Elsevier

Gynecologic Oncology

Volume 123, Issue 1, October 2011, Pages 88-94
Gynecologic Oncology

Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40 years of age and younger

https://doi.org/10.1016/j.ygyno.2011.06.005Get rights and content

Abstract

Background

The hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to examine risk factors and outcomes in patients 40 years of age and younger with endometrial cancer.

Methods

We performed a retrospective cohort study of patients aged 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry was performed. Cases were analyzed according to the presence of DNA MMR protein defects. Standard two-sided statistical tests were performed.

Results

Of the 56 identified patients, the median age was 36 years (range, 24–40). The majority of the endometrial carcinomas were of endometrioid histology (91%), stage I (71%), and FIGO grade 1 (59%). Abnormal DNA MMR was found in 9 cases (16%). Cases with abnormal DNA MMR had lower body mass index (BMI) (P = 0.05), and had a family history suggestive of Lynch syndrome (P = 0.001). Tumors were more likely to have advanced stage disease (P < 0.001), be high grade (P < 0.001), have deep myometrial invasion (P < 0.001), and have lymphovascular invasion (P = 0.002). Cases with abnormal DNA MMR had significantly worse overall survival (P = 0.028) and progression-free survival (P = 0.042).

Conclusions

Endometrial cancer is rare in women aged 40 years or less. In this group of patients, loss of DNA MMR was associated with lower BMI, worse clinicopathologic factors, and worse outcome. These results may have implications when young women diagnosed with endometrial cancer are counseled regarding prognosis.

Research highlights

►HNPCC-associated endometrial cancers comprise a minority of cases in young patients. ►HNPCC-associated endometrial cancers have worse outcome compared with sporadic cases.

Introduction

Lynch syndrome, also known as Hereditary Non-Polyposis Colon Cancer (HNPCC), is associated with 40–60% lifetime risk of endometrial cancer. More than half of the women with Lynch syndrome and metachronous gynecologic and colon cancers present with either endometrial or ovarian cancer as the sentinel cancer [1]. As a result, there is increasing awareness of HNPCC in the gynecologic cancer population.

Lynch syndrome is caused by an inherited defect in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). Defects in these genes result in accumulation of unstable microsatellite sequences and microsatellite instability (MSI). Numerous studies have evaluated MSI status and clinicopathologic characteristics, but with conflicting results. In a large study with a cohort of 473 patients, MSI+ tumors were associated with higher proportion of advanced stage disease, myometrial invasion, endometrioid tumors, and improved disease-free and disease-specific survival [2]. In another large study with a cohort of 443 patients with endometrial cancer of endometrioid histology only, MSI was associated with higher grade disease and younger age, but had no association with survival [3]. While the majority of HNPCC-associated endometrial cancer is MSI+, approximately 20–30% of sporadic endometrial cancers can also display MSI as. With the genetic implications of Lynch syndrome and its association with abnormalities in mismatch repair gene function, recently attention has turned to utilization of immunohistochemistry testing of endometrial cancer tumors from patients less than 50 years of age, those with pathologic characteristics suggestive of Lynch syndrome, or those with personal or family history of Lynch-associated cancers to identify patients that may be at risk for Lynch syndrome [4], [5], [6], [7], [8], [9], [10], [11], [12], [13].

Criteria for identification of patients with Lynch syndrome include the Amsterdam criteria, created by the International Collaborative Group on HNPCC in 1990. In 1999, the Amsterdam criteria were revised to include extra-colonic malignancies associated with Lynch syndrome. These criteria are intentionally stringent to increase specificity, but as a result only 13–36% of families with molecularly-confirmed Lynch syndrome will meet these criteria [14], [15]. Secondary to this issue, the Bethesda guidelines were created in 1996 and revised in 2002 to describe criteria for tumors which should undergo MSI testing. Both of these criteria were initially created for patients in the setting of colon cancer, and despite revisions, sensitivity is still inadequate in the gynecologic cancer population [16]. In 2007, the Society of Gynecologic Oncologists (SGO) published a committee statement to help guide risk assessment for Lynch syndrome in the gynecologic cancer population [17].

Young patients with endometrial cancer represent a minority. Several studies have addressed this population, specifically identifying risk factors. Nulliparity [18], [19], [20], body mass index (BMI) [19], [21], infertility or irregular menstrual cycles [20], myometrial invasion [21], and synchronous ovarian cancer [20], [22] are associated with young patients with endometrial cancer. There are important implications in these patients due to their age. Many of these patients may desire future fertility and must be counseled regarding the careful selection for conservative fertility-sparing treatment of endometrial cancer [22], [23], [24], [25]. In addition, due to the young age of these patients, they will require prolonged surveillance for developing other primary malignancies, as will their family members [26]. Few prior studies on young patients with endometrial cancer have focused on the subgroup of patients aged 40 or less. We chose this specific subgroup of patients to evaluate the implications of mismatch repair protein dysfunction and possible associated Lynch syndrome in patients who are very young and may desire future fertility.

Previously we reported on the pathologic characteristics of a cohort of patients with endometrial cancer aged 40 years and less that was treated at our institution. In that study, our objective was to evaluate tumor characteristics, immunohistochemical (IHC) analysis for DNA mismatch repair (MMR) proteins, and estrogen receptor/progesterone receptor expression [27]. The purpose of our study was to describe the clinical characteristics and outcome of this cohort of patients after a longer follow-up period.

Section snippets

Methods

After Institutional Review Board (IRB) approval was obtained, an institutional database was queried to identify all patients aged 40 and younger who were diagnosed with endometrial carcinoma from the study period of January 1993 to May 2008. All patients underwent hysterectomy at our institution. Medical records—including operative reports, pathology reports, and chemotherapy or radiotherapy records—were reviewed.

All available hematoxylin and eosin-stained slides for our study group were

Results

A total of 56 patients were identified. All were 40 years of age and younger, underwent hysterectomy for endometrial carcinoma at our institution, and had paraffin-embedded specimens available for IHC testing. Clinical characteristics and follow-up data for the patients are detailed in Table 1. The median age was 36 years (range, 24–40) and median BMI was 26.6 kg/m2 (range, 16.8–69.5). The majority (73.2%) of patients was Caucasian and had stage I disease (71.4%). Median follow-up for the cohort

Discussion

Endometrial cancer in premenopausal women is uncommon. However, there are more implications regarding etiology and management of these patients. Over the past decade, the association of Lynch syndrome with endometrial cancer patients less than 50 years of age has become increasingly evident [31]. The majority of endometrial cancer cases in premenopausal women is still sporadic, especially with the risk factor of estrogen excess associated with obesity, nulliparity, and infertility.

In this study

Conflict of interest statement

No conflict of interest.

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