CD Markers - CD44

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CD Markers

CD44

Reviewers: Nat Pernick, M.D., (see Reviewers page)
Revised: 8 February 2011, last major update February 2011
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.

General
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● Cell membrane glycoprotein involved in cell-cell interactions, cell adhesion and migration

Terminology
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● Also called CD44s (standard isoform) or CD44H, which lacks all alternative exons; all references below are to standard isoform unless stated otherwise
● Also known as phagocytic glycoprotein 1

Physiology
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● Family of cell surface glycoproteins with numerous isoforms and posttranslational modifications involving glycosylation (CD44v6 is common variant) generated by alternate splicing of mRNA
● Important in epithelial cell adhesion (cell-cell and cell-matrix) to hyaluronate in basement membranes, and maintaining polar orientation of cells; this process may contribute to tissue remodeling and may stimulate cell proliferation and migration
● CD44 also binds hyaluronic acid, laminin, collagen, fibronectin, osteopontin, matrix metalloproteinases and E-selectin/CD62E (J Exp Med 2005;201:1183)
● Also considered a marker of activated B cells
● Important in development of T cells; double negative (CD4-, CD8-) immature thymocytes are divided into developmental stages based on the expression of CD44 and CD25 (Immunol Res 2010;47:45)
● Involved in leukocyte attachment and rolling on endothelial cells, homing to peripheral lymphoid organs (by binding to mucosal addressin, a protein present on high endothelial cells of Peyer’s patches and lymph nodes), and leukocyte chemotaxis and aggregation

Clinical features
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● CD44 splicing variants may mediate invasion of trophoblast into maternal tissue in early pregnancy (Eur J Obstet Gynecol Reprod Biol 2006;128:243)
● CD44 may help lymphomas disseminate by binding to high endothelial venules
● May be an activity marker in multiple sclerosis (J Neuroimmunol 2005;166:189)
● CD44 splice variants are assumed to have a critical role in the malignant progression of many human tumors, but the clinical significance of CD44 expression is not yet understood
● Enhanced cell surface CD44v6 and v9 expression by osteopontin in breast cancer epithelial cells facilitates tumor cell migration (Clin Exp Metastasis 2005;22:663)
● The Indian blood group (MIM 609027) has antigens In(a) and In(b), which reside on CD44
● Cardiovascular disease: CD44 may induce monocytes to become foamy macrophages and cause atherosclerotic lesions (Biochem Biophys Res Commun 2006;339:846); there is increased expression of CD44 and variants in atheroma and abdominal aortic aneurysm (Am J Pathol 2004;165:1571); high levels on monocytes are associated with coronary arteriogenesis and development of collateral vessels (Circulation 2004;109:1647); closure of ductus arteriosis with wall remodeling involves CD44v6+ smooth muscle cells versus CD44v6 neg smooth muscle cells in patent or closed ductus arteriosis (Am J Cardiol 2006;97:1056)

Uses
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● Marker of squamous epithelium
● Expression in flow cytometry may differentiate Burkitt's lymphoma (low) from CD10+ diffuse large B cell lymphoma (Am J Clin Pathol 2010;133:718)
● May help differentiate reactive urothelium (diffuse full thickness staining) from carcinoma in situ (variable basal cell membranous staining, Am J Surg Pathol 2001;25:1074)

Prognostic significance
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● In general, loss of CD44 expression is a poor prognostic factor, and expression of particular variants may be a poor prognostic factor for particular diseases
● Breast carcinoma: CD44v7-v8 expression is associated with poor long term prognosis (Exp Clin Cancer Res 2005;24:75), but CD44s expression is associated with increased disease free survival in node negative patients (Clin Cancer Res 2005;11:3309)
● Carcinoid tumors: loss of CD44s is associated with nodal metastases (Mod Pathol 2002;15:1333)
● Colon carcinoma: high levels of CD44s are associated with responding to treatment (Oncol Rep 2004;11:41)
● Gastrointestinal stromal tumor: in gastric tumors, loss of CD44s is associated with poor clinical outcome (Am J Surg Pathol 2004;28:168)
● Laryngeal carcinoma: reduced expression of CD44 is a poor prognostic factor (Anticancer Res 2005;25:1115)
● Lung carcinoma: reduced CD44v3 expression is associated with poor prognosis in non-small cell lung cancer (Hum Pathol 2000;31:1088)
● Lymphoma: high serum soluble CD44 levels are associated with poor prognosis in non-Hodgkin’s lymphoma (Leuk Res 2002;26:241)
● Melanoma: reduced cell surface CD44 is associated with poor prognosis (Am J Pathol 2000;157:957)
● Myeloma: presence of CD44v9 is associated with poor prognosis
● Neuroblastoma: CD44 is powerful predictive factor for outcome at initial staging - increased levels are associated with better prognosis (J Clin Oncol 1996;14:25, Eur J Cancer 1997;33:2101)
● Ovarian carcinoma: high CD44 expression is associated with favorable outcome (Clin Cancer Res 2003;9:5318)
● Pheochromocytoma: loss of CD44S is associated with metastases (Mod Pathol 2004;17:1119)
● Prostate cancer: loss of CD44 is associated with poor outcome
● Thymoma: increased CD44v5 expression is associated with poorer survival (Ann Thorac Surg 2003;76:213)
● Tongue carcinoma: reduced expression is a poor prognostic factor (Anticancer Res 2003;23:5197)
● Urothelial neoplasms, papillary: loss of CD44 immunoreactivity (restricted to basal cell layer in normal urothelium) is associated with increasing tumor grade and stage in pTa and pT1 patients (Mod Pathol 2000;13:1315)

Micro images
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Increased CD44 expression in macrophage rich areas in atheroma and abdominal aortic aneursym

Bladder and CD44:   normal urothelium;   papilloma;    papillary urothelial neoplasm of low malignant potential
papillary carcinoma-low grade;   papillary carcinoma-high grade

Left-adenosquamous carcinoma; right-breast carcinoma

Ovarian carcinoma

Left-sclerosing hemangioma of lung (fig D); right-squamous cell carcinoma (various)

Pheochromocytoma (fig d/e)

Positive staining - normal
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● Most tissues are CD44+; including astrocyte restricted precursor cells (Dev Biol 2004;276:31), breast myoepithelial cells (CD44v6), colon, lung type II pneumocytes, red blood cells, stomach, urothelial basal cells, uterus, white blood cells

Positive staining - disease
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● Colorectal carcinoma (80%), glioma (higher expression in high grade tumors, J Neurooncol 2001;53:115); Langerhans cell histiocytosis (Am J Pathol 1994;144:466), oligodendroglioma (Clin Neuropathol 2003;22:169), prostatic small cell carcinoma (Hum Pathol 2009;40:252), pulmonary sclerosing hemangioma (Arch Pathol Lab Med 2005;129:915), sinonasal invasive papilloma (CD44s expression is often lost with invasive disease, Am J Clin Pathol 1998;109:309), squamous cell tumors including adenosquamous carcinoma (standard form and variants, Arch Pathol Lab Med 2000;124:212), thymoma (Ann Thorac Surg 2003;76:213)

Negative staining
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● Biliary epithelium, cardiac muscle, hepatocytes (J Clin Pathol 1999;52:730), kidney tubular epithelium, platelets, testis, thymus (CD44s, CD44v5, CD44v6, Ann Thorac Surg 2003;76:213)
● Basal cell carcinoma (downregulation of CD44v6, Hum Pathol 1999;30:1328), esophageal adenocarcinoma, leiomyosarcoma (absent CD44v3 expression, Hum Pathol 2001;32:1190), papillary serous endometrial carcinoma (usually, Int J Gynecol Cancer 2003;13:480), urothelial carcinoma, well differentiated adenocarcinoma

Additional references
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● MIM 107269

End of CD Markers > CD44

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