Mesothelioma Misdiagnosis

Mesothelioma misdiagnosis is a significant clinical problem that affects an estimated 10–30% of patients during the initial pathology review. Malignant mesothelioma is a rare cancer with histological features that can closely resemble several other malignancies, making accurate diagnosis challenging even for experienced pathologists. Misdiagnosis can lead to inappropriate treatment, delayed access to effective therapies, and missed opportunities for patients to pursue legal compensation for asbestos exposure.¹

The most common misdiagnoses for mesothelioma include lung adenocarcinoma, non-small cell lung cancer (NSCLC), metastatic carcinoma, sarcoma (for sarcomatoid mesothelioma), and reactive mesothelial hyperplasia (a benign condition). Epithelioid mesothelioma is most commonly confused with adenocarcinoma, while sarcomatoid mesothelioma can be mistaken for various soft tissue sarcomas or sarcomatoid carcinoma. Biphasic mesothelioma, which contains both epithelioid and sarcomatoid elements, may be misclassified if the biopsy sample captures only one component.²

Accurate diagnosis of mesothelioma requires a comprehensive immunohistochemical (IHC) panel that tests for markers expressed by mesothelioma cells (positive markers: calretinin, WT1, CK5/6, D2-40) and markers expressed by carcinoma cells (negative markers: CEA, MOC-31, Ber-EP4, TTF-1). A diagnosis should not be made based on morphology alone or on a limited IHC panel. The International Mesothelioma Interest Group (IMIG) guidelines recommend testing for at least two positive and two negative markers.³

Patients who receive a mesothelioma diagnosis — or who have been diagnosed with another cancer but have a history of asbestos exposure — should strongly consider seeking a second opinion from a pathologist experienced in mesothelioma. Expert pathology review at an NCI-designated cancer center or mesothelioma specialty center can confirm or correct the diagnosis, ensuring patients receive appropriate treatment and can pursue any applicable legal claims.

Misdiagnosis patterns vary by mesothelioma cell type:

• Epithelioid mesothelioma — most commonly confused with lung adenocarcinoma, metastatic carcinoma, or reactive mesothelial hyperplasia
• Sarcomatoid mesothelioma — may be misdiagnosed as sarcoma, sarcomatoid carcinoma, fibrous pleurisy, or desmoplastic mesothelioma misidentified as benign fibrous pleuritis
• Biphasic mesothelioma — if the biopsy captures only one component, may be classified as purely epithelioid or sarcomatoid; can also be confused with synovial sarcoma or carcinosarcoma

Several factors contribute to mesothelioma misdiagnosis:

• Rarity of the disease — many pathologists encounter few mesothelioma cases during their careers, limiting diagnostic experience
• Morphological similarity — mesothelioma cells can closely resemble adenocarcinoma, sarcoma, and reactive mesothelial cells under the microscope
• Inadequate biopsy sampling — small biopsies may not capture the full tumor architecture or both components of biphasic disease
• Incomplete IHC panels — using too few immunohistochemical markers increases the risk of misclassification
• Clinical assumption bias — because lung cancer is far more common than mesothelioma, clinicians may default to a lung cancer diagnosis in patients with pleural disease

Preventing mesothelioma misdiagnosis requires a rigorous diagnostic approach:

• Comprehensive IHC panel — test for at least 2 positive mesothelioma markers (calretinin, WT1, CK5/6, D2-40) and 2 negative markers (CEA, MOC-31, Ber-EP4, TTF-1, claudin-4)
• Adequate tissue sampling — larger biopsy specimens (core biopsy or surgical biopsy) are preferred over fine-needle aspiration for accurate diagnosis
• Clinical correlation — integration of pathology findings with imaging, asbestos exposure history, and clinical presentation
• Expert pathology review — referral to a pathologist with mesothelioma expertise, particularly for unusual presentations or equivocal findings
• Molecular testing — loss of BAP1 expression or CDKN2A deletion (detected by FISH) can help distinguish mesothelioma from reactive mesothelial proliferation

The consequences of mesothelioma misdiagnosis on patient outcomes can be significant:

• Misdiagnosis as adenocarcinoma leads to treatment with regimens not optimized for mesothelioma
• Misdiagnosis as a benign condition (reactive mesothelial hyperplasia) delays all cancer treatment
• Delayed correct diagnosis reduces eligibility for curative-intent surgery due to disease progression
• Incorrect diagnosis may disqualify patients from mesothelioma-specific clinical trials
• Average treatment delay due to misdiagnosis is estimated at 2–6 months, which can significantly impact prognosis

Steps to reduce the risk of mesothelioma misdiagnosis:

• Ensure your pathologist uses a comprehensive IHC panel with multiple positive and negative markers
• Request a sufficiently large tissue sample — surgical biopsy or thoracoscopic biopsy is preferred
• Inform your medical team of any asbestos exposure history to ensure mesothelioma is included in the differential diagnosis
• Seek a second opinion from a mesothelioma specialty center, especially if your diagnosis was made at a community hospital
• Ask about molecular testing (BAP1, CDKN2A FISH) if the diagnosis is uncertain