Current and emerging trends in Lynch syndrome identification in women with endometrial cancer

doi:10.1016/j.ygyno.2009.03.003

Gynecologic Oncology

Volume 114, Issue 1, July 2009, Pages 128-134

https://doi.org/10.1016/j.ygyno.2009.03.003 Get rights and content

Abstract

Objective

Lynch syndrome is a heritable, cancer susceptibility syndrome. This study aims to review current and emerging trends in the identification of Lynch syndrome in the endometrial cancer patient population.

Methods

We performed a comprehensive review of past and present screening algorithms for Lynch syndrome, including a review of the utility of both the Amsterdam criteria and Bethesda guidelines. Because non-colon cancers have historically not been the focus of Lynch syndrome research, current literature is ripe with questions regarding screening among this patient population. Low BMI, age less than 50, positive family history and pathologic features have all been identified as risk factors in endometrial cancer patients who might benefit from Lynch screening. Additionally, based on experience at our own institution we offer a feasible screening algorithm for these patients.

Results

A comprehensive review of the data demonstrated that immunohistochemistry is becoming an efficient, inexpensive way to screen tumors at risk for mismatch repair deficiency. The sensitivity and specificity of immunohistochemistry for predicting Lynch syndrome approaches 100%. Ideally, prospective screening of all endometrial cancer patients with IHC is a feasible, cost-efficient way to detect Lynch in this patient population given the limitations of using personal/family history of malignancy as well as pathologic risk factors.

Conclusion

It is imperative that clinicians be mindful of the risk of Lynch syndrome in women with endometrial cancer. Given the opportunity for colon cancer screening and prevention strategies to be initiated, the identification of probands with endometrial cancer as a result of Lynch syndrome will lead to a reduction in morbidity and mortality for these patients and their families.

Section snippets

Background

In this era of personalized medicine, genetic susceptibility to cancer is quickly becoming one of the most researched areas of the biomedical sciences. Greater public understanding of the role that genes play in the development of cancer and potential testing requires that today's physician be aware of these genetic predispositions, understand how to take a detailed family history and be knowledgeable about the genetic testing for this disorder. Lynch syndrome is one such heritable, cancer

The public health dilemma

The public health dilemma of screening for Lynch syndrome among the endometrial cancer population is evident in the original name for this syndrome described by Henry Lynch. The name “hereditary non-polyposis colon cancer” seems to reduce the importance of non-colon cancer diagnoses in this syndrome. Subsequently, public and health care professional knowledge of the risk of Lynch syndrome in the endometrial cancer population is lacking. Because non-colon cancers have historically not been the

Current screening strategies

Recent decades have seen a refinement of the tools that clinicians may use to screen high-risk patients for Lynch syndrome. While the initial inclusion criteria for screening solely included those with a personal or family history of CRC, it has now been realized that in small families, gynecologic malignancy may be the only manifestation of Lynch syndrome. Additionally, large studies of the statistical validity of these screening tools are mostly limited to the colon cancer population.

Amsterdam criteria

The original goal of the Amsterdam criteria was to identify those who could be classified as Lynch families on the basis of clinical history. These criteria, created in 1991 by the International Collaborative Group on HNPCC, stated that Lynch syndrome could be diagnosed if the following were all met: 1) at least three family members had been diagnosed with CRC 2) two or more generations had CRC 3) one affected member was a first-degree relative of the other two and 4) at least one individual

Bethesda guidelines

Although the Amsterdam criteria were revised in order to include those families with a high incidence of extra-colonic cancers associated with Lynch syndrome, the Bethesda guidelines were created in 1997 and subsequently revised in 2002. The objective of the Bethesda criteria was quite different than that of the Amsterdam criteria. The Bethesda guidelines are aimed at determining which tumors should undergo microsatellite instability (MSI) testing. The revised Bethesda guidelines state that MSI

Limitations of Amsterdam criteria and/Bethesda guidelines

The evolution of the genetic screening criteria over the past two decades includes revisions of both the Amsterdam and Bethesda criteria. It is difficult to completely outline the performance of these clinical criteria in the gynecologic population; they were not created for this population and thus, the validity of these tests is mainly limited to the colon cancer population. The current Bethesda guidelines are the best tool we have for identifying those individuals whose tumors require

Current guidelines

The Society of Gynecologic Oncologists (SGO) recently published a committee statement on the risk assessment for inherited gynecologic malignancies [19]. In these recommendations patients are triaged to a genetic counselor or genetic testing based on the perception of risk (Table 1). This document offered the caveat that there are select patients who may not meet these extensive criteria but who may warrant genetic screening. These patients include those with few female relatives, unknown

Screening algorithms

While the SGO guidelines are a reflection of some of the current literature they lack recommendations regarding the form of screening that should be undertaken. Recent literature does suggest that IHC for the MMR proteins may be used as primary triage for Lynch syndrome. Walsh et al. retrospectively identified, by IHC, presumptive Lynch syndrome in 26 (18%) out of 146 newly diagnosed endometrial cancer patients less than 50 years of age [9]. Six of the twenty-six patients met Amsterdam II

Mode of testing

As important a question as who to screen for Lynch syndrome is how to screen. Currently, both colon cancer MSI testing and IHC are used as primary triage to determine which individuals require genetic counseling regarding further analysis with sequencing. Immunohistochemistry is fast becoming an efficient, inexpensive way to screen tumors at risk for mismatch repair deficiency. Defective MMR is typically defined as lack of staining of any single MMR protein. Hampel et al. recently published the

The future

The goal of a screening test for Lynch syndrome is identifying all patients with the syndrome while discriminating those without Lynch syndrome. Currently, the recommendation of testing based on family and personal history is inadequate, and many patients with endometrial cancer as a result of Lynch syndrome are not being identified. We propose general, simplified criteria that will allow community-based gynecologic oncologists, gynecologists, medical oncologists, general surgeons, primary care

Conclusion

It is imperative that clinicians be mindful of the risk of Lynch syndrome in women with endometrial cancer. While most women with endometrial cancer present with early stage, curable endometrial disease, a diagnosis of colon cancer has a significantly worse prognosis. Given the opportunity for colon cancer screening and prevention strategies to be initiated, the identification of probands with endometrial cancer as a result of Lynch syndrome will lead to a reduction in morbidity and mortality

Conflict of interest statement

David Cohn has no conflicts of interest.

Kimberly Resnick has no conflicts of interest.

Richard Fishel is an inventor on patents for the sequencing of the MMR genes MSH2, MLH1 and PMS2. These patents are owned by the University of Vermont.

Heather Hampel sat on the Lynch syndrome advisory board (6/08) Myriad Genetics Laboratories, Inc. She also received an honorarium for speaking at Falco Biosystems.

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With institutional review board approval, we identified patients with endometrial cancer meeting American Brachytherapy Society criteria of high-risk features treated with adjuvant HDR between 2004 and 2010. HDR doses were 21Gy in 3 fractions delivered to either the full-length or partial-length vagina. Acute and late toxicities were evaluated using the Radiation Therapy Oncology Group scale and Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer grading, respectfully. Vaginal recurrences were assessed by physical examination and pap smears. Statistical analyses were performed using SPSS version 23 software.
Of 240 patients treated with HDR brachytherapy, 121 were treated with FLV brachytherapy, and 119, with PLV brachytherapy. The median follow-up was 9.5 years (range, 8-11 years) for FLV patients and 8.5 years (range, 7-10 years) for PLV patients; 0% of patients had vaginal recurrences, and 1.4% and 0.9% had proximal vaginal recurrences, respectively (P = .54). All patients treated with FLV brachytherapy developed grade 3 mucositis of the lower vagina/introitus (P < .0001) and had increased analgesics use compared with those treated with PLV brachytherapy (P < .0001). In total, 23% of patients treated with FLV brachytherapy developed grade 3 stenosis of the lower vagina/introitus, in contrast to 0% of patients treated with PLV brachytherapy (P < .0001).
PLV brachytherapy is as effective as FLV brachytherapy in reducing local recurrence and causes a significantly lower incidence of acute and late toxicities. The results of this study caution radiation oncologists regarding the careful use of FLV brachytherapy in patients with endometrial cancer and high-risk features.
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In a study performed on a Chinese cohort with endometrial cancer, IHC and MSI test (using a multiplex polymerase chain reaction (PCR)-capillary electrophoresis MSI detection kit) were highly concordant, and consistent results were seen in 73 out of 77 cases.44 In addition, IHC seems to be more reliable in the detection of MSH6 germline mutation compared with MSI testing.43,45 However, IHC is not a substitute for MSI testing in general, as MSI phenotype may still be possible even when staining for MMR proteins by IHC is retained.23
Microsatellite instability (MSI) is caused by defects in DNA mismatch repair (MMR) components. Inactivation of any MMR gene(s), including hMLH1, hMSH2, hMSH6, and hPMS2, can result in MSI. Immunohistochemistry (IHC) is a sensitive and specific screening tool for MSI that can detect loss of expression of one or more MMR components. Of the four MMR markers, hMLH1 and hMSH2 are considered most informative of MSI status. There has been renewed interest in MSI status in view of its favorable association with response to immune checkpoint inhibitors in some cancers. MMR expression patterns in acute myeloid leukemia (AML) have not been evaluated systematically.
We used clinically-validated IHC assays to assess the expression of hMLH1, hMSH2, hMSH6, and/or hPMS2 in formalin-fixed paraffin-embedded tissue sections of bone marrow core biopsies from patients diagnosed with AML. Mutation profiling was performed using next-generation sequencing to assess for mutations in MMR genes.
The study group included 236 patients with AML, including a cohort treated on a clinical trial of azacitidine and nivolumab (NCT02397720). In addition, hMSH6, and/or hPMS2 expression was assessed in 99 AML patients with diploid karyotype. All patients, except two, had retained expression of all MMR markers assessed: One patient from the azacytidine+nivolumab group had zonal patchy loss of staining of hMLH1 and, to a lesser extent, a similar staining pattern of hMSH2; and one patient from the AML with diploid karyotype group had loss of hMSH2 but retained expression of hMLH1, hMSH6 and hPMS2. In addition, a retrospective analysis on a separate cohort of 139 patients with primary AML, on which next generation sequencing profiling was performed, identified 14 cases with alterations in MMR genes.
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ReviewCurrent and emerging trends in Lynch syndrome identification in women with endometrial cancer

Abstract

Objective

Methods

Results

Conclusion

Section snippets

Background

The public health dilemma

Current screening strategies

Amsterdam criteria

Bethesda guidelines

Limitations of Amsterdam criteria and/Bethesda guidelines

Current guidelines

Screening algorithms

Mode of testing

The future

Conclusion

Conflict of interest statement

Gynecol. Oncol.

Gastroenterology

Am. J. Hum. Genet.

Gastroenterology

Clin. Gastroenterol. Hepatol.

Gynecol. Oncol.

Case record of the Massachusetts General Hospital. Case 13-2007. A 46-year old woman with gynecologic and intestinal cancers

N. Eng. J. Med.

Gynecologic manifestations of hereditary nonpolyposis colon cancer. From inherited to sporadic disease

Oncology (Williston Park)

Familial endometrial cancer in female carriers of MSH6 germline mutations

Nat. Genet.

Screening for Lynch syndrome (hereditary nonpolyposis colon cancer) among endometrial cancer patients

Cancer Res.

(Comment on) Screening for Lynch syndrome (hereditary nonpolyposis colon cancer) among endometrial cancer patients

Cancer Res.

The role of genetic testing for cancer susceptibility in gynecologic practice

Obstet. Gynecol.

Cancer risk in mutation carriers of DNA mismatch repair genes

Int. J. Cancer

Prospective determination of Lynch syndrome in young women with endometrial cancer

J. Clin. Oncol.

Lynch syndrome in women less than 50 years of age with endometrial cancer

Obstet. Gynecol.

Correlation between patient weights and defects in DNA mismatch repair: is this the link between and increased risk of previous cancer in thinner women with endometrial cancer?

Int. J. Gynecol. Cancer

Lynch syndrome in women less than 50 years of age with endometrial cancer

Obstet. Gynecol.

Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colon cancer syndrome

Obstet. Gynecol.

Sensitivity and specificity of clinical criteria for hereditary non-polyposis colon cancer as mutations in MSH2 and MLH1

J. Med. Genet.

Revised Bethesda guidelines for hereditary non-polyposis colon cancer (Lynch syndrome) and microsatellite instability

J. Natl. Cancer Inst.

A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colon cancer

Cancer Res.

Review
Current and emerging trends in Lynch syndrome identification in women with endometrial cancer