Mesothelioma

Asbestos-driven pleural and peritoneal malignancy — BAP1 biology, late detection, and the nivolumab + ipilimumab IO doublet replacing platinum-pemetrexed as first-line standard

Key Points

Epidemiology & Incidence

Malignant mesothelioma is a rare but aggressive malignancy arising from mesothelial cells lining the pleura (~75–80%), peritoneum (~20%), pericardium (<1%), and tunica vaginalis testis (<1%). In the United States, approximately 3,000 new cases are diagnosed annually, with a near 1:1 incidence-to-mortality ratio reflecting uniformly poor prognosis. Incidence peaked in the US and Western Europe in the 1980s–2000s and has since plateaued or slightly declined, reflecting regulatory bans on asbestos use (US ban on new asbestos mining in 2002; broader bans in the EU). However, global incidence…

Etiology & Genetic Predisposition

Asbestos is the dominant causal agent in MPM. All commercial asbestos fiber types (chrysotile, crocidolite, amosite) are carcinogenic; amphibole fibers (crocidolite, amosite) carry the highest mesothelioma risk. Asbestos fibers, once inhaled, lodge in the pleura, causing chronic inflammation, reactive oxygen species, and DNA damage. The latency period between initial exposure and MPM diagnosis is exceptionally long — typically 30–50 years — meaning patients diagnosed today were exposed in the 1970s–1980s. Other etiologic factors: • Erionite: Naturally occurring fibrous mineral in volcanic…

Clinical Presentation

Malignant pleural mesothelioma most commonly presents with: • Progressive dyspnea: The cardinal symptom; caused by accumulating pleural effusion or restricted lung expansion from tumor encasement. Often insidious — patients may not seek evaluation for months after symptom onset. • Chest wall pain: Dull, aching, non-pleuritic chest or shoulder pain from direct pleural and chest wall invasion; advanced disease can cause severe, refractory neuropathic pain from intercostal nerve involvement. • Unilateral pleural effusion: Present in ~80–90% at diagnosis; often large and recurrent despite…

Staging & Histologic Subtypes

Malignant pleural mesothelioma is staged using the IASLC/AJCC 8th Edition TNM staging: Stage I: T1 N0 M0 — tumor limited to ipsilateral parietal pleura ± visceral pleura Stage II: T2 N0 M0 — involving ipsilateral diaphragmatic muscle or lung parenchyma Stage IIIA: T3 N0 M0 — locally advanced but potentially resectable Stage IIIB: T1–3 N1–2 or T4 any N, M0 — unresectable locally advanced Stage IV: M1 — distant metastatic disease Histologic subtypes (critical for prognosis and treatment): • Epithelioid (~60%): Tubular, tubulopapillary, or solid patterns; best prognosis (median OS ~14–18 months…

Unresectable/Metastatic Treatment

The majority of patients (~80%) present with unresectable disease. Systemic therapy is the primary treatment modality. First-line treatment — the field shifted in 2021: • Nivolumab + ipilimumab: FDA-approved (October 2020) for unresectable MPM based on CheckMate 743. mOS 18.1 months (IO doublet) vs. 14.1 months (pemetrexed + platinum); HR 0.74. Benefit was most pronounced in non-epithelioid histology (sarcomatoid/biphasic): mOS 18.1 vs. 8.8 months (HR 0.46). For epithelioid histology: mOS 18.7 vs. 16.5 months (HR 0.85 — benefit less pronounced). Overall survival benefit was durable at 3…

Surgical & Multimodal Approaches

Surgery plays a role only in a carefully selected minority of MPM patients — those with early-stage (I–IIIA), epithelioid-histology disease and excellent performance status, treated at experienced thoracic oncology centers. Surgical procedures: • Extrapleural pneumonectomy (EPP): En bloc removal of the pleura, lung, ipsilateral diaphragm, and pericardium. Offers maximal cytoreduction but carries high perioperative morbidity (30-day mortality 5–7% in high-volume centers, up to 25% elsewhere). EPP followed by hemithoracic radiation (adjuvant intensity-modulated RT, IMRT) is used in some…