Fulminant Hepatic Failure Secondary to Primary Hepatic Angiosarcoma

Background. Hepatic angiosarcoma is a rare and aggressive tumor that often presents at an advanced stage with nonspecific symptoms. Objective. To report a case of primary hepatic angiosarcoma in an otherwise healthy man with normal liver function tests two months prior to presenting with a short period of jaundice that progressed to fulminant hepatic failure. Methods. Case report and review of literature. Conclusion. This case illustrates the rapidity of progression to death after the onset of symptoms in a patient with hepatic angiosarcoma. Research on early diagnostic strategies and newer therapies are needed to improve prognosis in this rare and poorly understood malignancy with limited treatment options.


Case Report
A 75-year-old man presented to our hospital with threeweek history of anorexia, abdominal fullness, chills, and three-day history of jaundice. He was diagnosed with AV nodal reentry tachycardia (AVNRT) six months earlier which terminated with the Valsalva maneuver. His medication included Diltiazem and Aspirin. He had no further episodes of AVNRT and liver enzymes were normal at routine followup in the cardiology clinic two months before presentation. On admission he was afebrile and reported no abdominal pain, hematemesis, melena, or pale stools. Physical examination revealed a frail looking man with skin and scleral icterus, normal heart sounds, and blood pressure. Abdominal examination revealed epigastric tenderness without organomegaly or ascites. Laboratory tests were significant for total bilirubin 9 mg/dL, albumin 4.0 g/dL, alkaline phosphatase 383 U/L, gamma-glutamyl transferase 701 U/L, aspartate aminotransferase, 104 U/L, alanine aminotransferase 206 U/L, and lactate dehydrogenase 451 U/L. Carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) levels were normal and CA19-9 was 38.8 IU/mL. Human immunodeficiency virus (HIV) and hepatitis panel were negative. Chest X-ray was normal and ECG showed sinus tachycardia. Abdominal ultrasound scan was negative for cholelithiasis and cholecystitis. Contrast enhanced triple-phase computerized tomography scan of his abdomen showed a hepatic mass measuring 13 × 11 × 10 cm with small dilated bile ducts surrounding the mass (Figure 1). There was no common bile duct (CBD) dilatation. Liver abscess, metastases, atypical hepatocellular carcinoma (HCC), and hepatic cystadenocarcinoma were considered in the differential diagnosis. He developed a fever on the second day of hospitalization and was started on piperacillin-tazobactam. Pan cultures were negative and he continued to spike fevers despite intravenous antibiotics. Eventually, his fever subsided and he underwent CT guided percutaneous biopsy of the hepatic mass. He was discharged home uneventfully 4 days later. Histopathology confirmed high grade primary angiosarcoma of the liver (Figures 2(a) and 2(b)). He was seen in clinic 2 weeks later at his posthospital follow-up appointment to discuss the biopsy result and management options. Unfortunately, he was admitted to another hospital within 1 month of discharge and died of fulminant hepatic failure.

Epidemiology.
Hepatic angiosarcoma (HAS) is a very rare and aggressive tumor that accounts for about 1.8-2% of all primary liver cancers. Epidemiologically, it is associated with exposure to polyvinyl chloride (PVC), thorium dioxide (thorothrast), arsenic, and inorganic copper [1,2]. Hepatic angiosarcoma has also been associated with anabolic steroids, hemochromatosis, and neurofibromatosis (NF-1) [3,4]. Based on studies from national registries of the United States and United Kingdom, the time period from risk factor exposure to development of disease is about 25-35 years, with peak incidence in the 6th and 7th decade of life [1,2]. Hepatic angiosarcoma affects more males than females (3 : 1) and most cases are associated with occupational exposure or iatrogenic exposure to thorothrast during radiological investigations [1,2]. There appears to be a younger age of onset and higher incidence of hepatic angiosarcoma in Asia, particularly based on reports from China, Korea, and Japan [5][6][7]. However, these reports are mainly hospital based and should be interpreted with caution. Median survival is about 6 months with treatment and at best 16 months [5]. There are recent reports of longer survival following hepatic resection of single tumors detected at a relatively early stage when hepatic resection is feasible [8]. We report an illustrative case of primary angiosarcoma of the liver in an otherwise healthy man who presented with a short onset of jaundice that progressed to fulminant hepatic failure. Our patient had none of the risk factors associated with hepatic angiosarcoma and his liver enzymes were normal two months prior to presentation providing no clue to suspect underlying liver pathology (Table 1).

Clinical Presentation and Diagnosis.
The presenting symptoms of hepatic angiosarcoma are nonspecific and may be confused with any other hepatobiliary disorder [9]. The most commonly reported symptoms include abdominal pain,    malaise, jaundice, ascites, and massive hepatomegaly [9]. In view of the long latency between exposure and development of the tumor the full extent of occurrence and symptoms may not be known for about thirty-five years [1]. Progression of disease is often fast and fatal with death occurring within a few weeks from intra-abdominal bleeding, hepatic coma, fulminant hepatic failure, or sepsis [9,10]. Diagnosis is challenging because most patients such as the patient described in this report do not have any identifiable risk factors [9,10]. Second, radiological investigations may reveal an inconclusive multifocal or focal hepatic mass that has broad differential diagnoses such as liver abscess, hepatocellular cancer (HCC), metastases, primary hepatic lymphoma, hepatic cystadenocarcinoma, hemangioblastoma and hepatic epithelioid hemangioendothelioma (HEHE) ( Table 2). Third, patients present at an advanced stage with such severe illness that diagnoses is made at autopsy. Necropsy studies have showed considerable, often massive, replacement of liver tissue by unifocal or multifocal tumor with necrosis and hemorrhage [1]. In patients with reasonable performance status, liver biopsy is often required to make the diagnosis. There are two main approaches to liver biopsy; percutaneous and transjugular. There is some controversy regarding what the best approach is. Ultrasound guided percutaneous biopsy has been associated with a few reports of fatal intra-abdominal bleeding [11,12]. The transjugular approach has been reported to be safer and associated with less complications from intra-abdominal bleeding. However, percutaneous biopsy has been shown to be faster, safe, and effective in establishing the diagnosis of hepatic angiosarcoma [13]. The classic pathologic findings on microscopic analysis are proliferation of single or multilayered tumor cells along liver sinusoids, atrophy of liver cell cords, and a solid tumor nest composed of spindle shaped and polyhedral cells without significant vascular spaces. Immunohistochemical staining with factor VIII-related antigen, CD31, and CD34 provides additional evidence in support of the diagnosis [9,10]. The differentials in the histopathologic diagnosis of hepatic angiosarcoma include epithelioid hemangioendothelioma, hepatocellular carcinoma (hemorrhagic), Kaposi sarcoma (in HIV-positive cases), undifferentiated sarcoma (most common in children), and peliosis hepatis in cases of anabolic steroid use and bacillary angiomatosis, among other causes. The macroscopic (gross), microscopic (histological), and immunohistochemical features of these entities in the differential are discussed in Table 3 [14,15].

Hepatic Angiosarcoma and Liver
Failure. Fulminant liver failure (FHF) due to HAS is very rare and the mechanism of liver failure is multifactorial. There have been six cases of FHF secondary to HAS reported in the literature to date and the available evidence suggests that a combination of hepatic ischemia leading to parenchymal infarction, vascular occlusion of portal vein flow by tumor, thrombi, and nonocclusive infarction of the liver due to shock from secondary causes such as sepsis or cardiac dysfunction may play a role [16][17][18][19]. Disseminated intravascular coagulation (DIC) is rare in HAS, occurring in less than 5% of cases [20,21]. (1) Gattuso et al. [14].
A rare association with Kasabach-Merritt syndrome was reported in one case [22]. Mortality in the reported cases was secondary to consumptive coagulopathy and massive intra-abdominal bleeding [20][21][22]. Other mechanisms of FHF secondary primary or metastatic liver cancer include (1) localized submassive liver cell necrosis resulting from sudden reduction in portal perfusion which has been inadequate because of tumor thrombosis, combined with hypotension of hepatic arteries and (2) malignant infiltration and replacement of hepatocytes by tumor leading to secondary necrosis of hepatocytes and development of liver failure [23][24][25]. In our opinion, malignant infiltration and secondary necrosis was the most likely mechanism leading to the development of liver failure in our patient.

Management.
Treatment of the tumor to date is empirical [26]. Radical surgery with adjuvant chemotherapy appears to be the most promising treatment with the possibility of cure if the tumor is solitary and is diagnosed early with reported median survival of about 17 months [5,26,27]. There are few case reports describing extended survival beyond one year following surgical resection [8,17,28]. However, no standardized surgical procedure has been established, and it should be noted that the average age of patients operated in the only major series was 55.5 years [8]. The current management approach to primary liver cancer is the determination of eligibility for liver transplant. Liver transplantation (LT) has showed survival benefit in the management of other primary liver cancers such as HCC and HEHE [29]. However, LT has not shown a survival benefit in HAS when compared with surgical resection in reported studies [8,19,28,30,31]. The dismal survival reported after liver transplantation for HAS (mean 7.2 ± 2.6 months) with no patient surviving after 23 months is attributed to early recurrence after transplantation (mean 5.0 ± 2.6 months) and poor performance status of patients with HAS [31]. Transarterial chemoembolization (TACE) has been used as palliative therapy to control intra-abdominal bleeding in patients with hepatic angiosarcoma [32]. Two small case series comprised of a total of 9 patients with HAS treated with different chemotherapy regimens have shown limited efficacy in treating hepatic angiosarcoma; survival from time of diagnosis ranged from <3 months to >53 months [10,33,34]. Targeted therapies such as bevacizumab and sorafenib have been shown to have limited efficacy in treating primary angiosarcoma of other organs; however only one case of HAS was included in these studies [35,36]. There are currently very limited studies investigating new therapies or early diagnostic strategies [26]. However, prevention of occupational or iatrogenic exposure to established risk factors such as PVC is effective in reducing the incidence of HAS [37,38]. This was demonstrated following an outbreak of four cases of HAS at a PVC factory in the United States between 1967 and 1973; an industry-wide law to reduce average exposure to vinyl chloride was key to reducing exposure to PVC and new cases of HAS among PVC factory workers [38]. Such policy decisions with appropriate enforcement by law are a potential strategy for reducing exposure to established risk factors in countries without such legislation and rapid industrialization. Research on early diagnostic strategies and newer therapies are needed to improve prognosis. However, the rarity of this disease inhibits progress.