A Guide to Hepatic Adenoma: Clinical Presentation to Management

What is Hepatic Adenoma? : Guide Hepatic Adenoma

Guide Hepatic Adenoma The term ‘Hepatic Adenoma’ is derived from two words: ‘hepatic‘ refers to anything related to the liver, and ‘adenoma‘ is a noncancerous (benign) tumor that arises from glandular tissues. Thus, ‘Hepatic Adenoma’ (HA), also known as Hepatocellular Adenoma, refers to rare benign hepatocellular neoplasms of the liver most commonly associated with hormonal and metabolic influences. Although rare in nature, they are more prevalent in women of childbearing age who have a history of oral contraceptive use. Still, they can also occur in men who have taken anabolic or androgenic hormonal therapy.^[1]

It is usually asymptomatic and is often an incidental finding during an ultrasound or MRI. In smaller lesions, treatment involves discontinuing the external hormones. However, in larger lesions (>5cm), surgical excision is carried out.

Prevalence of HA

Hepatic Adenoma is more prevalent in women, especially those with a history of oral contraceptive pill use. About 3-4 women in 100,000 are at risk of developing HA. Overall, the annual incidence is approximately 1–1.3 cases per million people.

The incidence of HA has increased after the 1960s, with the increasing use of oral contraceptive pills and hormonal therapies.

Who is at risk of developing HA?

The people who are at risk for developing HA are as follows:

1. Women of reproductive age with a history of oral contraceptive pill therapy.
2. Hepatic adenomas are less common in men, but when they do occur, they are most strongly associated with anabolic–androgenic steroid use (synthetic drugs that mimic the effects of the male hormone testosterone). In men, hepatic adenomas are more likely to belong to the β-catenin–activated subtype, which carries a higher risk of malignant transformation, regardless of tumor size.
3. Rarely, in individuals with a history of excess androgen exposure, such as androgen steroid therapy for Fanconi’s anemia.
4. Obese individuals, due to increased inflammation.
5. Individuals with metabolic syndrome, a cluster of metabolic abnormalities associated with chronic low-grade inflammation.
6. Occasionally, in glycogen storage disease types I and III.
7. Rare diseases such as Maturity-Onset Diabetes of the Young Type 3 (MODY3), a disease caused by mutation in the HNF-1α.

Rare cases have also been reported in various other diverse clinical settings.^[2]

What causes HA?

Hepatic Adenoma is caused by gene mutations in the liver cells (hepatocytes). Continuous long-term hormonal stimulation of the hepatocytes in the form of oral contraceptives, synthetic hormones, metabolic diseases, or obesity can lead to such genetic changes in the DNA of the hepatocytes. Henceforth, these mutations disrupt normal cellular regulatory pathways, resulting in uncontrolled but benign proliferation and the formation of a well-defined mass.

The genomic instability caused by chronic hormonal stimulation affects the following genes: Hepatocyte Nuclear Factor -1α (HNF1A), Catenin-β (CTNNB1), Interleukin 6 cytokine family signal transducer (IL6ST); each giving rise to its own subtype discussed below.

What are the types of Hepatocellular Adenoma?

Hepatic Adenoma is classified based on the molecular behaviour patterns. Biolauc-Sage developed this phenotype-genotype classification.^[3] It divides HA into 4 main groups:

1. Hepatocyte Nuclear Factor -1α (HNF-1α) Inactivated Mutations:

• 35% to 40% of HAs are of this type.
• HNF-1α gene codes for a protein that is involved in hepatocyte differentiation, liver development, and glucose and lipid metabolism.
• The mutation in this gene disrupts the normal functioning of liver cells. This results in the accumulation of a mass of abnormal cells.
• The risk of hemorrhage and malignant transformation is among the lowest of all the phenotypes.

2. β-Catenin Activated Mutations

• It occurs in 15% to 20% of liver adenoma cases.
• Adenomas in this group have an increased malignant transformation risk.
• It is more common in men and individuals with risk factors such as glycogen storage disease or anabolic steroid use.
• CTNNB1 codes for Beta-catenin, a multitasking protein that plays a crucial role in cell adhesion and gene regulation. A mutation in its gene can cause its overactivation, resulting in atypical growths.

3. Inflammatory Hepatic Adenomas

• It occurs in 40% to 50% of patients with HA.
• Risk factors include female sex, high body mass index (BMI), excessive alcohol consumption, and systemic inflammatory syndrome.
• Excessive expression of inflammatory proteins, such as Interleukin-6 (IL-6), is the key causative factor in this type. IL-6 plays a crucial role in cell signalling in the immune system, helping fight infections.
• However, excess IL-6 inflammatory pathway activation (modulated by IL6ST gene) causes the arteries of the liver to have thickened walls and dilations, i.e., dystrophic vessels and telangiectasia.
• They are often larger in size.
• Due to their high vascularity, these can be prone to rupture and hemorrhage (bleeding).

4. Unclassified Type

• It occurs in up to 10% of hepatic adenoma cases.
• The lesions are negative for inflammatory proteins and β-catenin, but exhibit typical liver fatty acid-binding protein (LFABP) staining.
• Thus, they can not be classified into any other type and are unclassified.

Distribution of hepatic adenoma subtypes, illustrating the relative proportions of inflammatory (40%), HNF-1α inactivation (35%), β-catenin activation (15%), and other variants (10%). Graphic created using Canva.

Morphology of Hepatic Adenoma

Hepatic adenomas present themselves in various forms:

• The lesion is benign, well-demarcated, and occasionally encapsulated (about 17%)^[4]
• They are usually solitary, and occasionally pedunculated (attached via a stem).
• Additionally, they come in various sizes, ranging from a few millimeters up to 30 cm.
• On cut sections, it is of “fleshy” appearance, with the color ranging from white to brown.
• It is a highly vascular tumor, and the dilated vessels can even be seen on macroscopic imaging. Upon observing in the microscope, small, thin blood vessels are visible throughout the lesion.^[5]

Symptoms of Hepatic Adenoma

Hepatic Adenoma generally does not express any symptoms and is asymptomatic. It is typically found as an incidental finding during an abdominal scan. The patient might not even know that they carry the tumor.

Alternatively, if the tumor were to spontaneously rupture and bleed (occurs in about 27%^[6] of cases), the patient could present to the clinic with:

• Severe abdominal pain or ill-defined epigastric pain
• Bloating
• Dizziness
• Vomiting
• Fever
• Tachycardia (fast heartbeat)
• Lethargy

Further investigations, such as liver function tests, could indicate slight abnormalities but do not provide significant diagnostic values. The liver function abnormalities are related to the size of the tumour; the larger the space that the tumour occupies, the more liver function will be impaired. Serum alkaline phosphatase and gamma-glutamyl transferase levels (GGT) are generally elevated.^[7]

Hepatic Adenoma Vs Hepatocellular Carcinoma

Hepatic adenoma (also called hepatocellular adenoma) is a benign liver tumor, while hepatocellular carcinoma is malignant. Imaging, size, and subtype help doctors distinguish between them.

Feature	Hepatic Adenoma	Hepatocellular Carcinoma (HCC)
Nature	Benign liver tumor	Malignant liver tumor
Common Patients	Women on hormones, obesity	Adults with liver disease/cirrhosis
Symptoms	Usually none; pain if large	Pain, jaundice, weight loss
Treatment	Monitor small; surgery if >5 cm	Surgery, transplant, or therapy
Prognosis	Excellent	Variable, depends on stage

How is Hepatic Adenoma diagnosed?

As discussed above, Hepatic Adenoma is an asymptomatic disease, and clinicians usually find it as an accidental finding. Healthcare providers make the initial diagnosis with an abdominal ultrasound, followed by specialized imaging modalities such as iodinated or gadolinium-based contrast agent–enhanced CT scan, or an MRI, respectively.^[8]

Thereupon, on an imaging scan, the most noticeable feature of the lesion is the presence of fat or vascular malformation. So, the imaging modality should be fat sensitive and use a contrast agent to diagnose vascular dilatations.^[9] On MRI, radiologists describe findings using terms such as T1-weighted and T2-weighted images:

• T2-weighted images highlight fluid, inflammation, or dilated blood vessels, making some adenomas appear brighter.
• T1-weighted images help identify fat or old bleeding within the tumor.

Characteristic features include:

• Many hepatic adenomas show arterial phase enhancement, meaning the tumor briefly lights up when contrast first reaches the liver, reflecting its rich blood supply.
• Hyperintensity on T1 weighting
• Cystic areas
• Hemorrhagic areas
• Diffuse intralesional steatosis

Diagnostic features of each subtype show:

• HNF1A mutated HA: It often contains fat, which causes the signal to drop on specific MRI sequences.
• β-Catenin mutated HA: T2-hyperintense central scar and shows peak enhancement in the arterial phase that may persist to the portal venous phase. They are evaluated carefully because of their higher cancer risk.^[10]
• Inflammatory HA: Marked hyperintensity on T2-weighted sequences, hyperintense rim on T2-weighted sequence, which corresponds to sinusoidal dilatation, also known as “atoll sign.”^[11]

Since the CT and MRI scans are able to provide characteristic features of the lesions, biopsy is rarely required for diagnosis. It may be considered in unclear or obscure lesions.

As discussed earlier, the liver function tests do not play a significant role since they are usually normal to slightly elevated. Alpha-fetoprotein may aid in ruling out malignancy in high-risk cases.

Ultrasound image demonstrating a well-circumscribed hepatic adenoma (indicated by arrow). Image sourced by: Sabawoon Mirwais. “Ultrasound of a hepatic adenoma.”WikiDoc. Licensed under CC BY-SA 3.0.

Can a benign HA turn malignant?

Yes, benign lesions can become malignant and convert into cancers through the accumulation of genetic mutations. Hepatic Adenomas with β-Catenin Activated Mutations are the most prone to malignant transformation. Correspondingly, (HNF-1α) Inactivated Mutations type has the lowest malignant transformation rate. In total, approximately 4% to 5% of the lesions are at risk for malignant transformation from benign Hepatic Adenomas to Hepatic Carcinoma. The risk increases with Fanconi anemia and androgen treatments.

How is Hepatic Adenoma treated?

Management of Hepatic Adenomas is carried out based on the size of the lesion, gender, and risk factors.

1. Conservative approach:

Hepatic Adenomas in women, that are less than 5cm in size, and linked to oral contraceptive use, are approached conservatively. Hence, the withdrawal of these oral contraceptive pills is the first step. This is followed by regular and periodic imaging scans (CT scan or MRI) to monitor the lesion. Numerous cases show regression of the tumor size.^[12]

Most hepatic adenomas remain stable during pregnancy. Tertiary centers often monitor adenomas smaller than 5 cm regularly in pregnancy every 3 months, and after birth during the postpartum period. Patients with small adenomas are not discouraged from getting pregnant.

2. Surgical Resection

All male patients are advised to undergo a surgical resection of the lesion, regardless of size. Women with tumors larger than 5cm are also recommended for surgery.^[13]

3. Transarterial Embolization

Inflammatory Hepatic Adenomas are prone to rupture and bleeding due to the dilation of the blood vessels. If the tumor undergoes haemorrhage or rupture, interventional radiologists stabilize it via a minimally invasive procedure called ‘Transarterial Embolization’ (TEA). TEA is indicated within 48-72 hours of hemorrhage.

The ‘National Cancer Institute Dictionary’ defines TEA as: “A procedure in which the blood supply to a tumor or an abnormal area of tissue is blocked. During transarterial embolization, a small incision (cut) is made in the inner thigh, and a catheter (thin, flexible tube) is inserted and guided into an artery near the tumor or abnormal tissue. Once the catheter is in place, small particles made of tiny gelatin sponges or beads are injected. This blocks the artery and stops the flow of blood to the tumor or abnormal area of tissue.”^[14]

Additionally, if the patient presents with hemodynamic stability, the multidisciplinary team can perform TAE first and then follow it with the elective surgical removal of the lesion.

Gross liver specimen from a patient with a spontaneously ruptured hepatocellular adenoma. The adenoma is 6cm in length. Image sourced from Open-i, U.S. National Library of Medicine (NLM). Image sourced from “Late Surgical Treatment for Spontaneous Rupture of Hepatocellular Adenoma: Case Report,”Open-i, U.S. National Library of Medicine, under a Creative Commons Attribution (CC BY) license.

In conclusion, the type of treatment is determined by the clinical presentation, risk factors, and complications present in the tumor.

References

[1] Paulson EK, McClellan JS, Washington K, Spritzer CE, Meyers WC, Baker ME. Hepatic adenoma: MR characteristics and correlation with pathologic findings. American Journal of Roentgenology. 1994 Jul 1;163(1):113–6.

[2] Micchelli STL, Perumal Vivekanandan, Boitnott JK, Pawlik TM, Choti MA, Torbenson M. Malignant transformation of hepatic adenomas. Modern Pathology. 2008 Feb 1;21(4):491–7.

[3] Frenette C, Mishal Mendiratta-Lala, Salgia R, Wong RJ, Sauer BG, Pillai A. ACG Clinical Guideline: Focal Liver Lesions. The American Journal of Gastroenterology [Internet]. 2024 Jan 26;119(7):1235–71., Shreenath AP, Kahloon A. Hepatic Adenoma [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2020.

[4] Paulson EK, McClellan JS, Washington K, Spritzer CE, Meyers WC, Baker ME. Hepatic adenoma: MR characteristics and correlation with pathologic findings. American Journal of Roentgenology. 1994 Jul 1;163(1):113–6.

[5] Colombo M, Forner A, Ijzermans J, Paradis V, Reeves H, Vilgrain V, Zucman-Rossi J; on behalf of the European Association for the Study of the Liver.EASL Clinical Practice Guidelines on the management of benign liver tumours.Journal of Hepatology.2016; 65(2): 386–398.

[6] Shreenath AP, Kahloon A. Hepatic Adenoma [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2020

[7] Donato M, Jahromi AH, Andrade AI, Kim R, Shabnum Ilyas Chaudhery, Sangster G. Hepatic Adenomatosis: A Rare but Important Liver Disease With Severe Clinical Implications. International Surgery [Internet]. 2015 May 1;100(5):903–7

[8] Frenette C, Mishal Mendiratta-Lala, Salgia R, Wong RJ, Sauer BG, Pillai A. ACG Clinical Guideline: Focal Liver Lesions. The American Journal of Gastroenterology [Internet]. 2024 Jan 26;119(7):1235–71

[9] Colombo M, Forner A, Ijzermans J, Paradis V, Reeves H, Vilgrain V, Zucman-Rossi J; on behalf of the European Association for the Study of the Liver.EASL Clinical Practice Guidelines on the management of benign liver tumours.Journal of Hepatology.2016; 65(2): 386–398.

[10] Tse JR, Felker ER, Naini BV, Shen L, Shen J, Lu DSK, et al. Hepatocellular Adenomas: Molecular Basis and Multimodality Imaging Update. Radiographics. 2023 Mar 1;43(3).‌

[11] Abdelmalak M, Yablonski J, Pendse A.Hepatocellular adenoma[Internet]. PathologyOutlines.com; Editorial Board: Gonzalez R, Vyas M; Deputy Editor-in-Chief: Huber AR.

[12] Colombo M, Forner A, Ijzermans J, Paradis V, Reeves H, Vilgrain V, Zucman-Rossi J; on behalf of the European Association for the Study of the Liver.EASL Clinical Practice Guidelines on the management of benign liver tumours.Journal of Hepatology.2016; 65(2): 386–398.

[13] European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of benign liver tumours.J Hepatol. 2016;65(2):386–398.

[14] National Cancer Institute – Dictionary