Management of pancreatic cysts: the evidence is not here yet.

his issue of Gastroenterology Tcontains a technical review commissioned by the American Gastroenterological Association (AGA) on the diagnosis and management of pancreatic cysts, as well as guidelines for the management of neoplastic pancreatic cysts derived from this review and developed by the AGA’s Clinical Practice Guideline Committee. The authors are to be commended for performing a titanic review of the literature. They identified >1,500 papers on the subject, and ultimately cited >250. Using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework and the PICO (Patient problem or population, Intervention, Comparison and Outcome) format they attempted to answer very relevant questions, and reach conclusions that are interesting, because in several aspects they differ substantially from what is currently accepted practice in the field. Without doubt, identification of increasing numbers of pancreatic cysts in asymptomatic patients has become a clinical problem. The vast majority of these incidentally discovered cysts are small (average size is about 8 mm), and many may to be branch duct (BD) intraductal papillary mucinous neoplasms (IPMNs), although firm pathologic proof that this is the case is lacking. The problem with these small, subcentimeter cysts, however, is different from that of larger pancreatic cysts, which constitute a much smaller proportion of patients. In the latter group, clinical, radiologic, and endoscopic ultrasound (EUS) features can often point to 1 of about different 10 diagnoses, and because many of these larger cysts (>1 cm) have undergone operative resection, we have proof that our preoperative diagnoses are reasonably accurate. We have also learned that some of these larger lesions are harmless for the most part (eg, serous cystadenomas, lymphangiomas, lymphoepithelial cysts), but others have potential to be or become malignant (IPMNs, mucinous cystic neoplasms, cystic neuroendocrine tumors, solid pseudopapillary neoplasms). The drive to create the guidelines that we authored in 2006 and then revised in 2012 was to help the clinician understand and manage IPMNs. These tumors constitute, by far, the most common neoplastic pancreatic cyst, and although by definition are premalignant, it was clear back then, and continues to be now, that as long as the disease is limited to the branches of the pancreatic ductal system, the overall risk of these cysts harboring high-grade dysplasia or invasive cancer is very low. Because of this, in 2006 we recommendedoperative resection for patients with main duct IPMN, and, based on some limited published series and the nonpublished experiences of the experts who drafted the guidelines, proposed to limit surgery in branch -duct IPMNs to patients who had symptoms, a cyst >3 cm, presence of nodules, or an associated dilated pancreatic duct. This stratification proved to be quite good, because several retrospective series published subsequently showed that practically no cases of invasive cancer would have been missed if the guidelines had been followed in the past, although some cases with high-grade dysplasia would not have undergone resection. As a consequence of the guidelines, fewer patients with BD-IPMN (ie, BD disease) are being operated on and are now being managed with surveillance. Robust long-term studies are lacking, but at least some series with a median followup of 5 years show that about 15% of patients that are being followed eventually require an operation, and that missing the opportunity to treat an invasive cancer within the cyst is a rare event. Application of these guidelines has also shown that about 75% of the patients who undergo surgery for presumed BD-IPMNwho undergo resection because they meet the 2006 criteria do not have invasive cancer or high-grade dysplasia. This led to the 2012 revision, which deemphasized the 3-cm threshold, and recommended observation, albeit with very close surveillance, for large asymptomatic cysts without a solid component or associated pancreatic duct dilation. On the other hand, because patients with high-grade dysplasia were clearly being missed with the old guidelines (and potentially more would be with the new size criteria), the 2012 guidelines recommended EUS with fluid aspiration, not so much to confirm the diagnosis, but to obtain cytology. If the cytology suggested high-grade atypia or worse, then resection was recommended. The AGA technical review in this issue of the journal concludes that all the evidence in the literature regarding management of pancreatic cysts is of very low quality. This grading implies that the PICO statements have “great uncertainty regarding the estimate of effect.” Despite this apparent lack of evidence, controversial new guidelines are provided. The main differences with the international guidelines described above are as follows. (1) Surgery for an asymptomatic patient only if a cyst has 2 of the 3 concerning features (size>3 cm, nodule, or duct dilation) and EUS shows malignancy (even though the authors acknowledge that the sensitivity of cytologic examination obtained by EUS is only 60%), (2) surveillance intervals of 2 years, regardless of the size of the cyst, and (3) discontinuation of surveillance after 5 years of no significant change or after resection of the cyst. The guidelines give 10 recommendations. It is remarkable that, except for the first one, which is a generic statement that appropriately indicates that risks and benefits of the management strategy need to be discussed upfront with the patient, 8 of the remaining 9 statements (all of which were based on very low quality evidence) are conditional (or weak) recommendations.