Original ArticlesUtility of Nuclear Grading System in Epithelioid Malignant Pleural Mesothelioma in Biopsy-heavy Setting An External Validation Study of 563 CasesZhang, Yu Zhi MBBS, MSci*,†; Brambilla, Cecilia MD, FRCPath†; Molyneaux, Philip L. MBBS, PhD, FRCP‡,§; Rice, Alexandra MBChB, FRCPath†,‡; Robertus, Jan L. MD, PhD, FRCPath†,‡; Jordan, Simon MD, FRCS∥; Lim, Eric MD, FRCS‡,∥; Lang-Lazdunski, Loic MD, PhD, FRCS¶; Begum, Sofina MBChB, FRCS∥; Dusmet, Michael MD, FMH∥; Anikin, Vladimir MD, FRCS∥,#; Beddow, Emma MBBS, FRCS∥; Finch, Jonathan MBBS, FRCS∥; Asadi, Nizar MD, FRCS∥; Popat, Sanjay MBBS, PhD, FRCP‡,**; Cookson, William O.C. MD, PhD, FRCP, FMedSci*,‡; Moffatt, Miriam F. PhD, FMedSci*,‡; Nicholson, Andrew G. DM, FRCPath†,‡Author Information *National Centre for Mesothelioma Research, National Heart & Lung Institute ‡National Heart & Lung Institute, Imperial College London Departments of †Histopathology ∥Thoracic Surgery, Royal Brompton and Harefield NHS Foundation Trust §NIHR Respiratory Clinical Research Facility, Royal Brompton Hospital ¶Lung Centre, BUPA Cromwell Hospital **Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom #Department of Oncology and Reconstructive Surgery, I.M. Sechenov First Moscow State Medical University, Moscow, Russia Conflicts of Interest and Source of Funding: Supported by the National Centre for Mesothelioma Research, established via a Department of Health (United Kingdom) grant awarded to M.F.M. and W.O.C.C. Y.Z.Z. was supported by a clinical research fellowship from the National Centre for Mesothelioma Research. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Andrew G. Nicholson, DM, FRCPath, Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom (e-mail: email@example.com). Online date: December 3, 2019 The American Journal of Surgical Pathology: March 2020 - Volume 44 - Issue 3 - p 347-356 doi: 10.1097/PAS.0000000000001416 Buy SDC Metrics Abstract Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P<0.001 except 2-tier nuclear grade, P=0.001). In the scenario of a single- site biopsy with tissue dimension ≤10 mm, none but age (P=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum tissue dimension of at least 20 mm from a single site is optimal for nuclear grade assessment. In conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy cohort provided the tissue sample met minimum dimensional criteria. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.