CD 57

Becton Dickinson (Leu7), Biodesign (NC1), GenTrak, Immunotech (NC1), Sanbio (6-13-19-1) and Serotec (NC-1).

Most antibodies are reactive in fixed paraffin-embedded tissues and immunoreactivity is enhanced by heat-induced epitope retrieval.

CD 57 antibodies detect a 110 kd protein encoded by a gene on chromosome 11. The protein is present on some peripheral lymphocytes but not in monocytes, granulocytes, platelets or erythrocytes. CD 57+ lymphocytes increase with age and represent 10-20% of lymphocytes in most adults. They mostly include a subset of CD 8+ T lymphocytes as well as natural killer (NK) cells (Abo & Balch, 1982). A subpopulation of peripheral lymphocytes that reacts with this marker includes large granular lymphocytes. This antibody also reacts with both CD 3+ and CD 3-, non-B lymphocytes. The CD 3lymphocytes demonstrate NK cell activity and have large cytoplasmic granules that are not seen in the CD 3+ cells. CD 3+/CD 57+ T cells are primarily suppressor lymphocytes with CD 8 expression though CD 4+/CD 8/CD 57+ T cells have been described and CD 8+/CD 57+/HLA-DR+ T cells have also been identified. CD 3+/CD 8+/CD 57+ lymphocytes are positive for CD 45RA but not CD 45RO. While this phenotype is characteristic of na«e T lymphocytes, the CD 57+ cells differ from other na«e T cells by failing to lose the CD 45RA antigen when stimulated with alloantigens. These cells also differ from other T lymphocytes by their increased ability to acquire the HLA-DR antigen in the absence of antigen-specific cytotoxic activity against allogeneic target cells.
The frequency of CD 57+ lymphocytes in solid tissues varies according to site. They are increased in term placental tissue, but not in decidua of early pregnancy. They are decreased in bronchoalveolar lavage specimens compared with peripheral blood in the same patient and represent less than 2% of all nasal mucosal lymphocytes. CD 57+ lymphocytes are rare in both the endometrium and uterine cervix. They are also rare in the thymus and in the bone marrow; they constitute no more than 1% of all nucleated cells.
CD 57+ lymphocytes have a different distribution from that of CD 8+ cells in the tonsils and lymph nodes, with the CD 57 + cells located primarily within the germinal centers. These germinal center cells are CD 3+ T cells, which also express the CD 4 antigen. Similar to the CD 57+/CD 4+ T cells in cytomegalovirus (CMV) carriers, the CD 4+ germinal center cells do not display the usual helper activity of classic CD 4+ lymphocytes (Swerdlow & Murray, 1984). CD 57+ cells in the spleen are seen mostly in the germinal centers of the white pulp or as a rim of cells around the central white pulp (Griffiths et al, 1989).
The HNK-1/Leu7 antibody also reacts with cells other than lymphocytes. CD 57 antibodies react with an antigen present in the central and peripheral nervous system myelin and oligodendroglia and Schwann cells. Some neural adhesion molecules also contain a carbohydrate epitope that is recognized by CD 57 antibodies. The reactivity is due to part of the myelin-associated glycoprotein having a similar molecular mass (110 kD) to the CD 57 lymphocyte antigen. Besides neural-associated cells, CD 57 antibodies immunoreact with prostatic epithelium, pancreatic islets, adrenal medulla, renal loops of Henle and proximal tubules, chromaffin cells of the gut, gastric chief cells, epithelial cells of the outer thymic cortex and some cells in the fetal bronchus. They are also detected in the prostatic seminal fluid (Arber & Weiss, 1995).

CD 57+ lymphocytes are increased in patients following bone marrow transplantation. This increase often persists for years after the procedure. The majority of these cells are CD 57-/CD 8+ T lymphocytes which form up to two-thirds of the peripheral blood T lymphocytes, with a small expansion in CD 57+/CD 4+ cells.
The relationship of this increase in CD 57+ cells and graft-versus-host disease is controversial, some workers finding a correlation between the increase in CD 57+ cells and the onset of disease while others have not. Some investigators have noted the expansion of the CD 57+ population with reactivation of CMV after transplantation, similar to the increase in CD 57+ cells seen in healthy carriers of CMV.
CD 57+ cells are also elevated in the peripheral blood in some solid organ transplant patients. Up to 20% of renal allograft, 66% of cardiac allograft and 44% of liver allograft recipients had greater than 20% peripheral blood CD 57+/CD 3+ lymphocytes, the majority of these cells also being CD 8+. As with bone marrow transplantation, the elevation of CD 57+ correlated with a rise in CMV titers and may show poorer graft survival (Legendre et al, 1989).
CD 57+ cells are also elevated in human immunodeficiency virus infections. CD 57+/CD 8+ lymphocytes are increased through the clinical progression of the infection while CD 57+/NK and CD 57- NK cells remain normal.
Peripheral blood CD 57+ cells may be increased in patients with adult-onset cyclic neutropenia whereas no elevation was seen in childhood-onset cases. The adultonset variant of cyclic neutropenia was found to be steroid responsive.
Circulating CD 57- lymphocytes are elevated in patients with Crohn's disease with many of these cells being CD 8+, corresponding to the increase in suppressor cell function found in such patients, Elevations in peripheral blood CD 57+ cells may also be seen in rheumatoid arthritis.
Large granular lymphocytosis (LGL) is by far the most common CD 57+ lymphoproliferative disorder. LGL are usually CD 2+ and may be divided into T cell and NK cell types based on CD 3 expression. CD 3+ cases are generally associated with clonal T-cell gene rearrangement. The T-cell cases are usually CD 57- and CD 8+ and may be further typed according to the presence (type 1) or absence (type 2) of the NK-associated antigen CD 16. Immunostaining of the spleen may be useful in the evaluation of resected spleens in LGL patients. CD 57+ lymphocytes are found in the splenic red pulp, while the expanded while pulp nodules are usually not involved.
Elevations of peripheral blood CD 57+ lymphocytes may be associated with non-neoplastic states such as in CMV carriers, possibly in chronic hepatitis, in ankylosing spondylitis and more frequently in rheumatoid arthritis and Felty's syndrome. Synovial fluid CD 57+ cells may also be elevated in rheumatoid arthritis. Clonal T-cell receptor gene rearrangement has been demonstrated in some cases of rheumatoid arthritis, especially those with Felty's syndrome.
NK/T-cell lymphomas frequently affect the nasal and extranodal sites and show similarities to LGL. The lymphoma cells display large cytoplasmic granules with either a T cell or NK cell phenotype. They are also mostly positive for the Epstein-Barr virus and display an angiocentric pattern of infiltration with necrosis and an aggressive clinical course. Unlike LGL, NK/T-cell lymphomas are CD 57+ in less than 10% of cases, with most cases being CD 56+ so that CD 57 antibodies alone are unreliable NK cell markers of such lymphomas. (Ng et al, 1987; Nakumara et al, 1995) CD 57 expression is seen in just over 20% of T-lymphoblastic lymphomas, but the expression of CD 57 does not correlate with NK activity in these cases and the significance expression of this antigen is unknown. Less than 2% of other types of T-cell lymphoma are CD 57+ and the antigen does not appear to be expressed in B-cell lymphomas, monocytic leukemia or Langerhans histiocytosis. Increases in presumably non-neoplastic CD 57+ cells may be seen in the neoplastic follicles of follicular lymphomas, especially of the small cleaved cell type, and in cases of nodular L&H Hodgkin's disease where the positive cells often does not correlate with NK activity in these cases and the significance expression of this antigen is unknown. Less than 2% of other types of T-cell lymphoma are CD 57+ and the antigen does not appear to be expressed in B-cell lymphomas, monocytic leukemia or Langerhans histiocytosis. Increases in presumably non-neoplastic CD 57+ cells may be seen in the neoplastic follicles of follicular lymphomas, especially of the small cleaved cell type, and in cases of nodular L&H Hodgkin's disease where the positive cells often rosette around CD 20+ L&H cells, providing a useful pointer to the diagnosis. The CD 57+ cells in the latter condition are also CD 4+ and can be seen in about 25-30% of cases of nodular lymphocyte-predominant Hodgkin's disease. Similar distribution and increases in CD 57+ cells were not found in nodular sclerosing Hodgkin's disease, T-cell rich B-cell lymphoma or follicular lymphoma (Sun et al, 1992; Kamel et al, 1993).
CD 57 expression may be observed in a variety of solid tumors, the most common of which are lung tumors. Almost half of small cell lung carcinomas and about 85% of carcinoid tumors are CD 57+. In non-small cell lung carcinoma, the identification of neuroendocrine-associated antigens such as CD 57 has been shown to be predictive of response to chemotherapy. The expression of CD 57 antigen in small cell carcinoma and carcinoid is generally widespread in the tumor but only focal in non-small cell lung carcinomas. Sampling errors should be taken into consideration in the assessment and because of the low sensitivity and specificity of CD 57 antibodies, other neuroendocrine-associated markers such as chromogranin, synaptophysin and neuron-specific enolase should be employed.
Other non-hematopoietic neoplasms that express CD 57 include the majority of the thyroid carcinomas, especially papillary carcinoma, while it is present in only 30% of benign thyroid proliferations. CD 57 may be used to separate medullary carcinomas from other thyroid carcinomas, although there have been some reported examples of positivity in medullary carcinomas. Strong CD 57 staining of the majority of the tumor cells is indicative of papillary or follicular carcinoma and uncommon in benign thyroid proliferations and medullary carcinoma (Ghali et al, 1992). The CD 57 antigen is expressed in prostatic epithelium but the marker does not discriminate between benign and neoplastic cells. Epithelial cells of thymomas are usually CD 57+ while only some thymic carcinomas express the antigen. Over half of malignant mesotheliomas are reported to express CD 57 although they generally do not react with other neuroendocrine markers. Among the soft tissue tumors, the majority of neural tumors, especially neuromas, schwannomas and neurofibromas, react with CD 57 antibodies. Most malignant peripheral nerve sheath tumors are CD 57+ but the antigen may also be expressed by other sarcomas such as synovial sarcoma and leiomyosarcoma. Therefore the marker on its own is not a useful diagnostic discriminant and should be used in an appropriate panel of antibodies in order to separate the various spindled and pleomorphic soft tissue tumors. Similarly, because CD 57 may be expressed by a variety of small round cell tumors including neuroblastomas, it is not a useful diagnostic discriminant for this group of poorly differentiated tumors (Bunn et al, 1985; Michels et al, 1987; Linnoila et al, 1994).
In the central nervous system, CD 57 expression may be seen in normal oligodendroglia and other nervous system cells as well as in their corresponding tumors (Motoi et al, 1985). Oligodendrogliomas perhaps show the most extensive degree of CD 57 positivity compared to astrocytomas and glioblastomas, which, demonstrate fewer positive cells. Among skin tumors, the expression of CD 57 closely paralleled that of S100 protein although the two were not identical. Neither was useful in the distinction of eccrine from apocrine tumors (Kanitakis et al, 1987). Melanocytic proliferations and melanomas may show variable positivity for CD 57, whereas reports of the expression of this antigen in Merkel cell carcinoma are conflicting, the antigen being absent in some series and positive in half the tumors in another study. CD 57 positivity is also seen in other tumors including a large proportion of granular cell tumors, paragangliomas and pheochromocytomas. Embryonal carcinomas and dysgerminomas are also reported to be positive for CD 57 in most cases.

The CD 57 antigen is most useful in the identification of large granular lymphocyte disorders and assists in the identification of L&H cells of lymphocyte-predominant Hodgkin's disease. The CD 57+ cells that are CD 4+ T cells form rosettes around CD 20+ L&H cells. Elevation of peripheral blood CD 57+ lymphocytes may be seen following some viral infections, such as CMV, in patients following bone marrow or solid organ transplantation. CD 57 should not be used alone as a marker of NK cells neuroendocrine cells or neural cells and must be employed in neuroendocrine cells or neural cells and must be employed in combination with other antibodies in a panel, particularly if used for diagnostic purposes. The antibody is immunoreactive in fixed, paraffin-embedded tissues, especially following heat-induced epitope retrieval.

•Abo T, Balch CM 1982. A differentiation antigen of human NK and K cells identified by a monoclonal antibody (HNK-1). Journal of Immunology 129: 1758-1761.

•Arber DA, Weiss LM 1995. CD57. A review. Applied Immunohistochemistry 3: 137-152.

•Bunn PA, Linnoila I, Minna JD, Carney D, Gazdar AF 1985. Small cell lung cancer, endocrine cells of the fetal bronchus, and other neuroendocrine cells express the Leu 7 antigenic determinant present on natural killer cells. Blood 65: 764-768.

•Ghali VS, Jimenez JS, Garcia RL 1992. Distribution of Leu 7 antigen (HNK-1) in thyroid tumors: its usefulness as a diagnostic marker for follicular and papillary carcinomas. Human Pathology 23: 2125.

•Griffiths DFR, Jasani B, Standen GR. 1989 Pathology of the spleen in large granular lymphocytic leukemia. Journal of Clinical Pathology 42:885-890.

•Kamel OW, Gelb AS, Shibuya RB, Warnke RA 1993. Leu 7 (CD 57) reactivity distinguishes nodular lymphocyte predominance Hodgkin's disease from nodular sclerosing Hodgkin's disease, T-cell rich B-cell lymphoma and follicular lymphoma. American Journal of Pathology 142:541-546.

•Kanitakis J, Zambruno G, Viac J et al 1987. Expression of neural-tissue markers (S100 protein and Leu7 antigen) by sweat gland tumors of the skin. Journal of the American Academy of Dermatology 17: 187-191.

•Legendre CM, Forbes RDC, Loertscher R, Guttmann RD 1989. CD 4+/Leu 7+ large granular lymphocytes in long-term renal allograft recipients. A subset of atypical T cells. Transplantation 47:964-971.

•Linnoila RI, Piantadosi S, Ruckdeschel JC 1994. Impact of neuroendocrine differentiation in non-small cell lung cancer. The LCSG experience. Chest 106 (suppl): 367S-371S.

•Michels S, Swanson PE, Robb JA, Wick MR 1987. Leu-7 in small cell neoplasms. An immunohistochemical study with ultrastructural correlations. Cancer 60:2958-2964.

•Motoi M, Yoshino T, Hayashi K et al 1985. Immunohistochemical studies on human brain tumors using anti-Leu 7 monoclonal antibody in paraffin-embedded specimens. Acta Neuropathologica 66:75-77.

•Nakumara S, Suchi T, Koshikawa T et al 1995. Clinicopathologic study of CD 56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract. American Journal of Surgical Pathology 19: 284-296.

•Ng CS, Chan JKC, Lo STH 1987. Expression of natural killer cell markers in non-Hodgkin's lymphomas. Human Pathology 18: 1257-1262.

•Sun T, Brody J, Koduru P et al 1992. Study of the major phenotype of large granular T cell lymphoproliferative disorder. American Journal of Clinical Pathology 98:516-521.

•Swerdlow SH, Murray LJ 1984. Natural killer (Leu 7+) cells in reactive lymphoid tissues and malignant lymphomas. American Journal of Clinical Pathology 81: 459-463.

Manual of diagnostic antibodies for immunohistology / Anthony S.-Y. Leong, Kumarasen Cooper, F. Joel W.-M. Leong.