Lynch Syndrome and Urologic Malignancies

A Contemporary Review

Amy Lim; Priya Rao; Surena F. Matin


Curr Opin Urol. 2019;29(4):357-363. 

In This Article

Abstract and Introduction


Purpose of review: An overview of urologic malignancies in Lynch syndrome and the current state of research.

Recent findings: Upper tract urothelial carcinoma (UTUC) is the third most common malignancy in Lynch syndrome. Establishment and utilization of a sensitive and practical screening method for Lynch syndrome in patients presenting with UTUC is overdue. Next-generation sequencing to evaluate for microsatellite instability (MSI) and detect mutations of mismatch repair (MMR) genes may be the future of Lynch syndrome screening. Epidemiologic data and molecular characterization suggest bladder urothelial carcinoma (BUC) and prostate cancer (PCA) as unrecognized components of Lynch syndrome. Small studies suggest that Lynch syndrome may predispose individuals to adrenocortical carcinoma. Testicular cancer literature focuses on characterizing MSI and MMR gene expression as it relates to chemotherapy sensitivity; outcomes suggest a potential avenue to investigate its relationship to Lynch syndrome.

Summary: Patients with Lynch syndrome have an increased risk of urologic malignancies, including UTUC and likely BUC and PCA. BUC and PCA have a lower penetrance than UTUC for unknown reasons. Established Lynch syndrome-associated genitourinary tumors will necessitate the development of methods to diagnose Lynch syndrome in patients presenting with these malignancies, in addition to establishing screening guidelines for patients with Lynch syndrome-associated genitourinary tumors.


Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition most commonly associated with an increased risk of colorectal and endometrial cancer. It is also associated with increased risk of cancers of the ovary, stomach, small bowel, hepatobiliary system, central nervous system, skin and urologic tract.[1,2] Lynch syndrome is a result of a mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or EPCAM, which is a gene adjacent to MSH2 that when mutated, can cause the MSH2 gene to be inactivated. Mutations in these genes cause a defect in the proof reading system of DNA replication, which results in errors, most commonly in regions of short repeating sequences known as microsatellites, resulting in microsatellite instability (MSI). These mutations lead to the increased risk of the previously mentioned cancers that characterize Lynch syndrome. This review will focus on recent developments in Lynch syndrome as it relates to urologic malignancies. Current interest in the field focuses on screening approaches and methods for Lynch syndrome in patients who present with upper tract urothelial carcinoma (UTUC), if bladder urothelial carcinoma (BUC), prostate cancer (PCA) and adrenocortical carcinoma (ACC) should be included in the Lynch syndrome spectrum and how patients with Lynch syndrome be screened for urologic malignancies (Figure 1).

Figure 1.

Summary of genitourinary malignancies and Lynch syndrome including rates of mismatch repair (MMR) germline mutations, loss of MMR protein expression and microsatellite instability (MSI). IHC, immunohistochemistry; MSI-H, MSI-high.