Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically

doi:10.1016/S0003-4975(99)01038-3

The Annals of Thoracic Surgery

Volume 68, Issue 5, November 1999, Pages 1799-1804

Presented at the Poster Session of the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

https://doi.org/10.1016/S0003-4975(99)01038-3 Get rights and content

Abstract

Background. The factors influencing outcome after resection of malignant pleural mesothelioma (MPM) are controversial. This analysis of a prospective surgical database identifies important prognostic factors.

Methods. Tumors were staged by the International Mesothelioma Interest Group staging system, and patients were followed until death. Prognostic factors were analyzed by log rank and Cox regression, and were considered significant if p was less than 0.05.

Results. From Oct 1983 to May 1998, 231 patients underwent thoracotomy, 115 had extrapleural pneumonectomy (EPP), and 59 pleurectomy/decortication (P/D). Among patients having EPP or P/D, 142 received adjuvant therapy. The median survival for stage I tumors was 29.9 months, for stage II 19 months, for stage III 10.4 months, and for stage IV 8 months. By multivariate analysis, stage, histology, gender, adjuvant therapy, but not the type of surgical resection, were significant.

Conclusions. The better survival previously reported for P/D compared with EPP is not seen in a large database with long follow-up. Stages I and II have better survival rates than generally assumed for MPM. Locally advanced T and N status, and nonepithelial histology, identify poor prognosis patients who should be considered for novel treatment regimens.

Section snippets

Patients and methods

All patients entered in this prospective registry had biopsy-proven MPM and underwent exploratory thoracotomy by the same surgeon (V.R.). The pathological diagnosis was based on both histology and immunohistochemistry, and when necessary, electron microscopy. Data collected in the registry included patient name, gender, age, date of operation, preoperative platelet count, type of procedure, extent of resection, tumor histology, extent of the primary tumor and presence of nodal metastases,

Results

From October 1983 to May 1998, 231 consecutive patients underwent thoracotomy for possible resection of malignant mesothelioma. There were 192 men and 39 (16.8%) women, with a median age of 62 years (range 24 to 80 years). Only 5 of the women (12.8%) compared with 138 of the men (71.8%) had known asbestos exposure. Of the 231 patients who underwent surgical exploration, 174 (75%) had a complete resection via either extrapleural pneumonectomy in 115 cases (50%) or pleurectomy/decortication in 59

Comment

The treatment of malignant pleural mesothelioma remains controversial, partly because the natural history, the role of surgical resection, and the factors influencing prognosis have not been fully defined 3, 5. The recent development of an international staging system by the IMIG provides the means to compare clinical outcome across institutions around the world, an important issue with respect to developing treatment for this uncommon malignancy [6]. Although the staging system was developed

Acknowledgements

We thank Melody Owens for her outstanding assistance in data management and manuscript preparation.

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A preoperative validation system for predicting the clinical outcome of extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) is required, as EPP for MPM is one of the most invasive operation types. Recently, several inflammatory and nutritional parameters, such as C-reactive protein (CRP) and albumin, have been re-focused on as useful prognostic factors for several types of cancer; however, few of these reports involved MPM.
As a retrospective study, clinicopathological characteristics and preoperative inflammatory and nutritional parameters were calculated in consecutive patients with MPM who underwent EPP. The prognostic value of the variables was examined using Cox regression, and the candidate preoperative parameters were entered into a multivariate model to determine their independent effects.
Of the 61 eligible cases, the CRP/albumin ratio (CAR) was associated with histology, and the CRP index multiplied by the neutrophil ratio (C-NR index) was associated with histology and pathological stage. Patients with CAR >0.125 had a significantly poor survival outcome, and patients with a C-NR index >0.58 also had a significantly poor prognosis. Multivariate analysis showed that age, histology, CRP, albumin, CAR, and C-NR index were independent predictors of 5-year overall survival.
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Despite becoming the preferred surgical technique for malignant pleural mesothelioma, pleurectomy/decortication has received few prospective clinical trials. Therefore, the Japan Mesothelioma Interest Group conducted a prospective multi-institutional study to evaluate the feasibility of neoadjuvant chemotherapy followed by pleurectomy/decortication.
Patients with histologically confirmed, resectable malignant pleural mesothelioma underwent neoadjuvant chemotherapy comprising pemetrexed 500 mg/m² plus cisplatin 75 mg/m² for 3 cycles, followed by pleurectomy/decortication. The primary end point was macroscopic complete resection rate regardless of the surgical technique used.
Among the 24 patients enrolled, 20 received neoadjuvant chemotherapy and 18 proceeded to surgery, all of whom achieved macroscopic complete resection. Pleurectomy/decortication was performed in 15 patients. The trial satisfied the primary end point, with a macroscopic complete resection rate of 90% (18/20, 95% confidence interval, 68.3-98.8). No treatment-related 30- and 90-day mortality occurred. The overall survival after 1 and 2 years and median overall survival after registration were 95.0% (95% confidence interval, 69.5-99.3), 70.0% (95% confidence interval, 45.1-85.3), and 3.45 years (95% confidence interval, 1.64 to not available), respectively. The cumulative incidence of progression after 1 and 2 years and median time to progression were 33.3% (95% confidence interval, 17.3-64.1), 61.1% (95% confidence interval, 42.3-88.3), and 1.71 years (95% confidence interval, 1.00-2.99), respectively. The best postoperative value for forced expiratory volume was 78.0% of preoperative values.
Neoadjuvant chemotherapy followed by pleurectomy/decortication was feasible with acceptable survival and mortality/morbidity. Postoperative pulmonary function was approximately 80% of the preoperative pulmonary function.
The 2021 WHO Classification of Tumors of the Pleura: Advances Since the 2015 Classification
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Substantial changes in the 2021 WHO Classification of Tumors of the Pleura and Pericardium since the 2015 WHO Classification include the following: (1) pleural and pericardial tumors have been combined in one chapter whereas in the 2015 WHO, pericardial tumors were classified with cardiac tumors; (2) well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumor given growing evidence that these tumors exhibit relatively indolent behavior; (3) localized and diffuse mesothelioma no longer include the term “malignant” as a prefix; (4) mesothelioma in situ has been added to the 2021 classification because these lesions can now be recognized by loss of BAP1 and/or MTAP by immunohistochemistry and/or CDKN2A homozygous deletion by fluorescence in situ hybridization; (5) the three main histologic subtypes (i.e., epithelioid, biphasic, and sarcomatoid) remain the same but architectural patterns and cytologic and stromal features are more formally incorporated into the 2021 classification on the basis of their prognostic significance; (6) nuclear grading for epithelioid diffuse mesothelioma is introduced, and it is recommended to record this and other histologically prognostic features in pathology reports; (7) BAP1, EZH2, and MTAP immunohistochemistry have been found to be useful in separating benign mesothelial proliferations from mesothelioma; (8) biphasic mesothelioma can be diagnosed in small biopsies having both epithelioid and sarcomatoid components even if the amount of one component is less than 10%; and (9) the most frequently altered genes in diffuse pleural mesothelioma include BAP1, CDKN2A, NF2, TP53, SETD2, and SETDB1.
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Lymph node (LN) involvement is a poor prognostic factor for malignant pleural mesothelioma (MPM). However, to our knowledge, postresection outcomes of node-negative (cN0/pN0), occult pathologic nodal disease (cN0/pN+), and clinical node-positive disease (cN+) have not been compared to date.
The National Cancer Data Base was queried for newly diagnosed, resected MPM with known clinical/pathologic LN information. Three cohorts were compared: cN0/pN0, cN+, and cN0/pN+. Multivariable logistic regression examined predictors of pathologic nodal upstaging. Kaplan-Meier analysis with propensity matching assessed overall survival (OS); multivariate Cox proportional hazards modeling examined predictors thereof.
Of 1369 patients, 687 (50%) had cN0/pN0, 457 (33%) cN+, and 225 (16%) cN0/pN+ disease. Median follow-up was 29 months. In patients with cN0 disease, factors associated with pathologic nodal upstaging were younger age, greater number of examined LNs, and nonsarcomatoid histology (P < .05 for all). Relative to pN0 cases, occult LN involvement (65% being pN2) was associated with 51% higher hazard of mortality on multivariate analysis (P = .005). Following propensity matching, the OS of cN0/pN+ was similar to cN+ cases (P = .281). On multivariate analysis, the number of involved LNs (continuous variable, P = .013), but not nodal tumor, node, metastasis (TNM) classification or LN ratio (P > .05 for both), was associated with OS.
Detecting occult nodal disease during resection for cN0 MPM is associated with poorer prognosis, with similar survival as cN+ cases, underscoring the importance of routine preoperative pathologic nodal assessment for potentially resectable MPM. The number of involved LNs (rather than current location-based classification) may provide more robust prognostic stratification for future TNM staging.
The Prognostic Role of TNM Staging Compared With Tumor Volume and Number of Pleural Sites in Malignant Pleural Mesothelioma
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Age, sex, stage, histotype, and surgery are the most recognized prognostic factors for malignant pleural mesothelioma (MPM). Tumor volume (TV) was suggested as an alternative prognostic evaluation. We aimed to assess the prognostic role of Tumor, Node, Metastases (TNM) versus TV and number of pleural sites (NPS).
Information on stage, TV, and NPS was collected for 52 MPM patients (pts) at our institution from 2009 to 2012. Baseline computed tomography imaging was performed to define TNM, TV, and NPS. Pts were divided in 3 stage groups: early (I-II), III, and IV. A dedicated computer system calculated TV. Pts were divided in 2 groups according to mean baseline TV (483 cm³). NPS was defined on the basis of the NPS macroscopically involved by disease (1-3). The association between TNM, tumor size (T), TV, NPS, TV and NPS, and overall survival was assessed using Cox models adjusted for age, sex, histology, and treatment.
Most pts were male; mean age was 62 years. We showed an association between TV, TNM, and T. Stage III (hazard ratio [HR], 4.71; P = .02) and IV (HR, 7.40; P < .01), T3 (HR, 5.07; P < .01) and T4 (HR, 5.09; P < .01), TV > 483 cm³ (HR, 3.47; P < .01) and NPS 2 (HR, 3.00; P = .08) and 3 (HR, 6.05; P < .01) were predictive of worse survival. However, the TV and NPS combination performed better than TV, NPS, and TNM alone as a prognostic classifier.
We showed that TV is related to TNM staging and T, in particular. Improved prognostic performance might be achievable using quantitative clinical staging combining TV and NPS.
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Malignant pleural mesothelioma is a rare disease. Ninety percent of cases are attributed to asbestos exposure. Surgical options include extrapleural pneumonectomy or pleurectomy and decortication. The role of chemotherapy and radiation in resectable disease is controversial. For unresectable or metastatic disease, the standard treatment is the combination of a platinum drug and an antifolate drug.
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Original ArticlesImportant prognostic factors in patients with malignant pleural mesothelioma, managed surgically

Abstract

Section snippets

Patients and methods

Results

Comment

Acknowledgements

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Chest

Ann Thorac Surg

Lung Cancer

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients

Ann Surg

Diffuse malignant mesothelioma of the pleura in Ontario and Quebeca retrospective study of 332 patients

J Clin Oncol

A proposed new international TNM staging system for malignant pleural mesothelioma

Chest

Original Articles
Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically