Rare Malignant Liver Tumors

Although hepatocellular carcinoma (HCC) is by far the most common malignant liver tumor, there are several rare malignant tumors that are important to keep in mind when making a differential diagnosis. These tumors include cholangiocarcinoma; hepatoblastoma and mesenchymal tumors, such as epithelioid hemangioendothelioma (EHE); and angiosarcoma. While these conditions differ in their etiology and pathology, they often present similarly, with nonspecific symptoms such as fatigue, weight loss, and abdominal discomfort. Diagnosis is by imaging, which can be supported by a biopsy. Surgical excision is the only curative approach for these tumors.

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Cholangiocarcinoma

Epidemiology and etiology

  • 2nd most common primary malignant liver tumor
  • Accounts for 7.6% of cancer deaths worldwide and 3% of cancer deaths in the United States
  • Very common in Southeast Asian countries due to a higher prevalence of liver fluke infestation:
    • Thailand
    • Laos
    • Cambodia

Pathogenesis and risk factors

Genetic disorders: 

  • Lynch syndrome (hereditary nonpolyposis colorectal cancer)
  • Cystic fibrosis
  • Multiple biliary papillomatosis

Toxins:

Cholangiocarcinoma is associated with work in the following industries:

  • Automotive 
  • Rubber 
  • Chemical
  • Wood finishing 

Precursor/pre-malignant lesions:

  • Biliary intraepithelial neoplasia: can become cholangiocarcinoma
  • Mucin-producing bile duct tumors of the hepatobiliary system, noninvasive and invasive types

Other causes:

  • Chronic inflammatory conditions involving the bile ducts → injury and reaction promote acquisition of cancer driver mutations
  • Primary sclerosing cholangitis
  • Infestation by liver flukes (Opisthorchis and Clonorchis spp.)
  • Hepatolithiasis (recurrent pyogenic cholangitis)
  • Chronic liver diseases that predispose to hepatocellular carcinoma (HCC):
    • Hepatitis B and C
    • Nonalcoholic fatty liver disease

Pathology

  • Arises from epithelial cells of intrahepatic and extrahepatic bile ducts
  • Firm, gray-white mass or masses
  • Klatskin tumor: extrahepatic tumor at junction of the right and left hepatic ducts; represents 60%–70% of extrahepatic tumors
  • Common bile duct: 30%–40% of extrahepatic tumors
    • Discovered earlier because they cause obstructive jaundice early
    • Morphology varies: solid, infiltrative, or papillary
  • Microscopic appearance:
    • Adenocarcinoma, well to moderately differentiated
    • Abundant fibrous stroma
    • Lymphovascular and perineural invasion are common.
    • Combined hepatocellular-cholangiocarcinoma also occurs.

Clinical presentation

  • Symptoms related to biliary obstruction (jaundice, pruritus)
  • Weight loss 
  • Symptomatic liver mass: RUQ discomfort

Diagnosis

Cholangiocarcinoma may be detected incidentally on imaging or may present with symptoms.

Laboratory tests: 

  • Assess for cholestasis:
    • Alkaline phosphatase
    • Gamma-glutamyltransferase (GGT)
    • Bilirubin (total, direct, and indirect) 
  • AST and ALT may be normal or minimally elevated. 
  • Biomarkers: 
    • Carbohydrate antigen (CA 19-9) 
    • Carcinoembryonic antigen (CEA) 
    • Both are usually elevated.

Imaging:

  • Ultrasound to exclude a benign cause of obstruction
  • MRCP:
    • Distal extrahepatic cholangiocarcinoma: intrahepatic and extrahepatic ductal dilation
    • Perihilar cholangiocarcinoma: intrahepatic ductal dilatation with normal-caliber extrahepatic ducts
    • Intrahepatic cholangiocarcinoma: mass lesion
  • Biopsy: if imaging not conclusive
Photomicrographs of intrahepatic cholangiocarcinoma

Photomicrographs of intrahepatic cholangiocarcinoma:
a: markedly atypical epithelial cells (H&E, 200x)
b and c: immunohistochemical stains for the cytokeratins CK7 (b) and CK19 (c), supporting the diagnosis of cholangiocarcinoma (immunohistochemistry, 200x)

Image: “Photomicrographs of intrahepatic cholangiocarcinoma” by Liu ZY, Sun JJ, He KW, Zhuo PY, Yu ZY. License: CC BY 4.0

Management

  • Surgical resection
  • Neoadjuvant or adjuvant chemotherapy

Prognosis

  • Overall prognosis is poor: 20%–40% survival after surgical resection
  • Metastatic disease is present in 50%–60% of patients at presentation.
  • Recurrences are common after surgery.
  • Favorable if surgical resection margins are negative and there is no lymph node involvement.

Hepatoblastoma

Epidemiology and etiology

  • The most common primary hepatic malignancy in early childhood
  • 1% of all childhood malignancies
  • Boys:girls ratio: 2:1 
  • Most occur in the first 2 years of life. 
  • Arises from primitive cells

Pathogenesis and risk factors

  • Prematurity with a very low birth weight
  • Early exposure to hepatitis B infection
  • Biliary atresia
  • Genetic conditions: 
    • Beckwith-Wiedemann syndrome
    • Familial adenomatous polyposis (FAP)
    • Trisomy 21

Pathology

  • Well-circumscribed single or multiple lesions, up to 20 cm (8 in)
  • Hemorrhage and necrosis due to rapid growth 
  • Microscopically: 
    • Malignant liver cells, at various stages of maturation
    • Scattered mesenchymal components, including bone and cartilage

Clinical presentation

  • Often asymptomatic at presentation
  • Abdominal distension, rapidly growing abdominal mass
  • Anorexia, weight loss
  • Fatigue
  • Disease is advanced at diagnosis in 40% of patients, with pulmonary metastases in 20% of cases.
  • Death may occur from tumor rupture, and may be the 1st manifestation of the disease.

Diagnosis

  • Serum alpha-fetoprotein levels are markedly elevated. 
  • Imaging: All modes may be used. 
    • Ultrasound
    • CT
    • MRI
    • Radionuclide bone scanning
    • PET scanning
  • Biopsy: open surgical biopsy preferred (if tumor not resected) because of the high vascularity of the tumor

Management

  • Surgical resection
  • Neoadjuvant or adjuvant chemotherapy
  • Adjuvant radiotherapy may be used.

Prognosis

The overall survival rate has greatly improved over the past 4 decades and now stands at 81%.

Mesenchymal Tumors

Epithelioid hemangioendothelioma (EHE)

Epithelioid hemangioendothelioma is a low-grade malignant vascular neoplasm. 

  • Epidemiology: more common in women than men
  • Pathology
    • Tumor arises around medium- and large-sized veins. 
    • Vascular channels are inconspicuous; +/- calcification, fibrosis
    • Neoplastic cells are plump and often cuboidal.
  • Clinical presentation: 
    • Abdominal pain
    • Abdominal mass
    • Weight loss
    • Malaise
  • Management:
    • Surgical excision curative in most cases
    • 40% recurrence rate
    • 20%–30% of EHE metastasize.
    • 15% of patients will die from their tumor.

Angiosarcoma

Angiosarcoma is a high-grade malignant vascular neoplasm.

  • Epidemiology: 
    • The most common sarcoma arising in the liver 
    • Mostly older patients (> 60 years old)
    • Men > women
  • Etiology: various risk factors account for 25% of cases, and include:
    • Vinyl chloride
    • Arsenic (e.g., in pesticides)
    • Anabolic steroids
    • Oral contraceptives
    • Radiation
    • Thorium dioxide
  • Pathology:
    • Morphology varies from well-differentiated tumors that resemble hemangiomas to anaplastic lesions.
    • Forms many variably sized hemorrhagic nodules
    • The entire liver is often involved.
    • Invades and grows into sinusoids and branches of portal, hepatic veins
    • Immunostaining shows positivity for vascular markers.
  • Clinical presentation:
    • Abdominal pain
    • Fatigue
    • Jaundice
    • Ascites
    • Weight loss
    • Hepatomegaly, +/- splenomegaly
    • Thrombocytopenia
  • Management: surgical excision
  • Prognosis: 
    • Metastases occur frequently and rapidly to the spleen, lymph nodes, lung, bone, and adrenals.
    • Liver failure and intraabdominal bleeding due to liver rupture are common causes of death.
    • 5-year survival is approximately 30%.
Photomicrograph of hepatic angiosarcoma

Photomicrograph of hepatic angiosarcoma showing spindle-shaped malignant endothelial cells and neoplastic vascular channels:
Scant residual hepatocytes are present (H&E, 400x).

Image: “Haematoxylin and eosin stain” by Li Q, Wang J, Sun Y, Cui Y, Hao X. License: CC BY 2.0

Mnemonic

Risk factors of hepatic angiosarcoma can be remembered as “VAT”:

  • Vinyl chloride
  • Arsenic
  • Thorium dioxide

Differential Diagnosis

The following conditions encompass the most important benign lesions included in the differential diagnosis of a solid mass in the liver:

  • Hepatic hemangioma (cavernous hemangioma): the most common benign liver lesion. More common in women than men. Usually asymptomatic, with an excellent prognosis.
  • Focal nodular hyperplasia (FNH): a proliferation of hyperplastic hepatocytes surrounding a central stellate scar. More common in women than men. Management includes transarterial embolization, radiofrequency ablation, and surgical resection.
  • Hepatocellular adenoma (hepatic adenoma): develops in normal liver. Solitary lesion mostly in young women who use estrogen-containing medications and in patients with glycogen storage disease or metabolic syndrome. Management includes observation and surveillance, transarterial embolization, and surgical resection.
  • Regenerative nodules: usually seen in cirrhosis as a response to liver injury; consist of proliferations of hepatocytes and stroma. 

References

  1. Gill, R.M., Kakar S. (2020). Liver and Gallbladder. In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.), Robbins & Cotran Pathologic Basis of Disease. 10th ed. pp. 868–872. Elsevier, Inc.
  2. Ranganathan, S., Lopez-Terrada, D., & Alaggio, R. (2020). Hepatoblastoma and Pediatric Hepatocellular Carcinoma: An Update. Pediatric and Developmental Pathology. 23(2), 79–95. https://doi.org/10.1177/1093526619875228
  3. Yasir, S., Torbenson, M. S. (2019). Angiosarcoma of the Liver: Clinicopathologic Features and Morphologic Patterns. The American Journal of Surgical Pathology. 43(5), 581–590. https://doi.org/10.1097/PAS.0000000000001228
  4. Rosenberg, A., Agulnik, M. (2018). Epithelioid Hemangioendothelioma: Update on Diagnosis and Treatment. Current Treatment Options in Oncology. 19(4), 19. https://doi.org/10.1007/s11864-018-0536-y
  5. El-Diwany, R., Pawlik, T. M., & Ejaz, A. (2019). Intrahepatic Cholangiocarcinoma. Surgical Oncology Clinics of North America. 28(4), 587–599. https://pubmed.ncbi.nlm.nih.gov/31472907/

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