12 m p intestinal pathology

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Intestinal Polyps, adenoma, colorectal cancer Dr Sabin Ranabhat MBBS, MD

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Sessile leaf

No Stalk

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Leaves with stalk

Stalk

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Gastrointestinal Polyp • Definition: - A polyp is any mass lesion that projects above the level of surrounding mucosa.

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Gross Classification of Polyps • On the basis of presence or absence of stalk, polyps are of two types: i. Pedunculated: stalk is present. ii. Sessile: stalk is not present.

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Histologic Classification of Polyps 1. Non-neoplastic (90 % of polyps in colon) - Hyperplastic, - Inflammatory, - Hamartomatous 2. Neoplastic (adenomatous): - Tubular - Tubulovillous - Villous 1/29/17

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Genetic classification of Polyps •

Polyps can be classified on the basis of whether they are hereditary or sporadic: 1. Sporadic polyps: Polyp is solitary or multiple. -. Hyperplastic polyp -. Inflammatory polyp -. Hamartomatous polyp -. Adenoma 1/29/17

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2. Hereditary polyposis syndrome: - Polyps are always multiple in number.

a. Hyperplastic polyposis syndrome b. Hamartomatous polyposis syndrome -. Peutz-Jeghers Syndrome -.

Familial Juvenile Polyposis

c. Familial Adenomatous Polyposis

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Malignant Potential • Sporadic polyps, except adenomas and inflammatory polyps of inflammatory bowel disease, have almost no potential of malignant transformation. • Inherited polyps and adenomas can transform into malignant one.

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• Site: - In GI tract, polyps are most common in the colon.

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Inflammatory polyps • Occur in: - inflammatory bowel disease - infectious colitis

• develop as a regenerative response to localized or diffuse inflammation and ulceration of the mucosa.

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• Gross features: - sessile or pedunculated

• Microscopic features: -

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Mixed inflammatory infiltrate Granulation tissue Epithelial hyperplasia

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Hamartomatous polyps • -

A hamartoma is defined as: a tumor-like growth composed of mature tissues that are normally present at the site in which they develop.

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Hamartomatous polyps Occur: a). Sporadically or, b). in the context of various inherited or acquired syndromes.

Two types: – Juvenile Polyps – Peutz-Jeghers Syndrome 1/29/17

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Juvenile Polyp

• • •

Age: occurs in children <5 years of age. Site: majority located in rectum. C/F: rectal bleeding.

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• Occurs as: a). Sporadic form: - solitary lesions and may be referred to as retention polyp.

b). Inherited form: - It is called Familial Juvenile polyposis, an autosomal dominant disorder. - Polyps are multiple. 1/29/17

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• Gross features: - < 3 cm in diameter - pedunculated

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• Microscopic features: - cystic spaces d/t dilation of glands which are filled with mucin and inflammatory cells. - lamina propria has mixed inflammatory infiltrates.

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Juvenile Polyp

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Peutz-Jeghers Syndrome • rare autosomal dominant syndrome d/t mutations of STK11 (LKB1) tumor suppressor gene.

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• It is of following types: i. Familial: genetic mutation inherited from parents. ii. Sporadic: genetic mutation acquired after birth.

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• Polyps are multiple and pedunculated, and occur most commonly in:-

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the small intestine, followed by: colon stomach rectum

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• This syndrome is associated with increased risk for: - GI (esophagus, stomach, intestine, pancreas), and - non-GI (ovaries, endometrium, breast) malignancies

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• Patient has mucocutaneous hyperpigmentation (e.g around mouth, in palm).

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Microscopic features • tree-like branching of muscularis mucosae covered by normal epithelium.

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Adenoma • Definition: - A neoplastic polyp which has at least low-grade epithelial dysplasia.

• Epithelial dysplasia is characterized by: 1/29/17

stratification, nuclear enlargement, increased N/C ratio hyperchromatic nuclei decreased mucus production 29

• Etiology: mutation in APC gene. • -

Prevalence: 20% to 30% before age 40 40% to 50% after age 60

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Classification of Adenomas • On the basis of microscopic architecture: 1. Tubular: most common type (>80%) 2. Tubulovillous: second most common 3. Villous: least common (1%)

• Most adenomas (75%) are single.

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• -

Villus: latin word= shaggy hair (untended hair) - Intestinal villi project from intestinal wall like hairs. - This term was first coined by Berengarius, an Italian anatomist, in 1524. 1/29/17

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Villus= shaggy hair

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• Most adenomas (90%) are colonic. • Most colonic adenomas (75%) are in the rectosigmoid.

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Morphology 1. -. -.

Tubular: Most are pedunculated. Head of adenoma: ďƒ˜ Is covered with dysplastic epithelium; it is composed of glands. ďƒ˜ dysplasia ranges from low grade to high grade

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Pedunculated tubular adenoma Head Stalk

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Tubules in tubular adenomas

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Morphology contd. 2. Villous adenoma: - Most are sessile. - Villi (fingerlike extensions of the mucosa) are covered by dysplastic epithelium. - Glands are not present. 1/29/17

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Villous adenoma

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Morphology contd. 3. Tubulovillous adenoma: - pedunculated or sessile - are composed of both tubular and villous areas.

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Malignant potential • Any type of adenoma may transform into malignant tumor (1 in 20 or less): a). Risk increases as the size increases. b). Type of adenoma: Villous adenoma has the highest risk followed by tubulovillous and tubular adenoma.

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Familial adenomatous polyposis • • •

aka: adenomatous polyposis coli (APC) autosomal dominant disorder APC gene on chromosome 5 is mutated.

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• Adenomas appear during second to third decade of life. Most are tubular in type. • A minimum of 100 polyps is required for Dx.

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Numerous adenomas carpet the colonic mucosa.

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• The risk of colonic cancer is 100% by age 60 years.

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Colorectal carcinoma • Peak incidence: 60 - 70 years of age. • M > F by 20%.

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Premalignant conditions 1. Ca colon almost always arises from adenomas. - Sporadic adenomas (80%) or - Adenomas in Hereditary colorectal cancer syndromes eg. Familial Adenomatous Polyposis (20%)

2]. Inflammatory Bowel Disease: - Ulcerative colitis - Crohn’s disease 1/29/17

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Etiopathogenesis A]. Genetic factors: - Spontaneous mutations (sporadic colorectal carcinoma): 80% of Ca colon - Inherited mutations (hereditary colorectal cancer syndromes): 20 % of Ca colon

B]. Environmental factors which predispose to sporadic mutations: - Dietary factors are the most important. 1/29/17

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Hereditary Colorectal Cancer Syndromes a. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch syndrome: -

Colonic polyps are few. d/t mutation in DNA mismatch repair genes.

b. Familial adenomatous polyposis (FAP)

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c. Hamartomatous polyposis: -

Peutz-Jeghers Syndrome Familial Juvenile Polyposis

d. Hyperplastic polyposis syndrome: --

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Hyperplastic polyps are present.

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HPS

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Environmental factors • Diet with: -

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low content of vegetable fiber high saturated fat content (as from red meat) high content of refined carbohydrates decreased intake of micronutrients: vitamins A, C, and E

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How dietary factors predispose to mutation ? ď ś Reduced fiber content: - Fecal retention time is increased b/o decreased stool bulk.

- As a result, prolonged contact of colonic mucosa with toxic products occurs.

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How dietary factors predispose to mutation ? Contd.

ď ś High fat intake - synthesis of cholesterol and bile acids by liver is increased which are converted into carcinogens by intestinal bacteria.

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How dietary factors predispose to mutation ? Contd.

ď ś Refined diets also contain less of oxygen radical scavengers. vitamins A, C, and E.

ACE

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Molecular Carcinogenesis in Ca Colon • Ca colon develops by the accumulation of mutations over several years. • There are 2 pathogenetically distinct pathways of genetic mutations:

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Molecular Carcinogenesis in Ca Colon contd. A]. The first pathway is: “Adenoma – carcinoma sequence or APC/ß catenin pathway” - It accounts for 80% of colorectal cancers. - The following multiple steps occur sequentially and this process is called multistage carcinogenesis.

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First step: Loss of APC gene in chromosome 5 is the initiating event. ďƒ˜ Hyperplasia and dysplasia of epithelial cells in the crypt, and early adenoma formation occur.

Second step: Activation of K-RAS gene in chromosome 12 ďƒ˜ Formation of intermediate adenoma occurs. 1/29/17

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• Third step: loss of chromosome 18q which contains three tumor suppressor genes: - DCC, SMAD2, and SMAD4. - Growth of adenoma increases. Dysplasia becomes more severe.

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• Fourth step: Loss of p53 gene in chromosome 17: - Invasive carcinoma develops in this stage.

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B]. The second pathway is: - genetic mutation in DNA mismatch repair genes (MSH, MLH, PMS) - It is involved in 10% to 15% of sporadic cases and in HNPCC. - In this pathway, ďƒ˜ either precursor lesion is absent or ďƒ˜ tumors develop from sessile serrated adenoma. 1/29/17

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• In this pathway, there is no readily identifiable adenoma-carcinoma sequence.

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Morphology • Site: - 22% arise in cecum or ascending colon, - 11% in transverse colon, - 6% in descending colon - 55% in rectosigmoid colon - Other sites 6%.

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Gross features • Tumors in the proximal colon: - Grow as polypoid, exophytic masses because cecum and ascending colon have large diameter. - Intestinal obstruction is uncommon.

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• Tumors in the distal colon: - are annular, encircling lesions - produce napkin-ring constrictions of the bowel - Intestinal obstruction is more likely.

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Microscopic features • Almost all colorectal carcinomas are adenocarcinomas: -

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Glands lined by malignant cells. Mucin secreted by glands. Mitotic figures are frequently seen. Necrosis may be present.

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Clinical features • • •

Slow progressive weakness Altered bowel habit Iron deficiency anemia due to chronic blood loss from ulcerated tumor surface. • “Iron deficiency anemia in an older man means gastrointestinal cancer until proved otherwise.”

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•THANK YOU !!

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• Defective DNA repair caused by inactivation of DNA mismatch repair genes is the fundamental and the most likely initiating event in colorectal cancers that follow this path. Inherited mutations in one of five DNA mismatch repair genes (MSH2, MSH6, MLH1, PMS1, and PMS2) give rise to the hereditary nonpolyposis colon carcinoma (HNPCC). Of these, MLH1 and MSH2 are the ones most commonly involved in HNPCCderived and sporadic colon carcinomas with DNA mismatch repair gene defects. Loss of DNA mismatch repair genes leads to a hypermutable state in which simple repetitive DNA sequences, called microsatellites, are unstable during DNA replication, giving rise to widespread alterations in these repeats. 1/29/17

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• The resulting microsatellite instability (MSI) is the molecular signature of defective DNA mismatch repair, and hence this pathway is often referred to as the MSI pathway. • Because of the multiple mutations caused as a consequence of the defect in DNA repair, the defect is considered to lead to the establishment of a mutator phenotype. 1/29/17

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• Most microsatellite sequences are in noncoding regions of the genes. However, some microsatellite sequences are located in the coding or promoter region of genes involved in regulation of cell growth. Such genes include type II TGF-β receptor and BAX. TGF-β signaling inhibits the growth of colonic epithelial cells, and the BAX gene product causes apoptosis. Loss of mismatch repair leads to the accumulation of mutations in these and other growth-regulating genes, culminating in the emergence of colorectal carcinomas. 1/29/17

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- Normal epithelium - Hyperproliferative epithelium (dysplasia) - Alterations in DNA methylation (early adenoma) - Intermediate adenoma - Late adenoma - Carcinoma - Metastasis 1/29/17

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• Genes in the SMAD gene family provide instructions for producing proteins that help regulate the activity of particular genes as well as cell growth and division (proliferation). The proteins carry out these functions as part of the transforming growth factor beta (TGF-β) pathway, which transmits signals from the outside of the cell to the nucleus. 1/29/17

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• The signaling process begins when a protein called TGF-β attaches (binds) to a receptor on the surface of the cell, which then turns on (activates) a group of SMAD proteins (called receptor-regulated SMADs or R-SMADs). The R-SMADs include the SMAD1, SMAD2, SMAD3, SMAD5, and SMAD8 proteins. These R-SMADs then bind together in multiple protein groups (or complexes) with another SMAD protein, SMAD4, also called the common mediator SMAD (or CoSMAD). Once the SMAD protein complexes form, they are transported to the nucleus. In the nucleus, the SMAD complexes bind to specific areas of DNA, where they control the activity of particular genes and regulate cell proliferation. 1/29/17

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• When the signaling pathway needs to be turned off, two SMAD proteins, SMAD6 and SMAD7 (known as the inhibitory SMADs or ISMADs), inactivate the receptors for the TFG-β protein on the cell surface. The I-SMADs are also thought to interfere with the formation of SMAD-SMAD4 complexes and interfere with the interaction between the SMAD complex and DNA in the cell nucleus. 1/29/17

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• Because TGF-β signaling normally inhibits the cell cycle, the loss of these genes may allow unrestrained cell growth.

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Multi-stage carcinogenesis • Cancer initiation and progression requires the sequential accumulation of mutations, most importantly in tumor suppressor genes and in oncogenes. • Crypts are involutions of the colonic epithelium. Stem cells are thought to be located at the base of the crypts. These are undifferentiated cells which can keep dividing and which give rise to differentiated epithelial cells. It is thought that stem cells divide asymmetrically. That is, stem cell division creates one new stem cell and one cell which embarks on a journey of differentiation. 1/29/17

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• The differentiating cells travel up the crypt, perform their function, and die by apoptosis after about a week. Because the epithelial cells are relatively short lived, stem cell division has to give rise to new differentiated cells continuously in order to replenish the tissue. For this process to function in a healthy way, it is crucial that the differentiated cells die by apoptosis. If this cell death fails, we observe an accumulation of transformed cells around the crypts, and this gives rise to a mass of cells called a dysplastic crypt.

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• This is the first stage of colon cancer. In molecular terms, the death of differentiated cells is induced by the APC gene. APC is a tumor suppressor gene. Data suggest that the majority of colon cancers are initiated through the inactivation of the APC gene. Both copies of the APC gene must be lost for adenomas to develop. the functions of the APC protein are intimately linked to β-catenin. Normal APC promotes the degradation of β-catenin; with loss of APC function, the accumulated βcatenin translocates to the nucleus and activates the transcription of several genes, such as MYC and cyclin D1, which promote cell proliferation.

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• β-catenin is a dual function protein, regulating the coordination of cell–cell adhesion and gene transcription. In humans, the CTNNB1 protein is encoded by the CTNNB1 gene. β-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway. It is a member of the catenin protein family and homologous to γ-catenin. 1/29/17

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• The K-RAS gene encodes a signal transduction molecule that oscillates between an activated guanosine triphosphate-bound state and an inactive guanosine diphosphate-bound state. As discussed in, mutated RAS is trapped in an activated state that delivers mitotic signals and prevents apoptosis. K-RAS is mutated in fewer than 10% of adenomas less than 1 cm, in 50% of adenomas larger than 1 cm, and in 50% of carcinomas. 1/29/17

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• 18q21 deletion. Loss of a putative cancer suppressor gene on 18q21 has been found in 60% to 70% of colon cancers. Three genes have been mapped to this chromosome location: DCC (deleted in colon carcinoma), SMAD2, and SMAD4. The SMAD genes are considered to be the most relevant ones for colon carcinogenesis. They encode components of the transforming growth factor β (TGF-β) signaling pathway. Because TGF-β signaling normally inhibits the cell cycle, the loss of these genes may allow unrestrained cell growth. 1/29/17

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• Loss of p53. Loss of this tumor suppressor gene is noted in 70% to 80% of colon cancers, yet similar losses are infrequent in adenomas, suggesting that mutations in p53 occur late in colorectal carcinogenesis. The critical role of p53 in cell cycle regulation was discussed in Chapter 6.

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• p53, also known as TP53 or tumor protein is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression. P53 has been described as "the guardian of the genome", referring to its role in conserving stability by preventing genome mutation. The name is due to its molecular mass: it is in the 53 kilodalton fraction of cell proteins. The human p53 gene is located on the seventeenth chromosome (17p13.1).

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• In normal cells, the p53 protein level is low. DNA damage and other stress signals may trigger the increase of p53 proteins, which have three major functions: growth arrest, DNA repair and apoptosis (cell death). The growth arrest stops the progression of cell cycle, preventing replication of damaged DNA. During the growth arrest, p53 may activate the transcription of proteins involved in DNA repair. Apoptosis is the "last resort" to avoid proliferation of cells containing abnormal DNA. 1/29/17

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• The cellular concentration of p53 must be tightly regulated. While it can suppress tumors, high level of p53 may accelerate the aging process by excessive apoptosis. The major regulator of p53 is Mdm2, which can trigger the degradation of p53 by the ubiquitin system.

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• p53 is a transcriptional activator, regulating the expression of Mdm2 (for its own regulation) and the genes involved in growth arrest, DNA repair and apoptosis. Some important examples are listed below.

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• One of its transcriptional target gene, p53R2, encodes ribonucleotide reductase, which is important for both DNA replication and repair. p53 also interacts directly with AP endonuclease and DNA polymerase which are involved in base excision repair. • (a) The cell cycle progression into the S phase requires the enzyme Cdk2, which can be inhibited by p21. The progression into the M phase requires Cdc2 which can be inhibited by p21, GADD45 or 14-3-3s. p53 regulates the expression of these inhibitory proteins to induce growth arrest. • (b) Apoptosis can be induced by the binding of Caspase 9 to cytochrome c and Apaf1. p53 may activate the expression of Apaf1 and Bax. The latter can then stimulate the release of cytochrome c from mitochondria (see Mitochondria, Apoptosis and Aging). 1/29/17

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• KRAS gene= Kirsten rat sarcoma viral oncogene homolog This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. • Function: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity 1/29/17

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• 98% of all cancers in the large intestine are adenocarcinomas.

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• When found in a young person, pre-existing UC or one of the polyposis syndromes must be suspected.

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• Gardner syndrome and the much rarer Turcot syndrome seem to share the same genetic defect as FAP. These syndromes differ from FAP with respect to the occurrence of extraintestinal tumors in the latter two: osteomas, gliomas, and soft tissue tumors, to name a few.

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• Adenomas are most commonly found within raised lesions, up to 27 to 36 percent are flat (having a height less than one-half the diameter of the lesion) and up to 1 percent are depressed. Fourth type of colon adenoma: Sessile serrated adenoma (SSA):



- Serrated dysplastic epithelium lining the crypts.

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• All adenomas are dysplastic. • A new system that recognizes two grades of dysplasia - HIGH and LOW. • Similarly, the older terms "carcinoma in situ" or "intramucosal adenocarcinoma" should both be described as high-grade dysplasia. • Invasive malignancy is defined by a breach of the muscularis mucosa by neoplastic cells. • Because there are no lymphatic vessels in the lamina propria, they are not associated with metastasis, and can be managed along conventional guidelines in adenoma follow 1/29/17 97

• large polyp, left in situ, has a cumulative • risk of malignancy at 20 years of only 24%

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Hyperplastic Polyposis syndrome •

•

The genetic basis for hyperplastic polyposis syndrome is unknown, but patients with this syndrome clearly have high risk for developing colorectal cancer. As defined by the World Health Organization, hyperplastic polyposis must satisfy one of three criteria: 5 histologically diagnosed hyperplastic polyps (HPs) occurring proximal to the sigmoid colon (of which at least 2 are >10 mm in diameter)

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1 HP occurring proximal to the sigmoid colon in an individual who has at least one first-degree relative with hyperplastic polyposis

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>30 HPs distributed throughout the colon

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• • • • • • • • • • •

The most common types of hyperplastic polyp or serrated polyp are solitary and benign and are not viewed as being subject to malignant transformation, at least directly. These include microvesicular, goblet-rich, and mucin-poor subtypes (Table 3; Fig. 7). The other types include sessile serrated adenoma (SSA), traditional serrated adenoma (TSA), and mixed polyps (TSA and tubular adenomas) and have replaced older nomenclatures (Table 3; Fig. 7). All these polyps tend to be flat and diminutive and, thus, may escape recognition at the time of colonoscopy.

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• • • • • • • •

Table 3. Hyperplastic or serrated polyps Common subtypes Microvesicular Goblet-rich Mucin-poor Sessile serrated adenoma (SSA) Traditional serrated adenoma (TSA) Mixed polyps (TSA and tubular adenomas)

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• Germline mutations in BMPR1A (bone morphogenic • protein receptor 1A), SMAD4, or ENG (endoglin, an accessory • receptor for TGF-) are reported in FJP (Howe et • al. 1998, 2001; Sweet et al. 2005), suggesting that the • TGF- pathway is critical in the pathogenesis of FJP.

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Colorectal cancer • 4th most common cancer (after lung, prostate, and breast cancers)

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HNPCC • The Amsterdam II criteria, used to clinically diagnose HNPCC, include all the following: three or more relations with colon cancer, one of whom is a first-degree relative of the other two; colon cancer involving at least two generations in the family; and at least one colon cancer diagnosed before age 50

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• Cells with mismatch repair gene mutations cannot repair spontaneous DNA errors and progressively accumulate mutations with succeeding DNA replications throughout the genome, resulting in genetic hypermutability and chaos. Accumulation of mutations in oncogenes and tumor suppressor genes can result in colon cancer. 1/29/17

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