J Clin Gastroenterol
Volume 49, Number 2, February 2015
REFERENCES 1. Hyun HJ, Shim JJ, Kim JW, et al. The prevalence of elevated alanine transaminase and its possible causes in the general Korean population. J Clin Gastroenterol. 2014;48:534–539. 2. Alanine Aminotransferase (ALT) (GPT), Serum: Mayo Medical Laboratories, USA. Available at: http://www.mayomedi callaboratories.com/test-catalog/Clinical + and + Interpretive/8362. Accessed June 19, 2014. 3. Park SH, Heo NY, Kim CH, et al. Upper reference limits for aminotransferase activities and the prevalence of elevated aminotransferase activities in a Korean population. J Clin Gastroenterol. 2013; 47:76–82. 4. Kim BK, Han KH, Ahn SH. “Normal” range of alanine aminotransferase levels for Asian population. J Gastroenterol Hepatol. 2011;26:219–220. 5. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342:1266–1271.
Role of K-ras Mutation Analysis in EUS-FNA Samples Obtained From Pancreatic Solid Mass To the Editor: Pathologic diagnosis based on endoscopic ultrasonography–guided fine needle aspiration (EUS-FNA) is occasionally inconclusive and can contradict a clinical conviction of pancreatic cancer (PC). Factors such as insufficient, very well differentiated, crushed, necrotic, or degenerated samples can be raised as the reasons for this difficulty. In such situations, objective findings of molecular assays may help us in diagnosis. Hence, I read with great interest the article by Bournet et al,1 who reported the effect of K-ras mutation assay for the differential diagnosis of pancreatic solid masses in 186 cases of EUS-FNA samples. K-ras mutation analysis compensated for 15% (73% to 88%) of the cases that had false-negative pathologic
The author declares that there is nothing to disclose.
Copyright
r
diagnosis. In addition, the negative predictive value and accuracy improved from 67% to 88% and 85% to 94%, respectively.1 Addition of K-ras analysis is thought to be beneficial from both financial and physical perspectives for the patients, as it can eliminate the need for a reexamination by EUS-FNA. These results and the conclusions drawn are excellent and support previous molecular pathologic studies.2–5 K-ras mutation is recognized in various pancreatic neoplasms, specifically those of ductal origin with mucous cell metaplasia,2–4 from the very early stage of pancreatic carcinogenesis, and in up to 90% of PC.2–4 In our previous study, we found a vast difference in the numbers of K-ras mutant epithelial foci between PC and mass-forming pancreatitis,5 which suggested a possible application to the FNA samples for their differential diagnosis. One concern was the possibility that small foci of pancreatic intraepithelial neoplasia2 or epithelial hyperplasia scattered in a massforming pancreatitis5 might give rise to false-positive results. From the recent meta-analyses,6 false-positive results were more often recognized by K-ras mutation assay than the pathologic diagnosis. However, in the study by Bournet et al,1 K-ras mutation was not recognized in any of 20 cases with chronic pancreatitis, but only in 1 case with low-grade intraductal papillary mucinous neoplasm. Presumable factors for null false-positive result were the sensitivity of K-ras mutation assay and disease type of selected benign group. Sensitivity of Taqman genotyping assay performed in this study was 10% of heterozygous allele,1 which was not supersensitive and supposed to be suitable for the tissue analysis. Usually, pancreatic intraepithelial neoplasia or mucus cell–type hyperplasia is less frequent in the mass-forming pancreatitis,5 unlike in the pancreas with ductectatic or cystic lesions. K-ras mutation is now proposed as a biomarker for the use of antiEGFR agents7 and as a prognostic marker8 of PC. Further studies must be performed to confirm these results. However, as in the patients with lung cancer9 and colorectal10 cancer, we must take advantage of K-ras mutation analysis aptly for the patients with PC. Acquisition of the histologic and/ or molecular evidence is crucial for contemporary medicine. Standardization of K-ras mutation analysis is expected for the clinical use in the samples from patients with PC.
2014 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor
Hiroyuki Matsubayashi, MD, PhD Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Shizuoka, Japan
REFERENCES 1. Bournet B, Selves J, Grand D, et al. Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with a KRAS mutation assay using allelic discrimination improves the diagnosis of pancreatic cancer. J Clin Gastroenterol. 2015;49:50–56. 2. Hruban RH, Maitra A, Goggins M. Update on pancreatic intraepithelial neoplasia. Int J Clin Exp Pathol. 2008; 1:306–316. 3. Moore PS, Orlandini S, Zamboni G, et al. Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer. 2001;84: 253–262. 4. Matsubayashi H, Watanabe H, Nishikura K, et al. Determination of pancreatic ductal carcinoma histogenesis by analysis of mucous quality and Kras mutation. Cancer. 1998;82:651–660. 5. Matsubayashi H, Watanabe H, Ajioka Y, et al. Different amounts of K-ras mutant epithelial cells in pancreatic carcinoma and mass-forming pancreatitis. Pancreas. 2000;21:77–85. 6. Fuccio L, Hassan C, Laterza L, et al. The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. Gastrointest Endosc. 2013;78: 596–608. 7. Heinemann V, Vehling-Kaiser U, Waldschmidt D, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013; 62:751–759. 8. Ogura T, Yamao K, Hara K, et al. Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. J Gastroenterol. 2013;48:640–646. 9. Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol. 2013;31: 1112–1121. 10. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to antiepidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091–2096.
www.jcge.com |
173
Volume 49, Number 2, February 2015
REFERENCES 1. Hyun HJ, Shim JJ, Kim JW, et al. The prevalence of elevated alanine transaminase and its possible causes in the general Korean population. J Clin Gastroenterol. 2014;48:534–539. 2. Alanine Aminotransferase (ALT) (GPT), Serum: Mayo Medical Laboratories, USA. Available at: http://www.mayomedi callaboratories.com/test-catalog/Clinical + and + Interpretive/8362. Accessed June 19, 2014. 3. Park SH, Heo NY, Kim CH, et al. Upper reference limits for aminotransferase activities and the prevalence of elevated aminotransferase activities in a Korean population. J Clin Gastroenterol. 2013; 47:76–82. 4. Kim BK, Han KH, Ahn SH. “Normal” range of alanine aminotransferase levels for Asian population. J Gastroenterol Hepatol. 2011;26:219–220. 5. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342:1266–1271.
Role of K-ras Mutation Analysis in EUS-FNA Samples Obtained From Pancreatic Solid Mass To the Editor: Pathologic diagnosis based on endoscopic ultrasonography–guided fine needle aspiration (EUS-FNA) is occasionally inconclusive and can contradict a clinical conviction of pancreatic cancer (PC). Factors such as insufficient, very well differentiated, crushed, necrotic, or degenerated samples can be raised as the reasons for this difficulty. In such situations, objective findings of molecular assays may help us in diagnosis. Hence, I read with great interest the article by Bournet et al,1 who reported the effect of K-ras mutation assay for the differential diagnosis of pancreatic solid masses in 186 cases of EUS-FNA samples. K-ras mutation analysis compensated for 15% (73% to 88%) of the cases that had false-negative pathologic
The author declares that there is nothing to disclose.
Copyright
r
diagnosis. In addition, the negative predictive value and accuracy improved from 67% to 88% and 85% to 94%, respectively.1 Addition of K-ras analysis is thought to be beneficial from both financial and physical perspectives for the patients, as it can eliminate the need for a reexamination by EUS-FNA. These results and the conclusions drawn are excellent and support previous molecular pathologic studies.2–5 K-ras mutation is recognized in various pancreatic neoplasms, specifically those of ductal origin with mucous cell metaplasia,2–4 from the very early stage of pancreatic carcinogenesis, and in up to 90% of PC.2–4 In our previous study, we found a vast difference in the numbers of K-ras mutant epithelial foci between PC and mass-forming pancreatitis,5 which suggested a possible application to the FNA samples for their differential diagnosis. One concern was the possibility that small foci of pancreatic intraepithelial neoplasia2 or epithelial hyperplasia scattered in a massforming pancreatitis5 might give rise to false-positive results. From the recent meta-analyses,6 false-positive results were more often recognized by K-ras mutation assay than the pathologic diagnosis. However, in the study by Bournet et al,1 K-ras mutation was not recognized in any of 20 cases with chronic pancreatitis, but only in 1 case with low-grade intraductal papillary mucinous neoplasm. Presumable factors for null false-positive result were the sensitivity of K-ras mutation assay and disease type of selected benign group. Sensitivity of Taqman genotyping assay performed in this study was 10% of heterozygous allele,1 which was not supersensitive and supposed to be suitable for the tissue analysis. Usually, pancreatic intraepithelial neoplasia or mucus cell–type hyperplasia is less frequent in the mass-forming pancreatitis,5 unlike in the pancreas with ductectatic or cystic lesions. K-ras mutation is now proposed as a biomarker for the use of antiEGFR agents7 and as a prognostic marker8 of PC. Further studies must be performed to confirm these results. However, as in the patients with lung cancer9 and colorectal10 cancer, we must take advantage of K-ras mutation analysis aptly for the patients with PC. Acquisition of the histologic and/ or molecular evidence is crucial for contemporary medicine. Standardization of K-ras mutation analysis is expected for the clinical use in the samples from patients with PC.
2014 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor
Hiroyuki Matsubayashi, MD, PhD Division of Endoscopy, Shizuoka Cancer Center, Suntogun, Shizuoka, Japan
REFERENCES 1. Bournet B, Selves J, Grand D, et al. Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with a KRAS mutation assay using allelic discrimination improves the diagnosis of pancreatic cancer. J Clin Gastroenterol. 2015;49:50–56. 2. Hruban RH, Maitra A, Goggins M. Update on pancreatic intraepithelial neoplasia. Int J Clin Exp Pathol. 2008; 1:306–316. 3. Moore PS, Orlandini S, Zamboni G, et al. Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer. 2001;84: 253–262. 4. Matsubayashi H, Watanabe H, Nishikura K, et al. Determination of pancreatic ductal carcinoma histogenesis by analysis of mucous quality and Kras mutation. Cancer. 1998;82:651–660. 5. Matsubayashi H, Watanabe H, Ajioka Y, et al. Different amounts of K-ras mutant epithelial cells in pancreatic carcinoma and mass-forming pancreatitis. Pancreas. 2000;21:77–85. 6. Fuccio L, Hassan C, Laterza L, et al. The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. Gastrointest Endosc. 2013;78: 596–608. 7. Heinemann V, Vehling-Kaiser U, Waldschmidt D, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013; 62:751–759. 8. Ogura T, Yamao K, Hara K, et al. Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. J Gastroenterol. 2013;48:640–646. 9. Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol. 2013;31: 1112–1121. 10. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to antiepidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091–2096.
www.jcge.com |
173
