What is polyposis?

What is Polyposis?

Polyposis refers to a group of syndromes characterized by the presence of multiple polyps in the gastrointestinal tract, particularly the colon, with varying cancer risks depending on the specific syndrome and polyp histology. 1

Classification by Polyp Histology

Polyposis syndromes are classified into three main categories based on the microscopic appearance of the polyps 1:

• Adenomatous polyposis: Polyps with dysplastic epithelium and malignant potential 1
• Hamartomatous polyposis: Polyps with abnormal tissue architecture but originally non-neoplastic nature 1
• Serrated polyposis: Polyps with serrated architecture 1

Major Polyposis Syndromes

Familial Adenomatous Polyposis (FAP)

FAP is the most common hereditary polyposis syndrome with a known genetic cause, affecting less than 1% of all colorectal cancer cases. 1

• Classical FAP: Characterized by >100 adenomatous polyps throughout the colon, with nearly 100% risk of colorectal cancer by age 40 if untreated 1
• Attenuated FAP: Presents with 10-100 adenomas, preferentially in the right colon, with later onset 1
• Caused by germline mutations in the APC gene on chromosome 5q21, with 30-40% arising from de novo mutations 1
• Associated extracolonic manifestations include hepatoblastoma in children, duodenal adenomas, thyroid cancer, desmoid tumors, osteomas, and dental anomalies 1

MUTYH-Associated Polyposis (MAP)

• Recessively inherited polyposis due to biallelic mutations in the MUTYH base excision repair gene 1
• Presents with attenuated phenotype of 10-100 adenomatous polyps 1
• Lifetime colorectal cancer risk approximately 60% compared to 6% in the general population 1
• Less than 5% develop extracolonic cancers 1

Juvenile Polyposis Syndrome (JPS)

JPS is characterized by hamartomatous polyps with distinctive microscopic features including dense edematous stroma, cystic mucus-filled glands, and prominent inflammatory infiltration. 2, 3

• Occurs in approximately 1 per 100,000 newborns, making it 10 times less common than FAP 1, 2, 3
• Diagnostic criteria require any one of: ≥5 juvenile polyps in the colorectum, juvenile polyps throughout the GI tract, or any number of juvenile polyps with positive family history 2, 3
• Cumulative lifetime colorectal cancer risk of 39-68% and gastric cancer risk of 21% in those with gastric polyps 2, 3
• Caused by mutations in SMAD4 (20%) or BMPR1A (20%) genes 2
• Typical polyp numbers range from 50-200 in the colon 1, 3

Critical pitfall: The term "juvenile polyp" refers to a specific histologic type, not the age at diagnosis—solitary juvenile polyps in children are common and NOT associated with cancer risk, unlike syndromic juvenile polyposis. 2, 4

Peutz-Jeghers Syndrome (PJS)

• Autosomal dominant syndrome with hamartomatous polyps and characteristic mucocutaneous pigmentation at the vermillion border of the lips 1
• Polyps exhibit distinctive branching smooth muscle architecture (arborizing pattern) extending to villus tips 1
• Predominantly affects the small intestine but also occurs in stomach and colon 1
• Caused by mutations in the LKB1 gene on chromosome 19p 1
• 80-500-fold excess risk of gastrointestinal cancers 1
• Cumulative cancer risk: 1-2% by age 20, >30% by age 50, >80% by age 70 1
• Intussusception occurs in 15% by age 10 and 50% by age 20 1

Clinical Implications

Cancer Risk Stratification

The cancer risk varies dramatically by syndrome 1, 5:

• FAP: Nearly 100% colorectal cancer risk without prophylactic colectomy 1
• JPS: 39-68% colorectal cancer risk, 21% gastric cancer risk 2, 3
• MAP: 60% colorectal cancer risk 1
• PJS: >80% cumulative cancer risk by age 70 across multiple organ systems 1

Distinguishing Features

Histopathologic examination is essential for accurate classification, as clinical presentation alone can be misleading. 6

• Adenomatous polyps show dysplastic epithelium with nuclear abnormalities and tubular/villous architecture 2
• Juvenile polyps have hamartomatous architecture with edematous stroma and lack smooth muscle branching 2, 4
• Peutz-Jeghers polyps have distinctive arborizing smooth muscle pattern absent in juvenile polyps 2

Important caveat: Juvenile polyps can develop adenomatous dysplasia (8.5% show mild-moderate dysplasia, 0.3% show severe dysplasia or cancer), which can lead to misdiagnosis as FAP if comprehensive evaluation is not performed. 6

Genetic Testing Considerations

• Full germline genetic testing should include DNA sequencing and large rearrangement analysis 1
• Multigene panels can analyze multiple polyposis genes (APC, MUTYH, POLE, POLD1, NTHL1, SMAD4, BMPR1A) simultaneously 1
• A large proportion of polyposis cases remain genetically unexplained despite advances in genetic testing 5