Feasibility of multimodality treatment, including pleurectomy decortication, in carefully selected patients with sarcomatoid mesothelioma

Introduction

Pleural mesothelioma (PM) represents an exceptionally lethal, rare malignancy. It originates from mesothelial cells with a median longevity of 8 months across all affected individuals (1). Sarcomatoid PM is defined by fewer than 10% epithelial and greater than 90% sarcomatoid cells in the tumor tissues (2,3) and constitutes the least common but most aggressive histologic subtype (4-6). The National Cancer Database (NCDB) reports that sarcomatoid mesothelioma comprises about 12.3% of all PM cases (7). Investigations of operative case series have revealed the predictive influence of histological classifications on patient overall survival. Within the Surveillance, Epidemiology, and End Results (SEER) registry, the median lifespan among individuals with epithelioid, biphasic, and sarcomatoid tissue variants who received surgical intervention was 19, 12, and 4 months, respectively (8). Cancer-directed surgery in the database was used in 58/224 (26%) with sarcomatoid histology. Median survival was four months for the surgical group and three months for the patients who did not undergo surgery. The authors concluded that the poor prognosis of sarcomatoid mesothelioma may not be favored by operative treatment. The treatment recommendations issued by the European Society of Thoracic Surgery (ESTS) guidelines (9,10), the American society of clinical oncology (ASCO) (11) and the National Comprehensive Cancer Network (NCCN) (12-14) do not endorse the implementation of tumor directed operative approach to sarcomatoid mesothelioma except within the context of research. If surgical resection is considered, it should be reserved for carefully selected patients, carried out as part of a multimodality treatment strategy—preferably within clinical trials—and performed in expert centers with proven low morbidity and mortality rates. Interestingly, by querying the NCDB, Nelson et al. demonstrated improvement (P=0.01, although less favorable than in other PM histologies) in hazard of death among sarcomatoid PM patients after cancer directed surgery (15). Herein we analyzed the results of a single high-volume mesothelioma program using pleurectomy decortication (PD) as part of a multimodal approach for patients with sarcomatoid mesothelioma. We demonstrate the overall survival and identify potential novel prognostic factors. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-990/rc).

Methods

This study presents a retrospective review of a prospectively compiled database from a single academic medical center, encompassing all patients who underwent PD for sarcomatoid PM over a 13-year period at Brigham & Women’s Hospital. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Dana-Farber Cancer Institute (DFCI) IRB (98-063), and informed consent was obtained from all patients. Brigham and Women’s Hospital (BWH) and DFCI are core members of the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC), a long-standing integrated partnership. In practice, patients receive thoracic surgery at BWH and systemic therapy at Dana-Farber, within a single coordinated cancer program.

A retrospective review of medical records was undertaken to re-examine and enrich a previously established prospective dataset, capturing details of preoperative assessment, surgical intervention, and perioperative management, in addition to histopathologic and imaging data. Clinical outcomes and longitudinal follow-up were ascertained during scheduled outpatient visits and, when necessary, through direct communication with referring clinicians or patients. Prior to surgery, all individuals completed a diagnostic workup consisting of chest X-ray (CXR), contrast-enhanced thoracic computed tomography (chest-CECT), thoracic magnetic resonance imaging (chest MRI), positron emission tomography combined with computed tomography (PET-CT), transthoracic echocardiography, pulmonary function testing, and ventilation-perfusion scan. Patients who were diagnosed with mediastinal nodal tumor involvement during cervical mediastinoscopy or endobronchial ultrasound underwent neoadjuvant chemotherapy prior to re-evaluation for surgery. This was also the case in select patients with ipsilateral disease extending to critical structures or the chest wall, as well as in a small number of patients who had not undergone their initial evaluation at our center.

Each case was reviewed by a multidisciplinary team comprising medical oncologists, imaging specialists, and thoracic surgeons, and surgical candidacy was established before proceeding to operation. The surgical objective was removal of the entire parietal and visceral pleural surfaces, with possible resection of the diaphragm and/or pericardium—constituting an extended pleurectomy/decortication—when gross tumor involvement or intraoperative frozen-section findings indicated invasion into those structures, in order to accomplish macroscopic complete resection (MCR). Reconstruction of the diaphragm and pericardium using permanent patches (Gore-Tex with pericardial fenestrations) was performed when indicated, based on intraoperative judgment of the operating surgeon.

Mediastinal, hilar, intercostal, and mammary vascular lymph nodes were sampled. The pleural cavity was irrigated with saline, water, and peroxide, and the chest wall along with any areas of remaining visceral pleura were treated with argon beam painting. Subsequently, intraoperative heated chemotherapy (IOHC) with Cisplatin (175–225 mg/m²) was circulated as a 42 °C lavage for up to 60 minutes, with renal protection as previously described (16,17). Intraoperative heated chemo is generally given once MCR is achieved and there is no perioperative instability or diminished creatinine clearance. Postoperative chemotherapy, as part of a multidisciplinary treatment plan, is generally recommended immediately following surgical resection for patients who did not receive neoadjuvant therapy and were found to have positive lymph nodes during PD, advanced T stage, or non-epithelioid histology. Tumor staging for these patients was performed postoperatively according to the 8th edition of the American Joint Committee on Cancer (AJCC). Mortality status was documented in the database using information obtained from electronic health record alerts, searches of the Social Security Death Index, and publicly available obituary notices. Overall survival and duration of hospitalization were measured from the date of the operative procedure.

Statistical analysis

Survival outcomes were analyzed using descriptive methods in conjunction with Kaplan-Meier survival curves and Cox proportional hazards regression. Associations between clinical or disease-related variables were examined with Wilcoxon rank-sum tests for continuous measures and Fisher’s exact tests for categorical variables. Differences in overall survival between groups were evaluated using Kaplan-Meier estimates, while Cox regression models were applied to explore the impact of candidate prognostic variables on overall survival. All statistical tests were two-sided, with P<0.05 indicating statistical significance.

Results

From January 2007 to December 2019, thirty-four consecutive patients with sarcomatoid PM underwent PD. Surgical scope varied across cases, with diaphragmatic resection performed in 20 patients (58.8%), pericardial resection in 9 patients (26.5%), and removal of involved chest wall segments in 12 patients (35.3%). Eleven prior diagnostic surgical tracts were resected, none showed malignant cell dissemination.

Twenty-five patients (73.5%) had a history of asbestos exposure, including 74.2% of males and 66.6% of females.

Among the 34 patients ultimately confirmed to have sarcomatoid mesothelioma on postoperative pathology, the initial preoperative diagnosis was sarcomatoid in 29 (85.2%), biphasic in 4 (11.8%), and non-specific mesothelioma subtype in 1 (3%). In five patients with pre-operative diagnosis of sarcomatoid mesothelioma the postoperative diagnosis was biphasic (not included in this manuscript). Diagnosis of PM was based on thoracoscopy in 22 patients, CT guided biopsy in 11 patients and pleural fluid analysis in one patient. Across the whole cohort of 34 patients (Table 1) there were 31 (91.2%) males, 24 (70.6%) right sided operations, the median age was 71.5 (range, 51–85, mean 69.1 years). Eight (24.2%) patients received neoadjuvant treatment, IOHC was administered in 23 (67.7%) patients, and adjuvant therapy in 19 (65.5%) patients. Lymph node involvement with cancer was proved in just three cases (8.8%).

The median hospital length of stay was 13 days (3–38 days). The mortality observed at 30 and 90 days was 2.9% [95% confidence interval (CI): 0.0–8.5%] and 14.7% (95% CI: 1.9–25.8%), respectively. The reasons for post-operative mortality are summarized in Table S1. The median overall survival (Figure 1) for all patients was 7.4 months (95% CI: 6.54–14.7 months), 9.53 months (95% CI: 5.36–20.1 months) in the MCR group, and 15.42 months in early T status (Figure 2) (95% CI: 9.53–NA). Importantly, in a group of nine patients with forced expiratory volume in 1 second (FEV1) ≥80%, the median survival was 20.1 months (Figure 3) (95% CI: 7.33–NA). Among patients undergoing PD, MCR was achieved in 22 (64.7%). In 12 (35.3%) patients, MCR could not be achieved during surgery due to a strong association with more advanced disease stage on pathologic examination. Failure to achieve MCR was attributed to extensive chest wall disease in seven patients, invasion of major vascular structures (including the aorta, vena cava, or LIMA to LAD coronary artery bypass graft) in four patients, and one octogenarian patient whose frailty and widespread diaphragmatic involvement precluded complete resection.

Figure 1 Kaplan-Meier plot depicting estimated survival functions in patients with sarcomatoid mesothelioma.

Figure 2 Kaplan-Meier plot depicting estimated survival functions according to T status (T1+T2/T3+T4).

Figure 3 Kaplan-Meier plot depicting estimated survival functions according to pre-operative percentage of FEV1. FEV1, forced expiratory volume in 1 second.

Within the group achieving MCR, 20 patients (90.9%) were male, and right-sided procedures accounted for 16 cases (72.7%). The median patient age was 71 years (range, 51–81 years; mean, 69.1 years), and four individuals (19%) had received neoadjuvant therapy (Table 1). IOHC was delivered to 21 patients (95.4%), while postoperative adjuvant treatment was administered to 10 patients (52.6%). The median duration of hospitalization was 13 days, with a range of 3 to 38 days.

Pathologic tumor staging within this cohort demonstrated T1 disease in 1 patient (4.5%), T2 in 6 patients (27.3%), T3 in 7 patients (31.8%), and T4 in 8 patients (36.4%). Nodal assessment revealed no lymph node involvement (N0) in 20 patients (90.9%), whereas 2 patients (9.1%) had N1 disease.

Evaluating variables individually through univariable analysis, Kaplan-Meier plots (Table 2) revealed a meaningful disparity in patient overall survival based on FEV1 status (P=0.01) and administration of adjuvant therapy (P=0.03). Interestingly, neither gender, administration of IOHC (Figure 4), nor N classification appeared to affect overall survival. Applying multivariate analysis demonstrates that FEV1 status (P=0.01) and adjuvant therapy (P=0.01) are independently associated with overall survival. In the MCR group (Table 3), multivariate analysis demonstrates that both factors, FEV1 (P=0.05) and adjuvant therapy (P=0.03), are independently associated with overall survival.

Figure 4 Kaplan-Meier plot depicting estimated survival functions according to IOHC status. IOHC, intraoperative heated chemotherapy.

Discussion

Sarcomatoid PM is a rare and highly aggressive subtype, and data on its biology, treatment, and prognosis remain limited. We report one of the largest single-institution surgical series of patients who underwent PD with the intent to achieve MCR. This cohort includes 34 consecutive patients, of whom 22 achieved MCR.

Most patients (70.6%) underwent right-sided surgery. Laterality showed no association with the ability to achieve MCR (P=0.70) or with overall survival (P=0.75). Although published studies generally do not identify laterality as a prognostic factor (18,19), some have suggested a potential influence in select groups (20).

Sarcomatoid PM was significantly less common in females (8.8%) compared with epithelioid (27.6%) and biphasic (22.4%) subtypes (P=0.04). This pattern is consistent with NCDB findings, where 91.2% of patients with sarcomatoid histology were male.

We included in this manuscript 34 patients with post PD diagnosis of sarcomatoid PM. Importantly, discrepancies between pre-operative and postoperative histologic diagnosis were not rare. In our series, five patients diagnosed pre-operatively with sarcomatoid PM were found to have biphasic histology after PD, and four showed the opposite pattern. These findings highlight the limited accuracy of pre-operative histologic classification and underscore the need for multiple biopsies from different thoracic locations before surgery.

Compared with other histologic subtypes in our prior studies (19,21), the MCR rate in sarcomatoid PM was significantly lower (64.7% vs. 86% in epithelioid/biphasic PM, P=0.009). This occurred despite the use of thorough imaging-based preoperative assessments (CT, PET-CT, and chest MRI) and reevaluation after neoadjuvant therapy. These observations are consistent with the recognized difficulty of achieving MCR in sarcomatoid PM, which responds poorly to chemotherapy and more frequently invades adjacent structures (22). Supporting this, lymph node involvement was lower in sarcomatoid histology (8.8%) than in biphasic (30.5%) or epithelioid (39.1%) (P=0.005), while the T4 rate was significantly higher compared to non-sarcomatoid histology (41.2% vs. 15–16%, P=0.009). Prior work by Pajaneen et al. similarly linked sarcomatoid PM with more advanced anatomical disease (23).

Thirty- and ninety-day mortality in this cohort was 2.9% and 14.7%, respectively lower than NCDB-reported mortality for sarcomatoid PM patients undergoing cancer-directed surgery (9.7% and 29.8%). While the 30-day mortality aligns with published data (17), the higher 90-day mortality likely reflects the short median survival of sarcomatoid PM [3–4 months in SEER (8)].

Although the difference did not reach statistical significance, likely due to small sample size, patients who achieved MCR had numerically longer survival. Their median survival is twice as long as that reported for surgically treated sarcomatoid patients in the SEER database. Our findings align with Kim et al. (24), who showed that cancer-directed surgery is associated with improved survival in early-stage sarcomatoid PM and was an independent predictor of outcome in multivariate analysis.

It is important to note that, at the time of this study, chemotherapy was the sole FDA-approved therapy and was administered to most patients either as neoadjuvant or adjuvant treatment (11,25,26) (Table S2). Immunotherapy trials provide useful context for interpreting our results (Table S3). In the CheckMate 743 trial, patients with unresectable ECOG performance status 0 or 1 and non-epithelioid PM treated with chemotherapy had a median survival of 8.8 months (27). However, more than half had biphasic—rather than sarcomatoid histology, which is associated with better outcomes (12–18 months) (8,15,21). The KEYNOTE-483 trial similarly reported a median survival of 8.2 months in predominantly biphasic non-epithelioid PM treated with chemotherapy (28). The most appropriate reference is the SEER database, which reports a median survival of 4 months for pure sarcomatoid PM treated with surgery. Against this benchmark, our cohort demonstrated a median overall survival of 7.4 months, increasing to 9.5 months among patients who achieved MCR. For comparison with the immunotherapy arms of the CheckMate 743 and KEYNOTE-483 trials, we should rely on the results of recent and upcoming studies evaluating the role of immunotherapy—including anti-programmed death 1 (PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agents—in combination with surgery for non-epithelioid PM (29,30).

In contrast to our study, which is based just on post-PD diagnosis of sarcomatoid PM, we assume that many non-epithelioid cases in non-surgical cohorts may include misclassified epithelioid tumors, potentially inflating survival estimates. Our previous publications documented frequent pre-operative misclassification, reinforcing this concern (21).

We also observed biological and clinical differences among histologic subtypes. Female sex, known to be a favorable prognostic factor in epithelioid PM (31-34), did not confer benefit in sarcomatoid or biphasic PM. Similarly, although epithelioid PM shows improved outcomes when IOHC is added, this advantage is not evident in sarcomatoid PM—likely due to differences in biology and their poorer chemosensitivity (35).

Patterns of disease spread also differed: while epithelioid PM often metastasizes to lymph nodes, sarcomatoid PM less commonly does so (19,36,37). This may explain why nodal status did not predict survival in our cohort, consistent with reports by Lococo et al. (38). Furthermore, unlike epithelioid PM (where port-site dissemination occurs in ~25% of patients), no port-site dissemination was observed in sarcomatoid PM (39).

Although the median survival of sarcomatoid MCR patients (9.6 months) was far lower than that of epithelioid PM (32.1 months), a subset of sarcomatoid patients achieved much longer survival. For example, patients with preserved lung function (FEV1 ≥80%) had a median survival of 20.4 months. Kanayama et al. similarly reported a median survival of 15.9 months in sarcomatoid PM treated with multimodality therapy (40), and rare long-term survivor after curative-intent surgery have been described (41).

The primary limitations of our study are its retrospective design and small sample size. Despite being the largest consecutive single-center cohort of sarcomatoid PM undergoing PD, the sample remains modest, and therefore any proposed prognostic associations require cautious interpretation and validation in larger studies.

Conclusions

This study confirms that PD for sarcomatoid mesothelioma can be performed with a low 30-day mortality. Given the poor prognosis of this subtype characterized by short overall survival, low rates of MCR, and the associated prolonged postoperative recovery after major surgery, it is evident that most patients derive limited benefit from PD. Nonetheless, a small subset of patients, such as those with early T-stage sarcomatoid mesothelioma and preserved pulmonary function, may still be suitable candidates for PD as part of a multimodality treatment approach. Surgical resection should be carried out as part of a multimodality treatment strategy and performed in expert centers with proven low morbidity and mortality rates. Future surgical candidate selection should be guided by preoperative CT and volumetric assessment to identify patients with early clinical T-stage disease, along with thorough functional evaluation using pulmonary function tests (PFTs). We await the results of ongoing clinical trials, such as the Alliance Phase II trial (NCT05647265), which investigates the role of surgery as part of multimodality treatment incorporating immunotherapy in sarcomatoid PM (29).

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-990/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-990/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-990/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-990/coif). M.L. reports receiving payments from AstraZeneca and Roche. R.B. reports receiving grants from Verastem, Genentech, Roche, Myriad Genetics, Novartis, Siemens, Gritstone, Epizyme, MedGenome, Merck, Bicycle Therapeutics, and Bayer; consulting fees from Regeneron, Covidien/Medtronic, Helios Cardio Inc., and DiNAQOR; payment for expert testimony from Public Health Advocacy Institute, Thornton Law Firm LLP, Blankingship & Keith, PC, MRHFM Law, LLC, Carpenter, Zuckerman & Rowley, and Phillips & Paolicelli, LLP, and Foster & Eldridge, LLP; patents with Navigation Sciences licensed to BWH; holds equity in Navigation Sciences; and consulting payments include stock options under certain circumstances from Helios Cardio. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the DFCI IRB (98-063), and informed consent was obtained from all patients. BWH and DFCI are core members of the DF/BWCC, a long-standing integrated partnership. In practice, patients receive thoracic surgery at BWH and systemic therapy at Dana-Farber, within a single coordinated cancer program.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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