Hereditary Syndromes Manifesting as Endometrial Carcinoma: How Can Pathological Features Aid Risk Assessment?

Adele Wong,Joanne Ngeow

doi:10.1155/2015/219012

Abstract

Endometrial carcinoma is the most common gynecological tumor worldwide. It can be the presenting malignancy, acting as the harbinger, of an undiagnosed hereditary syndrome. Up to 50% of females with Lynch syndrome present in this manner. Differentiation between Lynch, Muir-Torre, and Cowden syndromes can at times be challenging due to the overlapping features. Our review emphasizes on the strengths, pitfalls, and limitations of microscopic features as well as immunohistochemical and polymerase chain reaction- (PCR-) based tests used by laboratories to screen for DNA mismatch repair (MMR) and PTEN gene mutations in patients to enable a more targeted and cost effective approach in the use of confirmatory gene mutational analysis tests. This is crucial towards initiating timely and appropriate surveillance measures for the patient and affected family members. We also review the evidence postulating on the possible inclusion of uterine serous carcinoma as part of the spectrum of malignancies seen in hereditary breast and ovarian carcinoma syndrome, driven by mutations in BRCA1/2.

Highlights

Many genetic mutations have been elucidated in the past half century leading to either the discovery or better understanding of hereditary syndromes associated with malignancies in the female genital tract
Nonhereditary somatic mutation is due to promoter hypermethylation of the MLH1 gene resulting in silencing of the gene causing similar Microsatellite instability (MSI) levels in the genome seen in 10% to 25% of sporadic tumors, especially colorectal and endometrial carcinomas [15]
Muir-Torre syndrome (MTS) is mostly due to germline mutations in MSH2 and MLH1 [81]. It is characterized by sebaceous gland neoplasms and keratoacanthoma with 57% of patients presenting with diagnostic skin lesions as their sentinel pathology [81, 82]

Summary

Introduction

Many genetic mutations have been elucidated in the past half century leading to either the discovery or better understanding of hereditary syndromes associated with malignancies in the female genital tract. It is imperative that syndromes are identified in probands who present with malignancies to enable prompt initiation of appropriate counseling and testing for the individual and family to reduce morbidity and mortality amongst these individuals [7] With the advent of immunohistochemical (IHC) markers and molecular testing for specific gene mutations, anatomic pathologists play a bigger role than ever aiding oncologists and geneticists towards a more directed approach towards confirmatory genetic testing This is so for proband patients with sentinel tumors as the initial manifestation for any given family. The less common syndromes such as Muir-Torre syndrome and Cowden syndrome are emphasized as these may be missed if clinicians do not actively consider them when assessing patients

Lynch Syndrome

Identification of Lynch Syndrome amongst Proband

Cowden Syndrome

Findings

Conclusion