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Nuclear Grade and Necrosis Predict Prognosis in Malignant

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Nuclear Grade and Necrosis Predict Prognosis in Malignant Modern Pathology (2018) 31, 598–606 598 © 2018 USCAP, Inc All rights reserved 0893-3952/18 $32.00 Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study Lauren E Rosen1, Theodore Karrison2, Vijayalakshmi Ananthanarayanan3, Alexander J Gallan1, Prasad S Adusumilli4, Fouad S Alchami5, Richard Attanoos6, Luka Brcic7, Kelly J Butnor8, Françoise Galateau-Sallé9, Kenzo Hiroshima10, Kyuichi Kadota11, Astero Klampatsa12, Nolween Le Stang9, Joerg Lindenmann13, Leslie A Litzky14, Alberto Marchevsky15, Filomena Medeiros16, M Angeles Montero17, David A Moore18, Kazuki Nabeshima19, Elizabeth N Pavlisko20, Victor L Roggli20, Jennifer L Sauter21, Anupama Sharma22, Michael Sheaff23, William D Travis21, Wickii T Vigneswaran24, Bart Vrugt25, Ann E Walts15, Melissa Y Tjota1, Thomas Krausz1 and Aliya N Husain1 1Department of Pathology, The University of Chicago Medicine, Chicago, IL, USA; 2Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA; 3Department of Pathology, Loyola University Medical Center, Chicago, IL, USA; 4Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK; 6Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, UK; 7Medical University of Graz, Institute of Pathology, Graz, Austria; 8Department of Pathology, University of Vermont Medical Center, Burlington, VT, USA; 9Centre Léon Bérard, BioPathologie, Lyon, France; 10Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan; 11Department of Diagnostic Pathology, Kagawa University, Takamatsu, Japan; 12Division of Pulmonary, Allergy and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 13Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Medical University of Graz, Graz, Austria; 14,Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 15Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 16Basildon & Thurrock University Hospital, Department of Pathology, Basildon, UK; 17Department of Histopathology, Royal Brompton and Harefield Hospitals Imperial College of London, London, UK; 18Department of Cancer Studies, University of Leicester, Leicester, UK; 19Fukuoka University, Department of Pathology, Fukuoka, Japan; 20Department of Pathology, Duke University Medical Center, Durham, NC, USA; 21Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 22Department of Pathology, University of Pittsburgh Medical Center and VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; 23Department of Pathology, Barts Health NHS Trust, London, UK; 24Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Chicago, IL, USA and 25University Hospital Zurich, Institute for Pathology and Molecular Pathology, Zurich, Switzerland A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I–III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases Correspondence: Dr AN Husain, MBBS, Department of Pathology, The University of Chicago, 5841 S. Maryland Avenue, MC6101, Chicago, IL 60637, USA. E-mail: [email protected] Received 20 July 2017; revised 15 October 2017; accepted 16 October 2017; published online 12 January 2018 www.modernpathology.org Prognosis in epithelioid pleural mesothelioma LE Rosen et al 599 were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P = 0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (o0.0001), and mitosis and necrosis score (o0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis–necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis–necrosis score is also proposed. Modern Pathology (2018) 31, 598–606; doi:10.1038/modpathol.2017.170; published online 12 January 2018 The most common primary malignant tumor of the approvals from each institution were obtained for pleura is malignant mesothelioma, which shows a this study. Clinical variables collected included age, strong association with asbestos exposure.1 Malig- sex, date of diagnosis, surgical procedure, T stage, N nant pleural mesotheliomas are aggressive tumors status, and date of death or last follow-up. Median with a median survival of 9–12 months despite overall survival was measured in months since multimodality therapy.1-4 Owing to the poor out- initial diagnosis. come, much effort has been made to define prog- Pathologic diagnosis was based on accepted nostic factors that accurately stratify patients for histologic and immunohistochemical criteria.8,9 His- therapy. It is well established that tumors with tologic features were evaluated by one pathologist for epithelioid histology have a more favorable prog- three institutions (University of Chicago, Duke nosis compared to sarcomatoid and biphasic University and Tokyo Women’s Medical University) types.2,3 Histology is the most important prognostic and independently by pathologists from the remain- variable that, together with TNM staging, forms the ing institutions. An average of three representative basis for treatment decisions.3,5 hematoxylin and eosin (H&E)-stained slides were A group from Memorial Sloan Kettering Cancer reviewed from each case (range 2–20). Nuclear Center sought to identify additional pathologic atypia and mitotic count were evaluated as described factors that predict prognosis in epithelioid malig- previously by Kadota et al.6 Nuclear features were nant pleural mesothelioma.6,7 In addition to histolo- evaluated at × 400. Mitoses were counted after gic subtyping, histologic grading was assessed in identifying the areas of highest mitotic activity as which seven nuclear features were evaluated, and an average of mitotic figures per 10 high power fields while five correlated with the length of overall (HPF) (Figure 1a). Tumors were divided into three survival, only two, nuclear atypia and mitotic count, groups based on the mitotic count: low 0 − 1/10 HPF, were found to be independent prognostic factors.6,7 intermediate 2 − 4/10 HPF, and high ≥ 5/10 HPF. The These two features were used to create a three-tier low, intermediate, and high groups were assigned nuclear grading system that proved itself an inde- mitotic count scores of 1, 2, and 3 respectively. pendent predictor of overall survival.6 The goals of Nuclear atypia was assessed in the area with the this study are (1) to validate the Memorial Sloan highest degree of atypia and was classified as mild Kettering Cancer Center nuclear grading system atypia—uniform small nuclei with inconspicuous using a large number of cases from multiple institu- nucleoli, moderate atypia—nuclei intermediate in tions, (2) to evaluate the prognostic significance of size with variability in shape and variably prominent additional histologic features including necrosis and nucleoli, and severe atypia—bizarre, enlarged growth pattern, and (3) to determine whether this nuclei, multinucleation, and macronucleoli in system is still valid when nuclear grading is 45% of tumor cells. Mild, moderate, and severe performed independently by pathologists from dif- atypia were given nuclear atypia scores of 1, 2, and 3, ferent institutions. respectively (Figure 2). A composite nuclear grade was assigned to each case upon addition of scores for nuclear atypia and mitotic count. Nuclear grade I Materials and methods was assigned to tumors with a score of 2 − 3, grade II for scores 4 − 5, and grade III for score 6. Clinical and pathologic data on patients diagnosed Necrosis was evaluated at 400 × and scored as with epithelioid malignant pleural mesothelioma present or absent (Figure 1b). A mitosis–necrosis between 1998 and 2014 was collected
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