How does mesothelioma differ from non-small cell (NSC) and small cell (SC) lung cancers, and is it classified under either category?

Mesothelioma vs. Non-Small Cell and Small Cell Lung Cancers

Mesothelioma is a distinct malignancy that originates from mesothelial cells of the pleura and is not classified as either non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). 1

Key Differences Between Mesothelioma and Lung Cancers

Origin and Classification

• Mesothelioma: Arises from mesothelial cells lining the pleura (serosal membrane)
• NSCLC/SCLC: Originate from lung parenchymal tissue

Histopathological Features

1. Mesothelioma:

   • Characterized by mesothelial markers (calretinin, WT-1, D2-40, cytokeratin 5/6)
   • Ultrastructurally shows long, slender microvilli without core rootlets
   • Typically presents as diffuse pleural thickening, though rare localized forms exist
   • Can rarely present with small cell features that mimic SCLC 2

2. NSCLC (80-85% of lung cancers):

   • Larger cells with moderate cytoplasm
   • Vesicular/coarse chromatin pattern
   • Prominent nucleoli
   • Subtypes: adenocarcinoma, squamous cell carcinoma, large cell carcinoma 3

3. SCLC (14% of lung cancers):

   • Small cells (2-3× size of lymphocytes)
   • Scant cytoplasm, high nuclear-to-cytoplasmic ratio
   • Nuclear molding, finely granular chromatin
   • Absent/inconspicuous nucleoli
   • Extensive necrosis and chromatin smearing 1

Immunohistochemical Differentiation

• Mesothelioma positive markers: Calretinin, WT-1, D2-40 (podoplanin), cytokeratin 5/6
• Adenocarcinoma positive markers: CEA, MOC-31, B72.3, Ber-EP4, TTF-1
• SCLC markers: TTF-1, neuroendocrine markers (chromogranin A, synaptophysin, CD56) 1

Diagnostic Approach

A panel of immunohistochemical markers is recommended to distinguish mesothelioma from lung adenocarcinoma:

• Two markers positive in mesothelioma (calretinin, cytokeratin 5/6 or WT-1)
• Two markers positive in adenocarcinoma but negative in mesothelioma (CEA, MOC-31, B72.3, or Ber-EP4) 1

Epidemiology and Prevalence

• NSCLC: 80-85% of all lung cancers 3
• SCLC: 14% of lung cancers (~30,000 new cases/year in the US) 1
• Mesothelioma: Much rarer than lung cancer, with approximately 3,000 new cases annually in the US

Risk Factors

• Mesothelioma: Strong association with asbestos exposure (80-90% of cases) 2
• NSCLC: Primarily tobacco smoking (80% of cases) 3
• SCLC: Almost exclusively in heavy smokers 1

Diagnostic Pitfalls

1. Small cell mesothelioma can be mistaken for SCLC due to similar morphology 4, 2
2. Pleural-based adenocarcinoma can mimic epithelioid mesothelioma
3. Sarcomatoid mesothelioma may show negative staining with mesothelial markers, making diagnosis challenging 1

Clinical Implications

The distinction between these entities is critical as:

• Treatment approaches differ significantly
• Prognosis varies (mesothelioma generally has poor prognosis with mean survival of 8-12 months for advanced disease)
• Legal implications exist for asbestos-related mesothelioma

Ultrastructural analysis by transmission electron microscopy can provide additional diagnostic information when immunohistochemistry is inconclusive, showing characteristic long, slender microvilli in mesothelioma versus short, blunted microvilli in adenocarcinoma 1.