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Cytological Diagnosis of Mesothelioma

Dr Sampurna Roy MD 







Cytological diagnosis of Mesothelioma is difficult.

Industrial compensation is at stake so suspicious diagnoses should be recorded.

A persistent effusion with atypical mesothelial cells is suggestive of mesothelioma since reactive effusions are usually selflimiting.

Of the three main histological types of mesothelioma (Epithelial ; Mixed and Fibrous or Sarcomatous)  the epithelial variety is the most frequent source of effusions and therefore the type most often seen cytologically.

The sarcomatous variant is the least frequent type to produce an effusion.

Macroscopic features of Effusions in Mesothelioma:

Fluid frequently bloodstained and may be a copious effusion, sometimes small.

Supernatant fluid can be very viscous, like synovial fluid, due to hyaluronic acid content.


Microscopic features (low power)

1. A highly cellular deposit, unless too heavily blood stained.

2. Mesothelial cells predominate, arranged singly, paired and in clusters giving an exaggerated picture  of reactive change.

3. Large cell balls may be present, sometimes with a connective tissue core (papillary structures).

4. Finely granular pink staining backround (hyaluronic acid) in viscous fluids (a minority of cases).

Microscopic features:  (high power)


1. A spectrum from normal looking mesothelial cells to abnormally large forms, instead of two distinct cell populations as seen in metastatic carcinoma.

2. Bi- and multinucleated cells seen, with nuclear pleomorphism.

3. Nuclei enlarged but also voluminous ; nucleocytoplasmic ratio remains relatively low.

4. Mitoses may be present, but but these also occur in reactive effusions.

5. Cytoplasmic features: densely stained cytoplasm but may show foamy or fatty vacuolation or larger vacuoles containing hyaluronic acid.

6. Biphasic cytoplasmic staining in Papanicolaou preparations: central pink staining, periphery green.

7. Close cell to cell apposition with a narrow window between the two cells (a characteristic mesothelial cell arrangement).

8. Cell in cell engulfment is frequently seen.

9. Fringes of microvilli and pseudopodia (cytoplasmic knobs) often present.

10. Pyknotic shrunken cells develop a "squamous"  look in Pap preparation.

11. Nuclear chromatin not well seen with Giemsa stain, may be irregular in Pap preparations.

12. Occasionally psammoma bodies are present.  

Special Techniques in the Diagnosis of Mesothelioma:

1. Histochemistry:  PAS positive due to glycogen. PAS diastase negative i.e. not mucin secreting.

2. Immunohistochemistry:

  Benign mesothelial cells    Mesothelioma  Adenocarcinoma
 CEA       -       -         +
 EMA       - some cases show strong cytoplasmic & membrane positivity         +
 CA-125      +          +         +
 BerEP4       -          -         +
 Ca1 and 2       -  sometimes +   often +
 CK7 and 20 sometimes +  sometimes +          +


N.B.  There are no specific markers for mesothelial cells or for malignancy. A panel of  antibodies is therefore necessary and may not always be conclusive.

3. Electron Microscopy: Prominent long microvilli, thinner than in normal mesothelial cells.

4. AgNOR staining: Can be used in tissue sections to distinguished mesothelioma from benign mesothelial cells, but usefulness not yet established in effusions.

5. Cytogenetics: Demonstration of a clone of mesothelial cells with an abnormal karyotype is conclusive proof of mesothelioma.

6. Cytomorphometry: To distinguish the larger size range of adenocarcinoma cells from mesothelial cells.

7. Effusion Biochemistry: Hyaluronic acid > 400mg/ml is highly suggestive of mesothelioma (benign effusions < 40mg/ml). CEA: levels over 15mg/ml highly suggestive of adenocarcinoma (mesothelioma cases < 5mg/ml).


Differential Diagnosis of Mesothelioma in Effusions:

Mesothelioma must be differentiated from metastatic carcinoma at one extreme and from a benign reactive effusion at the other end of spectrum.

Both of these may prove extremely difficult and suspicious reports are therefore more frequent than eith other tumours,but it is important to record suspicious diagnoses to add weight to an industrial compensation claim.

Repeated examination of fluid may be necessary and recurring abnormal picture adds weight to a diagnosis of mesothelioma rather than a reactive effusion.

The diagnosis of mesothelioma requires a combination of appropriate clinical features, past asbestos exposure, persistent effusion, consistent radiological findings and characteristic histology and cytology.


Summary of Effusion Cytology-Mesothelioma:

1. The correct diagnosis is usually possible given an adequate cytological sample.

2. The easiest samples are those with many epithelial-type aggregates and many single malignant cells.

3. Cell aggregates are the most helpful feature in diagnosing the mesothelial nature of the malignancy.

4. Single cells or small clusters are the most helpful feature in diagnosing the mesothelial nature of malignancy.

5. A panel of special stains and immunocytochemical markers is necessary to distinguish mesothelioma from adenocarcinoma.


Further reading

Primary diagnosis of malignant mesothelioma by fine-needle aspiration of a supraclavicular lymph node. 

Image analysis and flow cytometric DNA studies of benign and malignant body cavity fluids: reappraisal of the role of current methods in the differential diagnosis of reactive versus malignant conditions.

Cytologic differential diagnosis among reactive mesothelial cells, malignant mesothelioma, and adenocarcinoma: utility of combined E-cadherin and calretinin immunostaining.

Reactivity of six antibodies in effusions of mesothelioma, adenocarcinoma and mesotheliosis: stepwise logistic regression analysis.

Cell-block immunocytochemical characterization of effusions. Use of antibody panel: calretinin, Ber-EP4, keratin and CD68.

Cytologic diagnosis of malignant mesothelioma, with particular emphasis on the epithelial noncohesive cell type.

Complementary value of five carcinoma markers for the diagnosis of malignant mesothelioma, adenocarcinoma metastasis, and reactive mesothelium in serous effusions.

Malignant mesothelioma: immunohistochemistry and DNA ploidy analysis as methods to differentiate mesothelioma from benign reactive mesothelial cell proliferation and adenocarcinoma in pleural and peritoneal effusions. 

Ber-EP4 for differentiating adenocarcinoma from reactive and neoplastic mesothelial cells in serous effusions. Comparison with carcinoembryonic antigen, B72.3 and Leu-M1.



Dr Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)






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