Mesothelioma Biopsy

Mesothelioma biopsy is a tissue sampling procedure that is absolutely required for a definitive diagnosis of mesothelioma. No treatment plan — whether surgery, chemotherapy, immunotherapy, or clinical trial enrollment — can proceed without histological (tissue-level) confirmation of the disease. While imaging studies such as CT scans and PET scans can raise suspicion, and thoracentesis fluid cytology can sometimes identify malignant cells, only a tissue biopsy provides the architectural and immunohistochemical information needed to confirm the diagnosis and classify the tumor subtype.¹

The central diagnostic challenge in mesothelioma is distinguishing it from metastatic adenocarcinoma — a far more common cancer that can involve the pleura and closely mimic mesothelioma on both imaging and cytology. These two cancers require completely different treatment approaches, making accurate differentiation critical. Pathologists resolve this challenge using a panel of immunohistochemical (IHC) stains applied to the biopsy tissue. Mesothelioma characteristically stains positive for markers such as calretinin, WT1, D2-40 (podoplanin), and CK5/6, while staining negative for adenocarcinoma markers such as CEA, TTF-1, MOC-31, and BerEP4. A minimum of two positive mesothelial markers and two negative carcinoma markers is recommended by the International Mesothelioma Interest Group for a confident diagnosis.²

Three principal biopsy techniques are available: CT-guided needle biopsy, thoracoscopic (VATS) biopsy, and open surgical biopsy. The choice depends on the location and accessibility of the tumor, the patient's fitness for surgery, and whether the procedure also needs to serve a therapeutic purpose (such as draining a pleural effusion or performing pleurodesis). VATS biopsy is generally considered the gold standard because it provides large tissue samples under direct visualization and allows simultaneous fluid drainage and pleurodesis.³

In addition to confirming the diagnosis, biopsy tissue is essential for determining the histological subtype — epithelioid, sarcomatoid, or biphasic — which has major implications for prognosis and treatment selection. Epithelioid mesothelioma, accounting for approximately 60–70% of cases, carries the most favorable prognosis, while sarcomatoid mesothelioma is more aggressive and less responsive to treatment.²

Several biopsy techniques are used to obtain tissue for mesothelioma diagnosis, ranging from minimally invasive needle procedures to surgical approaches:³

• CT-guided (percutaneous) needle biopsy — A cutting needle is advanced through the chest wall under CT guidance to sample areas of pleural thickening or mass. This is the least invasive approach and can be performed under local anesthesia with sedation. It is best suited for patients with visible, accessible pleural thickening on imaging. The main limitation is that needle biopsies obtain relatively small tissue cores, which may not provide sufficient architectural detail for subtyping, particularly for sarcomatoid mesothelioma. Diagnostic sensitivity ranges from 77–86%.³
• Thoracoscopic (VATS) biopsy — Considered the gold standard. The surgeon inserts a thoracoscope through small incisions under general anesthesia, directly visualizes the pleural surfaces, and obtains large, targeted biopsies from areas of tumor involvement. VATS provides diagnostic sensitivity exceeding 95% and allows simultaneous pleural fluid drainage, staging assessment, and talc pleurodesis if indicated. Multiple samples can be taken from different locations to capture tumor heterogeneity.¹
• Open surgical biopsy (mini-thoracotomy) — Involves a small incision in the chest wall to directly access the pleura. This is reserved for cases where VATS is technically difficult — for example, when extensive adhesions prevent safe insertion of the thoracoscope. Open biopsy provides excellent tissue samples but is more invasive and requires longer recovery.³
• Ultrasound-guided biopsy — For peripheral pleural lesions that are visible on ultrasound, a real-time ultrasound-guided needle biopsy may be performed at the bedside. This is less common than CT-guided biopsy but offers the advantage of no radiation exposure and real-time needle visualization.⁴

A biopsy is typically pursued when a patient presents with symptoms and imaging findings suggestive of mesothelioma, including:¹

• Persistent or progressive shortness of breath (dyspnea)
• Unilateral pleural effusion visible on chest imaging
• Chest pain — often dull, diffuse, and not well-localized
• Pleural thickening seen on CT scan, particularly if nodular or circumferential
• Unexplained weight loss and fatigue
• History of asbestos exposure (occupational, environmental, or secondary)
• Inconclusive or negative pleural fluid cytology despite high clinical suspicion

The pathological analysis of biopsy tissue is the definitive step in mesothelioma diagnosis. The process involves multiple layers of evaluation:²

• Histological examination — The tissue is processed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E). The pathologist evaluates cellular architecture, growth patterns, and the relationship between tumor cells and surrounding stroma. Epithelioid mesothelioma shows tubulopapillary, acinar, or solid patterns; sarcomatoid shows spindle cells resembling fibrosarcoma; biphasic contains both components²
• Immunohistochemistry (IHC) panel — This is the critical step. A panel of antibodies is applied to the tissue sections to identify protein expression patterns. The recommended panel includes at least two mesothelial markers (calretinin, WT1, D2-40, CK5/6) and two carcinoma markers (CEA, TTF-1, MOC-31, BerEP4, claudin-4). Mesothelioma is expected to be positive for mesothelial markers and negative for carcinoma markers²
• Special stains and molecular testing — In difficult cases, additional studies may include BAP1 (BRCA-associated protein 1) immunohistochemistry — loss of BAP1 expression is seen in approximately 60% of epithelioid mesotheliomas and strongly supports the diagnosis. Fluorescence in situ hybridization (FISH) for p16/CDKN2A deletion is another ancillary test that supports mesothelioma when positive⁵
• Second-opinion pathology — Because of the diagnostic complexity, expert review by a pathologist experienced in mesothelioma is strongly recommended, particularly when treatment decisions hinge on the diagnosis. Mesothelioma is rare enough that many community pathologists encounter very few cases²

The biopsy results directly determine the treatment pathway for mesothelioma patients. Once the diagnosis and subtype are confirmed, the multidisciplinary team can develop a treatment plan:¹

• Epithelioid subtype — The most favorable histology, potentially eligible for aggressive multimodal treatment including surgery (pleurectomy/decortication or extrapleural pneumonectomy), chemotherapy (pemetrexed + cisplatin/carboplatin), immunotherapy (nivolumab + ipilimumab), and radiation therapy¹
• Sarcomatoid subtype — More aggressive biology with poorer response to chemotherapy. Immunotherapy with checkpoint inhibitors (nivolumab + ipilimumab) has shown particular benefit in sarcomatoid and biphasic subtypes in the CheckMate 743 trial. Surgery is generally not recommended for pure sarcomatoid tumors⁵
• Biphasic subtype — Treatment depends on the proportion of epithelioid to sarcomatoid components. Higher epithelioid percentage is associated with better outcomes and may support surgical candidacy
• Clinical trial eligibility — Confirmed histological diagnosis and subtype are prerequisites for enrollment in clinical trials. Biopsy tissue may also be tested for molecular markers (such as BAP1 loss or PD-L1 expression) that determine eligibility for targeted or immunotherapy trials

The biopsy itself is a low-risk procedure when performed by experienced operators, and it provides the information essential for prognostic assessment:³

• Procedural risks — VATS biopsy complications include pneumothorax, bleeding, infection, and port-site tumor recurrence (tract metastasis). The risk of tract metastasis after thoracoscopy is approximately 10–20%, though prophylactic radiotherapy to the port sites can reduce this risk. CT-guided needle biopsy has lower procedural risk but a slightly lower diagnostic yield³
• Subtype and prognosis — Median survival for epithelioid mesothelioma is approximately 14–20 months; biphasic 8–13 months; sarcomatoid 4–8 months. These figures reflect the overall patient population and can vary significantly based on stage, performance status, and treatment received²
• Importance of adequate sampling — Insufficient tissue can lead to misdiagnosis or inability to subtype the tumor accurately. This is particularly important for biphasic mesothelioma, where small biopsies may sample only one component and miss the other. VATS biopsy's ability to obtain large, representative samples is a key advantage²