No Evidence of Microsatellite Instability and Loss of Mismatch-Repair-Protein Expression in Squamous Cell Carcinoma of the Penis

Abstract

Objective: Microsatellite instability (MSI) and a defective mismatch repair (MMR) system were described as beneficial tumor features for response to immune checkpoint therapy (PD-1 blockade). Meanwhile, the FDA approved PD-1/PD-L1 inhibition treatment for any solid tumor showing MSI and/or defects in the MMR system. For squamous cell carcinoma (SCC) of the penis, no data on the frequency of MSI and altered MMR protein expression are available to date. Therefore, we investigated the MSI status and the expression of MMR proteins in a large cohort of penile SCCs. Methods: The MSI status of 105 archival formalin-fixed, paraffin-embedded penile SCCs was analyzed using the 5 markers of the NCI consensus panel for MIS testing (BAT25, 26, D2S123, D17S250, and D5S346), or, in cases without representative nontumorous tissue using a validated panel of 5 quasimonomorphic mononucleotide repeat markers (BAT 25, 26 and NR21, 24, 27). The expression of the MMR proteins MLH1, MSH2, MSH6, and PMS2 was analyzed using immunohistochemistry and a tissue microarray of a subset of penile SCCs from our cohort (n = 75). Results: Overall, in 96/105 cases, at least 4 microsatellite markers gave interpretable results. None of the cases showed MSI. Immunohistochemistry for MMR proteins was analyzable in 70/75 cases. All cases showed a regular expression of the MMR proteins. Conclusion: MSI and defects in MMR protein expression are not regular features of penile SCC and might not act as biomarkers for PD-1/PD-L1 blockade therapy in penile carcinoma.

Metastatic penile squamous cell carcinoma with dramatic response to combined checkpoint blockade with ipilimumab and nivolumab

“…19 Interestingly, presence of high TMB, MSIhigh, and dMMR is not frequently encountered in pSCC. 20,21 Our patient's tumor exhibited high PD-L1 expression, high TMB, MSI-high, and alterations in mismatch repair genes, which likely explains his great clinical response to checkpoint inhibitors.…”

Tislelizumab Combination With Chemotherapy Successfully Converted Unresectable Advanced Penile Cancer Into Complete Surgical Excision: a Case Report and Literature Review

“…Microsatellite instability high (MSI-H) is another valid marker of sensitivity to ICIs. Our case was microsatellite stable (MSS), the literature reports a low incidence of MSI-H in PSCC [9]. More interesting, patient's laboratory testing got human papillomavirus (HPV) 16 DNA.…”

Immunotherapy in Penile Squamous Cell Carcinoma: Present or Future? Multi-Target Analysis of Programmed Cell Death Ligand 1 Expression and Microsatellite Instability

“…So far, in addition to this study, only a report of data of the MSI status in penile SCC has been published ( 13 ). Stoehr et al analyzed the MSI status of 105 FFPE penile SCCs through PCR and the immunohistochemical expression of the MMR proteins.…”

“…Until present, few data on the frequency of MSI and altered MMR protein expression are available for PC ( 13 ). In this context, we investigated the PD-L1 expression and the dMMR/MSI-H status in a large cohort of PCs could provide a rationale for a new frontier in the treatment of PC patients based on the immune checkpoint inhibitors.…”