Coordinate expression of cytokeratins 7 and 20

Specific cytokeratin expression gives valuable information as to the primary site of a carcinoma. Cytokeratins 7 and 20 are most useful in this respect.

(When we are trying to determine the line of differentiation of a tumour, we not uncommonly are forced to rely on very limited immunoreactivity as the best available evidence. This is not appropriate when evaluating specific cytokeratins. It is important to know the thresholds for positivity which vary between papers, in some cases the threshold being set as low as 1% of cells^1,7, often at 10% of cells, but at the most stringent requiring at least 50% of cells to show at least moderate staining².)

Predominantly CK7+/CK20-
	CK7+/CK20+	CK7+/CK20-	CK7-/CK20+	CK7-/CK20-
Lung, adenocarcinoma	6/541, 6/74 (Tumours were considered positive if at least 10% of cells showed at least moderate immunoreactivity.)2, 2/155, 2/438, 1/1010	39/541, 64/74 (Tumours were considered positive if at least 10% of cells showed at least moderate immunoreactivity.)2, 12/155, 16/17 (signet ring cell carcinomas)6, 41/438, 9/1010	0/541, 0/74 (Tumours were considered positive if at least 10% of cells showed at least moderate immunoreactivity.)2, 0/155, 0/1010	9/541, 4/74 ((Tumours were considered positive if at least 10% of cells showed at least moderate immunoreactivity.))2, 1/155, 0/1010
Lung, bronchoalveolar	0/31, 8/28 (7 mucinous and 1 mixed)8	3/31, 20/28 (1 mucinous, 4 mixed and 15 non-mucinous)8	0/31	0/31
Malignant mesothelioma	0/161, 0/1710	11/161, 11/1710	0/161, 0/1710	5/161, 6/1710
Breast, infiltrating ductal	6/381, 0/2010	31/381, 19/2010	1/381, 0/2010	0/381, 1/2010
Breast, infiltrating lobular	1/111, 0/610	10/111, 6/610	0/111, 0/610	0/111, 0/610
Thyroid neoplasms	0/55 (24 were adenomas, 16 were medullary carcinomas, five were follicular carcinomas, and 10 were papillary carcinomas)10	54/55 (24 were adenomas, 16 were medullary carcinomas, five were follicular carcinomas, and 10 were papillary carcinomas)10, 49/59 (adenomas: 6/6 follicular and 6/6 oncocytic. carcinomas: 3/4 follicular, 8/8 papillary, 6/7 poorly differentiated, 4/6 Hurtle cell, 1/2 medullary, 0/4 anaplastic and 15/16 metastatic carcinomas)12	0/55 (24 were adenomas, 16 were medullary carcinomas, five were follicular carcinomas, and 10 were papillary carcinomas)10	1/55 (24 were adenomas, 16 were medullary carcinomas, five were follicular carcinomas, and 10 were papillary carcinomas)10, 10/59 (adenomas: 0/6 follicular and 0/6 oncocytic. carcinomas: 1/4 follicular, 0/8 papillary, 1/7 poorly differentiated, 2/6 Hurtle cell, 1/2 medullary, 4/4 anaplastic and 1/16 metastatic carcinomas)12
Salivary gland	0/9 (five were mixed tumors, two were Warthin’s tumors, and two were mucoepidermoid carcinomas)10	9/9 (five were mixed tumors, two were Warthin’s tumors, and two were mucoepidermoid carcinomas)10	0/9 (five were mixed tumors, two were Warthin’s tumors, and two were mucoepidermoid carcinomas)10	0/9 (five were mixed tumors, two were Warthin’s tumors, and two were mucoepidermoid carcinomas)10
Thymoma	0/810, 0/3414	0/810, 28/3414	0/810, 0/3414	8/810, 6/3414
Oesophageal adenocarcinoma	1/30 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 11/11 (oesophagus and oesophago-gastric junction)7	27/30 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 0/11 (oesophagus and oesophago-gastric junction)7	1/30 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 0/11 (oesophagus and oesophago-gastric junction)7	1/30 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 0/11 (oesophagus and oesophago-gastric junction)7
Ovarian serous and endometrioid	0/191, 1/24 (12 were serous papillary, four were clear cell, and eight were endometrioid)10, 2/11 (endometrioid carcinomas: CK20 focally positive)15	19/191, 23/24 (12 were serous papillary, four were clear cell, and eight were endometrioid)10, 9/11 (endometrioid carcinomas)15	0/191, 0/24 (12 were serous papillary, four were clear cell, and eight were endometrioid)10, 0/11 (endometrioid carcinomas)15	0/191, 0/24 (12 were serous papillary, four were clear cell, and eight were endometrioid)10, 0/11 (endometrioid carcinomas)15
Endometrial	3/251, 0/1010	20/251, 10/1010	0/251, 0/1010	2/251, 0/1010
Cervix, squamous cell carcinoma	0/1510	13/1510	0/1510	2/1510
Predominantly CK7-/CK20+
	CK7+/CK20+	CK7+/CK20-	CK7-/CK20+	CK7-/CK20-
Appendiceal adenocarcinoma	1/7 (well differentiated)7, 8/23 (These adenocarcinomas were metastatic to the ovary and included seven signet ring cell carcinoma of appendix: also 4 of 31 low grade adenomatous mucinous tumours)18	0/77, 0/23 (These adenocarcinomas were metastatic to the ovary and included seven signet ring cell carcinoma of appendix: also 0 of 31 low grade adenomatous mucinous tumours)18	6/7 (well differentiated)7, 15/23 (These adenocarcinomas were metastatic to the ovary and included seven signet ring cell carcinoma of appendix: also 27 of 31 low grade adenomatous mucinous tumours)18	0/77, 0/23 (These adenocarcinomas were metastatic to the ovary and included seven signet ring cell carcinoma of appendix: also 0 of 31 low grade adenomatous mucinous tumours)18
Appendiceal goblet cell carcinoid	1/97, 4/6 (appendiceal mixed goblet cell carcinoid / adenocarcinoma)7	0/97, 0/6 (appendiceal mixed goblet cell carcinoid / adenocarcinoma)7	8/97, 2/6 (appendiceal mixed goblet cell carcinoid / adenocarcinoma)7	0/97, 0/6 (appendiceal mixed goblet cell carcinoid / adenocarcinoma)7
Colorectal adenocarcinoma (non-mucinous and mucinous): note that CK7 positivity may be more common in rectal carcinomas.	5/511, 16/772, 4/29 (2 well/moderately differentiated and 2 poorly differentiated)7, 4/30 (colorectal adenocarcinoma metastatic to lung)8, 1/2010, 12/225 (Low grade 5/158, high grade 7/67 . Study used tissue arrays.)16, 0/11 (Metastases to ovary . Study used tissue arrays.)16, 1/24 (only focal expression of CK7)17, 3/28 (These tumours were metastatic to the ovary and included one signet ring cell carcinoma of colorectum; all 3 were focally CK7+ and diffusely CK20+)18	0/511, 0/772, 1/29 (poorly differentiated)7, 1/30 (colorectal adenocarcinoma metastatic to lung)8, 0/2010, 9/225 (Low grade 3/158, high grade 6/67 . Study used tissue arrays.)16, 0/11 (Metastases to ovary . Study used tissue arrays.)16, 0/28 (These tumours were metastatic to the ovary and included one signet ring cell carcinoma of colorectum)18	40/511, 59/772, 23/29 (19 well/moderately differentiated and 4 poorly differentiated)7, 25/30 (colorectal adenocarcinoma metastatic to lung)8, 19/2010, 3/3 (metastatic to ovary)15, 153/225 (Low grade 118/158, high grade 35/67 . Study used tissue arrays.)16, 10/11 (Metastases to ovary . Study used tissue arrays.)16, 22/2417, 23/28 (These tumours were metastatic to the ovary and included one signet ring cell carcinoma of colorectum; 17 were diffusely CK20+, 6 were focally CK20+)18	6/511, 2/772, 1/29 (poorly differentiated)7, 0/2010, 51/225 (Low grade 32/158, high grade 19/67 . Study used tissue arrays.)16, 1/11 (Metastases to ovary . Study used tissue arrays.)16, 1/2417, 2/28 (These tumours were metastatic to the ovary and included one signet ring cell carcinoma of colorectum)18
Merkel cell carcinoma	0/910	0/910	7/910	2/910
Predominantly CK7+/CK20+
	CK7+/CK20+	CK7+/CK20-	CK7-/CK20+	CK7-/CK20-
Small intestinal adenocarcinoma	16/2417	8/2417	0/2417	0/2417
Ovarian mucinous	14/151, 10/18 (invasive tumours[CK7 diffuse / CK20 focal; 4, CK7 diffuse / CK20 diffuse; 6]: also 29 of 35 borderline tumours [CK7 diffuse / CK20 focal; 14, CK7 focal / CK20 focal; 4, CK7 diffuse / CK20 diffuse; 10, CK7 focal / CK20 diffuse; 1])18	1/151, 8/18 (invasive tumours[all diffusely CK7+]: also 4 of 35 borderline tumours[ CK7 diffuse; 3, focal 1])18	0/151, 0/18(invasive tumours: also 2 of 35 borderline tumours[CK20 diffuse; 1, focal; 1])18	0/151, 0/18 (invasive tumours: also 0 of 35 borderline tumours)18
Endocervical adenocarcinoma	7/818	1/818	0/818	0/818
Bladder, transitional cell carcinoma	17/191, 12/264, 17/289, 6/24 (well differentiated transitional cell carcinomas were more likely to be CK 20 positive)10	2/191, 12/264, 6/289, 15/2410	0/191, 1/289, 1/2410	0/191, 4/289, 2/2410
Cholangiocarcinoma	31/4813, 6/1410, 3/418	15/4813, 7/1410, 0/418	2/4813, 0/1410, 1/418	0/4813, 1/1410, 0/418
Pancreatic adenocarcinoma	15/231, 8/1310, 11/14 (These tumours were metastatic to the ovary )18	6/231, 4/1310, 3/14 (These tumours were metastatic to the ovary )18	2/231, 0/1310, 0/14 (These tumours were metastatic to the ovary )18	0/231, 1/1310, 0/14 (These tumours were metastatic to the ovary )18
Predominantly CK7-/CK20-
	CK7+/CK20+	CK7+/CK20-	CK7-/CK20+	CK7-/CK20-
Head and neck, squamous cell carcinoma	0/3010	8/3010	2/3010	20/3010
Lung, squamous cell	0/121, 0/1510	0/121, 7/1510	1/121, 0/1510	11/121, 8/1510
Lung, small cell	0/111, 0/710	2/111, 3/710	0/111, 0/710	9/111, 4/710
Lung, carcinoid	0/910, 0/1611	2/910, 9/1611	0/910, 0/1611	7/910, 7/1611
Oesophagus, squamous cell carcinoma	0/1410	3/1410	0/1410	11/1410
Gastrointestinal carcinoid	0/1510	2/1510	1/1510	12/1510
Colonic high grade neuroendocrine carcinoma	0/57	0/57	0/57	5/5 (2 small cell carcinomas, 2 large cell neuroendocrine carcinomas, 1 mixed small cell / large cell neuroendocrine carcinoma)7
Hepatocellular carcinoma	2/301, 0/1110	5/301, 1/1110	0/301, 1/1110	23/301, 9/1110
Renal cell carcinoma	0/171, 0/1910	4/171, 2/1910	1/171, 0/1910	12/171, 17/1910
Prostatic adenocarcinoma	1/131, 1/599, 0/1810	1/131, 5/599, 0/1810	3/131, 5/599, 0/1810	8/131, 48/599, 18/1810
Germ cell tumour	0/14 (six were embryonal carcinomas, four were seminomas, three were teratomas, and one was a yolk sac tumor)10	1/14 (six were embryonal carcinomas, four were seminomas, three were teratomas, and one was a yolk sac tumor)10	0/14 (six were embryonal carcinomas, four were seminomas, three were teratomas, and one was a yolk sac tumor)10	13/14 (six were embryonal carcinomas, four were seminomas, three were teratomas, and one was a yolk sac tumor)10
Epithelioid sarcoma	0/1210	0/1210	0/1210	12/1210
Adrenal cortical tumour	0/1010	0/1010	0/1010	10/1010
Variable
	CK7+/CK20+	CK7+/CK20-	CK7-/CK20+	CK7-/CK20-
Gastric adenocarcinoma	11/291, 5/14 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 27/38 (5 well/moderately differentiated and 22 poorly differentiated)7, 1/810, 75/289 (Intestinal type 26/112, diffuse type 49/177 . Study used tissue arrays.)16, 16/43 (Metastases to ovary . Study used tissue arrays.)16, 4/518	5/291, 3/14 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 8/38 (3 well/moderately differentiated and 5 poorly differentiated)7, 2/810, 132/289 (Intestinal type 52/112, diffuse type 80/177 . Study used tissue arrays.)16, 18/43 (Metastases to ovary . Study used tissue arrays.)16, 0/518	10/291, 3/14 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 3/38 (all 3 poorly differentiated)7, 3/810, 42/289 (Intestinal type 19/112, diffuse type 23/177 . Study used tissue arrays.)16, 8/43 (Metastases to ovary . Study used tissue arrays.)16, 1/518	3/291, 3/14 (Tumours were considered positive if at least 50% of cells showed at least moderate immunoreactivity.)3, 0/387, 2/810, 40/289 (Intestinal type 15/112, diffuse type 25/177 . Study used tissue arrays.)16, 1/43 (Metastases to ovary . Study used tissue arrays.)16, 0/518

One must note that the cut-off percentage of staining for a positive result is varies in different studies from 1%¹ to 5%¹⁰, which in part may contribute to differences in the results in some groups of carcinomas between studies. In addition, the CK 20 monoclonal antibody that was used varied (American Research Products [APR], Inc., Belmont, MA¹⁰, DAKO¹).

Neither CK7 nor CK20 alone reliably differentiated pulmonary from colonic carcinomas: however, the combination is reliable, with tumours that are CK7+/CK20+ or CK7-/CK20- being of indeterminate origin. If an adenocarcinoma within the lung is being examined, TTF-1 will also be informative in combination with these cytokeratins.

Only one paper has analysed the effect of the grade on expression: aberrant cytokeratin expression is more common in poorly differentiated adenocarcinomas⁷.

References

¹ Coordinate expression of cytokeratins 7 and 20 defines unique subsets of carcinomas. NP Wang et al. Applied Immunohistochemistry 1995; 3:99-107.

² Loy TS, Calaluce RD. Utility of cytokeratin immunostaining in separating pulmonary adenocarcinomas from colonic carcinomas. Am J Clin Pathol 1994;102:764-767.

³ Ormsby AH et al. The utility of cytokeratin subsets in distinguishing Barrett's-related oesophageal adenocarcinoma form gastric adenocarcinoma. Histopathology 2001;38:307-311.

⁴ Jiang, J., Ulbright, T. M., Younger, C., Sanchez, K., Bostwick, D. G., Koch, M. O., Eble, J. N., Cheng, L. Cytokeratin 7 and cytokeratin 20 in primary urinary bladder carcinoma and matched lymph node metastasis, Arch Pathol Lab Med 2001;125:921-3.

⁵ Amin, M. B., Tamboli, P., Merchant, S. H., Ordonez, N. G., Ro, J., Ayala, A. G., Ro, J. Y. Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol 2002;26:358-364.

⁶ Merchant, S.H., Amin, M.B, Tamboli, P., Ro, J., Ordonez, N.G., Ayala, A.G., Czerniak, B.A. and Ro, J.Y. Primary signet-ring cell carcinoma of lung: immunohistochemical study and comparison with non-pulmonary signet-ring cell carcinomas. Am J Surg Pathol 2001;25:1515-9.

⁷ Kende, A.I., Carr, N.J. and Sobin, L.H. Expression of cytokeratins 7 and 20 in carcinomas of the gastrointestinal tract. Histopathology 2003;42:137-40.

⁸ Barbareschi, M., Murer, B., Colby, T.V., Chilosi, M., Macri, E., Loda, M. and Doglioni, C. CDX-2 Homeobox Gene Expression Is a Reliable Marker of Colorectal Adenocarcinoma Metastases to the Lungs. Am J Surg Pathol 2003;27:141-9.

⁹ Bassily, N.H., Vallorosi, C.J., Akdas, G., Montie, J.E. and Rubin, M.A. Coordinate expression of cytokeratins 7 and 20 in prostate adenocarcinoma and bladder urothelial carcinoma. Am J Clin Pathol 2000;113:383-8.

¹⁰ Chu, P., Wu, E., Weiss, L. M. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol 2000;13:962-972

¹¹ Cai, Y. C., Banner, B., Glickman, J., Odze, R. D. Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors. Human Pathol 2001;32:1087-1093

¹² Bejarano, P. A., Y. E. Nikiforov, et al. (2000). "Thyroid transcription factor-1, thyroglobulin, cytokeratin 7, and cytokeratin 20 in thyroid neoplasms." Appl Immunohistochem Mol Morphol 8(3): 189-94.

¹³ Rullier, A., Le Bail, B., Fawaz, R., Blanc, J. F., Saric, J., Bioulac-Sage, P. Cytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tract but still differs from that in colorectal carcinoma metastasis. Am J Surg Pathol 200; 24:870-6.

¹⁴ Kuo, T. (2000). "Cytokeratin profiles of the thymus and thymomas: histogenetic correlations and proposal for a histological classification of thymomas." Histopathology 36(5): 403-14.

¹⁵ Jimenez-Linan M et al. Cytokeratin immunostaining differentiates endometrioid carcinoma of ovary from metastatic colorectal carcinoma. Pathological Society July 2004, abstract 78.

¹⁶ Park, S. Y., H. S. Kim, et al. (2002). "Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary." Hum Pathol 33(11): 1078-85.

¹⁷ Chen, Z. M. and H. L. Wang (2004). "Alteration of cytokeratin 7 and cytokeratin 20 expression profile is uniquely associated with tumorigenesis of primary adenocarcinoma of the small intestine." Am J Surg Pathol 28(10): 1352-9.

¹⁸ Vang R, Gown AM, Barry TS, et al. Cytokeratins 7 and 20 in Primary and Secondary Mucinous Tumors of the Ovary: Analysis of Coordinate Immunohistochemical Expression Profiles and Staining Distribution in 179 Cases. Am J Surg Pathol 2006; 30:1130-1139

This page last revised 24.9.2006.

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