Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal

Our plain-English summary of Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal, by G. Pelosi, M. Papotti, L. Righi, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: G. Pelosi, M. Papotti, L. Righi, G. Rossi, S. Ferrero, S. Bosari, F. Calabrese, I. Kern, P. Maisonneuve, A. Sonzogni, A. Albini, S. Harari, F. Barbieri, E. Capelletto, A.M. Catino, D. Cavone, A. De Palma, N. Fusco, F. Lunardi, E. Maiorano, A. Marzullo, S. Novello, N. Papanikolaou, G. Pasello, A. Pennella, F. Pezzuto, A. Punzi, E. Prisciandaro, F. Rea, L. Rosso, A. Scattone, G. Serio
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(11):1750-1761
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials.

Methods: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (κ > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM.

Conclusions: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or ≥10 = 4 points), and Ki-67 labeling index based on 2000 cells (<30% = 0 points versus ≥30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki-67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1-point increase in score being 1.46 (95% confidence interval: 1.36-1.56) in the training set and 1.28 (95% confidence interval: 1.22-1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors).

Discussion: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This was a retrospective study at five Italian institutions. It built and tested a pathologic grading score for malignant pleural mesothelioma in 940 patients diagnosed between October 1980 and June 2015. The score was built on 328 patients from Bari and checked on 612 patients from the Milan, Modena, Padua and Turin series; 24 Padua cases came from Golnik, Slovenia. Asbestos exposure was recorded as a background characteristic: 226 of 328 and 331 of 612 patients were reported as exposed. The score ran from 0 to 8 points. Points were given for sarcomatoid tumor type, necrosis (dead tumor tissue), mitotic count and Ki-67 labeling index, features on which pathologists agreed well. Median survival in the two sets was 26.3 and 26.9 months at score 0, 12.8 and 14.4 months at scores 1 to 3, and 3.7 and 7.7 months at scores 4 to 8. After adjustment for age and, when available, stage, each extra point had a hazard ratio of 1.46 (95% CI 1.36–1.56) in the first set and 1.28 (95% CI 1.22–1.34) in the second. The authors noted that stage was missing for about 60% of patients. They concluded that the score effectively predicted survival.

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: Multicenter, retrospective, observational study that developed a grading score in a training cohort and tested it in a separate validation cohort
• Who was studied: 940 consecutive patients with malignant pleural mesothelioma diagnosed on biopsy or resection specimens between October 1980 and June 2015 at five Italian institutions. The training cohort was 328 patients from Bari. The validation cohort was 612 patients from the Milan, Modena, Padua and Turin sets, and 24 of the Padua cases came from the Golnik Center in Slovenia.
• Exposure: The study examined tumor features under the microscope, not asbestos. Asbestos exposure was recorded only as a patient characteristic. It was reported as 'yes' for 226 of 328 training patients (68.9%) and 331 of 612 validation patients (54.1%). Exposure was missing for 137 validation patients (22.4%). Fiber types are not given, and the main text does not report survival by asbestos exposure.
• Main results:
  • Only features with excellent agreement between pathologists (kappa above 0.75) were used: histologic subtype, necrosis, Ki-67 labeling index and mitotic count. Cell atypia and nucleoli were left out.
  • In the training cohort, multivariate hazard ratios for death were used to assign points. Necrosis present: 1.60 (95% CI 1.22–2.09), 1 point. Sarcomatoid type: 2.04 (1.39–2.99), 2 points. Ki-67 labeling index of 30% or more: 1.54 (1.19–2.00), 1 point. Mitotic count 3 to 5: 1.90 (1.32–2.74), 1 point. Mitotic count 6 to 9: 2.79 (1.89–4.12), 2 points. Mitotic count of 10 or more: 4.26 (2.61–6.95), 4 points.
  • Median survival in the training and validation sets, respectively: 26.3 and 26.9 months at score 0; 12.8 and 14.4 months at scores 1 to 3; 3.7 and 7.7 months at scores 4 to 8.
  • After adjustment for age at diagnosis and (when available) tumor stage, the hazard ratio for each 1-point increase in score was 1.46 (95% CI 1.36–1.56) in the training set and 1.28 (95% CI 1.22–1.34) in the validation set. No heterogeneity was seen across the four validation centers.
  • The integrated area under the curve for the score over time was 0.761 in the training cohort and 0.731 in the validation cohort.
  • Across all 940 patients, risk of death rose 34% per 1-point increase in score. The increase was lower among patients unable to receive chemotherapy (HR 1.05, 95% CI 0.96–1.13) and among those with sarcomatoid tumors (HR 1.10, 95% CI 0.99–1.23).
• The authors' conclusion: The authors concluded that their simple and reproducible multiparametric pathologic grading system effectively predicted survival in patients with malignant pleural mesothelioma.
• Limitations the authors state:
  • Tumor stage information was missing for a large proportion of patients (about 60%). The authors noted that the score's association with survival was weaker among patients with missing stage.

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: Pleural Mesothelioma, Clinical Trial, Multivariate Analysis, Hazard Ratio, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Necrosis.

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