Calretinin

Calretinin is a 29 kD calcium-binding protein and a member of the family to EF-hand proteins, to which S-100 also belongs. Its function is thought to be to buffer intracellular calcium.

Immunohistochemical expression

Normal tissues:

Tumours:

 

conclusion regarding usefulness

adenocarcinoma

mesothelioma

Doglioni 19969 (Polyclonal, variously Swant and Chemicon) 

yes

28/294

44/44

Gotzos 199610 (Polyclonal, non-commercial)

yes

0/4

22/23

Riera 199713 (Polyclonal, Chemicon)

no

13/221

24/57

Ordonez 199814 (Polyclonal, Zymed) 

yes

14/155

38/38

Leers 199815 (Polyclonal, Swant) 

yes

1/21

20/20

Cury 20008 (Polyclonal, Zymed) 

yes

1/59

47/51

Brockstedt 20004 (Polyclonal, Zymed) 

yes

16/57

110/119

Oates 200024 (Polyclonal, Chemicon)

no

28/40

25/26

Kayser 20015 (Polyclonal, Dako)

yes

20/146

97/118

Carella 20017 (Polyclonal, Chemicon) 

yes

2/20

40/46

Comin 200112 (Polyclonal, Swant) 

yes

2/23

42/42

Miettinin 200129 (Polyclonal, Zymed) 

 

 

30/30

Foster 200125 (Polyclonal, Chemicon) 

no

35/51

35/67

Foster 200125 (Polyclonal, Zymed)

?

9/15

3/15

Roberts 200126 (Polyclonal, Chemicon) 

no

8/18

44/112

Tot 200127 (Polyclonal, Zymed) 

yes

0/37

13/14

Miettinin 200321

 

31/255

27/28

Abutaily 20023 (Polyclonal, Zymed) 

yes

2/35

33/41

Ordonez 200328 (Polyclonal, Zymed) 

yes

4/50

60/60

Overall

YES

14% (204/1486)

80% (751/936)

A systematic review of seventeen studies (consisting of 885 epithelioid mesotheliomas and 912 pulmonary adenocarcinomas) reported sensitivities and specificities of calretinin for epithelioid mesothelioma of 82% and 85%39.

There are some controversy as to whether there is nuclear as well as cytoplasmic staining in mesothelioma, and which component is diagnostically reliable. Staining is reportedly weaker in post mortem specimens that in the corresponding ante mortem specimens from the same patients19.

Similar studies have been done on cytological material:

 

conclusion regarding usefulness

adenocarcinoma

mesothelioma

Barberis 199730 (Polyclonal, Swant)

yes

3/13

8/8

Simsir 199931 (Polyclonal, Chemicon)

no

9/29

15/26

Chhieng 200032 (Polyclonal, Zymed)

yes

0/21

14/16

Wieczorek 200033 (Polyclonal, Zymed)

yes

3/39

26/29

Davidson 200134 (Polyclonal, Swant)

yes

3/98

11/12

Simsir 200135 (Polyclonal, Zymed)

yes

2/15

 

15/17

Overall

YES

9% (20/215)

82% (89/108)

 

Most studies have been of mesothelioma versus pulmonary adenocarcinoma. Some metastatic carcinomas, such as renal cell carcinoma, pose particular problems.

 

Calretinin positivity appears to be more common in colonic carcinomas, particularly those that are poorly differentiated. Based on a total of 82 cases:

well-differentiated

5% of cases20

 

moderately differentiated

20% of cases20

poorly differentiated

67% of cases20

overall

22/5% of cases20

 

Most studies compare mesothelioma with pulmonary adenocarcinoma. There are relatively few studies breaking down adenocarcinomas by subtype, or of other types of pulmonary tumour. Where positive, staining is typically both nuclear and cytoplasmic.

adenocarcinoma

acinar type, differentiated

17/14821

acinar type, solid, poorly-differentiated, mucin-positive

8/4821

bronchoalveolar, mucinous

0/6 21

bronchoalveolar, non-mucinous

0/7 21

acinar with focal neuroendocrine differentiation

3/22 21

neuroendocrine

3/18 21

clear cell

0/6 21

large cell

NOS

45/120 21, 0/814

with focal neuroendocrine differentiation

1/10 21

neuroendocrine carcinoma

15/33 21

small cell carcinoma

20/41 21

squamous cell

keratinising

21/62 21

non-keratinising

19/62 21

NOS

11/2814

sarcomatoid carcinoma, spindle cell

1/6 21

giant cell carcinoma

4/6 21

 

adult granulosa cell tumour

13/132, 35/3517, 6/1418

juvenile granulosa cell tumour

4/42, 4/417

thecoma

9/917

fibrothecoma

10/112, 14/1417, 0/818

Leydig cell tumour

3/32

Sertoli cell tumour

4/417

Sertoli-Leydig cell tumour

1/12, 13/1317, 10/1018

sex cord-stromal tumour with annular tubules

2/22

gynandroblastoma

1/12

sclerosing stromal tumour

1/12, 2/217

steroid cell

3/317

sex-cord stromal tumour, unclassified

1/12, 3/317

sex cord-stromal tumours, overall

36/372, 87/8717

fibroma

19/2017

adenofibroma (stromal component)

6/917

fibrosarcoma

8/817

serous carcinoma

3/1117

atypical mucinous neoplasm

6/1917

endometrioid adenocarcinoma

2/62, 3/1517

clear cell carcinoma

1/717

endometrial stromal neoplasm

1/72

ovarian carcinoid tumour

1/22

Brenner tumour

3/42, 1/1317

malignant mixed Mullerian tumour

0/217

ovarian leiomyomatous tumour

0/12

metastatic lobular carcinoma

1/42

lymphoma

1/52

testicular seminoma

1/42

dysgerminoma

0/717

yolk sac tumour

0/517

choriocarcinoma

0/117

embryonal carcinoma

0/117

immature teratoma

0/417

mixed germ cell tumour

0/417

desmoplastic small round cell tumour

0/22

small cell carcinoma

0/117

clear cell sarcoma

0/117

female adnexal tumour of probable Wolffian origin

91% of 25 cases16

   

Extra-ovarian tumours which may enter the differential of metastatic granulosa cell tumour:

gastrointestinal stromal tumours

1/3222

leiomyosarcoma

11/2822

endometrial stromal sarcoma

1/1522

uterine undifferentiated sarcoma

0/422

   

 

 

calretinin

primary left atrial myxoma

19/19

primary right atrial myxoma

5/5

myxoma emboli

1/1

mural thrombus

0/10

jaw myxoma

0/6

papillary fibroelastomas

0/2

Other stromal tumours:

 

Malignant peripheral nerve sheath tumour arising from neurofibroma

2/1529

 

Solitary fibrous tumour of the pleura

0/1629

Epithelioid sarcoma

0/1629

Leiomyosarcoma

0/2029

GIST

0/2029

Angiosarcoma

0/2029

   

 

Diagnostic utility

References

1 LM Terracciano et a. Calretinin as a marker for cardiac myxoma. Am J Clin Pathol 2000;114:754-759.

2 McCluggage, W. G., Maxwell, P. Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord-stromal tumours. Histopathology 2001;38:403-408.

3 Abutaily, A.S., Addis, B.J. and Roche, W.R. Immunohistochemistry in the distinction between malignant mesothelioma and pulmonary adenocarcinoma: a critical evaluation of new antibodies. J Clin Pathol 2002;55:662-8.

4 Brockstedt U, Gulyas M, Debra K. An optimized batter of eight antibodies that can distinguish most cases of epithelial mesothelioma form adenocarcinoma. Am J Clin Pathol 2000;114:203-9.

5 K Kayser et al. Glyco- and immunohistochemical refinement of the differential diagnosis between mesothelioma and metastatic carcinoma and survival analysis of patients. J Pathol 2001;193:175-180.

7 Carella R et al. Immunohistochemical panels for differentiating epithelial malignant mesothelioma from lung adenocarcinoma. Am J Surg Pathol 2001;25:43-50.

8 Cury, 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;13:107-112.

9 Doglioni, C., Tos, A. P., Laurino, L., Iuzzolino, P., Chiarelli, C., Celio, M. R., Viale, G. Calretinin: a novel immunocytochemical marker for mesothelioma. Am J Surg Pathol 1996;20:1037-46.

10 Gotzos, V., Vogt, P., Celio, M. R. The calcium binding protein calretinin is a selective marker for malignant pleural mesotheliomas of the epithelial type [published erratum appears in Pathol Res Pract 1996 Jun;192(6):646]. Pathol Res Pract 1996;192:137-47.

12 Comin, 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 Human Pathol 2001;32:529-536.

13 Riera, J. R. Astengo-Osuna, C. Longmate, J. A. Battifora, H. The immunohistochemical diagnostic panel for epithelial mesothelioma: a reevaluation after heat-induced epitope retrieval. Am J Surg Path 1997;21:1409-19.

14 Ordonez, N. G. Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma. Mod Pathol 1998;11:929-933.

15 Leers, M. P., Aarts, M. M., Theunissen, P. H. E-cadherin and calretinin: a useful combination of immunochemical markers for differentiation between mesothelioma and metastatic adenocarcinoma. Histopathology 1998;32:209-216.

16 Devouassoux-Shisheboran, M., Silver, S. A., Tavassoli, F. A. Wolffian adnexal tumor, so-called female adnexal tumor of probable Wolffian origin (FATWO): immunohistochemical evidence in support of a Wolffian origin. Hum Pathol 1999;30:856-63.

17 Movahedi-Lankarani, S. and Kurman, R.J. Calretinin, a more sensitive but less specific marker than alpha- inhibin for ovarian sex cord-stromal neoplasms: an immunohistochemical study of 215 cases. Am J Surg Pathol 2002;26:1477-83.

18 Cao, Q.J., Jones, J.G. and Li, M. Expression of calretinin in human ovary, testis, and ovarian sex cord- stromal tumors. Int J Gynecol Pathol 2001;20:346-52.

19 Roberts, 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.

20 Gotzos, V., Wintergerst, E.S., Musy, J.P., Spichtin, H.P. and Genton, C.Y. Selective distribution of calretinin in adenocarcinomas of the human colon and adjacent tissues. Am J Surg Pathol 1999;23:701-11.

21 Miettinen, M. and Sarlomo-Rikala, M. Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types: an immunohistochemical analysis of 596 tumors in comparison with epithelioid mesotheliomas of the pleura. Am J Surg Pathol 2003;27:150-8.

22 Shah, V.I., Freites, O.N., Maxwell, P. and McCluggage, W.G. Inhibin is more specific than calretinin as an immunohistochemical marker for differentiating sarcomatoid granulosa cell tumour of the ovary from other spindle cell neoplasms. J Clin Pathol 2003;56:221-4.

24 Oates, J. and C. Edwards (2000). "HBME-1, MOC-31, WT1 and calretinin: an assessment of recently described markers for mesothelioma and adenocarcinoma." Histopathology 36(4): 341-7.

25 Foster, M. R., J. E. Johnson, et al. (2001). "Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas." Arch Pathol Lab Med 125(10): 1316-20.

26 Roberts, 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. (Initial publication of data as abstract 8Harper CM. Evaluation of a commercially available immunohistochemical diagnostic panel for malignant mesothelioma. J Pathol 2001:193(suppl):39A.)

27 Tot, T. (2001). "The value of cytokeratins 20 and 7 in discriminating metastatic adenocarcinomas from pleural mesotheliomas." Cancer 92(10): 2727-32.

28 Ordonez, 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.

29 Miettinen, M., J. Limon, et al. (2001). "Calretinin and other mesothelioma markers in synovial sarcoma: analysis of antigenic similarities and differences with malignant mesothelioma." Am J Surg Pathol 25(5): 610-7.

30 Barberis, M. C., M. Faleri, et al. (1997). "Calretinin. A selective marker of normal and neoplastic mesothelial cells in serous effusions." Acta Cytol 41(6): 1757-61.

31 Simsir, A., P. Fetsch, et al. (1999). "E-cadherin, N-cadherin, and calretinin in pleural effusions: the good, the bad, the worthless." Diagn Cytopathol 20(3): 125-30.

32 Chhieng, D. C., H. Yee, et al. (2000). "Calretinin staining pattern aids in the differentiation of mesothelioma from adenocarcinoma in serous effusions." Cancer 90(3): 194-200.

33 Wieczorek, T. J. and J. F. Krane (2000). "Diagnostic utility of calretinin immunohistochemistry in cytologic cell block preparations." Cancer 90(5): 312-9.

34 Davidson, B., S. Nielsen, et al. (2001). "The role of desmin and N-cadherin in effusion cytology: a comparative study using established markers of mesothelial and epithelial cells." Am J Surg Pathol 25(11): 1405-12.

35 Simsir, A., P. Fetsch, et al. (2001). "Calretinin immunostaining in benign and malignant pleural effusions." Diagn Cytopathol 24(2): 149-52.

36 Ordonez NG. Role of immunohistochemistry in distinguishing epithelial peritoneal mesotheliomas from peritoneal and ovarian serous carcinomas. Am J Surg Pathol 1998; 22:1203-14

37 Attanoos RL, Webb R, Dojcinov SD, et al. Malignant epithelioid mesothelioma: anti-mesothelial marker expression correlates with histological pattern. Histopathology 2001; 39:584-8

38 Jorda M, De MB,Nadji M. Calretinin and inhibin are useful in separating adrenocortical neoplasms from pheochromocytomas. Appl Immunohistochem Mol Morphol 2002; 10:67-70

39 King JE, Thatcher N, Pickering CA, et al. Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data. Histopathology 2006; 48:223-32

 

This page last revised 16.2.2006.

©SMUHT/PW Bishop