Assessing Follow-Up Duration in Intraductal Papillary Mucinous Neoplasm Patients

Introduction

Intraductal papillary mucinous neoplasm (IPMN) is a type of pancreatic cystic neoplasm (PCN) originating from the epithelium of the main pancreatic duct (MPD) or branch pancreatic duct (BPD) [1]. IPMN is an important precancerous lesion of pancreatic ductal adenocarcinoma (PDAC) [2], characterized by papillary hyperplasia, cyst formation, and cellular atypia [3]. IPMN is commonly found in the head of the pancreas (70%), followed by the body/tail (20%), with 5–10% of patients having multifocal lesions [4]. IPMN can be divided into low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and patients with HGD are at risk of developing invasive carcinoma (IC) [5]. According to the site of origin, IPMN can be divided into main pancreatic duct type IPMN (MD-IPMN), branched pancreatic duct type IPMN (BD-IPMN), and mixed type IPMN (MT-IPMN) [6]. BD-IPMN presents as pancreatic cysts communicating with MPD exceeding 5 mm. MD-IPMN is characterized by segmental or diffuse expansion of the MPD beyond 5 mm without cysts that are associated with MPD or other causes of MPD obstruction. MT-IPMN satisfies all the characteristics of MD-IPMN and BD-IPMN simultaneously [3]. For IPMN patients in the HGD or IC stage, surgical treatment is considered the first choice and patients have a better prognosis compared to PDAC cases. For patients with LGD, the goal of treatment is to prevent malignant progression or alleviate symptoms, and minimize unnecessary surgical interventions [7,8]. This indicates that many patients do not require immediate surgery, but instead may receive corresponding regular follow-up after multidisciplinary evaluation. Accurate determination of subtypes and assessment of malignant potential are necessary when diagnosing IPMN patients to make a choice between surgical treatment and regular follow-up [9].

Commonly used guidelines for the clinical management of IPMN patients include the 2015 American Gastroenterological Association Institute guideline [10], the 2017 revisions of international consensus Fukuoka guidelines [6], the 2018 American College of Gastroenterology clinical guideline [11], and the 2018 European evidence-based guidelines [12]. The risk factors associated with malignant progression of IPMN recommended by these clinical guidelines are sometimes inaccurate in determining the malignancy of IPMN. Some patients with IPMN at the stage of LGD have also been treated surgically, resulting in unnecessary surgical intervention [13]. Many LGD patients progress from IPMN to IC for a long period of time, and may even never progress to HGD or IC during their lifetimes. Therefore, when formulating personalized management strategies, the potential benefits of long-term monitoring need to be weighed against the psychological burden on patients, the cost-effectiveness of follow-up, and the potential benefits of surgical resection [14]. On the other hand, the progression of PDAC from IPMN and the concomitant occurrence of PDAC may have different risk factors, demonstrating the complexity of IPMN diagnosis and treatment, and increasing the challenge of IPMN management [15,16]. Therefore, more prospective follow-up studies and active exploration of risk factors related to malignant progression of IPMN are needed to better understand the mechanism of IPMN development and to improve diagnostic accuracy. The International Association of Pancreatology has recently revised the international consensus Fukuoka guidelines and released the international evidence-based Kyoto guidelines [17], which have made modifications and additions to the definition of risk features, surveillance and management of surgical and non-surgical patients, as well as pathological and molecular diagnosis of IPMN, to better guide the clinical management of IPMN patients. The Kyoto guidelines follow the classification methods of the Fukuoka Guidelines for risk features, dividing IPMN malignant progression-related risk features into worrisome features (WFs) and high-risk stigmata (HRS). Through analysis and summary of previous guidelines and more extensive research, modifications have been made to the content of WFs and HRS.

Most IPMN patients usually have no symptoms and the neoplasms are often discovered incidentally during imaging examinations [7]. These cysts are small and have no obvious signs of malignancy, so many patients prefer regular follow-up rather than surgical treatment. However, there is a lack of consensus among different guidelines and scholars on the follow-up intervals and deadline for IPMN patients. Most guidelines and studies recommend determining follow-up time based on cyst size, but some small cysts with significant risk features have a high risk of progressing to IC, and monitoring them solely based on cyst size is unreliable. Appropriate follow-up intervals allow timely detection of disease progression to reduce the development of pancreatic cancer and minimize unnecessary screening. The aim of this study was to explore the appropriate follow-up intervals for non-surgical patients with IPMN containing multiple risk features, and the possible associated risk factors for malignant progression of IPMN.

Material and Methods

PATIENT INCLUSION AND EXCLUSION CRITERIA:

We retrospectively analyzed the information on patients who were diagnosed with IPMN and received regular follow-up until June 2023 in Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University (Hangzhou, China). We reviewed the radiological and clinical data of 1602 patients with suspected IPMN using an electronic medical record system, and 520 patients ultimately met the inclusion criteria. Reasons for exclusion were as follows: Age ≤18 years old; follow-up time ≤6 months and progression to invasive carcinoma or surgery within 6 months (n=450); previous surgery for pancreatic diseases or surgery for other diseases involving the pancreas (n=27); extrapancreatic diseases involving the pancreas (n=34), such as tumors of the biliary system close to the pancreas and gastroduodenal tumors invading the pancreas; imaging and laboratory tests were not performed regularly after the initial diagnosis (n=335); clinical or imaging follow-up data were incomplete (n=191); non-IPMN pancreatic disease (n=45), included pancreatitis or pseudocyst (n=4), mucinous cystic neoplasm (n=10), serous cystic neoplasm (n=22), and pancreatic carcinoma (n=9) (Figure 1).

FOLLOW-UP AND OUTCOME:

The follow-up period started from the first imaging or puncture pathology diagnosis of IPMN and ended on June 30, 2023. All patients underwent at least 1 cross-sectional imaging or puncture pathology examination at initial diagnosis (eg, computed tomography [CT] scan or enhancement, magnetic resonance imaging (MRI) scan or enhancement, magnetic resonance cholangiopancreatography [MRCP], and endoscopic ultrasound [EUS]±fine-needle aspiration [FNA]), and IPMN was considered first. Patients underwent regular imaging and laboratory examinations at intervals of 3 months, 6 months, or 1 year during follow-up. If a patient underwent surgery or IPMN progressed to IC during follow-up, the date of surgery or the date of first diagnosis of pancreatic carcinoma was regarded as the termination time of follow-up. The time interval between the initial diagnosis and the appearance of a new WF or HRS was also recorded. The diagnosis of WFs/HRS and IC in IPMN patients relied on imaging or cellular pathological examination.

DEFINITIONS:

In recent years, the management of IPMN had often used the 2017 revisions of the International Consensus Fukuoka Guidelines for the classification of WFs and HRS based on risk features [6]. The latest international evidence-based Kyoto guidelines had revised the previously released Fukuoka guidelines [17], redefining WFs and HRS. The HRS defined in this article included: (1) obstructive jaundice in IPMN patients with cystic lesions of the pancreatic head, (2) enhancing mural nodules ≥5 mm, (3) cysts contained solid components, (4) dilatation of the MPD diameter ≥10 mm, and (5) suspicious or positive cytological examination results. The WFs defined in this article included: (1) acute pancreatitis, (2) elevation of serum carbohydrate antigen 19-9 (CA19-9) level (≥37.00 IU/mL), (3) new or acutely aggravated diabetes in the past year, (4) cyst sizes ≥30 mm, (5) enhancing mural nodules <5 mm, (6) cyst-walls thickening or enhancement, (7) MPD diameter ≥5 mm and <10 mm, (8) sudden change of pancreatic duct diameter with distal pancreatic atrophy, and (9) enlargement of peripancreatic lymph nodes.

DATA COLLECTION:

All data were collected from patient medical records, outpatient follow-up, telephone follow-up, and email communication. The data collected included demographics information (eg, sex, age, height, weight, body mass index [BMI]), imaging features (eg, cyst size, cyst location, cyst type, MPD diameter), laboratory test data (eg, CA19-9 level, carcinoembryonic antigen [CEA] level, total bilirubin level), and clinical data (eg, surgical records, pathology reports of puncture or operation).

STATISTICAL ANALYSIS:

Normally distributed continuous variables are presented as mean±standard deviation (SD). If the Shapiro-Wilk test failed to show normal distribution, the median and corresponding 95% confidence interval (CI) were used to reflect intermediate level. Categorical variables are expressed as frequency and percentage. The t test was used to compare normally distributed continuous variables. We compared continuous variables that did not fit the normal distribution using the Wilcoxon Mann-Whitney test and evaluated categorical variables using the chi-square test or Fisher’s exact test. Kaplan-Meier (K-M) analysis and log-rank test were used to compare the time intervals of the emergence of new risk features between all groups. The Bonferroni method was used for multiple comparisons between groups, and Bonferroni-corrected P value <0.05 was regarded as indicating statistically significant differences. Case-control study and univariate and multivariate logistic regression analysis were used to explore the risk factors associated with IPMN progression in surgical patients and calculate hazard ratio (HR) and corresponding 95% CI. Risk variables with P value <0.05 in univariate analysis were included in multivariate analysis. All statistical analyses were performed using SPSS software (version 27.0, IBM Corp, Armonk, NY, USA).

Results

PATIENT DEMOGRAPHIC CHARACTERISTICS:

A total of 1602 patients with suspected IPMN on initial imaging were eligible for the study, and 520 patients ultimately met the inclusion criteria. The baseline characteristics of patients are summarized in Table 1. A total of 254 men and 266 women with a median age of 67 years old were included in the study. The percentage of cystic neoplasm located in pancreatic head/uncinate process, neck, body/tail and diffuse were 47.3%, 11.2%, 28.3%, and 13.3%, respectively. Among the 520 patients, there were 472, 13, and 35 patients with BD-IPMN, MD-IPMN, and MT-IPMN, respectively. Most patients presented with abdominal pain and they accounted for 17.7% of the follow-up population. Six of 520 patients had a family history of pancreatic carcinoma. Among the 520 patients, 75 patients had a history of long-term smoking, and.8% of patients had a previous history of pancreatitis. The median BMI of 520 patients was 22.7 (IQR, 20.9–24.2) kg/m2, the median CEA level was 2.65 (IQR, 1.74–3.87) ng/mL, and the median total bilirubin level was 13.6 (IQR, 10.2–18.0) μmol/L. At diagnosis, the median initial MPD diameter was 2.5 (IQR, 2.1–3.2) mm, the median initial cyst size was 14.5 (IQR, 10.0–20.0) mm, and the median initial CA19-9 level was 11.68 (IQR, 6.79–19.75) U/mL. After a median follow-up period of 40.5 (IQR, 18.8–63.0) months, the median final MPD diameter was 2.6 (IQR, 2.2–3.9) mm, the median final cyst size was 17.0 (IQR, 12.0–26.0) mm, and the median final CA19-9 level was 15.79 (IQR, 8.38–25.30) U/mL.

NEWLY DEVELOPED WFS/HRS DURING FOLLOW-UP:

At diagnosis, a total of 159 individuals had WFs/HRS. There were 24 patients with 29 HRS, but no patient was cytologically positive, and 197 WFs were present in 151 patients. At the end of follow-up, there were 56 patients with 77 HRS, and 361 WFs were present in 222 patients (Table 2). There were 143 patients who developed newly diagnosed WFs/HRS during follow-up. Patients with newly developed WFs/HRS had a longer median follow-up period compared with patients without newly developed WFs/HRS (48.0 months vs 39.0 months; P=0.034). At diagnosis, the median initial cyst size in patients with newly developed WFs/HRS was larger than that in patients without newly developed WFs/HRS (19.0 mm vs 13.0 mm; P<0.001), the median MPD diameter was wider in patients with newly developed WFs/HRS than in patients without newly developed WFs/HRS (3.0 mm vs 2.4 mm; P<0.001), and the median initial CA19-9 level was higher in the group with newly developed WFs/HRS than in the group without newly developed WFs/HRS (14.96 U/mL vs 10.41 U/mL; P<0.001). At the end of follow-up, patients with newly developed WFs/HRS had a larger median cyst size (30.0 mm vs 15.0 mm; P<0.001), a wider median MPD diameter (4.1 mm vs 2.5 mm; P<0.001), and a higher median CA19-9 level (24.29 U/mL vs 13.28 U/mL; P<0.001) compared to patients without newly developed WFs/HRS. The MPD dilatation rate (0.20 mm/year vs 0.00 mm/year; P<0.001) and cyst growth rate (1.7 mm/year vs 0.5 mm/year; P<0.001) were faster in patients with newly developed WFs/HRS than those without newly developed WFs/HRS (Table 3).

PROGRESSION IN IPMN PATIENTS ACCORDING TO CYST SIZE:

Many studies have suggested that cyst size is an important risk factor for malignant progression of IPMN [18–22]. The risk of malignant progression of IPMN increases with the enlargement of cysts [23–25]. In particular, patients with cysts ≥20 mm [21,26,27] or ≥30 mm [15,18,22,28] are considered to be at higher risk of malignant progression. The 143 patients with newly developed WFs/HRS during follow-up were divided into 3 groups based on the initial cyst size: group 1, cyst <20 mm; group 2, 20 mm ≤ cyst <30 mm; and group 3, cyst ≥30 mm. The time intervals between the initial diagnosis and the discovery of newly developed WFs/HRS were recorded. The median time interval for newly developed WFs/HRS in patients with cysts ≥30 mm was 7.5 (95% CI, 7.0–16.0) months, which was significantly shorter than in the other 2 groups (29.0 months vs 24.5 months vs 7.5 months; P<0.001) (Figure 2A). Thus, patients with cysts ≥30 mm had a higher risk of IPMN malignant progression than those with cysts <30 mm. For patients with cysts ≥30 mm, it was recommended to follow up every 6 months. There was no statistically significant difference in the median time interval for newly developed WFs/HRS between patients with cysts <20 mm and those with 20 mm ≤ cysts <30 mm (29.0 months vs 24.5 months; P=0.724). The shortest intervals of newly developed WFs/HRS were less than half a year in all 3 groups. After 6 months of close follow-up, patients with cysts <30 mm should be followed up every 2.0 years (Table 4).

PROGRESSION IN IPMN PATIENTS WITH WFS/HRS ACCORDING TO NUMBER OF RISK FEATURES:

Some studies have shown that patients with multiple risk features have a higher risk of malignant progression [25,29,30]. The risk of malignant progression in patients with IPMN containing 3 WF reached 59%, much higher than 22% with 1 WF and 34% with 2 WF, and could even reach 100% in patients with ≥4 WF [31]. If multiple WFs/HRS are present in IPMN patients, some studies suggest building predictive models to assess the risk of progression in IPMN patients and determine follow-up strategies [32–34], but the constructed predictive models are not universally applicable. Perhaps follow-up based on the number of risk features is more applicable in clinical practice. A total of 143 patients developed newly diagnosed WFs/HRS during follow-up. These patients were divided into 4 groups according to the number of risk features at diagnosis: group 1, patients without WFs/HRS; group 2, patients with ≤2 WFs; group 3, patients with >2 WFs; and group 4, patients with HRS. The time interval from diagnosis to the appearance of a new WF or HRS was traced. The median intervals for the 4 groups were 30.0 (95% CI, 23.0–39.0) months, 21.0 (95% CI, 19.0–30.0) months, 7.0 (95% CI, 5.0-NA) months, and 10.0 (95% CI, 7.0–16.0) months, respectively, and there was a statistically significant difference in the median interval for the occurrence of a new WF/HRS among the 4 groups (P<0.001) (Figure 2B). The time intervals for newly developed WFs/HRS between group 1 and the group 2 (30.0 months vs 21.0 months; P=1.000), as well as between the group 3 and the group 4 (7.0 months vs 10.0 months; P=1.000), were not statistically significant, but there were significant differences between any other 2 groups. A 1.5- to 2.0-year follow-up was more suitable for IPMN patients without WFs/HRS or with ≤2 WFs, and a follow-up interval of 6 months to 1 year could be used for patients with >2 WFs and those with HRS (Table 5).

PROGRESSION IN IPMN PATIENTS ACCORDING TO MPD DIAMETER:

Many studies have found a close relationship between MPD diameter and development of IPMN, which is an important risk factor for malignant progression of IPMN [20,23,26,35]. IPMN patients with MPD diameter ≥5 mm [15,24,30] or ≥10 mm [22,36] have a significantly higher risk of malignant progression. The 143 patients with newly developed WFs/HRS were divided into 3 groups based on MPD diameter: group 1, MPD <5 mm; group 2, 5 mm ≤ MPD <10 mm; and group 3, MPD ≥10 mm. The time intervals from diagnosis to the discovery of newly developed WFs/HRS were recorded for each group. There was a significant difference between the 3 groups in the median interval from the first discovery to the appearance of a new WF or HRS (25.0 months vs 21.5 months vs 10.5 months; P<0.001) (Figure 2C). It may be appropriate for IPMN patients with MPD ≥10 mm to undergo imaging and laboratory examinations every 6 months to 1 year. There was no statistically significant difference in the time interval for new-onset risk features between group 1 and group 2 (25.0 months vs 21.5 months; P=1.000). For patients with MPD <5 mm and 5 mm ≤ MPD <10 mm, the follow-up interval should be 1.5 to 2.0 years. Interestingly, from the point of view of MPD ≥10 mm as an HRS, follow-up at intervals of 6 months to 1 year is also recommended. While 5 mm ≤ MPD <10 mm is regarded as a WF, monitoring every 1.5 to 2.0 years was deemed appropriate (Table 6).

IPMN PATIENTS UNDERGOING SURGICAL TREATMENT DURING FOLLOW-UP:

Among the 520 IPMN patients included in our study, 29 underwent surgical treatment during follow-up. According to the postoperative pathological results, the 29 patients were divided into LGD and HGD/IC groups. Due to the small number of surgical patients, there might be statistical bias. Compared to patients in the HGD/IC group, patients in the LGD group were younger at initial diagnosis, and there was a significant difference in average age between the 2 groups of patients (59.8 years old vs 69.4 years old; P=0.027). However, there was no significant difference in the median time interval from initial diagnosis to surgery between the 2 groups of patients (23.0 months vs 19.0 months; P=1.000). There were no statistically significant differences in the median MPD diameter at diagnosis (2.9 mm vs 6.0 mm; P=0.077), median cyst size at diagnosis (20.5 mm vs 13.0 mm; P=0.723) and median CA19-9 level at diagnosis (11.35 U/mL vs 12.77 U/mL; P=0.706) between the 2 groups of patients. At the end of follow-up, there were no significant differences in median MPD diameter (4.7 mm vs 10.0 mm; P=0.081), median cyst size (29.5 mm vs 30.0 mm; P=0.671), and median CA19-9 level (14.54 U/mL vs 24.29 U/mL; P=0.239) between the 2 groups. Moreover, there were no statistically significant differences in median cyst growth rate (3.7 mm/year vs 4.0 mm/year; P=0.759) and median MPD dilatation rate (0.52 mm/year vs 2.29 mm/year; P=0.258) between the 2 groups of patients (Table 7). We also conducted univariate and multivariate logistic regression analysis on IPMN patients undergoing surgery and found that older age is an independent risk factor for the malignant progression of IPMN from LGD to HGD/IC (HR=1.11, 95% CI: 1.01–1.23, P=0.040) (Table 8).

Discussion

In clinical practice, the target population for follow-up is predominantly asymptomatic IPMN patients without indication for surgery, but there is a lack of consensus on the interval and duration of follow-up [35]. Many studies have adopted the international consensus Fukuoka guidelines as reference standards for the clinical management of patients with IPMN, which recommend surgical treatment for patients with HRS and EUS examination for patients with WFs to identify the presence of malignant features [6]. The European evidence-based guidelines classify related risk features into absolute and relative indications for surgery [12]. Although the Fukuoka guidelines and the European evidence-based guidelines have shown high sensitivity in distinguishing malignant IPMN, 83% and 76% of patients have received unnecessary surgical treatment, respectively. The American Gastroenterological Association Institute guideline has a sensitivity of only 27% in distinguishing malignant IPMN, but its missed diagnosis rate is as high as 26% [37]. More clinical and basic research is urgently needed to find suitable methods to determine the possibility of malignant progression of IPMN based on risk features. Recently, the International Association of Pancreatology has made modifications to the Fukuoka guidelines and released the international evidence-based Kyoto guidelines in December 2023 to improve the clinical management of IPMN patients [17]. The Kyoto guidelines recommend determining follow-up intervals based on cyst size, but do not specify clear follow-up intervals for patients with multiple WFs/HRS. If multiple WFs/HRS are present in IPMN patients, diagnostic tools such as nomograms are recommended to determine surgical indications, but nomograms need to be constructed based on the realities of each research center [17]. This article mainly explored widely applicable follow-up intervals for IPMN patients with multiple risk features.

Since IPMN was first confirmed by the World Health Organization in 1996 [38], research on follow-up of non-surgical patients with IPMN has shown a trend of vigorous development, while the included study population has gradually expanded. Multiple studies have found that after long-term monitoring, IPMN patients still have a higher incidence of PDAC compared to the general population [20,35]. There are also studies suggesting that elderly IPMN patients are more likely to develop PDAC [15,39]. A long-term follow-up study suggested that advanced age may be a WF in IPMN patients [40]. Therefore, some scholars suggest that IPMN patients should be continuously monitored until they are not suitable or unwilling to undergo surgery [41], but there are also studies indicating that lifelong monitoring is unnecessary for most IPMN patients [42]. Some studies support that for IPMN patients who are older or have shorter life expectancy, have smaller cysts, and remain stable, monitoring can be stopped after 5 years of follow-up [27,28]. IPMN patients without significant disease progression within 5 years are considered to have a relatively low risk of progression to IC, but more reliable validations in large clinical studies are needed. Some researchers have also studied the follow-up deadline based on cyst size and gender to determine the optimal age to stop monitoring under different circumstances [43]. It is now known that BD-IPMN patients have a lower risk of developing malignant tumors than MD-IPMN and MT-IPMN patients [1]. Therefore, for optimal monitoring and safe follow-up of unresected IPMN, some studies suggested reducing monitoring frequency for patients with suspected BD-IPMN <20 mm and no other WFs [44]. The Kyoto guidelines suggest that monitoring can be stopped for patients with cyst sizes <20 mm and no morphological changes or WFs/HRS after 5 years of surveillance, but this is due to considerations of the patient’s condition and life expectancy [17]. There are also studies suggesting a need for active surgical treatment for IPMN patients with significantly elevated CA19-9 levels [45]. The 5-year survival rate of IPMN patients is closely related to the presence of invasive components in the cysts. The 5-year survival rate of non-IC IPMN patients is 80–100%, while the 5-year survival rate of IPMN patients who progress to IC is 40–60% [46]. This significant prognostic difference is mainly due to the higher malignancy of IPMN progressing to IC. Therefore, discovering the risk features that promote the progression of IPMN to HGD/IC has important clinical significance. The survival rate of IPMN patients is also closely related to their age and comorbidities, and IPMN follow-up strategies should be adjusted based on these actual situations [47]. Appropriate follow-up intervals are beneficial for timely detection of risk features and can reduce the cost of medical examinations. During the follow-up process, if the cysts are found to grow rapidly and have obvious malignant features, timely surgical treatment is needed to remove the lesions.

In our research, the growth rates of cysts in patients with cyst sizes ≥30 mm were significantly faster than that in patients with cysts <20 mm and 20 mm ≤ cysts <30 mm. The dilatation rates of MPD in patients with MPD diameter ≥10 mm were significantly faster than that in patients with MPD <5 mm and 5 mm ≤ MPD <10 mm. The dilatation of MPD and the enlargement of cysts did not slow down over time. On the contrary, as MPD dilated and cysts grew, the speed of MPD dilatation and cyst growth accelerated, and the risk of IPMN progression seemed to accumulate over time. IPMN patients with newly developed risk features during follow-up had larger cyst sizes and wider MPD diameters at initial diagnosis. Furthermore, patients with newly developed WFs/HRS during follow-up periods had faster velocities of MPD dilatation and cyst growth compared to patients without newly developed WFs/HRS. This study retrospectively recorded the time intervals between the initial diagnosis and the appearance of a newly developed WF/HRS in IPMN patients, and found that the intervals between the appearance of newly developed WFs/HRS in patients without WFs/HRS initially and in patients with ≤2 WFs were not significantly different, and there was a longer median interval between the onset of new WFs/HRS than in patients with >2 WFs or with HRS at diagnosis. Follow-up intervals for IPMN patients could therefore be determined from the number of WFs/HRS and cyst size rather than solely depending on cyst size, which may be overlooked in some patients with smaller cysts but who have high risk of malignant progression.

The present study assessed the relationship between the follow-up intervals of IPMN patients and the number of risk features. For patients with cysts ≥30 mm, close follow-up should be conducted every 6 months. For patients with cysts <30 mm containing ≤2 WFs and containing >2 WFs or HRS, after 6 months of close follow-up excluding rapid progression of IPMN, follow-up examinations once every 1.5 to 2.0 years and once every 0.5 to 1.0 years were appropriate. This was validated in follow-up according to MPD diameter, with 5 mm ≤ MPD <10 mm versus MPD ≥10 mm being one WF and one HRS, respectively, with appropriate follow-up intervals of 1.5 to 2.0 years and 0.5 to 1.0 years, respectively. For patients with MPD <5 mm, the median time interval for the onset of new WFs/HRS was relatively longer. According to the postoperative pathology results, IPMN patients undergoing surgery were divided into an LGD group and an HGD/IC group. Statistical analysis showed that there was no significant difference between the 2 groups except for the age of onset. Univariate and multivariate logistic regression also revealed that age is an independent correlated factor for the progression of IPMN from LGD to HGD/IC. Patients in the HGD/IC group were significantly older at initial diagnosis, indicating that advanced age may be an important risk factor for IPMN patients. This was consistent with some previous research findings [15,39,40].

IPMN patients are often incidentally discovered on routine medical imaging examinations. To address the challenges of IPMN diagnosis and management, some scholars suggested establishing a multidisciplinary pancreatic cyst clinic within the healthcare system [48]. This strategy of regular follow-up is more helpful in detecting changes in cysts in a timely manner and improving the quality of life and survival of IPMN patients than relying solely on surgery to solve the problems. Moreover, long-term image-based follow-up of IPMN patients can improve the surgical and survival outcomes of patients with PDAC developing concomitantly with IPMN [49]. However, the present study was a single-center, retrospective study and some IPMN patients’ long-term monitoring data were lost, which may have introduced study bias. To provide more reliable evidence on the follow-up of IPMN patients, future studies need to be large-scale, prospective, and multicenter in design. The controversies in recent research also provide opportunities for future studies, prompting more multidisciplinary collaborations and clinical studies to gain a clearer understanding of the mechanisms of IPMN progression, to further optimize IPMN management strategies.

Conclusions

In conclusion, there are differences in the rates of malignant progression between IPMN patients with ≤2 WFs at diagnosis and those with >2 WFs or HRS, which could be followed up every 1.5–2.0 years and 0.5–1.0 years after 6 months of close follow-up, respectively. This may be applicable to patients with cysts <30 mm or even smaller, rather than follow-up solely on the basis of cyst size. For patients with cysts ≥30 mm, semiannual imaging and laboratory examinations are appropriate. We also found that advanced age may be an important risk factor for malignant progression in IPMN patients.