Genitourinary manifestations of Lynch syndrome in the urological practice

Objective: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.Methods:Previous literature was assessed through Medline,Scopus,and Google Scholar data-bases.A narrative review of the most relevant articles from January 1996 to June 2021 on urological manifestations of LS was provided.Results: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 multidisci-plinary 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.Conclusion: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 evaluationandgenetic 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.

The association of type and number of high-risk criteria with cancer-specific mortality in prostate cancer patients treated with radical prostatectomy

Objectives:This study aimed to test the association between of type and number of D'Amico high-risk criteria(DHRCs)with cancer-specific mortality(CSM)in high-risk prostate cancer patients treated with radical prostatectomy.Materials and methods:In the Surveillance,Epidemiology,and End Results database(2004–2016),we identified 31,281 radical prostatectomy patients with at least 1 DHRC,namely,prostate-specific antigen(PSA)>20 ng/mL(hrPSA),biopsy Gleason Grade Group(hrGGG)score of 4 and 5,or clinical tumor stage≥T3(hrcT).Multivariable Cox regression models and competing risks regression models(adjusting for other cause mortality)tested the association between DHRCs and 5-year CSM.Results:Of 31,281 patients,14,394(67%)exclusively harbored hrGGG,3189(15%)harbored hrPSA,and 1781(8.2%)harbored hrcT.Only 2132 patients(6.8%)harbored a combination of the 2 DHRCs,and 138(0.6%)had all 3 DHRCs.Five-year CSMrates ranged from 0.9%to 3.0%when any individual DHRC was present(hrcT,hrPSA,and hrGGG,in that order),1.6%to 5.9%when 2 DHRCs were present(hrPSA-hrcT,hrcT-hrGGG,and hrPSA-hrGGG,in that order),and 8.1%when all 3 DHRCs were present.Cox regression models and competing risks regression confirmed the independent predictor status of DHRCs for 5-year CSM that was observed in univariable analyses,with hazard ratios from 1.00 to 2.83 for 1 DHRC,2.35 to 5.88 for combinations of 2 DHRCs,and 7.13 for all 3 DHRCs.Conclusions:Within individual DHRCs,hrcT and hrPSA exhibited weaker effects than hrGGG did.Moreover,a dose-response effect was identified according to the number of DHRCs.Accordingly,the type and number of DHRCs allow further risk stratification within the high-risk subgroup.