Prognosis factors of predicting survival in spontaneously ruptured hepatocellular carcinoma

One-hundred-and-twenty-seven patients with spontaneously ruptured HCC were enrolled in our institution between January 2010 and December 2020. The diagnostic criteria of HCC followed Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma [7]. Spontaneous rupture of HCCs was diagnosed as abrupt abdominal pain; disruption of the peritumoral liver capsule with enhanced fluid collection in the perihepatic area adjacent to HCC by contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound; and hematoma around the liver as revealed by radiological examinations and/or bloody ascites by abdominal paracentesis. Patient data at the time of HCC rupture were recorded, including demographics, hemodynamic status, medical history, tumor characteristics, laboratory data, treatment modality, therapeutic strategies in the follow-up, and survival. This study was conducted in accordance with the Declaration of Helsinki and approved by our institution’s Ethics Committee.

All patients with ruptured HCC immediately received careful conservative treatment, including anti-shock measures and patient condition assessment. Blood biochemical indices and imaging characteristics of HCC were rapidly investigated in the emergency department. Following the evaluation of key variables, including hemodynamic state, tumor status, laboratory data, Child–Pugh score, MELD score, Eastern Cooperative Oncology Group (ECOG) score, and cardiopulmonary function, therapeutic strategies were designed by surgeons, interventional physicians, and patients’ families within 48 h.

The surgical indications included a stable hemodynamic state, satisfactory hepatorenal and cardiopulmonary reservation, and tumor resection or packing. The contraindications included poor liver function (Child C), multifocal HCC, poorly controlled hepatic encephalopathy, severe coagulopathy, main portal vein or hepatic vein invasion, metastasis, and poor heart or lung function. All operations were performed by experienced hepatobiliary surgeons.

Patients contraindicated for surgery were recommended to undergo transarterial chemoembolization/transcatheter arterial embolization (TACE/TAE), and the contraindications included main portal vein thrombosis, arteriovenous fistula, Child–Pugh C cirrhosis, severe coagulopathy, and hepatic encephalopathy. Tumor blood feeding and location were observed through transcatheter hepatic arterial angiography. After a microcatheter was selectively inserted into the feeding tumor artery, embolization was performed with lipiodol, gelatin sponge, or polyvinyl alcohol particles. Common hepatic angiography was then repeated to confirm successful embolization of tumor-feeding arteries.

Patients contraindicated for surgery and TACE/TAE received careful conservative treatments, including intensive care, hemostasis treatment, antishock measures, parenteral nutrition, correction of coagulopathy, and analgesics.

Follow-up was performed every 1–3 months. Contrast-enhanced CT/MRI, lung CT, liver function, and alpha-fetoprotein levels were evaluated to determine further therapy for these patients. If patients failed to follow up for more than 6 months, the reason was investigated and recorded by doctors via telephone. Overall survival (OS) was defined as the interval from the date of rupture to the date of death or the last follow-up.

One-hundred-and-twenty-seven patients with a diagnosis of spontaneous HCC rupture were enrolled in our study. The mean age of the patients was 55 years. Thirty-eight (29.9%) patients were diagnosed with liver cancer and received TACE treatment before tumor rupture. At the time of rupture, 42 (33.1%), 61 (48.0%) and 24 (18.9%) patients received surgery, TACE/TAE, and conservative treatment, respectively. The surgical management included HCC curative resection (36/42, 85.7%) and perihepatic packing (6/42, 14.3%). Follow-up treatment was started at an average of 13.1 days after HCC rupture, 40 (31.5%) patients received consequent TACE including one plus sorafenib, 87 (68.5%) patients underwent conservative treatment including five cases of sorafenib, no patients received tumor ablation or radiation, and no HCC curative resection or liver transplantation was performed. No patients experienced recurrence of hemorrhage in the follow-up. The mean survival time was 303.0 days, and the median survival time was 165 days. The baseline characteristics and outcomes of the patients are summarized in Table 1.

Univariate analysis showed that the largest tumor size, tumor number, Up-to-seven criteria, Barcelona-Clinic Liver Cancer (BCLC) C stage, Union for International Cancer Control (UICC) TNM IV stage, prothrombin time (PT) level, international normalized ratio (INR) level, activated partial thromboplastin time (APTT) level, total bilirubin (TBil) level, creatinine (Cr) level, Child–Pugh score and MELD score were significantly associated with poor survival in patients with HCC rupture. In addition, TACE treatment after rupture, prothrombin time activity (PTA) level, and albumin (ALB) level were inversely associated with poor survival. Compared with conservative treatment at rupture, TACE/TAE and surgery were protective factors for patient survival (Table 2).

Stepwise multivariate regression analysis for overall survival was performed following univariate analysis. Up-to-seven criteria and TNM stage were confounding factors for BCLC stage. Child–Pugh score, MELD score and PT were confounding factors for INR and/or TBil. No confounding factors were included in the multivariable analysis (Table 3). The multivariate regression analysis revealed that the largest tumor size [hazard ratio (HR) 1.127; 95% CI 1.056–1.203; p < 0.001], BCLC C stage (HR 2.184; 95% CI 1.116–4.276; p = 0.023), INR level (HR 3.895; 95% CI 1.344–11.895; p = 0.012) and TBil level (HR 1.014; 95% CI 1.003–1.026; p = 0.014) were independent risk factors. TACE treatment after rupture (compared with conservative treatment) (HR 0.549; 95% CI 0.321–0.939; p = 0.029), TACE/TAE and surgery at rupture, and ALB level (HR 0.949; 95% CI 0.908–0.990; p < 0.017) were independent protective factors. The cumulative overall survival rates of ruptured HCC patients with different treatments at rupture differed significantly. The median survival time in patients with conservative treatment, TACE/TAE, and surgery at rupture was 62 days, 206 days, and 599 days, respectively (p < 0.001) (Fig. 1). Pairwise comparison using the Bonferroni method showed that differences in conservative vs. TAE/TACE, conservative vs. surgery, and TAE/TACE vs. surgery were also significant (χ² = 11.903, p = 0.001; χ² = 36.830, p < 0.001; χ² = 7.315, p = 0.007). Compared with conservative treatment, patients receiving TACE treatment after HCC rupture exhibited longer survival. The median survival time was 477 days for patients receiving TACE treatment after HCC rupture and 170 days for patients who underwent conservative treatment after HCC rupture (p < 0.001) (Fig. 2). Independent risk factors for overall survival in patients treated with surgery, TACE or conservative treatment at HCC rupture were also analyzed. The results are shown in the supplementary materials (Table S1, Table S2 and Table S3).

To investigate the predictive power of the MELD, Child–Pugh and SPHR model scores for 30 day survival, ROC curve analysis was conducted. The area under the curve (AUC) of the MELD score was 0.767, and the cutoff value for the MELD score was 13.4 for 30 day survival of HCC ruptured patients, with a sensitivity and specificity of 58.3% and 86.2%, respectively. In addition, the cutoff value for the MELD score was 9.0, with a sensitivity and specificity of 83.3% and 51.6%, respectively. The AUC of Child–Pugh score was 0.757, and the cutoff value was 8.5 for the 30 day survival of HCC ruptured patients, with a sensitivity and specificity of 54.2% and 84.2%, respectively. The SPHR model was described by the formula: Y = 0.078 × the largest tumor size + 0.250 × BCLC (A/B: 0, C: 1) + − 0.568 × TACE at rupture (No: 0, Yes: 1) + − 0.903 × Surgery at rupture (No: 0, Yes: 1) + 0.022 × ALB + 0.024 × TBil + 5.839 × INR–11.389. The AUC of SPHR was 0.925, the cutoff value for SPHR was 0.415, and the sensitivity and specificity were 75.0% and 97.9%, respectively. The AUC of the SPHR differed significantly from the AUC of the MELD score and Child–Pugh score (p = 0.010 and p = 0.002, respectively), and no significant difference in the AUC was found between the MELD score and Child–Pugh score (p = 0.849) (Fig. 3). Moreover, the predictability of SPHR in HBV and non-HBV HCC patients was evaluated, and the AUCs of SPHR in HBV and non-HBV HCC patients were 0.910 and 0.979, respectively (Supplementary Figure S1).