Reactive Mesothelial Cells vs. Malignant Mesothelial Cells, focusing on cytology, histology, immunohistochemistry, and clinical significance.
Mesothelial cells line the pleural, pericardial, and peritoneal cavities, and they play a key role in serosal fluid dynamics and immune responses. In cytopathology and surgical pathology, distinguishing reactive mesothelial cells from malignant mesothelial cells—especially in the context of malignant mesothelioma—is one of the most challenging diagnostic dilemmas. Misdiagnosis can lead to either over-treatment of benign conditions or under-treatment of aggressive malignancies.
This blog explores the critical features that help differentiate reactive from malignant mesothelial proliferations, including cytologic features, immunohistochemical markers, and molecular diagnostics.
1. Understanding the Basics
Reactive Mesothelial Cells
- Occur in response to inflammation, infection, trauma, surgery, or effusion of any cause.
- Proliferation is polyclonal, self-limited, and non-invasive.
- Often associated with benign pleural or peritoneal effusions.
Malignant Mesothelial Cells (Mesothelioma)
- Represent clonal neoplastic proliferation of mesothelial cells.
- Show infiltrative growth, potential for metastasis, and poor prognosis.
- Most commonly linked to asbestos exposure.
2. Cytologic Features: Reactive vs. Malignant
Cytologic analysis of body cavity fluids (e.g., pleural effusion) is often the first diagnostic step.
3. Histologic Features in Tissue Biopsy
When effusion cytology is inconclusive, pleural or peritoneal biopsy may be required.
Reactive Mesothelial Proliferation
- Preserved mesothelial architecture
- No invasion into fat or underlying tissue
- Cells may pile up but remain superficial
Malignant Mesothelioma
- Invasive growth into fat, muscle, or adjacent organs
- Desmoplastic stroma in sarcomatoid subtype
- Disorganized architecture with loss of polarity
4. Immunohistochemistry (IHC): Key to Diagnosis
IHC helps distinguish malignant mesothelioma from reactive mesothelial hyperplasia and metastatic carcinoma.
Common Mesothelial Markers (Positive in Both)
- Calretinin
- WT-1
- D2-40
- CK5/6
These cannot distinguish reactive from malignant on their own.
5. Molecular and Genetic Testing
A. BAP1 IHC
- Loss of BAP1 expression is specific (but not 100% sensitive) for malignant mesothelioma.
- Especially helpful in distinguishing epithelioid mesothelioma from reactive processes.
B. CDKN2A (p16) Deletion via FISH
- Detected in ~60–80% of malignant mesotheliomas, especially sarcomatoid type.
- Rarely seen in reactive conditions, making it a very specific test.
6. Clinical Correlation is Crucial
Clinical Factors Favoring Reactivity:
- Acute illness (infection, pneumonia)
- Trauma, surgery
- Lack of mass lesion on imaging
Clinical Factors Favoring Malignancy:
- History of asbestos exposure
- Recurrent, unexplained pleural effusions
- Pleural thickening or nodules on imaging
- Older age, male predominance
7. When in Doubt: A Stepwise Diagnostic Strategy
- Start with cytology: Look for architecture, nuclear features, and cluster patterns.
- Apply basic IHC panel: Confirm mesothelial origin (calretinin, WT-1, CK5/6).
- Use malignancy-specific markers: BAP1, EMA, Glut-1, p16 FISH.
- Correlate with clinical and radiologic data.
- Consider biopsy: Especially if effusion studies are indeterminate.
Differentiating reactive mesothelial proliferations from malignant mesothelioma remains one of the most complex areas in diagnostic pathology. While cytology and immunohistochemistry offer valuable clues, no single feature is definitive. A multimodal approach—combining morphology, IHC, molecular diagnostics, and clinical context—is essential for accurate diagnosis and appropriate patient management.
Early recognition and correct classification are key, particularly because malignant mesothelioma has significant implications for prognosis and treatment.
WHO Classification of Thoracic Tumors, 5th Edition
PathologyOutlines.com – Mesothelioma and Reactive Mesothelial Hyperplasia
College of American Pathologists (CAP) Diagnostic Protocols
Churg et al., "Diagnosis of Mesothelioma," Archives of Pathology & Laboratory Medicine, 2018
