Although neoplasia is caused by clonal proliferation of cells, the resulting tumors are frequently heterogeneous, being composed of both neoplastic and reactive cells. Therefore, identification of tumors as neoplastic processes is frequently obscured. We studied cutaneous angiofibroma, which is a tumor of unknown etiology. Combined analysis using immunohistochemistry, selective tissue microdissection, fluorescence in situ hybridization, sequencing analysis, and deletion analysis of the multiple endocrine neoplasia type 1 locus succeeded in the identification of a population of genetically altered, neoplastic cells in these tumors. This approach may be valuable in the future in identifying the etiology of other tumors of unknown etiology.