S100

(S-100 protein)
Characteristics

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).

Neoplasms

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.

Application

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).

Controls

Appendix is recommended as primary positive and negative tissue control for S100. In the appendix virtually all adipocytes and Schwann cells of peripheral nerves, must show an as strong as possible nuclear and cytoplasmic staining reaction without any staining reaction of the smooth muscle or epithelial cells.

As supplement when using pAb Z0311 tonsil can be used. 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 centres should show an at least weak to moderate nuclear and cytoplasmic staining reaction.

Selected references

Hagen EC, Vennegoor C, Schlingemann RO, Van der Velde EA, Ruiter DJ. Correlation of histopathological characteristics with staining patterns in human melanoma assessed by (monoclonal) antibodies on paraffin sections. Histopathol 1986;10:689-700. Schafer BW, Heizmann CW. The S100 family of EF-hand calcium-binding proteins: functions and pathology. Trends Biochem Sci. 1996 Apr;21(4):134-40. Schafer BW, Wicki R, Engelkamp D, Mattei MG, Heizmann CW. Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome 1q21: rationale for a new nomenclature of the S100 calcium-binding protein family. Genomics. 1995 Feb 10;25(3):638-43. Soo V, Shen P, Pichardo R, Azzazy H, Stewart JH, Geisinger KR, Levine EA. Intraoperative evaluation of sentinel lymph nodes for metastatic melanoma by imprint cytology. Ann Surg Oncol. 2007 May;14(5):1612-7. Vrbic S, Filipovic S, Pejic I, Vrbic M, Filipovic A. Sensitivity, specificity, positive and negative predictive value of serum S-100 beta protein in patients with malignant melanoma. J BUON. 2003 Apr-Jun;8(2):139-41. Yu CH, Chen HH, Liu CM, Jeng YM, Wang JT, Wang YP, Liu BY, Sun A, Chiang CP. HMB-45 may be a more sensitive maker than S-100 or Melan-A for immunohistochemical diagnosis of primary oral and nasal mucosal melanomas. J Oral Pathol Med. 2005 Oct;34(9):540-5.

11.12.15 - ET/MV/LE