Is Your Patient At Risk of Having Lynch Syndrome? David Strassler, MD Martin’s Point Health Care Biddeford, Maine

Since reading these s on Lynch syndrome I've become a little more watchful when an unusual family history of neoplasms is discovered when taking a family history. I want to run a scenario by you folks to see if there is any more that I should do here. I have a 34 year old asymptomatic male in my office for a CDL physical with a father that died from gastric cancer and the father's sister, age 58, who was recently diagnosed with colon cancer. Coincidentally, the paternal great-uncle died from gastric cancer at age 81. It doesn't appear that there are any other known neoplasms and I am uncertain if the aunt's tumor was tested for microsatellite instability. Any suggestions?

How do I know who to refer for Genetic Counseling for Lynch Syndrome?

How do you read the pathology report for colon cancer? How do you understand the Genetic Counselor report? What is microsatellite instability? What is MLH1, MSH2, MSH6, PMS2?

Suzanne is a 36 yo married white woman who was referred to me for a screening colonoscopy, which was normal. She had a colonoscopy 5 years before that was also normal. Prior to doing the colonoscopy, I suggested that she might want to see a geneticist because of her family history, and that she might have Lynch Syndrome. What about her family history made me come to that conclusion? Mother was diagnosed with gastric cancer at age 41, was treated with surgery followed by chemoradiation therapy. She developed recurrent disease and died at the age of 46. (At her first colonoscopy, she thought her mother was first diagnosed with colon cancer at age 31) Her maternal aunt died of colon cancer at age 37 One maternal first cousin had colon cancer at age 30. The geneticist recommended that: “the most meaningful information for the entire family would be derived by testing the youngest effected family member”.

Lynch et al Diagnosis and management of hereditary colorectal cancer syndromes: Lynch syndrome as a model Canadian Medical Association Journal 2009;181(5):273

Maradiegue et al Scoping the family history: Assessment of Lynch syndrome in primary care settings Journal of the Academy of Nurse Practitioners 2008;20:76

Weissman et al Genetic Counseling in the evaluation of families for Lynch syndrome-a review Journal of Genetic Counseling 2011;20:5

Suzanne is a 36 yo married white woman who was referred to me for a screening colonoscopy, which was normal. She had a colonoscopy 5 years before that was also normal. Prior to doing the colonoscopy, I suggested that she might want to see a geneticist because of her family history, and that she might have Lynch Syndrome. What about her family history made me come to that conclusion? Mother was diagnosed with gastric cancer at age 41, was treated with surgery followed by chemoradiation therapy. She developed recurrent disease and died at the age of 46. (At her first colonoscopy, she thought her mother was first diagnosed with colon cancer at age 31) Her maternal aunt died of colon cancer at age 37 One maternal first cousin had colon cancer at age 30. The geneticist recommended that: “the most meaningful information for the entire family would be derived by testing the youngest effected family member”.

Bryan is a 51 yo married white who informed at his recent annual physical that both his brother and his first cousin (on his mother’s side) were tested positive for Lynch Syndrome. His mother died at age 36 of colon cancer. His sister has a history of benign colon polyps. He has had normal colonoscopies every 5 years since age 39 yo. He does not want to be tested for Lynch Syndrome. If I can convince him about the importance of being tested, and he is positive, will it make a difference to his future medical care?

Weissman et al Genetic Counseling in the evaluation of families for Lynch syndrome-a review Journal of Genetic Counseling 2011;20:5

Joanne is a 80 yo white woman with COPD and mild hypoxia from a long history smoking cigarettes. Her past history is otherwise significant for: 1993-bladder cancer, grade 1, treated with a local incision. Yearly cystoscopies were normal till… 2004-bladder cancer extending into the left ureter treated surgically with a left nephrectomy, ureterectomy and bladder cuff excision. December, 2005-her first colonoscopy. FH significant for a father with colon cancer. Colonoscopy normal with a good prep. December, 2008-came to the ER with a 4 day history of rectal bleeding. Colonoscopy by the on call Gastroenterologist revealed a transverse colonic mass. Biopsy report: Adenocarcinoma (interval cancer). CT scan measured it at 4.5 cm. without metastasis seen. A transverse colectomy was done. Adenocarcinoma pT3, N0 high grade tumor with lymphovascular invasion. Histological features linked with DNA microsatellite instability-Present (Crohn’s-like reaction)

The tumor was submitted for microsatellite instability testing. The tumor cells show loss of expression of DNA mismatch repair enzymes MLH1 and PMS2. Expression of MSH2 and MSH6 remains intact. “This impaired DNA mismatch repair function within the tumor could be an epigenetic phenomenon, or less likely to be associated with a heritable defect in DNA mismatch repair (Lynch Syndrome/HNPCC) Family history: Father-colon cancer diagnosed in his 80’s Paternal aunt-bladder cancer diagnosed at an unknown age Mother-stomach cancer diagnosed at age 80. Geneticist: “It is important to note that most individuals with her tumor-based IHC findings do not have Lynch Syndrome. Nevertheless, these findings raise concern in light of her personal and family history. Additional testing (BRAF mutation testing and MLH1 hypermethylation testing) is available to evaluate her tumor further”. January, follow up colonoscopy by myself was normal. Tumor surveillance by her oncologist was normal ‘till…… August, her follow up CT scan of the abdomen/pelvis revealed a suspicious lesion in the gastric fundus/GE junction with no metastasis seen. An EGD was performed, showing an ulcerated lesion in the gastric cardia extending to the squamocolumnar junction. Biopsy report: invasive moderately to poorly differentiated adenocarcinoma, with signet features.

Since reading these s on Lynch syndrome I've become a little more watchful when an unusual family history of neoplasms is discovered when taking a family history. I want to run a scenario by you folks to see if there is any more that I should do here. I have a 34 year old asymptomatic male in my office for a CDL physical with a father that died from gastric cancer and the father's sister, age 58, who was recently diagnosed with colon cancer. Coincidentally, the paternal great-uncle died from gastric cancer at age 81. It doesn't appear that there are any other known neoplasms and I am uncertain if the aunt's tumor was tested for microsatellite instability. Any suggestions?

Bibliography Boland et al Evaluation and Management of Lynch Syndrome Clinical Advances in Hematology & Oncology 2007;5(11):851 Boland et al The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior of Lynch syndrome: from bench to bedside Family Cancer 2008;7(1):41 Lynch et al Hereditary factors in cancer: study of two large Midwestern kindreds Archives Internal Medicine 1966;117:206 Lynch et al Diagnosis and management of hereditary colorectal cancer syndromes: Lynch syndrome as a model Canadian Medical Association Journal 2009;181(5):273 Maradiegue et al Scoping the family history: Assessment of Lynch syndrome in primary care settings Journal of the Academy of Nurse Practitioners 2008;20:76 UpToDate Lynch Syndrome: Screening and management of patients and families/Clinical features and diagnosis 2012 Weissman et al Genetic Counseling in the evaluation of families for Lynch syndrome-a review Journal of Genetic Counseling 2011;20:5