Colon tumor
Familial polyposis syndromes of colon
Familial adenomatous polyposis of colon, classic

Author: Jennifer Findeis-Hosey, M.D. (see Authors page)
Editorial board review: Raul Gonzalez, M.D.

Revised: 27 May 2016, last major update February 2016

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: Familial adenomatous polyposis [title] colon
Definition / General
  • Autosomal dominant familial polyposis syndrome due to a defect in the APC gene (5q21) which prototypically results in numerous (>100) colonic adenomatous polyps
Essential Features
Terminology
  • Also known as familial polyposis coli or adenomatous polyposis coli
Epidemiology
  • Incidence of 1 per 7 - 30,000 individuals
  • Males and females are equally affected
  • Colon polyps typically are present by the end of the 2nd decade (mean age: 15.9 years)
  • Essentially 100% of patients develop colonic adenocarcinoma without surgical intervention (average age: 39 years old)
  • 25% of patients will be diagnosed with colorectal carcinoma at time of presentation
Sites
  • In addition to colonic adenomatous polyps, patients may develop polyps in the stomach (fundic gland polyps) and small intestine
  • May also develop carcinoma of thyroid gland, gallbladder and adrenal gland
  • Desmoid tumors are a common extraintestinal manifestation (10 - 25%) - they frequently develop in the abdominal wall following local surgery / trauma
  • May develop bone lesions (i.e., osteomas), skin lesions (i.e., epidermal inclusion cysts), dental abnormalities (i.e., supranummary or absent teeth), ocular problems (i.e., congenital hypertrophy of retinal pigment epithelium [CHRPE]) or juvenile nasopharyngeal angiofibromas
  • Gardner syndrome encompasses the subset of FAP patients with extraintestinal tumors
  • Turcot syndrome encompasses the subset of FAP patients with brain tumors, which are typically medulloblastomas
Pathophysiology
  • APC (adenomatous polyposis coli) is a tumor suppressor gene involved in cell cycle control and downregulation of beta-catenin through the Wnt signaling pathway
  • The APC protein is normally involved in apoptosis of colonic epithelial cells
  • APC mutations may cause expansion of the crypt base cell population, including crypt stem cells
  • When APC is mutated, beta-catenin is no longer downregulated, and can function to stimulate cell growth
  • As explained by the two hit hypothesis, patients with a germline APC mutation develop adenomatous polyps when there is inactivation of the remaining normal APC allele
  • Colorectal adenocarcinomas in FAP develop in a similar fashion to sporadic-type colorectal adenocarcinomas (i.e., mutations in KRAS, TP53)
  • The abundance of adenomatous polyps results in the near certain development of colorectal adenocarcinoma
Diagnosis
  • Diagnostic criteria:
    • 100 or more colorectal adenomatous polyps, or
    • Germline mutation in APC, or
    • Family history of FAP with colorectal adenomas (age < 30), or
    • Family history of FAP and presence of at least one epidermoid cyst, osteoma or desmoid tumor
  • Patients with a history of > 10 colorectal adenomas, a family history of adenomatous polyposis syndromes or a history of adenomas with FAP-type extracolonic lesions should undergo assessment for adenomatous polyposis syndrome (Am J Gastroenterol 2015;110:223)
Prognostic Factors
  • Location of the mutation in APC has an impact on the phenotypic presentation, including number of polyps and presence or absence of desmoid tumors and congenital hypertrophy of retinal pigment epithelium
  • Most common causes of non-colorectal carcinoma deaths in FAP patients are duodenal / ampullary carcinoma and complications of desmoid tumor
Case Reports
Treatment
  • Prophylactic colectomy in late second to early third decade
  • Must monitor rectal stump if preserved
  • FAP patients who undergo consistent colorectal screening with subsequent surgery have a significantly decreased rate of mortality from colorectal malignancies
  • Children at risk for FAP should undergo sigmoidoscopy every 1 - 2 years, beginning at age 10 - 12 years
  • Relatives should also be screened
  • NSAIDs and aspirin use have been studied to decrease polyp regrowth following subtotal colectomy
Gross Description
  • Most adenomatous polyps are small (< 0.5 cm) and sessile
  • Polyps are more common in the left sided colon, although the entire length of the colon is typically involved
  • Polyps may be flat or depressed (Int J SurgPathol 2006;14:133)
Gross Images

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Carpet of adenomatous polyps

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Numerous polyps

Micro Description
  • Most polyps are tubular adenomas
  • Adenomatous epithelium may be present in only a single crypt taken from flat, endoscopically unremarkable mucosa (unicryptal adenoma)
  • Histologic features of FAP-associated colorectal adenomas and carcinomas are similar to sporadic-type lesions
Micro Images

Images hosted on PathOut server:

Contributed by Dr. Jennifer Findeis-Hosey, University of Rochester Medical Center (USA):

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Adenoma involving few crypts

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Tubular adenoma polyp, FAP patient



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Adenoma and adenocarcinoma

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FAP vs. non-FAP

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BCL2

Molecular / Cytogenetics Description
  • Hereditary colorectal cancer syndromes are usually due to defect in APC gene at 5q21
    • Polyposis patients without APC mutations often have mutations in MYH gene
    • Autosomal dominant trait with high degree of penetrance (> 90%)
    • 20% represent a new de novo APC mutation without family history
Videos



Differential Diagnosis
  • Attenuated FAP: polyposis syndrome also due to an APC mutation, but patients have fewer than 100 colorectal polyps
  • MYH-associated polyposis: polyposis syndrome caused by a mutation in the MYH gene