CK 5/6

Immunohistochemical expression

See Cytokeratins in normal epithelia and specific cytokeratins in common carcinomas.

• basal cells of bronchial epithelium and of prostatic glands⁶

• squamous cell carcinoma⁵ and large cell carcinoma of lung⁵: adenocarcinoma of the lung is generally negative⁶.

• transitional cell carcinoma⁵

• mesothelium and mesothelioma is frequently positive: by comparison, adenocarcinomas are much less often positive. Initially K5 was suggested as a marker for mesothelioma. The antibody AE14 against K5 reacted with 12 of 13 mesothelioma but none of 21 pulmonary adenocarcinomas in cryostat sections⁷. In the absence of antibodies specific for CK5 and effective on formalin-fixed paraffin-embedded tissues, a monoclonal antibody against both CK5 and CK6 has been used:

	adenocarcinoma	mesothelioma
Clover 19974	5/27 (lung adenocarcinomas. Staining in 4 cases was equivocal)	23/23
Ordonez 19985	14/123 (0/30 lung adenocarcinomas, 10/30 ovarian, 2/10 endometrioid, 1/18 breast, 1/7 thyroid, 0/10 kidney, 0/10 colonic, 0/8 prostate. Staining was weak and focal.)	40/40
Cury 20001	9/63 (lung = 19; breast = 21; ovary = 6; colon = 10; kidney = 4; uterus, epididymis, pancreas = 1 case each)	56/61
Kayser 2001 (It is not clear whether these results are for cytokeratin 5 or cytokeratin 5/6)2	72/146 (33/82 lung, 27/47 breast, 1/3 colon, 1/2 kidney, 10/12 site not known)	90/118 (74/99 epithelioid, 10/12 mixed and 6/7 sarcomatoid)
Carella 20013	1/20 (the positive case was an adenosquamous carcinoma)	40/46 (included all histological types)
Atanoos 200110	not studied	51/92 (included 6 small cell mesotheliomas)
Kaufmann11	30/141 (various sites of origin)	14/14
Miettinen 200110	not studied	22/30 (21/23 epithelioid, 1/7 sarcomatoid)
Tot 2001	6/79 (various sites of origin)	9/14
Abutaily 20029	2/35 (lung adenocarcinomas: staining in two cases was both cytoplasmic and membranous)	26/41 (19 cases membranous and cytoplasmic, 7 cases cytoplasmic only: positive in 10//11 epithelioid, 15/23 mixed and 1 of 7 sarcomatoid mesotheliomas))
Chu 200215	1/21 (lung adenocarcinomas)	13/17 (all biphasic mesotheliomas)
Miettinen 20038	25/254	26/28 (10 of 10 tubulopapillary, 5 of 6 combined tubulopapillary and poorly differentiated, 11 of 12 poorly differentiated)
Ordonez 200313	1/50 (lung adenocarcinomas: 1 case showed positivity of 5% of tumour cells, possibly in association with squamous differentiation)	60/60 (all epithelioid mesotheliomas: 32 cases >75% of cells, 16 cases 50-75% of cells, 7 cases 25-50% of cells, 3 cases 1-25% of cells, 2 cases <1% of cells)
Overall	17% (166/959)	80% (470/584)

A systematic review of eight studies (consisting of 402 epithelioid mesotheliomas and 402 pulmonary adenocarcinomas) reported sensitivities and specificities of CK5/6 for epithelioid mesothelioma of 83% and 85%¹⁶.

Most studies compare mesothelioma with pulmonary adenocarcinoma. There are relatively few studies breaking down pulmonary adenocarcinomas by subtype, or of other types of pulmonary tumour.

adenocarcinoma	acinar type, differentiated	17/146 (8 cases more than 10% of cells staining, 9 cases less than 10% of cells staining) 8
	acinar type, solid, poorly-differentiated, mucin-positive	7/49 (7 cases more than 10% of cells staining) 8
	bronchoalveolar, mucinous	0/6 8
	bronchoalveolar, non-mucinous	1/7 (1 case less than 10% of cells staining) 8
	acinar with focal neuroendocrine differentiation	0/22 8
	neuroendocrine	0/18 8
	clear cell	0/6 8
	NOS	3/2914
large cell	NOS	67/120 (53 cases more than 10% of cells staining, 14 cases less than 10% of cells staining) 8
	with focal neuroendocrine differentiation	3/10 (2 cases more than 10% of cells staining, 1 cases less than 10% of cells staining) 8
	neuroendocrine carcinoma	6/33 (5 cases more than 10% of cells staining, 1 cases less than 10% of cells staining) 8
small cell carcinoma		11/41 (4 cases more than 10% of cells staining, 7 cases less than 10% of cells staining) 8, 0/1515
squamous cell	keratinising	62/62 (61 cases more than 10% of cells staining, 1 cases less than 10% of cells staining) 8
	non-keratinising	54/62 (47 cases more than 10% of cells staining, 7 cases less than 10% of cells staining) 8
	NOS	27/36 (23 cases showed staining of >25% of tumour cells)14
sarcomatoid carcinoma, spindle cell		1/6 (1 case less than 10% of cells staining) 8
giant cell carcinoma		3/6 (2 cases more than 10% of cells staining, 1 cases less than 10% of cells staining) 8
poorly differentiated carcinoma		1/314
carcinoid		1/1015

Some metastatic carcinomas, such as renal cell carcinoma, pose particular problems.

Extra-pulmonary tumours:

Melanoma: 1/24 (one case showed staining of ~5% of cells)¹⁴

• Glioblastoma: 0/23¹⁴

Diagnostic utility

differentiation of mesothelioma from adenocarcinoma. It does not differentiate mesothelioma from squamous cell carcinoma which are usually positive. Positivity is also common in large cell carcinomas.

differentiation of benign (immunoreactive) from malignant (unreactive) glands in prostatic needle biospies⁶, for which it may be superior to 34bE12, although there is less experience than with 34bE12. Both antibodies stain the basal cells, which are deficient in adenocarcinoma. Useful in conjunction with P504S.

		benign		malignant
		CK5/6	34bE12	CK5/6	34bE12
negative		0/306	4/306	12/126	12/126
positive	<50% of glands	0/306	5/306	0/126	0/126
	50-75% of glands	1/306	9/306	0/126	0/126
	75-95% of glands	0/306	10/306	0/126	0/126
	>95% of glands	29/306	2/306	0/126	0/126

CK5/6, unlike LP34, does not produce weak staining of luminal cells and therefore it is easier to identify acini showing two layers of cells in lobular atrophy¹¹. However, the staining is slightly weaker than for LP34 and intermittent in benign acini¹¹. Staining is strengthened by increasing the time of antigen retrieval¹¹. CK5/6 may be superior for differentiation adenocarcinoma from lobular atrophy, while LP34 may be superior in the distinction of adenocarcinoma from PIN¹¹.

Identification of squamous differentiation in poorly differentiated carcinoma from various sites, particularly when coexpressed with p63¹³.

References

¹ 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;13:107-12.

² 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.

³ Carella R et al. Immunohistochemical panels for differentiating epithelial malignant mesothelioma from lung adenocarcinoma. Am J Surg Pathol 2001;25:43-50.

⁴ Clover, J., Oates, J., Edwards, C. Anti-cytokeratin 5/6: a positive marker for epithelioid mesothelioma. Histopathology 1997;31:140-143.

⁵ Ordonez, N. G. (1998). "Value of cytokeratin 5/6 immunostaining in distinguishing epithelial mesothelioma of the pleura from lung adenocarcinoma." Am J Surg Pathol 22(10): 1215-21.

⁶ Abrahams, N.A., Ormsby, A.H. and Brainard, J. Validation of cytokeratin 5/6 as an effective substitute for keratin 903 in the differentiation of benign from malignant glands in prostate needle biopsies. Histopathology 2002;41:35-41.

⁷ Moll, R., Dhouailly, D. and Sun, T.T. Expression of keratin 5 as a distinctive feature of epithelial and biphasic mesotheliomas. An immunohistochemical study using monoclonal antibody AE14. Virchows Arch B Cell Pathol Incl Mol Pathol 1989;58:129-45.

⁸ 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.

⁹ 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.

¹⁰ 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.

¹¹ Freeman, A., K. Treurnicht, et al. (2002). "A comparison of basal cell markers used in the prostate." Histopathology 40(5): 492-4.

¹² Jerome Marson, V., J. Mazieres, et al. (2004). "Expression of TTF-1 and cytokeratins in primary and secondary epithelial lung tumours: correlation with histological type and grade." Histopathology 45(2): 125-34.

¹³ Kaufmann, O., E. Fietze, et al. (2001). "Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas." Am J Clin Pathol 116(6): 823-30.

¹⁴ Reis-Filho JS, Simpson PT, Martins A, Preto A, Gartner F,Schmitt FC Distribution of p63, cytokeratins 5/6 and cytokeratin 14 in 51 normal and 400 neoplastic human tissue samples using TARP-4 multi-tumor tissue microarray. Virchows Arch 2003; 443:122-32 This study used tissue microarrays.

¹⁵ Chu PG,Weiss LM Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases. Mod Pathol 2002; 15:6-10

¹⁶ 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