Genitourinary manifestations of Lynch syndrome in the urological practice

Lynch syndrome (LS) is an autosomal dominant hereditary disorder resulting from germline mutation in at least one of the four mismatch repair genes or in EPCAM gene. From a clinical perspective, LS patients exhibit an increased predisposition to multiple primary malignancies and early age of onset compared to general population. We aimed to provide a comprehensive overview of all the genitourinary manifestations of LS, focusing on incidence, diagnosis, clinical features, therapeutic strategies, and screening protocols.

Previous literature was assessed through Medline, Scopus, and Google Scholar databases. A narrative review of the most relevant articles from January 1996 to June 2021 on urological manifestations of LS was provided.

In the LS tumor spectrum, upper tract urothelial carcinoma (UTUC) represents the third most frequent malignancy, and the first most common cancer in the urological field, with an approximately 14-fold increased risk of developing UTUC compared to general population. LS diagnosis among patients experiencing UTUC as first malignancy is a step-by-step process, including (i) clinical criteria, (ii) molecular testing, and (iii) genetic testing to confirm the hereditary disorder. The current European Association of Urology (EAU) guidelines recommend to perform molecular testing among UTUC patients under 65 years old, or UTUC patients with personal history of LS-related tumor, or UTUC patients with one first-degree relative under the age of 50 years with LS-related tumor, or UTUC patients with two first-degree relatives with LS-related tumor regardless of age of onset. Newly diagnosed LS patients should be referred to a multidisciplinary management, including gastroenterologists and gynecologists. Finally, considering the increased risk of metachronous recurrence, treatments other than radical nephroureterectomy may be a valuable therapeutic alternative. Whether urological malignancies other than UTUC should be included in the LS tumor spectrum is still controversial.

Considering the strict association between UTUC and LS, we believe that the urologist should recognize patients at increased risk for hereditary disease according to current EAU clinical criteria and address them to a comprehensive diagnostic algorithm, including molecular evaluation and genetic testing. To date, literature lacks clear evidence regarding the role of LS in developing bladder cancer, prostate cancer, or renal cell carcinoma, and current data are still inconclusive, highlighting the urgent need for further studies.