Biphasic Mesothelioma A Combination of Treatment Challenges

Biphasic mesothelioma represents a particularly complex and aggressive form of cancer primarily associated with exposure to asbestos, a fibrous mineral widely used in industries such as construction and manufacturing until decades ago. This type of mesothelioma is characterized by the presence of two types of tumor cells: epithelioid cells, which are more structured and respond better to treatment, and sarcomatoid cells, which are more irregular, aggressive, and resistant to conventional therapies. The combination of these cells in a single tumor, which must represent more than 10% of each type to be classified as biphasic, complicates clinical management, as the cancer's behavior depends largely on the ratio of both cellular components. It primarily affects the lining of the lungs (pleural), but can also manifest in the abdominal peritoneum or, in rare cases, the pericardium or testicles. Its incidence is low, representing between 20% and 35% of all malignant mesotheliomas, but its impact is significant due to the difficulty in early diagnosis and effective treatment. Patients are usually people over 60 years of age with a history of occupational exposure to asbestos, although cases without obvious exposure are also reported, adding a layer of mystery to its etiology.

Exposure to asbestos is the main risk factor, as inhaled or ingested fibers lodge in the mesothelium, the thin membrane that covers internal organs, causing chronic inflammation and genetic mutations that lead to cancer after a latency period that can extend from 20 to 50 years. In biphasic mesothelioma, this cellular transformation results in a hybrid tumor that exhibits characteristics of both histological types, making it unpredictable. For example, if the epithelioid component predominates, the tumor tends to grow more slowly and be more amenable to surgical intervention, while a sarcomatoid predominance accelerates progression and reduces therapeutic options. Other risk factors include prior radiation, viral infections such as SV40, and genetic mutations in genes such as BAP1, which increase susceptibility in exposed individuals. However, not all exposed individuals develop the disease, highlighting the interaction between environmental and genetic factors in its pathogenesis.

The initial symptoms of biphasic mesothelioma are often nonspecific and are mistaken for benign conditions, delaying diagnosis and compounding treatment challenges. Patients commonly experience persistent chest pain, shortness of breath, dry cough, and fatigue, symptoms that arise when the tumor compresses the lungs or invades adjacent structures. In peritoneal cases, abdominal swelling, loss of appetite, nausea, and bowel disturbances due to fluid accumulation (ascites) or organ obstruction occur. These signs can take months to become apparent, allowing the cancer to spread before being detected. Symptom variability, influenced by tumor location and cell proportion, further complicates early identification, as symptoms do not always directly correlate with the aggressiveness of the sarcomatoid component.

Diagnosing biphasic mesothelioma requires a combination of advanced techniques but faces significant obstacles due to its rarity and similarity to other cancers. Initially, imaging tests such as computed tomography (CT) scans, magnetic resonance imaging (MRI), or ultrasound are used to detect abnormal masses in the chest or abdomen. However, these do not distinguish between cell types, so a biopsy is essential. During the biopsy, tumor tissue is removed for pathological analysis, where the presence of epithelioid (round and uniform) and sarcomatoid (elongated and disorganized) cells is identified through microscopy and immunohistochemistry. Markers such as calretinin, WT-1, and cytokeratins help confirm the diagnosis and differentiate it from adenocarcinomas or sarcomas. The challenge lies in diagnostic reproducibility, as cell proportions can vary in different tumor samples, potentially leading to misclassification and inappropriate treatment plans. Furthermore, staging, which assesses the extent of the cancer, is crucial but challenging in early stages, where the tumor may be localized but already aggressive due to the mixed component.

Once diagnosed, treatment of biphasic mesothelioma becomes a multifaceted puzzle, as cellular duality imposes limitations on standard therapies. A multimodal approach, combining surgery, chemotherapy, radiotherapy, and immunotherapy, is the mainstay, but its efficacy varies depending on cellular dominance. For example, in tumors with a higher epithelioid proportion, cytoreductive surgery—which removes as much visible tumor as possible—followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in peritoneal cases, extending survival in selected patients. However, when the sarcomatoid component predominates, the cells are more resistant to chemotherapy, such as the combination of pemetrexed and cisplatin, which is the standard first-line treatment but achieves only partial responses in many cases. This resistance is due to the aggressive nature of sarcomatoid cells, which spread rapidly and form adhesions that complicate surgical interventions.

Surgery represents one of the greatest challenges in the treatment of biphasic mesothelioma, as it is not always feasible due to the extent of the tumor at the time of diagnosis. Procedures such as pleurectomy decortication or extrapleural pneumonectomy aim to remove the affected tissue in pleural mesothelioma, but they require the patient to be in good physical condition and for the tumor not to have invaded vital structures. In biphasic mesothelioma, the presence of sarcomatoid cells increases the risk of postoperative recurrence, as these cells are more prone to metastasis. Multicenter studies have shown that, although multimodal surgery improves long-term survival in selected patients, only a subgroup with epithelioid predominance truly benefits, while for others, the procedure may be palliative rather than curative. Furthermore, postoperative complications, such as infections or respiratory failure, add risks, especially in older patients with comorbidities.

Systemic chemotherapy faces its own obstacles in biphasic mesothelioma, where response is inconsistent due to cellular heterogeneity. The standard regimen of platinum and pemetrexed can shrink tumors and relieve symptoms, but the inherent resistance of sarcomatoid cells limits its duration. Recent research has explored combinations with angiogenesis inhibitors or therapies targeting specific mutations, such as in the BAP1 gene, but results are variable and depend on tumor composition. In advanced cases, chemotherapy is used palliatively to control pain and fluid accumulation, but it does not cure the disease, highlighting the need for personalized approaches based on genetic profiles.

Immunotherapy has emerged as a hope in the treatment of biphasic mesothelioma, offering durable responses in subgroups of patients. Checkpoint inhibitors such as nivolumab plus ipilimumab have been shown to improve first-line survival, especially in tumors with high PD-L1 expression, common in the sarcomatoid component. However, not everyone responds, and immune-mediated side effects, such as fatigue or autoimmune problems, pose additional challenges. Clinical trials have reported discordant responses, where parts of the tumor respond while others progress, reflecting biphasic duality. This variability underscores the importance of biomarkers for patient selection, but the lack of reliable predictors complicates its routine implementation.

Radiation therapy, although useful for local tumor control, faces limitations in biphasic mesothelioma due to the proximity of vital organs. Techniques such as intensity-modulated radiation therapy can reduce collateral damage, but their role is primarily adjuvant or palliative, relieving pain or preventing post-surgical recurrences. The challenge lies in the resistance of sarcomatoid cells to radiation, which requires high doses with risks of toxicity. In combination with other modalities, it can extend survival, but is not curative alone.

The prognosis for biphasic mesothelioma is generally guarded, with a median survival of 10 to 18 months, influenced by cell proportion, stage, and response to treatment. Tumors with more than 50% epithelioid cells have a two-year survival rate of 22%, while sarcomatoid predominance dramatically reduces this. Factors such as age, overall health, and access to multimodal treatments improve the outlook, but the inherent aggressiveness of the cancer limits cures. Recent studies indicate that aggressive approaches in early stages can extend life by years in selected cases, but most face recurrences.

Clinical trials represent a crucial avenue for overcoming the challenges in the treatment of biphasic mesothelioma, exploring innovative therapies such as CAR-T cells or inhibitors of specific molecular pathways. However, the rarity of the disease limits recruitment, and tumor heterogeneity complicates the interpretation of results. Limited funding and the need for international collaboration are additional barriers.

Palliative care is integral in the management of biphasic mesothelioma, focusing on improving quality of life in the face of therapeutic challenges. Pain management, nutritional support, and psychological care help mitigate the impact of symptoms and treatments. In advanced stages, interventions such as paracentesis for ascites or pleurodesis for pleural effusions provide symptomatic relief.

Prevention remains key, with strict asbestos regulations reducing future exposures, although the legacy of past use persists. Public awareness and occupational vigilance are essential to minimize risks.

In summary, biphasic mesothelioma represents a combination of treatment challenges due to its dual nature, requiring personalized and multidisciplinary approaches. Advances in immunotherapy and targeted therapies offer hope, but more research is needed to overcome its aggressiveness and improve outcomes.