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.

Biopticka Laborator S R O Pilsen Czech Republic

Cleveland Clinic Department of Anatomic Pathology Robert J Tomsich Pathology and Laboratory Medicine Institute Cleveland OH USA

Cytopathos S R O Bratislava Slovakia

Department of Medical Genetics Faculty of Medicine in Plzeň Charles University Prague Pilsen Czech Republic

Department of Urology Faculty of Medicine in Plzeň Charles University Prague Pilsen Czech Republic

Onco Team Diagnostic Bucharest Romania

Šikl's Department of Pathology The Faculty of Medicine and Faculty Hospital in Pilsen Charles University Alej Svobody 80 304 60 Pilsen Czech Republic

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Watson P, Vasen HFA, Mecklin JP, Bernstein I, Aarnio M, Jarvinen HJ et al (2008) The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123(2):444–449. https://doi.org/10.1002/ijc.23508 PubMed DOI PMC

Audenet F, Colin P, Yates DR, Ouzzane A, Pignot G, Long JA et al (2012) A proportion of hereditary upper urinary tract urothelial carcinomas are misclassified as sporadic according to a multi-institutional database analysis: proposal of patient-specific risk identification tool. BJU Int 110(11 Pt B):E583-589. https://doi.org/10.1111/j.1464-410X.2012.11298.x PubMed DOI

Rasmussen M, Madsen MG, Therkildsen C (2022) Immunohistochemical screening of upper tract urothelial carcinomas for Lynch syndrome diagnostics: a systematic review. Urology 165:44–53. https://doi.org/10.1016/j.urology.2022.02.006 PubMed DOI

Goldberg H, Wallis CJD, Klaassen Z, Chandrasekar T, Fleshner N, Zlotta AR (2019) Lynch syndrome in urologic malignancies - What does the urologist need to know? Urology 134:24–31. https://doi.org/10.1016/j.urology.2019.07.004 PubMed DOI

Roupret M, Seisen T, Birtle AJ, Capoun O, Comperat EM, Dominguez-Escrig JL et al (2023) European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2023 update. Eur Urol 84(1):49–64. https://doi.org/10.1016/j.eururo.2023.03.013 PubMed DOI

Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93(18):9821–9826. https://doi.org/10.1073/pnas.93.18.9821 PubMed DOI PMC

Vankova B, Vanecek T, Ptakova N, Hajkova V, Dusek M, Michal M et al (2020) Targeted next generation sequencing of MLH1-deficient, MLH1 promoter hypermethylated, and BRAF/RAS-wild-type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions. Genes Chromosomes Cancer 59(10):562–568. https://doi.org/10.1002/gcc.22861 PubMed DOI

Soukupova J, Zemankova P, Lhotova K, Janatova M, Borecka M, Stolarova L et al (2018) Validation of CZECANCA (CZEch CAncer paNel for Clinical Application) for targeted NGS-based analysis of hereditary cancer syndromes. PloS one 13(4):e0195761. https://doi.org/10.1371/journal.pone.0195761 PubMed DOI PMC

Benard-Slagter A, Zondervan I, de Groot K, Ghazavi F, Sarhadi V, Van Vlierberghe P et al (2017) Digital multiplex ligation-dependent probe amplification for detection of key copy number alterations in T- and B-cell lymphoblastic leukemia. J Mol Diagn 19(5):659–672. https://doi.org/10.1016/j.jmoldx.2017.05.004 PubMed DOI

Nygren AO, Ameziane N, Duarte HM, Vijzelaar RN, Waisfisz Q, Hess CJ et al (2005) Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res 33(14):e128. https://doi.org/10.1093/nar/gni127 PubMed DOI PMC

Lindner AK, Schachtner G, Tulchiner G, Thurnher M, Untergasser G, Obrist P et al (2021) Lynch syndrome: its impact on urothelial carcinoma. Int J Mol Sci 22(2). https://doi.org/10.3390/ijms22020531

Gayhart MG, Johnson N, Paul A, Quillin JM, Hampton LJ, Idowu MO et al (2020) Universal mismatch repair protein screening in upper tract urothelial carcinoma. Am J Clin Pathol 154(6):792–801. https://doi.org/10.1093/ajcp/aqaa100 PubMed DOI

Joost P, Therkildsen C, Dominguez-Valentin M, Jonsson M, Nilbert M (2015) Urinary tract cancer in Lynch syndrome; increased risk in carriers of MSH2 mutations. Urology 86(6):1212–1217. https://doi.org/10.1016/j.urology.2015.08.018 PubMed DOI

Harper HL, McKenney JK, Heald B, Stephenson A, Campbell SC, Plesec T et al (2017) Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome. Mod Pathol 30(1):146–156. https://doi.org/10.1038/modpathol.2016.171 PubMed DOI

Urakami S, Inoshita N, Oka S, Miyama Y, Nomura S, Arai M et al (2018) Clinicopathological characteristics of patients with upper urinary tract urothelial cancer with loss of immunohistochemical expression of the DNA mismatch repair proteins in universal screening. Int J Urol 25(2):151–156. https://doi.org/10.1111/iju.13481 PubMed DOI

Ju JY, Mills AM, Mahadevan MS, Fan J, Culp SH, Thomas MH et al (2018) Universal Lynch syndrome screening should be performed in all upper tract urothelial carcinomas. Am J Surg Pathol 42(11):1549–1555. https://doi.org/10.1097/PAS.0000000000001141 PubMed DOI

Moller P, Seppala TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D et al (2018) Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 67(7):1306–1316. https://doi.org/10.1136/gutjnl-2017-314057 PubMed DOI

Smith SC, Fine SW (2022) Genitourinary system and Lynch syndrome. In: WHO Classification of tumours - Urinary and male genital tumours, 5th edn. IARC, Lyon (France), pp 487–489

Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM et al (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104(5):1535–1549. https://doi.org/10.1016/0016-5085(93)90368-m PubMed DOI

Cohen SA, Leininger A (2014) The genetic basis of Lynch syndrome and its implications for clinical practice and risk management. Appl Clin Genet 7:147–158. https://doi.org/10.2147/TACG.S51483 PubMed DOI PMC

Crockett DG, Wagner DG, Holmang S, Johansson SL, Lynch HT (2011) Upper urinary tract carcinoma in Lynch syndrome cases. J Urol 185(5):1627–1630. https://doi.org/10.1016/j.juro.2010.12.102 PubMed DOI

Donahue TF, Bagrodia A, Audenet F, Donoghue MTA, Cha EK, Sfakianos JP et al (2018) Genomic characterization of upper-tract urothelial carcinoma in patients with Lynch syndrome. JCO Precis Oncol 2018:PO.17.00143. https://doi.org/10.1200/PO.17.00143