Hepatocellular carcinoma v cholangiocarcinoma v metastatic adenocarcinoma

In the United States and Europe, primary malignancies of the liver account for only 2-3% of all malignancies of the gastrointestinal tract and are greatly outnumbered by metastatic tumours in the liver⁵. Hepatocellular carcinoma accounts for 90% of primary liver malignancies. In part of Africa and the Far East, hepatocellular carcinoma is far more common.

Some hepatocellular carcinomas recognisably resemble hepatocytes, or produce identifiable bile. But pseudoglandular formation, clear cell change and poor differentiation may make this difficult. The tumours which need to be differentiated include cholangiocarcinoma, combined hepatocellular and cholangiocarcinoma and metastatic carcinomas. The sclerosing variant of hepatocellular carcinoma can mimic cholangiocarcinoma. It is possible that tumours with biliary differentiation retain some molecular attributes of hepatocytes, such as expression of albumin mRNA¹⁴.

 It is generally accepted AFP has specificity (it is also positive in germ cell tumours and acinus cell carcinomas, but these are uncommon differential diagnosis) but lacks sensitivity for hepatocellular carcinoma. AFP may be useful in poorly differentiated hepatocellular carcinomas, which are more commonly positive and which may lack canaliculi and therefore not show a specific pattern with p-CEA and CD10.

CD10 and polyclonal CEA both produce a specific pattern of canalicular staining in hepatocellular carcinomas: this may be combined with non-canalicular membrane and cytoplasmic staining which are not specific for hepatocellular carcinoma. Canalicular immunoreactivity for CD10 is specific but lacks the sensitivity of p-CEA and ISH^albumin : but it may be useful if a laboratory does not stock polyclonal CEA.

Hepatocellular carcinomas are usually negative for monoclonal CEA, while about 84% of all carcinomas are positive.

ISH^albumin is not totally specific, with positivity in occasional cholangiocarcinomas^4,14 and biliary cystadenocarcinomas¹⁵. However, outside of primary liver tumours, no tumours other than those with hepatoid features show positivity for ISH^albumin.

Hep Par 1 is a usefully specific marker for hepatocellular carcinoma, although some cholangiocarcinomas are also positive.

Ber-Ep4 is negative in hepatocellular carcinoma⁸ but positive in many adenocarcinomas, including cholangiocarcinomas.

Cytokeratins 7, 19 and 20 are absent from most hepatocellular carcinomas⁸ but positive in many adenocarcinomas, including cholangiocarcinomas. However, adrenal and renal carcinomas, that may mimic HCC, may be negative for both CK7 and CK20.

Cytoplasmic imunoreacitivty for TTF-1 has been reported as useful in the diagnosis of hepatocellular carcinoma

a-1-antitrypsin, a-1-antichymotrypsin, factor XIII, ferritin blood group antigens, fibrinogen and albumin have all been used as markers for hepatocellular carcinoma without much success.

Histochemical staining for bile produced by hepatocytes has a low sensitivity of 5 to 33%⁴. Mucin secretion is common in cholangiocarcinoma and metastatic adenocarcinoma but rare in hepatocellular carcinoma.

Reports of laminin immunoreactivity in hepatocellular carcinomas are controversial: it is also present in cholangiocarcinomas⁴.

Reports of factor XIII immunoreactivity by hepatocytes are probably fallacious.

Reports of inhibin immunoreactivity by hepatocytes are probably fallacious.

Parathyroid hormone-related peptide has been reported to stain cholangiocarcinomas but not hepatocellular carcinoma, nor most metastatic carcinomas⁵: this requires confirmation. Breast carcinomas are commonly positive⁵.

Cholangiocarcinoma is positive for chromogranin A: staining of hepatocellular carcinoma is much weaker⁵. However, gastrointestinal carcinomas may also be positive for chromogranin.

		AFP	PTHrP	Hep Par 1	p-CEA			m-CEA12	CD10		ISHalbumin
					cytoplasm	non-canalicular membrane	canalicular	0/74	non-canalicular membrane	canalicular
hepatocellular carcinoma	grade 1	0/143			3/143	4/143	13/143		3/143	12/143	6/83
	grade 2	12/453			15/453	18/453	44/453		7/453	30/453	24/253
	grade 3	3/43			3/43	3/43	3/43		0/43	1/43	0/23
	overall	4/131, 15/633, 30/969, 5/1213	0/115	30/324, 37/386, 289/2907, 88/969	21/633	25/633	12/131, 60/633, 73/969, 10/1213		10/633	43/633, 50/969	30/353, 12/1213
cholangiocarcinoma		0/141, 0/713	11/11 : including one case of extrahepatic bile duct carcinoma5	4/324	13/141		0/141, 0/713				0/713
combined hepatocellular and cholangiocarcinoma		2/31, 4/1713	2/2 : positivity in areas of cholangiocellular differentiation5	5/54			3/31, 11/2513				22/2513
metastatic carcinoma results are dependent on the site of the primary tumour.		0/271, 0/253	2/22 : gastrointestinal tract; 0/14, breast; 2/5, endometrium; 0/1, ovarian serous papillary; 0/25	0/134	26/271, 12/253	2/253	0/271, 0/253	84%	4/253	0/253	0/233

Deciding which panel of markers to use depends on the various combinations of immunoreactivity with multiple markers.

		AE1	MOC-31	CK7	CK19	CK20	BerEP4
hepatocellular carcinoma		3/3211, 0/1213	0/131	4/131, 2/3010, 2/1213	4/324 , 79/2907, 0/3010, 3/1213	0/131, 2/324, 0/3010, 5/1213	1/131
cholangiocarcinoma	peripheral			19/192		9/192
	central			27/29 : intrahepatic bile duct; 5/6, hilar; 9/10, extrahepatic bile duct; 13/132		25/29 intrahepatic bile duct; 5/6, hilar; 8/10, extrahepatic bile duct; 12/132
	not specified	10/1011, 7/713	13/141	13/141, 29/3010, 7/713	32/324,  10/105, 23/3010, 7/713	2/141, 3/324, 3/3010, 7/713	14/141
combined hepatocellular-cholangiocarcinoma		1/111, 21/2213	3/31	3/31, 23/2513	5/54, 22/2413	0/31, 2/54, 7/2513	2/31
metastatic adenocarcinoma : results very dependent on the site of the primary tumour: reference 3: squamous oesophagus x2, squamous cervix x2, squamous lung x1, transitional cell bladder x2, small cell lung x3, non-small cell lung x2, neuroendocrine stomach x1, neuroendocrine pancreas x2, breast x4, adenocarcinoma caecum x1, ovary x1, kidney x2, anaplastic carcinoma panaceas x2, reference 4: colon x9, pancreas x2, stomach x2, gallbladder x2, breast x2, bladder x1, endometrium x1.1.		10/1011	27/271	15/271, 6/25 (metastases from colorectum)2, 1/30 (metastatic colorectal metastases)10	10/134, 19/19 : gastrointestinal; 14/14 , breast 5/55, 19/30 (metastatic colorectal adenocarcinoma)10	12/271, 31/31 (metastases from colorectum)2, 9/134, 22/30 (metastatic colorectal adenocarcinoma)10	26/271

Reference

¹Porcell, A. I., De Young, B. R., Proca, D. M., Frankel, W. L. Immunohistochemical analysis of hepatocellular and adenocarcinoma in the liver: MOC31 compares favorably with other putative markers. Mod Pathol 2000;13:773-8.

²Rullier, 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.

³Borscheri, N., Roessner, A., Rocken, C. Canalicular immunostaining of neprilysin (CD10) as a diagnostic marker for hepatocellular carcinomas. Am J Surg Pathol 2001;25:1297-1303.

⁴Leong, A. S., Sormunen, R. T., Tsui, W. M., Liew, C. T. Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumours and metastatic carcinoma. Histopathology 1998;33:318-324.

⁵Roskams, T., Willems, M., Campos, R. V., Drucker, D. J., Yap, S. H., Desmet, V. J. Parathyroid hormone-related peptide expression in primary and metastatic liver tumours. Histopathology 1993;23:519-525.

⁶Wennerberg, A. E., Nalesnik, M. A., Coleman, W. B. Hepatocyte paraffin 1: a monoclonal antibody that reacts with hepatocytes and can be used for differential diagnosis of hepatic tumors. Am J pathol 1993;143:1050-4.

⁷Wu, P. C., Fang, J. W., Lau, V. K., Lai, C. L., Lo, C. K., Lau, J. Y.Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol 1996;149:1167-75.

⁸Lamps, L.W. and Folpe, A.L. The diagnostic value of hepatocyte paraffin antibody 1 in differentiating hepatocellular neoplasms from nonhepatic tumors: a review. Adv Anat Pathol 2003;10:39-43.

⁹Chu, P.G., Ishizawa, S., Wu, E. and Weiss, L.M. Hepatocyte antigen as a marker of hepatocellular carcinoma: an immunohistochemical comparison to carcinoembryonic antigen, CD10, and alpha-fetoprotein. Am J Surg Pathol 2002;26:978-88.

¹⁰Maeda, T., K. Kajiyama, et al. (1996). "The expression of cytokeratins 7, 19, and 20 in primary and metastatic carcinomas of the liver." Mod Pathol 9(9): 901-9.

¹¹Johnson, D. E., B. G. Herndier, et al. (1988). "The diagnostic utility of the keratin profiles of hepatocellular carcinoma and cholangiocarcinoma." Am J Surg Pathol 12(3): 187-97.

¹²Salomao, D. R., R. V. Lloyd, et al. (1997). "Hepatocellular carcinoma: needle biopsy findings in 74 cases." Diagn Cytopathol 16(1): 8-13.

¹³Tickoo, S. K., S. Y. Zee, et al. (2002). "Combined hepatocellular-cholangiocarcinoma: a histopathologic, immunohistochemical, and in situ hybridization study." Am J Surg Pathol 26(8): 989-97.

¹⁴D'Errico, A., P. Baccarini, et al. (1996). "Histogenesis of primary liver carcinomas: strengths and weaknesses of cytokeratin profile and albumin mRNA detection." Hum Pathol 27(6): 599-604.

¹⁵D'Errico, A., G. Deleonardi, et al. (1998). "Diagnostic implications of albumin messenger RNA detection and cytokeratin pattern in benign hepatic lesions and biliary cystadenocarcinoma." Diagn Mol Pathol 7(6): 289-94.

This page last revised 28.12.2003.

©SMUHT/PW Bishop