Cholangiocarcinoma is the second most common primary hepatobiliary malignancy originating from the epithelium of the intrahepatic, perihilar, or extrahepatic bile ducts, with the frequencies of 5 to 30%, 40 to 50%, and 20 to 30%, respectively [1-5]. The incidence of intrahepatic cholangiocarcinoma is increasing worldwide, especially in Asia, while the incidence of extrahepatic cholangiocarcinoma is somewhat stable or declining [6-11]. Surgical resection remains the only curative treatment option for cholangiocarcinoma, but most patients are far advanced at the time of presentation, which leads to a poor survival outcome [12-16]. In addition, spreading widely through bile ductules and extensive invasion to adjacent organs, cholangiocarcinoma has frequent locoregional or distant recurrences via lymphatic chains or hematogenous metastasis [4,5,12,17,18]. Kobayashi et al. [19] reported distant metastases were more common than locoregional recurrence after R0 resection in patients with perihilar cholangiocarcinoma.

The 5-year overall survival rate after surgical resection of cholangiocarinoma is reported to be 5 to 40%, and the median overall survival time and median recurrence-free survival time is 27 to 33 and 9 to 27 months, respectively [6-8,10,13,15,18-20]. Many published series have reported the risk factors for poor survival and recurrence; perineural invasion via lymphatic pathway and the proximity to the peripheral nerve plexus, presence of lymph node metastasis, poor differentiation, higher T stage, positive surgical resection margin and high level of carbohydrate antigen (CA) 19-9 [12,15,17,19-21]. The recurrence sites vary from local or locoregional recurrence in abdominal cavity to distance metastasis including abdominal or chest wall, skeletal muscles, lung, bone or brain [1,6,5,22,23].

Repeated hepatic resection for large, resectable tumors or radiofrequency ablation (RFA) for several small nodules have demonstrated their effectiveness on survival for the treatment of recurrent intrahepatic cholangiocarcinoma in some series [17,18,24].

However, there is no large-scale series to verify beneficial effects in terms of survival through surgical treatments including other types of recurrent cholangiocarcinomas. Thus, we attempted to identify whether or not there is a survival benefit to patients with recurrent cholangiocarcinoma who had undergone surgical resection with curative intent according to the recurrent sites and the types of resection.

The long-term survival outcomes of patients who undergo surgical treatment for cholangiocarcinoma is still disappointing, although there have been recent advances in imaging modalities, peri-operative treatment, and surgical techniques. Additionally, because of the advanced stage at presentation, inadequate identification of anatomic location, and/or poor medical conditions, surgical resection is often non-curative [10]. To this end, therapeutic strategies for advanced or metastatic cholangiocarcinoma have been developed, such as systemic chemotherapy, brachytherapy, photodynamic therapy and hepatic-arterial embolization or cryoablation [7,10,19,26]. However, most have limited roles in representing satisfactory outcomes on survival.

It is reported that liver and abdominal lymph nodes around the hepatoduodenal ligament, periportal, common hepatic artery, and posterior pancreatoduodenal areas are common sites of recurrence in patients with cholangiocarcinoma [5,19,27,28]. Occasionally, distant lymph nodes in the posterior mediastinum or supraclavicular area can be involved. These findings have commonly been accepted to reflect disease progression and are associated with a poor prognosis.

Repeated liver resection in intrahepatic cholangiocarcinoma, repeated RFA, or a combination for locoregional recurrent tumor have been reported to be effective with respect to survival in highly selected patients [9,17,18,25]. However, our study extended the concept of repeated resection beyond the liver to extrahepatic intra-abdominal locoregional recurrences, abdominal or chest wall and lung or pleura. In addition to performing repeated hepatectomy or RFA for recurrent hepatic lesions, resection of recurrences in the abdominal cavity and abdominal or chest wall were attempted. In our experience, there were two of five cases showing positive resection margins after metastasectomy of the abdominal wall. Second recurrences occurred in these two patients, so they underwent repeated resection around the previous area of resection. Thus, wider excision must be considered during metastasectomy of the abdominal or chest wall, and mesh could be useful for covering large fascial defects in these cases.

In this series, the recurrence rate of cholangiocarcinoma showed 34.3%, and about 57% of recurrence occurred within 1 year. However, only 8.3% of patients with recurrence were treated surgically in this period, while 10.0% and 19.6% of patients were treated from 1 to 2 years and above 2 years, respectively. Thus, early surgical resection should be considered to acquire greater survival benefits.

There are some drawbacks in this retrospective study. First, differences in the clinical course and pathogenesis among the three types of cholangiocarcinoma may exist. But it was reported that there were no significant differences in clinical presentation, disease stage and survival between intra- and extra-hepatic cholangiocarcinoma [6]. Second, a relatively smaller incidence of recurrence than in previous studies was identified. It might be influenced not by the development of the palliative treatment options, but also missed patients who were previously treated surgically. In fact, patients with cholangiocarcinoma have been increasing recently who were treated surgically or with RFA. Therefore, further follow-up studies for these patients are warranted to understand tumor biology and diverse patterns of tumor recurrence to make up for these limitations. Francis et al. [9] and Zhang et al. [4] introduced regulation of cholangiocarcinoma from a biologic point of view. Their reviews suggested that genetic hypermethylation, interleukin-6, growth factors, gastrointestinal hormones, neuroregulatory molecules, angiogenesis, or E-cadherin-mediated cell-to-cell adhesion expressed by the Slug gene are related to growth or invasiveness of the tumor. Third, although most of the clinicopathologic characteristics were similar in our two groups, the rate of patients who underwent adjuvant CCRT was higher in group A. This selection bias could be an interference factor in drawing our conclusion. Finally, overall survival has room for modification because the recurrence patterns between the two groups were not similar. Thus, further prospective controlled study is needed to overcome this limitation.

In conclusion, according to this large-series study in a single center, we have to consider surgical procedures to resectable recurrent lesions to prolong survival in patients with recurrent cholangiocarcinoma. Moreover, adjuvant chemoradiotherapy alone could not acquire a meaningful beneficial outcome on survival without resection of recurrent lesions. Although this series did not confirm any beneficial effect of surgical procedures to recurrent masses in the liver, lung, pleura, or multiple sites on survival, surgical resection of locoregional recurrence in the abdominal cavity and of the abdominal or chest wall metastatic lesions showed remarkable benefits in terms of range of survival. This consideration might help to determine patterns of recurrence and adequate therapeutic options for recurrent cholangiocarcinoma.