Pleomorphic Sarcoma: Diagnosis, Markers, and Subtypes

Pleomorphic sarcoma is a rare and aggressive soft tissue cancer primarily affecting adults. Previously classified as malignant fibrous histiocytoma (MFH), it has been redefined due to advances in molecular pathology. This tumor’s significant cellular variability makes diagnosis challenging.

Accurate identification and classification are essential for treatment planning. Understanding its diagnostic markers, imaging techniques, subtypes, and prognostic indicators helps guide clinical decisions.

Histopathological Features

Pleomorphic sarcoma exhibits striking cellular heterogeneity, with tumor cells varying in shape, size, and nuclear atypia. The hallmark of this malignancy is its high-grade spindle cell component mixed with bizarre multinucleated giant cells. Mitotic activity is brisk, often with atypical mitoses, reflecting the tumor’s aggressive nature. Necrosis is common in larger lesions due to rapid proliferation outpacing vascular supply. These features complicate diagnosis, requiring careful differentiation from other high-grade sarcomas.

The stromal composition is diverse, often with a myxoid or fibrous background and varying collagen deposition. Growth patterns range from storiform or fascicular to haphazard spindle cell arrangements. Inflammatory infiltrates, including lymphocytes and histiocytes, may be present, further complicating histological interpretation. Some tumors exhibit osteoid or chondroid differentiation, particularly those with mesenchymal plasticity. These variations underscore the need for thorough histopathological evaluation.

Immunohistochemical staining aids differentiation from similar tumors. While pleomorphic sarcomas lack specific lineage markers, they typically express vimentin, a general mesenchymal marker. Some cases show focal positivity for smooth muscle actin (SMA) or desmin, though inconsistently. The absence of S100 (indicative of neural or melanocytic differentiation) and cytokeratins (associated with epithelial malignancies) helps exclude other diagnoses. Given the histological overlap with undifferentiated pleomorphic sarcoma and other sarcomas, a panel of stains is often required.

Molecular Markers

Molecular studies reveal a heterogeneous genetic landscape without a single defining alteration. Unlike translocation-associated sarcomas, pleomorphic sarcoma exhibits complex karyotypic abnormalities, including copy number variations, chromosomal aneuploidy, and structural rearrangements. Sequencing studies identify recurrent mutations in tumor suppressor genes TP53 and RB1, both key regulators of cell cycle control. Their loss contributes to unchecked proliferation and genomic instability, hallmarks of high-grade sarcomas.

Beyond TP53 and RB1, next-generation sequencing has identified additional mutations that drive tumor progression. ATRX mutations, associated with chromatin remodeling and telomere maintenance, correlate with aggressive behavior. Alterations in PTEN and PIK3CA suggest activation of the PI3K/AKT/mTOR pathway, a signaling cascade implicated in tumor growth. These findings highlight potential therapeutic targets, though no molecularly targeted therapies are yet standard treatment.

Gene expression profiling has revealed dysregulated pathways, including upregulation of mesenchymal-associated transcription factors such as TWIST1 and SNAI1, which promote epithelial-to-mesenchymal transition (EMT) and enhance invasiveness. Overexpression of MDM2 in some cases suggests p53 dysfunction, though MDM2 amplification, characteristic of dedifferentiated liposarcoma, is not a defining feature here. Epigenetic modifications, including DNA hypomethylation and histone changes, further contribute to tumor complexity.

Imaging Modalities

Imaging plays a critical role in tumor evaluation, guiding localization, extent assessment, and treatment planning. Magnetic resonance imaging (MRI) is preferred for soft tissue evaluation due to its superior contrast resolution. T1-weighted sequences reveal a heterogeneous mass with hemorrhage and necrosis, while T2-weighted imaging highlights hyperintense regions corresponding to myxoid or edematous components. Gadolinium contrast enhances delineation between viable tumor tissue and necrotic zones, informing surgical planning. MRI also helps assess neurovascular involvement, influencing resectability.

Computed tomography (CT) is useful for evaluating osseous involvement, particularly when the tumor affects bone or causes cortical destruction. CT is also essential for staging, as pulmonary metastases are common in advanced disease. Up to 40% of patients present with lung metastases at diagnosis or during follow-up, underscoring the importance of high-resolution chest CT. In cases where MRI is contraindicated, contrast-enhanced CT can serve as an alternative.

Positron emission tomography (PET) combined with CT (PET/CT) assesses metabolic activity and detects occult metastases. Pleomorphic sarcomas exhibit high fluorodeoxyglucose (FDG) uptake due to their aggressive nature and elevated glucose metabolism. A study in Clinical Cancer Research found FDG-PET/CT had over 90% sensitivity in identifying metastatic lesions in soft tissue sarcomas. PET/CT is also useful for monitoring treatment response, as persistent FDG avidity after neoadjuvant therapy may indicate residual disease.

Subclassification

Pleomorphic sarcoma includes a diverse group of high-grade malignancies with overlapping histological features but distinct biological behaviors. Advances in molecular pathology and immunohistochemistry have refined its classification. Historically grouped under malignant fibrous histiocytoma (MFH), this designation has been largely abandoned due to its lack of specificity. The World Health Organization (WHO) now recognizes undifferentiated pleomorphic sarcoma (UPS) as the most common variant, defined by the absence of definitive lineage-specific markers.

UPS is a diagnosis of exclusion, requiring the absence of features indicative of other sarcoma subtypes. It displays significant pleomorphism, with spindle and epithelioid cells in a disorganized pattern. Most cases arise in the extremities, particularly the lower limbs, though retroperitoneal tumors tend to be more aggressive. Distinguishing UPS from pleomorphic liposarcoma, which contains lipoblasts and adipocytic differentiation markers, is crucial, as pleomorphic liposarcomas generally have a worse prognosis and may respond differently to therapy.

Pleomorphic rhabdomyosarcoma, defined by skeletal muscle differentiation and desmin and myogenin expression, primarily affects adults and carries a poor prognosis due to its high metastatic potential. Similarly, pleomorphic leiomyosarcoma, marked by smooth muscle differentiation and positivity for SMA and h-caldesmon, often arises in deep soft tissues or the retroperitoneum. The presence of myogenic differentiation in these subtypes provides opportunities for targeted therapies, as leiomyosarcomas may respond to agents that disrupt smooth muscle contractile mechanisms.

Prognostic Factors

Several factors influence pleomorphic sarcoma prognosis, including tumor size, depth, and anatomical location. Lesions exceeding 5 cm or arising in deep soft tissues carry a higher risk of recurrence and metastasis. Extremity tumors generally have better surgical outcomes than retroperitoneal ones, where complete resection is more challenging. Histological grade, particularly nuclear atypia, mitotic activity, and necrosis, further impacts prognosis. High-grade tumors with extensive necrosis and brisk mitotic rates are associated with worse survival.

Molecular alterations also affect outcomes, with TP53 and RB1 mutations linked to poorer survival due to their role in genomic instability. While no single biomarker definitively predicts treatment response, some gene expression profiles indicate disease progression risk. High MDM2 expression has been associated with reduced chemotherapy sensitivity. Additionally, PI3K/AKT/mTOR pathway activation has been implicated in resistance to standard treatments, highlighting potential avenues for targeted therapy. Understanding these prognostic variables allows for more personalized treatment approaches, optimizing patient management and improving long-term outcomes.