Biphasic Mesothelioma: A Diagnostic Challenge

What Makes Biphasic Mesothelioma Unique?

Biphasic mesothelioma is a complex and unique form of mesothelioma that contains both epithelioid and sarcomatoid components. Unlike purely epithelioid mesothelioma, which tends to have a better prognosis, or sarcomatoid mesothelioma, which is more aggressive, biphasic mesothelioma falls somewhere in between. For a diagnosis of biphasic mesothelioma, at least 10% of the tumor must be composed of each component.

Why does this matter? Because biphasic tumors in the pleura can resemble many other cancers, and distinguishing mesothelioma from metastatic biphasic tumors is critical for proper treatment.

Differentiating Biphasic Mesothelioma From Other Tumors

While biphasic mesothelioma is the most common biphasic tumor of the pleura, it is far from the only possibility. The differential diagnosis includes:

• Carcinosarcomas
• Sarcomatoid carcinomas
• Synovial sarcoma
• Sarcomatoid renal cell carcinoma
• Malignant melanoma
• Neurogenic tumors
• Vascular tumors
• Desmoplastic small round cell tumor

Each of these has overlapping histologic features with biphasic mesothelioma, but key differences in immunohistochemistry, clinical presentation, and molecular markers help sort them out.

Carcinosarcomas and Sarcomatoid Carcinomas

Carcinosarcomas and sarcomatoid (spindle cell) carcinomas can appear biphasic, just like mesothelioma. The key difference? Carcinosarcomas are most commonly primary tumors of the lung, whereas mesothelioma arises from the pleura.

How to Differentiate Them

• Carcinosarcomas of the lung can involve the pleura by direct invasion or metastasis, but they still originate in the lung.
• Sarcomatoid carcinoma is a highly aggressive variant of lung cancer and often expresses glandular epithelial markers like TTF-1 and napsin A.
• Mesothelioma, on the other hand, is typically negative for TTF-1 and napsin A but positive for calretinin, WT-1, and CK5/6.

Key Takeaway: If a pleural tumor stains positive for TTF-1, think lung primary rather than mesothelioma.

Sarcomatoid Renal Cell Carcinoma

Sarcomatoid renal cell carcinoma (RCC) is another major mimic of biphasic mesothelioma. RCC can metastasize to the pleura and mimic mesothelioma both histologically and immunohistochemically.

How to Differentiate It

• RCC often expresses PAX8, while mesothelioma does not.
• RCC may be positive for EMA, which is also seen in mesothelioma, so EMA alone is not a reliable differentiator.
• A history of kidney cancer is a major clue that should always be considered.

Key Takeaway: If a pleural tumor expresses PAX8, think metastatic RCC rather than mesothelioma.

Malignant Melanoma

Metastatic malignant melanoma can mimic biphasic mesothelioma when it exhibits both epithelioid and spindle cell components. However, melanoma has a different set of immunohistochemical markers.

Key Diagnostic Differences

• Mesothelioma markers:
  • Calretinin
  • WT-1
  • Cytokeratin 5/6
• Melanoma markers:
  • S-100
  • HMB-45
  • Melan-A

Key Takeaway: If a pleural tumor is positive for S-100, HMB-45, or Melan-A, consider melanoma before mesothelioma.

Synovial Sarcoma

Synovial sarcoma can be primary or secondary in the pleura, making it a major diagnostic challenge. These tumors tend to appear in younger patients without asbestos exposure.

Key Features That Distinguish Synovial Sarcoma

• Tends to affect younger patients (20s to 40s).
• Often lacks asbestos exposure history.
• More well-circumscribed and sometimes pedunculated, unlike the diffuse spread of mesothelioma.
• Often expresses CD99 and bcl-2.
• Chromosomal translocation t(x;18)(p11.2;q11.2) is characteristic.

Key Takeaway: If a biphasic pleural tumor in a young patient lacks asbestos exposure, consider synovial sarcoma.

Neurogenic Tumors and Vascular Tumors

• Malignant peripheral nerve sheath tumors (MPNSTs) can have biphasic areas, but they express S-100 and lack mesothelial markers.
• Vascular tumors, such as epithelioid hemangioendothelioma, can also have epithelioid and spindle cell features.
• Vascular tumors express CD31 and CD34, while mesotheliomas do not.

Key Takeaway: If a biphasic pleural tumor stains positive for CD31 or CD34, consider a vascular tumor instead of mesothelioma.

Desmoplastic Small Round Cell Tumor (DSRCT)

DSRCT is a rare but aggressive tumor that can present in the pleura, mimicking mesothelioma. However, DSRCT has a unique molecular signature.

Key Features That Distinguish DSRCT

• Common in young males (under 40 years old).
• EWSR1-WT1 gene fusion (t(11;22)(p13;q12)) is diagnostic.
• Expresses desmin and WT-1, but lacks calretinin.

Key Takeaway: If a pleural tumor in a young male is WT-1 positive but calretinin negative, consider DSRCT before mesothelioma.

Final Thoughts

Diagnosing biphasic mesothelioma requires a multi-modal approach.

• Histology alone is insufficient—immunohistochemistry and molecular testing are crucial.
• Knowing the patient’s history (asbestos exposure, age, prior cancers) can provide important diagnostic clues.
• A well-selected IHC panel is key—TTF-1 for lung cancer, PAX8 for renal cancer, S-100 for melanoma, CD31/CD34 for vascular tumors, and calretinin for mesothelioma.
• Synovial sarcoma, DSRCT, and neurogenic tumors should always be on the differential when encountering biphasic pleural tumors.

Key Takeaway: If a pleural tumor has both epithelioid and spindle cell components, don’t assume it’s mesothelioma—rule out metastases, sarcomas, and rare biphasic tumors first.