S-100

**Biochemistry:** S-100 is a family of small (~10–12 kDa) acidic, EF-hand calcium-binding proteins. The name comes from solubility in 100% saturated ammonium sulfate. It is involved in calcium signaling, cell proliferation and differentiation, and cytoskeletal regulation. Because it is found in the cytoplasm and nucleus, staining is nuclear and cytoplasmic.

**Cells that express S-100 (neural crest derivatives and others):** - Melanocytes (and nevus cells) - Schwann cells - Langerhans cells (and interdigitating dendritic cells) - Astrocytes and other glia - Chondrocytes - Adipocytes - Myoepithelial cells

**Tumors that are S-100 positive (high-yield):** - **Melanoma:** S-100 is a very sensitive marker (~95–100%) but not very specific. Pair it with more specific markers such as HMB-45, Melan-A (MART-1), and SOX10. Metastatic melanoma is a classic "poorly differentiated tumor" scenario. - **Schwannoma:** diffusely and strongly positive. This is a benign tumor of Schwann cells, such as a vestibular schwannoma at the cerebellopontine angle (CN VIII) in NF2. It shows Antoni A (cellular, with Verocay bodies) and Antoni B (loose) areas. - **Neurofibroma:** positive, with a mix of cell types. It is associated with NF1. - **Malignant peripheral nerve sheath tumor:** variably positive, and often only focally. - **Langerhans cell histiocytosis:** positive for S-100, CD1a, and langerin (CD207). Electron microscopy shows Birbeck granules ("tennis racket" shape). It presents with lytic bone lesions and a "histiocytosis X" spectrum (Letterer-Siwe, Hand-Schüller-Christian, eosinophilic granuloma). - **Clear cell sarcoma** (melanoma of soft parts, t(12;22) EWSR1-ATF1), chordoma (S-100 positive, along with cytokeratin and brachyury), and cartilaginous tumors (chondrosarcoma, chondroblastoma). - Also positive in granular cell tumor, paraganglioma (sustentacular cells), and neuroblastoma (variable).

**Comparison with other markers (commonly tested):** - Cytokeratin: carcinomas - Vimentin: mesenchymal tumors (sarcomas) - Desmin: muscle tumors - GFAP: astrocytes and glial tumors (astrocytoma, glioblastoma) - Chromogranin and synaptophysin: neuroendocrine tumors - LCA (CD45): lymphoma - HMB-45, Melan-A, tyrosinase: melanoma (more specific, less sensitive than S-100) - CD1a, langerin: Langerhans cells

**Clinical pearls:** - An S-100 positive spindle or epithelioid tumor in the skin suggests melanoma. - S-100B in serum is used as a prognostic and monitoring marker in melanoma (higher levels indicate a higher tumor burden and a worse prognosis). It is also studied as a biomarker of brain injury (for example, to avoid CT after mild head trauma) and CNS damage. - S-100 is not a specific marker. Always interpret it as part of a panel.