Role of resection for Bismuth type IV hilar cholangiocarcinoma and analysis of determining factors for curative resection

Hilar cholangiocarcinoma (HCCA), also known as Klatskin's tumor, is a relatively rare tumor typically affecting the hepatic duct confluence. Complete surgical resection is the only therapeutic strategy offering the chance of a cure to patients with HCCA [1, 2, 3, 4]. Recently, the use of aggressive surgical management, including major hepatectomy, has increased tumor resectability and has improved long-term results for patients [1, 4].

HCCA is classified on the basis of the involvement of the hepatic confluence into four types according to Bismuth's scheme [5]. A type IV lesion is a combination of Bismuth type IIIa and IIIb lesions, in which the tumor invades the second-order bile duct tributaries of both hepatic ducts [6]. In the past, type IV lesions had been considered unresectable [7, 8], with that opinion being included in the American Joint Committee on Cancer (AJCC) cancer staging manual (7th edition) [9].

Although extended liver resection may provide long-term survival in patients with HCCA, there are few reports on factors influencing resectability of Bismuth type IV HCCA. The aim of this study was to identify anatomical factors that predict curative-intended resection in patients with Bismuth type IV HCCA.

Even though diagnosis of Bithmuth type IV HCCA has markedly improved with advanced imaging modalities, patients with Bithmuth type IV HCCA have not been considered as candidates for curative resection [7, 17, 18]. However, recent reports have suggested that certain patients with Bismuth type IV HCCA are able to undergo curative resection [8, 17, 18]. In the present study, 33 of 159 patients (20.8%) underwent CIR. Among those, most patients (21/33) had negative surgical margins (R0 resection).

The proportion of CIR patients with BDV types A2 to A4 (especially, A2 hilar trifurcation BDV) was markedly higher than that in patients with common bile ducts (type A1) (Table 1). A2 BDV has typically short lengths of first-order bile duct compared to type A1 BDV. As a result, Bismuth type IV HCCA with A2 type BDV is actually similar to Bismuth types IIIa or IIIb, right- or left- sided hepatic resection as CIR could be possible.

In the present study, the distance from the hilum to the left second bile duct confluence and the extent of tumor infiltration over the left second bile duct confluence in right-sided CIR patients were significantly shorter than those lengths in left-sided CIR patients (Table 2). Also, the proportion of left-sided CIR patients with tumor infiltration of less than 5 mm over the right second bile duct confluence was marginally larger than that in right-sided CIR (Table 3). This result may be because the relatively short length of the first-order bile duct makes the anatomical characteristics of Bismuth type IV similar to those of Bismuth types IIIa or IIIb. Thus, we suggest that basing the selection of the operative procedure on of the length of the first-order bile duct and on the tumor extension over the second confluence along the bile duct is crucial for patients with Bismuth type IV HCCA.

With regard to vascular variation, we assumed that not only some type of hepatic artery variation, such as types 2, 3, or 4, but also some type of portal venous variation, such as type III or IV, had potential benefit for performing CIR due to the relatively close anatomical proximity between tumor and vasculatures. However, presently there were no significant differences in CIR rate among vascular variations (Table 1). This might be due to our relatively small study cohort or to there being no actual contribution of those variables to the resectability of Bismuth type IV HCCA. As a result, we suggest that further study is needed to determine the diagnostic usefulness of vascular variation.

Several reports including our previous report indicate that adjuvant CRT might be useful in patients with HCCA [19, 20, 21, 22]. In the present study, there was a survival gain in patients who received adjuvant CRT compared to non-CRT patients (Table 4). Thus, we believe that adjuvant CRT after surgical resection can be beneficial in Bismuth type IV HCCA patients.

Recent studies have established that the important prognostic factors for long-term survival in HCCA patients are negative surgical margins, lymph node status, and tumor differentiation grade [3, 20, 21, 23, 24]. Among these, the most consistently reported independent determinant for long-term survival after HCCA resection is the surgical margin status of the resected bile duct [3, 20, 21, 23, 24]. In the present study, there was no significant difference in survival related to resection status (Table 4). However, patients who underwent CIR showed more prolonged survival than that in non-CIR patients (Fig. 3). This result can be explained because surgical resection with a positive margin has a better prognosis if adjuvant treatment, such as CRT, is combined with surgical resection [19, 21, 22].

To obtain a negative resection margin, a more extensive hepatic resection is essential in HCCA. Some authors suggest that an extensive hepatic resection, such as performing a right or left trisectionectomy with caudate lobectomy, may be an effective surgical procedure that can achieve a low mortality rate and high pathological curability for HCCA [25, 26]. However, in-hospital deaths from postoperative hepatic failure have been the greatest contributor to poor survival rates [2, 25]. As a partial solution to this poor survival rate, preoperative PVE is widely used to minimize the risk of liver failure when extensive liver resection is anticipated [4, 7]. Here, however, there was no indication of a survival gain with implementation of preoperative PVE (Table 4). As a result, we suggest that preoperative PVE should be selectively used, perhaps in patients with an expected fingerling future liver remnant.

This study has several limitations. The first is the existence of inaccuracies in the performance of imaging analyses. Imaging analysis was performed in 18 patients after placing a drainage catheter in the bile duct. The presence of such a catheter may have limited the accurate evaluation of the enhancing or intraluminal lesion secondary to luminal collapse or there may be some interfering effect related to tube's presence. Second, although modern imaging techniques provide sufficient details to identify clearly the longitudinal and radial extents of the tumor [27, 28], a subset of patients had unexpectedly extensive tumor infiltration along the biliary tree. This may be related to a submucosal extension along the bile duct, as is often observed in the periductal-infiltrating and nodular-infiltrating types of HCCA [10]. In contrast, there was overestimation of tumor extent from preoperative imaging modalities in some patients. Periductal fibroplastic and inflammatory reactions may cause such overestimation, particularly if adjacent to a major vascular structure, as the cicatrizing effect may lead to strictures without adventitial invasion [29, 30]. For further evaluation of this potential source of limitation, we will analyze an ongoing prospective study of longitudinal tumor extent when it is assessed by preoperative imaging and pathologic examination.

With careful selection, patients with Bismuth type IV HCCA can be considered as candidates for CIR with an expectation of prolonged survival. Presence of type A2 BDV, the length of the hilum to the contralateral second bile duct confluence, and the extent of tumor infiltration over the second confluence of right- or left-dominant Bismuth type IV HCCA were the important factors for selection of a CIR procedure.