Cystic pancreatic lesions are being increasingly diagnosed using modern imaging.22
In a recent study, abdominal MR scans of 616 patients without any pancreas related symptoms revealed cystic lesions in 13.5% of the patients, of which 40% were found to be multifocal.23
Even higher incidence rates of asymptomatic pancreatic cysts can be derived from autopsy series, with incidental cysts reported in up to 25% of necropsies.24
Given that there are ever increasing numbers of abdominal CT and MR scans performed annually, the potential exists for a veritable epidemic of such asymptomatic cysts being identified. At our institution, and at other high-volume pancreatic surgery centers, IPMNs already represent the second most frequent indication for pancreatic surgery (after pancreatic ductal adenocarcinoma).25
The reported rate of multifocality of IPMNs either synchronous or metachronous varies drastically in literature (). The use of different technologies by different studies and the failure to histological document multifocality may explain some of this variability.26,27
Although modern imaging techniques are capable of detecting minimal changes in the pancreatic parenchyma, potential multifocality of IPMN lesions can best be ascertained by a meticulous histopathological analysis of the resection specimen. Lesions that appear solitary on imaging sometimes prove to be multifocal on assessment of the resection specimen. For example, in a study by Rodriguez et al, the investigators reported that histopathological examination of BD-IPMNs revealed the presence of more multifocal IPMNs than reported within preoperative radiologic evaluation (25.6% vs 14.5%). In contrast, single “grape-like” localized BD-IPMNs often mimic multifocal IPMNs, as microscopic examination of these latter lesions frequently shows an extensive solitary neoplasm with intraductal extension. Even a thorough histopathologic analysis cannot always unambiguously distinguish between a complex IPMN and multifocal independent lesions. As another example, a clear distinction between a large PanIN lesions and a small IPMN is often challenging both contributing to a misjudgment of multifocality in IPMNs. In the present study, we only included cases with histologically documented multifocality according to the final pathology report, and it is likely that the real number of multifocal IPMNs is much higher.
To characterize better the clinicopathologic correlates of multifocal IPMNs, we only included patients who had histologically documented multifocal disease. The age distribution of patients with multifocal IPMNs was similar to previous studies of solitary IPMNs.26,27
The fact that the median age of patients with synchronous IPMNs was higher than the age at primary surgery in the metachronous group (69 years vs. 64 years) may reflect greater symptomatology in patients with multifocal IPMNs, or it may be that surgeons are more likely to intervene earlier in patients with multifocal disease than they are in patients with solitary disease. The number of patients with metachronous disease was too small to draw final conclusions about onset and course of disease.
Several larger outcome studies of the recent years now allow a more evidence-based therapeutic approach for IPMNs, and there is an emerging consensus that not all pancreatic cysts require surgical resection. Criteria for the surgical versus conservative management of IPMNs were proposed at a 2004 conference organized by the International Association of Pancreatology (IAP) in Sendai, Japan, and subsequent reports have broadly validated these recommendations. On the basis of the literature that main duct IPMNs are more frequently associated with an invasive carcinoma than are branch duct-type IPMNs, it was recommended that main duct lesions should be resected. In contrast, smaller asymptomatic BD-IPMNs (ie, asymptomatic <30mm in maximum diameter without mural nodules) are mostly benign, and periodic observation without resection is considered justifiable in the majority of patients.2,10,14,26–30
For example, a retrospective study from the University of Verona and Massachusetts General Hospital assessed the histopathology of resected BD-IPMNs from 145 patients who underwent surgery.26
The rate of malignancy (defined as either invasive cancer or IPMN with high-grade dysplasia) was 22%, and strict adherence to the “Sendai criteria” would have identified cysts with high-grade dysplasia or an associated invasive carcinoma, and deemed the corresponding patients as candidates for surgery. Similarly, Salvia and colleagues31
retrospectively analyzed 109 patients with BD-IPMNs, of which 20 (~18%) underwent surgical resection on the basis of resection criteria outlined in the Sendai recommendations, whereas the remaining 89 were followed conservatively with periodic radiological examination. Five patients in the conservative observation group developed worrisome cyst features and subsequently had their lesion surgically resected, whereas the remaining 84 (~95%) patients, including 57 (64%) with multifocal lesions, remained asymptomatic without any disease-related complications for the follow up period of 32 months.
The most appropriate management of multifocal IPMNs has not been established. Some insights into the natural history of multifocal IPMNs have emerged from the previously cited study by Salvia and colleagues,31
in which 57 patients (64%) with multifocal IPMNs were followed for 32 months in the absence of surgical intervention or antecedent complications. In 2009 the same group published a retrospective study which exclusively focused on 131 patients with multifocal BD-IPMNs, 121 (92%) of whom were conservatively managed, and the entire cohort was alive after a median follow up of 40 months. Nine of the 10 patients who underwent surgical resection were alive without any signs of recurrence after a median of 56 months. The tenth patient presented with invasive carcinoma arising in association with an IPMN, and died of hepatic metastases 88 months postoperatively.32
The overall conclusion of this study was that carefully selected subsets of patients with multifocal BD-IPMNs can be followed without surgical intervention, as long as the involved cystic lesions are radiologically evaluable over time for the appearance of ominous signs. Similarly, Tajima et al33
reported the case of a 66-year-old woman who underwent pylorus-preserving pancreaticoduodenectomy for a BD-IPMN demonstrating as a grape-like multilocular cyst of 3.5 cm in the head along with numerous small BD-IPMNs in the entire rest of the pancreas. This patient is reported to be doing well without relapse 9 years after surgery.
The majority of the multifocal IPMNs included in our series were of gastric-foveolar subtype, with only low to intermediate dysplasia of the lining epithelium. Thus, on the basis of our series, and previously published data, it is reasonable to conclude that multifocality, in itself, is not a risk factor for aggressive disease, and that the “Sendai criteria” can reasonably be applied to multifocal lesions as they are to solitary IPMNs.
We also observed distinct genetic alterations among multifocal IPMNs from the same patient, suggesting that these IPMNs are genetically distinct events.
We selected KRAS
gene mutations as an important determinant of clonality, because this gene has been shown to be altered early in most IPMNs.34–36
In addition, we selected 4 microsatellite loci in 2 chromosomal regions frequently lost in IPMNs.19–21
In contrast to Izawa et al,37
we restricted the analysis to true multifocal IPMNs, rather than a combination of solitary IPMNs and associated PanIN lesions. We also carefully excluded patients with a family history from the genetic component of this study, since such patients are likely to harbor a constitutional genetic predisposition in every cell in the body, including the pancreas, and may develop multifocal lesions akin to what is observed in colorectal polyposis. We observed evidence of clonal heterogeneity in as many as 69% of multifocal IPMNs studied in our series, including low grade BD-IPMN lesions. This finding helps establish that multifocal IPMNs are truly multifocal, and not simply a single lesion with multiple dominant genetically identical cysts.
Our finding of metachronous IPMNs reinforces a long-held clinical observation that the remnant pancreas in many IPMN patients remains at risk for the development of an invasive carcinoma whereas total pancreatectomy, although associated with its own risks, averts the risk of an invasive cancer arising from a metachronous IPMN.16
In conclusion, this study on multifocal IPMNs confirms that the vast majority of such lesions arise in the branch ducts, and harbor low to intermediate grades of dysplasia in the lining epithelium, which is typically of the gastric-foveolar histological subtype. Patients with multifocal IPMNs in the nonfamilial setting can be conservatively followed as long as the entire pancreatic field is amenable to careful radiological examination. The demonstration of clonal heterogeneity and distinct molecular alterations in synchronous IPMNs helps establish that multifocal IPMNs are independent lesions.