Benign Liver Tumors

The most common benign liver tumors include hepatic hemangiomas, focal nodular hyperplasia, and hepatic adenomas. These tumors are mostly asymptomatic and/or found incidentally on abdominal imaging. While these tumors are benign, large lesions can cause symptoms such as upper abdominal pain, or produce complications such as bleeding. Malignant potential is a concern for hepatic adenoma, depending on risk factors. The diagnosis is based on imaging studies, with characteristic findings defining the tumor. Biopsy generally is reserved for equivocal cases. Management is observation for most small, asymptomatic, and non-growing tumors. However, high-risk factors, symptoms, increasing tumor size, and complications dictate the need for surgical intervention.

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Overview

Introduction

  • Most common benign liver tumors:
    • Hepatic hemangioma
    • Focal nodular hyperplasia (FNH)
    • Hepatocellular adenoma (HCA) or hepatic adenoma
  • Clinical significance:
    • These lesions can cause symptoms and complications.
    • Some lesions have a risk of developing hepatocellular carcinoma (HCC).

Epidemiology

  • Advances in imaging have led to many incidental findings.
  • Liver lesions are noted in the following imaging studies:
    • Ultrasound (US)
    • Computed tomography (CT) scan 
    • Magnetic resonance imaging (MRI) 
  • Incidental hepatobiliary detection in screening chest CT: prevalence of 6%
  • Epidemiologic findings for benign tumors:
    • Hepatic or cavernous hemangioma:
      • Most common benign liver tumor
      • Prevalence: 0.4%–20% of the population
      • Women > men
      • Often found at 30–50 years of age
    • FNH:
      • 2nd-most common benign liver tumor
      • Prevalence: 2%–3% of the population
      • Women > men
      • Often found at 35–50 years of age
    • HCA:
      • Rare
      • Women > men
      • Diagnosed frequently at 35–40 years of age

General comparison of hepatic tumors

  • It is important to distinguish benign tumors from malignancy, as management and prognosis are affected.
  • An outline of differentiating characteristics is summarized below.
Table: Comparison of liver tumors
Hepatic hemangiomaFocal nodular hyperplasiaHepatocellular adenomaHepatocellular carcinoma
Characteristics and pathologic featuresCavernous vascular spacesCentral stellate scar + portal tracts, bile ductules, Kupffer cellsSheets of enlarged hepatocytes; no portal tracts or bile ductulesWell-differentiated (similar to normal hepatocytes); poorly differentiated (marked cytologic atypia)
Predominant gender affectedWomenWomenWomenMen
Clinical historyOral contraceptive pills (OCPs) may affect growth.OCP effect not proven; little or no effect on development or growthOCPs, anabolic steroids a factorHistory of cirrhosis and risk factors (e.g., hepatitis B)
Malignancy potentialNoneNoneYesN/A
MRI (contrast): arterial phasePeripheral nodular enhancementEarly homogeneous/diffuse enhancementWell-demarcated enhancement; heterogeneous (due to hemorrhage, necrosis, steatosis)Hyperenhancement
MRI (contrast): venous phaseProgressive centripetal fill-inIsointense with central scar enhancementVariable late phase
  • Inflammatory: Enhancement persists.
  • HNF1-ɑ mutation: Arterial enhancement does not persist.
Portal venous washout
Additional key points
  • Can use technetium-99m pertechnetate-labeled red blood cell scan
  • Biopsy not recommended (high risk of hemorrhage)
60%–70% positive uptake in sulfur colloid scanNo MRI-specific pattern was identified for β-catenin–mutated HCA.Rim enhancement on delayed post-contrast images causing a capsule-appearance: relatively specific for HCC

Hemangioma

Features

  • Gross examination: 
    • Often solitary, but may present as multiple lesions
    • Red-brown spongy mass, frequently with a capsule
    • Size:
      • Most are < 5 cm
      • If the lesion is ≥ 10 cm: giant hemangioma
    • Location: frequently in the right lobe
  • Microscopic examination:
    • Consists of cavernous vascular spaces, with a layer of endothelium
    • May contain thrombi

Pathogenesis

  • Unclear pathogenetic process
  • Believed to result from a congenital vascular malformation, with dilation as the growth pattern 
  • Risk factors: Estrogen such as in OCPs or pregnancy may promote its growth.

Clinical presentation

  • Typically asymptomatic
  • Frequently discovered incidentally on imaging studies
  • May cause right upper quadrant (RUQ) pain/fullness
  • If large enough (> 10 cm), may compress other organs and manifest as nausea, early satiety, and bloating
  • Physical examination often normal, but may show a palpable liver mass
  • Kasabach-Merritt syndrome: 
    • A giant hemangioma may cause this rare coagulation disorder.
    • Associated with thrombocytopenia, consumption coagulopathy, and bleeding
    • Mortality rate of up to 37%

Diagnosis

  • Ultrasound: 
    • Homogeneous hyperechoic mass
    • Doppler can show blood flow within the hemangioma.
    • With contrast: 
      • Enhanced ultrasound signal from the flowing blood
      • Arterial phase: peripheral nodular enhancement 
      • Late phase: continued enhancement, with centripetal filling-in
  • MRI:
    • Well-demarcated homogeneous mass 
    • Hypointense lesion on T1; high signal intensity on T2-weighted images
    • With contrast: peripheral nodular enhancement, with progression centripetally
  • CT: 
    • Without contrast: well-demarcated hypodense mass
    • With contrast: peripheral enhancement on early phase and with centripetal filling seen on late phase
  • Biopsy is not recommended:
    • Risks of hemorrhage or rupture with invasive procedure
    • Low diagnostic yield

Management

  • Observation if asymptomatic:
    • ≤ 5 cm: no further imaging
    • > 5 cm: 
      • Repeat imaging in 6–12 months. 
      • If lesion is stable (growth rate ≤ 3 mm/year), no further testing
  • Consider surgery (liver resection or enucleation):
    • Persistent symptoms and/or rapid enlargement (> 3 mm/year)
    • Symptomatic patients
  • Transcatheter arterial embolization can be used to decrease lesion size prior to surgery.

Focal Nodular Hyperplasia

Features

  • Gross examination: 
    • Firm, solitary lesion, without a capsule
    • Characteristic central stellate scar (multiple branches from an artery radiating to the periphery)
    • Size: often < 5 cm
    • Location: usually subcapsular 
    • FNH has atypical variants.
  • Microscopic examination:
    • Grouped hepatocytes, divided by fibrous septa, radiating from the central scar
    • Septa contain arteries, portal veins, bile ductules, and Kupffer cells.
    • Strong cytoplasmic glutamine synthetase staining within groups of hepatocytes

Histologic features of classic FNH: Tumor was subdivided into nodules by fibrous septa (A, white arrowhead) originating from a central scar (A, white arrow). Malformed arteries (B, black arrow) and bile ductular proliferation are demonstrated (B, black arrowhead).

Image: “Histological features of the classic focal nodular hyperplasia” by Department of Radiology, PLA General Hospital, #28 Fuxing Road, Beijing, 100853, China. License: CC BY 4.0

Pathogenesis

  • Regenerative response of hepatocytes to altered perfusion from anomalous arteries (in the center of the nodule) 
  • No malignant potential
  • Increased risk of FNH in hereditary hemorrhagic telangiectasia

Clinical presentation

  • Asymptomatic
  • Often found incidentally on imaging
  • If symptomatic, commonly the symptom is abdominal pain.
  • Physical examination: usually normal, but may show an abdominal mass

Diagnosis

  • US:
    • Non-contrast: isoechoic mass
    • With contrast:
      • FNH: enhancement sustained in arterial phase and early venous phase
      • Central arteries seen with spoke-wheel pattern on arterial phase (centrifugal)
  • MRI scan: 
    • Highest diagnostic accuracy
    • Pre-contrast: isointense on T1; slightly hyperintense on T2-weighted images
    • With contrast: 
      • Arterial phase: rapid/early homogeneously enhanced hypervascular mass
      • Delayed phase: isointense mass, with enhancement of the central scar
  • CT scan:
    • Pre-contrast: isodense
    • With contrast:
      • Arterial phase: homogeneous hyperdense lesion 
      • Venous phase: isodense, similar to liver parenchyma; the central scar becomes hyperdense.
  • Nuclear medicine (technetium-99m sulfur colloid scan): 
    • Increased uptake of sulfur colloid (Kupffer cell activity) is seen in 60%–70% of patients. 
    • Helps to differentiate FNH from adenoma (which has no Kupffer cell activity)
  • If imaging findings are not typical of FNH, a biopsy may be required.

Computed tomography findings of FNH: Mixed phase (hepatic arterial phase/portal venous phase during hepatic enhancement) shows intense homogeneous enhancement with hypodense focal central scar (a); on delayed phase (b), the lesion appears substantially isodense to liver parenchyma with persistent enhancement of central scar.

Image: “Fig3” by Department of Surgical and Biomedical Sciences, Division of Radiology 2, Perugia University, S, Maria della Misericordia Hospital, S, Andrea delle Fratte, 06134 Perugia, Italy. License: CC BY 4.0

Management

  • For asymptomatic patients: no routine surveillance recommended as lesion rarely grows
  • For symptomatic patients: may undergo transarterial embolization, radiofrequency ablation, or surgical resection

Hepatocellular Adenoma

Features

  • Gross examination: 
    • Typically a solitary lesion with well-defined margin, but can occur as multiple lesions
    • Varied sizes, from small to several centimeters
    • Lacks a fibrous capsule (risk for rupture and bleeding)
    • Location: often in the right lobe of the liver
  • Microscopic examination:
    • Sheets of enlarged hepatocytes with small nuclei, glycogen, and lipid
    • Large arteries present
    • Generally, no portal tracts or bile ductules (differentiates HCA from FNH); inflammatory subtype is an exception

Hepatic adenoma: well-differentiated neoplasm composed of normal-appearing hepatocytes arranged in sheets and thin cords with patchy pseudoacinar growth pattern (thin arrows), scattered inflammatory foci, and bands of fibrosis with unpaired large arteries (thick arrow)

Image: “Hepatic adenoma” by M. I. Montenovo. License: CC BY 4.0

Pathogenesis

  • Benign glandular epithelial tumor, with the following risk factors: 
    • Use of OCPs, anabolic steroids 
    • Genetic syndromes such as glycogen storage diseases and familial adenomatous polyposis
    • Obesity, metabolic syndrome
  • Subtypes based on the molecular behavior of HCA:
    • Adenomas with hepatocyte nuclear factor 1 alpha (HNF1-ɑ) mutation:
      • 35%–40%
      • Have loss-of-function mutations in the HNF1-ɑ gene
      • Findings: steatosis or prominent fat in hepatocytes
      • Predominantly affects women 
      • Low risk of malignant transformation
      • Associated with mature-onset diabetes of the young (MODY 3)
    • β-catenin–activated HCA:
      • 10%–20% 
      • Associated with mutations of the CTNNB1 (β-catenin) gene or other Wnt pathway components
      • Frequently in men
      • Linked to anabolic steroid use
      • Findings: atypical cytologic features
      • High risk for HCC development
    • Inflammatory adenomas:
      • 40%–50%
      • Findings: inflammatory infiltrates, sinusoidal dilation
      • More prevalent in women with obesity or diabetes
    • Unclassified: up to 10%

Clinical presentation

  • May be asymptomatic, but 25% of patients present with RUQ pain or mass
  • Hemorrhage: higher risk when size is > 5 cm
    • Bleeding into the lesion can manifest as abdominal pain.
    • In severe cases, rupture into the peritoneum presents with severe pain and hypotension.

Diagnosis

  • US: 
    • Without contrast: nonspecific heterogeneous mass
    • With contrast: hyperenhancement from periphery to center (centripetal)
  • CT scan: 
    • Without contrast: isodense lesion
    • With contrast: 
      • Arterial phase: may have peripheral enhancement 
      • Portal venous phase: with centripetal flow
    • If with areas of hemorrhage, necrosis, and calcification, adenoma appears heterogeneous.
  • MRI with contrast:
    • Superior to other modalities for HCA diagnosis
    • Arterial phase: well-demarcated, enhanced lesion (heterogeneous due to hemorrhage, necrosis, steatosis)
    • Pattern in later phases correlates with molecular subtypes in majority of cases (inflammatory and HNF1-ɑ type):
      • Inflammatory adenoma: Arterial enhancement persists into the portal venous and delayed phases.
      • HCA with HNF1-ɑ mutation: Arterial enhancement does not persist.
      • β-catenin–activated HCA: no specific MRI characteristics
  • Core needle biopsy: for clarification if imaging is equivocal

Magnetic resonance imaging in a patient with adenoma with bleeding: white arrow, hematoma; black arrow, hepatic adenoma.
A: T2 sequence with fat saturation shows a hepatic subcapsular nodule with hyposignal.
B: Pre-contrast T1 sequence shows a lesion with hypersignal, signifying products of hemoglobin degradation.
C: Post-contrast T1 sequence in the arterial phase emphasizes the hepatic lesion.

Image: “MRI” by Enio Campos AMICO, José Roberto ALVES et al. License: CC BY 4.0

Management

  • Discontinue anabolic steroids or OCPs.
  • Weight loss
  • Observation and surveillance:
    • Women with tumor < 5 cm: contrast-enhanced MRI in 6 months and annually thereafter if there is no growth
    • Asymptomatic women, tumor > 5 cm with OCP use:
      • May try OCP discontinuation
      • If MRI shows lesion remains > 5 cm after 6 months, proceed with surgical resection.
  • Surgical resection:
    • Tumor is > 5 cm: surgical resection due to increased risk of rupture, bleeding, or malignant transformation
    • Men with HCA (regardless of size)
    • Proven β-catenin mutation
  • Transarterial embolization: 
    • Tumor complicated by bleeding and hemodynamic instability
    • If after the procedure there is residual lesion noted on follow-up imaging, perform surgical resection.

Differential Diagnosis

  • HCC: a type of cancer that develops in patients with liver cirrhosis. Typically presents with abdominal pain and is found on imaging of the liver. Treatment is with surgery, radiation, and chemotherapy. There are specific imaging features of hepatic hemangioma (peripheral enhancement) and FNH (central stellate scar) that can help to differentiate these tumors from HCC. Further differentiation may require a biopsy of the lesion.
  • Liver metastases: present as masses in the liver parenchyma. These lesions are seen as multiple ring-enhancing lesions of the liver on contrast CT scan, which help distinguish them from benign lesions. Patients often have a history of extrahepatic malignancy that makes metastasis a more likely cause of liver lesions. 
  • Liver abscess: presents as a mass in the liver parenchymal due to infection in the liver. Patients often present with diarrhea (in cases of amebic liver abscess), abdominal pain, and/or fever. Systemic symptoms help differentiate abscesses from other tumors. 
  • Hepatic cysts: benign liquid-filled lesions on the liver, often presenting as incidental liver masses. On ultrasound, the cyst is an anechoic, round lesion with dorsal acoustic enhancement. On CT scan, the cyst is seen as a well-delimited lesion with no contrast enhancement, which helps to differentiate hepatic cysts from benign liver tumors.

References

  1. Chopra, S. (2019). Focal nodular hyperplasia. Runyon, B., Robson, K. (Eds). UpToDate. Retrieved 22 Nov 2020 from https://www.uptodate.com/contents/focal-nodular-hyperplasia
  2. Colombo, M. (2020). EASL Clinical Practice Guidelines on the Management of Benign Liver Tumors. Retrieved 22 Nov 2020 from https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/cld.933
  3. Curry, M., Chopra, S. (2019). Hepatic hemangioma. Lindor, K., Robson, K. (Eds). UpToDate. Retrieved 22 Nov 2020 from https://www.uptodate.com/contents/hepatic-hemangioma
  4. Friedman L.S. (2021). Benign liver neoplasms. Papadakis M.A., & McPhee S.J., & Rabow M.W.(Eds.), Current Medical Diagnosis & Treatment 2021. McGraw-Hill.
  5. Gill, R., Kakar, S. (2020). In Kumar, V., Abbas, A. K., Aster, J.C., (Eds.), Robbins & Cotran Pathologic Basis of Disease. (10th ed., pp. 865-867). Elsevier, Inc
  6. Leon, M., Chavez, L., Surani, S. (2020). Hepatic hemangioma: what internists need to know. World J Gastroenterol. 26(1): 11–20. doi: 10.3748/wjg.v26.i1.11
  7. Llovet J.M. (2018). Tumors of the liver and biliary tree. Jameson J, & Fauci A.S., & Kasper D.L., & Hauser S.L., & Longo D.L., & Loscalzo J (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.
  8. Raveendran, S., Lu, Z. (2018). A short review on early HCC: MRI findings and pathological diagnosis. Radiology of Infectious Diseases, Volume 5, Issue 2, pp. 91-97. https://doi.org/10.1016/j.jrid.2017.08.008
  9. Shreenath, A., Kahloon, A. (2020). Hepatic Adenoma. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK513264/

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