Epithelioid Mesothelioma: Diagnosis, Challenges, and Key Features
Last updated on September 12, 2024
Epithelioid Mesothelioma: Diagnosis, Challenges, and Key Features
The Complexity of Diagnosing Epithelioid Mesothelioma
Epithelioid mesothelioma is the most common subtype of mesothelioma, making up about 60-70% of all cases. While it has a better prognosis than biphasic or sarcomatoid mesothelioma, diagnosing it correctly is no easy task. The biggest challenge? Distinguishing it from adenocarcinoma, particularly metastatic lung adenocarcinoma.
Since epithelioid mesothelioma and adenocarcinoma can look nearly identical under the microscope, pathologists rely on a combination of cytology, histology, immunohistochemistry, and ultrastructural features to make the right call.
Distinguishing Epithelioid Mesothelioma from Adenocarcinoma
The debate on how to best separate epithelioid mesothelioma from adenocarcinoma has been going on for decades. Today, pathologists use advanced histochemical and immunohistochemical techniques, but difficult cases still exist, where electron microscopy or molecular testing may be required.
Key Diagnostic Differences
While no single test is definitive, the combination of multiple tests helps in making the correct diagnosis.
| Feature | Favors Mesothelioma | Favors Adenocarcinoma |
|---|---|---|
| Cell Arrangement | Solid aggregates, papillary formations, mulberry-like structures | Well-formed glands, hollow centers in cell clusters |
| Cytoplasm | Dense, abundant glycogen | Mucin-producing cells |
| Nuclear Placement | Central nuclei | Eccentric nuclei |
| Psammoma Bodies | 5-10% of cases (non-specific) | Common in papillary adenocarcinomas |
| Cell Apposition | Windows between cells | No gaps, tightly packed |
| Hyaluronic Acid Presence | Frequently present in effusions | Rare in adenocarcinoma |
Key Takeaway: No single feature is enough to distinguish these tumors; a panel of tests is required.
Effusion Cytology: Diagnosing Mesothelioma in Fluid Samples
In 60% of cases, epithelioid mesothelioma can be diagnosed just from effusion cytology (fluid samples taken from the pleural, peritoneal, or pericardial cavities). However, 20% require additional tests, and another 20% remain undiagnosable using cytology alone.
Macroscopic Clues in Effusion Cytology
- Highly viscous pleural fluid may suggest mesothelioma due to a high hyaluronic acid content.
- Hyaluronic acid vacuoles in cells are strongly predictive of mesothelioma.
- A foreign tumor population mixed with benign mesothelial cells favors adenocarcinoma.
Microscopic Features That Differentiate Mesothelioma from Adenocarcinoma
- Smooth contoured aggregates → Adenocarcinoma
- Mulberry-like solid aggregates with papillary structures → Mesothelioma
- Columnar cell morphology → Adenocarcinoma
- Dense cytoplasm with abundant glycogen → Mesothelioma
- Cell-to-cell apposition with window-like gaps → Mesothelioma
- Eccentric nuclei → Adenocarcinoma
Effusion cytology is useful, but it isn’t perfect. That’s why histology and immunohistochemistry remain critical for confirmation.
Histology: The Role of Biopsy in Diagnosis
Histological examination of biopsy specimens presents similar challenges to cytology. The gold standard for diagnosis is thoracoscopic biopsy, but even small biopsy samples may not provide a definitive diagnosis.
Key Histologic Features of Epithelioid Mesothelioma
- Tubulopapillary or microcystic architectures
- Papillary formations with connective tissue cores
- Cuboidal cell morphology (as opposed to columnar in adenocarcinoma)
- Psammoma bodies (5-10% of cases)
- Bland nuclei and lack of cohesion between tumor cells
Poorly differentiated cases can be even harder to diagnose, as they may lack these classical features.
The Role of Immunohistochemistry in Diagnosis
Because morphological features alone are not enough, immunohistochemistry (IHC) is essential in distinguishing epithelioid mesothelioma from adenocarcinoma.
Commonly Used Immunohistochemical Markers
| Marker | Positive in Mesothelioma | Positive in Adenocarcinoma |
|---|---|---|
| Calretinin | Positive | Negative |
| WT-1 | Positive | Negative |
| Cytokeratin 5/6 (CK5/6) | Positive | Negative |
| D2-40 (Podoplanin) | Positive | Negative |
| Ber-EP4 | Negative | Positive |
| CEA (Carcinoembryonic Antigen) | Negative | Positive |
| MOC-31 | Negative | Positive |
| TTF-1 (Thyroid Transcription Factor-1) | Negative | Positive (Lung Adenocarcinoma) |
A standard diagnostic panel often includes at least two positive mesothelial markers (calretinin, WT-1, CK5/6, or D2-40) and two negative adenocarcinoma markers (CEA, Ber-EP4, or TTF-1).
Key Takeaway: A properly selected panel of at least four markers helps differentiate mesothelioma from adenocarcinoma with high accuracy.
The Role of Electron Microscopy and Molecular Testing
In difficult cases, electron microscopy (EM) or molecular testing can provide additional confirmation.
Electron Microscopy (EM) Features of Mesothelioma
- Long, slender microvilli (a defining feature)
- Tonofilaments and desmosomes
- No mucin production (unlike adenocarcinoma)
Molecular Markers
- BAP1 Loss → Highly specific for mesothelioma
- CDKN2A Deletion (p16 FISH test) → Present in 60-80% of mesotheliomas, rare in adenocarcinoma
These tests are often used when routine immunohistochemistry is inconclusive.
Treatment and Prognosis of Epithelioid Mesothelioma
Epithelioid mesothelioma has the best prognosis among mesothelioma subtypes, with a median survival of 12-24 months compared to 5-10 months for sarcomatoid mesothelioma.
Treatment Options
- Multimodal Therapy (Surgery + Chemotherapy + Radiation)
- Immunotherapy (Checkpoint Inhibitors like Nivolumab + Ipilimumab)
- Palliative Care (Pleurodesis, Pain Management)
Survival Based on Histology
| Histology | Median Survival |
|---|---|
| Epithelioid | 12-24 months |
| Biphasic | 10-12 months |
| Sarcomatoid | 5-10 months |
Final Thoughts
- Epithelioid mesothelioma is the most common and treatable subtype.
- Distinguishing it from adenocarcinoma requires a combination of histology, immunohistochemistry, and sometimes molecular testing.
- A proper immunohistochemical panel improves diagnostic accuracy.
- Electron microscopy and molecular tests like BAP1 loss and p16 FISH are helpful in difficult cases.
- Early diagnosis improves survival and treatment options.
Key Takeaway: The more tools we use to diagnose epithelioid mesothelioma, the better we can tailor treatment and improve patient outcomes.