Every now and then a disease emerges that manages to

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1 Mini-Reviews and Perspectives Intraductal Papillary Mucinous Neoplasms of the Pancreas CARLOS FERNÁNDEZ DEL CASTILLO* and N. VOLKAN ADSAY *Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Pathology, Emory University, Atlanta, Georgia See related article, Shirts BH et al, on page 812 in CGH. Every now and then a disease emerges that manages to transform a medical field. Such is the case of intraductal papillary mucinous neoplasms (IPMN) in pancreatology. Over the last 20 years, this diagnosis has gradually permeated the thinking of physicians and researchers involved in pancreatic diseases, and suddenly pancreatic symptoms have a broader differential diagnosis, cysts and dilated pancreatic ducts have different implications, and even pancreatic cancer is being seen through a different prism. The purpose of this mini-review is to provide a state-of-the-art of our knowledge of this entity and to describe where future research is needed. Epidemiology The first cases of IPMN were described in Japan in the early 1980s, and it took a decade for the rest of the world to recognize this entity. 1 Even by the mid 1990s, the disease was considered extremely rare, and the cases reported were mostly symptomatic IPMNs affecting the main pancreatic duct, with gross dilation and overproduction of mucus. 2,3 As we became aware that the disease could be confined to the branches of the pancreatic ductal system, more and more cases were identified, fueled in part by increased use of cross-linear imaging. 4,5 For many years, IPMNs, particularly of the branch duct (BD) type, were confused or misdiagnosed with mucinous cystic neoplasms of the pancreas, and many reports indeed overlap both tumor types. It is now clear that these are 2 separate entities. Mucinous cystic neoplasms, which characteristically contain an ovarian-like stroma, do not arise in the ductal system of the pancreas. They also are single lesions located mostly in the body and tail of the pancreas, and have a unique epidemiologic profile, affecting almost exclusively middle-aged women. 6 The true incidence of IPMN is unknown. Cases that have undergone surgical resection (and therefore have pathologic confirmation) comprise about 15% of pancreatectomies. Because we resect at least twice as many pancreatic cancer cases (and these in turn represent only 15% of pancreatic cancer patients), we can assume that the minimum incidence of IPMN is about 1/13th of that of pancreatic cancer, equivalent to 0.8 per 100,000. By contrast, an increasing number of asymptomatic patients have pancreatic cysts, many of which are felt to be BD- IPMNs. A recent study using helical CT demonstrated a prevalence of 2.6%, with a mean pancreatic cyst size of 8.9 mm. 7 It is impossible to determine how many of these represent BD-IPMNs (versus nonneoplastic cysts or other types of cystic tumors), but even if only 10% of them were IPMNs, then the prevalence of the disease would be much greater than that of pancreatic cancer. Initially, IPMN was described as a disease affecting older men, often with a history of cigarette smoking. Analysis of recent series reveals geographic differences in the gender of patients with resected IPMN. 8 In Japan and Korea, the male-to-female ratio of main and BD-IPMN are 3 and 1.8, respectively, whereas in the United States these ratios are 1.1 and 0.76, and in Europe 1.5 and 0.66, respectively. The mean age at the time of resection is similar across regions, and ranges between 62 and 67 years. Clinical Manifestations Currently, most patients diagnosed with IPMN are asymptomatic. 9 The incidental discovery of IPMN, mostly of the BD variety, is made by computed tomography (CT) or magnetic resonance imaging (MRI) done for unrelated problems (urologic, gynecologic, vascular, or even thoracic problems, where cross-linear imaging includes cuts of the upper abdomen). When associated with symptoms, IPMN can present with abdominal pain, weight loss, jaundice, steatorrhea, diabetes, and pancreatitis. The latter was a sentinel symptom in 58 of the 389 (15%) cases, and occurred with equal frequency in main duct and BD-IPMNs. 10 It is not uncommon for patients who present with symptoms to have had them for many years before diagnosis. Radiology, Endoscopy, and Diagnosis The radiologic and endoscopic features of IPMN vary with the morphologic types. In classic main-duct 2010 by the AGA Institute /$36.00 doi: /j.gastro GASTROENTEROLOGY 2010;139:

2 IPMN, the pancreatic duct is markedly dilated (often 1 cm) and tortuous, with the dilation extending into the secondary branches that sometimes appear cystic. 11 The dilation can be confined to the distal pancreas, or, if the disease is located in the head of the gland, can be present throughout, because partial obstruction of ductal flow leads to dilation of the unaffected segment. Solid components can be observed within the lumen of the duct or in its walls, and calcification occurs in about 11%. 12 The pancreas can seem to be enlarged and show signs of pancreatitis, or can be atrophic. Endoscopically, the classic patulous papilla extruding mucus is seen in about 25% of cases, and when present is diagnostic. 13 Pancreatogram during endoscopic retrograde cholangiopancreatography (ERCP) can show filling defects within the duct, some representing tumors, and some inspissated mucus, and allows for brushings and obtention of pancreatic duct fluid 14 ; if pancreatoscopy is performed, it may visualize the papillary or villous growths within the duct. Endoscopic ultrasound (EUS) can readily identify the dilated main pancreatic duct and provide morphologic detail of any solid component within it, and also allows for sampling of fluid and targeted biopsies by fine-needle aspiration or core biopsies. 15 Radiologically, BD-IPMN manifests as either a cyst or cluster of cysts without dilation of the main pancreatic duct. 11 The cysts can be located anywhere in the pancreas, but are more common in the head, particularly in the uncinate process, and in the neck of the gland. In a series of 147 BD-IPMNs, 39% were multifocal. 16 This percentage is likely much greater among nonoperated patients, particularly when evaluated with magnetic resonance cholangiopancreatography (MRCP), where multifocality is described in up to 64% of patients. 17 Postprocessing of CT and MRI often allows demonstration of the communication between the cyst (or cluster of cysts) and the main pancreatic duct. ERCP is less useful in the evaluation of BD-IPMN, but EUS can identify readily these lesions, detect solid components within them, and sample their contents. 15 Examination of the fluid of an IPMN can help to make the diagnosis. Typically, the fluid is viscous, although that is not always apparent. Mucin or mucinous cells can be seen in the aspirate, but this needs to be interpreted cautiously because the puncture is done through the gastric or duodenal wall, and therefore the needle can carry these cells. 18 Carcinoembryonic antigen (CEA) in the fluid is elevated in about two thirds of IPMNs, and less frequently so in other cystic lesions (except in the mucinous cystic neoplasm). 19 The levels of CEA, however, have no bearing whatsoever on the degree of dysplasia. 20 DNA from the fluid can be analyzed also for its quantity, allelic imbalance, and to specific mutations, such as in K-ras, all of which can also be helpful to make the diagnosis and to a limited extent make a possible prediction regarding likelihood of malignancy. 21 Pathology and Molecular Genetics The category of IPMN 22 was created originally to embrace all mass-forming, preinvasive neoplasia comprising mucinous ductal cells, arising from the native pancreatic ducts, but unaccompanied by an ovarian type stroma, which distinguishes them from mucinous cystic neoplasms. 23,24 Accordingly, included in this broad entity is a wide spectrum of lesions, some small, minimally proliferative, and predominantly cystic, whereas others exhibiting florid papillary nodular neoplasms filling the entire ductal system. The degree of neoplastic transformation is also highly variable, from those with an entirely innocuous cell population, typically resembling gastric epithelium and lacking any cytologic atypia (formerly referred to as hyperplasia ) to those that have progressively increasing degrees of cytoarchitectural atypia, thereby reflecting stepwise dysplastic transformation into an in situ carcinoma. 25 As such, IPMNs represent by analogy an adenoma carcinoma sequence, and as in adenomas of the colon, the neoplastic transformation may culminate in invasive carcinoma in some patients. IPMNs are ductal type neoplasia and thus express ductal lineage markers and mucin-related glycoproteins. Molecular alterations that characterize ductal adenocarcinomas such as mutation in K-ras and p53, expression of epidermal growth factor, and ERBB2, and loss of CDKN2A are also detected in IPMNs but to a lesser degree and mostly in the more advanced examples. Interestingly, SMAD4 (DPC4), which is lost in about half of ductal adenocarcinomas, is retained in most IPMNs. 26 In Peutz-Jeghers patients with IPMN, bi-allelic inactivation of STK11 is noted. 27 Insights into the pathogenesis of IPMNs and mucinous cystic neoplasms have emerged through the generation and characterization of genetically engineered mouse models. 28,29 Cellular Diversity in Preinvasive Components of IPMNs Cystic but nonpapillary components of IPMNs often exhibit a tall, columnar mucinous epithelium with morphologic characteristics very similar to that of gastric foveolar epithelium. Some authors refer to this as null cell type. This appearance is very similar to the recently characterized pancreatic duct glands, 30 and indeed one could speculate that these may be the site of origin of IPMNs. As the neoplastic transformation progresses and papillae begin to form, 1 of 4 distinct cell types emerge 24,31 (Figure 1): 1. The gastric type, similar to the null cells in cystic components of IPMNs, is virtually indistinguishable 709

3 Figure 1. Morphologic and histologic subtypes of IPMNs, as well as the types of invasive cancer. The heavy arrows indicate the most prevalent associations, whereas the thin and dotted arrows indicate less common and rare associations, respectively. By far, BD-IPMNs are the most common, and are mostly of a gastric phenotype. Although the majority do not progress to invasive cancer, when they do, the carcinomas are of the tubular type. By contrast, main and combined duct IPMNs are mostly of the intestinal type, and most do progress into invasive cancer, which is of the colloid type. 710

4 from gastric mucosa. It has low proliferative activity, and rarely exhibits malignant transformation. The vast majority of BD-IPMNs are of this type. Invasion is uncommon, but when it occurs, is usually of the tubular type. 2. The intestinal type, which is morphologically very similar to colonic villous adenomas, expresses the intestinal lineage markers CDX2 and MUC2. A majority of the main duct type IPMNs are of this type, raising the suspicion that this metaplastic intestinal pathway may be the result of exposure of the main duct mucosa to a refluxate from the duodenum. Intestinal type IPMNs tend to be large, complex, and prone to have invasive carcinoma; however, the invasive carcinomas arising from this type are more commonly of the colloid type (a tumor that also expresses CDX2 and MUC2) and have a more protracted clinical course if removed surgically without any intraoperative contamination. 3. The pancreatobiliary type is less common. It is characterized by a complex papillary configuration. Many cases previously reported as papillary adenocarcinoma in the pancreas would now be classified as this. The cells are cuboidal and demonstrate significant atypia that typically qualify for at least carcinoma in situ (CIS). This group is often seen in an intimate mixture with less atypical gastric type epithelium, and for this reason, some observers believe that this represents the highgrade dysplastic version of gastric type rather than a specific type of its own. This variant is characterized by MUC1 expression (marker of aggressive phenotype in the pancreas), and lack of intestinal differentiation markers (MUC2/CDX2). Invasive carcinomas arising from this group are often the tubular type, seldom of the colloid type, and tend to have a more aggressive behavior. 4. The oncocytic type was originally described as a separate category under the category of intraductal oncocytic papillary neoplasm. 32 This group is now regarded as a distinct subset of IPMN, although it shows some peculiar characteristics. The papillae are often very delicate and arborizing, and the cells contain abundant mitochondria, which lead to the distinctive oncocytic appearance with voluminous acidophilic granular cytoplasm and single prominent nucleoli. Despite their highly proliferative nature and atypical cytology qualifying them as CIS, most examples are devoid of invasive carcinoma, and, if present, invasion is usually limited in amount. Many of the molecular markers characteristic of ductal neoplasia of the pancreas including other subsets of IPMNs such as mutation of K-ras oncogene seldom occur in oncocytic IPMNs. 33 Invasion in IPMNs Invasive carcinomas arising in IPMNs are typically of 2 types (Figure 1): 1. Tubular-type, characterized by infiltrating small tubular elements that are widely separated by desmoplastic stroma, and that is morphologically indistinguishable from ordinary pancreas cancer (ductal adenocarcinoma). 2. Colloid ( muconodular or mucinous noncystic ) type, which is morphologically very similar, if not identical, to those of other exocrine organs, namely the breast and skin. Colloid carcinomas are characterized by paucicellular pools of mucin that contain scant carcinoma cells. In the breast and skin, pure examples of this entity have an excellent prognosis, and there is now strong evidence that same is also true for pancreatic examples, which almost invariably develop in association with IPMN. 34 Management and Prognosis The management of IPMN has evolved over the last 2 decades. Initially, it was felt that this lesion, even if detected in its benign phase, would inevitably evolve into invasive cancer, and therefore, resection was recommended in all cases. Because this was an uncommon diagnosis and its discovery happened at a time when pancreatic surgery had become safer, the validity of this premise was not questioned. However, as increasing numbers of IPMNs were removed and found to harbor no malignancy, and most of these were occurring in elderly, asymptomatic patients, the unconditional operative resection policy was challenged, and several centers throughout the world began to monitor some of these patients rather than operating on them. In 2004, a group of gastroenterologists, pathologists, and surgeons met in Sendai, Japan, and reviewed the existing published evidence, as well as the cumulative experience from the centers represented by the participants. This led to the publication of the International consensus guidelines for the management of IPMN and mucinous cystic neoplasms. 35 These guidelines proposed strict adherence to the histologic criteria of presence of an ovarian-like stroma to diagnose a mucinous cystic neoplasm, thereby avoiding the frequent overlap and confusion between these lesions and BD-IPMNs. They also continued to recommend operative resection for all surgically fit patients with IPMN affecting the main pancreatic duct (either alone or in combination with branch ducts), based on the very high prevalence of invasive and CIS seen in resected specimens (70%), and which was present regardless of the presence or absence of symptoms. By contrast, the Sendai guidelines acknowledged that the prevalence of malignancy in BD-IPMNs was much lower (25%), and that unlike main duct IPMN, its presence could be predicted on the basis of symptoms, size, and other morphologic criteria. Because of this, the group recommended observation alone for asymptom- 711

5 atic patients with BD-IPMN measuring 3 cm, with no nodules or ductal dilation (which if present, would imply a combined type IPMN), with repeat imaging at 6 months, and then annually thereafter, unless there was an increase in size, development of nodules, or onset of symptoms. At least 3 large, retrospective series validated the safety of these recommendations. 16,36,37 Encompassing 250 patients with resected IPMNs, they found that indeed no patients who met the above criteria had cancer within the surgical specimen. An increasing number of patients with presumed BD-IPMNs are now being monitored, and although median follow-up is still brief, these series indicate that the percentage of patients that require surgery because of progression (ie, increase in size, development of nodules, duct dilation, or symptoms) is small, averaging about 15%, and that within those, the proportion who have cancer is 20%. 9,16,17,38,39 Although a few reports have described malignancy within IPMNs that would have met criteria for observation alone, these constitute the exception and have not challenged the robustness of the Sendai guidelines. 39,40 A recent decision analysis with Markov modeling concluded that for patients focused on survival, a 2-cm threshold for resection may be more appropriate, whereas for those focused on quality-adjusted survival, the 3-cm guideline may be best. 41 An evolving issue is the presence of concomitant pancreatic ductal adenocarcinoma (PDAC; either synchronous or metachronous) in patients with BD-IPMN. These are carcinomas distinct (ie, not contiguous) to the IPMN. In 1 study, PDAC was found in 11% of 200 patients with BD-IPMN, 42 and in another report the incidence of PDAC was estimated to be 1.1% per year (representing a standardized index ratio of 26) in a cohort of 60 patients with BD-IPMN who were being followed. 43 It is unclear if this translates into the presence of a field defect or if this is a random event (given the high prevalence of asymptomatic cystic lesions in elderly patients), but it is important to point that these ductal adenocarcinomas would not have been prevented by removing the IPMN, unless we were to perform total pancreatectomies in these patients at the time of diagnosis of the BD-IPMN or we hypothesize that a humoral factor from the IPMN triggered the carcinogenesis. The operative management of main duct IPMN involves complete resection of the lesion with assurance of negative margins and a lymphadenectomy. The precise location and determination of the tumor extent is done differently throughout the world. At the very minimum, it requires a high-quality CT and/or MRI with MRCP. Some centers routinely perform preoperative ERCP with pancreatoscopy and sampling, whereas others pursue EUS, and still others rely on intraoperative ultrasound and pancreatoscopy. Because most main duct IPMNs are located in the head of the pancreas, the most common operation is a pancreatoduodenectomy (Whipple procedure). Because IPMN extends along the pancreatic duct and can do so without any obvious macroscopic tumor, it is important to exclude residual tumor in the margin by frozen section. Surgery for BD-IPMNs is more problematic, because many are multifocal and a negative margin therefore does not indicate complete removal. It is not uncommon to do surgery that removes the dominant lesion or lesions (those that meet size or morphologic criteria), and leave others behind and continue to survey them to avoid a total pancreatectomy. Because of the potential to modify or extend the resection plans intraoperatively, it is important that the surgeon discuss and evaluate preoperatively the risks and consequences of a total pancreatectomy with the patient. In our experience with 285 resected patients, this was needed in 18.5% of patients with main or combined IPMN, and 1.4% of those with BD-IPMN. 13,36 The prognosis of completely resected IPMN with low, moderate, or high-grade dysplasia (formerly CIS) is excellent, with 95% 10-year disease-specific survival for both main duct and BD-IPMN. 10 Recurrences can be seen (and can potentially harbor invasive cancer) in patients with BD-IPMNs or in those with main duct IPMN and a falsely negative transection margin because of denuded epithelium. For patients with invasive IPMN, the 5-year overall survival is approximately 40%. 44 It is unclear if this better survival, when compared with PDAC, is related to an earlier stage of presentation or detection (ie, smaller tumors and less likelihood of nodal metastases in IPMN) and/or due to a different biology. Patients with colloid and oncocytic invasive carcinoma have much better survival than those with tubular carcinoma. 45 Uncontrolled data suggest a benefit of chemoradiation following resection for invasive IPMN, particularly in the presence of lymph node metastases or positive margins. 46 Other Forms of Treatment A number of reports, including a small randomized trial, have evaluated the use of ethanol as ablative treatment for BD-IPMN. 47 In a few cases that have been resected after ablation, the epithelial lining of the cyst has found to be destroyed, and in some patients treated with ethanol, the cysts have not recurred. However, follow-up has been short, and it is unclear if there was any benefit from the ablation, because these patients all had small cysts without nodules who could have been managed by observation alone. Limitations of ethanol ablation include the multicystic nature of many BD-IPMNs and potential passage of ethanol into the main ductal system with resultant scarring. Another study described the use of sulindac in 10 patients with BD-IPMN who met criteria for resection but refused surgery, and found a de- 712

6 crease in both cyst size and nodule height over 18 months. 48 At present, both of these modalities should not be utilized outside of a strict clinical trial. Future Directions IPMN is a disease with a great evolution of insights into pathogenesis, diagnosis, and therapy, but unanswered questions remain, which offer fertile ground for study. Foremost, there is an urgent need for longitudinal studies to define the natural history of incidentally discovered BD-IPMN. If indeed 2.8% of the adult population has pancreatic cysts, and this prevalence increases with age, the cost of lifelong surveillance with MRI or CT will be staggering undoubtedly. We need to figure out the optimal evaluation for these patients and ways to stratify those at higher risk of progression, because the opportunity of treating early pancreatic cancer cannot be missed. The molecular genetics of noninvasive and invasive IPMN need to be unraveled and compared with PDAC, because this knowledge has the potential to identify therapeutic targets to improve survival in the nearly patients who die each year with pancreatic cancer. Supplementary Material Note: The first 5 references associated with this article are available below in print. The remaining references accompanying this article are available online only with the electronic version of the article. To access the remaining references, visit the online version of Gastroenterology at and at doi: / j.gastro References 1. Ohashi K, Murakami Y, Maruyama M. Four cases of mucin-producing cancer of the pancreas on specific findings of the papilla of Vater. Prog Dig Endoscopy 1982;20: (in Japanese). 2. Bastid C, Bernard JP, Sarles H, et al. Mucinous ductal ectasia of the pancreas: A premalignant disease and a cause of obstructive pancreatitis. Pancreas 1991;6: Loftus EV, Olivares-Pakzad BA, Batts KP, et al. Intraductal papillary-mucinous tumors of the pancreas: clinicopathologic features, outcome, and nomenclature. Gastroenterology 1996;110: Terris B, Ponsot P, Paye F, et al. Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct. Am J Surg Pathol 2000;24: Matsumoto T, Aramaki M, Yada K, et al. Optimal management of the branch duct type intraductal papillary mucinous neoplasms of the pancreas. J Clin Gastroenterol 2003;36: Reprint requests Address requests for reprints to Carlos Fernández-del Castillo, MD, Director, Pancreas and Biliary Surgery Program, Massachusetts General Hospital, Professor of Surgery, Harvard Medical School, 15 Parkman St, ACC 460, Boston, Massachusetts cfernandez@partners.org. Conflicts of interest The authors disclose no conflicts of interest. 713

7 713.e1 Mini-Reviews and Perspectives GASTROENTEROLOGY Vol. 139, No. 3 References (Online Only) 6. Crippa S, Salvia R, Warshaw AL, et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg 2008;247: Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. AJR 2008;191: Ingkakul T, Thayer SP, Ferrone CR, et al. Epidemiology of intraductal papillary mucinous neoplasms of the pancreas: gender differences between 3 geographic regions. Journal of the Japan Pancreas Society 2010;25: Ferrone CR, Correa-Gallego C, Warshaw AL, et al. Current trends in pancreatic cystic neoplasms. Arch Surg 2009;144: Crippa S, Fernández-del Castillo C, Salvia R, et al. Mucin-producing neoplasms of the pancreas: an analysis of distinguishing clinical and epidemiologic characteristics. Clin Gastroenterol Hepatol 2010;8: Sahani DV, Kadavigere R, Blake M, et al. 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