Screening for Lynch syndrome in unselected women with endometrial cancer

Reporter: J Taylor Whaley, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2013

Presenter: Sarah E. Ferguson, MD
Presenter's Affiliation: Princess Margaret Hospital, Toronto, ON, Canada
Absract #: 5508


    • Lynch Syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited cancer susceptibility syndrome that increases the risk of many types of cancer, including colon, endometrial, upper GI tract, brain, and skin.
    • It is inherited in a dominant fashion, meaning if a person has the disease, their children will have a 50% risk of inheriting the disease.
    • The disease does not cause cancer but it does predispose individuals to develop future cancers as it involves genetic mutations in several genes, namely the MLH1, MSH2, MSH6, and PMS2 genes. These genes are involved in the repair of DNA during the replication cycle and are collectively known as Mismatch Repair genes (MMR). When these genes are mutated, genetic mistakes accumulate faster than usual, increasing the risk for the development of cancer.
    • Approximately 3-5% of new colon cancers are associated with Lynch Syndrome. Additionally, cancer in a person with Lynch syndrome tends to appear several years earlier in a person’s life than those in an individual without the syndrome.
    • Although the disease is classically associated with colon cancer, new evidence has shown that endometrial cancer may be more as commonly associated with the disease in women.
    • Endometrial cancer is often the sentinel cancer in women with Lynch Syndrome; however, the syndrome is often not recognized in this population. Furthermore, because endometrial cancer tends to be diagnosed years earlier than colorectal cancer, the proper appreciation and diagnosis will allow lead time for screening and prevention of future cancers in affected individuals (10 years on average).
    • Current screening for Lynch syndrome occurs predominantly in patients with diagnosis of colon cancer at an early age or a family history of HNPCC; however, rarely are patients with endometrial cancer screened for HNPCC.
    • There are 2 predominant criteria currently used to help clinicians identify families at risk for Lynch Syndome, which if positive, will prompt a genetic evaluation.
    • Amsterdam criteria:
      • 3 or more relatives with an associated cancer (colorectal cancer, endometrial cancer, upper GI, etc);
      • 2 or more successive generations affected;
      • 1 or more relatives diagnosed before the age of 50 years;
      • 1 should be a first-degree relative of the other two;
      • Familial adenomatous polyposis should be excluded;
      • Tumors should be verified by pathologic examination.
    • Revised Bethesda Guidelines:
      • Colorectal carcinoma diagnosed in a patient < 50 years old;
      • Presence of synchronous or metachronous colorectal cancer or other Lynch syndrome-associated tumors, regardless of age;
      • Colorectal cancer with high microsatellite instability histology diagnosed in a patient < 60 years old;
      • Colorectal cancer diagnosed in one first-degree relative with a Lynch syndrome-associated tumor, with one of the cancers being diagnosed at < 50 years of age;
      • Colorectal cancer diagnosed in two or more 1st-degree or 2nd-degree relatives with Lynch syndrome-associated tumors, regardless of age
    • Despite the existence of these criteria, the diagnosis of endometrial cancer as the sentinel cancer in an affected individual is frequently not appreciated, and estimates suggest that 2/3 of all patients with Lynch syndromes and a first cancer diagnosis of endometrial cancer are missed.
    • In order to determine which screening strategy was superior in identifying women with Lynch Syndrome and endometrial cancer, the authors performed a prospective cohort study comparing family history, immunohistochemistry (IHC) for mismatch repair (MMR) proteins, tumor morphology with microsatellite instability, and germline mutation status in MMR genes in unselected women with endometrial cancer.

Materials and Methods

  • All women with newly diagnosed endometrial cancer between July 2010 and June 2011 were asked to participate in the prospective screening protocol for Lynch syndrome
  • The screening protocol included completing an extended family history questionnaire (eFHQ), a brief family history questionnaire (bFHQ), tumor assessment for Lynch syndrome-associated morphologic features, IHC testing of pathologic testing, as well as germline mutation testing in blood samples.
  • The eFHQ is very comprehensive and evaluates a 3 generation pedigree. Patients also completed a brief family health questionnaire, which was easier to complete and designed to flag patients at risk.
  • Germline mutation testing was performed on collected blood samples from each patient.
  • Tumor morphology was evaluated by a single expert pathologist , who was blinded to clinical details of each case. Lynch syndrome is classically associated with microsatellite instability.


  • 119 (65%) of patients with newly diagnosed endometrial cancer consented to the study.
  • The median age was 61 years old (26-91).
  • 96 (81%) of tumors were stage I, and 42 (35%) had high risk histology.
  • 105 women completed the eFHQ with 14 patients meeting criteria for genetic counseling.
    • The bFHQ flagged 25 patients as at increased risk.
  • 29% of women with possible Lynch syndrome refused genetic counseling.
  • There were 6 (7.4%, n = 81) women that were germline mutation positive (MLH1 N=3; MSH6 n = 2; MSH2 n =1), representing a mutation positive rate of at least 5% in this cohort (6/119).
  • 12% of women less than 60 years old were mutation positive.
  • Median age of women with Lynch syndrome was 42 vs 62 years old for women without Lynch syndrome.
  • All 3 MLH1 mutation positive women had low grade histology while mutations in MSH2/6 were exclusively found in women with high risk histology.
  • Of 118 women who had IHC performed, 10 had IHC MMR detected.
  • Two of the six mutation positive women were not identified by family history.
  • Mutation positivity was higher in women under age 50 (23%; 5/22) compared to women > 50 years old (1%; 1/97)( (p = 0.0008).
  • Lynch syndrome-morphologic features were found in 58 (59%, n = 98) women.
  • The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the LS-associated features in predicting Lynch syndrome mutation status was 100%, 42.6%, 7.9% and 100% compared to IHC which was 100%, 76%, 18% and 100% and eFHQ which was 67%, 84%, 27%, 97%.

Screening Outcomes






Tumor Morphology










Family History-eFHQ





Family History- bFHQ





  • The outcomes for each arm can be seen in the table above.
  • Tumor morphology demonstrated the poorest sensitivity and specificity.
  • IHC and bFHQ demonstrated the best sensitivity and specificity.

Author's Conclusions

  • In this unselected population of women with newly diagnosed endometrial cancer, the germline mutation rate for LS was 2-3 times that has previously been reported.
  • Previously described LS-associated morphologic features were not specific to germline mutation status and family history missed 1/3 of women with Lynch syndrome.
  • IHC was the best strategy (most sensitive and specific) to identify women with endometrial cancer who should undergo germline mutation testing.
  • Screening guidelines should be amended and broadened to detect more individuals with risk factors for Lynch syndrome. Within this patient population, the authors proposed all women <60 years old with endometrial cancers should have IHC performed to screen for Lynch syndrome.

Clinical Implications

  • The authors presented a prospective, comprehensive study evaluating 3 types of screening for Lynch syndrome in women with endometrial cancer. This is an area of much interest for today's gynecologic oncologists.
  • Identification of Lynch syndrome as early as possible in high risk individuals is very important to help screen individuals as well as family members for potential cancers. The under appreciation of endometrial cancer as the sentinel cancer is very problematic in the current era of medicine.
  • Because these women have high cure rates, the risk of second cancers related to the syndrome is very high. Additionally, the rate of germline mutations for Lynch syndrome in endometrial is higher than previously thought at 5% of this entire cohort.
  • Although previous studies have demonstrated similar results, there has not been an improvement in screening of newly diagnosed patients with endometrial cancer for Lynch syndrome, and this study highlights the importance of improved screening for high risk populations. Within the U.S. population, approximately 50,000 women will be diagnosed this year with endometrial cancer. If 20% of those women are premenopausal and 2-5% have Lynch syndrome, 1,000-2,500 patients should be diagnosed; however, the vast majority of these patients will not have IHC testing performed.
  • This study also emphasized the lack of accuracy of family history in detecting Lynch syndrome. The medical community must continue to strive to improve screening and education of the risk of Lynch syndrome.

Patient Summary: What Does This Mean For Me?

Lynch Syndrome (LS, also known as HNPCC) is a hereditary disorder that increases the risk of colorectal and other cancers, including endometrial cancer. While doctors are likely to evaluate patients with colorectal cancer for LS risk, women with endometrial cancer are not being identified as at risk. In this study, 12% of women under 60 diagnosed with endometrial cancer had HNPCC. While family history is typically used to evaluate risk of LS, this study found that laboratory testing of the tumor (using immunohistochemistry) that detected "mismatch repair" (MMR) was the best predictor of LS. The authors suggest that women under 60 diagnosed with endometrial cancer have testing for MMR, and if positive, be referred for genetic counseling and testing. Detecting these otherwise unidentified cases of LS allows these women to undergo appropriate screening for other LS related cancers as well as the possibility of testing family members for their risk. Women who were diagnosed with endometrial cancer before age 60 should discuss their risk with their oncology team.


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