Identifying Endometrial Cancer Survivors with Lynch Syndrome

TON - June 2011, Vol 4, No 4 — June 26, 2011

Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), is the most common cause of hereditary endometrial cancer. It accounts for at least 2% to 3% of all endometrial cancer cases and 9% to 10% of endometrial cancer cases in women diagnosed younger than 50 years of age.1-3 Women with Lynch syndrome have a high lifetime risk for colorectal (30%- 52%)4 and endometrial (20%-71%)5 cancer. Risks for other cancers associated with Lynch syndrome are lower and include stomach, ovary, hepatobiliary tract, urinary tract, small bowel, and brain/central nervous system, as well as sebaceous neoplasms. The average age of onset for endometrial cancer associated with Lynch syndrome is 54 years.1 Among women with Lynch syndrome who develop colon and gynecologic malignancies in their lifetime, approximately 50% present first with a gynecologic cancer. Further, the median number of years between diagnosis of gynecologic cancer and co lorectal cancer is estimated to be 11.6

Identifying survivors of endometrial cancer with Lynch syndrome is imperative in medical management. Survivors are at an increased risk of developing a second primary cancer, especially co lo - rectal cancer. Individuals with Lynch syndrome need colonoscopies every 1 to 2 years beginning at age 25.7 Each colorectal cancer survivor with Lynch syndrome has at least 3 relatives also with Lynch syndrome.8 It is likely this number is similar for endometrial cancer survivors. Identifying “previvors” with Lynch syndrome allows for tailored medical management that prevents cancer or catches it in its earliest, most treatable stage. In addition, after a mutation for Lynch syndrome has been identified, atrisk family members can be tested for the particular mutation in the family.

As Lynch syndrome is an autosomal dominant cancer syndrome, offspring, siblings, and parents of pro bands have a 50% chance of carrying the familial mutation. Not only does testing en dometrial cancer survivors provide more useful information for family members with negative germline results, it also can reduce the cost of germline analysis substantially, from several thousand dollars to several hundred dollars per individual tested.

Lynch syndrome is associated with mutations in the mismatch repairs (MMR) genes: MLH1, MSH2, MSH6, and PMS2. Mutations in EPCAM also have been demonstrated to cause Lynch syndrome by affecting the ability of MSH2 to function. Given mutations in 5 genes are associated with Lynch syndrome, the average age of onset for endometrial cancer is older than 50 years, and the syndrome has a variable phenotype, diagnosing an individual with Lynch syndrome can be challenging.

Typically, identification of individuals with Lynch syndrome has depended on clinical guidelines, such as the Amsterdam and Bethesda criteria. These criteria rely on young age at diagnosis, history of colorectal cancer, and/or detailed family history. Such approaches fail to identify up to 70% of Lynch syndrome cases—missed opportunities for reducing morbidity and mortality in survivors, as well as their children, siblings, and extended relatives.1

Many centers have implemented routine screening of colorectal and endometrial cancer tissue via immunohistochemistry (IHC) analysis. IHC is a cost-effective pathology technique used to triage patients at risk for Lynch syndrome.9 The results help provide a road map for additional genetic analysis. Most cases of loss of staining are associated with a germline mutation; however, in up to 30% of cases it is a result of hypermethylation of the MLH1 promoter, an epigenetic event.10 In cases not caused by promoter hypermethylation, loss of expression can be correlated with single-gene analysis for the gene most likely to harbor a mutation, including EPCAM. Patients with loss of expression then are referred to an expert in genetics for genetic counseling and possible germline testing.

A normal IHC result suggests that the 4 MMR proteins are expressed normally. As with any test, the quality of IHC results can vary by sample and/or laboratory performing the analysis. In addition, some mutations associated with Lynch syndrome make a protein that can be visualized on staining; however, the protein does not work correctly in the body.11 Therefore, although a normal IHC result in an endometrial cancer survivor greatly reduces the chance of Lynch syndrome, individuals with a personal and/or family history that is highly suspicious for a hereditary syndrome should be further evaluated by an expert in genetics. It is possible that a woman could have a mutation not detected by IHC or in a gene associated with a different hereditary cancer syndrome.

References

  1. Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66:7810-7817.
  2. Lu KH, Schorge JO, Rodabaugh KJ, et al. Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol. 2007;25:5158-5164.
  3. Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993; 71:677-685.
  4. Watson P, Vasen HF, Mecklin JP, et al. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med. 1994;96:516-520.
  5. Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129:415-421.
  6. Lu KH, Dinh M, Kohlmann W, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol. 2005;105:569-574.
  7. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. V.2.2001. www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed May 12, 2011.
  8. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with co lorectal cancer. J Clin Oncol. 2008;26:5783-5788.
  9. Resnick K, Straughn JM, Backes F, et al. Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients. Obstet Gynecol. 2009; 114:530-536.
  10. Modica I, Soslow RA, Black D, et al. Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. Am J Surg Pathol. 2007;31:744-751.
  11. Boland C, Koi M, Chang K, Carethers J. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Fam Cancer. 2008; 7:41-52.

Applying Knowledge to Clinical Practice

A Case Example for Nurses

Is Jane a candidate for genetic services, such as genetic counseling? Why or why not?

Jane is a 54-year-old woman recently diagnosed with an endometrial adenocarcinoma. Her only paternal aunt was diagnosed with endometrial cancer at age 56. Family history also includes a father who died in a car accident at age 31 and a paternal grandfather diagnosed with colorectal cancer at age 60. Per Jane’s report, her grandfather has had colon polyps removed since his diagnosis. In addition, she has zero paternal cousins and paternal uncles. Her pathology report indicates that expressions of MLH1, MSH2, MSH6, and PMS2 were normal. Maternal family history is negative for malignancy.

While interacting with Jane, she expresses that she has 3 children, 2 daughters aged 30 and 25 years and 1 son aged 28 years. She is concerned about their chance of developing a “female” cancer and inquires what tests their doctors should order. She also expresses that she is relieved she doesn’t have to have another colonoscopy until age 62, because her screening colonoscopy at age 52 was normal.

As the number of centers implementing routine screening of endometrial cancer tissue via immunohistochemistry (IHC) increases, it is likely oncology nurses will encounter patients who have undergone IHC analysis for the mismatch repairs proteins. Under standing the benefits and limitations of IHC in identifying endometrial cancer survivors with Lynch syndrome is essential in assessing the appropriateness of genetic services and in educating patients. Many of the competencies stated in the Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators apply to Jane’s case. Three of these include the ability to1:

  • Identi(fy) clients who may benefit from specific genetic and genomic information and/or services based on assessment data
  • Facilitate referrals for specialized genetic and genomic services for clients as needed
  • Use health promotion/disease prevention practices that incorporate knowledge of genetic and/or genomic risk factors.

Jane is a candidate for referral to genetic counseling by an expert in genetics, such as a certified genetic counselor or advanced practice nurse with training in genetics. You know that most but not all cases of Lynch syndrome are identified by IHC. Jane’s personal and family history of cancer is suspicious for Lynch syndrome, especially because she has a small family size and her paternal grandfather has had colon polyps removed—which may have prevented a second, primary colon cancer. Genetic counseling can help address Jane’s questions about cancer risks for other family members and medical management options.

Further, endometrial cancer survivors with Lynch syndrome are at high risk of developing colorectal cancer. By having colonoscopies every 1 to 2 years, individuals with Lynch syndrome significantly reduce their risk of developing colorectal cancer. Thus, if Jane has Lynch syndrome, she would need a colonoscopy before the age she plans to undergo screening, 62 years. By having a basic understanding of IHC and Lynch syndrome, oncology nurses can identify individuals who may benefit from genetic services, encourage referral to local genetic providers, and educate patients about health promotion/disease prevention practices associated with genetic knowledge.

Reference

  1. Consensus Panel on Genetic/Genomic Nursing Competencies. Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators. 2nd ed. Silver Spring, MD: American Nurses Association; 2009.

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