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 ISHalbumin : 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.

ISHalbumin is not totally specific, with positivity in occasional cholangiocarcinomas4,14 and biliary cystadenocarcinomas15. However, outside of primary liver tumours, no tumours other than those with hepatoid features show positivity for ISHalbumin.

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.

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

Reference

1 Porcell, 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.

2 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.

3 Borscheri, 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.

4 Leong, 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.

5 Roskams, 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.

6 Wennerberg, 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.

7 Wu, 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.

8 Lamps, 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.

9 Chu, 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.

10 Maeda, 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.

11 Johnson, 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.

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

13 Tickoo, 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.

14 D'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.

15 D'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.

16 Lei JY, Bourne PA, diSant'Agnese PA, et al. Cytoplasmic staining of TTF-1 in the differential diagnosis of hepatocellular carcinoma vs cholangiocarcinoma and metastatic carcinoma of the liver. Am J Clin Pathol 2006; 125:519-25

This page last revised 28.12.2003.

©SMUHT/PW Bishop