The mismatch repair system is not affected in medullary thyroid carcinoma independent of stromal desmoplasia or ret proto-oncogene mutation

Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine neoplasia of the thyroid with 10 year overall survival of 50% and limited therapeutic options. High tumor mutational burden because of microsatellite instability (MSI) seems to be a predictor of response to immune checkpoint inhibitor therapy in different tumors. Therefor in 2017 the U.S. Food and Drug Administration (FDA) permitted the therapy of solid tumors with proven Microsatellite instability (MSI) with PD1 antibody Pembrolizumab independently of their origin. As little is known about MSI in MTC and new therapeutic strategies would be eligible we tried to find out, if therapy with PD1-inhibitors could be promising. We performed MSI-analyses of 38 cases of MTC. Included were MTCs with and without stromal desmoplasia and with/without lymph node metastases. We also checked the immunhistochemical expression of PD-L-1 and performed next generation sequencing for genetic alterations. All cases revealed stable conditions of the microsatellites and showed immunohistochemically positive staining of the four mismatch repair proteins. PD-L-1- Immunostaining was negative in all cases. Our data show there is no MSI in MTCs, irrespectively of their status of desmoplasia, metastases and/or ret-mutation. Therefore a positive effect of PD1 inhibitors, because of MSI-associated high tumor mutational burden, seems to be unlikely. •PDL-1 expression is completely negative in MTC using PDL-1 antibody 22C3.•MTC widely express mismatch repair proteins MSH6, MSH2, MLH1 and PMS2.•No microsatellite instability can be detected independent of desmoplasia or mutations in ret or hras genes.•A positive effect of PD1 inhibitors because of MSI-associated high tumor mutational burden seems to be unlikely.