Endoscopy 2009; 41(6): 552-557
DOI: 10.1055/s-0029-1214717
Original article

© Georg Thieme Verlag KG Stuttgart · New York

Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with KRAS mutation assay to distinguish pancreatic cancer from pseudotumoral chronic pancreatitis

B.  Bournet1 , A.  Souque1 , P.  Senesse2 , E.  Assenat2 , M.  Barthet3 , N.  Lesavre3 , A.  Aubert4 , D.  O'Toole4 , P.  Hammel4 , P.  Levy4 , P.  Ruszniewski4 , M.  Bouisson1 , J.  Escourrou1 , P.  Cordelier1 , L.  Buscail1
  • 1Department of Gastroenterology and INSERM U858, University of Toulouse, CHU Rangueil, Toulouse, France
  • 2Val d’Aurelle Center, Montpellier, France
  • 3Department of Gastroenterology and Centre d’Investigation Clinique, CHU Nord, Marseille, France
  • 4Department of Gastroenterology, Beaujon Hospital, Clichy, France
Further Information

Publication History

submitted 18 September 2008

accepted after revision 25 February 2009

Publication Date:
16 June 2009 (online)

Background and study aims: Differential diagnosis between pancreatic adenocarcinoma (PADC) and pseudotumoral forms of chronic pancreatitis remains difficult. Mutation of KRAS oncogene is present in 75 % to 95 % of PADC. This study aimed to evaluate whether the combined analysis of KRAS mutation with cytopathological findings from endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) might improve discrimination between PADC and chronic pancreatitis.

Patients and methods: This prospective multicenter study included 178 patients with solid pancreatic masses (men 104, women 74; mean age 64.5 years). Cytopathological examination and KRAS mutation analysis (codon-12 and codon-13, restriction fragment length polymorphism [RFLP] and direct sequencing) were performed on EUS-FNAB material. Final diagnoses were obtained on EUS-FNAB analysis and/or a second biopsy and/or clinical follow-up and/or surgery: PADC, n = 129; chronic pancreatitis, n = 27; other pancreatic neoplasms, n = 16; and benign lesions, n = 6.

Results: KRAS status analysis was successful in all EUS-FNAB samples. Codon-12 KRAS point mutation was found in 66 % of PADC samples. No case of chronic pancreatitis displayed KRAS mutation. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of cytopathology alone for diagnosis of PADC versus chronic pancreatitis were 83 %, 100 %, 100 %, 56 % and 86 %, respectively. When KRAS mutation analysis was combined with cytopathology, these values reached 88 %, 100 %, 100 %, 63 % and 90 % respectively.

Conclusion: Although the value of KRAS analysis in addition to EUS-FNAB is limited for distinguishing pancreatic mass lesions, when chronic pancreatitis presented as a pseudotumor a negative finding (wild-type KRAS), was useful in strongly suggesting a benign lesion.

References

  • 1 Warshaw A L, Fernandez del Castillo C. Pancreatic carcinoma.  N Eng J Med. 1992;  326 455-465
  • 2 Buscail L, Pagès P, Berthelémy P. et al . Role of EUS in the management of pancreatic and ampullary carcinoma: a prospective study assessing resectability and prognosis.  Gastrointest Endosc. 1999;  50 34-40
  • 3 Hahn S A, Schmiegel W H. Recent discoveries in cancer genetics of exocrine pancreatic neoplasia.  Digestion. 1998;  59 493-501
  • 4 Koorstra J BM, Hustinx S R, Offerhaus G JA. et al . Pancreatic carcinogenesis.  Pancreatology. 2008;  8 110-125
  • 5 Van Laethem J L, Vertongen P, Deviere J. et al . Detection of c-Ki-ras gene codon 12 mutations from pancreatic duct brushings in the diagnosis of pancreatic tumours.  Gut. 1995;  36 781-787
  • 6 Berthélemy P, Bouisson M, Escourrou J. et al . Identification of KRAS mutations in pancreatic juice in the early diagnosis of pancreatic cancer.  Ann Intern Med. 1995;  123 188-191
  • 7 Tascilar M, Caspers E, Sturm P D. et al . Role of tumor markers and mutations in cells and pancreatic juice in the diagnosis of pancreatic cancer.  Ann Oncol. 1999;  10 (Suppl 4) 107-410
  • 8 Costentin L, Pagès P, Bouisson M. et al . Frequent deletions of tumor suppressor genes in pure pancreatic juice from patients with tumoral or nontumoral pancreatic diseases.  Pancreatology. 2002;  2 17-25
  • 9 Varadarajulu S, Tamhane A, Eloubeidi M A. Yield of EUS-guided FNA of pancreatic masses in the presence or the absence of chronic pancreatitis.  Gastrointest Endosc. 2005;  62 728-736
  • 10 Fritscher-Ravens A, Brand L, Knöfel W T. et al . Comparison of endoscopic ultrasound-guided fine needle aspiration for focal pancreatic lesions in patients with normal parenchyma and chronic pancreatitis.  Am J Gastroenterol. 2002;  97 2768-2775
  • 11 Wiersema M J. Accuracy of endoscopic ultrasound in diagnosing and staging pancreatic carcinoma.  Pancreatology. 2001;  1 625-632
  • 12 Buscail L, Faure P, Bournet B. et al . Interventional endoscopic ultrasound in pancreatic diseases.  Pancreatology. 2006;  6 7-16
  • 13 Bhutani M S, Logroño R. Endoscopic ultrasound-guided fine-needle aspiration cytology for diagnosis above and below the diaphragm.  J Clin Ultrasound. 2005;  33 401-411
  • 14 Savides T J, Donohue M, Hunt G. et al . EUS-guided FNA diagnostic yield of malignancy in solid pancreatic masses: a benchmark for quality performance measurement.  Gastrointest Endosc. 2007;  66 277-282
  • 15 Tada M, Komatsu Y, Kawabe T. et al . Quantitative analysis of K-ras gene mutation in pancreatic tissue obtained by endoscopic ultrasonography-guided fine needle aspiration: clinical utility for diagnosis of pancreatic tumor.  Am J Gastroenterol. 2002;  97 2263-2270
  • 16 Takahashi K, Yamao K, Okubo K. et al . Differential diagnosis of pancreatic cancer and focal pancreatitis by using EUS-guided FNA.  Gastrointest Endosc. 2005;  61 76-79
  • 17 Khalid A, Nodit L, Zahid M. et al . Ultrasound fine needle aspirate DNA analysis to differentiate malignant and benign pancreatic masses.  Am J Gastroenterol. 2006;  101 2493-2500
  • 18 Maluf-Filho F, Kumar A, Gerhardt R. et al . Kras mutation analysis of fine needle aspirate under EUS guidance facilitates risk stratification of patients with pancreatic mass.  J Clin Gastroenterol. 2007;  41 906-910
  • 19 Bournet B, Migueres I, Delacroix M. et al . Early morbidity of endoscopic ultrasound: 13 year's experience at a referral center.  Endoscopy. 2006;  38 349-354
  • 20 Voss M, Hammel P, Molas G. et al . Value of endoscopic ultrasound guided fine needle aspiration biopsy in the diagnosis of solid pancreatic masses.  Gut. 2000;  46 244-249
  • 21 Jiang W, Kahn S M, Guillem J G. et al . Rapid detection of ras oncogenes in human tumors: applications to colon, esophageal, and gastric cancer.  Oncogene. 1989;  4 923-928
  • 22 Pellisé Uquiza M, Fernandez-Esparrach G, Solé M. et al . Endoscopic ultrasound-guided fine needle aspiration: predictive factors of accurate diagnosis and cost-minimization analysis of on-site pathologist.  Gastroenterol Hepatol. 2007;  30 319-324
  • 23 Klapman J B, Logrono R, Dye C E, Waxmann I. Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration.  Am J Gastroenterol. 2003;  98 1289-1294
  • 24 Janssen J, Schlörer E, Greiner L. EUS elastography of the pancreas: feasibility and pattern description of the normal pancreas, chronic pancreatitis and focal pancreatic lesions.  Gastrointest Endosc. 2007;  65 971-978
  • 25 Kitano M, Sakamoto H, Matsui U. et al . A novel perfusion imaging technique of the pancreas: contrast-enhanced harmonic EUS.  Gastrointest Endosc. 2008;  67 141-150
  • 26 Hirche T O, Ignee A, Barreiros A P. et al . indications and limitations of endoscopic ultrasound elastography for evaluation of focal pancreatic lesions.  Endoscopy. 2008;  40 910-917
  • 27 Löhr M, Klöppel G, Maisonneuve P. et al . Frequency of KRAS mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis.  Neoplasia. 2005;  7 17-723
  • 28 Orth M, Gansauge F, Gansauge S. et al . KRAS mutations at codon 12 are rare events in chronic pancreatitis.  Digestion. 1998;  59 120-124
  • 29 Löhr M, Maisonneuve P, Lowenfels A B. K-RAS mutations and benign pancreatic disease.  Int J Pancreatol. 2000;  27 93-103
  • 30 Arvanitakis M, Van Laethem J L, Parma J. et al . Predictive factors for pancreatic cancer in patients with chronic pancreatitis in association with K-ras gene mutation.  Endoscopy. 2004;  36 535-542
  • 31 Furuya N, Kawa S, Akamatsu T. et al . Long-term follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice.  Gastroenterology. 1997;  113 593-598

L. BuscailMD PhD 

Department of Gastroenterology
CHU Rangueil

1 avenue Jean Poulhès, TSA 50032
31059 Toulouse Cedex 9
France

Fax: +33-5-61323599

Email: Buscail.L@chu-toulouse.fr

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