Previous reports showed that the presence of HRS is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients. In IPMN with HRS, 3-year pancreatic carcinoma risk of obstructive jaundice, enhancing solid component, and main pancreatic duct > 10 mm were 79.8%, 37.3%, and 39.4%, respectively. Thus, in the follow-up of BD-IPMN, HRS is considered to be the most important factor for predicting the appearance of IPMN-derived carcinoma. In this study, we evaluated the risk factors associated with the development of HRS during follow-up.
Reports have evaluated the risk factors of malignancy associated with individual cyst features of BD-IPMN, and cyst size > 3 cm, presence of mural nodule, and MPD dilatation > 5 mm proved to be the strongest predictors of pancreatic malignancy.[8, 9]
In our study, in addition to the dilation of MPD, rapid cyst growth and multiple WFs were significant factors in the development of HRS. Kang et al. reported that cysts growing faster than 2 mm/year presented a significantly higher risk of malignancy in all 201 subjects with an initial cyst size of < 30 mm without MPD dilation and no mural nodule. Kolb JM et al. studied a group of 188 patients with low-risk IPMN and 12 patients developed WF. Among them, the rate of BD-IPMN growth was greater in patients who developed WF than in those who did not (2.84 mm/year vs 0.23 mm/year; P < .001). In a recent study, rapid cyst growth rate (≥ 2.5 mm/year) is the main predictor of malignancy development in presumed BD-IPMN without WF or HRS. In our study, of the 21 patients with a cyst growth rate ≥ 2.5 mm/year, 3 patients (14.3%) developed HRS. Although most BD-IPMNs are indolent and dormant, some cysts rapidly grow with the development of HRS. During surveillance of BD-IPMN, a particular focus should be placed on the cyst growth rate.
In a recently published multi-institutional study by Wilson et al., high-grade dysplasia and invasive carcinoma was found in 57.4% of patients with multiple WFs, 31.1% with single WF, and 24.6% with non-WF, in surgical cases of IPMN. This study indicated that the number of WFs was associated with malignancy of BD-IPMN. Other studies scored the morphology of IPMN and created a risk model for malignancy, arguing that the larger the nodule diameter, cyst size, and main pancreatic duct diameter, the higher the risk of malignancy. Consistent with these studies, the group with multiple WF developed HRS more frequently compared to the other groups in this study. However, another study found that WF counts were not related to the risk of malignant-IPMN. In surgical cases, the mean WF counts were 1.52, 2.11, 2.14, and 2.20 for low-grade, intermediate-grade, high-grade dysplasia, and invasive carcinoma, respectively. Therefore, additional confirmatory studies are necessary to support our results.
Cyst size > 3 cm was not a significant factor in the development of HRS, but larger cysts had a greater cyst growth rate in this study. Han et al. reported that larger cysts, particularly those larger than 2 cm, showed significantly faster annual growth rates, and patients with initially larger cysts developed more WF during surveillance. Thus, the initial cyst size is an important factor for the follow-up of BD-IPMN because it is related to the rate of cyst growth. Although a mural nodule, which has been reported to be associated with cancer in many reports, was not extracted as a risk factor, our study was underpowered to detect the difference for the small cases with mural nodule at the initial diagnosis.[16, 17]
The American Gastroenterological Association guidelines recommend discontinuing surveillance of non-progressive IPMNs within 5 years. Conversely, accumulating evidence suggests that patients with BD-IPMN may remain at high risk of developing pancreatic carcinoma after 5-year surveillance.[19–21] In a Japanese study involving 804 patients with BD-IPMNs followed for > 5 years, the overall cumulative incidence of pancreatic cancer was 3.5% at 10 years from initial diagnosis. In a study at a US referral center, high-grade dysplasia and invasive carcinoma were observed in 20 (5.5%) and 16 (4.4%) patients, respectively, of 363 patients included at the time of 5 years of follow-up. Consistent with these studies, 5 out of the 10 patients who developed HRS appeared HRS after 5 years in our study, providing evidence supporting prolonged surveillance of patients with BD-IPMN. Further investigation is warranted to create surveillance programs based on these results.
This study has some limitations. First, it was a retrospective single-center study with a small sample size. Therefore, the possibility of unintentional selection bias in the selection of patients could not be fully excluded. Second, there were only 10 patients out of 285 who met the primary outcome (development of HRS). Due to the small outcome number, multivariate analysis was not performed. A further study in a large patient cohort with a long follow-up period is required to validate our results.
In conclusion, this study shows that BD-IPMN without HRS at the initial diagnosis developed HRS in 3.5% during surveillance, and the dilation of MPD, rapid cyst growth, and multiple WF were significant risk factors for the development of HRS. In the presence of such features, it is necessary to closely follow the development of HRS and be careful not to miss the timing of surgery.