CD56

Synonyms: Neural cell adhesion molecule (N-CAM), Leu-19

by Assia Bassarova

Background

CD56, is a surface adhesion glycoprotein, member of the immunoglobulin superfamily. The gene is located in 11q23-24. Three main isoforms exist of CD56 (NCAM-120, NCAM-140, and NCAM-180), all generated by alternative splicing from one single gene, differing in their intracellular domain length. CD56 is engaged in both so-called homophilic and heterophilic interactions. CD56 mediates cell-cell and cell-matrix interaction via homophilic binding and heterophilic binding to heparin/heparin sulphate and collagens. Very little is known regarding the functional role of CD56 on immune cells. One key function in the development of NK cells is the CD56-driven migratory behavior of NK cells on stromal cells, forming a developmental synapse. NK cells acquire motility with progressive maturation, correlated with the expression of CD56 on developing NK cells. Blocking of CD56 therefore perturbs both NK cell motility and maturation. CD56+ immune cells are also able to form strong immune synapses with each other through CD56 binding. For example, CD56+ DCs have been shown to induce the preferential activation and expansion of CD56+ γδ T cells via CD56. In particular, homophilic interaction between CD56 molecules on CD56+ cells can be formed, including immune cells but also, for example, tumor cells.

Staining in normal tissues

CD56 is often considered a marker of neural lineage commitment due to its discovery site. 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. However, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is most stringently associated with, but certainly not limited to, natural killer (NK) cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) T cells and activated CD8+ T cells, as well as on dendritic cells (DCs). Also, in the bone marrow, at the site where hematopoiesis occurs, CD56 fulfills a pivotal role. Mesenchymal stromal cells provide niches for hematopoietic stem cells by, inter alia, the expression of adhesion molecules comprising CD56, maintaining long-term hematopoiesis.
CD56 is also expressed in various epithelia (enterocytes and newly formed bile ductular cells), ovarian stromal cells, uterine smooth muscle cells and osteoblasts.

Staining in tumors

Numerical and functional deficiencies and phenotypic alterations of CD56+ immune cells have been reported in patients with various infectious, autoimmune or malignant diseases.
Aberrant CD56 expression is seen in a range of hematological malignancies [e.g., multiple myeloma and leukemia] as well as solid tumors [e.g., lung cancer, ovarian cancer, and neuroblastoma].

  1. Haematological malignancies:
  • 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; MGUS is positive in <10% of the cases
  • acute myeloid and actue lymphoblstic leukemia
  1. Neurological tumors:
  • neuroblastoma and ganglioneuroblastoma
  • astrocytoma
  • oligodendroglioma
  • ependymoma
  • meningioma
  • schwannoma
  1. Soft tissue tumors:
  • synovial sarcoma
  • mesenchymal chondrosarcoma
  • osteosarcoma
  • rhabdomyosarcoma
  • leiomyomatous tumours (except vascular types)
  1. Various:
  • ovarian sex cord-stromal tumours
  • Wilms’ tumor
  • phaeochromocytoma/paraganglioma
  • desmoplastic small cell tumour
  • CD56 is found in most cases of, 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

Staining pattern

Distinct, moderate to strong, predominantly membranous staining pattern in all expressed cells and tissues.

Control tissue

Tonsil / appendix is recommendable suitable tissue control. Virtually all the NK-cells and CD4/CD8 double positive T-cells must show a strong, predominantly membranous staining reaction. The fibroblastic reticular cells (meshwork) and the NK-cells should be clearly visible even at very low magnification (2,5x objective). All other subtypes of lymphocytes must be negative.
Appendix shows very strong staining of the peripheral nerves and weaker staining of the NK and double positive T-cells..

Application

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.

Selected references

  1. Acker HH, Capsomidis A, Smits EL, Van Tendeloo VF. CD56 in the Immune System: More Than a Marker for Cytotoxicity? Front Immunol. 2017 Jul 24;8:892. doi: 10.3389/fimmu.2017.00892. PMID: 28791027; PMCID: PMC5522883.
  2. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001 Nov;22(11):633-40. doi: 10.1016/s1471-4906(01)02060-9. PMID: 11698225.
  3. Cichocki F, Grzywacz B, Miller JS. Human NK Cell Development: One Road or Many? Front Immunol. 2019 Aug 29;10:2078. doi: 10.3389/fimmu.2019.02078. PMID: 31555287; PMCID: PMC6727427.
  4. Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The Broad Spectrum of Human Natural Killer Cell Diversity. Immunity. 2017 Nov 21;47(5):820-833. doi: 10.1016/j.immuni.2017.10.008. PMID: 29166586; PMCID: PMC5728700.
  5. Di Bona E, Sartori R, Zambello R, et al. Prognostic significance of CD56 antigen expression in acute myeloid leukemia. Haematologica. 2002 Mar;87(3):250-6. PMID: 11869936.
  6. Petrella T, Bagot M, Willemze R, Beylot-Barry M, Vergier B, Delaunay M, Meijer CJ, Courville P, Joly P, Grange F, De Muret A, Machet L, Dompmartin A, Bosq J, Durlach A, Bernard P, Dalac S, Dechelotte P, et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol. 2005 May;123(5):662-75. PMID: 15981806.
  7. Yap LW, Brok J, Pritchard-Jones K. Role of CD56 in Normal Kidney Development and Wilms Tumorigenesis. Fetal Pediatr Pathol. 2017 Feb;36(1):62-75. doi: 10.1080/15513815.2016.1256358. Epub 2016 Dec 9. PMID: 27935326.