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Hepatology Research 2016; 46: 13–21

doi: 10.1111/hepr.12498

Review Article

Spontaneous ruptured hepatocellular carcinoma Hiroshi Yoshida,1 Yasuhiro Mamada,2 Nobuhiko Taniai2 and Eiji Uchida2 1

Department of Surgery, Nippon Medical School Tama Nagayama Hospital, and 2Department of Surgery, Nippon Medical School, Tokyo, Japan

The incidence of hepatocellular carcinoma (HCC) is rising worldwide. Spontaneous rupture of HCC occasionally occurs, and ruptured HCC with intraperitoneal hemorrhage is potentially lifethreatening. The most common symptom of ruptured HCC is acute abdominal pain. The tumor size in ruptured HCC is significantly greater than that in non-ruptured HCC, and HCC protrudes beyond the original liver margin. In the acute phase, hemostasis is the primary concern and tumor treatment is secondary. Transcatheter arterial embolization (TAE) can effectively induce hemostasis. The hemostatic success rate of TAE ranges 53–100%. A one-stage surgical operation is a treatment modality for selected patients. Conservative treatment is usually given to patients in a

moribund state with inoperable tumors and thus has poor outcomes. Patients with severe ruptures of advanced HCC and poor liver function have high mortality rates. Liver failure occurs in 12–42% of patients during the acute phase. In the stable phase, tumor treatment, such as transarterial chemoembolization or hepatic resection should be concerned. The combination of acute hemorrhage and cancer in patients with ruptured HCC requires a two-step therapeutic approach. TAE followed by elective hepatectomy is considered an effective strategy for patients with ruptured HCC.

INTRODUCTION

(AJCC/UICC), which is based on tumor extension and used worldwide. The General Rules for the Clinical and Pathological Study of Primary Liver Cancer, compiled by the Liver Cancer Study Group of Japan (LCSGJ), base their classifications on TNM staging. Both the TNM staging system of the 7th edition of the UICC and the 5th edition of the LCSGJ rules classify ruptured HCC as T4, the most advanced stage, even if the tumor is small, solitary, and with no vascular or bile duct invasion.8,9

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EPATOCELLULAR CARCINOMA (HCC) is one of the most common types of cancer in the world, with more than 500 000 cases newly diagnosed annually.1 The incidence of HCC is rising worldwide because of the increasing prevalence of hepatitis C virus infections.2,3 More than 80% of HCC develop in cirrhotic livers.1,4–6 Spontaneous rupture of HCC occasionally occurs, and ruptured HCC with intraperitoneal hemorrhage is potentially lifethreatening.7 Various methods for managing ruptured HCC have been proposed. The outcomes of ruptured HCC are poor. Mortality rates remain high, but are gradually decreasing. This article reviews the current status of spontaneous ruptured HCC.

Tumor–node–metastasis (TNM) classification Hepatocellular carcinoma is usually staged according to the TNM classification system of the American Joint Committee on Cancer/Union for International Cancer Control

Correspondence: Xx Dr Hiroshi Yoshida, Department of Surgery, Nippon Medical School Tama Nagayama Hospital, 1-7-1 Nagayama, Tama City, Tokyo 206-8512, Japan. Email: [email protected] Received 25 November 2014; revision 23 January 2015; accepted 26 January 2015.

© 2015 The Japan Society of Hepatology

Key words: hepatectomy, hepatocellular carcinoma, rupture

Incidence There are distinct geographic variations in the reported incidences of spontaneous ruptured HCC. Ruptured HCC occurs in less than 26% of patients with HCC.7,10–31 In the West, the incidence of HCC is increasing, but ruptured HCC is relatively uncommon, with an incidence of less than 3%.18,19,21,24 In Asia, however, the incidence is considerably higher, ranging 2.3–26%.7,10–17,19,20,23,32 Approximately 10% of patients with HCC die of rupture in Asia per year.17 Owing to the earlier detection of HCC, the incidence of ruptured HCC is decreasing.

Mechanism and tumor characteristics The mechanism of spontaneous ruptured HCC has not been fully elucidated. Some investigators believe that

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disruption of a friable feeding artery or development of a tear in the surface of a tumor subjected to high pressure can cause rupture. Rapid growth of the tumor and necrosis are associated with increased intratumoral pressure caused by progressive or sudden occlusion of branches of hepatic veins due to tumor invasion. This in turn causes venous congestion within the tumor in conjunction with factors such as central tumor necrosis and coagulopathy. Vascular dysfunction caused by the degeneration of elastin and the degradation of type IV collagen can render blood vessels stiff and weak. These factors can subsequently lead to bleeding and rupture.10–13,19,27,33–40 Several studies have reported that tumor size is significantly greater in spontaneously ruptured HCC than in non-ruptured HCC.7,31 When HCC protrudes beyond the original liver margin, the risk of rupture may be higher than that associated with tumors surrounded by normal liver parenchyma.7,10,36,41 Chen et al.7 reported that HCC in the left lobe may be more prone to rupture than that in the right lobe. This is probably because the anatomical span of the left hepatic lobe is less than that of the right lobe, and HCC in the left lobe may protrude outward more easily than HCC in the right lobe.7 Chearanai et al.13 reported that bleeding from a laceration in a superficially located tumor secondary to minimal trauma, triggered by an external event or normal respiratory movement, can cause rupture, especially when the tumor is situated under the right diaphragm. Bruls et al.42 reported a case of ruptured HCC occurring after transarterial chemoembolization (TACE). Necrotic tumor rupture is a serious complication of TACE. Rombola et al.43 described a case of ruptured HCC in a patient who was receiving sorafenib. Sorafenib is a multikinase inhibitor of the vascular endothelial growth factor pathway and was recently introduced for the management of advanced HCC. Sorafenib may increase the risk of bleeding and ruptured HCC in susceptible individuals.

Clinical presentation/diagnosis The most common symptom of ruptured HCC is acute abdominal pain (66–100%).11,16,17,23,44 Shock is present in 33–90% of patients.11,16,17,23,44,45 The rate of clinical diagnosis of ruptured HCC has gradually improved owing to the development of imaging modalities such as ultrasonography (US) and computed tomography (CT); in previous studies, 75% of the diagnoses were confirmed by CT, US or both.20,30,36,41,46–52 However, some cases are still initially diagnosed on emergency exploratory laparotomy.18,20 Abdominal paracentesis is a reliable means of confirming the diagnosis.11,13,35,46,53

© 2015 The Japan Society of Hepatology

Computed tomography is a useful technique for detecting HCC, defining the numbers, sizes and locations of tumors, determining the presence or absence of tumor bleeding, and serially following up changes in hematoma density. Hemoperitoneum and surrounding hematoma are most evident on non-enhanced CT.54 Moreover, highest-attenuation hematomas are usually closest to sources of bleeding on CT scans, whereas lowerattenuation unclotted blood tends to be located further from bleeding sites.55 HCC size and the degree of extrahepatic protrusion have been associated with subsequent rupture.7,10,31,36,41 HCC protruding beyond the original liver margin and discontinuity or disruption of the hepatic surface neighboring or contacting a HCC are primary CT findings in ruptured HCC.41 However, the site of active bleeding can seldom be demonstrated. Hepatic angiography demonstrates extravasation of contrast material from tumors in 13.2–35.7% of patients with a ruptured HCC.22,48,53,56 Active arterial extravasation of contrast material in HCC can be differentiated from clotted blood because the CT attenuation values of extravasated contrast materials indicate the presence of intravenous contrast material in blood and are thus significantly higher than those of clotted blood.57

MANAGEMENT

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HERE ARE VARIOUS treatments for ruptured HCC. A lower initial hemoglobin level and a higher demand for blood transfusion may indicate more severe hemorrhage resulting from tumor rupture.17,20,48,56,58,59 In the management of ruptured HCC, hemostasis is the primary concern and tumor treatment is secondary. Because patients with ruptured HCC may have pre-existing coagulopathy and liver dysfunction, careful evaluations of liver function, coagulopathy, and tumor size and location are imperative. Patients with stable hemodynamics should be systematically evaluated to determine factors such as the extent of tumor and preserved liver function while conservative management is being initiated.46

Transcatheter arterial embolization (TAE) Acute (unstable) phase The effectiveness of TAE has been demonstrated in previous studies since the mid-1980s,35,53,60 and it has become a widely used treatment option. After diagnosis of ruptured HCC on US, CT or both, emergency TAE can effectively induce hemostasis in hemodynamically unstable patients. Owing to the unstable status of patients, no sedation should be used, and hepatic angiography is performed

Hepatology Research 2016; 46: 13–21

via a femoral arterial approach with local anesthesia. The catheter is inserted super-selectively into the hepatic subsegmental artery supplying the target tumor, as close as possible to the tumor. Super-selective catheterization of the relevant hepatic artery reduces the risk of liver failure after embolization. Administration of the embolization material is terminated when the tumor vessels are filled and tumor staining disappears on imaging. Various agents can be used for embolization, including sterile absorbable gelatin sponges (Gelfoam [Pfizer, New York, NY, USA], Gelpart [Nippon Kayaku, Tokyo, Japan]), stainless steel coils and polyvinyl alcohol sponges (Ivalon [Fabco, New London, CT, USA]). Stainless steel coils and Ivalon particles can produce permanent occlusion of the hepatic artery, while gelatin sponges induce only temporary occlusion. Iodized oil (Lipiodol Ultra-Fluid; Guerbet, Aulnaysous-Bois, France) is occasionally mixed with gelatin sponges. The injection is discontinued when the suspension has fully accumulated in the tumor vessels.61 The rate of bleeding must generally exceed 1 mL/min before bleeding can be detected on angiography, and extravasation of contrast medium occurs in less than 20% of cases.49 In patients without angiographically detectable extravasation of active contrast media, the site for TAE can be based on CT localization of the ruptured HCC as indicated by the presence of contrast leakage or hyperdense hematoma adjacent to the ruptured tumor. The success rate of TAE for hemostasis ranges 53–100%, but recurrent bleeding and liver failure can occur, with an in-hospita mortality rate of 0–55.5%.16,18,20,25–30,34,35,46–48,50,56,59,62–71 The mortality rate remains high among patients with portal vein tumor thrombosis (PVTT), a high serum creatinine level, acute respiratory failure, impaired neurological status and a high serum total bilirubin level. Portal vein tumor thrombosis is occasionally detected in patients with advanced HCC. Whether PVTT and the attendant risk of hepatic insufficiency affect the survival of patients with ruptured HCC managed by TAE remains controversial.48,56 TAE is generally contraindicated in patients with complete occlusion due to main PVTT because of the high risk of hepatic infarction, but super-selective TAE may prevent the development of huge hepatic infarcts. TAE of HCC associated with PVTT may still be a safe technique in patients with collateral circulation and adequate hepatic reserve.33,50,72 The total serum bilirubin level is an indicator of liver function at the time of rupture.20,50,58,59,65 Some studies have shown that TAE rarely prolongs survival in patients with a serum bilirubin level higher than 2.92 mg/dL (50 μmol/L).48,50,56,59,73

Ruptured HCC

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The most common complication of TAE is postembolization syndrome (26–85%), associated with fever, abdominal pain, nausea and liver enzyme elevation.30,50 The syndrome usually resolves within 1–2 weeks. However, in patients with severe liver dysfunction, liver failure occasionally develops after TAE. Stable phase In the stable phase, TACE is performed to treat inoperable HCC. TACE is most frequently performed using iodized oil (Lipiodol Ultra-Fluid) as a vehicle to locally deliver anticancer drugs to tumors.

Surgical procedures Hepatic resection Acute (unstable) phase: Emergency (one-stage) hepatic resection. Hepatic resection is one of the best treatment options for ruptured HCC, but is technically difficult to perform in patients with unstable hemodynamic status or severe cirrhosis. The Pringle maneuver74 is useful for reducing blood loss during hepatic resection. Xia et al.75 reported that the addition of continuous occlusion of the proper hepatic artery to the intermittent Pringle maneuver74 significantly reduces intraoperative blood loss in emergency partial hepatectomy as compared with the intermittent Pringle maneuver alone. Emergency hepatic resection has an in-hospital mortality rate of 16.5–100%.15,16,22,64 In hemorrhagic shock, preserved liver function and the tumor stage cannot be evaluated in detail. Furthermore, in patients with poor liver function, hemorrhage is associated with coagulopathy. Recently, laparoscopic hepatic resection has been used to treat liver tumors,76,77 including ruptured HCC.78 Laparoscopic hepatic resection is a minimally invasive treatment, but is difficult to perform in the presence of massive hemorrhage. Several studies have suggested that one-stage surgery is a treatment option for selected patients with peripheral lesions who are stable hemodynamically and have adequate liver function (Child–Pugh A or B).66,67,70,79 Stable phase: Staged hepatic resection. In the stable phase, preserved liver function and tumor stage can be evaluated in detail. Many reports have described patients who underwent hepatic resection for the treatment of ruptured HCC.17,20,25,33,44,64,66,68,80–83 TAE followed by elective hepatectomy is considered an effective strategy for patients with ruptured HCC. Lin et al.84 performed peritoneal lavage with distilled water after hepatic resection in patients with ruptured

© 2015 The Japan Society of Hepatology

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HCC. The rate of tumor recurrence was lower in the peritoneal lavage group. Peritoneal lavage resulted in significantly better disease-free survival and overall survival in patients with ruptured HCC. Perihepatic packing, suture plication or both. In hemodynamically unstable patients with ruptured HCC, perihepatic packing, suture plication or both are useful procedures for achieving hemostasis by tamponade. However, laparotomy is invasive for patients who are in an unstable condition. The rate of intra-abdominal abscess and sepsis within 72 h of packing ranges 23–32%,85,86 but pack removal also carries the risk of rebleeding.11,86 Miyamoto et al.17 described 30 patients who underwent packing, suture plication or both. The 3-month survival rate was 26.9%, with a mean survival of 81.5 days. In patients who are in hemodynamically unstable condition, perihepatic packing, suture plication or both should be performed if TAE is ineffective or contraindicated. Hepatic artery ligation. Hepatic artery ligation reduces blood flow to the tumor to achieve hemostasis. Selective hepatic artery ligation is preferable to common hepatic artery ligation because it has a lower risk of postoperative liver failure. Hepatic artery ligation achieves a relatively high rate of hemostasis (68.1–100%), but has a high in-hospital mortality rate (67–76.6%).10,11,13,15,16 Perihepatic packing, suture plication or both are sometimes performed simultaneously to achieve hemostasis. However, laparotomy is invasive in patients with intraabdominal bleeding, and the effect is only temporary.87 In patients who are in a hemodynamically unstable condition, hepatic artery ligation should also be performed if TAE is ineffective or contraindicated.

Radiofrequency ablation (RFA) Recently, RFA has been used to manage small, nonruptured HCC. RFA is a minimally invasive treatment and can be performed percutaneously, laparoscopically or during open surgery in patients who are in poor general condition or who have liver dysfunction.88 Because ruptured HCC protrudes beyond the original liver margin, however, it is difficult to treat by percutaneous RFA. Only a few reports have described the treatment of ruptured HCC by RFA.89–92 Sun et al.92 repeatedly performed RFA as both salvage therapy and curative treatment for spontaneous rupture of a giant medial lobe HCC. Manikam et al.91 reported two cases of ruptured HCC in which percutaneous RFA successfully achieved hemostasis. RFA is one treatment that can be used to achieve hemostasis, especially percutaneously.

© 2015 The Japan Society of Hepatology

Others Other alternative treatments have been described in small studies or case reports, including the use of RFA,89–92 alcohol injection,93 or new chemicals such as isoamyl 2-cyanoacrylate (CA)94 and OK-432,95 with some success. Conservative treatment Conservative treatment can be justified for patients who are in a hemodynamically stable condition.20,23,25,44 However, conservative therapy is most commonly performed in patients in a moribund condition who have inoperable tumors.10,15,28,96 Poor results were thus obtained in some studies.13,17,53,71 Leung et al.44 reported the outcomes of 112 patients with ruptured HCC treated by a conservative approach, followed by an aggressive approach in selected patients. All patients initially received conservative treatment. For the aggressive approach, a hemostatic procedure was performed unless the patient’s condition was moribund. The differences between the aggressive and the conservative approaches in the overall in-hospital mortality rate (62% vs 51%) and the median survival time (7 vs 12 days) were not significant. They concluded that the conservative approach gave similar results to the aggressive approach.

SURVIVAL Short-term survival

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UPTURED HCC IS associated with a high in-hospital mortality rate ranging 25–100%.7,10–20,22,23,25,28,44,47,58,64 Liver failure occurs in 12–42% of patients during the acute phase.17,20,22,23,35,48,50,56,59,65 In a published work review of 15 studies including 835 patients with ruptured HCC, the average 30-day mortality rates among patients who received conservative treatment, emergency hepatic resection and TAE were 71%, 50% and 48%, respectively.58 Factors influencing short-term survival Various factors have been linked to short-term mortality, such as the presence of cirrhosis,69,70 the presence of hepatic encephalopathy,73 a high Child–Pugh score,69–71,73,97 a high serum bilirubin level,20,63,71,73 a high serum aspartate aminotransferase level,69,73 a high serum alkaline phosphatase level,69 a prolonged prothrombin time,63 an increased indocyanine green retention rate at 15 min,69 a low serum albumin level (all of which are associated with poor liver function),63,71,73 a high serum α-fetoprotein level,69 the severity of hemorrhage from the rupture (shock and hemoglobin level on admission),1,15,20,23,63,69–71,73 a high creatinine level,71 a higher

Hepatology Research 2016; 46: 13–21 incidence of acute respiratory failure,71 worse neurological status,71 the presence of PVTT,71 a large maximum tumor size73 and unsuccessful TAE (best supportive care only).63,73 Patients with severe ruptures of advanced HCC and poor liver function had high mortality rates.

Long-term survival Overall survival is poorer in patients with ruptured HCC than in those with non-ruptured HCC. Aoki et al.31 analyzed 1160 ruptured HCC in Japan and reported that the 1-, 3- and 5-year overall survival rates were 41.4%, 21.1% and 13.3%, respectively. In ruptured HCC treated by hepatic resection, the 1-, 3- and 5-year overall survival rates were 76.0%, 48.6% and 33.9%, respectively. We previously reported that the 1-, 3- and 5-year overall survival rates were respectively 90.0%, 67.5% and 67.5%, in patients who underwent staged hepatectomy for ruptured HCC.98 As compared with one-stage emergency hepatic resection, staged hepatic resection has a much lower in-hospital mortality rate (0–9%) and higher survival rates: 1-year survival rate, 54.2–100%; 3-year survival rate, 21.2–67.5%; and 5-year survival rate, 15–67.5%.18,20,22,25,28,31,64,66–68,80–83,98

Factors influencing long-term survival Battula et al.70 reported that the multifocal nature of the tumor (33.3%) and large tumor size (mean, 11.3 cm) can help explain the risk of decompensation and poor outcomes. A multivariate analysis performed by Kirikoshi et al.73 indicated that tumor size was the only independent factor influencing long-term survival among patients in whom initial TAE was successfully performed.

Ruptured versus non-ruptured HCC (staging of ruptured HCC) Aoki et al.31 compared ruptured and non-ruptured HCC and reported that the following variables were independently related to spontaneous tumor rupture in a multivariate logistic regression analysis: maximum tumor diameter (odds ratio [OR], ≥16.34 [>5 vs ≤2 cm]; 4.66 [2–5 vs ≤2 cm]; 3.50 [>5 vs 2–5 cm]), Child–Pugh grade (OR, 2.57),99 plasma des-γ-carboxyprothrombin value (OR, 1.66), platelet count (OR, 0.71), age (OR, 0.71 [≥60 vs

Spontaneous ruptured hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) is rising worldwide. Spontaneous rupture of HCC occasionally occurs, and ruptured HCC with intraperito...
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