Background
Hepatocellular carcinoma (HCC) represents one of the most common causes of cancer related deaths worldwide [
1]. The incidence of HCC demonstrates a striking geographic variability, with the highest rates in East and South-East Asia and Sub-Saharan Africa [
1]. It is also one of the top three causes of cancer death in the Asia Pacific region, as a result of the high prevalence of the main etiological agents, hepatitis B virus and C virus infections [
2]. In the United States and Europe, where chronic hepatitis C virus infections have been rising, the incidence of HCC is expected to increase further in the next two to three decades [
3]. China is an area with epidemic hepatitis B virus, and is estimated to account for half of HCC related deaths worldwide [
4].
The presence of brain metastases (BM) is associated with significant morbidity and mortality, and considerable research has focused on improving both survival and quality of life for these patients. BM are most frequently diagnosed in patients with lung, breast and melanoma primaries [
5]. However, BM from HCC is extremely rare, with a reported frequency ranging from 0.2% to 2.2% at autopsy [
6‐
9]. Recent therapeutic advances in surgical techniques, including transarterial chemoemobolization (TACE), local ablation, and chemotherapeutic agents, have all contributed to improved survival rates [
3]. As a result, the incidence of BM is expected to increase as a result of longer survival for some patients [
8]. However, the prognosis for patients with BM is extremely poor, with a median survival of only 1-2 months [
7,
10,
11]. Furthermore, due to its rarity, the identification of prognostic factors and optimal treatment strategies are still being researched. To date, only a few studies from Asia and a small series from America and Europe have been reported [
7,
8,
10‐
15]. Similar studies from China are lacking. Therefore, in the present study we retrospectively reviewed those patients treated in Sun Yat-sen University Cancer Center (SYSUCC) in China, in an attempt to explore both the clinical characteristics and potential prognostic factors associated with survival in patients with HCC and BM.
Discussion
With longer survival of patients and enhanced imaging detection techniques, the reported incidence of extra-hepatic metastases in patients with HCC patients is increasing [
18]. The most common site for metastases is the lung, followed by regional lymph nodes, bone, the adrenal gland, and occasionally the peritoneum, pancreas, and kidney [
18,
19]. BM from HCC is a less common occurrence, with various incidence rates reported in the literature. A small series from Korea and Japan reported an incidence of brain metastases between 0.05 and 2.2% [
6,
8,
9,
11,
20]. The most recent literature from Korea compiled the largest cohort to date, with 62 cases of BM secondary to HCC, an incidence of 0.9% [
7]. In our study, the incidence of BM from HCC was 0.47%. However, as has been stated by Choi et al. [
7], these figures probably underestimate the true frequency. In our institution, brain scans are not routine for HCC patients. Almost all patients included in this study were diagnosed on the basis of symptoms. As a result, asymptomatic patients with BM may have been missed.
The prognosis in HCC with BM is very poor. As reported in most of the larger studies, overall survival from the time of BM diagnosis is between 1 and 3.7 months [
7,
10,
21]. Our survival result of 3 months concurs with these reports. However, some subsets of patients may benefit from aggressive treatment. In some case reports, survival extended to 12 months after comprehensive treatment [
22]. Larger studies have reported a survival time of more than 4 months in patients who received surgery and/or radiotherapy [
7,
10,
11]. The median survival of patients who underwent resection and WBRT can increase to almost 9 months [
7]. On the other hand, median survival in patients who received supportive care only was less than 1 month [
7,
10]. In our study, median survival was 4.5 months for patients who underwent resection and/or radiotherapy, compared to 1.5 months for those treated with supportive care alone. However, not all patients with BM would benefit from aggressive treatment. The identification of prognostic factors would serve to guide the physician into making optimal treatment decisions.
The RPA class has been proposed as an independent prognostic factor for patients with BM from other primary tumors [
23,
24]. In a study by Choi et al. [
7], 62 patients with HCC and BM were included, and patients in RPA classes I and II demonstrated an improved survival when compared to those in RPA class III. However, this relationship was not found to be significant in a further small report [
11]. In our study, RPA class was shown to be an independent prognostic factor in multivariate analysis. This result suggests that patients in RPA class I and II may benefit from aggressive treatment.
Patients with extracranial metastases at the time of diagnosis of BM were usually considered to have a high burden of tumor. In patients with BM from other primary tumors, the presence of extracranial metastases has been shown to be associated with a poor prognosis [
23,
25]. The impact of the presence of BM on survival in patients with HCC remains unclear. In a study by Chung et al. [
11], the presence of extracranial metastases was negatively associated with progression free survival. However, this association was not statistically significant. A further study revealed a positive association between median survival and the presence of extracranial metastases [
7], although statistical significance was again not achieved. On the other hand, the presence of extracranial metastases prior to a diagnosis of BM was shown to be positively associated with survival in our study. We also found that 87.5% of patients died from progressive BM, whereas only 51.6% of patients with extracranial metastases died from progressive BM. In addition, it was found that patients who did not have lung metastases were more likely to die of progressive brain lesions, which may imply that patients with HCC and BM first, may have tumors that are more poorly differentiated and result in a more aggressive neurovascular invasion. Further studies are needed to elucidate the impact of the presence of extracranial metastases on survival in patients with BM from HCC.
Other important factors may impact on survival of patients with HCC and BM. As the majority of those with HCC have concurrent cirrhosis [
3], the activity of the primary tumor and liver function will influence decisions on treatment, and thereby survival. The Child-Pugh classification is used to evaluate the status of liver function, and serum AFP is the most useful tumor marker to reflect tumor burden in HCC [
3]. Both parameters have been shown to influence survival in patients with HCC and BM [
7]. A recent study demonstrated that a controlled primary tumor was an independent prognostic factor for patients with HCC and extra-hepatic metastases [
20]. However, a further retrospective report failed to confirm this association [
7]. Additionally, the number of brain lesions is also an important prognostic factor. Many studies have shown that a limited number of brain lesions is associated with a relatively improved survival rate [
26], and the median survival of patients with single brain lesions appears longer than that observed in those with multiple lesions [
7]. However, we failed to identify any of these parameters as prognostic factors in the present study.
The cause of death for patients with BM from HCC has, to date, been largely unknown. In the present study, the majority of patients were followed up successfully. We explored the relationship between patient characteristics and the cause of death. The results showed that patients in a low RPA class were more likely to die from systemic disease, rather than from progression of BM. Additionally, a properly aggressively treatment had a significant impact on the cause of death, which again confirms its influence on prognosis in patients with BM from HCC. A more rigorous determination of systemic versus neurological causes of death could be clarified in a larger study.
Hepatitis B infection is the greatest risk factor for HCC in most geographic areas, with the highest rates in China, Taiwan and Korea [
1]. Therefore, similar to previous reports from Korea and Taiwan [
7,
10,
11], the majority of patients in this study had been infected with hepatitis B. The interval between diagnosis of HCC and diagnosis of BM varies in different reports, ranging from 2-54 months [
13]. The most recent large series from Korea and Taiwan reported a median interval of 10.5-18.5 months [
7,
10,
11]. Our results were similar, with a median interval between diagnosis of the primary disease and discovery of brain lesions of 15 months. According to previous reviews and reports [
7,
10,
11,
13], BM from HCC usually occurs concurrently with a high rate of extracranial metastases. This was confirmed in our study, where 80.5% of patients had concurrent extracranial metastasis. In line with other reports, the lung was the most common site of extracranial metastases (75.6%), followed by bone (22%) [
7,
10,
11,
13,
18,
19]. These results indicate that BM from HCC is indicative of late stage disease, and the presence of systemic metastases should be assessed in HCC patients with BM.
The characteristics of brain lesions described in this study were similar to other reports [
7,
10,
11,
13,
21]. The distribution of metastasis was supratentorial in 70.7% of our patients compared with 54.8%-83.3% in previous reports [
7,
10,
11,
21]. The occurrence of a single metastasis was also similar to earlier studies: 58.5% vs. 50%-66.7%. BM from HCC is frequently associated with hemorrhage as has been reported on many occasions [
7,
10,
11,
13,
21]. Similarly, 46.3% of patients in our study presented with hemorrhagic brain metastases. Some experts [
7] suggest that the hypervascularity of HCC and the underlying coagulopathy due to liver cirrhosis may explain this observation. Hsieh et al. [
21] compared the clinical characteristics of patients with and without intracranial hemorrhage, and found that only habitual alcohol consumption was a significant predictor of intracranial hemorrhage in patients with HCC and BM.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
XJ, CK, and YM participated in the study design. XJ, CK, GZ, XZ, and KS participated in data collection and analysis. XJ, ZC and YM participated in editing and proof reading. All authors read and approved the final manuscript.