Primary hepatic angiosarcoma (PHAS) is a rare and highly aggressive vascular or lymphatic origin tumor. It accounts for less than 2% of soft tissue sarcomas in humans. Most cases are elderly adult patients. Its diagnosis is very difficult, especially if patients have no risk of exposure to carcinogens such as arsenic and vinyl chloride. Liver transplantation (LT) for patients with PHAS remains controversial because of a poor survival rate with almost all PHAS recurring within the first six months after LT [1]. These tumors originate from hepatic endothelium and aggressively fill hepatic sinusoids, leading to hepatic atrophy [2,3]. We herein present the clinical sequence of two patients with PHAS who underwent deceased donor LT (DDLT) due to hepatic failure from cryptogenic liver cirrhosis. This study was approved by the Institutional Review Board (IRB) of Asan Medical Center (IRB No. 2022-2570).

Case1

The patient was a 61-year-old male who had been previously healthy. One year before, the patient complained of dyspepsia and abdominal distension. He was diagnosed with cryptogenic liver cirrhosis. His liver biopsy showed findings suggestive of venous outflow obstruction such as Budd-Chiari syndrome. One year later, hypervascular multiple nodular lesions were identified in both hepatic lobes on routine computed tomography (CT) checkup (Fig. 1A). These lesions were presumed to be multiple hepatocellular carcinomas (HCCs) without liver biopsy. To treat these lesions, transarterial chemoembolization (TACE) was performed (Fig. 1B). Soon after the TACE, his general condition deteriorated with the development of hepatic encephalopathy due to progressive hepatic failure (Fig. 1C, D).

Figure 1. Pretransplant imaging findings of the Case 1. (A) Multiple hypervascular tumors were identified on liver magnetic resonance imaging. (B) Transarterial chemoembolization (TACE) was performed, in which multiple nodular tumor staining in both lobes was visualized. (C, D) Liver computed tomography showed increased hepatic volume compared with pre-TACE status, showing multiple hepatic nodules with heterogeneous parenchymal density.

The patient was transferred to our institution for LT. At the time of admission, he had prolonged prothrombin time (international normalized ratio [INR]: 8.45) and elevated total bilirubin level (29 mg/dL). In addition, metabolic acidosis progressed with very poor urine output. Thus, continuous renal replacement therapy was applied. His model for end-stage liver disease (MELD) score was 40. Serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II) levels were 1.2 ng/mL and 44 mAU/mL, respectively. Hepatomegaly was identified on CT scan. However, viable tumors were not clearly identified. Considering overt hepatic failure with low expression of HCC tumor markers, we decided to enroll him for DDLT. The patient underwent DDLT after waiting for two days. He received a whole liver graft and recovered uneventfully. He was discharged from hospital at 45 days after LT (Fig. 2A, B).

Figure 2. Gross photograph of the explant liver of the Case 1. The specimen showed diffusely enlarged liver replacing with hemorrhagic nodules, up to 2.5 cm in greatest dimension. There were five totally necrotic nodules (1 and 2). These findings were suggestive of Budd–Chiari syndrome associated with angiosarcoma involving entire liver.

The pathology report of the explant liver showed that the liver was similar to that of Budd-Chiari syndrome and that all five nodules were completely necrotic (Fig. 3). At three months after the LT, the patient was readmitted due to left-side clonic seizure. Brain magnetic resonance imaging (MRI) showed mild swelling in both temporo-occipital areas. Considering his clinical features, posterior reversible encephalopathy syndrome was diagnosed. Multifocal osteolytic lesions were identified in the scanned range of the skull. CT scan showed multiple bone metastasis. However, at that time, there was no significant elevation of serum AFP (3.5 ng/mL) or PIVKA-II level (45 mAU/mL). We suspected of metastasis from a malignancy other than HCC. A CT-guided core needle biopsy was performed on the 10th thoracic vertebra, in which biopsy finding was compatible with angiosarcoma. Meanwhile, follow-up CT scans showed gradual increase in focal low-density lesions of the graft liver (Fig. 2C). Positron emission tomography-CT showed multiple bone metastasis from recurrent angiosarcoma (Fig. 2D). The pathology of the explanted liver was retrospectively reviewed and immunohistochemical staining status was positive for cluster of differentiation (CD)31 and erythroblast transformation-specific-related gene (ERG).

Figure 3. Posttransplant imaging findings of the Case 1. (A, B) Computed tomography (CT) taken two months after transplantation showed no abnormal finding. (C) CT taken at three months showed multiple nodular lesions in the liver graft. (D) Positron emission tomography-CT showed multiple bone metastasis from recurrent angiosarcoma.

Considering the poor general condition of the patient and rapid tumor progression, no specific chemotherapy was provided. The patient passed away at 5 months after LT due to tumor progression.

Case 2

The patient was a 74-year-old male. At 4 months before, ascites was found and he was diagnosed with cryptogenic liver cirrhosis. His liver function deteriorated with a decrease in urine output. He was diagnosed with hepatorenal syndrome and hemodialysis was performed. Liver CT scan and MRI showed numerous small nodules. Thus, tiny multiple HCCs were suspected (Fig. 4). Because the tumor size was very small, it was difficult to accurately evaluate them with CT or MRI. His serum AFP and PIVKA-II levels were 2.1 ng/mL and 427 mAU/mL, respectively. His MELD score was 40. Thus, he underwent DDLT using a whole liver graft after waiting for 4 days (Fig. 5A, B).

Figure 4. Pretransplant imaging findings of the Case 2. (A, B) Computed tomography showed heterogeneous enhancement with multiple nodular lesions in the whole liver. (C, D) Liver magnetic resonance imaging showed multiple small nodules replacing the cirrhotic liver.

Figure 5. Posttransplant imaging findings of the Case 2. (A, B) Computed tomography (CT) taken two months after transplantation showed no abnormal finding. (C, D) CT taken at six months showed heterogeneous enhancement of the liver graft at the arterial and portal phases.

Final pathology result of the explanted liver showed Budd–Chiari syndrome with low-grade angiosarcoma involving the whole liver (Fig. 6). Immunohistochemical staining was positive for CD31, CD34, and ERG. No recurrence was identified on positron emission tomography-CT scan taken two months after LT. Because of his old age and poor general condition, he was hospitalized for 3 months with tracheostomy and swallowing rehabilitation.

Figure 6. Gross photograph of explant liver of the Case 2. The whole liver was replaced with micronodules up to 0.1 cm in greatest dimension. There was no definite mass-like lesion. Multiple localized and diffuse sinusoidal spreading atypical endothelial cells proliferation was identified. These findings were suggestive of Budd–Chiari syndrome associated with low-grade angiosarcoma involving the entire liver.

At 6 months after the LT, he was admitted due to elevated liver enzyme levels. Dynamic CT scan showed heterogeneous enhancement of the liver graft (Fig. 5C, D). Transjugular liver biopsy finding was compatible with angiosarcoma recurrence at the liver graft. We presumed that the cause of jaundice was extensive infiltration by tumors. Considering the poor general condition and old age of the patient, no specific chemotherapy was provided. The patient passed away at 12 months after LT due to tumor progression.

PHAS is usually diagnosed in the sixth to seventh decades of life with a 3:1 male-to-female predominance [3,4]. Environmental carcinogens, especially vinyl chloride, are associated with an increased risk of developing hepatic angiosarcoma. However, the underlying cause remains unknown in most cases [5], as shown in our two cases. The overall prognosis of PHAS is very poor, with an average survival of less than six months from the time of diagnosis [5]. There is currently no standard treatment. Less than 20% of PHAS patients have resectable lesions at the time of diagnosis [5]. The tumor does not respond to radiation therapy. No standard chemotherapy is available [6]. The European Transplant Registry lists PHAS as an absolute contraindication to LT [7]. Our two patients were diagnosed with PHAS only at the explant livers. PHAS was not suspected before LT.

A report on six LT cases with PHAS showed that all patients had no evidence of metastatic disease at the time of LT [2]. However, all patients showed tumor recurrence after LT with a median interval of recurrence of two months. Only one patient survived for more than one year [2]. A case report presented that the patient died five months after LT due to tumor recurrence [1]. Another case report presented that one patient had recurrence after nine months and passed away 27 months after LT and that another patient had immediate tumor recurrence and passed away six months after LT [8]. A literature review of 22 cases reported that the median survival was six months, with a mortality of 77% due to tumor recurrence [5]. An analysis of European Liver Transplant Registry presented that all 22 patients died before 2 years after LT with the longest survival period of 23 months [9]. A recent case report presented the long survival period of 31 months after LT in a patient with PHAS [10].

This is the first report of two adult cases of LT recipients with PHAS in Korea. If we had recognized the possibility of PHAS, the decision to perform transplant would not have been taken easily despite the urgent situation with a MELD score of 40. Our experience suggests that PHAS still remains as a contraindication of LT from the viewpoint of posttransplant prognosis.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: SMK, SH. Data curation: All. Formal analysis: All. Funding acquisition: CSA, TYH, GWS, DHJ, GCP, WHK, YIY. Investigation: All. Methodology: SMK. Project administration: SH. Supervision: SH. Validation: SH. Visualization: SH. Writing – original draft: SMK, SH. Writing – review & editing: SMK, CSA, TYH, GWS, DHJ, GCP, WHK, YIY, SH.