Uncommon Diagnostic Challenges in Epithelioid Mesothelioma

Why Diagnosing Epithelioid Mesothelioma Can Be Tricky

Mesothelioma is a deceptive cancer, often mimicking other malignancies, making an accurate diagnosis one of the toughest challenges in pathology. In most cases, a combination of histology, immunohistochemistry (IHC), and electron microscopy (EM) is enough to distinguish epithelioid mesothelioma from other cancers. However, some rare and unusual scenarios create gray areas, where even the best diagnostic tools struggle.

This article dives into the most challenging differential diagnoses of epithelioid mesothelioma, helping clinicians, pathologists, and oncologists navigate these complexities.

Mesothelioma vs. Peritoneal and Ovarian Serous Carcinomas

One of the biggest diagnostic dilemmas in peritoneal cancer is distinguishing epithelial peritoneal mesothelioma from papillary serous carcinoma. Since both can present as diffuse peritoneal involvement, making the correct call is critical for treatment decisions—serous carcinoma responds to chemotherapy, while mesothelioma typically does not.

Key Diagnostic Clues

• Mucin Stains:

  • Serous carcinomas may be positive for mucin, while mesotheliomas rarely are.
  • However, mucin staining is not always reliable, as some serous carcinomas lack detectable mucin.

• CEA Positivity:

  • Serous carcinoma: CEA positive in some cases.
  • Mesothelioma: CEA negative.

• Immunohistochemistry Panel:

  • Mesothelioma Markers:
    • Calretinin
    • WT-1
    • Cytokeratin 5/6
  • Serous Carcinoma Markers:
    • MOC-31
    • Ber-EP4
    • CA19-9

🔬 Key Takeaway: If a peritoneal or pleural tumor stains positive for Ber-EP4, B72.3, or MOC-31, it’s more likely a serous carcinoma rather than mesothelioma.

Pseudomesotheliomatous Adenocarcinoma of the Lung

Some lung adenocarcinomas mimic mesothelioma by diffusely infiltrating the pleura. These cases, termed pseudomesotheliomatous adenocarcinoma, present a serious diagnostic challenge.

How to Differentiate Them

• Histology:

  • Adenocarcinoma: May have papillary, glandular, or tubulopapillary structures.
  • Mesothelioma: Forms solid sheets or tubulopapillary growth.

• Mucin Staining:

  • Adenocarcinoma: Mucin positive.
  • Mesothelioma: Mucin negative.

• Key Immunohistochemical Markers:

  • Mesothelioma:
    • Calretinin
    • CK5/6
    • D2-40
  • Adenocarcinoma:
    • CEA
    • TTF-1
    • Napsin A

Important Note: Some mesotheliomas do stain positive for mucin, so always use a complete immunohistochemical panel.

Large Cell Undifferentiated Epithelioid Malignancy of the Pleura

A rare but difficult category involves pleural tumors where the cells are so undifferentiated that they lack glandular or mesothelial features. These tumors stain positive for cytokeratins, but negative for classic mesothelioma and carcinoma markers.

Key Issues

• Neither adenocarcinoma nor mesothelioma markers are expressed.
• Ultrastructural features are absent, making EM unhelpful.
• Definitive diagnosis is often impossible.

Clinical correlation and follow-up biopsy may be the only way to establish the correct diagnosis over time.

Localised Mesothelioma

Mesothelioma is typically diffuse, but rare cases grow as localized masses, making them hard to distinguish from other tumors. These cases can mimic:

• Solitary fibrous tumors
• Metastatic carcinomas
• Pleural synovial sarcomas

How to Recognize Localized Mesothelioma

• Histology resembles classic mesothelioma.
• Radiology shows a well-defined mass instead of diffuse pleural thickening.
• Immunohistochemistry remains critical.

Key Takeaway: If the tumor resembles mesothelioma histologically, but imaging suggests a single mass, always consider localized mesothelioma.

Mucin-Positive Mesothelioma

Normally, mesotheliomas do NOT produce mucin. But in rare cases, mesotheliomas stain positive for mucin, leading to misdiagnosis as adenocarcinoma.

Why Does This Happen?

• Some mesotheliomas have Alcian Blue-positive acidic mucin, but not neutral mucin.
• Some mesotheliomas weakly stain for CEA, LeuM1, or Ber-EP4, typically markers of adenocarcinoma.

What to Do?

• Always use a full immunohistochemical panel.
• Electron microscopy can help confirm mesothelioma in borderline cases.

Epithelioid Vascular Tumors vs. Mesothelioma

Epithelioid vascular tumors (like epithelioid hemangioendothelioma and epithelioid angiosarcoma) mimic mesothelioma, causing diagnostic confusion.

Key Features That Suggest a Vascular Tumor

• Histology: Tumors show abortive blood vessel formation and intracytoplasmic lumina.
• Immunohistochemistry:
  • Vascular Markers:
    • CD31
    • CD34
    • FLI-1
  • Mesothelioma Markers:
    Negative for WT-1, CK5/6, and calretinin.

Key Takeaway: If a tumor stains positive for CD31 or CD34 but negative for mesothelial markers, consider a vascular tumor rather than mesothelioma.

Final Thoughts

• Mesothelioma mimics several other malignancies, requiring a careful and multi-modal approach to diagnosis.
• Histology alone is often insufficient—always use a full immunohistochemistry panel.
• Mucin staining, CEA, and Ber-EP4 are key markers to rule out adenocarcinoma.
• Electron microscopy is helpful in borderline cases, particularly when IHC is inconclusive.
• Rare presentations, such as localized mesothelioma or mucin-positive mesothelioma, require extra caution.

Key Takeaway: No single test is foolproof—a combination of histology, IHC, and electron microscopy is the best way to accurately diagnose mesothelioma and avoid misdiagnosis.