Colorectal and endometrial cancers are the only malignancies routinely screened for Lynch syndrome through loss of MMR expression, MSI or for mutations in an MMR gene. The only recommendation for Lynch syndrome testing in UTUC is by the European Association of Urology, which proposes that UTUC patients with suspected Lynch syndrome undergo germline DNA sequencing; however, this may not be a good screening tool based on cost. In colorectal and endometrial cancer, screening approaches rely on the Amsterdam criteria (AMS) I/II, based on personal and family cancer history, tumor immunohistochemistry (IHC) for loss of MMR proteins and PCR to detect degree of MSI. Typically, MSI-high defined by having two or more of the five microsatellite markers with instability in the Bethesda panel  or MSI-intermediate, having one marker of instability, being the cutoff for most studies.
Traditionally, MSI is identified using PCR-based methods and loss of MMR protein using IHC. Next-generation sequencing (NGS) has been utilized to assign an MSI sensor score which is determined through a computer-based algorithm using tumor and matched normal DNA to determine the percentage of unstable loci and may be more sensitive in detecting MMR loss or MSI than the PCR-based method [11,12]. Audenet et al.[13▪] looked at the genomic differences between UTUC and BUC to determine the relatedness of temporally distinct tumor by utilizing NGS. They also used NGS to assign MSI sensor scores and determine a mutational signature analysis to assess if these metrics could reliably identify Lynch syndrome-associated UTUC. Of the 12 tumors with an MSI at least 10, which they defined as being equivalent to MSI-H, 10 had a Lynch syndrome -associated germline mutation, one did not have consent for germline mutation analysis and one had a somatic Lynch-like MSI-high tumor. Of the 12 patients who had germline testing and likely had a mutation associated with Lynch syndrome, only 10 of them had an MSI at least 10, suggesting that an MSI cut-off of 10 may not be sensitive enough to detect every patient with Lynch syndrome. Mutational signature analysis for a predominant MMR/MSI signature only identified six of the 12 patients with Lynch syndrome. Although these data suggest that individually, these metrics are not sensitive enough to screen tumors for Lynch syndrome -associated germline mutations, it does introduce other molecular-based methods to screen for Lynch syndrome.
PCA is the most common malignancy in men and the second leading cause of cancer deaths in the United States with an estimation of more than 31 000 deaths in 2019 . Although some studies do not suggest a link between Lynch syndrome and PCA [29,30], several studies report an increased risk of PCA ranging from 2.1 to 4.87-fold in patients with Lynch syndrome [21,24,31–33].
Taking recent molecular and epidemiologic data together, strong consideration should be taken to include PCA as a part of Lynch syndrome tumor spectrum. Although many PCA with MSI-high or absent MMR expression will harbor somatic mutations, the data suggest that a significant proportion will have associated germline inheritable mutations. Upon further data supporting the inclusion of PCA, future studies should focus on developing general PCA screening guidelines for patients with Lynch syndrome.
ACC is rare with only 1–2 cases per million each year and is associated with a poor prognosis . Although it is known to be part of the tumor spectrum of Li Fraumeni syndrome because of a TP53 mutation, its association with Lynch syndrome is less studied. Raymond et al. identified and prospectively followed 94 patients with a diagnosis of ACC. Three (3.2%) were subsequently found to have germline mutations (MSH2, MLH1 or MSH6). Of the 135 patients from the retrospective cohort, two (1.5%) were identified, both with MSH2 mutations. Four tumors were available for analysis and interestingly did not demonstrate MSI, but did have a loss of MMR on IHC. Other studies include case reports of ACC in patients with Lynch syndrome and germline MSH2 mutations [41–44]. The rarity of this disease makes establishing a relationship to Lynch syndrome difficult, and will only be clarified with further studies. Routine screening recommendations cannot be made at this time; however, clinicians should maintain ACC in their differential in patients with Lynch syndrome with adrenal masses or stigmata of excess adrenal hormones.
Testicular cancer is the most common malignancy in men between the ages of 15 and 44 in the United States . Testicular cancer is currently not considered a part of the Lynch syndrome tumor spectrum, although there are reports of MSI and MMR deficiency in tumors. Most studies focus on the presence of MSI and MMR protein loss in testicular cancer as it relates to the clinical behavior of the disease. Although some studies suggest that MSI and loss of MMR proteins may be related to chemotherapy resistance, shorter time to or chance of recurrence [46–50], other studies demonstrated no association  or lack of or low frequency of MSI instability and/or loss of MMR protein expression in testicular tumors [52,53]. Although the data are mixed, it is likely still worthwhile to explore patients with chemoresistant or recurrent testicular cancer for a possible association with Lynch syndrome.
Currently, UTUC is the only urologic malignancy that is definitively and widely accepted as part of the Lynch syndrome tumor spectrum, although emerging data support strong consideration of including BUC and PCA as well. The challenge in researching BUC and PCA is the apparent lower penetrance in Lynch syndrome, whereas there is high prevalence in the general population. Over 5% of UTUC may be associated with Lynch syndrome, therefore it is of utmost importance for the urologist to consider the possibility of a hereditary cause and refer for the appropriate screening. Even with BUC, PCA, ACC and testis cancers, the vigilant urologist can probably identify inheritable cases when a careful family history is obtained or clinical suspicion is raised. Although the relationship between these other urologic malignancies and Lynch syndrome is less well established, data continue to emerge and will inform future management in terms of recommendations for tumor tissue testing to screen for MSI, loss of MMR expression and germline testing for Lynch syndrome-associated mutations in addition to screening recommendations for these urologic malignancies in patients with Lynch syndrome.
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