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P131: DNA mismatch repair testing in upper tract urothelial carcinoma patients - Is Universal Lynch Syndrome screening necessary?

Drs. O.J.A. (Orlane) Figaroa
Figaroa O.J.A.1, Bins A.D.2, Baard J.3
1Amsterdam University Medical Centre, Dept. of Oncology and Urology, Amsterdam, The Netherlands, 2Amsterdam University Medical Centre, Dept. of Medical Oncology, Amsterdam, The Netherlands, 3Amsterdam University Medical Centre, Dept. of Urology, Amsterdam, The Netherlands
14th European Multidisciplinary Congress on Urological Cancers
10 November 2022
Urothelial Cancer - Diagnosis, Pathology & Biopsies

Introduction & Objectives

Lynch Syndrome (LS) is the most common hereditary cancer syndrome, characterized by germline mutations in at least one of the DNA mismatch repair (MMR) genes. Those genes include MLH1, MSH2, MSH6, PMS2. Additionally germline mutations in EPCAM can result in heritable silencing of MSH2. LS leads to development of tumors in various organs and is detectable as genomic instability of DNA repeats, so-called microsatellite instability (MSI). Genetic assessment is the golden standard for the conformation of LS. With 4% to 6% of the Lynch patients affected with Upper Tract Urothelial Carcinoma (UTUC), it is the third most common LS associated malignancy after colorectal and endometrial carcinoma. There are recommendations regarding universal LS screening of all new colorectal and endometrial carcinoma cases based on their incidences. This retrospective cohort study of archival tissues of known UTUC cases researched the incidence of MMR deficiency with the potential to introduce universal LS screening for all new identified UTUC patients.

Materials & Methods

An Amsterdam University Medical Centre (Amsterdam UMC)UTUC database was screened to include all confirmed UTUC cases within the Amsterdam UMC. Of the included cases, the glass slides and the formalin-fixed paraffinembedded (FFPE) tissue blocks were retrieved from the Pathology archives to screen if there was sufficient malignant tissue available to make a Tissue Micro Array (TMA). Three TMAs were made, two with malignant tissue and one control. Glass slides were prepared from the TMAs, and stained to analyze the presence of the four different MMR proteins.


103 cases were included and tested for loss of MMR expression. 6 cases (5.8%) show a deficiency of at least one MMR protein. Of those cases, 5 are known with Lynch Syndrome (83.3%). In the 6th case no consent for germline testing could be obtained due to death of the patient. 4 of these cases met the Amsterdam II criteria. When comparing the MMR proficient patients (n=97) vs the MMR deficient patients (n=6) we found a significant difference in sex (P=0.032)with overpresentation of females, fulfillment of the Amsterdam II criteria (P<0.001) and previous malignancies (P=0.022). There was no significance found in age of onset (P=0.301).


The incidence of MMR deficiency in UTUC found in this study are similar to the incidence of Lynch Syndrome in colorectal and endometrial carcinoma. Since screening with the Amsterdam II criteria seems to be unhelpful with no significant difference in age of onset, we propose to routinely screen all new UTUC cases on MMR deficiency using immunohistochemical methods similar to those in place for colorectal and endometrial carcinoma. The fact that in most cases MMR deficiency in UTUC is based on a germline mutation, underlines the importance of universal LS screening in UTUC patients.

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