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10.1245/ASO.2004.04.028
Annals of Surgical Oncology 11:606-611 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Hepatic Resection of the Intraductal Papillary Type of Peripheral Cholangiocarcinoma

Chun-Nan Yeh, MD, Yi-Yin Jan, MD, FACS, Ta-Sen Yeh, MD, PhD, Tsann-Long Hwang, MD, FACS and Miin-Fu Chen, MD, FACS

From the Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.

Correspondence: Address correspondence and reprint requests to: Yi-Yin Jan, MD, FACS, Department of Surgery, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan; Fax: 886-3-328-5818; E-mail: ycn{at}adm.cgmh.org.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Peripheral cholangiocarcinoma (PCC) can be grossly classified into mass-forming, periductal-infiltrating, and intraductal papillary (IP) types. Information on IP-PCC patients undergoing hepatectomy is sparse because of the small number of cases.

Methods: The clinical features of 40 IP-PCC patients undergoing hepatectomy between 1977 and 2000 were reviewed. The clinical features of 94 PCC patients without IP growth undergoing hepatectomy were used for comparison.

Results: IP-PCC and non–IP-PCC groups had similar age distributions (P = .674), sex ratios (P = .079), and positive rates for serum carcinoembryonic antigen and CA 19-9 (P = .121 and .795, respectively). The two groups also exhibited similar rates of association between hepatolithiasis and PCC (P = .230). However, more IP-PCC patients exhibited signs during admission, and more had ALT values >36 IU/L; they also had smaller tumors, more mucobilia association, and tumors in earlier stages and had undergone more postoperative chemotherapy. Multivariate logistic regression analysis showed that only ALT >36 IU/L differentiated IP-PCC from non–IP-PCC patients. The two groups exhibited similar operative mortality (P = 1.0). Follow-up ranged from 1.6 to 125.2 months (mean and median, 44.6 and 5.7 months, respectively). The 1-, 3-, and 5-year overall survival rates were 72.9%, 41.2%, and 24.7%, respectively, in the IP-PCC group and 43.3, 6.03%, and 2.01% in the non–IP-PCC group. The prognosis was favorable for the IP-PCC patients (P < .00001), particularly for IP-PCC patients who received curative hepatectomy (P = .013).

Conclusions: IP-PCC patients had significantly better survival than non–IP-PCC patients, and aggressive curative hepatic resection is associated with a longer survival.

Key Words: Hepatic resection • Intraductal papillary type • Peripheral cholangiocarcinoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Peripheral cholangiocarcinoma (PCC) is a malignant tumor that occurs in the liver or arises from second-order or more distal branches of the intrahepatic bile ducts (IHDs).1 The incidence of PCC exhibits a wide range of geographical variation and generally accounts for 5% to 30% of primary liver cancers. According to the Japan Liver Cancer Society, histologically proven PCC constituted 3.58% of all primary liver cancers.2

PCC can be grossly classified into mass-forming (MF), periductal-infiltrating (PI), and intraductal papillary (IP) types.2 In 1992, Yamamoto et al.3 demonstrated different clinical behaviors of the MF and PI types. The MF type creates an apparent lesion in the liver, with frequent recurrence in the remnant liver after hepatic resection. The PI type causes a stricture or an obstruction of the IHD without forming a definitive mass in the liver; it spreads along Glisson’s capsule and causes metastasis to the hilar lymph nodes. Later, Yamamoto et al.4 considered another type of PCC, namely, IP-PCC. The IP tumor shows IP or granular growth (or both) and is sometimes associated with superficial mucosal carcinoma or intraductal tumor thrombus.

Although this type of PCC is not novel, only a few reports on surgical outcomes, mostly based on a few cases, have been published.5,6 The clinicopathologic features and outcomes of IP-PCC patients undergoing hepatectomy must be clarified. This study retrospectively evaluated the influence of gross morphology of IP type on PCC patients’ clinicopathologic characteristics and prognoses and the role of hepatectomy with this peculiar type of PCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From 1977 to 2000, 307 consecutive patients with histologically proven PCC underwent surgical treatment at the Department of Surgery, Chang-Gung Memorial Hospital, Taipei, Taiwan. PCC was defined as carcinoma arising from second-order or more distal branches of the IHDs, and 134 of the 307 PCC patients undergoing curative hepatectomy were enrolled in this investigation. The 134 patients were classified into IP-PCC (n = 40; 29.9%) and non–IP-PCC (n = 94; 70.1%) groups. IP-PCC is histologically defined as IP neoplasia of the liver type 3 and 4, as described previously.7 Type 3 showed an IP neoplasia of the liver lined by in situ and microinvasive adenocarcinoma, and type 4 showed type 2 and 3 biliary lesions with variable invasion of adenocarcinoma.7 Curative resection was defined by the observation of a negative resection margin during histopathologic examination. Laboratory tests were performed on the day before surgery. Serum CA 19-9 and serum carcinoembryonic antigen were measured by radioimmunoassay. Clinical staging (tumor-node-metastasis system) was determined according to the guidelines of the American Joint Committee on Cancer.8 Stages I and II were classified as early-stage and stages III and IV as advanced-stage PCC. Adjuvant chemotherapy was mainly performed with a 5-fluorouracil–based regimen. Adjuvant radiotherapy was performed with external beam radiotherapy, brachytherapy, or both to treat positive margins or local recurrences. Differences in demographics, symptoms, physical examination results, laboratory data, operative findings, pathologic features, and long-term survival of the two groups (IP-PCC and non–IP-PCC) were compared. Seven patients died within 1 month after operation (mortality rate, 5.2%), and five patients were lost to follow-up (three IP-PCC and two non–IP-PCC) and were therefore excluded from the survival analysis.

All data are presented as percentages of patients or mean and SD. Numerical data were compared by independent two-sample t-test. Pearson’s {chi}2 test and Fisher’s exact test were used for nominal variables. The survival rate was calculated and plots were constructed by the Kaplan-Meier method, and data were compared between groups by using the log-rank test. All statistical analyses were performed with SPSS (version 10.0; SPSS Inc., Chicago, IL). A P value <.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 134 PCC patients with an age range of 34 to 83 years (mean and median, 58.1 and 57.5 years, respectively) were investigated. The IP-PCC group included 13 men and 27 women, and the non–IP-PCC group included 46 men and 48 women. The groups had similar age distributions and sex ratios (P = .746 and .079, respectively).

Right hypochondralgia was the most common symptom in the IP-PCC patients (Table 1). The percentage of IP-PCC patients with physical signs during admission was higher than that of non–IP-PCC patients. However, the two groups exhibited similar clinical presentations and physical findings (Table 1).


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  		TABLE 1. Clinical manifestations and associated diseases of IP-PCC patients and non–IP-PCC patients
 
Table 2 summarizes the laboratory data. The IP-PCC patient group had higher AST and ALT levels than the non–IP-PCC patient group (P = .015 and .016, respectively). The positive serum carcinoembryonic antigen and CA 19-9 rates of the IP-PCC and non–IP-PCC groups were similar (20% and 61.5% vs. 37.3% and 65.6%, respectively; Table 2).


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  		TABLE 2. Laboratory data on IP-PCC and non–IP-PCC patients
 
Table 3 lists the operative, macroscopic, and microscopic findings. IP-PCC patients had smaller tumors, which were generally in earlier stages than those of the non–IP-PCC patients (P = .011 and .006, respectively). The two groups had a similar hepatolithiasis association rate with PCC (67.5% vs. 56.4%). More mucobilia association was evident in the IP-PCC patients than in the non–IP-PCC patients (30.0% vs. 5.3%; P < .0001). The IP-PCC and non–IP-PCC groups exhibited similar percentages of curative resections. Similar percentages of patients in both groups underwent postoperative adjuvant radiotherapy, but postoperative adjuvant chemotherapy was conducted more frequently in the IP-PCC group (P = .034). Both groups had similar operative morbidity and mortality rates (Table 3). Table 4 shows that an increased ALT level was the only independent factor that differentiated IP-PCC from non–IP-PCC patients.


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  		TABLE 3. Operative and pathologic status of IP-PCC and non–IP-PCC patients
 

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  		TABLE 4. Univariate and multiple forward stepwise logistic regression analysis of clinicopathologic features in 134 PCC patients with IP and non-IP morphology
 
All 134 PCC patients who underwent hepatectomy received regular follow-up until death or the time this article was written. Seven patients died within 1 month after operation (surgical mortality rate, 5.2%), and five patients were excluded from the survival analysis because of a lack of follow-up. Follow-up durations ranged from 1.6 to 125.2 months (mean and median, 44.6 and 5.7 months, respectively). Figure 1A plots the overall actuarial survival of the IP-PCC and non–IP-PCC groups. The 1-, 3-, and 5-year overall survival rates were 72.9%, 41.2%, and 24.7%, respectively, in the IP-PCC group and were 43.3%, 6.03%, and 2.01% in the non–IP-PCC group. Univariate log-rank analysis identified that the prognosis was significantly better for the IP-PCC patients with increased alkaline phosphatase values, tumors in early stages, and treatment with curative hepatectomy (P = .0306, .0003, and .0013, respectively; Tables 5 and 6 Go). Moreover, IP-PCC patients who underwent curative hepatic resection had significantly better overall survival rates than IP-PCC patients with noncurative hepatic resection, as demonstrated by Cox’s multivariate proportional hazard analysis (Table 7; Fig. 1B).



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  		FIG. 1. (A) Overall survival of 35 IP peripheral cholangiocarcinoma patients and 87 non-IP peripheral cholangiocarcinoma patients. (B) Overall survival rate of 35 IP-PCC patients in terms of curative hepatic resection and noncurative hepatic resection. IP, intraductal papillary.

 

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  		TABLE 5. Univariate analysis of factors that influenced the overall survival rate of 35 IP-PCC patients
 

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  		TABLE 6. Univariate analysis of factors that influenced the overall survival rate of 35 IP-PCC patients
 

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  		TABLE 7. Cox regression analysis factors that influenced the overall survival rate of 35 IP-PCC patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
PCC can be grossly classified into MF, PI, and IP types. The IP type is the least common and exhibits predominant intraductal growth with no or mild extension beyond the bile duct walls. The incidence of the IP type has been reported as 8.3% to 14.3% of surgically resected PCC.5,6 This study showed that the incidence of the IP type of resected PCC is 29.9%. The study was the largest series dealing with the effect of the IP type on PCC surgical results. The IP-PCC patients differed from non–IP-PCC patients in many respects.

A higher percentage of IP-PCC patients than non–IP-PCC patients presented physical signs during admission. The percentage of presented biliary tract infections (including hypochondria, fever, chills, and jaundice) was higher in the IP-PCC patients, but it was not statistically significant.

Laboratory data and tumor markers were similar in both groups. Increased AST and ALT levels were, however, observed in the IP-PCC group, and the increased ALT level was the only independent factor that could differentiate IP-PCC from non–IP-PCC patients.

IP-PCC had a similar hepatolithiasis association compared with non–IP-PCC. Our previous report emphasized that the IP type of PCC infrequently occurred with hepatolithiasis in Japan and Korea but frequently occurred with hepatolithiasis in Taiwan.7 This study confirmed this claim and determined an IHD association of 67.5%. To our knowledge, the pathogenesis of PCC remains unknown. PCC occurs in association with hepatolithiasis, probably as the cumulative result of many possible causes, including nutritional, genetic, environmental, and immunological factors.9–12

The IP-PCC patients had smaller tumors, a greater mucobilia association, and tumors in earlier stages, and a higher percentage of them underwent postoperative adjuvant chemotherapy; however, multivariate logistic regression analysis showed that none of these factors differentiated IP-PCC from non–IP-PCC patients. IP-PCC, namely, IP neoplasia of the liver type 3 and 4, is a specific type of biliary epithelial neoplasia with frequent gastrointestinal metaplasia associated with the overproduction of mucin and mucobilia.8 The special nature of this condition explains why more papillary adenocarcinoma and more mucobilia were noted in this study. Although mucobilia occurs under various conditions, including biliary papillomatosis, cholangiocarcinoma, and biliary cystadenoma and cystadenocarcinoma of the liver,13 the presence of mucobilia is an important clue to the early, even preoperative, diagnosis of PCC, especially for IP-PCC.14 Otherwise, IP-PCC will progress to a larger tumor and a more advanced stage.

Suh et al.5 reported that IP-PCC patients exhibited a higher survival rate than non–IP-PCC patients, as determined for only a few cases. This study confirmed that IP-PCC patients had a substantially more favorable prognosis than non–IP-PCC patients.

Our previous studies have demonstrated that an increased alkaline phosphatase level adversely affects the long-term overall and disease-free survival of cirrhotic and noncirrhotic HCC patients.15,16 This study, in contrast, revealed that an increased alkaline phosphatase level improved the overall survival of IP-HCC patients who had undergone hepatectomy. An increased alkaline phosphatase level may imply the presence of liver disease and bile duct obstruction. Furthermore, a high preoperative alkaline phosphatase level may be correlated with increased mortality after hepatectomy for metastatic disease.17

Although a previous Japanese report proposed a new staging system based mainly on the MF type of PCC to challenge the tumor-node-metastasis staging system,18 this study reveals that a tumor-node-metastasis staging system remains the most reliable prognostic factor for predicting the outcome of IP-PCC patients undergoing hepatectomy. IP-PCC patients with more advanced tumors displayed a considerably worse prognosis, as determined only by univariate log-rank analysis.

Hepatic resection is the preferred treatment for PCC.1 This study demonstrated that IP-PCC patients undergoing curative hepatic resection exhibited significantly better survival rates than those who did not. This study also confirmed that the absence of curative hepatic resection in IP-PCC patients increased the chances of reducing long-term survival by 7.194 times, according to Cox’s multivariate proportional hazard analysis. This fact emphasizes that curative hepatic resection is associated with a long-term overall survival.

In conclusion, this study compared the clinical features and outcomes of 40 IP-PCC patients with those of 94 non–IP-PCC patients undergoing hepatectomy in terms of clinical, operative, and pathologic findings and long-term results. IP-PCC patients had a substantially more favorable survival rate than non–IP-PCC patients; aggressive curative hepatic resection is associated with longer survival.


   FOOTNOTES
 
This study compared the clinical features and outcomes of 40 IP-PCC patients with those of 94 non–IP-PCC patients who underwent hepatectomy. IP-PCC patients had significantly better survival than non–IP-PCC patients; aggressive curative hepatic resection is associated with a longer survival.

Received for publication April 28, 2003. Accepted for publication February 18, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  2. Liver Cancer Study Group of Japan. Classification of Primary Liver Cancer. Tokyo: Kanehara, 1997.
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  8. Sobin LH, Wittekind C, eds. TNM Classification of Malignant Tumours. 5th ed. New York: Wiley-Liss, 1997.
  9. Koga A, Ichimiya H, Yamaguchi K, et al. Hepatolithiasis associated with cholangiocarcinoma: possible etiologic significance. Cancer 1985; 55: 2826–9.[CrossRef][Medline]
  10. Ohta T, Nagakawa T, Ueda N. Mucosal dysplasia of the liver and intraductal variant of peripheral cholangiocarcinoma in hepatolithiasis. Cancer 1991; 68: 2217–23.[CrossRef][Medline]
  11. Ohta G, Nakayama Y, Terata T. Intrahepatic calculi. In: Nakayama F, ed. Pathology of Hepatolithiasis: Cholangitis and Cholangiocarcinoma. New York: Alan R. Liss, 1984: 91–113.
  12. Sanes S, MacCallum JD. Primary carcinoma of the liver. Cholangioma in hepatolithiasis. Am J Pathol 1942; 18: 674–83.
  13. Chen MF. Mucobilia: the clinical spectrum, diagnosis and treatment. J Gastroenterol Hepatol 1998; 13: 1084–90.[Medline]
  14. Chen MF, Jan YY, Chen TS. Clinical studies of mucin-producing cholangiocarcinoma. A study of 22 histopathology-proven cases. Ann Surg 1998; 227: 63–9.[CrossRef][Medline]
  15. Yeh CN, Chen MF, Lee WC, Jeng LB. Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis. J Surg Oncol 2002; 81: 195–202.[CrossRef][Medline]
  16. Chen MF, Tsai HP, Jeng LB, et al. Prognostic factors after resection for hepatocellular carcinoma in noncirrhotic livers: univariate and multivariate analysis. World J Surg 2003; 27: 443–7.[Medline]
  17. Klompje J, Petrelli NJ, Herrera L, Mittelman A. The prognostic value of preoperative alkaline-phosphatase for resection of solitary liver metastasis from colorectal carcinoma. Eur J Surg Oncol 1987; 13: 345–7.[Medline]
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