Epithelioid Mesothelioma

Epithelioid mesothelioma is the most common histological subtype of malignant mesothelioma, accounting for approximately 60–70% of all diagnosed cases. It is characterized by uniform, cuboidal or polygonal cells that resemble normal mesothelial cells and tend to grow in organized, recognizable patterns. Among the three primary cell types — epithelioid, sarcomatoid, and biphasic — epithelioid mesothelioma carries the most favorable prognosis.¹

The relatively better outcomes associated with epithelioid mesothelioma stem from several biological characteristics. Epithelioid cells tend to divide more slowly than sarcomatoid cells, adhere more tightly to one another (reducing the rate of metastasis), and respond more effectively to systemic chemotherapy regimens, particularly the standard combination of cisplatin and pemetrexed.² Patients with epithelioid histology are also more likely to be candidates for aggressive surgical interventions such as extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D).

Accurate identification of cell type through tissue biopsy and immunohistochemistry is critical for treatment planning. Epithelioid mesothelioma can mimic adenocarcinoma and other epithelial malignancies, requiring careful pathological differentiation. Common immunohistochemical markers used to confirm the diagnosis include calretinin, WT1, D2-40, and CK5/6.³

Like all forms of mesothelioma, epithelioid mesothelioma is primarily caused by exposure to asbestos. The latency period between initial exposure and diagnosis is typically 20 to 50 years. Early detection and multimodal treatment — combining surgery, chemotherapy, and sometimes radiation — offer the best chance of extending survival.⁴

Epithelioid mesothelioma is further classified into histological subtypes based on cellular growth patterns. These subtypes can influence prognosis and treatment response:

• Tubulopapillary — cells form tubular and papillary structures; generally the most favorable subtype with the best treatment response
• Acinar — cells arrange in gland-like clusters; associated with relatively favorable outcomes
• Solid — cells grow in dense sheets without distinct architectural patterns; associated with somewhat less favorable prognosis
• Trabecular — cells form ribbon-like cords or trabeculae; intermediate prognosis
• Micropapillary — small papillary clusters without fibrovascular cores; associated with more aggressive behavior
• Pleomorphic — significant variation in cell size and shape; considered the most aggressive epithelioid subtype, sometimes approaching sarcomatoid behavior

Symptoms of epithelioid mesothelioma depend on the primary site of disease and are generally consistent with symptoms of mesothelioma overall:

• Persistent shortness of breath (dyspnea)
• Chest wall pain or tightness (in pleural disease)
• Abdominal pain, swelling, or distension (in peritoneal disease)
• Persistent dry cough
• Unexplained weight loss and fatigue
• Pleural effusion (fluid buildup around the lungs)
• Night sweats and low-grade fever

Symptoms typically develop gradually over weeks to months and are often initially attributed to more common respiratory or gastrointestinal conditions.

The primary cause of epithelioid mesothelioma is exposure to asbestos fibers. When asbestos fibers are inhaled or ingested, they can become lodged in the mesothelial lining of the lungs, abdomen, or other body cavities, causing chronic inflammation and DNA damage that eventually leads to malignant transformation.

• Occupational exposure — construction, shipbuilding, mining, insulation work, automotive brake repair
• Secondary exposure — family members of asbestos workers exposed through contaminated clothing
• Environmental exposure — living near asbestos mines, processing plants, or naturally occurring asbestos deposits

The latency period between asbestos exposure and diagnosis ranges from 20 to 50 years. There is no safe level of asbestos exposure, and even brief exposures can potentially lead to mesothelioma decades later.

• Asbestos exposure — the dominant risk factor for all mesothelioma cell types
• Duration and intensity of exposure — longer and heavier exposure increases risk, though even brief exposure can cause disease
• Type of asbestos fiber — amphibole fibers (crocidolite, amosite) are considered more carcinogenic than chrysotile, though all types carry risk
• Age — most diagnoses occur between ages 65 and 80
• Sex — approximately 80% of mesothelioma patients are male, reflecting historical occupational exposure patterns
• Radiation exposure — prior thoracic radiation therapy has been associated with increased mesothelioma risk in rare cases
• BAP1 gene mutation — germline mutations in the BAP1 tumor suppressor gene increase susceptibility to mesothelioma

Accurate diagnosis of epithelioid mesothelioma requires tissue biopsy and specialized pathological analysis:

• Imaging — chest X-ray, CT scan, or PET-CT to identify tumors, effusions, and disease extent
• Thoracentesis or paracentesis — fluid analysis may reveal malignant cells, though cytology alone is often insufficient for definitive diagnosis
• Tissue biopsy — obtained via thoracoscopy (VATS), laparoscopy, or CT-guided needle biopsy
• Immunohistochemistry — essential for distinguishing epithelioid mesothelioma from adenocarcinoma; positive markers include calretinin, WT1, CK5/6, and D2-40; negative markers include CEA, MOC-31, TTF-1, and BerEp4
• Electron microscopy — may be used in difficult cases to identify characteristic long, slender microvilli

Misdiagnosis is common because epithelioid mesothelioma closely resembles lung adenocarcinoma and other epithelial cancers. A pathologist with mesothelioma experience is strongly recommended for definitive diagnosis.

Epithelioid mesothelioma (when arising in the pleura) is staged using the TNM system adopted by the American Joint Committee on Cancer (AJCC) and the International Mesothelioma Interest Group (IMIG):

• Stage I — tumor confined to the pleura on one side of the chest; no lymph node involvement
• Stage II — tumor has spread from the pleura into the lung tissue or diaphragm on the same side; no lymph node involvement
• Stage III — tumor has invaded deeper structures (chest wall, mediastinum, pericardium) and/or spread to regional lymph nodes
• Stage IV — tumor has spread to distant sites (opposite chest, peritoneum, distant organs) or distant lymph nodes

Patients with epithelioid histology diagnosed at stage I or II are the strongest candidates for curative-intent surgery.

Epithelioid mesothelioma is the most treatment-responsive cell type, and multimodal therapy offers the best outcomes:

• Surgery — pleurectomy/decortication (P/D) is increasingly preferred over extrapleural pneumonectomy (EPP) for eligible patients, as it preserves the lung while removing visible tumor and affected pleura. EPP — removal of the affected lung, pleura, diaphragm, and pericardium — may be considered for select patients with early-stage disease
• Chemotherapy — first-line treatment is cisplatin combined with pemetrexed (Alimta), which has been shown to improve median survival by approximately 3 months compared to cisplatin alone²
• Immunotherapy — nivolumab (Opdivo) plus ipilimumab (Yervoy) was approved by the FDA in 2020 for unresectable pleural mesothelioma; clinical trials suggest epithelioid patients may benefit, though the response rate is somewhat lower than for non-epithelioid types⁵
• Radiation therapy — used adjuvantly after surgery to reduce local recurrence, or palliatively to manage pain
• Multimodal approach — combination of surgery, chemotherapy, and radiation offers the best survival outcomes for eligible patients

Epithelioid mesothelioma carries the most favorable prognosis among mesothelioma cell types:

• Median survival with treatment is 12–24 months, compared to 6–12 months for biphasic and 6 months or less for sarcomatoid
• Patients who undergo multimodal therapy (surgery + chemotherapy ± radiation) may survive 2–5 years or longer
• The tubulopapillary subtype has the best prognosis; pleomorphic has the worst among epithelioid subtypes
• Earlier stage at diagnosis, younger age, and good overall health are positive prognostic indicators
• Female patients tend to have slightly better outcomes than male patients

While epithelioid mesothelioma remains a serious and life-threatening diagnosis, advances in immunotherapy and surgical techniques continue to improve outcomes for eligible patients.

Prevention of epithelioid mesothelioma centers on avoiding asbestos exposure:

• Strict adherence to OSHA asbestos regulations in occupational settings
• Professional asbestos abatement for buildings constructed before 1980
• Use of appropriate respiratory protection when asbestos exposure is possible
• Awareness of secondary exposure risks — workers should not bring contaminated clothing home
• Regular medical monitoring for individuals with known asbestos exposure history

A diagnosis of epithelioid mesothelioma impacts every aspect of daily life. Key considerations include:

• Seek specialized care — treatment at a National Cancer Institute (NCI)-designated cancer center with mesothelioma expertise can significantly affect outcomes
• Nutritional support — maintaining weight and nutrition during chemotherapy is essential; consult an oncology dietitian
• Palliative care — early integration of palliative care alongside curative treatment improves quality of life and may extend survival
• Clinical trials — ask your oncologist about available clinical trials for new therapies, especially immunotherapy combinations
• Emotional and caregiver support — mesothelioma support groups, counseling, and caregiver resources are available through organizations like the Mesothelioma Applied Research Foundation