Elevated hepatocyte paraffin 1 and neprilysin expression in hepatocellular carcinoma are correlated with longer survival
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Abstract
Hepatocyte paraffin 1 (Hep Par 1) and neprilysin (CD10) are well-known markers of hepatocellular carcinoma (HCC). To assess their potential prognostic role, we conducted a retrospective analysis of 97 formalin-fixed and paraffin-embedded HCC from patients treated by surgery with curative intent, using standard immunohistochemical procedures and semiquantitative analysis. Strong Hep Par 1 expression and canalicular CD10 staining pattern were significantly correlated with smaller tumor size (p=0.007 and 0.04, respectively). On univariate analysis, longer overall survival was observed in patients with strong Hep Par 1 expression (p=0.0005) and in patients with a CD10can staining pattern (p=0.02). On multivariate analysis, the combined immunohistochemical score (CIS) obtained by addition of Hep Par 1 and CD10can scores and subtraction of cytoplasmic CD10 score was retained as the single most important prognostic factor (p=0.001). Patients with a CIS <4 had a 3.5-fold increased risk of death, as compared to those with a CIS ≥4. In conclusion, strong Hep Par 1 expression, presence of CD10can labeling, and absence of CD10cyt staining are favorable prognostic factors in HCC, which can be easily combined into a single immunohistochemical score for routine clinical use.
Keywords
Carcinoma Hepatocellular Immunohistochemistry Antibodies Monoclonal PrognosisNotes
Acknowledgements
We thank M. Gillet (Department of Surgery, CHUV, Lausanne) for the patient data, S. Pampallona (Evolène, Switzerland) for advice on statistical analysis, and P. Chaubert and P. Shaw (Department of Pathology, CHUV, Lausanne) for help in immunohistochemistry and for critical review of the manuscript, respectively.
This study has been conducted in accordance with current Swiss law and been approved by the ethical committee of our institution.
References
- 1.Adachi E, Maeda T, Kajiyama K, Kinukawa N, Matsumata T, Sugimachi K, Tsuneyoshi M (1996) Factors correlated with portal venous invasion by hepatocellular carcinoma: univariate and multivariate analyses of 232 resected cases without preoperative treatments. Cancer 77:2022–2031PubMedCrossRefGoogle Scholar
- 2.Anthony PP (2001) Hepatocellular carcinoma: an overview. Histopathology 39:109–118PubMedCrossRefGoogle Scholar
- 3.Armitage P, Berry G, Matthews JNS (1987) Statistical methods in medical research, 2nd edn. Blackwell, OxfordGoogle Scholar
- 4.Bene MC, Faure GC (1997) CD10 in acute leukemias. GEIL (Groupe d'Etude Immunologique des Leucemies). Haematologica 82:205–210PubMedGoogle Scholar
- 5.Borscheri N, Roessner A, Rocken C (2001) Canalicular immunostaining of neprilysin (CD10) as a diagnostic marker for hepatocellular carcinomas. Am J Surg Pathol 25:1297–1303PubMedCrossRefGoogle Scholar
- 6.Christensen E (1987) Multivariate survival analysis using Cox's regression model. Hepatology 7:1346–1358PubMedCrossRefGoogle Scholar
- 7.Chu P, Arber DA (2000) Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms. Frequent expression in renal cell carcinoma and endometrial stromal sarcoma. Am J Clin Pathol 113:374–382PubMedCrossRefGoogle Scholar
- 8.Chu PG, Ishizawa S, Wu E, Weiss LM (2002) Hepatocyte antigen as a marker of hepatocellular carcinoma: an immunohistochemical comparison to carcinoembryonic antigen, CD10, and alpha-fetoprotein. Am J Surg Pathol 26:978–988PubMedCrossRefGoogle Scholar
- 9.Colombo M (1992) Hepatocellular carcinoma. J Hepatol 15:225–236PubMedCrossRefGoogle Scholar
- 10.Cox D (1972) Regession models and life tables. J R Stat Soc B 34:187–220Google Scholar
- 11.Dragovic T, Deddish PA, Tan F, Weber G, Erdos EG (1994) Increased expression of neprilysin (neutral endopeptidase 24.11) in rat and human hepatocellular carcinomas. Lab Invest 70:107–113PubMedGoogle Scholar
- 12.Dragovic T, Sekosan M, Becker RP, Erdos EG (1997) Detection of neutral endopeptidase 24.11 (neprilysin) in human hepatocellular carcinomas by immunocytochemistry. Anticancer Res 17:3233–3238PubMedGoogle Scholar
- 13.Edmondson H, Steiner P (1954) Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer 7:462–503PubMedCrossRefGoogle Scholar
- 14.El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745–750PubMedCrossRefGoogle Scholar
- 15.Greenwood M (1926) Reports on public health and medical subjects: the natural duration of cancer. HMSO 33:1–16Google Scholar
- 16.Hamilton SR, Aaltonen LA (eds) (2000) Pathology and genetics of tumors of the digestive system. IARC Press, LyonGoogle Scholar
- 17.Hanazaki K, Kajikawa S, Koide N, Adachi W, Amano J (2001) Prognostic factors after hepatic resection for hepatocellular carcinoma with hepatitis C viral infection: univariate and multivariate analysis. Am J Gastroenterol 96:1243–1250PubMedCrossRefGoogle Scholar
- 18.Inagawa S, Itabashi M, Adachi S, Kawamoto T, Hori M, Shimazaki J, Yoshimi F, Fukao K (2002) Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res 8:450–456PubMedGoogle Scholar
- 19.Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
- 20.Kobayashi T, Sugawara Y, Shi YZ, Makuuchi M (2002) Telomerase expression and p53 status in hepatocellular carcinoma. Am J Gastroenterol 97:3166–3171PubMedCrossRefGoogle Scholar
- 21.Kumagai I, Masuda T, Sato S, Ishikawa K (2001) Immunoreactivity to monoclonal antibody, Hep Par 1, in human hepatocellular carcinomas according to histopathological grade and histological pattern. Hepatol Res 20:312–319PubMedCrossRefGoogle Scholar
- 22.Lamps LW, Folpe AL (2003) The diagnostic value of hepatocyte paraffin antibody 1 in differentiating hepatocellular neoplasms from nonhepatic tumors: a review. Adv Anat Pathol 10:39–43PubMedCrossRefGoogle Scholar
- 23.Lauwers GY, Terris B, Balis UJ, Batts KP, Regimbeau JM, Chang Y, Graeme-Cook F, Yamabe H, Ikai I, Cleary KR, Fujita S, Flejou JF, Zukerberg LR, Nagorney DM, Belghiti J, Yamaoka Y, Vauthey JN (2002) Prognostic histologic indicators of curatively resected hepatocellular carcinomas: a multi-institutional analysis of 425 patients with definition of a histologic prognostic index. Am J Surg Pathol 26:25–34PubMedCrossRefGoogle Scholar
- 24.Lauwers GY, Vauthey JN (1998) Pathological aspects of hepatocellular carcinoma: a critical review of prognostic factors. Hepatogastroenterology 45:1197–1202PubMedGoogle Scholar
- 25.Leong AS, Sormunen RT, Tsui WM, Liew CT (1998) Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumours and metastatic carcinoma. Histopathology 33:318–324PubMedCrossRefGoogle Scholar
- 26.Medina-Franco H, Sellers MT, Eckhoff DE, Bynon JS, Urist MM, Heslin MJ (2001) Multimodality treatment for patients with hepatocellular carcinoma: analysis of prognostic factors in a single Western institution series. J Gastrointest Surg 5:638–645PubMedCrossRefGoogle Scholar
- 27.Minervini MI, Demetris AJ, Lee RG, Carr BI, Madariaga J, Nalesnik MA (1997) Utilization of hepatocyte-specific antibody in the immunocytochemical evaluation of liver tumors. Mod Pathol 10:686–692PubMedGoogle Scholar
- 28.Morrison C, Marsh W Jr, Frankel WL (2002) A comparison of CD10 to pCEA, MOC-31, and hepatocyte for the distinction of malignant tumors in the liver. Mod Pathol 15:1279–1287PubMedCrossRefGoogle Scholar
- 29.Nzeako UC, Goodman ZD, Ishak KG (1996) Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients. Am J Clin Pathol 105:65–75PubMedGoogle Scholar
- 30.Okuda K (2002) Natural history of hepatocellular carcinoma including fibrolamellar and hepato-cholangiocarcinoma variants. J Gastroenterol Hepatol 17:401–405PubMedCrossRefGoogle Scholar
- 31.Sato Y, Itoh F, Hareyama M, Satoh M, Hinoda Y, Seto M, Ueda R, Imai K (1999) Association of cyclin D1 expression with factors correlated with tumor progression in human hepatocellular carcinoma. J Gastroenterol 34:486–493PubMedCrossRefGoogle Scholar
- 32.Schoniger-Hekele M, Muller C, Kutilek M, Oesterreicher C, Ferenci P, Gangl A (2001) Hepatocellular carcinoma in Central Europe: prognostic features and survival. Gut 48:103–109PubMedCrossRefGoogle Scholar
- 33.Sezaki N, Ishimaru F, Tabayashi T, Kataoka I, Nakase K, Fujii K, Kozuka T, Nakayama H, Harada M, Tanimoto M (2003) The type 1 CD10/neutral endopeptidase 24.11 promoter: functional characterization of the 5′-untranslated region. Br J Haematol 123:177–183PubMedCrossRefGoogle Scholar
- 34.Sobin LH, Wittekind C (eds) (2002) TNM classification of malignant tumors. Wiley, New YorkGoogle Scholar
- 35.Thiery JP, Humbert P, Russell S, Richardson H (2002) Epithelial-mesenchymal transitions in tumour progression Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
- 36.Turner AJ, Isaac RE, Coates D (2001) The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. Bioessays 23:261–269PubMedCrossRefGoogle Scholar
- 37.Turner AJ, Tanzawa K (1997) Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. Faseb J 11:355–364PubMedGoogle Scholar
- 38.Wennerberg AE, Nalesnik MA, Coleman WB (1993) Hepatocyte paraffin 1: a monoclonal antibody that reacts with hepatocytes and can be used for differential diagnosis of hepatic tumors. Am J Pathol 143:1050–1054PubMedGoogle Scholar
- 39.Wu PC, Fang JW, Lau VK, Lai CL, Lo CK, Lau JY (1996) Classification of hepatocellular carcinoma according to hepatocellular and biliary differentiation markers. Clinical and biological implications. Am J Pathol 149:1167–1175PubMedGoogle Scholar
- 40.Xiao SY, Wang HL, Hart J, Fleming D, Beard MR (2001) cDNA arrays and immunohistochemistry identification of CD10/CALLA expression in hepatocellular carcinoma. Am J Pathol 159:1415–1421PubMedGoogle Scholar