Biphasic Mesothelioma

Biphasic mesothelioma is the second most common histological subtype of malignant mesothelioma, accounting for approximately 20–30% of all diagnosed cases. It is defined by the presence of both epithelioid and sarcomatoid cell populations within the same tumor, with each component comprising at least 10% of the total tumor volume.¹

The prognosis and treatment response of biphasic mesothelioma depend heavily on the ratio of epithelioid to sarcomatoid cells within the tumor. Tumors with a predominantly epithelioid composition — for example, 70% epithelioid and 30% sarcomatoid — tend to behave more favorably and respond better to treatment than those with a predominantly sarcomatoid composition. This ratio is therefore one of the most important prognostic factors and directly influences treatment planning.²

Accurate diagnosis of biphasic mesothelioma requires adequate tissue sampling, as the two cell populations may be unevenly distributed throughout the tumor. Small biopsy specimens can miss one component entirely, leading to misclassification as purely epithelioid or purely sarcomatoid. Surgical biopsies that capture larger tissue volumes provide the most reliable histological assessment.³

Like all forms of mesothelioma, biphasic mesothelioma is caused by asbestos exposure, with a latency period typically spanning 20 to 50 years between initial exposure and diagnosis. Treatment approaches combine surgery, chemotherapy, immunotherapy, and radiation, tailored to the specific cellular composition and extent of disease.

Biphasic mesothelioma is not further subdivided into formal subtypes. However, it is clinically characterized by its cellular composition:

• Predominantly epithelioid biphasic — more than 50% epithelioid cells; generally associated with better treatment response and longer survival
• Predominantly sarcomatoid biphasic — more than 50% sarcomatoid cells; associated with more aggressive disease behavior and shorter survival, approaching the prognosis of pure sarcomatoid mesothelioma
• Balanced biphasic — roughly equal proportions of both cell types; intermediate prognosis

The distribution of cell types may vary within different regions of the same tumor, which is why large, representative biopsy samples are essential for accurate classification.

Biphasic mesothelioma symptoms are consistent with those of mesothelioma generally, and their severity may correlate with the predominant cell type:

• Progressive shortness of breath
• Chest pain or pressure (in pleural mesothelioma)
• Abdominal pain, bloating, or ascites (in peritoneal mesothelioma)
• Unexplained weight loss
• Chronic fatigue
• Persistent dry cough
• Pleural effusion
• Night sweats or low-grade fever

Patients with predominantly sarcomatoid biphasic tumors may experience more rapid symptom progression and earlier development of chest wall masses.

The established cause of biphasic mesothelioma is exposure to asbestos fibers:

• Occupational exposure — the most common route, affecting workers in construction, shipbuilding, insulation, mining, and industrial manufacturing
• Secondary exposure — family members exposed to asbestos fibers brought home on workers' clothing, hair, or skin
• Environmental exposure — communities near asbestos mines, vermiculite processing plants (e.g., Libby, Montana), or areas with naturally occurring asbestos

The latency period between exposure and diagnosis typically ranges from 20 to 50 years. It remains unclear why some patients develop epithelioid mesothelioma while others develop biphasic or sarcomatoid subtypes from similar exposures.

• Asbestos exposure — the primary established risk factor
• Duration of exposure — cumulative exposure increases risk, though even brief exposure can result in disease
• Asbestos fiber type — amphibole fibers carry higher risk than chrysotile
• Male sex — reflecting historical occupational exposure patterns
• Age over 60 — consistent with the long latency period
• BAP1 mutations — inherited mutations in the BAP1 tumor suppressor gene may increase susceptibility
• SV40 virus exposure — a controversial potential co-factor; research remains inconclusive

Diagnosing biphasic mesothelioma accurately is essential because the cell type ratio directly affects treatment decisions:

• Imaging — CT scans and PET-CT reveal pleural thickening, effusions, or peritoneal masses; imaging alone cannot determine cell type
• Tissue biopsy — surgical biopsy (thoracoscopy or laparoscopy) is strongly preferred over fine-needle aspiration to obtain sufficient tissue for assessment of both cell populations
• Immunohistochemistry — essential for confirming the presence of both epithelioid and sarcomatoid components; epithelioid regions stain positive for calretinin, CK5/6, and WT1, while sarcomatoid regions may show diminished mesothelial marker expression but retain pancytokeratin positivity
• Quantitative assessment — pathologists estimate the percentage of each cell type, which directly informs prognosis and treatment planning

A critical diagnostic challenge is sampling error. If a biopsy captures only the epithelioid component, the tumor may be misclassified. Larger tissue samples and expert pathological review reduce this risk.³

Biphasic pleural mesothelioma is staged using the same TNM system applied to all pleural mesotheliomas (AJCC/IMIG):

• Stage I — tumor confined to the pleural lining on one side of the chest
• Stage II — tumor extends into the adjacent lung tissue or diaphragm
• Stage III — locally advanced disease with chest wall invasion or lymph node involvement
• Stage IV — distant metastasis or spread to the contralateral hemithorax

Staging determines surgical eligibility, and patients with predominantly epithelioid biphasic tumors at stages I–II may be considered for curative-intent surgery.

Treatment for biphasic mesothelioma is guided by the predominant cell type and the extent of disease:

• Surgery — patients with predominantly epithelioid biphasic mesothelioma at early stages may be candidates for pleurectomy/decortication (P/D) or, less commonly, extrapleural pneumonectomy (EPP). Those with predominantly sarcomatoid tumors are less likely to benefit from aggressive surgery
• Chemotherapy — first-line treatment is cisplatin plus pemetrexed; response rates are generally intermediate between epithelioid and sarcomatoid mesothelioma
• Immunotherapy — nivolumab plus ipilimumab (CheckMate 743) is FDA-approved for unresectable pleural mesothelioma and has shown benefit for non-epithelioid histologies, including biphasic⁴
• Radiation therapy — used adjuvantly after surgery or palliatively for symptom management
• Multimodal therapy — the combination of surgery, chemotherapy, and radiation provides the best outcomes for eligible patients with predominantly epithelioid tumors

Treatment decisions should be made at specialized mesothelioma centers where a multidisciplinary tumor board can evaluate the histological composition and recommend the optimal approach.

The prognosis for biphasic mesothelioma falls between that of epithelioid and sarcomatoid subtypes:

• Median survival is approximately 8–14 months with treatment
• Tumors with more than 50% epithelioid composition have significantly better outcomes than those with predominantly sarcomatoid composition
• Patients eligible for multimodal therapy may achieve survival of 18 months or longer
• Stage at diagnosis, performance status, and cell type ratio are the most important prognostic factors
• Female patients and those under age 65 tend to have relatively better outcomes

Prevention of biphasic mesothelioma requires minimizing asbestos exposure:

• Compliance with OSHA and EPA asbestos regulations
• Professional asbestos inspection and abatement in older buildings before renovation or demolition
• Proper use of respiratory protection in occupational settings
• Avoiding disturbance of asbestos-containing materials in homes and buildings
• Regular medical monitoring for individuals with documented asbestos exposure