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Mesothelioma: HELP
Articles by Sanja Dacic
Based on 18 articles published since 2010
(Why 18 articles?)
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Between 2010 and 2020, S. Dacic wrote the following 18 articles about Mesothelioma.
 
+ Citations + Abstracts
1 Guideline Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group. 2018

Husain, Aliya Noor / Colby, Thomas V / Ordóñez, Nelson G / Allen, Timothy Craig / Attanoos, Richard Luther / Beasley, Mary Beth / Butnor, Kelly Jo / Chirieac, Lucian R / Churg, Andrew M / Dacic, Sanja / Galateau-Sallé, Françoise / Gibbs, Allen / Gown, Allen M / Krausz, Thomas / Litzky, Leslie Anne / Marchevsky, Alberto / Nicholson, Andrew G / Roggli, Victor Louis / Sharma, Anupama K / Travis, William D / Walts, Ann E / Wick, Mark R. ·From the Department of Pathology, University of Chicago Medical Center, Chicago, Illinois (Drs Husain and Krausz) · the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona (Dr Colby, emeritus) · the Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston (Dr Ordóñez) · the Department of Pathology, University of Texas Medical Branch, Galveston (Dr Allen) · the Department of Cellular Pathology, University Hospital of Wales and Cardiff University, Cardiff, South Glamorgan, Wales (Dr Attanoos) · the Department of Pathology, Mount Sinai Medical Center, New York, New York (Dr Beasley) · the Department of Pathology, University of Vermont College of Medicine, Burlington (Dr Butnor) · the Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (Dr Chirieac) · the Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg) · the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic) · Centre National Référent MESOPATH Departement de Biopathologie, Lyon Cedex, France (Dr Galateau-Sallé) · the Department of Pathology, University Hospital of Wales, Penarth, South Glamorgan, Wales (Dr Gibbs) · the Department of Pathology, PhenoPath Laboratories, Seattle, Washington (Dr Gown) · the Department of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, (Dr Litzky) · the Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California (Drs Marchevsky and Walts) · the Department of Histopathology, Royal Brompton & Harefield National Health Service Foundation Trust and the National Heart and Lung Institute, Imperial College, Chelsea, London, England (Dr Nicholson) · the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Roggli) · the Department of Pathology, University of Pittsburgh, and the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (Dr Sharma) · the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Travis) · and the Department of Pathology, University of Virginia Medical Center, Charlottesville (Dr Wick). ·Arch Pathol Lab Med · Pubmed #28686500.

ABSTRACT: CONTEXT: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: - To provide updated, practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. CONCLUSIONS: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

2 Guideline Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group. 2013

Husain, Aliya N / Colby, Thomas / Ordonez, Nelson / Krausz, Thomas / Attanoos, Richard / Beasley, Mary Beth / Borczuk, Alain C / Butnor, Kelly / Cagle, Philip T / Chirieac, Lucian R / Churg, Andrew / Dacic, Sanja / Fraire, Armando / Galateau-Salle, Francoise / Gibbs, Allen / Gown, Allen / Hammar, Samuel / Litzky, Leslie / Marchevsky, Alberto M / Nicholson, Andrew G / Roggli, Victor / Travis, William D / Wick, Mark / Anonymous2710735. ·Department of Pathology, University of Chicago, Chicago, IL 60637, USA. aliya.husain@uchospitals.edu ·Arch Pathol Lab Med · Pubmed #22929121.

ABSTRACT: CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To provide updated practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS: There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

3 Review Recent Advances in the Diagnosis of Malignant Mesothelioma: Focus on Approach in Challenging Cases and in Limited Tissue and Cytologic Samples. 2018

Monaco, Sara / Mehrad, Mitra / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh, Pittsburgh, PA. · Department of Pathology, Vanderbilt University, Nashville, TN. ·Adv Anat Pathol · Pubmed #29227332.

ABSTRACT: Mesothelial proliferations can be diagnostically challenging in small specimens, such as body fluid cytology and small tissue biopsies. A great morphologic challenge for pathologists is the separation of benign reactive mesothelial proliferations from malignant mesotheliomas. Reactive mesothelial proliferations may have histologic features that resemble malignancy including increased cellularity, cytologic atypia, and mitoses. Recent advances in mesothelioma genetics resulted in identification of BAP1 mutations and p16 deletions as features of malignant mesotheliomas. Hence, BAP1 immunohistochemistry and fluorescence in situ hybridization for p16 emerged as 2 most common diagnostically helpful ancillary studies used on limited samples when the question is whether the proliferation is malignant or benign. In contrast, separation of mesothelioma from other malignancies is relatively straight forward using morphology and immunohistochemical stains. The choice of antibody panel to be applied in an individual case is driven by morphology, either epithelioid or sarcomatoid. This brief review will focus on morphology and ancillary testing of mainly pleural mesothelial proliferations.

4 Review The differential diagnosis between pleural sarcomatoid mesothelioma and spindle cell/pleomorphic (sarcomatoid) carcinomas of the lung: evidence-based guidelines from the International Mesothelioma Panel and the MESOPATH National Reference Center. 2017

Marchevsky, Alberto M / LeStang, Nolwenn / Hiroshima, Kenzo / Pelosi, Giuseppe / Attanoos, Richard / Churg, Andrew / Chirieac, Lucian / Dacic, Sanja / Husain, Aliya / Khoor, Andras / Klebe, Sonja / Lantuejoul, Silvie / Roggli, Victor / Vignaud, Jean-Michel / Weynard, Birgit / Sauter, Jennifer / Henderson, Douglas / Nabeshima, Kasuzi / Galateau-Salle, Francoise. ·Department of Pathology Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address: Alberto.Marchevsky@cshs.org. · Department of Pathology, MESOPATH-MESOBANK, Centre León Bérard, Lyon, France. · Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. · Interhospital Pathology Division, Università degli Studi di Milano and IRCCS MultiMedica Group, Milan, Italy. · Department of Pathology University of Wales and Cardiff University, Cardiff, U.K. · Department of Pathology, University of British Columbia, Vancouver, BC. · Department of Pathology, Brigham and Women's Hospital, Boston, MA. · Department of Pathology UPMC-PUH, Pittsburgh, PA. · Department of Pathology, Chicago University, Chicago, IL. · Department of Pathology, Mayo Clinic, Jacksonville, FL. · SA Pathology at Flinders Medical Cemtre, Bedord Park, SA. · Department of Pathology, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. · Department of Pathology Duke University, Durham, NC. · Department of Pathology, CHU de Nancy, Nancy, France. · University Hospital Leuven, Leuven, Belgium. · Department of Pathology Sloan Kettering Memorial Cancer Center, New York, NY. · Department of Pathology Fukuoka University Hospital, Fukuoka, Japan. ·Hum Pathol · Pubmed #28782639.

ABSTRACT: Immunohistochemistry is used to distinguish sarcomatoid malignant mesotheliomas (SMM) from spindle cell and pleomorphic carcinomas (SPC) but there are no guidelines on how to interpret cases that show overlapping or equivocal immunohistochemical findings. A systematic literature review of the immunophenotype of these lesions was performed and the experience with 587 SMM and 46 SPC at MESOPATH was collected. Data were analyzed with Comprehensive Meta-Analysis 2.0 software (Biostat, Englewood, NJ). There were insufficient data to evaluate the differential diagnosis between SPC and localized SMM or peritoneal SMM. Meta-analysis showed considerable overlap in the immunophenotype of these neoplasms and significant data heterogeneity amongst many of the results. Survival data from MESOPATH patients showed no significant differences in overall survival between SMM and SPC patients. Best available evidence was used to formulate several evidence-based guidelines for the differential diagnosis between pleural SMM and SPC. These guidelines emphasize the need to correlate the histopathological findings with clinical and imaging information. Diffuse SMM can be diagnosed with certainty in the presence of malignant spindle cell pleural lesions showing immunoreactivity for cytokeratin and mesothelial markers and negative staining for epithelial markers. Criteria for the interpretation of various other combinations of immunoreactivity for cytokeratin and mesothelial and/or epithelial markers are proposed. Localized sarcomatoid mesotheliomas can only be diagnosed in the presence of spindle cell malignancies that exhibit immunoreactivity for cytokeratin and mesothelial markers and negative immunoreactivity for epithelial lesions, in patients that show no multifocal or diffuse pleural spread and no evidence for extrapleural lesions.

5 Review Scientific Advances in Thoracic Oncology 2016. 2017

Soo, Ross A / Stone, Emily C A / Cummings, K Michael / Jett, James R / Field, John K / Groen, Harry J M / Mulshine, James L / Yatabe, Yasushi / Bubendorf, Lukas / Dacic, Sanja / Rami-Porta, Ramon / Detterbeck, Frank C / Lim, Eric / Asamura, Hisao / Donington, Jessica / Wakelee, Heather A / Wu, Yi-Long / Higgins, Kristin / Senan, Suresh / Solomon, Benjamin / Kim, Dong-Wan / Johnson, Melissa / Yang, James C H / Sequist, Lecia V / Shaw, Alice T / Ahn, Myung-Ju / Costa, Daniel B / Patel, Jyoti D / Horn, Leora / Gettinger, Scott / Peters, Solange / Wynes, Murry W / Faivre-Finn, Corinne / Rudin, Charles M / Tsao, Anne / Baas, Paul / Kelly, Ronan J / Leighl, Natasha B / Scagliotti, Giorgio V / Gandara, David R / Hirsch, Fred R / Spigel, David R. ·Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute of Singapore, Singapore; School of Surgery, University of Western Australia, Perth, Australia. · Department of Thoracic Medicine, St. Vincent's Hospital, Kinghorn Cancer Centre, Sydney, Australia. · Hollings Cancer Center Medical University of South Carolina, Charleston, South Carolina. · National Jewish Health, Denver, Colorado. · Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, The University of Liverpool, Liverpool, United Kingdom. · Department of Pulmonary Diseases, University Medical Center Groningen, Groningen, The Netherlands. · Internal Medicine, Graduate College, Rush University Medical Center, Chicago, Illinois. · Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan. · Institute of Pathology, University Hospital Basel, Basel, Switzerland. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Thoracic Surgery, Hospital Universitari Mutua Terrassa, University of Barcelona, Network of Biomedical Research Centers in Respiratory Diseases (CIBERES) Lung Cancer Group, Terrassa, Barcelona, Spain. · Department of Surgery, Yale University, New Haven, Connecticut. · Academic Division of Thoracic Surgery, The Royal Brompton Hospital and Imperial College, London, United Kingdom. · Division of Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan. · Cardiothoracic Surgery, New York University School of Medicine, New York, New York. · Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California. · Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. · Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. · Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands. · Department of Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia. · Seoul National University Hospital, Seoul, Republic of Korea. · Sarah Cannon Research Institute, Nashville, Tennessee. · Department of Oncology, National Taiwan University Hospital, Taipei, Republic of China. · Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. · Section of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea. · Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. · Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. · Division of Hematology/Oncology, Vanderbilt Ingram Cancer Center, Nashville, Tennessee. · Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. · Medical Oncology and Thoracic Malignancies, Oncology Department, University Hospital Center Vaudois, Lausanne, Switzerland. · International Association for the Study of Lung Cancer, Aurora, Colorado. · Radiotherapy Related Research, Division of Cancer Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital NHS Trust, Manchester, United Kingdom. · Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York. · Mesothelioma Program, Thoracic Chemo-Radiation Program, Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas. · Department of Chest Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. · Deptartment of Medical Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. · Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada. · San Luigi Hospital, University of Turin, Orbassano, Italy. · Thoracic Oncology Program, University of California Davis Comprehensive Cancer Center, Sacramento, California. · Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora. Electronic address: Fred.Hirsch@ucdenver.edu. ·J Thorac Oncol · Pubmed #28579481.

ABSTRACT: Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

6 Article Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center. 2020

Galateau Salle, Francoise / Le Stang, Nolwenn / Tirode, Franck / Courtiol, Pierre / Nicholson, Andrew G / Tsao, Ming-Sound / Tazelaar, Henry D / Churg, Andrew / Dacic, Sanja / Roggli, Victor / Pissaloux, Daniel / Maussion, Charles / Moarii, Matahi / Beasley, Mary Beth / Begueret, Hugues / Chapel, David B / Copin, Marie Christine / Gibbs, Allen R / Klebe, Sonja / Lantuejoul, Sylvie / Nabeshima, Kazuki / Vignaud, Jean-Michel / Attanoos, Richard / Brcic, Luka / Capron, Frederique / Chirieac, Lucian R / Damiola, Francesca / Sequeiros, Ruth / Cazes, Aurélie / Damotte, Diane / Foulet, Armelle / Giusiano-Courcambeck, Sophie / Hiroshima, Kenzo / Hofman, Veronique / Husain, Aliya N / Kerr, Keith / Marchevsky, Alberto / Paindavoine, Severine / Picquenot, Jean Michel / Rouquette, Isabelle / Sagan, Christine / Sauter, Jennifer / Thivolet, Francoise / Brevet, Marie / Rouvier, Philippe / Travis, William D / Planchard, Gaetane / Weynand, Birgit / Clozel, Thomas / Wainrib, Gilles / Fernandez-Cuesta, Lynnette / Pairon, Jean-Claude / Rusch, Valerie / Girard, Nicolas. ·MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. Electronic address: francoise.galateau@lyon.unicancer.fr. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. · University Claude Bernard Lyon, INSERM, CNRS, Research Cancer Center of Lyon, Centre Léon Bérard, Lyon, France. · OWKIN Paris, France. · Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom. · University Health Network, Princess Margaret Cancer Centre and University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada. · Mayo Clinic, Scottsdale, Arizona. · Columbia University and Department of Pathology Vancouver, Canada. · FISH and Developmental Laboratory at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Duke University Medical Center, Department of Pathology, Durham, North Carolina. · Department of BioPathology-FISH Laboratory, Centre Leon Berard Lyon, France. · Mount-Sinai Medical Center, Department of Pathology, New York, New York. · CHU Bordeaux, Haut Leveque Hospital, Department of Pathology, Bordeaux, France. · University of Chicago, Department of Pathology, Chicago, Illinois. · University. Lille-CHU, Department of Pathology, Lille, France. · University of Wales, Department of Cellular Pathology, Cardiff, United Kingdom. · Department of Anatomical Pathology, Flinders University, Adelaide, Australia. · Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan. · CHU Nancy, INSERM, University of Lorraine, Lorraine, France. · Department of Pathology, Graz, Austria. · CHU Pitié Salpétrière Paris, Department of Pathology, Paris, France. · Brigham and Women's Hospital, Boston, Massachusetts. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bichat Department of Pathology, University Paris VII, Paris, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Cochin-Hotel Dieu, Department of Pathology, Paris, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CH Le Mans, Department of Pathology, Pays de la Loire, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Hospital Nord, Marseille, University Aix-Marseille, Marseille, France. · Tokyo Women's Medical University, Department of Pathology, Tokyo, Japan. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Mayo Clinic, Scottsdale, Arizona; CHU Nice, Department of Clinical and Experimental Pathology (LPCE), Nice, France. · Aberdeen Royal Infirmary, Department of Pathology, Aberdeen, Scotland. · Scotland Cedars-Sinai Medical Center, Department of Pathology, Los Angeles, California. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Henri Becquerel Centre, Rouen, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; IUCT-Oncopôle, Department of Pathology, Toulouse, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nantes, INSERM, Thorax Institute, Hôpital Laënnec CHU Nantes, Nantes, France. · Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, New York. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Hospices Civils, East Hospital Group, Department of Pathology, Lyon, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHU Caen, Caen, France. · UZ Leuven, Department of Pathology, Leuven, Belgium. · Genetic Cancer Susceptibility Group International Agency for Research on Cancer World Health Organization, Lyon, France. · INSERM, UPEC, Faculty of Medicine and CHI Creteil, Professional Pathologies and Environment Department, IST-PE, Creteil, France. · Memorial Sloan Kettering Cancer Center, Department of Thoracic Surgery, New York, New York. · Department of Thoracic Oncology Institute Curie Paris, France and European Reference Network EURACAN, Centre Leon Berard, France. ·J Thorac Oncol · Pubmed #32165206.

ABSTRACT: INTRODUCTION: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort. METHODS: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors. RESULTS: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification. CONCLUSION: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.

7 Article Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens. 2020

Berg, Kyra B / Churg, Andrew M / Cheung, Simon / Dacic, Sanja. ·Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. ·Cancer Cytopathol · Pubmed #31821740.

ABSTRACT: BACKGROUND: The separation of benign from malignant mesothelial proliferations on effusion cytology can be difficult. Loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry is an established marker of malignancy in mesothelial proliferations, but to the authors' knowledge largely has been applied only to biopsies. The current study was conducted to determine the usefulness of MTAP immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens. METHODS: A total of 21 effusion cytology cases of malignant mesothelioma were stained for MTAP and BRCA-associated protein 1 (BAP1), with 15 reactive mesothelial cytology cases used as a control. Fourteen cases had a paired surgical specimen for comparison, and 7 cases were run for CDKN2A deletion by fluorescence in situ hybridization. RESULTS: Complete loss of MTAP cytoplasmic staining was noted in 7 of 21 effusion samples (33%), and no loss was observed in 11 effusion samples (52%); 11 of these cases had a matching surgical specimen and all 11 specimens demonstrated the same MTAP pattern. Partial loss was observed in 3 effusion specimens (80%, 40%, and 40% intact staining, respectively), but in all 3 the surgical specimen demonstrated 100% staining. None of the 15 reactive mesothelial cytology specimens demonstrated MTAP cytoplasmic loss. CDKN2A FISH demonstrated concordance in 5 of 7 cases (71%). MTAP immunohistochemistry had a sensitivity of 33% and a specificity of 100% for this differential diagnosis. CONCLUSIONS: MTAP staining demonstrated generally good concordance between the cytologic and surgical specimens and appears to be useful in the diagnosis of mesothelioma on effusion specimens. Complete loss of MTAP is a reliable marker of malignancy, but the significance of partial loss of MTAP staining is unclear.

8 Article EURACAN/IASLC Proposals for Updating the Histologic Classification of Pleural Mesothelioma: Towards a More Multidisciplinary Approach. 2020

Nicholson, Andrew G / Sauter, Jennifer L / Nowak, Anna K / Kindler, Hedy L / Gill, Ritu R / Remy-Jardin, Martine / Armato, Samuel G / Fernandez-Cuesta, Lynnette / Bueno, Raphael / Alcala, Nicolas / Foll, Matthieu / Pass, Harvey / Attanoos, Richard / Baas, Paul / Beasley, Mary Beth / Brcic, Luka / Butnor, Kelly J / Chirieac, Lucian R / Churg, Andrew / Courtiol, Pierre / Dacic, Sanja / De Perrot, Marc / Frauenfelder, Thomas / Gibbs, Allen / Hirsch, Fred R / Hiroshima, Kenzo / Husain, Aliya / Klebe, Sonja / Lantuejoul, Sylvie / Moreira, Andre / Opitz, Isabelle / Perol, Maurice / Roden, Anja / Roggli, Victor / Scherpereel, Arnaud / Tirode, Frank / Tazelaar, Henry / Travis, William D / Tsao, Ming-Sound / van Schil, Paul / Vignaud, Jean Michel / Weynand, Birgit / Lang-Lazdunski, Loic / Cree, Ian / Rusch, Valerie W / Girard, Nicolas / Galateau-Salle, Francoise. ·Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom. Electronic address: a.nicholson@rbht.nhs.uk. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Medical School, University of Western Australia, Perth, Australia. · Section of Hematology/Oncology, Department of Medicine, University of Chicago Medicine, Chicago, Illinois. · Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massacheusetts. · Department of Thoracic Imaging, Hospital Calmette, University Centre of Lille, France. · Department of Radiology, The University of Chicago, Chicago, Illinois. · Section of Genetics, International Agency for Research on Cancer (IARC/WHO), Lyon, France. · Division of Thoracic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Cardiothoracic Surgery, NYU Langone Health, New York, New York. · Department of Cellular Pathology, University Hospital of Wales, School of Medicine, Cardiff University, United Kingdom. · Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. · Department of Pathology, Mount Sinai Medical Center, New York, New York. · Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria. · Department of Pathology & Laboratory Medicine, The University of Vermont Medical Center, Burlington, Vermont. · Department of Pathology, Brigham and Women's Hospital, Boston, Massacheusetts. · Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Owkin Inc., Paris, France. · Department of Pathology University of Pittsburgh Medical Center, Pennsylvania. · Division of Thoracic Surgery, Princess Margaret Cancer Centre, Toronto, Canada. · Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland. · Department of Cellular Pathology, Cardiff and Vale UHB, Cardiff, Wales, United Kingdom. · Center for Thoracic Oncology, Mount Sinai Health System, New York, New York. · Department of Pathology, Tokyo Women's Medical University, Yachiyo Medical Center, Tokyo, Japan. · Department of Pathology, University of Chicago, Chicago, Illinois. · Department of Anatomical Pathology, SA Pathology and Flinders University, Adelaide, Australia. · Department of Biopathology and of Translational Research and Innovation, CNR MESOPATH, Centre Leon Berard Lyon, and Grenoble Alpes University, France. · Department of Pathology, New York University Langone Health, New York, New York. · Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Pathology, Duke University Medical Center, Durham, North Carolina. · Pulmonary and Thoracic Oncology Department, University Lille, CHU Lille, France. · Université Lyon, Centre Léon Bérard, Cancer Research Center of Lyon, France. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona. · Department of Pathology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada. · Department of Thoracic and Vascular Surgery, Antwerp University Hospital and Antwerp University, Belgium. · CHU Nancy, Université Lorraine, Nancy, France. · Department of Pathology, UZ Leuven, Leuven, Belgium. · Cromwell Hospital, London, United Kingdom. · International Agency for Research on Cancer (IARC), Lyon, France. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Institut Curie, Institut du Thorax Curie Montsouris, Paris, France. · MESOPATH Centre Leon Berard, Lyon, France. ·J Thorac Oncol · Pubmed #31546041.

ABSTRACT: INTRODUCTION: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes. METHODS: A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification. RESULTS: Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome. CONCLUSIONS: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.

9 Article Integrative Molecular Characterization of Malignant Pleural Mesothelioma. 2018

Hmeljak, Julija / Sanchez-Vega, Francisco / Hoadley, Katherine A / Shih, Juliann / Stewart, Chip / Heiman, David / Tarpey, Patrick / Danilova, Ludmila / Drill, Esther / Gibb, Ewan A / Bowlby, Reanne / Kanchi, Rupa / Osmanbeyoglu, Hatice U / Sekido, Yoshitaka / Takeshita, Jumpei / Newton, Yulia / Graim, Kiley / Gupta, Manaswi / Gay, Carl M / Diao, Lixia / Gibbs, David L / Thorsson, Vesteinn / Iype, Lisa / Kantheti, Havish / Severson, David T / Ravegnini, Gloria / Desmeules, Patrice / Jungbluth, Achim A / Travis, William D / Dacic, Sanja / Chirieac, Lucian R / Galateau-Sallé, Françoise / Fujimoto, Junya / Husain, Aliya N / Silveira, Henrique C / Rusch, Valerie W / Rintoul, Robert C / Pass, Harvey / Kindler, Hedy / Zauderer, Marjorie G / Kwiatkowski, David J / Bueno, Raphael / Tsao, Anne S / Creaney, Jenette / Lichtenberg, Tara / Leraas, Kristen / Bowen, Jay / Anonymous6511115 / Felau, Ina / Zenklusen, Jean Claude / Akbani, Rehan / Cherniack, Andrew D / Byers, Lauren A / Noble, Michael S / Fletcher, Jonathan A / Robertson, A Gordon / Shen, Ronglai / Aburatani, Hiroyuki / Robinson, Bruce W / Campbell, Peter / Ladanyi, Marc. ·Department of Pathology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. · Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts. · Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · GenomeDx Biosciences, Vancouver, British Columbia, Canada. · Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Computational Systems Biology, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan. · Genome Science Division, The University of Tokyo, Tokyo, Japan. · Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, California. · Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Institute for Systems Biology, Seattle, Washington. · The University of Texas at Dallas, Richardson, Texas. · Division of Thoracic Surgery, The Lung Center and International Mesothelioma Program, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. · Department of Pathology, Quebec Heart and Lung Institute, Quebec, Canada. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. · MESOPATH. Cancer Center Leon Berard, Lyon, France. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, University of Chicago, Chicago, Illinois. · Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Oncology, University of Cambridge, Cambridge, UK. · Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, New York. · Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Pulmonary Medicine, Brigham and Women's Hospital, Boston, Massachusetts. · School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia. · The Research Institute at Nationwide Children's Hospital, Columbus, Ohio. · National Cancer Institute, Bethesda, Maryland. · Department of Pathology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. ladanyim@mskcc.org. ·Cancer Discov · Pubmed #30322867.

ABSTRACT: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of

10 Article Utility of Methylthioadenosine Phosphorylase Compared With BAP1 Immunohistochemistry, and CDKN2A and NF2 Fluorescence In Situ Hybridization in Separating Reactive Mesothelial Proliferations From Epithelioid Malignant Mesotheliomas. 2018

Berg, Kyra B / Dacic, Sanja / Miller, Caitlyn / Cheung, Simon / Churg, Andrew. ·From the Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada (Dr Berg) · the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic and Ms Miller) · and the Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada (Dr Churg and Mr Cheung). ·Arch Pathol Lab Med · Pubmed #30059257.

ABSTRACT: CONTEXT.—: The separation of reactive from malignant mesothelial proliferations is often a difficult morphologic problem. There is contradictory information in the literature on whether methylthioadenosine phosphorylase (MTAP) immunohistochemistry can be used for this purpose. OBJECTIVE.—: To determine the utility of MTAP immunohistochemistry in distinguishing reactive from malignant mesothelial proliferations. DESIGN.—: We stained a tissue microarray containing 20 epithelioid malignant mesotheliomas and 17 reactive mesothelial proliferations. For the mesotheliomas, comparisons were made between MTAP staining and BRCA-associated nuclear protein 1 (BAP1) immunohistochemistry, cyclin-dependent kinase inhibitor 2A ( CDKN2A) fluorescence in situ hybridization, and neurofibromin 2 ( NF2) fluorescence in situ hybridization, which are established techniques for making this separation. RESULTS.—: Loss of MTAP was seen in 0 of 17 reactive mesothelial proliferations and 13/20 (65%) malignant mesotheliomas. Almost all cases with loss showed loss in 100% of mesothelial cells. Background inflammatory and stromal cells served as a positive internal control. CDKN2A fluorescence in situ hybridization on the mesotheliomas showed concordance with MTAP staining in 14 of 17 evaluable cases. BAP1 immunohistochemistry showed loss of nuclear staining in 11 of 20 mesotheliomas (55%). No cases showed loss of NF2. A total of 18 of 20 mesotheliomas (90%) showed loss of either MTAP or BAP1. CONCLUSIONS.—: In the context of a mesothelial proliferation, loss of MTAP staining is 100% specific for malignant mesothelioma. In this study the combination of MTAP and BAP1 immunohistochemical staining allowed separation of reactive from epithelial malignant mesothelial proliferations in 90% of cases.

11 Article New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center. 2018

Galateau Salle, F / Le Stang, N / Nicholson, A G / Pissaloux, D / Churg, A / Klebe, S / Roggli, V L / Tazelaar, H D / Vignaud, J M / Attanoos, R / Beasley, M B / Begueret, H / Capron, F / Chirieac, L / Copin, M C / Dacic, S / Danel, C / Foulet-Roge, A / Gibbs, A / Giusiano-Courcambeck, S / Hiroshima, K / Hofman, V / Husain, A N / Kerr, K / Marchevsky, A / Nabeshima, K / Picquenot, J M / Rouquette, I / Sagan, C / Sauter, J L / Thivolet, F / Travis, W D / Tsao, M S / Weynand, B / Damiola, F / Scherpereel, A / Pairon, J C / Lantuejoul, S / Rusch, V / Girard, N. ·MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. Electronic address: francoise.galateau@lyon.unicancer.fr. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. · Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom. · Department of Pathology, British Columbia University, Vancouver, Canada. · Department of Biopathology, Centre Léon Bérard, and- INSERM U1052, Cancer Research Center of Lyon, Lyon, France. · Department of Anatomical Pathology, Flinders University, Adelaide, Australia. · Department of Pathology, Duke University Medical Center, Durham, North Carolina. · Mayo Clinic, Scottsdale, Arizona. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nancy, INSERM U954, Université de Lorraine, Nancy, France. · Department of Cellular Pathology, University of Wales, Cardiff, United Kingdom. · Department of Pathology, Mount- Sinai Medical Center, New York, New York. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bordeaux, Department of Pathology, Hopital Haut Leveque, Bordeaux, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHU Pitié Salpétrière Paris, Paris, France. · Harvard Medical School, Boston, Massachusetts. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHRU-Hopital Calmette, Lille, France. · FISH and Developmental Laboratory at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bichat, Departement de Pathologie, University Paris VII, Paris, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CH Le Mans, Le Mans, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Hopital Nord, University AIX-Marseille, Marseille, France. · Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nice, Department of Clinical and Experimental Pathology (LPCE), Nice, France. · Department of Pathology, University of Chicago, Chicago, Illinois. · Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, Scotland. · Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California. · Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Centre Henri Bequerel, Rouen, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, IUCT- Oncopôle, Toulouse, France. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nantes, INSERM U1087, l'institut du Thorax, Hôpital Laënnec CHU Nantes, Nantes, France. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Hospices Civils, Groupe Hospitalier EST, Lyon, France. · Department of Pathology, University Health Network and Princess Margaret Hospital, Toronto, Ontario, Canada. · Department of Pathology, UZ Leuven, Belgium. · Pulmonary and Thoracic Oncology, Univ Lille, CHU Lille, INSERM U1019, CIIL, Institut Pasteur de Lille, MESOCLIN, F59000 Lille, France. · INSERM U955, équipe 4, UPEC, Faculté de médecine and CHI Creteil, Service de Pathologies professionnelles et de l'Environnement, IST-PE,Creteil, France. · Memorial Sloan Kettering Cancer Center, Department of Thoracic Surgery, NY, USA. · Department of Thoracic Oncology Institut Curie Paris, France and EURACAN. ·J Thorac Oncol · Pubmed #29723687.

ABSTRACT: INTRODUCTION: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components. METHODS: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis. RESULTS: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02). CONCLUSIONS: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator.

12 Article Malignant mesothelioma in situ. 2018

Churg, Andrew / Hwang, Harry / Tan, Larry / Qing, Gefei / Taher, Altaf / Tong, Amy / Bilawich, Ana M / Dacic, Sanja. ·Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada. · PhenoPath Laboratories, Seattle, WA, USA. · Division of Thoracic Surgery, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. · Department of Pathology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. · Department of Pathology, Memorial University of Newfoundland, St John's, NF, Canada. · Department of Medicine, Memorial University of Newfoundland, St John's, NF, Canada. · Department of Radiology, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Histopathology · Pubmed #29350783.

ABSTRACT: AIMS: The existence of malignant mesothelioma in situ (MIS) is often postulated, but there are no accepted morphological criteria for making such a diagnosis. METHODS AND RESULTS: Here we report two cases that appear to be true MIS on the basis of in-situ genomic analysis. In one case the patient had repeated unexplained pleural unilateral effusions. Two thoracoscopies 9 months apart revealed only visually normal pleura. Biopsies from both thoracoscopies showed only a single layer of mildly reactive mesothelial cells. However, these cells had lost BRCA1-associated protein 1 (BAP1) and showed loss of cyclin-dependent kinase inhibitor 2 (CDKN2A) (p16) by fluorescence in-situ hybridisation (FISH). NF2 was not deleted by FISH but 28% of the mesothelial cells showed hyperploidy. Six months after the second biopsy the patient has persisting effusions but no evidence of pleural malignancy on imaging. The second patient presented with ascites and minimal omental thickening on imaging, but no visual evidence of tumour at laparoscopy. Omental biopsy showed a single layer of minimally atypical mesothelial cells with rare tiny foci of superficial invasion of fat. BAP1 immunostain showed loss of nuclear BAP1 in all the surface mesothelial cells and the invasive cells. There was CDKN2A deletion, but no deletion of NF2 by FISH. CONCLUSIONS: These cases show that morphologically bland single-layered surface mesothelial proliferations with molecular alterations seen previously only in invasive malignant mesotheliomas exist, and presumably represent malignant MIS. More cases are need to understand the frequency of such changes and the time-course over which invasive tumour develops.

13 Article Reproducibility for histologic parameters in peritoneal mesothelioma. 2017

Hartman, Douglas J / Borczuk, Alain / Dacic, Sanja / Krasinskas, Alyssa. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213. Electronic address: hartmandj@upmc.edu. · Department of Pathology, Weill Cornell Medical College, New York, NY 10021. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213. · Department of Pathology, Emory University, Atlanta, GA 30322. ·Hum Pathol · Pubmed #28712777.

ABSTRACT: Histologic subtype is recognized as a prognostic factor in malignant pleural mesothelioma. Specifically, epithelial morphology is associated with a better prognosis than other subtypes, and the same association is observed in peritoneal malignant mesothelioma. Recently, prognostic differences based on morphologic subtypes of epithelial peritoneal malignant mesothelioma were reported. Herein, we report the interobserver variability across four pathologists at three institutions. The authors independently reviewed 67 cases of malignant peritoneal epithelioid mesotheliomas and subclassified them according to their epithelial subtype: papillary, tubulopapillary, trabecular, micropapillary, solid and/or pleomorphic. The cases were also evaluated by each author for several other histopathologic parameters including depth of invasion, nuclear grade, lymphocytic host response, mitotic count/index, presence of lymphovascular invasion, and stromal desmoplasia. The interobserver agreement for histopathologic parameters was highest for mitotic rate (κ=0.36) and primary epithelial subtype (κ=0.32). The interobserver variability for solid subtype pattern was moderate (κ=0.49). We found that the interobserver variability for most histopathologic parameters is poor.

14 Article The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. 2016

Singhi, Aatur D / Krasinskas, Alyssa M / Choudry, Haroon A / Bartlett, David L / Pingpank, James F / Zeh, Herbert J / Luvison, Alyssa / Fuhrer, Kimberly / Bahary, Nathan / Seethala, Raja R / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. · Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Mod Pathol · Pubmed #26493618.

ABSTRACT: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n=25, 29%), hemizygous NF2 loss (n=30, 35%), and/or loss of BAP1 protein expression (n=49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progression-free survival (P<0.02) and poor overall survival (P<0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (P<0.01) and overall survival rate of 18% with a median of 8 months (P<0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

15 Article Prognostic significance of morphological growth patterns and mitotic index of epithelioid malignant peritoneal mesothelioma. 2016

Krasinskas, Alyssa M / Borczuk, Alain C / Hartman, Douglas J / Chabot, John A / Taub, Robert N / Mogal, Ashish / Pingpank, James / Bartlett, David / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. · Department of Pathology and Cell Biology, Columbia Presbyterian, College of Physicians and Surgeons, New York, NY, USA. · Department of Surgery, Columbia Presbyterian, College of Physicians and Surgeons, New York, NY, USA. · Department of Oncology, Columbia Presbyterian, College of Physicians and Surgeons, New York, NY, USA. · Department of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Histopathology · Pubmed #26272336.

ABSTRACT: AIMS: The prognostic significance of histological subtyping of epithelioid pleural mesotheliomas has been recently reported, but similar data are lacking for peritoneal mesotheliomas. The aim of this study was to investigate possible relationships between histological growth patterns of epithelioid peritoneal mesotheliomas, clinicopathological features, and patient outcome. METHODS AND RESULTS: Eighty-four cases of chemotherapy-naive epithelioid peritoneal mesothelioma were classified into tubulopapillary, micropapillary, papillary, tubular, solid and trabecular growth patterns. Pathological features such as depth of invasion, lymphocytic host response, mitotic count, nuclear grade, lymphovascular invasion, lymph node metastasis and stromal desmoplasia were analysed. The most common histological patterns were solid (n = 37, 44%), tubulopapillary (n = 24, 29%), and micropapillary (n = 11, 13%). The overall median survival was 36 months. Patients with solid mesothelioma had shorter overall survival (median, 29 months) than patients with tubulopapillary and micropapillary growth patterns (median, 51 and 53 months, respectively; P = 0.053). A high mitotic index (>5 in 50 high-power fields) was found to be associated with poor survival (P < 0.03). A moderate to severe lymphocytic host response was associated with longer median survival (P = 0.13). CONCLUSIONS: Our study highlights the prognostic importance of the solid growth pattern among diffuse epithelioid peritoneal mesotheliomas, and reaffirms mitotic index as a predictor of overall survival.

16 Article p16 Deletion in sarcomatoid tumors of the lung and pleura. 2013

Tochigi, Naobumi / Attanoos, Richard / Chirieac, Lucian R / Allen, Timothy Craig / Cagle, Philip T / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. ·Arch Pathol Lab Med · Pubmed #23627453.

ABSTRACT: CONTEXT: The diagnosis of sarcomatoid neoplasms of the lung and pleura can be challenging. Homozygous deletion of 9p21, the locus harboring the p16 gene, has been reported as the most common genetic alteration in malignant mesotheliomas that is of potential diagnostic and prognostic significance. OBJECTIVES: To evaluate the frequency of 9p21 deletion by fluorescence in situ hybridization in the primary sarcomatoid neoplasms of the lung and pleura and to determine its potential diagnostic utility. DESIGN: Ninety-two sarcomatoid neoplasms of the lung and pleura (32 sarcomatoid mesotheliomas, 15 sarcomatoid carcinomas, 32 solitary fibrous tumors, and 13 high-grade sarcomas) were examined for 9p21 deletion by fluorescence in situ hybridization. RESULTS: Deletion of 9p21 was most frequently seen in malignant mesotheliomas (81%), followed by sarcomatoid carcinomas (53%), sarcomas (25%), and solitary fibrous tumors (12.5%). Malignant mesotheliomas showed mostly homozygous deletion, whereas sarcomatoid carcinomas showed either homozygous or hemizygous deletion. None of the sarcomas showed homozygous deletion. There was a trend toward more frequent occurrence of 9p21 deletion in recurrent solitary fibrous tumors, but this did not reach statistical difference. CONCLUSIONS: Deletion of 9p21 is common in sarcomatoid tumors of the lung and pleura. Despite statistically significant differences in the frequency of 9p21 deletion, and because of the large overlap among the study groups, this genetic abnormality cannot be used as a reliable diagnostic tool in the assessment of sarcomatoid lesions of the lung and pleura. A potential use of p16 deletion in predicting the biology of solitary fibrous tumors should be further explored.

17 Article The diagnostic utility of p16 FISH and GLUT-1 immunohistochemical analysis in mesothelial proliferations. 2011

Monaco, Sara E / Shuai, Yongli / Bansal, Mona / Krasinskas, Alyssa M / Dacic, Sanja. ·Dept of Pathology, University of Pittsburgh Medical Center, PA 15232, USA. ·Am J Clin Pathol · Pubmed #21411785.

ABSTRACT: Two promising ancillary tests used in the diagnosis of mesothelioma include GLUT-1 immunohistochemical analysis and fluorescence in situ hybridization (FISH) testing for the p16 deletion. This study compared the diagnostic usefulness of p16 FISH and GLUT-1 immunohistochemical analysis in the diagnosis of mesothelial proliferations in 158 cases with a diagnosis of benign (45.4%), atypical (10.4%), or malignant/mesothelioma (44.2%). Of the 70 benign cases, none had a deletion of p16 and 5 cases (7%) were positive for GLUT-1. Of the 68 mesotheliomas, 40 (59%) had a deletion of p16 (sensitivity, 59%; specificity, 100%) and 27 (40%) were positive for GLUT-1 (sensitivity, 40%; specificity, 93%). GLUT-1 showed lower sensitivity in pleural (56% vs 70%) and peritoneal (29% vs 51%) mesotheliomas (P = .004). Our results demonstrate that p16 FISH is a more sensitive and specific test than GLUT-1 immunohistochemical analysis and can be a more reliable ancillary tool to support the diagnosis of mesothelioma.

18 Article CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival. 2010

Krasinskas, Alyssa M / Bartlett, David L / Cieply, Kathleen / Dacic, Sanja. ·Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2546, USA. krasinskasam@upmc.edu ·Mod Pathol · Pubmed #20081810.

ABSTRACT: Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases. MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of CDKN2A deleted cases. This study examines the genetic alterations in peritoneal mesotheliomas, which may have a different pathogenesis than their pleural counterparts. Twenty-six cases of peritoneal mesotheliomas in a triplicate tissue microarray were studied. Dual-color fluorescence in situ hybridization was performed with CDKN2A and MTAP locus-specific probes. Nine of 26 (35%) peritoneal mesotheliomas had homozygous deletion of CDKN2A; MTAP was co-deleted in every case. All cases with CDKN2A deletions had loss of p16 protein expression; five cases had loss of p16 protein without evidence of CDKN2A deletions. All patients with CDKN2A deletions were men (P, NS) and were significantly older (mean, 63 years) than the patients with no deletions (mean, 52 years) (P=0.033, t-test). An association with asbestos exposure could not be proved in this study. Similar to pleural mesotheliomas, patients with CDKN2A deletions and loss of p16 protein expression had worse overall and disease-specific survival (P=0.010 and 0.006, respectively; Kaplan-Meier log rank). Detection of CDKN2A-MTAP co-deletion in peritoneal mesotheliomas, coupled with a p16 immunohistochemical stain as an inexpensive screening tool, can help identify those patients who may have an unfavorable outcome after aggressive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and those who may respond to targeted therapy of the MTAP pathway.