Path 3 C

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COLON - LEE - FRIDAY FEB 16

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NON-NEOPLASTIC POLYPS

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what types of non-neoplastic polyps exist (5)?

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1) hyperplastic polyps; 2) juvenile polyps; 3) hamartomatous polyps; 4) inflammatory polyps; 5) lymphoid polyps

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what are the most common colonic polyps, and what % does it account for?

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hyperplastic polyps (90% of epithelial polyps)

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at what age are they most common?

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sixth and seventh decades

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what symptoms do hyperplastic polyps cause?

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asymptomatic

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what area are they usually in?

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rectosigmoid area

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how large are hyperplastic polyps?

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small (<5mm)

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what do they look like histologically, and what particular feature is seen?

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well-formed glands or crypts lined by goblet or absorptive cells - infolding of the crowded epithelial cells with a "saw toothed" or serrated profile

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what malignant potential do hyperplastic polyps have?

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virtually none

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what are juvenile polyps?

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uncommon hamartomatous polyps

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what disease can they be associated with, and who do they occur in?

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associated with familial juvenile polyposis (or sporadic) and occurring inchildren younger than age 5

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what symptom do juvenile polyps cause?

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painless rectal bleeding after dfecation

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where are most juvenile polyps located?

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80% are located in the rectum

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how large are juvenile polyps, and what are they shaped like?

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large (1-3 cm in diameter), rounded, smooth with a stalk

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what are glands like, and what is seen in them (2)?

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cystically dilated glands, with: 1) ulceration and; 2) inflammation

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when do juvenile polyps have malignant potential?

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none in sporadic cases, but high risk in juvenile polyposis syndrome

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what are hamartomatous polyps?

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localized outgrowth of normal glands and smooth muscle

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what syndrome must we know that hamartomatous polyps occur in?

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Peutz-Jeghers syndrome

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what other syndromes (2) were they mentioned to occur in?

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1) Cowden; 2) Cronkhite-Canada

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what is another name for inflammatory polyps, and who do they primarily occur in?

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pseudopolyps - primarily in patients with inflammatory bowel disease

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what are lymphoid polyps?

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mucosal bumps containing lymphoid tissue

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NEOPLASTIC POLYPS

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what was said about neoplastic polyps, and their growth patterns?

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different growth patterns of the same neoplastic process

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what features does the malignant risk with adenomas correllate with (3)?

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1) polyp size; 2) histologic architecture; 3) severity of dysplasia

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what is the most common type of neoplastic polyp?

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tubular adenomas (adenomatous polyps)

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what is the least common type of neoplastic polyp?

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villous adenomas

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what is the most ominous type of neoplastic polyp?

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villous adenomas

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what is the largest type of neoplastic polyp?

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villous adenomas

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at what age are tubular adenomas most common?

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after 60 (40-50%)

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in what area are tubular adenomas most common?

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rectosigmoid area

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what are they like morphologically?

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usually pedunculated with slender stalk and raspberry like heads

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what type of appearance do they have histologically?

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pseudostratification ("picket fence" appearance)

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what are nuclei like?

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elongated with hyperchromasia and increased nuclear-cytoplasmic ratio

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what are villous adenomas like in architecture (composition)?

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more than 50% villous

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what symptoms come from villous adenomas (3)?

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1) rectal bleeding; 2) hypoproteinemia; 3) hypokalemia

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what are villous adenomas shaped like?

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sessile, usually no stalk, with finger-like or branching papillae

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what does sessile mean?

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attached by the base

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what other type of neoplastic polyp is there, and what is its composition like?

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tubulovillous - usually 25-50% villous component

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what are they usually shaped like?

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pedunculated

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DYSPLASIA

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what is architecture like in high grade dysplasia (what type of arrangement)?

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severe architectural complexity (back-to-back arrangement) and marked cytologic atypia

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what metastatic potential do high grade dysplasias (CIS) have?

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none

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what % of removed colorectal adenomas are high grade dysplasias?

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12%

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what is the treatment, and what is the prognosis after treatment?

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cured by endoscopic polypectomy

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what is a "malignant polyp"?

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colorectal adenoma containing invasive carcinoma

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where is the invasive carcinoma located (layer)?

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in the submucosa

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what % of removed colorectal adenomas are "malignant polyps" (contain invasive carcinoma)?

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5%

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what is the metastatic potential of malignant polyps?

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low

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what is the normal treatment?

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polypectomy alone

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what is the treatment when there are poor prognostic factors?

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colectomy

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what are three poor prognostic factors for malignant polyps?

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1) carcinoma at the resected margin; 2) poorly differentiated carcinoma; 3) lymphovascular invasion

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what types of serrated adenomas exist (2)?

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1) traditional; 2) sessile

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what pathway are these involved in?

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serrated polyp neoplasia pathway for colorectal cancer

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HEREDITARY SYNDROMES - FAMILIAL ADENOMATOUS POLYPOSIS SYNDROME (FAP)

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how many adenomas are seen in the GIT, and where (2)?

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innumerable adenomas (average 1,000, at least 100) in the colon and small intestine

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where are they particularly prevalent in the small intestine (2)?

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1) around the ampulla of Vater; 2) around the stomach

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what is the ampulla of Vater?

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union of common bile duct and pancreatic duct

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how is FAP inherited?

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autosomal dominant

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what gene is mutated, and what chromosome is it on?

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APC gene, on chromosome 5q21

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what fraction of cases have spontaneous mutation?

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one third

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at what age do adenomas begin to develop?

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second and third decades

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what is the incidence of malignant transformation?

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very high - 100% at 40 years

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what is the treatment?

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prophylactic proctocolectomy

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how is early detection done?

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DNA marker (APC gene)

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what treatment begins at age 12?

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flexible sigmoidoscopy

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how do variants of FAP arise?

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APC mutations in different codons

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what are the three variants?

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1) attenuated FAP; 2) Gardner syndrome; 3) Turcot syndrome

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what is attenuated FAP?

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fewer than 100 adenomas, and later age of onset (44 for adenomas, 56 for cancer)

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where does attenuated FAP occur?

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preferentially in the right (ascending) colon

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what is Gardner syndrome (3 things in addition to FAP)?

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FAP + 1) fibromatosis; 2) multiple osteomas; 3) epidermal cysts

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what is Turcot syndrome?

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FAP + tumors of the CNS

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what mutation occurs in most patients (2/3) and what mutation occurs in the other 1/3?

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APC mutation in 2/3, germ-line defect in DNA mismatch repair in one third

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JUVENILE POLYPOSIS SYNDROME

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how is juvenile polyposis syndrome inherited?

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autosomal dominant

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how many polyps occur?

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50-100

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what genes have been identified (2)?

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1) DPC4/SMAD4; 2) BMPR1A

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what is there a high risk for?

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GI adenocarcinoma, primarily colorectal cancer

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PEUTZ-JEGHERS SYNDROME

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how is this disease inherited, and what gene is often mutated?

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autosomal dominant - LKB1/STK11 mutation (in 60% of familial and 50% of sporadic cases)

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what type of polyps are seen?

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hamartomatous polyps (large and pedunculated)

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what % of cases involve the small bowel, colon, and stomach?

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100%, 30%, 25%

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what other sign is seen in PJS?

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melanocytic mucosal and cutaneous pigmentation

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where is it seen (5)?

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1) lips; 2) oral mucosa; 3) face; 4) genitalia; 5) palmar surfaces

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what is the malignant potential of PJS?

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none

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what is there increased risk of developing?

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carcinomas (breast, lung, ovary, uterus)

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HEREDITARY NONPOLYPOSIS COLORECTAL CANCER SYNDROME (LYNCH SYNDROME)

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how is this condition inherited (mode of transmission, type of genes)?

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autosomal dominant condition caused by inherited defects in DNA mismatch repair genes (hMSH2, hMLH1, hMSH6, hPMS1, hPMS2)

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what do these mutations lead to?

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microsatellite instability

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what are microsatellites?

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repeated sequences of DNA

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what % of colon cancers does this represent?

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5% of all colon cancers - the most common form of hereditary colon cancer

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what is the risk for colon cancer in those with the genetic defects?

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80-90%

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what is the age of onset, and most common location?

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early age of onset, right colon - cancers can be synchronous

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how many adenomas occur?

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low numbers <10-20

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what is there an increased risk for?

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extraintestinal cancer (especially endometrial)

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COLORECTAL CARCINOMA

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how does colorectal cancer rank in prevalence among visceral cancers and cancer deaths in the USA?

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third most common visceral cancer and cancer death (150,000 new cases and 60,000 deaths each year)

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in what populations is there the highest incidence?

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high socioeconomic populations

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why is incidence rising in "low risk" areas (Japan, Korea, etc)?

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acquisition of "Western" lifestyle (diet) - among immigrants and descendants, rates rapidy reach those of the adopted country

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what is the dietary etiology of colorectal carcinoma?

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"Western" type of diet - high fat, low fiber

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what other dietary factors are particularly associated with colorectal carcinoma (2)?

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1) high calorie intake; 2) meat (particularly animal fat)

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what foods have an inverse association with colorectal carcinoma (2)?

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1) fiber; 2) vegetables

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what is the increased risk for first degree relatives?

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2 to 4 fold increased risk

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what hereditary syndromes were mentioned to be associated with colorectal cancer (2)?

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1) HNPCC; 2) FAP (classic, attenuated, Gardner, and Turcot syndrome)

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what other diseases were mentioned to be associated with colorectal carcinoma (2)?

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1) colorectal adenomas; 2) ulcerative colitis

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what are the two pathologically distinct pathways that lead to colorectal carcinoma?

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1) APC/Beta-catenin pathway; 2) serrated polyp neoplasia pathway

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what concept do both pathways involve?

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the "multi-hit" concept - stepwise accumulation of multiple mutations

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what is the first hit in the APC/beta-catenin pathway?

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APC at 5q21 (inherited or acquired)

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what does the second hit involve?

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beta-catenin - methylatin abnormalities, inactivation of normal alleles

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what are hits farther down the line?

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1) proto-oncogene mutation (K-RAS); 2) homozygous loss of cancer suppressor genes (p53, LOH, SMAD); 3) overexpression of COX-2; 4) additional mutations and gross chromosomal alterations (telomerase, many genes)

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what mutations does the serrated polyp neoplasia pathway involve (2)?

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1) BRAF mutation; 2) high DNA (CpG island) methylation (CIMP-high)

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what formation does the serrated polyp neoplasia pathway start with?

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hamartomatous polyps

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what is the peak age of colorectal carcinoma?

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7th decade

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what % of cases occur before age 50?

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20%

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what is the most common location, and what % of cases occur there?

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rectosigmoid colon (55% of cases)

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how does colorectal carcinoma often present?

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inconstant occult bleeding or change in bowel habit

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what side is the lesion if there is unexplained anemia (iron deficiency anemia)?

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generally right sided (ascending colon)

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what other presentations will right sided lesions have (3)?

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1) weakness; 2) weight loss; 3) right lower quadrant pain

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how can left-sided (descending, sigmoid) lesions present (3)?

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1) gross blood in stools; 2) small caliber "pencil stools"; 3) obstructive symptoms

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what types of lesions are seen grossly on the left side?

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encircling lesion (napkin-ring constriction)

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what types of lesions are seen grossly on the right side (2)?

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1) bulky cauliflower-like polypoid mass; 2) large sessile lesion

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what is the most prevalent type of cancer microscopically, and what % of cancers are of this type?

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95% adenocarcinoma

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what test is positive in 60-70% of cases?

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CEA

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what is it a highly reliable indicator of?

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recurrent tumor

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what other tests can be used (list)?

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fecal occult blood test (FOBT), fecal immunochemical test (FIT), digital rectal examination, flexible sigmoidoscopy, colonoscopy, double contrast barium enema, CT colonography ("virtual colonoscopy")

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what is the single most important prognostic indicator?

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extent of tumor at time of diagnosis (staging)

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what is the system most widely used?

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TNM classification and staging system (Tis, T1=4, NX, N0-2, MX, M0-1)

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where was colorectal carcinoma said to spread (3)?

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1) regional lymph node; 2) liver; 3) lung

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DIVERTICULAR DISEASE (DIVERTICULOSIS)

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who is this one of the most common GI diseases of?

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elderly

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what is the most common site?

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sigmoid colon

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where in the world is diverticulosis most common?

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developed countries

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what type of diet is a risk factor?

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low fiber diet

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what are underlying problems of diverticulosis (2)?

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1) increased intraluminal pressure; 2) focal weakness in colonic wall

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what is the usual clinical picture of diverticulosis like?

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usually asymptomatic (80%)

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where may pain occur?

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left lower quadrant

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what other symptoms may occur (list)?

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constipation, diarrhea, rectal bleeding, fever, nausea, vomiting

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what is seen grossly, and how big is it?

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small flask -like or spherical outpouching (0.5 to 1 cm in diameter)

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what is seen in the surrounding areas?

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pronounced muscular hypertrophy

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what is present in 10-25% of cases?

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diverticulitis

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what are complications of diverticular disease (5)?

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1) bleeding; 2) muscular hypertrophy with obstruction; 3) pericolic abscess; 4) perforation; 5) fistula