Most cystic neoplasms of the pancreas, with the exception of serous cystadenomas and rare entities like lymphangiomas and lymphoepithelial cysts, have the potential to be or to become malignant. Prior reports from this institution7–9
have indicated that common cystic tumors, which have a mucinous epithelial lining, contain carcinoma in situ or invasive cancer in up to 60% of resected cases.8
However, because of imaging for a variety of clinical indications, smaller cystic neoplasms are being discovered more frequently. There is also a new appreciation that the evolution from small benign cystic neoplasms may be very slow and allow for selective treatment based on identifiable morphologic characteristics. Observations such as these led to an international consensus conference held in Sendai, Japan, in 2004. The International Association of Pancreatology and the Japanese Pancreas Society proposed guidelines stating that asymptomatic branch-duct IPMNs less than 3 cm and without mural nodules or solid components were unlikely to contain cancer and could be safely watched for worrisome changes with periodic imaging. Resection was recommended for all main-duct IPMNs because of the imminent risk of cancer and for large (>3 cm) symptomatic or nodule-harboring branch-duct IPMNs.14
Other reports have generally validated these guidelines on the basis of the findings on resected pancreatic cystic lesions,9,15
most of which have been symptomatic. We found invasive cancer in 29 of 255 (11%) of the cystic lesions that were resected; however, the overall incidence of invasive cancer in this cohort (although we do not have pathological confirmation for patients under observation) is only 7%. The rate of invasive cancer was much higher in patients with main-duct IPMN (24%), of whom only 19% were asymptomatic.
By providing a large series of pancreatic cystic neoplasms, 71% of which were found incidentally, this study gives further support to the safety of the Sendai guidelines. These tumors were relatively small on average and were not producing symptoms. One hundred fifty-nine patients did not undergo resection at the point of diagnosis but were kept under surveillance with CT or MRI/MRCP imaging. Thirteen of the 159 eventually underwent resection because of symptoms, growth, or other new findings. Only 1 of these 13 patients had a lesion containing an invasive cancer. These findings confirm the safety of surveillance in a selected population, which probably accounts for a substantial majority of newly discovered pancreatic cystic lesions, especially the very common subcentimeter branch-duct IPMN. However, the short follow-up warrants caution and surveillance with cross-sectional imaging will need to continue indefinitely until more information regarding the long-term natural history of these lesions is established.
When compared with our prior experience with pancreatic cysts from 1997 to 2002,4
the present series shows that the proportion of incidentally discovered cysts has nearly doubled (from 36% to 71%) and that the mean size of these asymptomatic lesions is smaller (3.3 vs 2.7 cm). Our conduct toward the incidentally discovered cyst has also changed markedly from an aggressive resectional policy (close to 80%) to the current 50%. Additionally, the average size of the symptomatic lesions has decreased from 4.6 cm to 3.1 cm, and the prevalence of malignancy (in situ and invasive) is also lower (40% vs 26% in symptomatic cysts and 17% vs 7% in those incidentally discovered). These changes are likely due to increased awareness of pancreatic cystic lesions by clinicians and radiologists, as well as the improved resolution and availability of cross-sectional imaging. We currently recommend resection for symptomatic patients and those with lesions measuring 30 mm or more or with a solid component.
One of our aims was to retrospectively review the contribution of EUS to the management of cystic lesions of the pancreas. We evaluated not only the data obtained from our institution, but also the information that referred patients brought with them from community hospitals, since EUS is now widely available. Nearly half of the patients in this series underwent EUS, and somewhat unexpectedly, we found that the proportion of patients with incidentally discovered cysts who underwent this test was the same as in the group with symptoms even though the majority of the latter would require resection regardless of the information obtained by this test.
The role of EUS and FNA for cyst-fluid sampling is still being explored and clarified with respect to improving the differential diagnosis, detecting cancer, and aiding in surveillance. Endosonic ultrasonography can be particularly helpful in demonstrating septae and solid components, communication with pancreatic ducts, and guiding FNA for cytological examinations and fluid analysis. Although the retrospective nature of this study precludes a rigorous analysis, we found that morphologic features derived from EUS allowed the endoscopist to suggest a diagnosis in about two-thirds of cases and that this matched the final histopathological diagnosis in 41% and 52% of symptomatic and asymptomatic cysts, respectively.
One important finding was related to the detection of nodules, where EUS performed more sensitively than cross-sectional imaging, although the pathologist confirmed the presence of nodules in less than 50% of those patients. The reasons for this lack of correlation are unclear, and only prospective studies will be able to determine if some of these presumed nodules represent debris.
The yield of cytology, similar to other reports,16,17
was disappointingly low since the majority of cancers (11 of 17) were not identified. Somewhat troubling was the high proportion of false-positive results for adenocarcinoma in the asymptomatic group (4 of 6).
The study also confirms that most patients with an elevated fluid CEA level have an IPMN or an MCN, although the sensitivity continues to be low. In the past, identifying mucinous lesions was germane because most patients were offered resection. Currently, because most mucinous lesions found are asymptomatic branch-duct IPMNs, this test has become less relevant. As predicted, the majority of patients with IPMN had an elevated fluid amylase level, reflecting connection with the pancreatic duct. However, unexpectedly, so did 11 of 16 patients with MCNs and 7 of 13 patients with “other” lesions (other than serous cystadenoma). This is similar to the Mayo Clinic experience reported by Pelaez-Luna and Chari.18
It is difficult from a retrospective study to determine how truly helpful EUS was. What is clear from this review is that its use is unsystematic. Since experience of the endosonographer and cytologist matter, perhaps EUS for evaluation of pancreatic cysts should be done only in high-volume centers. There is an ongoing need for tests that can accurately identify malignancy within pancreatic cysts, and other tumor markers, proteomics, or DNA analysis of cyst fluid should be carefully evaluated. One group19,20
reported that positron emission tomography with fluorodeoxyglucose F 18 can effectively discriminate malignant vs nonmalignant cysts, but this finding has not been confirmed.21
We are currently evaluating this modality.
In summary, this contemporary experience shows that the majority of pancreatic cystic neoplasms are now incidentally discovered but provides evidence that, with the exception of main-duct IPMN, most cystic neoplasms of the pancreas—those that are asymptomatic, less than 3 cm in diameter, and free of nodules or solid components—can be managed safely with periodic surveillance using CT or MRCP. In this study, only 8% of patients underwent resection over the next several years, and only 1 of those patients developed a cyst with a microscopic focus of invasive cancer (which was still resected for probable cure). These observations have led to a major revision of our treatment strategy from aggressive advocacy of resection4
to a much more conservative, highly selective stance. The role of EUS in both the initial evaluation and subsequent surveillance of pancreatic cystic neoplasms continues to evolve.