2012-01-27 20:19:31 UTC

Actively Seeking Lynch Syndrome

Jan. 27, 2012


Heather Hampel, MS, CGC

Associate Director, Division of Human Genetics; Professor, Internal Medicine; Genetic Counselor, The Ohio State University Comprehensive Cancer Center, Columbus


I am a proponent of universal screening for Lynch syndrome (LS) among all newly diagnosed colorectal cancer (CRC) patients. In the universal screening approach, all newly diagnosed CRC patients are screened for LS using one of two tumor screening tests: microsatellite instability testing (MSI) or immunohistochemistry (IHC) staining for the four mismatch repair proteins.1-3 One out of every 35 CRC patients has LS, and if the tumor has MSI or abnormal IHC, there is a one in five chance that the patient has LS.2, 3 As a result, these screening tests identify a subset of CRC patients more likely to have LS who can be offered genetic counseling and testing.

In our experience, patient notification works best if genetic counselors are responsible so that pathologists provide direct notification of genetics for all cases with abnormal IHC. For institutions without genetic services available on site, referral can be made to a local genetic counselor and often, arrangements can be made for that counselor to provide outreach genetic counseling services on site. Notification of the patients also seems most effective when the patients are notified in person at their post-operative surgical or oncology visit (67 percent tested; 8/12) versus notification by telephone (21 percent tested; 7/34).

This process has been studied thoroughly for clinical and analytic validity and clinical utility by the Evaluation of Genomic Applications in Practice and Prevention Working Group, which has recommended that universal screening be adopted because it leads to a reduction in morbidity and mortality among the family members who are also diagnosed with LS.4, 5 In addition, universal screening for LS has been shown to be cost-effective.6, 7 As a result, there has been an exponential increase in the number of hospitals that are adopting either universal or subset screening of CRCs for LS. So, what questions remain?

There are still many patients being seen for colonoscopy who have LS but do not know it. This leads to the question: what is the best way for a gastroenterologist to determine whether or not his unaffected colonoscopy patient may have LS and could benefit from a genetics referral? Family history and assessment are still the best tools in these cases. I would suggest using a modified version of the revised Bethesda guidelines as follows.8

A cancer genetics referral is necessary for anyone with:

  • One first-degree relative with colorectal or endometrial cancer diagnosed under age 50.
  • One first-degree relative with a colorectal or endometrial cancer diagnosed at or above age 50 if they also have a second colorectal or endometrial cancer themselves or a relative on the same side of the family with colorectal or endometrial cancer diagnosed under age 50.
  • Three total cases of colorectal and/or endometrial cancer on the same side of the family regardless of the ages at diagnosis.

Alternatively, gastroenterologists could run the online PREMM1,2,6 model9 and refer any unaffected individual with greater than a 5 percent chance of having LS. Working together as a team, geneticists and gastroenterologists can identify these families and ensure that they receive appropriate medical management.

Another important question for the gastroenterologist is whether to screen the diagnostic biopsies obtained during colonoscopy or the surgical CRC resection specimens. The pros and cons for each approach are listed in the figure and are debated regularly at my own institution. Screening of biopsies might afford the most benefit to the individuals with CRC given that a subtotal colectomy is a recommended consideration for patients known to have LS.

Universal screening for LS and the testing of at-risk relatives will result in more unaffected individuals coming to gastroenterology with a known diagnosis of LS. This will enable the gastroenterologist to make appropriate CRC surveillance recommendations. Individuals with LS require colonoscopy every one to two years beginning at age 20 to 25.10, 11 Some feel that chromo-endoscopy is more effective in these very high-risk patients since the high a priori risk for CRC means that the removal of every polyp is critical.12 More studies comparing chromo-endoscopy to narrow band imaging are needed to answer these questions. LS patients also require upper GI endoscopy, but current guidelines vary significantly with regard to the frequency and the age at which this screening should be initiated. Again, more data is necessary so we can provide our patients with guidance about appropriate cancer surveillance.

Women with LS have been recommended to have endometrial cancer screening, including annual transvaginal ultrasound and endometrial biopsies beginning at age 30 to 35.10, 11 There is also data that risk-reducing hysterectomy and bilateral salpingo-oophorectomy is extremely effective in preventing both endometrial and ovarian cancers in women with LS.13 However, there is no data suggesting that endometrial cancer surveillance improves outcomes or what the optimal timing is for the gynecologic surgery.

In the area of chemoprevention, long-term aspirin use by individuals with LS has been shown to reduce the risk for CRC by around 40 percent.14 Follow-up studies have been called for to determine the optimal dose and duration of aspirin therapy.

Ms. Hampel had no conflicts to disclose.

1. Hampel H. Point: justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer. J Natl Compr Canc Netw May 2010;8(5):597-601.
2. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol Dec 10 2008;26(35):5783-5788.
3. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med May 5 2005;352(18):1851-1860.
4. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med Jan 2009;11(1):35-41.
5. Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med Jan 2009;11(1):42-65.
6. Mvundura M, Grosse SD, Hampel H, Palomaki GE. The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet Med 2010;12(2):93-104.
7. Gudgeon JM, Williams JL, Burt RW, Samowitz WS, Snow GL, Williams MS. Lynch syndrome screening implementation: business analysis by a healthcare system. Am J Manag Care 2011;17(8):e288-300.
8. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst Feb 18 2004;96(4):261-268.
9. Kastrinos F, Steyerberg EW, Mercado R, et al. The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology Jan 2011;140(1):73-81.
10. Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA Sep 27 2006;296(12):1507-1517.
11. Vasen HF, de Vos Tot Nederveen Cappel WH. An evidence-based review on surveillance for Lynch syndrome. Dis Colon Rectum Nov 2006;49(11):1797-1798; author reply 1799.
12. Lecomte T, Cellier C, Meatchi T, et al. Chromoendoscopic colonoscopy for detecting preneoplastic lesions in hereditary nonpolyposis colorectal cancer syndrome. Clin Gastroenterol Hepatol Sep 2005;3(9):897-902.
13. Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med Jan 19 2006;354(3):261-269.
14. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet Oct 27 2011.

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