Abstract
Background
A high serum cytokeratin 19 fragment (CYFRA21-1) concentration in patients with various cancers is associated with poor prognosis. This study aimed to establish the clinical significance of preoperative serum CYFRA21-1 in patients with intrahepatic cholangiocarcinoma.
Methods
CYFRA21-1, carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 concentrations were measured in sera from 71 patients with intrahepatic cholangiocarcinoma. The prognostic significance of serum CYFRA21-1 levels was assessed by univariate and multivariate analyses.
Results
Analysis of the areas under the receiver operator characteristic (ROC) curves clearly showed better discrimination between intrahepatic cholangiocarcinoma and benign liver diseases for CYFRA 21-1 than for CEA or CA 19-9. Based on the maximization of the Youden’s index, the optimal cut-off value was 2.7 ng ml−1 for CYFRA 21-1 (sensitivity, 74.7%; specificity, 92.2%). The serum CYFRA21-1 concentration was related to tumor stage, since the CYFRA21-1 concentrations varied according to tumor size, vascular invasion, and number of tumors. The 3-year recurrence-free survival rates for patients with high and low concentrations of CYFRA21-1 were 25.0% and 76.2%, respectively (log-rank test, p < 0.01). The 3-year overall survival rates for patients with high and low concentrations of CYFRA21-1 were 39.4% and 63.6%, respectively (p = 0.01). On multivariate analysis, a high concentration of CYFRA21-1, nodal metastases, and a microscopic resection margin involvement were independent prognostic factors associated with both tumor recurrence and postoperative death.
Conclusions
A high serum CYFRA21-1 concentration is associated with tumor progression and poor postoperative outcomes in patients with intrahepatic cholangiocarcinoma.
Similar content being viewed by others
Reference
Kobayashi M, Ikeda K, Saitoh S, et al. Incidence of primary cholangiocellular carcinoma of the liver in Japanese patients with hepatitis C virus-related cirrhosis. Cancer 2000; 88:2471–7
Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: A case-control study. Gastroenterology 2005; 128:620–6
Kawarada Y, Mizumoto R. Cholangiocellular carcinoma of the liver. Am J Surg 1984; 147:354–9
Kawarada Y, Mizumoto R. Diagnosis and treatment of cholangiocellular carcinoma of the liver. Hepatogastroenterology 1990; 37:176–81
Yamanaka N, Okamoto E, Ando T, et al. Clinicopathologic spectrum of resected extraductal mass-forming intrahepatic cholangiocarcinoma. Cancer 1995; 76:2449–56
Chu KM, Lai EC, Al-Hadeedi S, et al. Intrahepatic cholangiocarcinoma. World J Surg 1997; 21:301–6
Kim HJ, YunN SS, Jung KH, et al. Intrahepatic cholangiocarcinoma in Korea. J Hep Bil Pancr Surg 1999; 6:142–8
Uenishi T, Hirohashi K, Kubo S, et al. Clinicopathologic factors predicting outcome after resection of mass-forming intrahepatic cholangiocarcinoma. Br J Surg 2001; 88:969–74
Pujol JL, Grenier J, Daures JP, et al. Serum fragment of cytokeratin subunit 19 measured by CYFRA 21-1 immunoradiometric assay as a marker of lung cancer. Cancer Res 1993; 53:61–6
Sugama Y, Kitamura S, Kawai T, et al. Clinical usefulness of CYFRA assay in diagnosing lung cancer: measurement of serum cytokeratin fragment. Jpn J Cancer Res 1994; 85:1178–84
Takada M, Masuda N, Matsuura E, et al. Measurement of cytokeratin 19 fragments as a marker of lung cancer by CYFRA 21-1 enzyme immunoassay. Br J Cancer 1995; 71:160–5
Brechot JM, Chevret S, Nataf J, et al. Diagnostic and prognostic value of Cyfra 21-1 compared with other tumour markers in patients with non-small cell lung cancer: a prospective study of 116 patients. Eur J Cancer 1997; 33:385–91
Nisman B, Lafair J, Heching N, et al. Evaluation of tissue polypeptide specific antigen, CYFRA 21-1, and carcinoembryonic antigen in nonsmall cell lung carcinoma: does the combined use of cytokeratin markers give any additional information? Cancer 1998; 82:1850–9
Uenishi T, Kubo S, Hirohashi K, et al. Cytokeratin-19 fragments in serum (CYFRA 21-1) as a marker in primary liver cancer. Br J Cancer 2003; 88:1894–9
Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000; 127:498–505
Shirabe K, Shimada M, Harimoto N, et al. Intrahepatic cholangiocarcinoma: Its mode of spreading and therapeutic modalities. Surgery 2002; 131(1 Suppl):S159–64
Moro D, Villemain D, Vuillez JP, et al. CEA, CYFRA21-1 and SCC in non-small cell lung cancer. Lung Cancer 1995; 13:169–76
Takei Y, Minato K, Tsuchiya S, et al. CYFRA 21-1: an indicator of survival and therapeutic effect in lung cancer. Oncology 1997; 54:43–7
Pujol JL, Molinier O, Ebert W, et al. CYFRA 21-1 is a prognostic determinant in non-small-cell lung cancer: results of a meta-analysis in 2063 patients. Br J Cancer 2004; 90:2097–105
Mizuguchi S, Nishiyama N, Iwata T, et al. Clinical value of serum cytokeratin 19 fragment and sialyl-Lewis x in non-small cell lung cancer. Ann Thorac Surg 2007; 83:216–21
Doweck I, Barak M, Uri N, et al. The prognostic value of the tumour marker Cyfra 21-1 in carcinoma of head and neck and its role in early detection of recurrent disease. Br J Cancer 2000; 83:1696–701
Brockmann JG, St Nottberg H, Glodny B, et al. CYFRA 21-1 serum analysis in patients with esophageal cancer. Clin Cancer Res 2000; 6:4249–52
Shimada H, Nabeya Y, Okazumi S, et al. Prognostic significance of CYFRA 21-1 in patients with esophageal squamous cell carcinoma. J Am Coll Surg 2003; 196:573–8
Nakata B, Takashima T, Ogawa Y, et al. Serum CYFRA 21-1 (cytokeratin-19 fragments) is a useful tumour marker for detecting disease relapse and assessing treatment efficacy in breast cancer. Br J Cancer 2004; 91:873–8
Nakata B, Chung YS, Kato Y, et al. Clinical significance of serum CYFRA 21-1 in gastric cancer. Br J Cancer 1996; 73:1529–32
Sobin LH, Wittekind CH. TNM classification of malignant tumors, Fifth edition. New York: Wiley-Liss, 1997
Metz CE, Herman BA, Roe CA. Statistical comparison of two ROC-curve estimates obtained from partially-paired datasets. Med Decis Making 1998; 18:110–21
Youden WJ. Index for rating diagnostic tests. Cancer 1950; 3:32–5
Loyer EM, Chin H, DuBrow RA, et al. Hepatocellular carcinoma and intrahepatic peripheral cholangiocarcinoma: enhancement patterns with quadruple phase helical CT-a comparative study. Radiology 1999; 212:866–75
Iwata Y, Shiomi S, Sasaki N, et al. Clinical usefulness of positron emission tomography with fluorine-18-fluorodeoxyglucose in the diagnosis of liver tumors. Ann Nucl Med 2000; 14:121–6
Jadvar H, Henderson RW, Conti PS. [F-18] fluorodeoxyglucose positron emission tomography and positron emission tomography: computed tomography in recurrent and metastatic cholangiocarcinoma. J Comput Assist Tomogr 2007; 31:223–8
Harrison LE, Fong Y, Klimstra DS, et al. Surgical treatment of 32 patients with peripheral intrahepatic cholangiocarcinoma. Br J Surg 1998; 85:1068–70
Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998; 28:921–5
Yamamoto S, Kubo S, Hai S, et al. Hepatitis C virus infection as a likely etiology of intrahepatic cholangiocarcinoma. Cancer Sci 2004; 95:592–5
Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg 2002; 89:1525–31
Madariaga JR, Iwatsuki S, Todo S, et al. Liver resection for hilar and peripheral cholangiocarcinoma: A study of 62 cases. Ann Surg 1998; 227:70–9
Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997; 185:429–36
Kawarada Y, Yamagiwa K, Das BC. Analysis of the relationships between clinicopathologic factors and survival time in intrahepatic cholangiocarcinoma. Am J Surg 2002; 183:679–85
Shimada M, Yamashita Y, Aishima S, et al. Value of lymph node dissection during resection of intrahepatic cholangiocarcinoma. Br J Surg 2001; 88:1463–6
Nakagawa T, Kamiyama T, Kurauchi N, et al. Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma. World J Surg 2005; 29:728–33
Uenishi T, Yamazaki O, Horii K, et al. A long-term survivor of intrahepatic cholangiocarcinoma with paraaortic lymph node metastasis. J Gastroenterol 2006; 41:391–2
Murakami Y, Yokoyama T, Takesue Y, et al. (2000) Long-term survival of peripheral intrahepatic cholangiocarcinoma with metastases to the para-aortic lymph nodes. Surgery 2000; 127:105–6
Stathopoulos EN, Sanidas E, Kafousi M, et al. Detection of CK-19 mRNA-positive cells in the peripheral blood of breast cancer patients with histologically and immunohistochemically negative axillary lymph nodes. Ann Oncol 2005; 16:240–6
Chen TF, Jiang GL, Fu XL, et al. CK19 mRNA expression measured by reverse-transcription polymerase chain reaction (RT-PCR) in the peripheral blood of patients with non-small cell lung cancer treated by chemo-radiation: an independent prognostic factor. Lung Cancer 2007; 56:105–14
Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol 2004; 15:1339–43
Cho JY, Paik YH, Chang YS, et al. Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer 2005; 104:2753–8
Kim ST, Park JO, Lee J, et al. A phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer 2006; 106:1339–46
Hsu C, Shen YC, Yang CH, et al. Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer 2004; 90:1715–9
Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96:896–902
Nakeeb A, Tran KQ, Black MJ, et al. Improved survival in resected biliary malignancies. Surgery 2002; 132:555–64
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Uenishi, T., Yamazaki, O., Tanaka, H. et al. Serum Cytokeratin 19 Fragment (CYFRA21-1) as a Prognostic Factor in Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 15, 583–589 (2008). https://doi.org/10.1245/s10434-007-9650-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-007-9650-y