The body’s serosal cavities — the pleura, peritoneum, and pericardium — are lined by a single layer of mesothelial cells. These specialized cells play vital roles in fluid exchange, immune response, and maintaining homeostasis. When disease strikes these regions, cytopathology — the study of individual cells — becomes a powerful diagnostic tool.
Mesothelial cytopathology refers to the evaluation of mesothelial cells and their behavior in exfoliative cytology, typically from body cavity effusions. This field plays a critical role in distinguishing benign, reactive, and malignant processes — a task that is often nuanced and challenging.
Why Study Mesothelial Cytopathology?
Mesothelial cytopathology is essential for:
- Diagnosing effusion-related diseases
- Detecting malignancies like mesothelioma or metastatic carcinoma
- Monitoring inflammatory or infectious conditions
- Avoiding unnecessary invasive procedures
Cytology is often the first line of investigation when pleural, peritoneal, or pericardial fluid is obtained.
Sources of Specimens
The most common fluids studied in mesothelial cytopathology include:
- Pleural fluid (thoracentesis)
- Peritoneal fluid (paracentesis, peritoneal washings)
- Pericardial fluid
- Pelvic washings (often collected during gynecologic surgery)
Normal Mesothelial Cells: Cytologic Features
In their resting state, mesothelial cells are:
- Polygonal or round
- With central round nuclei
- A moderate to abundant amount of pale blue cytoplasm
- Sometimes binucleated
- Often appear in clusters or sheets, occasionally in a "windowed" pattern (where cells appear to have spaces between them)
In cytological smears, benign mesothelial cells show a uniform appearance with smooth nuclear contours and low nuclear-to-cytoplasmic (N:C) ratios.
Reactive Mesothelial Cells
Mesothelial cells often undergo reactive changes due to:
- Infection
- Trauma or surgery
- Inflammation
- Chemical irritation (e.g., from dialysis fluid)
Cytologic Features of Reactive Mesothelial Cells:
- Increased size
- Prominent nucleoli
- Multinucleation
- Cytoplasmic blebbing
- Sometimes form three-dimensional clusters or papillary structures
Reactive mesothelial cells can closely mimic malignancy, particularly mesothelioma or carcinoma, making diagnosis complex.
Malignant Mesothelial Cells
Malignant mesothelioma can exfoliate into body fluids and may closely resemble reactive mesothelial cells, but certain features raise suspicion:
Cytologic Features Suggestive of Malignancy:
- Large, irregular nuclei
- High N:C ratio
- Chromatin irregularities
- Cellular crowding
- Cellular atypia across multiple fields
- Prominent nucleoli
- Loss of typical “windows” between cells
However, malignancy cannot be diagnosed on cytology alone in most cases — a tissue biopsy and immunohistochemistry (IHC) are often needed to confirm the diagnosis.
Immunocytochemistry in Mesothelial Cytopathology
Immunostains can be applied to cell block preparations from cytology specimens to help distinguish mesothelial cells from carcinoma.
Markers Expressed in Mesothelial Cells:
- Calretinin
- WT-1
- D2-40 (podoplanin)
- Cytokeratin 5/6
- Mesothelin
Markers for Carcinoma (usually negative in mesothelial cells):
- Ber-EP4
- MOC-31
- CEA (carcinoembryonic antigen)
- B72.3
Using panels of markers is critical — no single stain is completely specific.
Differential Diagnoses in Mesothelial Cytopathology
The cytopathologist must consider several possibilities:
Cytologic FindingCytologic Finding
Malignant mesothelial cells
Cytologic Finding
Adenocarcinoma cells
Cytologic Finding
Mixed population
Careful evaluation of cell morphology, clinical history, and ancillary testing helps avoid misdiagnosis.
Challenges in Interpretation
Mesothelial cytopathology is one of the most difficult areas in diagnostic pathology because:
- Reactive cells may mimic malignancy
- Malignant mesothelial cells may appear bland
- Sampling errors can lead to false negatives
- Immunostaining has limitations, especially in poorly preserved samples
Experienced cytopathologists often recommend correlation with imaging, clinical history, and surgical pathology.
Role of Advanced Techniques
Newer tools help refine mesothelial cytology:
- Digital image analysis for nuclear morphometry
- Molecular testing (e.g., BAP1 loss or CDKN2A deletion for mesothelioma)
- Fluorescence in situ hybridization (FISH) for chromosomal alterations
- Next-generation sequencing (NGS) to explore mutations and gene expression
These methods may enhance accuracy, particularly in borderline cases.
Mesothelial cytopathology is a critical but nuanced field that sits at the intersection of morphology, clinical medicine, and molecular diagnostics. While routine effusion analysis often reveals benign or reactive findings, the occasional detection of malignancy — and the challenge of distinguishing it from benign mimics — makes expert cytologic evaluation essential.
As diagnostic techniques advance, so too does our ability to interpret mesothelial cells accurately, improving patient outcomes through better-informed clinical decisions.
