COLORECTAL CANCER

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COLORECTAL CANCER
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EPIDEMIOLOGY

• Men
• - incidence 11 (prostate 33, lung 14)
• - mortality 10 (lung 31, prostate 10)
• Women
• - incidence 11 (breast 32, lung 12)
• - mortality 11 (lung 25, breast 15)

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• The peak incidence 60-79 years
• - only 20 before age of 50 (ulcerative colitis,
  polyposis syndromes)

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• High incidence (and death rates)
• - USA, Eastern Europe, Australia, New Zealand
• 10x lower rates in
• - Mexico, South America, Africa
• Environmental factors are implicated in these
  striking contrasts in incidence

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• Dietary factors
• - excess dietary caloric intake
• - low content of vegetable fibres - high content
  of refined carbohydrates
• - red meat
• - decreased intake of protective micronutrients
  (vit. A, C, E)

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COLORECTAL CARCINOGENESIS
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ADENOMAS

• Adenomas are a precursor lesion for invasive
  colorectal carcinomas
• - benign epithelial neoplasms
• - MF, familial predisposition, age
• - 3 histological types
• - tubular adenomas
• - tubulovillous 5-10
• - villous 1

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• The malignant risk is correlated with
• - polyp size
• - histologic variant
• - severity of dysplasia
• cancer is rare in small tubular adenomas
• the risk of cancer is high (40) in large
  villous adenomas

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• Most colorectal carcinomas occur sporadically in
  the absence of familial syndromes
• Familial syndromes AD
• I. Familial adenomatous polyposis syndrome (FAP)
• - APC gene mutation (5q21)
• - classic, attenuated, Gardner, Turcot syndromes

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• - classic - multiple intestinal adenomas
  (500-2500)
• - attenuated fewer polyps (30), proximal colon
• - Gardner syndrome - intestinal polyps osteomas
  epidermal cysts
• - Turcot syndrome adenomas CNS tumors

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• II. Lynch syndrome (Hereditary Nonpolyposis
  Colorectal Cancer)
• - DNA repair genes mutation
• - increased risk of colorectal cancer and
  extraintestinal cancers (endometrium)

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• The model of colorectal carcinogenesis proposed
  by Fearon and Vogelstein in 1996
• adenoma carcinoma sequence

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• - populations with high prevalence of adenomas
  have a high prevalence of colorectal cancer and
  vice versa
• - the distribution of adenomas is comparable to
  that of carcinoma

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• - the peak incidence of adenomas antedates by
  some years the peak for colorectal cancer
• - the risk of cancer is related to the number of
  adenomas

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MOLECULAR CARCINOGENESIS
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• Two pathogenetically different pathways for the
  development of colon cancer
• Both involve the stepwise accumulation of
  multiple mutations
• The accumulation of mutations is more important
  than their occurrence in a specific order

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I. APC / ß-catenin pathway

• APC tumor-suppressor gene has been mapped to 5q21
• Normal APC promotes cell adhesion and regulates
  proliferation
• Mutated APC decreases cell adhesion and increases
  proliferation
• Mutated APC in FAP and in sporadic cancers (80)

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• Mutation of K-ras oncogene
• - in 50 of colorectal carcinomas
• Loss of SMAD2 SMAD4 (18q21)
• Loss of p53 (17p)
• - in 70-80 colon cancers

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II. MSI pathway

• Genetic lesions involve DNA mismatch repair genes
  - in 90 MSH2 and MLH1
• With errors in MMR MSI develops
• 10-15 of sporadic cancers and in HNPCC syndrome
• - extraintestinal cancers- endometrial, ovarian,
  gastric, pancreatic

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MORPHOLOGY

• - cecum and ascending colon - 22
• - transverse colon - 11
• - descending colon - 6
• - rectosigmoid colon - 55
• - other sites - 6
• 99 occur singly, 1-3 in patients with familial
  syndromes or IBD (ulcerative colitis, Crohn
  disease)

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• Proximal colon
• - polypoid, exophytic masses, obstruction is
  uncommon
• Distal colon
• - annular, encircling, constrictions of the bowel
• Both forms penetrate the bowel wall

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• Histology
• - adenocarcinomas (mucin), ranging from highly
  differentiated to undifferentiated, frankly
  anaplastic
• - endocrine differentiation in 10
• - adenosquamous carcinoma
• - desmoplastic stromal response

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• HNPCC colon cancers
• - right-sided
• - exophytic, well circumscribed
• - mucin-producing, signet ring cells,
  undifferentiated
• - extensive necrosis
• - better prognosis

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• - spread by direct extension into adjacent
  structures
• - metastases through the lymphatics and blood
  vessels
• - regional lymph nodes
• - liver, lungs, bones
• - serosal membranes, peritoneal cavity, brain and
  others

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• Astler-Coller classification
• A- 100
• B1- 67
• B2- 54
• C1- 43
• C2- 23
• D- distant metastases- liver, lungs, bones

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