Lynch syndrome
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Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is caused by a germline mutation in mismatch repair genes and is associated with increased risks of colorectal, endometrial, ovarian and other cancers. The Amsterdam criteria and Bethesda guidelines provide guidance for diagnosing Lynch syndrome based on family history and age of cancer onset. Screening recommendations include annual endometrial biopsy and pelvic exams/ultrasounds to screen for endometrial and ovarian cancers starting at age 30-35 or 5-10 years before the earliest cancer in the family. Risk reducing surgery is recommended after childbearing.
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Lynch syndrome
- 2. LYNCH SYNDROME Named after Dr. Henry Lynch HNPCC – Hereditary Nonpolyposis Colorectal Cancer Colorectal, endometrial, ovarian, upper urologic tract, gastric, small bowel, Biliary/pancreatic, brain tumors(glioma), sebaceous gland tumors
- 3. AUTOSOMAL DOMINANT Germ line mutation in mismatch repair genes MSH2, MLH1 account for 90% of heterozygous germ line mutations identified I Lynch Syndrome MSH6 has the highest risk of endometrial cancer PMS2 described in relatively few Lynch Families
- 5. CRITERIA FOR LYNCH SYNDROME Amsterdam Criteria Bethesda Guidelines
- 6. AMSTERDAM CRITERIA There should be at least three relatives with an HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis) One should be a first degree relative of the other two At least two successive generations should be affected At least one should be diagnosed before age 50 Familial adenomatous polyposis should be excluded in the colorectal cancer case(s) if any Tumors should be verified by pathological examinationVasen, HF, Watson, P, Mecklin, JP, et al. Gastroenterology 1999; 116:1453
- 7. BETHESDA CRITERIA 1. Colorectal cancer diagnosed in a patient who is less than 50 years of age. 2. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors*, regardless of age. 3. Colorectal cancer with the MSI-H•-like histologyΔ diagnosed in a patient who is less than 60 years of age◊. 4. Colorectal cancer diagnosed in a patient with one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years. 5. Colorectal cancer diagnosed in a patient with two or more first- or second-degree relatives with HNPCC- related tumors, regardless of age.
- 8. HISTOLOGY Lynch syndrome associated endometrial cancers are mostly endometriod Uterine papillary serous carcinoma, clear cell, and uterine mixed mullerian subtypes have all been reported Usually diagnosed early stage and have favorable prognosis Tumor location: Uterine Corpus versus Lower Uterine Segment Can be confused with cervical adenocarcinoma LUS tumors were found to be of higher grade
- 10. OVARIAN CANCER Majority Epithelial Papillary Serous Endometriod, Mucinous and clear cell have been reported More likely than general population to be Stage I or II No difference in 5 year survival
- 11. SCREENING Start at age 30-35 (or 5-10 years prior to index case) Yearly Endometrial biopsy to screen for endometrial cancer Yearly pelvic exam, TVUS, and +/- CA-125 (q6- 12months) to screen for ovarian cancer
- 12. SUMMARY Autosomal dominant Germline mutation of MMR gene 27-71% chance of endometrial cancer 3-14% chance of ovarian cancer Risk reducing surgery after childbearing If undergoing surgery for colorectal cancer should be offered concurrent risk reducing surgery Annual EMB for screening endometrial cancer Annual pelvic exam, TVUS, q6-12 month CA-125 Oral contraceptives for premenopausal chemoprevention
Editor's Notes
- In women with Lynch syndrome, the lifetime risk of endometrial cancer is 27 to 71 percent compared with 3 percent in the general population (figure 1) [5,6]. Risk is between 27 and 60 percent for women with MLH1 and MSH2 mutations and 60 to 71 percent for those with mutations in MSH6. The mean age at endometrial cancer diagnosis in women with Lynch syndrome is 46 to 54 years, compared with a mean age of 60 years in other women [15-18]. Some women with Lynch syndrome may develop endometrial cancer before age 40. As an example, in a study that included 69 women with Lynch syndrome-associated endometrial cancer, 18 percent were diagnosed under the age of 40 years
- The revised Bethesda guidelines for testing colorectal tumors for microsatellite
- Tumors from individuals should be tested for MSI in the following situations: * Hereditary nonpolyposis colorectal cancer (HNPCC)-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (usually glioblastoma as seen in Turcot syndrome) tumors, sebaceous gland adenomas and keratocanthomas inMuir-Torre syndrome, and carcinoma of the small bowel. • MSI-H:microsatellite instability-high in tumors refers to changes in two or more of the five National Cancer Institute-recommended panels of microsatellite markers. Δ Presence of tumor infiltrating lymphocytes. Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern. ◊ There was no consensus among the Workshop participants on whether to include the age criteria in guideline 3 above; participants voted to keep less than 60 years of age in the guidelines. Reproduced with permission from Umar, A, et al. J Natl Cancer Inst 2004; 96:261. Copyright © 2004 Oxford University Press.
- Also similar to women with sporadic endometrial cancer, the majority of Lynch syndrome-associated endometrial cancers are diagnosed with early stage disease and, thus, have a favorable prognosis [16,17]. As an example, a study in women with endometrial cancer that matched for age at diagnosis and cancer stage found similar five-year survival in 50 women with Lynch syndrome and 100 matched controls (88 versus 82 percent) [16]. Endometrial tumor location, however, may differ in some women with Lynch syndrome. Endometrial cancer arises most commonly in the uterine corpus rather than the lower uterine segment (LUS) in all women, but in Lynch syndrome, there appears to be a higher proportion of LUS tumors. These tumors can be misdiagnosed as cervical adenocarcinoma. The largest series to investigate this included over 1000 women with endometrial cancer; 10 of 35 of the LUS tumors were found in women with Lynch syndrome [21]. LUS tumors were higher grade and more invasive than corpus cancer. Thus, although LUS tumors account for a small number of Lynch-associated endometrial cancers, a finding of tumor at this site should prompt risk assessment for Lynch syndrome (see 'Genetic testing for Lynch syndrome' above).
- Lifetime risk for colon, endometrial and ovarian cancer in individuals compared with the general population. Ovarian cancer — The lifetime risk of ovarian cancer in women with Lynch syndrome is 3 to 14 percent compared with 1.5 percent in the general population (figure 1) [5,6]. Women with Lynch syndrome develop ovarian cancer younger than other women (43 to 50 versus 60 years old) [22,23
- TAH/BSO and chemoprevention Weak recommendation: Benefits and risks closely balanced and/or uncertain Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with serious flaws