The perivascular epithelioid cell (PEC) is a cell type constantly present in a group of tumors called PEComas. PEC expresses myogenic and melanocytic markers, such as HMB45 and actin. Recently, recurrent chromosomal alterations have been demonstrated in PEC. At present, PEComa is a widely accepted entity. In the past 10 years, the use of this term has allowed to report and describe numerous cases permitting to start highlighting the biology of this group of lesions. PEComas are related to the genetic alterations of tuberous sclerosis complex (TSC), an autosomal dominant genetic disease due to losses of TSC1 (9q34) or TSC2 (16p13.3) genes which seem to have a role in the regulation of the Rheb/mTOR/p70S6K pathway. There are some open questions about PEComas regarding its histogenesis, the definition of epithelioid angiomyolipoma and the identification of the histological criteria of malignancy. An innovative therapeutic trial using rapamycin is under way for tumors occurring in TSC such as renal angiomyolipoma and lymphangioleiomyomatosis. Its success could provide the rationale for the use of the same drug in other lesions composed of PECs, especially in the malignant ones.Keywords PEComa . PEC . Angiomyolipoma . Lymphangioleiomyomatosis . Sugar tumor . TSC . mTOR . RapamycinWhat is the perivascular epithelioid cell?The perivascular epithelioid cell (PEC) (Fig. 1) is a cell type constantly present in a group of tumors including angiomyolipoma (AML), clear-cell "sugar" tumor (CCST) of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear-cell myomelanocytic tumor of the falciform ligament/ligamentum teres and rare clear-cell tumors of other anatomical sites.It has morphologic, immunohistochemical, ultrastructural and genetic distinctive features such as an epithelioid appearance with a clear to granular cytoplasm, a round to oval, centrally located nucleus and an inconspicuous nucleolus. PEC has mild to any atypia and a typical perivascular location [13]. At present, PEC has not a known normal counterpart.Immunohistochemically, PEC expresses myogenic and melanocytic markers, such as HMB45, HMSA-1, MelanA/ Mart1, microophtalmia transcription factor (Mitf), actin and, less commonly, desmin [13,55,126]. Its immunoreactivity for vimentin is usually incospicuous.At ultrastructural analysis, PEC contains microfilament bundles with electron-dense condensation, numerous mithocondria and membrane-bound dense granules [11,118].It is thought that PEC can modulate its morphology and immunophenotype: given all the characteristics described above (Fig. 2), PEC can show muscular features with a spindle shape and a stronger positivity for actin than for HMB45 or it can have an epithelioid feature with a strong positivity for HMB45 and a mild, if any, reaction for actin (Fig. 3). PEC can also become vacuolized acquiring the feature of an adipocyte. Progesterone receptor positivity has been described in PEC with spindle morphology; this suggests a possible role of progesterone in this morphologic modulation [...

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Renal epithelial tumors (carcinoma and oncocytoma) have been reported with higher a frequency than expected in patients with the tuberous sclerosis complex. However, the recent identification of a monotypic, epithelioid variant of angiomyolipoma, closely simulating renal cell carcinoma, has cast doubt on the real frequency of carcinoma. Immunohistochemical analysis with a panel of antibodies, including melanogenesis marker HMB45, can discriminate between carcinoma and carcinoma-like angiomyolipoma. We studied five tumors previously reported as carcinoma and found that only one of them showed an immunohistochemical phenotype indicative of an epithelial tumor (Ker+, HMB45-). Three tumors exhibited a phenotype compatible with the monotypic epithelioid variant of angiomyolipoma (HMB45+, Ker-), and two of the three patients died of metastatic disease. The last patient had unusual clinical features, and the tumor was positive both for HMB45 and keratin. It is concluded that (1) renal cell carcinoma is less common in tuberous sclerosis complex than previously believed, (2) some cases called renal cell carcinoma probably represent a monotypic, epithelioid variant of angiomyolipoma, and (3) epithelioid angiomyolipoma is a potentially malignant tumor with invasion and metastases. These findings indicate that all reported renal carcinomas in tuberous sclerosis complex, therefore, must be reevaluated.