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Characteristics of combined hepatocelluarcholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma S.H. Kim a, Y.N. Park b, J.H. Lim c, G.H. Choi c, J.S. Choi c, K.S. Kim c,* a
Department of Surgery, Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital, Wonju, Republic of Korea b Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea c Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea Accepted 28 April 2014 Available online - - -
Abstract Background: The 7th American Joint Committee on Cancer (AJCC) currently classifies combined hepatocellular-cholangiocarcinoma (cHCC-CC) and intrahepatic cholangiocarcinoma (ICC) into one category. Study outcomes comparing the two carcinomas have shown contrary results. This study was designed to compare the survival and prognostic factors of both carcinomas. Methods: We retrospectively reviewed the medical records of 107 patients with cHCC-CC or ICC who underwent liver resection between January 2000 and December 2009. Results: Thirty patients (28%) were diagnosed with cHCC-CC, and 77 patients (72%) had ICC. Disease-free survival (DFS) was poorer in the cHCC-CC patients (six months), and the overall survival (OS) durations were similar ( p ¼ 0.477) between cHCC-CC (58 months) and ICC (45 months) patients. A tumor size larger than 5 cm, vascular invasion and lymph node (LN) metastasis were prognostic factors in all patients. However, tumor size and LN metastasis in cHCC-CC patients and carbohydrate antigen 19-9, differentiation and LN metastasis in ICC patients were found to be independent prognostic factors. Conclusions: Patients with cHCC-CC showed poorer DFS and similar OS rates compared to those with ICC. Our study revealed different prognostic factors in cHCC-CC. To understand more accurately cHCC-CC’s prognosis, difference of genetic characteristics and tumor biology should be further evaluated. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Cholangiocarcinoma; Tumor size
Introduction Most primary liver malignancies are either hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). The 6th American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system grouped HCC and ICC into one stage.1 However, the 7th AJCC TNM staging system divided HCC and ICC into independent stages.2 Additionally, combined hepatocellular* Corresponding author. Department of Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Tel.: þ82 2 2228 2125; fax: þ82 2 313 8289. E-mail address: [email protected] (K.S. Kim).
cholangiocarcinoma (cHCC-CC) has been grouped into the stage of ICC in the 7th AJCC TNM staging system.2 Nathan et al.3 found that tumor size was not a prognostic factor in patients with ICC according to the Surveillance, Epidemiology and End Results (SEER) database. The 7th AJCC TNM staging system created a unique staging system for ICC. However, cHCC-CC originates from cells with histological features of HCC and CC.4 It is a very rare primary liver cancer, and its incidence ranges from 0.4% to 14.2% in different regions.4e8 Most reports for cHCC-CC have emerged from Eastern countries. Risk factors and clinical and pathological features of cHCC-CC are similar to those of HCC in Eastern reports: male predominance, a high hepatitis virus infection
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2014.04.016 Please cite this article in press as: Kim SH, et al., Characteristics of combined hepatocelluar-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.04.016
2
S.H. Kim et al. / EJSO xx (2014) 1e6
rate, elevated alpha-fetoprotein level, and pathologically chronic liver disease.9e12 However, Jarnagin et al.4 reported that cHCC-CC showed similar characteristics to CC in Western series. The median survival results in patients with cHCC-CC after liver resection were diverse. Some studies reported that the median survival rate of cHCCCC was worse than those of other types,4,11,13 and other studies showed intermediate median survival rate between HCC and ICC.14e16 It was also reported that the median survival rate of cHCC-CC was similar to that of ICC but worse than that of HCC.17 In this study, we compared the prognostic factors and survival rates in patients with cHCC-CC and ICC and analyzed survival in the patients. Patients and methods Patients From January 2000 to December 2009, 107 patients with cHCC-CC or ICC underwent liver resection at Severance Hospital of the Yonsei University Health System in Seoul, Korea. Thirty patients were diagnosed with cHCC-CC, and 77 patients received an ICC diagnosis. According to the Allen and Lisa classification,6 all cHCC-CC types were mixed. Computed tomography and magnetic resonance imaging were performed to evaluate the status of disease and extrahepatic metastasis. Alpha-fetoprotein (AFP) and Proteins Induced by Vitamin K Absence or Antagonist-II (PIVKAII) were tested in cases with suspected HCC, while the test of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) were added in cases suspected of having a CC component. CEA and CA 19-9 were routine tested in cases with suspected CC. Our hospital policy was that lymph node dissection was not performed in HCC cases. Pathologic diagnosis cHCC-CC was defined as a tumor containing unequivocal, intimately mixed elements of both HCC and CC. The hepatocellular component was well-, moderately or poorly differentiated. The biliary component was a typical adenocarcinoma, well-, moderately, or poorly differentiated, often accompanied by abundant stroma. CC which arosed in any portion of intrahepatic biliary tree was included for this study. The case of separate HCC and CC arising in the same liver was excluded.
resection was defined as the resection more than 3 Couinaud segments. Outcomes We compared the clinicopathological characteristics between cHCC-CC and ICC. Disease-free survival (DFS) and overall survival (OS) in patients with cHCC-CC or ICC were also calculated and compared. Prognostic factors were evaluated in patients with cHCC-CC or ICC. Statistics Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) v 15.0 software (SPSS Inc., Chicago, IL, US). All continuous variables were presented as the median and range. All categorical results were presented as number and percentage. The continuous and categorical variables in cHCC-CC and ICC were compared using the Fisher’s exact test and ManneWhitney U test. The DFS and OS rates were analyzed with the KaplaneMeier test. Cox’s proportional hazard model (backward stepwise method) was applied in univariate and multivariate analyses of prognostic factors. A p-value less than 0.05 was defined as statistically significant. Results Baseline characteristics Thirty patients underwent liver resection with curative intent and were diagnosed with a cHCC-CC. Eight hundred forty seven patients with HCC underwent surgical treatment during same period and the incidence of cHCC-CC in our hospital was 3.1%. Baseline characteristics of patients with cHCC-CC are presented in Table 1. The maleto-female ratio was 5:1, and the median age was 54 years. Twenty-six (86.7%) patients had underlying liver diseases, and hepatitis B virus (HBV) infection was the most common comorbid disease (n ¼ 20; 66.7%) and two and five patients had chronic hepatitis C virus infection and alcoholic liver disease. Median alpha-fetoprotein level was 19.9 IU/mL, and half of the patients had an AFP greater than 20 IU/mL. According to the pathological examination, 22 (73.3%) patients had chronic liver disease and 5 patients had steatohepatitis. Characteristics comparison between cHCC-CC and ICC
Surgery Surgeon decided to the extent of surgery according to the residual liver function and liver volume. Residual liver function was estimated by ICG R15 and laboratory tests and liver volume was estimated by volumetry. Major liver
The results of a characteristics comparison between cHCC-CC and ICC are presented in Table 1. Male gender was predominant in both tumors. The median age was higher in patients with ICC than it was in patients with cHCC-CC ( p ¼ 0.001). The prevalence of hepatitis was
Please cite this article in press as: Kim SH, et al., Characteristics of combined hepatocelluar-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.04.016
S.H. Kim et al. / EJSO xx (2014) 1e6 Table 1 Characteristics comparison according to tumor type. cHCC-CC (n ¼ 30) ICC (n ¼ 77) Gender Female Male Age Preoperative symptoms No Yes Hepatitis No Yes AFP, IU/mL CA 19-9, U/mL Size of tumor (cm) Number of tumors Single Multiple AJCC stage Stage I Stage II Stage III Stage IVA Stage IVB Type of operation Minor Major Extent of resection R0 R1 Vascular invasion No Yes Perineural invasion No Yes Intrahepatic metastasisa No Yes
0.403 0.414 0.013
up period, 16 patients with cHCC-CC and 33 patients with CC expired because of disease progression. One-, three- and five-year DFS rates in patients with cHCC-CC were 40%, 16% and 10.7%, respectively, and the average OS rates were 69.4%, 51% and 37.2%, respectively. One-, three- and five-year DFS rates in patients with CC were 66.2%, 41.2% and 29%, respectively, and the average OS rates were 88.7%, 593.7% and 39.9%, respectively. The patients with cHCC-CC underwent R0 resection had poorer median DFS (7 months) than that (24 months) in patients with ICC (Fig. 1A top). In intend to treat analysis, those with cHCC-CC showed also poor DFS (Fig. 1B top). However, the OS duration was similar between cHCC-CC and ICC (Fig. 1A and B bottom).
0.485
Prognostic factors in patients with cHCC-CC or ICC
p 0.062
5 (16.7) 25 (83.3) 54 (35e69)
27 (35.1) 50 (64.9) 61 (36e84)
8 (26.7) 22 (73.3)
39 (50.6) 38 (49.4)
8 (26.7) 22 (73.3) 19.9 (2.23e2648.0) 9.6 (0e2240) 4.5 (1e17)
61 (79.2) 16 (20.8)
26 (86.7%) 4 (13.3%)
75 (97.4%) 2 (2.6%)
3 (10%) 17 (56.6%) 2 (6.7%) 6 (20%) 2 (6.7%)
17 (22.1%) 18 (23.4%) 11 (14.3%) 28 (36.4%) 3 (3.9%)
13 (43.3) 17 (56.7)
11 (14.3) 66 (85.7)
23 (76.7) 7 (23.3)
65 (84.4) 12 (15.6)
6 (20) 24 (80)
26 (33.8) 51 (66.2)
29 (96.7) 1 (3.3)
57 (74) 20 (26)
19 (63.3) 11 (36.7)
64 (83.1) 13 (16.9)
0.001 0.07
ScienceDirect EJSO xx (2014) 1e6
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Characteristics of combined hepatocelluarcholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma S.H. Kim a, Y.N. Park b, J.H. Lim c, G.H. Choi c, J.S. Choi c, K.S. Kim c,* a
Department of Surgery, Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital, Wonju, Republic of Korea b Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea c Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea Accepted 28 April 2014 Available online - - -
Abstract Background: The 7th American Joint Committee on Cancer (AJCC) currently classifies combined hepatocellular-cholangiocarcinoma (cHCC-CC) and intrahepatic cholangiocarcinoma (ICC) into one category. Study outcomes comparing the two carcinomas have shown contrary results. This study was designed to compare the survival and prognostic factors of both carcinomas. Methods: We retrospectively reviewed the medical records of 107 patients with cHCC-CC or ICC who underwent liver resection between January 2000 and December 2009. Results: Thirty patients (28%) were diagnosed with cHCC-CC, and 77 patients (72%) had ICC. Disease-free survival (DFS) was poorer in the cHCC-CC patients (six months), and the overall survival (OS) durations were similar ( p ¼ 0.477) between cHCC-CC (58 months) and ICC (45 months) patients. A tumor size larger than 5 cm, vascular invasion and lymph node (LN) metastasis were prognostic factors in all patients. However, tumor size and LN metastasis in cHCC-CC patients and carbohydrate antigen 19-9, differentiation and LN metastasis in ICC patients were found to be independent prognostic factors. Conclusions: Patients with cHCC-CC showed poorer DFS and similar OS rates compared to those with ICC. Our study revealed different prognostic factors in cHCC-CC. To understand more accurately cHCC-CC’s prognosis, difference of genetic characteristics and tumor biology should be further evaluated. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Cholangiocarcinoma; Tumor size
Introduction Most primary liver malignancies are either hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). The 6th American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system grouped HCC and ICC into one stage.1 However, the 7th AJCC TNM staging system divided HCC and ICC into independent stages.2 Additionally, combined hepatocellular* Corresponding author. Department of Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Tel.: þ82 2 2228 2125; fax: þ82 2 313 8289. E-mail address: [email protected] (K.S. Kim).
cholangiocarcinoma (cHCC-CC) has been grouped into the stage of ICC in the 7th AJCC TNM staging system.2 Nathan et al.3 found that tumor size was not a prognostic factor in patients with ICC according to the Surveillance, Epidemiology and End Results (SEER) database. The 7th AJCC TNM staging system created a unique staging system for ICC. However, cHCC-CC originates from cells with histological features of HCC and CC.4 It is a very rare primary liver cancer, and its incidence ranges from 0.4% to 14.2% in different regions.4e8 Most reports for cHCC-CC have emerged from Eastern countries. Risk factors and clinical and pathological features of cHCC-CC are similar to those of HCC in Eastern reports: male predominance, a high hepatitis virus infection
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2014.04.016 Please cite this article in press as: Kim SH, et al., Characteristics of combined hepatocelluar-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.04.016
2
S.H. Kim et al. / EJSO xx (2014) 1e6
rate, elevated alpha-fetoprotein level, and pathologically chronic liver disease.9e12 However, Jarnagin et al.4 reported that cHCC-CC showed similar characteristics to CC in Western series. The median survival results in patients with cHCC-CC after liver resection were diverse. Some studies reported that the median survival rate of cHCCCC was worse than those of other types,4,11,13 and other studies showed intermediate median survival rate between HCC and ICC.14e16 It was also reported that the median survival rate of cHCC-CC was similar to that of ICC but worse than that of HCC.17 In this study, we compared the prognostic factors and survival rates in patients with cHCC-CC and ICC and analyzed survival in the patients. Patients and methods Patients From January 2000 to December 2009, 107 patients with cHCC-CC or ICC underwent liver resection at Severance Hospital of the Yonsei University Health System in Seoul, Korea. Thirty patients were diagnosed with cHCC-CC, and 77 patients received an ICC diagnosis. According to the Allen and Lisa classification,6 all cHCC-CC types were mixed. Computed tomography and magnetic resonance imaging were performed to evaluate the status of disease and extrahepatic metastasis. Alpha-fetoprotein (AFP) and Proteins Induced by Vitamin K Absence or Antagonist-II (PIVKAII) were tested in cases with suspected HCC, while the test of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) were added in cases suspected of having a CC component. CEA and CA 19-9 were routine tested in cases with suspected CC. Our hospital policy was that lymph node dissection was not performed in HCC cases. Pathologic diagnosis cHCC-CC was defined as a tumor containing unequivocal, intimately mixed elements of both HCC and CC. The hepatocellular component was well-, moderately or poorly differentiated. The biliary component was a typical adenocarcinoma, well-, moderately, or poorly differentiated, often accompanied by abundant stroma. CC which arosed in any portion of intrahepatic biliary tree was included for this study. The case of separate HCC and CC arising in the same liver was excluded.
resection was defined as the resection more than 3 Couinaud segments. Outcomes We compared the clinicopathological characteristics between cHCC-CC and ICC. Disease-free survival (DFS) and overall survival (OS) in patients with cHCC-CC or ICC were also calculated and compared. Prognostic factors were evaluated in patients with cHCC-CC or ICC. Statistics Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) v 15.0 software (SPSS Inc., Chicago, IL, US). All continuous variables were presented as the median and range. All categorical results were presented as number and percentage. The continuous and categorical variables in cHCC-CC and ICC were compared using the Fisher’s exact test and ManneWhitney U test. The DFS and OS rates were analyzed with the KaplaneMeier test. Cox’s proportional hazard model (backward stepwise method) was applied in univariate and multivariate analyses of prognostic factors. A p-value less than 0.05 was defined as statistically significant. Results Baseline characteristics Thirty patients underwent liver resection with curative intent and were diagnosed with a cHCC-CC. Eight hundred forty seven patients with HCC underwent surgical treatment during same period and the incidence of cHCC-CC in our hospital was 3.1%. Baseline characteristics of patients with cHCC-CC are presented in Table 1. The maleto-female ratio was 5:1, and the median age was 54 years. Twenty-six (86.7%) patients had underlying liver diseases, and hepatitis B virus (HBV) infection was the most common comorbid disease (n ¼ 20; 66.7%) and two and five patients had chronic hepatitis C virus infection and alcoholic liver disease. Median alpha-fetoprotein level was 19.9 IU/mL, and half of the patients had an AFP greater than 20 IU/mL. According to the pathological examination, 22 (73.3%) patients had chronic liver disease and 5 patients had steatohepatitis. Characteristics comparison between cHCC-CC and ICC
Surgery Surgeon decided to the extent of surgery according to the residual liver function and liver volume. Residual liver function was estimated by ICG R15 and laboratory tests and liver volume was estimated by volumetry. Major liver
The results of a characteristics comparison between cHCC-CC and ICC are presented in Table 1. Male gender was predominant in both tumors. The median age was higher in patients with ICC than it was in patients with cHCC-CC ( p ¼ 0.001). The prevalence of hepatitis was
Please cite this article in press as: Kim SH, et al., Characteristics of combined hepatocelluar-cholangiocarcinoma and comparison with intrahepatic cholangiocarcinoma, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.04.016
S.H. Kim et al. / EJSO xx (2014) 1e6 Table 1 Characteristics comparison according to tumor type. cHCC-CC (n ¼ 30) ICC (n ¼ 77) Gender Female Male Age Preoperative symptoms No Yes Hepatitis No Yes AFP, IU/mL CA 19-9, U/mL Size of tumor (cm) Number of tumors Single Multiple AJCC stage Stage I Stage II Stage III Stage IVA Stage IVB Type of operation Minor Major Extent of resection R0 R1 Vascular invasion No Yes Perineural invasion No Yes Intrahepatic metastasisa No Yes
0.403 0.414 0.013
up period, 16 patients with cHCC-CC and 33 patients with CC expired because of disease progression. One-, three- and five-year DFS rates in patients with cHCC-CC were 40%, 16% and 10.7%, respectively, and the average OS rates were 69.4%, 51% and 37.2%, respectively. One-, three- and five-year DFS rates in patients with CC were 66.2%, 41.2% and 29%, respectively, and the average OS rates were 88.7%, 593.7% and 39.9%, respectively. The patients with cHCC-CC underwent R0 resection had poorer median DFS (7 months) than that (24 months) in patients with ICC (Fig. 1A top). In intend to treat analysis, those with cHCC-CC showed also poor DFS (Fig. 1B top). However, the OS duration was similar between cHCC-CC and ICC (Fig. 1A and B bottom).
0.485
Prognostic factors in patients with cHCC-CC or ICC
p 0.062
5 (16.7) 25 (83.3) 54 (35e69)
27 (35.1) 50 (64.9) 61 (36e84)
8 (26.7) 22 (73.3)
39 (50.6) 38 (49.4)
8 (26.7) 22 (73.3) 19.9 (2.23e2648.0) 9.6 (0e2240) 4.5 (1e17)
61 (79.2) 16 (20.8)
26 (86.7%) 4 (13.3%)
75 (97.4%) 2 (2.6%)
3 (10%) 17 (56.6%) 2 (6.7%) 6 (20%) 2 (6.7%)
17 (22.1%) 18 (23.4%) 11 (14.3%) 28 (36.4%) 3 (3.9%)
13 (43.3) 17 (56.7)
11 (14.3) 66 (85.7)
23 (76.7) 7 (23.3)
65 (84.4) 12 (15.6)
6 (20) 24 (80)
26 (33.8) 51 (66.2)
29 (96.7) 1 (3.3)
57 (74) 20 (26)
19 (63.3) 11 (36.7)
64 (83.1) 13 (16.9)
0.001 0.07
