The cell of origin and direction of differentiation of the clear cell tumor of the lung (the so-called sugar tumor) remains enigmatic. Recognition of HMB-45 immunoreactivity and identification of melanosomes have suggested a relationship to angiomyolipoma of kidney or liver and lymphangiomyoma. This has given rise to the concept that clear cell tumors are neoplasms of so-called perivascular epithelioid cells--PEComas. Herein we report the existence of four similar tumors occurring in extrapulmonary sites, one of which had malignant features. The three benign tumors occurred in females ages 9, 20, and 40 years; two were located in the rectum and one in the vulva. The malignant tumor occurred in the inter-atrial cardiac septum of a 29-year-old man. Common histologic features were a richly vascular organoid architecture, tumor cells with clear to pale eosinophilic cytoplasm, abundant glycogen, and immunoreactivity for HMB 45, but not S100, multiple keratin, neuroendocrine, or muscle markers. Benign tumors demonstrated low mitotic activity, no necrosis, and good circumscription; the malignant tumor showed considerable mitotic activity, necrosis, and an infiltrative growth pattern. Ultrastructurally, glycogen was present, mitochondria were abundant, and membrane-bound lamellated bodies consistent with premelanosomes were present in two cases, and equivocal in one. Because these tumors have light microscopic, immunohistochemical, and electron microscopic features similar to pulmonary sugar tumors, we propose the name primary extrapulmonary sugar tumor (PEST) for them. Although most PEST's are probably benign, malignant forms appear to exist. These cases further support the concept of a family of systemic HMB-45 positive tumors that include sugar tumors, angiomyolipoma of kidney or liver, lymphangiomyomas, and clear-cell myomelanocytic tumors of the falciform ligament/ligamentum teres.