Liver & intrahepatic bile ducts
Benign / nonneoplastic
Hepatocellular adenoma
Author: Avani Pendse, M.D., Ph.D.
Editorial Board Member: Raul S. Gonzalez, M.D.
Editor-in-Chief: Debra Zynger, M.D.
Topic Completed: 1 October 2018
Minor changes: 1 August 2020
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PubMed Search: Hepatocellular adenoma[TI] free full text[sb]
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Diagrams / tables | Clinical features | Diagnostic criteria | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Differential diagnosis | Board review style question #1 | Board review answer #1 | Board review style question #2 | Board review answer #2Cite this page: Pendse A. Hepatocellular adenoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livertumorhepatocellularadenoma.html. Accessed August 14th, 2020.
Definition / general
- Benign neoplasm of hepatocellular origin arising in the noncirrhotic liver
- Majority are solitary; adenomatosis when > 10 lesions
- Rare cases associated with glycogen storage disease (type 1a), maturity onset diabetes of the young type 3 and Fanconi anemia
- 5 main subtypes based on gene mutations
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
- 6 day old boy with multiple adenomas and microvillus inclusion disease (Dig Dis Sci 2013;58:2784)
- 20 year old man with malignant transformation of β catenin mutated adenoma (Oncology 2017;92:16)
- 23 year old woman with diabetes and malignant transformation of HNF1α mutated adenoma (Semin Liver Dis 2015;35:444)
- 31 year old woman with recurrent adenoma requiring liver transplant (Rev Esp Enferm Dig 2014;106:494)
- 36 year old woman with hematoma following remote trauma (World J Gastroenterol 2013;19:4422)
- 11 cases of malignant transformation of adenoma (Mod Pathol 2014;27:1499)
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
- Cytologically bland hepatocytes on smears; uniform, regular nuclei with low N/C ratios and rare mitoses (Cibas: Cytology - Diagnostic Principles and Clinical Correlates, 4th Edition, 2014)
- Diagnosis is difficult by cytology alone given that a well differentiated hepatocellular carcinoma is in the differential diagnosis and presence or lack of invasion cannot be evaluated on smears alone
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:
Negative stains
- Glypican 3, arginase: majority negative (Am J Surg Pathol 2008;32:433)
- CD34: negative or incomplete positive (rare complete positive) (Am J Surg Pathol 2008;32:433)
- Characteristic staining for individual subtypes:
- HNF1α mutated hepatocellular adenoma (HA-H): LFABP (positive in background liver)
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:
- 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 style 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?
- β catenin mutated hepatocellular adenoma
- Focal nodular hyperplasia
- Inflammatory type hepatocellular adenoma
- Poorly differentiated hepatocellular carcinoma
Board review answer #1
Board review style question #2
Which of the following is most strongly associated with hepatocellular adenoma?
- Alcohol
- Cigarette smoking
- Nulliparity
- Oral contraceptives
Board review answer #2
