POLYPS OF SMALL AND LARGE INTESTINES • Epithelial tumors of the intestines
– major cause of morbidity and mortality worldwide.
• Colon & rectum, is host to more primary neoplasms than any other organ in the body. • Adenocarcinomas; represent 70% of all malignancies in GIT. • Small intestine is an uncommon site for tumors
Polyps • A mass that protrudes into the lumen of the gut; – Pedunculated; traction on the mass may create a stalk – Sessile; without a definable stalk.
• Hyperplastic polyps – formed due to abnormal mucosal maturation or inflammation – non-neoplastic with no malignant potential – most common polyps of the colon and rectum
• Adenomatous polyps or adenomas. – arise as the result of epithelial proliferation
Polyps: Pedunculated & Sessile, Hyperplastic & Adenoma
Non-Neoplastic Polyps • Majority sporadically, in colon, and increase in frequency with age. • Represent about 90% of all epithelial polyps in 60 years or older. • Most are hyperplastic polyps
Hyperplastic polyps • • • •
Small (<5 mm ), nipple-like, hemispherical, smooth Single or multiple. Anywhere in colon; over half in rectosigmoid region.. Histology: – abundant crypts lined by well-differentiated goblet or absorptive epithelial cells, separated by lamina propria. – majority have no malignant potential, but so-called sessile serrated adenomas of right side of the colon, may be precursors of colorectal Ca
Juvenile polyps • Hamartomatous proliferations of lamina propria, enclosing widely spaced, dilated cystic glands. – most frequently in children younger than 5 years – in older age group c/a retention polyps.
• Morphology:
– large in children (1-3 cm in diameter) but smaller in adults; – round, smooth, or slightly lobulated may have a stalk – In general, they occur singly and in the rectum, – no malignant potential – may be source of rectal bleeding – in some become twisted on their stalks to undergo painful infarction
Adenomas: Adenomatous polyps • Neoplastic polyps • Small to large lesions • Usually sessile • Colonic adenomas; 20% to 30% before age 40, rising to 40% to 50% after age 60. • Males and females are affected equally. • Well-defined familial predisposition • Fourfold greater risk of colorectal carcinoma
Types of adenomatous polyps • Tubular adenomas
• mostly tubular glands, recapitulating mucosal topology – Small and pedunculated – Low malignant potential
• Tubulovillous adenomas- a mixture of the above • Villous adenomas
• villous projections – Large and sessile – High malignant potential
Malignant risk with adenomatous polyp • Correlated with three interdependent features: – polyp size, – histologic architecture, and – severity of epithelial dysplasia
• Cancer is rare in tubular smaller than 1 cm in diameter. • Likelihood of cancer is high (approaching 40%) in sessile villous adenomas larger than 4 cm • Severe dysplasia, when present, is often found in villous
Morphology: Tubular adenomas • Gross: – Arises anywhere, about half in the rectosigmoid – Single or two or more lesions – Smallest are sessile; lesions up to 0.3 cm – Larger tubular (up to 2.5 cm) have stalks & and raspberry-like heads
Morphology: Tubular adenomas • Microscopy: • Stalk covered by normal colonic mucosa • Head is composed of neoplastic epithelium, – forming branching glands lined by tall, hyperchromatic, somewhat disorderly cells, – may or may not show mucin secretion – glands are separated by lamina propria
Morphology: Villous adenoma • Gross: – Usually larger – Tend to occur in older persons, – Most commonly in rectum and rectosigmoid, – Generally are sessile, up to 10 cm in diameter, velvety or cauliflower-like masses
Morphology: Villous adenoma • Microscopy: – Frondlike villiform extensions of the mucosa – Mucosa covered by dysplastic, piled-up, columnar epithelium – All degrees of dysplasia may be encountered, – Invasive carcinoma is found in 40% of these lesions
Morphology: Tubulovillous adenomas • Composed of a broad mix of tubular and villous areas. • Intermediate between the tubular and the villous lesions in their frequency of: – having a stalk or – being sessile, – their size, – degree of dysplasia, – risk of harboring intramucosal or invasive carcinoma.
Clinical Features • Smaller; usually asymptomatic, until occult bleeding leads to clinically significant anemia. • Villous; frequently symptomatic because of overt or occult rectal bleeding. • Distal villous adenomas secrete profuse amount of mucoid material rich in protein and potassium; – hypoproteinemia or hypokalemia.
Familial polyposis syndromes • Uncommon autosomal dominant disorders • Have malignant transformation potetial • Individuals with familial adenomatous polyposis (FAP) typically develop 500 to 2500 colonic adenomas that carpet the mucosal surface • Minimum100 is required for diagnosis. • Most are tubular adenomas; occasional have villous features.
Familial adenomatous polyposis (FAP) • Usually become evident in adolescence or early adulthood. • Risk of colonic cancer is virtually 100% by midlife, unless a prophylactic colectomy is performed. • Genetic defect underlying FAP has been localized to the APC gene on chromosome 5q21, – Loss of the APC tumor suppressor gene
Peutz-Jeghers polyps • Uncommon hamartomatous polyps • Occurs as a part of autosomal dominant PeutzJeghers syndrome, characterized in addition by; – Melanotic mucosal and cutaneous pigmentation.
• Syndrome is caused by germ-line mutations in the LKB1 gene, which encodes a serine threonine kinase.
COLORECTAL CARCINOMA • Adenocarcinomas: 98%. • Most begin as adenomatous polyps • 60 to 70 yrs (<20% before 50 yrs). • M>F • Highest incidence : US, Canada, Australia, New Zealand, Denmark. • Low incience: India, Nepal, South America, and Africa.
Pathogenesis: COLORECTAL CARCINOMA • Genetic and environmental • In a young person- ulcerative colitis or polyposis syndromes • HNPCC (Lynch syndrome), - high risk • Dietary factors:
• a low content of unabsorbable vegetable fiber • high content of refined carbohydrates and fat – oxidative byproducts of carbohydrate degradation – fat: converted into potential carcinogens by intestinal bacteria
Pathogenesis: Colorectal Carcinoma: Cont.. • decreased intake of vitamins A, C, and E. • aspirin - decreased incidence of colon cancer. ( inhibition of cyclooxygenase-2). • PGE2 - favor epithelial cell proliferation, inhibit apoptosis, and enhance angiogenesis VEGF. • Others: • IBD esp Ulcerative colitis • Diverticular disease • Tobacco
Pathogenesis: Colorectal Carcinoma: Cont • General observations:development of Ca from adenoma : – high prevalence of adenomas – high colorectal Ca, and vice versa. – distribution of adenomas comparable to that of colorectal Ca – peak incidence of adenomatous polyps antedates by some years the peak for colorectal cancer. – surrounding adenomatous tissue; invasive carcinoma. – risk of cancer is directly related to the number of adenomas,
Colorectal Carcinogenesis • two pathogenetically distinct pathways : – APC/β-catenin pathway (or the adenomacarcinoma sequence), – mismatch repair (microsatellite instability) pathway • Both -stepwise accumulation of multiple mutations
Colorectal Carcinogenesis: adenoma-carcinoma sequence (APC/β-catenin/ chromosome instability)
• Chromosomal instability – stepwise accumulation of mutations in a number of oncogenes and tumor suppressor genes.
• Initially- localized epithelial proliferation. • Followed by the formation of small adenomas • progressively enlarge- dysplastic • ultimately develop into invasive cancers. • accounts for about 80% of sporadic colon tumors.
Colorectal Carcinogenesis:1 Loss of the APC tumor suppressor gene
• Earliest event in the formation of adenomas. • Both copies of the APC gene must be lost for adenomas to develop. – Normal APC promotes the degradation of β-catenin; – loss of APC function- accumulated β-catenin translocates to the nucleus - promote cell proliferation.
• Mutations - 60% to 80% of sporadic colon cancers.
Colorectal Carcinogenesis: Other genetic abnormalities (adenoma-carcinoma sequence) • Mutation of K-RAS. – mutated RAS is trapped in activated state-delivers mitotic signals and prevents apoptosis. • 18q21 deletion.
– Loss of a cancer suppressor gene on 18q21 SMAD2: 60% -70% cancers. – SMAD- encode components of TGF-β- normally inhibits cell cycle
• Loss of p53.
– 70% to 80% of colon cancers, – infrequent in adenomas – Causes activation of Telomerase
Colorectal Carcinogenesis:
mismatch repair genes (MSI) • involved in 10% to 15% of sporadic cases. • may be no detectable antecedent lesions, or the tumors may develop from sessile serrated adenomas. • MSH2, MSH6, MLH1, PMS1, and PMS2 • Inherited mutations 1/5 DNA mismatch repair genes -HNPCC. • MLH1 and MSH2 - most commonly involved • Microsatellites are unstable during DNA replication-giving rise to widespread alterations in these repeats.
• Most microsatellite sequences are in noncoding regions of the genes. • Some - located in the coding or promoter region of genes involved in regulation of cell growth. (type II TGF-β receptor and BAX). • Loss of mismatch repair leads to the accumulation of mutations in these and other growth-regulating genes, culminating in the emergence of colorectal carcinomas.
Morphology • 25% - cecum or ascending colon • 25- rectum and distal sigmoid. • 25% - descending colon and proximal sigmoid • Tumors in the proximal colon - polypoid, exophytic masses • Obstruction is uncommon. • When carcinomas in the distal colon - annular, napkin-ring constrictions of the bowel and narrowing of the lumen • Both neoplasm directly penetrate the bowel wall
• adenocarcinomas range from welldifferentiated –undifferentiated • Many tumors produce mucin
Clinical Features • asymptomatic for years • Cecal and right colonic cancers - fatigue, weakness, and iron deficiency anemia. • Left-sided - occult bleeding, changes in bowel habit, or crampy left lower quadrant discomfort. • spread - direct extension into adjacent structures • metastasis - lymphatics and blood vessels. • sites for metastasis are the regional lymph nodes, liver, lungs, and bones • Treatment: surgery