Cancer, Liver Angiosarcoma


Article Author:
Anila Kumar
Bashar Sharma


Article Editor:
Hrishikesh Samant


Editors In Chief:
Alexandra Caley
Sameh Boktor


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/24/2019 11:23:43 AM

Introduction

Angiosarcoma is described as a high-grade, malignant neoplasm of endothelial cells of blood or lymphatic vessels. It occurs most commonly in the head and neck, followed by breast but the liver is the fifth most common site of angiosarcomas. Primary hepatic angiosarcoma is a rare but aggressive malignancy and is the most common primary malignant mesenchymal tumor of the liver in adults. [1][2][3]

Etiology

Around 75% of tumors have no known etiology, but the most common known etiologic factors are exposure to vinyl chloride monomer and other industrial materials, iatrogenic exposure to colloidal thorium dioxide (Thorotrast), androgenic steroid use, chronic arsenic ingestion, and exposure to radium. There have also been studies showing an association between cancer and exposure to diethylstilbestrol, urethane, cyclophosphamide, and oral contraceptives. Hepatic angiosarcoma due to environmental exposure has a prolonged latency period of 10-40 years. 

Vinyl chloride was formerly used in the production of polyvinyl chloride. It was recognized in 1949 that the highly reactive epoxide chloroethylene oxide produced during the reaction caused hepatorenal damage. The latency period is about 20 years. Cancer-associated with vinyl chloride monomer exposure has been found to have TP53 mutations.

Thorotrast was used as a radiocontrast material, but its use was stopped shortly after following several reports of organ damage and fatalities. In the liver, the substance is taken up and stored by Kupffer cells and then gets stored in the periportal area after its destruction. This results in periportal, periacinar and Glisson’s capsule fibrosis. KRAS-2 mutations have been found in cancer cells from thorotrast exposure.

Chronic arsenic intoxication initially results in hepatomegaly followed by the development of steatosis, cell necrosis, fibrosis, and cirrhosis. [1][4][5][6]

Epidemiology

Hepatic angiosarcoma accounts for 0.1-2% of all primary hepatic malignancies, but it is still considered to be the third most common primary hepatic malignancy. It usually occurs in older men with a peak incidence in the sixth or seventh decade of life. Males are more frequently affected than females with a ratio of 3-4:1. However, in childhood, there is a higher incidence amongst girls compared to boys.[1][7][8]

Pathophysiology

Hepatic angiosarcoma is primarily made up of vessels or lymphatic endothelial cells, so it is made up of abundant vasculature. Spindle or pleomorphic cells line or grow into the lumina of pre-existing vascular spaced like sinusoids and terminal hepatic venules, causing hepatocyte atrophy and formation of vascular channels. It can sometimes form into solid masses of a tumor. Hepatic angiosarcoma should be considered when a hepatic bleeding mass is encountered. Metastatic spread usually occurs in the lungs and hilar lymph nodes but can also spread to the spleen and bones. [1][2][9]

Histopathology

Histologically, the malignancy is composed of spindle-shaped and polyhedral cells, demonstrating various patterns of vascular channels. Solid areas that resemble fibrosarcoma and polynuclear giant cells may also be seen. It is common to see tumor invasion of a portal and hepatic vein branches. Areas of infarct, atrophy, and fibrosis are also commonly seen as parenchymal loss causes scarring and occlusion of pre-existing vessels. CD31, CD34, Ulex europeas agglutinin I, and Factor VIII-related antigen are immunohistochemical markers that can be used to aid diagnosis. Due to the highly vascular nature of the tumor, liver biopsy has a high risk of morbidity and mortality.[1][9][10][11][12]

History and Physical

Hepatic angiosarcoma usually presents with non-sepcific symptoms including right upper quadrant abdominal pain, weight loss, distention, jaundice and fatigue.[1] Physical examination can reveal jaundice, ascites and hepatomegally.[13] They can also be asymptomatic and found incidentally on imaging. 

Evaluation

Diagnosing hepatic angiosarcoma remains a challenge due to the non-specificity of symptoms. Liver tumors are most commonly detected incidentally on abdominal imaging. It is difficult to differentiate hepatic angiosarcoma from other hepatic tumors radiologically due to the hypervascular characteristic of hepatic angiosarcoma. Ultrasonography shows multiple nodules or solitary mass with varying echogenicity from necrosis and hemorrhage in hepatic angiosarcoma lesions. Many studies concluded that contrast-enhanced computed tomography is the best method for diagnosis of hepatic angiosarcoma. Lesions appear hypodense with multiple patterns of enhancement and postcontrast; the lesions become partly or completely isodense in comparison with the hepatic tissue. MRI can also be used to identify hepatic angiosarcoma as it can reflect the hemorrhagic, heterogeneous and hypervascular nature of the lesions.

Laboratory studies in patients with hepatic angiosarcoma will show elevated alanine transaminase and aspartate transaminase, as well as thrombocytopenia and anemia, as normal liver parenchyma is replaced by tumor. Tumor markers like AFP, CEA, CA19-9, and CA125 are in normal range or only slightly elevated. Diagnosis of hepatic angiosarcoma should be made with a correlation of radiological findings and histological interpretation (as described previously). It is important to bear in mind that even with a correct diagnosis, rapid progression of the tumor yields poor prognosis. [1][2][3][6][9][12]

Treatment / Management

Primary hepatic angiosarcoma has an aggressive clinical course and prognosis is poor in inoperable cases. Majority of patients die within six months of diagnosis, and even with treatment, only around 3% of patients live more than two years. Complete hepatic resection or radical resection of the tumor is the most effective forms of treatment for single lesions; however, it is not always feasible in metastatic disease. Liver transplant is not recommended in these cases due to the high rate of recurrence and the rapid progression of the disease. Survival after liver transplant is less than seven months. Unfortunately, no effective chemotherapy has been established. There has been one report that showed the efficacy of using 5-FU-carboplatin with doxorubicin or ifosfamide in patients with unresectable hepatic angiosarcoma and distant metastasis. A study with a large patient population showed a significant survival benefit of surgical treatment for stage I hepatic angiosarcoma and prognosis of patients that underwent surgical treatment were better than patients who received non-operative treatment. Transcatheter arterial chemoembolization (TACE) can also be used with the palliative intention or to control bleeding. Unfortunately, there are no established guidelines on optimal treatment modalities regarding surgery, chemotherapy, and radiation as there are different outcomes that have been studied. [10][14][11][15]

Differential Diagnosis

Differential diagnosis of hepatic angiosarcoma include: 

  • Inflammatory disorders of the liver
  • Benign vascular diseases of the liver
  • Kaposi’s sarcoma
  • Liver metastasis from angiosarcoma arising in other organs
  • Epitheloid haemangioendothelioma
  • Hepatocellular carcinoma
  • Fibrosarcoma [1]

Staging

Clinical staging of angiosarcoma is based on the American Joint Committee on Cancer Staging System for soft tissue sarcoma - which is based on tumor size, depth, the presence or absence of regional lymph nodes, distant metastases and histological grade. All hepatic angiosarcomas are considered deep tumors, as they are located beneath superficial fascia. Stage II and III hepatic angiosarcomas are rare making their outcomes more difficult to predict. Majority of cases in studies were stage I or IV. [15]

Prognosis

Hepatic angiosarcoma is a rapidly growing and fatal tumor. Majority of patients die within six months of diagnosis from liver failure or hemorrhage, and most die within a year, even after surgical resection. Patients with tumor rupture often die within one month. [1][2]

Complications

It is a rapidly fatal tumor with mortality within six months from liver failure or hemorrhage. Tumor rupture may occur and result in hemoperitoneum. Once this happens, transarterial embolization is usually the first intervention done to stabilize the patient and stop the bleed. However, there is no definite recommendation on treating acute bleeding of liver angiosarcoma due to the rarity of the tumor. Some patients have also been reported to develop features of disseminated intravascular coagulation. [3][1][12]

Deterrence and Patient Education

The diagnosis of hepatic angiosarcoma remains difficult during the early stages due to unspecific symptoms. Prognosis is poor due to its rapid progression, high recurrence rate and resistance to traditional chemotherapy and radiotherapy. Surgical resection remains the most definite curative therapy. However, there are no therapeutic guidelines established to date due to the rarity of cancer. Exposure to environmental and chemical substances as previously mentioned remains the most common known etiology of the disease. [1][3]

Enhancing Healthcare Team Outcomes

Unfortunately, due to the small number of cases of this rare malignancy, therapeutic guidelines have not been definitively established. Diagnosing hepatic angiosarcoma remains a challenge due to the non-specificity of presenting symptoms such as weight loss and abdominal pain. Laboratory cancer markers are also non-specific to the diagnosis and diagnosing the tumor on radiological imaging is difficult. Biopsy of the lesion carries risks of bleeding due to the highly vascular nature of cancer. It is essential that a collaborative effort is made between primary care doctors, hepatologists, radiologist and pathologists in making a diagnosis. Once a diagnosis of hepatic angiosarcoma is made, prognosis remains very poor, and treatment would include surgery versus palliative care. Surgeons, oncologists and palliative care doctors must get involved at this point to determine the best course of action based on the patient’s wishes and prognosis [Level IV]. [15]


  • Image 8642 Not availableImage 8642 Not available
    Image courtesy S Bhimji MD
Attributed To: Image courtesy S Bhimji MD

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Cancer, Liver Angiosarcoma - Questions

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A patient has worked at a PVC pipe manufacturing plant for 30 years. For which of the following cancers is he at high risk?



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A 64-year-old male presented for a follow up after he was found to have an incidental 3 cm liver mass on imaging. He is asymptomatic except for occasional right upper quadrant pain. His physical exam is unremarkable. Vital signs are within normal limits. Labs were significant for alanine aminotransferase (ALT) 60 U/L and aspartate aminotransferase (AST) 55 U/L with alkaline phosphatase 140 U/L and normal bilirubin levels. He also had thrombocytopenia with platelet count at 110/microliter. CT liver protocol showed a hypodense lesion that becomes isodense with areas of hyperdensity after contrast. Liver biopsy showed solid spindle cell proliferation with areas of infarct. The patient mentioned that he used to work in a factory about 30 years ago. What was he likely exposed to during his job?



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A 62-year-old female presents to the clinic for a follow after she was found to have an incidental 6 cm liver mass on Imaging. She reports right upper quadrant pain. Her physical examination is remarkable for hepatomegaly. Vital signs are within normal limits. Labs are significant for ALT 90 IU/L and AST 79 IU/L with ALP 180 IU/L and bilirubin levels of 2.4 mg/dL. CT liver protocol shows a 6 cm hypodense lesion with enhancement after contrast. Liver biopsy shows evidence of spindle cell proliferation with areas of hemorrhage. What is the most likely site of metastasis of this tumor?



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A 62-year-old female presents to the hospital with right upper quadrant pain and nausea. Her physical examination is significant for hepatomegaly. Vital signs are within normal limits. Labs are significant for ALT 75 IU/L and AST 70 IU/L with ALP 160 U/L and bilirubin levels of 1.5 mg/dL. CT abdomen with contrast shows a 5 cm lesion with enhancement after contrast. Liver biopsy shows evidence of solid spindle cell proliferation without hemorrhage. Immunohistochemistry is positive for CD31 and CD34. PET/CT is negative for distant local or distant metastasis. What is the best next step in the management of this patient?



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A 69-year-old female presents to the hospital with right upper quadrant pain and nausea. She reports decreased appetite and weight loss of 25 lbs over the past six months. Her physical examination is significant for hepatomegaly. Vital signs are within normal limits. Labs are significant for hemoglobin 10.1 g/dL, platelet count of 89000/microL, ALT 120 IU/L and AST 115 IU/L with ALP 220 IU/L and bilirubin levels of 2.7 mg/dL. CT abdomen with contrast reveals multiple hypodense liver lesions, the largest being a 6 cm; the lesions have areas of hyperdensities after contrast. She also has multiple enhancing lesions in her spleen. She undergoes a CT chest that shows a 3 cm right upper lobe lung nodule. Liver biopsy reveals evidence of solid spindle cell proliferation with areas of hemorrhage and necrosis. Immunohistochemistry is positive for CD31 and CD34. What is the best next step in the management of this patient?



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A 72-year-old male is admitted to the medicine floors after he presented to the hospital with poor oral intake and a 25-pound unintentional weight loss for the past three months. Social history includes a 40 pack year history, and he was a retired PVC factory worker. Physical examination is remarkably for hepatomegaly, and labs reveal ALT 100 IU/L, AST 110 U/L, ALP 215 U/L and total bilirubin 3 mg/dL. Triple-phase CT shows multiple hypodense liver lesions, with some lesions becoming hyperdense after contrast is administered. Liver biopsy shows solid spindle cell proliferation and necrosis. What is the most effective treatment of this patients liver condition?



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Cancer, Liver Angiosarcoma - References

References

Chaudhary P,Bhadana U,Singh RA,Ahuja A, Primary hepatic angiosarcoma. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2015 Sep;     [PubMed]
Yi LL,Zhang JX,Zhou SG,Wang J,Huang YQ,Li J,Yu X,Wang RN, CT and MRI studies of hepatic angiosarcoma. Clinical radiology. 2019 Jan 24;     [PubMed]
Chien CY,Hwang CC,Yeh CN,Chen HY,Wu JT,Cheung CS,Lin CL,Yen CL,Wang WY,Chiang KC, Liver angiosarcoma, a rare liver malignancy, presented with intraabdominal bleeding due to rupture--a case report. World journal of surgical oncology. 2012 Jan 26;     [PubMed]
Tripke V,Heinrich S,Huber T,Mittler J,Hoppe-Lotichius M,Straub BK,Lang H, Surgical therapy of primary hepatic angiosarcoma. BMC surgery. 2019 Jan 10;     [PubMed]
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Averbukh LD,Mavilia MG,Einstein MM, Hepatic Angiosarcoma: A Challenging Diagnosis. Cureus. 2018 Sep 11;     [PubMed]
Millan M,Delgado A,Caicedo LA,Arrunategui AM,Meneses CA,Villegas JI,Serrano O,Caicedo L,Duque M,Echeverri GJ, Liver Angiosarcoma: Rare tumour associated with a poor prognosis, literature review and case report. International journal of surgery case reports. 2016;     [PubMed]
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Tsunematsu S,Muto S,Oi H,Naka T,Kitagataya T,Sasaki R,Taya Y,Baba U,Tsukamoto Y,Uemura K,Kimura T,Ohara Y, Surgically Diagnosed Primary Hepatic Angiosarcoma. Internal medicine (Tokyo, Japan). 2018 Mar 1;     [PubMed]
Kim HR,Rha SY,Cheon SH,Roh JK,Park YN,Yoo NC, Clinical features and treatment outcomes of advanced stage primary hepatic angiosarcoma. Annals of oncology : official journal of the European Society for Medical Oncology. 2009 Apr;     [PubMed]
Matsumoto M,Tamura M,Komiya T,Aridome G,Narita R,Hisaoka M,Ohtsuki M,Otsuji Y, Hepatic angiosarcoma: a rare liver tumor in a hemodialysis patient. Clinical nephrology. 2009 May;     [PubMed]
Huang NC,Kuo YC,Chiang JC,Hung SY,Wang HM,Hung YM,Chang YT,Wann SR,Chang HT,Wang JS,Ho SY,Guo HR, Hepatic angiosarcoma may have fair survival nowadays. Medicine. 2015 May;     [PubMed]
Huang IH,Wu YY,Huang TC,Chang WK,Chen JH, Statistics and outlook of primary hepatic angiosarcoma based on clinical stage. Oncology letters. 2016 May;     [PubMed]
Forbes A,Portmann B,Johnson P,Williams R, Hepatic sarcomas in adults: a review of 25 cases. Gut. 1987 Jun     [PubMed]

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