Upper tract urothelial carcinoma (UTUC) is the third most common malignancy associated with Lynch syndrome (LS). The current European urology guidelines recommend screening for LS in patients with UTUC up to the age of 60 years. In this study, we examined a cohort of patients with UTUC for potential association with LS in order to establish the sensitivity of current guidelines in detecting LS. A total of 180 patients with confirmed diagnosis of UTUC were enrolled in the study during a 12-year period (2010-2022). Loss of DNA-mismatch repair proteins (MMRp) expression was identified in 15/180 patients (8.3%). Germline analysis was eventually performed in 8 patients confirming LS in 5 patients (2.8%), including 4 germline mutations in MSH6 and 1 germline mutation in MSH2. LS-related UTUC included 3 females and 2 males, with a mean age of 66.2 years (median 71 years, range 46-75 years). Four of five LS patients (all with MSH6 mutation) were older than 65 years (mean age 71.3, median 72 years). Our findings indicate that LS-associated UTUCs can occur in patients with LS older than 60 years. In contrast to previous studies which used mainly highly pre-selected populations with already diagnosed LS, the most frequent mutation in our cohort involved MSH6 gene. All MSH6 mutation carriers were > 65 years, and UTUC was the first LS manifestation in 2/4 patients. Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history.

• Klíčová slova
• Immunohistochemistry, Lynch syndrome, MMR, Screening algorithm, Upper urinary tract, Urothelial carcinoma,
• MeSH
• dědičné nepolypózní kolorektální nádory * diagnóza   genetika   patologie   MeSH
• karcinom z přechodných buněk * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mismatch repair endonukleáza PMS2 genetika   MeSH
• MutL homolog 1 genetika   MeSH
• nádory močového měchýře * MeSH
• oprava chybného párování bází DNA MeSH
• senioři MeSH
• urologie * MeSH
• zárodečné mutace MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• mismatch repair endonukleáza PMS2 MeSH
• MutL homolog 1 MeSH

Approximately 4-5% of patients with metastatic colorectal cancer (mCRC) have mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumours. These tumours present challenges in the clinical practice due to variant response to fluoropyrimidine-based chemotherapy and, perhaps, also non-immunologic targeted therapies. Recently, a breakthrough in the treatment of dMMR/MSI-H mCRC has been achieved with several clinical trials showing dramatic long-term benefit of immunotherapy using checkpoint inhibitors. Nevertheless, several questions remain regarding the optimisation of immunotherapy regimens and the use of biomarkers to identify populations set to derive the greatest benefit from immunotherapy. Combination regimens and/or the use of immunotherapy as a maintenance after induction non-immunologic systemic therapy may be the way forward to improve outcomes.

• Klíčová slova
• chemotherapy, colorectal cancer, ipilimumab, mismatch repair, nivolumab, pembrolizumab,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH