Abstract
Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.
Highlights
Lynch syndrome (LS), known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary type of colon cancer, accounting for 3% of new colon cancer diagnoses [1]
The aim of this review article is to focus on LS-associated urothelial cancer (UC) of the upper urinary tract (UUT) and bladder, highlighting genetics, molecular subtype classifications, and germline variant profiles compared to sporadic UC, the impact of genetic testing, incidence, outcomes, and potential future treatment strategies such as immune checkpoint inhibitors (ICI), which might help to optimize treatment in LS-associated cancer
Urothelial mucosa staining positive for mutL homolog 1 (MLH1), PMS2, mutS homolog 6 (MSH6), and mutS homolog 2 (MSH2) (arrow in (A–D)) versus lost expression expression of of MSH6
Summary
Lynch syndrome (LS), known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary type of colon cancer, accounting for 3% of new colon cancer diagnoses [1]. Apart from early onset colon cancer with proximal predominance and an excess of synchronous and/or metachronous colon cancer [2], the cancer types most frequently associated with LS are endometrial and ovarian cancer [3], and malignancies affecting the stomach, small bowel, prostate, breast, brain, and hepato-biliary tract [4,5,6,7]. Due to the increased recognition of tumor heterogeneity in LS, LS-associated cancer types include urothelial cancer (UC) as the third most common cancer in subsets of these families as first described by Lynch et al in 1990 [8].
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