S100 is a 21kDa highly acidic and water soluble protein first isolated from brain but later shown to be produced by a wide variety of normal and neoplastic cells of mesodermal, neuroectodermal, and epithelial origin. S-100 protein may be found in the cell membranes, cytoplasm and nuclei. The protein is a dimer, having two subunits, alpha and beta, with extensive sequence homology. There are 3 forms of S-100 protein: alpha-alpha, known as S-100A0; alpha-beta, known as S-100A and beta-beta, known as S-100B. The S-100 alpha gene is assigned to chromosome 1q21. At present, 10 types of alpha chains have been identified. The S100 beta gene is assigned to chromosome 21q22. Only one type of beta chain has been identified. As most cells containing S-100 protein also express the beta chain (marked exceptions being neurones and histiocytes), this has become almost synonymous with the protein. S100 has varying affinity to calcium and other metals. Its properties are related to many basic cell functions such as cation diffusion across lipid membranes, microtubule assembly, and RNA polymerase activity. In neurones, S100 is involved in the plasma membrane function as well as interaction with chromosomes and synaptosomes. S100 (beta protein) is present in glial cells, Schwann cells and satellite cells (but not perineurial cells), melanocytes, myoepithelial cells, some glandular epithelia (breast, kidney), skeletal and heart muscle cells, fat cells and chondrocytes, and follicular dendritic cells. Cerebral overexpression of S100 appears to be neurotoxic and is of pathogenetic importance in Alzheimer disease and Down syndrome (trisomy 21).
The following neoplasms express S100 in more than 90% of the cases: Astrocytoma, glioblastoma, oligodendroglioma, ependymoma and other glial tumours, schwannoma, neurofibroma, benign and malignant melanocytic tumours, granular cell tumour, myoepithelial tumours, polymorphous low grade adenocarcinoma, Langerhans cell histiocytosis, xanthogranuloma, chordoma, and most types of benign and malignant lipomatous tumours. The following express the protein in 50-90% of the cases: Primitive neuroectodermal tumours (neuroblastoma and others), malignant peripheral nerve sheath tumour, clear cell sarcoma, rhabdomyosarcoma, benign and malignant chondroid tumours, sweat gland carcinoma, serous and endometrioid cystadenoma and carcinoma, renal cell carcinoma, papillary and follicular thyroid carcinoma, and acute monoblastic/monocytic leukaemia. S-100 protein is found in 10-50% of the following: Granulosa cell tumour, Sertoli-Leydig cell tumours, alveolar soft part sarcoma, synovial sarcoma, Ewing sarcoma, vascular tumours, gastrointestinal stromal tumour, meningioma, adenocarcinomas of breast and gastrointestinal tract, carcinoids and other neuroendocrine tumours, anaplastic thyroid carcinoma. The following rarely or never express S100: adenocarcinomas of the alimentary tract, lung, and prostate, transitional cell carcinoma, malignant mesothelioma, fibromatosis, fibrohistiocytic tumours, smooth muscle tumours, malignant lymphomas and germinal cell tumours. In some tumours, the S-100 protein positivity is restricted to so-called sustentacular cells: phaeochromocytoma/paraganglioma (particularly when benign), and medullary thyroid carcinoma. S-100 positive dendritic cells are particularly numerous in sclerosing variant of papillary carcinoma.
The immunohistochemical evaluation of S-100 (beta) protein expression is important in the diagnosis of undifferentiated malignant tumours of unknown primary origin and should be included in the so-called primary panel. S100 is a very sensitive marker for malignant melanoma of all types, a negative staining is exceedingly rare. Because of its low specificity, other markers should be included in a panel for malignant melanoma, such as vimentin and Melan-A. S100 may be used in the differential diagnosis of sarcomas (e.g., the distinction between liposarcoma and other myxoid tumours) and spindle cell tumours (e.g., the distinction between schwannoma, leiomyoma and gastrointestinal stromal tumour).
Appendix and tonsil is recommended as positive and negative tissue controls for S100. In the appendix virtually all adipocytes, Schwann cells and dendritic cells must be stained as strongly as possible without any staining reaction of the smooth muscle or epithelial cells. In the tonsil, interfollicular dendritic cells and Langerhans cells of the squamous epithelium, must display a moderate to strong staining intensity whereas the follicular dendritic cell meshwork of the germinal centers must show an at least weak to moderate nuclear and cytoplasmic staining reaction.
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