1. Context

Hepatocellular carcinoma (HCC) is a highly vascular tumor and one of the most common cancer types around the world (1). It can rapidly develop and directly invade the surrounding parenchyma and capsule, resulting in spontaneous rupture. The incidence of spontaneous HCC rupture is reportedly less than 3% in the Western population, while the highest rate is 26% in Asian countries (2-4). Generally, it is a serious and life-threatening complication, which ranks the third among the causes of HCC deaths (4-6). Although the incidence of spontaneous HCC rupture has decreased with the improvement of early diagnosis in recent years, the 30-day mortality rate is still as high as 17 - 71% (2, 3, 7-10).

Patients with spontaneous HCC rupture usually experience shock, hypoperfusion, and multiple organ dysfunction. The primary treatment goal for these patients is to achieve a stable hemodynamic state and save their lives. In previous studies, the safety and efficacy of transarterial embolization/chemoembolization (TAE/TACE) have been fully demonstrated for critically ill patients with spontaneous HCC rupture (4, 8, 10, 11). Nevertheless, the clinical outcomes of emergency TAE/TACE in patients with spontaneous HCC rupture remain unpredictable. Despite successful embolization for bleeding termination, a significant number of patients still have a short survival. In previous studies, the 30-day mortality rate of patients with spontaneous HCC rupture significantly differs following emergency TAE/TACE (7.7%~75%), and the influential factors for mortality are inconsistent (1, 4, 6, 9, 12-31). Therefore, it is necessary to conduct a meta-analysis of 30-day mortality data after emergency TAE/TACE for patients with spontaneous HCC rupture.

2. Objectives

This study aimed to conduct a comprehensive quantitative evaluation of early mortality after emergency TAE/TACE for spontaneous HCC rupture and to perform an overall analysis of risk factors to obtain more representative data.

3. Methods

3.1. Search Strategy

This study was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines (32). The PubMed/Medline, Web of Science, and Embase databases were searched for relevant publications. The used keywords included “hepatocellular carcinoma” OR “hepatoma” OR “liver cell carcinomas” OR “liver cancer” OR “hepatic carcinoma” OR “HCC” AND “rupture”. Taking PubMed as an example, the detailed search strategy is shown in Appendix 1. All databases were searched from November 1, 2000 until November 1, 2021.

3.2. Study Selection

The inclusion criteria were as follows: (1) evaluation of adult patients with a definite diagnosis of HCC and spontaneous rupture; (2) use of interventions, including TAE/TACE for emergency hemostasis; (3) evaluation of the main outcome of this study, i.e., the 30-day mortality after TAE/TACE (or our calculation based on the available data); (4) study types, including published cross-sectional studies, single-arm clinical trials, case-control studies, and randomized controlled trials; and (5) English-language publications. In the included studies, the data of single-arm clinical trials consisted of baseline data, while cohort studies and randomized controlled trials only included the TAE/TACE group data.

On the other hand, the exclusion criteria were as follows: (1) age younger than 18 years; (2) evaluation of other types of liver malignancies; and (3) poor-quality studies.

3.3. Data Extraction

According to the abovementioned inclusion and exclusion criteria, two authors (C.M. and Y.W.) selected the papers independently. Data, including the title, authors, year, and country of the study, demographic characteristics of the patients, 30-day mortality after TAE/TACE, patients’ history, liver function grade, and preoperative laboratory indicators, were extracted from the articles.

3.4. Quality Assessment

The literature quality assessment was conducted by two authors using the Downs and Black Checklist (33) (see Appendix 2).

3.5. Statistical Analysis

After the mortality data were transformed by double arcsine transformation (34), the random-effects model was used to combine the transformed effect sizes. Next, the combined mortality data and 95% confidence intervals (CI) were obtained after the formula was returned. Heterogeneity between studies was analyzed by I² statistic, where values above 50% indicated moderate heterogeneity. If I² values were above 50%, the source of heterogeneity was explored, and a subgroup analysis was performed according to factors that may lead to heterogeneity. Differences within subgroups were examined using the Q-value method. Additionally, a linear regression analysis was performed to evaluate the effects of confounding factors on the 30-day mortality and to find the source of heterogeneity.

In this study, a sensitivity analysis was conducted. If outlier studies were found, they were removed, and then, a combined analysis was performed after removing all sensitive items to appraise the stability of the results. The Egger’s test, Begg’s test, and funnel plots were used to evaluate publication bias. If necessary, the trim-and-fill method was employed to correct for bias (35). All the mentioned calculations and analyses were performed in Stata Version 15.1 and R Project 4.1.2. The level of statistical significance was set at P < 0.05 in all tests (two-tailed).

4. Results

4.1. Study Characteristics

A total of 24 studies were included in this meta-analysis (Figure 1). In these studies, there were considerable variations in the patients’ age (47.4 - 69.8 years), tumor characteristics, liver functional reserve, and preoperative assay results. Of 24 studies, two (8.3%) were conducted in Europe (6, 15), one (4.2%) in North America (9), and 21 (87.5%) in Asia (1, 4, 6, 12-14, 16-31). All studies were retrospective. A summary of the characteristics of the included studies is presented in Tables 1-4. The Downs and Black checklist was used to assess the quality of the included papers (Appendix 2 and Appendix 3). Based on the evaluations, the scores of the included studies were mainly 7 - 12, and the quality of the included studies was generally average.

Figure 1.An overview of the inclusion and exclusion of studies based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart

4.2. Meta-analysis of 30-Day Mortality After Transarterial Embolization/Chemoembolization for Spontaneous Hepatocellular Carcinoma Rupture

The combined 30-day mortality of patients with spontaneous HCC rupture, who underwent emergency TAE/TACE treatment (n = 1,083 in 24 studies), was 28.8% (95% CI: 23.4 - 34.4%). There was moderate heterogeneity between studies (I² = 65.8%, P < 0.0001) (Figure 2). Hepatic failure was the most common cause of 30-day mortality after the procedure (13 studies, accounting for 42.34% of total deaths) (Tables 1-4).

Figure 2.The forest plot showing the overall 30-day mortality after transarterial embolization/chemoembolization (TAE/TACE) for spontaneous hepatocellular carcinoma (HCC) rupture.

4.3. Subgroup Analysis

According to the results pertaining to the influential factors in the literature, further subgroup analysis was conducted according to different factors (Table 5). The results of subgroup analysis revealed that a bilobar tumor distribution (P = 0.0011) was significantly associated with increased 30-day mortality after TAE/TACE (Figure 3A).

Figure 3.The forest plot of 30-day mortality based on different subgroups: A, Tumor extent: Bilobar distribution and one-lobe involvement; B, Period of time: 2020 - 2021, 2018 - 2019, 2016 - 2017, 2014 - 2015, 2012 - 2013, and 2001 - 2010; C, Procedure method: Transarterial embolization/chemoembolization (TAE/TACE).

After stratification by publication time of studies, it was found that the 30-day mortality after TAE/TACE treatment for spontaneous HCC rupture has decreased significantly in the past two years (P = 0.0074); the corresponding value was 19.1% (95% CI: 14.3 - 24.3%) during 2020 - 2021 and 31.6% (95% CI: 26.4 - 36.9%) during 2001 - 2010 (Figure 3B).

Based on the comparison of TAE and TACE groups, although the P-value was 0.01 between the subgroups, the CIs of the two data groups overlapped (Figure 3C). So their difference was not statistically significant, this finding was further analyzed in the regression analysis. In some other subgroups, the number of studies and sample size were relatively small. The I² statistic did not change significantly after the interaction between subgroups was excluded by Q-test, suggesting that other factors were not a source of heterogeneity in the 30-day mortality after TAE/TACE.

4.4. Meta-regression Analysis

To further evaluate the influential factors of early postoperative mortality after TAE/TACE and to explore the sources of heterogeneity between studies, a univariate regression analysis was performed on various possible influential factors (Table 6). The results revealed that preoperative liver cirrhosis (P = 0.0057) and bilobar tumor distribution (P = 0.0015) were significantly associated with increased 30-day mortality after TAE/TACE. Compared to earlier years (2001 - 2010), the period of time (2020 - 2021) was significantly associated with reduced 30-day mortality after TAE/TACE (P = 0.0002). All the mentioned factors may be potential causes of heterogeneity. Meanwhile, there was no significant difference between the TAE and TACE groups (P = 0.2227).

4.5. Sensitivity Analysis

This study investigated whether sequentially excluded individual studies influenced the overall 30-day mortality after TAE/TACE for spontaneous HCC rupture (Figure 4). As shown in Figure 4, the combined effect size of the remaining studies fluctuated around 28.8%, and no significant outliers were found, indicating the acceptable stability of the included studies.

Figure 4.Sensitivity analysis results. After sequentially excluding individual studies, the combined effect size fluctuation in the remaining studies is around 28.8%, and no significant outliers are found.

4.6. Publication Bias Analysis

The funnel plot revealed that the merger rates of original studies were symmetrical in the upper middle part of the graph, but not in the lower half (Figure 5). The Egger’s test (P = 0.4407) and Begg’s test (P = 0.7468) were also carried out. After correction with the trim-and-fill method (Figure 5), one small sample was added to the left mirror position of the funnel plot, and the overall 30-day mortality after TAE/TACE was estimated at 28.1% (95% CI: 22.7 - 33.6%), which was not significantly different from the original result. According to this result, there was no significant publication bias in the 24 included studies.

Figure 5.The funnel plot of publication bias for the original studies (solid circle, the combined effect size is the double-arcsine transformed proportion of 30-day mortality). After correction with the trim-and-fill method, one study was added to the left mirror position of the funnel plot (hollow circle).

5. Discussion

Spontaneous HCC rupture is one of the most common emergency complications in advanced HCC, with a commonly poor prognosis (36). In the event of spontaneous HCC rupture, the main goal is to achieve rapid and effective hemostasis, which is the most important factor in determining early mortality (37).

Today, the main hemostatic methods for patients with spontaneous HCC rupture include conservative treatment, partial hepatectomy, and TAE/TACE. There are also some less commonly used hemostatic methods, such as perihepatic packing, suturing and folding of hemorrhagic tumors, absolute alcohol injection, and hepatic artery ligation (3). The results of conservative treatment alone are usually poor. In a multi-center study by Zhong et al. on patients with spontaneous HCC rupture, the 30-day survival was much higher after partial hepatectomy or TAE compared to conservative treatment (88.2% vs. 8.6%; P < 0.001) (1). In another study by Shinmura et al., the prognosis of TAE was better than that of conservative treatment (median survival time, 28 vs. 16 days; 30-day survival rate, 39% vs. 63%), although no significant difference was found in the overall survival rate between the two groups (18).

Currently, it is believed that conservative treatment should be only applied for dying patients with decompensation of liver function and progressive tumor, for which TAE/TACE or hepatic resection is not feasible. Hepatic resection is also one of the effective treatment options for ruptured HCC. However, relative to TAE/TACE, it is not suitable for patients with an unstable hemodynamic status or severe liver cirrhosis and coagulation dysfunction (2). Although in some previous studies, no significant difference was found in the efficacy or safety of emergency TAE/TACE and surgical resection in patients with spontaneous HCC rupture (3, 23, 37), a recent meta-analysis of the efficacy and safety of TAE/TACE and emergency surgery for spontaneous HCC rupture reported that the incidence of complications in the TAE/TACE group was only one-third of the emergency surgery group (odds ratio (OR): 0.36; P < 0.0001). The in-hospital mortality rate in this group was also half the rate reported in the emergency surgery group (OR: 0.52; P = 0.03) (38).

In previous research, the success rate of emergency TAE/TACE hemostasis in patients with spontaneous HCC rupture was as high as 53 - 100% (2, 37), and the early postoperative mortality rate was 7.7 - 75% (1, 4, 6, 9, 12-31). After combining the results of previous studies, the 30-day mortality of patients with spontaneous HCC rupture after emergency TAE/TACE was 29.0% (95% CI: 23.7 - 34.5%), which is significantly lower than the previously reported rate in these patients undergoing emergency open surgery (28 - 75%) (8).

In the present study, the 30-day mortality following TAE/TACE treatment for spontaneous HCC rupture has decreased significantly in the past two years compared to earlier years (19.1% in 2020 - 2021 vs. 31.6% in 2001 - 2010); apparently, the mortality rate is about 12% lower than earlier years, which is clinically important. This finding may be related to the following phenomena. First, development of magnetic resonance imaging (MRI), enhanced computed tomography (CT) scan, contrast-enhanced ultrasonography (CEUS), and other techniques has made the diagnosis of ruptured tumors more rapid, and it is now simpler to identify the location of ruptured tumors more accurately and achieve successful embolization. Second, with the development of interventional instruments and technologies, many previously inaccessible microvessels can now be successfully entered for more precise embolization (39, 40). Finally, with the progress of intensive care management, active initial resuscitation, effective correction of hypovolemic shock, and increased awareness of the importance of preventing decompensated liver failure in patients with potential liver cirrhosis, early mortality after TAE/TACE can be reduced.

The factors contributing to early mortality after emergency TAE/TACE in patients with spontaneous HCC rupture vary greatly in previous studies. In the current study, liver cirrhosis was an important factor affecting the early mortality of TAE/TACE in patients with spontaneous HCC rupture. HCC has always been recognized as the leading cause of death in patients with liver cirrhosis. Regardless of the stage of liver cirrhosis, 1 - 8% of patients develop HCC every year (41, 42). Zhu et al. found that liver cirrhosis is an independent predictor of spontaneous HCC rupture (43). Following cirrhosis, the liver microenvironment undergoes a series of changes. Through changes in the biomechanical properties of the liver, secretion of specific cytokines, and activation of various signaling pathways, tumor growth can be stimulated, and resistance to chemotherapy drugs can be developed (44); these characteristics may reduce the efficacy of TAE/TACE (44, 45).

In TAE/TACE, polyvinyl alcohol (PVA), embosphere, gelatin sponge particles, lipiodol, or chemotherapeutic agents emulsified with lipiodol are usually used to block the ruptured tumor blood supply artery to achieve the purpose of hemostasis and induce tumor ischemic necrosis. When liver cirrhosis occurs, the production of endothelin-1 increases, the sensitivity of its receptors enhances, and the production of nitric oxide decreases (46). After acting on hepatic stellate cells (HSC), they cause vascular remodeling in the hepatic sinusoid (contraction of HSC), which increases vascular resistance (46); consequently, embolic agents may not reach more distant and thinner blood vessels of the liver tumor, thereby reducing the effect of TAE/TACE.

Additionally, patients with liver cirrhosis often have poorer liver functional reserves, a higher risk of infection, potential coagulation disorders, and pancytopenia (due to portal hypertension and hypersplenism) (26, 27, 47). The combined effects of these factors may be also an important reason for the high early mortality rate after TAE/TACE in patients with spontaneous HCC rupture in liver cirrhosis (26, 27, 46). Tan et al. found that liver cirrhosis was an important factor, affecting the increase in 30-day mortality in patients with spontaneous HCC rupture (30). Moreover, in a multicenter study by Zhong et al., liver cirrhosis was an independent factor influencing the overall survival rate of patients with spontaneous HCC rupture (1).

In the current study, bilobar tumor distribution was an important factor affecting early mortality after TAE/TACE in patients with spontaneous HCC rupture. First, bilobar tumor distribution indicates a poor liver functional reserve (16), resulting in greater susceptibility to ischemic injury by TAE/TACE, which is closely linked to early liver failure (12). Second, bilobar tumor distribution suggests that a larger embolization area may be needed during TAE/TACE (both left and right hepatic arteries need to be entered, selective embolization should be carried out, and sometimes, the embolization scope is inevitably expanded), while the probability of post-embolization syndrome, liver failure, liver abscess/biloma, and other complications of large-scale embolization is greatly increased (9, 48). In some studies, extensive bilobar tumor involvement is even considered an absolute contraindication for TACE (48, 49). In an early study by Shin et al., bilobar tumor distribution affected the poor prognosis of patients with spontaneous HCC rupture after TAE/TACE (26). In another retrospective study, bilobar tumor distribution was an independent predictor of increased 30-day mortality after TAE in patients with spontaneous HCC rupture (OR = 29.6; P < 0.001) (16), which is consistent with the results of the present study.

In our subgroup analysis, based on the comparison of the TAE group with the TACE group, the P-value was 0.01 between the subgroups. However, the CIs of the two data groups overlapped. In the regression analysis, no significant difference was found between the TAE and TACE groups; based on the results, TACE and TAE do not appear to have different effects on the patients’ 30-day mortality. In some early studies, it was believed that TAE should be performed for hemodynamically unstable patients, while TACE is feasible for patients with a relatively stable status (4, 6, 25-31). However, in recent years, this view has not been widely accepted. Some studies suggest that for hemodynamically unstable patients with an apparent continuous hemorrhage, TACE can be considered if the liver functional reserve is not very poor (3, 17). Many centers also choose emergency TACE for patients with shock (14, 15). Nevertheless, compared to TAE, the use of chemotherapy drugs may cause further damage to the liver function. Our findings also suggest that hepatic failure is the most common cause of 30-day mortality after the procedure.

In most recent studies, TAE is still used more commonly than TACE in relatively “critically ill” patients, especially those with a poor liver function (1, 18-20, 22). Clinically, it is unclear whether TAE or TACE is superior for patients with spontaneous HCC rupture. The type of embolization agents used during TAE/TACE is important regardless of whether chemotherapeutic agents are used, but is not accurately described in most papers (Tables 1-4), and we were unable to conduct further subgroup and regression analyses. Also, there is no literature directly comparing the efficacy of these interventional strategies for patients with spontaneous HCC rupture; these questions warrant further analysis. In the current study, no detailed subgroup or regression analysis was performed. Nonetheless, the number of papers in many subgroups was limited after stratification, which can be considered a limitation. Also, this may be the reason why many other factors proposed in other papers, possibly contributing to an increase in early mortality after TAE/TACE, were not significant in our study; these factors can be also significant if the number of studies was large enough. We can simply divide the mentioned factors into three categories.

The first category includes indicators of poor liver functional reserve, including the model for end-stage liver disease (MELD) score, Child-Pugh classification, and bilirubin level (9, 12, 13, 17, 18, 24, 26, 29, 30). In many studies, the MELD score was an independent predictor of increased 30-day mortality after TAE/TACE in patients with spontaneous HCC rupture (9, 12, 17). However, the optimal critical value remains controversial. In some studies using the Child-Pugh classification, a Child-Pugh score ≥ 8 was significantly associated with poor prognosis following TAE/TACE in patients with spontaneous HCC rupture (12, 13, 18, 24, 26, 29, 30). Meanwhile, compared to conservative treatment, patients with spontaneous HCC rupture and Child-Pugh scores of 12/13 showed no significant advantage for TAE/TACE (19). Regarding the bilirubin level, although it has been included in the Child-Pugh score, there are still many studies analyzing bilirubin level as a separate influential factor. Despite the fact that the total serum bilirubin level is the main factor affecting early mortality after TAE/TACE, the optimal critical value is still unclear (12, 14, 16, 26, 27, 29).

The second category includes indicators of bleeding severity after HCC rupture, including shock on admission, hemoglobin level, albumin level, and blood transfusion volume (4, 13, 22, 24, 25, 27, 29). During hemorrhagic shock, the function of oxygen transport decreases, tissue perfusion reduces, and cell hypoxia causes serious damage to important organs. Moreover, hemorrhagic shock makes the liver function more fragile than usual, and coagulation dysfunction of patients with impaired liver function can further increase the risk of shock death. Kim et al. found that the 30-day postoperative mortality rate of TACE was 16.7% in patients with ruptured HCC, and a higher preoperative hemoglobin level was an independent influential factor reducing the postoperative mortality rate (P = 0.036) (24).

Kung et al. analyzed the prognosis of 167 patients with spontaneous HCC rupture, accompanied by hemodynamic instability after TAE and found that patients who died early had lower hemoglobin and albumin levels and more blood transfusions (P < 0.05 for all) (29). Additionally, in a retrospective study by Li et al., the early death of patients with spontaneous HCC rupture treated with TAE was associated with a low hemoglobin level, low serum albumin level, and prolonged prothrombin time (27). Serum creatinine level is also an important index reflecting the systemic hemodynamic status of critically ill patients. The significant increase in serum creatinine level usually represents greater blood loss. In the study by Kung et al., along with lower hemoglobin and albumin levels and higher transfusion volume, a serum creatinine level ≥ 1.5 mg/dL was an independent predictor of increased 30-day mortality (29).

Finally, the third category includes large tumor diameter, high alpha-fetoprotein (AFP) level, portal vein tumor thrombus formation, distant metastasis, and absence of tumor capsule, all of which suggested a significant increase of tumor load (12, 17-19, 22, 26, 28-30). In a retrospective study by Zhang et al., in addition to the MELD score, AFP ≥ 1000 ng/mL, maximum tumor diameter ≥ 10 cm, and absence of capsules around tumors were independent risk factors for 30-day mortality after TACE (17). Shinmura et al. found that distant metastasis is an independent prognostic factor for TAE and conservative treatment in patients with spontaneous HCC rupture (P = 0.023) (18). In patients without distant metastasis, the formation of portal vein tumor thrombus is an important prognostic factor (P = 0.015) (18). These important influential factors should be considered by clinicians before TAE/TACE treatment for patients with spontaneous HCC rupture.

This study had some limitations. First, there are relatively few high-quality studies on early mortality after TAE/TACE for spontaneous HCC rupture in this meta-analysis. Many studies did not include complete confounding factors; therefore, some factors proposed in many other studies, which might have contributed to an increase in early mortality after TAE/TACE, were not found significant in our study. Second, the number of studies in many subgroups was very small after stratification; consequently, the statistical efficiency of the estimated mortality in some subgroups may be insufficient. Third, the current study was not registered, and there may be small bias; nevertheless, we strictly adhered to the PRISMA guidelines. It is necessary to conduct prospective large-scale randomized clinical trials to further investigate the effect of TAE/TACE and other methods on the early mortality of spontaneous HCC rupture.

In conclusion, in recent years, the early mortality rate following emergency TAE/TACE for spontaneous HCC rupture has been significantly lower than before, but it is still not negligible. Before TAE/TACE, it is necessary for clinicians to predict the adverse outcomes, along with the patients' risk factors and disease-related factors, and to formulate appropriate intervention measures.

References

1. Zhong F, Cheng XS, He K, Sun SB, Zhou J, Chen HM. Treatment outcomes of spontaneous rupture of hepatocellular carcinoma with hemorrhagic shock: a multicenter study. Springerplus.. 2016; 5(1):1101. PubMed | DOI
2. Yoshida H, Mamada Y, Taniai N, Uchida E. Spontaneous ruptured hepatocellular carcinoma. Hepatol Res.. 2016; 46(1):13-21. PubMedDOI
3. Moris D, Chakedis J, Sun SH, Spolverato G, Tsilimigras DI, Ntanasis-Stathopoulos I. Management, outcomes, and prognostic factors of ruptured hepatocellular carcinoma: A systematic review. J Surg Oncol.. 2018; 117(3):341-53. PubMedDOI
4. Liu CL, Fan ST, Lo CM, Tso WK, Poon RT, Lam CM. Management of spontaneous rupture of hepatocellular carcinoma: single-center experience. J Clin Oncol.. 2001; 19(17):3725-32. PubMedDOI
5. Vergara V, Muratore A, Bouzari H, Polastri R, Ferrero A, Galatola G. Spontaneous rupture of hepatocelluar carcinoma: surgical resection and long-term survival. Eur J Surg Oncol.. 2000; 26(8):770-2. PubMedDOI
6. Bassi N, Caratozzolo E, Bonariol L, Ruffolo C, Bridda A, Padoan L. Management of ruptured hepatocellular carcinoma: implications for therapy. World J Gastroenterol.. 2010; 16(10):1221-5. PubMed | DOI
7. Aoki T, Kokudo N, Matsuyama Y, Izumi N, Ichida T, Kudo M. Prognostic impact of spontaneous tumor rupture in patients with hepatocellular carcinoma: an analysis of 1160 cases from a nationwide survey. Ann Surg.. 2014; 259(3):532-42. PubMedDOI
8. Lai EC, Lau WY. Spontaneous rupture of hepatocellular carcinoma: a systematic review. Arch Surg.. 2006; 141(2):191-8. PubMedDOI
9. Monroe EJ, Kogut MJ, Ingraham CR, Kwan SW, Hippe DS, Padia SA. Outcomes of emergent embolisation of ruptured hepatocellular carcinoma in a western population. Clin Radiol.. 2015; 70(7):730-5. PubMedDOI
10. Miyamoto M, Sudo T, Kuyama T. Spontaneous rupture of hepatocellular carcinoma: a review of 172 Japanese cases. Am J Gastroenterol.. 1991; 86(1):67-71. PubMed
11. Xu HS, Yan JB. Conservative management of spontaneous ruptured hepatocellular carcinoma. Am Surg.. 1994; 60(8):629-33. PubMed
12. Cheng YT, Teng W, Lui KW, Hsieh YC, Chen WT, Huang CH. MELD score is the better predictor for 30-day mortality in patients with ruptured hepatocellular carcinoma treated by trans-arterial embolization. Am J Cancer Res.. 2021; 11(7):3726-34. PubMed |
13. Zhou C, Zu QQ, Liu XL, Wang B, Zhou CG, Shi HB. Treatment strategies and prognosis for initially unresectable ruptured hepatocellular carcinoma: a single-center experience in 94 patients. Diagn Interv Radiol.. 2020; 26(3):223-9. PubMed | DOI
14. Zou J, Li C, Chen Y, Chen R, Xue T, Xie X. Retrospective analysis of transcatheter arterial chemoembolization treatment for spontaneously ruptured hepatocellular carcinoma. Oncol Lett.. 2019; 18(6):6423-30. DOI
15. Patidar Y, Khisti R, Yadav A, Mukund A, Sarin SK. Outcome of conventional transarterial chemoembolization (cTACE) in the management of spontaneously ruptured hepatocellular carcinoma. Indian J Radiol Imaging.. 2019; 29(2):177-81. PubMed | DOI
16. Lee KH, Tse MD, Law M, Cheng AK, Wong HF, Yu ML. Development and validation of an imaging and clinical scoring system to predict early mortality in spontaneous ruptured hepatocellular carcinoma treated with transarterial embolization. Abdom Radiol (NY).. 2019; 44(3):903-11. PubMedDOI
17. Zhang W, Zhang ZW, Zhang BX, Huang ZY, Zhang WG, Liang HF. Outcomes and Prognostic Factors of Spontaneously Ruptured Hepatocellular Carcinoma. J Gastrointest Surg.. 2019; 23(9):1788-800. PubMedDOI
18. Shinmura K, Choi YH, Shimohira M, Baba Y, Ikeda S, Hayashi S. Comparison of conservative treatment versus transcatheter arterial embolisation for the treatment of spontaneously ruptured hepatocellular carcinoma. Pol J Radiol.. 2018; 83:e311-8. PubMed | DOI
19. Fan WZ, Zhang YQ, Yao W, Wang Y, Tan GS, Huang YH. Is Emergency Transcatheter Hepatic Arterial Embolization Suitable for Spontaneously Ruptured Hepatocellular Carcinoma in Child-Pugh C Cirrhosis? J Vasc Interv Radiol.. 2018; 29(3):404-12. PubMedDOI
20. Wu PZ, Zhou J, Zhang YW. Gelatin sponge microparticles for the treatment of the spontaneous rupture of hepatocellular carcinoma hemorrhage. Exp Ther Med.. 2016; 12(4):2201-7. PubMed | DOI
21. Yang H, Chen K, Wei Y, Liu F, Li H, Zhou Z. Treatment of spontaneous ruptured hepatocellular carcinoma: A single-center study. Pak J Med Sci.. 2014; 30(3):472-6. PubMed | DOI
22. Lin HM, Lei LM, Zhu J, Li GL, Min J. Risk factor analysis of perioperative mortality after ruptured bleeding in hepatocellular carcinoma. World J Gastroenterol.. 2014; 20(40):14921-6. PubMed | DOI
23. Jin YJ, Lee JW, Park SW, Lee JI, Lee DH, Kim YS. Survival outcome of patients with spontaneously ruptured hepatocellular carcinoma treated surgically or by transarterial embolization. World J Gastroenterol.. 2013; 19(28):4537-44. PubMed | DOI
24. Kim JY, Lee JS, Oh DH, Yim YH, Lee HK. Transcatheter arterial chemoembolization confers survival benefit in patients with a spontaneously ruptured hepatocellular carcinoma. Eur J Gastroenterol Hepatol.. 2012; 24(6):640-5. PubMedDOI
25. Zhang XF, Wei T, Liu XM, Lv Y. Spontaneous tumor rupture and surgical prognosis of patients with hepatocellular carcinoma. Scand J Gastroenterol.. 2012; 47(8-9):968-74. PubMedDOI
26. Shin BS, Park MH, Jeon GS. Outcome and prognostic factors of spontaneous ruptured hepatocellular carcinoma treated with transarterial embolization. Acta Radiol.. 2011; 52(3):331-5. PubMedDOI
27. Li WH, Cheuk EC, Kowk PC, Cheung MT. Survival after transarterial embolization for spontaneous ruptured hepatocellular carcinoma. J Hepatobiliary Pancreat Surg.. 2009; 16(4):508-12. PubMedDOI
28. Kirikoshi H, Saito S, Yoneda M, Fujita K, Mawatari H, Uchiyama T. Outcomes and factors influencing survival in cirrhotic cases with spontaneous rupture of hepatocellular carcinoma: a multicenter study. BMC Gastroenterol.. 2009; 9:29. PubMed | DOI
29. Kung CT, Liu BM, Ng SH, Lee TY, Cheng YF, Chen MC. Transcatheter arterial embolization in the emergency department for hemodynamic instability due to ruptured hepatocellular carcinoma: analysis of 167 cases. AJR Am J Roentgenol.. 2008; 191(6):W231-9. PubMedDOI
30. Tan FL, Tan YM, Chung AY, Cheow PC, Chow PK, Ooi LL. Factors affecting early mortality in spontaneous rupture of hepatocellular carcinoma. ANZ J Surg.. 2006; 76(6):448-52. PubMedDOI
31. Castells L, Moreiras M, Quiroga S, Alvarez-Castells A, Segarra A, Esteban R. Hemoperitoneum as a first manifestation of hepatocellular carcinoma in western patients with liver cirrhosis: effectiveness of emergency treatment with transcatheter arterial embolization. Dig Dis Sci.. 2001; 46(3):555-62. PubMedDOI
32. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med.. 2009; 6(7)PubMed | DOI
33. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health.. 1998; 52(6):377-84. PubMed | DOI
34. Barendregt JJ, Doi SA, Lee YY, Norman RE, Vos T. Meta-analysis of prevalence. J Epidemiol Community Health.. 2013; 67(11):974-8. PubMedDOI
35. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics.. 2000; 56(2):455-63. PubMedDOI
36. Li J, Huang L, Liu CF, Cao J, Yan JJ, Xu F. Risk factors and surgical outcomes for spontaneous rupture of BCLC stages A and B hepatocellular carcinoma: a case-control study. World J Gastroenterol.. 2014; 20(27):9121-7. PubMed | DOI
37. Sahu SK, Chawla YK, Dhiman RK, Singh V, Duseja A, Taneja S. Rupture of Hepatocellular Carcinoma: A Review of Literature. J Clin Exp Hepatol.. 2019; 9(2):245-56. PubMed | DOI
38. Xu X, Chen C, Liu Q, Huang X. A Meta-analysis of TAE/TACE Versus Emergency Surgery in the Treatment of Ruptured HCC. Cardiovasc Intervent Radiol.. 2020; 43(9):1263-76. PubMedDOI
39. Young S, Rostambeigi N, Golzarian J. The Common but Complicated Tool: Review of Embolic Materials for the Interventional Radiologist. Semin Intervent Radiol.. 2021; 38(5):535-41. PubMed | DOI
40. Ierardi AM, Piacentino F, Pesapane F, Carnevale A, Curti M, Fontana F. Basic embolization techniques: tips and tricks. Acta Biomed.. 2020; 91(8-S):71-80. PubMed | DOI
41. Hu X, Chen R, Wei Q, Xu X. The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We? Int J Biol Sci.. 2022; 18(2):536-51. PubMed | DOI
42. Renzulli M, Brandi N, Argalia G, Brocchi S, Farolfi A, Fanti S. Morphological, dynamic and functional characteristics of liver pseudolesions and benign lesions. Radiol Med.. 2022; 127(2):129-44. PubMedDOI
43. Zhu Q, Li J, Yan JJ, Huang L, Wu MC, Yan YQ. Predictors and clinical outcomes for spontaneous rupture of hepatocellular carcinoma. World J Gastroenterol.. 2012; 18(48):7302-7. PubMed | DOI
44. Ebeling Barbier C, Heindryckx F, Lennernas H. Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma. Int J Mol Sci.. 2021; 22(23):13051. PubMed | DOI
45. Tahmasebi Birgani M, Carloni V. Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int J Mol Sci.. 2017; 18(2):405. PubMed | DOI
46. Kim MY, Baik SK, Lee SS. Hemodynamic alterations in cirrhosis and portal hypertension. Korean J Hepatol.. 2010; 16(4):347-52. PubMed | DOI
47. Yoshiji H, Nagoshi S, Akahane T, Asaoka Y, Ueno Y, Ogawa K. Evidence-based clinical practice guidelines for Liver Cirrhosis 2020. J Gastroenterol.. 2021; 56(7):593-619. PubMed | DOI
48. Makary MS, Khandpur U, Cloyd JM, Mumtaz K, Dowell JD. Locoregional Therapy Approaches for Hepatocellular Carcinoma: Recent Advances and Management Strategies. Cancers (Basel).. 2020; 12(7):1914. PubMed | DOI
49. Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev.. 2011; 37(3):212-20. PubMedDOI