CONTEXT: Pathologists may encounter problems in the differential diagnosis of malignant melanoma, spindle and epithelioid neoplasms of peripheral nerves, and fibrohistiocytic tumors. Tyrosinase has been demonstrated to be a sensitive marker for melanoma. OBJECTIVE: To determine the specificity of tyrosinase expression in the differential diagnosis of melanoma, desmoplastic melanoma, and peripheral nerve sheath tumors. DESIGN: Immunoreactivity for tyrosinase, HMB-45 (anti-gp100 protein), S100 protein, CD34, and vimentin was studied in 70 tumors, including 15 melanomas (5 desmoplastic, 4 amelanotic, 6 melanotic), 13 malignant peripheral nerve sheath tumors; 10 schwannomas (1 pigmented), 12 neurofibromas (4 pigmented), and 20 fibrohistiocytic tumors (10 dermatofibrosarcoma protuberans and 10 dermatofibromas). Microwave-based antigen retrieval was performed in 10mM citrate buffer, pH 6.0, for 20 minutes at 121 degrees C. RESULTS: All melanomas demonstrated positive immunostaining for tyrosinase, HMB-45, and S100 protein. Immunoreactivity for HMB-45 was generally stronger than that for tyrosinase in amelanotic lesions and significantly stronger in 1 of the desmoplastic lesions. The 4 pigmented neurofibromas were focally positive for tyrosinase, but did not stain for HMB-45. The pigmented schwannoma was focally positive for both tyrosinase and HMB-45. The malignant peripheral nerve sheath tumors, dermatofibrosarcoma protuberans, and dermatofibromas were nonreactive for tyrosinase and HMB-45. CONCLUSIONS: Our results support the sensitivity of tyrosinase expression and demonstrate the relative specificity of tyrosinase as a marker for melanocytic lesions, including desmoplastic melanoma, although pigmented peripheral nerve tumors may demonstrate focal positive staining. Immunoreactivity for tyrosinase and HMB-45 may have been enhanced by the microwave-based antigen-retrieval technique used in this study.