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Birt-Hogg-Dub (BHD) is an autosomal dominant disorder characterized clinically by cutaneous fibrofolliculomas,kidney tumors and pulmonary cysts;occasionally lesions in other systems are also identified.The mutations of BHD gene are believed to be responsible for BHD syndrome.Oncocytic hybrid tumors are the most common types of renal tumors in BHD patients.Studies characterizing these BHD associated tumors are very limited.Expression microarray,IHC and EM have not been well documented.We studied 12 hybrid tumors from 8 patients with BHD syndrome.Gene expression microarrays were performed on 4 cases and compared to our established database of other kidney neoplasms.Histopathologic and immunohistochemical features (CA9, vimentin, c-Kit and CK7) were evaluated.Electronic microscopy (EM) was performed.Lesions of other organ systems in these BHD patients were also studied.In all cases, BHD gene mutations were confirmed.In two cases, pulmonary cysts and skin fibrofolliculoma were found in addition to kidney tumors.In one case, a parotid oncocytic tumor was present.Histologically, the kidney hybrid tumors showed prominent cell membranes and dense eosinophilic cytoplasm.In addition, the hybrid tumors contained scattered clear epithelial cells of low nuclear grade intermingled with oncocytic cells.By immunohistochemistry,hybrid tumors were positive for C-kit and showed patchy Ck7 positivity.Ultrastructurally, hybrid tumors contained small membrane-bound microvesicles.By molecular clustering analysis, hybrid tumors were located between chromophobe renal cell carcinomas and oncocytomas.The most prominent molecular feature of BHD associated kidney tumors is the high expression level of genes associated with mitochondria and oxidative phosphorylation.Comparative genomic microarray analysis showed minimal chromosomal losses similar to oncocytomas, whereas chromophobe renal cell carcinomas show numerous chromosomal losses.In our study, the molecular signature of BHD associated hybrid oncocytic tumors has been defined.We also report here the morphological and immunohistochemical characteristics of these renal tumors and other lesions in other systems.Recognition of link between these lesions and BHD is important for diagnosis of the syndrome.These hybrid renal tumors should be considered a distinct subtype based on their morphologic, molecular genetic and immunohistochemical characteristics.