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Election year fever? Voting on EUS criteria for chronic pancreatitis
EDITORIAL
Election year fever? Voting on EUS criteria for chronic pancreatitis Chronic pancreatitis is characterized by persistent inflammation associated with irreversible morphologic changes that typically cause pain and loss of exocrine and/ or endocrine function.1 As for most organ-based disorders, a histopathologic classification of the disease would be ideal. Obtaining tissue from the pancreas in a minimally invasive manner is challenging, however, because of the retroperitoneal location of the pancreas. As a consequence, multiple nontissue-based classification systems have been proposed as a basis for diagnosis, treatment, and research.2-4 In advanced disease, morphologic features can often be diagnostic of chronic pancreatitis. These can be appreciated by various methods, including radiography, CT, MRCP, and ERCP. However, these imaging modalities are suboptimal in detecting early and minimal change disease.1 EUS was first described as a method to detect chronic pancreatitis more than 20 years ago.5 EUS is promising compared with the other imaging modalities, because it potentially can detect earlier forms of chronic pancreatitis. Multiple studies were conducted to determine the diagnostic accuracy of EUS in chronic pancreatitis. These studies suffer, however, from a wide range of EUS-based criteria by using different criterion standards and by applying different thresholds of the number of criteria necessary to diagnose chronic pancreatitis. Other differing aspects of these studies include technique and type of echoendoscopes used, which has contributed to suboptimal interobserver variability.6-11 Collectively, these studies have not contributed in a meaningful way to our understanding of the natural history of the disease. Nor have they provided the treating gastroenterologist with a reliable measure of the activity or prognosis of the disease. In this issue of Gastrointestinal Endoscopy, Catalano et al12 propose a new consensus-based system of EUS criteria for chronic pancreatitis, designated the Rosemont classification. Thirty-two experienced endosonographers, along with a panel of 5 experts, reviewed existing data on EUS criteria for the diagnosis of chronic pancreatitis. After a review of the literature and an opportunity for discourse, each participant anonymously voted on the definitions, terminology, and perceived predictive value of parenchymal and ductal
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2008.09.024
1262 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 7 : 2009
features of chronic pancreatitis. Based on the voting, a rank order of major and minor criteria were created. A consensus, defined as a more than two thirds agreement among the participants, was required for inclusion of any criteria and its rank order of perceived accuracy. The final result was a classification system that stratifies the probability of chronic pancreatitis based on a combination of major and minor EUS findings. Major criteria included hyperechoic foci with shadowing, main pancreatic-duct calculi, and lobularity with honeycombing. Minor criteria included cysts, stranding, lobularity without honeycombing, hyperechoic
An ideal classification system of chronic pancreatitis will need to be durable over time for diagnosis, treatment, and clinical investigation.
foci without shadowing, irregular main pancreatic duct contour, dilated side branches, main pancreatic duct dilatation, and hyperechoic margins of the main pancreatic duct. Based on various combinations of major and minor features found in a patient, the Rosemont classification system categorizes the patient as having EUS features that are ‘‘consistent with chronic pancreatitis,’’ ‘‘suggestive of chronic pancreatitis,’’ ‘‘indeterminate for chronic pancreatitis,’’ and ‘‘normal.’’ Does the Rosemont classification system represent a significant and necessary step forward in the clinical investigation of EUS for chronic pancreatitis? By consensus, the investigators provided a common language to standardize EUS-based diagnosis and to guide future clinical investigation. If broadly accepted into clinical practice, then the probability of identifying a homogeneous cohort of patients with early chronic pancreatitis is improved. Such cohorts are particularly important to identify, because there are currently no reliable diagnostic tests for early forms of the disease.13 This can lead to evaluation of therapies that might arrest chronic inflammation and, therefore, modify the natural history of the disease. There are some aspects to this classification that warrant further consideration. After an extensive review of the literature among the 32 participants, the investigators reported a very good interobserver variability (kappa O 0.7) for each www.giejournal.org
Park & Van Dam
feature. Because of inherent bias arising from participating in the consensus conference, it would be more helpful and meaningful to validate the interobserver variability in another group of practicing endosonographers. This can be critical, particularly when interpreting EUS features, such as lobularity with and without honeycombing. This relatively new concept of lobularity with honeycombing, defines contiguous lobularity of O3 lobules as a major feature and!3 lobules (no honeycombing) as a minor feature. According to this classification, a subtle difference in interpretation then can lead to a very different conclusion. An ideal classification system will be durable over time for diagnosis, treatment, and clinical investigation. This classification system will likely evolve as EUS technology continues to improve and further understanding of the impact of various clinical variables on EUS morphology develops. As an example, Yusoff and Sahai14 identified male sex as an independent predictor of having more than 5 EUS features consistent with chronic pancreatitis, even though male sex is not an established independent risk factor for pancreatic disease. At the time, the investigators correctly chose not to incorporate adjustments for various clinical variables based on a lack of stronger evidence. However, because further research may identify clinical factors that may affect the diagnostic accuracy of EUS criteria, appropriate revisions to the classification system are likely. The more likely a classification changes, the less value it has as an instrument for clinical investigation. Where do we go from here? The next step is to validate this classification. Ideally, a validation study should compare the classification’s performance with a tissue diagnosis. On histologic examination, chronic pancreatitis shows features of chronic inflammation, fibrosis, and atrophy. These findings are widely accepted as definitive. However, pancreatic-tissue acquisition has remained a formidable limitation for the majority of diagnostic investigations of chronic pancreatitis. Tissue diagnosis is also neither 100% sensitive nor specific. Chronic pancreatitis can be focal and patchy, and previously published autopsy studies demonstrated fibrosis and atrophy in elderly asymptomatic patients not diagnosed with chronic pancreatitis.15,16 Despite being less than the perfect criterion standard, it remains the best to date. If the proper prospective study was performed on a cohort of clinically suspected chronic pancreatitis and control groups, and EUS criteria proved to correlate well with histology, then perhaps it could become a minimally invasive standard for the diagnosis of chronic pancreatitis. The investigators are to be congratulated for their efforts in advancing the field of this difficult disease. The Rosemont classification begins to define a common language of EUS imaging characteristics of chronic pancreatitis. By creating a basis for classifying the level of disease activity, the investigators provided a framework to start to study both the natural history of chronic pancreatitis and potentially the response to treatments in a useful way. www.giejournal.org
Editorial
DISCLOSURE All authors disclosed no financial relationships relevant to this publication. Walter G. Park, MD Jacques Van Dam, MD, PhD Division of Gastroenterology Department of Medicine Stanford University Medical Center Stanford, California, USA
REFERENCES 1. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682-707. 2. Singer MV, Gyr K, Sarles H. Revised classification of pancreatitis. Report of the Second International Symposium on the Classification of Pancreatitis in Marseille, France, March 28-30, 1984. Gastroenterology 1985;89:683-5. 3. Sarles H, Adler G, Dani R, et al. The pancreatitis classification of Marseilles-Rome 1988. Scand J Gastroenterol 1989;24:641-2. 4. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756-9. 5. Sivak MV, Kaufman A. Endoscopic ultrasonography in the differential diagnosis of pancreatic disease. A preliminary report. Scand J Gastroenterol Suppl 1986;123:130-4. 6. Chong AK, Hawes RH, Hoffman BJ, et al. Diagnostic performance of EUS for chronic pancreatitis: a comparison with histopathology. Gastrointest Endosc 2007;65:808-14. 7. Sahai AV, Zimmerman M, Aabakken L, et al. Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc 1998;48:18-25. 8. Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;48:11-7. 9. Kahl S, Glasbrenner B, Leodolter A, et al. EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study. Gastrointest Endosc 2002;55:507-11. 10. Conwell DL, Zuccaro G, Purich E, et al. Comparison of endoscopic ultrasound chronic pancreatitis criteria to the endoscopic secretinstimulated pancreatic function test. Dig Dis Sci 2007;52:1206-10. 11. Stevens T, Conwell DL, Zuccaro G Jr, et al. Comparison of endoscopic ultrasound and endoscopic retrograde pancreatography for the prediction of pancreatic exocrine insufficiency. Dig Dis Sci 2008;53:1146-51. 12. Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc 2009;69:1251-61. 13. Banks PA. Classification and diagnosis of chronic pancreatitis. J Gastroenterol 2007;42(Suppl 17):148-51. 14. Yusoff IF, Sahai AV. A prospective, quantitative assessment of the effect of ethanol and other variables on the endosonographic appearance of the pancreas. Clin Gastroenterol Hepatol 2004;2: 405-9. 15. Wachtel MS, Miller EJ. Focal changes of chronic pancreatitis and ductarteriovenous relationships: avoiding a diagnostic pitfall. Am J Surg Pathol 2005;29:1521-3. 16. Stamm BH. Incidence and diagnostic significance of minor pathologic changes in the adult pancreas at autopsy: a systematic study of 112 autopsies in patients without known pancreatic disease. Hum Pathol 1984;15:677-83.
Volume 69, No. 7 : 2009 GASTROINTESTINAL ENDOSCOPY 1263
Election year fever? Voting on EUS criteria for chronic pancreatitis Chronic pancreatitis is characterized by persistent inflammation associated with irreversible morphologic changes that typically cause pain and loss of exocrine and/ or endocrine function.1 As for most organ-based disorders, a histopathologic classification of the disease would be ideal. Obtaining tissue from the pancreas in a minimally invasive manner is challenging, however, because of the retroperitoneal location of the pancreas. As a consequence, multiple nontissue-based classification systems have been proposed as a basis for diagnosis, treatment, and research.2-4 In advanced disease, morphologic features can often be diagnostic of chronic pancreatitis. These can be appreciated by various methods, including radiography, CT, MRCP, and ERCP. However, these imaging modalities are suboptimal in detecting early and minimal change disease.1 EUS was first described as a method to detect chronic pancreatitis more than 20 years ago.5 EUS is promising compared with the other imaging modalities, because it potentially can detect earlier forms of chronic pancreatitis. Multiple studies were conducted to determine the diagnostic accuracy of EUS in chronic pancreatitis. These studies suffer, however, from a wide range of EUS-based criteria by using different criterion standards and by applying different thresholds of the number of criteria necessary to diagnose chronic pancreatitis. Other differing aspects of these studies include technique and type of echoendoscopes used, which has contributed to suboptimal interobserver variability.6-11 Collectively, these studies have not contributed in a meaningful way to our understanding of the natural history of the disease. Nor have they provided the treating gastroenterologist with a reliable measure of the activity or prognosis of the disease. In this issue of Gastrointestinal Endoscopy, Catalano et al12 propose a new consensus-based system of EUS criteria for chronic pancreatitis, designated the Rosemont classification. Thirty-two experienced endosonographers, along with a panel of 5 experts, reviewed existing data on EUS criteria for the diagnosis of chronic pancreatitis. After a review of the literature and an opportunity for discourse, each participant anonymously voted on the definitions, terminology, and perceived predictive value of parenchymal and ductal
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2008.09.024
1262 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 7 : 2009
features of chronic pancreatitis. Based on the voting, a rank order of major and minor criteria were created. A consensus, defined as a more than two thirds agreement among the participants, was required for inclusion of any criteria and its rank order of perceived accuracy. The final result was a classification system that stratifies the probability of chronic pancreatitis based on a combination of major and minor EUS findings. Major criteria included hyperechoic foci with shadowing, main pancreatic-duct calculi, and lobularity with honeycombing. Minor criteria included cysts, stranding, lobularity without honeycombing, hyperechoic
An ideal classification system of chronic pancreatitis will need to be durable over time for diagnosis, treatment, and clinical investigation.
foci without shadowing, irregular main pancreatic duct contour, dilated side branches, main pancreatic duct dilatation, and hyperechoic margins of the main pancreatic duct. Based on various combinations of major and minor features found in a patient, the Rosemont classification system categorizes the patient as having EUS features that are ‘‘consistent with chronic pancreatitis,’’ ‘‘suggestive of chronic pancreatitis,’’ ‘‘indeterminate for chronic pancreatitis,’’ and ‘‘normal.’’ Does the Rosemont classification system represent a significant and necessary step forward in the clinical investigation of EUS for chronic pancreatitis? By consensus, the investigators provided a common language to standardize EUS-based diagnosis and to guide future clinical investigation. If broadly accepted into clinical practice, then the probability of identifying a homogeneous cohort of patients with early chronic pancreatitis is improved. Such cohorts are particularly important to identify, because there are currently no reliable diagnostic tests for early forms of the disease.13 This can lead to evaluation of therapies that might arrest chronic inflammation and, therefore, modify the natural history of the disease. There are some aspects to this classification that warrant further consideration. After an extensive review of the literature among the 32 participants, the investigators reported a very good interobserver variability (kappa O 0.7) for each www.giejournal.org
Park & Van Dam
feature. Because of inherent bias arising from participating in the consensus conference, it would be more helpful and meaningful to validate the interobserver variability in another group of practicing endosonographers. This can be critical, particularly when interpreting EUS features, such as lobularity with and without honeycombing. This relatively new concept of lobularity with honeycombing, defines contiguous lobularity of O3 lobules as a major feature and!3 lobules (no honeycombing) as a minor feature. According to this classification, a subtle difference in interpretation then can lead to a very different conclusion. An ideal classification system will be durable over time for diagnosis, treatment, and clinical investigation. This classification system will likely evolve as EUS technology continues to improve and further understanding of the impact of various clinical variables on EUS morphology develops. As an example, Yusoff and Sahai14 identified male sex as an independent predictor of having more than 5 EUS features consistent with chronic pancreatitis, even though male sex is not an established independent risk factor for pancreatic disease. At the time, the investigators correctly chose not to incorporate adjustments for various clinical variables based on a lack of stronger evidence. However, because further research may identify clinical factors that may affect the diagnostic accuracy of EUS criteria, appropriate revisions to the classification system are likely. The more likely a classification changes, the less value it has as an instrument for clinical investigation. Where do we go from here? The next step is to validate this classification. Ideally, a validation study should compare the classification’s performance with a tissue diagnosis. On histologic examination, chronic pancreatitis shows features of chronic inflammation, fibrosis, and atrophy. These findings are widely accepted as definitive. However, pancreatic-tissue acquisition has remained a formidable limitation for the majority of diagnostic investigations of chronic pancreatitis. Tissue diagnosis is also neither 100% sensitive nor specific. Chronic pancreatitis can be focal and patchy, and previously published autopsy studies demonstrated fibrosis and atrophy in elderly asymptomatic patients not diagnosed with chronic pancreatitis.15,16 Despite being less than the perfect criterion standard, it remains the best to date. If the proper prospective study was performed on a cohort of clinically suspected chronic pancreatitis and control groups, and EUS criteria proved to correlate well with histology, then perhaps it could become a minimally invasive standard for the diagnosis of chronic pancreatitis. The investigators are to be congratulated for their efforts in advancing the field of this difficult disease. The Rosemont classification begins to define a common language of EUS imaging characteristics of chronic pancreatitis. By creating a basis for classifying the level of disease activity, the investigators provided a framework to start to study both the natural history of chronic pancreatitis and potentially the response to treatments in a useful way. www.giejournal.org
Editorial
DISCLOSURE All authors disclosed no financial relationships relevant to this publication. Walter G. Park, MD Jacques Van Dam, MD, PhD Division of Gastroenterology Department of Medicine Stanford University Medical Center Stanford, California, USA
REFERENCES 1. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682-707. 2. Singer MV, Gyr K, Sarles H. Revised classification of pancreatitis. Report of the Second International Symposium on the Classification of Pancreatitis in Marseille, France, March 28-30, 1984. Gastroenterology 1985;89:683-5. 3. Sarles H, Adler G, Dani R, et al. The pancreatitis classification of Marseilles-Rome 1988. Scand J Gastroenterol 1989;24:641-2. 4. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756-9. 5. Sivak MV, Kaufman A. Endoscopic ultrasonography in the differential diagnosis of pancreatic disease. A preliminary report. Scand J Gastroenterol Suppl 1986;123:130-4. 6. Chong AK, Hawes RH, Hoffman BJ, et al. Diagnostic performance of EUS for chronic pancreatitis: a comparison with histopathology. Gastrointest Endosc 2007;65:808-14. 7. Sahai AV, Zimmerman M, Aabakken L, et al. Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc 1998;48:18-25. 8. Catalano MF, Lahoti S, Geenen JE, et al. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;48:11-7. 9. Kahl S, Glasbrenner B, Leodolter A, et al. EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study. Gastrointest Endosc 2002;55:507-11. 10. Conwell DL, Zuccaro G, Purich E, et al. Comparison of endoscopic ultrasound chronic pancreatitis criteria to the endoscopic secretinstimulated pancreatic function test. Dig Dis Sci 2007;52:1206-10. 11. Stevens T, Conwell DL, Zuccaro G Jr, et al. Comparison of endoscopic ultrasound and endoscopic retrograde pancreatography for the prediction of pancreatic exocrine insufficiency. Dig Dis Sci 2008;53:1146-51. 12. Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc 2009;69:1251-61. 13. Banks PA. Classification and diagnosis of chronic pancreatitis. J Gastroenterol 2007;42(Suppl 17):148-51. 14. Yusoff IF, Sahai AV. A prospective, quantitative assessment of the effect of ethanol and other variables on the endosonographic appearance of the pancreas. Clin Gastroenterol Hepatol 2004;2: 405-9. 15. Wachtel MS, Miller EJ. Focal changes of chronic pancreatitis and ductarteriovenous relationships: avoiding a diagnostic pitfall. Am J Surg Pathol 2005;29:1521-3. 16. Stamm BH. Incidence and diagnostic significance of minor pathologic changes in the adult pancreas at autopsy: a systematic study of 112 autopsies in patients without known pancreatic disease. Hum Pathol 1984;15:677-83.
Volume 69, No. 7 : 2009 GASTROINTESTINAL ENDOSCOPY 1263