Pocket Oncology (Pocket Notebook Series), 1st Ed.

LYNCH SYNDROME & FAP

Payal D. Shah and Zsofia K. Stadler

LYNCH SYNDROME (LS, FORMERLY HNPCC)

Biology

• Caused by germline Mt in DNA MMR gene (MLH1, MSH2, MSH6 >> PMS2) or 3′ del in EPCAM/TACSTD 1 gene (leads to MSH2 silencing)

• Phenotypic hallmark of LS in presence of microsatellite instability or MSI (accumulation of errors during DNA replication, especially in repetitive sequences known as microsatellites) in the tumor

• Autosomal dominant inheritance, up to 70% lifetime risk of CRC & 60% risk of endometrial CA penetrance

Epidemiology & Clinical Presentation

• Accounts for 3% of all CRC

• Dx: Mean age at CRC dx 43; more rapid progression from adenoma to carcinoma than in sporadic CRC; predilection for proximal colon

• Pathology of LS-associated CRC: MSI-H, poorly differentiated w/medullary features, mucinous histology, peritumoral lymphocytic infiltration

• Other LS-associated CA: Endometrial (25–60%); gastric, ovarian, pancreatic, urethral, renal pelvic, brain (GBM), small intestinal (all <10%)

• Muir–Torre syndrome: Variant of LS a/w sebaceous neoplasms, most often seen in MSH2 Mt carriers

Risk Assessment Models

• Amsterdam II criteria (1999): Specific (50% people meeting criteria have MMR gene Mt) but not sensitive (stringent criteria miss up to 68% Pt w/LS)

• Revised Bethesda guidelines (2002): Broader criteria than Amsterdam model, cost-effective, but difficult to apply in practice

• Newer online models: PREMM1,2,6 (Dana Farber), HNPCC predict model, MMRpro—give probability of Mt and/or development of LS-associated CA

Genetic Testing

• Test tumor tissue first

• If positive tumor tissue testing (MSI-H or IHC abnl) refer for genetic counseling, germline Mt testing

• Reflex testing: Tumor testing of CRC & endometrial CA regardless of FHx to determine who should undergo genetic testing (performed at some NCCN institutions, cost-effective for CRC)

• If no tumor tissue available in pt w/strong FHx: Consider testing large polyps (↓ Sn) or proceeding directly to germline sequencing

Management of Individuals with Lynch Syndrome

• CRC risk: Begin colonoscopy age 20–25 or 2–5 y younger than youngest affected relative (whichever 1st), repeat q1–2y; if not a candidate for surveillance, t/c subtotal colectomy

• Endometrial & ovarian CA: Education for enhanced recognition of sx (ie, dysfunctional uterine bleeding), consideration of TAH/BSO upon completion of child-bearing; additional recommendations (annual endometrial sampling, TVUS, serum CA-125) individualized

• Other CA: Consider upper EGD & non-invasive capsule endoscopy q2–3y beginning age 30–35; consider annual UA age 25–30y; site-specific evaluation & heightened attention to symptomatic

• Chemoprevention: ASA reduced CA risks in carriers of hereditary CRC (CAPP2 Trial, Lancet 2011;378:2081); optimal dose unclear

Treatment

• While a/w an improved prognosis, MSI-H tumors may be more resistant to tx w/fluorouracil-based chemotherapy (J Clin Oncol 2010;28:3219) though not yet universally practice-changing

FAP (FAMILIAL ADENOMATOUS POLYPOSIS)

Biology

• Mt of APC gene on chromosome 5q21; 25% of Mt occur de novo

• Two variants: Classical FAP & attenuated FAP (AFAP); phenotypic variability dependent on location of particular APC Mt

• Inheritance: Autosomal dominant; penetrance for classical FAP: Essentially 100%

Epidemiology

• Incidence/prevalence: FAP + AFAP account for <1% of all CRC

Clinical Presentation:

• FAP: >100 (typically hundreds to thousands) polyps by teens to 30s; lifetime risk of CRC approaches 100% by age 50; AFAP typically <100 polyps; later onset of disease (incidence rises sharply after age 40, approaches 70% by age 80)

• Location of disease: FAP: L-sided CRC more common; AFAP: R-sided CRC

• Associated non-malignant findings (more common w/FAP): Desmoid tumors (distal APC Mt), congenital hypertrophy of retinal pigment epithelium (CHRPE, a/w central APC Mt), mandibular osteomas, supernumerary teeth, epidermal cysts, adrenal cortical adenomas

• Associated malignant conditions: Thyroid tumors, gastric small intestinal polyps w/5–10% risk of duodenal or ampullary adenocarcinoma, Turcot syndrome (colonic polyposis + brain tumors), possibly pancreatic CA

Genetic Testing

• Sn to identify APC gene Mt currently 70–90%

• If unknown familial Mt, first perform sequencing; if negative, test for large rearrangements & APC gene deletions

• For clinical AFAP, if an APC Mt is not identified, perform MUTYH testing for MYH-associated polyposis (MAP), an autosomal recessive CRC/polyposis predisposition

Screening and Risk Reduction of FAP and AFAP

• Personal h/o FAP: Begin flex sigmoidoscopy or colonoscopy age 10–15; repeat q12mo; review surgical options (colectomy or proctocolectomy) once adenomas develop; prophylactic proctocolectomy usually indicated in the 2nd decade for classical FAP

• Personal or FHx of AFAP: Begin colonoscopy & polypectomy late teens, repeat q2–3y; consider prophylactic surgery if polypectomy no longer feasible

• At-risk, no testing (preference or access): Offer annual flexible sigmoidoscopy or colonoscopy age 10–15 until age 24; if negative, less frequent intervals; if using flexible sigmoidoscopy, consider colonoscopy q5y beginning age 20 in case Pt has AFAP

• Consider chemoprevention w/NSAIDs (PreSAP, NEJM 2006;355:885) & (APC, NEJM 2006;355:873)

Additional Surveillance

• Bowel surveillance following surgery: If retained rectum, endoscopic exam q6–12mo of remaining tract & ileal pouch/ileostomy

• Annual thyroid exam ± U/S

• Consider abdominal CT or MRI if FHx of sx desmoids