1. Hereditary Colorectal Cancer Syndromes Philip Kam Queen Elizabeth Hospital

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

3. 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

4. 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

5. 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

6. 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

7. FAP - Surveillance  Sigmoidoscopy / Colonoscopy every 1-2 years from age 10-12  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 25-30  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

8. 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

9. 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

10. Lynch Syndrome

11. Lynch Syndrome - Presentation  Fulfills clinical criteria with germline mutation found  Major outcome is colorectal cancer, with mean age of diagnosis at 44-60 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

12. LS - Extracolonic involvements Giardiello et al. 2014

13. 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

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

15. 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

16. 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

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

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

19. 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

20. 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 30- 35  Ovarian Ca: annual TV USG from age 30-35  Consider prophylactic TAHBSO in women with LS at age 40 or finish child-bearing Giardello et al 2014; Stoffel et al 2014; NCCN 2014

21. Lynch Syndrome - Surveillance Surveillance strategy:  Gastric Ca: OGD from age 30-35 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 30-35  CNS cancer: annual neurological exam Giardello et al 2014; Stoffel et al 2014; NCCN 2014

22. 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

23. 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

24. 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

25. Thank you

26. References HK Cancer Registry 2013; available at http://www3.ha.org.hk/cancereg/Summary%20of%20CanStat%202011.pdf Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis and medicolegal ramifications. Clin Genet. 2009; 76(1): 1–18 Rustgi AK, The genetics of hereditary colon cancer. Genes & Dev. 2007; 21:2525–2538 Giardello FM, Allen JI, Axibund JE, Boland CR. et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Dis Colon Rectum 2014; 57: 1025-1048 Kohlmann W. Lynch Syndrome. GeneReviews, NCBI Bookshelf, last updated May 22, 2014. Available at http://www.ncbi.nlm.nih.gov/books/NBK1211 http://www.ncbi.nlm.nih.gov/books/NBK1211 Vilar E, Gruber SB, Microsatellite instability in colorectal cancer—the stable evidence. Nature Review Cliincal Oncology, 2010 7(3):153-62 Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, et al. Hereditary Colorectal Cancer Syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines. J Clin Oncol 2014 (ahead of print; available at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.58.1322 )http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.58.1322 Church J, Simmang C, The Standards Task Force The American Society of Colon and Rectal Surgeons. Treatment of patients with dominantly inherited colorectal cancer (Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colorectal Cancer) Diseases of the Colon & Rectum 2003;46(8):1001-1012 S. Parry, A.K. Win, B. Parry, et al., Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 2011; 60:950–957. K. Win, S. Parry, B. Parry, et al., Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers, Ann Surg Oncol 2013; 20:1829–1836. D.L. Edelstein, J.E. Axilbund, M. Baxter, et al., Rapid development of colorectal neoplasia in patients with lynch syndrome, Clin Gastroenterol Hepatol 2011; 9:340–343. M.F. Kalady, J. Lipman, E. McGannon, et al., Risk of colonic neoplasia after proctectomy for rectal cancer in hereditary non- polyposis colorectal cancer, Ann Surg 2012; 225:1121–1125 Hedge M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis) Genetics in Med 2014; 16(1);101-116 Jasperson KW and Burt RW APC-associated polyposis condition.. GeneReviews, NCBI Bookshelf, last updated March 27, 2014. Avaialble at http://www.ncbi.nlm.nih.gov/books/NBK1345http://www.ncbi.nlm.nih.gov/books/NBK1345 Campos FG Surgical treatment of familial adenomatous polyposis: dilemmas and current recommendations. World J Gastroenterol 2014; 20(44): 16620-16629 Aziz O, Athanasiou T, Fazio VW, Nicholls RJ, Darzi AW, Church J, Phillips RK, Tekkis PP. Meta-analysis of observational studies of ileorectal versus ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg 2006; 93: 407-417 Pommaret E, Vienne A, Lefevre JH, et al. Prevalence and risk factors for adenomas in the ileal pouch and the afferent loop after restorative proctocolectomy for patients with familial adenomatous polyposis Surg Endosc 2013; 27; 3816-3822 Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO Review of current risk-reducing surgery in common hereditary cancer syndromes. J Clin Onco 2006; 24(28); 4642-4660