Clinical Research
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2005; 11(12): 1779-1784
Published online Mar 28, 2005. doi: 10.3748/wjg.v11.i12.1779
Prognostic analysis of surgical treatment of peripheral cholangiocarcinoma: Two decades of experience at Chang Gung Memorial Hospital
Yi-Yin Jan, Chun-Nan Yeh, Ta-Sen Yeh, Tse-Ching Chen
Yi-Yin Jan, Chun-Nan Yeh, Ta-Sen Yeh, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, China
Tse-Ching Chen, Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, China
Author contributions: All authors contributed equally to the work.
Correspondence to: Yi-Yin Jan, M.D., FACS, Department of Surgery, Chang Gung Memorial Hospital, 5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan, China. ycn@adm.cgmh.org.tw
Telephone: +886-3-3281200-3219 Fax: +886-3-3285818
Received: October 13, 2004
Revised: October 14, 2004
Accepted: November 29, 2004
Published online: March 28, 2005

Abstract

AIM: To analyze the prognostic factors influencing the overall survival of peripheral cholangiocarcinoma (PCC) patients undergoing surgical treatment during 25 years at a single institution.

METHODS: This study retrospectively reviewed prospectively collecting data about 373 patients with histologically proven PCC who underwent surgical treatment between 1977 and 2001.

RESULTS: Three hundred and seventy-three PCC patients (159 men and 214 women) underwent surgical treatment from 1977 to 2001. Among them, 187 PCC patients underwent hepatectomy and 135 had curative resection (curative resectability rate: 36.2%). The follow-up duration ranged from 1.05 to 167.6 mo (mean/median = 14.1/7.2 mo). Overall cumulative survival rates at 1, 3, and 5 years were 32.5%, 9.2%, and 4.1%, respectively. Univariate log-rank analysis identified the following as adverse influences on overall survival: presence of symptoms, absence of mucobilia, elevated CEA and CA 19-9 levels, non-papillary tumor type, receiving non-hepatectomy, advanced tumor staging, lack of post-operative chemotherapy, and radiotherapy. Meanwhile, multivariate Cox’s proportional hazard analysis demonstrated that absence of mucobilia, non-papillary tumor type, advanced tumor staging, non-hepatectomy, and lack of post-operative chemotherapy were the five independent prognostic factors that adversely affected overall survival.

CONCLUSION: Favorable overall survival of PCC patients undergoing surgical treatment depends on early tumor stage, presence of mucobilia, papillary tumor type, hepatic resection, and post-operative chemotherapy.

Key Words: Prognostic factor, Surgical treatment, Peripheral cholangiocarcinoma


Citation: Jan YY, Yeh CN, Yeh TS, Chen TC. Prognostic analysis of surgical treatment of peripheral cholangiocarcinoma: Two decades of experience at Chang Gung Memorial Hospital. World J Gastroenterol 2005; 11(12): 1779-1784
INTRODUCTION

Peripheral cholangiocarcinoma (PCC) is a malignant tumor occurring in the liver or arising from the second or more distal branches of the intrahepatic bile ducts[1]. The incidence of PCC exhibits wide geographical variation, and generally accounts for between 5% and 30% of primary liver cancers[1]. According to the Japan Liver Cancer Society, histologically proven PCC represented 3.58% of all primary liver cancers[2].

Although no specific etiological factor has been identified for PCC, various well-recognized predisposing conditions involving chronic inflammation of the bile ducts exist. These conditions include infestation with the liver flukes Opisthorchis viverrini in Thailand[3] and Clonorchis sinensis in other Asian countries[4,5]; hepatolithiasis, prevalent in countries such as Taiwan and Japan[6-8]; primary sclerosing cholangitis[9,10]; choledochal cysts[11,12]; and Caroli’s disease[4,5].

Clinically, PCC remains challenging because it is difficult to diagnose in its early stages, and patients typically do not present because of vague symptoms until the disease is quite advanced. Curative resection with clear margins and without vascular or lymphatic invasion is infrequent and recurrence is common. Three- to five-year survival rates even with resection remains dismal[13-18]. Moreover, radiation therapy or current chemotherapy does not significantly improve long-term survival rates[16,19]. Tumor biological behavior and early intrahepatic and extrahepatic spread limit the efficacy of surgery, and yet complete surgical removal currently is the curative option for PCC. Although liver transplantation has provided an alternative in the surgical management of PCC, high rates of PCC recurrence following transplantation limit liver transplantation for PCC patients[20]. Despite considerable progress in diagnostic procedures, surgical techniques, and adjuvant therapies, the prognosis of PCC remains extremely poor, because most tumors are advanced by the time of diagnosis. The literature contains few reports of successful surgical treatment of PCC and evaluation of its prognostic factors, and most such reports deal with small numbers of cases[21-25]. This study examines the influence of clinicopathologic characteristics of PCC undergoing surgical treatment on PCC patient’s overall survival to improve the prognosis of PCC patients.

MATERIALS AND METHODS

From January 1977 to December 2001, 608 consecutive patients with histologically proven bile duct adenocarcinoma underwent surgical treatment at the Department of Surgery, Chang-Gung Memorial Hospital, Taipei, Taiwan. Based on tumor location, the 608 patients were classified into common bile duct cancer (n = 102; 16.8%), bile duct adenocarcinoma with hilar invasion (n = 133; 21.9%), and PCC (n = 373; 61.3%). PCC was defined as carcinoma arising from second order or more distal branches of the intrahepatic ducts. IP-PCC is histologically defined as intraductal papillary neoplasia of the liver (IPN-L) type 3 and 4, as described previously[8]. Type 3 showed an IPN-L lined by in situ and microinvasive adenocarcinoma, and type 4 showed with types 2 and 3 biliary lesions with variable invasion of adenocarcinoma[8]. Meanwhile, curative resection was defined as negative resection margin observed during histopathological examination. The 373 PCC patients comprised 159 men and 214 women with a mean age of 57.8 years (range 28-93 years). Table 1 lists the clinical manifestations and histological classifications. Right upper abdominal pain with tenderness was the most common symptom and sign on admission. Table 2 lists the distribution of the operative procedures, and indicates that 187 patients had hepatectomy, with a 36.2% curative resectability rate (curative resection cases: 135/373). Meanwhile, Table 3 lists the causes of surgical mortality, and reveals a surgical mortality rate of 6.7% (25/373). Surgical mortality is defined as the death occuring within one month after surgery. PCC patients undergoing non-hepatectomy procedure had a significantly higher surgical mortality (2.7 vs 10.8%; P = 0.002). Sepsis due to biliary tract infection is the main cause of surgical mortality. Laboratory tests were conducted on the day before surgery. Serum carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) were measured by radioimmunoassay. The tumors were preoperatively evaluated by abdominal ultrasonography (US), endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, computed tomography (CT), magnetic resonance image with cholangiopancreatography (MRCP), and hepatic arteriography, as appropriate. Tumor stage was defined according to the pathological tumor node metastasis (pTNM system) classification proposed by the UICC. Stages I and II were conditioned as early-stage, and stages III and IV as advanced-stage PCC. Adjuvant chemotherapy was systemically performed with a 5-flurouracil-based regimen due to either a positive section margin or local recurrence. Meanwhile, adjuvant radiotherapy was performed with intra-operative radiotherapy, external beam radiotherapy and/or brachytherapy due to either a positive section margin or local recurrence.

Table 1 Clinical manifestations and histological classification of 373 PCC patients who underwent surgical treatment.
SymptomsCase No%
Right hypochondria26671.7
Fever and chills13536.4
Body weight loss9926.7
Jaundice7620.5
Negative143.8
Physical findings
Abdominal tenderness or rebounding pain16043.1
Icteric sclera and yellow discoloration7219.4
Abdominal mass174.6
Negative10929.4
Histological classifications
Papillary adenocarcinoma5014.9
W-D adenocarcinoma3215.8
M-D adenocarcinoma6620.5
P-D adenocarcinoma5615.8
Mucinous adenocarcinoma328.6
Adenosquamous carcinoma143.8
Hepatocholangiocarcinoma92.4
Adenocarcinoma; unclassified5615.1
Table 2 Surgical procedures of 373 PCC patients.
Surgical proceduresPatient Number%
Hepatectomy18750.1
Left hepatectomy125
Segment 1, 2, 3, and 46
Segment 2, 3, and 467
Segment 2 and 349
Segment 2, 3, and bile duct resection2
Segment 11
Right hepatectomy36
Segment 5, 6, 7, and 815
Segment 5, 6, 7, 8, and bile duct resection5
Segment 5, 6, and 71
Segment 5 and 69
Segment 6 and 74
Segment 7 and 82
Bilateral hepatectomy14
Segment 4, 5, 6, 7, and 89
Segment 4, 5, and 83
Segment 2, 3, 4, and 51
Segment 2, 3, 4, 5, and 81
Partial hepatectomy12
Choledochotomy with T-tube10427.9
Laparotomy with biopsy8222
Total373100
Table 3 Operative mortality of 373 PCC patients undergoing surgical treatment.
Hepatectomy (n = 187)Non-hepatectomy (n = 186)
Cause of death
Sepsis (biliary)28
GI bleeding01
Intra-abdominal bleeding with shock02
Terminal status of cancer06
Necrotizing fascitis with sepsis01
CVA01
Hepatic failure10
Respiratory failure01
Gastrocutaneous fistula20
Total520
Mortality rate2.70%10.80%
Follow-up study

Follow-up evaluation included clinical physical examinations and blood chemistry tests at each visit. Additionally, serum CA 19-9 and CEA were measured, and the remnant liver was examined with US every three months. When US detected a new lesion or elevated CA 19-9 or when CEA were noted, abdominal CT or MRCP was performed for confirmation. Moreover, when patients complained of bone pain, bone scans were performed to detect metastasis. If any of the above procedures indicated recurrence, the patient was readmitted for more compressive assessment, including angiographic evaluation or MRI. Methods for treating recurrence include surgery, systemic chemotherapy, external beam radiotherapy, intraluminal radiotherapy, interventional radiological therapy, and conservative treatment.

Statistical analysis

The cumulative survival rates were calculated with the Kaplan-Meier method. Seventeen clinicopathological variables were selected for difference analysis by the log-rank test. The Cox proportional hazards model was employed for multivariate regression analysis. SPSS for Windows statistics software (SPSS version 10.0, Chicago, IL) was used for the statistical analysis. P≤0.05 was considered statistically significant.

RESULTS
Survival

Three hundred and seventy-three PCC patients undergoing surgical treatment received regular follow-up until death. This study showed that 187 PCC patients underwent hepatectomy and 135 had curative resection (curative resectability rate: 36.2%). Sixty-two patients were excluded from the survival analysis, including 25 patients who died within one month after surgery and a further 37 patients who were lost to follow-up. Totally 312 PCC patients undergoing surgical treatment were enrolled into survival analysis. The follow-up duration ranged from 1.05 to 167.6 mo (mean/median = 14.1/7.2 mo). Overall cumulative survival rates at 1, 3, and 5 years were 32.5%, 9.2%, and 4.1%, respectively.

Prognostic factors for survival

Univariate log-rank analysis identified the following as adverse influences on overall survival of 312 PCC patients, namely: presence of symptoms, absence of mucobilia, elevated CEA and CA 19-9 levels, non-papillary tumor type, lack of hepatectomy, advanced tumor staging, lack of post-operative chemotherapy, and radiotherapy (Table 4 and 5). Meanwhile, multivariate Cox’s proportional hazard analysis demonstrated that absence of mucobilia, non-papillary tumor type, non-hepatectomy, and lack of post-operative chemotherapy were the five independent prognostic factors that adversely affected overall survival (Table 6, Figures 1A-F).

Figure 1
Figure 1 A: The overall survival rates of 312 PCC patients who underwent surgical treatment; B: in terms of mucobilia; C: in terms of tumor spreading type; D: in terms of operative procedures; E: in terms of tumor staging; F: in terms of post-operative chemotherapy.
Table 4 Univariate analysis of factors influencing the overall survival of the 312 PCC patients.
FactorsSurvival time (mo)
P
Medianmean3-yr (%)5-yr (%)
Gender
Male (n = 128)7.7914.6611.782.27
Female (n = 184)6.8418.4110.888.610.941
Age (yr)
≤58 (n = 163)6.2117.0711.696.86
>58 (n = 149)8.3517.1510.76.050.471
Symptoms
Positive (n = 303)6.916.5810.756
Negative (n = 9)20.4541.6730.4830.480.024
Physical examination
Positive (n = 222)6.6415.78.084.54
Negative (n = 90)9.6720.5520.4613.560.053
AST (IU/L)
≤34 (n = 121)7.8915.6911.565.51
>34 (n = 161)7.3018.8512.027.280.936
ALT (IU/L)
≤36 (n = 139)7.3314.949.265.15
>36 (n = 107)8.3521.3815.129.30.326
ALP (IU/L)
≤94 (n = 63)10.3916.3112.123.64
>94 (n = 214)6.6417.2210.756.460.2143
Serum CEA (ng/dL)
>5 (n = 70)4.579.581.991.99
≤5 (n = 103)10.3923.1717.969.950.0001
Serum CA 19-9 (ng/dL)
>37 (n = 76)7.411.9310.27N.A.
≤37 (n = 29)13.2825.4923.7615.840.008
Associated with biliary stones
With biliary stones (n = 186)6.9417.8611.967.18
Without biliary stones (n = 126) 7.4016.509.775.860.693
Type of operation
Hepatectomy (n = 157)12.9925.3117.8810.15
Non-hepatectomy (n = 155)3.659.034.422.76<0.0001
Table 5 Univariate analysis of factors influencing the overall survival of the 312 PCC patients.
FactorsSurvival time (mo)
P
Medianmean3-yr (%)5-yr (%)
Mucobilia
Positive (n = 33)24.0745.7940.325.65
Negative (n = 279)6.4813.057.413.89<0.0001
Tumor spreading type
Papillary (n = 57)22.5938.1931.7720.42
Non-papillary (n = 255)5.8512.326.353.3<0.0001
TNM staging
I (n = 17)45.950.5460.0045
II (n = 58)24.0737.7428.8917.78
III (n = 88)8.5211.452.65N.A
IV (n = 149)4.187.666.08N.A.<0.0001
Tumor staging
Early stage (I+II) (75)24.9941.1935.2922.83
Advanced stage (III+IV) (237)5.039.093.92N.A.<0.0001
Post-operative chemotherapy
With chemotherapy (n = 118)11.4424.2517.7411.88
Without chemotherapy (n = 194)4.6412.357.163.58<0.0001
Post-operative radiotherapy
With radiotherapy (n = 63)11.722.1216.636.65
Without radiotherapy (n = 249)6.2515.899.657.170.0197
Table 6 Cox’s proportional hazards analysis.
FactorsRelative risk (95% confidence interval)P
Mucobilia (without mucobilia/mucobilia )2.185 (1.324–3.605)0.002
Tumor spreading type (non-papillary/papillary)1.455 (1.028–2.060)<0.001
Type of operation (non-hepatectomy/hepatectomy)1.946 (1.477–2.564)<0.001
Tumor staging
(II/I)1.637 (0.786–3.406)0.188
(III/I)3.334 (1.615–6.882)0.001
(IV/I)4.049 (1.940–8.449)<0.001
Post-operative chemotherapy (no chemotherapy/chemotherapy)1.823 (1.413–2.353)<0.001
DISCUSSION

This study used univariate and multivariate analysis to calculate overall survival rates of 312 PCC patients after surgical treatment in terms of 17 clinicopathologic factors.

In univariate analysis, patients’ symptoms, preoperative tumor marker (CEA and CA19-9), presence of mucobilia, tumor spreading pattern, treatment option, tumor staging, and post-operative adjuvant therapy (chemotherapy and radiotherapy) significantly influenced overall survival of PCC patients after surgical treatment. Applying the multivariate Cox’s proportional hazard model to data from this investigation revealed that long-term overall survival depends on the presence of mucobilia, hepatectomy, early tumor stage, post-operative adjuvant chemotherapy, and radiotherapy.

Patients had PCC diagnosed asymptomatically and incidentally had a favorable survival, demonstrated by univariate log-rank survival analysis. This study revealed the fact that PCC remains clinically challenging because it is difficult to diagnose in its early stages, and patients typically do not present because of vague symptoms until the disease is quite advanced. So we should seek a certain novel tumor marker for the early detection of PCC in high-risk patient groups.

Diagnostic adjuncts for PCC, such as a serum marker, are useful for the clinical management of this disease. Several investigators have reported that CA 19-9 and CEA determinations are useful for diagnosing PCC in primary sclerosing cholangitis[26]. These investigators also demonstrated that serum CA 19-9 values are related to tumor burden, and suggested that values were elevated in patients with PCC related to unresectable disease[26]. A previous Japanese study has also demonstrated that elevated serum tumor marker, including CEA and CA19-9, was a predictor of a dismal prognosis[21]. Although the reason is unclear, this study also demonstrated that elevated CEA and CA 19-9 were predictors of dismal prognosis in univariate log-rank analysis.

The association between intrahepatic stone and PCC is well recognized.

Mucobilia occurs in various conditions, including biliary papillomatosis, cholangiocarcinoma, and biliary cystadenoma and cystadenocarcinoma of the liver[27]. The presence of mucobilia is important for the early diagnosis of PCC, even preoperatively[28]. Our previous study demonstrated that mucobilia was a prognostic variable predicting better survival in PCC patients undergoing surgical treatment[29]. This study confirmed the same observation and reemphasizes the importance of recognition in this specific clinical presentation as a hope of favorable overall survival of PCC patients.

Papillary type PCC, namely intraductal papillary neoplasia of the liver, is a specific type of biliary epithelial neoplasia with frequent gastrointestinal metaplasia associated with overproduction of mucin and mucobilia[8]. The special nature of this condition explains why more papillary adenocarcinoma and mucobilia were noted in this study. Tumor spreading type was also a favorable prognostic variable for PCC survival[29-33]. Patients with intraductal papillary type PCC had displayed significantly better survival rates than periductal infiltrating or mass forming type PCC. Meanwhile, this study confirmed that the absence of papillary growing in PCC patients undergoing surgical treatment increased the chances of reducing long-term survival by 1.946 times according to multivariate Cox’s proportional hazard analysis.

Although a previous Japanese report has proposed a new staging system mainly based on mass forming type PCC to challenge the TNM staging system[25], this study revealed that TNM staging system remains the most reliable prognostic factor for predicting the outcome of PCC patients undergoing surgical treatment for various types of PCC. Patients with more advanced tumors displayed a significantly worse prognosis, revealed not only by univariate log-rank analysis but also multivariate Cox’s proportional hazard analysis.

Hepatic resection is the preferred treatment for PCC[1]. This study demonstrated that PCC patients undergoing hepatic resection had significantly better survival than those without hepatic resection[29,34]. However, prognosis of PCC in our series is poor when compared with the other series[35]. The fact that only about 50.1% of 373 PCC patients receive hepatic resection and more advanced tumor staging patients exist may explain the poor prognosis in this study. This poor prognosis may be caused by the large number of PCC patients presenting with advanced tumors and unresected status (76.9% and 49.9%, respectively). Hepatic resection significantly prolongs the survival of PCC patients, as demonstrated by multivariate Cox’s proportional hazard analysis.

The utilization of adjuvant chemotherapy and radiation in PCC remains controversial[1]. However, this study showed that postoperative adjuvant chemotherapy was independent significant predictors for PCC patients with good long-term survival undergoing surgical treatment. Several authors have reported varying degrees of success with chemotherapy, either by systemic route or by intra-arterial hepatic route in PCC treatment[35-37]. The efficacy of chemotherapy has not been evaluated prospectively in patients with PCC[35]. No good chemotherapy regimen is currently available, but 5-flurocil (5-FU) is the standard base regimen. Several combinations with 5-FU have been reported to produce transient partial remission in a small portion of patients[35-37].

In conclusion, long-term survival of PCC patients undergoing surgical treatment depends on early tumor stage, presence of mucobilia and papillary tumor type, hepatic resection, and post-operative chemotherapy.

Footnotes

Science Editor Li WZ Language Editor Elsevier HK

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