The value of KRAS mutation testing with CEA for the diagnosis of pancreatic mucinous cysts

Background and aims: Pancreatic cyst fluid (PCF) CEA has been shown to be the most accurate preoperative test for detection of cystic mucinous neoplasms (CMNs). This study aimed to assess the added value of PCF KRAS mutational analysis to CEA for diagnosis of CMNs.

Patients and methods: This is a retrospective study of prospectively collected endoscopic ultrasonography (EUS) fine-needle aspiration (FNA) data. KRAS mutation was determined by direct sequencing or equivalent methods. Cysts were classified histologically (surgical cohort) or by clinical (EUS or FNA) findings (clinical cohort). Performance characteristics of KRAS, CEA and their combination for detection of a cystic mucinous neoplasm (CMN) and malignancy were calculated.

Results: The study cohort consisted of 943 patients: 147 in the surgical cohort and 796 in the clinical cohort. Overall, KRAS and CEA each had high specificity (100 % and 93.2 %), but low sensitivity (48.3 % and 56.3 %) for the diagnosis of a CMN. The positivity of KRAS or CEA increased the diagnostic accuracy (80.8 %) and AUC (0.84) significantly compared to KRAS (65.3 % and 0.74) or CEA (65.8 % and 0.74) alone, but only in the clinical cohort (P < 0.0001 for both). KRAS mutation was significantly more frequent in malignant CMNs compared to histologically confirmed non-malignant CMNs (73 % vs. 37 %, P = 0.001). The negative predictive value of KRAS mutation was 77.6 % in differentiating non-malignant cysts.

Conclusions: The detection of a KRAS mutation in PCF is a highly specific test for mucinous cysts. It outperforms CEA for sensitivity in mucinous cyst diagnosis, but the data does not support its routine use.

• References

• 1 Mortele KJ. Cystic pancreatic neoplasms: imaging features and management strategy. Semin Roentgenol 2013; 48: 253-263
• 2 Brugge WR. The use of EUS to diagnose cystic neoplasms of the pancreas. Gastrointest Endosc 2009; 69: 203-209
• 3 Pitman MB, Lewandrowski K, Shen J et al. Pancreatic cysts: preoperative diagnosis and clinical management. Cancer Cytopathol 2010; 118: 1-13
• 4 Rogart JN, Loren DE, Singu BS et al. Cyst wall puncture and aspiration during EUS-guided fine needle aspiration may increase the diagnostic yield of mucinous cysts of the pancreas. J Clin Gastroenterol 2011; 45: 164-169
• 5 de Jong K, van Hooft JE, Nio CY et al. Accuracy of preoperative workup in a prospective series of surgically resected cystic pancreatic lesions. Scand J Gastroenterol 2012; 47: 1056-1063
• 6 Chai SM, Herba K, Kumarasinghe MP et al. Optimizing the multimodal approach to pancreatic cyst fluid diagnosis: developing a volume-based triage protocol. Cancer Cytopathol 2013; 121: 86-100
• 7 Khalid A, Zahid M, Finkelstein SD et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc 2009; 69: 1095-1102
• 8 Sawhney MS, Devarajan S, O'Farrel P et al. Comparison of carcinoembryonic antigen and molecular analysis in pancreatic cyst fluid. Gastrointest Endosc 2009; 69: 1106-1110
• 9 Talar-Wojnarowska R, Pazurek M, Durko L et al. A comparative analysis of K-ras mutation and carcinoembryonic antigen in pancreatic cyst fluid. Pancreatology 2012; 12: 417-420
• 10 Nikiforova MN, Khalid A, Fasanella KE et al. Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts. Mod Pathol 2013; 26: 1478-1487
• 11 Sreenarasimhaiah J, Lara LF, Jazrawi SF et al. A comparative analysis of pancreas cyst fluid CEA and histology with DNA mutational analysis in the detection of mucin producing or malignant cysts. JOP 2009; 10: 163-168
• 12 Bosman F. WHO classification of tumours of the digestive system. Lyon, France: IARC Press; 2010
• 13 Pitman MB, Centeno BA, Daglilar ES et al. Cytological criteria of high-grade epithelial atypia in the cyst fluid of pancreatic intraductal papillary mucinous neoplasms. Cancer Cytopathol 2014; 122: 40-47
• 14 Brugge WR, Lewandrowski K, Lee-Lewandrowski E et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004; 126: 1330-1336
• 15 Tanaka M, Chari S, Adsay V et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006; 6: 17-32
• 16 Tanaka M, Fernandez-del Castillo C, Adsay V et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012; 12: 183-197
• 17 Al-Haddad M, DeWitt J, Sherman S et al. Performance characteristics of molecular (DNA) analysis for the diagnosis of mucinous pancreatic cysts. Gastrointest Endosc 2014; 79: 79-87
• 18 Shen J, Brugge WR, Dimaio CJ et al. Molecular analysis of pancreatic cyst fluid: a comparative analysis with current practice of diagnosis. Cancer 2009; 117: 217-227
• 19 Thornton GD, McPhail MJ, Nayagam S et al. Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis. Pancreatology 2013; 13: 48-57
• 20 Khalid A, McGrath KM, Zahid M et al. The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol 2005; 3: 967-973
• 21 Rockacy MJ, Zahid M, McGrath KM et al. Association between KRAS mutation, detected in pancreatic cyst fluid, and long-term outcomes of patients. Clin Gastroenterol Hepatol 2013; 11: 425-429
• 22 Al-Haddad MA, Kowalski T, Siddiqui A et al. Integrated molecular pathology accurately determines the malignant potential of pancreatic cysts. Endoscopy 2015; 47: 136-142
• 23 Wu J, Matthaei H, Maitra A et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 2011; 3: 92ra66
• 24 Singhi AD, Nikiforova MN, Fasanella KE et al. Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clin Cancer Res 2014; 20: 4381-4389
• 25 Magnin S, Viel E, Baraquin A et al. A multiplex SNaPshot assay as a rapid method for detecting KRAS and BRAF mutations in advanced colorectal cancers. J Mol Diagn 2011; 13: 485-492
• 26 Anderson SM. Laboratory methods for KRAS mutation analysis. Expert Rev Mol Diagn 2011; 11: 635-642