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Endoscopy 2009; 41(11): 965-970
DOI: 10.1055/s-0029-1215227
Original article

© Georg Thieme Verlag KG Stuttgart · New York

Staining for intracytoplasmic lumina and CAM5.2 increases the detection rate for bile duct cancers

A.  W.  Jahng1 , D.  Chung2 , B.  Pham2 , S.  Reicher2 , B.  Yee3 , L.  Abramyan3 , R.  Venegas3 , S.  French3 , V.  E.  Eysselein2
  • 1Department of Internal Medicine, Harbor-UCLA Medical Center, Torrance, California, USA
  • 2Division of Gastroenterology, Harbor-UCLA Medical Center, Torrance, California, USA
  • 3Department of Pathology, Harbor-UCLA Medical Center, Torrance, California, USA
Further Information

Publication History

submitted 3 December 2008

accepted after revision 5 August 2009

Publication Date:
28 October 2009 (online)

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Commentaire de travail de A. W. Jahng et al., pp. 965Endoscopy 2009; 41(11): 1009-1009
DOI: 10.1055/s-0032-1306756

Background and study aims: Endoscopic biopsies have a low sensitivity for diagnosing malignant bile duct strictures. Tumor markers detected by mucin staining and immunohistochemistry may help to determine the malignancy of a biopsy specimen where histologic evaluation alone is nondiagnostic.

Patients and methods: 61 patients who underwent forceps biopsies were retrospectively identified, yielding 49 and 40 biopsy specimens for strictures finally diagnosed as benign and malignant, respectively. Biopsy specimens were histologically evaluated and stained for p53, Ki-67, carcinoembryonic antigen (CEA), CA19-9, CAM5.2, and presence of intracytoplasmic lumina (ICL). Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (PLR and NLR) were calculated to evaluate the performance of each test.

Results: Histology alone provided sensitivity and specificity of 53 % and 100 %. Addition of ICL or CAM5.2 increased sensitivity to 73 % or 60 %, respectively, and provided excellent specificity, PPV, and PLR (ICL, 98 %, 97 %, and 36; CAM5.2, 100 %, 100 %, and infinite). Both stains in combination increased the sensitivity to 75 %. Staining for Ki-67, p53, CEA, and CA19-9 increased the sensitivity to detect malignancy (range 60 % to 83 %), but significantly reduced the specificity, PPV and PLR (ranges 73 % to 90 %, 72 % to 86 %, and 3 to 7, respectively). Markers in all combinations performed poorly as a negative test (NPV 69 % to 87 %, and NLR 0.19 to 0.55).

Conclusions: Staining for tumor markers ICL and CAM5.2 can improve the diagnostic value of endoscopic biopsies, and may change the course of management for patients with indeterminate histological findings.

References

  • 1 Kubota Y, Takaoka M, Tani K. et al . Endoscopic transpapillary biopsy for diagnosis of patients with pancreaticobiliary ductal strictures.  Am J Gastroenterol. 1993;  88 1700-1704
    PubMedGoogle Scholar
  • 2 Domagk D, Poremba C, Dietl K H. et al . Endoscopic transpapillary biopsies and intraductal ultrasonography in the diagnostics of bile duct strictures: a prospective study.  Gut. 2002;  51 240-244
    CrossrefPubMedGoogle Scholar
  • 3 Sugiyama M, Atomi Y, Wada N. et al . Endoscopic transpapillary bile duct biopsy without sphincterotomy for diagnosing biliary strictures: a prospective comparative study with bile and brush cytology.  Am J Gastroenterol. 1996;  91 465-467
    PubMedGoogle Scholar
  • 4 Rösch T, Hofrichter K, Frimberger E. et al . ERCP or EUS for tissue diagnosis of biliary strictures? A prospective comparative study.  Gastrointest Endosc. 2004;  60 390-396
    CrossrefPubMedGoogle Scholar
  • 5 Pugliese V, Conio M, Nicolò G. et al . Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: a prospective study.  Gastrointest Endosc. 1995;  42 520-526
    CrossrefPubMedGoogle Scholar
  • 6 Schoefl R, Haefner M, Wrba F. et al . Forceps biopsy and brush cytology during endoscopic retrograde cholangiopancreatography for the diagnosis of biliary stenoses.  Scand J Gastroenterol. 1997;  32 363-368
    PubMedGoogle Scholar
  • 7 Ponchon T, Gagnon P, Berger F. et al . Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study.  Gastrointest Endosc. 1995;  42 565-572
    CrossrefPubMedGoogle Scholar
  • 8 Jailwala J, Fogel E L, Sherman S. et al . Triple-tissue sampling at ERCP in malignant biliary obstruction.  Gastrointest Endosc. 2000;  51 383-390
    PubMedGoogle Scholar
  • 9 Kitajima Y, Ohara H, Nakazawa T. et al . Usefulness of transpapillary bile duct brushing cytology and forceps biopsy for improved diagnosis in patients with biliary strictures.  J Gastroenterol Hepatol. 2007;  22 1615-1620
    CrossrefPubMedGoogle Scholar
  • 10 Weber A, von Weyhern C, Fend F. et al . Endoscopic transpapillary brush cytology and forceps biopsy in patients with hilar cholangiocarcinoma.  World J Gastroenterol. 2008 (Feb 21);  14 1097-1101
    CrossrefPubMedGoogle Scholar
  • 11 Vergara I A, Norambuena T, Ferrada E. et al . StAR: a simple tool for the statistical comparison of ROC curves.  BMC Bioinformatics. 2008;  9 265
    CrossrefPubMedGoogle Scholar
  • 12 Eng J. ROC analysis: web-based calculator for ROC curves. Baltimore; Johns Hopkins University Available from: http://www.jrocfit.org; Publication date: Sep 11 2007; cited Feb. & March 2009
    Google Scholar
  • 13 Perkins N J, Schisterman E F. The inconsistency of ”optimal” cutoff points obtained using two criteria based on the receiver operating characteristic curve.  Am J Epidemiol. 2006;  163 670-675
    CrossrefPubMedGoogle Scholar
  • 14 Ramage J K, Donaghy A, Farrant J M. et al . Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis.  Gastroenterology. 1995;  108 865-869
    CrossrefPubMedGoogle Scholar
  • 15 Brugge W R. Endoscopic techniques to diagnose and manage biliary tumors.  J Clin Oncol. 2005;  23 4561-4565
    CrossrefPubMedGoogle Scholar
  • 16 Patel T, Singh P. Cholangiocarcinoma: emerging approaches to a challenging cancer.  Curr Opin Gastroenterol. 2007;  23 317-323
    CrossrefPubMedGoogle Scholar
  • 17 Weber A, Schmid R M, Prinz C. Diagnostic approaches for cholangiocarcinoma.  World J Gastroenterol. 2008;  14 4131-4136
    CrossrefPubMedGoogle Scholar
  • 18 Remy L. The intracellular lumen: origin, role and implications of a cytoplasmic neostructure.  Biol Cell. 1986;  56 97-105
    PubMedGoogle Scholar
  • 19 Nakajima T, Kondo Y. Well-differentiated cholangiocarcinoma: diagnostic significance of morphologic and immunohistochemical parameters.  Am J Surg Pathol. 1989;  13 569-573
    CrossrefPubMedGoogle Scholar
  • 20 Quincey C, Raitt N, Bell J, Ellis I O. Intracytoplasmic lumen – a useful diagnostic feature of adenocarcinomas.  Histopathology. 1991;  19 83-87
    CrossrefPubMedGoogle Scholar
  • 21 Battifora H. Intracytoplasmic lumen in breast carcinoma: a helpful histopathologic feature.  Arch Pathol. 1975;  99 614-617
    PubMedGoogle Scholar
  • 22 O’Donnell M, al-Nafussi A I. Intracytoplasmic lumen and mucinous inclusions in ovarian carcinomas.  Histopathology. 1995;  26 181-184
    CrossrefPubMedGoogle Scholar
  • 23 Lau S K, Prakash S, Geller S A, Alsabeh R. Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma.  Hum Pathol. 2002;  33 1175-1181
    CrossrefPubMedGoogle Scholar
  • 24 Van Eyken P, Sciot R, van Damme B. et al . Keratin immunohistochemistry in normal human liver. Cytokeratin pattern of hepatocytes, bile ducts and acinar gradient.  Virchows Arch A Pathol Anat Histopathol. 1987;  412 63-72
    CrossrefPubMedGoogle Scholar
  • 25 Tan G, Yilmaz A, De Young B R. et al . Immunohistochemical analysis of biliary tract lesions.  Appl Immunohistochem Mol Morphol. 2004;  12 193-197
    PubMedGoogle Scholar
  • 26 Ponsioen C Y, Vrouenraets S M, van Milligen de Wit A W. et al . Value of brush cytology for dominant strictures in primary sclerosing cholangitis.  Endoscopy. 1999;  31 305-309
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Stewart C J, Burke G M. Value of p53 immunostaining in pancreatico-biliary brush cytology specimens.  Diagn Cytopathol. 2000;  23 308-313
    CrossrefPubMedGoogle Scholar
  • 28 Bergquist A, Glaumann H, Stål P. et al . Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma.  J Intern Med. 2001;  249 69-75
    CrossrefPubMedGoogle Scholar
  • 29 Kaplan I, Vered M, Moskona D. et al . An immunohistochemical study of p53 and PCNA in inflammatory papillary hyperplasia of the palate: a dilemma of interpretation.  Oral Dis. 1998;  4 194-199
    CrossrefPubMedGoogle Scholar
  • 30 Krishna M, Woda B, Savas L. et al . Expression of p53 antigen in inflamed and regenerated mucosa in ulcerative colitis and Crohn’s disease.  Mod Pathol. 1995;  8 654-657
    PubMedGoogle Scholar
  • 31 Da Rocha A O, Coutinho L M, Scholl J G, Leboutte L D. The value of p53 protein expression in gallbladder carcinoma: analysis of 60 cases.  Hepatogastroenterology. 2004;  51 1310-1314
    PubMedGoogle Scholar
  • 32 Khurana K K, Ramzy I, Truong L D. p53 immunolocalization in cell block preparations of squamous lesions of the neck: an adjunct to fine-needle aspiration diagnosis of malignancy.  Arch Pathol Lab Med. 1999;  123 421-425
    PubMedGoogle Scholar
  • 33 Gansauge S, Schmid R M, Muller J. et al . Genetic alterations in chronic pancreatitis: evidence for early occurrence of p53 but not K-ras mutations.  Br J Surg. 1998;  85 337-340
    CrossrefPubMedGoogle Scholar
  • 34 Maxwell P, Davis R I, Sloan J M. Carcinoembryonic antigen (CEA) in benign and malignant epithelium of the gall bladder, extrahepatic bile ducts, and ampulla of Vater.  J Pathol. 1993;  170 73-76
    CrossrefPubMedGoogle Scholar
  • 35 Davis R I, Sloan J M, Hood J M, Maxwell P. Carcinoma of the extrahepatic biliary tract: a clinicopathological and immunohistochemical study.  Histopathology. 1988;  12 623-631
    CrossrefPubMedGoogle Scholar
  • 36 Tsuji M, Kashihara T, Terada N, Mori H. An immunohistochemical study of hepatic atypical adenomatous hyperplasia, hepatocellular carcinoma, and cholangiocarcinoma with alpha-fetoprotein, carcinoembryonic antigen, CA19-9, epithelial membrane antigen, and cytokeratins 18 and 19.  Pathol Int. 1999;  49 310-317
    CrossrefPubMedGoogle Scholar
  • 37 Juntavee A, Sripa B, Pugkhem A. et al . Expression of sialyl Lewis(a) relates to poor prognosis in cholangiocarcinoma.  World J Gastroenterol. 2005;  11 249-254
    PubMedGoogle Scholar
  • 38 Levy M J, Baron T H, Clayton A C. et al . Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures.  Am J Gastroenterol. 2008;  103 1263-1273
    CrossrefPubMedGoogle Scholar
  • 39 Moreno Luna L E, Kipp B. et al . Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures.  Gastroenterology. 2006;  131 1064-1072
    CrossrefPubMedGoogle Scholar
  • 40 Euscher E D, Marsh Jr. W L, Lucas J G, Frankel W L. Histologic and immunohistochemical changes in the stented common bile duct.  Appl Immunohistochem Mol Morphol. 2007;  15 299-304
    PubMedGoogle Scholar

V. E. EysseleinMD 

David Geffen UCLA School of Medicine
Harbor-UCLA Medical Center

Torrance, CA 90509
USA

Fax: +1-310-212-7837

Email: veysselein@labiomed.org