Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are becoming recognized more frequently and attracting increasing attention. The reasons for this increased interest are 4-fold: (1) greater recognition associated with the widespread use of imaging technologies; (2) changing indications for surgical resection; (3) improved knowledge of malignant transformation; and (4) an unexpectedly high incidence of concomitant but distinct ordinary-type adenocarcinoma of the pancreas. Accumulating evidence has led to a better understanding and increased awareness of this entity, but some controversies and unsolved issues remain regarding its management, especially of branch duct IPMN (BD-IPMN). This review addresses current controversies and future perspectives of IPMN.
The international consensus guidelines on the management of IPMN and mucinous cystic neoplasm of the pancreas were published in 2006 (Sendai)1 and revised in 2012 (Fukuoka).2 The Fukuoka guidelines proposed 2 main changes: a lower threshold size (≥5 mm) of the main pancreatic duct (MPD) and branch duct for the recruitment of main duct IPMN (MD-IPMN) and BD-IPMN, respectively, to increase the sensitivity of the diagnosis; and the use of 2-phase criteria for the preoperative prediction of malignancy, that is, worrisome features warranting thorough examination by endosonography and high-risk stigmata of probable malignancy indicating surgical resection in fit patients.
Both of these guidelines are based on consensus among international expert investigators, including 5 from Japan, 3 from the United States, and 1 from Europe in the case of the Sendai guidelines and 6 from the United States, 5 from Japan, 2 from Europe, and 1 from Korea for the Fukuoka guidelines. We are aware that the ultimate goal is to establish “evidence-based” guidelines and currently await more evidence, especially regarding the morphological classification, prediction of malignant changes, and indications for surgical resection. It is therefore possible that subsequent guidelines may be based on forthcoming evidence.
In particular, more evidence is needed regarding the appropriate surveillance methodology and time intervals needed to detect malignant changes in BD-IPMN (Fig. 1) and/or to reveal the development of distinct pancreatic ductal adenocarcinoma.
The mixed-type category was retained in the morphological classification of IPMN in the Fukuoka guidelines, although the justification for this category has long been questioned.2 Dilation of the MPD is considered a significant factor in predicting malignant transformation of BD-IPMN as a malignant stigmata (≥10 mm) and worrisome feature (5–9 mm), and the mixed-type category may therefore not be needed in practice. However, the true involvement of the MPD in IPMN can only be confirmed by histological examination of resected specimens, and the mixed-type category may be necessary to indicate the involvement of the MPD in patients with BD-IPMN from the histopathological viewpoint, but not for the preoperative radiological classification of IPMN.
Intraductal papillary mucinous neoplasm in the extreme upstream region of the MPD in the tail of the pancreas is not uncommon, but its classification is also unclear, and the classification of an IPMN arising in the arborizing branches of the pancreatic duct in the extreme tail of the pancreas as BD type or MD type needs to be clarified.3 Most investigators currently judge the type classification in relation to the longitudinal axis of the MPD; an IPMN at the end branch of the MPD along its longitudinal axis is regarded as MD-IPMN, whereas one in the other direction would tend to be classified as BD-IPMN. However, IPMN usually involves multiple branches, making such distinctions impractical. The oncological behavior of IPMN in this particular region needs to be clarified to provide evidence to address this issue.
INDICATIONS FOR SURGICAL RESECTION
Pathological analyses of resected IPMN specimens always include noninvasive carcinoma or high-grade dysplasia (HGD). The surgical indication for these patients is based on the presence of indirect predictors in diagnostic images, and whether noninvasive carcinoma or HGD should be operated on or can still be observed remains an unsolved practical question, given the lack of information on the natural history of IPMN progression after malignant transformation. The period when noninvasive carcinoma turns into invasive carcinoma is not yet known, and most investigators therefore prefer to include noninvasive carcinoma within the surgical indications.
We previously demonstrated that noninvasive carcinoma and T1a carcinoma of IPMN, formerly called minimally invasive carcinoma, that is, within the 5-mm depth of invasion, were associated with a 100% survival rate after resection, although T1a carcinomas may be accompanied by lymph node metastasis in 20% of cases.4 Although this rate of lymph node metastasis was lower than the 53.1% reported for “massively” invasive carcinomas, it would be preferable to excise IPMN in its noninvasive phase to avoid the risk of recurrence from lymph node metastasis. It is therefore essential to be able to predict the presence of noninvasive carcinoma, although this is not yet possible.
PREDICTORS OF MALIGNANCY IN IPMN
The high incidence of malignancy in MD-IPMN is obvious; however, the factors predicting malignancy in BD-IPMN, including HGD, have not yet been established. The Sendai criteria, including symptomatic, more than 3 cm, or mural nodules, were established on the basis of accumulating evidence and gained widespread popularity.1,5 Of these criteria, the presence of mural nodules proved to be the most reliable predictive sign of malignancy and were most accurately demonstrated by endoscopic ultrasonography (EUS). Ohno et al6 further characterized mural nodules into 4 types, namely, low papillary, polypoid, papillary, and invasive. Among these, the papillary type (a protruding component with a thickened wall of BD-IPMN or MPD or with an irregular, villous structure) and invasive type (papillary nodules connected to an ill-defined hypoechoic area) were indicative of malignancy. Although the presence of enhanced mural nodules was repeatedly reported to be a predictor of malignancy,7–9 the size criteria for the mural nodules have varied, and 5 mm,10,11 7 mm,12 and 10 mm13 have all been applied. The size criterion for mural nodules to predict malignancy therefore needs to be defined in greater detail.
The frequency of malignancy in BD-IPMNs greater than 3 cm without mural nodules is relatively low, being only 13% to 23%,14,15 whereas there have been a few reports of malignant BD-IPMNs 3 cm or less without mural nodules.16,17 In view of the low frequency of malignancy in such “flat” BD-IPMNs, the size criterion has been excluded from high-risk stigmata in the Fukuoka guidelines.2 Nevertheless, given that a proportion of flat BD-IPMNs contain HGD, concerns remain over how long HGD can be left without risking invasion.
Kang et al18 reported that an increased rate of cyst growth (4.1 mm per year for malignant vs 1.0 mm per year for benign, P = 0.001) may also predict malignant changes of IPMN. Ohtsuka et al19 reported that an increase in the number of predictive factors in the Sendai guidelines indicated a greater likelihood of malignancy, whereas Shimizu et al20 proposed a nomogram consisting of multiple factors to predict malignancy.
Pedrazzoli et al21 reported that positron emission tomography was more accurate than the Sendai guidelines criteria for distinguishing between malignant and benign IPMNs. Positron emission tomography was performed in patients with clinically or radiologically suspected malignancy or when tumor markers were increased and was considered positive when the standardized uptake value was 2.5 or greater. However, the Sendai criteria were rarely evaluated by EUS in this study. It is necessary to develop new strategies to detect and stratify malignancy or malignant potential in IPMNs to ensure that appropriate treatment can be pursued.
Cytology is the criterion standard for the diagnosis of malignancy in IPMNs and can be evaluated by the examination of pancreatic juice collected during endoscopic retrograde cholangiopancreatography (ERCP) or of cyst fluid obtained by EUS-guided fine-needle aspiration (FNA). Endoscopic retrograde cholangiopancreatography cytology is performed mainly in Japan and Korea, whereas EUS-FNA cyst fluid cytology is used chiefly in the United States, although both techniques have inherent advantages and disadvantages.
Pancreatic juice cytology is notorious for its relatively low sensitivity for diagnosing malignancy,22 although its sensitivity can be increased to 80% by repeated sampling through a nasopancreatic catheter placed in the pancreatic duct.23 Irrigation of the pancreatic duct during ERCP cytology was also reported to raise the sensitivity to 78%.24 Cytology combined with mucin (MUC) staining is a reliable method for diagnosing IPMN subtypes preoperatively, with an accuracy of 89%.25 Malignant grades, including HGD and invasive IPMN, could be diagnosed with 77.2% sensitivity, 85.7% specificity, and 80.5% accuracy. However, acute pancreatitis remains a major and serious drawback.
Histological subtypes as well as histological grades can be fairly accurately diagnosed by cell block cytology of preoperative pancreatic juice samples26; however, histological grading by cell block cytology only plays a supplementary role, being consistent with histological results from resected specimens in 100% of MD-IPMNs and mixed-type IPMNs, but only 55.6% of BD-IPMNs.25,27
Cyst fluid obtained by EUS-FNA provides a sensitivity and specificity of 67% and 88%, respectively, for the diagnosis of malignant BD-IPMN.28 A higher sensitivity of 80% and similar specificity of 85% have also been reported.29 Pitman et al30 noted the significance of “atypical epithelial cells” in combination with carcinoembryonic antigen of greater than 2500 ng/mL as more accurate indicators of malignancy.
The disadvantages of cyst fluid analysis for the diagnosis of malignant BD-IPMN include acute pancreatitis, bleeding, and rarely, but most seriously, gastric-wall seeding and peritoneal dissemination of cancer cells.31,32 Duodenal fluid is currently being explored as an alternative to pancreatic juice or cyst fluid and may provide a breakthrough toward the safer and more effective preoperative prediction of malignant IPMNs, with the aid of biomarkers identified by modern analytical methods.33,34
Evidence for potential new biomarkers for the diagnosis of malignant changes in IPMN are accumulating through immunohistochemical, molecular, and genetic studies. Masuda et al35 demonstrated that MUC2 expression was an independent predictor of HGD and invasive carcinoma in mixed-type IPMN. REG4 expression was significantly higher in colloid carcinoma, and its mRNA expression level was significantly higher in its precursor, intestinal subtype IPMN, than in other subtypes.36 Patients with pancreatic ductal adenocarcinoma with higher claudin-4 expression showed longer survival,37 and claudin-4 expression was associated with neoplastic progression of IPMN, especially intestinal subtype.38 In contrast, positive expression of thrombospondin 1 was frequently detected in the pancreatobiliary and oncocytic types of IPMN.39 However, all these investigations were performed immunohistochemically using resected samples of IPMN, and their usefulness for the preoperative prediction of malignancy in IPMNs is not clear.
The detection of mutations by next generation sequencing has the potential to improve the diagnostic and prognostic stratification of IPMNs.40 KRAS, GNAS, and RNF43 are frequently mutated in IPMN,40–43 although these findings are also based on the analysis of resected IPMN specimens.
Direct sampling of cyst fluid and/or pancreatic juice has facilitated attempts to improve the preoperative prediction of malignancy. Telomerase activity and human telomerase reverse transcriptase were expressed in association with histological grade progression of IPMNs.44–47 Interleukin 1β in cyst fluid was also demonstrated to be a significant predictor of high-risk IPMNs.48 These activities can be assessed in pancreatic juice or cyst fluid and could be used as a preoperative adjunct to cytological diagnosis.44,45,47 The inherent drawbacks of sampling pancreatic juice by ERCP and cyst fluid by EUS-FNA may be eliminated in the near future by using duodenal fluid instead.34,49,50 In addition, recent sophisticated proteomic assessments may reveal other, more efficient and accurate biomarkers.51
STRATEGIES FOR THE SURVEILLANCE OF IPMN
The international consensus guidelines and some investigators advocate lengthening the surveillance interval after 2 years of no change on imaging.1,2,52 However, there is currently no evidence to support the value of lengthening the surveillance interval. On the contrary, the development of concomitant pancreatic cancer has been reported by many Japanese investigators and poses an important and serious problem to the surveillance of IPMN.53–60 These investigators claimed that lengthening the surveillance period may be harmful, in view of the relatively high incidence of concomitant but distinct pancreatic cancer, as stated in the Fukuoka consensus guidelines.2 Tamura et al61 demonstrated that even a 6-month interval might not be sufficient to diagnose a concomitant pancreatic cancer in a patient with IPMN.
Appropriate methods for the early detection of concomitant pancreatic cancer, in addition to surveillance, need to be established as soon as possible. Alternate computed tomography (CT) and magnetic resonance imaging (MRI) may miss early concomitant pancreatic cancers,61 and this approach is therefore inadequate. Kamata et al62 followed up 102 patients with BD-IPMN by EUS every 6 months for a median of 3.5 years and found concomitant pancreatic cancers in 7 patients, whereas CT, MRI, and percutaneous ultrasonography performed immediately after the EUS diagnosis revealed the pancreatic cancer in only 56%, 50%, and 39% of those patients, respectively. This highlights the lack of sensitivity of ultrasound, CT and MRI for the diagnosis of pancreatic cancer. Sakamoto et al63 stressed the importance of EUS with additional contrast enhancement for diagnosing small pancreatic cancers concomitant with IPMN. We would also like to emphasize the significance of ERCP cytology for the very early detection of pancreatic cancer in patients with IPMN.64
Pancreatic carcinogenesis may be present in multiple sites within the pancreas in patients with IPMN and may continue to exist even after resection of IPMN or the concomitant pancreatic cancer. Surgeons and pathologists responsible for patients with IPMN sometimes detect multifocal cancers in a resected pancreas harboring IPMN.65 A recent study revealed that multiple IPMNs (≥10) were associated with a higher prevalence of noninvasive or invasive concomitant pancreatic cancer.66 This may be attributable to “field carcinogenesis” of the pancreas affected by IPMN in the presence or even absence of a family history of pancreatic cancer.1,67 This field carcinogenesis may give rise to pancreatic cancers even after resection of invasive or noninvasive IPMN or concomitant pancreatic cancer, necessitating indefinite close surveillance.68,69
In conclusion, we still need more accurate methods to predict noninvasive carcinoma or at least T1a carcinoma in IPMNs. How long HGD can exist without a risk of invasion also remains a concern. A detailed size criterion of mural nodules as the most reliable predictor has yet to be defined, and more efficient and accurate biomarkers are needed for examination of pancreatic juice and cyst fluid. Finally, recognition of concomitant pancreatic cancer is questioning the value of lengthening the surveillance interval and the adequacy of computed tomography and MRI for the surveillance of IPMNs.
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