International consensus guidelines suggest that there should be no time limit for follow-up after resection of IPMNs, but the specific surveillance protocol remains unclear . The aim of this study was to clarify the optimal surveillance strategy according to risk factor analysis for Rem-Panc and Ex-Panc recurrence after resection. RFS and OS differed between the recurrence patterns: Ex-Panc recurrence tended to occur earlier in the postoperative period and to result in a poorer prognosis than Rem-Panc recurrence. In the comparison of clinical background characteristics between patients with intrapancreatic or extrapancreatic recurrence, as shown in Figure 2, all Ex-Panc recurrences occurred in primary IPMC cases. In addition, Ex-Panc recurrence showed a higher serum CA19-9 level, jaundice, and advanced UICC stage. Namely, Ex-Panc recurrence could rely heavily on primary tumor biology, and systemic screening during the early postoperative period would be preferable. Perhaps adjuvant chemotherapy or neoadjuvant chemotherapy should be considered in these cases.
On the other hand, Rem-Panc recurrence also depends on primary tumor biology. IPMC or HGD as primary pathology showed higher and earlier Rem-Panc recurrence than LGD. Furthermore, IPMC or HGD as a positive surgical margin could be an independent risk factor for Rem-Panc recurrence. On the basis of these results, the potential of field carcinogenesis of Rem-Panc would be reflected in the degree of differentiation of the primary tumor. Furthermore, the fact that LGD showed Rem-Panc recurrence even after 5 years suggests that surveillance of Rem-Panc after resection of IPMN should be continued throughout the patient’s lifetime, regardless of tumor grading. Regarding post-Rem-Panc recurrence survival, only repeated surgery could be a curative treatment option that would contribute to long-term survival. The main reason why 10 cases of Rem-Panc recurrence did not have the opportunity for repeat pancreatectomy was locally advanced Rem-Panc IPMC or ductal cell carcinoma with distant metastasis, because of the delayed diagnosis of recurrent disease.
As the present results show, about half of the patients with risk-positive disease develop Rem-Panc recurrence within 5 years after surgery, suggesting that repeated imaging checks each year, especially focusing on the pancreatic duct by MRCP, are recommended for early detection of Rem-Panc recurrence. Hirono reported recurrence patterns and risk factors after surgical resection of 1,074 IPMNs as a project study of the Japan Pancreas Society. In this analysis, recurrence type was classified into “High-risk lesions in the remnant pancreas” and “Extrapancreatic recurrence”. Preoperative clinical symptoms, pancreatic body/tail as the IPMN location, main duct size > 10 mm, and HGD/invasive IPMC were identified as independent risk factors for “High-risk lesions in the remnant pancreas”. In addition to these findings, we first identified that preoperative EUS findings could be an important predictor of Rem-Panc recurrence after IPMN resection, including HGD/IPMC at the surgical margin and main duct stenosis or disruption as a preoperative EUS feature. According to previous studies, there are contradictory opinions about the surgical margin. It has been reported that a positive margin is associated with the risk of postoperative recurrence , whereas another paper showed there was no relationship . Interestingly, Frankel reported that dysplasia at the margin after pancreatectomy for non-invasive IPMN is associated with recurrence in the remnant gland . They considered that, when dysplasia is present at multiple locations within the pancreas, such as the surgical margin and/or extra-cystic duct, patients are at increased risk of developing recurrent IPMN, supporting the concept of a ‘field defect’. Knowledge about the correlation between recurrence risk and stenosis/disruption of the main pancreatic duct has been insufficient. Pea advocated three different mechanisms to explain the development of malignant lesions in the residual pancreas after IPMN surgery: (1) tumor resection at the surgical margin of the pancreas; (2) spread of tumor cells into pancreatic ducts or parenchyma; and (3) independent multifocal lesions. The features of the main pancreatic duct might suggest tumor spread into remnant pancreatic parenchyma as in the second mechanism. In general, most studies did not report any major difference in the risk of obstructive pancreatitis between benign and malignant IPMNs [21-23], because mucous embolism of the main pancreatic duct is more frequent in intestinal type with a better prognosis[24, 25]. In addition, the maximum diameter of the main pancreatic duct was correlated with the distance of tumor spread in the main pancreatic duct .
Consequently, a specific surveillance protocol for IPMN should be stratified, focusing on two different types of recurrence, since a half of patients with a high risk of Rem-Panc recurrence would recur within 5 years after surgery. Therefore, Rem-Panc patients should be closely checked by various diagnostic modalities, including EUS or MRCP [27, 28]. Even in patients without any risk factors, the possibility of Rem-Panc recurrence persists throughout the patients’ lifetime; thus, uninterrupted surveillance is necessary. On the other hand, Ex-Panc recurrence was characterized only by IPMC as the primary lesion and would recur within two years. Careful follow-up 3-4 times a year for 2 years after surgery is desirable, and selection of neo-adjuvant and adjuvant chemotherapy in addition to surgery is an issue for further study.
Some limitations of our study were that it was a retrospective study at a single center, and the surveillance strategy was not standardized throughout the follow-up period. Nonetheless, despite these limitations, the following follow-up strategy might be considered based on the risk factors for Rem-Panc or Ex-Panc.