Immunohistochemical stains play a vital role in the diagnosis of amelanotic, spindle cell, and epithelioid variants of melanoma and their distinction from poorly-differentiated carcinomas as well as mesenchymal tumors. A classic case of melanoma is immunoreactive for S-100 protein, HMB-45, Melan-A, tyrosinase, Microphthalmia Transcription Factor (MITF), and vimentin. S-100 protein is a highly sensitive marker for melanomas but lacks specificity. It is positive (both nuclear and cytoplasmic staining) in 94-100% of primary and metastatic tumors. However, it is also positive in a variety of mesenchymal cells and their tumors, including Schwann cells, myoepithelial cells, adipocytes, chondrocytes, and Langerhans cells. Some breast carcinomas and undifferentiated carcinomas may also stain with S-100 protein. The image shows S-100 positivity in the dermal component of a desmoplastic melanoma. This male patient was a renal transplant recipient and developed lentigo maligna melanoma on the forehead. Image copyright: pathorama.ch.