International consensus guidelines suggest that there should be no time limit for follow-up after the resection of IPMNs, but the specific surveillance protocol remains unclear [3]. This study aimed to assess the clinical features of IPMN recurrence which could contribute to establishment of optimal surveillance protocols. RFS and OS differed between the recurrence patterns: Ex-Panc recurrence tended to occur earlier in the postoperative period and to resulted in a poorer prognosis than Rem-Panc recurrence. In the comparing of clinical background characteristics between patients with intrapancreatic or extrapancreatic recurrence, as shown in Fig. 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. Based on these results, the potential for ductal instability 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 five 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 ten patients 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 the risk-positive disease develop Rem-Panc recurrence within five 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 1074 IPMNs as a project study of the Japan Pancreas Society [14]. This analysis classified recurrence types 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 essential 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 [15, 16], whereas another paper showed there was no relationship [17, 18]. Interestingly, Frankel reported that dysplasia at the margin after pancreatectomy for non-invasive IPMN is associated with recurrence in the remnant gland [19]. In their analysis, 85% of Rem-Panc recurrence occurred at distant sites of Rem-panc epithelium from the surgical margin. 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’. Similarly, 67% (4/6) of positive surgical margin resulted in Rem-Panc recurrence at the distant site from the surgical margin in our subject. Thus, IPMNs with positive margins would mean that pancreatic ductal epithelium with high carcinogenic potential is present in the entire remaining pancreas, and the residual pancreas is prone to recurrence. Moreover, Rem-Panc recurrence could occur not only at the actual surgical margin but at distant sights of Rem-Panc epithelium from the margin. Hence, it is suggested that a positive margin is more likely a marker of diffuse ductal instability rather than a local oncologic failure.
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 [20]: (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 significant difference in the risk of obstructive pancreatitis between benign and malignant IPMNs [21,22,23] 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 [26].
Consequently, a specific surveillance protocol for IPMN should be stratified, focusing on two different types of recurrence since half of the patients with a high risk of Rem-Panc recurrence would recur within five 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. Therefore, careful follow-up 3-4 times a year for two years after surgery is desirable, and the selection of neo-adjuvant and adjuvant chemotherapy in addition to surgery is an issue for further study.
Practically, the following surveillance protocol according to the grade of IPMN could be suggested. In cases of IPMC, whole-body CT should be performed every three months for the first two years, alternating CT and MRCP to Rem-Panc for 3-5 years, and twice-yearly MRCP focusing on Rem-Panc for life after the 5th year. On the other hand, in cases of HGD or LGD, MRCP for Rem-Panc should be performed twice a year and once a year, respectively, for a lifetime. Moreover, in cases with some risks of Rem-Panc recurrence, surveillance should be enhanced more closely for the first five years and include proactive use of EUS.
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. And though adjuvant chemotherapy for IPMC is generally accepted, it seemed not to improve Rem-Panc recurrence in our patients’ cohort. However, it should also be noted that the small size of the subjects and the likelihood of bias and heterogeneity made it difficult to analyze various aspects with great statistical power. It would be appropriate to address this topic explicitly in the future. Nonetheless, despite these limitations, it could be worthwhile to suggest the follow-up protocol based on the risk factors for Rem-Panc or Ex-Panc recurrence.