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MIM.114051 16q22.1

Wednesday 7 July 2004

calbindin-2, calretinin, calretinine


Definition: Calbindin-2 (CALB2, calretinin) is a calcium-binding protein belonging to the troponin C superfamily (MIM.191040), close to the S-100 proteins (S100s). Calcium binding protein structurally related to S-100 and inhibin.

Calretinin is a calcium-binding protein expressed in different normal and neoplastic tissues.


- tubal adenomatoid tumor and STIC - calretinin IHC

Expression in tissues

In normal tissues, a particularly strong expression was found in Leydig cells of the testis, neurons of the brain, theca-lutein and theca interna cells of the ovary, and mesothelium.

Calretinin is abundantly expressed in central and peripheral neural tissues, particularly in the retina and in the neurons of the sensory pathways, and calretinin may play an important role in the survival of nerve cells during disturbances in calcium homeostasis.

Calretinin is also expressed by both normal and neoplastic mesothelial cells, and it has been suggested as a useful marker for the identification of malignant mesotheliomas of the epithelial type and for the differentiation of these malignancies of lung adenocarcinoma.

- subtypes of central and peripheral neurons
- mast cells
- Leydig cells of the testis
- neurons of the brain
- theca-lutein and theca interna cells of the ovary
- mesothelium.

Expression in tumors

In tumors, strong calretinin expression was most frequently found in malignant mesotheliomas, Leydig cell tumors of the testis, adenomas of adrenal gland, and adenomatoid tumors.

- malignant mesothelioma
- granular cell tumor (100%)
- schwannoma (100%)
- neurofibroma (7%)
- Leydig cell tumor of the testis
- adenomas of adrenal gland
- adenomatoid tumor

- malignant mesotheliomas

  • Early studies suggested that calretinin is a useful marker to differentiate adenocarcinomas from malignant mesotheliomas of the lung.
  • Calretinin can be expressed in several other tumor types.

Metastases of various different origins must be included in the differential diagnosis of calretinin-positive pleura tumors.

Diagnostic use

- pleural mesothelioma

  • Differentiate (as part of a panel) epithelioid pleural mesothelioma (positive) from lung adenocarcinoma (negative, Am J Surg Pathol 2003;27:1031)
  • Differentiate (as part of a panel) epithelioid peritoneal mesothelioma (positive) from ovarian serous papillary carcinoma (usually negative, Am J Surg Pathol 2007;31:1139)
  • Differentiate reactive mesothelial cells (positive) from carcinomas (negative) in effusion cytology (Am J Clin Pathol 2001;116:709, Cytopathology 2008;19:218), ascites fluid / peritoneal lavage (Tohoku J Exp Med 2005;206:31) or pleural biopsies (Am J Surg Pathol 2007;31:914)
  • Differentiate (as part of a panel) mesothelioma (positive) from metastatic renal cell carcinoma (negative, Histopathology 2002;41:301)
  • Identify peritoneal invasive implants of serous borderline tumors of the ovary by lack of calretinin+ mesothelial cells (Mod Pathol 2006;19:364)

- adrenal cortical tumors

  • Differentiate (as part of a panel) adrenal cortical lesions (calretinin+) from metastatic clear cell renal cell carcinoma (negative, Am J Surg Pathol 2011;35:678)
    - Differentiate (as part of a panel) adrenal cortical lesions (calretinin+) from pheochromocytoma (negative, Am J Surg Pathol 2010;34:423)

- ovarian Sertoli-Leydig tumors

  • Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord-stromal tumours. (11422476)
  • Differentiate (as part of a panel) ovarian Sertoli-Leydig tumors (positive) from sertoliform endometroid carcinoma (negative) (Arch Pathol Lab Med 2007;131:979).
  • Ovarian sex cord-stromal tumours are a heterogeneous group of neoplasms which may be confused morphologically with a wide variety of tumours.
  • Calretinin positivity has been demonstrated in a small number of ovarian sex cord-stromal tumours.
  • Calretinin is a sensitive immunohistochemical marker of ovarian sex cord-stromal tumours and may be useful in a diagnostic setting.
  • However, the value is somewhat limited since occasional neoplasms which enter into the morphological differential diagnosis may be positive.
  • Calretinin positivity may be of value in the diagnosis of an ovarian sex cord-stromal tumour and its differentiation from other neoplasms.(11422476)

- schannoma

  • Differentiate schwannoma (strong staining) from neurofibroma (negative or weak / focal staining, Am J Clin Pathol 2004;122:552)

- olfactory neuroblastoma

  • Differentiate olfactory neuroblastoma (calretinin+, p63-) from other sinonasal small round blue cell tumors (calretinin-, p63+, Am J Surg Pathol 2011;35:1786)

- ameloblastoma

  • Differentiate ameloblastoma (calretinin+) from keratocystic odontogenic tumor (negative, Am J Surg Pathol 2008;32:256)

- Marker for normal functional endometrial stromal cells (Pathol Res Pract 2007;203:79)

- loss of calretinin expression indicates aganglionosis in Hirschsprung’s disease (15220363)


- Calretinin Staining Facilitates Differentiation of Olfactory Neuroblastoma From Other Small Round Blue Cell Tumors in the Sinonasal Tract. Wooff JC, Weinreb I, Perez-Ordonez B, Magee JF, Bullock MJ. Am J Surg Pathol. 2011 Oct 20. PMID: 22020045

- Kapur RP, Reed RC, Finn L, Patterson K, Johanson J, Rutledge JC. Calretinin immunohistochemistry versus acetylcholinesterase histochemistry in the evaluation of suction rectal biopsies for Hirschsprung disease. Pediatr Dev Pathol. 2008 Apr 28:1. PMID: 18442301

- Barshack I, Fridman E, Goldberg I, Chowers Y, Kopolovic J. The loss of calretinin expression indicates aganglionosis in Hirschsprung’s disease. J Clin Pathol. 2004 Jul;57(7):712-6. PMID: 15220363

- Calretinin expression in human normal and neoplastic tissues: a tissue microarray analysis on 5233 tissue samples. Lugli A, Forster Y, Haas P, Nocito A, Bucher C, Bissig H, Mirlacher M, Storz M, Mihatsch MJ, Sauter G. Hum Pathol. 2003 Oct;34(10):994-1000. PMID: 14608532

- Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord-stromal tumours. McCluggage WG, Maxwell P. Histopathology. 2001 May;38(5):403-8. PMID: 11422476