Perivascular Epithelioid Cell Tumors (PEComas) are a rare family of mesenchymal neoplasms. They arise from the perivascular epithelioid cell (PEC), a distinctive cell type that exhibits features of both smooth muscle and melanocytic cells. The “sarcoma” designation indicates an aggressive, malignant tumor with the potential for rapid growth and metastasis. PEComas are challenging because they can appear in almost any organ and display variable biological behavior.
Defining Perivascular Epithelioid Cell Tumors
The cells constituting a PEComa have a unique dual lineage, expressing markers typically found in both muscle and pigment cells. These perivascular epithelioid cells are defined by their appearance around blood vessels and their clear to eosinophilic cytoplasm, though they are not found in healthy tissue. The PEComa family includes specific diagnoses such as renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM), and tumors found in the uterus, liver, and gastrointestinal tract.
The behavior of these tumors ranges from benign to highly aggressive. Malignant classification, or sarcoma, relies on specific histological features, often guided by the Folpe criteria. Features indicating a higher risk of malignant behavior include:
- Tumor size greater than five centimeters.
- Increased mitotic rate.
- Presence of necrosis within the tumor.
- Evidence of vascular invasion.
Tumors lacking these features are generally considered benign. Those with only one or two risk factors are categorized as having uncertain malignant potential.
Genetic Factors and Tuberous Sclerosis Complex
A significant proportion of PEComas are linked to Tuberous Sclerosis Complex (TSC), a genetic disorder. This association stems from mutations affecting the tumor suppressor genes TSC1 or TSC2. These genes encode the proteins hamartin and tuberin, which normally form a complex that regulates cell growth.
The TSC1/TSC2 complex acts as a GTPase-activating protein (GAP) for the protein Rheb, controlling a major cellular pathway. Inactivation of TSC1 or TSC2 leads to the loss of this complex, allowing Rheb to remain constantly active. This unrestrained activity causes excessive activation of the mechanistic Target of Rapamycin complex 1 (mTORC1). mTORC1 is a central regulator of cell proliferation, protein synthesis, and growth, and its dysregulation is the primary molecular driver for PEComa development. A smaller subset of PEComas, often those in bone and soft tissue, may also be driven by TFE3 gene rearrangements, which similarly activate the mTOR pathway.
Symptoms and Confirmation of Diagnosis
Symptoms of PEComa sarcoma are highly variable, depending on the tumor’s size and anatomical location. Abdominal or pelvic tumors may present with non-specific symptoms such as pain, a palpable mass, or compression of surrounding organs. If the tumor is located in the uterus, patients might experience abnormal vaginal bleeding. Large tumors carry the risk of hemorrhage or rupture.
Many PEComas are discovered incidentally during imaging performed for unrelated reasons due to their non-specific presentation. Initial diagnosis uses imaging techniques like computed tomography (CT) or magnetic resonance imaging (MRI). However, these scans cannot definitively distinguish PEComa from other soft tissue tumors. A definitive diagnosis requires a tissue sample obtained via core needle biopsy. Pathologists analyze this sample using immunohistochemistry (IHC) to confirm the tumor’s identity. The defining characteristic is the co-expression of melanocytic markers (HMB-45 and Melan-A) along with myogenic markers (smooth muscle actin (SMA) or desmin).
Current Approaches to Treatment
The primary treatment for localized PEComa sarcoma is complete surgical removal (radical resection) with clear margins. Since these tumors can arise in complex locations, such as the retroperitoneum or visceral organs, surgery often requires a specialized sarcoma surgical team. Achieving a microscopically negative margin is associated with a better long-term prognosis and is the main goal of initial intervention.
Systemic therapy is necessary when the tumor is locally advanced, unresectable, or metastatic. Conventional treatments like cytotoxic chemotherapy and external beam radiation therapy have historically shown limited effectiveness, as PEComas are generally resistant to these approaches. The targeted molecular mechanism of the disease has led to the successful use of mTOR inhibitors, which address the underlying genetic dysregulation. Drugs such as sirolimus, everolimus, and nab-sirolimus inhibit the overactive mTORC1 pathway, suppressing tumor cell growth. Nab-sirolimus has received regulatory approval for advanced malignant PEComa and has demonstrated durable responses in clinical trials.
Long-Term Outlook and Recurrence Monitoring
The long-term outlook depends heavily on the tumor’s malignant characteristics at diagnosis, especially its size and mitotic activity. Benign tumors or those with uncertain malignant potential typically have an excellent prognosis following complete resection. Malignant PEComas, however, carry a significant risk of recurrence and metastasis, most commonly to the lungs, liver, or lymph nodes.
Because of the potential for late recurrence, patients require rigorous and prolonged surveillance after initial treatment. Monitoring typically involves regular physical examinations, blood work, and imaging studies, such as CT scans of the chest and abdomen. Recurrence has been documented many years, sometimes over a decade, after the primary tumor was removed. Management of this rare sarcoma is best handled by multidisciplinary teams at specialized sarcoma centers.