Vol.2, No.8, 439-444 (2013) Case Reports in Clinical Medicine
Hepatic angiosarcoma presenting as acute liver
failure in young adults. Report of two cases and
review of literature
Rocío López1,2*, Diana Castro-Villabón1, Johanna Álvarez1,2, Alonso V era3, Rafael Andrade1,2
1Pathology Department, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá D.C., Colombia;
*Corresponding Author: rocio.lopez@fsfb.org.co, rolopez@uniandes.edu.co
2Faculty of Medicine, Universidad de Los Andes, Bogotá D.C., Colombia
3Surgery Department, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá D.C., Colombia
Received 7 September 2013; revised 3 October 2013; accepted 30 October 2013
Copyright © 2013 Rocío López et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Hepatic angiosarcoma is a rare
tumor of endothelial origin that accounts for up
to 2% of all primary neoplasms of the liver. It is
uncommon in young adults and acute liver fail-
ure is a very unusual presentation of this dis-
ease. Case Presentation: We report the cases of
two young male adults who presented with acute
liver failure. One of them was diagnosed with
primary hepatic angiosarcoma after transplanta-
tion based on the complete evaluation of the heap-
tectomy specimen; while the other was diagnosed
through a liver biopsy which was done as part of
the work-up for transplantation. Both patients
had a rapidly worsening clinical course and died
within 2 months of diagnosis. Conclusion: He-
patic angiosarcoma is a poor prognosis disease
with high and early mortality. Therefore, a high
level of suspicion should be presen t to promptly
diagnose it, especially when dealing with pa-
tients with a rapidly worsening liver disease.
Keyw ords: Liver; Hepatic Angiosarcoma; Acute
Liver Failure
Hepatic Angiosarcoma (HAS) is a malignant vascular
tumor that accounts for up to 2% of all primary liver tu-
mors [1]. It usually develops during the sixth and seventh
decades of life, and is more frequent in males [2]. Given
that HAS clinical, laboratory, and radiologic presenta-
tions are nonspecific, its diagnosis is difficult and often
delayed. Theref ore, this is con sid ered as a poor progno sis
disease, with a high mortality rate, and with few thera-
peutic o p tions.
Even though it is a rare tu mor, it has be come a top ic of
great interest in occupational medicine due to the strong
association with hepatic carcinogens like polyvinyl chlo-
ride, thorium dioxide, arsenic, among others [2-6]. How-
ever, most of the cases arise without any associated risk
Herein, we report the clinical manifestations, patho-
logic evaluation, and treatment of two cases of young
adults with HAS that came to our institution in the last 4
years. Both cases presented as acute liver failure (ALF),
which is an extremely rare presentation of a primary liver
tumor [7]. They had a progressively declining clinical
course and died within 2 months of the diagn o sis.
A thirty-one year-old male was referred to us from a
local hospital to the Inten sive Care Unit (ICU) for further
management, after he suddenly developed severe hypo-
glycemia and acute liver failure.
Three days before admission he visited the local hos-
pital complaining of asthenia, anorexia, progressive
jaundice, and abdominal distention for one month. His
past medical history included marijuana and cocaine
consumption years before, but not recently. He reported
possible occupational exposure to vinyl chloride while
staining fabric material for making clothes for many
years. Upon examination the patient was jaundiced, with
edema, ascites, and hepatosplenomegaly.
Laboratory tests on admission showed a hemoglobin
of 13.4 gr/dL; hematocrit 44%; WBCs: 4500; platelets:
44,000/cm3; PT: 22/11 seconds; INR: 2.2; total bilirubin:
26.4 mg/dL and direct bilirubin 16 mg/dL; AST: 646
IU/L and ALT: 302 IU/L; alkaline phosphatase 137 IU/L;
Copyright © 2013 SciRes. OPEN ACCESS
R. López et al. / Case Reports in Clinical Medicine 2 (2013) 439-444
albumin 2.5 g/dL; creatinine: 0.7 mg/dL. Serology for
hepatitis A, B, C and autoimmune markers were negative.
An abdominal paracentesis was performed and th e ascitic
fluid evidenced proteins of 2.3 g/dL and a serum-ascites
albumin gradient (SAAG) of 1.1 g/dL. Doppler ultra-
sound (US) of the liver demonstrated a heterogeneous
parenchyma with irregular borders, and no focal lesions.
Plus, the portal vein, hepatic artery, and suprahepatic
vein blood flow was within normal limits. Following
these findings a liver biopsy was done and it revealed
venous blood flow obstruction suggestive of Budd-Chiari
The patient experienced rapid deterioration of his
neurological status, renal failure, and he required hemo-
dynamic and ventilatory support. As a consequence, he
was listed for an urgent transplantation, and on the fifth
day after his admission to our center, he underwent a
successful liver transplantation.
The hepatectomy specimen weighed 2489 gr; it had a
spongy appearance and multiple hemorrhagic areas
(Figure 1).
Microscopically, there was massive invasion of the
liver parenchyma by the tumor. Neoplastic cells were
pleomorphic and spind le shap ed with high mitotic active-
ity (Figures 2 and 3), and they were positive for CD31,
CD34, factor VIII, and CD10 inmunohistochemistry
markers (Figure 4). The proliferation index was estab-
lished with the Ki67 marker (50%).
One month after the transplantation the patient had
recurrence of the tumor involving the bone marrow. He
received 3 cycles of chemotherapy, but he had a torpid
clinical course and died 2 months later.
A twenty year-old male, who worked as a car techni-
cian, presented at the emergency room because of som-
nolence, disorientation, and disturbances of the sleep-
wake cycle for 5 days. Additionally, he presented with
Figure 1. Gross appearance of the liver. The explanted speci-
men shows multiple cystic and hemorrhagic areas.
Figure 2. H & E Stain (20×). The microscopic section of the
explanted liver shows diffuse infiltration of the hepatic paren-
chyma by the tumor, vascular spaces of varying shapes and
sizes, areas of hemorrhage, and extramedullary hematopoiesis.
Figure 3. H & E Stain (20×). The microscopic section of the
explanted liver shows vascular spaces lined by atypical endo-
thelial cells with hyperchromatic nuclei. Giant pleomorphic
neoplastic cells are observed.
upper abdominal pain and increased abdominal girth.
Initially, he was admitted to a local hospital and an
abdominal US, a paracentesis, and a liver biopsy were
performed. The results demonstrated a mass in the liver
suggestive of hemangioendothelioma. His past medical
history was unremarkable.
Physical examination on admission revealed a patient
who had altered level of consciousness, mucocutaneous
jaundice, ascites, hepatosplenomegaly, and edema of the
lower limbs. Laboratory data: hemoglobin: 14.4 gr/dL;
hematocrit: 43.2%; WBCs: 4900; platelets: 18,000/ cm3;
PT: 39.5/27.5 seconds; INR: 1.7; AST: 446 IU/L and
ALT 140 IU/L; alkaline phosphatase: 285 IU/L; total
bilirrubin: 17.65 mg/dL and direct bilirrubin: 10.45
mg/dL; albumin: 0.94 g/dL. The abdominal CT scan
showed hepatomegaly and multiple focal lesions that
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R. López et al. / Case Reports in Clinical Medicine 2 (2013) 439-444 441
Figure 4. Immunohistochemistry studies showed positivity of
neoplastic cell for vascular markers: CD10 and CD34 (4×).
compromised most of the hepatic parenchyma; some of
them showed a necrotic center.
As part of the work-up for transplantation, a new liver
biopsy was taken. The histological and immunohisto
chemistry findings (positive CD31 and Factor VIII; Ki67:
50%) were consistent with angiosarcoma (Figures 5 and
6). Hence, the patient could not be listed for transplanta-
tion and he was referred for oncologic and palliative
therapy. This was considered an occupational disease due
to the chronic exposure to vinyl chloride.
The patient had rapid deterioration of his clinical
course and 17 days after admission he died .
Hepatic angiosarcoma is a malignant neoplasia of
mesenchymal origin that arises from endothelial and fi-
broblastic tissues, which grow and compromise the bloo d
vessels [8]. It is a rare tumor which accounts for up to
2% of all primary hepatic malignancies [1,7]. However,
it is the most common p rimary sarcoma of this organ [9].
The incidence and prevalence in the western world is
estimated at 0.5 - 1 per million and 0.14 - 0.25 per mil-
lion, respectively [10]. These patients have a poor prog-
Figure 5. H & E Stain (10×). The Liver biopsy shows complete
disruption of the liver parenchyma by neoplastic cells. Tumor
cells are pleomorphic, with hyperchromatic nuclei.
Figure 6. Immunohistochemical studies showed strong positivity
of the neoplastic cells for endothelial markers: Factor VIII and
CD31 (10×).
nosis and without treatment the median survival is less
than 6 months [11,12].
It is most common during the sixth and seventh dec-
ades of life (50 - 59-year-old) [3,13]; although there are
cases reported in children and young adults [14-18].
There is a male predominance with a ratio varying be-
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R. López et al. / Case Reports in Clinical Medicine 2 (2013) 439-444
tween 3:1 and 4:1 [3,4,14]. Metastases are usually to
lung (38%), spleen (18%), and bone (18 %), still there are
cases described with metastasis to the stomach and left
gastric vein [11,18].
In up to 75% of the cases its etiology is unknown and
no associated risk factors are found [17]. Nevertheless, it
has been related with the exposure to thorium dioxide,
polyvinyl chloride, arsenic and radium compounds, in-
organic copper, anabolic steroids, and radiation [3-5,
8,19]. There is also an association with hemochromatosis
and von Recklingh ausen disease [7,13].
Thorotrast was a radiologic contrast medium used in
the US, Europe, and Japan from 1930s until the late
1950s [2,3]. It is a colloidal solution composed of 25%
thorium dioxide (Th232) and dextrin [2,19]. After intra
vascular injection, Th232 is stored in the reticulo-endo-
thelial system, particularly the liver, spleen, and bone
marro w [ 19].
Th232 is a radioactive isotope that emits α particles and
it is the chronic α radiation the one responsible for the
development of angiosarcoma [2,19]. The people af-
fected have a mean latency of exposure to tumor of 24 -
42 years [3].
Vinyl chloride (VC) is a gas used in the production of
plastic piping and conduit, floor covering, furniture,
electrical applications, and packaging [3]. In 1974 in the
US, the carcinogenicity of this compound was recog-
nized, and since then the allowed exposure levels were
reduced, reaching current levels of <1 ppm [2,3]. It is
rapidly metabolized and it generates metabolites that
react with the proteins, DNA and RNA, creating new
mutations in K-ras and p53 [2,8]. The mean latency for
vinyl-chloride-induced angiosarcoma is between 19 to 22
years [3].
The liver is a target of carcinogenesis from arsenic
exposure [5]. Arsenic is absorbed in the gastrointestinal
tract and the liver is the principal site for its detoxifica-
tion [5]. Initially, it was used as a drug. Fowler’s solution
(1% arsenic trioxide) was considered as part of the
treatment for psoriasis, anemia, asthma, cholera, syphilis,
among others [6]. Then, from 1931 until 1953, it was one
of the first medications used for the management of
chronic myelogenous leukemia [6]. Nowadays, Fowler’s
solution, the consumption of contaminated water, and the
exposure to pesticides made up of arsenic, have been
reported as possible risk factors for angiosarcoma [4].
4.1. Clinical Characteristics
HAS is a tumor that is difficult to diagnose because of
its nonspecific clinical presentation. Most of the cases
are recognized in advanced stages, which makes this a
poor prognosis disease and it has few therapeutic op-
Clinical presentation may be variable. The most com-
mon initial symptoms are diffuse abdominal pain, asthe-
nia, and weight loss [3,8]. Other systemic findings, like
weakness and anorexia may be present in 25% - 50% of
patients [4]. In a series of 5 patients reported by Molina
and Hernandez, fever was documented as a presenting
symptom in 2 patients for the first time. It is believed
that the causes of this symptom are the hemorrhage and
the necrosis related to the tumor [20]. Cases presenting
as lower back pain, epigastric pain, abdominal discom-
fort, hemoptysis, chest discomfort, and dyspnea have
been described as well [4,10,12,20]. Physical signs in-
clude ascites, hepatomegaly, splenomegaly, and jaundice
[2,3,7]. Hemoperitoneum, due to the rupture of blood
vessels or after instrumentation, happens in 17% to 27%
of the cases and it is associated with a high morbidity
and mortality [3].
Acute liver failure is a very unusual presentation of
HAS [21]. This clinical syndrome is marked by en-
cephalopathy and coagulopathy in a patient with no prior
evidence of liver disease [7,22]. The most common
causes for ALF are acetaminophen overdose (46%), drug
toxicity (11%) and hepatitis (1 0%) [23 ]. In co ntrast, there
are few case reports of infiltrative metastatic neoplasms
affecting the liver that present as ALF, for example he-
matological malignancies, adenocarcinoma, melanoma,
anaplastic tumors, breast, colon, gastric, and lung cancer
[7,13,24-26]. There are even fewer cases of primary liver
cancer presenting as ALF [21].
In HAS, ALF is thought to be a consequence of the
combination of ischemia of the parenchyma, portal vein
occlusion by tumor thrombi, non-occlusive infarct due to
septic shock or cardiogenic dysfunction, and the re-
placement of the hepatocytes by malignant cells that lead
to secondary necrosis [7,17].
4.2. Laboratory and Radiologic Findings
Laboratory data show elevation of liver enzymes with
a predominance of cholestasis [8]. The most common
finding is the increase of the alkaline phosphatase levels
[2]. In more than 50% of the cases, thrombocytopenia
and negative tumor markers are observed [3]. Also, cases
of microangiopathic hemolytic anemia secondary to
blood cell damage by passing through the tumoral vas-
cular c h annels h a v e been reported [2].
From a radiologic point of view, it is difficult to dis-
tinguish HAS from other hepatic tumors of mesenchymal
or vascular origin [3,10].
Through imaging 4 growth patterns have been identi-
fied: multiple nodules, solitary mass, mixed pattern with
a dominant mass and multiple nodules, and infiltrative
micronodular type [1,10]. In most cases it appears as
multiple lesions or as a heterogeneous dominant mass [1,
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R. López et al. / Case Reports in Clinical Medicine 2 (2013) 439-444 443
In certain cases, abdominal X-rays show a mass in the
right upper quadrant (RUQ) and thorium dioxide depos-
its at the periphery of the liver [3]. The US may show a
solitary mass or multiple nodules with different echo-
genicity depending on the necrosis and the hemorrhage
The various morphologic appearances on CT and mag-
netic resonance explain why the differential diagnosis
with other primary liver tumors is difficult [10]. In the
CT scan without contrast, lesions are hypodense; how-
ever, when contrast media are used multiple patterns of
enhancing may be observed [3,9]. On the other hand, the
magnetic resonance with contrast demonstrates the hem-
orrhagic, heterogeneous and hypervascular characteris-
tics of the dominant mass [1,2,27]. This image shows the
different levels of attenuation in the arterial and portal
phases [2].
4.3. Pathologic Findings
The final diagnosis is made with a histologic evalua-
This is a tumor of endothelial origin [20]. Macro-
scopically, it is composed of brown-gray areas mixed
with hemorrhagic foci and cavitations [17].
Microscopically it is characterized by the proliferation
of neoplastic cells around preformed vascular channels:
sinusoids, hepatic terminal venules and branches of the
portal vein [17,27]. The growth of the sinuso ids is related
to their dilation and atrophy of the hepatic cells [3]. The
tumor nests are made up of epithelioid, spindle and pleo-
morphic cells with small vascular spaces; mitotic figures
are commonly seen [3,17]. In the solid areas, fibrosis and
hemosiderin deposits may be found [1]. Areas of hemor-
rhage, infarction, calcifications and necrosis can be seen
as well [17]. The immunohistochemistry stains reveal the
expression of: vimentin, CD31, CD34, Factor VIII and
Ki67 [3,8,17].
4.4. Treatment
Treatment options for HAS are few and there are no
established regimens due to the low frequency and rap-
idly worsening course of the tumor [3,17].
Although complete resection is the best treatment,
curative surgeries are difficult to perform. In most of the
cases, by the time of diagnosis, the disease is in an ad-
vanced state, presenting as a large tumor or with metas-
tasis [3,17].
This neoplasm is radioresistant and no chemothera-
peutic regimen has been established for its treatment
[3,12]. Chemotherapy is palliative and is indicated for
patients with HAS that cannot be resected [8,12]. In this
case, the recommendation includes 5FU-carboplatin with
doxorubicin or ifosfamide [12].
Liver transplantation is an absolute contraindication
for the management of HAS [10]. In those patients who
received a transplant, they did not show improvement in
their survival and it is the hepatic neoplasm with the
highest rate of recurrence after transplantation [1,7,8].
According to information of the European Liver Trans-
plant Registry median survival after transplant is less
than 7 m o n ths [10].
Hepatic angiosarcoma is a very infrequent tumor in
patients younger than 35-year-old, and acute liver failur e
is a very unusual presentation of this disease. This un-
usual combination of clinical characteristics was part of
the two cases we reported. Both patients had a progres-
sively worsening clinical course and died within 2
months of diagnosis. This demonstrates the rapid evolu-
tion, poor prognosis, and the need to find a therapy that
improves survival.
We would like to mention that we had another case of
a young (26-year-old) female patient with a diagnosis of
HAS. Her case was not included as part of the case re-
ports because her disease presented as usual, with an
insidious onset of diffuse abdominal pain and weight loss
for 3 months. Additionally, she was being studied for a
concomitant myeloproliferative disorder.
Even though the clinical manifestations are nonspe-
cific, one should think of HAS as part of the differential
diagnosis when dealing with a young patient that has a
worsening clinical course and a rapidly progressive liver
disease. A diagnosis made soon, will make a difference
in the treatment options, outcome and prognosis of these
[1] Maluf, D., Cotterel l, A., Cla rk, B., Stravitz, T., Kauffman,
H.M., et al. (2005) Hepatic angiosarcoma and liver trans-
plantation: Case report and literature review. Transplan-
tation Proceedings, 37, 2195-2199.
[2] Bioulac-Sage, P., Laumonier, H., Laurent, C., Blanc, J.F.
and Balabaud, C. (2008) Benign and malignant vascular
tumors of the liver in adults. Seminars in Liver Disease,
28, 302-314.
[3] Molina, E. and Hernandez, A. (2003) Clinical manifesta-
tions of primary hepatic angiosarcoma. Digestive Dis-
eases and Sciences, 48, 677-682.
[4] N.-C. Huang, S.-R. Wann, H.-T. Chang, S.-L. Lin, J.-S.
Wang, H.-R. Guo, et al. (2011) Arsenic, vinyl chloride,
viral hepatitis, and hepatic angiosarcoma: A hospital-
based study and review of literature in Taiwan. BMC
Gastroenterology, 11, 142.
Copyright © 2013 SciRes. OPEN ACCESS
R. López et al. / Case Reports in Clinical Medicine 2 (2013) 439-444
Copyright © 2013 SciRes. OPEN ACCESS
[5] Liu, J. and Waalkes, M.P. (2008) Liver is a target of arse-
nic carcino-genesis. Toxicological Sciences, 105, 24-32.
[6] Jolliffe, D.M. (1993) A history of the use of arsenicals in
man. Journal of the Royal Society of Medicine, 86, 287-
[7] Bhati, C.S., Bhatt, A.N., Starkey, G., Hubscher, S.G. and
Bramhall, S.R. (2008) Acute liver failure due to primary
angiosarcoma: A case report and review of literature.
World Journal of Surgical Oncology, 6, 104.
[8] Egea, J., López, M., Pérez, F.J., Garre, C., Martínez, E., et
al. (2009) Hepatic angiosarcoma. Presentation of two case s.
Revista Espanola de Enfermedades Digestivas, 101, 430-
[9] Fulcher, A.S. and Sterling, R.K. (2002) Hepatic neo-
plasms: Computed tomography and magnetic resonance
features. Journal of Clinical Gastroenterology, 34, 463-
[10] Orlando, G., Adam, R., Mirza, D., Soderdahl, G., Porte,
R.J., Paul, A., et al. (2012) Hepatic hemangiosarcoma: An
absolute contraindication to liver transplantation—The
European liver transplant registry experience. Transplan-
tation, 95, 872-877.
[11] Kim TO, Kim GH, Heo J, Kang DH, Song GA and Cho
M. (2005) Metastasis of hepatic angiosarcoma to the sto-
mach. Journal of Gastroenterology, 40, 1003-1004.
[12] Kim, H.R., Rha, S.Y., Cheon, S.H., Roh, J.K., Park, Y.N.,
et al. (2009) Clinical features and treatment outcomes of
advanced stage primary hepatic angiosarcoma. Annals of
Oncology, 20, 780-787.
[13] Alexopoulou, A., Koskinas, J., Deutsch, M., Delladetsima,
J., Kountouras, D., et al. (2006) Acute liver failure as the
initial manifestation of hepatic infiltration by a solid
tumor: Report of 5 cases and review of the literature.
Tumori, 92, 354-357.
[14] Bernardos, L., Garcia, A., Rey, C., Martin, J. and Turé-
gano, F. (2008) Hepatic angiosarcoma. Revista Espanola
de Enfermedades Digestivas, 100, 804-806.
[15] Deyrup, A.T., Miettinen, M., North, P.E., Khoury, J.D.,
Tighiouart, M., et al. (2009) Angiosarcomas arising in the
viscera and soft tissue of children and young adults. The
American Journal of Surgical Pathology, 33, 264-269.
[16] Geramizadeh, B., Safari, A., Bahador, A., Nikeghbalian,
S., Salahi, H., Kazemi, K., et al. (2011) Hepatic angiosar-
coma of childhood: a case report and review of literature.
Journal of Pediatric Surgery, 46, e9-e11.
[17] Granados-López, S.L., Gómez-Jiménez, L.M., Chávez-
Bravo, N.C. and Sánchez-Rodríguez, C. (2012) Angio-
sarcoma hepático idiopático. Informe de un caso. Revista
Médica del Instituto Mexicano del Seguro Social, 50,
[18] Nakayama, H., Masuda, H., Fukuzawa, M., Takayama, T.
and Hemmi, A. (2004) Metastasis of hepatic angiosar-
coma to the gastric vein. Journal of Gastroenterology, 39,
193-194. http://dx.doi.org/10.1007/s00535-003-1274-9
[19] van Kampen, R.J., Erdkamp, F.L. and Peters, F.P. (2007)
Thorium dioxide related haemangiosarcoma of the liver.
The Netherlands Journal of Medicine, 65, 279-282.
[20] Duan, X.F. and Li, Q. (2012) Primary hepatic angiosar-
coma: A retro-spective analysis of 6 cases. Journal of
Digestive Diseases, 13, 381-385.
http:/ /d x.doi.org/10 .1111/j.1751-2980.2012.00600.x
[21] Baumhoer, D., Lorf, T., Gunawan, B., Ar mbrust, T., Füzesi,
L., et al. (2005) Hepatic tumorigenesis in acute hepatic
failure. European Journal of Gastroenterology & Hepa-
tology, 17, 1125-1130.
[22] Lee, W.M. (2012) Recent developments in acute liver
failure. Best Practice & Research Clinical Gastroente-
rology, 26, 3-16.
[23] Lee, W.M., Squires Jr., R.H., Nyberg, S.L., Doo, E.,
Hoofnagle, J.H. (2008) Acute liver failure: Summary of a
workshop. Hepatology, 47, 1401-1415.
[24] Hanamornroongruang, S. and Sangchay, N. (2013) Acute
liver failure associated with diffuse liver infiltration by
metastatic breast carcinoma: A case report. Oncology
Letters, 5, 1250-1252.
[25] Miyaaki H, Ichikawa T, Taura N, Yamashima M, Arai H,
Obata Y, et al. (201) Diffuse liver metastasis of small cell
lung cancer causing marked hepatomegaly and fulminant
hepatic failure. Internal Medicine, 49, 1383-1386.
[26] Rowbotham, D., Wendon, J. and Williams, R. (1998) Acute
liver failure secondary to hepatic infiltration: A single
centre experience of 18 cases. Gut, 42, 576-580.
[27] Yang, K.F., Leow, V.M., Hasnan, M.N. and Subramaniam,
M.K. (2012) Primary hepatic angiosarcoma: Difficulty in
clinical radiological, and pathological diagnosis. Medical
Journal of Malaysia, 67, 127-128.