What is the pathophysiology of a hepatic-like angiomyolipoma variant of Perivascular Epithelioid Cell Tumor (PEComa) in an adult patient with a tumor located in the right thigh and no significant comorbidities?

Pathophysiology of Hepatic-like Angiomyolipoma Variant of PEComa in the Right Thigh

The hepatic-like angiomyolipoma variant of PEComa arises from perivascular epithelioid cells (PECs) that demonstrate dual myomelanocytic differentiation, characterized by coexpression of melanocytic and smooth muscle markers, with the tumor cells arranged around blood vessels in a nested pattern. 1

Cellular Origin and Differentiation

• PEComas originate from perivascular epithelioid cells, a distinctive cell type that exhibits both melanocytic and smooth muscle characteristics, representing a unique dual differentiation pattern 1

• The tumor cells demonstrate myomelanocytic lineage, expressing both melanocytic markers (HMB-45, cathepsin K, melan-A) and smooth muscle markers (smooth muscle actin, desmin, caldesmon) on immunohistochemistry 1, 2, 3

• These neoplasms are part of the PEComa family, which includes angiomyolipoma, lymphangioleiomyomatosis, and clear cell "sugar" tumors, all sharing similar immunophenotypic profiles 1, 4, 2

Molecular Pathogenesis

Genetic Alterations in Typical PEComas

• Most conventional PEComas are associated with inactivation of TSC1 or TSC2 genes (tuberous sclerosis complex genes), leading to constitutive activation of the mTOR pathway 1

• However, Xp11 translocation PEComas represent a distinct molecular subtype that does NOT exhibit TSC1/TSC2 inactivation and are not associated with tuberous sclerosis complex 1

Xp11 Translocation Variant

• Xp11 translocation PEComas most commonly harbor the SFPQ-TFE3 gene fusion, resulting in overexpression of the TFE3 transcription factor 1

• These tumors almost always demonstrate an exclusively epithelioid clear cell morphology with minimal to no immunoreactivity for muscle markers, distinguishing them from typical PEComas 1

• Xp11 translocation PEComas affect younger patients and show no hereditary basis or association with tuberous sclerosis 1

Histopathological Architecture

Cellular Composition

• The hepatic-like variant is composed of epithelioid cells with clear to eosinophilic granular cytoplasm arranged in a nested pattern around blood vessels 1, 4, 2

• Unlike classic angiomyolipoma, these tumors lack overt epithelial structures (tubules or papillae) and may have minimal or absent lipomatous and vascular components 1, 2

• The tumor cells demonstrate perivascular arrangement, which is the defining architectural feature of all PEComas 1, 3

Stromal Features

• Some variants show extensive stromal hyalinization and sclerosis, creating cords and trabeculae of epithelioid cells embedded in densely sclerotic stroma 3

• The sclerosing variant lacks the delicate nesting vascular pattern typical of other PEComas, instead showing more prominent stromal collagenization 3

Immunophenotypic Profile

• Positive markers include: HMB-45 (melanocytic), cathepsin K (melanocytic), smooth muscle actin, desmin, caldesmon, and microphthalmia transcription factor 1, 2, 3

• Negative markers include: cytokeratins, epithelial membrane antigen, PAX8 (renal tubular marker), S-100 protein (usually negative), and CD117/KIT 1, 2, 3

• For Xp11 translocation variants, strong diffuse nuclear TFE3 immunoreactivity is characteristic, though TFE3 break-apart FISH is more reliable for diagnosis 1

Biological Behavior and Risk Stratification

Prognostic Features

• Worrisome histological features that predict aggressive behavior include: tumor size ≥7 cm, infiltrative border, mitotic rate >1/10 mm², necrosis, vascular invasion, and PEComa NOS subtype 5

• High-risk tumors (≥3 worrisome features) have approximately 25% risk of metastasis, while intermediate-risk tumors (1-2 features) have 3% risk 5

• Malignant transformation is characterized by coagulative necrosis, marked nuclear atypia, high mitotic activity (>20/10 HPF), and loss of CD117 expression 6

Metastatic Potential

• Approximately 50% of Xp11 translocation PEComas have metastasized, making this molecular subtype particularly aggressive 1

• Common metastatic sites include lung, liver, peritoneum, and abdominal wall 5, 6

Clinical Implications for Soft Tissue Location

• While most PEComas arise in visceral organs (liver, kidney, uterus), soft tissue locations including the thigh are well-documented and follow similar pathophysiological mechanisms 3

• The retroperitoneum and pararenal region are common sites for sclerosing PEComa variants, though extremity locations can occur 3

• Adult patients without tuberous sclerosis presenting with soft tissue PEComas should be evaluated for Xp11 translocation variants, which have higher malignant potential 1