This series, which to our knowledge represents the largest single-institution cohort of resected cystic neoplasms of the pancreas, shows that during the last 3 decades, the landscape of these lesions has changed. Cystic pancreatic neoplasms are now being diagnosed in far greater numbers compared with earlier time-periods, and the majority of the diagnoses are made incidentally at the time of evaluation for unrelated symptoms. This trend has been associated with a marked decrease in patients found to have invasive cancer. Diagnoses like IPMN and CNEN were very rare 20 years ago but are seen in greater numbers more recently. The approach and management of patients with pancreatic cysts has also changed over time, with an increase in the use of MRI, EUS, and FNA as seen in our results, and a parallel decrease in the use of ERCP. Operative resection was associated with very low operative mortality (0.5%) but the complication rate remained high. For patients with cystic neoplasms of the pancreas, long-term survival after resection is usually the case; >85% of patients were alive 5 years after resection.
Review of other published series5–11
of resected cystic neoplasms of the pancreas indicates that large, academic referral centers have similar experiences with regard to patient presentation, management, and postoperative outcomes. Gaujoux et al11
published recently an updated experience with pancreatic cystic neoplasms at the Memorial Sloan-Kettering Cancer Center. They showed that during a 15-year period, the use of MRI and EUS/FNA increased markedly and that there was a concomitant decrease in the percentage of patients who presented with symptoms. In addition, among the 422 pancreatic resections for cystic neoplasms in their report, operative mortality was low (0.7%) but morbidity (≥grade III) was still 36%. These results echo our 20-year trend.
When compared with series that included fewer patients, we observed small differences with respect to the relative proportions of different pathologic diagnoses. In a study that included 125 resections from the Cleveland Clinic, Walsh et al12
noted that IPMN and MCN constituted 21% and 36% of their patient populations, respectively whereas in the series by Spinelli et al,13
only 22% of the patients were diagnosed with an IPMN. By contrast, IPMN was the diagnosis in almost 40% of our series and constituted nearly one-half of the resections in the last 5-year time period. A lesser prevalence of IPMN has also been reported in other series outside of the United States. In a study that comprised patients at the Singapore General Hospital, Goh et al7
examined 220 resected cystic neoplasms, of which 21% were IPMN, 14% were MCN, 21% were SCA, and 4% were CNEN. Comparable with data from our study, approximately 40% of the patients were diagnosed incidentally, and postoperative mortality and morbidity were low. All these studies confirm that at large academic centers, the diagnoses of pancreatic cystic neoplasms are being made incidentally in increasing numbers, undoubtedly the result of our advanced techniques of cross-sectional imaging.
One of the more interesting findings of our study is the notable increase in the relative proportion of IPMN during the last 3 decades. IPMN accounted for 2% of cases before 1991, whereas they are currently the diagnosis in 49% of patients with a resected cystic neoplasm. There has been considerable debate over the perceived increase in the incidence of IPMN and whether this represents a true increase in incidence as the result of unknown environmental factors or whether the increased rate of detection is simply a reflection of larger numbers of incidentally discovered neoplasms attributed to better imaging and different pathologic classification of mucin-producing neoplasms.
Some authors have performed a review of archived histologic slides in an attempt to reclassify and correctly identify IPMNs. In a study of resected IPMN, Niedergethmann et al5
reevaluated pathology slides from previous reports, and among 207 cases, they reclassified 54 as IPMN that were diagnosed incorrectly in the original pathology report. These cases represented a more than 125% increase because there were only 43 patients who had been diagnosed primarily as IPMN among the original cases. Their results also showed that patients were more likely to be diagnosed incorrectly in the earlier time-period (1996–2001) of their study.
Supportive of the aforementioned results is a study from the Mayo Clinic by Tollefson et al.14
In this study, pathology reports for all patients diagnosed with unusual variants of pancreatic cancer between 1960 and 1980 were revaluated and, histo-logic slides re-reviewed in those cases where the descriptors “mucinous”, “cystic” or “papillary” were present in the report. Among the 84 cases that were re-reviewed, 21 cases of IPMN were diagnosed incorrectly initially, indicating that IPMNs did
exist before the first report of IPMN by Ohashi and Murakami15
in 1982. The authors concluded that these neoplasms have been confused with unusual forms of chronic pancreatitis or adenocarcinoma of the pancreas. Although an increase in incidental detection of IPMN certainly plays a role in the greater proportion of this diagnosis amongst resected cystic neoplasms in our series, analysis of our results also supports the notion that improved pathologic classification is an important factor, because overall, the percentage contribution of muci-nous neoplasms (IPMN, MCN) has remained stable between 50% and 70% throughout the time periods.
In the 1991 report by Warshaw et al,3
62% of the patients were classified as MCN, whereas this diagnosis currently comprises only 16%. We believe it s quite likely that many (perhaps even the majority) of those MCNs would currently be classified as IPMNs, because many were in elderly or male patients or the tumor located in the head of the pancreas. Compliance with the currently accepted pathologic criteria that require the presence of ovarian-like stroma to diagnose an MCN indicate that >95% of cases occur in women with a mean age of 53 years and are located in the body and tail of the pancreas.16
A definitive answer to the question of erroneous classification of MCN and IPMN before 1991 would require comprehensive pathologic review of the archival material that unfortunately is incomplete.
Another change over time has been the 3-fold increase in pancreatic CNENs. Currently, 1 of every 12 resected pancreatic cystic neoplasms is a CNEN, and most of these are either incidentally discovered or detected because of surveillance of patients with MEN-1. We have described previously that MEN-1 was three and half times more likely to be present in a patient with a pancreatic CNEN relative to a solid neuroendocrine neoplasm.17
Of the 62 CNENs in this series, 84% were nonfunctional and 12% were part of the MEN-1 complex reflecting our referral practice.
Our data indicate that between 46% and 50% of patients who underwent resection for a cystic neoplasm of the pancreas in the time-periods of 2000 to 2004, and 2005 to 2010 were incidentally diagnosed. This trend represents a 20% increase relative to the prior time period (1995–1999) and is related likely to the increased availability and use of both CT and MRI.18,19
This trend is opposite to the prevalence of malignancy in the resected specimens, which has been 12% since 2000, but was 28% between 1995 and 1999. Because we are resecting many more pancreatic cystic lesions, it could be argued that we are perhaps doing unnecessary resections in many patients. This question cannot be answered with the data we have, although it is clear that we are operating only on a small fraction of all the newly discovered asymptomatic pancreatic cysts.
Recent studies have shown that up to 13.5% of patients with no pancreatic history will have a pancreatic cystic area recognized by MRI20
and 2.6% by CT.21
Most of these “cysts” are thought to represent BD–IPMN, and current guidelines22
recommend resection for only a minority of them (lesions >3 cm, or for smaller ones that have mural nodules, symptoms, or concomitant dilation of the pancreatic duct). Although it is true that the majority of cystic neoplasms that meet criteria for resection are not malignant, it is important to underscore that the goal is not only to remove lesions that have invasive cancer but also those with high-grade, and perhaps moderate, dysplasia. Of the 326 IPMNs of this series, 23% had invasive cancer, 15% had high-grade dysplasia (formerly carcinoma in situ), 21% had moderate dysplasia (formerly borderline neoplasms), and only 41% were adenomas with low-grade dysplasia. Ideally, we would like to remove all lesions before
they become invasive cancer and at the same time spare resection for lesions that have no or very little risk of progressing to moderate or high-grade dysplasia.
Multiple efforts in cyst imaging and analysis of the cystic fluid are underway to try to refine this differential diagnosis.23–25
Our data show that the overall 5-year survival after resection is 87% for all cystic lesions and 62% for those with malignancy. Furthermore, these operations, although still fraught with complications in approximately one-third of patients, have an operative mortality of less than 1%. In the future, studies addressing the risk/benefit of resection of incidentally discovered pancreatic cysts need to address not only the risk of malignancy or dysplasia in the lesions and the risk of dying or having a serious complication from the operation, but also long term sequelae from the resection including, the development of diabetes and pancreatic exocrine insufficiency, as well as effects on quality of life.