EDITORIAL Intraductal Papillary Mucinous Neoplasm of the Pancreas: Changing Perspective of the Impact of Surgery on Patient Outcome espite our evolving understanding of intraductal papillary mucinous neoplasms (IPMNs), these lesions of the pancreas present both diagnostic and therapeutic challenges to the physician. Observational series evaluating the clinical course of IPMNs demonstrate the potential for malignant transformation, similar to that observed with colonic polyps.1,2 Mean frequency of malignancy was summarized as 61.6% in main duct IPMN and 25.5% in branch duct IPMN in surgical series, but the annual rate of progression for clinically observed branch duct IPMN is lower; 2%–3% annually or 5-year risk of 15% for malignant transformation.3–5 Unlike colonic polyps, resection of IPMNs requires invasive surgical intervention such as pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy. Even with the advent of the laparoscopic approach, such treatment has nonnegligible mortality (2%–5%) and can result in appreciable morbidity (30%–40%).6–8 Moreover, an increasing number of cystic lesions of the pancreas are incidentally recognized in asymptomatic individuals because of greater use of various highresolution radiographic imaging modalities,9,10 and this increased incidence of IPMN has been confirmed by a retrospective cohort study using a regional database.11 As such, choosing patients who would benefit from surgical resection has been the focus of research stratifying IPMNs preoperatively to the high-risk and low-risk categories for malignant transformation. The first consensus guidelines for the clinical management of IPMNs was published in 2006 by the International Association of Pancreatology (international consensus criteria; often referred to as Sendai criteria) and recently revised in 2012 with a review of the evergrowing corpus of data on IPMN and its clinical course.3,4 These recommendations address not only diagnostic criteria for various cystic lesions of the pancreas (with a special focus on different types of mucinous cystic lesions of the pancreas, including subtypes of IPMN), but also which lesions are better managed by surgical excision rather than surveillance. High-risk stigmata, including obstructive jaundice, enhanced solid component, and main duct dilation over 10 mm, direct patients to immediate surgical consideration, whereas worrisome features, such as dilation of main duct (5–9 mm), nonenhanced mural nodules, thickened cystic wall, overall size 30 mm, abrupt main duct caliber change with distal pancreatic atrophy, and lymphadenopathy, require further evaluation by endoscopic ultrasound (EUS) and possible consideration for surgery. International consensus criteria stratify cystic

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Clinical Gastroenterology and Hepatology 2014;12:492–495

lesions by the risk for the progression to or the presence of malignancy in order to reduce mortality from invasive cancer arising from cystic lesions of pancreas by early intervention; however, there have been few data showing how such strategies of surgical intervention benefit patients with IPMNs that meet these criteria. In this issue of Clinical Gastroenterology and Hepatology, Kawakubo et al12 present a prospectively collected cohort study comparing the disease-specific mortality in individuals deemed otherwise adequate for surgery after being diagnosed with an IPMN harboring high-risk stigmata and/or cyst size of >30 mm. The treatment group, including those who underwent surgical excision, was compared with a matched control group that did not have surgery due to patients’ preference or comorbidities and opted rather for surveillance. Using a logistic regression model, and adjusting for patient characteristics to limit inherent selection bias, their data demonstrates that only the presence of a hypoattenuating area on computed tomography (CT) significantly increased the risk for pancreatic cancer–specific mortality, and that surgical intervention reduced diseasespecific mortality in this group. Only trends toward significant risk reduction were demonstrated for other commonly accepted high-risk features including associated symptoms, main duct type, cyst diameter, and main duct caliber. It is worth highlighting that invasive malignancy was confirmed in 100% (10/10) with the finding of a hypoattenuation seen on CT as compared to only 36% (12/33) with a mural nodule alone, indicating that a hypoattenuation is a highly specific indicator for the presence of malignancy. A mural nodule, on the other hand, may represent nonneoplastic debris or a dysplastic epithelium that may not have yet reached high-grade dysplasia (HGD) or invasive cancer. The current article suggests that the only absolute criterion for a benefit of surgical resection is a hypoattenuating area on CT. This underscores the importance of patient selection when parsing between those best treated by surgical treatment and those more appropriate for observation. Clearly, those with an IPMN with malignant transformation should be immediately considered for surgery; however, the difficulty arises in assessing those with a lesion with uncertain probability for malignant transformation. The recent meta-analysis published by Anand et al evaluated the risk associated with the worrisome and high-risk features detailed by the consensus criteria by analyzing all available and appropriate published data since the time of the World Health Organization’s classification of the intraductal papillary mucinous neoplasm in 1996 through late 2011.13 A total of 41 studies with 5788 patients and 3304 branch duct IPMNs were included into the final analyses. In this meta-analysis, all of the cyst features proposed by the recent update to the consensus

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guidelines were associated with an increased risk of malignancy. Here, cyst size of >30 mm was most strongly associated with malignant IPMN. Dilation of the main pancreatic duct >6 mm and presence of a mural nodule were also variables found to statistically increase risk for malignancy, albeit with lower odds ratios. Interestingly, this finding somewhat conflicts with the expert opinion incorporated into the revised international consensus guidelines (ICG), which deemphasize cyst size criterion. However, several well-conducted observational studies evaluating the natural history of branch duct IPMN suggest that those lesions without a mural nodule on initial endoscopic evaluation tend not to progress to malignant transformation, irrespective of size.14,15 In addition, another recent meta-analysis focusing on branch duct IPMN showed cyst size to be a significant factor. It was, however, the least significant out of 4 factors (cyst size greater than 3 cm, mural nodule, main duct dilation, and thick septum/wall).16 In most studies, mural nodules constitute a high-risk finding for presence of malignancy (odds ratio 6–9.3 in 2 meta-analyses), although limited by low specificity. EUS identifies mural nodules better with sensitivity of 75% compared to that of CT (24%), but with lower specificity of 83% compared to 100%.17 Defining the mural nodule by contrast-enhanced EUS was reported to increase specificity for diagnosis of malignant nodules to 92.9%, but this technique is not universally available.15 Positron emission tomographic (PET) scan with or without CT has been reported to be more specific in identifying malignant IPMN (HGD and invasive carcinoma) compared with ICG, with sensitivity 83% and specificity 100% compared with 93% and 22% of ICG, respectively.18 In a recent meta-analysis of studies on PET scan for discriminating benign versus malignant IPMNs, sensitivity and specificity were 88% and 98%.19 Authors acknowledged there was a heterogeneity of the studies and a lack of standardized methods and a gold standard (histopathologic diagnosis). Apparently, PET imaging by itself suffers with relatively lower sensitivity missing those with HGD or cancer; however, it provides significantly higher specificity. In a recent study comparing PET with histologic diagnoses of surgically resected specimens, PET/CT scan had 88% sensitivity and 88% specificity.20 Furthermore, when dual-phase PET was evaluated incorporating delayed phase value (retention index), specificity increased to 94%. It was noted that a higher number of patients (>50%) had HGD in the malignant IPMN group compared with previous studies (invasive carcinoma comprised the majority of malignant IPMNs), which may explain initial lower specificity. This study also evaluated PET specifically for branched duct IPMN to distinguish malignant from benign IPMNs. It showed high sensitivity and specificity of PET (79% and 92%, respectively) compared with individual ICG criteria, which had either lower sensitivity or specificity.20 PET scan would not be in a routine protocol for an evaluation of IPMN, yet it would provide additional information in certain cases

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when more reliable data are needed to decide on surgical intervention. The accuracy of predictive risk factors of malignant IPMNs in selecting patients for surgical intervention has been well defined. However, its effect on pancreatic cancer–specific mortality has not been defined, especially with the lack of randomized trials. The current study attempts to address this knowledge gap through the use of a matching algorithm, which statistically removed significant differences in baseline characteristics (eg, age, sex, body mass index, diagnostic clues, history of smoking, family history of pancreatic cancer, history of diabetes mellitus, comorbidity score, cyst diameter, main duct diameter, mural nodules, multiplicity and location of IPMNs, main duct type, hypoattenuating area on CT, and date of diagnosis) among the surgical and nonsurgical groups within a large cohort of patients. Prior to this analytic manipulation, there were significant differences between the groups in smoking history, main duct caliber (>6 mm), presence of mural nodule, main duct type, and finding of associated hypoattenuating area, though not of cyst size >30 mm, as this appears to be the leading factor for recommending surgery for both groups. Following propensity score matching, subsequent multivariate analysis washed out all queried risks of pancreatic cancer–specific mortality, with the exception of the hypoattenuating area on CT. Importantly, pancreatic cancer death was the authors’ definitive outcome, not the risk of progression toward malignancy. Therefore, information regarding new diagnosis of pancreatic cancer during the follow up period in the nonsurgical group was not provided. Given the dismal prognosis of pancreatic cancer, one would suspect the occurrence of pancreatic cancer to result in mortality. However, cumulative incidence of pancreatic malignancy over the observation period (18–87 months) in this high-risk group would have been very informative. As with most rules in medicine, nothing is absolute. Recently published data by Kawakubo et al demonstrated both comorbidity and age at diagnosis as significant determinants of mortality unrelated to pancreatic cancer in patients with IPMN.21 Therefore, careful selection of patients in favor of surveillance would be reasonable in those with an expected shortened life expectancy due to comorbidity, as well as those with lesions diagnosed at an older age that have less future potential for malignant transformation. It is notable, however, that more experienced surgeons, at larger pancreas surgical centers, have lower mortality and morbidity for both pancreaticoduodenectomy (

Intraductal papillary mucinous neoplasm of the pancreas: changing perspective of the impact of surgery on patient outcome.

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