Japanese Journal of Clinical Oncology 33:283-287 (2003)
© 2003 Foundation for Promotion of Cancer Research
Combined Hepatocellular and Cholangiocarcinoma: a Clinicopathologic Study of 26 Resected Cases
1 Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, 2 Department of Surgery, Cancer Institute Hospital, Tokyo, 3 Pathology Division, National Cancer Center Research Institute, Tokyo and 4 Hepatobiliary Pancreatic Surgery Division, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Background: Combined hepatocellular and cholangiocarcinoma (cHCC-CC) is an uncommon subtype of primary liver cancer, the clinicopathological features of which have rarely been reported in detail. The aim of this study was to clarify the characteristics of cHCC-CC in comparison with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC).
Methods: The clinicopathological features of 26 cHCC-CC patients, who were surgically treated, were reviewed by comparing them with the features of patients suffering from ordinary hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC).
Results: The cHCC-CC patients showed greater similarity with HCC patients than with CC patients with regard to male/female ratio, status of hepatitis viral infection, serum alpha-fetoprotein (AFP) level, and non-tumor liver histology. The disease stage of the cHCC-CC patients was more advanced than that of either the HCC or CC patients. The cHCC-CC tumors were significantly more invasive to the portal vein than the HCC tumors and were comparable to the CC tumors. The overall 3-, 5-, and 10-year survival rates and the median survival times (95% confidence interval) were 34.6%, 23.1%, 11.5% and 1.8 (0.7–3.0) years for cHCC-CC patients, 86.7%, 66.2%, 46.8% and 4.6 (4.3–5.0) years for HCC patients, and 68.5%, 32.3%, 23.9% and 1.9 (1.1–2.7) years for CC patients, respectively. Survival of patients with cHCC-CC was significantly poorer than that of HCC or CC patients. Among the 26 patients, six survived for >5 years.
Conclusions: In most cases, cHCC-CC seems to be a variant of ordinary HCC with cholangiocellular features, rather than a true intermediate disease entity between HCC and CC. The surgical approach is recommended for selected patients with cHCC-CC.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Almost all primary liver carcinomas are broadly classified either as hepatocellular carcinoma (HCC), derived from hepatocytes, or cholangiocarcinoma (CC), arising from intrahepatic bile duct epithelium. A few cases involving both hepatocellular and cholangiocellular components in the same tumor have been designated as ‘combined hepatocellular and cholangiocarcinoma (cHCC-CC),’ and 1.0–4.7% of such cases have been reported among primary liver cancer patients (1–7). While HCC and CC differ in their etiological, epidemiological and clinical features (8,9), the characteristics of patients with cHCC-CC have rarely been reported in detail (2,3,5–7,10). The aim of this study was to clarify the characteristics of cHCC-CC by comparing the background clinical factors, pathologic findings, and surgical outcomes of 26 resected cHCC-CC cases with those of ordinary HCC and CC cases.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Patients
We reviewed 1174 cases of primary liver cancer that were surgically resected at the Department of Surgery, National Cancer Center Hospital, between January 1978 and December 1998. Of these, 1093 cases were diagnosed as HCC, 53 as CC, and 28 (2.4%) as cHCC-CC. According to Allen and Lisa (1), patients with cHCC-CC were grouped into three subtypes; type A: separate masses constituting either HCC or CC (double cancer) (one patient), type B: contiguous but independent masses of HCC and CC (combined type) (one patient), and type C: an intimate intermingling of hepatocellular and glandular elements (mixed type) (26 patients). In the current study, only type C tumors were included to simply and rigorously analyze the characteristics of combined tumors. The histopathological definition of cHCC-CC was based on the criteria proposed by the World Health Organization (11): a hepatocellular element showing bile production, an intercellular bile canaliculi or trabecular growth pattern, and a cholangiocellular component showing mucin production (confirmed by periodic acid–Schiff or Alcian blue stain) or definite gland formation (Fig. 1). When a definite diagnosis was difficult, further immunoreactivity studies were conducted for carcinoembryonic antigen (CEA), carbohydrate antigen 19–9 (CA19-9), and cytokeratins (CK7 and CK19) to confirm the CC component, and for alpha-fetoprotein (AFP) to confirm the HCC component.
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A diagnosis of combined HCC-CC was established when a significant amount of both HCC and CC components (>10%) was confirmed in one tumor.
Factors Analyzed
The case records of patients who underwent surgery for cHCC-CC, HCC and CC were reviewed and compared for the following variables: age, sex, serum hepatitis B surface antigen (HBsAg) and serum hepatitis C virus antibody (HCV) status, and serum AFP (normal value <20 ng/ml) and CEA levels (normal value <5 ng/ml). The pathologic findings of the resected specimens were also comparatively analyzed with regard to the number, size, and intrahepatic distribution of the tumor(s); the status of portal vein invasion, bile duct invasion, lymph node metastasis, intrahepatic metastasis, capsule formation, noncancerous liver parenchyma, and the pTNM stage. The survival rate was calculated from the date of surgery to the date of death or the last follow-up. These factors were analyzed with respect to their prognostic significance for survival.
Statistical Analysis
Cumulative overall survival rates were calculated using the Kaplan–Meier method, and differences in survival rates were assessed using the log-rank test. Differences in proportion were tested by the chi-square test. Differences in the means of each subgroup were tested using the Student’s t-test. Significance levels were set at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Patient Characteristics
Combined HCC-CC patients showed greater similarity with HCC patients than with CC patients in terms of sex ratio, hepatitis viral infection status, and frequency of elevated serum AFP values (Table 1). The surgical procedures used in the case of 26 patients with cHCC-CC included an extended hemihepatectomy for four patients (15%), a hemihepatectomy for two patients (8%), resection of a single Healey segment for six patients (23%), resection of a single Couinaud segment for six patients (23%), and a limited resection for eight patients (31%).
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Pathological Features
Based on the number, size, and lobar distribution of tumors, patients with cHCC-CC had more advanced tumors than those with HCC or CC. Combined tumors were also significantly more invasive to the portal vein than HCC tumors and were comparable to CC tumors in this regard. With respect to the status of bile duct invasion, regional lymph node metastases and capsule formation, combined tumors exhibited intermediate features, between those of HCC and CC. While cHCC-CC and HCC tumors arose from cirrhotic liver conditions with the same frequency, 23% of cHCC-CC tumors originated from normal liver conditions (Table 1).
Detailed Profiles of Patients with Multiple Tumors
Among the 18 patients with multiple tumors, eight had two tumors, two had three tumors, and the other eight had four or more deposits. All ten patients with three or more deposits and two patients with two nodules had multiple tumors on an intrahepatic metastasis basis. The background liver tissue was normal in three patients, while four patients had chronic hepatitis and three patients had cirrhosis. Five of the remaining six patients with two deposits had a distinct HCC nodule in a cirrhotic liver, while the sixth patient had them in chronic hepatitis. The maximum tumor size of cHCC-CC ranged from 2.1 to 17 cm.
Overall Survival after Hepatectomy and Pattern of Recurrence
Three in-hospital deaths occurred (in-hospital mortality rate = 11.5%); two patients died from hepatic failure 25 and 92 days after surgery. Another patient died from aggressive tumor recurrence 118 days after hepatectomy. The overall 3-, 5-, and 10-year survival rates and the median survival times (95% confidence interval) were 34.6%, 23.1%, 11.5% and 1.9 (0.70–3.0) years for cHCC-CC patients, 86.7%, 66.2%, 46.8% and 4.6 (4.3–5.0) years for HCC patients, and 68.5%, 32.3%, 23.9% and 1.86 (1.1–2.7) years for CC patients, respectively. Survival of patients with cHCC-CC was significantly poorer than that of HCC or CC patients. Among the 26 patients, six survived for >5 years, and five eventually died from tumor recurrence (Fig. 2). By univariate analysis, the macroscopic vascular invasion (P = 0.004) and bilobar tumor (P = 0.05) were found to be significant predictors of poor outcome. Tumor size (<6 cm vs. 
6 cm) was a marginally significant factor for survival (P = 0.06). Other factors including number of tumors, and surgical margin were not associated with reduced survival after surgery. Recurrence was not evaluated in the case of two patients who died in the hospital and in the case of three patients who died during the follow-up period. Among the remaining 21 patients, 20 (95%) developed recurrence. The sites of recurrence were the remnant liver (15), lymph node (2), lung (3), bone (1) and right adrenal gland (1). Metastatic lymph node tumors were made up of cHCC-CC cells in one patient and CC cells in another. The adrenal gland metastasis was made up of cHCC-CC cells. In cases of recurrence, the median time (range) for the event was 10 months (0.4–173 months).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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The ratio of ordinary HCC to cHCC-CC tumors reportedly varies between 17:1 in an autopsy series (2) and 35:1 in a clinical series (3). In an earlier study, the ratio in surgically resected series was 27:1 (5), while the ratio in the present series was 39:1. The true incidence is likely to be much higher than that of the surgical series because in both, our series and the earlier report, patients with cHCC-CC were at a more advanced stage of the disease than those with ordinary HCC (5).
Goodman et al. (3) identified criteria, different from Allen and Lisa’s definition, for a pathomorphological diagnosis of cHCC-CC, and classified this disease into three subtypes, based on histological patterns. According to this classification, type I, ‘collision tumors,’ contain separate and apparently coincidental areas of HCC and CC, including tumors in different parts of the liver; type II, ‘transitional tumors,’ exhibit hepatocellular differentiation, with transition areas to adenocarcinoma or to a mixed hepatocellular glandular tumor; and type III, ‘fibrolamellar tumors,’ exhibit a combination of hepatocellular and cholangiocellular differentiation throughout the tumor, without separate areas of one or the other. Goodman’s type I tumor corresponds to Allen and Lisa’s type A and type B. Type III tumor, however, is not equivalent to Allen and Lisa’s type C but represents a special variant of fibrolamellar HCC. In the current study, combined tumors, classified as Allen and Lisa’s type C or Goodman’s type II, were included to make a simple and strict interpretation of the results.
With regard to the histogenesis of Allen and Lisa’s type C or Goodman’s type II combined tumor, the following possibilities have been proposed (12): (1) the CC component arises from the main HCC tumor, and (2) the entire cancer arises from a stem cell potentially differentiating into hepatocytes and bile duct epithelium. Based on the similarity in the clinicopathological characteristics (average age, male/female ratio, hepatitis viral positivity, serum AFP level, and the presence of cirrhosis) of the two diseases, some researchers (2,5,12) have speculated that the CC components in the cHCC-CC tumors were those transformed from part of the HCC tumors. In the present series, a similarity in the clinical backgrounds of the cHCC-CC patients seems to indicate that cHCC-CC represents a variant of ordinary HCC that exhibits cholangiocellular metaplasia, rather than a true intermediate disease entity between HCC and CC, as previously reported in several studies (3,5). Imai et al. (13) showed the same p53 gene mutational pattern in both HCC and CC components, and the same Rb-1 locus replication error pattern in both components in some patients with cHCC-CC, thus providing genetic evidence that both components had the same origin. However, the reports mentioned above are from Asia, where the instances of HCCs, caused by a virus-infected liver, are greater than in western countries. Recently, Jarnagin et al. (7) reported a large western series of cHCC-CC, which were selected on the basis of a rigorous pathological definition. It is noteworthy that the clinical background of patients with combined tumors was most similar to that of CC patients. The lack of an association between chronic liver disease and cHCC-CC in the western series indicated the presence of other histogenesis mechanisms. In our study, cHCC-CC was detected more frequently in normal liver conditions than in a HCC condition, although the frequency of viral infection was similar. Yano et al. (14) established a human cHCC-CC cell line expressing the functional characteristics of HCC on a plastic dish, which was capable of producing adenocarcinoma features in the subcutaneous tissue of nude mice. Robrechts et al. (15) have reported a primary liver tumor made up of immature cells displaying features of both hepatocytes and bile duct epithelial cells, thereby suggesting the presence of stem cells in the human liver. These data suggest the possible existence of an amphi-potential progenitor cell.
Vascular invasion by HCC always appears in the form of an intravascular tumor thrombus, which is one of the most conspicuous growth patterns of this disease (16). In contrast, CC invades the connective tissue of the portal triad, obstructing or narrowing the lumen of the invaded vessels (17). In the present series, among the 15 cHCC-CC patients with portal vein invasion, five exhibited a macroscopic portal vein thrombus, showing the same mode of portal vein invasion as HCC tumors. Regional lymph node metastases were observed in two patients at the time of the initial hepatectomy and in two patients as a post-resection recurrence; thus, cHCC-CC tumors have a higher propensity towards the lymphatic system than HCC tumors. The intermediate frequency of bile duct invasion and capsule formation also indicated that established cHCC-CC tumors seemed to exhibit the invasive characteristics of both HCC and CC tumors.
Combined HCC-CC patients showed a significantly poorer rate of survival after surgery than patients with either HCC or CC. A western series indicated a much better post-resection outcome for larger combined tumors (8). And in their report, there was no difference in survival rates among cHCC-CC, HCC and CC patients. The difference in the results in the current series might be explained by the fact that the tumor stage observed in patients with cHCC-CC was more advanced than that in HCC and CC patients. In addition, the degree of compromised liver function was greater in cHCC-CC patients than in CC patients. In addition, in cases of HCC arising in the cirrhotic liver, the patient’s life is continuously jeopardized by recurrence as a result of multifocal tumor occurrence from the carcinogenic background liver, even if the initial tumor nodule is completely removed by surgical resection (18,19). The linear declines in the 5-year survival curves in patients with HCC or cHCC-CC were clearly different from that in CC patients. This may be due to a similarity in virus status and the presence of cirrhosis in these two groups.
No report has been published about nonsurgical therapy for cHCC-CC. Considering that six patients survived for >5 years (two of whom survived for >10 years) after surgery, a surgical approach, if possible, is presently the best treatment available for cHCC-CC.
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ACKNOWLEDGMENT |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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This study was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Junji Yamamoto, 1–37–1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. E-mail: jyamamoto{at}jfcr.or.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Received January 10, 2003; accepted April 25, 2003
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