7. Polyposis Syndromes

 

 

Lynch Syndrome (HNPCC)

  • Genetics: Autosomal dominant; germline mutation in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or EPCAM gene.
  • Pathophysiology: Microsatellite instability (MSI) seen in Lynch syndrome and sporadic colorectal cancer (15%).
  • Cancer Risks:
    • Colorectal cancer (CRC): 10–47%, depending on the gene and sex.
    • Other cancers: Endometrial, small bowel, ureter, and renal pelvis.
  • Amsterdam Criteria (3-2-1 Rule):
    • 3 relatives with Lynch-associated cancer.
    • 2 successive generations affected.
    • 1 diagnosed before age 50.
    • Only 22% sensitive but used when MMR testing unavailable.
  • Surveillance Recommendations (BSG):
    • Colonoscopy every 2 years:
      • Start at age 25 for MLH1 and MSH2 carriers.
      • Start at age 35 for MSH6 and PMS2 carriers.
    • Aspirin use reduces CRC risk.
    • Screen all CRC patients for Lynch syndrome.

Familial Adenomatous Polyposis (FAP)

  • Genetics: Autosomal dominant; mutation in the APC gene (tumor suppressor gene).
  • Features:
    • Multiple adenomatous colon polyps; ~95% have polyps by age 35.
    • Extra-colonic manifestations:
      • Gastric fundic polyps, duodenal adenomas (Spigelman criteria).
      • Congenital hypertrophy of retinal pigment epithelium (CHRPE).
      • Osteomas, dental anomalies.
  • Surveillance:
    • Colonoscopy from age 12 (1–3 yearly).
    • Upper GI endoscopy from age 25; frequency based on Spigelman score.
  • Management: Prophylactic colectomy.
  • Desmoid Tumors:
    • Mesenchymal tumors causing compression; managed with sulindac (NSAID) and tamoxifen.

MUTYH-Associated Polyposis (MAP)

  • Genetics: Autosomal recessive; MUTYH gene mutation (base excision repair).
  • Features:
    • 10–100 colorectal adenomas by age 60.
    • Gastric/duodenal polyps; risk of duodenal, ovarian, thyroid, and skin cancers.
    • 60% of homozygotes present with CRC; heterozygotes have a 5% lifetime CRC risk.
  • Surveillance:
    • Annual colonoscopy from age 18.
    • Upper GI endoscopy from age 35; Spigelman score determines frequency.
    • Annual thyroid ultrasound recommended.

Peutz-Jeghers Syndrome (PJS)

  • Genetics: Autosomal dominant; STK11 mutation (de novo cases possible).
  • Features:
    • Hamartomatous polyps in the small bowel (most common), stomach, and colon.
    • Mucocutaneous hyperpigmentation (lips, buccal mucosa).
    • Cancer risks: GI (stomach, colon), pancreatic, breast, and germ cell tumors.
  • Surveillance:
    • Baseline OGD, colonoscopy, and capsule endoscopy at age 8.
    • If normal, defer until age 18, then repeat every 1–3 years.
    • Polypectomy for polyps >1.5 cm or symptomatic to prevent intussusception.

Juvenile Polyposis Syndrome (JPS)

  • Genetics: Autosomal dominant; mutations in SMAD4 and BMPR1A.
  • Features:
    • Hamartomatous polyps throughout the GI tract, often by age 20.
    • Increased GI cancer risk (9–50%).
  • Surveillance:
    • Colonoscopy starting at age 15.
    • OGD from age 18 (SMAD4) or 25 (BMPR1A).
    • Repeat every 1–3 years depending on phenotype.

Serrated Polyposis Syndrome

  • Definition (WHO 2019):
    • ≥5 serrated lesions ≥5 mm in size proximal to the rectum, with 2 ≥10 mm.
    • 20 serrated lesions throughout the colon, with ≥5 proximal to the rectum.
  • Cancer Risk: 15–30% lifetime CRC risk.
  • Surveillance:
    • BSG: Colonoscopy every 1–2 years.
    • ESGE: 1-year interval if advanced polyp(s) present; otherwise 2 years.

Cowden’s Syndrome

  • Genetics: Autosomal dominant; PTEN mutation (may occur spontaneously).
  • Features:
    • Widespread hamartomas in the GI tract, breast, thyroid, and kidney.
    • Mucocutaneous lesions: Oral papillomas and facial papules.

Cronkhite-Canada Syndrome

  • Features: Non-hereditary hamartomatous syndrome.
    • Symptoms: Diarrhea, malabsorption, nail changes, and dysgeusia.

 

Polyposis Syndromes: Summary Table

Syndrome

Inheritance

Pathophysiology

Key Features

Cancer Risks

Screening Recommendations

Lynch Syndrome (HNPCC)

Autosomal Dominant

Germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM. Microsatellite instability.

Right-sided adenomas, rapid progression; associated cancers: endometrial, small bowel, ureter, renal pelvis.

CRC: 10-47%; other cancers: endometrial, small bowel, ureter, renal pelvis.

Colonoscopy every 2 years: from age 25 (MLH1/MSH2) or 35 (MSH6/PMS2); daily aspirin recommended.

FAP

Autosomal Dominant

APC gene mutation; loss of tumor suppression.

Multiple adenomas by age 35; extracolonic: gastric, duodenal polyps, osteomas, CHRPE.

High risk of CRC if untreated.

Colonoscopy annually from age 12; OGD from age 25, interval based on Spigelman classification.

MUTYH-Associated Polyposis (MAP)

Autosomal Recessive

Base excision repair mutation; multiple adenomas.

10-100 adenomas by age 60; associated gastric and duodenal polyps.

CRC: 60% in homozygotes; gastric, duodenal cancers.

Colonoscopy annually from age 18; OGD from age 35 based on Spigelman classification.

Peutz-Jeghers Syndrome (PJS)

Autosomal Dominant

STK11 mutation; hamartomatous polyps.

Hamartomatous polyps (small bowel, stomach, colon), mucocutaneous pigmentation; risk of intussusception.

GI, breast, pancreatic, ovarian, testicular cancers.

Upper/lower/capsule endoscopy from age 8; repeat every 1-3 years; earlier if symptomatic.

Juvenile Polyposis Syndrome (JPS)

Autosomal Dominant

SMAD4 or BMPR1A mutation; hamartomatous polyps.

Hamartomatous polyps throughout GI tract; most develop by age 20.

CRC and GI cancers: 9-50%.

Colonoscopy from age 15; OGD from age 18 (SMAD4) or 25 (BMPR1A); 1-3 yearly.

Serrated Polyposis Syndrome (SPS)

Unknown

Multiple serrated polyps; WHO 2019 criteria: ≥5 polyps proximal to rectum ≥5 mm or >20 polyps overall.

Serrated lesions; cumulative polyp burden; proximal polyps often large.

CRC: 15-30%.

Colonoscopy every 1-2 years; adjust based on advanced/non-advanced polyp burden. FDR: every 5 years from 40/45.

Additional Notes:

  • Desmoid Tumors (FAP): Mesenchymal tumors; managed with sulindac + tamoxifen (BSG).
  • Spigelman Classification (FAP/MAP): Guides OGD surveillance frequency for duodenal polyps.
  • Gastric Cancer Risk (MAP, PJS): Emphasized in syndromes with gastric/duodenal polyps.

Specific conditions:

1.         Acromegaly: Start screening colonoscopy aged 40. If there are polyps on index scope, or active disease (raised IGF1) - 3-yearly Otherwise - 5- yearly

2.         Inflammatory bowel disease: see IBD guidelines.

3.         Cystic fibrosis: Colonoscopy screening should begin at age 40 for individuals with cystic fibrosis. Low Risk: Every 5 years if no polyps are detected or other risk factors are absent. High Risk: More frequent surveillance intervals (e.g., every 3 years), especially if polyps or signs of dysplasia are present.

 

References

  1. ESGE Guidelines on Colorectal Cancer Screening.
  2. BSG Guidance on Polyposis Syndromes.

Images

  1. Rare Disease Study. Link
  2. Comprehensive Guidelines in Gastroenterology. Link
  3. Gorlin Syndrome Report. Link
  4. Medscape Overview of GI Disorders. Link