Skip to main content
PMC home page
Journal of Clinical and Experimental Hepatology logoLink to Journal of Clinical and Experimental Hepatology
. 2011 Aug 26;1(1):6–12. doi: 10.1016/S0973-6883(11)60110-2

Circulating CYFRA 21-1 is a Specific Diagnostic and Prognostic Biomarker in Biliary Tract Cancer

Michael H Chapman *,†, Neomal S Sandanayake *,†, Fausto Andreola *, Dipok K Dhar *, George J Webster *,†, James S Dooley *, Stephen P Pereira †,*
PMCID: PMC3252025  NIHMSID: NIHMS335491  PMID: 22228935

Abstract

Background

Biliary tract cancer (BTC) has a poor prognosis, in part related to difficulties in diagnosis. Cytokeratin 19 (CK19) is a constituent of the intermediate filament proteins of epithelial cells. CK19 fragments (CYFRA 21-1) are rarely identified in the blood of healthy individuals. We assessed the utility of CYFRA 21-1 as a diagnostic and prognostic marker of BTC.

Methods

Blood was prospectively collected from patients with benign biliary disease (n = 39), primary sclerosing cholangitis (n = 19), PSC-related cholangiocarcinoma (n = 6) and sporadic BTC (n = 60). CYFRA 21-1 levels were measured in duplicate by ELISA.

Results

CYFRA 21-1 (≤1.5 ng/mL) had a sensitivity of 56% and specificity of 88%, compared with figures of 79% and 78% for CA 19-9 (≤37 U/mL). Using a higher cut-off of 3 ng/mL, CYFRA 21-1 had a sensitivity of 30% and specificity of 97%. Combination of CYFRA 21-1 (≤1.5 ng/mL) and CA 19-9 (≤37 U/mL) resulted in sensitivity and specificity of 45% and 96%. In contrast to CA 19-9, CYFRA 21-1 (≤3.0 ng/mL) alone was a strong predictor of prognosis (median survival 2 months vs 10 months, p = 0.001).

Conclusion

Elevated circulating CYFRA 21-1 is a specific, but less sensitive diagnostic marker than CA 19-9, predicts a poor outcome and may act as a surrogate marker of circulating tumor cells in BTC. Further prospective studies of its utility in assessing operability and response to chemotherapy are needed.

Keywords: Biliary tract cancer, CA 19-9, CYFRA 21-1, primary sclerosing cholangitis

Abbreviations: BTC, biliary tract cancer; CA 19-9, carbohydrate antigen 19-9; CC, cholangiocarcinoma; CK19, cytokeratin 19; CYFRA 21-1, cytokeratin-19 fragments; ELISA, enzyme linked immunosorbent assay; ERCP, endoscopic retrograde cholangiopancreatography; PSC, primary sclerosing cholangitis

Full Text

The Full Text of this article is available as a PDF (126.0 KB).

References

  • 1.Bergquist A, Ekbom A, Olsson R. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36:321–327. doi: 10.1016/s0168-8278(01)00288-4. [DOI] [PubMed] [Google Scholar]
  • 2.Chalasani N, Baluyut A, Ismail A. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology. 2000;31:7–11. doi: 10.1002/hep.510310103. [DOI] [PubMed] [Google Scholar]
  • 3.Fisher A, Theise ND, Min A. CA 19-9 does not predict cholangiocarcinoma in patients with primary sclerosing cholangitis undergoing liver transplantation. Liver Transpl Surg. 1995;1:94–98. doi: 10.1002/lt.500010204. [DOI] [PubMed] [Google Scholar]
  • 4.Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ. The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol. 2000;95:204–207. doi: 10.1111/j.1572-0241.2000.01685.x. [DOI] [PubMed] [Google Scholar]
  • 5.Siqueira E, Schoen RE, Silverman W. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointest Endose. 2002;56:40–47. doi: 10.1067/mge.2002.125105. [DOI] [PubMed] [Google Scholar]
  • 6.Lindberg B, Amelo U, Bergquist A. Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis. Endoscopy. 2002;34:909–916. doi: 10.1055/s-2002-35298. [DOI] [PubMed] [Google Scholar]
  • 7.Mann DV, Edwards R, Ho S, Lau WY, Glazer G. Elevated tumor marker CA 19-9: clinical interpretation and influence of obstructive jaundice. Eur J Surg Oncol. 2000;26:474–479. doi: 10.1053/ejso.1999.0925. [DOI] [PubMed] [Google Scholar]
  • 8.Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005;50:1734–1740. doi: 10.1007/s10620-005-2927-8. [DOI] [PubMed] [Google Scholar]
  • 9.Nagrath S, Sequist LV, Maheswaran S. Isolation of rare circulating tumor cells in cancer patients by microchip technology. Nature. 2007;450:1235–1239. doi: 10.1038/nature06385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Ntouroupi TG, Ashraf SQ, McGregor SB. Detection of circulating tumor cells in peripheral blood with an automated scanning fluorescence microscope. Br J Cancer. 2008;99:789–795. doi: 10.1038/sj.bjc.6604545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Maeda T, Kajiyama K, Adachi E, Takenaka K, Sugimachi K, Tsuneyoshi M. The expression of cytokeratins 7, 19, and 20 in primary and metastatic carcinomas of the liver. Mod Pathol. 1996;9:901–909. [PubMed] [Google Scholar]
  • 12.Takada M, Masuda N, Matsuura E. Measurement of cytokeratin 19 fragments as a marker of lung cancer by CYFRA 21-1 enzyme immunoassay. Br J Cancer. 1995;71:160–165. doi: 10.1038/bjc.1995.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Brechot JM, Chevret S, Nataf J. Diagnostic and prognostic value of CYFRA 21-1 compared with other tumor markers in patients with non-small cell lung cancer: a prospective study of 116 patients. Eur J Cancer. 1997;33:385–391. [PubMed] [Google Scholar]
  • 14.Andreadis C, Touloupidis S, Galaktidou G, Kortsaris AH, Boutis A, Mouratidou D. Serum CYFRA 21-1 in patients with invasive bladder cancer and its relevance as a tumor marker during chemotherapy. J Urol. 2005;174:1771–1775. doi: 10.1097/01.ju.0000176742.53556.25. discussion 1775-6. [DOI] [PubMed] [Google Scholar]
  • 15.Nakata B, Takashima T, Ogawa Y, Ishikawa T, Hirakawa K. Serum CYFRA 21-1 (cytokeratin-19 fragments) is a useful tumor marker for detecting disease relapse and assessing treatment efficacy in breast cancer. Br J Cancer. 2004;91:873–878. doi: 10.1038/sj.bjc.6602074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Nakata B, Chung YS, Kato Y. Clinical significance of serum CYFRA 21-1 in gastric cancer. Br J Cancer. 1996;73:1529–1532. doi: 10.1038/bjc.1996.288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Pujol JL, Molinier O, Ebert W. 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;90:2097–2105. doi: 10.1038/sj.bjc.6601851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kashihara T, Ohki A, Kobayashi T. Intrahepatic cholangiocarcinoma with increased serum CYFRA 21-1 level. J Gastroenterol. 1998;33:447–453. doi: 10.1007/s005350050112. [DOI] [PubMed] [Google Scholar]
  • 19.Uenishi T, Yamazaki O, Tanaka H. Serum cytokeratin 19 fragment (CYFRA 21-1) as a prognostic factor in intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2008;15:583–589. doi: 10.1245/s10434-007-9650-y. [DOI] [PubMed] [Google Scholar]
  • 20.Chapman RW, Arborgh BA, Rhodes JM. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut. 1980;21:870–877. doi: 10.1136/gut.21.10.870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Moreno Luna LE, Gores GJ. Advances in the diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis. Liver Transpl. 2006;12(Suppl 2):S15–S19. doi: 10.1002/lt.20938. [DOI] [PubMed] [Google Scholar]
  • 22.Tischendorf JJ, Kruger M, Trautwein C. Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Endoscopy. 2006;38:665–669. doi: 10.1055/s-2006-925257. [DOI] [PubMed] [Google Scholar]
  • 23.de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341:1368–1378. doi: 10.1056/NEJM199910283411807. [DOI] [PubMed] [Google Scholar]
  • 24.Jarnagin WR, Fong Y, DeMatteo RP. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234:507–517. doi: 10.1097/00000658-200110000-00010. discussion 517-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Farley DR, Weaver AL, Nagorney DM. “Natural history” of unresected cholangiocarcinoma: patient outcome after noncurative intervention. Mayo Clin Proc. 1995;70:425–429. doi: 10.4065/70.5.425. [DOI] [PubMed] [Google Scholar]
  • 26.Ito F, Agni R, Rettammel RJ. Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence. Ann Surg. 2008;248:273–279. doi: 10.1097/SLA.0b013e31817f2bfd. [DOI] [PubMed] [Google Scholar]
  • 27.Charatcharoenwitthaya P, Enders FB, Hailing KC, Lindor KD. Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology. 2008;48:1106–1117. doi: 10.1002/hep.22441. [DOI] [PubMed] [Google Scholar]
  • 28.Liu L, Liao GQ, He P. Detection of circulating cancer cells in lung cancer patients with a panel of marker genes. Biochem Biophys Res Commun. 2008;372:756–760. doi: 10.1016/j.bbrc.2008.05.101. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical and Experimental Hepatology are provided here courtesy of Elsevier

RESOURCES