Synonyms: Neural cell adhesion molecule (N-CAM), Leu-19. Nature: Cell surface glycoprotein, adhesion protein of the immunoglobulin gene superfamily. Gene and structure: 11q23-24. At least 27 alternatively-spliced CD56 mRNAs are produced, giving a wide diversity of isoforms. The three main isoforms are 120kDa (glycosylphosphatidylinositol [GPI] anchored), 140kDa (short cytoplasmic domain), 180kDa (long cytoplasmic domain). Occurrence and function: CD56 mediates cell-cell and cell-matrix interaction via homophilic binding and heterophilic binding to heparin/heparin sulphate and collagens. CD56 occurs widely in the central nervous system (neurons and glia cells but not choroid plexus), peripheral nerves and skeletal muscles, most types of neuroendocrine cells and various epithelia (enterocytes and newly formed bile ductular cells), ovarian stromal cells, uterine smooth muscle cells and osteoblasts. In the haematopoietic system, CD56 is the prototypic marker of NK cells (80-90%), but also present on subsets of CD4+ and CD8+ T cells.


+ The following tumours are always or almost always CD56 positive: acute and chronic myeloid leukaemia, ovarian sex cord-stromal tumours, Wilms' tumor, neuroblastoma and ga nglioneuroblastoma, phaeochromocytoma/paraganglioma, astrocytoma, oligodendroglioma, ependymoma, meningioma, schwannoma, synovial sarcoma, mesenchymal chondrosarcoma, osteosarcoma, rhabdomyosarcoma, leiomyomatous tumours (except vascular types), and desmoplastic small cell tumour. +/- CD56 is found in most cases of natural killer (NK) and NK/T-cell lymphomas (nasal and nasal-type NK/T-cell lymphomas, aggressive NK cell leukemia and blastic NK leukemia/lymphoma), multiple myeloma, mesotheliomas, well differentiated neuroendocrine tumor and neuroendocrine carcinoma, thyroid adenoma/carcinoma (with the exception of papillary carcinoma), adrenal cortical adenoma/carcinoma, renal cell carcinoma, pancreatic solid pseudopapillary tumor, Wilms' tumor. -/+ Many other types of carcinoma, sarcoma and lymphoma show CD56 positivity in minor numbers of cases. Often conflicting results across different studies. Ewing’s sarcoma/peripheral neuroectodermal tumour is reported positive in 10-25% of the cases. -(+) MGUS is positive in <10% of the cases. - The following tumour types are CD56-: Neurofibroma, granular cell tumor, solitary fibrous tumor, juvenile fibromatosis, vascular leiomyoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, and angiosarcoma. In glial tumors CD56 is downregulated in the development of malignancy. Occurrence of CD56 has in colon adenocarcinoma shown negative correlation to liver metastases and positive correlation to survival. In adenocarcinomas of colorectum, pancreas and biliary tract CD56 has shown a role in the development of perineural invasion.


CD56 may be used in the differential diagnosis of • NK-cell lymphoma (CD56+/-) vs. other lymphomas (CD56-(+)). • Multiple myeloma (CD56+) vs. lymphoplasmacytic lymphoma, reactive plasmacytosis and monoclonal gammopathy of undetermined significance (MGUS) (CD56-(+)). • Myeloid leukaemic cells (CD56+) vs. normal myeloid cells (CD56-) • Non-papillary thyroid tumours (CD56+) vs. papillary thyroid carcinoma (CD56-) • Schwannoma (CD56+) vs. neurofibroma (CD56-) • The small cell tumours neuroblastoma, osteosarcoma, chondrosarcoma and small cell carcinoma (CD56+) vs. Ewing’s sarcoma/peripheral neuroectodermal tumour (CD56-/+) CD56 is frequently used as a very sensitive marker for neuroendocrine tumours but should be applied in a panel because of low specificity. It has shown useful in the identification of small cell lung carcinoma in crushed biopsies.


Tonsil is recommendable as positive and negative tissue control, in which virtually all the NK-cells and CD4/CD8 double positive T-cells must show a strong, predominantly membranous staining reaction. Indicative for an optimal calibrated protocol is, that the fibroblastic reticular cells (meshwork) and the NKcells should be clearly visible even at very low magnification (2,5x objective). All other subtypes of lymphocytes must be negative.
Appendix is not recommendable as control, as peripheral nerves only display high level of CD56, and limit of detection of CD56 hereby not possible to evaluate and consequently risking misdiagnosis of tumours displaying low level of CD56 expression.

Selected references

El Demellawy D, Nasr AL, Babay S, Alowami S. Diagnostic utility of CD56 immunohistochemistry in papillary carcinoma of the thyroid. Pathol Res Pract. 2009;205(5):303-9. Epub 2009 Jan 18. PubMed PMID: 19153015. Figarella-Branger D, Lepidi H, Poncet C, Gambarelli D, Bianco N, Rougon G, Pellissier JF. Differential expression of cell adhesion molecules (CAM), neural CAM and epithelial cadherin in ependymomas and choroid plexus tumors. Acta Neuropathol. 1995;89(3):248-57. PubMed PMID: 7754745. Kontogianni K, Nicholson AG, Butcher D, Sheppard MN. CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact. J Clin Pathol. 2005 Sep;58(9):978-80. PubMed PMID: 16126882; PubMed Central PMCID: PMC1770835. Kremer M, Ott G, Nathrath M, Specht K, Stecker K, Alexiou C, Quintanilla-Martinez L, Fend F. Primary extramedullary plasmacytoma and multiple myeloma: phenotypic differences revealed by immunohistochemical analysis. J Pathol. 2005 Jan;205(1):92-101. PubMed PMID: 15586381. Lanza F, Bi S, Castoldi G, Goldman JM. Abnormal expression of N-CAM (CD56) adhesion molecule on myeloid and progenitor cells from chronic myeloid leukemia. Leukemia. 1993 Oct;7(10):1570-5. PubMed PMID: 7692192. McCluggage WG, McKenna M, McBride HA. CD56 is a sensitive and diagnostically useful immunohistochemical marker of ovarian sex cord-stromal tumors. Int J Gynecol Pathol. 2007 Jul;26(3):322-7. PubMed PMID: 17581419. McNiff JM, Cowper SE, Lazova R, Subtil A, Glusac EJ. CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: magic bullet, diagnostic pitfall, or both? J Cutan Pathol. 2005 Sep;32(8):541-5. PubMed PMID: 16115052. Sasaki H, Yoshida K, Ikeda E, Asou H, Inaba M, Otani M, Kawase T. Expression of the neural cell adhesion molecule in astrocytic tumors: an inverse correlation with malignancy. Cancer. 1998 May 15;82(10):1921-31. PubMed PMID: 9587126.

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