Combined Hepatocellular-Cholangiocarcinoma: A Population-Level Analysis of an Uncommon Primary Liver Tumor

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1 LIVER TRANSPLANTATION 20: , 2014 ORIGINAL ARTICLE Combined Hepatocellular-Cholangiocarcinoma: A Population-Level Analysis of an Uncommon Primary Liver Tumor Mattia Garancini, 1 Paolo Goffredo, 1 Fabio Pagni, 2 Fabrizio Romano, 1 Sanziana Roman, 3 Julie Ann Sosa, 3 and Vittorio Giardini 1 Departments of 1 General Surgery and 2 Pathology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy; and 3 Section of Endocrine Surgery, Department of Surgery, Duke University, Durham, NC Combined hepatocellular-cholangiocarcinoma (chcc-cc) is a rare primary liver cancer. Our aims were to analyze the demographic, clinical, and pathological characteristics of chcc-cc at a population level and to investigate the effects of these features as well as different management strategies on the prognosis. The Surveillance, Epidemiology, and End Results (SEER) database was analyzed for Data analyses were performed with chi-square tests, analyses of variance, Kaplan- Meier curves, and Cox proportional hazards regression. Four hundred sixty-five patients with chcc-cc, 52,825 patients with hepatocellular carcinoma (HCC), and 7181 patients with cholangiocarcinoma (CC) were identified. chcc-cc was more common in patients who were white, male, and older than 65 years. Treatment was more frequently nonsurgical/interventional. Patients with chcc-cc, HCC, and CC had 5-year overall survival (OS) and disease-specific survival rates of 10.5%, 11.7%, and 5.7% (P < 0.001) and 17.8%, 21.0%, and 11.9% (P < 0.001), respectively. For chcc-cc patients, an increasing invasiveness of the therapeutic approach was significantly associated with prolonged survival (P < 0.001). In a multivariate model, black race, a distant SEER stage, and a tumor size of 5.0 to 10.0 cm were independently associated with lower survival for chcc-cc patients; a year of diagnosis after 1995 and surgical treatment with minor hepatectomy, major hepatectomy (MJH), or liver transplantation (LT) were independently associated with better survival for chcc-cc patients. Patients diagnosed with chcc-cc, HCC, and CC and treated with LT had 5-year OS rates of 41.1%, 67.0%, and 29.0%, respectively (P < 0.001). In conclusion, chcc-cc patients appear to have intermediate demographic, clinical, and survival characteristics in comparison with HCC and CC patients. chcc-cc patients undergoing LT showed inferior survival in comparison with HCC patients, and the role and indications for LT in chcc-cc have yet to be defined. At this time, MJH may be considered the best therapeutic approach for such patients. Liver Transpl 20: , VC 2014 AASLD. Received January 9, 2014; accepted April 21, Hepatocellular carcinoma (HCC), which originates from hepatocytes, and cholangiocarcinoma (CC), which arises from the intrahepatic bile duct epithelium, are the most common primary liver cancers. Combined hepatocellular-cholangiocarcinoma (chcc- CC) is a rare primary liver cancer displaying a mixture of histological characteristics of HCC and CC. It accounts for 0.4% to 14.2% of all primary hepatic tumors, with the incidence varying in different regions. 1-4 chcc-cc is considered an aggressive tumor associated with poor long-term survival. It is frequently misdiagnosed in the preoperative setting as either HCC or CC; usually, liver resection is considered the best therapeutic approach Previous studies of chcc-cc have mostly been single-center, retrospective analyses based on small Abbreviations: ABL, ablation; CC, cholangiocarcinoma; chcc-cc, combined hepatocellular-cholangiocarcinoma; DSS, diseasespecific survival; HCC, hepatocellular carcinoma; LT, liver transplantation; MJH, major hepatectomy; MNH, minor hepatectomy; NIT, no interventional treatment; NS, not significant; OS, overall survival; SEER, Surveillance; Epidemiology, and End Results. No funds, grants, or other financial support was received for this study. The authors have no conflicts of interest to declare. Address reprint requests to Mattia Garancini, M.D., Department of General Surgery, San Gerardo Hospital, University of Milano-Bicocca, Via Pergolesi 33, 20900, Monza (MB), Italy. Telephone: ; FAX: ; mattia_garancini@yahoo.it DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2014 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 GARANCINI ET AL. 953 series or literature reviews; no meta-analyses have been reported. Two population-level studies have been performed with data from a national database. One focused on epidemiological analysis, but it lacked information regarding therapeutic management 13 ; the second compared outcomes for patients with chcc- CC and HCC after liver transplantation (LT) or surgical resection but investigated only 3-year survival data for only 54 patients. 14 Therefore, to date, data on chcc-cc remain scarce. The current study was aimed at analyzing demographic, clinical, and pathological characteristics of chcc-cc versus HCC and CC at a population level, investigating prognostic factors of chcc-cc, and determining the impact of different therapeutic strategies on the survival of patients with this rare neoplasm. PATIENTS AND METHODS Data Sources and Study Patients The Surveillance, Epidemiology, and End Results (SEER) database was employed to identify patients diagnosed with chcc-cc, HCC, or CC between 1988 and This database uses the International Classification of Diseases for Oncology, 3rdedition, 16 for histology coding (chcc-cc, code 8180; HCC, codes ; and CC, codes ). Data were collected from 18 registries [San Francisco Oakland, Connecticut, metropolitan Detroit, Hawaii, Iowa, New Mexico, Utah (since 1973), Seattle Puget Sound (since 1974), metropolitan Atlanta (since 1975), Alaska, San Jose Monterey, Los Angeles, rural Georgia (since 1992), greater California (excluding San Francisco, Los Angeles, and San Jose), Kentucky, Louisiana, New Jersey, and greater Georgia (excluding Atlanta and rural Georgia, since 2000)], which represented nearly 28% of the US population. 17,18 Patients under the age of 18 years were excluded, and so were patients diagnosed between 1973 and 1987 because of the lack of data for surgical procedures before The demographic variables of interest were patient sex, age at diagnosis, race, marital status, and year of diagnosis. The age at diagnosis was classified as follows: 18 to 50, 51 to 65, 66 to 75, and 76 years. Race was recoded as white, black, or other; the marital status was categorized as married or single. The year of diagnosis was treated as a categorical variable divided into the following intervals: 1988 to 1995, 1996 to 2002, and 2003 to Clinical variables included overall survival (OS) and disease-specific survival (DSS) at 5 years and treatments. Interventional treatments were divided into 5 categories: no interventional treatment (NIT), ablation (ABL; including electrocautery, fulguration, cryosurgery, and alcohol injection), minor hepatectomy (MNH; including wedge resections and removal of 2 or fewer hepatic segments), major hepatectomy (MJH; removal of more than 2 segments), and LT. Pathological information included the tumor size, SEER stage, and lymph nodes examined. Tumors were divided into 4 groups according to size: 3.0, 3.1 to 5.0, 5.1 to 10.0, and >10.1 cm. Tumors > 25.0 cm were excluded because of the possibility of coding errors. According to the SEER system, a tumor is described as local if it is entirely limited to the organ, regional if it extends beyond the primary site to nearby lymph nodes or tissues, and distant if it metastasizes to distant organs or distant lymph nodes. 16 Lymph nodes were categorized as follows: none (no lymph nodes were examined), negative (all lymph nodes examined were negative), or positive. SEER data are publicly available, and all patient information is de-identified; therefore, the current study was deemed exempt from institutional review board approval. Statistical Analyses Demographic, clinical, and pathological data were analyzed with basic statistics; chi-square tests and analyses of variance were employed for the analyses of categorical and continuous variables, respectively. The Kaplan-Meier method was used to determine prognostic factors, and the log-rank test and the Breslow test were used to calculate statistical significance. Cox proportional hazards regression was used to identify variables independently associated with better survival. Hazard ratios and 95% confidence intervals were calculated for the strength of the association between each variable and survival. Data analyses were performed with SPSS 19.0 (SPSS, Inc., Chicago, IL); all tests were 2-sided, and statistical significance was set at P < RESULTS Demographic, Clinical, and Pathological Characteristics of Patients With chcc-cc A total of 52,825 patients with HCC, 7181 patients with CC, and 465 patients with chcc-cc were identified in the SEER database. chcc-cc was more common among patients who were white, male, and older than 65 years; the mean age at diagnosis was years. Treatment was more frequently noninterventional for all 3 types of tumors. Among chcc-cc patients, 65.2% did not receive any invasive treatment, 4.0% underwent tumor ABL, 7.6% underwent MNH, 10.0% underwent MJH, and 13.1% underwent LT. chcc-cc patients presented with a mean tumor size of cm. The SEER stage at diagnosis was local for 41.3% of the chcc-cc patients, regional for 29.1%, and distant for 29.6%. Among 54 patients with chcc-cc who underwent regional lymph node removal, 24.1% had lymph node metastases according to a pathological analysis. All results for patient characteristics are reported in Table 1.

3 954 GARANCINI ET AL. LIVER TRANSPLANTATION, August 2014 TABLE 1. Demographic, Clinical, and Pathological Characteristics of Patients Diagnosed With chcc-cc, HCC, and CC: SEER, Patient Characteristics chcc-cc (n 5 465) HCC (n 5 52,825) CC (n ) P Value Demographics Sex (%) <0.001* Male Female Age at diagnosis (years) <0.001 Age at diagnosis (%) years <0.001* years years Race (%) <0.001* White Black Other Marital status (%) 0.011* Married Single Year of diagnosis (%) <0.001* Clinical 5-year survival (%) OS <0.001 DSS <0.001 Treatment (%) k <0.001 NIT ABL MNH MJH Transplant Pathological Tumor size (cm) Tumor size (%) 3 cm <0.001* cm cm >10.1 cm SEER stage (%) <0.001* Local Regional Distant Regional lymph nodes examined (%) No <0.001* Yes <0.001* Negative Positive NOTE: Percentages have been rounded and may not add up to 100. *Chi-square test. The data are presented as means and standard deviations. Analysis of variance Log-rank test. k Data were available for 420 chcc-cc patients, 48,471 HCC patients, and 6350 CC patients. The OS rates at 5 years for chcc-cc, HCC, and CC patients were 10.5%, 11.7%, and 5.7%, respectively (P < 0.001); the 5-year DSS rates were 17.8%, 21.0%, and 11.9%, respectively (P < 0.001). DSS curves for chcc-cc, HCC, and CC are shown in Fig. 1. Analysis of Risk Factors for Compromised Survival in chcc-cc Patients In the univariate analysis, black race, regional and distant SEER stages, and a tumor size > 3 cm were

4 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 GARANCINI ET AL. 955 associated with lower DSS; a year of diagnosis after 1995, interventional treatments (ABL, MJH, MNH, and LT), and an absence of regional lymph node metastases Figure 1. DSS curves for chcc-cc, HCC, and CC. were positive prognostic factors (Table 2). In the univariate analysis, LT was associated with better 5-year OS in a direct comparison with liver resection (major and minor; P ; data not shown in the tables). In the multivariate analysis, black race, distant SEER stage, and a tumor size of 5.1 to 10.0 cm remained independently associated with compromised 5-year DSS; patients diagnosed after 1995 and patients who were treated with surgery that included MNH, MJH, or LT had better outcomes (Table 3). Because black race was newly found to be a negative prognostic factor, differences between white and black patients were analyzed in terms of disease presentation and type of treatment. Black patients did not differ fromwhitepatientsintermsofage(p ), tumor size (P ), or SEER stage (P ) at presentation or in terms of the type of treatment (P ). Patients diagnosed with chcc-cc and treated with LT, MJH, MNH, ABL, and NIT had 5-year OS rates of 41.1%, 28.1%, 27.1%, 0%, and 0%, respectively, and DSS rates of 52.8%, 46.5%, 31.9%, 0%, and 3.2%, respectively (P < for both; Fig. 2). Surgical therapy with LT or liver resection (major or minor) granted longer DSS than more conservative treatments. In order to investigate whether the survival results of these subgroups of patients could have been due to selection criteria, patients who underwent different treatment strategies were stratified by tumor size and TABLE 2. Univariate Analysis of Disease-Specific Mortality Characteristics Hazard Ratio* 95% Confidence Interval P Value Race White 1 Reference Black Other NS Year of diagnosis Reference <0.001 SEER stage Local 1 Reference Regional <0.001 Distant <0.001 Treatment NIT 1 Reference ABL MNH <0.001 MJH <0.001 Transplant <0.001 Tumor size cm 1 Reference cm cm < cm <0.001 Lymph nodes examined Negative 1 Reference Positive <0.001 No *A hazard ratio less than 1 indicates better survival.

5 956 GARANCINI ET AL. LIVER TRANSPLANTATION, August 2014 TABLE 3. Cox Multivariate Regression Analysis of Factors Independently Associated With Disease-Specific Death Risk Factor Hazard Ratio* 95% Confidence Interval P Value Black race Year of diagnosis, Year of diagnosis, Distant SEER stage <0.001 Tumor size, cm MNH <0.001 MJH <0.001 Transplant <0.001 NOTE: The total number was 271, and the number of events was 151. The reference groups are white race; year of diagnosis, ; localized SEER stage; tumor size, cm; and no surgery. *A hazard ratio less than 1 indicates better survival. Figure 2. DSS curves (univariate analysis) for chcc-cc patients stratified by the type of treatment. SEER stage. Patients treated with MJH, MNH, and LT did not differ in SEER stage (P ), but LT was mostly performed in patients with small tumors (3 cm), whereas liver resection (particularly MJH) was mostly performed in patients with larger tumors (>3 or even >5 cm, P < 0.001; Fig. 3). Finally, the 3 groups of tumors were compared in terms of survival after LT. Patients diagnosed with chcc-cc, HCC, and CC had 5-year OS rates of 41.1%, 67.0%, and 29.0%, respectively (P < 0.001), and 5-year DSS rates of 52.8%, 80.2%, and 46.6%, respectively (P < 0.001). DISCUSSION Figure 3. Subgroups of patients with chcc-cc receiving different treatments are detailed in terms of SEER stages and tumor sizes. To the best of our knowledge, the current study includes the largest published cohort of patients diagnosed with chcc-cc. This malignancy showed a clinical course intermediate between the courses of HCC and CC. The 5-year DSS rate was 17.8%. Surgical treatment with liver resection or transplantation was associated with prolonged DSS. The incidence of chcc-cc in published series of primary liver-based cancers ranges from 0.4% to 14.2%. 2-4 In our cohort, chcc-cc was observed in 465 of 60,471 patients (0.77%) with primary liver

6 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 GARANCINI ET AL. 957 cancer. The true incidence was likely higher because patients who did not undergo interventional procedures may have been clinically misdiagnosed with HCC or CC. Patients diagnosed with chcc-cc had intermediate features of HCC and CC. In the literature, chcc-cc has been reported to be similar to HCC in terms of patient demographic and clinical characteristics: a male-to-female ratio of 1 has been described as well male prevalence, an average age at presentation between 50 and 60 years, and an elevation of serum alpha-fetoprotein. 6,9,10,13 Our analyses showed that men were more commonly affected than women (66%), and patients were older than 60 years at the time of diagnosis (mean age at diagnosis years). Data regarding hepatitis virus infections, background liver status, and biomarkers such as alphafetoprotein were not captured in the SEER database before 2004 and, consequently, were not included in the present analysis; they have been analyzed in the literature with contrasting results. 2,6,9,10,19,20 Our findings with respect to pathological characteristics, including the mean tumor size at diagnosis and lymph node metastases, were consistent with previous surgical series. 10 Nevertheless, our data probably led to an underestimation because of the low number of patients receiving surgical treatment. In a Japanese study based on 12,887 autopsies performed in patients with primary liver cancers, 76% of 49 patients with chcc-cc had lymph node metastases. 21 After adjustments for several factors, including tumor size and SEER stage, we did not observe lower survival outcomes for patients with nodal metastases, and this confirmed the findings of previous investigators. 2,8,10,22 A diagnosis in recent years appeared to be associated with a better prognosis; in fact, long-term survival rates for many types of cancers have substantially improved over the past decades because of advances in early detection and treatment. 23 Black race was newly found to be a negative prognostic factor. Several studies published on chcc-cc have focused on Asian populations because of the higher incidence of hepatic neoplasms in those countries; Asians were poorly represented in our series, so we could not analyze this subset of patients. In the present study, all 3 types of analyzed neoplasms had a 5-year DSS rate lower than 21%. These results could appear disappointing, especially because 5-year survival rates up to 60% to 70% can be achieved for well-selected HCC patients. 24,25 Nevertheless, these results include the fact that 65% to 84% of the patients included in this study did not receive any kind of interventional treatment. This might have been due to a diagnosis performed in a setting of advanced disease (regional or distant SEER stage, large tumors, and multiple nodules). In the literature, the long-term survival of patients with chcc-cc is controversial: Yin et al. 10 reported a 5-year OS rate of 36.4% for resected chcc-cc patients; Kim et al. 6 reported a 3-year OS rate of 15.3%; and the 5-year OS rates for resected patients were 24% and 7.9% according to Jarnagin et al. 2 and Zuo et al. 9 Tang et al. 26 analyzed 13 patients who had undergone resection and reported a 5-year OS rate- > 50% for select patients with early-stage chcc-cc. 26 Our results clearly show how the survival of chcc- CC patients is strictly related to the type of treatment received: patients not undergoing any invasive therapy or treated with local ABL had a much poorer prognosis than those undergoing LT and liver resection (Fig. 2). HCC is a universally accepted indication for LT with excellent 5-year OS (exceeding 70% in select patients). 27,28 CC is not currently considered a standard indication for LT. Previous studies of LT for intrahepatic CC reported discouraging 5-year survival rates of 20% to 30% or less, mainly because of high recurrence rates (>50%) Nevertheless, in more recent years, some studies restricted to patients with CC located at the hepatic hilum who were treated with neoadjuvant chemoradiation therapies showed remarkable survival benefits; the most important report in this sense is the experience of the Mayo Clinic, which achieved a 5-year survival rate of 82% for patients with CC located at the hepatic hilum. 32 Therefore, some authors now believe that additional research should be aggressively pursued, and this potentially effective treatment should be balanced with the severe organ shortage. 33 Similarly to CC, chcc-cc is not yet considered an indication for LT, and in the present study (as in the literature), most of the patients who underwent LT for chcc-cc probably had a misdiagnosis of HCC. In the literature, studies including patients with chcc-cc treated with LT are seldom reported, and this makes an evaluation of possible indications quite challenging. Maganty et al. 34 described long-term survival (>5 years) for 1 patient among 3 carriers of chcc-cc who had undergone LT. Panjala et al. 35 reported a 5-year cumulative survival rate of 16% for a cohort of 12 patients with chcc-cc treated with LT. Sapisochin et al. 36 reported a 5-year recurrence-free survival rate of 32% for a study group including chcc-cc and CC patients treated with LT for misdiagnosed HCC; within this study group of patients, they found that the patients with chcc-cc had a worse prognosis, a higher rate of tumor recurrence, and a shorter period of disease-free survival in comparison with the patients with CC. Employing the SEER database ( ), Groeschl et al. 14 compared the surgical management of chcc-cc and HCC. Among patients with chcc- CC, the 3-year OS rates after LT and liver resection were similar (48% versus 46%, P ); moreover, they reported significantly worst OS for chcc-cc patients versus HCC patients after LT. Our univariate analysis of chcc-cc patients showed that individuals who underwent LT had better 5-year OS than those who were treated with MJH or MNH (P ). These results were not confirmed in the multivariate analysis, in which LT, MJH, and MNH had similar hazard ratios (0.28, 0.25, and 0.29, respectively).

7 958 GARANCINI ET AL. LIVER TRANSPLANTATION, August 2014 In the current study, patients treated with LT achieved interesting 5-year OS and DSS rates of 41.1% and 52.8%, respectively, which can be considered intermediate results between those obtained for HCC and intrahepatic CC in the present study and in the literature. 24,29-31 The results of the multivariate analysis devalued this supposed survival benefit of LT for chcc-cc patients and showed that patient selection probably played a relevant role. On the other hand, it is remarkable that among 55 patients with chcc-cc who underwent LT, 16 were SEER-staged as regional, and 4 had a tumor size > 5 cm; overall, 17 of the 55 patients (30.9%) had at least 1 of these 2 well-known negative prognostic factors for LT in the setting of HCC. Therefore, better patient selection may improve these outcomes. Nonetheless, HCC patients had similar outcomes before the definition of the Milan criteria in ,37-39 Currently, organ allocation in the United States of America does not give priority to patients with chcc-cc; most of the patients who underwent LT for chcc-cc in this study probably had a misdiagnosis of HCC and underwent transplantation within the Milan criteria, which were designed for HCC and not for chcc-cc. This aspect should be considered when the potential role of LT for chcc-cc is analyzed. More clinical data on chcc-cc are clearly needed, and the organ shortage represents the main limitation in this sense. Previous studies seldom detailed the type of liver resection performed; in some cases, a distinction between radical resection and palliative resection was reported. 9 In the present study, we subdivided resective surgical treatments into MJH and MNH. Interestingly, both were independently associated with better survival, but patients undergoing MJH had better OS and DSS. Compared to patients undergoing LT or MNH, patients undergoing MJH had similar SEER stages (P ) but larger tumors (P < 0.001; Fig. 3). Because MJH was associated with higher 5-year OS and DSS rates than MNH for patients with similar (or worst) demographic and clinical characteristics and because the role and indications of LT for chcc-cc patients have yet to be defined, our results suggest that at this time, MJH should be considered the best surgical approach. Clearly, the background status of the liver (the presence of cirrhosis or chronic hepatitis with impaired liver function) should be taken into account, and the benefits of surgery should be weighed against the morbidity and mortality associated with major liver resections. 40 The role of nonsurgical therapies such as local ablative therapy and transarterial chemoembolization in chcc-cc requires further evaluation. Some studies have reported that they could play a role in the presence of unresectable or recurrent disease. 2,10 This study has some limitations. This is a retrospective study, and consequently, some bias may have affected the analysis. Moreover, the SEER database lacks information before 2004 regarding patient status with respect to the presence or absence of viral hepatitis or cirrhosis in the background liver as well as alpha-fetoprotein and carbohydrate antigen 19-9 levels and the use of chemotherapy. Nevertheless, chemotherapy for HCC, CC, and chcc-cc has shown little impact on patient survival. Moreover, SEER lacks a central review by an expert pathologist. However, the SEER database has been well validated for cancer research by several studies In conclusion, chcc-cc appears to show intermediate demographic, clinical, and survival characteristics of HCC and CC. 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