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

Our plain-English summary of New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center, by F. Galateau Salle, N. Le Stang, A.G. Nicholson, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: F. Galateau Salle, N. Le Stang, A.G. Nicholson, D. Pissaloux, A. Churg, S. Klebe, V.L. Roggli, H.D. Tazelaar, J.M. Vignaud, R. Attanoos, M.B. Beasley, H. Begueret, F. Capron, L. Chirieac, M.C. Copin, S. Dacic, C. Danel, A. Foulet-Roge, A. Gibbs, S. Giusiano-Courcambeck, K. Hiroshima, V. Hofman, A.N. Husain, K. Kerr, A. Marchevsky, K. Nabeshima, J.M. Picquenot, I. Rouquette, C. Sagan, J.L. Sauter, F. Thivolet, W.D. Travis, M.S. Tsao, B. Weynand, F. Damiola, A. Scherpereel, J.C. Pairon, S. Lantuejoul, V. Rusch, N. Girard
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(8):1189-1203
• Cited by: 76 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.

In plain English

This study by the French mesothelioma reference center MESOPATH and an international panel tested how consistently expert pathologists diagnose biphasic mesothelioma, which has both epithelioid and sarcomatoid (spindle-cell) parts. Fourteen experts reviewed scanned slides from 42 biopsies randomly chosen from 971 biphasic cases collected from 1998 to 2016, giving 544 diagnoses. Patients averaged 76 years; 90% were male and 71% had an asbestos exposure history. Agreement was moderate (weighted kappa 0.45). Reviewers called the tumors biphasic in 385 of 544 opinions, epithelioid in 93 and sarcomatoid in 66. Median survival was 8 months. At least 7 of 14 reviewers saw a "transitional" pattern in some cases. Those cases had a median survival of 6 months, against 12 months without the pattern. In a multivariate analysis the pattern's hazard ratio was 3.2 (95% CI 1.6 to 8.0 in the text, 1.3 to 8.0 in Table 3). A FISH test found homozygous CDKN2A (p16) deletion, meaning no copy of the gene, in 5 of 8 low-grade spindle-cell components of biphasic cases. The authors concluded their results further validate the transitional pattern as a poor prognostic indicator. They noted that few FISH tests were done.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multi-institutional interobserver agreement study: 14 expert pathologists independently reviewed scanned slides of previously diagnosed cases. Survival analysis and BAP1 and CDKN2A (p16) testing were added.
• Who was studied: 42 surgical biopsy samples diagnosed as biphasic mesothelioma by the French MESOPATH expert panel. They were randomly selected from 971 biphasic cases (plus 5219 epithelioid and 465 sarcomatoid) collected in France from January 1998 to June 2016. Patients had a mean age of 76 and 90% were male.
• Exposure: The study did not examine an exposure. It reports that 71% of the 42 patients had a history of asbestos exposure. No fiber types, jobs or doses are given.
• Main results:
  • Agreement among the 14 pathologists on tumor type was moderate (weighted kappa 0.45).
  • Of 544 opinions on cases originally classified as biphasic, 385 (71%) agreed they were biphasic, 93 (17%) called them pure epithelioid and 66 (12%) pure sarcomatoid.
  • Median overall survival of the 42 biphasic cases was 8 months, with 38% alive at 1 year.
  • Among the biphasic cases, survival was significantly better when the sarcomatoid component, as scored by the French panel, was less than 80% (median survival 12 months).
  • Patients whose spindle-cell component was high grade showed a trend toward shorter survival than the low-grade group (p = 0.08).
  • Biphasic cases with a transitional pattern (recognized by at least 7 of 14 reviewers) had a median survival of 6 months. Cases without it had a median survival of 12 months.
  • In multivariate analysis, the transitional pattern was a worse prognostic indicator: hazard ratio 3.2, 95% CI 1.6 to 8.0, p = 0.003. Table 3 gives the CI as 1.3 to 8.0.
  • The transitional cases (n = 16) were compared with the large MESOPATH cohort. Median survival was 6 months for transitional, 4 months for sarcomatoid (n = 465) and 14 months for epithelioid (n = 5219) mesothelioma.
  • Survival curves for sarcomatoid, transitional, and pleomorphic mesotheliomas (a series of 40 pleomorphic cases) were very close to each other.
  • BAP1 loss was found in 21 of 42 cases (50%), and in both components in 11 of 41 (27%). BAP1 loss did not differ significantly between transitional and non-transitional cases.
  • CDKN2A (p16) homozygous deletion by FISH was present in 28 of 38 cases (74%) and in 80% of the transitional group. The difference was not statistically significant.
  • Median survival was 13 months when the p16 homozygous deletion was in the epithelioid component alone, and 5 months when it was in both components. Deletion in both components had a hazard ratio of 4.5 (95% CI 1.2 to 16.3, p = 0.02) compared with deletion in the epithelioid component only.
  • Homozygous CDKN2A (p16) deletion by FISH was present in 5 of 8 (62.5%) low-grade spindle-cell components of biphasic cases. The authors treated homozygous deletion in the spindle-cell component as a criterion for malignancy.
• The authors' conclusion: The authors concluded that their multivariate results further validate the transitional pattern as a poor prognostic indicator. They also stated that FISH detection of CDKN2A (p16) homozygous deletion was useful, compared with BAP1 loss, for separating benign stromal reaction from a true sarcomatoid component in ambiguous cases.
• Limitations the authors state:
  • The FISH results must be considered with caution because few FISH analyses were performed.
  • Different cutoffs for the percentage of sarcomatoid component did not reach significance, which the authors attribute to the small number of cases and probably to the size of tissue samples.
  • Too few cases showed BAP1 loss only in the epithelioid component to evaluate its prognostic impact.
  • The authors state that the results need confirming in a larger series.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Biphasic Mesothelioma, Mesothelioma, WHO Classification, Malignant Mesothelioma, Epithelioid, Sarcomatoid, BAP1, CDKN2A.

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