Long-term 14-year survival with primary hepatic angiosarcoma

Abstract

Primary hepatic angiosarcomas (PHAs) are rare primary liver malignancies with poor outcomes due to their aggressive nature and the difficulty it presents in terms of diagnosis and management. However, early diagnosis and aggressive surgical resection combined with ongoing surveillance can confer prolonged survival in patients with PHA. Additionally, adjuvant radiotherapy may be of benefit in cases of involved surgical margins. Here we report the longest surviving patient with PHA in literature to date. The patient had an initial right hemihepatectomy 14 years ago and 10 years later had a segment III segmentectomy for recurrence on surveillance imaging. This was followed with adjuvant radiotherapy for involved margins. There has been no further recurrence noted on imaging to date, and the patient is continuing to thrive in the community.

Background

Primary hepatic angiosarcoma (PHA) is a rare and highly aggressive tumour arising from hepatic endothelial cells.¹ PHA represents only 0.1%–2% of all primary liver malignancies and is a challenge for clinicians to diagnose and manage, given its rarity and non-specific appearance on imaging, as well as a lack of clear guidelines on its management, respectively.² Delayed diagnosis combined with the aggressive nature of PHA contributes to its poor prognosis with an overall survival of only 6 months postdiagnosis and a 1-year, 3-year and 5-year survival rate of only 30%, 8% and 5%, respectively.^{3 4} As such, early diagnosis and timely aggressive surgical resection are crucial and generally the most effective treatment for PHA.^{4 5}

Here we report the successful management of a patient with PHA requiring multiple aggressive hepatic resections and is to date the longest reported survivor post-PHA diagnosis.

Case presentation

A woman in her 50s presented to her general practitioner 14 years ago with 12 months of intermittent sharp upper abdominal pain radiating from her epigastrium to her back and a 1-month history of postprandial nausea and vomiting. She also had 12 months of irregular bowel motions with intermittent fresh blood on a background of known haemorrhoids banded 5 years prior. She denied any B symptoms, and her medical history included only previous hepatitis B infection, hypertension and two uncomplicated caesarean sections. Her family history included renal cancer, and she denied any alcohol or smoking history or previous exposure to vinyl chloride, thoroplast and arsenic.

Her abdomen was soft on examination with right upper quadrant tenderness. Her liver edge was just palpable, but no other masses were felt. Her laboratory investigations (table 1) demonstrated only mild hypokalaemia and moderately deranged liver function tests. Her coagulation studies were unremarkable, and tumour markers were normal (table 1).

Table 1.

Blood investigations of patient with primary hepatic angiosarcoma on initial presentation

FBC			CHEM20
Haemoglobin	125 g/L	(115–160)	Na	140 mmol/L	(135–145)
WCC	7.4×109/L	(4–11)	K+	3 mmol/L	(3.5–4.5)
Platelets	237×109/L	(140–400)	Cl−	102 mmol/L	(95–110)
			Urea	2.6 mmol/L	(2.1–7.1)
Coagulation studies			Creat	66 µmol/L	(50–100)
INR	1.1	(0.9–1.2)	eGFR	87 mL/min/1.73 m2	(>60)
Prothrombin	10 s	(9–12)	Bilirubin	11 µmol/L	(<20)
APTT	32 s	(24–39)	ALP	146 U/L	(53–141)
			GGT	56 U/L	(<38)
Tumour markers			ALT	34 U/L	(<34)
AFP	1.8 µg/L	(<10)	AST	46 U/L	(<31)
CEA	<1.0 µg/L	(<5.0)	LDH	592 U/L	(120–250)
CA19-9	23 kU/L	(<35)

AFP, alpha fetoprotein; ALP, alkaline phosphatase; ALT, alanine transaminase; APTT, Activated partial thromboplastin clotting time; AST, aspartate transaminase; CA19-9, Cancer Antigen 19-9; CEA, carcinoembryonic antigen; eGFR, estimated glomerular filtration rate; FBC, full blood count; GGT, gamma-glutamyl transferase; INR, international normalised ratio; LDH, lactate dehydrogenase; WCC, white cell count.

An ultrasound (US) abdomen showed a 100 mm intrahepatic mass with peripheral vascularity and distorted adjacent vasculature. CT imaging revealed an enhancing 100 mm × 70 mm right liver lesion with satellite lesions.

Given her history of irregular bowels with intermittent fresh blood, she was referred for a colonoscopy preoperatively, and two pedunculated polyps were found and removed from the transverse and sigmoid colon with the largest being 20 mm in size. On histopathology, the transverse colon lesion showed tubular adenoma with low grade dysplasia, and the sigmoid lesion showed a moderately differentiated adenocarcinoma arising within a tubulovillous adenoma with high grade dysplasia with clear stalk margins. She was followed up with serial colonoscopies with no evidence of recurrence or malignant invasion.

She subsequently had a right hepatectomy that year with an uneventful postoperative recovery period and was discharged 8 days later. Her pathology confirmed angiosarcoma of the liver measuring 120 mm × 85 mm × 65 mm with clear margins and no suggestions of any other malignancies (ie, colorectal primary) or local invasion into the diaphragm. The specimen displayed a central trabeculating, creamy grey and necrotic region with a brown-red rubbery appearance peripherally. Microscopic examination revealed solid spindle cell regions as well as areas with slit-like and irregular vessels lined by atypical cells (figure 1). Mitotic figures were frequent, and areas of necrosis and haemorrhage were present. Immunohistochemistry showed strong staining for CD31 (figure 2), CD34 and factor VIII-related protein. Liver stains revealed minimal iron deposition with no alpha-1 antitrypsin bodies, Mallory’s hyaline or Shikata reactions.

Figure 1.

H&E staining and microscopic examination of the hepatic angiosarcoma showing irregular and ill-defined channels lined by atypical endothelial cells which are characteristics of the tumour.

Figure 2.

CD31 staining showing strong staining of tumour tissue on the right compared with normal liver tissue on the left of the slide.

Ten months postoperatively, the patient developed a subphrenic collection which was discovered to be an unusual late-onset bile leak, and it was radiologically drained. A temporary plastic biliary stent was inserted via endoscopic retrograde cholangiopancreatography and removed 3 months later. The patient was followed up regularly every 3–6 months with CT and MRI progress scans at least annually.

A progress CT 5 years later revealed two small 16 mm × 15 mm and 15 mm × 16 mm lesions in segments II and III, respectively. A third lesion was identified on MRI later that year. These were slow growing with fatty infiltration and were followed up with regular scans. Further growth was noted over the next 2 years, and this prompted an image-guided liver biopsy which revealed changes suggestive of hepatocellular adenoma with no recurrence of angiosarcoma. The segment II lesion continued to slowly enlarge over the next 2 years, and the patient subsequently underwent transarterial bland embolisation for this lesion. She developed a moderate left haemothorax day 2 postembolisation which was conservatively managed.

Her follow-up imaging 1 year later revealed a new segment III lesion with features concerning for malignancy. Her case was discussed at the hepatopancreatobiliary multidisciplinary team meeting, and given the lesion location and difficulty for a percutaneous biopsy, an open resection of the segment III lesion was recommended and performed without complications.

Her histopathology revealed a 50 mm × 35 mm × 37 mm lesion with pleomorphic tumour cells with large hyperchromatic oval to elongated nuclei, moderate amounts of cytoplasm and numerous atypical mitoses. Vascular channels formed by malignant cells containing red cells and large areas of necrosis were noted. Singly dispersed malignant cells were seen within the sinusoids of the normal appearing liver. This extended to the diathermied parenchymal resection margin indicating positive margins despite the main tumour mass lying 5.5 mm away from the nearest resection margin. Immunohistochemical staining was positive for CD31 and erythroblast transformation-specific related gene (ERG), which combined with above features are consistent with angiosarcoma.

Given the involved margins, she was referred for adjuvant radiotherapy for local control given her prolonged survival. She completed treatment 3 years ago after five fractions of stereotactic body radiation therapy which was cut short due to side effects of melaena, nausea and vomiting. She continued to have 6 monthly follow-up with imaging. Her last CT earlier this year did not show any evidence of recurrence or metastasis.

The patient is currently well and thriving with a survival duration of 160 months postinitial PHA diagnosis and is the longest reported surviving patient with PHA in literature.

Discussion

PHA is a rare primary tumour of the liver which arises from hepatic vascular endothelial cells. It is difficult to diagnose and manage owing to its rarity and a lack of clear treatment guidelines. Aggressive R0 surgical resection is the only curative treatment;⁶ however, some patients are precluded from this due to the rapid progressive nature of the disease. The pathogenesis of PHA is still uncertain although higher rates have been attributed to occupational exposures or medicinal carcinogens such as thorium dioxide, vinyl chloride, arsenic, androgenic anabolic steroid use or radiation.^{7 8}

Clinically, manifestation of PHA is highly variable and non-specific with most patients presenting with vague symptoms of abdominal pain or distension,^{3 4} fatigue, weight loss or anorexia.^{3 4 9} Examination findings may include hepatomegaly, jaundice, ascites and rarely hepatic bruits on auscultation due to the vascular nature of PHA.^{3 4 10} These general and non-specific symptoms result in the misdiagnosis of PHA as other hepatic cancers and/or haemangioma in 90.5% of cases.³ Additionally, a third of cases have distant metastasis on initial presentation with the most common sites being lung (37.5%), bone (28.6%), spleen (19.6%) and abdominal cavity (8.9%).³

Unlike other malignant tumours of the liver, markers including AFP, CEA and CA19-9 are often not elevated, and only 41% of patients showed elevated transaminases.³ While CT, MRI and US are used for initial assessment, features of PHA tend to be non-specific with no known pathognomonic features.^{1 11}

As such, diagnosis of PHA requires formal pathological and immunohistochemical detection.³ Imaging guided percutaneous biopsy and fine needle aspiration have been described as a possible avenue for obtaining tissue samples but are associated with high rates of mortality secondary to bleeding owing to the vascular nature of PHA.^{12 13} Additionally, the high frequency of necrotic and haemorrhagic foci within the tumour contributes to high false negative rates.¹⁰

Histologically, PHA shows malignant atypical endothelial cells which infiltrate along preformed or self-formed vascular channels, solid nodules or cavernous spaces.¹ Surrounding atrophic hepatocytes, areas of haemorrhage, necrosis and infarcts are also commonly found.¹⁴ Immunohistochemically, there are no generally accepted specific markers of PHA; however, in a cohort study, ERG expression was noted to be the most sensitive and specific marker for PHA followed by CD34, CD31 and factor VIII related antigen.¹⁵ In this reported case, immunohistochemical staining also demonstrated positive ERG and CD31 staining.

Treatment of PHA includes surgical resection, transarterial embolisation, transarterial chemoembolisation (TACE), chemotherapy and/or radiation therapy and is dependent on the presentation of the patient, evidence of metastasis and/or rupture. Surgical treatment with R0 resection remains the mainstay of treatment and can significantly prolong survival.⁶ In a multi-institutional analysis of 44 cases, only 22.7% of patients presented with resectable disease.⁴ R0 resection was achieved in 60% of these patients and 30% achieved a R1 resection.⁴ The only survivors at 5 years were those who had undergone a surgical resection.⁴ Transarterial embolisation is often used for the acutely haemodynamically unstable patient with haemorrhage.¹⁶ Chemotherapy and TACE often tend to be palliative in nature, and liver transplantation is contraindicated and has not shown to confer any significant survival benefit.^{16 17} Radiotherapy is not often employed as a primary treatment option due to the inherent radioresistive properties of the lesion.¹⁸ In the current case, an R0 surgical resection was achieved initially in 2008, and an R1 surgical resection was achieved in the second resection in 2018, with microscopic singly dispersed tumour cells within the sinusoids at the diathermied resection margin. After a multidisciplinary discussion, radiotherapy was employed for local control with good effect, and no evidence of recurrence was noted on imaging 3 years postresection.

Overall, PHA is a rare primary malignancy of the liver with very poor prognosis; however, timely diagnosis, aggressive R0 surgical resections with targeted therapy and regular surveillance for recurrence and metastasis can confer prolonged survival for this cohort of patients.

Learning points.

• Early diagnosis and aggressive surgical resections are crucial to the prolonged survival in patients with primary hepatic angiosarcoma.

• Long-term regular surveillance is important for detecting recurrence.

• Adjuvant radiotherapy may be of benefit in the management of primary hepatic angiosarcoma.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).