PMID- 29723687
OWN - NLM
STAT- MEDLINE
DCOM- 20190930
LR  - 20220408
IS  - 1556-1380 (Electronic)
IS  - 1556-0864 (Print)
IS  - 1556-0864 (Linking)
VI  - 13
IP  - 8
DP  - 2018 Aug
TI  - New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A 
      Multi-Institutional Evaluation by the International Mesothelioma Panel From the 
      MESOPATH Reference Center.
PG  - 1189-1203
LID - S1556-0864(18)30551-3 [pii]
LID - 10.1016/j.jtho.2018.04.023 [doi]
AB  - 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.
CI  - Copyright (c) 2018 International Association for the Study of Lung Cancer. All 
      rights reserved.
FAU - Galateau Salle, F
AU  - Galateau Salle F
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France. Electronic address: francoise.galateau@lyon.unicancer.fr.
FAU - Le Stang, N
AU  - Le Stang N
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France.
FAU - Nicholson, A G
AU  - Nicholson AG
AD  - Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust 
      and National Heart and Lung Institute, Imperial College, London, United Kingdom.
FAU - Pissaloux, D
AU  - Pissaloux D
AD  - Department of Pathology, British Columbia University, Vancouver, Canada.
FAU - Churg, A
AU  - Churg A
AD  - Department of Biopathology, Centre Leon Berard, and- INSERM U1052, Cancer 
      Research Center of Lyon, Lyon, France.
FAU - Klebe, S
AU  - Klebe S
AD  - Department of Anatomical Pathology, Flinders University, Adelaide, Australia.
FAU - Roggli, V L
AU  - Roggli VL
AD  - Department of Pathology, Duke University Medical Center, Durham, North Carolina.
FAU - Tazelaar, H D
AU  - Tazelaar HD
AD  - Mayo Clinic, Scottsdale, Arizona.
FAU - Vignaud, J M
AU  - Vignaud JM
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; CHU Nancy, INSERM U954, Universite de Lorraine, Nancy, France.
FAU - Attanoos, R
AU  - Attanoos R
AD  - Department of Cellular Pathology, University of Wales, Cardiff, United Kingdom.
FAU - Beasley, M B
AU  - Beasley MB
AD  - Department of Pathology, Mount- Sinai Medical Center, New York, New York.
FAU - Begueret, H
AU  - Begueret H
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; CHU Bordeaux, Department of Pathology, Hopital Haut Leveque, Bordeaux, 
      France.
FAU - Capron, F
AU  - Capron F
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; Department of Pathology, CHU Pitie Salpetriere Paris, Paris, France.
FAU - Chirieac, L
AU  - Chirieac L
AD  - Harvard Medical School, Boston, Massachusetts.
FAU - Copin, M C
AU  - Copin MC
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; Department of Pathology, CHRU-Hopital Calmette, Lille, France.
FAU - Dacic, S
AU  - Dacic S
AD  - FISH and Developmental Laboratory at the University of Pittsburgh Medical Center, 
      Pittsburgh, Pennsylvania.
FAU - Danel, C
AU  - Danel C
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; CHU Bichat, Departement de Pathologie, University Paris VII, Paris, 
      France.
FAU - Foulet-Roge, A
AU  - Foulet-Roge A
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; Department of Pathology, CH Le Mans, Le Mans, France.
FAU - Gibbs, A
AU  - Gibbs A
AD  - Department of Cellular Pathology, University of Wales, Cardiff, United Kingdom.
FAU - Giusiano-Courcambeck, S
AU  - Giusiano-Courcambeck S
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; CHU Hopital Nord, University AIX-Marseille, Marseille, France.
FAU - Hiroshima, K
AU  - Hiroshima K
AD  - Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
FAU - Hofman, V
AU  - Hofman V
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; CHU Nice, Department of Clinical and Experimental Pathology (LPCE), Nice, 
      France.
FAU - Husain, A N
AU  - Husain AN
AD  - Department of Pathology, University of Chicago, Chicago, Illinois.
FAU - Kerr, K
AU  - Kerr K
AD  - Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, Scotland.
FAU - Marchevsky, A
AU  - Marchevsky A
AD  - Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California.
FAU - Nabeshima, K
AU  - Nabeshima K
AD  - Department of Pathology, Fukuoka University School of Medicine and Hospital, 
      Fukuoka, Japan.
FAU - Picquenot, J M
AU  - Picquenot JM
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; Department of Pathology, Centre Henri Bequerel, Rouen, France.
FAU - Rouquette, I
AU  - Rouquette I
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; Department of Pathology, IUCT- Oncopole, Toulouse, France.
FAU - Sagan, C
AU  - Sagan C
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; CHU Nantes, INSERM U1087, l'institut du Thorax, Hopital Laennec CHU 
      Nantes, Nantes, France.
FAU - Sauter, J L
AU  - Sauter JL
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New 
      York.
FAU - Thivolet, F
AU  - Thivolet F
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France; Department of Pathology, Hospices Civils, Groupe Hospitalier EST, Lyon, 
      France.
FAU - Travis, W D
AU  - Travis WD
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New 
      York.
FAU - Tsao, M S
AU  - Tsao MS
AD  - Department of Pathology, University Health Network and Princess Margaret 
      Hospital, Toronto, Ontario, Canada.
FAU - Weynand, B
AU  - Weynand B
AD  - Department of Pathology, UZ Leuven, Belgium.
FAU - Damiola, F
AU  - Damiola F
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France.
FAU - Scherpereel, A
AU  - Scherpereel A
AD  - Pulmonary and Thoracic Oncology, Univ Lille, CHU Lille, INSERM U1019, CIIL, 
      Institut Pasteur de Lille, MESOCLIN, F59000 Lille, France.
FAU - Pairon, J C
AU  - Pairon JC
AD  - INSERM U955, equipe 4, UPEC, Faculte de medecine and CHI Creteil, Service de 
      Pathologies professionnelles et de l'Environnement, IST-PE,Creteil, France.
FAU - Lantuejoul, S
AU  - Lantuejoul S
AD  - MESOPATH, MESONAT, MESOBANK Department of BioPathology Centre Leon Berard, Lyon, 
      France.
FAU - Rusch, V
AU  - Rusch V
AD  - Memorial Sloan Kettering Cancer Center, Department of Thoracic Surgery, NY, USA.
FAU - Girard, N
AU  - Girard N
AD  - Department of Thoracic Oncology Institut Curie Paris, France and EURACAN.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
DEP - 20180430
PL  - United States
TA  - J Thorac Oncol
JT  - Journal of thoracic oncology : official publication of the International 
      Association for the Study of Lung Cancer
JID - 101274235
SB  - IM
CIN - J Thorac Oncol. 2020 Jun;15(6):884-887. PMID: 32471562
MH  - Aged
MH  - Biopsy
MH  - Female
MH  - Humans
MH  - Immunohistochemistry
MH  - Lung Neoplasms/*diagnosis/pathology
MH  - Male
MH  - Mesothelioma/*diagnosis/pathology
MH  - Mesothelioma, Malignant
MH  - Reproducibility of Results
PMC - PMC7558835
MID - NIHMS1633913
OTO - NOTNLM
OT  - BAP1
OT  - Biphasic mesothelioma
OT  - Grade
OT  - Interobservor agreement
OT  - Survival
OT  - p16 deletion
COIS- Disclosures: Drs. Churg, Klebe, Roggli, Attanoos, Beasley, Gibbs, Marchevsky, and 
      Travis have received personal fees from various legal offices for consultation 
      and/or being an expert witness regarding asbestos/mesothelioma litigation. Dr. 
      Dacic has received personal fees from Bristol-Myers Squibb and Astra Zeneca. Dr. 
      Rusch has received a grant from Genelux, Inc. The remaining authors declare no 
      conflict of interest.
EDAT- 2018/05/04 06:00
MHDA- 2019/10/01 06:00
PMCR- 2020/10/15
CRDT- 2018/05/04 06:00
PHST- 2018/01/25 00:00 [received]
PHST- 2018/03/28 00:00 [revised]
PHST- 2018/04/05 00:00 [accepted]
PHST- 2018/05/04 06:00 [pubmed]
PHST- 2019/10/01 06:00 [medline]
PHST- 2018/05/04 06:00 [entrez]
PHST- 2020/10/15 00:00 [pmc-release]
AID - S1556-0864(18)30551-3 [pii]
AID - 10.1016/j.jtho.2018.04.023 [doi]
PST - ppublish
SO  - J Thorac Oncol. 2018 Aug;13(8):1189-1203. doi: 10.1016/j.jtho.2018.04.023. Epub 
      2018 Apr 30.