Bühler et al. were the first to recognize the connection between HCA and oral contraceptives in 1982, but as early as 1977 Edmondson et al. described the regression of HCA after discontinuation of oral contraceptives.
HNF-1A-inactivated HCA was the first subtype to be described by Bluteau et al. in 2002 (Wang 2022). In 2017, a group of French researchers recommended a new classification of HCA based on a genome analysis and identified 3 new subtypes (Renzulli 2019).
Hepatocellular adenoma (HCA) is a heterogeneous group (Wang 2022) of a monoclonal benign liver tumor (Herold 2022) that can occur singly or in multiples (Berg 2023).
HCA is a benign tumor of the liver (Heise 2023). It can reach a diameter of more than 10 cm. Over the last two decades, there has been considerable progress in the research and diagnosis of HCA, which has led to the molecular and immunohistologic classification of HCA (Bioulac- Sage 2022).
HCA is currently divided into 6 different main subtypes, which are associated with specific risk factors and show different biological behavior (Klompenhouwer 2020):
1. H- HCA (HNF1A inactivated HCA [Klompenhouwer 2020]):
- Risk factors: MODY type 3, HNF1A germline mutations, microsatellite instability
- Clinical features: Hepatic adenomatosis
- Histological features: Intralesional steatosis (Hahn 2020)
- Frequency: 30 - 35 % (Renzulli 2019)
2nd I- HCA (inflammatory HCA [Klompenhouwer 2020]):
- Risk factors: obesity, alcohol, glycogenosis
- Clinical features: Inflammatory syndrome
- Histological features: Inflammatory infiltrate, sinusoidal enlargement
- Frequency: 30 - 50 % (Hahn 2020)
3. b ex3- HCA
- Risk factors: androgen therapy, male sex, hepatic vascular disease
- Clinical features: Frequently occurring malignant degeneration
- Histological features: Slight nuclear atypia, pseudoacinar formation (Hahn 2020)
- Frequency: 7 % (Renzulli 2019)
4. b- ex- 7.8 HCA
- Risk factors: No specific risk factors known
- Clinical features: No specific clinical features known
- Histological features: No specific features known (Hahn 2020)
- Frequency: 3 % (Renzulli 2019)
5. sh- HCA
- Risk factors: Obesity
- Clinical features: Symptomatic bleeding
- Histological features: Intratumoral hemorrhage (Hahn 2020)
- Frequency: 4 % (Renzulli 2019)
6th U- HCA (unclassified HCA [Klompenhouwer 2020])
- Risk factors: No specific risk factors known
- Clinical features: No specific clinical features known
- Histologic features: No specific features known
- Frequency: 7 % (Hahn 2020)
HCA occurs only rarely. Women are affected 4 times more frequently than men (Herold 2022). Nevertheless, it is the second most common benign lesion of hepatocellular origin after focal nodular hyperplasia (FNH) in non-cirrhotic patients (Renzulli 2019).
The mean age of onset is 36 - 38 years (Wang 2022). However, HCA has been described at any age, even in infants (Bioulac - Sage 2017). In children, the average age of onset is 14 years (Hahn 2020).
Risk factors for the occurrence of HCA are:
- Oral estrogen-containing contraceptives
- Anabolic steroids (Herold 2022)
- Obesity (Berg 2023)
- Hereditary glycogen storage disorders (GDS) such as type I and III HGS (Kasper 2015)
- Liver vascular diseases (Wang 2022)
- Metabolic syndrome (Renzulli 2019)
- Alcohol consumption
- Chronic viral hepatitis (Hahn 2020)
HCA is caused by a monoclonal, benign proliferation of hepatocytes. The tumor cells normally resemble normal hepatocytes (Klompenhouwer 2020).
In most cases, HCA is discovered as an incidental finding during abdominal ultrasonography (Heise 2023).
The diagnosis of HCA can be made using abdominal sonography, contrast-enhanced ultrasound (CEUS), color Doppler, MRI and biopsy, etc. (Herold 2022).
An exact differentiation of the subtypes b- HCA, sh- HCA and U- HCA is currently not possible through imaging (Klompenhouwer 2020).
Sonography
Smaller HCA, i.e. with a diameter of < 5 cm, are generally isoechogenic to the liver tissue. Larger HCA are usually superficial (Herold 2022).
MRI
MRI is superior to all other imaging techniques in the detection of HCA. Up to 80 % of HCAs can be typed with it (Renzulli 2019). In particular, it is possible to differentiate between H- HCA and I- HCA: H- HCA with a sensitivity of 87 - 91 % and a specificity of 89 - 100 %, I- HCA with a sensitivity of 85 - 88 % and a specificity of 88 - 100 % (Herold 2022 / Renzulli 2019).
Since H- HCA and I- HCA account for the majority of all HCAs with a total of 95%, MRI is by far the superior diagnostic method (Renzulli 2019).
Contrast-enhanced CT
This allows visualization of lesion enhancement patterns as well as dilatation of intratumoral sinusoids (Klompenhouwer 2020).
Biopsy
If there are uncertainties in the diagnosis, a biopsy is recommended (Herold 2022). However, biopsy is sometimes questionable due to the heterogeneity of the tumor. It is still unclear how many biopsies are required for a diagnosis (Renzulli 2019).
Biopsy shows:
- Absence of bile ducts
- Absence of central veins
- Often hemorrhages and necrosis (Herold 2022)
- Malignant liver tumors (Renzulli 2019)
- Focal nodular hyperplasia (Klompenhouwer 2020)
Bleeding
Bleeding occurs in approx. 15 - 20 % of cases (Nault 2017). In the case of a large HCA, the tumor may even rupture with life-threatening bleeding (Herold 2022).
Infarcation
Another complication is the infarction of the tumor (Herold 2022).
Malignant degeneration
Malignant degeneration is possible in certain high-risk subtypes (Wang 2022). Malignant degeneration is found in around 5 % of patients with HCA (Nault 2017).
Spontaneous regression of HCA under oestrogen deprivation has been described (Renzulli 2019 / Edmondson 1977). In the last decade, several studies have shown that weight reduction in obese patients can also lead to a regression of the HCA (Klompenhouwer 2020).
A large superficial HCA is always an indication for surgery (for more details, see "Surgical therapy"). However, the histological type should always be determined before surgery (Berg 2023), as the risk of complications depends on the subtype (Wang 2022).
Gender also plays a role in terms of complications and the risk of malignant transformation. Wang (2022) now recommends surgical removal for all men with HCA.
After determining the HCA subtype, women should first be monitored for 6 months, during which oral contraceptives should be discontinued, body weight reduced and the size of the tumor checked. For tumors that are > 5 cm in size or continue to grow despite lifestyle changes, resection is recommended regardless of the subtype (Wang 2022).
For tumors < 5 cm with evidence of subtype H-HCA, inflammatory changes and beta-catenin negative, conservative therapy is recommended. Surgical resection is recommended for b-HCAs, b-IHCAs and A-HCAs/HUMPs, regardless of the size of the tumor (Wang 2022).
Surgical removal is always indicated for beta-catenin-activated adenomas, as there is an increased risk of malignant transformation (Herold 2022).
If HCA is detected, anabolic steroids and oestrogens are contraindicated. In addition, weight normalization should be sought (Herold 2022).
Until now, patients with a non-resectable HCA were advised not to become pregnant, as a 2004 study by Cobey et al. reported a mortality risk of 44% for the mother and 38% for the foetus due to HCA rupture. However, in 2011, Noels et al. were able to show that in patients with an HCA < 5 cm who were already pregnant, the pregnancy proceeded without rupture. In 25 %, only a growth of the tumor was observed (Klompenhouwer 2020).