Liver and intrahepatic bile ducts - tumor
Benign tumors / conditions
Hepatocellular adenoma

Author: Avani Pendse, M.D., Ph.D.
Editorial Board Member Review: Raul S. Gonzalez, M.D.
Editor-in-Chief Review: Debra Zynger, M.D.

Revised: 6 December 2018, last major update October 2018

Copyright: (c) 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Hepatocellular adenoma[TI] free full text[sb]

See also: Atypical hepatocellular adenomaPigmented liver cell adenoma
Cite this page: Pendse A. Hepatocellular adenoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/livertumorhepatocellularadenoma.html. Accessed December 14th, 2018.
Definition / general
Essential features
  • Arises in noncirrhotic liver
  • Female > male, strong association with oral contraceptive exposure
  • Unpaired arteries with absence of interlobular bile ducts
Terminology
  • Also known as hepatic adenoma and liver cell adenoma
  • 5 main subtypes:
    • HNF1α mutated hepatocellular adenoma (HA-H, ~35%)
    • β catenin mutated hepatocellular adenoma (HA-B, ~10%)
    • Inflammatory hepatocellular adenoma (HA-I, ~35%)
    • Sonic hedgehog (SHH) hepatocellular adenoma (HA-sh, ~5%)
    • Hepatocellular adenoma, not otherwise specified (HA-U, ~7%)
ICD coding
  • D13.4: Benign neoplasm of liver
Epidemiology
  • Female > male
  • Annual incidence: 1 - 1.5 cases per million population with significantly higher incidence in women taking oral contraceptive pills, approximately 3 per 100,000 (N Engl J Med 1976;294:470)
  • Additional risk factors include anabolic steroids, noncontraceptive estrogen supplements, obesity and metabolic syndrome
  • Mean age = 37 - 41 years
    • Rare in pediatric patients
Sites
  • Liver
Pathophysiology
  • Based on specific subtypes:
    • HNF1α mutated hepatocellular adenoma (HA-H): somatic mutations of TCF1 (HNF1A) gene and rare (< 5%) heterozygous germline mutations of CYP1B1 gene; resultant increase in lipogenesis by promotion of fatty acid synthesis and by downregulation of liver type fatty acid binding protein (LFABP) (Nat Genet 2002;32:312)
    • β catenin mutated hepatocellular adenoma (HA-B): β catenin gene activating mutations (exon 7 - 8 and exon 3), resultant stabilization of β catenin protein and increased or nontransient activation of Wnt / β catenin signaling pathway (Hepatology 2006;43:515)
    • Inflammatory hepatocellular adenoma (HA-I): gain of function mutations of the IL6ST gene, activation of STAT3 signaling pathway and acute phase inflammatory response (Nature 2009;457:200)
    • Sonic hedgehog (SHH) hepatocellular adenoma (HA-sh): activation of sonic hedgehog pathway via fusion of promoter of INHBE with GLI1 (Gastroenterology 2017;152:880); also upregulation of argininosuccinate synthase 1, which may indicate increased risk of hemorrhage (Hepatology 2017;66:2016, Hepatology 2018;68:964)
Diagrams / tables

Images hosted on PathOut server:

Contributed by Avani Pendse, M.D., Ph.D.

Subtypes

Clinical features
  • May be asymptomatic and incidentally diagnosed due to imaging performed for an unrelated indication
  • Symptomatic lesions present with abdominal pain or hemorrhage
  • Risk of hemorrhage increases with size
Diagnostic criteria
  • Unpaired arteries are characteristic; interlobular bile ducts are absent
  • Cytologic atypia is unusual
  • Thin or mildly thickened hepatocyte cell plates
Laboratory
  • Liver function tests tend to be normal
  • Mild elevation in alpha fetoprotein in some cases
Radiology description
  • MRI is the most optimal imaging modality
  • Features characteristic of a hepatocellular adenoma over focal nodular hyperplasia include strong hyperintensity on T2 weighting, hyperintensity on T1 weighting, cystic areas, hemorrhagic areas and diffuse intralesional steatosis (Diagn Interv Radiol 2014;20:193)
  • Specific features for some subtypes:
    • HNF1α mutated hepatocellular adenoma (HA-H): homogeneous dropout of signal on T1 weighted out of phase sequence
    • Inflammatory hepatocellular adenoma (HA-I): marked hyperintensity on T2 weighted sequences, hyperintense rim on T2 weighted sequence which corresponds to sinusoidal dilatation, also known as "atoll sign"
Radiology images

Images hosted on other servers:

HA-H MRI

HA-B MRI

Prognostic factors
  • Risk of malignant transformation is higher in
    • Men
    • β catenin mutated hepatocellular adenoma (HA-B)
    • Larger tumors
Case reports
Treatment
  • Male patients: surgical excision irrespective of size
  • Female patients: surgical excision if > 5 cm in size and with β catenin activating mutations (Therap Adv Gastroenterol 2016;9:898)
  • Nonsurgical cases: suspension of oral contraceptive pills (if applicable) and imaging follow up
Gross description
  • Majority are solitary and well circumscribed
  • Uncapsulated or develop ill defined pseudocapsule
  • Lighter in color compared to surrounding liver
  • Foci of necrosis, hemorrhage and bile staining
  • Usually lack significant fibrosis (including central scar) and nodularity
Gross images

Images hosted on PathOut server:

Contributed by Avani Pendse, M.D., Ph.D.

HA-I



Images hosted on other servers:

HA-H, HA-I, HA-B

Multiple adenomas

Malignant transformation

Microscopic (histologic) description
  • Well defined border between the lesion and background liver
  • Composed of hepatocytes with no significant cytologic atypia
  • Arranged as thin or only mildly thickened cell plates, 1 - 2 cells thick
  • May have pseudoacinar arrangement and steatotic foci
  • Characterized by unpaired arteries; interlobular bile ducts are absent, some cases show bile ductules
  • Foci of hemorrhage, ischemic changes and necrosis
  • No cytologic atypia, atypical mitoses and portal / parenchymal invasion
  • Reticulin stain helpful to establish near normal hepatocyte plate thickness, with only focal loss particularly in the steatotic areas
  • Microscopic features of specific subtypes include:
    • HNF1α mutated hepatocellular adenoma (HA-H): characterized by steatosis (fat accumulation in lesional hepatocytes), reticulin staining is mostly intact, some cases / areas show "packeting," i.e. prominent pericellular staining or almost complete circling of small groups of hepatocytes by reticulin fibers
    • β catenin mutated hepatocellular adenoma (HA-B): pseudoacinar arrangement; cytologic abnormalities including nuclear pleomorphism and atypia, multinucleation, prominent nucleoli; steatosis is rare, no significant inflammation
    • Inflammatory hepatocellular adenoma (HA-I): may have irregular, poorly circumscribed borders; inflammatory infiltrates and sinusoidal dilatation; may have "pseudoportal tracts," which are islands of thick walled arteries with no definite bile ducts but associated ductular reaction
    • Hepatocellular adenoma, not otherwise specified (HA-U): morphology characteristic of adenoma but no specific characteristics of the individual subtypes; lesions with extensive hemorrhage and necrosis are currently grouped into this subtype
  • References: Burt: MacSween's Pathology of the Liver, 7th Edition, 2017, Diagn Pathol 2016;11:27, Clin Mol Hepatol 2016;22:199, Hepatology 2006;43:515, Arch Pathol Lab Med 2014;138:1090, Front Med (Lausanne) 2017;4:10
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Avani Pendse, M.D., Ph.D.

HA-I: sinusoidal dilatation

HA-I: inflammation

HA-I: SAA

HA-I: β catenin

HA-I: glutamine synthetase

HA-I: glypican 3



Contributed by Raul S. Gonzalez, M.D.

HA-B: focal pseudoacinar architecture



Images hosted on other servers:

HA-H, HA-B,
HA-I, HA-U

HA-H

HA-B

HA-I

Malignant transformation

Cytology description
Positive stains
  • HepPar1
  • Reticulin: intact staining pattern with focal loss in steatotic areas (Arch Pathol Lab Med 2015;139:537)
  • Characteristic staining for individual subtypes:
    • β catenin mutated hepatocellular adenoma (HA-B): β catenin nuclear (often focal), glutamine synthetase (strong and diffuse)
    • Inflammatory hepatocellular adenoma (HA-I): SAA, CRP
Negative stains
Differential diagnosis
  • Focal nodular hyperplasia (Clin Mol Hepatol 2016;22:199):
    • Prominent central scar detected by imaging or gross evaluation
    • Radiating fibrous septa with inflammatory infiltrate and prominent thick walled, abnormal vessels and associated ductular reaction
    • Map-like glutamine synthetase positive staining pattern
  • Well differentiated hepatocellular carcinoma:
    • Thickened cell plates, wider than 2 cells thick
    • Trabecular and pseudoacinar architecture
    • Cytologic atypia and increased mitoses
    • Stromal and vascular invasion
    • Complete CD34 positivity, reticulin highlights thickened hepatocyte plates
  • Mass effect adjacent to mass lesion:
    • Sinusoidal dilation may mimic HA-I, especially on biopsy (Hum Pathol 2017;61:105)
    • Unpaired arteries and CD34 positivity help confirm HA-I
Board review question #1
A representative section of a well differentiated hepatocellular lesion shows strong and diffuse positive staining for glutamine synthetase. Which entity should be considered in the differential diagnosis?



  1. β catenin mutated hepatocellular adenoma
  2. Focal nodular hyperplasia
  3. Inflammatory type hepatocellular adenoma
  4. Poorly differentiated hepatocellular carcinoma
Board review answer #1
A. β catenin mutated hepatocellular adenoma (Gastroenterol Hepatol (N Y) 2017;13:740)

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Board review question #2
Which of the following is most strongly associated with hepatocellular adenoma?

  1. Alcohol
  2. Cigarette smoking
  3. Nulliparity
  4. Oral contraceptives
Board review answer #2
D. Oral contraceptives

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