Journal of Cancer 2017, Vol.

8 2312

Ivyspring
International Publisher
Journal of Cancer
2017; 8(12): 2312-2318. doi: 10.7150/jca.19056
Research Paper

Pattern of distant extrahepatic metastases in primary

liver cancer: a SEER based study
Wenrui Wu1,2*, Xingkang He3*, Dewi Andayani1,2*, Liya Yang1,2, Jianzhong Ye1,2, Yating Li1,2, Yanfei Chen1,2,
Lanjuan Li1,2,
1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou,
China
2. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
3. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University Medical School, Hangzhou 310016, China

*Authors contributed equally to this work.

 Corresponding author: State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang
University, Hangzhou 310003, P. R. China. Tel.: +86-571-8723-6458; Fax: +86-571-8723-6459; E-mail: [email protected].

© Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license
(https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Received: 2017.01.04; Accepted: 2017.05.02; Published: 2017.07.21

Abstract
Background and Aims: Primary liver cancer remains still the common cause of cancer-related
deaths globally and the prognosis for patients with extrahepatic metastasis is poor. The aim of our
study was to assess extrahepatic metastatic pattern of different histological subtypes and evaluate
prognostic effects of extrahepatic metastasis in patients with advanced disease.
Methods: Based on the Surveillance, Epidemiology and End Results (SEER) database, eligible
patients diagnosed with primary liver cancer was identified between 2010 to 2012. We adopted
Chi-square test to compared metastasis distribution among different histological types. We
compared survival difference of patients with different extrahepatic metastasises by Kaplan-Meier
analysis. Cox proportional hazard models were performed to identify other prognostic factors of
overall survival.
Results: We finally identified 8677 patients who were diagnosed with primary liver cancer from
2010 to 2012 and 1775 patients were in distant metastasis stages. Intrahepatic cholangiocarcinoma
was more invasive and had a higher percentage of metastasis compared with hepatocellular
carcinoma. Lung was the most common metastasis and brain was the least common site for both
hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Extrahepatic metastasis could
consider as an independent prognostic factor for patients with liver cancer. Patients with brain
metastasis had the worst prognosis, compared with other metastasis in overall survival (OS) and
cancer-specific survival (CSS) analysis.
Conclusions: Different histological subtypes of liver cancer had different metastasis patterns.
There were profound differences in risk of mortality among distant extrahepatic metastatic sites.
Results from our studies would provide some information for follow-up strategies and future
studies.
Key words: Neoplasm Metastasis, Liver Neoplasms, SEER Program, Survival analysis

Introduction
Primary Liver cancer is the sixth common cancer (745,000 deaths, 9.1% of the total death)2. Despite the
globally, after cancers of the lung, breast, colorectal, prevalence of liver cancer is more frequent in
prostate and gastric1. However, the extremely poor developing country, it is still a significant health
prognosis for primary liver cancer makes it the second burden in many parts of the developed regions,
leading cause of cancer-related death globally including North America and central Europe3-5. In

http://www.jcancer.org
Journal of Cancer 2017, Vol. 8 2313

contrast to stable or declining trends of other cancers extrahepatic metastasis profiles due to rare data of
in US (such as lung, breast, and colorectal cancers), liver cancer metastasis. Patterns of extrahepatic
the incidence and death rates of primary liver cancer metastasis still need further clarification. Besides, it is
increased rapidly among men and women in recent unclear whether different metastatic sites would be
decades6. Unlike hepatitis B viral infection as the translated into distinct clinical outcomes. Thus, it is
predisposing factor for liver cancer in Asian, the crucial to elucidate the metastatic distribution for
increasing incidence in American is largely attributed better treatments and survival benefits. Therefore, in
to infection of chronic hepatitis C virus (HCV)7. Other the present study we retrospectively reviewed data
predominant risk factors included alcohol abuse, from SEER population-based cancer registry, in an
non-alcoholic fatty liver diseases (NAFLD), aflatoxin attempt to explore metastasis profiles of primary liver
B1 exposure and diabetes mellitus8, 9. Histologically, cancer. Furthermore, we analysed the clinical
the majority of liver cancer is either hepatocellular characteristics and prognosis according to their
carcinoma (HCC) or intrahepatic cholangiocarcinoma distinct metastatic sites. We sought to explore clinical
(ICC), while combined hepatocellular carcinoma and and demographic differences among patients with
cholangiocarcinoma is less common10. Currently, primary liver cancer.
potentially curative therapies for liver cancer include
liver transplantation, hepatic resection and Methods
radiofrequency ablation. However, these modalities
Cohort population
are not readily available to advanced patients11.
Though these treatments have shown modest The Surveillance, Epidemiology, and End
improvement in overall survival in early stage Results (SEER) Program is the largest publicly
disease, the 5-year relative survival for distant available cancer dataset and is maintained by the
metastasis patients is still low (3.1%). As we all know, National Cancer Institute. The SEER
primary liver cancer preferentially metastasize to the population-based cancer registries contain
portal vein and extrahepatic metastasis including information from various locations and sources
lungs, bones, brain, lymph nodes, and adrenal throughout the United States, which represents
glands12-14. Thus far, few detailed studies explored approximately 28% of the U.S. population. Data was
based on Incidence-SEER 18 Regs Research
Data + Hurricane Katrina Impacted
Louisiana Cases, Nov 2015 Sub (1973-2013
varying). The detailed population selection
procedure was summarized in Figure 1.
Briefly, we included patients aged ≥ 18
years with diagnosis of primary liver
cancer between 2010 and 2012 identified
from the SEER database. We excluded
patients whose metastasis status and
follow-up information was unknown. We
performed a retrospective cohort study
through the SEER database to identify the
distant metastasis pattern of primary liver
cancer. This database only includes
metastasis to the bone, brain, liver, lung
and distant lymph nodes at the time of
diagnosis since 2010. The study was
approved by the review board of the First
Affiliated Hospital, School of Medicine,
Zhejiang University, Zhejiang, China.
Statistical analysis
We used descriptive statistics to
summary demographic and clinical
characteristics of population. Chi-square
test and Student’s t test were performed to
Figure 1. Flowchart of included population in this study. HCC, hepatocellular carcinoma; ICC,
intrahepatic cholangiocarcinoma.
compare categorical and continuous

http://www.jcancer.org
Journal of Cancer 2017, Vol. 8 2314

variables among different groups of patients, population with different histological subtypes was
respectively. Overall survival among different shown in Supplementary Table 2. For both HCC and
metastatic sites was analysed with Kaplan–Meier ICC patients, lung and brain were still the most and
curves and log-rank test. Furthermore, we performed least frequent extrahepatic metastatic sites, separately
univariate and multivariate Cox proportional hazards (Figure 2). However, several differences in
models to identify other variables that might extrahepatic metastatic patterns were existed between
influence the prognosis. Statistical significance was histological subtypes. Percentage of lung metastasis
considered at two-sided P value < 0.05. All of (38.4% vs. 27.6%, P < 0.05), bone metastasis (32.6% vs.
statistical analyses were performed using statistical 18.9%, P < 0.05), and distant lymph (24.6% VS 11.4%, P
software package SPSS 20.0 (SPSS, Inc., Chicago, IL, < 0.05) were higher in HCC patients while there was
USA). no difference among incidence rate of brain metastasis
between HCC and ICC (Figure 2).
Results Multiple metastatic sites were found in patients
with HCC and ICC. Figure 3 summarizes
Patients characteristics and metastasis pattern
combinations of metastasis patterns according to
From SEER database, we finally identified 8,677 histological subtypes. Among HCC, there were no
patients who were diagnosed with primary liver differences among percentages of combinations of
cancer from 2010 to 2012. The detailed selection lung and any other metastasis site. A similar
procedure of population was displayed in Figure 1. phenomenon was noted for bone metastasis,
Primary liver cancer included 7681 hepatocellular combined with any other metastasis site. In ICC
carcinomas (88.5%), 986 intrahepatic cholangio- patients, lung metastases were always frequently
carcinoma (11.4%), 10 combined hepatocellular observed in combination with bone metastases and
carcinoma and intrahepatic cholangiocarcinoma other two combinations (lung and brain, lung and
(0.1%). Baseline clinical characteristics of patients distant lymph) were less common.
were presented in Table 1. As shown in Table 1, there
were no significant differences of age, marital status, Table 1. Baseline clinical characteristics of primary liver cancer
gender between metastasis and non-metastasis patients in SEER database
patients. Although intrahepatic cholangiocarcinoma
Characteristic No metastasis Metastasis P value
consists a small part of liver cancer, ICC tended to be Number (%) Number (%)
more likely to distant metastasis compared with HCC Age 0.333
<60 2643 38.3 709 39.9
(36.4% vs. 18.4%, P < 0.01). Patients with advanced 60-74 3038 44.0 773 43.5
stages received less surgery and more radiation ≥75 1221 17.7 293 16.5
therapy. Marital status
Married 3663 53.1 891 50.2 0.080
Among 8677 patients, there were 1775 patients at Unmarried 2898 42.0 797 44.9
distant metastasis stages (20.5%) when they were Unknown 341 4.9 87 4.9
diagnosed. Since the SEER only included metastatic Race 0.043
White 4680 67.8 1236 69.6
site information related to lung, liver, bone, distant Black 958 13.9 259 14.6
lymph and brain at the time of diagnosis, we focused Other 1264 18.3 280 15.8
on extrahepatic sites (lung, bone, distant lymph and Gender 0.178
Male 5138 74.4 1349 76.0
brain) in further study. Detailed clinical features of Female 1764 25.6 426 24.0
extrahepatic metastatic patients were presented in Histology <0.001
Supplementary Table 1. The four extrahepatic HCC† 6269 90.8 1412 79.5
ICC‡ 627 9.1 359 20.2
metastatic sites accounted for 73.2% (1300/1775) of all Combined HCC and 6 0.1 4 0.2
advanced cases at the time of diagnosis. Lung was the ICC
Grade <0.001
most common metastatic site and brain was least High 1322 19.2 128 7.2
common site, accounting for 36.2% (642/1775) and Moderate 2050 29.7 272 15.3
1.9% (34/1775), respectively. Poor 881 12.8 286 16.1
Undifferentiation 62 0.9 24 1.4
Unknown 2587 37.5 1065 60.0
Distant metastasis pattern and combination of Surgery therapy <0.001
metastasis according to histology Surgery 2887 41.8 94 5.3
No surgery 4001 58.0 1678 94.5
HCC and ICC were different in clinical features, Unknown 14 0.2 3 0.2
therefore we analysed metastasis patterns according Radiation therapy <0.001
to histological subtypes. Since limited cases of Radiation 461 6.7 304 17.1
No Radiation 6404 92.8 1465 82.5
combined HCC and ICC, we did not include this type Unknown 37 0.5 6 0.3
for our analysis. The detailed clinical information of
Abbreviation: †, HCC, hepatocellular carcinoma; ‡, ICC, cholangiocarcinoma.

http://www.jcancer.org
 Journal of Cancer 2017, Vol. 8 2315

variate Cox regression analysis to identify

other variables that might influence the
survival. We found that race, gender, age,
marital status, histology, grade, and therapies
could influence overall survival among
patients with liver cancer (Table 2). In
addition, different extrahepatic metastatic sites
were associated with distant risk of mortality
(Table 3). Compared with non-metastasis,
patients with brain metastasis had the worst
prognosis (OS, HR, 4.12, 95%CI, 2.92, 5.82;
Figure 2. Distribution of distant metastatic sites according to histology (hepatocellular CSS, HR, 4.54, 95%CI, 3.20, 6.45). and patients
carcinoma and intrahepatic cholangiocarcinoma). DL, distant lymph. *P < 0.05 (Chi-square test).
with distant lymph metastasis had better
survival rate (OS, HR, 2.17, 95%CI, 1.94, 2.42;
CSS, HR, 2.36, 95%CI, 2.11, 2.64).

Table 2. Univariate and multivariate overall survival analysis of

liver cancer in SEER database
Variable Univariate analysis Multivariate analysis
HR† (95% CI‡) P HR (95% CI) P
Race
White Reference Reference
Black 1.19 <0.001 1.12 (1.04,1.21) 0.002
(1.11,1.28)
Other 0.81 <0.001 0.89 (0.83,0.96) 0.002
(0.75,0.87)
Gender
Male Reference Reference
Female 0.93 0.011 0.86(0.81,0.92) <0.001
(0.87,0.98)
Age
<60 Reference Reference
60-74 1.02 0.434 1.02 (0.96-1.08) 0.600
(0.97-1.09)
≥75 1.45 <0.001 1.29 (1.20-1.39) <0.001
(1.35-1.56)
Marital status
Married Reference Reference
Unmarried 1.29 <0.001 1.19 (1.13,1.26) 0.000
(1.22,1.36)
Unknown 1.08 0.212 1.02 (0.89,1.15) 0.820
(0.96,1.23)
Histology
HCC§ Reference Reference
ICC¶ 1.37 <0.001 1.28 (1.18,1.39) 0.000
(1.27,1.48)
Combined HCC 0.71 0.448 1.37 (0.57,3.30) 0.482
and ICC (0.30,1.71)
Grade
High Reference Reference
Figure 3. Relative rates of combination-metastatic sites in HCC and ICC. HCC, Moderate 1.10 0.043 1.31 (1.20,1.44) <0.001
hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; DL, distant lymph (1.00,1.20)
Poor 1.99 <0.001 2.11 (1.91,2.33) <0.001
(1.80,2.19)
Undifferentiation 2.38 <0.001 2.69(2.10,3.45) <0.001
(1.85,3.05)
Survival analysis Unknown 2.01 <0.001 1.56 (1.43,1.69) <0.001
(1.85,2.18)
The survival difference associated with distant Surgery therapy
metastatic sites were illustrated by Figure 4. Since Surgery Reference Reference
No surgery 4.84 <0.001 4.47 (4.16,4.81) <0.001
short duration of follow-up, we estimated the 1-year (4.51,5.19)
overall (OS) and cancer-specific survival (CSS) for Unknown 5.36 <0.001 4.95 (2.97,8.25) <0.001
(3.22,8.93)
patients with different extrahepatic metastases in Radiation therapy
current study. The 1-year OS was 15%, 13.7%, 10%, Radiation
No Radiation
Reference
0.89 0.009
Reference
1.20(1.10 1.31) <0.001
5.9% for patients with bone, distant lymph, lung, (0.82,0.97)
Unknown 1.11 0.567 0.96(0.67,1.38) 0.837
brain metastasis, respectively. The 1-year CSS was (0.77,1.60)
16.5%,14.8%, 12.6%, 6.3% for patients with bone, Abbreviations: †, HR, hazard ratio; ‡, CI, confidence interval; §, HCC,
distant lymph, lung, brain metastasis, respectively. hepatocellular carcinoma; ¶, ICC, cholangiocarcinoma.

Furthermore, we performed univariate and multi-

http://www.jcancer.org
 Journal of Cancer 2017, Vol. 8 2316

Figure 4. Kaplan-Meier analysis of overall survival in liver cancer patients with and without metastasis. A, with and without bone metastasis (log rank P < 0.0001). B, with and
without distant lymph metastasis (log rank P < 0.0001). C, with and without lung metastasis (log rank P < 0.0001). D, with and without brain metastasis (log rank P < 0.0001). DL,
distant lymph

Table 3. Multivariate analysis of overall and cancer-specific Relationship between metastatic status and
survival in related to metastatic sites
survival across liver cancer by race, gender,
Variable Overall survival Cancer specific survival marital status
HR† (95% CI‡) * P HR (95% CI) * P
No metastasis Reference Reference According to previous studies, race, gender,
Lung metastasis 2.63 (2.40, 2.88) <0.001 2.72 (2.48,2.99) <0.001 marital status-related discrepancies in prognosis of
Bone metastasis 2.31 (2.09, 2.56) <0.001 2.47 (2.22, 2.75) <0.001 various cancer had been demonstrated. Therefore, we
Distant lymph 2.17 (1.94, 2.42) <0.001 2.36 (2.11, 2.64) <0.001
Brain metastasis 4.12 (2.92, 5.82) <0.001 4.54 (3.20, 6.45) <0.001
performed further analysis to examine whether these
*Adjusted for race, gender, age, marital status, histology, grade, therapies. variables have different effects on association between
Abbreviations: †, HR, hazard ratio; ‡, CI, confidence interval. metastatic status and survival rate. On multivariate
overall survival analysis, the Black were found to
Table 4. Relationship between metastatic status and survival have a significantly worst prognosis, compared with
across liver cancer by race, gender, marital status. (non-metastatic other racial groups (HR,1.39,95%1.14-1.71). Female
status as reference) who were under metastatic status have higher risk of
Multivariate analysis Multivariate analysis mortality compared with male (HR,1.27,95%
Overall survival Cancer-specific survival 1.08-1.49). Regarding marital status, married patients
HR† (95% CI‡) * P HR (95% CI)* P have better survival than the unmarried
Race
White 1.24 (1.12-1.37) <0.001 1.20 (1.09-1.33) <0.001
(HR,1.37,95%1.21-1.55). Similar results were found in
Black 1.39 (1.14-1.71) 0.001 1.33 (1.07-1.64) 0.010 cancer-specific survival analysis.
Other 1.26 (1.04-1.54) 0.020 1.20 (0.98-1.47) 0.084
Gender Discussion
Male 1.26 (1.15-1.38) <0.001 1.21 (1.10-1.33) <0.001
Female 1.27 (1.08-1.49) 0.004 1.24 (1.05-1.47) 0.013 Unlike other common cancers with reductions in
Marital status the incidence and mortality, liver cancer shows
Married 1.21 (1.08-1.36) 0.001 1.17 (1.04-1.32) 0.010 unfavourable trends. The prognosis of liver cancer is
Unmarried 1.37 (1.21-1.55) <0.001 1.32 (1.16-1.50) <0.001
still poor, particularly for advanced patients with
*Adjusted for age, grade, therapies.
Abbreviations: †, HR, hazard ratio; ‡, CI, confidence interval. 5-year relative survival rates of 3.1%4. A clear
understanding of clinical features and metastatic sites
becomes important essential. With enhanced imaging
detection techniques, the reported incidence of

http://www.jcancer.org
Journal of Cancer 2017, Vol. 8 2317

extrahepatic metastases in patients with liver cancer is between biologic impacts with variables on prognosis
increasing. According to previous studies, the of liver cancer, although the details are remains
common location for extrahepatic metastasis from unclear).
primary HCC include the lungs, lymph nodes, To our knowledge, this is the first large
adrenal glands and bones15-18. The most common population-based study from SEER to explore the
extrahepatic metastatic site is the lung, which was extrahepatic metastasis of HCC and ICC, considering
consistent with our studies. It was firstly reported by them as separate entities. We summarized metastatic
Lee et al.13 that three leading sites of hepatoma were patterns of HCC and ICC and analysed the impact of
lung, portal vein, and portal lymph node(s). In 2000, metastasis disparity on survival of liver cancer
Katyal et al.17 reviewed 403 consecutive patients with patients. However, several potential limitations of our
HCC retrospectively and found that the lung, study should be considered. First, it is important to
abdominal lymph nodes, and bone were the main note that we only included synchronous extrahepatic
sites of extrahepatic metastatic HCC. They also found metastasis information. Some patients who would
that patients with more advanced intrahepatic develop metachronous metastasis lesions were not
tumour stage (stage IVA) at the diagnosis were more included in our study, which might lead to
likely to occur extrahepatic metastases17. Another underestimate extrahepatic metastasis of liver cancer.
study conducted by Natsuizaka et al.18 showed that Furthermore, the database only provided limited
73.8% of extrahepatic metastases patients had metastatic sites but other extrahepatic metastatic sites
intrahepatic liver cancer at stage T3 or T4 according to (such as adrenal glands, peritoneum) were unclear.
the TNM classification and concluded that the precise However, as we have noted, these four metastasis
evaluation of extrahepatic spread of HCC was crucial sites accounted for 73.2% of advanced liver cancer
for appropriate treatment. However, few studies patients. Lastly, data related to chemotherapy was not
reported the common extrahepatic metastases for available from SEER, which might influence survival
intrahepatic cholangiocarcinoma (ICC). Although the analysis.
metastasis profile of ICC was similar with HCC, ICC In conclusion, we found that both HCC and ICC
showed a more invasive biological characteristic patients present with similar extrahepatic metastatic
according to our studies. A better understanding of patterns (lung, followed by bone, distant lymph and
potential sites and clinical features of extrahepatic brain metastasis). Patients with distant lymph
metastases may be crucial to determine appropriate metastasis enjoyed best survival outcomes while
therapies, which ultimately influence patients’ patients with brain metastasis owned the worst
survival. prognosis in both OS and CSS analysis.
In the present study, we found that lung was the
most common extrahepatic site for both HCC and Supplementary Material
ICC, followed by bone, distant lymph and brain. The Supplementary tables.
main metastatic site of ICC is liver, whereas HCC was http://www.jcancer.org/v08p2312s1.pdf
significantly more frequent to develop lung and bone
metastasis than ICC. This suggested that we should Acknowledgements
pay more attention to extrahepatic metastasis of HCC The authors acknowledge the efforts of the SEER
patients. Furthermore, we analysed the survival rate Program cancer registries in the creation of the SEER
and found that race, gender, age, marital status, database.
histology, grade, and therapies were all significantly The work was funded by the Key Program of the
associated with OS. Besides, different extrahepatic National Natural Science Foundation of China (No.
metastatic sites also influenced overall and 81330011) and Science Fund for Creative Research
cancer-specific mortality. Sufficient treatments of both Groups of the National Natural Science Foundation of
surgery and radiation therapies may improve China (No.: 81121002).
prognosis even in advanced stage patients19, 20.
Survival rate for patient with brain metastasis was Competing Interests
worse than patients with bone metastasis. Hence, the The authors have declared that no competing
presence of brain metastasis was an indicator of poor interests exist.
survival for primary liver cancer, although it was rare.
Understanding of different extrahepatic metastatic References
sites was important for clinicians to adopt appropriate [1] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer
treatment choices. Furthermore, we observed that the statistics, 2012. CA Cancer J Clin. 2015; 65: 87-108.
[2] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality
Black, female, and unmarried patients had higher risk worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J
of mortality. Our study confirmed the association Cancer. 2015; 136: E359-86.

http://www.jcancer.org
 Journal of Cancer 2017, Vol. 8 2318
[3] Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in
mortality from hepatocellular carcinoma in Europe, 1980-2004. Hepatology.
2008; 48: 137-45.
[4] Ryerson AB, Eheman CR, Altekruse SF, et al. Annual Report to the Nation on
the Status of Cancer, 1975-2012, featuring the increasing incidence of liver
cancer. Cancer. 2016; 122: 1312-37.
[5] Hashim D, Boffetta P, La Vecchia C, et al. The global decrease in cancer
mortality: trends and disparities. Ann Oncol. 2016; 27: 926-33.
[6] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;
66: 7-30.
[7] Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of
hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver
cancer worldwide. J Hepatol. 2006; 45: 529-38.
[8] Makarova-Rusher OV, Altekruse SF, McNeel TS, et al. Population attributable
fractions of risk factors for hepatocellular carcinoma in the United States.
Cancer. 2016; 122: 1757-65.
[9] Welzel TM, Graubard BI, Quraishi S, et al. Population-attributable fractions of
risk factors for hepatocellular carcinoma in the United States. Am J
Gastroenterol. 2013; 108: 1314-21.
[10] Tang D, Nagano H, Nakamura M, et al. Clinical and pathological features of
Allen's type C classification of resected combined hepatocellular and
cholangiocarcinoma: a comparative study with hepatocellular carcinoma and
cholangiocellular carcinoma. J Gastrointest Surg. 2006; 10: 987-98.
[11] Njei B, Rotman Y, Ditah I, Lim JK. Emerging trends in hepatocellular
carcinoma incidence and mortality. Hepatology. 2015; 61: 191-9.
[12] Olubuyide IO. Pattern of metastasis of primary liver cancer at autopsy: an
African series. Trop Gastroenterol. 1991; 12: 67-72.
[13] Lee YT, Geer DA. Primary liver cancer: pattern of metastasis. J Surg Oncol.
1987; 36: 26-31.
[14] Jiang XB, Ke C, Zhang GH, et al. Brain metastases from hepatocellular
carcinoma: clinical features and prognostic factors. BMC Cancer. 2012; 12: 49.
[15] Sawabe M, Nakamura T, Kanno J, Kasuga T. Analysis of morphological factors
of hepatocellular carcinoma in 98 autopsy cases with respect to pulmonary
metastasis. Acta Pathol Jpn. 1987; 37: 1389-404.
[16] Uchino K, Tateishi R, Shiina S, et al. Hepatocellular carcinoma with
extrahepatic metastasis: clinical features and prognostic factors. Cancer. 2011;
117: 4475-83.
[17] Katyal S, Oliver JH, 3rd, Peterson MS, Ferris JV, Carr BS, Baron RL.
Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000; 216:
698-703.
[18] Natsuizaka M, Omura T, Akaike T, et al. Clinical features of hepatocellular
carcinoma with extrahepatic metastases. J Gastroenterol Hepatol. 2005; 20:
1781-7.
[19] Belghiti J, Kianmanesh R. Surgical treatment of hepatocellular carcinoma. HPB
(Oxford). 2005; 7: 42-9.
[20] Klein J, Dawson LA. Hepatocellular carcinoma radiation therapy: review of
evidence and future opportunities. Int J Radiat Oncol Biol Phys. 2013; 87: 22-32.

http://www.jcancer.org