CD138, also designated syndecan-1, is a member of the syndecan family of four transmembrane spanning proteins capable of binding to heparan sulfate and chondroitin sulfate molecules. The syndecans’ main functions are to control cell growth and differentiation as well as to maintain cell adhesion and cell migration. The syndecans are also involved in regulation of cell signaling by integrating external signals from circulating ligands and extracellular matrix with other cellular receptors. The syndecans interact primarily with basic fibroblast growth factors, vascular endothelial growth factors, hepatocyte growth factor or transforming growth factor-? and extracellular matrix proteins including fibronectin and laminin. CD138, the most studied member of the syndecan family and the only protein of diagnostic relevance, is encoded on chromosome 2p23-24. It is an important regulator of cell-cell and cell-extracellular matrix interactions particularly involved in regulating cell morphology and adhesion. Loss of CD138 expression under experimental conditions causes normal mammary epithelial cells to acquire a fibroblastic phenotype, while induced expression of the protein has the opposite effect on the morphology. Over-expression of CD138 inhibits cell growth and migration of the affected cells. In inflammation CD138 facilitates transepithelial leukocyte migration (together with IL-8 and matrilysin) by altering leukocyte-endothelium interactions. It is also been shown that expression of CD138 is required for wnt-1 induced tumorigenesis in mice. Under normal conditions CD138 is predominantly expressed on mature plasma cells and early preB-cells, while other haematolymphoid cells are negative. Various types of epithelial cells are also CD138 positive. Squamous epithelial cells show strong membranous and some cytoplasmic staining, except for the mature superficial squamous epithelial cells which are unstained. Mature mesenchymal and neural tissues are not stained. Syndecan-2 is mostly expressed under embryonic development and in adult life is involved in regulating of TGF-?. Syndecan-3 plays an important role in regulation of skeletal muscle differentiation and development. Syndecan-4 acts as a potent modulator of FGF2 signaling.
Among haematolymphoid neoplasms, CD138 is expressed in practically all cases of plasma cell malignancies. All variants of plasmacytoma including plasmablastic myeloma stain positive and plasma cells dyscrasias such as monoclonal gammopathy of undetermined significance (MGUS). Staining in other types of lymphoma usually reflects a degree of plasmacytoid differentiation in lymphoplasmacytic lymphoma and marginal zone lymphoma. Variable intensity of staining of small lymphocytes and stronger staining of paraimmunoblasts using mAb clone B-B4 has been described in 75% or more cases of B-CLL. In diffuse large B-cell lymphoma CD138 positivity is associated with a poorer prognosis (as it indicates activated B-cell phenotype - together with positivity for MUM1). Burkitt lymphoma is negative. Non-Hodgkin lymphomas arising in HIV patients are frequently CD138 positive. A varying percentage of classic Hodgkin lymphoma is also reported to show cytoplasmic positivity in Hodgkin and Reed-Sternberg cells using mAb clones B-B4 and Mi15, which may suggest their post-germinal center cell origin. The percentage is much higher in frozen material than in formalin fixed paraffin embedded material. In nodular lymphocytic predominant Hodgkin lymphoma, no CD138 reactivity is found. Recently, some publications have reported CD138 reactivity in cases of B-cell acute lymphoblastic leukemia/lymphoma. Among nonhaematolymphoid neoplasms the expression of CD138 is found in various types of carcinoma. In the following, the large majority of cases is CD138 positive: skin squamous cell carcinoma and basal cell carcinoma, colorectal adenocarcinoma, cholangiocarcinoma, transitional cell carcinoma, endometrial adenocarcinoma, ductal and lobular breast carcinoma, hepatocellular carcinoma, renal cell carcinoma, and lung adenocarcinoma. In the following carcinomas, a minority of cases is positive: prostate adenocarcinoma, adrenal cortical carcinoma, pancreas adenocarcinoma, gastric adenocarcinoma, serous carcinoma, medullary and papillary thyroid carcinoma, carcinoid tumor, neuroendocrine carcinoma and Merkel cell carcinoma. No staining has been reported in small cell carcinoma of lung, thymoma and germ cell tumors. The reactivity for CD138 is only rarely seen in malignant mesothelioma though staining in epithelioid variants has been reported. Among mesenchymal tumors, synovial sarcoma show strong positive staining for CD138 in cell membrane and cytoplasm in glandular areas of biphasic type and weaker in cytoplasm in spindle cell areas (mAb clone B-B4). Positive cases of GIST, leiomyosarcoma, alveolar soft part sarcoma are also reported. Regarding epithelioid sarcoma there are conflicting reports. Some membranous staining for CD138 is seen in cases of malignant melanoma. The expression of CD138 in predicting of tumor behavior varies with tumor type and differentiation grade. The expression is reduced in squamous cell carcinogenesis and low level of expression correlates with poor prognosis in head and neck carcinomas and squamous cells carcinoma of uterine cervix. Correlation of decreased CD138 reactivity with increasing nuclear grade in renal cell carcinomas is also reported. On the other hand a correlation between over-expression of CD138 and poorer prognosis in adenocarcinoma of the pancreas has been observed.
CD138 is a very sensitive and specific marker for identification of plasma cells and plasma cell differentiation within haematolymphoid tissues in benign and neoplastic conditions. The primary application is the identification and quantification of plasma cells in bone marrow and other tissue biopsies both in reactive conditions and in plasma cells dyscrasia (MGUS) as well as plasma cell differentiation in various types of lymphoma. The marker is used in a panel of antibodies in prognostic subtyping of diffuse large B-cell lymphomas. It is also shown that identification of plasma cells in tissue specimen may be a useful adjunct in diagnosis of chronic inflammatory conditions (i.e. endometritis). However, the expression of CD138 is not specific for plasma cells when tissues and tumors of non-haematolymphoid origin are considered: In setting of poorly differentiated neoplasm the interpretation of staining should be especially careful as the cells of metastatic carcinoma are also often stained positive, which occasionally may present a pitfall especially when diagnosing bone marrow biopsies. It is a potential diagnostic application to include CD138 in mesothelioma panels for separating mesothelioma from metastatic adenocarcinoma, since many metastatic carcinomas show positive staining, but it still needs more validation.
Normal tonsil is recommended as control for CD138. Plasma cells and squamous epithelial cells must show a strong predominantly membranous staining reaction, while late stage activated germinal centre B-cells must show an at least weak to moderate and distinct membranous staining reaction. No staining reaction must be seen in the mantle zone B-cells.
Selected references
Bai M, Panoulas V, Papoudou-Bai A, Horianopoulos N, Kitsoulis P, Stefanaki K, Rontogianni D, Agnantis NJ, Kanavaros P. B-cell differentiation immunophenotypes in classical Hodgkin lymphomas. Leuk Lymphoma. 2006 Mar;47(3):495-501. Bayer-Garner IB, Nickell JA, Korourian S. Routine syndecan-1 immunohistochemistry aids in the diagnosis of chronic endometritis. Arch Pathol Lab Med. 2004 Sep;128(9):1000-3. Chu PG, Arber DA, Weiss LM. Expression of T/NK-cell and plasma cell antigens in nonhematopoietic epithelioid neoplasms. An immunohistochemical study of 447 cases. Am J Clin Pathol. 2003 Jul;120(1):64-70. Gokden N, Greene GF, Bayer-Garner IB, Spencer HJ, Sanderson RD, Gokden M. Expression of CD138 (Syndecan-1) in renal cell carcinoma is reduced with increasing nuclear grade. Appl Immunohistochem Mol Morphol. 2006 Jun;14(2):173-7. Kambham N, Kong C, Longacre TA, Natkunam Y. Utility of syndecan-1 (CD138) expression in the diagnosis of undifferentiated malignant neoplasms: a tissue microarray study of 1,754 cases. Appl Immunohistochem Mol Morphol. 2005 Dec;13(4):304-10. Kumar-Singh S, Jacobs W, Dhaene K, Weyn B, Bogers J, Weyler J, Van Marck E. Syndecan-1 expression in malignant mesothelioma: correlation with cell differentiation, WT1 expression, and clinical outcome. J Pathol. 1998 Nov;186(3):300-5. O'Connell FP, Pinkus JL, Pinkus GS. CD138 (syndecan-1), a plasma cell marker immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms. Am J Clin Pathol. 2004 Feb;121(2):254-63. Orosz Z, Kopper L. Syndecan-1 expression in different soft tissue tumours. Anticancer Res. 2001 Jan-Feb;21(1B):733-7. Sanderson RD, Borset M. Syndecan-1 in B lymphoid malignancies. Ann Hematol. 2002 Mar;81(3):125-35. Saqi A, Yun SS, Yu GH, Alexis D, Taub RN, Powell CA, Borczuk AC. Utility of CD138 (syndecan-1) in distinguishing carcinomas from mesotheliomas. Diagn Cytopathol. 2005 Aug;33(2):65-70. Sutcliffe M, Oscier D, Wright DH. SYNDECAN-1 (CD138) expression in human non-Hodgkin's lymphomas. Br J Haematol. 2000 Jul;110(1):239-40.
14.11.12 - JK/MV/LE