Rare Histological Variants of Mesothelioma: A Guide to Identification and Diagnosis

Mesothelioma is notoriously diverse in its presentation, making diagnosis a challenging puzzle for pathologists. While the epithelioid, sarcomatoid, and biphasic subtypes are well-documented, there are several rare histological variants that can easily be misdiagnosed. These uncommon variants can mimic other malignancies, leading to delayed or incorrect treatment.

This article explores the rare subtypes of mesothelioma, their diagnostic pitfalls, and how to differentiate them from other conditions.

Small Cell Mesothelioma: The Great Mimic

The small cell variant of mesothelioma is a rare but significant entity because it mimics small cell carcinoma, a type of lung cancer.

Key Features of Small Cell Mesothelioma

• At least 50% of the tumor must show small cell morphology to be classified as this subtype.
• Often found in the pleura, but rare in the peritoneum.
• Unlike small cell carcinoma, it lacks haematoxyphilic nucleoprotein precipitates.
• Positive for mesothelial markers (calretinin, WT-1, cytokeratins).
• Negative for neuroendocrine markers (synaptophysin, chromogranin, TTF-1).

Key Takeaway: If a tumor resembles small cell carcinoma but is calretinin-positive and TTF-1-negative, consider small cell mesothelioma.

Lymphohistiocytoid Mesothelioma: A Confusing Blend

Lymphohistiocytoid mesothelioma is so rare that it makes up less than 1% of mesotheliomas, and it can be easily mistaken for lymphoma.

Key Features

• Contains spindle-shaped histiocytoid tumor cells.
• Background shows dense lymphocytic infiltration, sometimes resembling lymphoma.
• Cytokeratin and vimentin co-expression confirms mesothelial origin.

Key Takeaway: Lymphoma and mesothelioma can look alike, so always check for cytokeratin positivity—if it’s present, it’s likely mesothelioma.

Deciduoid Mesothelioma: The Peritoneal Aggressor

Deciduoid mesothelioma was first described in young women with peritoneal tumors, but it also occurs in men and in the pleura.

Key Features

• Large glassy, eosinophilic tumor cells resembling decidual cells.
• More aggressive than other mesothelioma subtypes.
• Positive for mesothelial markers, but can sometimes mimic serous carcinoma.

Key Takeaway: If an eosinophilic, deciduoid-like tumor is found in the peritoneum, think deciduoid mesothelioma—but always rule out serous carcinoma with WT-1 and estrogen receptor staining.

Desmoplastic Small Round Cell Tumor (DSRCT) vs. Mesothelioma

Although DSRCT is not typically classified as mesothelioma, it was once thought to be a primitive mesothelial tumor.

Key Differences

Key Takeaway: If a tumor is WT-1 nuclear positive and desmin positive, think DSRCT, not mesothelioma.

Benign/Low-Grade Mesothelial Proliferations

While most mesotheliomas are aggressive, some low-grade mesothelial proliferations can be mistaken for mesothelioma.

Key Variants

1. Well-Differentiated Papillary Mesothelioma (WDPM)

   • More common in young women.
   • Usually peritoneal, rarely pleural.
   • Bland papillary structures lined by uniform mesothelial cells.
   • Generally benign but can rarely behave aggressively.

2. Benign Multicystic Mesothelioma (Peritoneal Inclusion Cysts)

   • Large multicystic lesions in the pelvis or peritoneum.
   • Usually occurs after surgery.
   • Controversial origin—may be reactive rather than neoplastic.

3. Adenomatoid Tumor

   • Found mostly in the genital tract but can occur in the pleura.
   • Previously thought to be endothelial but now confirmed as mesothelial.

Key Takeaway: Not all mesothelial proliferations are aggressive—some, like WDPM and multicystic mesothelioma, are low-grade with better outcomes.

Common Pitfalls in Diagnosing Rare Mesothelioma Variants

Misdiagnosis of rare mesothelioma subtypes is common. To avoid errors:

1. Use immunohistochemistry panels.
   • Calretinin, WT-1, and cytokeratin are key mesothelial markers.
2. Consider clinical history.
   • Asbestos exposure favors mesothelioma, while a history of pelvic surgery suggests multicystic mesothelioma.
3. Look for distinctive histologic features.
   • Small cell mesothelioma lacks neuroendocrine markers.
   • Lymphohistiocytoid mesothelioma is keratin-positive despite mimicking lymphoma.
4. Utilize molecular studies where needed.
   • EWSR1-WT1 translocation suggests DSRCT, not mesothelioma.

Final Thoughts

• Mesothelioma is a highly variable disease, with several rare histological variants that complicate diagnosis.
• Small cell, deciduoid, and lymphohistiocytoid mesotheliomas can mimic other cancers, requiring a careful immunohistochemical approach.
• Low-grade mesothelial proliferations, such as well-differentiated papillary mesothelioma and benign multicystic mesothelioma, should not be overdiagnosed as aggressive mesothelioma.
• Molecular studies, immunohistochemistry, and clinical correlation are essential in differentiating mesothelioma from mimickers like DSRCT, lymphoma, and small cell carcinoma.

Key Takeaway: Pathologists and oncologists must be aware of these rare mesothelioma variants to ensure accurate diagnosis and appropriate treatment strategies.