Mesothelioma Histology: Classification and Tissue Features

Mesothelioma is a rare and aggressive cancer arising from the mesothelial cells lining the lungs, abdomen, heart, or testes. Accurate classification is essential for determining prognosis and guiding treatment, as different subtypes respond differently to therapy.

Histological analysis helps distinguish mesothelioma from other malignancies by identifying cellular patterns and characteristics in tissue samples.

Major Histological Subtypes

Mesothelioma is classified into three primary histological subtypes based on cellular composition: epithelioid, sarcomatoid, and biphasic. These classifications influence prognosis and treatment strategies.

Epithelioid

Epithelioid mesothelioma, the most common subtype, accounts for 50-70% of cases. It consists of uniform, polygonal, or cuboidal cells forming tubulopapillary, trabecular, or solid patterns. These cells have well-defined borders, abundant cytoplasm, and round to oval nuclei with prominent nucleoli. This subtype has a better prognosis due to slower progression and greater treatment responsiveness.

Histopathological examination often reveals stromal desmoplasia, where fibrous tissue surrounds tumor nests, and occasional psammoma bodies—concentrically layered calcifications. The differential diagnosis includes metastatic adenocarcinomas from the lung, breast, and gastrointestinal tract. Immunohistochemical staining helps distinguish epithelioid mesothelioma, as it expresses calretinin, WT-1, and cytokeratin 5/6 while lacking CEA and TTF-1, markers of lung adenocarcinoma.

Sarcomatoid

Sarcomatoid mesothelioma, the least common but most aggressive subtype, comprises 10-20% of cases. It consists of spindle-shaped cells arranged in a disorganized pattern, resembling fibrosarcoma or malignant fibrous histiocytoma. The cells exhibit elongated nuclei, a high degree of pleomorphism, and frequent mitotic figures, indicating rapid proliferation. This subtype is more resistant to conventional therapies and has a poorer prognosis.

Histological features include necrosis and collagen deposition, contributing to the tumor’s fibrotic appearance. Differentiating sarcomatoid mesothelioma from other spindle-cell neoplasms, such as sarcomas or reactive pleural fibrosis, can be challenging. Immunohistochemical staining aids diagnosis, with mesothelioma markers such as D2-40 and cytokeratin 5/6 being useful, though expression is often weaker than in the epithelioid form. Negative staining for desmin and S-100 helps exclude other mesenchymal tumors.

Biphasic

Biphasic mesothelioma, or mixed-type mesothelioma, accounts for 20-35% of cases and contains both epithelioid and sarcomatoid components. A diagnosis requires at least 10% of both histological patterns within a tissue sample. The clinical behavior depends on the proportion of each component, with a higher sarcomatoid fraction correlating with a worse prognosis.

Microscopic examination reveals epithelial-like cells forming glandular or papillary structures alongside spindle-shaped cells. The transition between these morphologies may be abrupt or gradual. This heterogeneity complicates diagnosis, necessitating thorough tissue sampling. The immunohistochemical profile reflects the mixed nature of the tumor, often displaying markers characteristic of both epithelioid and sarcomatoid mesothelioma. Recognizing this subtype is crucial for prognosis and treatment planning.

Microscopic Features in Tissue Samples

Histological examination of mesothelioma tissue samples reveals distinct cellular and structural characteristics. Tumor architecture varies by subtype: epithelioid mesothelioma exhibits cohesive cellular arrangements, sarcomatoid mesothelioma has a dispersed and fibrotic appearance, and biphasic mesothelioma presents a combination of both. The degree of cellular atypia, mitotic activity, and stromal composition offers insights into tumor aggressiveness.

A defining feature of mesothelioma is mesothelial proliferation with varying degrees of cytologic atypia. Well-differentiated epithelioid cases show uniform cells with minimal nuclear pleomorphism, while poorly differentiated tumors display nuclear irregularity, hyperchromasia, and increased mitotic figures. Epithelioid cells often have eosinophilic cytoplasm, which may appear vacuolated or granular due to intracellular mucin or glycogen accumulation. Sarcomatoid mesothelioma consists of spindle-shaped cells embedded in dense collagenous stroma, often interspersed with necrotic regions.

The stromal environment significantly influences mesothelioma’s histopathology. Desmoplasia, or dense fibrous tissue deposition, is common in sarcomatoid and biphasic subtypes, making it difficult to distinguish malignant cells from reactive mesothelial hyperplasia. Psammoma bodies—laminated calcified deposits—occasionally appear, particularly in epithelioid mesothelioma. Tumor vascularization varies, with some cases exhibiting prominent angiogenesis, which may correlate with increased invasiveness.

Cellular cohesion and invasion patterns further differentiate mesothelioma from other pleural neoplasms. Epithelioid mesothelioma often forms tubulopapillary, trabecular, or solid structures with a peripheral palisading arrangement of nuclei. Under electron microscopy, tumor cells exhibit long, slender microvilli, distinguishing mesothelioma from adenocarcinoma, which has shorter, irregular microvilli. Sarcomatoid mesothelioma demonstrates a more infiltrative growth pattern, intermingling with surrounding connective tissue.

Immunohistochemical Markers

Immunohistochemistry (IHC) is essential for distinguishing mesothelioma from other malignancies, particularly metastatic adenocarcinomas and sarcomas. The selection of markers depends on the suspected histological subtype, with epithelioid and sarcomatoid variants exhibiting distinct expression profiles.

Among the most reliable positive markers, calretinin consistently demonstrates strong nuclear and cytoplasmic staining in epithelioid tumors. Wilms Tumor-1 (WT-1) exhibits diffuse nuclear positivity, particularly in pleural mesothelioma. Cytokeratin 5/6 (CK5/6) supports diagnosis, as it is expressed in most mesothelioma cases but is rarely observed in lung adenocarcinoma. D2-40 (podoplanin) helps distinguish mesothelioma from reactive mesothelial proliferations, as it is more strongly expressed in malignant cells.

Negative staining for certain markers helps rule out other malignancies. Carcinoembryonic antigen (CEA) and thyroid transcription factor-1 (TTF-1), commonly expressed in lung adenocarcinoma, are typically absent in mesothelioma. Similarly, Ber-EP4 and MOC-31, which highlight epithelial cell adhesion molecules, are more characteristic of adenocarcinomas and rarely stain mesothelioma cells. In sarcomatoid cases, loss of epithelial markers such as CK5/6 can complicate diagnosis, making broad-spectrum cytokeratins (e.g., AE1/AE3 and CAM5.2) essential for confirming mesothelial lineage.

Role of Histological Analysis in Diagnosis

Accurate diagnosis of mesothelioma relies on histological examination, as it often mimics other malignancies and benign conditions affecting the mesothelial lining. Tissue biopsy remains the gold standard for confirmation, with histopathological analysis providing structural and cellular details necessary for classification. The choice of biopsy technique—thoracoscopic, percutaneous, or open surgical—affects the quantity and quality of tissue obtained. Larger biopsy samples, such as those from video-assisted thoracoscopic surgery (VATS), are preferred over fine-needle aspiration, as they better capture architectural patterns and stromal features.

Once a tissue sample is acquired, histological assessment begins with hematoxylin and eosin (H&E) staining, which highlights cellular morphology and tissue architecture. Pathologists evaluate nuclear features, cytoplasmic characteristics, and growth patterns to differentiate mesothelioma from other pleural or peritoneal malignancies. The presence of invasive growth, stromal desmoplasia, and cellular pleomorphism helps distinguish malignant mesothelioma from reactive mesothelial hyperplasia. Special stains, such as periodic acid-Schiff (PAS) with and without diastase digestion, may be used to rule out mimicking conditions like mucin-producing adenocarcinomas.