Mesothelioma is a rare and aggressive malignancy arising from the mesothelial cells lining the serosal surfaces of the body. It is most commonly associated with asbestos exposure and carries a grim prognosis due to its insidious onset and resistance to conventional therapies. Understanding the pathological features of mesothelioma is crucial for accurate diagnosis, staging, and treatment planning. This blog explores mesothelioma through the lens of pathology, outlining its key histological subtypes, diagnostic markers, differential diagnoses, and prognostic features.
1. Overview of Mesothelioma
Mesothelioma most commonly affects the pleura (~80% of cases), but can also involve the peritoneum, pericardium, and tunica vaginalis. Its long latency period (20–40 years after asbestos exposure) often results in delayed diagnosis.
Etiology:
- Primary risk factor: Asbestos exposure
- Others: SV40 virus (controversial), radiation, genetic predisposition (e.g., BAP1 mutation)
2. Pathologic Classification
Mesothelioma is classified into three major histologic subtypes, each with distinct morphology and prognostic implications.
A. Epithelioid Mesothelioma (~60–80%)
Most common and best prognosis
Microscopic Features:
- Tubulopapillary, acinar, or solid patterns
- Cells with round nuclei, abundant eosinophilic cytoplasm
- Low mitotic rate
- Immunohistochemistry (IHC):
- Positive: Calretinin, WT-1, CK5/6, D2-40
- Negative: CEA, TTF-1, Ber-EP4 (helps rule out adenocarcinoma)
B. Sarcomatoid Mesothelioma (~10–20%)
Worst prognosis
Microscopic Features:
- Spindle-shaped cells in fascicles
- Resembles fibrosarcoma or other sarcomas
IHC:
- Positive: Vimentin, D2-40, sometimes Calretinin
- Often less specific than epithelioid type
C. Biphasic Mesothelioma (~10–20%)
Contains both epithelioid and sarcomatoid components.
Prognosis depends on the proportion of each component (sarcomatoid dominance worsens prognosis).
3. Ancillary Diagnostic Tools
A. Immunohistochemistry Panel
Due to overlapping features with metastatic carcinomas, IHC is essential:
- Positive Mesothelial Markers: Calretinin, WT-1, CK5/6, D2-40, Mesothelin
- Negative Markers (carcinoma exclusion): CEA, Ber-EP4, TTF-1, MOC-31
B. Molecular Testing
- BAP1 loss: Detected by IHC or FISH; specific for mesothelioma, particularly useful in distinguishing from reactive mesothelial hyperplasia.
- CDKN2A (p16) homozygous deletion: FISH is a highly specific test for malignant mesothelioma.
4. Differential Diagnosis
Mesothelioma is a diagnostic challenge due to its similarity to:
- Metastatic adenocarcinoma (especially lung and breast primaries)
- Reactive mesothelial proliferation
- Synovial sarcoma (in sarcomatoid subtype)
Desmoplastic mesothelioma vs. fibrous pleuritis: Requires careful histological and molecular analysis
5. Gross and Cytological Features
Gross Pathology:
- Diffuse pleural thickening
- Encasing lung like a rind
- Nodular growth; often invades chest wall or peritoneum
Cytology:
- Often performed on pleural effusion samples
- Low sensitivity (~30–50%)
- Requires ancillary testing (IHC, molecular)
6. Staging and Prognosis
AJCC TNM Staging (8th Edition):
- Based on tumor extent (T), nodal involvement (N), and metastasis (M)
- Imaging (CT, PET) and sometimes surgical biopsy needed
Prognostic Factors:
- Histologic subtype (epithelioid is best)
- Tumor stage at diagnosis
- Molecular alterations (e.g., BAP1 status)
- Patient performance status
Median survival:
- Epithelioid: ~12–24 months
- Biphasic: ~10–15 months
- Sarcomatoid: ~6 months
7. Recent Advances and Research Directions
- Immunotherapy: Emerging as a new standard (e.g., nivolumab + ipilimumab)
- Targeted therapy: BAP1 and other molecular targets under investigation
- Liquid biopsies and circulating tumor DNA (ctDNA): Future diagnostic potential
Mesothelioma remains a formidable diagnostic and therapeutic challenge. Pathologists play a central role in diagnosis, leveraging histopathology, immunohistochemistry, and molecular tools to distinguish it from mimics and guide management. As research continues to uncover its molecular underpinnings, the hope is for more targeted, effective therapies to improve patient outcomes.
References:
WHO Classification of Thoracic Tumors (5th Edition)
College of American Pathologists (CAP) protocols
PathologyOutlines.com – Mesothelioma
AJCC Cancer Staging Manual, 8th Edition
