Original ArticlesHeterogeneity of PD-L1 Expression in Lung Mixed Adenocarcinomas and Adenosquamous CarcinomasZito Marino, Federica BD*; Rossi, Giulio MD†; Montella, Marco MD*; Botti, Gerardo MD‡; De Cecio, Rossella MD‡; Morabito, Alessandro MD§; La Manna, Carmine MD§; Ronchi, Andrea MD*; Micheli, Mariacarolina BD∥; Salatiello, Giuseppe BSc∥; Micheli, Pietro MD∥; Rocco, Danilo MD¶; Accardo, Marina MD*; Franco, Renato MD, PhD*Author Information *Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania “L. Vanvitelli” ‡Pathology Unit §Thoracic Department, National Cancer Institute, IRCCS—Fondazione G. Pascale ∥Pathology Unit ¶Pneumo-Oncology Unit, Monaldi Hospital Naples †Pathology Unit, S. Maria delle Croci Hospital, Ravenna, Italy Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Renato Franco, MD, PhD, Pathology Unit, Università degli Studi della Campania “Luigi Vanvitelli,” Via Luciano Armanni, 5, Napoli 80138, Italia (e-mail: email@example.com). Online date: October 29, 2019 The American Journal of Surgical Pathology: March 2020 - Volume 44 - Issue 3 - p 378-386 doi: 10.1097/PAS.0000000000001400 Buy Metrics Abstract Immune checkpoint inhibitors against programmed cell death protein 1/programmed death-ligand 1 (PD-L1) have proven to be remarkably effective in non–small cell lung cancer. PD-L1 represents a predictive biomarker in lung cancer, although its heterogenous expression represents an emerging challenge for accurate biomarker-based patient selection. Lung adenocarcinomas (ADCs) show a high rate of intratumor morphologic heterogeneity that may reflect a heterogenous molecular and immunophenotypic profile. The aim of our study was to analyze the expression of PD-L1 in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas (mADCs) and adenosquamous lung carcinomas (AdSqLCs). As many as 73 mADCs and 6 AdSqLCs were selected. Comprehensive histologic subtyping was performed, and PD-L1 expression was assessed by immunohistochemistry assay using different primary antibodies and automated immunostainers. Overall, PD-L1 expression was observed in 37 of 79 cases (39.2%) (31 mADCs and all AdSqLCs). PD-L1 expression was heterogenous in 22 of 37 PD-L1-positive cases (23.2% mADC and 83% AdSqLC). PD-L1 expression was observed more frequently in ADC with solid pattern. Heterogeneity of PD-L1 expression was significantly related to the presence of micropapillary (P=0.028) and solid (P=0.017) patterns. All PD-L1-positive cases were epidermal growth factor receptor wild-type, 2 cases harbored concomitantly PD-L1 expression and ALK rearrangement. Our data suggest that PD-L1 expression is quite heterogenous in mADCs and AdSqLCs, partly contributing to explaining the discrepant results between biopsy and surgical resections and discordant clinical effectiveness in regard to PD-L1-positive or negative ADC diagnosed on cytology/small biopsy. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.