GI polyposis

A patient (often a young adult or adolescent) found at colonoscopy or surgery to have multiple gastrointestinal polyps, with or without a personal or family history of colorectal cancer. The clinical posture is to anchor on histology first (adenomatous, hamartomatous, serrated, juvenile) because the histologic category sorts the differential cleanly, then layer in polyp count, age of onset, extracolonic features, and family history. The high-stakes question is whether the patient (and family) belongs in a hereditary surveillance program; the wrong answer is a missed cancer one or two decades downstream.

Four sorting axes:

1. Histology of the polyps: adenomatous (FAP, MAP, Lynch), hamartomatous (Peutz-Jeghers, juvenile polyposis, PTEN), serrated (serrated polyposis syndrome), mixed.
2. Number of polyps: classical FAP is hundreds to thousands; attenuated FAP and MAP are typically 10-100; Lynch is often few (5-10 or fewer, but accelerated to cancer); Peutz-Jeghers patients have a handful of large hamartomas.
3. Age of onset: adenomas starting in childhood/adolescence in FAP; adenomas in 40s-50s in attenuated FAP, MAP, and Lynch.
4. Extracolonic features: osteomas + desmoids + CHRPE (Gardner = FAP); medulloblastoma (Turcot = FAP); mucocutaneous melanotic macules (Peutz-Jeghers); macrocephaly + skin lesions (PTEN); telangiectasias + epistaxis (JPS/HHT overlap from SMAD4).

Adenomatous polyposis

• Familial adenomatous polyposis (FAP) (APC, AD; ~25% de novo): hundreds to thousands of colorectal adenomas starting in adolescence; near-100% lifetime risk of colorectal cancer without prophylactic colectomy. The variant location within APC predicts phenotype (5' and 3' variants tend toward attenuated; mid-gene variants tend toward classical and severe). Extracolonic features cluster into named variants of the same gene:
  • Gardner syndrome: FAP + osteomas + desmoid tumors + epidermoid cysts + CHRPE (congenital hypertrophy of retinal pigment epithelium).
  • Turcot syndrome (type 2): FAP + medulloblastoma.
  • Also: gastric and duodenal polyps + papillary thyroid cancer + hepatoblastoma in young children + adrenal adenomas.
• Attenuated FAP: 10-100 adenomas, often right-sided, onset typically in 30s-40s. Same APC gene; different variant locations.
• MUTYH-associated polyposis (MAP) (MUTYH, AR): looks phenotypically like attenuated FAP (10-100 adenomas) but inherited recessively, so the family history pattern lacks vertical dominance. Carrier frequency is ~1-2%; counseling parents and siblings of an affected proband is distinct from autosomal-dominant counseling. Slightly elevated risk in monoallelic carriers is debated.

Hamartomatous polyposis

• Peutz-Jeghers syndrome (STK11/LKB1, AD): mucocutaneous melanotic macules on the lips, buccal mucosa, perioral skin, and acral surfaces in childhood (the cosmetic pigment often fades in adulthood while the buccal pigment persists) + GI hamartomas prone to intussusception in the small bowel (the surgical emergency that often makes the diagnosis) + markedly elevated lifetime cancer risk across multiple sites: breast, colorectal, pancreatic, gastric, small bowel, gynecologic (ovarian sex-cord tumors with annular tubules, cervical adenoma malignum), testicular (large-cell calcifying Sertoli tumors).
• Juvenile polyposis syndrome (JPS) (SMAD4, BMPR1A, AD): juvenile-type polyps in the colon, stomach, or small bowel, typically presenting with rectal bleeding, anemia, or intussusception in childhood/adolescence. Colorectal, gastric, small bowel, and pancreatic cancer risks elevated. SMAD4 also causes hereditary hemorrhagic telangiectasia: the combined JPS-HHT overlap syndrome has telangiectasias, epistaxis, and pulmonary AVMs in addition to the polyps; recognition matters because pulmonary AVM screening changes management.
• PTEN hamartoma tumor syndrome (Cowden, Bannayan-Riley-Ruvalcaba) (PTEN, AD): macrocephaly + mucocutaneous lesions (trichilemmomas, papillomatous papules, acral keratoses) + GI hamartomatous polyps + thyroid (multinodular goiter, follicular carcinoma) + breast (fibroadenomas, increased breast cancer risk) + endometrial cancer risk. Lhermitte-Duclos disease (dysplastic gangliocytoma of cerebellum) is a hallmark adult finding.

Serrated polyposis

• Serrated polyposis syndrome (SPS): defined by clinical criteria (≥5 serrated polyps proximal to the rectum, with two or more > 10 mm; or ≥20 serrated polyps anywhere in the colon). Largely polygenic; rare RNF43 germline variants identified in a subset. Elevated colorectal cancer risk; surveillance is annual to biennial colonoscopy.

Lynch syndrome (a "polyposis-adjacent" diagnosis)

• Lynch syndrome (HNPCC) (MLH1, MSH2, MSH6, PMS2, EPCAM, AD): not a true polyposis because polyps are few (5-10 or fewer), but accelerated adenoma-to-carcinoma progression + right-sided colon predominance + multiple synchronous and metachronous cancers + characteristic extracolonic spectrum: endometrial (the second most common cancer in Lynch women), ovarian, gastric, urothelial, small bowel, biliary, brain (Turcot type 1: glioma + Lynch), sebaceous skin tumors (Muir-Torre). Screening operates through Amsterdam II and revised Bethesda criteria + tumor microsatellite instability (MSI-H) testing + MMR protein immunohistochemistry (loss of one or more of MLH1, MSH2, MSH6, PMS2) + germline confirmation.

1. Detailed personal cancer history + three-generation family history: ages, sites, polyp counts, surgeries, screening behaviors.
2. Polyp histology review: have pathology re-examine the slides; adenomatous vs hamartomatous vs juvenile vs serrated is the first sort.
3. Reflex tumor testing on any colorectal or endometrial cancer: MMR IHC (loss of MLH1/MSH2/MSH6/PMS2) + microsatellite instability + BRAF V600E (sporadic MLH1-deficient tumors) + MLH1 promoter methylation.
4. Skin exam + mucosal exam: Peutz-Jeghers pigment, Cowden trichilemmomas, sebaceous tumors (Muir-Torre).
5. Ophthalmology fundus exam: CHRPE for FAP/Gardner.
6. Targeted multi-gene panel: a "colorectal cancer and polyposis panel" typically covers APC, MUTYH, STK11, BMPR1A, SMAD4, PTEN, MLH1, MSH2, MSH6, PMS2, EPCAM, GREM1, POLE, POLD1, NTHL1, MSH3, AXIN2. Comprehensive panels increasingly replace single-gene testing because phenotypes overlap.
7. Imaging and endoscopic surveillance tailored to diagnosis: upper endoscopy + duodenoscopy in FAP (duodenal polyps + thyroid US + abdominal MRI for desmoids); video capsule enteroscopy in Peutz-Jeghers; thyroid US + breast imaging + endometrial sampling in Cowden; full colonoscopy + endometrial + gastric screening in Lynch.
8. Cascade testing of at-risk first-degree relatives once a pathogenic variant is identified in the proband.