Hereditary Colorectal Cancer Syndromes Philip Kam Queen Elizabeth Hospital

Overview  Features and genetics basis  Screening  Surveillance protocol  Surgical management

Colorectal cancers  Colorectal cancer (CRC) is commonest cancer in HK (~4450 new cases in 2011)  Worldwide incidence estimated ~1 million annually  about 20% has strong familial basis HK Cancer registry, 2013 Lynch et al 2009

Colorectal cancers  ~5% hereditary  Hereditary forms of colorectal cancers: strong penetrance among families with known genetic basis, i.e. germline mutations  Amongst them:  Familial Adenomatous Polyposis (FAP)  Lynch Syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer, HNPCC)  Rustgi 2007

Familial Adenomatous Polyposis (FAP)  Classical FAP:  Presence of 100 or more polyps, with extra-colonic manifestations  Attenuated FAP  Less than100 adenomas (~average 30); frequent right sided distribution  Presents with multiple colonic polyps since average of 16 year old  By age 35, ~95% FAP have polyps  Mean age of Colon cancer is 39 (~34-43)  Extra-colonic involvement include:  stomach, duodenum, osteoma, thyroid, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumor, desmoid tumor Jasperson and Burt 2014; Rustgi 2007

FAP - Genetics  Autosomal dominant  Defect in gene APC (Adenomatous polyposis coli), on Chrm 5p22.2  Pathogenic variants, with more than 1,500 germline mutations found  Detection by: Sequence analysis: ~90% Duplication / deletion analysis: 8-12%  Hedge et al, 2014

FAP - Surveillance  Sigmoidoscopy / Colonoscopy every 1-2 years from age  Annual colonoscopy once polyp found  OGD before colectomy or age 25, then every 1-3 years  Annual cervical USG to screen for thyroid cancer from at  CT or MRI abdomen as baseline to look for desmoid tumor if strongly family history  Small bowel enema / CT with oral contrast NCCN 2014, Stoffel 2014

FAP - Treatment ● For classic FAP, colectomy is recommended once adenoma emerge ● In presence of symptoms, or lesions with high grade dysplasia, colectomy should be as soon as possible Options: ● Total Colectomy with ileorectal anastomosis  if Attenuated FAP / rectum is spared of polyp ●Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) ● Total procotcolectomy with permanent ileostomy  Jasperson & Burt 2014, Campos 2014

FAP - Treatment options Total Colectomy + IRAProctocolectomy + IPAATotal proctocolectomy + stoma Risk of Ca rectum (5% in 10years) No risk of future Ca rectumMost “definitive”; but not the first line Lower complications risks Less re-operative rate Function might be poor: more frequent bowel movement, incontinence and soiling Difficult for young patients Quality of life betterStill has risks of polyp formation in IPAA; but risk of Ca rectum ? ~48% pouch adenoma For few polyps and rectum spared (<20) Severe rectal adenoma (>20) and severe colon load (>1000) For tumor involving sphincter / presence of desmoid tumor Church 2013; Guillem et al 2006

Lynch Syndrome

Lynch Syndrome - Presentation  Fulfills clinical criteria with germline mutation found  Major outcome is colorectal cancer, with mean age of diagnosis at years old (vs. 69 in sporadic)  Risk of CRC up to 75%-80% in life  Majority are right side tumor (60-80%)  High rate of metachronous tumor (16% in 10 years, 41% in 20 years)  Also a wide variety of extracolonic tumors  Risks of CRC and other tumors depend on which mutation  In HK, about 170 families of Lynch Syndrome identified thus far Giardiello et al 2014, Kohlmann 2014

LS - Extracolonic involvements Giardiello et al. 2014

Lynch Syndrome - Genetics  Autosomal dominant  At least 4 genes found implicated  MLH1, MSH2, MSH6, PMS2  All are Mismatch Repair (MMR) gene mutations  Leading to a loss of “proofreading” in DNA replication  Results in point-mutations, known as Microsatellite Instability (MSI)  Accumulation of mutations cause more rapid adenoma-carcinoma sequence → earlier onset  Kohlmann 2014

What is MMR? Vilar & Gruber 2010 In areas of long, tandem repeats of nucleotides, MMR can correct mismatch of single nucleotide!

Lynch Syndrome - who to suspect? Two major clinical guidelines have been developed to screen for Lynch Syndrome  Amsterdam Criteria  Revised Bethesda Guideline  Guidelines help to initiate genetic testing in tumor specimen to confirm diagnosis of LS in a proband  Microsatellite Instablity (MSI)  Immunohistochemical stain (IHC)  Germline sequence analysis

Screening Algorithms Amsterdam / Bethesda criteria met Endometrial Ca < age 50 Known LS in Family Mutation known Positive Lynch Syndrome surveillance Negative Average risk surveillance Mutation NOT known Tumor a/v Test for MSI and IHC for mutations, diagnosis and screening strategy accordingly Tumor NOT a/v Positive = Lynch syndrome surveillance and screening for family members NCCN guideline 2014 Stoffel et al 2014 Genetic for 4 MMR genes

LS - Amsterdam Criteria “3-2-1 rule” Sensitivity 22%; Specificity 98% Giardiello et al. 2014

LS - Revised Bethesda Developed to identify patients who need MSI- testing Sensitivity 82%; Specificity 77% Giardiello et al. 2014

Lynch Syndrome - Genetics Testing The tumor specimen can be tested for: MSI stability  A panel of 5 markers used; MSI-high, MSI-low, or MSI-stable Immunohistochemistry (IHC) staining:  To see which MMR gene protein is dysfunctional  90% of LS tumors are MSI-high. But 10-15% of sporadic cases are also MSI-H and abnormal IHC Germline molecular testing by sequence analysis  When tumor specimen is not available Lynch 2009; Giardello 2014; NCCN guideline 2014

Lynch Syndrome - Surveillance Surveillance strategy for extracolonic tumor once genetic test positive:  Colorectal Ca: Colonoscopy every 1-2 years starting age 20-25; or 2-5 years before youngest age of CRC in family if diagnosed before 25yo  Endometrial Ca: Annual pelvic exam and endometrial sampling at age  Ovarian Ca: annual TV USG from age  Consider prophylactic TAHBSO in women with LS at age 40 or finish child-bearing Giardello et al 2014; Stoffel et al 2014; NCCN 2014

Lynch Syndrome - Surveillance Surveillance strategy:  Gastric Ca: OGD from age with antral biopsy and H.pylori eradication; FU OGD every 2-3 years  Small bowel Ca: lacks evidence for use of small bowel enema / capsule endoscopy  NCCN: OGD with extended duodenoscopy  Urinary Ca: annual urinalysis from age  CNS cancer: annual neurological exam Giardello et al 2014; Stoffel et al 2014; NCCN 2014

LS - Treatment of Ca Colon If LS patient has CA colon or pre-malignant adenoma, colectomy is the choice:  If only partial colectomy, risks of 10-year CRC risks increases from 16-19% despite vigilant colonoscopy  Prophylactic subtotal colectomy or total colectomy with ileo- rectal anastomosis significantly reduced the risks to <3.4% Win et al 2013, Edelstein et al 2011  Retrospective review showed metachronous CRC reduced by 31% of every 10cm of large bowel resected Parry 2011

LS - Treatment of Ca rectum LS with Ca rectum (up to ~20% in LS):  Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) theoretically attains smaller risks of metachronous tumor  Anterior resection with intensive surveillance is an option?  risk of metachronous cancer / advanced neoplasia up to 51% Kalady et al 2012

Conclusion  Lynch syndrome and FAP should be suspected in young patients with cancer / multiple colonic adenoma  Clear family history important  Clinically should screen for other organ involvement  Genetically should arrange appropriate genetic testing  Surgically should tailor-made appropriate operation for curative and prophylactic purpose  Hopefully involving surgeons, oncologist, and geneticist

Thank you

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