CD44

CD44 is a family of transmembrane glycoproteins which mediate cell-extracellular matrix interactions. They are involved in cell surface binding to hyaluronate and interactions with cytoskeleton-related molecules including actin and ankyrin. It is therefore expressed on the basolateral surfaces of myoepithelial cells of ducts and acini. It has also been implicated in lymphocyte activation and homing and tumour invasion. The gene is located on chromosome 11 and contains at least 20 exons, 10 of which can be alternatively spliced to create a variety (at least 25) of isoforms¹⁰.

Antibodies are effective on paraffin-embedded tissue¹⁴.

Immunohistochemical expression

The CD 44 family of glycoproteins exist in a number of isoforms:

• CD 44s: the standard form found in mesoderm, including haemopoietic, fibroblastic and glial cells

  • reduced CD44s expression is related to tumour recurrence and cancer-related mortality in differentiated thyroid carcinomas.

  • in renal cell carcinomas, increased CD44s expression is correlated with large tumours, of high grade, with metastases⁶.

• CD 44v: found in epithelial cells. A correlation has been shown between increased expression and tumor progression for some tumours, although the reported correlations are variable¹:

  • up-regulation of CD44v6 is related to more aggressive behavior in various carcinomas, but reduced level of CD44v6 is associated with a poor outcome in pulmonary adenocarcinoma⁴, poorly differentiated squamous cell carcinoma, bladder and prostate carcinomas.

  • Neither the expression of CD44, not that of its variant isoform v3, are of prognostic significance in gastric carcinoma⁵.

• CD 44H is widely expressed in haemopoietic and mesodermal cells⁸. Increased CD44H expression predicts poor survival in renal cell carcinoma¹².

• CD44v3 is expressed by myometrium (32/32) and leiomyomas (32/32) but not leiomyosarcomas(0/12; non-neoplastic vessel walls remain positive)¹¹. In leiomyosarcomas, decreased CD44s expression correlated with high grade and high stage¹¹.

Diagnostic utility

• CD 44H; differentiation of mesothelioma from adenocarcinoma.

	adenocarcinoma	mesothelioma
Attanoos 19972	3/20 (Pulmonary adenocarcinomas. Staining was only focal [<10% of tumour].)	15/20 (Staining was diffuse, intense and membranous. All 20 biospies of reactive mesothelium also stained.)
Afify 19989	9/26 (Pulmonary adenocarcinomas.)	14/22
Filie 1998 (on cytological specimens)15	9/21	18/20
Cury 20003	27/60 (lung = 19, breast = 21, ovary = 6, colon = 10, kidney = 4, uterus = 1, epididymis = 1, pancreas = 1)	39/43 (epithelioid pleural mesotheliomas)
Ordonez 200016	44/132 (Lung; 19/40, breast; 4/25, ovary; 2/30, colon; 3/7, kidney; 4/10, thyroid; 7/10, prostate; 5/10)	36/50 (all epithelioid mesotheliomas)
Harper 20017	10/18	67/112
Comin 20018	13/23 (In 12 cases, staining was of <25% of cells. In only one case did over 75% of cells stain.)	42/42 (In all cases, staining was membranous and strong.)
Attanoos 200117	not studied	43/92 (60 pleural, 32 peritoneal, all epithelioid. Immunopositivity was membranous in location in all tumours. Immunoreactivity was most marked in the solid epithelioid (15/25, 65%) and adenomatoid patterns (7/11, 64%), compared with 23/61 (38%) tubulopapillary, 1/2 pleomorphic and 2/6 of small cell variant forms.)
Roberts 200118	10/18 (various primary sites)	68/112
Attanoos 200219	5/23 (5/20 serous ovarian and 0/3 peritoneal carcinomas)	15/32 (all epithelioid peritoneal mesotheliomas)
Ordonez 200320	24/50 (all primary lung adenocarcinomas: 1 case >75% of cells stained, 2 cases 50-75% of cells, 7 cases 25-50% of cells and 14 cases 1-25% of cells)	44/60 (all epithelioid mesotheliomas: 17 case >75% of cells stained, 11 cases 50-75% of cells, 4 cases 25-50% of cells, 7 cases 1-25% of cells and 5 cases <1% of cells. Positivity occurred along the cell membrane)
Overall	39% (154/391)	66% (401/605)

Staining is reportedly weaker in post mortem specimens that in the corresponding ante mortem specimens from the same patients¹³.

• CD44s may be useful in conjunction with p53 and cytokeratin 20 in the differentiation of normal and reactive urothelium from carcinoma-in-situ.

• Loss of CD44v3 may be useful in differentiating leiomyosarcomas from leiomyomas¹¹.

References

¹Bohm JP et al. Reduced CD44 standard expression is associated iwth tumour recurrence and unfavourable outcome in differentiated thyroid carcinoma. J Pathol 2000;192:321-327.

²Attanoos, R. L., Webb, R., Gibbs, A. R. CD44H expression in reactive mesothelium, pleural mesothelioma and pulmonary adenocarcinoma. Histopathology 1997;30:260-3.

³Cury, P. M.,et al. Value of the mesothelium-associated antibodies thrombomodulin, cytokeratin 5/6, calretinin, and CD44H in distinguishing epithelioid pleural mesothelioma from adenocarcinoma metastatic to the pleura. Mod Pathol 2000;13:107-12.

⁴S Ramasami et al. Expression of CD44v6 but not E-cadherin or ß-catenin influences prognosis in primary pulmonary adenocarcinoma. J Pathol 2000;192:427-432.

⁵L Setala et al. Expression of CD44 and its variant isoform v3 has no prognostic value in gastric cancer. Histopathology 2001; 38: 13-20.

⁶ Daniel L et al. CD44s and CD44v6 expression in localised T1-T2 conventional renal cell carcinomas. J Pathol 2001;193:345-349.

⁷Harper CM. Evaluation of a commercially available immunohistochemical diagnostic panel for malignant mesothelioma. J Pathol 2001:193(suppl):39^A.

⁸Comin, C. E., Novelli, L., Boddi, V., Paglierani, M., Dini, S. Calretinin, thrombomodulin, CEA, and CD15: a useful combination of immunohistochemical markers for differentiating pleural epithelial mesothelioma from peripheral pulmonary adenocarcinoma. Hum Pathol 2001;32:529-536.

⁹Afify. Applied Immunohistochemistry 1998;6:11-15.

¹⁰McKenney, J. K., Desai, S., Cohen, C., Amin, M. B. Discriminatory immunohistochemical staining of urothelial carcinoma in situ and non-neoplastic urothelium: an analysis of cytokeratin 20, p53, and CD44 antigens. Am J Surg Pathol 2001;25:1074-1078.

¹¹Poncelet, C., Walker, F., Madelenat, P., Bringuier, A. F., Scoazec, J. Y., Feldmann, G., Darai, E. Expression of CD44 standard and isoforms V3 and V6 in uterine smooth muscle tumors: a possible diagnostic tool for the diagnosis of leiomyosarcoma. Human Pathol ,2 001;32:1190-1196.

¹²Rioux-Leclercq, N., Epstein, J. I., Bansard, J. Y., Turlin, B., Patard, J. J., Manunta, A., Chan, T., Ramee, M. P., Lobel, B., Moulinoux, J. P. Clinical significance of cell proliferation, microvessel density, and CD44 adhesion molecule expression in renal cell carcinoma. Human Pathol 2001;32:1209-1215.

¹³Roberts, F., McCall, A. E., Burnett, R. A. Malignant mesothelioma: a comparison of biopsy and postmortem material by light microscopy and immunohistochemistry. J Clin Pathol 2001;54:766-70.

¹⁴Leong A S-Y, Cooper K and Leong FJ W-M. Manual of diagnostic antibodies for immunohistology. 2nd edition, 2003

¹⁵Filie, A. C., A. Abati, et al. (1998). "Hyaluronate binding probe and CD44 in the differential diagnosis of malignant effusions: disappointing results in cytology material." Diagn Cytopathol 18(6): 473-4.

¹⁶Ordonez, N. G. (2000). "Value of thyroid transcription factor-1, E-cadherin, BG8, WT1, and CD44S immunostaining in distinguishing epithelial pleural mesothelioma from pulmonary and nonpulmonary adenocarcinoma." Am J Surg Pathol 24(4): 598-606.

¹⁷Attanoos, R. L., R. Webb, et al. (2001). "Malignant epithelioid mesothelioma: anti-mesothelial marker expression correlates with histological pattern." Histopathology 39(6): 584-8.

¹⁸Roberts, F., C. M. Harper, et al. (2001). "Immunohistochemical analysis still has a limited role in the diagnosis of malignant mesothelioma. A study of thirteen antibodies." Am J Clin Pathol 116(2): 253-62.

¹⁹Attanoos, R. L., R. Webb, et al. (2002). "Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum." Histopathology 40(3): 237-44.

²⁰Ordonez, N. G. (2003). "The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma." Am J Surg Pathol 27(8): 1031-51.

This page last revised 6.5.2002.

©SMUHT/PW Bishop