Clinical and demographic characteristics
Of the 39773 HCC cases 141 (0.35%) had synchronous brain metastases at time of primary HCC diagnosis. Median age of brain metastases cases was 61 years (range, 33-92 years; standard deviation (SD),11.3 years), and median age of all HCC cases was 63 years (range, 18-106 years; SD, 10.9 years). Cases with age 18-30 years had no brain metastases. Baseline clinical and demographic characteristics of all HCC and brain metastases cases were significantly different between groups except for gender, age at diagnosis, ethnicity, and year of diagnosis (Table 1). Most of cases were male (78.0%) and Caucasian (72.4%). Of all initial brain metastases cases most were aged 50-59. 40.4% of cases were tumors >5 cm in size. 48.9% of cases were positive in preoperative AFP status, and 14.9% were negative. Initial lung or bone metastases were significantly associated with brain metastases (44.7%; all HCC: 8.3%) and this was also the case with synchronous metastases to both lung and bone (12.8%; all HCC: 1.0%).
Incidence
The incidence of HCC with synchronous brain metastases at time of diagnosis stratified by age is provided in Table 2. The 141 brain metastases cases accounted for 0.35% of all HCC cases and 2.37% of all initial metastatic cases. Although there were only 11 cases with primary brain metastases in ages 30-49, this accounted for an incidence rate of 0.47% in this age group.
On multivariable logistic regression analysis, initial metastasis to one site (vs no initial metastasis to lung or bone; OR 12.62, 95%CI 8.40-18.97, p<0.001), initial metastasis to two sites (vs no initial metastasis to lung or bone; OR 28.97, 95%CI 16.23-51.74, p<0.001) were independent predictors of the presence of brain metastases in all HCC cases (Figure 2). Initial metastasis to two sites (vs no initial metastasis to lung or bone; OR 1.88, 95%CI 1.08-3.30, p=0.03) was independently associated with an increased risk of the presence of brain metastases in all initially metastasized cases. No significant differences were observed for gender, ethnicity, and age at diagnosis, year of diagnosis, AFP status, primary tumor stage, primary tumor size, and tumor multiplicity.
Survival
The 1-year OS was 8.4% and the 1-year CSS was 16.3% in cases with synchronous brain metastases, respectively (Figure 3A and 3B). Median survival of all HCC cases was 11.0 months (IQR: 2.0-39.0 months). For cases with synchronous brain metastases, the median survival was 2.0 months (IQR: 0-6.0 months; standard error (SE), 0.35 months). Cases with no synchronous brain metastases had a significantly better survival compared to cases with synchronous brain metastases (median survival: 12 vs 2 months, p<0.001, Figure 3C). Median survival of brain metastases and all initial metastatic cases stratified by age at diagnosis were presented in Table 2. Overall survival of synchronous brain metastases stratified by age at diagnosis was significantly worse for the age group 70-79 (p=0.028, Figure 3D).
On multivariate survival analysis (Supplementary table), ethnicity (African American vs Caucasian; HR 1.68; 95%CI, 1.06-2.89; P = 0.03) and the presence of multiple lesions (HR 3.52; 95% CI, 1.28-9.69; P=0.01) were significantly associated with the worse OS for HCC cases with synchronous brain metastases. For the liver cancer specific survival, the results of multivariable cox regression indicated that ethnicity (African American vs Caucasian; HR 2.07; 95%CI, 1.16-3.70; P = 0.01) was still significantly associated with the inferior CSS among synchronous brain metastases cases. Gender, age at diagnosis, year of diagnosis, AFP status, primary tumor stage, primary tumor size, and metastatic sites to lung, bone, as well as surgery of the primary site were not associated with the prognosis of OS and CSS.