The apparent incidence of MPNs of the pancreas, and particularly of IPMNs, has increased markedly during the past 15 years; these now represent one of the most common indications for pancreatic resection at high-volume centers.14–17
The higher numbers of reported cases might be due to improved imaging techniques, greater awareness of this pathology by the gastroenterological community, and increased incidental diagnosis among asymptomatic individuals.
It is only in recent years that a clear distinction between MCNs and IPMNs and between branch-duct and main-duct IPMNs has emerged.13–18
Growing knowledge of their biologic behavior indicates that clear identification and distinction of MCNs and main-duct and branch-duct IPMNs are not only of taxonomic significance but have a practical impact on patient management. For example, branch-duct IPMNs appear to carry a much lower risk of malignant degeneration compared with main-duct IPMNs, and nonsurgical management with surveillance is feasible for many of these lesions, thereby avoiding “prophylactic” pancreatectomy with its associated risks.8,11,16,19–24
Nonetheless, in the past, a strict distinction was not made between the variants of IPMNs and MCNs.
As yet there has been no consensus as to whether main-duct and branch-duct IPMNs are 2 different neoplasms or a spectrum of the same condition, and whether combined IPMNs are a progression of main-duct or branch-duct type or a distinct disease as well.11,14,17
The latter question is of strategic importance because if combined IPMNs turn out to be a progression from branch-duct IPMNs, this would mandate a closer long-term surveillance of branch-duct IPMNs than is currently advised.
To provide clear-cut, reproducible distinctions between main-duct, branch-duct, and combined IPMNs and MCNs, we applied strict histopathologic criteria in our reviewing of 592 cases of MPNs of the pancreas. We excluded 35 mucinous lesions of indeterminate classification comprising 6% of the series.
Our study showed that branch-duct IPMNs have a specific profile, likely representing an entity distinct from other IPMNs, and that combined IPMNs show close overlapping similarities with main-duct IPMNs in regard to clinicopathologic and epidemiologic characteristics. For example, we found that main-duct and combined IPMNs have the same sex ratio (female, 44%; male, 56%), opposite to that of branch-duct type (female, 57%; male, 43%). Although the median age at presentation was similar in the 3 groups, patients affected by main-duct and combined IPMNs with invasive cancer were significantly older than those with noninvasive neoplasms. This age difference suggests progression from adenoma to invasive carcinoma, a finding that was not present in branch-duct IPMNs. Furthermore, branch-duct IPMNs were more likely to be asymptomatic, whereas the majority of patients with main-duct and combined IPMNs were symptomatic. Finally, most patients with branch-duct IPMNs had an adenoma (44%), whereas the prevalence of cancer was 22% (invasive cancer, 11%). In contrast, main-duct and combined IPMNs contained malignant elements in 68% and 62%, respectively, with invasive cancer present in 48% and 42%. Considering these findings, we conclude that combined IPMNs likely represent an extension of main-duct IPMNs to the branch ducts of the pancreas. The similar age differential between noninvasive and invasive tumors14,18
and the greater frequency of malignancy in both main-duct and combined IPMNs suggest that these 2 IPMN subgroups share not only common morphology but also an aggressive biology characterized by progression to invasive cancer.
No significant differences were found among the 3 groups with respect to disease-specific survival. The disease-specific survival rates found for all these types of IPMNs with invasive cancer appear to be higher than those seen in ductal adenocarcinoma of the pancreas and are consistent with other previously reported series.14,16,18
However, Schnelldorfer et al25
reported no differences in overall survival when comparing 63 patients with invasive IPMNs and 63 matched patients (by disease stage) with ductal adenocarcinoma (5-year survival, 31% versus 24%; P
=.26). A disease-specific survival analysis was not performed in this study. Larger studies with longer follow-up and careful patient stratification by disease stage and histopathologic prognostic criteria are needed to confirm these findings.
A surprising observation was the peritoneal recurrence 38 months from initial surgery in a patient with main-duct IPMN with in situ carcinoma who underwent total pancreatectomy. In retrospect, the specimen was divided during resection, thereby allowing mucin to spill from the resected duct, and we presume that tumor cells were seeded at this time. This experience, albeit rare, raises a concern about allowing egress of duct contents that might harbor tumor cells. Local recurrence or metachronous lesions in the pancreatic remnant were detected in patients with both invasive and noninvasive IPMNs, hypothesizing a “field defect” in the entire pancreas that could mandate lifetime surveillance.11,26,27
A second end point of the study was to compare MCNs and branch-duct IPMNs because MCNs and branch-duct IPMNs can be potentially confused, at least in the preoperative setting.11–13
Our data suggest that when strict histologic criteria are applied, in particular the presence of ovarian-like stroma, these neoplasms have very distinct clinicopathologic and epidemiologic features. In multivariate analysis, age, gender, site, and the presence of acute pancreatitis were independent predictors useful to distinguish MCNs and branch-duct IPMNs. Typically, MCNs present as a large cyst located in the distal pancreas of a middle-aged woman and have no connection with the ductal system. However, the differential diagnosis of small cysts located in the distal pancreas might be difficult. Modern imaging techniques, particularly magnetic resonance with cholangiopancreatography and endoscopic ultrasound, might demonstrate pancreatic duct branches emanating from the cyst lesion, thereby defining it as an IPMN.17,28
Multifocal cysts also indicate IPMNs, inasmuch as MCNs are always single.
The distinction among main-duct, branch-duct, and combined IPMNs and MCNs has major implications in clinical practice. Recent guidelines suggest that nonoperative management is safe for patients with asymptomatic branch-duct IPMNs <3 cm in size without nodules,11
whereas there is a general consensus that the risk of malignancy in any IPMN involving the MPD should be viewed with concerns (and resected).14,17,18
Our study indicated that the risk of cancer in MCNs (11% invasive and 6% in situ) is relatively low and potentially could allow for nonoperative management in the majority—those that are asymptomatic, less than 4 cm in diameter, and without solid components. However, because most of these are diagnosed in young women with long life expectancy, the cost-effectiveness and safety of this approach should be carefully considered and balanced with the potential costs of postoperative pancreatic endocrine insufficiency.13,15,16
In summary, the results of this study showed that MCNs of the pancreas comprise 3 (not 4) different neoplasms: MCNs, branch-duct IPMNs, and main-duct IPMNs including the combined type. These tumors have specific clinical and morphologic features that allow a reasonable degree of accuracy in preoperative differential diagnosis and thereby influence the strategy for clinical management.