. For example, hepatic insufficiency from frank neoplastic involvement, based on the clinical picture of jaundice and abnormal liver function, is a well-described

Figure 106-2 Chest radiograph of a patient with small cell lung cancer, demonstrating a left hilar mass extending into the (anterior) upper lobe. (Courtesy of Dr. Russell DeVore, Vanderbilt University.)

phenomenon to those who treat SCLC, and usually signals a poor outcome. If the same clinical picture is a result of extrahepatic biliary obstruction from nodal metastases, also well described in the literature, the patient has a better prognosis than one with diffuse liver replacement.

Pancoastâ&#x20AC;&#x2122;s syndrome, with ptosis, anhydrosis, facial edema, and sensory neuropathic pain and functional loss, is more commonly associated with NSCLC, but it has also been reported in patients with small cell disease. Obtaining a tissue diagnosis from an apical pulmonary mass is thus mandatory before radiotherapy or other treatment is started.

PARANEOPLASTIC PHENOMENA Many of the symptoms of lung cancer can be attributed to mass effect and direct impingement upon vital organs. However, tumor cells can act at a distance by secreting various biologically active agents, including antibodies, hormones, and other proteins. These so-called paraneoplastic phenomena can be seen in any type of lung cancer, but historically are most frequently associated with small cell lung cancers (Table 106-3). Most of these paraneoplastic phenomena can be placed into endocrine or neurologic categories.

Ectopic adrenocorticotropic hormone (ACTH) production by small cell carcinoma has been a well-recognized phenomenon since 1928. The secretion of ectopic ACTH

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Small Cell Lung Cancer

Table 106-3 Common Paraneoplastic Phenomena in SCLC Syndrome

Biologically Active Agent

Laboratory Finding

Frequency

SIADH

Antidiuretic hormone (ADH)

Hypo-osmolar hyponatremia

10%–15% in limited 30% in extensive

Cushing’s

Ectopic adrenocorticotropic (ACTH)

Hypercortisolemia

1.6%–4.5% with clinical syndrome ∼50% with elevated cortisol levels

Humoral hypercalcemia

Calcitonin

Elevated calcium Low-Normal PTH-rP

10% with hypercalcemia 50% with elevated calcitonin

Lambert-Eaton myasthenic syndrome (LEMS)

IgG auto-antibodies to P/Q-type voltage gated calcium channels

Positive antibody titers

∼5%

Paraneoplastic cerebellar degeneration

Auto-antibodies against cerebellar Purkinje cells

anti-Yo antibodies

∼2%

Paraneoplastic encephalomyelitis

Neuronal nuclear antibody Type 1

anti-Hu (ANNA-1) antibodies

Antibodies present in ∼25% of pts

results in bilateral adrenocortical hyperplasia and hyperfunction, leading to the clinical manifestations of Cushing’s syndrome. Cushing’s syndrome from small cell carcinoma differs slightly from Cushing’s disease (the same syndrome produced by a pituitary adenoma) in that the onset of symptoms in the former is usually abrupt. When signs and symptoms do occur, they tend to be those associated with acute hypercortisolism: hypokalemic alkalosis, hypertension, hyperglycemia, and rarely edema and muscle wasting. The features of chronic steroid overexposure seen in Cushing’s disease, such as the “buffalo hump,” striae, and moon facies, are usually absent.

Neuroendocrine tumors of the lung, including small cell carcinoma (27 percent) and pulmonary carcinoids (21 percent) represent about half of the cases of ectopic ACTH-producing tumors. As such, SCLC is the most common malignancy associated with Cushing’s syndrome. Although hypercortisolemia has been documented in up to 50 percent of SCLC cases, only 1.6 to 4.5 percent of SCLC patients have clinical Cushing’s syndrome. The effect of Cushing’s syndrome on survival is unclear, although some investigators hold that its onset heralds a more aggressive tumor behavior. Lethal infections, particularly those caused by fungi, often complicate the clinical course. Treatment with standard medications, such as metyrapone and ketoconazole, is largely ineffective due to extremely high cortisol levels. Some patients require bilateral adrenalectomy. Effective treatment of the underlying SCLC is generally the best treatment for Cushing’s syndrome.

The syndrome of inappropriate antidiuretic hormone (SIADH), with its resultant euvolemic, refractory, hypoosmolar hyponatremia, is a common SCLC-associated paraneoplastic disorder. Indeed, SCLC is estimated to represent about 80 percent of all ADH-secreting tumors, and is the most common malignant cause of acute or chronic SIADH. The incidence of hyponatremia ranges from 10 to 15 percent in patients with limited disease, and around 30 percent of patients with extensive stage disease. Roughly 25 percent of SCLC patients are estimated to have symptomatic SIADH at the time of diagnosis. As with other paraneoplastic syndromes, the best therapy for SIADH is effective treatment of the underlying SCLC. Vanderbilt University researchers demonstrated resolution of SIADH in 16 of 17 patients with SCLC 8 to 28 days after treatment with chemotherapy. The authors discussed temporizing measures for the hyponatremia while awaiting the effects of chemotherapy: They suggested that strict fluid restriction alone would maintain the serum sodium above 128 mEq/L in all patients. The use of demeclocycline, and agent that blocks the action of vasopressin at the level of the renal tubule, is another possible adjunctive measure. The starting dose is 150 mg orally four times a day (600 mg total), but the daily dosage may need to be increased to 1200 mg. Despite previous suggestions to the contrary, SIADH does not worsen the prognosis for SCLC patients, especially in the age of modern chemotherapy.

Although humoral hypercalcemia of malignancy is common in NSCLC patients, particularly those with

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squamous cell cancers, it is extremely unusual in SCLC. Serum calcium is elevated at presentation in only 10 percent of patients, although serum calcitonin levels are elevated in up to half of patients. The rare patients with hypercalcemia have been found to have inappropriately normal (i.e., not suppressed) levels of parathyroid hormone-related protein (PTH-rP). The precise mechanism for the hypercalcemia is unclear, although these patients almost always have extensive bone or marrow involvement. Local destruction of bone is not a satisfying hypothesis, however, as the vast majority of SCLC patients with bony involvement have normal calcium levels.

Neurologic paraneoplastic syndromes are frequently reported. These are often the result of production of antibodies that react with both the small cell cancer cells and with normal host tissue. Well-described syndromes include the Lambert-Eaton myasthenic syndrome (LEMS) and cerebellar degeneration. Less frequent abnormalities include subacute sensory neuropathy, autonomic disturbances, myelopathies, progressive encephalopathy, and a visual paraneoplastic syndrome. Nonspecific neurologic findings that may be related to ectopic hormone or antibody production include generalized weakness and anal sphincter dysfunction. LEMS is a result of IgG autoantibodies directed against presynaptic P/Q-type voltage-gated calcium channels. These antibodies are estimated to occur in 5 percent of patients with SCLC. Clinically, the syndrome presents with proximal muscle weakness, usually in the lower extremities, occasional autonomic dysfunction, and rarely with cranial nerve symptoms. As contrasted with patients with myasthenia gravis, strength improves with serial effort, and the weakness associated with LEMS improves over the course of the day. Plasma exchange and intravenous immunoglobulin can provide short-term benefit, whereas 3,4-diaminopyridine (which enhances the release of acetylcholine from presynaptic terminals), prednisone, and azathioprine can provide limited long-term benefit. Some patients who respond to chemotherapy have resolution of the neurologic abnormalities, and this is the initial treatment of choice.

The neuronal nuclear antibody type 1 (also called antiHu and ANNA-1), is associated with SCLC and a paraneoplastic encephalomyelitis or sensory neuropathy. These antibodies have been found in up to 25 percent of SCLC patients.

As with voltage-gated calcium channel antibodies, the presence of anti-Hu antibodies does not correlate with neurological symptoms, nor with an improved prognosis. Initially these two antibodies were thought to be associated with improved survival. Given that the diagnosis of the neurological syndrome often predates the diagnosis of SCLC, this may be reflective of lead-time bias, rather than an upregulated immune response.

Paraneoplastic cerebellar degeneration (PCD), manifesting with ataxia, dysarthria, and nystagmus, is also commonly associated with SCLC, as well as ovarian malignancies and lymphomas. Antibodies that react against cytoplasmic proteins of cerebellar Purkinje cells are often found in these patients. One such antibody, anti-Yo, attacks the cdr2 pro-

teins in the Purkinje cells. Treatment may include steroids, plasmapheresis, and chemotherapy.

Finally, elevations of gonadotropins, gastrin, βmelanocyteâ&#x20AC;&#x201C;stimulating hormone, and prostaglandins have all been described in SCLC patients. None has contributed significantly to a defined clinical syndrome.

EXTRAPULMONARY SMALL CELL CARCINOMA The knowledge that small cell cancers can arise from tissues other than the lungs has existed since 1930. Extrapulmonary small cell cancer (EPSCC) remains relatively rare, representing 2 to 4 percent of diagnosed small cell cancers, with an estimated 1000 cases occurring annually in the United States.

EPSCC has been described as arising in a wide variety of tissues, most commonly in the uterine cervix, gastrointestinal tract (esophagus and colon), upper airway and salivary glands, and genitourinary organs (prostate). The cell of origin of the extrapulmonary cancer is thought to be a totipotent stem cell that can differentiate into either epithelial cells or neuroendocrine (and thus, small cell cancer) elements. EPSCC has been recognized to be a distinct clinical entity, and can be distinguished from metastatic SCLC without a clear pulmonary primary site by the lack of deletion of chromosome 3p in the former. Ectopic hormone production is extremely rare, and the extrapulmonary variety of small cell cancer has a weaker correlation with smoking than SCLC. Staging of EPSCC is similar to the staging of small cell pulmonary tumors. Limited disease is still defined as that confined to a small anatomic compartment, and extensive disease as that extending beyond locoregional lymph nodes.

Most authorities would perform the same staging evaluation on these patients as on those with SCLC. Due to the paucity of cases, the optimal treatment of EPSCC is not clearly defined. Surgery has been shown to be curative in certain patients with disease confined to the organ of origin. Unfortunately, as with SCLC, tumors tend to clinically aggressive with early dissemination. Combined chemoradiotherapy can be used for limited stage disease. Extensive stage EPSCC responds to platinum-based chemotherapies in approximately 75 percent of the cases, but these responses are generally short-lived. In one series of 81 patients at the Mayo clinic, disease-free and overall survival at 5 years was 13 percent.

PROGNOSTIC FACTORS A variety of pretreatment factors have been reported as having value in predicting therapeutic outcomes for patients with small cell carcinoma. Since the aggressiveness of therapy may depend on this perceived outcome, it is important to determine before treatment how a patient is likely to do. The

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strongest and most consistent prognosticators from nearly all studies have been stage of disease (limited vs. extensive) and Karnofsky performance status at presentation. The importance of stage has already been mentioned. In general, extensive-stage patients have a lower chance of achieving a complete response to chemotherapy, shorter median survival times, and a much smaller chance of being cured. However, patients with extensive-stage disease, by virtue of having a single site of metastasis (especially in soft tissue, bone, or brain), often behave more like limited-stage patients and should be treated accordingly. Within the extensive-stage group, having an increasing number of affected sites, especially if these include bone marrow or abdominal disease, carries a worse outlook.

The performance status or ability of the patient to carry out normal daily activities has a profound effect both on the ability to tolerate chemotherapy and the efficacy of those drugs administered. In general, patients with poor performance status have a lower chance of response to chemotherapy and a higher chance of having clinical toxicity. However, poor performance status does not automatically exclude patients from receiving aggressive treatment, unlike non– small cell lung cancer. The occasional bedridden patient can experience clinical improvement and even be cured with chemotherapy. Similar to performance status, substantial weight loss (usually qualified as at least 10 percent of total body weight) is an independent prognostic factor for an adverse outcome. As seems logical, achieving complete remission with chemotherapy in general portends a better outcome than being nonresponsive or having only a partial response.

Similarly, relapse from remission clearly heralds short survival.

In many epidemiologic studies, female gender has been suggested to be a favorable prognostic factor in patients with SCLC. Women have a higher likelihood of responding to chemotherapy and obtaining a complete response. Their overall survival is also better than that of male patients. Variance in other epidemiologic factors, such as age (in the absence of poor performance status) and race, does not seem to be of consistent importance.

The continued use of tobacco is an adverse prognostic factor. Second malignancies, often smoking related, are a significant cause of death in long-term survivors of SCLC. Chronic tobacco use puts these patients at risk for chronic obstructive pulmonary disease and ischemic heart disease, which worsen with continued tobacco exposure. These two conditions represent significant sources of morbidity and mortality in patients with SCLC both during and after treatment.

Abnormalities in various laboratory parameters have long been held to have prognostic value. For example, a high serum lactate dehydrogenase, suggestive of more bulky disease, is an independent predictor of poor outcome for extensive-stage disease. In an analysis of the Southwest Oncology Group Small Cell Cancer Data Base, Albain and colleagues determined that good performance status, female sex, younger age (less than 70 years), white race, and normal serum

Small Cell Lung Cancer

lactate dehydrogenase were independent predictors for better survival. In extensive-stage patients, normal serum lactate dehydrogenase was the best predictor, followed by having a single metastatic focus of disease and receiving intensive combination chemotherapy. Hypoalbuminemia, hyponatremia, elevated alkaline phosphatase, and leukocytosis have been associated in various studies with poor prognosis. The serum tumor marker neuron-specific enolase (NSE) is more often elevated in extensive-stage than in limited-stage patients. Diagnostic specificity of this marker, however, is only 40 to 70 percent in limited SCLC, but specificity reaches to 80 to 100 percent in extensive disease. The baseline value increases in proportion to the number of metastases and baseline values and values after chemotherapy correlate with overall survival.

Nonetheless, measurement of this parameter has not proved clinically useful. Moreover, serum NSE levels can also be elevated in NSCLC and smokers.

Histologic classification is of prognostic significance.

Previously some investigators reported longer survival with the so-called “oat cell subtype” than with tumors of the non– oat cell subtype. However, it is now known that there is not much biologic or prognostic difference among the subtypes of pure small cell carcinoma. The importance of mixed elements by histology, including large cell neuroendocrine carcinoma (LCNEC) component, is less clear. LCNEC is considered to be a variant of non–small cell lung cancer, with a relative insensitivity to chemotherapy. In a study of intensive treatment of 375 patients with SCLC, Hirsch and colleagues noted a median survival of 168 days for those with pure SCLC (of various non–large cell subtypes) versus 280 days for those with tumors with any large cell features. Data from an Eastern Cooperative Oncology Group publication, however, point to a different conclusion. ECOG investigators examined all patients with the diagnosis of variant histology (small cell with large cell elements) placed on an ECOG chemotherapy protocol. They found that variant histology actually was rare (less than 10 percent of cases) and did not lead to lower response rates or a shorter median survival. Taken as separate entities, Japanese investigators have recently demonstrated that LCNEC and SCLC have roughly the same prognosis.

TREATMENT Surgery The role of surgery for SCLC has come full circle in the past four decades. The disease has been thought of as systemic from the outset, and chemotherapeutic treatment has long been standard. In the mid-twentieth century, however, the British Research Medical Council randomized patients with SCLC to surgery or thoracic radiation. The patients on the surgical arm had worse survival, but neither arm did particularly well, with less than 5 percent of patients alive at 5 years. Subsequently, The VA Surgical Oncology Group entered more than 2000 patients in a study looking at the role of adjuvant chemotherapy after resection of NSCLC. One

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hundred forty-eight patients with SCLC were incidentally entered in the study, and early-stage patients enjoyed superior survival.

Surgery for early stage small cell carcinoma, particularly those cancers presenting as small single pulmonary nodules, may be more appropriate, as these tumors may be biologically distinct from advanced disease. For example, in a retrospective study, Roswell Park Cancer Institute investigators identified a small number of SCLC patients with “isolated” lesions.

These patients did not receive “prompt” diagnosis or treatment of their cancers. Moreover, extremely slow growth of the tumors was documented, ranging from 14 to 40 months, and no lymph node involvement or metastatic disease was found at the time of surgery. Thus, this experience is not characteristic of SCLC in general. Nonetheless, other studies of resection for patients with T1N0M0 tumors have suggested a 50 to 80 percent 5-year survival rate, although it is extremely rare for patients to fall into this category. In the early 1990s University of Toronto investigators reviewed a 15-year surgical experience with SCLC at that institution. They reported that resection improved control at the primary site, and a significant proportion of patients with stage I (N0) disease achieved long-term survival and cure with combined modality therapy, including surgery. Moreover, stage II and IIIa patients had survival durations similar to stage IIIa non–small cell lung carcinoma treated surgically.

There may be other circumstances in which one might consider employing surgery with or without systemic therapies in selected patients with SCLC. First, small cell cancer treated with chemoradiotherapy still has a high local recurrence rate. Surgery for other thoracic malignancies, particularly esophageal cancer, affords significant improvement in local control, even when added to radiotherapy. Second, surgery immediately puts the patient into a “no clinical evidence of disease” category, and both chemotherapy and radiotherapy work better on small-volume or microscopic disease. Finally, many mixed histology SCLCs contain large cell elements that may be less responsive to irradiation or chemotherapy. NSCLC is notoriously resistant to chemotherapy, and surgery is the best curative option for this disease.

Therefore, an argument could be made for resection of residual disease after chemotherapy, especially if the remaining element represents a non–small cell fraction. There has been one randomized study testing this role for surgery in SCLC. The Lung Cancer Study Group gave limited-stage patients standard chemotherapy for five cycles, followed by PCI and thoracic irradiation; the patients were also randomized to receive or not receive surgery. It is interesting to note that 9 percent of patients who did undergo surgery had residual non–small cell elements. Actuarial 2-year survival was identical on the two arms at 20 percent; thus, no survival benefit was demonstrated for surgery. However, this study excluded patients who would have fallen into the extremely limited T1N0M0 or T2N0M0 non–small cell staging schema—the ones who had shown the most benefit from surgery in earlier studies. Thus this trial does not definitively exclude a role for postinduction surgery in SCLC, although admittedly such an

approach is likely to be exceedingly uncommon in clinical practice.

In summary, the benefits of surgical resection in SCLC are mainly seen in patients with TNM stage I disease with peripheral tumors and no nodal involvement, and who are able to tolerate the procedure. Adjuvant chemotherapy should be offered postoperatively.

Chemotherapy Unlike non–small cell lung cancer (NSCLC), SCLC is classically associated with exquisite chemosensitivity. Ironically, however, the survival of patients with metastatic NSCLC is actually quite comparable with that of SCLC patients with extensive-stage (ES) disease following platinum-based therapies. Nonetheless, in some quarters, the perception persists that SCLC is more “chemo-sensitive” than NSCLC. In limitedstage (LS) disease, chemotherapy combined with thoracic radiation achieves a response in over 80 percent of patients, and a complete response in the range of 40 to 60 percent. In ES disease, the response rate is lower (60–80 percent), with a rate of complete response around 15 to 35 percent. Chemotherapy has been shown to improve survival compared with supportive care. In LS disease, median survival in treated patients is 15 to 20 months, with 5-year survival rates of 10 to 13 percent. The median survival for ES patients treated with chemotherapy remains at 7 to 9 months, with few long-term survivors.

Early studies from the 1940s and 1950s showed nitrogen mustards had activity against anaplastic lung cancer, which presumably included cases of SCLC. In the late 1960s, a large VA Lung Cancer Study Group trial demonstrated the survival benefit of treatment with cyclophosphamide, an alkylating agent. As responses to single agents were rare, the focus changed to combinations of drugs, each with independent activity against SCLC. When given in combination, these drugs had synergistic activity, and lowered the likelihood of complete tumor resistance. Until the mid-1980s the combination of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) was commonly used as first-line therapy. Currently, the two-drug regimen of etoposide and cisplatin (EP) is the standard of care for SCLC chemotherapy. A large randomized trial demonstrated that an EP regimen conferred a significant survival benefit compared with the traditional CAV regimen in LS disease. The median survival in the EP arm was 14.5 months, compared with 9.7 months in the CAV arm. Hematological toxicity was diminished with EP, and this combination was more easily combined with radiation. The EP regimen is typically given every 3 weeks for four to six cycles. Although additional cycles of chemotherapy (i.e., using maintenance chemotherapy) may prolong time to progression, there is no survival benefit to extending chemotherapy past six cycles of induction chemotherapy.

In ES disease, the EP regimen has never shown a survival benefit over CAV, yet EP remains the standard of care due mainly to an improved side-effect profile. Likewise, carboplatin appears to be as effective as cisplatin when used

1909 Chapter 106

in combination with etoposide, and is often better tolerated by patients. A recent Phase III trial in Japan suggested that irinotecan plus cisplatin is superior to EP. The response rate (84 vs. 66 percent), median survival (12.8 vs. 9.4 months), and 2-year survival rate (19.5 vs. 5.2 percent) were significantly higher in the irinotecan group. However, an attempt to confirm these results in the United States failed to show any improvement in survival in a non-Japanese patient population. This may be due to genetic or unrecognized molecular differences between the two patient populations as seen in the markedly different mutational rates of the epidermal growth factor receptors in NSCLC. Oral topotecan plus cisplatin was recently shown to be similar to EP in first-line therapy of ES SCLC in a non-inferiority study. The authors suggest oral topotecan is also more convenient, but this is conjectural. Moreover, maintenance therapy with topotecan following standard EP therapy failed to demonstrate a survival benefit.

Based on the extant literature, it appears the optimal therapy for a majority of SCLC patients is EP with the addition of thoracic radiotherapy for those with limited stage disease [vide infra]. Treatment beyond four to six cycles in unwarranted in the first-line setting. There is little support for the use of dose intensification or so-called “dose dense” therapy as a course of routine treatment. Furthermore, the need for expensive supportive care drugs such as colony-stimulating factors or erythropoietin is greatly diminished if one uses EP at standard dosing.

Thoracic Radiotherapy As with chemotherapy, SCLC is clearly sensitive to irradiation. Radiation therapy as a single modality leads to a response rate of 75 percent in LS disease, and has been noted to cure as many as 5 percent of these patients. Initial clinical trials combining radiotherapy with chemotherapy yielded mixed results. For the most part, these early trials demonstrated a decrease in local recurrence coupled with significant host toxicity but no clear survival benefit. However, a 1992 meta-analysis of 13 prospective, randomized trials showed that combined chemoradiotherapy in LS disease provides a 5 percent survival benefit at 2 and 3 years post-treatment when compared with chemotherapy alone. However, several key questions relating to the optimization of thoracic radiotherapy (TRT) remain unanswered, including volume of irradiation, optimal total dose, fractionation, timing, and sequencing of radiation. Regarding optimal timing, concurrent treatment administered early, meaning within the first two cycles of induction chemotherapy, appears to yield the greatest survival benefit. Early concurrent radiotherapy comes with a cost in the form of increased toxicity to the patient, mainly severe esophagitis and greater myelosuppression. The optimal fractionation and dose of TRT also are unknown. ECOG investigators conducted a randomized trial of twice-daily radiation therapy combined with the EP regimen that yielded significantly improved median (23 vs. 19 months) and 5-year (27 vs. 11 percent) survival compared with once-daily radi-

Small Cell Lung Cancer

ation treatments. Nonetheless, the oncology community has not embraced this approach. Rather, most radiation oncologists tend to increase the total dose of radiotherapy under the assumption this has biological equivalent results; however, data supporting this supposition are lacking.

Radiation serves a purely palliative role in ES disease, and can be used for symptomatic control in bony, pulmonary, and CNS metastases. Certain ES patients may benefit from prophylactic cranial irradiation, as well.

Prophylactic Cranial Irradiation The need for prophylactic cranial irradiation (PCI) in patients with LS SCLC had long been an area of controversy until the late 1990s. This issue is critical in the management of limited stage disease for two key reasons: the CNS has long been considered a sanctuary site from many chemotherapeutic agents, and the brain is a common site of metastasis in this cancer. Limited stage SCLC successfully treated with induction chemoradiotherapy is estimated to have a 50 to 67 percent chance of relapse in the brain, with one-third of these patients having disease solely in the CNS. A meta-analysis of seven randomized trials published in 1999 demonstrated a significant benefit to PCI. Patients who received PCI were 5.4 percent more likely to be alive at 3 years, had a 54 percent reduction in the risk of brain metastases, and a 25 percent increase in disease-free survival.

Current guidelines recommend PCI for all patients with a good performance status who have attained remission after induction chemoradiation. This includes patients with extensive-stage disease in complete remission, although the benefit for this subset of patients is not as clear. PCI should be given sequentially, rather than concurrently, to avoid additional toxicity. Typically patients receive 25 to 36 Gy in 10 to 18 fractions. Although there is concern that PCI can lead to late cognitive impairment, patients randomized to PCI or observation showed no detectable difference in posttreatment cognitive impairment or quality of life at 1 year post treatment.

Second-Line Chemotherapy The majority of SCLC patients treated with first-line chemotherapy demonstrate tumor shrinkage but most eventually relapse. The time course after treatment is important when considering further treatment options. Those patients who relapse within 3 months of completing treatment are considered to have “refractory” (chemoresistant) disease, which responds to second-line treatments less than 10 percent of the time. Recurrence beyond 3 months is classified as “sensitive” relapsed (chemosensitive) disease. Patients with chemosensitive disease respond much better to second-line agents (30–40 percent response rate), and achieve a median survival of approximately 6 months. In the United States, the topoisomerase I inhibitor topotecan is currently the only drug approved for second-line treatment. Intravenous topotecan used as a single agent has a response rate of 11 to 37 percent.

1910 Part XV

Neoplasms of the Lungs

Modest response rates have been shown with the use of single agents such as irinotecan, paclitaxel, docetaxel, vinorelbine, and gemcitabine. These responses are rarely durable.

Recently, targeted therapy has made a significant impact in the treatment of certain cancers, most importantly in colorectal and renal cell cancers. In NSCLC, anti-angiogenic drugs directed at vascular endothelial growth factor (i.e., bevacizumab) and tyrosine kinase inhibitors (i.e., erlotinib and gefitinib) are currently in use. Certain targeted therapies, including inhibitors of c-kit, matrix metalloproteinases, farnesyl transferase, proteosomes, and the mammalian target of rapamycin (mTOR) have been investigated in SCLC. To date, the results of these trials have been negative. Targeted therapies are currently under investigation in SCLC, and these agents may provide the most hope for future treatment options.

Treatment in Patients with Poor Performance Status As the percentage of the population over 65 years old continues to grow rapidly, it is common to encounter older patients with SCLC. Oncologists have been taught that because of poor bone marrow, renal and hepatic reserves, elderly cancer patients do not tolerate chemotherapy as well as their younger counterparts. Curative chemotherapy is often not even attempted in the elderly for other malignancies, such as acute myelogenous leukemia. Additionally, given the lengthy smoking history in the majority of SCLC patients, many suffer from the cardiovascular and pulmonary sequelae of smoking, which diminishes performance status. Although it is true that elderly patients are, as a group, less able to tolerate chemotherapy, for those who do receive full-course treatment, survival is equal compared with comparable-stage younger patients.

Single-agent etoposide has been compared with combination chemotherapy in this subset of patients. Combination therapy provided a survival advantage and a better side-effect profile. Therefore, combination chemotherapy, often substituting carboplatin for cisplatin, remains the standard treatment for elderly and poor–performance-status patients.

LATE COMPLICATIONS The treatment of SCLC can cause more morbidity than the neoplasm itself. Both radiotherapy and chemotherapy cause side effects specific to the agent used. Irradiation can have early (esophagitis, pneumonitis, superficial skin burns) and late (pulmonary fibrosis, late cardiac disease, myelitis) toxicities. Chemotherapy toxicities depend on the specific regimen used, but they generally include alopecia, nausea and vomiting, and myelosuppression. Bone marrow suppression can lead to life-threatening bleeding episodes (from thrombocytopenia), but more commonly is associated neutropenic fevers, and occasionally fatal infections. Series have demonstrated that episodes of febrile neutropenia occur in roughly 30 percent of treated patients, documented infection in 5 to

15 percent, and fatal infection in 7 percent. Prevention of infection in patients treated with chemotherapy with or without irradiation has received significant attention: Measures have included prophylactic use of antibiotics and granulocyte colony-stimulating factor (GCSF). Recently, a large randomized trial showed that GCSF in addition to chemotherapy led to a reduction of the number of episodes of neutropenic fever and documented infections. Many oncologists do not agree that this is a cost-effective measure, however.

Given the tobacco abuse and older age of the vast majority of the SCLC patients, it is not surprising that cardiovascular, cerebrovascular, and pulmonary diseases are extremely common in this population. Thus, a large portion of long-term small cell lung cancers succumb to these other diseases. Up to one-third of all long-term surviving patients, especially those who continue to smoke, have recurrence of their small cell cancer, or more rarely, develop new small cell lung tumors. Other aerodigestive cancers, particularly NSCLC, are extremely common, leading some investigators to propose trials of chemoprevention agents in long-term survivors of small cell cancer. Finally, patients with SCLC have an increased risk of developing hematologic malignancy. Secondary leukemias are believed to be related to treatment, especially if chemotherapy with alkylating agents was employed.

Some of these post-treatment leukemias have also shown a deletion of chromosome 3, suggesting an underlying predisposition or common ancestor cell to both cancers, instead of a secondary leukemia arising from alkylating chemotherapyinduced genetic damage. Overall, the risk of second cancer in 2-year SCLC survivors is probably as high as 50 percent, making long-term surveillance mandatory in these otherwise cured patients.

CONCLUSION Small cell lung cancer is distinct from the other three major histologic varieties of pulmonary malignancies, which tend to behave similarly and are lumped together under the generic rubric “non–small cell lung cancer.” It is biologically more active, secreting multiple hormones and neural markers, resulting in a number of paraneoplastic syndromes. It is thought of as a systemic disease, and treatment nearly always includes chemotherapy. Although the tumor is highly responsive to chemotherapy, and survival is markedly prolonged with drug treatment, the complete eradication of SCLC remains a relatively rare event. Long-term survivors are still subject to a host of morbid cardiopulmonary conditions, as well as second malignancies and recurrence of their small cell cancer.

Over the last 30 years, clinical trials have made little progress in prolonging the survival of SCLC patients, especially when compared with trials involving tumors such as renal cell carcinoma and colorectal cancer. In the era of targeted therapies, there is hope that a new anti-angiogenic drug, monoclonal antibody, or small molecule tyrosine kinase inhibitor may show promise in clinical trials in the treatment of this aggressive and often fatal cancer.

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107 Primary Lung Tumors Other Than Bronchogenic Carcinoma: Benign and Malignant Reshma Biniwale Steven M. Keller

I. BENIGN TUMORS Mucous Gland Adenoma Squamous Papilloma Cavernous Hemangioma Ch ondroma Intrapulmonary Fibroma/Fibrous Tumor Inflammatory Pseudotumor (Plasma Cell Granuloma) Granular Cell Myoblastoma Hamartoma Leiomyoma

Bronchogenic carcinoma represents the overwhelming majority of pulmonary neoplasms; however, a great variety of tumors originate in the lung. Benign neoplasms of the lung (Table 107-1) comprise less than 1 percent of all resected lung tumors, and non-bronchogenic primary pulmonary malignancies (Table 107-2) account for 3 to 5 percent of all lung tumors. Numerous classifications of these rare tumors have been devised, although none are widely accepted. Due to the disparate histogenesis of these varied tumors, it is best to discuss them individually.

BENIGN TUMORS Mucous Gland Adenoma Mucus gland adenoma, also known as bronchial cystadenoma, originates in the bronchial submucous glands and presents as an exophytic endobronchial mass. The tumor

II. MALIGNANT TUMORS Pulmonary Blastoma Carcinoid Carcinosarcoma Epithelioid Hemangioendothelioma Lymphomas Plasmacytoma Malignant Melanoma Malignant Germ Cell Tumors Salivary Gland-Type Tumors Sarcomas

occurs in the segmental or lobar bronchi and symptoms are due to obstruction or hemorrhage. Histologically, mucousfilled acini are lined by well differentiated mucous-secreting cells, without any evidence of invasion. Radiologically, they appear as coin lesions on chest radiograph, or as an “airmeniscus” sign on computed tomography (CT) scan. Treatment is endoscopic local excision. However, lobectomy may be required if the distal lung is destroyed.

Squamous Papilloma Juvenile-onset recurrent respiratory papillomatosis (RRP) is associated with a bronchial papilloma in 5 percent of patients. Tracheobronchial extension of RRP is causally related to a previous tracheotomy in 92 percent of cases. Radiologically, it appears as a pulmonary nodule with central cavitary necrosis or as pneumatoceles. Histologically, papillomata consist of stratified squamous epithelium with a fibrovascular core. Parakeratosis and koilocytosis are typical. Infection with

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1918 Part XV

Neoplasms of the Lungs

Table 107-1 Benign Tumors of the Lung Solitary Tumors

Other Solitary Tumors

Multiple Tumors

Epithelial tumors Clara cell adenoma Mucous gland adenoma Oncocytoma Squamous papilloma Soft tissue tumors Cavernous hemangioma Chondroma Fibroma fibrous polyp Fibromyxoma Inflammatory pseudotumor—fibrous histiocytoma, fibroxanthoma, plasma cell granuloma Granular cell myoblastoma Hamartoma Leiomyoma Lipoma Neurilemoma—schwannoma Neurofibroma Pulmonary hyalinizing granuloma

Alveolar adenoma Pulmonary paraganglioma—chemodectoma Glomus tumor Nodular amyloid Pleomorphic adenoma—mixed tumor Pulmonary meningioma Sclerosing hemangioma—pneumocytoma Sugar tumor—benign clear cell tumor Teratoma

Benign metastasizing leiomyoma Lymphangioleiomyomatosis Cystic fibrohistiocytic tumors

HPV 11 rather than HPV6 is associated with a more severe course of RRP. Sporadic malignant transformation is seen after radiotherapy. Local endoscopic excision is the treatment of choice. Solitary bronchial papillomas are rare and affect adults in their fifth to seventh decade. They may cause obstructive bronchiectasis, which may necessitate resection of distally destroyed lung.

and 85 percent occur in females. Microscopically, they consist of benign cartilaginous tissue, although Carney also described foci of mature bone, and stellate mesenchymal cells in a myxoid stroma. Lung-sparing resections are curative in 44 percent, the rest develope new chondromas. Recently, MRIguided laser thermotherapy has been described for ablation of multiple chondromas.

Cavernous Hemangioma

Intrapulmonary Fibroma/Fibrous Tumor

Cavernous hemangiomas are extremely rare primary neoplasms of the lung, found in all age groups and may be single or multiple. They may be asymptomatic, or present with symptoms of hemoptysis, respiratory distress, or congestive heart failure. Histologically, they consist of flattened endothelial cells lining dilated vascular spaces. These cells stain positive for anti-von Willebrand factor antibody and CD34, identifying them as endothelial in origin. The treatment of choice for solitary lesions is surgical excision.

Intrapulmonary fibrous tumors are usually found in a subpleural location. They are diagnosed following resection of an asymptomatic lung mass found on routine radiography. The lung is the most common location of these tumors, but they may also be found in the retroperitoneum, mediastinum, and parietal surfaces of abdominal viscera. Histologically, interlacing bundles of spindle cells without nuclear atypia are seen in a collagenous stroma. Tumor cells are immunoreactive for vimentin but not keratin, desmin, or actin, suggesting fibroblastic differentiation from a submesothelial origin. Treatment is parenchyma-sparing resection.

Chondroma Chondromas of the lung may be solitary or multiple, unilateral, or bilateral, and are usually asymptomatic slow-growing tumors. The association of multiple peripheral pulmonary chondromas with gastric stromal sarcoma and extraadrenal paraganglionomas has been described as the “Carney triad.”

The majority of tumors present at a young age (7–48 years),

Inflammatory Pseudotumor (Plasma Cell Granuloma) Inflammatory pseudotumor of the lung (also known as fibrous histiocytoma, fibroxanthoma, and plasma cell granuloma) is the most common benign lung tumor in children,

1919 Chapter 107

Table 107-2 Rare Primary Malignant Neoplasms of the Lung Blastoma Carcinoid tumors Carcinosarcoma

Primary Lung Tumors Other Than Bronchogenic Carcinoma

Transbronchial/transthoracic biopsy often reveals mixed inflammatory cells with predominantly plasma cells in a background of fibroblastic proliferation, granulation tissue, and histiocytes with nuclear atypia. Thus, both fine-needle aspiration and frozen section are nonspecific and complete resection is necessary for establishing a diagnosis. Incomplete resection can result in recurrence, which can be treated with re-resection. Symptoms, incomplete resection, as well as large size are predictors of mortality. Steroids, chemotherapy, and radiation therapy are controversial in the treatment of inflammatory pseudotumors.

Epithelioid hemangioendothelioma (IVBAT)

Granular Cell Myoblastoma Malignant lymphoreticular disorders Hodgkinâ&#x20AC;&#x2122;s disease Non-Hodgkinâ&#x20AC;&#x2122;s lymphoma Plasmacytoma Malignant melanoma Malignant germ cell tumors Malignant teratoma Choriocarcinoma Salivary gland-type tumors Adenoid cystic carcinoma Mucoepidermoid carcinoma Acinic cell tumor Sarcoma Chondrosarcoma Osteosarcoma Soft tissue sarcoma Miscellaneous Ependymoma, malignant Ewingâ&#x20AC;&#x2122;s sarcoma Lymphoepithelioma Pseudomesotheliomatous carcinoma

although it is also commonly found in adults. Patients are usually symptomatic, presenting with cough, fatigue, or weight loss. Previously thought to be an unchecked inflammatory response to viral/foreign antigens, inflammatory pseudotumor has been confirmed to be of neoplastic origin with evidence of rearrangement of the anaplastic lymphoma kinase gene on chromosome 2p23, resulting in the expression of ALK-1 protein. Inflammatory pseudotumor is locally aggressive, and can be multifocal, relapse, and even metastasize. Radiologically, inflammatory pseudotumor presents as a large pulmonary mass or nodules closely related to the airways without evidence of mediastinal adenopathy. Histologically, plasma cells and spindle cells are seen with varying degrees of mitosis, necrosis, and vascular invasion. Inflammatory pseudotumor stains for vimentin, actin, and epithelial membrane antigen.

Granular cell tumors are uncommon benign neoplasms that are thought to arise from Schwann cells. Usually discovered incidentally on a chest radiograph, they are endobronchial in location and multicentric. Peribronchial extension is seen in half the tumors. However, distant metastases have not been reported. They occur equally in men and women, with a median age of 42 years. Microscopically, sheets of granular cells with abundant lysosomes that stain positive with periodic acid-Schiff stain are present. Tumor cells also stain positive for S-100 and myelin basic proteins. Large tumor size, necrosis, increased mitosis, and p53, as well as Ki-67 immunoreactivity are consistent with malignant change. Treatment consists of local excision, either endoscopically (laser) or by sleeve resection. Larger resections are reserved for postobstructive bronchiectasis or abscess. Up to 13 percent of granular cell tumors coexist with other neoplasms such as esophageal, renal, and lung carcinoma.

Hamartoma Hamartomas (mesenchymomas) are the most common benign tumors of the lung. They are derived from peribronchial mesenchyme, are slow-growing, present in adulthood, and have a 3/1 male predominance. Most are detected incidentally as peripheral round nodules on a chest radiograph, only 20 percent are endobronchial. The classic popcorn calcification is seen only in 30 percent of hamartomas. Cavitations are due to the fat content. Histologically, they consist of cartilage, fat, bone, connective tissue, and smooth muscle cells surrounding clefts lined by bronchial epithelium. Fine-needle aspiration has a high false-positive rate and low accuracy in diagnosing hamartomas. Malignant transformation is rare.

Therefore, small peripheral hamartomas may be safely observed. Excision is indicated for obstructive symptoms or if the diagnosis is in doubt (Fig. 107-1). Parenchyma sparing resection should be performed. Recurrences are rare, although hamartomas may be associated with increased risk of developing other primary lung cancers.

Leiomyoma Primary solitary leiomyoma accounts for 2 percent of all benign lung tumors and may present as pulmonary obstruction, or as an asymptomatic peripheral radiographic nodule.

1920 Part XV

Neoplasms of the Lungs

Figure 107-1 Pulmonary hamartoma seen at thoracoscopy. The tumor is easily visualized in a subpleural location.

Incising the overlying pleural allows the lesion to be ‘‘popped” out.

Patients are typically in their fourth decade. The tumor is slightly more common in women. Surgical resection is the treatment of choice, although laser resection of endobronchial tumors offers prolonged palliation. Benign metastasizing leiomyoma consists of multiple pulmonary nodules of well-differentiated smooth muscle, resulting from hematogenous spread from a benign uterine leiomyoma.

These tumors are ER and PR positive and respond to hormonal therapy.

MALIGNANT TUMORS Pulmonary Blastoma Pulmonary blastomas are divided into three subgroups: Biphasic pulmonary blastoma (BPB), well-differentiated fetal adenocarcinoma (WDFA), and pleuropulmonary blastoma (PPB). WDFA contains neoplastic epithelial glandular elements in an endometrial pattern without mesenchymal malignancy. PPB is a dysontogenic neoplasm having mesenchymal malignant elements (liposarcoma, rhabdomyosarcoma, or chondrosarcoma) without epithelial malignancy.

BPB contains both epithelial and mesenchymal malignant elements, which mimic fetal lung. PPB is further subclassified as type I (purely cystic), type II (cystic and solid), and type III (purely solid). PPB occurs in infants and young children, WDFA and BPB occur in young adults, with a mean age of 35 years. All three are fast-growing symptomatic tumors

that present in the periphery of the lung with a predilection for lower lobes. Radiologically they appear as large solitary smooth masses (Fig. 107-2). Fine-needle aspiration is usually non-diagnostic due to extensive necrosis and lack of cellular material. Neoadjuvant chemotherapy has been used to downstage the tumors before surgical resection. Adjuvant cisplatinum based chemotherapy is combined with local radiation for control after resection. Poor prognostic factors are large tumor size, mediastinal or pleural involvement, and nodal metastasis. CNS is the commonest site of distant metastasis followed by bone. Mutations of p53 gene are seen more frequently with BPB and PPB than with WDFA, suggesting a worse prognosis. Types II and III PPB have an overall survival of 42 percent at 5 years, despite multimodality treatment.

Carcinoid Carcinoid tumors are malignant neuroendocrine tumors arising from Kulchitsky (APUD system) cells and are classified by the World Health Organization into typical (TC) and atypical carcinoids (AC) on the basis presence of necrosis and greater than 2 mitosis per 2 square mm. Mean age at presentation is 55 years, but AC are seen in significantly older patients with a history of smoking. Seventy-five percent of carcinoids are central, endobronchial, and present commonly with postobstructive pneumonia, hemoptysis, or wheezing.

Uncommonly, carcinoids may present with paraneoplastic syndromes such as Cushing’s syndrome due to ectopic ACTH

1921 Chapter 107

Figure 107-2 Chest radiograph demonstrating a pulmonary blastoma. The lesion presented as a large mass in the right lower lobe of a 25-year-old nonsmoking woman.

production, or even acromegaly from ectopic GH and insulinlike growth factor-1 production.

Bronchoscopy frequently demonstrates a polypoid pinkish/yellow mass with intact overlying epithelium. Brushings and washings are usually nondiagnostic. Endobronchial biopsy is diagnostic in 51 percent of patients, but may precipitate a carcinoid crisis. Carcinoids are characterized by an organoid growth pattern with uniform cells containing finely granular eosinophilic cytoplasm and nuclei with a fine chromatin pattern. Radiologically, carcinoids present as solitary nodules (30 percent), infiltrates (60 percent), and as calcified nodules (30 percent) (Fig. 107-3). CT scan reveals a welldefined central tumor deforming an airway with punctate calcification and homogenous contrast enhancement with or without hilar lymphadenopathy. Carcinoids demonstrate high signal intensity on T2-weighted MRI. FDG-PET scans, however, have a high false-negative rate, as carcinoids are hypometabolic. Somatostatin receptor scintigraphy can be used in detecting occult primary tumors, staging, and localization of metastatic disease. Chromosome analysis shows evidence of 11q and 3p deletion in AC, with loss of 18q in metastatic carcinoid. Overexpression of p53 and loss of heterozygosity of 11q13 is seen in AC, which correlates with tumor aggressiveness. Five percent of patients with MEN I syndrome have associated sporadic carcinoids. Inactivation of the MEN I gene is seen in 67 percent of TC, and 25 percent of AC. Treatment of choice for TC is surgical resection. Lobectomy and lymph node dissection is preferred because 20 percent of TC and 60 percent of AC are associated with

Primary Lung Tumors Other Than Bronchogenic Carcinoma

nodal metastases. Bronchoplastic sleeve-resection for central lesions of early stage TC is preferable to pneumonectomy.

Cis-platinum and etoposide-based chemotherapy is indicated for unresectable disease as well as metastases. However, the response rate is only 22 percent with a median survival of 20 months. Bio-therapy with interferon alpha and octreotide is used for the treatment of carcinoid syndrome with symptomatic relief in 70 percent of patients. Liver embolization can be used to debulk liver metastases in symptomatic patients.

Targeted radiotherapy with radiolabeled octreotide or MIBG remains investigational.

Recurrence-free survival is commonly seen in TC. Tumor histology and nodal status are the main predictors of mortality. Completeness of resection, symptoms, and age are also significant prognostic factors. Five-year survival following complete resection of TC and AC is 87 to 100 percent and 44 to 77 percent, respectively. Survival decreases to 25 to 69 percent in the presence of nodal metastases. There is no correlation between tumor size and presence of nodal involvement.

Sixty-three percent of patients with nodal mediastinal nodal metastases develop distant metastases, most commonly in the liver. Carcinoid syndrome occurs rarely (2 percent) and results from release of 5HT. Urinary 5HIAA is used to monitor disease activity in patients with carcinoid syndrome.

Carcinosarcoma Carcinosarcoma is a biphasic tumor consisting of carcinomatous and sarcomatous elements containing differentiated cartilage, bone, or skeletal muscle. This tumor is seven times more common in males than females. The median age of presentation is 65 years. The upper lobes are affected in 60 percent of cases. Carcinosarcomas are divided into two groups: central endobronchial and peripheral solid parenchymal (Fig. 107-4). Symptoms of airway obstruction or postobstructive pneumonia are common. However, one-third of all patients are asymptomatic. These tumors eventually invade the mediastinum and chest wall, causing pain. Carcinosarcomas are firm, rubbery, or fleshy masses with areas of necrosis and cavitation. The carcinomatous elements are squamous cell carcinoma (46 percent), adenocarcinoma (31 percent), and adenosquamous carcinoma (19 percent). The sarcomatous elements are rhabdomyosarcoma (51 percent), chondrosarcoma, and osteosarcoma. The carcinomatous elements are often displaced to the periphery, suggesting rapid growth of the central sarcomatous elements, which form the bulk of the tumor. Immunohistochemical staining for keratin is positive for both the epithelial and mesenchymal components, suggesting that carcinosarcomas are of a monoclonal epithelial origin that has undergone sarcomatoid metaplasia. Metastases are found in lymph nodes, bone, kidney, liver, and lung and commonly contain only one of the components of the primary tumor. Complete surgical resection is usually possible and the 5-year survival rates ranges from 21 to 49 percent. Endobronchial location and tumor stage do not correlate with survival. However, tumor size greater than 6 cm is associated with poor survival.

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A

Figure 107-3 Solitary nodule presenting in a young asymptomatic woman. A. PA chest radiograph. B. Lateral film. The lesion was excised and found to be a typical carcinoid tumor with no evidence of mitoses or necrosis.

A

B

B

Figure 107-4 Carcinosarcoma. A. Endobronchial component of a carcinosarcoma. B. The parenchymal component of the same tumor bisected.

1923 Chapter 107

Epithelioid Hemangioendothelioma Originally named intravascular bronchoalveolar tumor (IVBAT), this neoplasm has since been demonstrated to be of endothelial origin on the basis of immunohistochemical staining for factor VIII–related antigen and CD34. Epithelioid hemangioendothelioma is best considered a low-grade sarcoma and is usually multicentric in origin. It is a disease of young women, with 80 percent of cases seen in women under the age of 40 years. Patients are usually asymptomatic, although they may present with respiratory symptoms. Multiple perivascular nodules less than 1cm in diameter or diffuse thickening of interlobular septae are present on CT scan. Microscopically, epithelioid hemangioendothelioma consists of eosinophilic cells forming trabeculae or nests with characteristic central acellular sclerotic areas and lymphovascular and bronchiolar invasion. Pleural, intravascular, and endobronchial spread is associated with a poor prognosis, as are liver and lymph node metastases. Complete resection is the treatment for localized tumors. Diffuse tumors have been treated with chemotherapy, interleukin-2 and interferon-α2b with mixed results. Radiation is ineffective and is used only for palliation of bone pain. Partial spontaneous regression also has been reported occasionally.

Lymphomas Primary pulmonary lymphomas (PPL) are rare neoplasms accounting for less than 1 percent of all lung cancers. Criteria used for diagnosis of primary pulmonary lymphoma include involvement of the lung with or without mediastinal involvement, and absence of extrathoracic lymphoma at the time of diagnosis or for 3 months thereafter.

Primary pulmonary B cell non-Hodgkin’s lymphoma (NHL) is also known as MALT (mucosa-associated lymphoid tissue) or BALT (bronchus-associated lymphoid tissue) and accounts for up to 80 percent of PPL. This is a low-grade small B lymphocyte lymphoma that is associated with a 5year survival greater than 80 percent. The tumor is thought to arise due to chronic inflammation secondary to smoking, infection or autoimmune disease (Sj¨ogren’s). Age of onset is 50 to 60 years, with equal distribution between the sexes. Half of the patients are asymptomatic on presentation. Pulmonary manifestations include cough, dyspnea, and hemoptysis. Extrapulmonary symptoms such as fever and weight loss occur in less than 25 percent of patients. Radiologically, a localized alveolar opacity with blurred margins is seen associated with air bronchograms. CT demonstrates bilateral multifocal disease in 70 percent of cases. CT-guided biopsy is diagnostic in 25 percent. Bronchoalveolar lavage is diagnostic if it shows lymphocytic alveolitis with greater than 10 percent of the total cells being B lymphocytes. Microscopically MALT PPL is defined as a lesion containing: small lymphoid cells, lymphoepithelial lesions showing migration of lymphoid cells from the marginal zone to bronchiolar epithelium, reactive follicular hyperplasia, and rare blastic cells (Fig. 107-5). Immunohistochemistry demonstrates B-cell phenotype (CD19, CD20) and monoclonality. Bone marrow biopsy may show

Primary Lung Tumors Other Than Bronchogenic Carcinoma

involvement in 25 percent of cases. Evaluation of other mucosal sites with endoscopy, ENT examination, and CT scan of salivary and lacrimal glands should be performed. Serum immunoelectrophoresis will reveal a monoclonal gammopathy (IgM) in 20 to 60 percent of patients. Elevated β2 microglobulin is associated with a poor prognosis. Solitary tumors should be removed. Long-term surveillance is necessary due to late local or systemic relapse after resection. Chemotherapy is recommended for residual, bilateral, progressive, or recurrent disease. Various regimens, including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) have been used with success.

High-grade PPL NHL-B, also known as large B-cell lymphoma, accounts for up to 15 percent of PPL. Immunosuppression, HIV infection, and Sj¨ogren’s syndrome are underlying disorders often associated with large B-cell lymphomas. These lymphomas are usually found in the elderly and commonly present with either pulmonary or systemic symptoms. A solitary lung mass often associated with a pleural effusion is present. Bronchoscopy may reveal infiltrative stenosis. Transbronchial biopsy is often diagnostic. Microscopically, large blast-like lymphoid cells with frequent mitosis, necrosis and bronchovascular invasion are seen. Survival is poorer than in small B-cell lymphomas, especially in those with underlying disorders. Resection is followed by combination chemotherapy. Progression of disease and recurrence occurs earlier and more commonly than in small B-cell lymphoma.

Lymphomatoid granulomatosis (LG) also known as an angiocentric immunoproliferative lesion (AIL) is rare. The age of onset is around 50 years. Almost all patients present with either pulmonary or systemic symptoms. Radiologically, multiple bilateral ill-defined nodular opacities, mainly affecting the lower lobes, are seen. These opacities can cavitate and disappear secondary to infarction of the granulomatosis lesions. Extrapulmonary involvement is seen mainly in the CNS, skin, ENT, or renal systems. Neurological deficits can be central, cranial nerve affection, or peripheral neuropathies.

Skin lesions are erythema or nodules with or without ulceration. Arthralgia and ocular and gastrointestinal manifestations have also been reported. Microscopically, an angiocentric lymphocytic infiltrate is seen mixed with occasional large blastic cells, which compresses the lumen of arterioles and erodes into bronchioles. Immunohistochemistry demonstrates the B-cell origin of the lymphocytes, which also express EBV LMP protein. Initial assessment should include brain MRI, CT scan of the abdomen for renal or lymphoid involvement, and a bone marrow biopsy. Localized LG should be removed. Combination chemotherapy is reserved for diffuse disease. Radiotherapy is useful in CNS involvement. Despite aggressive therapy the prognosis remains poor and median survival is about 4 years. Poor prognostic factors include early age of onset, CNS involvement, hepatosplenomegaly, leucopenia, fever, anergy, and predominant blast cells with necrosis on biopsy.

NK/T cell primary pulmonary lymphoma is an extremely rare diagnosis with only 13 cases reported in the

1924 Part XV

Neoplasms of the Lungs

A

B

Figure 107-5 Pulmonary lymphoma (BALT). A. Gross appearance of a BALT following wedge excision. B. Microscopic appearance of the same BALT lesion showing the lymphoid cells along with some residual epithelial elements.

world. Patients are elderly; females are twice as commonly affected as males. Radiographically, bilateral diffuse nodularities are seen. Diagnosis requires an open lung biopsy and immunohistochemistry, which reveals T-cell markers.

Microscopically, homogenous cells with architectural effacement and dysplasia are seen. Monoclonality of the T cells is demonstrated by TCR gene rearrangement. Prognosis is very poor despite surgical resection and CHOP based chemotherapy.

Primary pulmonary Hodgkinâ&#x20AC;&#x2122;s lymphoma is also very rare with 61 reported cases. There is a bimodal age dis-

tribution with peaks in the third and sixth decades. Most patients are female. Symptoms may be pulmonary or systemic. Radiologically, multinodular and massive parenchymal involvement is seen with occasional cavitation. Bronchoscopy and BAL are inconclusive, and often open biopsy is required to confirm the diagnosis. The most frequent histologic subtype is the nodular sclerosing variety. Combination chemotherapy, radiation, and surgery are the common modalities of treatment. A poor prognosis is predicted in patients with multilobar or bilateral disease.

1925 Chapter 107

Plasmacytoma Plasmacytomas are tumors arising from monoclonal plasma cells. The diagnostic criteria for extramedullary plasmacytoma are biopsy-proven plasma cell proliferation, absence of bone marrow infiltration and absence of osteolytic lesions, renal failure, and hypercalcemia. The average age of presentation is 54 years, with equal distribution between males and females. Plasmacytomas commonly present as a hilar mass, but lobar consolidation or bilateral diffuse infiltrates with air bronchograms may also be seen. Serum electrophoresis reveals an M-protein spike, which usually consists of IgG Îş chains, and correlates with the tumor burden. Treatment is surgical resection, but chemotherapy with melphalan and prednisolone has been used with good results. The 5-year survival rate is 40 percent. These tumors need to be distinguished from marginal zone B-cell lymphomas of MALT origin. Forty percent of patients develop multiple myeloma; therefore, surveillance with serum and urine electrophoresis, bone marrow biopsy, skeletal bone survey and clinical monitoring is necessary.

Malignant Melanoma Primary pulmonary melanoma is an extremely rare lung tumor for which several theories have been suggested: aberrant migration of melanocytes from the primitive foregut, melanogenic metaplasia of bronchial epithelium, or melanocytic differentiation of neuroendocrine precursor Kulchitsky cells. Jensen and Egedorf first suggested the clinical criteria for the diagnosis of primary pulmonary melanoma: no previously removed skin or ocular melanomas, solitary tumor, morphology compatible with a primary tumor, no melanoma in other organs at surgery, and no evidence of primary tumor elsewhere on autopsy. Histopathological criteria include junctional change with nesting of malignant cells beneath bronchial epithelium, and invasion of bronchial epithelium in an area without ulceration. Aggressive resection is the treatment of choice and offers the best chance for cure.

Chemotherapy and immunotherapy is used for widespread disease.

Malignant Germ Cell Tumors Malignant teratoma and choriocarcinoma are the two types of malignant germ cell tumors that arise in the lung. Teratomas show elements from all three germ layers. Half of the primary pulmonary teratomas are malignant. Patients present with cough, hemoptysis, or chest pain. The most specific symptom, trichoptysis, is rarely present. Radiologically, the mass may show calcification with peripheral radiolucency. Resection is the treatment of choice. Adjuvant chemotherapy is usually a combination of cis-platinum, bleomycin, and etoposide.

Choriocarcinomas are usually seen in women or elderly men who present with symptoms of feminization. The commonest symptom is cough with hemoptysis. Various theories have been postulated to explain the origin of choriocarcinomas of the lung. Neoplastic transformation of misplaced

Primary Lung Tumors Other Than Bronchogenic Carcinoma

primordial germ cells, spontaneous regression of an occult genital primary leaving behind pulmonary metastatic lesions, neoplastic transformation of placental emboli at the time of delivery or abortion, and neoplastic transformation of somatic neoplastic cells, have all been postulated. These tumors manifest as the choriocarcinoma syndrome: bleeding from the primary lung lesion and elevation of β-HCG. Differentiation from a large cell carcinoma producing ectopic human chorionic gonadotropin can be done by immunohistochemistry, which shows staining for thyroid transcription factor (TTF)-1 (a marker of pulmonary origin) and not for β-HCG. Histologically, cytotrophoblastic cell nests are seen covered by syncytiotrophoblasts, with evidence of widespread necrosis and hemorrhage, and a lack of fibrovascular stroma. Surgical resection is recommended, followed by adjuvant chemotherapy. Choriocarcinomas are unresponsive to radiation, unlike their gestational counterparts. Distant metastases can occur in the contralateral lung, brain, and kidney.

Salivary Gland-Type Tumors Adenoid cystic carcinoma (ACC) is the most common salivary-gland tumor found in the lung. It is believed to arise from ductal/myoepithelial cells of bronchial submucosal glands. Centrally located ACC arises in the trachea or mainstem bronchi and presents as an exophytic endobronchial mass causing obstructive symptoms. Overlying mucosa is often grossly normal. Peripheral ACC is uncommon. Males and females are equally affected. Histologically there are three subtypes: cribriform, tubular, and solid. ACC are slow-growing neoplasms that exhibit centripetal spread in the airways as well as perineural growth. Therefore, extensive resections are required. These tumors are extremely radiosensitive and local recurrences or residual disease may be treated with radiation.

Following complete resection, 5- and 10-year survivals of 91 and 76 percent, respectively, have been reported.

Mucoepidermoid carcinomas usually arise in mainstem bronchi or the proximal portion of the lobar bronchi. The right bronchial tree is more commonly affected in children.

Patients present with symptoms of obstruction due to a polypoid endobronchial mass. Bronchoscopic biopsy is diagnostic. Three histological grades have been defined (low, intermediate, and high) based on the presence of cystic spaces, cell type (mucous cells, intermediate cells, and epidermoid cells), cellular pleomorphism, and mitosis. Complete resection with mediastinal lymph node dissection is the treatment of choice. High-grade tumors are more common in adults and may invade adjacent structures, lymph nodes, vascular, and perineural spaces. Incomplete resection is more likely in high-grade tumors, and postoperative chemoradiation may be necessary. High-grade tumors are uniformly fatal in 11 to 28 months.

Acinic cell tumors (Fechner tumors) are usually found in the salivary glands, and hence a diligent search for an extrathoracic primary is essential. Symptoms vary and are determined by whether the tumor is central endobronchial or peripheral in location. Microscopy demonstrates a pattern

1926 Part XV

Neoplasms of the Lungs

resembling a neuroendocrine tumor and may need to be differentiated from the more common carcinoid tumor. Acinic cell tumors are slow-growing and recurrence or metastases after complete excision has not been reported.

Sarcomas Primary pulmonary sarcomas are rare tumors, accounting for less than 0.5 percent of all lung tumors. Mean age at presentation is 53 years, with a slight predominance in males.

A history of smoking or previous radiation exposure may be present. Usual symptoms are chest pain and cough. Sarcomas appear as large (mean diameter 5 cm), solitary peripheral or hilar nodular opacities usually located in the upper lobes.

Bronchoscopy may show either extrinsic compression or a polypoid endobronchial mass. The variety of soft tissue pulmonary sarcomas reflects the range of mesenchymal tissue found in the lung (Table 107-3). The most common primary pulmonary sarcoma is leiomyosarcoma (30 percent), followed by malignant fibrous histiocytoma and synovial sarcoma. Histological subtypes can be differentiated on the basis of immunohistochemical markers such as vimentin, desmin, actin, and epithelial membrane antigen. Treatment is wide resection with mediastinal lymph node dissection.

Residual disease is treated with radiotherapy or reresection.

Recurrences can be resected with good results. Ifosfamidebased chemotherapy has also been used in the neoadjuvant and adjuvant setting for positive margins or positive lymph nodes. Median survival is 48 months and 5-year survival is 38 to 69 percent. Size and grade do not correlate with in-

Table 107-3 Primary Soft Tissue Sarcomas of the Lung Leiomyosarcoma Spindle cell sarcoma Rhabdomyosarcoma Malignant fibrous histiocytoma Angiosarcoma Fibrosarcoma Malignant hemangiopericytoma Neurogenic sarcoma Synovial sarcoma Kaposi’s sarcoma Liposarcoma

creased mortality. Incomplete resection is associated with poor survival.

Chondrosarcomas of the lung can occur either within central bronchi or peripherally in the lung parenchyma.

Tumors consist of islands of chondroid and osteoid with foci of mineralization within sheets of small hyperchromatic mesenchymal cells. Chondrosarcomas are slow growing and rarely metastasize. Complete resection is usually curative.

Osteosarcomas of the lung present with cough or hemoptysis and appear as large cavitating masses. These are rapidly growing tumors with a poor prognosis. Recurrence is seen in 50 percent of patients after resection. The majority of patients succumb within months from metastases to the lung, liver, lymph nodes and bone. The role of adjuvant therapy for the treatment of this tumor is still unproved.

SUGGESTED READING Al-Ghamdi AM, Flint JD, Muller NL, et al: Hilar pulmonary granular cell tumor: a case report and review of the literature. Ann Diagn Pathol 4:245–251, 2000.

Asamura H, Kameya T, Matsuno Y, et al: Neuroendocrine neoplasms of the lung: A prognostic spectrum. J Clin Oncol 24:70–76, 2006.

Cadranel J, Wislez M, Antoine M: Primary pulmonary lymphoma. Eur Respir J 20:750–762, 2002.

Carney JA: Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): Natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 74:543–552, 1999.

Caruso RA, LaSpada F, Gaeta M, et al: Report of an intrapulmonary solitary fibrous tumor: fine-needle aspiration cytologic findings, clinicopathological, and immunohistochemical features. Diagn Cytopathol 14:64–67, 1996.

Cerfolio RJ, Allen MS, Nascimento AG, et al: Inflammatory pseudotumors of the lung. Ann Thorac Surg 67:933–936, 1999.

Cronin P, Arenberg D: Pulmonary epithelioid hemangioendothelioma: An unusual case and a review of the literature.

Chest 125:789–793, 2004. de Wilt JH, Farmer SE, Scolyer RA, et al: Isolated melanoma in the lung where there is no known primary site: Metastatic disease or primary lung tumour? Melanoma Res 15:531– 537, 2005.

Etienne-Mastroianni B, Falchero L, Chalabreysse L, et al: Primary sarcomas of the lung: A clinicopathologic study of 12 cases. Lung Cancer 38:283–239, 2002.

Fine SW, Whitney KD: Multiple cavernous hemangiomas of the lung: A case report and review of the literature. Arch Pathol Lab Med 128:1439–1441, 2004.

Hughes JH, Young NA, Wilbur DC, et al: Fine-needle aspiration of pulmonary hamartoma: A common source of falsepositive diagnoses in the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Arch Pathol Lab Med 129:19–22, 2005.

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Kanematsu T, Yohena T, Uehara T, et al: Treatment outcome of resected and nonresected primary adenoid cystic carcinoma of the lung. Ann Thorac Cardiovasc Surg 8:74–77, 2002.

Koss MN, Hochholzer L, Frommelt RA: Carcinosarcomas of the lung: A clinicopathologic study of 66 patients. Am J Surg Pathol 23:1514–1526, 1999.

Koss MN, Hochholzer L, Moran C, et al: Pulmonary plasmacytomas: A clinicopathologic and immunohistochemical study of five cases. Ann Diagn Pathol 2:1–11, 1998.

Kwon JW, Goo JM, Seo JB, et al: Mucous gland adenoma of the bronchus: CT findings in two patients. J Comput Assist Tomogr 23:758–760, 1999.

Patton KT, Cheng L, Papavero V, et al: Benign metastasizing leiomyoma: Clonality, telomere length and clinicopathologic analysis. Mod Pathol 19:130–140, 2006.

Primary Lung Tumors Other Than Bronchogenic Carcinoma

Priest JR, McDermott MB, Bhatia S, et al: Pleuropulmonary blastoma: A clinicopathologic study of 50 cases. Cancer 80:147–161, 1997.

Shintaku M, Hwang MH, Amitani R: Primary choriocarcinoma of the lung manifesting as diffuse alveolar hemorrhage. Arch Pathol Lab Med 130:540–543, 2006.

Skuladottir H, Hirsch FR, Hansen HH, et al: Pulmonary neuroendocrine tumors: Incidence and prognosis of histological subtypes. A population-based study in Denmark. Lung Cancer 37:127–135, 2002.

Soldatski IL, Onufrieva EK, Steklov AM, et al: Tracheal, bronchial, and pulmonary papillomatosis in children.

Laryngoscope 115:1848–1854, 2005.

Travis WD: Pathology of lung cancer. Clin Chest Med 23:65– 81, viii, 2002.

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108 Extrapulmonary Syndromes Associated with Lung Tumors Bruce E. Johnson

John P. Chute

I. HYPERCALCEMIA OF MALIGNANCY Biology Diagnosis Treatment II. HYPONATREMIA OF MALIGNANCY Biology Diagnosis Treatment

VI. NEUROLOGIC SYNDROMES Encephalomyelitis/Subacute Sensory Neuropathy Biology Diagnosis Treatment Paraneoplastic Cerebellar Degeneration Opsoclonus and Myoclonus

III. ECTOPIC ACTH SYNDROME Biology Diagnosis Treatment

VII. CANCER-ASSOCIATED RETINOPATHY Biology Diagnosis Treatment

IV. ACROMEGALY Biology Diagnosis Treatment

VIII. LAMBERT-EATON SYNDROME Biology Diagnosis Treatment

V. HEMATOLOGIC SYNDROMES Granulocytosis Thrombocytosis Thromboembolism

Lung cancers are the most common tumors associated with paraneoplastic syndromes. The paraneoplastic syndromes can be classified into endocrine, hematologic, and neurologic syndromes. Endocrine and hematologic syndromes associated with lung tumors are listed in Table 108-1.

The endocrine syndromes are characterized by the ectopic production of biologically active peptide hormones by tumor cells that bind to receptors in adjacent or dis-

This chapter has been slightly modified from the version that appeared in the third edition of Fishmanâ&#x20AC;&#x2122;s Pulmonary Diseases and Disorders.

IX. CONCLUSION

tant organs, giving rise to a clinical syndrome. The ectopic adrenocorticotropic hormone (ACTH) syndrome, the hyponatremia of malignancy, and hypercalcemia of malignancy are examples of this model. In order to establish the diagnosis of an endocrine paraneoplastic syndrome, the following criteria should be met: (1) a decrease in the level of the hormone after treatment of the tumor; (2) demonstration of hormone synthesis and secretion by tumor cells in vitro; (3) high concentrations of the hormone in the tumor; and (4) an arteriovenous gradient in hormone levels across the tumor bed.

Lung cancers also produce extrapulmonary syndromes by other mechanisms. Hematologic syndromes develop in

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 108-1 Endocrine and Hematologic Syndromes Associated with Lung Tumors Syndrome

Tumor

Proteins/Cytokines

Hypercalcemia of malignancy

Non–small-cell

Parathyroid hormone–related peptide Parathormone

Hyponatremia of malignancy

Small-cell Non–small-cell

Arginine vasopressin Atrial natriuretic peptide

Ectopic ACTH syndrome

Small-cell Carcinoid tumors

Adrenocorticotropic hormone Corticotropin-releasing hormone

Acromegaly

Carcinoid tumors Small-cell

Growth hormone–releasing hormone Growth hormone

Granulocytosis

Non–small-cell

G-CSF GM-CSF IL-6

Thrombocytosis

Non–small-cell Small-cell

IL-6

Thromboembolism

Non–small-cell Small-cell

Unknown

patients with lung cancer through the production of cytokines by tumor cells that activate progenitor cells in the bone marrow. Neurologic syndromes, such as encephalomyelitis and subacute sensory neuropathy, are caused by the induction of antibodies directed against proteins expressed by the lung cancer cells and antigens present on cells in the nervous system.

Although lung cancers produce and express various hormones, many (e.g., the gastrin-releasing peptide) do not cause a clinically evident syndrome. Other peptide hormones, such as ACTH precursors, are translated into prohormones, which are not processed into mature peptides. As a result, levels of the immunoreactive proteins in plasma are increased without a clinical syndrome.

This chapter focuses on the extrapulmonary syndromes that are encountered in clinical practice. An understanding of the extrapulmonary syndromes is important for several reasons: (1) the syndrome is often the presenting feature of the underlying cancer; (2) the course of the endocrine and hematologic syndromes usually parallels the course of the lung cancer, although the neurologic syndromes frequently do not; and (3) appropriate treatment of the extrapulmonary syndrome often reduces the patient’s morbidity and may allow definitive treatment of the cancer. In general, definitive treatment of the underlying tumor by surgical resection, radiotherapy, or chemotherapy is the most effective form of therapy for the paraneoplastic syndrome.

HYPERCALCEMIA OF MALIGNANCY Hypercalcemia is the most common paraneoplastic syndrome. Approximately 1 percent of patients with lung cancer have hypercalcemia when first seen, but 10 to 20 percent of patients develop hypercalcemia during the course of their disease. Lung cancer is the most common solid tumor associated with hypercalcemia, accounting for 30 to 40 percent of all paraneoplastic cases. Hypercalcemia is commonly seen in patients with squamous cell carcinoma of the lung, uncommonly in patients with adenocarcinoma, and very rarely in patients with small-cell lung cancer.

Hypercalcemia in patients with lung cancer is usually not caused by local osteolytic effects of bony metastases. Most cases of hypercalcemia in patients with lung cancer are caused by the ectopic production of parathyroid hormone–related peptide (PTHrP) by tumor cells (humoral hypercalcemia of malignancy).

Biology Ectopic production of PTHrP accounts for 80 to 90 percent of humoral hypercalcemia of malignancy in patients with lung cancer. The PTHrP gene expresses three messenger RNAs (mRNAs); these encode for three distinct peptides, which differ at the COOH-terminal region (Fig. 108-1). Eight of the first 13 amino acids in PTHrP are homologous with PTH, so

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Extrapulmonary Syndromes Associated with Lung Tumors

Figure 108-1 Parathyroid hormone and parathyroid hormone–related peptide. The human PTH gene has three exons, which constitute the protein-coding segments. The protein coding segments are represented by the black boxes.

The PTHrP gene is more complex, with eight exons. Through alternative splicing, three different isoforms of mRNA can be produced. These isoform mRNAs encode the pre-PTHrP proteins, which vary in size from 175 to 209 amino acids (aa). Thirty-six amino acids are removed from the amino terminal end as the signal peptide. Three different PTHrP molecules are produced, with 139 to 173 amino acids. The rectangular region at the carboxy terminal represents the different lengths of PTHrP. The N-terminal region (aa 1–34) mimics the classic PTH-like function (hatched box).

The midregion (aa 67–86) of the peptide stimulates placental calcium transport (shaded box). The C-terminal region (aa 107–111) inhibits osteoclastic bone resorption (double hatched box).

similar functional activity is shared between the two peptides.

PTHrP messenger RNA and peptides have been demonstrated in cancer cells from patients with lung cancer and hypercalcemia. PTHrP has been shown to bind to PTH receptors in the bone and kidney, causing increased osteoclastic bone resorption, decreased bone formation, and decreased calciuria, leading to hypercalcemia. Levels of 1,25-dihydroxyvitamin D3 are suppressed in patients with PTHrP-induced hypercalcemia but are raised in patients with primary hyperparathyroidism. This difference occurs because renal α-hydroxylase activity is low in PTHrP-induced hypercalcemia, unlike primary hyperparathyroidism. PTH production by lung cancer cells has also been described, but it is a very rare cause of humoral hypercalcemia.

Other factors that cause bone resorption have been identified in the plasma of patients with lung cancer, including transforming growth factor-α and a vitamin D metabolite. These are very rare, however, and their causative role in hypercalcemia has not been shown conclusively.

Diagnosis The early symptoms of hypercalcemia include thirst, malaise, fatigue, anorexia, polyuria, constipation, nausea, and vomiting. As the hypercalcemia becomes increasingly severe, confusion, lethargy, coma, and death can occur. The demonstration of an increased concentration (greater than 10.5 mg/dl) of calcium in the serum of a patient with non–small-cell lung cancer should suggest this paraneoplastic syndrome.

When hypercalcemia is identified in a patient with lung cancer, other potential causes of elevated serum calcium should be excluded. Thiazide diuretics, vitamin D or lithium administration, hyperthyroidism, and sarcoidosis are potential causes. A PTH radioimmunoassay should be performed because up to 10 percent of hypercalcemia in patients with cancer is caused by primary hyperparathyroidism. Bone scintiscan should be obtained to exclude bone metastases, and a PTHrP level should be determined. An elevated PTHrP level in the absence of bone metastases establishes the diagnosis of humoral hypercalcemia of malignancy caused by ectopic PTHrP.

Treatment As with other paraneoplastic syndromes, treatment of the underlying cancer is the most effective method of treating the humoral hypercalcemia associated with lung cancer. Patients in whom lung cancer cannot be eradicated can be treated with intravenous saline plus furosemide diuresis. Subcutaneous calcitonin has a rapid onset of action and is most useful in severe cases. Mithramycin and long-acting biphosphonates, such as pamidronate, are effective for long-term control of hypercalcemia. Corticosteroids exert their effect through inhibition of dihydroxyvitamin D3 synthesis and therefore have less effect in patients with elevated PTHrP. This syndrome usually develops in patients with advanced progressive cancer. Therefore, reversal of hypercalcemia should be undertaken only when there is some hope

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Neoplasms of the Lungs

for control of the underlying cancer. It may be inappropriate to treat hypercalcemia in patients with far-advanced lung cancer, having them regain consciousness only to die of their underlying disease.

HYPONATREMIA OF MALIGNANCY Hyponatremia is a frequent complication in patients with cancer. More than 90 percent of cases occur in patients with small-cell lung cancer. Ten to 15 percent of patients with small-cell lung cancer and 1 percent of patients with non–small-cell lung cancer present with hyponatremia. Most of these cases are caused by the ectopic production of arginine vasopressin (AVP). This subset of hyponatremia is recognized as the syndrome of inappropriate antidiuretic hormone (SIADH). Ectopic production of atrial natriuretic peptide (ANP) may also play a role in the hyponatremia of malignancy, but the exact contribution of this hormone remains to be defined.

Biology AVP is a 9–amino acid peptide normally produced by the neurohypophysis. The peptide binds to receptors in the kidney to reduce the excretion of free water. When plasma osmolality exceeds 280 mOsmol/kg, the release of arginine vasopressin from the pituitary increases, causing the kidney to retain more free water and maintain fluid and osmolar balance. In patients with small-cell lung cancer, ectopic production of AVP causes hyponatremia by inhibiting free-water excretion in the distal tubule of the kidney. Arginine vasopressin mRNA is expressed

in small-cell lung cancer cells, and the peptide is translated and secreted (Fig. 108-2). Levels of AVP in plasma are increased.

A subgroup of patients with small-cell lung cancer and hyponatremia have been identified in whom the cancer and the cancer cell lines do not produce ectopic arginine vasopressin. The tumors from these patients express ANP mRNA, secrete the peptide, and have high levels of ANP in their plasma. ANP is the leading candidate to be the natriuretic factor that Bartter and Schwartz proposed in their original description of SIADH. Further investigation into the precise role of ANP in patients with small-cell lung cancer and hyponatremia of malignancy is ongoing.

Diagnosis In patients with lung cancer, hyponatremia is most frequently diagnosed as a laboratory abnormality in the absence of significant symptoms. The symptoms associated with acute hyponatremia do not typically occur because the syndrome develops over a prolonged period in concert with the growth of the lung cancer. The symptoms of mild hyponatremia (more than 120 mEq/ml) include headache, difficulty concentrating, nausea, weakness, and fatigue. Patients who develop a more acute hyponatremia may manifest confusion, lethargy, seizures, coma, and death.

In patients with lung cancer, nonmalignant causes of hyponatremia—including diuretic use, renal disease, cardiac dysfunction, hypoadrenalism, thyroid disease, and dilutional hyponatremia—should be considered in the initial evaluation. Medications that can induce SIADH include the chemotherapeutic agents cisplatin, vincristine, cyclophosphamide, and melphalan, along with narcotics, which are

Figure 108-2 Arginine vasopressin. The three exons of the human AVP gene rise to a 700-base arginine vasopressin mRNA. The mRNA is translated into a 164-amino acid (aa) preprohormone with a 19–amino acid amino terminal signal peptide (SP).

The signal peptide is cleaved, giving rise to a 145– amino acid prohormone. This prohormone is processed into the AVP nonapeptide (AVP), a 93–amino acid neurophysin (NP), and a 40–amino acid glycoprotein (GP). The black portions of the boxes represent the protein-coding portion of the gene and mRNA.

1933 Chapter 108

commonly used in patients with lung cancer. The subgroup of hyponatremic patients with the diagnosis of SIADH should satisfy the following criteria: (1) plasma hypoosmolality (under 280 mOsmol/kg); (2) osmolality of urine greater than serum (usually over 500 mOsmol/kg); (3) persistent urinary excretion of sodium in the absence of diuretics (more than 20 meq/l); (4) absent signs of volume depletion; and (5) normal renal, adrenal, and thyroid function.

Treatment The initial therapy for hyponatremia caused by lung cancer is treatment of the underlying malignancy. This requires chemotherapy and/or radiotherapy for patients with smallcell lung cancer and surgery for non–small-cell lung cancers. In many patients, despite an initial tumor response to chemotherapy, the syndrome of hyponatremia persists or recurs after the cancer regrows. In these patients, the short-term treatment for mild hyponatremia is fluid restriction of 500 ml per day. Many patients with cancer cannot tolerate this level of fluid restriction for extended periods, so other treatments are usually required. Demeclocycline is the medication of choice for chronic management of SIADH in patients with small-cell lung cancer. When given in doses of 600 to 1200 mg orally per day, demeclocycline blocks the action of AVP on the renal tubule, inducing a diabetes insipidus that will correct the hyponatremia in most patients. Lithium and phenytoin also can be used to inhibit the effects of AVP on the renal tubule, but administration of these agents is limited by their neurologic side effects.

In patients who present with severe, symptomatic hyponatremia, the intravenous administration of 3 percent hypertonic saline, along with the intravenous administration of furosemide, is recommended. The intravenous administration of furosemide rapidly causes an increase in the net free-water clearance. This method has been used successfully in patients with small-cell lung cancer. It can increase the concentration of sodium in serum from 120 to 133 mEq/l in 6 to 8 h. Overly rapid correction of the level of sodium in serum (more than 2 mEq/h) in patients with hyponatremia has been associated with a central pontine myelinolysis. Therefore, frequent measurements of serum sodium during treatment with hypertonic saline are required to avoid this complication.

ECTOPIC ACTH SYNDROME Cushing’s syndrome was first recognized in a patient with lung cancer caused by the ectopic production of ACTH. Twenty to 30 percent of Cushing’s syndrome is caused by biologically active ACTH, which is produced by nonpituitary neoplasms.

Lung cancers are the most common neoplasms that cause ectopic ACTH production and Cushing’s syndrome, accounting for 50 percent of all cases. Small-cell carcinoma accounts for 80 to 90 percent of cases associated with lung cancers, but car-

Extrapulmonary Syndromes Associated with Lung Tumors

cinoid tumors (10 percent) and bronchial adenocarcinomas (5 percent) have also been reported to produce biologically active ACTH. Although one-half of all cases of ectopic ACTH production are caused by small-cell carcinoma, fewer than 3 percent of patients with small-cell lung cancer have Cushing’s syndrome at the time of diagnosis.

Biology Most cases of ectopic ACTH syndrome associated with lung cancers are caused by ectopic production of ACTH by the tumor. The precursor gene, pro-opiomelanocortin (POMC), is expressed in the cancer cells, and a 241–amino acid prohormone is translated and then cleaved into ACTH (39 amino acids), melanocyte-stimulating hormone, and opiatelike hormones (Fig. 108-3). The ACTH binds to receptors in the adrenal gland, causing them to produce excessive glucocorticoid and mineralocorticoid hormones.

A small number of patients with small-cell lung cancer or bronchial carcinoids have been reported to produce corticotropin-releasing hormone (CRH), thereby causing Cushing’s syndrome. CRH is a 41–amino acid normally produced in the paraventricular nuclei of the hypothalamus, which stimulates the release of ACTH from the pituitary. In patients with small-cell carcinoma or bronchial carcinoid, CRH is produced by the cancer cells, thereby stimulating ACTH production by the pituitary gland and causing Cushing’s syndrome.

Diagnosis Ectopic ACTH production occurs with equal frequency in males and females—unlike Cushing’s syndrome, which has an 8:1 female preponderance. Patients who have slow-growing tumors (carcinoids) often present with the clinical features of Cushing’s syndrome: truncal obesity, moon facies, striae, polyuria, and polydipsia. In contrast, patients with small-cell lung cancer often present with other signs of mineralocorticoid and glucocorticoid excess due to the rapidity of tumor growth: edema, weakness, hypertension, and hypokalemic alkalosis.

The diagnosis of ectopic ACTH syndrome is established by the demonstration of increased 24-h excretion of urinary free cortisol (more than 400 nmol a day), increased plasma cortisol level (more than 600 nmol/l), and increased plasma ACTH level (over 22 pmol/l), which do not decrease in response to the administration of high-dose dexamethasone.

Bronchial carcinoids are an exception because, in some tumors, ACTH and cortisol levels have been suppressed by dexamethasone. In patients in whom the dexamethasone suppression test does not establish the diagnosis of ectopic ACTH production, a CRH stimulation test or bilateral inferior petrosal vein sampling will provide the definitive diagnosis. After CRH infusion, pituitary tumors release increased amounts of ACTH, whereas pituitary-independent lung tumors should not. Similarly, in pituitary-dependent Cushing’s syndrome, petrosal vein sampling will reveal a gradient between the level

1934 Part XV

Neoplasms of the Lungs

Figure 108-3 Pro-opiomelanocortin. The three exons of the POMC gene give rise to a 1072-base POMC mRNA. The mRNA is translated into a 267-amino acid pre-POMC with a 26–amino acid amino terminal signal peptide (SP). The signal peptide is cleaved, creating the 241–amino acid POMC. The POMC peptide is cleaved into many products, including the N-terminal peptide (NT), the joining peptide (JP), a 39–amino acid mature ACTH, and β-lipotropin (BLPH).

The molecules can also undergo further processing. The black portions of the exons represent the protein-coding portion of the gene and mRNA.

of ACTH in the petrosal vein and the peripheral concentration. In contrast, patients in whom ACTH is ectopically produced demonstrate no gradient between the petrosal vein and the peripheral blood.

Treatment Management of a patient with lung cancer and ectopic ACTH syndrome requires therapy directed at both the underlying tumor and the hypercortisolism. The treatment for a patient with ectopic ACTH production is to remove the source of the ACTH. This requires combination chemotherapy, with or without irradiation, for patients with small-cell lung cancer and surgical resection and/or radiation for patients with carcinoid tumors. Chemotherapy for patients with small-cell lung cancer and ectopic ACTH syndrome has been only minimally successful. Patients often have a poor response to chemotherapy and are susceptible to early infection and death. Early control of a patient’s glucocorticoid excess is beneficial and may reduce the morbidity of treatment.

When removal of the ectopic source of ACTH is not possible, medical therapy directed at decreasing adrenal secretion may be successful. Ketoconazole is an imidazole derivative that inhibits steroidogenesis at both adrenal and gonadal sites. A recent review of medical therapy for ectopic ACTH syndrome suggests that ketoconazole may be the most effective and least toxic agent available. Metapyrone and aminoglutethimide also have shown limited success by inhibiting adrenal steroid synthesis. Octreotide, a so-

matostatin analogue, can suppress ectopic ACTH production and has been reported to be useful in some of these patients.

In some patients, the clinical signs and symptoms of ectopic ACTH production develop before the development of a clinically obvious lung cancer. In these cases, symptomatic management of hypercortisolism is undertaken and periodic imaging studies are performed because these patients may have a slow-growing carcinoid tumor that will be amenable to surgical resection.

ACROMEGALY Carcinoid tumors of the lung and intestine are responsible for 70 percent of cases of ectopic acromegaly. Ectopic production of growth hormone–releasing hormone (GHRH) by tumor cells can be demonstrated in most patients, whereas a minority of tumors produce growth hormone.

Biology The ectopic production of GHRH or GH by lung cancers has been demonstrated to cause acromegaly. In most cases, the GHRH gene is expressed by the cancer cells, and a 40– or 44– amino acid peptide is produced. This peptide is secreted into the circulation and binds to receptors in the pituitary gland, causing the production of excessive amounts of GH. GH then

1935 Chapter 108

mediates its effects through GH receptors in soft tissue and by stimulating the production of insulinlike growth factor–1 (IGF-1).

Immunoreactive GHRH can be identified in many bronchial carcinoids and small-cell lung cancers, but acromegaly occurs in a minority of these patients. Ectopic GHRH production may not cause clinically evident acromegaly because: (1) the tumor produces inadequate amounts of GHRH to cause the clinical syndrome; (2) the hormone is synthesized but not secreted; or (3) the rapid progress of the malignancy prevents the full development of clinical features of acromegaly.

Diagnosis The earliest features of GH excess are hypertrophy of the extremities and face (forcing increased glove, shoe, and ring size), thickened leathery skin, prominent skin folds, increased skin pigmentation, and hair growth. Bony changes, hypertension, and diabetes mellitus are later, less common findings.

The presentation of a patient with a lung mass and signs of acromegaly should raise suspicion of the paraneoplastic syndrome of acromegaly. This is particularly true if the lung tumor is a carcinoid. The diagnosis is established by the presence of increased levels of GHRH and IGF-1 in the patient’s plasma, the absence of a pituitary tumor, and the demonstration of GHRH or GH in tumor tissue by immunohistochemistry or mRNA expression studies. Because coincidental pituitary tumors and solid tumors have been described, patients who have lung cancer in association with low GHRH levels and high GH and IGF-1 levels should undergo magnetic resonance imaging (MRI) to exclude a pituitary tumor.

Treatment The treatment of choice for ectopic acromegaly is removal of the GHRH- or GH-secreting tumor. This can often be achieved in patients with lung carcinoid tumors. Radiation therapy has also been effective. Patients with ectopic acromegaly whose tumors cannot be removed or irradiated should undergo medical therapy using the somatostatin analogue octreotide or bromocriptine. Bromocriptine acts by inhibiting GH release by the pituitary; octreotide lowers both GH and IGF-1 levels in plasma and also appears to inhibit GHRH release by tumors. Clinical abatement of acromegalic features has been reported in patients treated with octreotide.

Extrapulmonary Syndromes Associated with Lung Tumors

logic syndromes, such as granulocytosis and thrombocytosis, clinical sequelae are often absent. As with the endocrine paraneoplastic syndromes, the most appropriate therapy for the hematologic syndromes is the treatment of the underlying neoplasm.

Granulocytosis Non–small-cell lung cancer is the most common cancer associated with granulocytosis. Twenty percent of patients with non–small-cell lung cancer have granulocytosis, with absolute white blood counts ranging from 10,100 to 25,000 (normal range is 4000 to 10,000).

Although granulocyte colony–stimulating activity can be demonstrated in serum and/or urine in 80 percent of patients, the specific peptide hormone causing the syndrome has not been identified. Tumor production of granulocyte colony–stimulating factor (G-CSF), granulocyte-monocyte colony–stimulating factor (GM-CSF), and interleukin-6 (IL-6) has been shown in a minority of patients.

Virtually all patients with lung cancer who present with tumor-associated granulocytosis are asymptomatic. The diagnosis is suggested by the presence of an increased white blood count in which neutrophils predominate without immature forms, in the absence of nonneoplastic causes. An increased leukocyte alkaline phosphatase score and a normal bone marrow are consistent with this diagnosis.

Thrombocytosis Thrombocytosis is common in patients with lung cancer, afflicting 40 percent of patients with both non–small-cell and small-cell tumors.

The pathogenesis of thrombocytosis in patients with lung cancer has not been definitively elucidated. IL-6, which is a cytokine for megakaryocytes, has been demonstrated in cell lines from patients with lung cancer and thrombocytosis, and increased levels of IL-6 have been demonstrated in the plasma of such patients. The recent identification of the thrombopoietin gene should lead to a better understanding of the role of this protein in paraneoplastic thrombocytosis.

Patients with thrombocytosis are nearly always asymptomatic and do not have an increased incidence of thromboembolism. The diagnosis of cancer-associated thrombocytosis is suggested by an increased platelet count (above 500,000/mm2 ) in a patient with newly diagnosed lung cancer.

A primary myeloproliferative disorder can be excluded only by a bone marrow biopsy.

Thromboembolism HEMATOLOGIC SYNDROMES Most hematologic syndromes associated with lung tumors are not as well characterized as the endocrine syndromes, because the ectopic hormone responsible for the syndrome has not been identified in most tumor tissues. In many of the hemato-

Twenty percent of patients with lung cancer develop venous thromboembolism during the course of their disease. Twenty percent of patients who present with recurrent idiopathic venous thrombosis are found to have an underlying diagnosis of cancer. The spectrum of causes of thrombosis in patients with lung cancer is broad, including disseminated intravascular

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coagulation (DIC), Trousseauâ&#x20AC;&#x2122;s syndrome (recurrent migratory venous thrombophlebitis), nonbacterial thrombotic endocarditis, and obstruction of great vessels. Surgical procedures and chemotherapy have also been demonstrated to increase cancer patientsâ&#x20AC;&#x2122; risk of thrombotic complications.

The treatment for venous thrombosis in patients with lung cancer depends on the underlying hematologic diagnosis. If the patient has an isolated venous thrombosis in the absence of DIC or Trousseauâ&#x20AC;&#x2122;s syndrome, oral warfarin therapy is appropriate with the aim of an international normalized ratio two to three times normal. If there are recurrent thromboses, long-term subcutaneous heparin is more efficacious than warfarin.

Hu, which reacts with the HuD antigen expressed by lung cancer cells and neuronal tissues, has been associated with the development of this syndrome.

Biology The anti-Hu antibody is an IgG antibody found in the sera of patients with sensory neuropathy and encephalomyelitis.

This antibody reacts with 35- to 40-kD neuronal nuclear antigens in the cerebral cortex, brain stem, cerebellum, spinal cord, and dorsal root ganglia, and it reacts with surface proteins on some small-cell lung cancer cells. The HuD gene has been mapped to the chromosome 1p region and appears to be a marker of neuroendocrine differentiation in these cells.

Diagnosis

NEUROLOGIC SYNDROMES Neurologic dysfunction as a paraneoplastic manifestation of lung cancer was first described more than 30 years ago.

Encephalomyelitis, cerebellar degeneration, retinopathy, opsoclonus/myoclonus, and the Lambert-Eaton syndrome have all been associated with lung tumors, most commonly smallcell lung cancer. Most of these neurologic paraneoplastic syndromes appear to be caused by an autoimmune response directed at antigens that are shared by the cancer cells and normal neural tissue. Unlike that of the endocrine and hematologic syndromes associated with lung cancer, the clinical courses of the neurologic syndromes are typically independent of the course of the underlying disease. The autoantibodies associated with each neurologic syndrome are listed in Table 108-2.

Encephalomyelitis/Subacute Sensory Neuropathy The paraneoplastic syndrome of encephalomyelitis/subacute sensory neuropathy was initially discovered in a patient with small-cell lung cancer. Currently, more than 70 percent of cases of paraneoplastic encephalomyelitis are diagnosed in patients with small-cell lung cancer. A specific antibody, anti-

The clinical features of this syndrome are diverse. One-half of patients undergo progressive sensory loss in the hands and feet. Others present with a limbic encephalopathy characterized by memory loss, behavioral changes, and seizures. Focal myelopathy with weakness, brain stem signs (nystagmus, dysarthria), and autonomic nervous system dysfunction also occur in patients with this syndrome. These clinical signs and symptoms can antedate the diagnosis of lung cancer, so a full evaluation for occult cancer in patients who present with encephalomyelitis or subacute sensory neuropathy is warranted. CT scans are typically normal in these patients, but MRI studies may show increased T2 signal in affected areas of the brain. Pathologic examination of brain biopsies show inflammatory infiltrates and neuronal destruction in the brain stem, hippocampus, spinal cord, and dorsal root ganglia. The demonstration of anti-Hu antibodies in a patient with encephalomyelitis and a diagnosis of small-cell lung cancer establishes the diagnosis.

Treatment Treatment of the encephalomyelitis/subacute sensory neuropathy syndrome associated with lung cancer is treatment of the primary tumor. Immunosuppressive therapy with

Table 108-2 Neurologic Syndromes Associated with Lung Cancer Syndrome

Tumor

Antibody

Antigen

Encephalomyelitis/subacute sensory neuropathy

Small-cell

Anti-Hu

Hu-D antigen: 35- to 40-kD neuronal nuclear protein

Cancer-associated retinopathy

Small-cell

Antirecoverin

23-kD protein specific to photoreceptor cells (recoverin)

Lambert-Eaton syndrome

Small-cell

Anti-P/Q channel

P/Q-type calcium channel

1937 Chapter 108

corticosteroids and plasmapheresis directed at removal of the offending immunoglobulin from the patientâ&#x20AC;&#x2122;s serum have been shown to be effective in only 10 to 20 percent of patients. Patients who are severely affected by the antiHu syndrome can die from neurologic sequelae (e.g., cardiovascular collapse) rather than from the underlying lung cancer.

Extrapulmonary Syndromes Associated with Lung Tumors

Biology Retinal ganglion cells and their processes are characteristically lost in this disorder because of the autoantibodies that bind to recoverin, a 23-kD photoreceptor-specific protein found in rods and cones as well as in small-cell lung cancer cells. The autoantibodies that cause the cancer-associated retinopathy specifically bind to the recoverin protein and do not recognize other retinal proteins.

Paraneoplastic Cerebellar Degeneration A syndrome of cerebellar degeneration has also been noted in patients with small-cell lung cancer. This is believed to be a variant of the paraneoplastic cerebellar degeneration (PCD) observed in patients with gynecologic and breast tumors. In patients with gynecologic tumors and PCD, a specific antiPurkinje cell antibody called anti-Yo has been identified that binds to 34- to 38-kD and 62- to 64-kD proteins in the cytoplasm of Purkinje cells. Patients with small-cell lung cancer and cerebellar degeneration have anti-Hu antibodies in their sera and do not have the anti-Yo antibody. These patients are considered to have the anti-Hu syndrome and frequently go on to develop encephalitis or sensory neuropathy.

Opsoclonus and Myoclonus Opsoclonus is a disorder consisting of involuntary rapid conjugate eye movements in vertical and horizontal directions.

It is often associated with myoclonus in patients with solid tumors. This syndrome of opsoclonus/myoclonus has been associated with both small-cell and nonâ&#x20AC;&#x201C;small-cell lung cancer in numerous case reports, but less is known about this syndrome than about the syndrome of paraneoplastic encephalomyelitis/subacute sensory neuropathy.

A specific antibody called anti-Ri has been identified that binds to 55-kD nuclear proteins expressed in the dentate nucleus. Although this antibody is considered to be the cause of the opsoclonus/myoclonus syndrome in patients with gynecologic tumors, the antibody has not been demonstrated in patients with lung cancer.

The anti-Hu antibody has been identified in some patients with small-cell lung cancer and opsoclonus/myoclonus.

As in patients with the anti-Hu antibody and cerebellar degeneration, patients who have opsoclonus and the anti-Hu antibody may have a variant of the encephalomyelitis/subacute sensory neuropathy syndrome. Patients who present with lung cancer and opsoclonus should be evaluated for the antiHu antibody.

Diagnosis The clinical triad of photosensitivity, ring-scotomata visual field loss, and attenuation of retinal arteriole caliber is considered highly suggestive of cancer-associated retinopathy. The typical patient presents with symptoms of rapid visual loss, night blindness, and color loss. On physical examination, most patients show visual field deficits, disk pallor, and cells in the vitreous body, along with arteriolar narrowing.

Demonstration of the antirecoverin antibody in a patient with signs of retinopathy establishes the diagnosis. As with paraneoplastic cerebellar degeneration, cancerassociated retinopathy is often the first sign of an occult carcinoma. Therefore, an evaluation for lung cancer should be performed in all patients who present with this syndrome.

Treatment In contrast to those with the other paraneoplastic neurologic syndromes, more than half of patients with cancer-associated retinopathy have been reported to respond with visual improvement after systemic steroid therapy. Treatment of the primary tumor without immunosuppressive therapy has not been shown to cause visual improvement in patients with cancer-associated retinopathy. Most of these patients develop progressive visual loss and blindness within 18 months.

LAMBERT-EATON SYNDROME The Lambert-Eaton syndrome afflicts fewer than 2 percent of lung cancer patients but has been reported in up to 5 percent of patients with small-cell lung cancer. Sixty percent of all patients who present with the Lambert-Eaton syndrome have small-cell lung cancer.

Biology CANCER-ASSOCIATED RETINOPATHY Cancer-associated retinopathy is a rare paraneoplastic syndrome that occurs predominantly in patients with small-cell lung cancer. Many autoantibodies have been identified in patients with this disorder; they bind to a photoreceptor-specific protein called recoverin.

In patients with Lambert-Eaton syndrome and small-cell lung cancer, an IgG autoantibody has been identified that binds to calcium channels in motor and autonomic nerve terminals, thereby inhibiting acetylcholine release. This antibody also binds to the 58-kD synaptic vesicle protein synaptotagmin, which is present in small-cell lung cancer cells. Recent evidence suggests that the P/Q calcium channel is the specific target of these antibodies. The antibody binding of the

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P/Q calcium channel weakens the neuromuscular signal, and neurologic dysfunction follows. It has also been postulated that these autoantibodies induce the production of acetylcholinesterase, which would also diminish the neuromuscular signal.

Diagnosis Clinical features include weakness of the pelvic girdle and thigh, fatigue, dry mouth, dysarthria, dysphagia, blurred vision, and muscle pain. Unlike the situation with myasthenia gravis, muscle strength improves with exercise and does not improve significantly with the administration of anticholinesterases (e.g., edrophonium). Electromyography performed in these patients demonstrates increased muscle action potential with repeated nerve stimulation. In patients with the Lambert-Eaton syndrome, IgG autoantibodies should be demonstrable in serum.

Treatment Treatment of the underlying small-cell lung cancer with chemotherapy can effectively treat the associated LambertEaton syndrome. For patients whose neuromuscular status does not improve with chemotherapy, immune modulation with azathioprine (2.5 mg/kg per day), plasma exchange, or intravenous γ -globulin (400 mg/kg per day for 5 days) has been shown to induce remissions. 3,4-Diaminopyridine in doses of 10 to 100 mg a day has also been used successfully to bring about short-term control of this syndrome.

CONCLUSION The paraneoplastic syndromes have long fascinated and perplexed oncologists, and only in recent years have the molecular bases for these syndromes been appreciated. Not only has this new knowledge led to more effective palliation of symptoms, but it may also offer new clues to the pathogenesis of malignancy. The presence of signs and symptoms that suggest a paraneoplastic syndrome should prompt a search for malignancy.

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Bender RA, Hansen H: Hypercalcemia in bronchogenic carcinoma: A prospective study of 200 patients. Ann Intern Med 80:205–208, 1974.

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Goldstein SM, Syed NA, Milam AH, et al.: Cancer-associated retinopathy. Arch Ophthalmol 117:1641–1645, 1999.

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Gross AJ, Steinberg SM, Reilly JG, et al.: Atrial natriuretic factor and arginine vasopressin production in tumor cell lines from patients with lung cancer and their relationship to serum sodium. Cancer Res 53:67–74, 1993.

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Extrapulmonary Syndromes Associated with Lung Tumors

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109 Pulmonary Metastases Richard S. Lazzaro

Joseph LoCicero, III

I. PATIENT SELECTION, OPERABILITY, AND RESECTABILITY II. TISSUE HISTOLOGY, DISEASE-FREE INTERVAL, AND NUMBER OF METASTASES Sarcoma Colorectal Cancer Metastatic Melanoma Non-Seminomatous Germ Cell Tumors Breast Carcinoma Other Cancers Metastatic to the Lungs

Pulmonary metastasis represents the dissemination of cancer cells with establishment of local residence in the pulmonary parenchyma. Recent advances in technology have allowed basic science to further elucidate not only the cellular and metastatic signature, but also the metastatic cascade.

Krishnan describes a six-step model of the metastatic cascade involving intravasation, resistance to anoikis, evasion of the immune system, extravasation, dormancy, and proliferation. Matrix metalloproteases, up-regulated by cancer cells, have the ability to degrade the extracellular matrix, allowing the cells access to the vasculature. Krishnan states, “Loss of cell-cell or cell-matrix interaction triggers the activation of the caspase proteases, the hallmark of cell death.”

Metastatic cancer cells that do not undergo apoptosis survive through the development of homotypic as well as heterotypic interactions, thereby resisting anoikis (apoptotic cell death when a cell loses interaction with the extracellular matrix).

These cells can avoid immunosurveillance through downregulation of antigens as well as production of immunosuppressive cytokines. Extravasation requires interaction of metalloproteases and degradation of extracellular matrix along with the addition of basement membrane to cell adhesion molecules (CAM). Metastases may remain dormant for many years, becoming clinically relevant only when turned on by angiogenesis controls, immune mediated growth suppres-

V. EXTENT OF AND APPROACH TO RESECTION VI. ROLE OF MEDIASTINAL NODAL EVALUATION AND EFFECT ON OUTCOME VII. ISOLATED LUNG PERFUSION VIII. CONCLUSIONS

sion, or other mechanisms. The process of neovascularization leads to proliferation. Potential therapeutic strategies include anti-VEGF monoclonal antibody, tyrosine kinase inhibitors, and the anti-EGFR antibody cetuximab.

However, the presence of metastatic disease connotes a negative prognosis for the patient. SEER (Surveillance Epidemiology and End Results) Cancer statistics review (1975– 2003; Table 109-1) shows 5-year survival rates for patients with colon and rectal carcinoma sink to 9.1 percent versus 90.5 percent for patients with distant versus localized disease. Five-year survival rates for breast cancer are reduced from 97.5 to 24.2 percent when the patient develops distant disease. Five-year survival from esophagus cancer is reduced from 29.4 to 2.5 percent when the patient goes from localized to distant disease. The SEER report shows similar trends for lung, pancreas, melanoma, and stomach cancer. Despite improvements in multimodality therapy for oncologic disease, survival from metastatic disease remains poor. However, multiple retrospective observational studies demonstrate a survival benefit for carefully selected patients who present with pulmonary metastasis and who can tolerate complete resection of all metastatic disease.

In 1882, Weinlechner performed the first lung resection for pulmonary metastasis. The principles established

by Alexander and Haight in 1947 regarding a controllable

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 109-1 Five Year Survival Data by Primary Cancer Site Primary Histology

Distant Disease

Local Disease

Lung

2%

59%

Breast

21%

100%

Colon and rectum

8%

96%

Pancreas

1.7%

17%

Melanoma Stomach

15.1% 2.8%

97.6% 60%

primary site of malignant disease, and the absence of extrapulmonary metastasis in conjunction with a medically fit patient remain cornerstones of surgical management decisions regarding patients with pulmonary metastasis. Furthermore, the international registry of lung metastases in 1997 developed a model of prognostic grouping, based on resectability, disease-free interval, and number of metastases. Resectable patients with isolated solitary pulmonary metastasis and prolonged disease-free interval of more than 36 months had a median survival of 61 months compared with resectable patients with a disease-free interval of less than 16 months and multiple metastases (greater than 1). In 2007, Petersen and colleagues reviewed their experience with 1720 patients with pulmonary metastatic melanoma and corroborated the above, noting that the number of pulmonary nodules, disease-free interval, and presence of extrathoracic metastasis are significant prognostic factors.

Metastasectomy has always and continues to be controversial. The current salient issues include: patient selection, operability and resectability, tissue histology, disease-free interval, number of metastasis, presence of extrathoracic disease, the role of mediastinal lymph node evaluation, open versus thoracoscopic approach, unilateral versus bilateral assessment, and the role of removal of radiographic disease versus palpable disease.

PATIENT SELECTION, OPERABILITY, AND RESECTABILITY Patients presenting with pulmonary metastatic disease often are evaluated by the thoracic surgical oncology team in a similar manner to a primary lung cancer patient. After establishing that the metastatic burden is confined to the lungs and that the primary site is controlled or controllable, cardiac

risk assessment and pulmonary functional assessment should be performed. Patients who can tolerate resection of all pulmonary metastases are recommended to undergo pulmonary metastasectomy. Patients with metastatic colorectal cancer to liver and lung are an exception to the requirement of no extrathoracic metastatic disease. Such patients can benefit from hepatic and pulmonary metastasectomy with anticipated 30 to 44 percent 5-year survival.

TISSUE HISTOLOGY, DISEASE-FREE INTERVAL, AND NUMBER OF METASTASES Sarcoma Following the principles previously outlined, pulmonary metastasectomy for osteosarcoma and soft tissue sarcoma can lead to 43.6 percent (range 22.6â&#x20AC;&#x201C;43.6 percent) 5-year survival.

Repeat metastasectomy also has prolonged 5-year survival.

Pfannschmidt et al. reported on pulmonary metastasectomy in 50 patients with soft tissue sarcoma who underwent systematic hilar and mediastinal lymph node dissection. Lymph node metastases were identified in 24 percent (n = 12). Survival was decreased in the patients with lymph node involvement, but was not statistically significant. Currently, routine mediastinal and hilar lymph node evaluation for patients with metastatic soft tissue sarcoma to the lungs cannot be recommended and needs further trials.

For sarcomas, a disease-free interval of more than 1 year and primary tumor necrosis greater than 98 percent following neoadjuvant chemotherapy have been shown to correlate with improved survival following pulmonary metastasectomy.

Colorectal Carcinoma Five-year survival rates between 35 and 45 percent can be achieved with pulmonary metastasectomy for colorectal pulmonary metastasis. Elevated CEA levels greater than 10 as well as regional hilar and mediastinal lymph node involvement are negative prognostic indicators. Saito et al. stated in 2002: Five-year survival was 53.6% for patients without hilar or mediastinal lymph node metastasis, versus 6.2% at 4 years for patients with metastases ( p < 0.001). Five-year survival of patients with a prethoracotomy carcinoembryonic antigen level less than 10 ng/mL was 42.7%, versus 15.1% at 4 years for patients with a carcinoembryonic antigen level 10 ng/mL or greater ( p < 0.0001).

Therefore, it seems prudent that routine mediastinal as well as hilar nodal sampling should be considered for patients undergoing pulmonary metastasectomy for colorectal metastasis.

Prolonged disease-free interval has not consistently correlated with improved outcome. Multiple pulmonary metastases (greater than 3 lesions) have been shown to negatively affect survival.

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Pulmonary Metastases

Metastatic Melanoma

Other Cancers Metastatic to the Lungs

Petersen and colleagues reviewed the Duke experience with 1720 patients who experienced metastatic pulmonary melanoma. Overall 5-year survival was 6 percent. Nodular histology of the primary tumor, two or more metastases, disease-free interval less than 5 years, and the presence of extrathoracic metastasis were associated with poorer prognosis.

Similar to the international registry of lung metastases, prognostic grouping was performed. Five-year survival decreased from 26 percent to 11 percent to 4 percent to 2 percent as associated risk factors increased from 0 to 1 to 2 to 3 or more.

They performed unilateral thoracotomy in 255 patients undergoing resection, thoracoscopy in 40 patients, and bilateral thoracotomy in 23 patients. Wedge resection was the most frequent type of resection.

Prolonged 5-year survival following pulmonary metastasectomy may be realized for renal cell carcinoma, uterine cancer, hepatocellular carcinoma, and head and neck cancers.

Non-Seminomatous Germ Cell Tumors Non-seminomatous germ cell tumors disseminate along the course of the thoracic duct, leading to mediastinal metastases as well as pulmonary metastases. Cisplatin-based chemotherapy is the primary treatment, with surgical salvage for residual disease. The majority of patients with residual disease have either conversion to mature teratoma (59 percent) or necrotic tumor (15 percent). Pulmonary metastasectomy is associated with prolonged survival in patients with metastatic non-seminomatous germ cell tumors, from 59 to 82 percent 5-year survival. The presence of an increase in elevated tumor markers (AFP and B-HCG), viable tumor cells, incomplete resection, four or more metastases, and pulmonary as opposed to mediastinal metastases negatively affect survival. The disease-free interval has not been shown to affect survival.

Breast Carcinoma Complete resection of pulmonary metastatic breast cancer can be accomplished in 77 to 84 percent of patients. Although 5-year survival following pulmonary metastasectomy secondary to breast carcinoma approaches 38 to 50 percent, effective medical oncologic management is preferred over surgery for initial treatment. Disease-free intervals greater than 36 months are associated with improved survival following metastasectomy. If the size of the largest metastasis is greater than 20 mm, there is negative impact on survival.

Although multiple metastatic lesions have not been shown conclusively to affect survival negatively, treatment of the solitary pulmonary nodule in a patient with a history of breast carcinoma remains a challenge. This is particularly true because the ability to distinguish a solitary metastasis from primary lung carcinoma may not be possible. Thus, solitary pulmonary nodules should be treated as primary lung carcinoma until proved otherwise. When treated as a primary lung cancer, the planned resection is different and includes mediastinal lymphadenectomy or nodal sampling.

EXTENT OF AND APPROACH TO RESECTION The goal of pulmonary metastasectomy is to accomplish a complete (R0) resection while using optimal pulmonary conservation techniques (i.e., wedge resection). Dowling, et al. at University of Pittsburgh reported the first use of video-assisted thoracic surgery (VATS) for pulmonary metastasectomy in 1992. Subsequent to that report, many centers routinely perform VATS pulmonary metastasectomy.

Ketchedjian et al. argue that VATS metastasectomy should be limited to two or fewer metastases located in the outer one-third of the lung and be resectable by VATS. Opponents of VATS or a minimally invasive approach to pulmonary metastasectomy argue that it is necessary to perform bimanual palpation of the lung to assess for additional metastases not identified on preoperative radiographic evaluation. Complete resection (R0) rendering the patient pathologically free of metastatic disease can be accomplished by this approach.

McCormack et al. from Memorial Sloan-Kettering Cancer Center (MSKCC) performed VATS metastasectomy of all radiographically identified nodules (inclusion criteria were no more than two unilateral nodules) followed by immediate conversion to thoracotomy and bimanual palpation. They found that additional malignant nodules were present in 10/18 (56 percent) of their patients. Helical CT was used in 2 of 18 patients. They concluded that VATS was an inadequate surgical option for resecting all disease (R0 resection). Despite the fact that pulmonary metastases are hematogenous in origin, mandatory exploration of the radiologically negative hemithorax is not the standard approach for these investigators and was not performed in this experimental cohort.

Of the International Registry of Lung Metastases database of 5206 patients who had metastasectomies, 4572 (88 percent) patients underwent R0 resections: 2.4 percent had residual microscopic disease (R1), and an additional 9.7 percent had residual macroscopic disease (R2). Of the 88 percent of patients who underwent an R0 resection, only 2 percent had minimally invasive approach or thoracoscopy and 58 percent had a monolateral thoracotomy. Based on pathological assessment, single metastases were identified in 46 percent of patients. Radiologic accuracy for unilateral thoracotomy was 75 percent; underestimation of tumor burden occurred in 16 percent. If one were to extrapolate the data from MSKCC regarding the finding that bimanual palpation reveals additional metastases in 56 percent of the patients, one would expect a lower percentage of solitary metastasectomy to have been performed in the international registry group.

This is not the case. Repeat metastasectomy in the international registry was associated with 44 percent 5-year survival

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(â&#x20AC;&#x153;remarkably goodâ&#x20AC;?). As we learn more about the metastatic cascade, it seems plausible that metastatic dormancy, avoidance of immunosurveillance through antigen downregulation, and production of immunosuppressive cytokines may be partially responsible for the good results achieved with VATS metastasectomy as well as unilateral thoracotomy for pulmonary metastasectomy.

With evolving technology, such as 64 slice CT scanners, the ability to detect smaller lesions will continue to improve.

The improvement in PET scans to detect probable mitotic activity continues to gain better resolution at lower levels. Use of intraoperative ultrasound as well as wire-guided localizations, in conjunction with minimally invasive techniques, will allow surgeons to identify and remove metastatic nodules not previously identified radiographically, but appreciated on bimanual palpation. Radiologic complete resection is merging with complete resection of all palpable disease. Thus, consideration for a new paradigm may be warranted. Now is the time to establish the category of radiographic complete resection (R-R0). Such an approach would require postoperative surveillance CT scans and possibly PET scans at 3-month intervals following resection.

dergoing pulmonary metastasectomy secondary to colorectal carcinoma prior to pulmonary metastasectomy. Mediastinal node involvement should be considered a contraindication to metastasectomy.

Pfannschmidt et al. later evaluated 191 patients with pulmonary metastases secondary to renal cell carcinoma and found a 29.8 percent incidence of lymph node metastases. Despite a significant decrease in 3-year survival from 55.4 to 31.4 percent for patients with mediastinal or pulmonary lymph node metastases ( p = 0.0038), prolonged survival is seen in patients with pulmonary and thoracic nodal metastatic renal cell carcinoma. Therefore, the presence of mediastinal adenopathy in these patients is not a contraindication to metastasectomy.

For other histology, further investigation is warranted to evaluate the role of mediastinal lymph node evaluation, mediastinal lymph node dissection, mediastinal lymph node impact on survival, and the decision to proceed with pulmonary metastasectomy.

ISOLATED LUNG PERFUSION ROLE OF MEDIASTINAL NODAL EVALUATION AND EFFECT ON OUTCOME Routine mediastinal and hilar nodal sampling is not performed uniformly. Although the International Registry of Lung Metastases found a 4.6 percent incidence of lymph node metastases, only 5 percent of patients underwent mediastinal lymph node evaluation. Autopsy studies of patients with non-pulmonary carcinoma demonstrate a 33 percent incidence of mediastinal lymph node metastases. Since there is a trend toward decreased survival when mediastinal or hilar lymph node metastases are present, Pfannschmidt and colleagues have attempted to elucidate further the incidence as well as impact of mediastinal lymph node metastases. They reported on pulmonary metastasectomy in 50 patients with soft tissue sarcoma who underwent systematic hilar and mediastinal lymph node dissection. Lymph node metastases were identified in 24 percent (n = 12). Survival tended to be decreased in the patients with lymph node involvement, but was not statistically significant from those without nodal metastasis. Routine mediastinal and hilar lymph node evaluation for patients with metastatic soft tissue sarcoma to the lungs currently cannot be recommended and needs further study.

Also, Pfannschmidt et al. evaluated mediastinal lymph nodes in 167 patients undergoing metastasectomy for colorectal carcinoma spread to the lungs. Lymph node metastasis was identified in 19.1 percent of patients. Five-year survival decreased from 38.7 to 0 percent when nodes were involved ( p < 0.03). At the current time, mediastinal lymph node evaluation should be considered for all patients un-

Isolated lung perfusion is a technique designed to allow the delivery of a variety of agents to the pulmonary parenchyma with minimal systemic exposure. Currently, tumor necrosis factor-Îą, doxorubicin, melphalan, cisplatin, and other agents have been studied. The pharmacokinetics of these agents as well as systemic agent leakage have been studied. Despite extensive study, isolated lung perfusion remains an investigational modality that may help in the multimodality approach to cancer. It may play a role in tumor reduction, conversion of unresectable patients to resectable, and ultimately survival.

CONCLUSIONS Pulmonary metastasectomy can be performed in selected patients with acceptable long-term survival, when other treatment options are not available. Patients must meet the tenets of controllable primary disease, no extrathoracic disease (colorectal and germ cell tumors may be exceptions), and have sufficient cardiac and pulmonary reserve to tolerate complete resection. Mediastinal lymph node evaluation prior to pulmonary metastasectomy should be performed on all patients with a primary colorectal cancer. Positive mediastinal nodal metastases, secondary to colorectal carcinoma, are a contraindication to pulmonary metastasectomy. The finding of positive mediastinal lymph node involvement for sarcoma, as well as for renal cell carcinoma, does not support routine mediastinal nodal evaluation for these patients. Routine mediastinal nodal evaluation prior to pulmonary metastasectomy for other primary tumors

1945 Chapter 109

needs further investigation and should be considered for mediastinoscopy or transtracheal, transbronchial fine-needle aspirate.

Since repeat pulmonary metastasectomy has been shown to have good survival, patients who undergo pulmonary metastasectomy must undergo routine surveillance CT and/or PET-CT scanning to identify recurrent disease at 3-month intervals. Minimally invasive approaches to pulmonary metastasectomy produce similar survival to open approaches and enable the surgeon to perform a complete radiologic resection (R-R0). A minimally invasive approach to pulmonary metastasectomy in conjunction with serial radiographic follow-up and repeat metastasectomy is essential for achieving a complete pathological response.

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Pulmonary Metastases

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SECTION SIXTEEN

Lymphoproliferative Disorders

110 CHAPTER

Lymphoproliferative and Hematologic Diseases Involving the Lung and Pleura Douglas B. Flieder

I. ANATOMY AND HISTOLOGY OF THE PULMONARY LYMPHOID SYSTEM II. GENERAL CONSIDERATIONS III. REACTIVE LYMPHOID PROCESSES Localized Reactive Lymphoid Processes Diffuse Reactive Lymphoid Processes IV. MALIGNANT LYMPHOID LESIONS Primary Pulmonary Non-Hodgkin’s Lymphoma Hodgkin’s Lymphoma

Lymphoproliferative disorders of the lung and pleura comprise a varied but rare group of localized and diffuse processes that span the morphologic gamut from reactive to neoplastic and include several peculiar lesions that do not fit conventional definitions of either hyperplasia or neoplasia. Although most diagnoses are based on light microscopy, immunohistochemical and molecular investigations are practically de rigueur. Nomenclature and classification schemes have undergone drastic changes over the past quarter century and current definitions appear reasonable. Malignant lesions are best classified according to the current World Health Organization (WHO) scheme. This chapter presents the clinico-

Secondary Lymphoma Involving the Lung Plasmacytoma/Multiple Myeloma V. POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER VI. LEUKEMIC INFILTRATES INVOLVING THE LUNG VII. PLEURAL LYMPHOMAS Primary Effusion Lymphoma Pyothorax-Associated Lymphoma VIII. CONCLUSIONS

pathologic features of primary and secondary pulmonary and pleural hematolymphoid lesions.

ANATOMY AND HISTOLOGY OF THE PULMONARY LYMPHOID SYSTEM Pulmonary lymphatics are divided into two interconnecting channels that drain to peribronchial, hilar, and/or mediastinal lymph nodes and eventually into the thoracic duct, right lymphatic duct, and subclavian veins. One system drains through

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Table 110-1 Diseases Associated with Hyperplasia of Bronchus-Associated Lymphoid Tissue

Figure 110-1 Bronchus-associated lymphoid tissue. The submucosal collection of lymphoid cells is intimately associated with overlying bronchiolar epithelium. Hematoxylin and eosin, 40× original magnification.

the visceral pleura around the lung into mediastinal lymph nodes and the other drains from central lung parenchyma to peribronchial and hilar lymph nodes. The lymphatics communicate at lobar, lobular, and pleural boundaries and thus serve each other as potential collaterals. Although not usually obvious in histologic sections of normal lung, lymphatics are prominent in disease states ranging from pulmonary edema to lymphangitic carcinoma. In the latter, lymphatic channels distended with malignant cells are apparent within the visceral pleura, interlobular septa, and adventitia of arteries, veins, and bronchioles. Of note, alveolar septa do not contain lymphatic channels. All lymphatics contain valves and flat endothelial cells line the discontinuous basal lamina. Larger lymphatics contain smooth muscle and collagen.

Small submucosal aggregates of lymphoid cells are often prominent at bronchial bifurcations and near distal respiratory bronchioles (pulmonary microtonsils) and represent bronchus-associated lymphoid tissue (BALT) (Fig. 110-1). Whether humans are born with this specialized secondary lymphoid system, or whether the aggregates of B lymphocytes, T lymphocytes, HLA-DR+ interdigitating cells, follicular dendritic cells, and lymphoid follicles with an overlying flattened and attenuated specialized epithelium develop in response to antigenic stimulation is controversial. Viruses, connective tissue disorders, tobacco use, and obstructive pneumonia are just a few pathologic processes known to induce BALT (Table 110-1). Unlike typical lymph nodes that rely on afferent lymphatics for antigen retrieval, BALT is integrated into lung tissue and antigen is sampled directly from the bronchial and bronchiolar lumens through specialized “lymphoepithelia.” Immunoglobulins, most notably IgA, are synthesized and secreted by lymphocytes directly into airway lumens. Amazingly, this system appears capable of mounting a competent adaptive immune response. In addition, BALT Blymphocytes circulate and “home” to other mucosal sites such as the conjunctiva, salivary glands, stomach, and intestines to create a common mucosal immune system, the mucosaassociated lymphoid system (MALT). Thus, responses in-

Autoimmune diseases Allergy such as asthma Autoimmune hemolytic anemia Celiac sprue Hashimoto’s thyroiditis Myasthenia gravis Pernicious anemia/ agammaglobulinemia Primary biliary cirrhosis Rheumatoid arthritis Systemic lupus erythematosus Sj¨ogren’s syndrome Transverse myelitis Immunodeficiency syndromes Common variable immunodeficiency Unexplained childhood immunodeficiency Virus-associated Epstein-Barr virus Hepatitis viruses Human immunodeficiency virus Drug-induced forms Allogeneic bone marrow transplantation Dilantin Infections Chylamydia Mycoplasma Tuberculosis Familial

duced in one location can be replicated at other sites. Malignant lymphomas arising in one MALT location can secondarily involve other MALT sites. Bronchus-associated lymphoid tissue appears to be the origin of many of the primary pulmonary lymphoid lesions.

Intrapulmonary lymph nodes (IPLs) may be part of the pulmonary immune system and may also be induced by antigenic stimuli rather normal embryologic development.

Autopsy studies suggest a prevalence of 18 percent, and although many are related to bronchi of the first few orders, peripheral subpleural locations are not uncommon. In this age of high-resolution computed tomography (HRCT) and lung cancer screening programs, up to 80 percent of reported cases occur in men with histories of tobacco use and almost 35 percent of cases are multiple. These up to 2.0 cm round to angulated sharply circumscribed subpleural opacities are found along interlobular septa or within major and minor fissures and histologically resemble classic lymph nodes with

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Figure 110-2 Intrapulmonary lymph node. Subpleural lymph nodes often accumulate carbon pigment and become fibrotic.

The radiologic differential diagnosis includes carcinoma while a fine needle aspirate sample may mimic malignant lymphoma.

Hematoxylin and eosin, 4× original magnification.

well-developed cortical and medullary areas. Sinus histiocytes frequently contain abundant anthracosilicotic pigment and silicotic nodules with calcifications may form (Fig. 110-2).

In patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), IPLs may be involved and, rarely, primary lung carcinoma or carcinoma from a nonpulmonary site can metastasize to IPLs. Most importantly, IPLs can be clinically, radiographically and cytologically mistaken for malignancy. Although fine-needle aspirates can exclude the possibility of carcinoma, an erroneous diagnosis of lymphoma might be considered.

GENERAL CONSIDERATIONS Although internists, pulmonologists, and radiologists often diagnose pulmonary diseases on the basis of clinical and radiographic findings and rely on tissue samples merely for confirmation, lymphoid lesions of the lung are often unsuspected diagnoses rendered by pathologists. Yet clinical and radiologic studies are essential in the interpretation of all lesions. Often, light microscopic considerations can be excluded purely on the basis of radiographic findings. For example, whereas pulmonary lymphomas can be localized or diffuse, lymphoid interstitial pneumonia (LIP) is always bilateral and diffuse.

Pulmonary lymphoid lesions almost always require wedge biopsies or excisions for diagnosis. Although fineneedle aspirate biopsies and transbronchial biopsies supplemented with ancillary studies may suffice for a diagnosis of malignant lymphoma, architectural and cytologic variability necessitates generous sampling. Such is especially the case, as cellular monotony is not the sole criterion for malignancy.

Whereas sheets of uniform cells may be diagnostic of lymphoma, many malignant processes such as Hodgkin’s lymphoma (HL) and T-cell lymphoma are polymorphous and

admixed with inflammatory cells. Secondary changes and biopsy-related artifacts may also confound the interpretation of a small sample.

Larger samples also allow for low-magnification pattern recognition. A “lymphatic distribution” may be seen in nonlymphoid processes such as sarcoidosis, yet is most striking in lymphoproliferative lesions reflecting the homing of lymphoid cells to endogenous pulmonary lymphatic routes. Although malignant lymphoid processes usually obliterate underlying lung architecture, diffuse alveolar septal expansion with lymphoid cells without a beaded lymphangitic pattern tends to represent an inflammatory rather than neoplastic process.

In addition to histologic examination, immunophenotyping is routinely performed and has become indispensable in diagnosing and classifying lymphoid lesions of the lung.

Immunohistochemical studies can be reliably performed on formalin-fixed, paraffin-embedded tissue, whereas flow cytometry is useful for demonstrating immunoglobulin lightchain restriction. Aberrant antigen expression by either method also allows for subclassification. Polymerase chain reaction (PCR) may be required in up to 20 percent of cases to prove clonality. Either rearrangement of the immunoglobulin heavy-chain gene joining region (J H ) or the T-cell receptor γ-chain gene (TCR-γ) can be investigated. Lastly, chromosomal abnormalities indicative of specific lymphomas such as t(14;18) translocation and bcl-2 gene rearrangement in follicular lymphoma or t(11;14) translocation and cyclin D1 (bcl-1) gene rearrangement in mantle cell lymphoma may be helpful.

Given the complex evaluation required of these lesions, it is incumbent upon the clinician to deliver the fresh tissue sample to the pathologist along with his or her concern for lymphoma. Although formalin-fixed or B5 fixed, paraffinembedded samples may suffice for diagnosis and immunohistochemical evaluation, cell suspensions and fresh-frozen tissue are required for flow cytometry, cytogenetics, and many molecular studies.

Lastly, although clonality indicates malignancy, clonality in pulmonary lymphoid lesions may not predict clinical outcome. Many pulmonary lymphomas have long indolent courses with 10-year survival rates of more than 80 percent yet lymphoid interstitial pneumonia, a polyclonal process, is progressive with one-third of affected patients dying of endstage pulmonary fibrosis.

REACTIVE LYMPHOID PROCESSES Although the terminology used to describe inflammatory processes of the lung has remained relatively static over the past 20 years, immunohistochemistry and molecular genetic analysis have redefined diagnostic criteria. Processes arising from BALT include nodular lymphoid hyperplasia (NLH), follicular bronchitis/bronchiolitis (FB/FBB), diffuse lymphoid hyperplasia (DLH), and LIP. Pulmonary hyalinizing granuloma is included in this section for historical reasons

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only. Although the lesions are best considered either localized or diffuse, clinicopathologic entities including Castleman’s disease can manifest with either distribution.

Localized Reactive Lymphoid Processes Nodular Lymphoid Hyperplasia Known to previous generations of pulmonologists and hematopathologists as “pseudolymphoma,” this reactive process was recognized as a form of BALT hyperplasia in the mid 1980s. Although once quite common, ancillary studies have convincingly demonstrated that most cases were actually lowgrade lymphomas. Thus NLH is now considered a legitimate but exceedingly rare polymorphous nodular lymphoid lesion of the lung. Neutrophilic microabscesses and foreign body giant cells found in several reported lesions indicate that the lesion may be the result of an inflammatory stimulus. Interestingly, immunohistochemical studies have documented B-cell lymphomas of BALT within preexisting reactive masses of BALT, such that one could, in the most general sense, consider NLH a precursor lesion.

Most affected individuals are middle-aged with a nearly equal gender incidence. Patients are usually asymptomatic, although a small percentage may have autoimmune diseases such as systemic lupus erythematosus or Sj¨ogren’s syndrome, or polyclonal hypergammaglobulinemia. Lesions most often appear as solitary subpleural radiographic nodules with air bronchograms, but several nodules or localized infiltrates can be seen, the latter finding serving as a reminder that the distinction between nodular and diffuse processes is arbitrary.

Up to one-third of cases feature regional lymphadenopathy.

Excised tan-white rubbery to firm nodules measure from 0.6 to 6.0 cm. Histologically, the well-demarcated lesions may feature slight extension along alveolar septa and central scarring. Normal lung parenchyma is overrun by large reactive germinal centers with well-preserved mantel zones, and lymphoepithelial lesions are not seen (Fig. 110-3). Interfollicular areas are filled with plasma cells and mature lymphocytes. The follicles are clearly reactive with a variety of cell types, mitoses, and tingible body macrophages. Regional lymph nodes often feature reactive follicular hyperplasia.

Immunohistochemical studies demonstrate a mixture of B- and T-cells. The B-cells express both κ and λ light chains, i.e., lack light chain restriction. Aberrant B-cell staining for CD5, CD23, or CD43 is not seen, and the germinal centers do not stain with BCL-2. Immunoglobulin heavy chain gene rearrangement or evidence of t(14,18) breakpoints is not observed. These ancillary findings are of the utmost importance since light microscopy alone may not differentiate NLH from an extranodal marginal zone B-cell lymphoma of MALT. The latter usually features infiltrative growth, but may have reactive follicles and polytypic plasma cells with only a focal monotypic cell population.

Surgical excision is usually curative, although a small percentage of patients develop local recurrences at the original surgical site. Neither systemic spread nor death has been reported.

Figure 110-3 Nodular lymphoid hyperplasia. The lesion is composed of benign reactive germinal centers. Although radiographically nodular, germinal centers spill out into surrounding lung. Immunohistochemistry is required to exclude a diagnosis of malignant lymphoma. Hematoxylin and eosin, 1× original magnification.

Pulmonary Hyalinizing Granuloma Pulmonary hyalinizing granuloma (PHG) is not a lymphoid lesion per se, but an ever-present lymphoid component allows for its discussion in a hematolymphoid chapter. This peculiar fibrosing process shares clinicopathologic and morphologic features with sclerosing mediastinitis, inflammatory pseudotumor of the orbit, Riedel thyroiditis, and idiopathic retroperitoneal fibrosis. In fact, approximately one-fourth of cases feature concomitant mediastinal or retroperitoneal disease. The etiology is unknown; however, probably represents either an autoimmune phenomenon or exaggerated host response to mycobacteria or fungi.

Age at presentation ranges from 24 to 77 years and women are affected twice as often as men. Most patients present with mild symptoms including cough, shortness of breath, fever, and fatigue but up to 25 percent of reported individuals are asymptomatic. Laboratory studies include positive antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, and Coombs’-positive hemolytic anemia. Skin testing usually demonstrates exposure to Mycobacterium tuberculosis or Histoplasma capsulatum, but cultures and stains for microbes are negative. Radiographs reveal less than 4.0 cm bilateral and multilobar ill-defined homogeneous nodules that resemble metastases. Unilateral and solitary cases measuring up to 15 cm have been reported. Although not common, focal central irregular calcification may suggest metastatic bone-forming neoplasms. Central cavitation is rare.

Lesions are sharply circumscribed white-tan rubbery masses composed of irregular concentric whorls of hyalinized collagen encasing vessels and airways (Fig. 110-4A). The center of the lesion is paucicellular, whereas peripheral thick collagen bands are separated by mature T-lymphocytes, plasma cells, fibroblasts, and occasional giant cells (Fig. 110-4B).

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Figure 110-4 Pulmonary hyalinizing granulomas. A. Multiple well-circumscribed tan firm nodules can compromise respiratory function. B. Pink hyalinized collagen bands encircle vessels. Scant benign lymphoid infiltrates percolate between the collagen. Hematoxylin and eosin, 10× original magnification.

Blood vessels may feature transmural inflammation without necrosis. Microscopic calcifications can be seen, but granulomas are not present despite the designation PHG. The tumoral interface with lung parenchyma features reactive germinal centers, whereas adjacent lung may feature organizing pneumonia and hyperplasia of BALT. The morphologic differential diagnosis includes rheumatoid nodule, amyloidosis, Wegener’s granulomatosis, malignant lymphoma, inflammatory myofibroblastic tumor, and infections. Clinicians should not be comfortable with a diagnosis of PHG rendered on anything less than a completely removed lesion.

Pulmonary hyalinizing granuloma tends to enlarge slowly and does not recur after surgical resection. However, growth of unresected or unresectable nodules can lead to respiratory compromise.

Amyloidosis and Light-Chain Deposition Disease Immunoglobulin light chains can accumulate in many tissues in different forms, depending on the underlying condition and particular organ cytoskeleton. Clinically recognizable disease in the lung can manifest as tracheobronchial disease, solitary or multiple nodules, or in a diffuse interstitial parenchymal pattern. Most cases of diffuse light chain deposition in the lung are part of multiorgan involvement, associated with plasma cell dyscrasia, have dismal clinical outcomes and are not discussed further in this section.

Solitary and multiple amyloidoma are seen most often in older individuals, with a mean age of 67 years. Central and solitary lesions are often incidental findings but airway or visceral pleural distortion may produce cough, hemoptysis, or pleuritic chest pain. A radiographic diagnosis can be suggested when calcification or ossification is noted (20–50 percent of the time); otherwise, the clinical impression is that of a neoplasm.

Serum or urine monoclonal proteins are found in 10 percent of patients, and this lung pathology may be associated with lymphoproliferative diseases such as benign mono-

clonal gammopathy of undetermined significance, Sj¨ogren’s syndrome, Crohn’s disease, NLH, lymphoid interstitial pneumonia, extranodal marginal zone B-cell lymphoma of MALT, or multiple myeloma. Solitary amyloidoma without underlying blood dyscrasias probably represent a hyperimmune response to unknown antigens.

Waxy hard gritty and yellow-tan nodules measure up to 15 cm and are composed of amorphous eosinophilic hyaline material that obliterates lung parenchyma but spares many arterioles (Fig. 110-5). Lymphocytes, plasma cells, and multinucleated giant cells percolate through the amyloid, but the infiltrate is most dense at the periphery of the nodules. Calcification and ossification with secondary marrow space formation is common. Congo red staining examined by polarizing microscopy reveals lesional apple-green birefringence. Immunohistochemical studies usually demonstrate λ

Figure 110-5 Nodular amyloidosis. Amorphous pink material replaces airspaces and overruns airways. In the absence of Congo red apple-green birefringence one should consider the possibility of nodular light chain deposition. Hematoxylin and eosin, 4× original magnification.

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light-chain composition and negative immunoreactivity for amyloid A and transthyretin. Plasma cells are most often polytypic; however, small foci of monoclonal plasma cells within foci of polytypic plasma cells have been identified.

Ultrastructurally, amyloid is composed of disorderly nonbranching hollow-core 8- to 10-nm fibrils. These extracellular deposits of chemically diverse proteins form a threedimensional twisted β-pleated sheet.

Surgical excision is curative, but patients should be screened for underlying monoclonal B-cell proliferations including multiple myeloma and overt B-cell malignancies.

In stark contrast to nodular amyloidosis, nodular deposition of light chain deposition disease (LCDD) is associated with an underlying blood dyscrasia or renal failure in more than 50 percent of affected individuals. Most patients have free κ monoclonal light chains (IgG, IgA, and IgM in decreasing order) in their urine or serum. The clinical and light microscopic appearance of LCDD is similar to amyloid, and one might mistake a case lacking the characteristic Congo red staining as simply a poorly stained example of amyloid. These light chain deposits are composed of amorphous granular or globular electron dense material. One should consider this entity when dealing with a non-amyloidotic deposit given its strong association with lymphoid malignancies.

Diffuse Reactive Lymphoid Processes Although NLH most likely represents a local response to an extrinsic stimulus and is clinically relevant owing to its radiographic appearance as a coin lesion and morphologic similarity with extranodal marginal zone B-cell lymphoma of MALT, the diffuse lymphoid hyperplasias FB/FBB and LIP represent a continuum of BALT hyperplasia often seen in patients with systemic diseases (Table 110-1). The extent of lung involvement is due in large part to host immune factors. Although thoracoscopic or open lung biopsies are required to establish these “diagnoses” and exclude other processes, including interstitial lung diseases and malignant lymphoma, morphology does not suggest etiology.

Follicular Bronchitis/Bronchiolitis and Diffuse Lymphoid Hyperplasia Diffuse lymphoid hyperplasia restricted to the walls of airways and peribronchial tissue is often seen in individuals with bronchiectasis, chronic infections, and chronic obstructive pulmonary diseases, including asthma. The pattern may manifest as pulmonary disease in those with connective tissue diseases, congenital or acquired immunodeficiencies, and bone marrow transplantation, or as a hypersensitivity reaction. When the process spreads along lymphatic routes of the pulmonary lobule some prefer the designation DLH instead of FB/FBB. Those with connective tissue disease are usually in their forties and most often suffer from rheumatoid arthritis (RA) or Sj¨ogren’s syndrome. Patients with immunodeficiency syndromes such as acquired immunodeficiency syndrome (AIDS), common variable immunodeficiency, IgA deficiency, and Evan’s syndrome present in childhood, whereas

a poorly defined subgroup with hypersensitivity syndromes is usually in their sixth decade of life. Those with DLH may also suffer with chronic low-grade infections such as Mycoplasma, Chlamydia, or Epstein-Barr virus (EBV).

Individuals present with dyspnea, cough, and fever; some may have recurrent pneumonia or weight loss. Pulmonary function tests reveal a restrictive pattern in most cases, but obstructive or normal patterns have been reported.

Those with RA often have a very high rheumatoid factor on the order of 1:640 to 1:2560. Peripheral eosinophilia may be noted in those with hypersensitivity syndromes. Arterial blood gases show arterial hypoxia with a widened AaPO2 gradient and hypocapnia. Chest radiographs feature bilateral diffuse reticular and nodular opacities, whereas high-resolution CT show up to 12-mm centrilobular and peribronchial nodules with or without areas of ground-glass opacity.

Gross pathology demonstrates numerous minute (1- to 2-mm) nodules adjacent to airways. Microscopically, nodular aggregates of B-cell rich lymphocytes and plasma cells with reactive germinal centers expand bronchial and/or bronchiolar submucosa and budge into and permeate overlying epithelium (Fig. 110-6). Rare T cells wander beyond the follicles into adjacent alveolar septa. Smaller airway lumens are distorted and narrowed predisposing to mucostasis and subsequent infections. Lymphoid follicles along interlobular septa and beneath the pleura represent a more diffuse form of lymphoid hyperplasia and warrant the descriptive diagnosis DLH. Treatment with corticosteroids has variable results since this lung pathology is essentially a manifestation of an underlying disease. Those with peripheral eosinophilia are reportedly steroid responsive.

Figure 110-6 Follicular bronchitis/bronchiolitis. Reactive germinal centers expand airway submucosa and compress the lumen.

Mucus accumulation often leads to infection and bronchiolectasis. Alveolar parenchyma is spared. Hematoxylin and eosin, 4× original magnification.

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Figure 110-7 Lymphocytic interstitial pneumonia. A. Diffuse alveolar septal expansion with lymphocytes is usually a manifestation of underlying disease. Hematoxylin and eosin, 50× original magnification. B. Benign lymphocytes and plasma cells interfere with gas exchange. The morphologic differential diagnosis includes Pneumocystis infection.

Hematoxylin and eosin, 60× original magnification.

Lymphocytic Interstitial Pneumonia Although LIP is included in the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias, this multi-factorial but rarely idiopathic process represents the most florid BALT hyperplasia and may be difficult to differentiate from DLH and low-grade malignant lymphoma. Almost all patients with LIP have immunologic disorders, dysproteinemias, or viral infections, including EBV and, especially in children, human immunodeficiency virus (HIV). The age and sex distribution reflect these different populations. This clinicopathologic process is exceedingly rare in the HIV-negative population, in which patients are usually middle-aged Caucasian women, but represents a pulmonary manifestation of chronic graftvs.-host disease in bone marrow transplant patients. A strong association with Sj¨ogren’s syndrome is also noted.

The clinical presentation is that of interstitial lung disease with cough and/or dyspnea in addition to symptoms and signs related to underlying diseases. More than 60 percent of patients have dysproteinemias which can precede the onset of LIP or occur any time during the clinical course.

Most are hypergammaglobulinemia, yet 10 percent of cases have a hypogammaglobulinemia. A monoclonal spike on serum immunoelectrophoresis suggests a diagnosis of lymphoma rather than LIP. Pulmonary function tests reveal reduced lung volumes and lowered diffusing capacity for carbon dioxide (DlCO ), and hypoxia is common. Bronchoalveolar lavage (BAL) analysis shows an increased percentage of lymphocytes.

Chest radiographs feature bilateral reticular and nodular opacities, ground-glass opacities, and parenchymal consolidation with lower lung zone predilections. Computed tomography demonstrates diffuse ground-glass opacities, illdefined centrilobular nodules, bronchovascular and interlobular thickening, and scattered less than 3.0 cm thin-walled cysts. Lymphadenopathy is more commonly seen than fibrosis and honeycomb lung.

The lungs are typically firm and tan-gray and endstage cases feature honeycomb change with subpleural cysts.

Although the radiographs and gross appearance suggest parenchymal consolidation, histologically LIP shows a diffuse prominently interstitial infiltrate of small lymphocytes, plasma cells, larger mononuclear cells, and histiocytes (Fig. 110-7A). Although these infiltrates are centered on airways, vessels, and interlobular septa, and include peribronchiolar lymphoid follicles, infiltration into alveolar septa is always present and distinguishes LIP from FB/FBB and DLH (Fig. 110-7B). Small non-necrotizing granulomas, reactive germinal centers, and infiltration into overlying respiratory epithelium are often seen, whereas lymphocytes frequently spill into alveolar spaces. In long-standing lesions, hyaline, collagen, or even amyloid widens the interstitium leading to honeycomb fibrosis.

The lymphoid follicles largely consist of cytologically bland B cells, whereas the interstitial lymphocytes are mostly T cells. This pattern suggests that the lung can function like a giant lymph node. Immunoglobulin heavy chain restriction or gene rearrangement is lacking. In addition to malignant lymphoma, nonspecific interstitial pneumonia-pattern interstitial lung disease (NSIP) and infections including Pneumocystis should be excluded.

Given the rarity of the process, controlled treatment trials have not been undertaken. Corticosteroids are the primary therapy in addition to other immunosuppressive agents, such as cyclophosphamide and chlorambucil with variable results.

One-third of patients have resolution, one third stabilize and the remaining third progress. Non-responders usually die of therapy-related infections, but occasional individuals die of end-stage pulmonary fibrosis. Lymphomatous change is very unusual; older reports of such most likely represented malignant lymphomas from the start.

In patients with HIV infections or AIDS, LIP is part of a spectrum of pulmonary lymphoid proliferations with virtually identical morphologies, but differing clinical

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Figure 110-8 Solitary Castleman’s disease. A. Involved peribronchial lymph nodes are often mistaken for pulmonary parenchymal disease. Airway and vessel distortion may cause symptoms. B. Solitary lymph nodes and rare lung lesions feature hyaline-vascular morphology. Small germinal centers are penetrated by hyalinized venules. The follicle mantle zone rings the burnt-out center in an onionskin pattern. Hematoxylin and eosin, 20× original magnification.

presentations. Individuals with so-called diffuse infiltrative lymphocytosis syndrome (DILS) featuring sicca syndrome with increased numbers of circulating CD8+ T-cells in the blood, generalized lymphadenopathy and enlarged parotid glands, are at high risk of developing LIP. Lymphocytic interstitial pneumonia is most common is HIV-positive children and is a CDC category B indicator condition in children younger than age 13. In fact, up to 17 percent of HIV-positive children have LIP. Most present in their second or third year with lung infiltrates, failure to thrive, and increasing respiratory distress. The chest radiograph shows a diffuse micronodular or linear interstitial pattern with hilar and mediastinal widening. Therapy is uncertain, response to steroids is unpredictable, and mean survival is 33 months.

In HIV-positive adults, LIP is quite rare, and tissue sampling is required for diagnosis. Most patients present with generalized lymphadenopathy and polyclonal hypergammaglobulinemia. Bronchoalveolar lavage samples feature lymphocytes with CD8+ cells comprising up to 90 percent of the lymphoid cells. Histologically, the lymphoid infiltrates are predominantly T cells with few plasma cells. Germinal center formation is not a frequent finding. HIV-positive adults with LIP rarely die of the process, but rather of other AIDS-related diseases.

Castleman’s Disease Castleman’s disease (CD), the eponymous term for angiofollicular lymph node hyperplasia, encompasses two clinically and pathologically distinct entities. Solitary lesions usually feature hyaline-vascular (HV-CD) morphology, whereas multicentric disease always has a plasma cell pattern (PC-CD).

Solitary CD is an uncommon form of lymphoid hyperplasia that usually presents as an incidental mediastinal mass in asymptomatic young to middle-aged individuals of

B

either gender. Pleural, chest wall, and extrathoracic involvement have been reported, but pulmonary parenchymal disease is a true rarity and most reported cases likely represent nodal rather than true pulmonary disease (Fig. 110-8A). Solitary HV-CD lesions are usually asymptomatic or rarely cause pressure-related symptoms.

Ninety percent of solitary CDs feature hyaline-vascular morphology, whereas the remainder are the plasma cell variant. Hyaline-vascular Castleman’s disease lymph nodes are enlarged and feature prominent lymphoid follicles with small atrophic germinal centers penetrated by hyalinized venules with plump endothelial cells originating in the interfollicular zone (Fig. 110-8B). Expanded mantle zones have concentric rings of lymphocytes imparting an onionskin appearance.

The solitary plasma cell variant only involves lymph nodes and has not been reported in the lung. Lymph nodes are hyperplastic with enlarged germinal centers and sheets of interfollicular plasma cells. Surgical extirpation is both diagnostic and therapeutic since clinical suspicion of malignancy requires excision and excision results in the disappearance of any symptoms.

Multicentric Castleman’s disease (MCCD) is best considered a virus-driven polyclonal lymphoproliferative process that shares virtually no features with solitary CD. In general, MCCD presents in the fourth and fifth decades of life but earlier in HIV-positive individuals. Signs and symptoms include fever, sweating, malaise, anemia, lymphadenopathy, hepatosplenomegaly, ascites, and pleural and pericardial effusions; all attributed to Kaposi’s sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) induction of interleukin-6.

Laboratory abnormalities include an elevated erythrocyte sedimentation rate, polyclonal hypergammaglobulinemia, and bone marrow plasmacytosis that may lead to pancytopenia. A chronic demyelinating polyneuropathy may present as part of POEMS syndrome (Crow-Fukase disease). Patients

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Figure 110-9 Multicentric Castleman’s disease. A. The bronchocentric nature of this KSHV/HHV8-driven systemic process is apparent at scanning microscopy. Hematoxylin and eosin, 1× original magnification. B. The lymphoplasmacytic infiltrate is confined to the pulmonary interstitium. Honeycomb change may develop. Hematoxylin and eosin, 10× original magnification. (Glass slides courtesy of Dr. J. English, University of British Columbia and Vancouver Hospital, Vancouver, BC.)

may also develop non-Hodgkin’s lymphoma. HIV-positive patients with MCCD have a greater likelihood of pulmonary involvement.

Histomorphology correlates with high-resolution CT scan findings of peribronchovascular interstitial thickening and centrilobular nodules (Fig. 110-9A). Polyclonal peribronchiolar lymphoplasmacytic infiltrates with focal extension into interlobular and alveolar septa may rarely be associated with honeycomb change (Fig. 110-9B). Polymerase chain reaction and in situ hybridization with a KSHV probe is almost always positive in lung samples including bronchoalveolar lavage fluid. Although MCCD shares many features with LIP, the plasma cell-rich nature of the infiltrate and presence of KSHV discriminate between the two.

Treatment is primarily nonsurgical but survival beyond 5 years is rare. Although splenectomy may provide brief relief from hematologic symptoms, chemotherapeutic regimens with or without immunotherapy, including anti-IL-6 and anti-CD20 monoclonal antibodies, appear to induce the longest remissions. Highly active anti-retroviral therapy is also utilized in the HIV-positive population.

MALIGNANT LYMPHOID LESIONS Within the hematopathology field, past decades will probably be best remembered for the myriad of classification schemes and ever-changing nomenclature. Thankfully, the current WHO classification represents a consensus list of lymphoid neoplasms that appear to be distinct clinical entities. Although complex, this scheme is reproducible among trained pathologists. Diagnoses are based on clinical, morphologic, immunophenotypic, and genetic features and not simply on morphologic, immunophenotypic, or even clinical subtleties. B-cell neoplasms, T- and NK-cell neoplasms, and Hodgkin’s lymphoma are subgrouped according to lineage

and stage of differentiation. Within this general context one can understand the practicality of a seemingly cumbersome diagnosis, such as pulmonary extranodal marginal zone Bcell lymphoma of MALT type, given the belief that these lymphomas arise from acquired BALT.

Primary Pulmonary Non-Hodgkin’s Lymphoma Although more than half of patients with nodal lymphoma have lung involvement, primary pulmonary lymphomas comprise less than 0.5 percent of primary lung neoplasms.

Furthermore, the most common primary lung lymphoma, marginal zone non-Hodgkin’s lymphoma of MALT origin, represents less than 10 percent of extranodal lymphomas.

Non-Hodgkin’s lymphomas are considered lung primaries when the lung is the major site of disease at the time of diagnosis. Thus, up to 20 percent of these lung lymphomas involve hilar and/or mediastinal lymph nodes. Pulmonary lymphomas have a range of morphologies and clinical aggressiveness such that separating the tumors into low- and high-grade categories is a dangerous oversimplification. Although most lung non-Hodgkin’s lymphomas differ from nodal lymphomas and are thought to have their origin in BALT, traditional nodal non-Hodgkin’s lymphomas, such as follicle center lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, and CD30+ anaplastic large cell lymphoma, also present as pulmonary primaries (Table 110-2).

Extranodal Marginal Zone B-Cell Lymphoma of MALT Type Recent recognition that most primary pulmonary lymphomas arise from BALT revolutionized our thinking about extranodal lymphoid lesions. This hypothesis suggests that some degree of lymphoid hyperplasia is a necessary precondition for the development of these lymphomas and explains

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Table 110-2 Lymphoid neoplasms commonly involving the lungs B-cell neoplasms Mature B-cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma Lymphoplasmacytic lymphoma Plasma cell myeloma Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT-lymphoma) Nodal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Intravascular large B-cell lymphoma Burkitt lymphoma/leukemia B-cell proliferations of uncertain malignant potential Lymphomatoid granulomatosis Post-transplant lymphoproliferative disorder T-cell and NK-cell neoplasms Mature T-cell and NK-cell neoplasms Mycosis fungoides S´ezary syndrome Peripheral T-cell lymphoma, unspecified Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma Hodgkin lymphoma Classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma

the association with inflammatory and autoimmune processes as well as the common finding of reactive germinal centers in lymphomas of BALT. These relatively indolent lymphomas must be discerned from both reactive processes, including NLH and LIP as well as more aggressive lymphomas.

Patients tend to be in their fifth through seventh decades of life with a slight male preponderance. Those younger, including children, almost always have preexisting immunosuppression such as HIV infection. Most individuals are asymptomatic and are noted to have an abnormality on a routine chest radiograph; however, dyspnea, cough, hemoptysis, and shortness of breath reflect extensive disease causing airway constriction, poor compliance, and atelectasis. “B” symptoms are rare. Mean lymphocyte counts are typically

normal and peripheral blood does not show a leukemic phase, whereas a monoclonal gammopathy, usually IgM, is noted in up to 30 percent of patients.

Chest radiographs and HRCT scans show either peripheral or perihilar solitary or multiple masses or alveolar opacities with air bronchograms. Cavitation, calcification, and pleural effusions are very rare, whereas hilar adenopathy is present in less than 25 percent of cases. The interval between the finding of a radiologic abnormality and definitive pathologic diagnosis has a mean of over 5 years, demonstrating the tendency of this tumor to remain localized for a long period.

Thus, it is not surprising that up to 80 percent of individuals present with stage I disease.

Grossly, nodular areas vary from 2.0 to 20 cm and are tan and fleshy. Underlying lung architecture may be preserved (Fig. 110-10A). At low magnification these lymphomas appear as diffuse infiltrates surrounding reactive follicles with peripheral tracking along bronchovascular bundles and interlobular septa (Fig. 110-10B and C). Invasion of bronchial cartilage and visceral pleura are common. At high magnification, the small lymphoid cells may have round nuclei with little cytoplasm (centrocyte-like) or irregular nuclear contours and abundant clear cytoplasm (monocytoid differentiation) (Fig. 110-10D). Plasmacytic differentiation is also common.

Scattered larger cells (immunoblasts) can also be seen. Malignant cells often infiltrate reactive germinal centers (follicular colonization) as well as bronchial, bronchiolar, and alveolar epithelium (lymphoepithelial lesions). This latter finding is seen in up to 90 percent of cases, but is not a useful diagnostic criterion. Secondary features include fibrosis, sclerosis, and amyloid and sarcoidal granulomas. Involved mediastinal lymph nodes feature typical morphology of nodal marginal zone B-cell non-Hodgkin’s lymphoma.

When light microscopic features favor a diagnosis of this lymphoma, all available ancillary studies should be utilized to make a definitive diagnosis. The neoplastic cells are monoclonal B cells, which may be identified with CD20 or CD79a stains. Light chain restriction is present in all cases with equal κ and λ percentages; however, amplification of the immunoglobulin heavy chain gene from paraffin sections with the PCR detects monoclonality in only 60 percent of tumors. Fifty to 60 percent of marginal zone B-cell lymphoma of MALT type demonstrate t(11;18), whereas t(1;14) or trisomy 3 may also occur.

The differential diagnosis includes NLH, LIP as well as pulmonary involvement with a variety of different malignant lymphomas, such as lymphoplasmacytoid lymphoma/ immunocytoma. These distinctions are of paramount importance and the surgical pathologist or hematopathologist has the necessary tools to make a correct diagnosis.

Pulmonary marginal zone B-cell lymphomas of MALT are indolent tumors with 85 to 95 percent 5- and 10-year survival rates. In several studies, median survival was not reached at 10 years. Thus, patients with resectable disease are treated with resection, but those with diffuse lung involvement may be followed and treated with chemotherapy with or without anti-CD20 antibodies. Patients with systemic symptoms at

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presentation may have a worse prognosis. Lymphoma recurs in the lungs or in other MALT sites such as salivary gland, orbital, or gastrointestinal tract in almost half of patients, and up to 15 percent of patients experience transformation of their lymphomas into more aggressive and usually deadly forms including diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL).

Figure 110-10 Extranodal marginal zone B-cell lymphoma of MALT type. A. Tan fleshy tumor fills alveolar spaces but preserves lobular architecture. B. Malignant lymphoid cells overrun lung tissue. Germinal centers are usually prominent. Hematoxylin and eosin, 4× original magnification. C. Malignant lymphoma often tracks along lymphatic pathways beyond the dominant mass lesion. If such a region was sampled the differential diagnosis would include diffuse lymphoid hyperplasia. Involvement of visceral pleura suggests the malignant nature of the process. Hematoxylin and eosin, 4× original magnification. D. Most pulmonary marginal zone B-cell lymphomas of MALT type are composed of small monotonous round (centrocyte-like) B-lymphocytes. Hematoxylin and eosin, 40× original magnification.

Other Non-Hodgkin’s Lymphomas Non-Hodgkin’s lymphomas other than extranodal marginal zone B-cell lymphomas originating in the lung are very rare and comprise less than one-fourth of primary lung lymphomas. These tumors represent a heterogeneous group consisting primarily of DLBCL with fewer cases of follicle center cell lymphoma, and rare examples of mantle cell lymphoma,

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lymphoplasmacytic lymphoma/immunocytoma, Burkitt’s lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphomas. The latter almost always represent secondary involvement by systemic lymphoma rather than lung primaries. Rare AIDS-related primary pulmonary B- and Tcell lymphomas related to severe immunodeficiency containing EBV RNA have also been described. Of note, only primary pulmonary DLBCL appears to arise from BALT and is also weakly associated with both fibrosing interstitial lung diseases and collagen vascular diseases.

Although each lymphoma subtype has particular morphologic features, primary pulmonary DLBCL is best characterized. Patients are usually adults but younger individuals with immunodeficiency states may be affected. Unlike those with extranodal marginal zone B-cell lymphomas of MALT, most patients present with shortness of breath, fever, chest pain and hemoptysis and often develop extrapulmonary lesions and paraneoplastic syndromes shortly after diagnosis.

Restrictive physiology is often observed while imaging studies reveal solitary or multifocal nodules or infiltrates measuring at least 3.0 cm. Cavitation and pleural effusions are frequently seen and regional lymph nodes are involved in up to 50 percent of cases.

Resected lesions are white-tan and fleshy with areas of necrosis. Histologically, largely necrotic nodules or striking lymphangitic growth with parenchymal destruction are accompanied by inflammatory infiltrates. Infarction is not uncommon. Sheets of malignant mitotically active B cells are two to four times the size of normal lymphocytes (Fig. 110-11). Vascular infiltration and pleural involvement are common features and airway destruction leads to postobstructive pneumonia. Residual BALT hyperplasia and lowgrade marginal zone lymphoma may be seen at the periphery of the mass.

Figure 110-11 Diffuse large B-cell lymphoma. This lymphoma is composed of large cells with irregular nuclear features and significant mitotic activity. The B-cell phenotype is demonstrated by flow cytometry or immunohistochemistry. This lymphoma not only looks more aggressive than marginal zone B-cell lymphoma of MALT type, but also follows an aggressive clinical course.

Hematoxylin and eosin, 40× original magnification.

Neoplastic cells express pan-B antigens CD20 and CD79a. Monotypic immunoglobulin light chain expression can be demonstrated with frozen tissue samples.

Although the cytologic atypia and necrosis in these lymphomas make it easy to distinguish them from benign lymphoid processes and extranodal marginal zone lymphomas, confusion with poorly differentiated carcinomas or Hodgkin’s lymphoma can occur.

Localized DLBCL is potentially curable with surgery and Adriamycin-based chemotherapy, but 5-year survival rates do not surpass 60 percent and the median survival is only 3 years. Only half of HIV-positive patients achieve clinical remission and those remissions usually last only 6 months.

Lymphomatoid Granulomatosis Lymphomatoid granulomatosis (LYG) is one of the most confusing lesions in all of human disease. The original investigators were not certain whether this lung-based process, which also involves the central nervous system, skin and other organs, was a malignant lymphoma or a variant of Wegener’s granulomatosis. Since that time erroneous ideas concerning its etiology and histogenesis have muddled the entity even further. We now recognize LYG as an EBV-driven B-cell lymphoproliferative disorder arising in individuals with either obvious or clinically undetected defects in cell-mediated and perhaps also humoral immunity. In many ways, LYG is similar to posttransplant lymphoproliferative disorders (PTLD) with a spectrum of clinical behaviors.

Although quite rare, LYG has characteristic clinical features. Patients usually present in the fifth or sixth decades of life but children and the elderly can be strickened. Men are affected two to three times as often as women. Dyspnea, cough, chest pain along with fever, and malaise and weight loss are the most common presenting complaints and up to 40 percent of patients also have skin nodules, ulcers, rashes, peripheral neuropathies, or other symptoms referable to central nervous system involvement. Gastrointestinal, musculoskeletal, or nodal involvement is uncommon, whereas a diagnosis following resection of an asymptomatic solitary lung nodule is very rare.

Laboratory findings can include either leukocytosis or leukopenia and elevated serum IgG or IgM. Cerebrospinal fluid may have abnormal protein and glucose levels. Serologies for autoimmune diseases are negative but evidence of EBV infection has been reported.

Radiographically, up to 70 percent of patients show bilateral middle and lower zone lung nodules as large as 10 cm.

Coalescence and cavitation are often seen. Nonspecific reticulonodular infiltrates as well as solitary infiltrates or masses are less common findings. Pleural effusion is present in up to one-third of patients.

Macroscopically the lungs and other affected organs contain yellow-white well-demarcated masses with either solid or granular textures (Fig. 110-12A). Microscopically LYG is composed of nodular lymphoid infiltrates centered

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Figure 110-12 Lymphomatoid granulomatosis. A. Most lesions are well circumscribed with central necrosis. However, this macroscopic appearance is not pathognomonic for LYG. B. Lung parenchyma often features irregular areas of necrosis with preserved vessels. Hematoxylin and eosin, 4× original magnification.

C. The lymphoid infiltrate expands a vessel wall. Morphology does not suggest lymphoma yet cytologic atypia is noted. This grade II lesion was treated with combination chemotherapy but clinical remission was not achieved. Hematoxylin and eosin, 60× original magnification.

on lymphatic routes including bronchovascular bundles. As the lesions increase in size, blood vessels are encircled, infiltrated, and perhaps occluded but not obliterated by the process (Fig. 110-12B). The infiltrate and nodules are composed of a heterogeneous population of small, intermediate and large lymphocytes (Fig. 110-12C). The large cells are in the minority but can be very atypical or pleomorphic, stain as B cells (CD20+ and CD79a+ ) and are EBV-infected according to PCR and in situ hybridization studies. CD30 positivity is also noted in infected monoclonal cells. The smaller and more numerous cells stain as T cells (CD3+ , CD4+ , and/or CD8+ ). Secondary features include interstitial and consolidative pneumonia. Despite its designation, granulomas are not seen.

Depending on the relative number of EBV-infected cells one observes more necrosis and a more aggressive clinical course. The grading system is based on the number of atyp-

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ical large EBV-infected cells (Table 110-3). Grade 1 lesions probably include cases of so-called benign lymphocytic angiitis and granulomatosis, whereas grade 3 proliferations are alternatively considered a subtype of diffuse large cell lymphoma (DLCL). Given the complex histologic features of LYG and need to identify scattered large cells in an inflammatory mass, diagnosis and accurate grading almost always requires a surgical lung biopsy.

Although similar to T-cell–rich B-cell lymphomas such as angiocentric nasal NK/T-cell lymphoma and PTLDs, the former entity lacks EBV-infected monoclonal B cells and the latter lacks the angiocentricity of LYG. Other diagnostic considerations include Hodgkin’s lymphoma and necrotizing inflammatory conditions.

The natural history is variable and clinical behavior ranges from indolent to aggressive. Spontaneous remissions and therapy-induced remissions occur but more than

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Table 110-3 Histologic and In Situ Hybridization Grading of Lymphomatoid Granulomatosis Grade 1 Angiocentric polymorphous infiltrate without atypia or necrosis Rare Epstein-Barr virus infected cells (<5 per high-power (40×) field) Grade 2 Angiocentric predominantly polymorphous infiltrate with occasional large or atypical lymphoid cells and parenchymal necrosis Scattered EBV-infected cells (5–20 per high-power (40×) field) Grade 3 Angiocentric and destructive monomorphous infiltrate with widespread necrosis Sheets of EBV-infected cells (>20 per high-power (40×) field)

60 percent of patients die with a median survival of 14 months.

Although most organ systems can be involved, lymphoid tissue including the spleen is only involved in the 25 percent of patients who develop grade 3 lesions. Hemophagocytic syndrome is related to systemic EBV infection rather than bone marrow involvement. Histologic grade correlates with outcome. Most patients have either grade 1 or 2 disease but only one-third of those with grade 1 lesions progress to grade 3/malignant lymphoma, whereas two-third of those with grade 2 lesions develop grade 3/malignant lymphoma. Asymptomatic patients or those with minimal disease and grade 1 or 2 histology may be observed; those with symptomatic grade 1 or 2 histology require treatment with corticosteroids or single or multiagent chemotherapy. Clinically aggressive grade 1 and 2 and all grade 3 lesions are treated as DLCL with combination chemotherapy. Therapies targeting EBV-bearing B-cells (interferon-α2β) or reactive T cells (i.e., cyclosporine) as well as stem cell transplantation, have been reported.

Intravascular Lymphomatosis Intravascular lymphomatosis (IVL) is a rare non-Hodgkin’s lymphoma characterized by lymphoma cells only in the lumina of small vessels, particularly capillaries. Although IVL most often manifests with neurologic or dermatologic manifestations, individuals in their fifth to seventh decades of life may complain of fever, dyspnea, cough, chest pain, or present with respiratory failure. Hypoxia and decreased diffusion capacity are seen and radiographs demonstrate reticulonodular infiltrates, whereas CT scans can show patchy ground glass opacities.

Figure 110-13 Intravascular large B-cell lymphoma. Malignant lymphoid cells remain confined to vascular channels (arrowheads). Hematoxylin and eosin, 60× original magnification.

Low magnification histology demonstrates a diffuse interstitial process resembling cellular interstitial pneumonia yet higher magnification reveals large cells with prominent nucleoli confined to arteries, veins, lymphatics, and especially capillaries (Fig. 110-13). Fibrin thrombi may be noted.

Although most reported cases of IVL are B-cell lymphoma (CD19+ , CD20+ , CD79a+ ) and the WHO classifies the process as intravascular large B-cell lymphoma, a T-cell phenotype associated with EBV has been described. Although the intravascular nature of the lymphoma is not understood, absence of adhesion molecules CD54 (I-CAM-1) and CD29 (β1 integrin) may prevent neoplastic cell–endothelial cell interactions and extravascular spread.

Half of cases are diagnosed at autopsy yet a diagnosis is possible on thoracoscopic and even transbronchial biopsies. Immunohistochemical stains are necessary to discern IVL from metastatic carcinoma, malignant melanoma, and leukemia. Although prognosis is poor, complete remission and long-term survival can be achieved with prompt diagnosis and aggressive combination chemotherapy.

Hodgkin’s Lymphoma Primary pulmonary HL is very rare. This is in part due to the requirement that, unlike non-Hodgkin’s lymphoma, regional lymph nodes be free of disease in order to qualify as a lung primary.

Primary pulmonary HL shows the usual bimodal age distribution of systemic HL but the age is slightly older with a mean of 42 years. Women outnumber men by 1.5 to 1. Symptoms include cough, dyspnea, hemoptysis, and chest pain and one-third of patients experience B symptoms. Radiographs demonstrate reticulonodular and linear infiltrates or multiple nodular lesions. Solitary lesions and consolidation are also seen. Upper lobe disease is most common, whereas atelectasis and cavitation are frequently observed.

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Tumors have a multinodular white firm macroscopic appearance and histologically grow along lymphatic routes in the lung. As small nodules coalesce, central necrosis becomes apparent. Visceral pleura is often infiltrated while bronchial involvement can result in plaque-like nodules, polypoid endobronchial masses, or airway collapse. Within the WHO histological classification of HL, one cannot be certain if nodular lymphocyte predominant HL and the four subtypes of classical Hodgkin’s lymphoma all involve the lung. Nodular sclerosis and mixed cellularity subtypes of HL are more commonly seen than lymphocyte rich, whereas lymphocyte depleted has not been reported in primary pulmonary HL. Diagnosis requires the identification of Reed-Sternberg cells or variants (usually CD15+ or CD30+ ) within the appropriate inflammatory background. Central necrosis, granulomatous inflammation, and vascular permeation by the polymorphous infiltrate are commonly seen.

The morphologic differential diagnosis includes inflammatory and malignant processes. Infections, Wegener’s granulomatosis, and sarcoidosis as well as poorly differentiated carcinomas, LYG, and a variety of non-Hodgkin’s lymphomas must be considered. The non-neoplastic entities can be discerned histologically, whereas the neoplasms require at least immunohistochemical studies.

The prognosis for patients with primary pulmonary HL is variable. Although individuals with all types and stages of

A

HL have a 5-year survival of almost 75 percent, small patient group studies suggest only a 50 percent 2-year disease-free period for this subgroup of clinical stage IE disease. Relapses occur in the lung and elsewhere and appear associated with multiple lobe involvement, pleural invasion, cavitation, and presence of B symptoms.

Secondary Lymphoma Involving the Lung Secondary lung involvement with nodal and extranodal lymphomas is significantly more common than primary pulmonary lymphoma. Lung involvement with common nodal and disseminated lymphomas surpasses 50 percent during life and at autopsy. Clinical and radiologic features may suggest an infectious process, but tissue samples demonstrate a lymphangitic pattern of disease (Fig. 110-14A).

Patchy infiltrates and endobronchial masses are, however, not uncommon.

Morphology does not usually allow for distinction between primary and secondary lung disease. For example, pulmonary involvement with nodal marginal zone lymphoma is indistinguishable from primary pulmonary extranodal B-cell lymphoma of MALT. Thus, clinical history and review of previous diagnostic material are necessary for proper diagnosis.

Secondary lymphomas involving the lung can also transform to more aggressive histology with increased numbers of large

B

Figure 110-14 Lung involvement with Hodgkin’s lymphoma. A. The striking lymphangitic distribution of this dense white tumor indicates secondary pulmonary involvement. B. A uninucleate Reed-Sternberg cell with typical prominent nucleolus (center) is surrounded by lymphocytes and eosinophils. Hematoxylin and eosin, 60× original magnification.

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cells. This phenomenon is not infrequently seen in samples from patients with CLL/SLL. Several particular systemic lymphoproliferative disorders that may present with significant lung pathology warrant additional discussion.

Mycosis fungoides may involve the lung after dissemination of cutaneous disease or as part of the S´ezary syndrome and is the second most common extracutaneous site after lymph nodes. Clinical and radiographic features often mimic pneumonia or even acute respiratory distress syndrome with nodular and diffuse disease. Tissue samples demonstrate airspace and interstitial infiltrates along lymphatic routes in addition to occasional granulomas, extensive vascular infiltration, and necrosis. Cells range from small with irregular twisted nuclei to large with prominent nucleoli.

The lungs are also frequently involved with angioimmunoblastic T-cell lymphoma. Although originally described as a reactive process (angioimmunoblastic lymphadenopathy with dysproteinemia), this malignant disease in the lung can be mistaken for interstitial pneumonia. However, the lymphatic distribution of atypical “clear” cells with indented nuclei admixed with immunoblasts, plasma cells, and histiocytes should be distinguished from HL. Pulmonary involvement with HL is recognized at presentation in more than 10 percent of patients with mediastinal or extrathoracic disease, 50 percent of patients have relapses in the lung and almost 60 percent are noted to have pulmonary involvement at autopsy. Unlike primary pulmonary HL, secondary involvement rarely manifests with large nodules, whereas infiltrates often surround blood vessels and may feature greater numbers of atypical cells and fewer inflammatory cells than in primary HL (Fig. 110-14B).

Plasmacytoma/Multiple Myeloma Extraosseous plasmacytomas most often affect the upper respiratory tract. Primary plasmacytomas of the lung are exceedingly rare; patients are usually in their fifth and sixth decades of life and asymptomatic. Cough, dyspnea, and hemoptysis have been reported. Unlike multiple myeloma, individuals may lack a serum M-protein or Bence Jones light chains in the urine. Radiographs demonstrate a midlung or hilar solitary mass, but peripheral lesions amenable to transthoracic needle aspiration biopsy occur.

Tumors range from 2.5 to 8.0 cm and most often involve a major bronchus with occasional involvement of regional lymph nodes. Histologically, sheets of plasma cells including binucleate forms overrun lung parenchyma and bronchial cartilage (Fig. 110-15). Fibrous bands course through the tumor and amyloid or light chain may be associated with the neoplasm. κ and λ light chains as well as IgG, IgA, and IgD can be expressed immunohistochemically or produced as M-proteins by the tumor. The pathologist must discriminate between plasmacytoma and marginal zone lymphoma with plasmacytoid features as well as inflammatory myofibroblastic tumor.

Figure 110-15 Plasmacytoma of lung. Sheets of plasma cells usually form a solitary nodule. Cytologic atypia is often seen.

Since this lesion is less common than pulmonary involvement with multiple myeloma, clinical correlation is always required.

Hematoxylin and eosin, 40× original magnification.

Although the natural history of this rare tumor is not well delineated, it appears that cases are either cured with either surgical excision or radiation therapy, or evolve into multiple myeloma. The presence or absence and amount of M protein may mirror tumor burden and clinical course while an increase or decrease in levels may be associated with recurrence or successful treatment. An overall 5-year survival of 40 percent has been reported.

Pulmonary involvement with multiple myeloma is more common than pulmonary plasmacytoma. Lung involvement may be nodular or have a diffuse lymphangitic pattern. Nodular or diffuse amyloid deposition may accompany the neoplastic cells. Intracytoplasmic crystalline casts similar to those seen in the kidney are occasionally observed.

POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER PTLD is a lymphoid proliferation or lymphoma that develops as a consequence of immunosuppression in solid organ or bone marrow allograft recipients. Eighty percent of cases are associated with EBV infection in the setting of decreased T-cell immune surveillance; the etiology of EBV negative PTLD is unknown. Most cases are of host origin while approximately 10 percent of cases are of donor origin. Those of donor origin are more common in lung and heart-lung transplantation patients due to the presence of donor BALT in the lungs.

Allograft and extranodal MALT sites including Waldeyer’s ring, lung and gastrointestinal tract, are usually involved and incidence varies based on type of allograft and immunosuppression regimen. One percent of renal transplant patients but almost 20 percent of lung transplant recipients are stricken. In solid organ transplants

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treated with azathioprine PTLD develops after years but those treated with cyclosporine A often present within weeks of transplantation.

Approximately 10 percent of PTLDs manifest with pulmonary lesions. Individuals may be asymptomatic or present with constitutional symptoms. In lung transplant patients, organ failure may occur. Radiographs demonstrate nodular or diffuse reticulonodular infiltrates, solitary nodules, or multiple mass lesions with or without regional lymphadenopathy.

Morphologic categories of PTLD include early lesions, polymorphic PTLD, monomorphic PTLD, Hodgkin’s lymphoma, and Hodgkin’s lymphoma-like PTLD (Table 110-4).

Most proliferations are B-cell processes, although T-cell lesions are seen. Early lesions usually involve lymph nodes and Waldeyer’s ring rather than lung; lymphoid tissue is hyperplastic with either sheets of plasma cells or paracortical expansion with immunoblasts. The latter resembles infectious mononucleosis morphology. Polymorphic and polyclonal proliferations feature mixtures of small lymphocytes, plasma cells, and immunoblasts and may progress to monomorphic monoclonal proliferations with sheets of large transformed cells resembling aggressive lymphoma (Figs. 110-16A and B).

In fact, the monomorphic monoclonal proliferations are subclassified according to lymphoma classification. Hodgkin’s lymphoma and Hodgkin’s lymphoma-like PTLD are very rare and purportedly similar to methotrexate-related HL. The morphologic findings may be difficult to differentiate from allograft rejection; immunophenotyping is essential, whereas molecular genetic testing for clonality and in situ hybridiza-

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Table 110-4 Posttransplant Lymphoproliferative Disorders Early lesions Reactive plasmacytic hyperplasia Infectious mononucleosis-like Polymorphic PTLD Monomorphic PTLD B-cell neoplasms Diffuse large B-cell lymphoma Burkitt’s/Burkitt-like lymphoma Plasma cell myeloma Plasmacytoma-like lesions T-cell neoplasms Peripheral T-cell lymphoma, unspecified Hodgkin’s lymphoma and Hodgkin’s lymphoma-like PTLD

tion studies for EBV may be necessary. For these reasons, tissue procurement rather than fine-needle aspiration biopsy is preferred for diagnosis.

Treatment starts with reductions in immunosuppression despite the risk of losing the allograft. Early lesions

B

Figure 110-16 Posttransplant lymphoproliferative disorder. A. This polymorphic lesion features small and large lymphocytes admixed with plasma cells. Hematoxylin and eosin, 60× original magnification. B. Monomorphic lesions are often comprised of large atypical cells with numerous mitoses. According to the WHO scheme this lesion is classified as a diffuse large B-cell lymphoma. Hematoxylin and eosin, 60× original magnification. (Photomicrograph courtesy of Dr. A. Chadburn, Weill Medical College of Cornell University, New York, NY.)

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usually regress while only a proportion of polymorphic and monomorphic PTLD respond. Neither morphology nor molecular characterization of the PTLD can predict response to reduction in immunosuppression. Non-responders are then treated with cytotoxic chemotherapy and perhaps radiation therapy. Anti-CD20 antibody therapy plays a limited role. Although early diagnosis with prompt reduction of immunosuppression followed by cautious chemotherapy administration has improved the prognosis of patients with PTLD, mortality rates in solid organ transplants and bone marrow transplant recipients are 60 and 80 percent, respectively.

LEUKEMIC INFILTRATES INVOLVING THE LUNG Significant lung involvement with leukemia affects less than 10 percent of individuals but secondary effects of leukemia or therapy including infections, alveolar proteinosis, leukemic cell lysis pneumopathy, hemorrhage, and chemotherapy toxicity afflict most leukemia patients. Leukemic lung infiltration is often found at autopsy or as an “incidental” finding in a tissue sample demonstrating an infectious process, and only causes symptoms in those patients with high (40 percent or greater) blast counts.

Cough, dyspnea, and hemoptysis may precede the leukemia diagnosis for months or develop suddenly. Bronchiolar involvement producing asthma-like symptoms has been reported. Radiographic findings run the gamut from localized to diffuse infiltrates.

All leukemia subtypes can involve the lung but acute myeloid leukemia, acute lymphoblastic leukemia, and CLL/SLL are most often seen. Infiltrates are predominantly restricted to the pulmonary lymphatic distribution and rarely form micronodules (Fig. 110-17). Bronchiolocentricity may be mistaken for bronchiolitis. Infiltrates can be subtle and chloroacetate esterase and myeloperoxidase stains may be useful in diagnosis and subtyping. Leukemic counts greater than 200,000/µm cause capillary leukostasis with resultant thrombosis. Pulmonary edema, infarct, and diffuse alveolar damage may result.

Patients with agnogenic myeloid metaplasia (myelofibrosis) occasionally have pulmonary manifestations. Diffuse and nodular foci of extramedullary hematopoiesis usually follow lymphatic routes and associated fibrous tissue can form large nodules. Interstitial fibrosis can result and may be mistaken for a primary chronic fibrosing interstitial pneumonia.

In addition to acute complications of leukemia, patients undergoing bone marrow transplantation for leukemia may experience a variety of pulmonary complications including pulmonary edema, diffuse alveolar damage/acute respiratory distress syndrome, bacterial, fungal, and viral infections and graft-vs.-host disease. Acute graft-v.-host (GVH) rarely involves the lung but lymphocytic bronchiolitis, LIP, constrictive bronchiolitis, and pulmonary fibrosis are all considered

Figure 110-17 Leukemic infiltrate in the lung. Primitive mononuclear cells with clumped chromatin (blasts) expand alveolar septa and spill into air spaces. Although an infectious process was suspected clinically, acute myeloid leukemia represented the only lung pathology. Hematoxylin and eosin, 60× original magnification.

within the spectrum of chronic pulmonary GVH. However, these manifestations may represent cytotoxic chemotherapeutic effect.

PLEURAL LYMPHOMAS Disseminated lymphomas frequently affect the visceral pleura and pleural cavity. Non-Hodgkin’s lymphomas often invade the visceral pleura while HL often causes pleural effusions due to mediastinal lymph node involvement and secondary lymphatic obstruction. Leukemia and multiple myeloma rarely manifest with pleural involvement. Diagnosis can be established with effusion cytology and parietal pleural biopsies are rarely required.

Primary pleural lymphomas are much less common and only two have been described; primary effusion lymphoma (PEL) and pyothorax-associated lymphoma (PAL).

Both are associated with EBV but similarities end there.

Primary Effusion Lymphoma Primary effusion lymphoma is a rare large B-cell lymphoma that presents as either a pleural, pericardial or peritoneal cavity effusion without a detectable tumor mass. All cases are associated with KSHV/HHV8 and most occur in young to middle-aged HIV-positive homosexual males. Rare cases have been reported in supposedly immunocompetent elderly individuals and HIV-negative cardiac transplant patients. Some

1965 Chapter 110

Lymphoproliferative and Hematologic Diseases Involving the Lung and Pleura

Figure 110-18 Primary effusion lymphoma. This pleural cytology demonstrates a large cluster of pleomorphic cells. This KSHV/HHV8 associated lymphoma is of B-cell origin despite the absence of immunohistochemical staining for B-cell markers.

Modified Wright-Giemsa, 60Ă&#x2014; original magnification.

patients have preexisting Kaposi sarcoma and rare cases are associated with MCCD. In addition, most cases are co-infected with EBV but a pathogenetic role for this virus has not been elucidated.

Effusion cytology specimens demonstrate large lymphoid cells with large round to irregular nuclei and frequent multinucleation as well as numerous mitotic figures (Fig. 110-18). Plasma cell features may be prominent and anaplastic cells can be seen. Biopsies feature tumor cells admixed with fibrin. Parietal or visceral pleura invasion is a very rare finding. B-cell lineage is confirmed by immunoglobulin gene rearrangement studies but neoplastic cells rarely express B-cell markers! Leukocyte common antigen (CD45), CD30, CD38, and CD138 (plasma cell-related markers) are expressed. These findings suggest a post-germinal center B cell origin. Two cases with T-cell lineage have been reported.

This lymphoma is extremely aggressive with survival measured in months. Combined antiviral therapy and chemotherapy are offered.

Pyothorax-Associated Lymphoma Pyothorax-associated lymphoma develops in the pleural cavities of immunocompetent patients with chronic suppurative pleuritis. Most cases arise following long-standing artificial pneumothorax for treatment of tuberculosis or pleuritis secondary to pulmonary asbestosis. Approximately 2 percent of individuals with chronic pyothorax develop PAL. EpsteinBarr virus is strongly associated but the pathogenesis is not clearly understood. It is postulated that immunocompetent

Figure 110-19 Pyothorax-associated lymphoma. Unlike primary effusion lymphoma, this aggressive large cell B-cell lymphoma is pathogenetically linked to EBV and forms a mass lesion.

Hematoxylin and eosin, 60Ă&#x2014; original magnification.

cells cannot enter the diseased pleural cavity resulting in local immunodepression facilitating proliferation of EBV-infected lymphocytes.

Patients are often in their sixth to eight decades of life and usually present with chest pain, back pain or shoulder pain and dyspnea. Radiographic studies demonstrate a visceral or parietal pleural mass invading chest wall, lung, pericardium, or diaphragm in the setting of pleural fibrosis and calcification. In contrast to PEL, pleural effusion is not seen.

Biopsy and resection specimens show masses composed of sheets of large atypical lymphoid cells with prominent nucleoli and basophilic cytoplasm (Fig. 110-19). Mitotic figures and apoptotic bodies as well as necrosis abound.

Immunohistochemical studies discern this high-grade lymphoma from PEL. Typically lymphoma cells stain for B-cell antigens CD20 and CD79a, plasma cell markers CD38 and CD138 and on occasion a T-cell marker such as CD2, CD3, CD4, or CD7. Immunohistochemistry is positive for EBV, whereas KSHV/HHV8 is absent.

The prognosis for patients with PAL is dismal with most deaths occurring within one year. However, combination chemotherapy and radiotherapy may prolong survival with 5-year survival rates of 20 percent.

CONCLUSIONS Pulmonary and pleural lymphomas and reactive processes are uncommon entities with rich historical contexts. Current immunohistochemical and molecular methods allow for

1966 Part XV

Neoplasms of the Lungs

accurate reproducible classification. Since most lesions arise from BALT, using this construct to order most lung lymphoid proliferations is very appealing. The wide variety of diseases associated with underlying immunologic disorders is only surpassed by the complexities of the primary lymphoproliferative disorders themselves. Clinicopathologic correlation is required for interpretation of virtually all these lesions. Sound diagnoses combined with improved therapies will hopefully improve patient quality of life and survival.

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