A Combination of MTAP and p16 Immunohistochemistry Can Substitute for CDKN2A Fluorescence In Situ Hybridization in Diagnosis and Prognosis of Pleural Mesotheliomas

Arch Pathol Lab Med. 2022 Jun 23. doi: 10.5858/arpa.2021-0331-OA. Online ahead of print.

Abstract

Context.—: Homozygous deletion (HD) of CDKN2A is one of the most frequent genetic abnormalities in pleural mesotheliomas. HD of CDKN2A by fluorescence in situ hybridization (FISH) is a reliable marker of malignancy in mesothelial proliferations; however, evaluation of CDKN2A deletion requires FISH. The 9p21 locus includes both CDKN2A and MTAP (methylthioadenosine phosphorylase); the latter is frequently codeleted with CDKN2A.

Objective.—: To examine the question of whether immunohistochemistry for MTAP and p16, the protein product of CDKN2A, can serve as a surrogate for CDKN2A HD by FISH.

Design.—: A random selection of 125 pleural mesothelioma cases was divided into 3 groups for evaluation of p16 and MTAP expression compared with FISH for CDKN2A deletion: 53 HD, 39 with heterozygous deletion, and 33 without deletion.

Results.—: By itself, loss of p16 nuclear expression (<1% staining) showed a high sensitivity (96%) but low specificity (43%) for CDKN2A HD by FISH. MTAP cytoplasmic expression loss (≤30% staining) showed a 97% specificity and 69% sensitivity. The combination of p16 nuclear (<1% staining) and MTAP cytoplasmic (≤30% staining) loss demonstrated both high specificity (96%) and high sensitivity (86%). Patients with retained p16 expression (≥1%) had the best prognosis, whereas a p16 (<1%)/MTAP loss combination was associated with a dismal prognosis.

Conclusions.—: MTAP immunohistochemical staining is a valid surrogate marker for CDKN2A HD by FISH; however, to obtain the same accuracy as the FISH assay, a combination of nuclear p16 and cytoplasmic MTAP staining is recommended. These findings correlate with prognosis.