F Galateau Salle1, N Le Stang2, A G Nicholson3, D Pissaloux4, A Churg5, S Klebe6, V L Roggli7, H D Tazelaar8, J M Vignaud9, R Attanoos10, M B Beasley11, H Begueret12, F Capron13, L Chirieac14, M C Copin15, S Dacic16, C Danel17, A Foulet-Roge18, A Gibbs10, S Giusiano-Courcambeck19, K Hiroshima20, V Hofman21, A N Husain22, K Kerr23, A Marchevsky24, K Nabeshima25, J M Picquenot26, I Rouquette27, C Sagan28, J L Sauter29, F Thivolet30, W D Travis29, M S Tsao31, B Weynand32, F Damiola2, A Scherpereel33, J C Pairon34, S Lantuejoul2, V Rusch35, N Girard36. 1. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. Electronic address: francoise.galateau@lyon.unicancer.fr. 2. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France. 3. Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College, London, United Kingdom. 4. Department of Pathology, British Columbia University, Vancouver, Canada. 5. Department of Biopathology, Centre Léon Bérard, and- INSERM U1052, Cancer Research Center of Lyon, Lyon, France. 6. Department of Anatomical Pathology, Flinders University, Adelaide, Australia. 7. Department of Pathology, Duke University Medical Center, Durham, North Carolina. 8. Mayo Clinic, Scottsdale, Arizona. 9. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nancy, INSERM U954, Université de Lorraine, Nancy, France. 10. Department of Cellular Pathology, University of Wales, Cardiff, United Kingdom. 11. Department of Pathology, Mount- Sinai Medical Center, New York, New York. 12. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bordeaux, Department of Pathology, Hopital Haut Leveque, Bordeaux, France. 13. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHU Pitié Salpétrière Paris, Paris, France. 14. Harvard Medical School, Boston, Massachusetts. 15. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CHRU-Hopital Calmette, Lille, France. 16. FISH and Developmental Laboratory at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 17. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Bichat, Departement de Pathologie, University Paris VII, Paris, France. 18. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, CH Le Mans, Le Mans, France. 19. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Hopital Nord, University AIX-Marseille, Marseille, France. 20. Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan. 21. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; CHU Nice, Department of Clinical and Experimental Pathology (LPCE), Nice, France. 22. Department of Pathology, University of Chicago, Chicago, Illinois. 23. Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, Scotland. 24. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California. 25. Department of Pathology, Fukuoka University School of Medicine and Hospital, Fukuoka, Japan. 26. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Centre Henri Bequerel, Rouen, France. 27. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, IUCT- Oncopôle, Toulouse, France. 28. 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. 29. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. 30. MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, France; Department of Pathology, Hospices Civils, Groupe Hospitalier EST, Lyon, France. 31. Department of Pathology, University Health Network and Princess Margaret Hospital, Toronto, Ontario, Canada. 32. Department of Pathology, UZ Leuven, Belgium. 33. Pulmonary and Thoracic Oncology, Univ Lille, CHU Lille, INSERM U1019, CIIL, Institut Pasteur de Lille, MESOCLIN, F59000 Lille, France. 34. INSERM U955, équipe 4, UPEC, Faculté de médecine and CHI Creteil, Service de Pathologies professionnelles et de l'Environnement, IST-PE,Creteil, France. 35. Memorial Sloan Kettering Cancer Center, Department of Thoracic Surgery, NY, USA. 36. Department of Thoracic Oncology Institut Curie Paris, France and EURACAN.
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.
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. HDCDKN2A(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 HDCDKN2A(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.
Authors: Harry C Hwang; Shawna Pyott; Stephanie Rodriguez; Ashlie Cindric; April Carr; Carmen Michelsen; Kim Thompson; Christopher H Tse; Allen M Gown; Andrew Churg Journal: Am J Surg Pathol Date: 2016-05 Impact factor: 6.394
Authors: Raphael Bueno; Eric W Stawiski; Leonard D Goldstein; Steffen Durinck; Assunta De Rienzo; Zora Modrusan; Florian Gnad; Thong T Nguyen; Bijay S Jaiswal; Lucian R Chirieac; Daniele Sciaranghella; Nhien Dao; Corinne E Gustafson; Kiara J Munir; Jason A Hackney; Amitabha Chaudhuri; Ravi Gupta; Joseph Guillory; Karen Toy; Connie Ha; Ying-Jiun Chen; Jeremy Stinson; Subhra Chaudhuri; Na Zhang; Thomas D Wu; David J Sugarbaker; Frederic J de Sauvage; William G Richards; Somasekar Seshagiri Journal: Nat Genet Date: 2016-02-29 Impact factor: 38.330
Authors: Aliya Noor Husain; Thomas V Colby; Nelson G Ordóñez; Timothy Craig Allen; Richard Luther Attanoos; Mary Beth Beasley; Kelly Jo Butnor; Lucian R Chirieac; Andrew M Churg; Sanja Dacic; Françoise Galateau-Sallé; Allen Gibbs; Allen M Gown; Thomas Krausz; Leslie Anne Litzky; Alberto Marchevsky; Andrew G Nicholson; Victor Louis Roggli; Anupama K Sharma; William D Travis; Ann E Walts; Mark R Wick Journal: Arch Pathol Lab Med Date: 2017-07-07 Impact factor: 5.534
Authors: Takashi Eguchi; Kyuichi Kadota; Marissa Mayor; Marjorie G Zauderer; Andreas Rimner; Valerie W Rusch; William D Travis; Michel Sadelain; Prasad S Adusumilli Journal: Oncotarget Date: 2017-09-12
Authors: Michele Carbone; Prasad S Adusumilli; H Richard Alexander; Paul Baas; Fabrizio Bardelli; Angela Bononi; Raphael Bueno; Emanuela Felley-Bosco; Francoise Galateau-Salle; David Jablons; Aaron S Mansfield; Michael Minaai; Marc de Perrot; Patricia Pesavento; Valerie Rusch; David T Severson; Emanuela Taioli; Anne Tsao; Gavitt Woodard; Haining Yang; Marjorie G Zauderer; Harvey I Pass Journal: CA Cancer J Clin Date: 2019-07-08 Impact factor: 508.702
Authors: Francoise Galateau Salle; Nolwenn Le Stang; Franck Tirode; Pierre Courtiol; Andrew G Nicholson; Ming-Sound Tsao; Henry D Tazelaar; Andrew Churg; Sanja Dacic; Victor Roggli; Daniel Pissaloux; Charles Maussion; Matahi Moarii; Mary Beth Beasley; Hugues Begueret; David B Chapel; Marie Christine Copin; Allen R Gibbs; Sonja Klebe; Sylvie Lantuejoul; Kazuki Nabeshima; Jean-Michel Vignaud; Richard Attanoos; Luka Brcic; Frederique Capron; Lucian R Chirieac; Francesca Damiola; Ruth Sequeiros; Aurélie Cazes; Diane Damotte; Armelle Foulet; Sophie Giusiano-Courcambeck; Kenzo Hiroshima; Veronique Hofman; Aliya N Husain; Keith Kerr; Alberto Marchevsky; Severine Paindavoine; Jean Michel Picquenot; Isabelle Rouquette; Christine Sagan; Jennifer Sauter; Francoise Thivolet; Marie Brevet; Philippe Rouvier; William D Travis; Gaetane Planchard; Birgit Weynand; Thomas Clozel; Gilles Wainrib; Lynnette Fernandez-Cuesta; Jean-Claude Pairon; Valerie Rusch; Nicolas Girard Journal: J Thorac Oncol Date: 2020-03-09 Impact factor: 15.609