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1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at REVIEWS AND COMMENTARY n EDITORIAL Alec J., MD, MPH Published online /radiol Radiology 2010; 254: From the Department of Radiology, NYU-Langone Medical Center, 550 First Ave, Room HCC 232, New York, NY Received November 27; revision requested December 6; revision received December 7; accepted December 8. Address correspondence to the author ( alec. megibow@nyumc.org ). Author stated no fi nancial relationship to disclose. See also the article by Tanaka et al in this issue. q RSNA, 2010 Are We Really Closer to Predicting the Development of Pancreatic Cancer? 1 The early, curable malignant lesion of the pancreas is silent. The initial symptoms are mild, indefinite, and not disturbing. Even when a presumptive diagnosis of such a lesion is made on a basis of the history in the absence of any demonstrable finding, the lesion proves to be inoperable. Magnificent advances have been made in the surgical management of pancreatic disease. Until similar advances can be made in diagnosis, the fruits to be enjoyed by pancreatoduodenectomy cannot be touched ( 1 ). These words, written in 1950, articulated the frustration shared by all individuals who treated patients with pancreatic diseases and served as a challenge to those attempting to diagnose them. In the introduction to their classic textbook, Radiology of the Pancreas and Duodenum, published in 1973, the editors S. Boyd Eaton and Joseph T. Ferrucci Jr wrote, During the past few years major advances in pancreatic radiology have produced significant change; nearly all pancreatic disease can now be demonstrated radiologically [although] true early diagnosis remains a rarity ( 2 ). That text reviewed the most common radiologic techniques available at the time: hypotonic duodenography and angiography. A single chapter was devoted to pancreatic ultrasonography (US) the editors recognizing that even the crudest (by today s standards) direct visualization of the gland would herald a major advance. In 1976, Sheedy and colleagues from the Mayo Clinic published the first report about the value of abdominal computed tomography (CT) scanning in the evaluation of pancreatic diseases ( 3 ). Similar reports from the Cleveland Clinic Foundation ( 4 ) and the Mallinckrodt Institute of Radiology ( 5 ) followed in rapid succession; the modern era of pancreatic imaging has begun. All of these reports raised the hope that by finally being able to directly visualize the entire pancreas, it may finally become possible to cure pancreatic cancer; the magnificent advance in diagnosis had finally been achieved. Nevertheless, despite continuous improvements in CT technology, improvements in US (without or with intravenous contrast material) quality, the advent of reliable high-quality body magnetic resonance (MR) images, endoscopic techniques such as endoscopic US and endoscopic retrograde cholangiopancreatography, there has been little, if any, impact on the overall survival of patients with pancreatic cancer. Today, in the United States, pancreatic cancer is the fourth leading cause of cancer death, with more than new cases expected in In a recently published 4-decade ( ) study of more than pancreatic cancer patients from the cancer registry of Norway, the incidence and mortality from the disease remained unchanged at six to eight per Diagnoses based on clinical examination findings alone decreased from 12.5% (in the 1950s) to less than 1% (in the 2000s), while use of imaging techniques, such as CT and MR imaging, increased from 3.6% to more than 30%. The authors emphasize that further elucidation of risk factors in pancreatic cancer is needed to enable effective prevention, early detection, and improved treatment strategies ( 6 ). The most widely accepted method currently advocated for screening patients at risk for development of pancreatic cancer is based on an epidemiologic approach of identifying patients at high risk for the disease, with focus primarily on patients with a genetic predisposition such as strong family history, Peutz-Jehgers syndrome, familial breast cancer syndrome, Lynch syndrome, familial atypical mole-malignant melanoma, and BRCA2 gene mutation 642 radiology.rsna.org n Radiology: Volume 254: Number 3 March 2010

2 among others, and intensively studying them at frequent but unspecified intervals. Evaluation of this subset of patients with endoscopic US has led to the detection of pancreatic cancer in a significant number of patients at a time when surgical therapy can positively impact survival ( 7,8 ). For the majority of individuals, however, there is no proved method to identify an individual at risk for the disease. In the current issue of Radiology, Tanaka and co-workers (investigators who are among the most experienced, well known, and widely regarded pancreatic researchers in the world) have reported a prospective study that attempted to identify risk factors that help predict the development of pancreatic cancer ( 9 ). A total of 1405 of patients examined at transabdominal US between 1998 and 2001 for a variety of clinical indications, including abdominal discomfort and mass lesion characterization, among others, had some form of pancreatic or peripancreatic abnormality. At the time of detection of the abnormality, a focused work-up that included directed imaging, pancreatic-juice cytology, biopsy, and/or other examinations revealed that pancreatic or peripancreatic neoplasm was present in 298, all of whom, as well as an additional 49 in whom the entire pancreas could not be seen at US, were excluded. The remaining 1058 patients (all of whom had an abnormal US finding but no proved malignancy at the time of enrollment ) were enrolled in the study from January 1998 to the end of December 2002 and were followed up until the end of 2007 or the development of pancreatic neoplasia. From this group, 12 went on to develop a pancreatic neoplasm, whereas 1046 did not. In comparing the two groups, the authors found that the presence of a pancreatic cyst and/or dilatation of the main pancreatic duct (MPD) were present in a significantly greater frequency in the patients who went on to develop pancreatic cancer than in those patients who did not develop cancer during the follow-up period. These imaging findings were more frequently represented in the 12 patients who developed can- cer than were traditional serum laboratory values such as fasting blood sugar, amylase, or elastase levels. The authors conclude that these imaging findings were strong independent predictors of the subsequent development of pancreatic cancer. MPD dilatation of 2 mm or more was seen in 551 of 1058 (52.1%) patients. A total of 540 of 1046 (51.6%) patients with an MPD dilatation of 2 mm or more did not develop pancreatic cancer, whereas increased MPD caliber was found in 11 of 12 (91.7%) patients who did develop pancreatic cancer; in five, the duct was 3 mm or more. The authors calculated a cumulative 5-year risk of pancreatic cancer development of 1.84% for a patient who presents with an MPD dilatation of 2.5 mm or more. The authors did not distinguish segmental from complete duct dilatation nor is there any indication of the specific cause of the duct dilatation in those patients who did not develop pancreatic cancer. Evaluation of the pancreatic duct is increasingly being recognized as an important component of routine crosssectional or US imaging assessment of the pancreas. MPD dilatation can occur as a result of chronic pancreatitis, main pancreatic duct intraductal papillary mucinous neoplasm, or aging ( 10 ) or can occur upstream from a stricture. Focal strictures are most frequently the result of neoplasm, scarring from prior episodes of acute pancreatitis, or immunoglobulin G4 sclerosing disease affecting the pancreas (autoimmune pancreatitis). Abrupt changes in duct caliber are frequently the only sign of a pathologic process in the pancreas. In a study ( 11 ) of 86 patients with pancreatic duct strictures, pancreatic neoplasm was determined to be the underlying cause in 71, whereas benign etiologies were present in the remaining 15. In a prior report, Tanaka and colleagues ( 12 ) observed that MPD dilatation of less than 2 mm was present in 65% of 39 patients who subsequently developed pancreatic cancer more than 1 year later, compared with duct dilatation in 5.35% of more than agematched control subjects who did not go on to develop pancreatic neoplasia. A dilated MPD was found in 51 of 76 patients with known risk factors for pancreatic cancer development, although 78% of these patients also had chronic pancreatitis ( 8 ). Gangi et al ( 13 ) retrospectively reviewed 62 imaging studies from 28 patients referred to the Mayo Clinic for treatment of pancreatic cancer. Their review found that 50% of these patients had abnormal findings in the pancreas as many as 18 months before clinical presentation, with pancreatic duct cutoff and dilatation being the most frequently recognized abnormality. Although US was the imaging procedure used in the study by Tanaka et al, with the widespread availability of multidetector CT technology and/or high-field strength fast gradient-echo MR imaging combined with three-dimensional acquisition and display, the pancreatic duct can be seen and evaluated as part of a routine examination ( 14,15 ). Unfortunately, in the current study, the authors do not give us a more precise morphologic information concerning the extent of pancreatic duct dilatation. It would be extremely valuable to know if the entire pancreatic duct was dilated or if a segment of the pancreatic duct was dilated. Also, the authors did not exclude patients with chronic pancreatitis from the study cohort; this disease being a well known risk factor for pancreatic cancer development. The specific predictive value of a dilated MPD in a patient with chronic pancreatitis for the development of cancer may be limited. Pancreatic cysts 5 mm or larger were present in 246 of 1058 (23.3%) patients. A total of 238 of 1046 (22.8%) patients with a cyst did not develop pancreatic cancer, whereas a cyst was present in eight of 12 (66.7%) patients who developed cancer. The presence of a cyst alone increased the cumulative 5-year risk for development of pancreatic cancer to 2.65%, whereas the presence of both cysts 5 mm or larger and an MPD dilatation of 2.5 mm or more was shown to have a cumulative 5-year risk of 5.62% for development of pancreatic cancer. In terms of the predicted incidence of pancreatic cancer, the cumulative 5-year risk in patients with a cyst and MPD dilatation was calculated Radiology: Volume 254: Number 3 March 2010 n radiology.rsna.org 643

3 at 1124 per , a 30-fold increase over the 375 per baseline incidence of pancreatic cancer in Japanese citizens years old. These results are compelling, to say the least; however, the potential implication of the authors results for early detection must be weighed against the even greater potential for over increased testing and over-diagnosis. Pancreatic cysts present a challenge to imagers, referring clinicians, and patients. One can group cysts in the pancreas into three broad categories: cystic neoplasms (the group that accounts for the largest percentage of cysts encountered in clinical practice) ( 16 ), cysts arising from inflammatory conditions (eg, pseudocysts), and small cystic formations that are found at autopsy ( 17 ) or at pathologic examination as pancreatic intraepithelial neoplasia. Pancreatic intraepithelial neoplasias are thought to be precursor lesions in the development of pancreatic carcinoma. These lesions are microscopic, although some produce multifocal lobulocentric parenchymal atrophy that may be detected at endoscopic US ( 18 ). From an imaging perspective, only the first two subgroups are reliably identified. The increasing recognition of pancreatic cysts is directly related to the widespread use of imaging. Their prevalence is estimated as high as in 19% of imaging studies ( 19 ). Cystic neoplasms are most often benign or low-grade indolent neoplasms ( 20 ). Characteristics that include size, location, presence of septa, mural nodules, calcification, and patient sex and symptoms have been extensively analyzed in an attempt to guide image interpretation and clinical decision-making for an individual patient. In a retrospective study ( 21 ) about the prevalence of malignancy, of 166 pancreatic cysts larger than 3 cm, 135 were benign. In the remaining lesions, the presence of malignancy correlated with male sex, age, symptoms, mural nodules, MPD dilatation, and common bile duct dilatation. Even knowing that the majority of cysts smaller than 3 cm are benign or indolent low-grade neoplasms, deciding whether to observe the patient or perform surgery remains controversial. In 2006, a workforce composed of wellknown gastroenterologists, surgeons, pathologists, and imagers proposed guidelines to address this issue; these guidelines have come to be known as the Sendai criteria. Cysts smaller than 1 cm are followed yearly with imaging; cysts between 1 and 3 cm are followed at 6-month intervals for 2 years and then longer if they remain stable in size or fail to develop mural nodule(s) or a dilated pancreatic duct or result in a positive cytologic finding; and cysts larger than 3 cm are thought to be appropriate for surgery ( 22 ). Validation of the 3-cm watershed between observation and surgery has been corroborated in several longitudinal studies ( ). Controversy remains concerning the frequency of follow-up ( 26 ) and the necessity for long-term follow-up of cysts smaller than 1 cm. Surgery is advised for growing lesions even if they are smaller than 3 cm; most clinicians will attempt to aspirate the cyst content before resection to exclude an inflammatory mass or a serous cystadenoma. The contribution of the presence of a cyst, even cysts smaller than 1 cm, to the development of pancreatic cancer in Tanaka and colleagues report is striking. Other large literature series that report serial data on pancreatic cysts have not detected a statistically significant increase in incidence of pancreatic adenocarcinoma developing in the patients; the majority of cysts, as documented in numerous reports in the literature, remain stable ( 25,27,28 ). There are few reports that specifically review the presence and type of cysts (other than imaging occult pancreatic intraepithelial neoplastic lesions) in patients who have undergone surgical treatment of pancreatic cancer. At our institution, we have found small pancreatic intraepithelial neoplasias and retention cysts in the vicinity of resected pancreatic adenocarcinoma in approximately 30% of surgical specimens (unpublished data). Therefore, before the presence of a pancreatic cyst larger than 5 mm, a frequently detected incidental finding on cross-sectional imaging studies, commits a patient and his/ her physician to a life of endless follow-up examinations, the data must be interpreted in the following contexts. First, it must be remembered that all of the patients enrolled in this study were referred for a US examination because of some clinical suspicion of upper abdominal disease. The presence of symptoms has been shown to significantly increase the likelihood that a pancreatic cyst smaller than 3 cm will be malignant ( 21 ). Therefore, these results cannot be applied to pancreatic cysts detected in the vast numbers of patients who undergo imaging tests for other conditions. Second, the authors do not clarify the development of pancreatic cancer within the cyst or in the vicinity of the cyst. The authors state that patients who were enrolled in the study had, at baseline US, various abnormal findings in or around the pancreas, such as pancreatic cysts, hypoechoic or hyperechoic regions in the pancreas, pancreatic stones, slight dilatation of MPD ( 2 mm), common bile duct dilatation ( 12 mm), or detectable lymph nodes adjacent to the pancreas. We are told that 279 of these were excluded from the study because a neoplasm was detected at the time of the baseline examination. It would have been of interest to know what percentage of those patients had findings of a cyst or MPD dilatation, and in those who did have a cyst, where was the tumor located. Reports are now appearing in the literature about the development of pancreatic adenocarcinoma at a distant site from the cyst itself in a small percentage of patients with pancreatic cysts of any size being followed up ( 29,30 ). This observation raises a fundamental question concerning cysts (most frequently an intraductal pancreatic mucinous neoplasm) in pancreatic carcinogenesis; specifically is the cyst at risk or does the presence of a cyst signal that the entire pancreas is at risk. Likely, other risk factors present in the individual patient will determine this dilemma; elucidation of these factors may refine follow-up criteria that at present are based almost exclusively on cyst size. Tanaka and colleagues might 644 radiology.rsna.org n Radiology: Volume 254: Number 3 March 2010

4 6. Søreide K, Aagnes B, Moller B, Westgaard A, Bray F. Epidemiology of pancreatic canhave provided important information to shed further light on this question had they attempted to differentiate malignant degeneration of a cyst or the cyst reflecting a pancreas at risk for the development of a tumor anywhere. Third, the majority of patients who had either a cyst 5 mm or larger (22.8%) or MPD dilatation of 2 mm or more (51.6%) did not develop cancer. The authors do not report the frequency of the cyst and MPD dilatation in patients who were surgically treated at their institution who were not enrolled in the follow-up cohort. This group would have been a useful control to assess the sensitivity and specificity of the imaging findings. As discussed above, other untested risk factors (for instance K-ras mutations in pancreatic juice) may have been present in the 12 patients in the study. The presence of these clinical parameters may have overwhelmed the significance of the imaging findings. Fourth, we must carefully examine the statistical evidence for the authors hypothesis. Even though the difference between the prevalence of the imaging findings in the small number of patients appears to be significantly higher than in the control group, the confidence intervals around both the baseline characteristics and the multivariate adjusted hazard ratios are extremely wide. Confidence intervals can be viewed as a measure of precision of the analyzed data, with the lower boundary representing the most minimal chance of occurrence and the upper boundary representing the highest likelihood of occurrence. Wide confidence intervals imply that more data need be collected before a definitive statement can be made about the parameter(s) in question. Other reasons why the hazard ratios are high relate to the extremely small number of cases that reached the endpoint (appearance of cancer) and that other (and perhaps more defining) risk factors were not tested. It is not clear why all of these parameters were not included in the follow-up evaluations. Inclusion of these parameters that were used to identify disease in the initial cohort could possibly have altered the results of the statistical analysis. The publication of the article by Tanaka et al will be beneficial in several ways. First, it will once again alert radiologists to the significance of a dilated MPD. Current multidetector CT technology and MR imaging capabilities provide data sets composed of isotropic voxels that can range from 0.6 to 1 mm the size range required to reliably visualize a 2-mm structure. Second, it can define possible patients that might benefit from rigorous evaluation of a variety of genetic and biochemical analyses of serum and pancreatic juice, thus contributing to larger cohorts of high-risk patients who could be closely followed up. On the other hand, a superficial reading of the article could be harmful. Wide scale imaging of patients with any detectable cyst (. 5 mm) will lead to over-diagnosis, over-testing, and increased cost. Readers of the article who first observe the apparent higher statistic associated with the observed parameters and then look at the P value purporting significance must also be cognizant of the wide confidence intervals around the results, the implication being more data need be collected before a definitive statement can be made. We look forward to more work from Tanaka and colleagues in the future to help further define the utility of the observations they have made. References 1. 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5 19. Zhang XM, Mitchell DG, Dohke M, Holland GA, Parker L. Pancreatic cysts: depiction on single-shot fast spin-echo MR images. Radiology 2002 ; 223 ( 2 ): Adsay NV. Cystic neoplasia of the pancreas: pathology and biology. J Gastrointest Surg 2008 ; 12 ( 3 ): Lee CJ, Scheiman J, Anderson MA, et al. Risk of malignancy in resected cystic tumors of the pancreas, or =3 cm in size: is it safe to observe asymptomatic patients? A multi-institutional report. J Gastrointest Surg 2008 ; 12 ( 2 ): 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 ( 1-2 ): Nagai K, Doi R, Ito T, et al. Single-institution validation of the international consensus guidelines for treatment of branch duct intraductal papillary mucinous neoplasms of the pancreas. J Hepatobiliary Pancreat Surg 2009 ; 16 ( 3 ): Sadakari Y, Ienaga J, Kobayashi K, et al. Cyst size indicates malignant transformation in branch duct intraductal papillary mucinous neoplasm of the pancreas without mural nodules. Pancreas 2009 Sep 10. [Epub ahead of print] 25. Allen PJ, D Angelica M, Gonen M, et al. A selective approach to the resection of cystic lesions of the pancreas: results from 539 consecutive patients. Ann Surg 2006 ; 244 ( 4 ): Das A, Wells CD, Nguyen CC. Incidental cystic neoplasms of pancreas: what is the optimal interval of imaging surveillance? Am J Gastroenterol 2008 ; 103 ( 7 ): Tanno S, Nakano Y, Nishikawa T, et al. Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results. Gut 2008 ; 57 ( 3 ): Rautou PE, Lévy P, Vullierme MP, et al. Morphologic changes in branch duct intraductal papillary mucinous neoplasms of the pancreas: a midterm follow-up study. Clin Gastroenterol Hepatol 2008 ; 6 ( 7 ): Tada M, Kawabe T, Arizumi M, et al. Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. Clin Gastroenterol Hepatol 2006 ; 4 ( 10 ): Tanno S, Nakano Y, Koizumi K, et al. Pancreatic ductal adenocarcinomas in long-term follow-up patients with branch duct intraductal papillary mucinous neoplasms. Pancreas 2009 Sep 8. [Epub ahead of print] 646 radiology.rsna.org n Radiology: Volume 254: Number 3 March 2010