Adenomatous Polyposis Syndromes: Familial Adenomatous Polyposis (FAP), Attenuated FAP (AFAP), MUTYH associated polyposis (MAP) ✓ Genetic test if > 10 cumulative adenoma, typical extra-colonic features, or relative of known index patient Familial Adenomatous Polyposis (FAP): - "CRC + Duodenal (ampullary!) + Thyroid + Breast *FAP" - Autosomal Dominant; close to 100% penetrant - >100 synchronous colorectal adenomas → 100% CRC risk if left untreated → Appear in 2nd or 3rd decade (mean 15.9), slight distal > proximal → Most < 1cm, mostly tubular adenoma w/o villous features → Unique histology: "Microadenomas" = dysplastic or adenomatous cells in single crypts or portions of crypts. Can be in normal tissue. - Germline APC mutation on chr5. APC is tumor suppressor. Inherit one damaged allele; other allele damaged over time → Location of mutation on gene → phenotype, extracolonic features - Variants: → Turcot Syndrome: FAP + Brain tumors (glioma, medulloblastoma). → Gardner syndrome: FAP + Osteomas, desmoids, fibromas, epidermoid cysts, sebaceous cysts, supernumerary teeth, congenital hypertrophy of retinal pigment Attenuated FAP (AFAP): - "mild, later onset FAP" - Autosomal Dominant - 10-100 adenomas - APC Mutation in proximal or distal end of gene - Polyps 10-20 years later than FAP → Proximal > Distal compared to FAP, relative rectal sparing - May never need colectomy if can be controlled endoscopically → Surgery = IRA (rectal sparing) MUTYH associated polyposis (MAP): - "Adenomas, Recessive", Autosomal Recessive - 20-99 adenomas, can have > 100 - CRC median age 48-53 - Biallelic MUTYH mutation (monoallelic ? Slight ↑ CRC) → proximal or distal, relative rectal sparing → Base excision repair gene; protein for DNA oxidative damage repair. Failure of gen → mutations in key genes (APC, KRAS, etc). Dean Ehrlich MD @DeanEhrlich_MD #Adenomatous #Polyposis #Syndromes #diagnosis #management #gastroenterology

Lynch Syndrome: • "CRC + Endometrial/Ovarian + Stomach + Urinary → Lynch Syndrome" • Autosomal Dominant, 1 in 279 people • Loss of expression in MLHI, MSH2, MSH6 or PMS2 or EPCAM genes → Mismatch Repair Defect → Microsatellite Instability (MSI) • Previously thought to be but can have polyps; Proximal > Distal by Dean Ehrlich MD @DeanEhrlich_MD #Lynch #Syndrome #diagnosis #management #gastroenterology

Hamartomatous Polyposis Syndromes - Peutz-Jeghers Syndrome (PJS), Juvenile Polyposis Syndrome (JPS), Cowden Syndrome (CS), Cronkhite-Canada (CC), Tuberous Sclerosis (TS) Peutz-Jeghers Syndrome (PJS): - "Spots + Hamartomas + GI Cancer + Uterine, Breast and Pancreas + Sex Cord Tumor → PJS" - Autosomal Dominant I STKII Gene Mutation - Classic mucocutaneous pigmentation, spots cross vermillion border on lips - Hamartomatous polyps throughout GI Tract - Genetic testing if FHx, ≥ 2 GI hamartomatous polyps, and/or pigmentation - Sx 2nd/3rd decade 2/2 large polyps bleeding/obstructing/intussusception - Histologically distinct hamartomatous polyps → Arborizing pattern w/ muscularis mucosa extending into branching fronds I "Pseudo-invasion" from epithelial infolding → Polyp epithelium from site of removal → Adenoma and cancer can occur in polyps Juvenile Polyposis Syndrome (JPS): - "Juvenile Polyps + CRC + Gastric CA JPS" - Autosomal Dominant I Mutation in SMAD4 (aka MADH4) or BMPR1A gene → Tumor suppressor gene in TGF-ß family - Criteria: >5 Juvenile colon polyps, juvenile polyps outside the colon, or FHx of JPS + Juvenile polyp - Small to >3cm polyps, Proximal>Distal, in 1st decade (dozens to 100s): Smooth, reddish, w/ white exudate, w/o fissures/lobulations - Histo: Epithelium from site of removal, abundant lamina propria w/ benign elongated cystically dilated glands | lack smooth muscle core - Sx 1st/2nd decade 2/2 large polyps bleeding/obstructing/intussusception Cowden Syndrome (CS): - "Varied polyps + PTEN + Trichilemmomas" - PTEN gene mutation - Colon polyps in 95%, throughout colon → Likely risk of CRC - Varied polyp types - Esophagus: Diffuse glycogenic acanthosis - Stomach/Small bowel: Hamartomatous - can be a/w autism, MR - Trichilemmomas (bumpy skin lesion) - Variant: Bannayan-Riley-Ruvalcaba: PTEN + Hamartomatous polyps + subcutaneous lipomas + macrocephaly +hemangioma Cronkhite-Canada (CC): - Non-inherited I GI Hamartomas + Nail Abnl + Hair Loss + Protein Losing Enteropathy Tuberous Sclerosis (TS): - AD, GI hamartomas, many organ system involvement by Dean Ehrlich MD @DeanEhrlich_MD #Hamartomatous #Polyposis #Syndromes #diagnosis #management #gastroenterology

Colorectal Cancer Screening and Polyp Surveillance Intervals Colon Cancer Screening - Modality - Interval: • Colonoscopy - q10 years • FIT - q1 year • Multitarget DNA stool test - q3 years • Flexible Sigmoidoscopy - q5-10 years • CT colonography - q5 years • Colon Capsule - q5 years Polyp Surveillance Intervals • Adenomatous Polyps • Serrated Polyps Dean Ehrlich MD @DeanEhrlich_MD #Colorectal #colon #Cancer #Screening #Polyp #Surveillance #Intervals #management #gastroenterology