CR

(Calretinin)
Characteristics
Calretinin is a calcium-binding protein, 29 kDa, member of the family of so-called EF-hand proteins, to which also the S-100 proteins belong. Calretinin is abundantly expressed in neurons. Outside the nervous system, calretinin is found in mesothelial cells, steroid producing cells (adrenal cortical cells, testicular Leydig cells, ovarian theca interna cells), testicular Sertoli cells, rete testis, ovarian surface epithelium, some neuroendocrine cells, breast glands, eccrine sweat glands, hair follicular cells, thymic epithelial cells, endometrial stromal cells, and fat cells. Convoluted tubules of kidney are calretinin positive when stained with the pAbs from SWant and Zymed, not with the mAbs that we have tested (DAK Calret 1; 5A5). The significance of this is at present not known. In calretinin positive cells, the protein is generally found in both the cytoplasm and nuclei.
Neoplasms
Calretinin is detected in most malignant mesothelioma. The proportion reaches 100% in some studies but the results are rather divergent, much depending on the protocol (including the antibody). Sarcomatoid and small cell mesothelioma is stained in considerably less than 100% of the cases. Other tumours usually found positive for calretinin are adenomatoid tumour, sex cord-stromal tumours (mostly Sertoli-stromal tumours), mesonephric cervical adenocarcinoma, Wolffian adnexal tumour, synovial sarcoma and ameloblastoma. Some adenocarcinomas also stain (e.g., adenocarcinomas of colon and pancreas are reported to be positive in 20% of the cases), however, the staining is usually more localized and often limited to the cytoplasm, while the nuclei are unstained. Studies of the occurrence of calretinin in, e.g., neural crest and neuroendocrine tumours have not been published.
Application
Calretinin is a useful marker for differentiating malignant mesothelioma from carcinomas. Calretinin is also applicable for the differential diagnosis of ovarian stromal tumours.
Controls
Adrenal gland and appendix are recommendable positive and negative tissue controls for CR. Adrenal gland will serve as a “low expressor” (LE) positive tissue control, in which an at least weak to moderate, distinct cytoplasmic and nuclear staining of the majority of the cortical epithelial cells must be seen. Appendix serves both as negative tissue and “high expressor” (HE) positive tissue control. Columnar epithelial cells and smooth muscle cells should be negative, while strong, distinct cytoplasmic and nuclear staining of the peripheral nerves (ganglion cells and axons) and macrophages should be seen. Furthermore, fat cells in the submucosa of the appendix could serve as an additional LE positive tissue control.
Selected references
Attanoos RL, Dojcinov SD, Webb R, Gibbs AR. Anti-mesothelial markers in sarcomatoid mesothelioma and other spindle cell neoplasms. Histopathology. 2000 Sep;37(3):224-31. Attanoos RL, Webb R, Dojcinov SD, Gibbs AR. Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum. Histopathology. 2002 Mar;40(3):237-44. Brockstedt U, Gulyas M, Dobra K, Dejmek A, Hjerpe A. An optimized battery of eight antibodies that can distinguish most cases of epithelial mesothelioma from adenocarcinoma. Am J Clin Pathol. 2000 Aug;114(2):203-9. Cao QJ, Jones JG, Li M. Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors. Int J Gynecol Pathol. 2001 Oct;20(4):346-52. Cury PM, Butcher DN, Fisher C, Corrin B, Nicholson AG. 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 Feb;13(2):107-12. McCluggage WG, Maxwell P. Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord-stromal tumours. Histopathology. 2001 May;38(5):403-8. Nogales FF, Isaac MA, Hardisson D, Bosincu L, Palacios J, Ordi J, Mendoza E, Manzarbeitia F, Olivera H, O'Valle F, Krasevic M, Marquez M. Adenomatoid tumors of the uterus: an analysis of 60 cases. Int J Gynecol Pathol. 2002 Jan;21(1):34-40. Cappello F, Barnes L. Synovial sarcoma and malignant mesothelioma of the pleura: review, differential diagnosis and possible role of apoptosis. Pathology. 2001 May;33(2):142-8. Oates J, Edwards C. HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma. Histopathology. 2000 Apr;36(4):341-7. Ordonez NG. The immunohistochemical diagnosis of epithelial mesothelioma. Hum Pathol. 1999 Mar;30(3):313-23. Review. Ordonez NG. Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma. Mod Pathol. 1998 Oct;11(10):929-33. Ordonez NG. Role of immunohistochemistry in distinguishing epithelial peritoneal mesotheliomas from peritoneal and ovarian serous carcinomas. Am J Surg Pathol. 1998 Oct;22(10):1203-14. Review. Tos AP, Doglioni C. Calretinin: a novel tool for diagnostic immunohistochemistry. Adv Anat Pathol. 1998 Jan;5(1):61-6. Review.
11.12.15 - MV/LE