The current study is an extended study of the previous study;2
it provides the results of clinical outcomes of CLPs after more than 5 years of follow-up. This study confirms the indolent nature and favorable prognosis of most CLPs as a result of long-term follow-up. However, this study also shows the potential for growth and malignant transformation of CLPs even after 5 years, which provides evidence to support long-term surveillance.
In the current study, the rate of malignant progression of CLPs during follow-up was 3.6% and the univariate and multivariate analysis showed that the presence of mural nodule or solid component was strongly associated with malignancy. Therefore, we evaluated the natural history of CLPs containing mural nodules or solid component. Although some mural nodules showed regression during follow-up, overall risk of malignancy in case of the presence of mural nodule or solid component was 30% in the current study. Furthermore the development of these intra-cystic components occurred even after follow-up for more than 5 years. Several studies also reported the variable factors associated the malignancy. Jang et al.23
presented the tumor size and the presence of a mural nodule as meaningful predictors of malignancy. However, in this study, only patients with IPMN proven pathologically were included. Brounts et al.16
reported that the presence of symptoms, male gender, and cystic loculation were associated with the risk for a malignancy. Lee et al.,1
on multivariate analysis of their 166 surgical cases, reported that the presence of weight loss, a solid component in the CLP, and common bile duct dilatation were independent predictors of a malignancy. These two studies, in contrast to the current study, included patients who underwent surgical resection immediately after the initial diagnosis.
Few studies have evaluated the natural history of CLPs for more than 5 years. Handrich et al.13
reported the clinical outcome of long-term follow-up (mean duration of 8 years) of CLPs. The number of patients, however, was only 22 and only patients with small CLPs (less than 2 cm) were included in their study. In the current study, the median duration of follow-up was 72.3 months and 81 patients (72.3%) received follow-up for more than 5 years. Among these 81 patients, CLPs in 6 patients were noted to begin growing even after 5 years of follow-up; three of these patients eventually received surgical resection. A total of seven patients underwent surgical resection after 5 years of follow-up and the pathologic results revealed malignancies in two patients. Furthermore, in all seven patients, changes in the features of the CLP or growth of the CLP occurred after 5 years of follow-up. Few studies have reported malignant change after 5 years of follow-up in CLPs with initial features of a benign lesion; this is the first study to report such findings. These results of long-term follow-up (more than 5 years) demonstrate the potential of growth and malignant transformation of CLPs even after 5 years of follow-up and provide evidence to support clinical and radiological follow-up of these lesions for more than this long-term duration.
Several studies have suggested guidelines for surveillance of CLPs. Das et al.10
reported that growth of CLPs was unlikely to occur before 2 years in CLPs 3 cm or less in size and without mural nodules; they suggested that the optimal imaging interval should be at 2 years from the initial diagnosis. Handrich et al.13
reported that 59% of patients with CLPs less than or equal to 2 cm remained unchanged over a minimum radiologic follow-up of 5 years and Lahav et al.8
suggested that asymptomatic CLPs without unfavorable EUS findings could be managed conservatively for at least a mean period of 4 years. In the current study, among 73 patients with a small CLP (<2 cm), 12.3% (nine out of 73 patients) underwent subsequent surgery. However, all subsequent surgeries occurred after 36 months of follow-up, and the risk of malignancy in this subgroup was only 2.7% (two out of 73 patients). Furthermore, none of the patients in this subgroup experienced growth of the CLP before 2 years of follow-up. According to the results of the current study, therefore, the suggestion of Das et al.10
about the optimal imaging interval (2 years from initial diagnosis) can be applied to clinical practice, especially in patients who have severe co-morbidities. However, further studies with larger number of patients and with more elaborately defined protocol will be needed to clarify this issue.
The limitations of this study include the followings. First, this study is a retrospective cohort study performed without elaborately defined protocol. However, to our knowledge, this is the first study both with duration of follow-up for more than 5 years and with the largest number of patients to date. Second, because only 92 out of 129 patients (71.3%) received additional follow-up, the absolute risk of malignant potential of CLPs might be underestimated. However, the baseline characteristics (except for gender) were not significantly different between the follow-up group and the non-follow-up group; the difference in gender was likely to be an incidental finding. Furthermore, the data was obtained from the Korean Registry of Birth and Death and the telephone contacts (for a total of 182 patients who have received follow-up from the previous study)2
to evaluate the effect of CLPs on long-term prognosis. According to the data, only one pancreas-related mortality occurred in this study. Third, because of low rate of malignancy (3.6%), the analysis for the identification of factors associated with malignancy could not be performed with sufficient accuracy in the current study; although the presence of septum and the increase in the size of CLPs tended to be associated with malignancy, these factors failed to show statistical significance. Further studies with larger number of patients (including only patients who received conservative management initially) are needed to identify the predictors of malignancy clearly. Fourth, only a small portion of patients (25.9%, 29 out of 112 patients) received EUS for the evaluation of CLPs. In fact, EUS was not available for many patients during the period of patient enrollment (from 1998 to 2004); most EUS procedures were performed after this time. EUS can be particularly helpful in demonstrating septae, solid components, and communication with pancreatic ducts, and guiding FNA for cytological examinations and fluid analysis.15,24
In this study, EUS influenced clinical decision in six patients by detecting change in the features of the CLPs.
In summary, according to the results of long-term follow-up, most CLPs, when conservative management is planned initially, have an indolent course and generally a favorable prognosis, irrespective of subsequent surgery during follow-up; although the rate of subsequent surgery for CLPs was considerable (23.2%), the overall rate of malignant progression during long-term follow-up was only 3.6%. However, in case of the development of mural nodule or solid component during follow-up, surgery should be considered because of considerable rate of malignancy. Moreover, the results of this study suggest that clinical and radiological surveillance should be maintained for at least more than 5 years because of the potential for growth and malignant transformation of CLPs even after this long-term duration.