Pleural Mesothelioma
Epithelioid, sarcomatoid, and biphasic pleural mesothelioma
DefinitionClick to collapse
Mesothelioma originates from the cells in the serosal lining (mesothelium) that surrounds the body cavities. Of all mesotheliomas, approximately 85% arise from the pleura, approximately 15% arise from the peritoneum, and the remainder (less than 1%) originate from the pericardium or the tunica vaginalis [1]. Pleural mesothelioma (PM), historically referred to as malignant pleural mesothelioma, is the most common type and affects the pleural space lining the lungs and chest wall [2,4]. In the United States, diffuse pleural mesothelioma affects approximately 3,000 patients each year, with an annual incidence of approximately 1 in 100,000 [2,3]. The purpose of the pathologic evaluation of mesothelioma is based on the pathologic assessment of tumor tissue, which can be obtained from core biopsy sampling, pleurectomy, or other more extensive resections such as extrapleural pneumonectomy (EPP). Given its rarity and overlapping microscopic features with other conditions, the histologic diagnosis of diffuse mesothelioma can be challenging [1]. The 2021 World Health Organization (WHO) Classification of Thoracic Tumors introduced new terminology: diffuse pleural mesothelioma (replacing diffuse malignant pleural mesothelioma) and localized pleural mesothelioma (replacing localized malignant pleural mesothelioma) [1,4]. A new entity, mesothelioma in situ, was also added. Almost all mesotheliomas (>99%) are diffuse; however, rare cases of localized pleural mesothelioma have been described, which are solitary, have a different pathogenesis, and harbor a relatively less aggressive clinical course [15-18]. Localized pleural mesothelioma includes three molecular groups (BAP1-mutant, TRAF7-mutant, and near-haploid) with similarities but also differences from diffuse pleural mesothelioma [18]. The BAP1 tumor predisposition syndrome is a hereditary cancer syndrome caused by heterozygous germline pathogenic variants in the BAP1 gene [1]. To establish a pathologic diagnosis of mesothelioma, diagnostic tools used clinically include histologic assessment, immunohistochemistry (IHC), cytogenetics, and molecular techniques such as targeted next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), and single-nucleotide polymorphism arrays [1]. Despite the multiple diagnostic toolkits, the diagnosis relies primarily on proper histologic assessment and IHC.
EpidemiologyClick to collapse
SubtypesClick to collapse
Epithelioid Mesothelioma
Epithelioid mesothelioma is characterized by epithelioid-to-round cells. It is the most common histologic type and has a more favorable prognosis compared with biphasic or sarcomatoid histologies [1,96]. Tumor cells are arranged in diverse architectural patterns that include tubulopapillary, trabecular, solid, acinar, micropapillary, or adenomatoid. Rare variants of epithelioid mesothelioma include clear cell, signet ring cell, rhabdoid, deciduoid, and small cell [6-8].
Sarcomatoid Mesothelioma
Sarcomatoid mesothelioma is characterized by spindled cells with tapered nuclei. Subtypes include conventional/spindle cell, desmoplastic, and lymphohistiocytoid [9-13]. A subset exhibits heterologous differentiation with osteosarcomatous, chondrosarcomatous, and/or rhabdomyosarcomatous elements [10].
Biphasic (Mixed) Mesothelioma
Biphasic mesothelioma contains both epithelioid and sarcomatoid components in various proportions, with each comprising at least 10% of the tumor [1]. Assignment of histologic type can be challenging given intertumoral and intratumoral morphologic heterogeneity. Studies comparing concordance between histologic type in initial biopsies with subsequent resections have shown that epithelioid histology in biopsies is not entirely specific and is changed to biphasic or sarcomatoid types in resections in up to 20% of patients [14].
Localized Pleural Mesothelioma
Localized pleural mesothelioma is microscopically identical to diffuse mesothelioma, although it is radiographically and grossly solitary and circumscribed [15-17]. Genetically, it includes three groups (BAP1-mutant, TRAF7-mutant, and near-haploid) with similarities but also differences from diffuse pleural mesothelioma [18].
Mesothelioma in Situ
Mesothelioma in situ is a preinvasive, single-layer surface proliferation of neoplastic mesothelial cells. The diagnosis requires either: 1) loss of BAP1 nuclear expression by IHC; and/or 2) CDKN2A homozygous deletion identified either by FISH or by MTAP IHC (cytoplasmic staining). Furthermore, no mass lesions should be identified on imaging or thoracoscopy [1].
Molecular PathogenesisClick to collapse
Pleural mesothelioma is characterized by recurrent mutations in tumor suppressors and epigenetic regulators. BAP1 (BRCA1-associated protein 1) is one of the most frequently altered genes; mechanisms of BAP1 inactivation include point mutations, copy number loss, inactivating structural rearrangements, and minute chromosomal deletions [56-58,61-63]. BAP1 IHC loss (aberrant protein expression, defined as absence of nuclear BAP1 staining) is present in approximately 50% to 70% of epithelioid mesothelioma and in less than 20% of sarcomatoid type [31-37]. BAP1 is a tumor suppressor implicated in the pathogenesis of mesothelioma, uveal melanoma, cholangiocarcinoma, and clear cell renal cell carcinoma [30]. Homozygous loss of CDKN2A (p16) by FISH testing is present in approximately 60% of mesotheliomas [51-53]. Hemizygous loss of NF2 by FISH is present in approximately 50% of pleural mesotheliomas [55]. Alterations in BAP1, NF2, TP53, SETD2, and other genes are identified, affecting multiple pathways in the regulation of cell cycle, RNA processing, histone regulation, and cell growth [56-60]. MTAP (methylthioadenosine phosphorylase) is located near CDKN2A on chromosomal region 9p21. Loss of cytoplasmic MTAP staining is reported in approximately 40% to 60% of mesothelioma but rarely in reactive proliferations [35-37]. Germline mutations are overall present in 12% to 16% of patients with pleural and peritoneal mesotheliomas and primarily involve genes in the DNA repair and cell cycle regulation, such as BAP1, BRCA2, CDKN2A, TMEM127, VHL, WT1, MRE11A, and MSH6 [42,66,67]. Germline mutations appear to be more common in patients who are young, have a family history of mesothelioma, or have a clinical history of other synchronous malignancies [42,66,68]. A rare subset of pleural mesothelioma harbors a peculiar near-haploid karyotype with extensive loss of heterozygosity involving nearly all chromosomes except chromosomes 5 and 7 [56]. Oncogenic EWSR1::ATF1 fusion has been described in pleural and peritoneal mesotheliomas in young adults [64,65]. ALK rearrangements have been identified in rare patients with peritoneal mesothelioma [43-45,48]. A rare subset harbors unusual genetic alterations including TP53 and/or SETDB1 mutations associated with genomic near-haploidization [56]. Peritoneal mesothelioma has distinct molecular features compared to pleural mesothelioma [64]. Patients with epithelioid mesothelioma with loss of BAP1 by IHC and retained p16 expression by IHC have prolonged survival in both univariate and multivariate analyses [40]. Patients with mesothelioma with germline BAP1 mutations have a prolonged survival [41,42].
Risk FactorsClick to collapse
Asbestos exposure (occupational)
Exposure to asbestos is the primary risk factor for pleural mesothelioma. Most mesotheliomas are associated with occupational exposure to asbestos [5,19,20]. The latency period between asbestos exposure and mesothelioma development is long, with a median latent period of greater than 32 years [15]. Some patients exposed to asbestos may only have benign pleural disease [24,25].
Asbestos exposure (non-occupational)
Individuals with non-occupational asbestos exposure also have increased risk of mesothelioma [21-23]. Environmental asbestos exposure in certain geographic locations contributes to disease risk.
Ionizing radiation
Patients exposed to ionizing radiation are thought to be at increased risk of developing mesothelioma [20,26-37]. A study evaluating patients from the SEER database found that patients treated with radiation therapy had a higher risk of developing mesothelioma as a secondary malignancy than those who were not irradiated [26].
Erionite exposure
Erionite is a naturally occurring fiber-like mineral that is more potent than asbestos; however, fewer people are at risk of developing mesothelioma from erionite as it is only found in certain geographic locations and is generally not used for commercial applications [38-42].
Germline BAP1 mutations
A high incidence of pleural mesothelioma has been reported in families in the absence of exposure to occupational asbestos or erionite; germline mutations in the BAP1 gene were identified as a risk factor [52]. BAP1 tumor predisposition syndrome is a hereditary cancer syndrome. Genetic counseling and germline testing may be warranted for patients with a young age at diagnosis, personal or family history suggestive of BAP1 tumor predisposition syndrome, or multi-BAP1-associated malignancies [43-52].
Other germline mutations (DNA repair/cell cycle genes)
Germline mutations in DNA repair and cell cycle regulation genes including BRCA2, CDKN2A, TMEM127, VHL, WT1, MRE11A, and MSH6 have been identified in 12% to 16% of patients with pleural and peritoneal mesotheliomas [42,66,67]. These appear to be more common in patients who are young, have a family history of mesothelioma, or have other synchronous malignancies.
Smoking (note: NOT a risk factor for mesothelioma)
Smoking is not considered a risk factor for mesothelioma [53,54]. However, patients who smoke and have been exposed to asbestos are at increased risk for lung cancer [55,56].
Clinical FeaturesClick to collapse
Typical Presentation
Pleural mesothelioma is a rare malignancy arising from the serosal lining of the pleura, accounting for approximately 85% of all mesotheliomas. It typically affects individuals over 60 years of age with a history of asbestos exposure, often with a latency period of more than 32 years [MS-2]. Patients commonly present with dyspnea and chest wall pain, which are often the most frequent symptoms [MS-3]. Additional symptoms include pleural effusion, fatigue, insomnia, cough, chest wall mass, loss of appetite, and weight loss [MS-3]. Most patients are diagnosed without distant metastases, and central nervous system involvement is rare [MS-3]. The clinical presentation can be insidious, leading to delayed diagnosis due to non-specific symptoms [PM-A]. On physical examination, signs may include decreased breath sounds, dullness to percussion, and palpable chest wall masses. Imaging typically reveals pleural thickening and effusion on chest CT with contrast [PM-1]. The diagnosis requires a multidisciplinary approach, including pathologic confirmation via biopsy, as cytology alone is often insufficient [MS-3].
Symptoms
Dyspnea
Shortness of breath, often progressive and due to pleural effusion or tumor burden. It is a cardinal symptom that may worsen with activity or at rest.
Chest wall pain
Pain may be localized or diffuse, often related to tumor invasion of chest wall structures or pleural irritation. It can be dull or sharp and may radiate.
Pleural effusion
Accumulation of fluid in the pleural space, causing respiratory symptoms such as dyspnea and cough. Effusions are often exudative and may be recurrent.
Fatigue
Generalized tiredness, may be related to cancer cachexia, anemia, or systemic inflammation.
Insomnia
Difficulty sleeping, potentially due to pain, dyspnea, or anxiety related to the disease.
Cough
May be dry or productive, related to pleural irritation, compression of airways, or infection.
Chest wall mass
Palpable mass in advanced cases, indicating local invasion of the chest wall or soft tissues.
Loss of appetite
Anorexia, contributing to weight loss and cachexia.
Weight loss
Unexplained weight loss, often significant, defined as >5% loss over 6 months. It is a poor prognostic indicator.
Signs
Decreased breath sounds
Due to pleural effusion or tumor consolidation, often unilateral.
Dullness to percussion
Indicative of pleural effusion or solid tumor, typically over the affected hemithorax.
Palpable chest wall mass
Sign of local invasion, seen in advanced disease, often tender or fixed.
Signs of pleural effusion on imaging
Chest CT often shows pleural thickening, which may be nodular or diffuse, and associated effusion [PM-1].
Red FlagsClick to collapse
Recurrent or unexplained pleural effusion: In patients with a history of asbestos exposure, this is a key alarm feature that necessitates further investigation, including cytologic assessment and biopsy to rule out mesothelioma [MS-3].
Pleural thickening on chest CT: Irregular, nodular, or diffuse pleural thickening should raise suspicion for mesothelioma and prompt biopsy, as it is a hallmark imaging finding [PM-1].
Unexplained weight loss or appetite loss: Unintentional weight loss of more than 5% over 6 months is a common alarm symptom of malignancy and requires urgent evaluation [MS-2].
Persistent chest pain or dyspnea: Symptoms that are progressive and not explained by other causes, especially in the context of asbestos exposure, warrant immediate diagnostic workup [MS-3].
Performance status 3-4: Patients presenting with poor performance status may have advanced disease and require immediate supportive care assessment and potential palliative interventions [PM-2].
Palpable chest wall mass: Indicates possible local invasion and advanced disease, necessitating urgent staging workup with imaging and biopsy [MS-3].
Rapid symptom progression: Quick worsening of symptoms such as dyspnea or pain may indicate aggressive disease or complications like malignant effusion, requiring urgent intervention [MS-3].
InvestigationsClick to collapse
Diagnostic
Chest CT with contrast
Initial imaging to evaluate pleural thickening, effusion, and extent of disease; recommended as part of initial evaluation to guide further steps [PM-1].
Thoracentesis for cytologic assessment
To obtain pleural fluid for cytologic analysis; however, cytology is often negative or inconclusive even in mesothelioma, limiting its diagnostic utility [MS-3].
Pleural biopsy
Essential for histologic confirmation and subtype determination; preferred method is thoracoscopic biopsy to obtain adequate tissue with minimal ports [PM-1]. Other methods include CT-guided core biopsy and open biopsy.
Soluble mesothelin-related peptide (SMRP)
Optional biomarker that may correlate with disease status and burden; not diagnostic but can support clinical assessment in context [MS-3].
Staging
Chest and abdominal CT with contrast
Standard staging imaging to assess local extent and abdominal involvement; recommended as part of pretreatment evaluation to guide treatment strategy [PM-2].
FDG-PET/CT
For patients being considered for surgery; helps identify metabolically active disease, assess lymph node involvement, and detect distant metastases. Should be performed before pleurodesis to avoid false-positive results from talc inflammation [PM-3].
Mediastinoscopy or EBUS/EUS with FNA
To assess mediastinal lymph node involvement; critical for accurate staging in surgical candidates, as N2 disease impacts prognosis and treatment [PM-3].
Chest MRI with contrast
Optional for further evaluation of chest wall, spinal, diaphragmatic, or vascular involvement based on CT findings; provides better soft tissue contrast [PM-3].
VATS and/or laparoscopy
To rule out contralateral or peritoneal disease if suspected, which would indicate stage IV (unresectable) disease and alter management [PM-3].
Biomarkers
Immunohistochemistry (IHC) panel
To confirm mesothelial differentiation and exclude mimics like carcinoma; recommended panel includes at least two mesothelial markers (e.g., calretinin, WT1, D2-40) and two carcinoma markers (e.g., claudin-4, TTF-1, polyclonal CEA) [PM-A].
BAP1 IHC
Specific marker to distinguish mesothelioma from reactive mesothelial proliferations; loss of nuclear BAP1 expression indicates malignancy and is present in ~50-70% of epithelioid mesothelioma [PM-A].
MTAP IHC
Surrogate for CDKN2A loss; loss of cytoplasmic MTAP staining is reported in ~40-60% of mesothelioma and rarely in reactive proliferations, aiding diagnosis [PM-A].
CDKN2A (p16) FISH
Homozygous deletion by FISH is present in ~60% of mesotheliomas and supports diagnosis, but it is not specific as it can occur in other tumors [PM-A].
Broad molecular tumor profiling
Recommended to identify rare driver alterations (e.g., NTRK or ALK fusions) for which effective drugs may be available or to counsel patients regarding clinical trials [PM-C].
StagingClick to collapse
AJCC Cancer Staging System, 9th edition [ST-1, ST-2].
T Categories
| Stage | Description |
|---|---|
| TX | Primary tumor cannot be assessed. |
| T0 | No evidence of primary tumor. |
| T1 | Tumor limited to the ipsilateral pleura with Psum ≤12 mm and no involvement of the fissure (Fmax ≤5 mm). Psum is the sum of three measurements of maximal pleural thickness along the chest wall or mediastinum in upper, middle, and lower divisions. Fmax is the maximal thickness along fissures on sagittal images [ST-1]. |
| T2 | Tumor involving each of the ipsilateral pleura with Psum ≤12 mm and with any of the following: involvement of the fissure (Fmax >5 mm), mediastinal fat invasion, solitary area of chest wall soft tissue invasion; OR tumor involving each of the ipsilateral pleura with Psum >12 mm but ≤30 mm, with or without involvement of the fissure, mediastinal fat invasion, or solitary area of chest wall soft tissue invasion [ST-1]. |
| T3 | Tumor involving the ipsilateral pleura with Psum >30 mm, with or without involvement of the fissure (Fmax >5 mm), mediastinal fat invasion, or solitary area of chest wall soft tissue invasion [ST-1]. |
| T4 | Tumor with invasion of any of the following: chest wall bony invasion (rib), mediastinal organs (heart, spine, esophagus, trachea, great vessels), diffuse chest wall invasion, direct tumor extension through the diaphragm or pericardium, direct tumor extension to the contralateral pleura, presence of malignant pericardial effusion [ST-1]. |
N Categories
| Stage | Description |
|---|---|
| NX | Regional lymph nodes cannot be assessed. |
| N0 | No tumor involvement of regional lymph node(s). |
| N1 | Tumor involvement of ipsilateral bronchopulmonary, hilar, or mediastinal (including the internal mammary, peridiaphragmatic, pericardial fat pad, or intercostal lymph nodes) regional lymph nodes [ST-2]. |
| N2 | Tumor involvement of contralateral mediastinal, ipsilateral, or contralateral supraclavicular lymph nodes [ST-2]. |
M Categories
| Stage | Description |
|---|---|
| M0 | No distant metastasis. |
| M1 | Distant metastasis [ST-2]. |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage I | T1 N0 M0 | Tumor limited to ipsilateral pleura without lymph node involvement or distant metastasis. | Not explicitly stated in the source; however, overall median survival for pleural mesothelioma is approximately 1 year, with 5-year survival about 5-10% [MS-2]. | For clinical stage I with epithelioid histology, systemic therapy is preferred, but surgical evaluation may be considered in select patients [PM-2]. |
| Stage II | T2 N0 M0 or T1 N1 M0 | Tumor with limited extension or ipsilateral lymph node involvement, but no distant metastasis. | Not specified; survival is poor with median OS around 1 year. | Systemic therapy is recommended; surgery is not recommended for stage II-IV regardless of histology [PM-2]. |
| Stage IIIA | T2 N1 M0 or T3 N0-N1 M0 or T1-T3 N2 M0 | Locally advanced tumor with possible mediastinal lymph node involvement, indicating more extensive disease. | Not specified; survival is diminished with N2 disease. | Systemic therapy; surgery may be considered only in clinical trials or at expert centers for N2 disease [PM-2]. |
| Stage IIIB | T4 Any N M0 | Tumor with invasion of adjacent structures, considered unresectable. | Poor; median OS likely less than 1 year. | Systemic therapy or supportive care. |
| Stage IV | Any T Any N M1 | Distant metastatic disease. | Very poor; median OS likely less than 1 year. | Systemic therapy and palliative care. |
Staging Pearls
- Staging is based on both clinical and pathological assessment; clinical staging uses imaging, while pathological staging is determined after surgical resection [ST-1, ST-2].
- Tumor thickness is measured using Psum (sum of three maximal pleural thickness measurements) and Fmax (maximal fissure thickness), which are specific to mesothelioma staging [ST-1].
- N2 disease is associated with substantially diminished prognosis, and surgical resection should only be considered in clinical trials or at centers with expertise in mesothelioma [PM-2].
- The 9th edition AJCC staging system incorporates specific measurements for pleural tumor extent, emphasizing the importance of accurate imaging and pathologic evaluation [ST-1].
- Epithelioid histology generally has a better prognosis than biphasic or sarcomatoid histology, but staging is uniform across histologic types [PM-A].
Management PrinciplesClick to collapse
Pleural mesothelioma (PM) is a rare cancer originating from mesothelial surfaces of the pleura, estimated to occur in approximately 3,000 people in the United States each year.1,2 PM accounts for approximately 85% of all mesotheliomas; approximately 15% arise from the peritoneum, and less than 1% from the pericardium or tunica vaginalis testis.2,4,5 Treatment philosophy centers on systemic therapy as the primary treatment modality for most patients with PM, regardless of resectability. The median overall survival (OS) is approximately 1 year after diagnosis, and 5-year OS is approximately 5% to 10%.7-14 Most patients diagnosed with PM are over 60 years of age.6,9 The disease occurs mainly in males with asbestos exposure, with a median latent period exceeding 32 years.15,16 Two immune checkpoint inhibitor (ICI)-containing regimens have demonstrated efficacy as first-line therapy: nivolumab plus ipilimumab (category 1) and pembrolizumab plus platinum/pemetrexed chemotherapy (category 1).9,8 Surgery is no longer considered a routine primary treatment for most patients, based on randomized trial data from MARS and MARS2 demonstrating that cytoreductive surgery does not improve survival compared with systemic therapy alone.187,188 Treatment decisions require a multidisciplinary approach integrating clinical stage, histologic subtype, performance status (PS), and patient preference. All regimens recommended for PM can also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma.155,156 Broad molecular tumor profiling is recommended to identify rare driver alterations such as NTRK or ALK fusions.25
Curative/Definitive
Select patients with clinical stage I PM with epithelioid histology, PS 0-2, who are medically operable
Systemic therapy as primary treatment with consideration of surgical evaluation for carefully selected patients; pleural IMRT may be considered sequentially. If surgery is pursued after multidisciplinary evaluation, P/D is recommended over EPP. The benefit of surgical resection is unclear and there is no evidence that patient survival is improved with surgery combined with systemic therapy versus systemic therapy alone.
Palliative/Non-curative
Patients with clinical stage II-IV PM with epithelioid histology; sarcomatoid or biphasic histology at any stage; medically inoperable patients at any stage; PS 0-2
Systemic therapy as primary treatment modality. Observation may be considered for asymptomatic patients with minimal disease burden if systemic therapy is planned at progression. RT is an effective palliative treatment for chest pain, bronchial or esophageal obstruction, or other symptomatic sites.
Best Supportive Care
Patients with PS 3-4
Best supportive care is recommended. RT and image-guided thermal ablation are palliative options for symptomatic pleural disease.
Management by a multidisciplinary pleural team with experience in pleural mesothelioma is recommended. The multidisciplinary team should include diagnostic imaging specialists, pulmonologists, surgeons, medical oncologists, and radiation oncologists. Recommendations regarding RT should be made by radiation oncologists with experience in managing pleural mesothelioma. The best timing for delivering RT after surgical intervention and/or in conjunction with chemotherapy should be discussed by a multidisciplinary team. Surgical resection should be performed on carefully evaluated patients by thoracic surgeons with experience in managing pleural mesothelioma.
Patients with PS 0-2 are candidates for active systemic therapy with or without consideration of surgical evaluation (for stage I epithelioid). Patients with PS 3-4 should receive best supportive care. The NCCN Panel recommends best supportive care for patients presenting with PS 3-4.
Management PathwaysClick to collapse
Branching: Clinical stage I, Epithelioid histology, Medical operability, PS 0-2, Surgical resectability
Branching: Clinical stage I, Epithelioid histology, Surgical resectability determined at exploration
Branching: Clinical stage II-IV, Histologic subtype (epithelioid, sarcomatoid, biphasic), Medical operability, PS 0-2
Branching: Prior therapy type (chemotherapy only), Disease progression, PD-L1 status
Branching: Prior ICI therapy, Disease progression
Branching: Prior therapy, Clinical factors, Availability
Branching: PS 3-4
Pretreatment EvaluationClick to collapse
Imaging
Pathologic Diagnosis
Laboratory/Markers
Mediastinal Staging
Cardiopulmonary Assessment
Additional Evaluation for Surgical Candidates
Symptom and Psychosocial Assessment
SurgeryClick to collapse
Surgery is no longer considered a routine primary treatment option for most patients with PM based on data from MARS and MARS2 randomized trials. Systemic therapy is now the preferred primary treatment for most patients. However, surgical evaluation may be considered for select patients with clinical stage I PM with epithelioid histology and PS 0-2 who are medically operable.
Surgical resection should be performed on carefully evaluated patients by thoracic surgeons with experience in managing pleural mesothelioma
Decisions regarding surgical options are highly dependent on accurate histology; cytology is generally not considered adequate for histologic differentiation required for treatment decisions
For patients being considered for surgery, a single-port thoracoscopy on the line of the potential incision is recommended
The goal of surgery is complete gross cytoreduction of the tumor (macroscopic complete resection)
If macroscopic complete resection is not possible (eg, multiple sites of chest wall invasion), surgery should be aborted
If most of gross disease can be removed to help with postoperative management with minimal impact on morbidity, surgery should be continued
Mediastinal nodal sampling should be performed with a goal to obtain at least 3 nodal stations
P/D is the preferred surgical treatment option over EPP
If N2 disease is identified, prognosis is substantially diminished; surgical resection should only be considered in clinical trials or at expert centers
Procedures
Pleurectomy/Decortication (P/D)
Clinical stage I PM with epithelioid histology in select patients after careful multidisciplinary evaluation; preferred surgical option when surgery is pursued
Extrapleural Pneumonectomy (EPP)
Rare circumstances requiring careful consideration of the total treatment plan by the patient and multidisciplinary team
Radiation TherapyClick to collapse
RT plays a supportive role in the treatment of PM. It is not routinely used as primary treatment but can be considered as sequential therapy after systemic therapy and/or P/D in select patients with stage I epithelioid histology. RT is an effective palliative treatment for relief of chest pain, bronchial or esophageal obstruction, or other symptomatic sites. Prophylactic RT is not routinely recommended to prevent instrument-tract recurrence.
Principles
- Recommendations regarding RT should be made by radiation oncologists with experience in managing pleural mesothelioma
- The best timing for delivering RT after surgical intervention and/or in conjunction with chemotherapy should be discussed by a multidisciplinary team
- PET scanning for treatment planning can be used as indicated
- Prophylactic RT is not routinely recommended to prevent instrument-tract recurrence after pleural intervention
- Pleural IMRT after P/D in the presence of an intact lung may be considered in centers with experience, given the technical difficulty of this treatment
- Advanced technologies may be used such as IGRT, SRS, SBRT, and IMPT
- Special attention should be paid to minimize radiation to the contralateral lung as the risk of fatal pneumonitis with IMRT is excessively high when strict limits are not applied
- Extensive elective nodal irradiation (ENI) is not recommended
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Palliative - Chest wall pain from recurrent nodules | 20-40 Gy or 30 Gy | 4 Gy or 3 Gy | 5-13 or 10 | 1-2 weeks or 2 weeks | Palliation of chest wall pain from recurrent pleural nodules |
| Palliative - Multiple brain or bone metastases | 30 Gy | 3 Gy | 10 | 2 weeks | Palliation of multiple brain or bone metastases |
| Post P/D - Higher dose to higher risk areas | 45-60 Gy | 1.8-2 Gy | 25-33 | 5-6 weeks | Adjuvant RT after pleurectomy/decortication; higher dose to higher risk areas |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Pleural Intensity-Modulated Radiation Therapy (IMRT) | 45-60 Gy in 1.8-2 Gy fractions | May be used in conjunction with systemic therapy; timing discussed by multidisciplinary team | Sequential therapy after systemic therapy and/or P/D for select patients with stage I PM with epithelioid histology at centers with experience | Phase 3 randomized trial (Trovo et al.) demonstrated substantially greater overall survival with sequential pleural IMRT compared to palliative RT (median OS 25.6 vs 12.4 months, P<.001; 2-year OS 58% vs 28%, HR 0.54, P=.031). IMPRINT phase 2 trial (Rimner et al.) evaluated safety with 30% grade >=2 radiation pneumonitis. | Grade >=2 radiation pneumonitis in 30% of patients; fatal pneumonitis risk if strict lung dose limits not maintained |
| Palliative Radiation Therapy | 20-40 Gy in fractions of >=4 Gy; or 30 Gy in 3 Gy fractions | N/A | Palliative treatment for chest pain, bronchial or esophageal obstruction, or other symptomatic sites | Daily doses of 4 Gy appear more efficacious than fractions of <4 Gy for chest pain relief | Depends on treatment volume |
| Stereotactic Body Radiation Therapy (SBRT)/Stereotactic Radiosurgery (SRS) | Varies by indication | N/A | Oligometastatic disease (brain, bone); may be considered for oligorecurrent pleural disease | Site-dependent |
Systemic TherapyClick to collapse
Systemic therapy is the primary treatment modality for most patients with PM. Historically, cytotoxic chemotherapy was the mainstay, but two ICI-containing regimens have now demonstrated efficacy in the first-line setting and are FDA approved. All regimens can also be used for pericardial mesothelioma and tunica vaginalis testis mesothelioma. Broad molecular tumor profiling is recommended to identify rare driver alterations (eg, NTRK, ALK). For patients with non-epithelioid histology, ICI-based therapy is favored as non-epithelioid PM appears less chemosensitive than epithelioid PM. PD-L1 testing is not required for prescribing ICI-containing regimens.
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Treatment Response Assessment for Pleural Mesothelioma
Timing
Response assessment should be performed periodically during and after systemic therapy. The specific interval depends on the treatment regimen and clinical context.
Response Logic
-
Response to first-line systemic therapy should be assessed with imaging (CT chest/abdomen with contrast) at regular intervals
-
Progression is defined by radiographic or symptomatic progression
-
Upon disease progression, subsequent therapy should be initiated based on the type of first-line treatment received
-
If chemotherapy was first-line, nivolumab with or without ipilimumab is preferred subsequent therapy
-
If ipilimumab/nivolumab was first-line, platinum/pemetrexed (with or without bevacizumab) is preferred subsequent therapy
-
Rechallenge with pemetrexed-based therapy may be considered if good response to front-line pemetrexed-based treatment
Imaging Recommendations
-
Chest CT with contrast for response assessment and surveillance
-
Chest and abdominal CT with contrast as part of staging
-
FDG-PET/CT may be used for staging and treatment planning; should be obtained before pleurodesis
-
Chest MRI with contrast optional for evaluating local extent of disease
Biopsy Or Salvage Logic
-
Tissue confirmation of progression is not routinely required before initiating subsequent therapy
-
Mediastinoscopy or EBUS/EUS may be performed for restaging if clinically indicated
-
For patients with progression on systemic therapy, options depend on prior treatment: ICI-based therapy if prior chemo-only; platinum/pemetrexed-based therapy if prior ICI-based therapy
-
Palliative RT or image-guided thermal ablation may be considered for symptomatic progressive pleural disease
SurveillanceClick to collapse
Clinical Follow Up Schedule
- No explicit, standardized follow-up schedule is provided in the NCCN Guidelines for pleural mesothelioma. Follow-up frequency and intensity are determined by the treating multidisciplinary team based on the treatment received, disease status, and patient factors.
Imaging Strategy
- Chest/abdomen CT with contrast is used for initial staging [MS-5].
- FDG-PET/CT may be used for initial staging and to assess metabolic activity, ideally before pleurodesis [MS-5].
- Response assessment and surveillance typically involve periodic CT scans, though the exact interval is not mandated.
Laboratory Monitoring
- Soluble mesothelin-related peptide (SMRP) is an optional biomarker that may correlate with disease status and be used for monitoring [PM-1, MS-3].
- Complete blood counts and metabolic panels are monitored during systemic therapy to assess toxicity.
Supportive Follow Up
- Ongoing assessment and management of symptoms (dyspnea, pain).
- Reassessment of nutritional status and psychosocial distress.
- Monitoring for and managing long-term sequelae of treatment (e.g., pulmonary fibrosis, cardiac issues).
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Recurrent pleural effusion causing dyspnea and chest discomfort. | Talc pleurodesis or placement of an indwelling pleural catheter for management. Drainage is preferred for potentially operable candidates; either drainage or pleurodesis is an option for inoperable patients [PM-B]. Therapeutic/palliative thoracentesis can also be used. |
| Chest wall pain from recurrent nodules or pleural disease. | Palliative radiation therapy. Daily doses of ≥4 Gy appear more efficacious for pain relief than lower fractions, though the optimal regimen is unclear [MS-11, PM-D]. |
| Bronchial or esophageal obstruction. | Palliative radiation therapy [MS-11, PM-D]. |
Supportive CareClick to collapse
Principles of supportive care and survivorship are integrated into the management of pleural mesothelioma to manage symptoms, treatment side effects, and improve quality of life. This includes management of pleural effusions, pain, nausea, distress, fatigue, immunotherapy toxicities, venous thromboembolic disease, and survivorship care [PM-B].
Referenced indirectly through general cancer supportive care principles; specific nutritional guidance for mesothelioma is not detailed in the source. Consultation with a dietitian is typically recommended.
Per NCCN Guidelines for Antiemesis [PM-B]. Regimen-dependent; highly emetogenic chemotherapy (e.g., cisplatin) requires aggressive prophylaxis.
Not explicitly detailed in the provided source. General oncology principles for neutropenia risk reduction with myelosuppressive chemotherapy apply.
Refer to the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease [PM-B]. Patients with mesothelioma are at risk, and vigilance for VTE symptoms is required.
Follow the NCCN Guidelines for Adult Cancer Pain. Options include radiation for chest wall pain, interventional procedures, and systemic analgesics [PM-B, MS-11].
Assess for distress at initial evaluation using tools like the NCCN Distress Thermometer and Problem List. Refer to the NCCN Guidelines for Distress Management [PM-1, PM-B]. Address social determinants of health.
Not specified in the provided source. General pre-treatment dental evaluation is recommended for patients receiving chemotherapy or radiation to the head/neck.
PrognosisClick to collapse
Pleural mesothelioma (PM) is a rare, aggressive cancer with a generally poor prognosis. Median overall survival (OS) after diagnosis is approximately 1 year, and the 5-year OS rate is about 5% to 10% [MS-3, 7-14]. The prognosis is heavily influenced by histologic subtype, with epithelioid histology conferring a more favorable prognosis than biphasic or sarcomatoid histologies [9,96]. Most patients present with advanced disease, and CNS metastases are rare [71]. Incidence is estimated at ~3,000 cases annually in the United States, with a latent period from asbestos exposure typically >32 years [15,16].
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| AJCC Stage I | Not explicitly provided as a standalone figure in the source. | Clinical stage I disease with epithelioid histology may be considered for surgical evaluation, but the benefit of surgical resection is unclear, and survival is not proven to be improved with surgery plus systemic therapy versus systemic therapy alone [MS-2]. The 5-year survival for all stages combined is 5%-10%. |
| AJCC Stage II-IV | Not explicitly provided as standalone figures. | Systemic therapy is the primary treatment modality for most patients with stage II-IV disease regardless of histology, or for those with sarcomatoid/biphasic histology at any stage. Prognosis with N2 disease is substantially diminished, and surgical resection is only considered in specialized centers or trials [MS-10, MS-13]. |
Prognostic Factors
- Histologic subtype (epithelioid is more favorable than biphasic or sarcomatoid) [9,96].
- Clinical stage (earlier stage is more favorable) [ST-2].
- Performance status (PS 0-2 is required for active treatment; PS 3-4 indicates best supportive care) [MS-2, MS-14].
- BAP1 expression and mutations: Patients with epithelioid mesothelioma and loss of BAP1 by IHC with retained p16 expression have prolonged survival [40]. Patients with germline BAP1 mutations have improved survival [41,42].
- PD-L1 expression: Its utility as a predictive biomarker for immunotherapy in mesothelioma remains unclear [49, MS-7].
Follow UpClick to collapse
Post Curative Treatment
For the rare patients who undergo what is considered curative-intent multimodality therapy (e.g., systemic therapy + surgery ± RT for stage I epithelioid), close follow-up is warranted to detect recurrence. No specific standardized post-curative schedule is provided in the NCCN document.
Surveillance Rationale
The primary rationale for surveillance is to detect disease progression or recurrence early to guide subsequent therapy, manage symptoms, and evaluate eligibility for clinical trials. Surveillance also monitors for long-term effects of treatment.
Late Effects Screening
- Screening for treatment-related toxicities: pneumonitis (after IMRT or immunotherapy), renal dysfunction (after cisplatin), cardiac toxicity (after radiation).
- Monitoring for second malignancies, particularly in patients with germline BAP1 mutations who have an increased risk of other cancers (e.g., uveal melanoma, cutaneous melanoma, renal cell carcinoma) [51].
- Assessment of respiratory function and quality of life.
Recurrence Patterns
Most recurrences are local-regional within the pleural cavity. Distant metastases can occur but are less common. CNS metastases are rare [71]. Pattern of failure after surgery and adjuvant IMRT may include mediastinal nodal failure (22%) and distant progression (48%) [195].
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| CheckMate 743 | First-line Nivolumab Plus Ipilimumab versus Chemotherapy in Patients with Unresectable Malignant Pleural Mesothelioma | 2021 | 713 | Nivolumab (3 mg/kg Q2W) + Ipilimumab (1 mg/kg Q6W) for up to 2 years. | Cisplatin (75 mg/m2) or Carboplatin (AUC 5) + Pemetrexed (500 mg/m2) Q3W for up to 6 cycles. | Unresectable malignant pleural mesothelioma, first-line. | Overall survival. | Median OS was 18.1 months with nivolumab+ipilimumab vs 14.1 months with chemotherapy (HR 0.75; 95% CI 0.64-0.88; p=0.002) at 3-year follow-up [9,148,149]. | In non-epithelioid histology (n=150), median OS was 18.1 vs 8.8 months (HR 0.48; 95% CI 0.33-0.68). Grade 3-4 treatment-related AEs: 31% vs 32% [148,149]. | Established nivolumab + ipilimumab as a preferred first-line option, particularly for non-epithelioid histology. | Lancet |
| MAPS | Bevacizumab for Newly Diagnosed Pleural Mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study | 2016 | 448 | Cisplatin (75 mg/m2) + Pemetrexed (500 mg/m2) + Bevacizumab (15 mg/kg) followed by Bevacizumab maintenance. | Cisplatin (75 mg/m2) + Pemetrexed (500 mg/m2). | Unresectable pleural mesothelioma, PS 0-2, chemotherapy-naive. | Overall survival. | Median OS was 18.8 vs 16.1 months (HR 0.77; 95% CI 0.62-0.95; p=0.0167) [6, MS-5]. | More grade 3-4 AEs with bevacizumab (71% vs 62%), including hypertension (23% vs 0%), proteinuria (3% vs 0%), and thrombotic events (6% vs 1%) [6, MS-5]. | Established the addition of bevacizumab to platinum/pemetrexed as a category 1 first-line option. | Lancet |
| CONFIRM | Nivolumab versus Placebo in Patients with Relapsed Malignant Mesothelioma | 2021 | 332 | Nivolumab (240 mg Q2W). | Placebo. | Relapsed malignant mesothelioma after platinum-based chemotherapy. | Overall survival. | Median OS was 10.2 vs 6.9 months (HR 0.69; 95% CI 0.52-0.91; p=0.009) [16, MS-8]. | Clinical benefit regardless of PD-L1 expression. Serious AEs similar (41% vs 44%) [16, MS-8]. | Established nivolumab as a preferred subsequent therapy option after platinum-based chemotherapy. | Lancet Oncology |
| RAMES | Gemcitabine with or without Ramucirumab as Second-line Treatment for Malignant Pleural Mesothelioma | 2021 | 161 | Gemcitabine (1000 mg/m2 D1,8) + Ramucirumab (8 mg/kg Q2W). | Gemcitabine (1000 mg/m2 D1,8) + Placebo. | Malignant pleural mesothelioma after progression on platinum/pemetrexed. | Overall survival. | Median OS was 13.8 vs 7.5 months (HR 0.71; 95% CI 0.50-0.98; p=0.028) [22, MS-8]. | Grade 3-4 treatment-related AEs: 44% vs 30% [22, MS-8]. | Supported the use of gemcitabine + ramucirumab as a subsequent therapy option. | Lancet Oncology |
| PROMISE-meso | Pembrolizumab versus Single-agent Chemotherapy for Advanced Pre-treated Malignant Pleural Mesothelioma | 2020 | 144 | Pembrolizumab (200 mg Q3W). | Investigator's choice: Vinorelbine (30 mg/m2 Q1W) or Gemcitabine (1000 mg/m2 D1,8,15 Q4W). | Advanced mesothelioma after progression on platinum-based chemotherapy. | Overall survival. | No significant difference in OS (HR 1.12; 95% CI 0.74-1.69; p=0.59) [165, MS-8]. | ORR: 22% vs 6%. Grade 3-5 AEs: 16% vs 21% [165]. | Based on this and other data, the Panel supports single-agent vinorelbine or gemcitabine over single-agent pembrolizumab as subsequent therapy. | Annals of Oncology |
| MARS | Mesothelioma and Radical Surgery Randomised Feasibility Study | 2011 | 50 | EPP after 3 cycles of platinum-based chemotherapy. | No EPP after 3 cycles of platinum-based chemotherapy. | Resectable mesothelioma, candidates for trimodality therapy. | Feasibility; overall survival. | 12-month survival rate: 52.2% (EPP) vs 73.1% (no EPP) (HR 1.9; p=0.082). Median survival: 14.4 vs 19.5 months. Perioperative deaths in EPP group (12.5%) [187, MS-9]. | Lower quality-of-life scores with EPP [187, MS-9]. | Demonstrated high morbidity/mortality of EPP and influenced the paradigm shift away from routine surgery. | Lancet Oncology |
| MARS 2 | Extended Pleurectomy Decortication and Chemotherapy versus Chemotherapy Alone for Pleural Mesothelioma | 2024 | 169 | 2 cycles platinum/pemetrexed, then P/D (or extended P/D), then 2-4 more cycles chemotherapy. | 2 cycles platinum/pemetrexed, then chemotherapy alone (2-4 more cycles). | Surgically resectable pleural mesothelioma, PS 0-2. | Overall survival. | Median OS was shorter in the surgery group: 19.3 vs 24.8 months (HR 1.28; 95% CI 1.02-1.62; p=0.032) [188, MS-10]. | HR for OS in epithelioid: 1.12; in non-epithelioid: 2.66. More grade ≥3 AEs and higher costs with surgery [188, MS-10]. | Confirms systemic therapy alone may be superior to systemic therapy plus P/D, reinforcing systemic therapy as the primary modality for most patients. | Lancet Respiratory Medicine |
Clinical PearlsClick to collapse
- Pearl 1: Mandatory multidisciplinary team evaluation is recommended for all patients with pleural mesothelioma [MS-2].
- Pearl 2: Histologic subtype (epithelioid vs. biphasic/sarcomatoid) is critical for prognosis and treatment planning, particularly regarding the role of surgery [9,96, MS-13].
- Pearl 3: Systemic therapy, specifically immunotherapy-based combinations, is now the preferred first-line treatment for most patients, regardless of surgical resectability, based on MARS and MARS2 trial results [187,188, MS-12, MS-13].
- Pearl 4: Nivolumab + ipilimumab is a preferred first-line option, especially for non-epithelioid histology where it showed superior OS compared to chemotherapy (HR 0.48) [9,149].
- Pearl 5: Pemetrexed-based chemotherapy has moved from 'Preferred' to 'Other Recommended' for subsequent therapy, while nivolumab ± ipilimumab is now preferred post-chemotherapy [PM-C].
- Pearl 6: Prophylactic radiotherapy to prevent procedure-tract metastases is not routinely recommended based on the SMART trial [230, PM-D].
- Pearl 7: Pleural IMRT after P/D can improve survival but should only be performed at experienced centers due to the high risk of fatal pneumonitis if lung dose constraints are not strictly met [194,195, PM-D].
- Pearl 8: Patients with germline BAP1 mutations have a better prognosis and require genetic counseling and surveillance for other BAP1-associated cancers [41,42, MS-3].
Special SituationsClick to collapse
Pericardial mesothelioma
Tunica vaginalis testis mesothelioma
Localized pleural mesothelioma
Mesothelioma in situ
Germline BAP1 mutation carriers
ALK-rearranged peritoneal mesothelioma
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Mesothelioma: Pleural
NCCN Guidelines for Patients: Malignant Pleural Mesothelioma
NCCN Guidelines for Distress Management
NCCN Guidelines for Management of Immune Checkpoint Inhibitor-Related Toxicities
NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease
WHO Classification of Tumours: Thoracic Tumours, 5th Edition
AJCC Cancer Staging System, 9th Edition
Protective FactorsClick to collapse
- Smoking cessation is recommended as it may negatively affect treatment outcomes, though smoking itself is not a risk factor for mesothelioma development [53-57]