Optimal surveillance of intraductal papillary mucinous neoplasms of the pancreas focusing on remnant pancreas recurrence after surgical resection

Background The international consensus guidelines for intraductal papillary mucinous neoplasm of the pancreas (IPMN) presented clinical features as indications for surgery. Whereas surveillance for recurrence, including de novo lesions, is essential, optimal surveillance protocols have not been established. Aim and methods This study aimed to assess the clinical features of recurrence at the remnant pancreas (Rem-Panc) and extra-pancreas (Ex-Panc) after surgery for IPMN. Ninety-one patients of IPMN that underwent detailed preoperative assessment and pancreatectomy were retrospectively analyzed, focusing especially on the type of recurrence. Results The IPMNs were finally diagnosed as low-grade dysplasia (LDA, n = 42), high-grade dysplasia (HAD, n = 19), and invasive carcinoma (IPMC, n = 30). Recurrence was observed in 26 patients (29%), of which recurrence was seen at Rem-Panc in 19 patients (21%) and Ex-Panc in 7 patients (8%). The frequency of Rem-Panc recurrence was 10% in LDA, 21% in HDA, and 37% in IPMC. On the other hand, Ex-Panc recurrence was observed only in IPMC (23%). Ex-Panc recurrence showed shorter median recurrence-free survival (RFS) and overall survival (OS) than Rem-Panc recurrence (median RFS 8 months vs. 35 months, p < 0.001; median OS 25 months vs. 72 months, p < 0.001). Regarding treatment for Rem-Panc recurrence, repeat pancreatectomy resulted in better OS than no repeat pancreatectomy (MST 36 months vs. 15.5 months, p = 0.033). On multivariate analysis, main duct stenosis or disruption as a preoperative feature (hazard ratio [HR] 10.6, p = 0.002) and positive surgical margin (HR 4.4, p = 0.018) were identified as risk factors for Rem-Panc recurrence. Conclusions The risk factors for Rem-Panc and Ex-Panc recurrence differ. Therefore, optimal surveillance on these features is desirable to ensure that repeat pancreatectomy for Rem-Panc recurrence can be an appropriate surgical intervention. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09650-w.


Introduction
For the clinical management of intraductal papillary mucinous neoplasms of the pancreas (IPMNs), an international consensus guideline was provided by the International Association of Pancreatology [1][2][3]. These guidelines for clinical management, including radiological and endoscopic follow-up and surgical indications, have been widely accepted. After surgical resection, the postoperative recurrence rate of IPMN was reported to 6.8-9.6% with non-invasive IPMN and 32.2-65% with invasive IPMN [4][5][6][7]. Notably, IPMN recurrences have various temporospatial distributions [7]. Previous studies of postoperative recurrence sites of IPMN showed that distant metastasis occurred mostly in invasive IPMN. The form of recurrence depends on the differentiation of the primary IPMN; the recurrence rates were 0-7.7% with remnant pancreas recurrence (Rem-Panc), 0-1.3% with extrapancreatic metastasis (Ex-Panc), and 0-0.8% with both sites in non-invasive IPMN, whereas they were 5.7-15.0%, 35.0-45.7%, and 2.9-8.8% in invasive cancer [4,5,8]. Perioperative risk factors for the recurrence pattern have been debated. Risk factors for Rem-Panc recurrence were reported to be presence of high-grade dysplasia in resected specimens, positive surgical margins, and family history of pancreatic ductal adenocarcinoma (PDAC). It was also suggested that the gastric or pancreatobiliary type as IPMN subtypes could be potential indicators of carcinogenic recurrence as PDAC in Rem-Panc [9,10].
Several guidelines for IPMN refer to the risk of postoperative recurrence and the follow-up policy. For noninvasive IPMN, including low-grade and high-grade dysplasia, surveillance with a focus on the remnant pancreas is recommended, because early detection of a malignant lesion and surgical resection may improve the prognosis. The International Consensus Guideline 2017 advocates that cross-sectional imaging be required for high-risk factors for Rem-Panc recurrence, such as: family history of pancreatic cancer; non-invasive IPMN or invasive IPMC at the surgical margin; and non-intestinal subtypes [3].
However, in reality, the rst two are relatively rare. In addition, the European Study Group On Cystic Tumors of The Pancreas guidelines specify high-grade dysplasia and main duct type as high-risk factors [11], and the AGA guidelines do not recommend periodic screening for low-grade dysplasia (LGD), because of its lack of cost-effectiveness [12]. Thus, there has not been consensus in this eld. From these points of view, this study aimed to assess the clinical features of IPMN recurrence.

Study subjects
A total of 91 cases of IPMN that underwent initial surgical resection with curative intent in Okayama University Hospital from May 2007 to December 2014 were retrospectively reviewed. Demographic information, symptoms at presentation, radiological and endoscopic ndings, surgical procedures, pathology, and postoperative course were collected from medical records.
With regard to precise preoperative tumor assessment, all patients were assessed by endoscopic ultrasonography (EUS) using contrast enhancement for intraductal mural nodules and by pancreatic juice cytology under endoscopic retrograde cholangiopancreatography (ERCP). The diameter of the main pancreatic duct or branched cyst was measured by computed tomography (CT) or MRI. De nite mural nodules or pancreatic duct features such as stenosis or disruption were determined by these diagnostic modalities. Preoperative pancreatitis and obstructive jaundice were judged by clinical ndings including laboratory or radiological imaging data.
Surgical indications, pathological examination, and postoperative follow-up Indications for surgery were determined on the basis of international consensus guideline 2006 [1] or 2012 [2]. Patients with a preoperative diagnosis or highly suspicious of invasive cancer underwent pancreatectomy with regional lymph node dissection. Resected specimens were reviewed by pathologists and classi ed into 3 groups according to the World Health Organization (WHO) classi cation: IPMN lowgrade dysplasia (LGD), IPMN high-grade dysplasia (HGD), and IPMN-associated invasive carcinoma (IPMC). If different grades coexisted in one lesion, the highest degree of dysplasia was adopted as the classi cation. Surgical margins were examined at pancreatic transection margins and dissected peripancreatic tissue margins, which were classi ed as negative or positive for LGD, HGD, and IPMC. Final staging was based on these ndings and the TNM classi cation in the seventh edition [13]. Adjuvant chemotherapy by gemcitabine or a uorouracil-based agent for six months was given to the patients with a nal pathological diagnosis of UICC-Stage 2. Postoperative follow-up with CT or MRI was performed according to the nal pathology. Follow-up intervals varied by IPMN-classi cation: 6 to 12 months for LGD, 3 to 6 months for HGD, and 3 months for IPMC. If tumor recurrence or metastasis was suspected, further examinations including EUS, CT, and MRI were performed as needed.
Tumor recurrence was classi ed into two types. One type was Rem-Panc recurrence, including de novo IPMN, PDAC, and obvious enlargement of preexisting IPMN in the remnant pancreas. The diagnosis of Rem-Panc recurrence required endoscopic biopsy. The other type was extrapancreatic (Ex-Panc) recurrence, including metastases to liver, lung, lymph node, and peritoneum (Supplemental Figure 1).

Statistical analysis
Clinical variables were compared using the Mann-Whitney U test for continuous data and Pearson's correlation coe cient for categorical data. Continuous variables are presented as medians and interquartile range (IQR). Values of p<0.05 were considered signi cant. Overall survival (OS), recurrencefree survival (RFS), and incidence of Rem-Panc recurrence were evaluated using the Kaplan-Meier method and compared using log-rank tests. Cox's proportional hazards model with clinical variables including high-risk stigmata and worrisome EUS features [2] was used to identify prognostic factors for Rem-Panc recurrence. For this analysis, clinical variables showing values of p<0.05 on univariate analyses were entered into the multivariate analysis. The event of Ex-Panc recurrence and other causes of death were treated as censored. Hazard ratios (HRs) and 95% con dence intervals (95%CIs) were calculated. All statistical analyses were performed using JMP version 14 (SAS Institute Inc., Cary, NC, USA).

Ethics approval and consent to participate
This study conformed to the Declaration of Helsinki on Human Research Ethics standards and was approved by the Okayama University Hospital Institutional Ethics Board (number 1902-019). The need for written, informed consent was waived by the Okayama University Hospital Institutional Ethics Board because of the retrospective design.

Results
Clinical and pathological background characteristics of the enrolled patients are summarized in Table 1.
Survival after Rem-Panc recurrence of patients treated by repeat pancreatectomy was better than that of patients without any surgical intervention (median OS 36 months vs 15.5 months, p=0.03) (Figure 4).

Discussion
International consensus guidelines suggest that there should be no time limit for follow-up after resection of IPMNs, but the speci c surveillance protocol remains unclear [3]. 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 eld carcinogenesis of Rem-Panc would be re ected 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 [14]. In this analysis, recurrence type was classi ed 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 identi ed as independent risk factors for "High-risk lesions in the remnant pancreas". In addition to these ndings, we rst identi ed that preoperative EUS ndings 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 [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]. They considered that, when dysplasia is present at multiple locations within the pancreas, such as the surgical margin and/or extracystic duct, patients are at increased risk of developing recurrent IPMN, supporting the concept of a ' eld defect'. Knowledge about the correlation between recurrence risk and stenosis/disruption of the main pancreatic duct has been insu cient. 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 major 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 speci c surveillance protocol for IPMN should be strati ed, 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.

Conclusion
The present study showed the possibility of IPMN strati cation by risk according to type of relapse using Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due owing to data privacy policy at our facility, but are available from the corresponding author on reasonable request.