This patient presented with rectal bleeding and weight loss and was found to have stage III adenocarcinoma. Given his family history of colorectal cancer in a first-degree relative at a young age, he is at high risk for hereditary non-polyposis colorectal cancer (HNPCC). HNPCC accounts for 5-7% of colorectal cancers and results from a mutation in DNA mismatch repair genes. Individuals with HNPCC have an increased lifetime risk of colorectal and other cancers. The patient was counseled on genetic testing and increased screening for relatives is recommended.

1. The Lebanese UniversityFaculty of medical sciencesGeneral surgery training programmeThe central military hospitalgeneral surgery department Clinical case, surgical technique and review of literature. Hippocrates (460 B.C. – 377 B.C.) - The father of medicine. 20 April 2010

2. Clinical Case Attended by: Dr. Ali Khalil. Prepared by: Mohomad Chour, PGY II, general surgery. Dungeness crab (Cancer magister).

3. Case presentation 25 y old male with lower GI bleeding . HPI: rectal bleeding, alteration of bowel mvt and weight loss of 5 Kg over the last year . PMHx:neg PSHx:Hemorrhoidectomy 3 y ago FHx: - mother DMII - father colorectal cancer at age 37 treated surgically and with chemo-radiotherapy with apparent recovery.

4. Physical exam Abd: non tender, soft, no mass, no organomegaly DRE: no abnormalities Left axillary mass (fibrotic related to previous trauma)

5. labs Hb 11.9 Ht 36.6 MCV 75 WBC 9100 PLT 264000 INR 1.35 Electr ,BUN , creat: normal Tumor markers : negative

6. Colonoscopy report(2/3/10) Anus: normal Rectum: at the rectosigmoidjuction ( 14 cm from AM) presence of a friable and infiltrating tumor, and reaching 20 cm from AM compatible with adenoca multiple bx taken . Left and transverse colon: normal Right colon: normal Cecum: normal

7. pathology Evidence of malignant cells suggestive of Adenocarcinoma

8. Abd and pelvic CT scan 16/3/10 Thickening of the sigmoid wall . No adenopathies .

9. decision Laparoscopic sigmoid + upper rectum colectomy

10. Operative report(24/3/10)… DD, modified lithotomy position, routine S&D. Pneumoperitoneum: Veress, umbilical trocar (10mm), 2 R midclavicular 5mm trocars ,PCO2 14 mmHg Evidence of an upper rectal tumor(adhesions or invasion of the posterior wall of the bladder) with narrow pelvic inlet converted to open .

11. Operative report… Midline laparotomy incision Identification of a tumor (some 6 cm in length) extending from just above the peritoneal reflection proximally. Mobilisation of the sigmoid starting laterally to proximal with minimal liberation of the splenic flexure . Identification of the left ureter. Further dissection of sigmoid and distal descending colon Identifiation of IMA ligation & section at its origin . Dissection continuing distally to the peritoneal reflection after sectioning the bowel 20 cm away from the tumor using GIA 60 .

12. Operative report Opening of the peritoneal reflection ,dissection through mesorectum around the upper and midrectum reaching almost the seminal vesicle : section using endoGIA 60. Perineal part: using CEEA 31 completing the colorectal anastomosis, checked for tightness. 1 drain Closure ,transferred to ICU .

13. The specimen

14. The specimen

16. Infiltrating through the wall into serosa and pericolic fat

17. Evidence of vascular invasion

18. Metastasis to 10/18 pericolic lymph nodes

19. Free surgical margins (with distal 2 cm free margins in the colon and 1.5 cm in frozen sections specimen)

21. Counseling Patient was counseled to attend a geneticist for DNA mapping. Possible HNPCC.

23. Hereditary Non-Polyposis Colorectal Cancer(HNPCC) A Review of Literature Plato and Aristotle, from School of Athens. Raphael, 1508-1511.

24. Introduction. Inherited colorectal carcinoma: Hereditary non-polyposis colorectal cancer (5-7% of cases of CRC) Familial adenomatouspolyposis and attenuated FAP(1%) Familial colorectal cancer (10-15%) Peutz-Jeghers syndrome (<1%) Juvenile polyposis syndrome (<1%)

25. Introduction. Inherited colorectal carcinoma: Hereditary non-polyposis colorectal cancer (5-7% of cases of CRC) Familial adenomatouspolyposis and attenuated FAP(1%) Familial colorectal cancer (10-15%) Peutz-Jeghers syndrome (<1%) Juvenile polyposis syndrome (<1%)

26. Historical perspectives. In 1985, the chairman of pathology at the University of Michigan, Dr. Alder Warthin, recognised this syndrome. Dr. Warthin’s seamstress prophesied that she would die of cancer because of her strong family history of endometrial, gastric and colon cancer. Dr. Warthin’s investigations of her family’s medical records revealed a pattern of autosomal dominant transmission of cancer risk. Dr. Henry Lynch fully investigated this entity in the early 1990’s and 2 hereditary syndromes were described: Lynch I and Lynch II.

27. Lynch syndromes. Lynch I Cancer of the colon occurring at a relatively young age (mean, 44 years), with proximal distribution (70% of cancers located in the right colon), predominance of mucinous or poorly differentiated (signet cell) adenocarcinoma, and the presence of tumour-infiltrating and peritumoural lymphocytes increased number of synchronous and metachronous cancers despite all the these poor prognostic indicators, a relatively good outcome after surgery.

28. Lynch syndromes. Lynch II Families are at increased risk for colorectal cancer and extracolonic cancers, endometrial ovarian gastric small intestinal pancreatic ureteral renal pelvic.

29. Lynch syndromes. Before genetic mechanisms underlying the Lynch syndromes were understood, the syndromes were defined by Amsterdam Criteria that were soon modified. Further modifications have affected the criteria and the Bethesda criteria emerged. Amsterdam, the Netherlands

30. Bethesda Criteria. Modified Amsterdam Criteria At least 3 relatives with HNPCC-associated cancer (colon, endometrium, small bowel, ureter, renal pelvis) and all of the following: One affected person is a first-degree relative of the other 2 affected persons 2 successive generations affected At least one case of cancer diagnosed before age 50 years FAP excluded Bethesda Criteria The Amsterdam criteria or one of the following: 2 cases of HNPCC-associated cancer in one patient, including synchronous or metachronous cancer Colon cancer and a first-degree relative with HNPCC-associated cancer and/or colonic adenoma (one case diagnosed before age 45 years and adenoma diagnosed before 40 years) Colon or endometrial cancer diagnosed before 45 years Right-sided colon cancer that has an undifferentiated pattern (solid-cribriform) or signet-cell histopathologic features diagnosed before 45 years Adenomas diagnosed before age 40 years Lynch HT, Riley BD, Weissman SM, et al; Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: problems in diagnosis, surveillance, and management. Cancer 100:53, 2004.

31. Introduction. HNPCC is inherited in an autosomal dominant fashion HNPCC accounts for 5-7% of colorectal cancers, it is the most frequent inherited CRC syndrome in the West. Results from a mutation in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS1, PMS2, MLH3, MSH3). Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348:919, 2003.

32. Genetics. Only 50-70% of patients meeting clinical criteria for HNPCC have an identifiable germline MMR mutation which suggests that one or more unidentifiable genes or other genetic events (e.g., large germline deletions) may be involved that result in microsatellite instability in 80-90% of cases. 20% of newly discovered cases have a spontaneous germline mutation, with no evident family history. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348:919, 2003.

33. Clinical features. Early-onset CRC. Predominance of lesions proximal to the splenic flexure (60-70%). Benign and malignant extracolonic tumours. Predilection for synchronous and metachronous colorectal tumours. The lifetime risk of CRC in HNPCC patients is approx. 80%. A better prognosis for cancer patients with HNPCC than for non-HNPCC patients with cancer of the same stage!!!

34. Clinical features. ACS Surgery: Principles & Practice, 2007.

35. Investigations. Colorectal cancer, or an HNPCC-related cancer, arising in a person < 50 years should raise the suspicion of this syndrome. The mainstay of the diagnosis of HNPCC is a detailed family history, yet 20% of newly discovered cases are caused by spontaneous germline mutations. CRC patients who belong to known HNPCC kindreds, who have a pedigree suggestive of HNPCC, or who meet the Bethesda criteria should be offered screening by MSI testing. Patients with MSI-high tumours should undergo testing for germline MMR mutations. If a mutation is identified then other family members can be tested after obtaining genetic counselling. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348:919, 2003.

36. Screening and surveillance. If a family member has tested negative for a specific MMR mutation identified in an index case => an average risk subject. If no genetic counselling, or positive for a given MMR mutation => screening recommendation as follows:

37. Management.Surgical therapy: When? What? Who? Prophylactic surgical intervention is considered for the following reasons: 80% lifetime risk of developing CRC 45% rate of metachronous tumours The possibility of an accelerated adenoma-carcinoma sequence. Candidates are HNPCC patients as defined by: their genotype Amsterdam or Bethesda criteria colon cancer and more than one advanced adenoma. Options include: Prophylactic total abdominal colectomy with ileo-rectal anastomosis Total proctocolectomy with ileal pouch-anal anastomosis (restorative proctocolectomy) Segmental colectomy with yearly colonoscopy.

38. Prophylactic surgical intervention.Mutation-positive patients with a normal colorectum? Normal rectal reservoir function Normal anal sphincter function A survival benefit of 1.8 years evident if performed at age 25 years. No survival benefit if performed at time of cancer development. 1- to 3-yearly colonoscopy, optimal < 2 year surveillance intervals. Quality of life benefit. Total abdominal colectomy with ileo-rectal anastomosis Colonoscopic surveillance Factors affecting the decision: Penetrance of disease in family The age of cancer onset in family members Functional and QoL considerations Likelihood of patient compliance to surveillance.

39. Management.Surgical therapy A coronal view of the anal canal and rectum. Rectosigmoid junction 10-12 cm The upper limit of the surgical anal canal. The pelvic floor. 8 cm The upper limit of the anatomical anal canal. (Dentate line). 4-5 cm 2-3 cm

40. Management.Surgical therapy Total abdominal colectomy with ileo-rectal anastomosis. This option is open only to patients with: Normal rectal reservoir function Normal anal sphincter function No evidence of rectal involvement. Lifelong surveillance is necessary because: the risk of developing a metachronous rectal cancer is 12 % at 10-12 years after the operation this risk is evidently less than among patients who have undergone segmental colectomy. Lynch HT, Lynch JF, Fitzgibbons R Jr: Role of prophylactic colectomy in Lynch syndrome. Clin Colorectal Cancer 3:99, 2003.

41. Management.Surgical therapy Total abdominal colectomy with ileo-rectal anastomosis. A -> K: Total abdominal colectomy.

42. Management.Surgical therapy Total proctocolectomy with ileal pouch-anal anastomosis (Restorative proctocolectomy). Indicated in patients with rectal cancer that is amenable to sphincter-preserving resection. The risk of developing a metachronous lesion in the remaining colon with an index rectal cancer in HNPCC patients is 17-45% at 10-12 years. The patient’s will to undergo extensive surveillance and concern on bowel function is decisive. Lynch HT, Lynch JF, Fitzgibbons R Jr: Role of prophylactic colectomy in Lynch syndrome. Clin Colorectal Cancer 3:99, 2003.

43. Management.Surgical therapy Total proctocolectomy with ileal pouch-anal anastomosis (Restorative proctocolectomy). A -> L: Total proctocolectomy.

44. Management.Surgical therapy Segmental colectomy with yearly colonoscopic surveillance. This option is the standard of care in terms of quality of life and preserved bowel function. The need for extensive surveillance on a one-yearly basis cannot be overemphasised. An accelerated adenoma-carcinoma sequence and microsatellite instability may lead cancers to develop in less than one-year intervals. Lynch HT, Lynch JF, Fitzgibbons R Jr: Role of prophylactic colectomy in Lynch syndrome. Clin Colorectal Cancer 3:99, 2003.

45. Management.Extracolonic disease. Endometrial and ovarian cancer. Female patients with a family history of uterine cancer should be offered prophylactic total abdominal hysterectomy + oophorectomy (TAHBSO) if childbearing is complete or if undergoing abdominal surgery for other conditions. 43% rate of endometrial cancer in mutation-positive patients. Inefficacy of screening for uterine cancers. The optimal timing is unclear yet cases < 35 years have been reported. Recommendation: begin surveillance at 25 years and delay prophylactic surgery until childbearing is complete. Lynch HT, Riley BD, Weissman SM, et al; Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: problems in diagnosis, surveillance, and management. Cancer 100:53, 2004.

46. Inherited colorectal carcinoma. Hereditary non-polyposis colorectal cancer (5-7% of cases of CRC) Familial adenomatouspolyposis and attenuated FAP(1%) Familial colorectal cancer (10-15%) Peutz-Jeghers syndrome (<1%) Juvenile polyposis syndrome (<1%)

47. Inherited colorectal carcinoma. Hereditary non-polyposis colorectal cancer (5-7% of cases of CRC) Familial adenomatouspolyposis and attenuated FAP(1%) Familial colorectal cancer (10-15%) Peutz-Jeghers syndrome (<1%) Juvenile polyposis syndrome (<1%)

48. Familial colorectal cancer. Non-syndromic familial colorectal cancer accounts for 10-15% of CRC cases. The lifetime risk of developing CRC increases with a family history of the disease and the age of onset in family. Average risk in USA: 6% If one first-degree relative affected: 12% If two first-degree relatives affected: 35% Screening colonoscopy is recommended every 5 years beginning at age 40 years or 10 years earlier than the index case. No specific genetic abnormalities are associated with familial CRC.

49. The take-home message. Every patient presenting with a malignant tumor involving the colon, rectum, stomach, uterus, ovaries, renal pelvis or ureters under the age of 50 years is to be screened or at least counseled for a possible inherited carcinoma syndrome. He/she and their first-degree relatives are to be counseled appropriately with the aid of a geneticist, if possible.

50. “There is a tremendous literature on cancer, but what we know for sure about it can be printed on a calling card.” - August Bier (Ger., 1861-1949). Thank you.