Surgery for Hilar Cholangiocarcinoma - Semantic Scholar

Original Paper Received: December 16, 2002 Accepted: October 17, 2003 Published online: March 15, 2004

Dig Surg 2004;21:114–122 DOI: 10.1159/000077335

Surgery for Hilar Cholangiocarcinoma: Feasibility and Results of Parenchyma-Conserving Liver Resection Hariharan Ramesh Kuruvilla Kuruvilla Ambadi Venugopal Vijayalakshmi Lekha George Jacob Department of Gastrointestinal Surgery, PVS Memorial Hospital, Cochin, India

Key Words Klatskin tumour W Hilar cholangiocarcinoma W Malignant biliary obstruction

Abstract Background/Aim: Major liver resection has improved the resectability rate of hilar cholangiocarcinomas, but morbidity and mortality may be significant. The aim of this study was to assess the value of parenchyma-conserving liver resection (resection of bile duct with liver segments I and IVb; PCLR) in hilar cholangiocarcinoma. Methods: Retrospective analysis of prospectively collected data. Factors influencing survival following three types of operations were studied by univariate and multivariate analyses. The three types of operations were: (1) local resection of the bile duct alone (LR); (2) major liver resection (resection of three or more segments, hepatic resection; HR), and (3) PCLR. Results: Forty-six patients (21 males, 25 females; age range 35–77 years, mean age 57, median age 57 years) underwent surgery. There were 11 LR, 12 HR, and 23 PCLR procedures. There were 3 deaths (mortality 6.5%). The mortality was higher following HR (3 out of 12; 25%) than following LR or PCLR (0 out of 34; p = 0.01). Survival was longer follow-

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ing curative resection (median 27 months) than after palliative resection (median 15 months; p = 0.001). Lymph nodal and perineural involvement were adverse factors on univariate, but not on multivariate analysis. PCLR produced better survival (median 29 months) as compared with LR (median 15 months) or HR (median 22.5 months; p ! 0.01). Conclusions: PCLR is applicable to selected patients with Bismuth-Corlette type III disease without major vascular involvement and produces survival rates comparable to those of LR and HR. PCLR may help avoid major liver resections in some patients with hilar cholangiocarcinoma. Copyright © 2004 S. Karger AG, Basel

Introduction

Carcinomas arising from the confluence of the hepatic ducts were first described by Altemeier et al. [1] in 1957. Klatskin [2] described the specific clinical characteristics in 1965, and the tumour is often referred to as the Klatskin tumour. These tumours are slowly growing and have a tendency to local spread. The resectability rates are low because of early infiltration of the tumour into adjacent structures such as hepatic artery, portal vein, and caudate

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lobe. The aims of surgery in hilar cholangiocarcinomas are: (1) to achieve macroscopic removal of the tumour; (2) to restore satisfactorily the bile flow to the gut, and (3) to minimize postoperative liver failure or death. At the beginning of the last decade, resection was possible only in 20% of the cases, and the operative mortality was 10%. The median survival was only 20 months, but resected patients enjoyed a good quality of life [3, 4]. The last decade has seen an aggressive approach to hilar cholangiocarcinomas with the increasing use of major hepatic resections [5–14]. The resectability rate increased to 80% with the addition of hepatic resection to bile duct resection without increasing the postoperative death rate. Bismuth et al. [15] and Pichlmayr et al. [16] have suggested a stagewise management strategy with the prime objective of achieving complete surgical resection of the tumour without leaving behind macroscopic residual disease. Patients with Bismuth types I and II were treated by bile duct resection. For Bismuth stage IIIa/IIIb lesions, resection of the corresponding hemiliver was recommended. However, major hepatic resection is a formidable operation in patients with a cholestatic liver and carries a high complication rate with a morbidity of up to 81% and mortality rates of between 6 and 10% in the most advanced centres [17–19]. This paper describes the experience of a single unit in the management of hilar cholangiocarcinomas and the results of resectional surgery. Conservative liver resection (resections of segments I and IVb alone) was performed in 23 patients without mortality. Major hepatic resection was avoided, unless there was extensive vascular and hepatic duct involvement in that lobe. Factors affecting survival were analyzed using univariate and multivariate analyses.

trasound in all patients, computerized tomography scan in 38, duplex sonography in 11, endoscopic retrograde cholangiography in 19, percutaneous transhepatic cholangiography in 9, and angiography in 2 patients. Magnetic resonance cholangiography was used in 11 patients and diagnostic laparoscopy in 8 cases prior to laparotomy. Pre-operative investigations aimed at assessing size of the primary tumour, extent of ductal involvement, spread to adjacent liver parenchyma or vessels, and distant metastases. The bile duct involvement was classified as Bismuth-Corlette [20] type 1 in 4 patients, as type 2 in 18, as type 3a in 11, and as type 3b in 13 cases. Overall final staging was performed using the pTNM staging. There were 9 patients with stage 2 tumours, 9 with stage 3 lesions, and 28 patients with stage IVa tumours [21]. Pre-operative endoscopic/percutaneous stenting was performed in 12 patients, including those with cholangitis (n = 8) and cases in whom surgery could not be scheduled within 24 h after cholangiography (n = 4). The interval between stenting and surgery ranged from 48 h to 20 days.

The data of 46 consecutive patients who underwent resection for hilar cholangiocarcinoma during the period 1987–2001 were studied retrospectively. There were 21 males and 25 females, and their ages ranged from 35 to 77 years (mean 57, median 57 years). All patients presented with painless progressive obstructive jaundice. There was evidence of cholangitis in 12 patients, of weight loss in 39, and of mild abdominal pain in 16 patients. Associated significant medical illness was present in 19 patients. During this period, 83 other patients with hilar cholangiocarcinomas were treated by palliative surgical drainage (54 patients) or nonoperative stent placement (29 patients). The resectability rate was, therefore, 35.7%. Pre-operative evaluation included clinical examination and tests for liver function, viral markers, coagulation parameters, and fluid and electrolyte balance. Specific diagnostic investigations were: ul-

Technique and Definitions All resectional procedures included dissection of the extrahepatic bile duct and clearance of the lymph nodes at the porta hepatis and along the hepatoduodenal ligament up to the coeliac axis. Extrahepatic and intrahilar portions of hepatic artery and portal vein were skeletonized. The extent of bile duct resection was defined by the extent of involvement of the tumour as described by Pichlmayr et al. [16]. The following procedures were employed: – Bismuth type I: level I resection (left and right duct anastomosis); – Bismuth type II: level II resection and 3–5 bile ducts anastomosed to the jejunum with additional resection of segments I and IVb; – Bismuth type IIIa or b with major infiltration of vessels to that lobe: right or left hemihepatectomy with hepaticojejunostomy, and – Bismuth type IIIa or b with minimal or no vascular involvement: bile duct resection with resection of segments I and IVb and intrahepatic duct-jejunum anastomosis. The process of decision making with regard to the type of resection was as follows: Local resection was planned in cases in whom there was no parenchymal or vascular involvement whatsoever. When there were lobar atrophy or imaging data suggesting vascular compromise to one lobe, then hepatic resection was the procedure of choice. In all other cases, exploration was carried out with a view to conserve the liver parenchyma. Segment IVb and a portion of segment V were mobilized to achieve access to intrahepatic radicles. If there was extensive intrahepatic duct involvement, or if there was involvement of hepatic artery and/and or portal vein, then a hepatic resection was performed. In all other cases, parenchyma-conserving liver resection (PCLR) was the surgical procedure preferred. Curative resection: Complete macroscopic clearance with a minimum tumour-free margin of 5 mm. Palliative resection: Obvious residual disease or tumour within 5 mm of the resection margin or involving it at histopathology. Local resection: Resection of the extrahepatic bile duct system including the tumour without resection of liver parenchyma. Hepatic resection: Resection of three or more segments of the liver along with the bile duct. PCLR: Resection of segments I and IVb (plus a small portion of segment V) along with the bile duct. No formal major hepatic resection. Technique of PCLR. The hilar plate was not lowered. Instead, the inferior part of segment IV was mobilized to reach the suprahilar

Conservative Hepatic Resection

Dig Surg 2004;21:114–122

Patients and Methods

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Table 1. Detailed data of patients

undergoing the three surgical procedures (n = 46)

Variable

p

Type of operation

Age, years (median) Male/female ratio Curative resection Liver involvement Lymph node involvement Perineural involvement Adjuvant therapy Bismuth type III lesions

LR (n = 11)

HR (n = 12)

PCLR (n = 23)

55 5:6 7 (64) 3 (27) 5 (45) 3 (27) 5 (45) 2 (18)

53.5 4:8 8 (67) 11 (92) 8 (67) 3 (25) 6 (50) 8 (67)

60 9:14 17 (74) 18 (78) 7 (33) 4 (17) 20 (86) 10 (43)

NS NS NS 0.039 0.052 (NS) NS NS 0.068 (NS)

LR = Local resection; HR = hepatic resection; PCLR = parenchyma-conserving liver resection; percentages are in parentheses.

portion of the hepatic confluence. Main artery and vein and their corresponding right and left branches were dissected out and taped. The Glissonian sheaths were dissected within the liver parenchyma and the site for transection of the bile duct chosen, allowing a minimum tumour-free margin of 5 mm. In order to clear the liver parenchyma around the right duct, a small tongue of segment V was also cleared to gain adequate exposure to the right pedicle and its branches. In cases in whom there was minimal infiltration of the portal vein to one lobe, resection of the vein was performed with reconstruction. The anterior portion of segment IV was left attached to the hilar bile duct for en bloc excision. The portal venous branches to the caudate lobe were then ligated and divided. The caudate lobe was mobilized from the inferior vena cava by a technique described previously [22]. Once the caudate lobe was lifted off from the vena cava, it was excised. At the end of resection, the vascular pedicles to the two lobes were completely free from hepatic parenchyma in the central portion of the liver (fig. 1). In some cases, the caudate lobe was delivered to the anterior aspect above the bifurcation of the portal vein and the specimen removed en bloc; in others, it was resected separately. Procedures Performed in this Study (n = 46 patients). Local resection was performed in 11 patients, major hepatic resection in 12, and PCLR in 23 patients. Three patients underwent resection of segments of the portal vein. All histological specimens were labeled carefully and sent for examination. Frozen sections of the cut ends were not used. The patients undergoing the three types of procedures were comparable with regard to age, sex, lymph node and perineural involvement, and number of curative resections. Liver involvement was more common among the patients undergoing hepatic resection or PCLR (table 1). Thirty-one patients underwent adjuvant therapy. Indications for adjuvant therapy were (1) palliative resection and (2) stage 3 or 4 disease. External radiotherapy (40 Gy in 20 fractions) was used in 15 patients, internal radiotherapy (using 192Ir wire placement through transhepatic tubes) in 7, and mitomycin C chemotherapy (10 mg/m2 on a 6-weekly schedule for six cycles) in 19 patients. Ten patients received both chemotherapy and radiotherapy.

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Fig. 1. PCLR technique.

Statistics The data of all patients were collected prospectively. Factors affecting mortality and survival were studied using univariate and multivariate analyses. Univariate analysis was performed using the chi-square or the Mann-Whitney test as appropriate, and p ! 0.05 was considered statistically significant. Multivariate analysis was performed using the Cox multiple stepwise regression model (SPSS statistical package version 7.5). Actuarial survival was estimated using the Kaplan-Meier method.

Ramesh/Kuruvilla/Venugopal/Lekha/Jacob

Table 2. Univariate analysis of risk factors

Factor

Observation

Patients Mean months

Median months

p

Sex

males females

19 24

27.9 26.8

25 21

NS

Type of resection

curative palliative

30 13

31.2 16.9

27 15

0.002

Liver involvement

yes no

31 12

28.9 23.1

25 23

0.659

Lymph node involvement

yes no

20 23

22 31

20 28

0.040

Perineural infiltration

yes no

10 33

17.9 30.1

15.5 27

0.021

Extent of resection

local hepatic parenchyma-conserving

11 9 24

18 20.9 33.7

15 22.5 29

0.010

Adjuvant therapy

yes no

31 12

27.8 26.1

24 26

0.926

Results

Mortality Three patients died (mortality rate 6.5%) on days 17, 27, and 48 after the operation due to septicaemia, adult respiratory distress syndrome, and hepatic failure, respectively. All these patients remained jaundiced and had abnormal liver function tests at the time of death. The mortality among patients who underwent major hepatic resection (3 out of 12) was significantly higher as compared with the mortality among patients who underwent the other two procedures (0 out of 34 patients; p = 0.019). Complications occurred in 21% of the survivors. There were bleedings from gastric erosions in 1 patient, reversible encephalopathy in 2, secondary haemorrhage from the biliary-enteric anastomosis treated by arterial embolization in 1, subphrenic abscess in 2 (treated by ultrasound-guided aspiration), and severe wound infection in 3 patients.

21.8% at 5 years. Thirty-two patients underwent curative resection with 1-, 3-, and 5-year survival rates of 94, 38, and 25%, respectively. The corresponding 1-year survival rate following palliative resection was 67%. The longest survival in this group was 32 months.

Survival The median survival following the resection procedures was 28 months. Twenty-five patients died over a follow-up period of 7–62 months. Eighteen patients are still alive over periods ranging from 12 to 69 months. The actuarial survival was 88.4% at 1 year, 32% at 3 years, and

Univariate and Multivariate Analyses Univariate and multivariate analyses were performed to identify risk factors affecting survival. Univariate Analysis. The results of univariate analysis are shown in table 2. Curative resection produced a significantly longer survival than palliative resection. Lymph nodal and perineural involvement adversely affected survival. Age, sex, associated medical illness, duration or grade of jaundice, pre-operative stenting, tumour grade, adjuvant therapy, and disease extension into adjacent liver parenchyma did not affect the outcome. PCLR produced better survival than major hepatic resection or bile duct resection alone. Multivariate Analysis. Curative resection (fig. 2), adjuvant therapy, and PCLR were significant factors on multivariate analysis. Survival following PCLR was significantly longer than that following local resection and hepatic resection (fig. 3). Since PCLR was a powerful determinant of survival, the analysis was performed after excluding PCLR as a variable. The results are shown in table 3.


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Fig. 2. Curative resection and survival.

Dashed line: palliative resection (PR); solid line: curative resection (CR).

Fig. 3. Type of operation and survival. Dot-

ted line: local resection (LR); dashed line: hepatic resection (HR); solid line: parenchyma-conserving liver resection (PCLR).

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Table 3. Multivariate analysis

Factor

Exp (B)

p

95% confidence limits lower

upper

Curative resection Perineural infiltration Lymph node involvement PCLR Liver involvement Adjuvant therapy

0.186 2.431 0.778 0.110 0.687 0.377

0.048 0.647 0.268 0.035 0.236 0.143

0.728 9.134 2.262 0.344 1.999 0.943

0.016 0.188 0.645 0.0001 0.491 0.048

Excluding PCLR as variable Curative resection Perineural infiltration Lymph node involvement Liver involvement Adjuvant therapy

0.145 3.356 2.245 0.887 0.789

0.072 0.935 1.403 0.134 0.358

0.457 6.457 3.998 7.345 1.927

0.007 0.064 0.032 0.663 0.089

Table 4. Mortality and survival in recent series of resected patients Series

Madariaga et al. [23] Klempnauer et al. [24] Su et al. [25] Miyazaki et al. [17] Burke et al. [26] Jarnagin et al. [27] Present series

Number of cases

Year

28 151 49 76 30 80 46

1998 1997 1996 1998 1998 2001 2002

% major liver resection

Mortality %

Median survival months

Survival, % 1 year

3 years

5 years

all 80 55 88 70 78 25

14 6 10 15 7 10 6.5

24 27 14 – 26 35 28

79 65 – – – – 88

39 – – 26 – – 32

8 27 15 – – 27 22

This series represents the experience of a single unit in the treatment of hilar cholangiocarcinomas over a period of 14 years. Hilar cholangiocarcinoma has a poor prognosis. The 5-year survival rates in various series published during the last 3 years ranged from 14 to 27% [17, 23–27] (table 4). Nagino et al. [28] reported improved resectability and survival with concomitant major liver resection in addition to excision of the bile duct tumour. However, major hepatic resection in patients with a hilar cholangiocarcinoma may carry a greater risk of postoperative hepatic dysfunction and mortality than bile duct resection alone. These patients may tolerate major liver resection poorly due to the following reasons: (1) resection for hilar cholangiocarcinoma involves removal of functioning liver as opposed to resection for hepatocellular carcinoma,

where the majority of the liver removed is affected by tumour and consequently not functioning, and (2) preexisting jeopardized liver function as a result of longstanding cholestasis (the average interval between onset of jaundice and referral to our centre was 4 weeks). In our series, all patients who died were in the major hepatic resection group. There are several reports in the literature showing a higher mortality with major liver resection [17– 19]. This paper highlights the potential use of PCLR in patients with hilar cholangiocarcinomas. Resection of a hemiliver in hilar cholangiocarcinomas is necessitated by ductal or vascular involvement to that lobe or when there is extensive parenchymal infiltration to a portion of one lobe. PCLR is advantageous in that resection of segment IVb and a portion of segment V allows the surgeon to gain access to the hepatic duct well within the parenchyma and


Dig Surg 2004;21:114–122

Discussion

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to avoid resection of that lobe. Similarly, infiltration to the perihilar portion of the liver parenchyma is also dealt with by this operation. Should there be vascular and ductal involvement to that lobe, then resection would necessarily include that lobe of the liver, and PCLR would then not be a feasible option. PCLR is, therefore, applicable only to patients with localized disease without vascular involvement. This is especially true in Bismuth type 3a lesions, where the short extrahepatic course of the right duct results in early infiltration of the liver parenchyma of segments IVb/V. These patients may then require a right hepatectomy. If PCLR is applied to such a patient, right hepatectomy may be avoided. 10 out of 18 patients with Bismuth 3 lesions and 18 out of 32 patients with liver parenchymal involvement were treatable by PCLR without hepatic resection. Univariate analysis showed that lymph nodal involvement and perineural infiltration were associated with poor survival rates (table 2). However, tumour extension to the adjacent liver parenchyma was not associated with an adverse prognosis. Due to the strategic location of the tumour in the hepatic hilus, there is early infiltration of surrounding liver parenchyma of segments I and IV. In our series 32 out of 46 patients had liver involvement (classified as IVa by TNM staging), and only 19 patients with such liver involvement had lymph node positivity. This underlines a potential weakness of the TNM staging. It appears from our data (tables 2, 3) that microscopic or even macroscopic infiltration of the adjacent liver parenchyma may not adversely affect survival. The post-resection histological identification of such infiltrations and their en bloc excision have been facilitated greatly by our present technique, where the hilar plate is not lowered, but the inferior part of segment IV is resected to achieve a suprahilar approach to the confluence. Jarnagin et al. [27] have proposed a T staging system which categorizes patients into various groups, depending on the extent of the biliary involvement and presence and extent of vascular (portal vein) involvement. This classification addresses some weaknesses of the existing TNM staging for hilar cholangiocarcinomas. The en bloc excision of the inferior part of segments I and IV provides a three-dimensional excision of hilar cholangiocarcinomas. In addition to the contiguous spread mentioned previously, non-contiguous tumour nodules were identified in the caudate lobe in 14 of 23 patients thus resected. Wattanasirichaigoon [29] reported the use of inferior segmentectomy IV to achieve access to the hilus in 11 patients. Secondary confluences of the sectorial ducts could be accessed, and a biliary-enteric anasto-

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mosis could be performed easily without the need for retraction of the segment IV. Miyazaki et al. [30] have reported the use of total excision of segments I and IV with construction of four to six biliary anastomoses. The procedure was performed in 3 patients, and there were no postoperative complications such as liver failure or mortality. Major hepatic resection was necessary primarily for type IIIa or type IIIb tumours, when there was involvement of portal vein and/or hepatic artery to that lobe. These tumours were more advanced, and there was spread to hilar lymph nodes in 8 out of 12 cases (table 1). Increasing radicality and liver resection in this group did not provide any survival benefit. In many type III tumours (especially in those without major vascular infiltration), PCLR provided access to intrahepatic bile ducts and allowed anastomosis even to subsectorial ducts. Additionally, involvement of small segments of the portal vein could be managed by resection and grafting/re-anastomosis. Kaplan-Meier survival curves showed a significant improvement in survival with PCLR as compared with local and hepatic resection procedures (fig. 3). A proximal tumour-free margin of 5 mm is considered sufficient to provide a curative resection [31], and this could be achieved with this approach in a number of patients. There is controversy as to whether perineural infiltration constitutes an adverse prognostic factor. While the group from Nagoya [32] found a strong correlation between perineural involvement and poor survival, Klempnauer et al. [24], in a large series of 151 resected patients, found no effect on survival. In our series, perineural infiltration was a significant factor on univariate analysis, but was not on multivariate analysis. Mizumoto and Suzuki [33] first highlighted the importance of caudate lobe resection in improving the surgical clearance of hilar cholangiocarcinomas. The largest series of caudate lobe resection for hilar cholangiocarcinomas was reported by Nimura et al. [6]. Involvement of ducts in the caudate lobe occurred in 44 out of 46 cases in their series, and resection of the caudate lobe improved survival. Similar results were reported by Ogura et al. [34] and Tashiro et al. [35]. Western surgeons preferred a more selective approach, with Blumgart and Benjamin [3] reporting nine caudate lobe resections among 22 patients in one series. Excision of the caudate lobe can provide a three-dimensional clearance of hilar cholangiocarcinoma when performed along with skeletonization of hilar vessels. Partial excision of the caudate lobe has been performed in several series, but this leaves the problem of anastomosis of large dilated multiple caudate lobe ducts.


In several previous series, the role of radiotherapy in hilar cholangiocarcinoma has been controversial [36–38]. Many investigators have reported benefit only in the palliated group or among patients undergoing palliative resections [37, 38]. In our series, adjuvant therapy did not improve survival on univariate analysis, but was a significant factor on multivariate analysis. However, larger numbers of patients are required to draw conclusions on the role of adjuvant therapy in the treatment of hilar cholangiocarcinomas. Overall, the results of multivariate analysis in this report need to be viewed with caution, owing to the small number of patients in each group. This is further highlighted by the impact of removing PCLR as a variable in the model (table 3).

In conclusion, resection of hilar cholangiocarcinomas provides long-term survival in a considerable number of patients. Resection of adjacent parenchyma in segments I and IV provides three-dimensional macroscopic clearance and has two advantages: (1) it avoids major liver resection and (2) provides easy access to intrahepatic bile ducts for anastomosis. Where feasible, PCLR could help to avoid major hepatectomy and to minimize the risk of postoperative liver dysfunction or mortality.

Acknowledgement The authors are grateful to Deepak Varma for providing the illustrations.

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