Sarcomatoid Mesothelioma: Clinical Traits and Prognosis

Sarcomatoid mesothelioma is a rare and aggressive subtype of malignant mesothelioma, primarily linked to asbestos exposure. It differs from other forms by its spindle-shaped tumor cells, which complicate diagnosis and contribute to poor treatment outcomes. Due to its rapid progression and resistance to conventional therapies, understanding its clinical traits is crucial for improving patient care.

Research continues to refine diagnostic methods and prognostic predictions, helping clinicians tailor management strategies.

Incidence And Distribution Patterns

Sarcomatoid mesothelioma accounts for 10–20% of malignant mesothelioma cases, making it the least common but most aggressive histological subtype. Its rarity complicates large-scale epidemiological studies, but available data indicate a strong correlation with prolonged asbestos exposure, particularly in occupational settings such as construction, shipbuilding, and mining. Unlike the epithelioid variant, which affects a broader demographic, sarcomatoid mesothelioma primarily occurs in older males, with most diagnoses in individuals over 60. This pattern reflects historical asbestos use in male-dominated industries during the mid-20th century.

Geographically, incidence rates align with regions that historically had high asbestos production and usage. Countries such as Australia, the United States, and the United Kingdom report higher case numbers due to extensive industrial exposure before regulatory restrictions. In contrast, nations with earlier asbestos bans, such as Sweden and the Netherlands, have seen a decline in cases. However, in countries with lax regulations or ongoing legacy exposure, new cases continue to emerge, often with delayed onset due to the disease’s long latency period, which can exceed 40 years.

Sarcomatoid mesothelioma most frequently arises in the pleura, accounting for nearly 80% of cases, followed by the peritoneum. Pericardial and testicular involvement is exceedingly rare but has been documented. Its aggressive nature leads to early invasion into adjacent structures, resulting in rapid disease progression and a higher likelihood of distant metastases compared to epithelioid mesothelioma.

Cellular And Histopathologic Features

Sarcomatoid mesothelioma is characterized by spindle-shaped tumor cells forming interwoven fascicles with a storiform or haphazard growth pattern. Unlike the epithelioid subtype, which has a more cohesive arrangement, sarcomatoid mesothelioma consists of elongated, fibroblast-like cells lacking defined intercellular junctions. These cells display marked pleomorphism, with variations in nuclear size and shape, and often exhibit hyperchromatic nuclei with prominent nucleoli. Mitotic activity is typically elevated, reflecting the tumor’s aggressive proliferative capacity. The extracellular matrix frequently contains abundant collagen deposition, contributing to a desmoplastic stroma that can resemble benign fibrotic processes, complicating histopathologic differentiation.

Distinguishing sarcomatoid mesothelioma from other spindle-cell neoplasms, such as sarcomas or reactive pleural fibrosis, is challenging. Immunohistochemical (IHC) staining is essential, as sarcomatoid mesothelioma often exhibits positivity for mesothelial markers like calretinin, WT-1, and cytokeratin 5/6, though less consistently than the epithelioid subtype. Sarcomatoid tumors frequently show strong vimentin expression, a mesenchymal marker, while demonstrating variable staining for epithelial markers like EMA or pancytokeratin. Loss of BAP1 expression, a characteristic finding in malignant mesothelioma, helps differentiate it from benign conditions. GATA3 and TTF-1 negativity also assist in excluding metastatic carcinomas with similar morphology.

Rare subtypes include desmoplastic and biphasic mesothelioma. Desmoplastic mesothelioma consists of dense collagenized tissue with scattered tumor cells, often requiring extensive sampling for diagnosis. It has a high tendency for tissue invasion, serving as a clue to its aggressive nature. Biphasic mesothelioma contains both epithelioid and sarcomatoid components, with prognosis largely dictated by the proportion of sarcomatoid differentiation. Tumors with a predominance of spindle cells behave similarly to pure sarcomatoid mesothelioma, exhibiting a more aggressive course.

Common Symptoms And Disease Presentation

Symptoms of sarcomatoid mesothelioma often emerge insidiously, with early signs frequently dismissed as benign respiratory or gastrointestinal issues. Most patients initially report fatigue, weight loss, and malaise, which can delay diagnosis. As the disease progresses, more localized symptoms develop, reflecting the tumor’s primary site.

In pleural cases, which are the majority, chest pain and dyspnea worsen due to tumor infiltration and progressive pleural effusion. Fluid accumulation restricts lung expansion, leading to breathlessness often misattributed to chronic lung conditions. Unlike epithelioid mesothelioma, which may progress more slowly, sarcomatoid mesothelioma grows rapidly and invades adjacent structures, causing severe pleuritic pain. Some patients develop chest wall masses or palpable nodules, indicating direct extension beyond the pleura.

In peritoneal cases, abdominal swelling and distension result from ascites, accompanied by diffuse pain and altered bowel habits. Tumor burden can lead to bowel obstruction, causing nausea, vomiting, and reduced appetite, further exacerbating weight loss.

Mediastinal involvement can lead to complications such as superior vena cava syndrome, presenting with facial swelling and upper extremity edema due to impaired venous return. Tumor encroachment on the recurrent laryngeal nerve may result in hoarseness, while pericardial invasion can cause constrictive pericarditis or pericardial effusion, worsening respiratory distress. Neuropathic pain and musculoskeletal dysfunction are common in advanced stages, particularly when the tumor affects intercostal nerves or spinal structures. These symptoms significantly impact quality of life, often necessitating palliative care.

Diagnostic Modalities

Diagnosing sarcomatoid mesothelioma is challenging due to its histologic overlap with other spindle-cell malignancies and the lack of distinct radiologic features. Diagnosis typically begins with imaging studies, as patients present with symptoms related to pleural or peritoneal involvement.

Computed tomography (CT) scans are the primary imaging modality, revealing pleural thickening, nodular masses, or irregular effusions. Unlike epithelioid mesothelioma, sarcomatoid lesions tend to appear as diffuse, infiltrative masses with extensive pleural rind formation. Magnetic resonance imaging (MRI) with contrast provides additional detail on soft tissue invasion, particularly for surgical planning. Positron emission tomography (PET) using fluorodeoxyglucose (FDG) aids in staging, as sarcomatoid tumors exhibit high metabolic activity, helping differentiate malignancy from benign pleural fibrosis.

Definitive diagnosis relies on histopathologic and immunohistochemical analysis. Tissue acquisition via image-guided core needle biopsy or video-assisted thoracoscopic surgery (VATS) is preferred over fine-needle aspiration, as larger samples improve diagnostic accuracy. Sarcomatoid mesothelioma often has sparse cellularity, making cytologic evaluation alone insufficient. Immunohistochemistry is essential, with a panel of mesothelial and mesenchymal markers aiding differentiation from sarcomas and reactive spindle-cell proliferations. Calretinin, WT-1, and cytokeratin 5/6 are commonly assessed, though their expression is less consistent in sarcomatoid subtypes than in epithelioid mesothelioma. Strong vimentin positivity and BAP1 loss further support the diagnosis, while negative staining for markers like S-100 and CD34 helps exclude alternative spindle-cell malignancies.

Prognostic Indicators

Sarcomatoid mesothelioma has a poor prognosis, with survival outcomes significantly worse than epithelioid or biphasic variants. Patients with pure sarcomatoid mesothelioma typically have median survival times of four to eight months due to its aggressive nature and resistance to treatment. The biphasic subtype offers slightly better outcomes, though prognosis depends on the proportion of sarcomatoid differentiation. Tumors with predominant spindle-cell composition behave similarly to pure sarcomatoid mesothelioma, progressing rapidly.

Tumor stage at diagnosis is a key prognostic factor. Advanced disease, characterized by extensive pleural involvement, mediastinal invasion, or distant metastases, is associated with shorter life expectancy. Lymph node involvement worsens prognosis, indicating systemic spread and reducing the effectiveness of locoregional treatments. Performance status, usually assessed using the Eastern Cooperative Oncology Group (ECOG) scale, also influences survival. Patients with higher functional impairment due to tumor burden or respiratory compromise tend to have shorter survival. Biomarkers such as high neutrophil-to-lymphocyte ratios and elevated lactate dehydrogenase (LDH) levels correlate with poorer outcomes, suggesting systemic inflammation and tumor metabolism contribute to disease progression.

Molecular Studies

Molecular profiling has revealed distinct genetic alterations in sarcomatoid mesothelioma that contribute to its aggressive behavior. Compared to the epithelioid subtype, sarcomatoid tumors more frequently exhibit tumor suppressor gene loss, particularly involving CDKN2A, BAP1, and NF2. CDKN2A deletions lead to cell cycle dysregulation, promoting unchecked proliferation. BAP1 inactivation, a hallmark of mesothelioma, is less common in sarcomatoid variants, potentially contributing to their resistance to DNA-damaging therapies. NF2 mutations disrupt the Hippo signaling pathway, enhancing invasiveness and resistance to apoptosis.

Epigenetic and transcriptomic alterations further drive tumor progression. DNA methylation profiling has identified promoter hypermethylation in key regulatory genes, while RNA sequencing studies show upregulation of epithelial-to-mesenchymal transition (EMT) genes, increasing migratory capacity and invasiveness. Overexpression of mesenchymal markers like ZEB1 and TWIST1 correlates with poorer survival, reinforcing EMT’s role in disease progression. These molecular insights are improving diagnostic accuracy and guiding targeted therapy development, with ongoing research into CDK4/6 inhibitors and epigenetic modulators to overcome treatment resistance.