Abstract
ObjectiveTo review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome diagnostics. Materials and methodsStudies were identified through PubMed on December 1, 2021. Eligibility criteria were universal immunohistochemical analyses for at least 2 MMR proteins in unselected, consecutively collected UTUC cohorts. Exclusion criteria included reviews, case-reports, non-English language, and non-humans. Risk of bias was assessed using a modified Newcastle-Ottawa scale. Meta-analyses were performed to compare the association between clinical criteria and Lynch syndrome diagnoses. ResultsFrom 12 included studies, 1628 surgically removed UTUC from 1626 patients were screened for MMR protein loss. In 11 studies, 140 of the 1559 patients had tumors with loss (9.0%) with 80.7% showing loss of MSH2, MSH6, or both. In 7 studies, genetic testing confirmed Lynch syndrome diagnosis for 20 of 970 patients (2.1%). In 8 studies, 31 patients were given a clinical Lynch syndrome diagnosis (2.6%). In total, 51 assumed or verified Lynch syndrome patients were identified among 1087 patients (4.7%). Meta-analyses of 3 studies showed significant association between previous cancer diagnosis and Lynch syndrome-associated UTUC (P = .038). ConclusionDespite the few studies conducted and lack of genetic testing, current data suggests that universal screening for MMR protein loss in UTUC may result in Lynch syndrome diagnoses in 4.7%. However, for the screening to be effective for Lynch syndrome diagnostics, follow-up investigations, such as genetic testing for MMR variants, are needed.
Highlights
Lynch syndrome is one of the most common hereditary cancer syndromes and it confers an increased risk of multiple cancers including colorectal and endometrial cancer [1]
mismatch repair (MMR) deficiency In the 12 studies, 1628 surgically removed upper tract urothelial carcinomas (UTUC) from 1626 patients were screened for loss of expression of at least two of the MMR proteins
As Lynch syndrome UTUC are characterized by early age at cancer diagnosis, a more even distribution between sexes and multiple cancers [3,8], we considered the use of additional clinical data such as age, sex, location, and cancer history to select UTUC for further genetic testing
Summary
Lynch syndrome is one of the most common hereditary cancer syndromes and it confers an increased risk of multiple cancers including colorectal and endometrial cancer [1]. The initiation of the tumorigenic development in Lynch syndrome individuals is based on the Knudson two-hit hypothesis in which the first hit is inactivation of one of the MMR alleles at conception when pathogenic variants are passed through generations, while the second hit in the other parental allele occurs sporadically Inactivation of both MMR alleles can be visualized as loss of protein expression utilizing immunohistochemical analyses. This has motivated universal screening of all newly diagnosed colorectal and endometrial cancers for MMR deficiency and Lynch syndrome diagnostics in some Western countries. We aimed to review the current data on universal immunohistochemical testing and MSI analyses in unselected UTUC cohorts and describe the effect of universal screening for Lynch syndrome
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