Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome

Abstract

Increased risk for upper tract urothelial carcinoma is described in patients with Lynch syndrome, caused by germline mutations in mismatch repair genes. We aimed to identify the frequency of mismatch repair protein loss in upper tract urothelial carcinoma and its potential for identifying an association with Lynch syndrome. We queried our database to identify upper tract urothelial carcinomas. Patients were cross-referenced for history of colorectal carcinoma or other common Lynch syndrome-associated neoplasms to enrich for potential Lynch syndrome cases. Tumor histopathologic characteristics were reviewed and each case was analyzed for loss of mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, by immunohistochemistry. Of 444 patients with upper tract urothelial carcinoma, a subset of 215 (encompassing 30 with upper tract urothelial carcinoma and another common Lynch syndrome-associated neoplasm) was analyzed for loss of mismatch repair protein expression. Of 30 patients with Lynch syndrome-associated neoplasms, six had documented Lynch syndrome, including two with Muir-Torre syndrome. Mismatch repair protein loss was identified in 7% of total upper tract urothelial carcinomas and 30% of patients with Lynch syndrome-associated neoplasms (including all patients with Lynch syndrome/Muir-Torre syndrome). Of patients without history of Lynch syndrome-associated neoplasms, 5 of 184 (2.7%) had loss of mismatch repair protein expression. Twelve cases with mismatch repair protein loss demonstrated loss of MSH2 and MSH6, and 2 had isolated loss of MSH6. MLH1 and PMS2 expression were consistently retained. Although increased intratumoral lymphocytes, inverted growth, pushing tumor-stromal interface, and lack of nuclear pleomorphism were more commonly seen in cases with mismatch repair protein loss, only intratumoral lymphocytes and presence of pushing borders were statistically significant. MLH1 and PMS2 testing appear to have little utility in upper tract urothelial carcinoma; however, mismatch repair protein loss of MSH2 and/or MSH6 by immunohistochemistry seems relatively sensitive and specific for identifying patients with potential Lynch syndrome.

Clinicopathological characteristics of patients with upper urinary tract urothelial cancer with loss of immunohistochemical expression of the DNA mismatch repair proteins in universal screening

“…The present study also showed combined MSH2/MSH6 loss in five patients. It is well known that the risk of UUTC is greater in individuals with MSH2/MSH6 loss (especially MSH2 germline mutations) than in those with other forms of MMR loss, which coincided perfectly with the present results …”

“…Therefore, putative LS‐associated UUTCs might be much more common than expected. In fact, a recent study has also reported that loss of MMR proteins was identified in 7% of all UUTCs . The present study also showed combined MSH2/MSH6 loss in five patients.…”

“…The average age for LS‐associated colorectal cancer is 45 years, or roughly 20–30 years younger than the average age of 72 years for colorectal cancer in the general population . In contrast, a recent case‐controlled study showed that patients with LS are diagnosed with UUTC several years younger than patients with sporadic onset are . It has been shown that LS patients develop UUTC approximately 15 years after developing other prior LS‐related forms of cancer .…”

“…In fact, low‐grade disease has been reported to be more frequent in hereditary UUTCs than in sporadic UUTCs . In contrast, there is another recent report that all UUTCs in patients with LS showed high‐grade morpholology, but these lacked significant pleomorphism and had pushing rather than destructive infiltrative growth . Therefore, its reproducible morphological tumor grade should be defined by further additional studies.…”

“…In other words, screening algorithms based on the revised Amsterdam criteria including age and personal/family cancer history would have failed to identify a significant proportion of LS‐associated UUTCs. In fact, 2.7% have been reported to show loss of MMR proteins in patients without a history of LS‐associated cancers . In addition, just 41% of LS‐related colorectal cancers with MMR gene mutations met the revised Amsterdam criteria .…”