CD Markers CD1 to CD49
Last revised 17 June 2009
Copyright © 2001-2009 PathologyOutlines.com, Inc.
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Primary references
American Journal of Clinical Pathology (AJCP), August 1975 to February 2006
American Journal of Surgical Pathology (AJSP), March 1977 to February 2006
Archives of Pathology and Lab Medicine (Archives), January 1976 to February 2006
Human Pathology (Hum Path), March 1970 to February 2006
Modern Pathology (Mod Path), January 1988 to February 2006
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); Mosby, 2004
Sternberg,
S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins,
2004
University of
Pittsburgh Medical Center Case Reports, cases 1-462
CD Marker websites: http://ca.expasy.org/cgi-bin/lists?cdlist.txt, Protein Reviews On the Web, http://www.ebioscience.com/ebioscience/whatsnew/humancdchart.htm
Background
CD: cluster designation or cluster of differentiation
Nomenclature proposed in 1982 at First International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA); workshops now called Human Cell Differentiation Molecules
Classification system for monoclonal antibodies generated by laboratories worldwide against cell surface molecules on leukocytes initially, now also antigens from other cell types
Data collated and analyzed by cluster analysis based on pattern of binding to leukocytes or other cell types
Must be at least two monoclonal antibodies for each antigen
“w" indicates the CD is not well characterized or is represented by only one monoclonal antibody
Interpretation should be based on cellular distribution of staining (i.e. membranous, cytoplasmic, nuclear), proportion of positively stained cells, staining intensity and cutoff levels
Used in immunohistochemistry and flow cytometry
References: J Immunol 1994;152:1, Bull World Health Organ 1997;75:385, J Immunol Methods 2003;275:1-8, Blood 2005;106:3123
Family of non-polymorphic MHC class I-like glycoproteins on surface of various antigen-presenting cells
Member of immunoglobulin superfamily
Has 5 different subsets (CD1a - CD1e), all noncovalently associated with beta 2 microglobulin, all on #1q22-23 (non MHC linked)
The different CD1 forms bind to different types of lipid antigen based on differences in their antigen binding grooves (Nat Rev Immunol 2005;5:387)
Cellular infection with live Mycobacteria tuberculosis or exposure to mycobacterial cell wall products converts CD1 negative myeloid precursors into competent CD1+ antigen presenting cells (J Immunol 2005;175:1758); pollen lipids are also recognized as antigens by T cells via CD1 dependent pathway (J Exp Med 2005;202:295); may generate inflammatory component in atherosclerotic lesions (Am J Pathol 1999;155:775)
Inhibition of CD1 expression may be a mechanism of immune system evasion by metastatic melanoma (Am J Path 2004;165:1853), Leishmania donovani (Infect Immun 2004;72:589), and some Mycobacterial infections
Function: involved in presentation of autologous and bacterial lipid antigens to T cells; may also mediate thymic T cell development
Uses: diagnosis of Langerhans cell histiocytosis
Positive staining (normal): cortical thymocytes (70%), activated T cells, Langerhans cells, interdigitating dendritic cells
Positive staining (disease): Langerhans cell histiocytosis, pre T ALL with cortical thymocyte phenotype; indolent T cell lymphoblastic proliferations (AJSP 1999;23:977; AJSP 2001;25:411), thymoma (Jpn J Thorac Cardiovasc Surg 2003;51:481)
Negative staining: mature peripheral T cells, peripheral T cell lymphomas
Also called Leu6
On chromosome 1q22-23 (not MHC linked)
T cell surface antigen important in dendritic cell presentation of glycolipids and lipopeptide antigens
May activate intrathyroidal T cells in Hashimoto’s thyroiditis and Grave’s disease (J Immunol 2005;174:3773)
Interpretation: membranous staining
Uses: diagnosis of Langerhans cell histiocytosis and exclusion of other entities that are CD1a negative
Micro images: Langerhans cell histiocytosis - (1) lung; (2) thyroid; (3) leprosy patient; (4) skin #1; (5) site unknown #1; #2; (6) cytology
other - (7) CD1a+ Langerhans cells in normal skin; (8) CD1a+ cortical thymocytes in normal thymus; (9) psoriasis
Positive staining (normal): cortical thymocytes, Langerhans cells (Langerin+, CD86+), immature dendritic cells (Langerin-, CD86-, HLA-DR low, CD40-low)
Positive staining (disease): Langerhans cell histiocytosis (fairly specific), myeloid leukemias, mycosis fungoides (variable), almost all cutaneous T cell lymphomas, T-ALL (age 28-60 years, AJCP 2002;117:252), dendritic cells in dermis/epidermis of benign inflammatory skin disorders including pseudolymphomatous folliculitis (AJSP 1999;23:1313), spongiotic dermatitis and lichen planus (Arch Dermatol Res 2002;294:297), psoriasis (J Cutan Pathol 1995;22:223); Barrett’s metaplasia of esophagus (Br J Cancer 2005;92:888), monocytes in most sickle cell anemia patients (Hum Immunol 2004;65:1370)
Negative staining: normal B cells, dendritic cells in most cutaneous B cell lymphomas (AJCP 2001;116:72), histiocytic lymphoma / sarcoma, histiocytoma, follicular dendritic cells, follicular dendritic cell tumor, interdigitating dendritic cells (variable, AJSP 1998;22:1048, AJCP 2001;115:589), interdigitating dendritic cell sarcoma, dendritic cell neurofibroma, juvenile xanthogranuloma, sinus histiocytosis with massive lymphadenopathy, Erdheim-Chester disease
References: AJSP 2001;25:630 (Langerhans cell histiocytosis), J Clin Invest 2004;113:701 (Langerhans cells), OMIM 188370
CD1b
On chromosome 1q22-23 (not MHC linked); noncovalently associated with beta2 microglobulin
Can present to antigen presenting cells a set of glycolipid species with broad range of variation in length of acyl chains (J Immunol 2004;172:2382), including those from pathogenic Mycobacteria tuberculosis and Mycobacteria leprae to cytotoxic T cells
Uses: no significant clinical use by pathologists
Micro images: leprosy patient
Positive staining (normal): cortical thymocytes, Langerhans cells (weaker staining than CD1a), myeloid dendritic cells, brain pyramidal cells, subpopulation of B cells
Positive staining (disease): dendritic cells in mycosis fungoides (J Cutan Pathol 1995;22:223); myeloid leukemias, some B and T cell malignancies, monocytes of most sickle cell anemia patients (Hum Immunol 2004;65:1370)
Negative staining: normal B cells
References: OMIM 188360
CD1c
On chromosome 1q22-23 (not MHC linked); noncovalently associated with beta 2 microglobulin
Activated by phospholipid antigen produced by Mycobacteria tuberculosis and M. bovis Bacille-Calmette-Guerin (J Exp Med 2004;200:1559, Nature 2000;404:884); assists with presentation of lipid antigens
May activate intrathyroidal T cells in Hashimoto’s thyroiditis and Grave’s disease (J Immunol 2005;174:3773); may promote autoantibodies in systemic lupus erythematosus (J Immunol 2000;165:5338)
B-CLL cells downregulate CD1c genes, which may mediate evasion of immune response (Leukemia 2002;16:2429)
Uses: no significant clinical use by pathologists
Positive staining (normal): cortical thymocytes, Langerhans cells (weaker than CD1a), immature myeloid dendritic cells, subset of normal peripheral B cells, activated T cells
Positive staining (disease): dendritic cells in mycosis fungoides (J Cutan Pathol 1995;22:223); myeloid leukemias and some B and T cell malignancies, monocytes of most sickle cell anemia patients (Hum Immunol 2004;65:1370)
Negative staining: many normal B cells
References: OMIM 188340
CD1d
On chromosome 1q22-23 (not MHC linked)
NK T cells are defined as CD1d dependent T cells that carry an invariant TCR alpha-chain and produce high levels of cytokines
CD1d is expressed in NK T cells active in autoimmune diabetes, tumor rejection and some microbial infections
May protect against lipid antigen-rich infectious microbes on human scalp (J Clin Pathol 2005;58:1278)
B-CLL cells downregulate CD1d genes, which may mediate evasion of immune response (Leukemia 2002;16:2429)
Uses: no significant clinical use by pathologists
Positive staining (normal): dendritic cells, intestinal epithelial cells, B cell subset, NK T cell subset (Immunol Lett 2005;100:42, J Immunol 2005;175:4416), low levels in thymus and monocytes
Positive staining (disease): some B and T cell malignancies; keratinocytes in psoriasis
References: OMIM 188410
CD1e
On chromosome 1q22-23 (not MHC linked); noncovalently associated with beta 2 microglobulin
Processes mycobacterial antigen (instead of presenting antigen directly), and helps expand repertoire of glycolipid T cell antigens to optimize the immune response (Science 2005;310:1321); presentment is done by CD1b
Uses: no significant clinical use by pathologists
Positive staining (normal): dendritic cells
References: OMIM 188411
Also called E rosette receptor (anti-CD2 antibodies inhibit formation of rosettes with sheep erythrocytes), LFA2 (leukocyte function antigen), T11
At 1p13.1; member of immunoglobulin superfamily
Early T cell marker
Functions: (a) binds CD58 (LFA3) on antigen-presenting cells, which enables T cells to respond to lower concentrations of antigen (J Exp Med 1999;190:1383); (b) induces costimulatory signals in T cells (c) induces T cell cytokine production; (d) mediates adhesion between T cells and antigen presenting cells; (e) regulates T and NK-mediated cytolysis; (f) inhibits apoptosis of activated peripheral T cells; (g) regulates T cell anergy
Uses: T cell marker (although CD3 is more common), marker of systemic mastocytosis
Interpretation: membranous staining
Micro images: T cell lymphoma-site unknown
Positive staining (normal): thymocytes (95%), mature peripheral T cells (almost all), NK cells (80-90%), thymic B cells (50%)
Positive staining (disease): T-ALL, other T cell lymphoma/leukemia, indolent systemic mastocytosis (Hum Path 2001;32:545), variable acute myeloid lymphoma-M0, rarely pyothorax associated B cell lymphoma (AJSP 2002;26:724, Univ Pittsburgh case report), rarely Reed-Sternberg/Hodgkin’s cells (Mod Path 2005;18:1542), rarely myeloma (Mod Path 1990;3:302), rarely myeloid leukemia
Negative staining: B cells, nonhematopoietic neoplasms (AJCP 2003;120:64), mast cells in non-mastocytosis disorders
CD2R
CD2 epitope present on activated T cells, unmasked by conformational change of CD2 glycoprotein during activation
Uses: no significant clinical use by pathologists
Positive staining (normal): activated T cells
Positive staining (disease): blood and synovial fluid T cells in rheumatoid arthritis; peripheral blood T cells in juvenile rheumatoid arthritis, SLE, ankylosing spondylitis and Lyme disease (Scand J Immunol 1991;34:351)
Also called OKT3
Member of immunoglobulin superfamily on 11q23
Complex of delta, epsilon, gamma, zeta and eta chains of integral membrane glycoproteins that associates with T cell antigen receptor (TCR), and is required for TCR cell surface expression and signal transduction
TCR-CD3 complex consists of either TCR alpha/beta or TCR gamma/delta heterodimers coexpressed at the cell surface with CD3
CD3 delta and epsilon defects cause autosomal recessive severe combined immunodeficiency (no T cells, normal B cells, normal NK cells, OMIM 608971, Curr Opin Allergy Clin Immunol 2004;4:479)
CD3 zeta interacts with HIV Nef protein (J Exp Med 1999;189:1489)
Uses: most specific T cell antibody; diminished expression in T cell cutaneous lymphoma (AJCP 2000;114:467), although another study finds CD8:CD3 ratio <25% in epidermal component of lymphocytic infiltrate in these tumors (Mod Path 2003;16:857); treatment with anti-CD3 antibodies may restore self-tolerance in autoimmune diseases (Curr Opin Immunol 2005;17:632, Ann NY Acad Sci 2004;1037:1)
Interpretation: cytoplasmic expression at early T cell differentiation, then membranous expression
Micro images:
NK/T cell lymphoma: (1) testes-CD3 epsilon+ (figure 3D); (2) acute cellular rejection; (3) autoimmune thyroiditis (figure 3)
Additional images: intraepithelial lymphocytes in duodenum (figure 1b); increased intraepithelial lymphocytes at villous tip (figure 2c)
Virtual slides: diffuse large B cell lymphoma (CD3+ reactive T cells)
Positive staining (normal): thymocytes, peripheral T cells, NK cells (CD3 epsilon, cytoplasmic in 56%, not membranous); also Purkinje cells of cerebellum; note: nonspecific cytoplasmic staining may be present in plasma cells and macrophages
Positive staining (disease): 80% of T cell lymphomas, NK lymphoma (cytoplasmic, not membranous), lymphomatoid granulomatosis, lymphomatoid papulosis; variable in primary effusion lymphoma and pyothorax associated lymphoma
Negative staining: most B cell lymphomas, NK large granular lymphocyte leukemia, Reed-Sternberg cells are negative in Hodgkin’s lymphoma but may be surrounded by CD3 epsilon+ rosettes, small cell carcinoma, melanoma, granulocytic sarcoma, post-transplant lymphoproliferative disorders
References: OMIM 186790 (CD3 delta), OMIM 186830 (CD3 epsilon), OMIM 186740 (CD3 gamma), OMIM 186780 (CD3 zeta); AJCP 2005;124:199 (adult T cell leukemia/lymphoma), AJSP 2001;25:1413 (achalasia in esophagectomy specimens)
Also called OKT4
At #12pter-p12
Nonpolymorphous glycoproteins belonging to immunoglobulin superfamily
Expressed on surface of T helper cells; serves as coreceptor in MHC class II-restricted antigen induced T cell activation
CD4+ CD25+ T cells maintain peripheral tolerance and prevent autoimmunity (Curr Top Microbiol Immunol 2005;293:115)
Serves as HIV receptor on T cells, macrophages, brain
Downregulated by HIV Nef protein during AIDS progression (J Virol 2003;77:11536, J Biol Chem 2003;278:33912)
Normally CD4 > CD8; in HIV patients, CD4/CD8 ratio is inverted (i.e. CD4 < CD8) and patients are at risk for opportunistic infections
Homologous to CD223
Uses: classify lymphomas and inflammatory conditions; serum levels are marker of HIV disease progression and response to therapy (CD4+ cells are killed by HIV); serum levels also increased by transient stress (AJCP 2002;117:819)
Drawings: (1) CD4+ T cell and antigen presenting cell; (2) HIV entry into T cells
Positive staining (normal): thymocytes (80-90%), T helper cells, macrophages, Langerhans cells, dendritic cells, granulocytes
Positive staining (disease): many post-thymic T cell leukemia/lymphomas, indolent T cell lymphoblastic proliferation, pityriasis lichenoides, CD4+ CD56+ hematodermic malignancies (blastic NK lymphoma), histiocytic lymphoma / sarcoma, acute myeloid leukemia (AJCP 1995;104:204), some pyothorax associated lymphomas, cutaneous lymphomatoid granulomatosis (AJSP 2001;25:1111), lymphomatoid papulosis (variable), florid antiviral inflammatory response (Mod Path 2003;16:166)
Negative staining: NK cells, T cell lymphoma with cytotoxic phenotype, hepatosplenic alpha/beta and gamma/delta lymphoma, enteropathy associated T cell lymphoma, B cell lymphoma (usually), Hodgkin’s lymphoma (usually), nonhematopoietic neoplasms
References: Cell 1985;42:93 (early article), OMIM 186940
Belongs to ancient scavenger receptor superfamily; at 11q13
CD5+ B cells, which may arise from B-1 cells (subset of B cells) produce “generalist antibodies” - polyreactive low affinity "natural" antibodies to exogenous antigens (tetanus toxoid, lipopolysaccharide) as well as autoreactive antibodies (Immunol Lett 1993;38:159)
First line of defense against antigens; have a low activation threshold; are the only line of defense for those who cannot produce specific antibody
Produce antibodies using germ line (non mutated) configuration of gene segments, usually IgM
CD5 production is elevated in rheumatoid arthritis (27-52% of circulating B cells vs. 20% normal)
CD5 may serve as a dual receptor, giving either stimulatory or inhibitory signals depending both on the cell type and the development stage
Key regulator of immune tolerance; abnormalities may produce autoimmunity (Immunol Res 2002;26:255)
Binds to CD72
Polymorphism in CD5 promoter associated with susceptibility to mantle cell lymphoma and CLL (AJCP 2005;123:646)
Uses: marker for CLL, mantle cell lymphoma, T cells (normal and malignant), thymic carcinoma
Micro images: (1) mantle cell lymphoma (figure 3D); (2) thymic carcinoma (nonkeratinizing squamous cell subtype); (3) CD5+ T-Cell/histiocyte-rich large B-cell lymphoma (figure 3D)
Flow cytometry images: mantle cell lymphoma #1 with coexpression of CD5 and CD19; #2
Positive staining (normal): thymocytes, almost all T cells, B cells of mantle zone of spleen and lymph nodes (12% of B cells in peripheral blood, AJCP 2004;121:368), B cells in peritoneal and pleural cavities
In fetus, most B cells in spleen and cord blood are CD5 positive
Positive staining (disease): B cell CLL/SLL, mantle cell lymphoma (80-90%), diffuse large B cell lymphoma (10%-usually aggressive), aggressive variant of follicular lymphoma (rare, AJCP 2005;124:182), most T cell malignancies, NK/T cell lymphoma (variable), prolymphocytic leukemia, atypical thymoma (some), thymic carcinoma (almost all), CASTLE (thyroid tumor)
Negative staining: enteropathy associated T cell lymphoma, hepatosplenic alpha-beta and gamma-delta T cell lymphomas, T cell large granular lymphocytic lymphoma, most B cell lymphomas other than mantle cell or CLL (although there rarely are CD5+ variant forms), Reed-Sternberg cells in Hodgkin’s lymphoma
References: OMIM 153340
Belongs to ancient scavenger receptor superfamily; at #11q13
Adhesion molecule mediating the binding of developing thymocytes with thymic epithelial cells
Antibodies to CD6 are used to deplete T cells from bone marrow transplants to prevent graft versus host disease (J Clin Oncol 2001;19:1152, Int J Hematol 1999;69:27)
Binds to CD166 (ALCAM); essential for stable T cell-antigen presenting cell contact and for T cell proliferation (Blood 2006;107:3212)
Uses: see above for bone marrow transplants
Positive staining (normal): low levels on immature (cortical) thymocytes, high levels on mature (medullary) thymocytes; also mature T cells, B cell subset (B1a cells), CNS cells
References: OMIM 186720
Member of immunoglobulin superfamily at 17q25.2-25.3
Has costimulatory activity for T cells (Immunol Res 2001;24:31)
Membrane expression early during T cell development, before TCR rearrangement; persists until terminal stages of T cell development
Plays important role in T cell-B cell interaction in early lymphoid development
Downregulated in infectious mononucleosis (AJCP 2003;120:49)
Loss of CD7 expression and altered cellular glycosylation may contribute to apoptosis resistance of malignant T cells in mycosis fungoides (Mod Path 2003;16:543)
Uses: may be useful in identifying mycosis fungoides
Micro images: (1) normal tonsil; (2) intestinal T cell lymphoma
Positive staining (normal): thymocytes, mature T cells (85%), NK cells (majority), monocytes, pluripotent hematopoietic progenitor cells, early myeloid cells, pre-B cells
Positive staining (disease): T-ALL (very good marker) and other malignant immature T cells, NK lymphomas, rarely B cell lymphomas (AJCP 2001;115:396), AML (some), chronic myelogenous leukemia, Down’s syndrome associated transient myeloproliferative disorder and AML (AJCP 2001;116:204), lymphocyte rich thymoma (AJCP 2004;121:268), pancreatic ductal carcinoma, cholangiocarcinoma and epithelioid sarcoma (AJCP 2003;120:64);
Negative expression: mature B cells, granulocytes, B cell ALL, mycosis fungoides, adult T cell leukemia/lymphoma, Reed-Sternberg cells in Hodgkin’s lymphoma (Mod Path 2005;18:1542)
References: OMIM 186820
Also called T cell suppressor/cytotoxic cells, OKT8
Cell surface glycoprotein, member of immunoglobulin superfamily; at 2p12
Heterodimer of an alpha and a beta chain linked by two disulfide bonds; heterodimer on thymocytes and homodimer on peripheral blood T cells
MHC class I restricted receptor; binds to nonpolymorphic region of class I molecules; may increase avidity of interactions between cytotoxic T cell and target cell during antigen-specific activation
Can kill target cells by recognizing peptide-MHC complexes on them or by secreting cytokines capable of signaling through death receptors on target cell surface
CD8 alpha cells promote survival and differentiation of activated T cells into memory CD8+ T cells, which may become clonal (but not malignant) in the elderly (Immunol Rev 2005;205:170)
Contribute to initiation, progression and regulation of autoimmune responses (Curr Opin Immunol 2005;17:624)
Associated with lymphoepithelioma-like carcinoma of lung (AJSP 2002;26:715); low CD8:CD3 ratio in epidermotrophic component of lymphoid infiltrate is suggestive of mycosis fungoides (Mod Path 2003;16:857)
Uses: cytotoxic T cell marker
Drawings: (1) CD8+ T cell interaction with antigen presenting cell #1; #2; (3) destruction of viral infected cell
Micro images: (4) infiltrating lymphocytes in lymphoepithelioma-like carcinoma of cervix-figure 3; (5) T cell lymphoma (type not specified); (6) sinus lining cells in splenic hamartomas #1 are CD8+; #2 (figure 3A); (8) nodal cytotoxic T cell lymphoma; (9) mycosis fungoides; (10) intraepithelial lymphocytes in duodenum (figure 1c); (11) increased intraepithelial lymphocytes at villous tip (figure 2e)
Positive staining (normal): cortical thymocytes (70-80%), T cells (25-35% of mature peripheral T cells, mostly cytotoxic T cells); NK cells (30%, which are also CD3 negative)
Positive staining (disease): epidermotrophic lymphocytes in mycosis fungoides (AJSP 2002;26:450), subcutaneous panniculitis-like T cell lymphoma, indolent T cell lymphoblastic proliferation, sinus lining cells in splenic hemartoma, heterotopic ovarian splenoma, NK/T cell lymphoma (variable), some post-thymic T cell lymphomas, rarely mantle cell lymphoma (AJCP 1998;109:689), rarely CLL (AJCP 1994;102:212, Archives 2000;124:1361), T cell infiltrate in 30% of cases of nodular regenerative hyperplasia of liver (Hum Path 2004;35:1241)
Negative stains: adult T cell leukemia/lymphoma, littoral cell hemangioma of spleen
References: Mod Path 2002;15:1131; OMIM 186910 (alpha chain), OMIM 186730 (beta chain)
Also called motility related protein 1 (MRP1)
Member of transmembrane 4 superfamily (tetraspanin family); at 12p13
Inhibits cell motility; also mediates cell development, activation, growth and adhesion
Triggers platelet activation and aggregation, supports myotube maintenance and promotes muscle cell fusion
Antibodies are used to purge bone marrow prior to peripheral stem cell bone marrow transplant
Expression downregulated in various tumors (other than brain), which may promote tumor dissemination (Cancer Res 2005;65:2617)
Uses: no significant clinical use by pathologists
Micro images: (1) astrocytomas; (2) benign CNS tumors; (3) normal cerebrum; (4) cervical carcinoma
Positive staining (normal): pre B cells, B cell subset, activated T cells, plasma cells, macrophages, platelets, eosinophils, basophils, megakaryocytes, brain, cardiac muscle, GI system, kidney (glomeruli, tubules and collective ducts), liver, lymphatic epithelium, ovarian surface epithelium, peripheral nerve, skin, spleen, thyroid, tonsil, vascular endothelial cells-varies by study
Positive staining (disease): pre-B ALL, AML-M3, astrocytoma (J Histochem Cytochem 2002;50:1195), ovarian surface carcinoma (90% of papillary serous and endometrioid, Hum Path 2004;35:1014), ovarian cortical inclusion cysts, renal carcinoma (all papillary and chromophobe, 50% of clear cell, Hum Path 2001;32:1071), renal oncocytoma, lymphangioma; also juvenile nasopharyngeal angiofibroma, angiosarcoma and Kaposi’s sarcoma (Mod Path 2003;16:1028)
Negative staining: red blood cells, renal collecting duct carcinomas (almost all)
Also called Common Acute Lymphoblastic Leukemia Antigen (CALLA), neutral endopeptidase 24.11, neprilysin, enkephalinase
90-110 kDa cell membrane metallopeptidase, characteristic marker of follicular center cells and follicular lymphoma, but also widely distributed in normal tissue and neoplasms; also localized to brush border in small bowel mucosa
At 3q21-27; inactivates bioactive peptides, including bombesin
Uses:
Acute lymphoblastic leukemia (ALL): one of the first markers to identify leukemic cells in children (hence its name)
Angioimmunoblastic T cell lymphoma: tumor cells are CD10+ at nodal and extranodal sites other than bone marrow (AJSP 2004;28:54, Hum Path 2005;36:784) versus CD10- for other T cell lymphomas; but benign T cells may be CD10+ (Mod Path 2003;16:879)
Breast: marker of myoepithelial cells (Mod Path 2002;15:397)
Burkitt’s lymphoma: confirm diagnosis
Diffuse large cell lymphoma: marker for germinal center phenotype (also bcl6), which has longer survival in some studies (Mod Path 2005;18:1113, Archives 2002;126:956-primary intestinal tumors); but not others (AJCP 2001;116:183-CD10+bcl2+ have lower remission rates, Virchows Arch 2004;445:545-no difference in survival)
Ectopic prostate: confirm diagnosis in uterus and vagina (AJSP 2006;30:209)
Endometrial stromal tumors: consistently CD10+ vs. CD10- smooth muscle tumors (Mod Path 2001;14:465), although leiomyoma and high grade leiomyosarcoma may be CD10+ (Mod Path 2002;15:923)
Endometriosis: helpful in identifying areas of endometriosis if sparse glandular tissue (Archives 2003;127:1003)
Follicular lymphoma: CD10+ may confirm diagnosis (AJCP 2002;117:291); CD10+ and bcl6+ patients have more favorable prognosis (AJCP 2004;121:34), but see AJCP 2001;115:582; high grade follicular lymphomas and interfollicular infiltrates may be CD10- (AJCP 2001;115:862)
Gynecologic tumors: mesonephric remnants and tumors are CD10+; CD10 differentiates metastatic renal cell carcinoma (CD10+, AJSP 2003;27:178) from primary clear cell carcinoma (CD10-); CD10 is not useful in differentiating muscle invasive endometrial adenocarcinoma (CD10+ desmoplastic stroma) from endometrial adenocarcinoma invading adenomysosis (CD10+ stroma, Mod Path 2003;16:22)
Hemangioblastoma: CD10-, CD10 differentiates from metastatic renal cell carcinoma (CD10+, Mod Path 2005;18:788)
Hepatocellular carcinoma vs. nonhepatocellular carcinomas: 52-68% sensitive and >95% specific with canalicular pattern (AJSP 2001;25:1297, AJSP 2002;26:978), although another study recommends Hepatocyte, MOC31, and pCEA but not CD10 (Mod Path 2002;15:1279)
Microvillous inclusion disease: strong CD10+ cytoplasmic staining vs. linear brush border staining in normals (AJSP 2002;26:902)
Pancreas: solid and pseudopapillary tumor is CD10+ (AJSP 2000;24:1361)
Aberrant expression in lymphoma: described in mantle cell lymphoma (AJCP 2004;122:122), marginal zone lymphoma (J Clin Pathol 1999;52:849), other lymphomas with CD5 coexpression (AJCP 2003;119:218, Archives 2001;125:951)
Micro images: (1) normal follicular center cells and CD10+ diffuse large B cell lymphoma; (2) pre-T ALL; (3) endometrial stromal sarcoma #1 (extrauterine, figure 4, inset ER); #2 (myxoid-fibrous variant, figure 4); #3 (leiomyosarcoma is CD10-); #4; (7) leiomyoma (focal CD10+); (8) CD10+ invasive breast ductal carcinoma (also ER-); (9) CD10 and smooth muscle actin in invasive breast ductal carcinoma; (10) CD10+ stroma cells in endometriosis; (11) CD10- stromal cells in endometriosis-like tissue; (12) CD10+ staining of hepatocellular carcinoma #1; #2; (14) reactive T cells may be CD10+; (15) diffuse large B cell lymphoma #1; #2; (16) canalicular pattern in hepatocellular carcinoma (figure B); (17) endometrial adenocarcinoma and adenomyosis; (18) malignant mixed mullerian tumor#1; #2; #3; (21) breast myoepithelium; (22) breast adenosis; (23) breast DCIS; (24) invasive ductal carcinoma of breast; (25) hemangioblastoma is CD10-; (26) metastatic renal cell carcinoma is CD10+; (27) staining in melanoma
Flow cytometry images: (28) CD10+ diffuse large B cell lymphoma; (29) CD10- diffuse large B cell lymphoma
Positive staining (normal): hematopoietic cells - pre-B cells, pre-T cells, follicular center (germinal center) cells, granulocytes, T cells (some); other cells - adrenal cortex, brain, choroid plexus, cortical thymocytes, endometrial stroma, endothelial cells, fibroblasts, genitourinary (male) epithelium, hepatocytes, kidney microvilli, liver, mesonephric remnants, myoepithelial cells (breast, Mod Path 2002;15:397, J Clin Pathol 2004;57:625), ovary, placenta (cytotrophoblast, intermediate trophoblast, syncytiotrophoblast), prostate basal and secretory cells, small intestine (linear brush border staining), wolffian (but not mullerian) type epithelium
Positive staining (disease): leukemia/lymphoma - preB ALL (75%), preT ALL (63%, Archives 2000;124:704); angioimmunoblastic T cell, Burkitt’s, CML in blast crisis (90%), diffuse large B cell (variable), follicular center cell (70%), hairy cell leukemia (10%, AJCP 2003;120:228), myeloma (some), plasmablastic (variable), primary cutaneous diffuse large B cell (variable), primary mediastinal B cell (32%, AJSP 2001;25:1277); other - breast cancer associated stroma, breast metaplastic carcinoma, choriocarcinoma, colonic carcinoma and high grade dysplasia associated stroma (Hum Path 2002;33:806), dermatofibroma, dermatofibrosarcoma, endometrial adenocarcinoma (may also be present in desmoplastic stroma, AJSP 2003;27:786), endometrial adenomyosis, endometrial stromal tumors, Ewing’s sarcoma, gastric carcinoma associated stroma (Jpn J Clin Oncol 2005;35:245), glioma, hepatocellular carcinoma (canalicular pattern similar to polyclonal CEA, Am J Pathol 2001;159:1415), malignant fibrous histiocytoma, malignant mixed mullerian tumors, mediastinal germ cell tumors, melanoma (40%, associated with tumor progression, Mod Path 2004;17:1251), mesonephric tumors (AJSP 2001;25:1540), microvillous inclusion disease (strong cytoplasmic staining), mullerian adenosarcoma, pancreatic adenocarcinoma (50%), pancreatic solid-pseudopapillary tumor, placental site trophoblastic tumor, prostate carcinoma (some Gleason pattern 4 and 5 cases), renal cell carcinoma (most clear cell, variable papillary, “aggressive” chromophobe subtypes, AJSP 2000;24:203, Mod Path 2005;18:535, Mod Path 2004;17:1455), renal cell sarcoma, rhabdomyosarcoma (60%) and other sarcomas, schwannoma (45%), tumor of wolffian origin of broad ligament and ovary, urothelial carcinoma (54%), uterine cellular leiomyoma (50%), uterine leiomyosarcoma and other uterine sarcomas, yolk sac tumor
Negative staining: leukemia/lymphomas - AML, Burkitt’s-like, CLL, EBV+ lymphoproliferative disorders, lymphoplasmacytic, mantle cell, marginal zone, pyothorax associated; other - myeloid and erythroid precursors, clear cell carcinomas of female genital tract, prostate adenocarcinoma (all Gleason patterns 2 and 3, some 4 and 5), high grade PIN and prostatic basal cell hyperplasia (Hum Path 2003;34:450), CNS hemangioblastoma
References: OMIM 120520; AJCP 2005;124:371-in urothelial neoplasms, more intense staining in high grade vs. low grade lesions), AJCP 2000;113:374-staining in nonhematopoietic tumors), Adv Anat Pathol 2004;11:310-expression in female genital tract tumors)
CD11a, 11b and 11c all have same beta chain (CD18); perhaps also CD11d since it is homologous to the others
Members of integrin receptor family; heterodimers of noncovalently associated alpha and beta subunits
Deficiency (leukocyte adhesion deficiency) is a rare, inherited disorder, causing recurrent severe bacterial infections early in life, possibly fatal (OMIM 116920, Hematol Oncol Clin North Am 1988;2:13)
CD11a
Also called integrin alpha L, LFA-1 alpha chain (in complex with CD18)
At 16p11-13.1
An alpha integrin chain that binds to CD18 and mediates leukocyte adhesion to endothelium, leukocyte trafficking through activated endothelium, lymphocyte blastogenesis, lymphocyte-endothelial cell adhesion, lymphocyte recirculation through lymph nodes; also binding to unopsonized bacteria (e.g. E. coli) and fungi (e.g. Histoplasma capsulatum), cytotoxic T cell mediated killing and antibody dependent killing by neutrophils and monocytes
With CD18, binds to ICAM1 (CD54), ICAM2 (CD102), ICAM3 (CD50) and ICAM4 (CD242)
Marker of differentiation in acute promyelocytic leukemia
Uses: anti-CD11a antibody therapy (efalizumab) improves moderate/severe plaque psoriasis (J Cutan Med Surg 2003;7:198, Arch Dermatol 2002;138:591)
Positive staining (normal): all leukocytes
Negative staining: platelets, various intermediate and high grade lymphomas
References: OMIM 153370
CD11b
Also called integrin alpha M, Mac-1
At 16p11-13.1
Mediates adhesion to substrates by opsonization with iC3b and subsequent phagocytosis, neutrophil aggregation, chemotaxis
Ligands include fibrinogen, Factor X, ICAM1, iC3b, Saccharomyces cerevisiae, Staphylococcus epidermidis, Histoplasma capsulatum,
Histoplasma capsulatum causes decreased cell surface CD11b expression and an antiapoptotic state on leukocytes (Scand J Immunol 2002;56:392)
Uses: common myeloid marker and natural killer cell antigen; differentiates recovery from acute agranulocytosis (CD11b+, CD117-) from acute promyelocytic leukemia (CD11b-, CD117+, AJCP 2002;118:31); differentiates Down’s syndrome patients with AML (usually CD13+, CD11b+) from transient myeloproliferative disorder (usually CD13-, CD11b-, AJCP 2001;116:204), documents maturation of tumor cells in acute promyelocytic leukemia patients receiving all-trans retinoic acid therapy (cells become CD11b+, CD16+, Archives 2003;127:e4) or arsenic trioxide (CD11b+, CD33+, Mod Path 2000;13:954)
Positive staining (normal): follicular dendritic cells, myeloid cells beginning with promyelocytes, granulocytes, macrophages, NK cells, some B/T cells
Positive staining (disease): AML-M1, M2 and M3 (35-70%), M4 and M5 (80-90%, AJCP 1997;107:283); hairy cell leukemia (virtually all), various lymphomas, sinus histiocytosis with massive lymphadenopathy (Hum Path 1992;23:647)
Negative staining: Gaucher’s cells (AJCP 2004;122:359)
References: OMIM 120980
CD11c
Also called integrin alpha X, CR4, LeuM5
At 16p11-13.1
Clears opsonized particles and immune complexes; also binds to fibrinogen and is involved in adhesion of monocytes and neutrophils to endothelium
Member of beta 2 family of integrin receptors
Uses: histiocytic marker, NK cell marker, diagnosis of hairy cell leukemia (with other markers)
Prognostic value: associated with good prognosis in B-CLL
Micro images: CD11c+ hairy cell leukemia
Contributed by Leica Microsystems, Biosystems Division: hairy cell leukemia (membranous staining)
Positive staining (normal): 50% of activated CD4/CD8+ T cells; granulocytes, lymphocytes, macrophages, NK cells
Positive staining (disease): AML-M4 and M5 (50%); hairy cell leukemia (classic and variant, virtually all cases, AJCP 1991;96:100), lymphoplasmacytic lymphoma (81%, AJCP 2005;124:414), SLL (AJCP 1998;110:582), splenic lymphoma with villous lymphocytes (AJCP 1988;90:250), Langerhans cell histiocytosis, sinus histiocytosis with massive lymphadenopathy (Hum Path 1992;23:647, Hum Path 1989;20:711), psoriatic skin lesions (Proc Natl Acad Sci USA 2005;102:19057), some follicular lymphomas
Negative staining: mantle cell lymphoma, AML-M3 (AJCP 1998;109:211), splenic and non-splenic marginal zone lymphoma (AJCP 1996;105:277)
References: OMIM 151510
CD11d
Also called integrin alpha D
At 16p11.2
Receptor for ICAM3 and VCAM1
May play a role in clearing lipoproteins from plaques and phagocytosis
Monoclonal anti-CD11d antibody may have a neuroprotective effect in spinal cord injury (J Neuroimmunol 2004;156:42)
Uses: no significant clinical use by pathologists
Positive staining (normal): myeloid and monocytic cells; peripheral blood leukocytes, splenic red pulp macrophages
Positive staining (disease): macrophage foam cells within atherosclerotic plaques
References: OMIM 602453
May have been deleted - minimal information is present as of February 2006
Uses: no significant clinical use by pathologists
Positive staining (normal): granulocytes, monocytes, NK cells, platelets
Negative staining: basophils, bone marrow precursors, AML
Also called Aminopeptidase N (APN)
Myeloid antigen, although CD33 is more specific
Peptide cleaving enzyme of brush border membranes of small intestine, renal proximal tubules and placenta
Also present on CNS synaptic membranes
Receptor for one strain of human coronavirus that causes many upper respiratory tract infections; serves an important function for early CMV infection
Defects appear to cause various leukemias/lymphomas
CD13 autoantibodies are strongly associated with chronic graft versus host disease after bone marrow transplantation
Uses: (a) differentiate Down’s syndrome patients with AML (usually CD13+, CD11b+) from transient myeloproliferative disorder (usually CD13-, CD11b-, AJCP 2001;116:204)
(b) myeloid marker to differentiate AML M0 from ALL (AJCP 2002;117:380)
(c) may be marker in chronic myelomonocytic leukemia if partial loss in mature mast cells (AJCP 2004;122:865)
Micro images: flow cytometry in CD13+ anaplastic large cell lymphoma
Contributed by Leica Microsystems, Biosystems Division: normal prostate
Positive staining (normal): macrophages, myelomonocytes, interdigitating dendritic cells, immature mast cells, granulocytes (most, but low levels in term babies, Mod Path 1993;6:414), large granular lymphocytes (some), fibroblasts, osteoclasts, perineurium of peripheral nerves, central nervous system synapses, endothelial cells, placenta, renal proximal tubules, prostate secretory cells, small intestine, bile duct canaliculi,
Positive staining (disease): AML M1-M5 (75-95%), M6 (usually), CML (90%), CML in blast transformation (Mod Pathol 1998;11:1211), neoplastic mast cells (AJSP 2003;27:1013), anaplastic large cell lymphoma (AJCP 2003;119:205 [47%], Archives 2000;124:1804 [case report], AJCP 2003;120:617 [leukemic]), chronic B cell lymphoproliferative disorders (Archives 1995;119:53), pre B ALL (7-10%), pre T ALL (rare), CLL/SLL (rare, AJCP 2003;119:824)
Negative staining: prostate adenocarcinoma (Am J Pathol 2004;165:1543)
Also called lipopolysaccharide (LPS) receptor, monocyte differentiation antigen
Pattern recognition receptor that detects antigenic molecules on the surface of bacteria (lipoteichoic acid on gram positive, LPS on gram negative), myobacteria (glycolipids), fungi (mannans), as part of the innate immune system
Adaptive immune system, by contrast, refers to lymphocytes recognizing microorganism proteins via T cell receptors and antibodies
Soluble form of CD14 is secreted by liver and monocytes; in low concentrations it confers LPS responsiveness to cells which are otherwise CD14 negative
Macrophages with a multiprotein complex of CD14, MD-2 and TLR4 bind to LPS, causing macrophage activation and release of cytokines; overstimulation may cause toxic shock syndrome
Detection of lipopolysaccharide induces IL-12 production (mediated by CD14), producing interferon gamma, which steers immune system away from allergy driven Thelper2 phenotype, associated with IgE production
Mutations can prevent adequate inflammatory response to infection, leading to systemic infections
Also involved in the clearance of apoptotic cells
Early promonocytes express MY4 epitope; mature monocytes express MO2 epitope; neoplastic monocytes also often express MY4 but not MO2 (AJCP 2005;124:930)
Uses: identify mature monocytes/macrophages
Images: CD14 signaling pathway; CD14 dependent vs. independent pathways; membrane bound and serum forms of CD14
Micro images: appendix macrophages and dendritic cells are CD14+; hepatic Kuppfer cells and sinusoidal endothelial cells; lymph node (normal); various images
Positive staining (normal): macrophages/monocytes (90%), granulocytes-weak (30%), Langerhans cells; dendritic cells, B cells
Positive staining (disease): B-CLL (90%), follicular center cell lymphoma (80%), diffuse large B cell lymphoma (40%); AML-M4/M5 (50-90%)
Negative staining: myeloid progenitors, AML M0-M2 (usually), M3, M6, M7; sinusoidal histiocytes with phagocytic properties (erythrophagocytosis, anthracosis, tingible body macrophages, Hum Path 2006;37:68), Gaucher's macrophages (Hum Path 1992;23:1410), most epithelial and endothelial cells
References: OMIM 158120
Also known as LeuM1, Lewis X, 3-fucosyl-N-acetyl-lactosamine
Synthesis is directed by FUT9 (OMIM 104230) in lymphoid cells and mature granulocytes and by FUT4 (OMIM 606865) in promyelocytes and monocytes
Associated with multipotent neural stem cells in mice (Glia 2006;53:277)
A carbohydrate adhesion molecule (not a protein) that mediates phagocytosis and chemotaxis
Interpretation: membranous, diffuse cytoplasmic or Golgi staining in Hodgkin’s lymphoma
Uses: confirm diagnosis of Hodgkin’s lymphoma (Reed-Sternberg cells are CD15+), help differentiate between Hodgkin’s lymphoma (CD15+) and anaplastic large cell lymphoma (usually CD15-), help differentiate between adenocarcinoma (CD15+) and mesothelioma (CD15-), granulocyte marker
Case reports: CD15+ pre-B ALL (Archives 2001;125:1227)
Micro images: Hodgkin’s lymphoma - figure 3A; membranous staining; cytoplasmic and Golgi staining; syncytial variant-figure 3; primary pulmonary-figure 3A; transverse colon-figure 4A
Other - Hodgkin’s, breast and lung carcinoma and neutrophils; normal granulocytes, breast and renal ductal epithelium; normal kidney; normal small intestinal Paneth cells (A: H&E; B: CD15; C: lysozyme)
Positive staining (normal): neutrophils and eosinophils; activated B and T cells (including infectious mononucleosis); proximal convoluted tubules of kidney; normal small intestinal Paneth cells (J Clin Pathol 1996;49:474); variable monocytes
Positive staining (disease): Reed-Sternberg cells (classic Hodgkin’s lymphoma and follicular Hodgkin’s lymphoma, AJCP 2002;117:29), 15% of peripheral T cell lymphoma (AJSP 2003;27:1513, Int J Oncol 2003;22:319), 50% of carcinomas, 5% of B cell lymphomas (some B-CLL and pre-pre B ALL, AJCP 2002;117:380. Archives 2001;125:1227), some AML, occasionally anaplastic large cell lymphoma (AJCP 2003;119:205, Archives 1992;116:1192, but usually negative, AJSP 2006;30:223)
Negative staining: non-activated lymphocytes, basophils, platelets, erythroid cells; L& H cells in Hodgkin’s lymphoma, diffuse large B cell lymphoma, granulocytic sarcoma (AJCP 1994;102:55), systemic mastocytosis (Hum Pathol 2001;32:545), pleural epithelial mesothelioma (usually, Hum Path 2001;32:529), hairy cell leukemia, malignant meningioma (Mod Path 2006;19:417), malignant histiocytes, Langerhans cell histiocytosis
References: quality control for CD15
CD15s
Also known as sialyl Lewis X
Mediates leukocyte rolling (Proc Natl Acad Sci USA 1997;94:3172)
Ligand (receptor) for CD62P and CD62E
May play a role in cluster formation in lymphoid follicles (Immunol Lett 2001;79:181)
Has borderline prognostic significance in colorectal cancer (Oncology 2003;65:52; J Surg Res 2002;103:68)
Expressed at high levels on peripheral lymphocytes after renal transplant rejection (Transplantation 2000;69:59)
Expression is strongly correlated with susceptibility to human granulocytic ehrlichiosis (J Clin Invest 1999;103:407)
Deficiency causes Rambam-Hasharon syndrome (#266265), a type of leukocyte adhesion deficiency (Emedicine)
Uses: no significant clinical use by pathologists for pathologists, but see above
Micro images: fluorescence associated with susceptibility to human granulocytic ehrlichiosis
Positive staining (normal): granulocytes, macrophages
Positive staining (disease): cirrhosis, metastatic carcinoma, fibrolamellar and other hepatocellular carcinoma (Archives 1992;116:643). CD4+ CD56+ neoplasia (Leuk Lymphoma 2003;44:281), Sezary syndrome (J Am Acad Dermatol 2001;44:456)
Negative staining: normal hepatocytes
CD15u
Also known as sulfated CD15
Adhesion protein
Uses: no significant clinical use by pathologists
Positive staining (normal): neutrophils, basophils, mature granulocytes, monocytes, NK cells and T lymphocytes; expression on lymphocytes is variable depending on the antibodies used for detection; also immature bone marrow cells and on endothelial cells of high endothelium (HEV) of peripheral lymph nodes
Positive staining (disease): myelomonocytic leukemia cells, adenocarcinoma
Also known as Fc gamma receptor III A, low affinity immunoglobulin gamma Fc region receptor III-A
Receptor for the Fc portion of IgG; binds various IgG molecules, including rheumatoid factor
Mediates antibody dependent cytotoxicity of foreign cells, phagocytosis and other antibody-dependent responses; also platelet satellitism (AJCP 1995;103:740)
Affinity to ligand is regulated by glycosylation (Immunology 2003;110:335)
CD14+ CD16+ monocytes have increased capacity to produce proinflammatory cytokines such as TNF-alpha, and are elevated in various inflammatory diseases, including coronary artery disease (Thromb Haemost 2004;92:419)
Polymorphisms influence: (a) the severity but not the incidence of IgA nephropathy in Japanese patients (Nephrol Dial Transplant 2005;20:2439); (b) pathogenesis of coronary artery disease (Atherosclerosis 2005;180:277), (c) clinical response to rituximab (Cancer Res 2004;64:4664)
If target cell has class I MHC, then NK cell's killer cell inhibitory receptor (KIR) inhibits cytolysis
Note: preincubation with CD16/CD32 antibodies is commonly used to prevent nonspecific binding
Uses: NK cell and macrophage marker; to subtype leukemia/lymphoma
Diagrams: NK cell mediated cytotoxicity [CD16 / FcgammaRIII is activating receptor on NK cell]
Positive staining (normal): NK cells (10-20%), granulocytes, macrophages, T cells (reactive), immature thymocytes, placental trophoblast
Positive staining (disease): NK proliferative disorders, T cell large granular lymphocyte leukemia, hepatosplenic gamma-delta T cell lymphoma
References: OMIM 146740
CD16b
Also known as Fc gamma receptor III B, low affinity immunoglobulin gamma Fc region receptor III-B
Highly homologous to CD16a
The most common receptor for the Fc domain of IgG on leukocytes
The only Fc receptor linked to the plasma membrane by a GPI (glycosylphosphatidylinositol) anchor
Bears allotypes that define the human neutrophil antigen-1 (HNA-1 and NA) system involved in major post-transfusional reactions (Tissue Antigens 2004;64:119)
Low copy number is associated with glomerulonephritis in systemic lupus erythematosus (Nature 2006;439:851)
CD16+ eosinophils are upregulated in allergic conditions (J Allergy Clin Immunol 2002;109:463)
Affinity to ligand is regulated by glycosylation (Immunology 2003;110:335)
Uses: no significant clinical use by pathologists
Positive staining: neutrophils
Also known as lactosylceramide
[ Note: “CD17” is also a type of mutation in beta-thalassemia, unrelated to CD markers ]
A glycosphingolipid that acts as a lipid second messenger in mediating TNF-alpha, platelet derived growth factor and oxidized LDL-induced phenotypic changes in cells of the vascular wall
The most abundant glycosphingolipid in neutrophils
Elevated levels are present in plasma of patients with familial hypercholesterolemia and plaque intima of aorta in patients who died of cardiovascular disease (Proc Natl Acad Sci USA 2004;101:6490)
Rapidly and extensively down-modulated on activated granulocytes
Binds to bacteria and may function in phagocytosis
Uses: no significant clinical use by pathologists
Positive staining (normal): granulocytes, macrophages/monocytes, platelets, basophils, CD19+ B cells, tonsillar dendritic cells
References: J Immunol 1989;142:2784
Forms the beta 2 chain of CD11a-c (leukocyte adhesion molecule)
Gene is designated ITGB2 (integrin beta 2)
Combines with alpha L chain to form the integrin LFA-1; combines with the alpha M chain to form the integrin Mac-1 (macrophage antigen 1, complement receptor 3)
Important for adhesion and signaling in the hematopoietic system (see CD11 a-c above); also for phagocytosis (J Immunol 2002;169:2003)
CD11b/CD18 is receptor for Bordetella pertussis adhesin filamentous hemagglutinin (FHA) and for the adenylate cyclase toxin (ACT), which blocks neutrophil function (Infect Immun 2005;73:7317, J Exp Med 2001;193:1035)
CD11b/CD18 induces neutrophilic response leading to killing of Steptococcus pyogenes (Eur J Immunol 2005;35:1472)
Group A Streptococci M5 protein blocks bacterial association with CD11b/CD18, which prevents ingestion of bacteria (J Immunol 2004;172:3798)
Leukocyte Adhesion Deficiency (LAD-1) is caused by CD18 defect coding for common B2 subunit; patients suffer from recurrent infections
Uses: no significant clinical use by pathologists
Positive staining: neutrophils, macrophages, monocytes, NK cells
References: OMIM 600065
Coreceptor with CD21
Earliest B cell antigen in fetal tissue
Regulates B cell development, activation and differentiation (J Immunol 2003;171:5921)
May define intrinsic and antigen receptor-induced signaling thresholds critical for clonal expansion of the B cell pool and humoral immunity (Curr Dir Autoimmun 2005;8:55)
More common in plasma cells in steroid resistant ulcerative colitis than Crohn’s disease (Virchows Arch 2006;448:412); presence of CD19+ cells in intestinal mucosa may predict long remission after infliximab (anti-TNF alpha) therapy in Crohn’s disease (Hepatogastroenterology 2005;52:1128)
Uses: diagnosis of B cells and B cell disorders; may be more sensitive than CD20 to detect B cell acute leukemias (Zhongguo Shi Yan Xue Ye Xue Za Zhi 2005;13:943), to differentiate follicular lymphoma (dimmer CD19 in CD10+ B cells by flow cytometry) from reactive hyperplasia (AJCP 2005;124:576)
Flow cytometry images: follicular lymphoma with IgG light chain restriction; biphenotypic acute leukemia with CD19 and myeloperoxidase coexpression (figure B); hairy cell leukemia variant: A-CD20 (bright) and CD22+; B-CD11c+ and CD22+; C-CD103+ and CD25 negative; D-CD19+ and FMC7+; E-kappa+; F-lambda negative
Positive staining (normal): Pre B cells, B cells (considered a pan B cell antigen); first B cell antigen after HLA-DR, follicular dendritic cells
Positive staining (disease): B cell lymphomas and leukemias but often weak/negative in follicular lymphoma or diffuse large B cell lymphoma (Histopathology 2006;48:239, Cytometry B Clin Cytom 2005;63:28), occasional myeloid leukemias (AML-AJCP 1998;109:211; AML-M0-AJCP 2001;115:876; CML blast phase-AJCP 2004;121:836), occasional anaplastic large cell lymphoma by flow cytometry (AJCP 2003;119:205)
Negative staining: plasma cells, myeloma (AJCP 2004;121:482), most T cell lymphomas, often L&H cells in lymphocyte predominant Hodgkin’s lymphoma, often post-transplant B cell lymphoproliferative disorder
References: OMIM 107265
Also called L26, membrane spanning 4 domains (MS4A1)
33kd phosphoprotein with 3 hydrophobic regions that traverse the cell membrane, creating a structure similar to an ion channel that allows for the influx of calcium required for cell activation
Initially expressed on B cells after CD19/CD10 expression and before CD21/CD22 and surface immunoglobulin expression; retained on mature B cells until plasma cell development
Delivers early signal in B cell activation, allowing resting B cells to respond to later antigens
Closely related to FMC7, which recognizes a CD20 epitope (Leukemia 2003;17:1384), particularly if there is strong CD20 expression (AJCP 2003;120:754)
Rituximab is a chimeric murine-human anti-CD20 antibody used to treat B cell lymphomas; treatment may cause selection of CD20 negative (but CD79a+) tumor subclones (AJSP 2005;29:1399)
Rituximab is also used to treat autoimmune disorders (Clin Immunol 2005;117:207), TTP/HUS (Acta Cytol 2005;19:423), ABO incompatible transplantation (Transplant Proc 2005;37:1205) and transplant rejection (Clin Transplant 2005;19:137)
Anti CD20-antibody attached to radioisotopes is also used to treat B cell lymphomas (Clin Exp Med 2006;6:1)
Case reports: CD20+ T cell lymphomas (Am J Hematol 2002;71:331, AJCP 1994;102:483, Mod Path 2001;14:105, Mod Path 2000;13:1244); rarely stains nucleoli of malignant T cells (Acta Cytol 2005;49:365), but see J Clin Pathol 2004;57:442
Uses: commonly used marker for B cells
Micro images: angioimmunoblastic T cell lymphoma (figure d)
diffuse large B cell lymphoma - bone; brain-#1; #4 (figure A); #5 (intravascular); #6 (intravascular); liver; nasal cavity (figure 3A); ovary CD20 (fig 3), CD3 (fig 4); sclerosing; skin (figure 1D); small intestine; unknown site #1-intravascular; #2-sclerosing subtype
other leukemia/lymphoma - follicular lymphoma #1; #2 (childhood); hairy cell leukemia #1; #2-variant type (figure D); Hodgkin’s lymphoma #1-lymphocyte predominant (figures C&D); #2 (figure C); #3-mostly negative Reed-Sternberg cells); lymphoplasmacytic lymphoma/ Waldenström macroglobulinemia #1 (brain-figure D); MALT lymphoma #1 of bladder; #2 of liver; #3 of lung;
post-transplantation lymphoproliferative disorder - #1; #2 (polymorphic subtype-figure C); #3 of liver: H&E, CD20, EBV
other - ectopic hamartomatous thymoma (figure C); lymphocytic mastitis: CD20+/CD3- lymphocytes (B, not T cells); immunoblastic myofibroblastic tumor (figure 2d-reactive B cells)
Additional images: intravascular large cell lymphoma (figure 2a); post-transplant lymphoproliferative disorder
Virtual slides: diffuse large B cell lymphoma
Flow cytometry images: hairy cell leukemia variant - A-CD20 (bright) and CD22+; B-CD11c+ and CD22+; C-CD103+ and CD25 negative; D-CD19+ and FMC7+; E-kappa+; F-lambda negative
Positive staining (normal): most B cells (considered a pan B cell antigen), also follicular dendritic cells
Positive staining (disease): 90% of B cell lymphomas; also B-CLL, hairy cell leukemia, spindle cell thymomas (AJSP 1992;16:988), 40% of pre B ALL/LBL; 80% of nodular lymphocyte predominant Hodgkin’s lymphoma, 20% of classic Hodgkin’s lymphoma (may be an adverse prognostic factor, Br J Haematol 2004;125:701); dimly expressed in T cells (benign and neoplastic, particularly in bone marrow, AJCP 1996;106:78, AJCP 1994;102:483), some myelomas (Mod Path 2004;17:1217, Blood 2003;102:1070)
Negative staining: non-hematopoietic cells, most T cells, plasma cells, mastocytosis
Note: staining does not work well with Bouin’s fixative
Flow cytometry: brighter expression in follicular lymphomas than normal B cells (AJCP 2005;124:576)
References: OMIM 112210, J Biol Chem 2004;279:19893 (presence in lipid rafts)
Also called CR2, C3d receptor, EBV receptor
Binds to Epstein Barr virus (EBV) and HHV8 (J Virol 2005;79:4651), breakdown products of complement component C3 (C3d), CD23 (plays a role in IgE synthesis) and possibly gamma interferon
Follicular dendritic cells produce a different isoform of CD21 than B cells (J Exp Med 1997;185:165)
CD21, CD23 and CD35 are dendritic cell markers
Hodgkin’s lymphoma demonstrates disruption of follicular dendritic cell-germinal cell clusters (evaluated by CD21 and CD23)
Note: although CD21 is the receptor for EBV, it is not necessarily expressed in EBV+ tumors
Shows variability in flow cytometry expression between specimens from same patient (AJCP 2002;117:615)
Uses: diagnose follicular dendritic cell sarcomas (AJSP 1996;20:944); assess follicular dendritic cell meshwork infrastructure (AJCP 2005;124:182, AJSP 2001;25:388), distinguish cutaneous or nodal mantle cell lymphoma from follicular lymphoma (AJSP 2001;25:732, Int J Surg Pathol 2005;13:73), distinguish splenic littoral cell angioma (CD21+ lining cells) from splenic hamartomas (CD21-, AJSP 1997;21:827), confirm that atypical cells have follicular dendritic origin in fine needle aspirates of hyaline-vascular Castleman’s disease (Diagn Cytopathol 2000;22:230)
Micro images: normal germinal center
follicular dendritic cell sarcoma - (1) liver (figure 2B); (2) figure 1: liver tumor (inset: splenic tumor); 2a/b: H&E; 2c: CD21; 2d: CD35; (3) stomach (figure 4 is CD21/CD35 cocktail)
follicular lymphoma - well organized clusters of dendritic cells in follicular lymphoma #1 (testicular)); #2 (head and neck); #3 (head and neck); peripheral T cell lymphoma resembling follicular lymphoma
Positive staining (normal): mature B cells (particularly marginal and mantle cells), follicular dendritic cells, pharyngeal and cervical epithelial cells, some thymocytes, some T cells
Positive staining (tumors): follicular dendritic cell sarcoma (AJSP 2004;28:988, AJSP 2001;25:721), hairy cell leukemia, B cell lymphomas (particularly mantle and marginal zone), hyaline vascular variant of Castleman's disease (AJSP 2002;26:662), splenic littoral cell angiomas (lining cells are CD21+, AJSP 1997;21:827), some T-ALL
Negative staining: dendritic cell neurofibroma with pseudorosettes (AJSP 2001;25:587), interdigitating dendritic cell sarcoma (AJCP 2001;115:589), histiocytic sarcoma (AJSP 2004;28:1133), inflammatory fibroid polyps of GI tract (AJSP 2004;28:107), splenic hamartomas, plasma cells
References: AJSP 2001;25:721, Mod Path 2002;15:50, OMIM 120650
Also called B lymphocyte cell adhesion molecule (BL-CAM)
Inhibits B cell receptor signaling via alpha 2,6 sialic acid ligand binding activity; also has properties of a lectin with adhesion properties (J Exp Med 2002;195:1207)
May localize B cells in lymphoid tissues; binds CD45
Shows variability in flow cytometry expression between specimens from same patient (AJCP 2002;117:615)
CMC-544 is a CD22-targeted cytotoxic immunoconjugate currently being evaluated in B-cell lymphoma patients (Clin Cancer Res 2004;10:8620); also epratuzumab (Clin Cancer Res 2004;10:5327)
Uses: pan B cell marker; diagnosis of hairy cell leukemia; aberrant CD22 expression is useful to detect monoclonal B cells admixed with benign polyclonal B cells in B-CLL (usually CD22 negative, AJCP 2005;123:826)
Micro images: CD22 in normal tonsil
Positive staining (normal): B cells (considered a pan B cell antigen)
Positive staining (disease): hairy cell leukemia; pre B ALL; other B cell leukemias/lymphomas (variable, AJCP 2002;117:615)
Negative staining: plasma cells
References: OMIM 107266
Also known as low affinity IgE receptor, Fc fragment of IgE receptor, FCER
A type C lectin that can be secreted
After physiologic germinal cell development, the follicular dendritic cell meshwork expands and follicular dendritic cells in the light zone of the germinal center become CD23 positive
CD23 acts as a B cell growth and activation factor, promoting differentiation into plasma cells
Regulates IgE synthesis through CD21 and IgE binding (J Exp Med 2005;202:751), and mediates IgE related immune responses (Clin Rev Allergy Immunol 2005;29:61)
Shows variability in flow cytometry expression between specimens from same patient (AJCP 2002;117:615)
CD21, CD23 and CD35 are dendritic cell markers
High expression on B cells in peripheral blood is associated with bullous pemphigoid (J Dermatol Sci 2004;35:53)
CD23 antibodies may decrease adherence of Plasmodium falciparum-infected erythrocytes (Cell Microbiol 2004;6:839)
Mantle cell lymphoma: usually CD23 negative, but rarely/often has CD23 present with dim intensity by flow cytometry, AJCP 2003;120:760 / AJCP 2001;116:893; CD23+ mantle cell cases have high cyclin D1 levels, AJCP 2002;117:237); rarely has CD23+ cells in peripheral blood (AJCP 2002;118:758)
Uses: differentiate SLL/CLL (CD23+) vs. mantle cell lymphoma or MALT lymphoma (CD23-); B cell marker, particularly for SLL/CLL, mediastinal large B cell lymphoma and lymphoplasmacytic lymphoma; distinguish nodal mantle cell lymphoma from follicular lymphoma by identifying a disrupted follicular dendritic cell pattern (Int J Surg Pathol 2005;13:73), may identify prognostically favorable cases of diffuse large B cell lymphoma (Clin Cancer Res 2003;9:722), high soluble CD23 is associated with aggressive disease and poorer prognosis in CLL (Leuk Lymphoma 2002;43:549, Clin Lab Haematol 2006;28:30)
Micro images: angioimmunoblastic T cell lymphoma (figure F: CD23 highlights extrafollicular meshworks of follicular dendritic cells); CD23 negative MALT lymphoma with CD23+ follicular centers; CD23 negative mantle cell lymphoma with CD23+ follicular center
contributed by Leica Microsystems, Biosystems Division: normal tonsil; follicular lymphoma
Positive staining (normal): activated mature B cells expressing IgM or IgD (particularly mantle cells), activated monocytes / macrophages, T cell subsets, platelets, eosinophils, Langerhans cells, follicular dendritic cells, intestinal epithelium (encodes IgE receptor, Gastroenterology 2005;129:928)
Positive staining (disease): B-cell CLL/SLL (almost all cases; high levels, Leuk Res 2002;26:809; atypical cases may have higher levels, AJCP 2001;116:655); follicular dendritic cell tumors (including inflammatory pseudotumor type- AJSP 2001;25:721), mediastinal large B cell lymphoma (70%, Histopathology 2004;45:619), lymphoplasmacytic lymphoma (61%, usually dim intensity by flow cytometry, AJCP 2005;124:414, Clin Lymphoma 2005;5:246), hairy cell leukemia (17%, AJCP 2006;125:251), diffuse large B cell lymphoma (16%),
Negative staining: other B cell lymphomas including Burkitt’s lymphoma, Burkitt-like lymphoma (AJSP 2005;29:1652), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (AJSP 1999;23:59, Mod Path 1998;11:967); also most T cell lymphomas, inflammatory fibroid polyps of the gastrointestinal tract (although of dendritic cell origin, AJSP 2004;28:107), follicular dendritic cell tumor, interdigitating dendritic cell tumor
References: OMIM 151445, Hum Path 1999;30:648 (early study)
Also called heat stable antigen homologue (HAS)
A glycosylphosphatidylinositol anchor protein (also CD14, CD16, CD48, CD55, CD58, CD59, CD67 and CD73) with mucin-like adhesion properties
Promotes antigen dependent proliferation of B cells
A ligand of P-selectin on tumor cells that is associated with in vitro invasiveness (Tumour Biol 2002;23:139, Cancer Res 2005;65:10783) and poorer prognosis in carcinoma (see Uses below)
Also prevents differentiation into plasma cells, and modifies risk for progression in multiple sclerosis (Proc Natl Acad Sci USA 2003;100:15041)
Relatively specific and sensitive for AML M4/M5 vs. AML M1/M2 (AJCP 1994;101:296)
Higher levels by RT-PCR in prostatic carcinoma vs. nodular hyperplasia (BMC Urol 2006;6:7)
Uses: strong expression is a poor prognostic factor in colorectal carcinoma (Clin Cancer Res 2005;11:6574), nonsmall cell lung carcinoma (Br J Cancer 2003;88:231), ovarian cancer (Am J Pathol 2002;161:1215), intrahepatic cholangiocarcinoma (Cancer Lett 2006;235:34)
Micro images: various images
Positive staining (normal): all B cells, granulocytes, kidney cells, epithelial cells, nucleus pulposus of intervertebral discs, fallopian tube, muscle (Proc Natl Acad Sci USA 2006;103:6374), some neurons
Positive staining (disease): carcinomas, most pre-B ALL / lymphoblastic lymphoma, virtually all B cell lymphomas, chordoma (Biochem Biophys Res Commun 2005;338:1890), various solid carcinomas (Pathol Res Pract 2005;201:479), Wilm’s tumor (Hum Pathol 1990;21:536)
Negative staining: T cells, monocytes, red blood cells, platelets, plasma cells, ovarian epithelium, multiple myeloma, chondrosarcoma
References: OMIM 600074
Also called IL-2 receptor alpha chain, TAG; exists in at least 3 forms
Considered to be an activation antigen (also CD30)
CD4+ CD25+ cells are regulatory T cells that (a) suppress the activation of self-reactive T cells and prevent autoimmunity (diagram), (b) may prevent cytotoxic T cells from killing tumor cells (J Hepatol 2006;45:254, Zhongguo Shi Yan Xue Ye Xue Za Zhi 2006;14:119), and (c) suppress immune cells reactive to host antigens and prevent graft versus host disease (Semin Cancer Biol 2006;16:150)
CD4+ CD25+ cells also suppress NK cells (Proc Natl Acad Sci USA 2006;103;5460, J Immunol 2006;176:1582), and may act directly on B cells (Blood 2006;107:3925)
Shows variability in flow cytometry expression between specimens from same patient (AJCP 2002;117:615)
Coexpression with CD134 on memory T cells is a marker for type 1 diabetes associated T cell immunity (Diabetes 2006;55:50)
High levels by flow cytometry are associated with advanced stage in esophageal and gastric cancer (Cancer Immunol Immunother 2005 23;1)
Anti-CD25 antibody is clinically useful in treating fulminating ulcerative colitis in children (J Pediatr Gastroenterol Nutr 2006;42:245) and in sequential therapy in renal transplants with risk of delayed graft function (Transplant Proc 2005;37:3736)
Uses: high CD25 expression is associated with advanced cutaneous T cell lymphoma and with clinical response to denileukin diftitox therapy, a recombinant fusion protein of diphtheria toxin and IL-2, which binds to CD25 (J Invest Dermatol 2006;126:575)
Micro images: human tonsil; hairy cell leukemia
Micro images: Contributed by Leica Microsystems, Biosystems Division: hairy cell leukemia (cytoplasmic and membranous staining of occasional tumor cells)
Flow cytometry images: B cells express CD103 but not CD25 in hairy cell leukemia variant
Positive staining: activated B and T cells, macrophages; some thymocytes, some myeloid precursors and some oligodendocytes
Positive staining (disease): hairy cell leukemia (most, AJCP 2006;125:251), anaplastic large cell lymphoma (AJCP 2003;119:205), most B cell neoplasms, adult T cell leukemia/lymphoma, Reed-Sternberg-like cells in peripheral T cell lymphoma (AJSP 2003;27:1513), most Hodgkin’s lymphomas, neuroblastoma, some mastocytosis (AJSP 2004;28:1319), idiopathic retroperitoneal fibrosis (AJSP 1993;17:482), some AML
Negative staining: non-neoplastic mast cells (AJCP 2004;122:560), marginal zone B cell lymphoma (AJCP 1996;105:277), T cell large granular leukemia/lymphoma (AJSP 2005;29:935), often/usually variant hairy cell leukemia (AJCP 2005;123:132)
References: OMIM 147730
Also called dipeptidyl-peptidase IV, DDPIV, adenosine deaminase complexing protein 2
Costimulatory molecule in T cell activation and proliferation; also regulates various chemokines and cytokines
Cleaves amino-terminal dipeptides; plays a role in cell spreading and migration
Either soluble in plasma or on cell surface
HIV1 TaT protein binds to CD26 and inhibits its activity (Proc Natl Acad Sci USA 1994;91:6594)
Acute kidney transplant rejection is associated with increased serum CD26 activity, and CD26 inhibition reduces acute and accelerated rejection (Adv Exp Med Biol 2003;524:133)
Reduced expression in melanoma, endometrial (Am J Obstet Gynecol 2003;188:670) and prostatic carcinoma but increased expression in thyroid carcinoma (Diagn Cytopathol 2002;26:366, AJCP 1991;96:306); functions as a tumor suppressor in non small cell lung carcinoma (Int J Cancer 2004;109:855)
Blastocyst implantation may occur by binding of endometrial CD26 to embryonal fibronectin (Mol Hum Reprod 2006;12:491)
High CD4+ CD26+ T cell counts may identify multiple sclerosis patients at high risk for developing an attack during interferon treatment (Mult Scler 2005;11:641)
Uses: absence of CD26 staining on peripheral blood CD4+ T cells by flow cytometry is useful to diagnose T cell lymphoma (AJCP 2001;115:885, Clin Exp Dermatol 2005;30:702); normally CD26 inactivates cutaneous SDF-1 which binds to CXCR4 in Sezary cells (Blood 2006;107:1108)
Micro images: benign and malignant prostate (b and c); prostate adenocarcinoma #1 (row 2, column 1); #2; #3
Positive staining (normal): activated T and B cells, NK cells, macrophages, endothelial cells, fibroblasts, mesothelial cells (Oncology 2002;63:158)
epithelium - endometrium, hepatocytes, lung, prostate, renal proximal tubular cells, small intestine
other - cytotrophoblast and extravillous trophoblast (J Clin Endocrinol Metab 2002;87:4287), biliary canaliculae, splenic sinus lining cells, mature thymocytes
Positive staining (disease): esophageal adenocarcinoma (2/3 of Barrett’s associated, also Barrett’s metaplasia, Hum Path 1999;30:1291), prostate carcinoma, thyroid anaplastic carcinoma (reduced expression in undifferentiated vs. differentiated areas (AJCP 2006;125:399), Wilm’s tumor (Hum Path 1990;21:536)
Negative/dim staining: normal thyroid gland, T cells in peripheral blood of mycosis fungoides / cutaneous T cell lymphoma (40%, BMC Clin Pathol 2002;2:5)
References: OMIM 102720
Also called tumor necrosis factor receptor superfamily member 7
Binds to CD70
Marker of T cell activation; also regulates B cell activation and immunoglobulin synthesis
Uses: help differentiate memory-type CD8+ T cells (CD27+) from effector-type CD8+ T cells (important against pathogens, CD27-); memory B cells (CD27+) from naďve B cells (CD27-)
Positive staining (normal): T cells, memory B cells, NK cells, plasma cells, medullary thymocytes
Positive staining (disease): myelomas (64%, Br J Haematol 2006;132:168)
Negative staining: hairy cell leukemia (Haematologica 2005;90:266)
References: OMIM 186711
T cells require 2 signals for full activation - the first by binding of the antigen/MHC complex on antigen presenting cell to the T cell receptor; the second is delivered by the interaction of CD28 with its ligands CD80 (B7-1) or CD86 (B7-2), found on activated B cells, and is called a costimulation signal (diagram of 2 signals)
However, “superantagonistic” anti-CD28 antibodies, awaiting clinical trials for autoimmune diseases, activate mature T cells with only one signal (Ann Rheum Dis 2005;64 Suppl 4:iv91)
The costimulatory signal induces T cell activation and survival, interleukin-2 production, T-helper type 2 development and clonal expansion
CD28 is a constitutive, high abundance, low affinity receptor; its binding also increases expression of CTLA4 (CD152), a structurally related cell surface receptor on T cells which has the same ligands but opposite effects (J Clin Immunol 2002;22:1, Curr Pharm Des 2006;12:149); CTLA4 competes with CD28 for the same ligands (diagram)
Imbalance in CTLA-4/CD28 expression at the maternal-fetal interface may confer susceptibility to unexplained pregnancy loss (Int J Gynaecol Obstet 2006;93:123)
CD8+, CD28+ T cells: antigen specific cytotoxic T cells (class I restricted) (90% of CD8+ T cells)
CD8+, CD28- T cells: suppressor T cells; increased in various infectious diseases and autoimmune diseases and associated with aging Loss of T cell CD28 expression is associated with aging, and frequency of CD28(null) T cells predicts immune incompetence in elderly; these T cells are functionally active and long-lived, but have no/limited proliferative capacity (Immunol Rev 2005;205:158)
Uses: no significant clinical use by pathologists
Positive staining (normal): CD4+ T cells (95%), CD8+ T cells (50%); activated B cells, plasma cells (some)
Positive staining (disease): myeloma (95%)
References: OMIM 186760, Blood 2005;105:13
Also called platelet GPIIa, integrin beta-1 (ITGB1), fibronectin receptor beta subunit, VLA (CD49) beta chain
Common beta subunit of integrins VLA1 to VLA6, which are also composed of alpha subunits alpha 1 to alpha 6 (CD49a-f)
Involved in lymphocyte and endothelial adhesion; important for lymphocyte trafficking and transvascular migration
Promotes or inhibits apoptosis, depending on the ligands and apoptotic insults (Cancer Res 2003;63:8302)
Effects of tracrolimus (FK506) may be due to early inhibitory effects of CD29 (Clin Exp Rheumatol 2004;22:197)
Uses: no significant clinical use by pathologists
Micro images: bile epithelium in alcoholic liver disease
Positive staining (normal): fibroblasts, platelets, T cells, monocytes, granulocytes (low), mast cells, endothelial cells, myoepithelium; also other diverse cell types
Positive staining (disease): bile duct epithelium in alcoholic liver disease (16%, Archives 1999;123:411), breast metaplastic carcinoma (90%, AJSP 2005;29:347), breast sarcomas NOS that are CD10+ (some, AJSP 2006;30:450), CD5+ diffuse large B cell lymphoma (CD29 mRNA present in lymphoma cells, associated with high serum LDH, Int J Oncol 2005;27:1241), myelomas in bone marrow (Br J Haematol 2002;119:70)
Negative staining: intravascular lymphomatosis (Hum Path 2000;31:220)
References: OMIM 135630
Also known as Ki-1, Ber-H2
Member of tumor necrosis factor family of cell surface receptors; also a lymphocyte activation antigen
Overexpression causes constitutive expression of nuclear factor-KB, which is considered the molecular basis for aberrant growth and cytokine expression that causes Hodgkin’s lymphoma (Am J Pathol 2003;163:633)
Ligand is CD153
May also be involved in elimination of autoreactive T cells in thymus
In renal transplants, high serum soluble CD30 levels in graft recipients predicts acute and chronic rejection and graft loss (Am J Transplant 2005;5:1922, Transplant Proc 2005;37:1776, Transplantation 2005;79:1154)
Anti CD30 antibodies are possible treatment for refractory Hodgkin’s lymphoma (J Clin Oncol 2005;23:4669)
Interpretation: membranous and Golgi type staining; doesn’t work well with prolonged formalin fixation or with B5 fixation
Uses: confirm diagnosis of anaplastic large cell lymphoma, classic Hodgkin’s lymphoma, embryonal carcinoma; other lymphoma diagnosis
Micro images: anaplastic large cell lymphoma - post liver transplant (figure B); primary cutaneous #1 (figure 4); #2 (post-transplant, figure 3a); brain tumor in HIV patient; primary brain tumor, figure B; sarcomatoid variant (figure 7); CD13+ scalp lesion (figure B); primary bone tumor (figure 2B)
classic Hodgkin’s lymphoma - #1; figure 3B (primary pulmonary); figure 3B; figure 2B; figure 1C; EBV+ ileal tumor-figure D; colon-figure 4b
other lymphoma - plasmablastic lymphoma (figure 4); primary mediastinal B cell lymphoma; atypical cells in follicular lymphoma
other - embryonal carcinoma #1-figure 6; #2-intratubular-figure 4; mesothelioma (figure 5)
Positive staining (normal): granulocytes, plasma cells (some, AJCP 1989;91:18), activated B, T and NK cells, monocytes, decidua (Am J Pathol 1994;145:276)
Positive staining (disease): lymphoma - anaplastic large cell lymphoma (systemic or primary cutaneous, 90%), classic Hodgkin’s lymphoma (Reed-Sternberg cells), also Reed-Sternberg like cells in follicular lymphoma (AJCP 2004;122:858, Archives 2001;125:1036), primary mediastinal large B cell lymphoma (usually focal, Am J Pathol 2003;162:243), peripheral T-cell lymphoma (occasional, AJSP 2003;27:1513), sprue associated lymphoma, Lennert’s lymphoma (occasional), primary effusion lymphoma (AJCP 1996;105:221), primary cutaneous CD30+ lymphoma, lymphomatoid papulosis (Blood 2002;100:578), granulocytic sarcoma (J Clin Pathol 1996;49:762), diffuse large cell lymphoma (variable, usually focal, AJSP 2002;26:1458), plasmablastic lymphoma (Archives 2004;128:581) and plasma cell neoplasms (some), eosinophil rich CD30+ lymphoproliferative disorder of oral mucosa (AJCP 2004;121:43), sinonasal NK/T cell lymphoma with large cell morphology (focal, AJSP 2000;24:1511), nasal NK/T cell lymphoma in Chinese patients (Hum Path 2006;37:54)
other - embryonal carcinoma of testis (100%, but variable intensity, AJSP 2004;28:935), yolk sac tumors (24%, Hum Path 1998;29:737), seminoma (6%, AJCP 2000;113:583), rarely mesothelioma (Archives 2000;124:1077), lymphocytes infected with HIV, HTLV-1, EBV, HHV8, hepatitis B, herpes (AJSP 2006;30:50); also non-neoplastic inflammatory cutaneous infiltrates (AJSP 2003;27:912)
Negative staining: nodular lymphocyte predominant Hodgkin’s lymphoma (AJCP 2003;119:192), T cell prolymphocytic leukemia (AJSP 2005;29:935), adult T cell leukemia/lymphoma, pre-B ALL, interdigitating dendritic cell sarcoma (AJCP 2001;115:589), follicular dendritic cell tumor, histiocytic sarcoma (AJSP 2004;28:1133), reticulohistiocytoma (AJSP 2006;30:521), Kikuchi’s disease/necrotizing lymphadenitis (AJSP 1999;23:1040), extramedullary myeloid tumors (AJSP 1993;17:1011), systemic mastocytosis (Hum Path 2001;32:545), melanoma, lymphoepithelioma-like carcinoma
References: OMIM 153243, J Clin Pathol 2002;55:162 (Hodgkin’s lymphoma)
CD30v
Variant form of CD30 which retains only the cytoplasmic domain
Uses: no significant clinical use by pathologists
Positive staining (normal): alveolar macrophages
Positive staining (disease): myeloid and lymphoid malignancies
Negative staining: bone marrow
References: Am J Pathol 1999;155:2029
Also known as platelet endothelial cell adhesion molecule, PECAM-1
Belongs to immunoglobulin superfamily; ligand is CD38
Cell adhesion molecule that plays a key role in leukocyte trafficking across endothelium (Blood 2003;101:2816); also angiogenesis and removal of aged neutrophils from body
May mediate signal-transduction pathway regulating capacitation in spermatozoa (J Cell Sci 2005;118:4865)
May act as a minor histocompatibility antigen in HLA-identical stem cell transplantation (Bone Marrow Transplant 2005;36:151)
Interpretation: membranous stain (not cytoplasmic); endothelium is a positive internal control; don’t confuse CD31+ macrophages (granular, membranous expression) with a vascular tumor (AJSP 2001;25:1167)
Uses: confirms vascular origin of tumors, highlight vessels and identify/confirm vascular invasion (J Clin Pathol 2003;56:786, Archives 2005;129:354); CD31 is the most sensitive and specific endothelial marker in paraffin sections; stains small and large vessels
Micro images: normal - appendix; hepatic sinuses
angiosarcoma - cardiac; cutaneous (figure 3A); liver (figure 4); lung (figure 4); oral cavity (figure B); paratesticular; small intestine (figure 6)
epithelioid angiosarcoma - figure 1A; right is Weibel-Palade body; figure 5; figure 4; lower leg
other - epithelioid hemangioendothelioma (figure F); hemangioma (hobnail) #1; #2; hemangioma (spleen); hemangiopericytoma is CD34+ (left) and CD31 negative (right); juvenile xanthogranuloma in an adult (figure 5); Kaposi’s sarcoma #1-tongue (figure 3); #2; Langerhans cell histiocytosis and sinus histiocytosis with massive lymphadenopathy (figures 1, 3 and 5); lymphangioma (figure 3); phyllodes tumor of breast; plasmacytoma (cutaneous); angiosarcoma (figure E)
Positive staining (normal): endothelial cells (at cell junctions) including glomeruli, alveolar wall capillaries, hepatic, lymphatic and splenic sinuses (J Histochem Cytochem 2006;54:385), platelets, megakaryocytes (Archives 2002;126:618), monocytes, macrophages, Kupffer cells, osteoclasts, granulocytes, T / NK cells, plasma cells (extramedullary-strong; bone marrow-focal, J Clin Pathol 1997;50:490), fibroblasts, brown fat (Archives 2006;130:480), trophoblast (Mol Hum Reprod 1998;4:357), spermatozoa
Positive staining (disease): vascular lesions - benign vascular proliferations (AJSP 2002;26:328) and blood vessels in tumors (usually); angiosarcoma; hemangioendothelioma (AJSP 2003;27:48, AJSP 2004;28:559); hemangioma; intravascular papillary endothelial hyperplasia (Hum Path 1996;27:986), Kaposi’s sarcoma; littoral cell angioma of spleen; lymphangioendothelioma (AJSP 2000;24:1047); lymphangioma (Mod Path 1999;12:569, Hum Path 2005;36:426); papillary endovascular angioendothelioma (AJSP 1999;23:1004), sclerosing angiomatoid nodular transformation of spleen (AJSP 2004;28:1268), splenic hamartoma
other - breast DCIS-high grade (J Pathol 2001;194:254); epithelioid sarcoma (focal in 7%, Hum Path 1999;30:934, Virchows Arch 2003;443:93, but proximal type is negative, AJSP 1997;21:130), Ewing’s sarcoma/PNET (focal in 5%, Appl Immunohistochem Mol Morphol 2000;8:19), granulocytic sarcoma (25%, AJCP 1994;102:55), hibernoma, histiocytes in granulomas, Langerhans cell histiocytosis and sinus histiocytosis with massive lymphadenopathy (Archives 2003;127:341); histiocytic sarcoma (AJSP 2004;28:1133); intimal sarcoma of large systemic vessels (AJSP 2005;29:1184); juvenile xanthogranuloma; lymphoblastic lymphoma (Appl Immunohistochem Mol Morphol 2000;8:19), plasmacytomas (50%); rare in carcinoma and mesothelioma (AJCP 1998;110:374)
Negative staining: normal - B cells, epidermal Langerhans cells, vascular adventitial fibroblastic cells; disease - adenomatoid tumor, gastrointestinal stromal tumor, giant cell fibroblastoma, lipomatous hemangiopericytoma (Hum Path 2000;31:1108), mesothelial cyst (AJSP 1997;21:334), nonvascular soft tissue tumors, mycobacterial pseudotumor (AJSP 1999;23:656), myeloma, myxoma, peripheral T cell lymphoma, pseudoangiomatous stromal hyperplasia of breast; sclerosing hemangioma of lung (Archives 2001;125:1335), solitary fibrous tumor (Hum Path 1995;26:440)
References: OMIM 173445
Also called Fc gamma RII; subtyped as Fc gamma RIIa, RIIb and RIIc
Low affinity receptor on white blood cells (see below) that binds to the Fc region of IgG immune complexes to remove foreign antigens
Alleles R131 and H131 differ in their ability to bind IgG2 (H131 provides optimal binding if homozygous)
Polymorphisms affects incidence or severity of some diseases, including antiphospholipid syndrome (Arthritis Rheum 2003;48:1930), IgA nephropathy (Nephrol Dial Transplant 2005;20:2439), malaria (Am J Trop Med Hyg 2003;69:565), myasthenia gravis (J Neuroimmunol 2003;144:143), peripheral atherosclerosis (Thromb Haemost 2004;92:1273), rheumatic fever (Clin Biochem 2004;37:925) and systemic lupus erythematosus (Arthritis Rheum 2002;46:1563)
Specific CD16 and CD32 alleles are associated with response of follicular lymphoma to rituximab (J Clin Oncol 2003;21:3940)
In dendritic cells, CD32a is considered an activating isoform and CD32b an inhibitory isoform; the balance between these receptors establishes a threshold of activation and enables immune complexes to mediate opposing effects on dendritic cell maturation and function (J Clin Invest 2005;115:2914)
Preincubation with CD16/CD32 antibodies is commonly used to prevent nonspecific binding
Uses: no significant clinical use by pathologists
Positive staining: monocytes, macrophages, B cells, NK cells, granulocytes, eosinophils, basophils, platelets, plasma cells (some)
Positive staining (disease): follicular lymphoma
Negative staining: T cells (usually, Immunology 1997;90:109)
References: OMIM 146790
Glycosylated transmembrane protein of sialic acid-binding immunoglobulin-like lactic (siglec) family
May mediate cell-to-cell adhesion; acts as receptor that inhibits the proliferation of normal and leukemic myeloid cells
Classic myeloid antigen (also CD13)
Anti-CD33 antibody, gemtuzumab ozogamicin, is used to treat AML (BioDrugs 2006;20:137, Cancer 2005;104:1442)
More intense in bone marrow vs. peripheral blood; intensity also varies between leukemias (AJCP 2002;118:560)
Uses: distinguish myeloid and lymphoid leukemia; identify monocytes by flow cytometry; negative selection for stem cells
Positive staining (normal): progenitor and other myeloid cells (decreasing expression with maturation, Am J Pathol 2001;158:1473); granulocytes (low level expression), most monocytic cells, mast cells (Am J Pathol 1996;149:1493), NK cells, T cells (some, J Leukoc Biol 2006;79:46), epidermal Langerhans cells (variable), circulating peripheral dendritic cells (variable)
Positive staining (disease): AML M0 (almost all, AJCP 2001;115:876), M1-M5 (75-85%), M6, M7 (variable), CML (90%); myeloid / granulocytic sarcoma (J Clin Pathol 2005;58:325), transient myeloproliferative disorder (AJCP 2001;116:204), CD4+ CD56+ acute leukemias (Blood 2005;105:1256) and lineage negative malignancies (weak in 44%, AJSP 2005;29:1274), myeloma and plasmacytoma (occasional reports), aberrant expression in anaplastic large cell lymphoma (AJCP 2003;119:205), Burkitt’s lymphoma (J Clin Pathol 1993;46:778), SLL/CLL (AJCP 2003;119:824) or T-ALL (AJCP 2000;113:823)
Negative staining: pluripotent stem cells, B cells, dendritic cells (tonsil, Am J Pathol 2001;159:285); most B and T cell lymphoma, usually blastic NK lymphoma; not expressed outside hematopoietic system
References: OMIM 159590
Intercellular adhesion protein and cell surface glycoprotein; ligand is CD62L (L-selectin)
May mediate attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells, although specific function is unknown
CD34+ stromal cells are called dendritic interstitial cells
Defines adult hematopoietic stem cells; can also differentiate into neural cells (Exp Neurol 2006;197:399)
Note: counting CD34+ mononuclear cells may overestimate myeloid blasts in bone marrow smears due to CD34+ hematogones and CD34+ megakaryocytes (Archives 2002;126:823)
In AML, detection of CD34+ cells by flow cytometry and immunohistochemistry are comparable (Archives 2001;125:1063)
Staining represents presence of protein, not cross reactivity, despite wide range of tissues that are CD34+ (Am J Pathol 2000;156:21)
CD34 staining of peritumoral stroma: positive: gastric adenocarcinoma-diffuse type invading muscularis propria (J Clin Pathol 2001;54:846); negative: breast carcinoma (J Clin Pathol 2003;56:271), colorectal adenocarcinoma (J Clin Pathol 2000;53:626), gastric adenocarcinoma-intestinal type and diffuse type confined to submucosa (J Clin Pathol 2004;57:183)
Interpretation: membranous stain; endothelium acts as a positive internal control
CD34 Uses: (a) distinguish DFSP and Kaposi’s sarcoma (CD34+) or epithelioid sarcoma (often CD34+) from dematofibroma (CD34-); (b) distinguish solitary fibrous tumor (CD34+) from desmoplastic mesothelioma (CD34-, Hum Path 1995;26:428); (c) distinguish hemangiopericytoma (CD34+) from endometrial stromal sarcoma (CD34-, Mod Path 2005;18:40); (d) distinguish vascular invasion from displaced epithelium (J Clin Pathol 2002;55:780); (e) differentiate lymphocyte rich thymoma (CD34+ cells) from T-ALL (usually CD34-, AJCP 2004;121:268); (f) quantify and purify lymphohematopoietic stem cell / progenitor cells for research and for clinical bone marrow transplantation (Folia Histochem Cytobiol 2006;44:53, Eur J Haematol 2006;76:160, Breast Cancer 2005;12:178); (g) identify blasts in hypoplastic marrows to distinguish acute leukemia and myelodysplastic syndrome (blasts present) from aplastic anemia (no blasts / low marrow CD34+ cells, Leukemia 2006;20:458); (h) determine vascularization of tumors or disease processes (Saudi Med J 2006;27:154); (i) poor prognostic factor in newly diagnosed AML (Neoplasma 2005;52:402), (j) may support diagnosis of essential thrombocythemia; (k) possibly confirm diagnosis of chronic intestinal pseudo-obstruction (AJSP 2003;27:228)
High microvessel density (using CD34): associated with poorer prognosis in esophageal squamous cell carcinoma (J Clin Pathol 2001;54:940), poor survival in nonsmall cell lung cancer (J Clin Pathol 2004;57:591), PSA recurrence (AJCP 2000;113:555)
CD34 Micro images: normal - blasts and megakaryocytes
gastrointestinal stromal tumor - compared to solitary fibrous tumor; extraintestinal; stomach; vaginal (figure 5)
solitary fibrous tumor - bladder; ear (figure 2d); hypoglossal nerve (figure 4); kidney #1 (figure 4A); #2; larynx (figure 5); liver (figure 4); malignant #1; nasal cavity (figure 5); pleura (figure 1a), staining lost with malignant transformation (1b); spinal nerve rootlet (figure 4)
vascular tumors - angiosarcoma of oral cavity (figure 7C); epithelioid angiosarcoma of lung; epithelioid hemangioendothelioma #1-pleura (figure 1B); #2-CNS (figure 2E); glomus tumor (figure 6); hemangioma-capillary of endometrium (figure 2C); hemangioma-capillary of testis (figure 1B); hemangioma-cavernous of lung (figure 1C); hemangioma-cavernous of spermatic cord (figure B); hemangioma-juvenile, FNA (figure 3B); hemangiopericytoma of CNS is CD34+ (figure 3) / CD31 neg (figure 4); Kaposi-like splenic angiosarcoma (figure 3b)
CD34 other - adenomatoid tumor of adrenal gland (CD34 neg); AML-M7 (CD34-red, podocalyxin-brown); angiolymphoid hyperplasia with eosinophilia (CD34 neg, figure 5); angiomyofibroblastoma of male inguinal region (figure 2C); chronic myelogenous leukemia #1-(figure 1B); #2-figure 4; cystic panfolliculoma-surrounding fibrotic stroma is CD34+ (figure 7); dendritic cells at margin of salivary gland tumors are CD34+ (figures 1B, 2B, 3B); hemangioblastoma (figure 2d); hepatocellular carcinoma #1, tumor is CD34 neg, sinusoids are CD34+; #2; #3 (figure 1d); inflammatory fibroid polyp of stomach; liver-alcoholic disease is CD34 neg with CD34+ endothelium (figure 7); liver-cirrhosis with buds of hepatocytes containing CD34+ endothelium (figure 9C); malignant peripheral nerve sheath tumor of neck; #2-breast (figure 3A); #3-scalp; pheochromocytoma-malignant, with irregular vascular patterns (figures C-F); phyllodes tumor of breast; plexiform fibrohistiocytic tumor (figure 4); pseudoangiomatous stromal hyperplasia of breast #1 (A: vimentin+; B: CD34+); #2; #3; solitary sclerotic fibroma of finger; spindle cell epithelioma of vagina (figure 3); spindle cell lipoma (figure D); various images: A/E: epithelioid sarcoma; B/F: malignant GIST; C/G: DFSP; D/H: myofibroblastoma
Additional images: GIST (figures C, D); hemangioma and intravascular large cell lymphoma (figure 2b)
CD34 Positive staining (normal): dendritic interstitial cells, dermal dendrocytes, endometrial stroma, endoneurium (Mod Path 2003;16:293), fibroblasts in breast, hair endothelial cells of blood vessels [includes alveolar wall capillaries, glomeruli and periportal hepatic sinusoids but not splenic sinusoids, J Histochem Cytochem 2006;54:385], endothelial cells of some lymphatics, fibrocytes, hematopoietic progenitor cells (pluripotent and erythroid-, lymphoid- and monomyeloid committed cells), follicle cells, interstitial cells of Cajal (20%, Am J Pathol 2000;156:1157), lymphocyte (B and T) precursors, neural stem cells in CNS (Exp Neurol 2006;197:399), perivascular stroma, umbilical cord blood (J Clin Pathol 2001;54:428), vascular adventitial fibroblastic cells in stomach
CD34 Positive staining (disease): preB-ALL (75%, AJCP 2004;121:512), alveolar soft part sarcoma, AML (40-60%, Archives 2003;127:42) but not M3, AML-M0 (almost all, AJCP 2001;115:876, particularly adults, AJCP 2000;113:193), AML-M7 (most), AML with t(6;9) (AJCP 2004;122:348), anal skin tags, angioblastoma (tufted angioma, J Clin Pathol 2005;58:214), angiomyofibroblastoma (variable, Archives 2000;124:1679, Hum Path 1997;28:1046), angiosarcoma (70%, AJSP 1998;22:683), atypical fibrous histiocytoma of skin (focal in 10%, AJSP 2002;26:35), benign epithelioid peripheral nerve sheath tumor (fibroblasts are CD34+, AJSP 2005;29:39), blood vessels in tumors, calcifying fibrous pseudotumor (Int J Surg Pathol 2002;10:189), cellular angiofibroma (60%, AJSP 2004;28:1426), cellular digital fibroma (J Cutan Pathol 2005;32:413), chordoid glioma (focal, AJSP 2002;26:1330), congenital / infantile fibrosarcoma, cystic panfolliculoma-surrounding fibrotic stroma is CD34+ (Archives 2006;130:389), dendritic fibromyxolipoma, dendritic interstitial cells at margin of salivary gland tumors (Archives 2001;125:232), dermal dendrocytoma (Am J Dermatopathol 2002;24:50), dermatofibrosarcoma protuberans (Br J Dermatol 1992;127:79, AJSP 2003;27:27), epithelioid hemangioendothelioma (AJCP 1991;96:25), epithelioid sarcoma (50%, Hum Path 1999;30:934, AJSP 1997;21:130), fibroadenoma (breast), ganglioglioma, glioneural hamartoma, gastric carcinoma-diffuse type-vascular adventitial fibroblastic cells (J Clin Pathol 2004;57:970), gastrointestinal stromal tumor (50-80%, AJSP 2005;29:52), giant cell angiofibroma (AJSP 2000;24:971), giant cell fibroblastoma (AJSP 2003;27:27), glomus tumor / glomangioma (variable, J Cutan Pathol 1993;20:15, Tohoku J Exp Med 1997;182:241), granulocytic sarcoma (47%, Archives 2001;125:1448), hamartomatous tumors of chronic drug resistant epilepsy, hemangioblastoma, hemangioma (variable, AJSP 1999;23:97), hemangiopericytoma (50-100%, including meningeal, AJSP 1999;23:1201, Hum Path 1998;29:636), hepatocellular carcinoma, inflammatory fibrous polyps of stomach/GI tract (Hum Path 2002;33:307, AJSP 2004;28:107), juxtaglomerular cell tumor (AJCP 2001;116:854, may be focal, AJSP 2004;28:1098), kaposiform hemangioendothelioma (AJSP 2004;28:559), Kaposi’s sarcoma (90%, strong and diffuse in spindle cells), Kaposi’s sarcoma-like pyogenic granuloma (J Clin Pathol 2002;55:619), lipomatous tumors (benign and malignant, AJSP 1997;21:195), liposarcoma (myxoid, pleomorphic, well differentiated, AJSP 2002;26:601), lymphangioma (50%, Hum Path 2005;36:426), lymphangioendothelioma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors (low grade stronger/more frequent th