Histopathology 2006, 48, 51–62. DOI: 10.1111/j.1365-2559.2005.02289.x
REVIEW
Classification of pleomorphic sarcomas: where are we now? A P Dei Tos Department of Pathology, Hospital of Treviso, Treviso, Italy
Dei Tos A P (2006) Histopathology 48, 51–62
Classification of pleomorphic sarcomas: where are we now? Until a decade ago, so-called pleomorphic and storiform malignant fibrous histiocytoma (MFH) represented the most frequently diagnosed sarcoma, accounting for approximately 40% of adult mesenchymal malignancies. However, the latest World Health Organization classification of soft tissue tumours considers MFH a synonym for undifferentiated pleomorphic sarcoma. Historically, the term MFH was introduced in the medical literature in 1963 by Ozzello, O’Brien and Stout, on the basis of the acquisition of phagocytic properties observed in cultured fibroblasts. The existence of MFH as a well-defined clinicopathological entity became rapidly very popular and by the mid 1980s MFH represented the most common sarcoma in adults. With the advent of electron microscopy, immuno-
histochemistry and molecular genetics, it became clear that the so-called ‘facultative fibroblast’ theory had no scientific grounds and, in 1992, a milestone paper eventually brought attention to the concept that MFH merely represented a morphological pattern shared by a wide variety of poorly differentiated malignant neoplasms, which include specific subtypes of pleomorphic sarcomas. Currently, accurate subclassification of pleomorphic sarcomas is mandatory as it enables recognition of non-sarcomatous lesions as well as pleomorphic neoplasms not associated with aggressive behaviour. Furthermore, as myogenic differentiation predicts aggressive clinical behaviour among pleomorphic sarcomas, precise histotyping allows prognostic stratification of patients.
Keywords: MFH, pleomorphic sarcoma Abbreviations: MFH, malignant fibrous histiocytoma; MPNST, malignant peripheral nerve sheath tumours
Introduction The evolution of the classification of pleomorphic sarcomas represents a prototype of the conceptual advances generated by the integration of immunophenotyping and conventional morphology. Until little more than a decade ago, so-called pleomorphic and storiform malignant fibrous histiocytoma (MFH) represented the most frequently diagnosed sarcoma, accounting for approximately 40% of adult mesenchymal malignancies. The latest World Health Organization (WHO) classification of soft tissue tumours has clearly indicated that MFH, at best, represents a Address for correspondence: Angelo P Dei Tos MD, Department of Pathology, Hospital of Treviso, Piazza Ospedale 1, 31100 Treviso, Italy. e-mail: apdeitos@ulss.tv.it 2006 Blackwell Publishing Limited.
synonym for undifferentiated pleomorphic sarcomas, denying the status of a distinct clinicopathological entity.1 This means that whoever wishes to remain loyal to the old terminology should be aware that MFH has become a diagnosis of exclusion for high-grade pleomorphic sarcomas showing no line of differentiation. However, the consensus achieved in the context of the new WHO classification of soft tissue tumours represents only the end of a long, as well as complex, conceptual evolution it is worthwhile briefly to reconstruct. Historically, the term MFH was introduced in the medical literature in the early 1960s by Ozzello, O’Brien and Stout. These authors, who are among the founders of modern surgical pathology, were impressed by the acquisition of phagocytic properties observed in cultured fibroblasts.2,3 Therefore, based on
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the combination of morphology and tissue culture analysis, they suggested that this group of soft tissue sarcomas, showing a pleomorphic phenotype and a storiform or cartwheel-like growth pattern, would be derived from histiocytes.2 As a result, the findings generated by an ‘ancillary technique’ overcame the observations of conventional morphology, leading to the creation of a novel nosological category. The existence of MFH as a well-defined clinicopathological entity became rapidly very popular and, by the mid 1980s, pleomorphic and storiform MFH represented the most common sarcoma in adults.4–6 However, in the same way that an ancillary technique to some extent created MFH, ancillary techniques significantly contributed to its demolition. In fact, with the advent of electron microscopy, immunohistochemistry and molecular genetics, it became clear that the so-called ‘facultative fibroblast’ theory had no scientific grounds.7 In 1992 a milestone paper eventually brought attention to the concept that MFH represented merely a morphological pattern shared by a wide variety of poorly differentiated malignant neoplasms.8 The careful analysis of a series of 159 ‘MFHs’ retrieved from the files of a single institution demonstrated that 63% of the cases could be reclassified (with the support of immunohistochemistry and ⁄ or electron microscopy) as specific types of pleomorphic sarcoma, and 12.6% as non-mesenchymal malignancies. Of the 42 cases (approximately half of which consisting of small biopsies) with no demonstrable line of differentiation, only a small fraction (13% of the total) were morphologically compatible with the MFH ‘category’. Almost 30 years since its creation, pleomorphic MFH appeared to be a heterogeneous group of unrelated lesions. Such a reappraisal generated sharp debate. However, even most recent gene profiling studies have further confirmed the validity of this conceptual shift, since MFHs do not form a discrete cluster.9–11 The main discussion nowadays, almost 15 years since that publication, focuses on whether accurate subclassification of pleomorphic sarcomas is worthwhile or not from the prognostic and therapeutic points of view. First of all, separation of true sarcomas from carcinomas, melanomas, and lymphomas showing sarcomatoid, pleomorphic morphology is of paramount importance if the difference in prognosis and, more importantly, in therapy is considered. Presently such differential diagnoses are mainly based on an accurate and careful histopathological examination, accompanied by an immunohistochemical work-up that includes a panel of differentiation markers. Second, it has also become evident that the presence of myogenic differentiation among high-grade pleo-
morphic sarcomas identifies a group of tumours characterized by particularly poor prognosis.12 This finding has been further confirmed by other studies, underlining beyond any doubt the clinical relevance of pleomorphic sarcoma histotyping.13,14 During the last decade, mostly as a consequence of more accurate phenotyping, the percentage of pleomorphic unclassifiable sarcomas that would fit in the former category of MFH has dropped dramatically.15 The aims of this review are to summarize the main clinicopathological features of pleomorphic sarcoma subtypes, as well as to analyse a group of lesions featuring pleomorphic morphology not associated with aggressive clinical behaviour.
Undifferentiated pleomorphic sarcoma, not otherwise specified (ex-pleomorphic and storiform MFH) The 2002 WHO classification recognizes the existence of an undifferentiated, unclassifiable category of pleomorphic sarcoma, and defines it as a group of pleomorphic high-grade sarcomas in which any attempt to disclose their line of differentiation has failed.1 It has to be underlined that this is a diagnosis of exclusion following thorough sampling and judicious use of ancillary techniques. Most of these cases in the past have contributed to the category of storiform and pleomorphic MFH. Currently, undifferentiated pleomorphic sarcoma accounts for no more than 5% of sarcomas occurring in adults. The term MFH as a possible synonym for undifferentiated pleomorphic sarcoma was maintained in the current WHO classification in order to have the opportunity to summarize the conceptual evolution (discussed above) to both pathologists and clinicians, but the term will probably disappear in future classifications. Undifferentiated pleomorphic sarcomas tend to occur in the extremities (most often lower limbs) of elderly patients (peak age is in the 6th and 7th decades). They present as deep-seated, progressively enlarging masses. Sometimes rapid growth is observed which may be associated with local pain. About 5% of patients exhibit distant metastases (mostly to the lungs) at presentation. Microscopically these lesions tend to be very heterogeneous; however, all share marked pleomorphism, often with bizarre giant cells, admixed with spindle cells and a variable (from many to none) number of foamy histiocytes (Figure 1). Immunohistochemical analysis is disappointing as it usually demonstrates an ‘only vimentin’ phenotype. The presence of scattered smooth muscle actin (SMA)-positive cells 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
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a
b Figure 1. Undifferentiated pleomorphic sarcoma ex-malignant fibrous histiocytoma. A mitotically active pleomorphic spindle cell proliferation is seen (haematoxylin and eosin).
should not be taken as evidence of myogenic differentiation.
Myxofibrosarcoma (ex-myxoid MFH) Myxoid MFH has been, for decades, the preferred synonym of myxofibrosarcoma,16,17 based on the presence of pleomorphic MFH-like morphology in high-grade examples. The current WHO classification adopted the term myxofibrosarcoma, first proposed by Angervall17 to underline the fibroblastic nature (and not fibrohistiocytic) of this spectrum of myxoid mesenchymal neoplasia.1,18 Myxofibrosarcoma is one of the commonest sarcomas in elderly patients. The vast majority of these lesions arise in the limbs and limb girdles, while occurrence in the trunk, head and neck and acral sites is much rarer. Approximately two-thirds tend to be superficially located and present as multinodular masses. As already mentioned, myxofibrosarcoma shows a broad spectrum of cellularity and pleomorphism. At the low-grade end of the spectrum, neoplastic cells exhibit elongated or stellate morphology associated with atypical, hyperchromatic nuclei. A variable number of pseudolipoblasts (vacuolated neoplastic cells containing mucin vacuoles instead of fat) is present. Neoplastic cells are invariably set in a variable amount of myxoid stroma containing characteristic thin-walled, archiform blood vessels (Figure 2a). Highgrade lesions exhibit morphological overlap with socalled MFH in showing, at least focally, a hypercellular proliferation of spindle and pleomorphic cells. Areas of lower grade are often present (Figure 2b). Intermediate-grade lesions simply exhibit cellularity and nuclear atypia intermediate between the low- and high-grade 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
Figure 2. Myxofibrosarcoma represents a spectrum of lesions ranging from low-grade (a) to high-grade sarcoma (b) (haematoxylin and eosin).
ends of the spectrum. Immunohistochemistry does not play a significant role as neoplastic cells most often express only vimentin and, focally, SMA. Local recurrences are observed in approximately half of the patients and is related to histological grade. The metastatic rate of high-grade myxofibrosarcoma ranges between 30 and 35% and therefore appears lower than that observed in other subtypes of pleomorphic sarcoma.12 In contrast to local recurrences, metastatic spread is more reliably predicted by grading to the extent that low-grade myxofibrosarcoma almost never metastasizes.18
Pleomorphic sarcoma showing myogenic differentiation Both leiomyosarcoma and rhabdomyosarcoma can display a pleomorphic phenotype. The recognition of pleomorphic leiomyosarcoma and rhabdomyosarcoma
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Figure 3. Pleomorphic rhabdomyosarcoma is characterized by a pleomorphic homogeneously eosinophilic cell population (a,b). Pleomorphic leiomyosarcoma exhibits less striking cytoplasmic eosinophilia (c). The presence of better differentiated areas showing more uniform spindle cells with a fascicular pattern represents a useful diagnostic clue (d). (Haematoxylin and eosin.)
on histological grounds alone may be challenging; however, the presence of large, spindled or polygonal, deeply eosinophilic cytoplasm should raise the suspicion of myogenic differentiation. In this context, immunohistochemical and ⁄ or ultrastructural studies play an important role.19–21 Pleomorphic leiomyosarcoma tends to occur in middle-aged or older patients and forms a significant subset of retroperitoneal sarcomas. It is also the most frequent sarcoma arising from large blood vessels, while it is somewhat less common in the limbs. Pleomorphic rhabdomyosarcoma occurs most exclusively in the deep soft tissue of the lower limbs. Peak incidence is in the sixth decade. Pleomorphic rhabdomyosarcoma is extremely rare in childhood; the vast majority of sarcomas displaying features of pleomorphic rhabdomyosarcoma in children actually repre-
sent examples of embryonal rhabdomyosarcoma with anaplastic features.22 Neoplastic cells in pleomorphic rhabdomyosarcoma tend to exhibit more striking cytoplasmic eosinophilia and more extreme variation in cell size than pleomorphic leiomyosarcoma (Figure 3a,b). Presence of better differentiated areas composed of fascicles of spindle cells featuring fibrillary eosinophilic cytoplasm represent a useful diagnostic clue in favour of leiomyosarcoma (Figure 3c,d). Ultrastructural analysis may demonstrate sarcomeric differentiation by showing Z-band material, myosin– ribosome complexes, or alternating thin (actin) and thick (myosin) filaments in a characteristic hexagonal pattern. Reactivity to desmin and to actin isoforms is ‘not helpful’ per se in distinction among them. There exists a trend for rhabdomyosarcoma to display a desmin+ ⁄ SMA– phenotype, but exceptions are more 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
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than occasional. Immunoreactivity for h-caldesmon is preferentially seen in leiomyosarcoma, while fast myosin is seen only in rhabdomyosarcoma. Nowadays, the demonstration of nuclear positivity for myogenin (a nuclear transcription factor involved in the commitment of primitive mesenchymal cells to striated muscle differentiation) is currently accepted as unquestionable demonstration of rhabdomyoblastic differentiation.23 Importantly, in contrast with what is usually observed in alveolar rhabdomyosarcoma, myogenin positivity is most often limited to a small fraction of neoplastic cells in pleomorphic rhabdomyosarcoma. Expression of myoglobin is also considered of diagnostic value in this context. It has to be remembered that heterologous striated muscle differentiation is rarely observed in other high-grade neoplasms, in particular malignant peripheral nerve sheath tumours (MPNSTs) (so-called malignant triton tumour) and in a small fraction of dedifferentiated liposarcomas. From the clinical standpoint both pleomorphic leiomyosarcoma and rhabdomyosarcoma behave as high-grade sarcomas and are associated with the poorest outcome among high-grade pleomorphic sarcomas, showing a 5-year metastatic rate ranging between 60 and 70% in leiomyosarcoma and between 90 and 100% in rhabdomyosarcoma.19,21
Pleomorphic liposarcoma Pleomorphic liposarcoma is a high-grade pleomorphic sarcoma showing histological evidence of adipocytic differentiation and represents the rarest variant of liposarcoma.24,25 The main diagnostic clue to define adipocytic differentiation in a pleomorphic sarcoma is the presence of lipoblasts, and their identification often requires careful histopathological examination of an optimally sampled neoplasm. Pleomorphic liposarcoma represents the rarest of lipomatous malignancies, accounting for no more than 5% of all liposarcomas. It occurs in patients usually in or after the sixth decade of life. It slightly predominates in the male sex, and the lower extremity, particularly the thigh, is the most frequent location, followed by the upper extremity and retroperitoneum. Rare cases of pleomorphic liposarcomas have also been reported in the skin; however, in these rare cases clinical outcome appears mostly benign, complete removal being usually curative.26 Lipoblasts are frequently large and show irregular, hyperchromatic, scalloped nuclei, prominent nuclei, set in a multivacuolated cytoplasm. Vacuoles are sharply punched out. Nuclear pseudoinclusions and multinucleation are frequent findings. Most cases tend to fit into one of three main morphological subsets: approximately two-thirds are represented by a non-distinctive 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
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high-grade pleomorphic ⁄ spindle cell sarcoma with scattered lipoblasts or sheets of lipoblasts (Figure 4a), in less than one-third a high-grade pleomorphic sarcoma with epithelioid areas27 and scattered lipoblasts is seen (Figure 4b), and a smaller group of cases overlaps morphologically with intermediate- to highgrade myxofibrosarcoma except for the presence of lipoblasts (Figure 4c). More rarely, pleomorphic liposarcoma in entirely composed of pleomorphic, multivacuolated lipoblasts (Figure 4d). These neoplasms are usually rich in mitotic figures, mostly atypical, and necrosis can be extensive. In those cases in which few lipoblasts are present, S100 protein may prove helpful in highlighting their presence.28 Pleomorphic liposarcoma is a high-grade sarcoma associated with relatively poor survival figures. The metastatic rate is between 30 and 50% and overall mortality ranges between 40 and 50%.
Other sarcomas with a possible pleomorphic phenotype The two additional distinct sarcoma subtypes that can rarely exhibit a pleomorphic morphology are represented by extraskeletal osteosarcoma and MPNSTs. Extraskeletal osteosarcoma is a rare lesion that occurs most frequently in the limbs of elderly patients. The main diagnostic clue is the presence of malignant osteoid produced by neoplastic cells (Figure 5). The cell population exhibits a variable morphology which includes spindle cell, round cell, epithelioid and pleomorphic variants. Extraskeletal osteosarcoma is a very aggressive neoplasm with a 5-year overall survival rate of 25%.29,30 MPNST accounts for approximately 5% of all sarcomas and in half of the cases is associated with the NF1 syndrome (von Recklinghausen’s disease). Two-thirds arise from neurofibromas (more often plexiform neurofibromas in the context of NF1 syndrome), while onethird are unrelated to pre-existing neural lesions.31 Association with a pre-existing schwannoma, ganglioneuroma and pheochromocytoma represents a very uncommon occurrence. Typically, MPNST is a spindle cell, fascicular neoplasm characterized by tapering nuclei and variation in cellularity associated with perivascular accentuation. Immunopositivity for S100 protein is observed in 40–50% of cases and most often involves no more than one-third of neoplastic cells. Heterologous (epithelial, rhabdomyoblastic, chondro ⁄ osteoblastic, angiosarcomatous) differentiation is observed in approximately 15% of cases.32 As mentioned, a minority of cases may exhibit striking
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Figure 4. Pleomorphic liposarcoma can present as a high-grade pleomorphic ⁄ spindle cell sarcoma with scattered lipoblasts (a) or sheets of lipoblasts; as a high-grade pleomorphic sarcoma with epithelioid areas and lipoblasts (b); as a lesion morphologically mimicking intermediate to high-grade myxofibrosarcoma except for the presence of lipoblasts (c); as high-grade sarcoma almost entirely composed of pleomorphic, multivacuolated lipoblasts (d). (Haematoxylin and eosin.)
pleomorphic morphology (Figure 6). MPNST is an aggressive neoplasm with an overall 5-year survival rate of 35% which is unrelated to histological grade.33
Pleomorphic mesenchymal lesions not to be confused with high-grade pleomorphic sarcomas Pleomorphism is not per se an unquestionable indicator of extreme biological aggression. There exist, in fact, neoplasms such as dedifferentiated liposarcoma and atypical fibroxanthoma that, despite featuring all the histological hallmarks of pleomorphic mesenchymal malignancies, behave much less aggressively than expected. Furthermore, pleomorphism is also present in completely benign lesions, good examples being the
cytological atypia of degenerative ⁄ regressive nature commonly found in so-called ‘ancient’ neurilemmomas or in symplastic (bizarre) leiomyoma of the uterus. A degenerative mechanism may also explain the cytological atypia observed typically in the rare lesion descriptively termed pleomorphic hyalinizing angiectatic tumour.
Dedifferentiated liposarcoma Dedifferentiated liposarcoma represents both a morphologically and biologically fascinating lesion, in which transition from well-differentiated liposarcoma to non-lipogenic sarcoma is observed (Figure 7a,b). First described by Evans in 1979,34 who co-opted the term from David Dahlin’s description of tumour 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
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Figure 5. The most important diagnostic clue in a pleomorphic extraskeletal osteosarcoma is represented by the presence of neoplastic osteoid (haematoxylin and eosin).
Figure 7. Dedifferentiated liposarcoma is characterized by the transition from well-differentiated liposarcoma (a) to non-lipogenic sarcoma (b) (haematoxylin and eosin).
Figure 6. Malignant peripheral nerve sheath tumours may rarely exhibit cytological pleomorphism (haematoxylin and eosin).
progression in chondrosarcoma,35 dedifferentiation in well-differentiated liposarcoma tends to occur more frequently in the primary tumour (90%) but can also be observed in recurrences (10%). The transition usually occurs in an abrupt fashion, but in some cases can be more gradual and, exceptionally, low-grade and high-grade areas appear to be intermingled. Dedifferentiated areas exhibit a variable histological picture but most frequently it overlaps with undifferentiated pleomorphic sarcoma (ex-MFH) or myxofibrosarcoma (exmyxoid MFH). Recently it has also been proposed that dedifferentiated liposarcoma should be further classified into low-grade and high-grade subtypes.36,37 Dedifferentiated liposarcoma may exhibit heterologous differentiation in about 5–10% of cases which apparently 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
does not affect the clinical outcome. Most often the line of heterologous differentiation is myogenic or osteo ⁄ chondrosarcomatous, but angiosarcomatous elements have also been reported. Recently, a peculiar ‘neurallike’ or ‘meningothelial-like’ whorling pattern of dedifferentiation has been described, but both immunohistochemistry and electron microscopy failed to elucidate the line of differentiation in these lesions.38,39 This pattern is often associated with ossification. Surprisingly, the biological behaviour of dedifferentiated liposarcoma tends to be much less aggressive than that of other types of high-grade pleomorphic sarcomas.40 At variance with well-differentiated liposarcoma, dedifferentiation is associated with a 15–20% metastatic rate. However, long-term survival rates for retroperitoneal dedifferentiated liposarcoma are not significantly worse than that observed in ordinary well-differentiated liposarcoma occurring at the same
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site, mortality being principally related to repeated destructive local recurrences rather than to metastatic spread. The fact the dedifferentiated liposarcoma can recur as an entirely well-differentiated liposarcoma also represents a morphological indicator of the unique biological behaviour of this liposarcoma subtype. Genetics as well as molecular pathology have recently provided data that, at least in part, may account for the discrepancy observed between morphology and biological aggressiveness. Interestingly, in contrast to the complex karyotypic aberrations observed in pleomorphic sarcomas, dedifferentiated liposarcoma usually retains the same basic cytogenetic anomalies as welldifferentiated liposarcoma, represented by the presence of ring and â „ or giant marker chromosomes,41 although there are often superimposed additional aberrations.42 A significant increase in the level of both MDM2 overexpression and amplification in the high-grade areas has been observed, which may account for the tumour progression in this subset of sarcomas.43,44 However, while high-grade pleomorphic sarcomas often contain concomitant aberrations of both MDM2 and TP53 (which correlate with poor outcome),45 in dedifferentiated liposarcoma TP53 integrity is almost always observed.43 Dedifferentiated liposarcoma therefore appears to be just one more step along the spectrum of well-differentiated adipocytic neoplasia, showing only an increased dosage of the same molecular targets involved in the molecular pathogenesis of well-differentiated liposarcoma.
Atypical fibroxanthoma Atypical fibroxanthomas also represent a biologically fascinating lesion that, despite extreme pleomorphism, is characterized by most often benign clinical behaviour.46,47 For many years, this distinct lesion has often been regarded as the superficial, cutaneous nonmetastasizing variant of so-called MFH. Currently, as a consequence of the described conceptual evolution, atypical fibroxanthoma is no longer considered a fibrohistiocytic lesion. With the advent of new techniques, especially immunohistochemistry, atypical fibroxanthoma has become the prototypic diagnosis of exclusion, main differential diagnoses being represented by malignant melanoma, spindle cell (sarcomatoid) carcinoma and leiomyosarcoma. Even if classic atypical fibroxanthoma is a pleomorphic lesion, a more monomorphic variant has been recognized as part of the spectrum of atypical fibroxanthoma and has been called spindle-cell non-pleomorphic atypical fibroxanthoma.48 Given the distinctive p53 mutations, as well as ultraviolet (UV) photoproducts, identified in
these lesions, it seems increasingly that atypical fibroxanthoma is best regarded as a UV-induced proliferation of dermal fibroblasts.49,50 Atypical fibroxanthoma presents as a solitary, polypoid, ulcerated lesion in sun-damaged skin, especially of the head and neck and less commonly on the dorsum of the hands, of elderly patients. A clinical history of rapid growth is most often reported. Those cases reported in the past to occur in non-actinically damaged skin in the limbs of young adults probably represent examples of atypical benign fibrous histiocytoma. Histologically, all atypical fibroxanthomas are centred in the dermis, quite often surrounded by an epidermal collarette. Growth tends to be expansile with only limited infiltration. Actinic degeneration of elastic fibres in the surrounding dermis is a prominent feature. Ulceration is present in most cases, making evaluation for the presence of epidermal dysplasia or junctional activity often difficult or even impossible. Classical atypical fibroxanthoma is composed of highly pleomorphic histiocyte-like cells and bizarre giant cells interspersed with a variable number of spindle-shaped cells and inflammatory cells. Mitotic activity is usually very high and is associated with the presence of atypical mitotic figures (Figure 8). The spindle cell (non-pleomorphic) variant of atypical fibroxanthoma is composed of fascicles of eosinophilic spindle cells with vesicular nuclei and one or multiple eosinophilic nucleoli. Mitotic figures, which are often atypical, are common but cytological pleomorphism is focal or even absent in this subset of cases. Importantly, subcutaneous or deeper invasion, necrosis or vascular or perineurial invasion should not be accepted as features
Figure 8. Atypical fibroxanthoma is represented by a dermal pleomorphic cell proliferation, usually associated with heavy actinic damage (haematoxylin and eosin). 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
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of atypical fibroxanthoma, although there may be focal, very superficial invasion into fat. Immunohistochemistry is essential for confirming the diagnosis of atypical fibroxanthoma. Vimentin is diffusely positive in all cases and a few are positive focally for SMA, suggestive of fibroblastic or myofibroblastic differentiation. Immunostains for keratins, S100 protein and desmin are always negative, and play a main role in ruling out the main three differential diagnoses, namely, spindle cell (sarcomatoid) squamous cell carcinoma, spindle cell melanoma and leiomyosarcoma. Behaviour is usually benign and complete excision is generally curative. Local recurrence is uncommon and should prompt re-analysis of the initial diagnosis. Those lesions reported in the past as metastatic atypical fibroxanthoma51 were characterized by deep infiltrative growth and, taking into account the limited or absent immunohistochemical work-up at that time, most probably represented examples of other high-grade sarcomas or non-mesenchymal malignancies, such as melanoma and squamous cell carcinoma.
Pleomorphic hyalinizing angiectatic tumour Described in 1996,52 pleomorphic hyalinizing angiectatic tumour is a very uncommon non-encapsulated mesenchymal lesion that occurs mostly in lower extremity subcutaneous tissue of middle-aged patients with no sex predilection. Histologically, this lesion presents as a proliferation of spindle and ⁄ or pleomorphic cells associated with ectatic thin-walled vessels surrounded by prominent eosinophilic fibrin ⁄ collagen deposition (Figure 9). Most often, the lesion has
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infiltrative borders; intratumoral haemosiderin deposits may be prominent and organized intravascular thrombi are commonly observed. The spindle and pleomorphic cells possess bizarre hyperchromatic, pleomorphic nuclei with frequent intranuclear pseudoinclusions. Mitoses are rare (usually absent or less than 1 per 50 high-power fields) and, when dealing with a mitotically more active lesion, a true pleomorphic sarcoma should be first considered. Chronic inflammatory cells can be found in or surrounding the lesion, as well as intratumoral aggregates of mast cells. The spindle ⁄ pleomorphic cells in pleomorphic hyalinizing angiectatic tumour are negative for S100 protein and vascular markers (CD31, factor VIII) but half of the tumours in the original series and in a subsequent report53 were CD34+. Because of the cellular pleomorphism, the haemorrhagic changes, and the occasional presence of prominent cytoplasmic intranuclear inclusions, the lesion may be confused with a high-grade pleomorphic sarcoma, although one should be alerted by the contrast between the extremely low mitotic rate and the marked pleomorphism of the lesion. The peculiar arrangement of vessels with heavy perivascular fibrin deposition is another clue to the diagnosis. Pleomorphic hyalinizing angiectatic tumour is also likely to be confused with benign lesions, especially ancient schwannoma, melanotic schwannoma (in cases with heavy intratumoral haemosiderin) or a long-standing haemangioma. The lack of immunoreactivity for S100 protein and vascular markers allows distinction from these latter.
MFH and MFHs: is there anything left?
Figure 9. Pleomorphic hyalinizing angiectatic tumour histologically presents as a proliferation of spindle and ⁄ or pleomorphic cells associated with ectatic thin-walled vessels surrounded by prominent eosinophilic fibrin ⁄ collagen deposition (haematoxylin and eosin). 2006 Blackwell Publishing Ltd, Histopathology, 48, 51–62.
Following the creation of the prototypical form of MFH, the storiform-pleomorphic variant, other MFH variants were generated: namely myxoid MFH,16 inflammatory MFH,54 giant cell MFH55 and angiomatoid MFH.56 Do they still exist as distinct clinicopathological entities? Unavoidably, the fall of the progenitor affected its progeny. As mentioned above, myxoid MFH has been now renamed ‘myxofibrosarcoma’ to underline the fibroblastic line of differentiation of this neoplasm. Inflammatory MFH was defined as a malignant neoplasm, most frequently occurring in the retroperitoneum, composed of a spindle cell and pleomorphic cell proliferation, containing numerous xanthomatous cells and ⁄ or acute and chronic inflammatory cells. Xanthomatous cells may appear cytologically either benign or malignant. It is now agreed that inflammatory MFH represents a heterogeneous group of unrelated lesions. Many of the cases diagnosed as such in the past
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actually represented lymphomas of both Hodgkin and non-Hodgkin types, leiomyosarcomas and sarcomatoid carcinomas. More importantly, recent molecular analysis of the 12q13-14 chromosome region of a large series of retroperitoneal ‘inflammatory MFH’ reached the conclusion that a significant subset of these cases actually represent examples of dedifferentiated liposarcoma.57 The inflammatory areas may sometimes be so abundant that the adipocytic component can be easily overlooked. Careful sampling and microscopic examination are mandatory before a diagnosis of undifferentiated inflammatory pleomorphic sarcoma (ex-inflammatory MFH) is rendered. Giant cell MFH also represents a wastebasket category which includes specific sarcoma types, such as leiomyosarcoma with osteoclastic giant cells, giant cell tumour of soft tissue58–60 and examples of extraskeletal osteosarcoma. It is worth considering that this concept had been anticipated in 1971 by Salm and Sissons;61 however, because of the widespread use of the MFH terminology, their observation had to wait three decades before being fully recognized. The last ‘MFH’ category is represented by angiomatoid MFH, which characteristically affects much younger patients than other ‘MFH’ variants. Currently, this entity is no longer considered a frankly malignant neoplasm (metastatic rate is lower than 2% of cases and metastases usually involve regional lymph nodes). Desmin immunopositivity has been observed in approximately 40% of cases, perhaps supporting a myogenic phenotype; however, epithelial membrane antigen is also positive in 40% of cases. The ultimate line of differentiation remains to be elucidated.62,63 Angiomatoid (M)FH no longer belongs to the fibrohistiocytic category and is currently classified within the lesions of uncertain differentiation. Importantly, angiomatoid FH should not be confused with aneurysmal FH, which represents a variant of benign dermal fibrous histiocytoma.
Conclusions The conceptual evolution in the classification of pleomorphic sarcomas represents a paradigm of how surgical pathology in general has evolved through the last two decades. Until recently, subclassification of this heterogeneous group of mesenchymal malignancies was regarded by clinicians (and also by many pathologists) as a mere academic exercise. Nowadays, it has been unequivocally demonstrated that accurate histological subtyping is clinically relevant. In fact, this not only allows recognition of non-sarcomatous lesions with consequent planning of proper therapy, but also permits identification of subsets of pleomorphic
sarcoma with especially unfavourable prognoses. This may allow stratification to more aggressive therapy or suitable clinical trials. In consideration of the recent advent of molecular therapies, it seems also likely that the accurate recognition of the different histotypes will represent a prerequisite for effective treatment of this rare group of malignancies.
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