**4. Pathology**

*Liver Disease and Surgery*

postoperatively [7].

**2. Epidemiology**

**3. Risk factors**

rupture and bleeding [9–12].

or liver cell adenoma, which are less desirable because these two can also include the bile duct adenoma [6]. Even though the prognosis of this type of tumor is not well established, it is important to differentiate it from other hepatic tumors since the hepatic adenoma has a particular therapeutic management. Differential diagnosis however can be challenging, but can be achieved preoperatively by imaging techniques. Positive diagnosis is a histopathological one and is often obtained

The incidence of HA has increased in recent years, but at the same time, imaging techniques have improved, and therefore, this higher incidence might be explained by the better diagnostic techniques nowadays available. Also, in recent years, it seems to be a change in epidemiology, as more cases of HA in male patients are described, particularly in Europe and Asia. This may be caused by an increased incidence of obesity, another recognized risk factor of HA. Moreover, in recent years, more and more cases of malignant transformation of HA have been reported, and

Although the link between HA and use or oral contraceptive in women of childbearing age is maintained, recent studies have shown other emerging important risk

The most important risk factor seems to be the use of oral contraceptives. Hepatic adenoma used to be exceptionally rare before the age of oral contraceptives, but after these became popular as a contraceptive solution, more and more cases of HA were reported. In women who were long-time users of oral contraceptives, the incidence was 1 in 30–40,000, whereas in women who have never used oral contraceptives, the incidence was 1 in 1 million, which proves a strong link between these two. Hepatic adenomas in women with prolonged use of oral contraceptives tend to be more numerous, more voluminous, and with a higher risk of spontaneous

Another important risk factor that became even more important than other known risk factors, such as glycogen storage diseases and diabetes mellitus type 2 alone, is the metabolic syndrome. Obesity is more and more prevalent in the general population, and thus, it became a more important risk factor in this pathology. Weight loss should be considered as the first therapeutic option in the management of HA in obese patients [13]. A recent study has proved that bariatric-induced weight loss results in significant regression of HA in severely obese women, which emphasizes the role of overweight in HA pathophysiology [14]. Even more so, patients with metabolic syndrome and hepatic adenomas seem to be associated with a higher rate of malignization [8]. The association between oral contraceptive use and metabolic syndrome on one hand and HA on the other tends to prove an important hormonal sensitivity of the tumor (obesity is associated with higher estrogen levels), and this is supported by the fact that adenomas may stop their evolution or even regress as a result of oral contraceptive cessation [15]. In spite of this, immunohistological studies failed to prove the direct effect of these hormones via steroid receptors in normal and adenomatous hepatic tissue, and so the mechanism by which high estrogen levels may cause an adenomatous transformation is still incompletely understood [16]. As a hyperestrogenic state, pregnancy has also been

this also might be a result of improved histopathological diagnosis.

factors such as metabolic syndrome [8].

**120**

HAs present as solitary lesions in most cases (70–80%), although multiple adenomas can exist of variable sizes. HAs usually occur in the right hepatic lobe. Macroscopically, HAs present as a smooth, tan-colored lesion, well demarcated from the normal hepatic tissue in spite of not having a capsule, often with areas of hemorrhage and necrosis (**Figure 1**). Large blood vessels that surround it are the source of hemorrhage in a complicated adenoma. The lack of a fibrous capsule means that the bleeding can extend into the liver parenchyma unrestricted.

Microscopically, adenomas are made of adenoma cells, which are typically larger than normal hepatocytes and contain glycogen and lipid inclusions (**Figures 2** and **3**). The nuclei are small and regular and mitoses are infrequent. The normal architecture of hepatic tissue is severely disrupted, with no portal tracts of bile ducts, while adenoma cells are disposed in trabeculae interspersed with arteries and thin-walled blood vessels and sinusoids. The absence of bile ducts is a notable feature that helps in the differential diagnosis of HA with nonneoplastic liver tissue and focal nodular hyperplasia. Kupffer cells may only rarely be present in HA.

**Figure 1.** *Resected specimen after mesohepatectomy for a large IHA.*

**Figure 2.** *Normal liver (left) and hepatocellular adenoma (right), HE ×40.*

#### **Figure 3.**

*Hepatocellular adenoma—benign hepatocytes (large, clear, and pale due to accumulation of glycogen) arranged in plates, cords, and sheets, HE ×200.*

Similarities with a well differentiated hepatocellular carcinoma (Edmonson I) makes the differential diagnosis a challenging one.

Based on an extensively characterized clinical, morphological, phenotypical, and genotypical profile, four distinct subtypes of HA have been identified [3, 21]:


Inflammatory and HNF1-mutated hepatic adenomas are the most frequent subtypes (80%).

The first group (H-HA) comprises 35–40% of all patients and almost exclusively includes women. It is related to the presence of transcription factor 1 gene mutations that inactivate hepatocyte nuclear factor 1α (HNF-1α). The nonfunctioning HNF-1α protein promotes lipogenesis and hepatocellular proliferation. Moreover, abnormal HNF-1α protein determines silencing of liver fatty acid-binding protein FABP1. FABP1 is a gene positively regulated by HNF-1α and expressed in normal

**123**

**Figure 4.**

*Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

small HA foci in vicinity.

tion, glycogenosis, and familial polyposis.

liver tissue, but in H-HA its downregulation results in impaired fatty acid trafficking in hepatocytes, which causes intracellular fat deposition [22]. H-HA is sometimes associated with maturity-onset diabetes of the young (MODY), type 3, and familial hepatic adenomatosis. Half of these patients have multiple HAs. More than 90% have a history of oral contraceptive use. The tumors are characterized by marked steatosis (**Figures 4**–**7**), a very low risk of complications, and a low risk of malignant transformation. On immunohistochemistry staining, H-HA is LFABP (liver fatty acid binding protein) negative, which is in contrast with normal expression in the surrounding nontumoral liver [21]. The sharp contrast between tumor and adjacent parenchyma in terms of steatosis and LFABP expression enables delineation of tumor borders which are often irregular and lobulated with often

The second group comprises 10–15% of all patients, includes mainly men, and is characterized by the presence of mutations that activate β-catenin and cellular abnormalities. β-Catenin is encoded by catenin β 1 gene (CTNNB1) on chromosome 3p21 and represents an important downstream effector of the Wnt/β-catenin pathway. This pathway is important in liver embryogenesis, cell adhesion, growth, zonation, and regeneration [22]. An activating β-catenin mutation is also associated with specific conditions such as glycogen storage disorders or androgen administration. The phenotype is represented by cellular atypia with high nuclear-cytoplasmic ratio, nuclear atypia, and pseudoglandular growth pattern. It is identified by immunohistochemistry due to a strong expression of glutamine synthetase with or without aberrant cytoplasmic and nuclear expression of β-catenin. β-HA has the highest risk of malignant transformation than other HA subtypes, and it is very difficult to be distinguished from the well-differentiated hepatocellular carcinoma (HCC). Some risk factors are related to β-HA, such as male hormone administra-

The third group (IHA) includes 50% of all patients and is most common in overweight women who suffer from metabolic syndrome or have had prolonged estrogen exposure. Patients with IHA demonstrate both serum and lesional indicators of an active inflammatory response. IHA is characterized histological by inflammation, marked sinusoidal dilatation or congestion, numerous thick-walled arteries, and ductular reaction (**Figures 8** and **9**). This subgroup was previously named 'telangiectatic focal nodular hyperplasia.' The extent of congestion, peliosis, and hemorrhage is different from case to case. Steatosis may be present in IHA but is not as extensive as in H-HA. In case of multiple tumors, the amount of steatosis

*Hepatocellular adenoma—HNF1 alpha mutated subtype—steatosis within the tumor, HE ×200.*

#### *Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

*Liver Disease and Surgery*

**Figure 2.**

**Figure 3.**

Similarities with a well differentiated hepatocellular carcinoma (Edmonson I)

*Hepatocellular adenoma—benign hepatocytes (large, clear, and pale due to accumulation of glycogen)* 

Based on an extensively characterized clinical, morphological, phenotypical, and genotypical profile, four distinct subtypes of HA have been identified [3, 21]:

3.Inflammatory hepatic adenomas (which harbor mutations involving the

Inflammatory and HNF1-mutated hepatic adenomas are the most frequent

The first group (H-HA) comprises 35–40% of all patients and almost exclusively includes women. It is related to the presence of transcription factor 1 gene mutations that inactivate hepatocyte nuclear factor 1α (HNF-1α). The nonfunctioning HNF-1α protein promotes lipogenesis and hepatocellular proliferation. Moreover, abnormal HNF-1α protein determines silencing of liver fatty acid-binding protein FABP1. FABP1 is a gene positively regulated by HNF-1α and expressed in normal

1.Hepatocyte nuclear factor-1 (HNF-1)—mutated HAs (H-HA)

makes the differential diagnosis a challenging one.

*arranged in plates, cords, and sheets, HE ×200.*

*Normal liver (left) and hepatocellular adenoma (right), HE ×40.*

2. β-Catenin-mutated hepatic adenomas (β-HA)

interleukin-6 signal transducer) (IHA)

4.Unclassified hepatic adenomas (U-HA).

**122**

subtypes (80%).

liver tissue, but in H-HA its downregulation results in impaired fatty acid trafficking in hepatocytes, which causes intracellular fat deposition [22]. H-HA is sometimes associated with maturity-onset diabetes of the young (MODY), type 3, and familial hepatic adenomatosis. Half of these patients have multiple HAs. More than 90% have a history of oral contraceptive use. The tumors are characterized by marked steatosis (**Figures 4**–**7**), a very low risk of complications, and a low risk of malignant transformation. On immunohistochemistry staining, H-HA is LFABP (liver fatty acid binding protein) negative, which is in contrast with normal expression in the surrounding nontumoral liver [21]. The sharp contrast between tumor and adjacent parenchyma in terms of steatosis and LFABP expression enables delineation of tumor borders which are often irregular and lobulated with often small HA foci in vicinity.

The second group comprises 10–15% of all patients, includes mainly men, and is characterized by the presence of mutations that activate β-catenin and cellular abnormalities. β-Catenin is encoded by catenin β 1 gene (CTNNB1) on chromosome 3p21 and represents an important downstream effector of the Wnt/β-catenin pathway. This pathway is important in liver embryogenesis, cell adhesion, growth, zonation, and regeneration [22]. An activating β-catenin mutation is also associated with specific conditions such as glycogen storage disorders or androgen administration. The phenotype is represented by cellular atypia with high nuclear-cytoplasmic ratio, nuclear atypia, and pseudoglandular growth pattern. It is identified by immunohistochemistry due to a strong expression of glutamine synthetase with or without aberrant cytoplasmic and nuclear expression of β-catenin. β-HA has the highest risk of malignant transformation than other HA subtypes, and it is very difficult to be distinguished from the well-differentiated hepatocellular carcinoma (HCC). Some risk factors are related to β-HA, such as male hormone administration, glycogenosis, and familial polyposis.

The third group (IHA) includes 50% of all patients and is most common in overweight women who suffer from metabolic syndrome or have had prolonged estrogen exposure. Patients with IHA demonstrate both serum and lesional indicators of an active inflammatory response. IHA is characterized histological by inflammation, marked sinusoidal dilatation or congestion, numerous thick-walled arteries, and ductular reaction (**Figures 8** and **9**). This subgroup was previously named 'telangiectatic focal nodular hyperplasia.' The extent of congestion, peliosis, and hemorrhage is different from case to case. Steatosis may be present in IHA but is not as extensive as in H-HA. In case of multiple tumors, the amount of steatosis

**Figure 4.** *Hepatocellular adenoma—HNF1 alpha mutated subtype—steatosis within the tumor, HE ×200.*

#### **Figure 5.**

*Hepatocellular adenoma—HNF1 alpha mutated subtype—steatosis and pseudoglandular formations, HE ×200.*

#### **Figure 6.**

*Hepatocellular adenoma—HNF1 alpha mutated subtype—pseudoglandular formations and steatosis within the tumor, HE ×200.*

**Figure 7.** *Hepatocellular adenoma—steatosis within the tumor, HE ×200.*

varies among the tumors in the same patient. Immunohistochemically, it is distinctive by a strong expression of inflammation-associated proteins such as serum amyloid A and C-reactive protein at mRNA and protein levels. The genetics of this

**125**

proteins [23].

necrosis or hemorrhage [21].

*Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

*Hepatocellular adenoma—inflammatory subtype, HE ×200.*

**Figure 8.**

**Figure 9.**

*the tumor.*

group is related to activation of the JAK/STAT pathway underlined by mutations in different genes. In 60%, there are somatic gain-of-function mutations of the interleukin-6 signal transducer gene (IL6ST), which is located at chromosome 5q11 and encodes for glycoprotein 130. Gain-of-function mutations in glycoprotein 130 activate JAK–STAT-3 without interleukin-6 binding. The other 40% show overexpression of wild-type glycoprotein 130, which activates STAT-3 through an unidentified mechanism. Marked peliosis is probably caused by suppression of albumin gene, insulin-like growth factor gene IGF1, and/or transthyretin gene. Mutations of β-catenin may coexist in 10% of IHA (β-IHA). These patients may have signs and symptoms of systemic inflammatory syndrome, manifested as fever, leukocytosis, and elevated serum levels of CRP. Abnormal results of liver function tests may occur, with elevation of alkaline phosphatase and γ-glutamyl transferase. Systemic AA amyloidosis is a rare complication of HA which causes nephrotic syndrome with deteriorating renal function. Resection of the tumor is followed by improvement in renal function and a marked decrease of the serum concentrations of acute phase

*Hepatocellular adenoma—inflammatory subtype, HE ×40, with sinusoidal dilatation and hemorrhage within* 

The last group that is unclassified (UHA) accounts for 5–10% of adenomas. For this

group, the genotype is unknown and the phenotype and immunohistochemistry unspecific. In this group is also included HA that cannot be classified due to near-total

The first important thing for the pathologist is to correctly identify the β-catenin-activated HA and to decide when immunostaining is needed. Morphology *Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

**Figure 8.** *Hepatocellular adenoma—inflammatory subtype, HE ×200.*

#### **Figure 9.**

*Liver Disease and Surgery*

**Figure 5.**

*HE ×200.*

**Figure 6.**

*the tumor, HE ×200.*

**124**

**Figure 7.**

varies among the tumors in the same patient. Immunohistochemically, it is distinctive by a strong expression of inflammation-associated proteins such as serum amyloid A and C-reactive protein at mRNA and protein levels. The genetics of this

*Hepatocellular adenoma—HNF1 alpha mutated subtype—pseudoglandular formations and steatosis within* 

*Hepatocellular adenoma—HNF1 alpha mutated subtype—steatosis and pseudoglandular formations,* 

*Hepatocellular adenoma—steatosis within the tumor, HE ×200.*

*Hepatocellular adenoma—inflammatory subtype, HE ×40, with sinusoidal dilatation and hemorrhage within the tumor.*

group is related to activation of the JAK/STAT pathway underlined by mutations in different genes. In 60%, there are somatic gain-of-function mutations of the interleukin-6 signal transducer gene (IL6ST), which is located at chromosome 5q11 and encodes for glycoprotein 130. Gain-of-function mutations in glycoprotein 130 activate JAK–STAT-3 without interleukin-6 binding. The other 40% show overexpression of wild-type glycoprotein 130, which activates STAT-3 through an unidentified mechanism. Marked peliosis is probably caused by suppression of albumin gene, insulin-like growth factor gene IGF1, and/or transthyretin gene. Mutations of β-catenin may coexist in 10% of IHA (β-IHA). These patients may have signs and symptoms of systemic inflammatory syndrome, manifested as fever, leukocytosis, and elevated serum levels of CRP. Abnormal results of liver function tests may occur, with elevation of alkaline phosphatase and γ-glutamyl transferase. Systemic AA amyloidosis is a rare complication of HA which causes nephrotic syndrome with deteriorating renal function. Resection of the tumor is followed by improvement in renal function and a marked decrease of the serum concentrations of acute phase proteins [23].

The last group that is unclassified (UHA) accounts for 5–10% of adenomas. For this group, the genotype is unknown and the phenotype and immunohistochemistry unspecific. In this group is also included HA that cannot be classified due to near-total necrosis or hemorrhage [21].

The first important thing for the pathologist is to correctly identify the β-catenin-activated HA and to decide when immunostaining is needed. Morphology and additional immunohistochemical markers can discriminate between different types of HA in more than 90% of cases [24]. Identification of beta-catenin positive adenomas has important implications in the decision for surveillance and treatment of these patients. Even if very specific, nuclear β-catenin immunostaining is of low sensitivity in accurate detection of β-HA and β-IHA due to uneven staining distribution or focal nuclear staining. Therefore, additional molecular biology is required. It is recommended to perform glutamine synthetase (GS) staining on every single HA, because GS is one of the target genes in case of β-catenin activation, and it is usually diffusely and strongly expressed in β-catenin-activated HA. GS staining can also be patchy or diffuse but less intense and still be an indication of β-catenin-activating mutations, but in this case, a molecular analysis must be performed to confirm it.

The second important thing for the pathologist is to correctly recognize foci of HCC inside HA. The problem is to avoid overdiagnosis in case of mild or focal cellular atypia. Some HAs may look worrisome due to the presence of architectural distortion, thicker liver cell plates, extensive pseudogland formation, and decreased reticulin framework together with increased CD34 staining (**Figure 10**). These are called "atypical HA," "borderline lesions," and, recently, "well-differentiated hepatocellular neoplasms of uncertain malignant potential." Reticulin staining (**Figure 11**) is the most powerful tool to identify foci of definite malignant transformation, especially in association with architectural distortion, cellular atypia, and increased CD34 staining. Glypican 3 is also very useful when it is positive (**Figure 12**), but its negativity does not rule out malignancy [25]. In most cases of HA and occasionally in HCC, the CD34 staining intensity is variable in different areas and virtually all HCCs have homogenous CD34-positive staining intensity and density [26]. Total loss of reticulin network and diffuse increased CD34 expression, possible presence of glypican 3, and increased MIB1 staining are indications for HCC foci. HSP70 can be also useful. There is no specific phenotype of HCC developed from HA, but some observed that these HCC are often pigmented or cholestatic.

The pathologist needs enough samples, some of them at the junction with the nontumoral liver. For immunohistochemical results, it is mandatory to have a biopsy of the nontumoral liver for comparison.

Interestingly, certain magnetic resonance imaging (MRI) features seem to correlate with the histologic subtypes, suggesting that it may be possible to classify them by MRI [7]. HNF1-inactivated HA and inflammatory HA can particularly be diagnosed by radiologists with considerable accuracy.

#### **Figure 10.**

*Hepatocellular adenoma—CD34 immunohistochemical stain for endothelial cells, few sinusoids are seen in the tumor, ×200.*

**127**

shunts [1, 30].

**4.1 Adenomatosis**

*immunohistochemical stain, ×200.*

**Figure 12.**

**Figure 11.**

*loss of reticulin network, Gomori ×200.*

Adenomatosis is a distinct clinical entity and was first described in 1985 [27] and since then has been defined by the presence of more than 10 adenomas, involving both hepatic lobes, in the absence of glycogen storage diseases, prolonged use of steroids, or resolution with steroid cessation [28]. It is estimated that adenomatosis affects both men and women, and, unlike HA, is correlated with a higher risk of impaired liver function, manifested as an increase in serum alkaline phosphatase and GGT levels [27] and also with a higher risk of bleeding. Instead, the malignant degeneration does not correlate with the number of lesions. There are two different patterns of adenomatosis: (1) the massive pattern, which is defined by the existence of larger lesions, up to 10 cm, that often result in gross hepatomegaly with deformed contour of the liver and (2) the multifocal pattern, which is characterized by smaller lesions, with diameter less than 4 cm, that rarely deform the liver, but has a tendency to progress fast and become symptomatic [29]. The etiology of hepatic adenomatosis is suspected to be linked to congenital or acquired abnormalities of hepatic vasculature. In a study of 15 patients with adenomatosis, 5 had abnormalities in hepatic vasculature: congenital absence of portal vein, portal venous thrombosis with cavernous modification, and intrahepatic portosystemic

*Hepatocellular adenoma—HNF1 alpha mutated subtype—mild lipofuscin deposits revealed by glypican 3* 

*Hepatocellular adenoma—reticulin stain—left normal liver and right hepatocellular adenoma—there is no* 

*Challenging Issues in Hepatic Adenoma DOI: http://dx.doi.org/10.5772/intechopen.87993*

#### **Figure 11.**

*Liver Disease and Surgery*

be performed to confirm it.

cholestatic.

biopsy of the nontumoral liver for comparison.

diagnosed by radiologists with considerable accuracy.

and additional immunohistochemical markers can discriminate between different types of HA in more than 90% of cases [24]. Identification of beta-catenin positive adenomas has important implications in the decision for surveillance and treatment of these patients. Even if very specific, nuclear β-catenin immunostaining is of low sensitivity in accurate detection of β-HA and β-IHA due to uneven staining distribution or focal nuclear staining. Therefore, additional molecular biology is required. It is recommended to perform glutamine synthetase (GS) staining on every single HA, because GS is one of the target genes in case of β-catenin activation, and it is usually diffusely and strongly expressed in β-catenin-activated HA. GS staining can also be patchy or diffuse but less intense and still be an indication of β-catenin-activating mutations, but in this case, a molecular analysis must

The second important thing for the pathologist is to correctly recognize foci of HCC inside HA. The problem is to avoid overdiagnosis in case of mild or focal cellular atypia. Some HAs may look worrisome due to the presence of architectural distortion, thicker liver cell plates, extensive pseudogland formation, and decreased reticulin framework together with increased CD34 staining (**Figure 10**). These are called "atypical HA," "borderline lesions," and, recently, "well-differentiated hepatocellular neoplasms of uncertain malignant potential." Reticulin staining (**Figure 11**) is the most powerful tool to identify foci of definite malignant transformation, especially in association with architectural distortion, cellular atypia, and increased CD34 staining. Glypican 3 is also very useful when it is positive (**Figure 12**), but its negativity does not rule out malignancy [25]. In most cases of HA and occasionally in HCC, the CD34 staining intensity is variable in different areas and virtually all HCCs have homogenous CD34-positive staining intensity and density [26]. Total loss of reticulin network and diffuse increased CD34 expression, possible presence of glypican 3, and increased MIB1 staining are indications for HCC foci. HSP70 can be also useful. There is no specific phenotype of HCC developed from HA, but some observed that these HCC are often pigmented or

The pathologist needs enough samples, some of them at the junction with the nontumoral liver. For immunohistochemical results, it is mandatory to have a

Interestingly, certain magnetic resonance imaging (MRI) features seem to correlate with the histologic subtypes, suggesting that it may be possible to classify them by MRI [7]. HNF1-inactivated HA and inflammatory HA can particularly be

*Hepatocellular adenoma—CD34 immunohistochemical stain for endothelial cells, few sinusoids are seen in the* 

**126**

**Figure 10.**

*tumor, ×200.*

*Hepatocellular adenoma—reticulin stain—left normal liver and right hepatocellular adenoma—there is no loss of reticulin network, Gomori ×200.*

#### **Figure 12.**

*Hepatocellular adenoma—HNF1 alpha mutated subtype—mild lipofuscin deposits revealed by glypican 3 immunohistochemical stain, ×200.*

#### **4.1 Adenomatosis**

Adenomatosis is a distinct clinical entity and was first described in 1985 [27] and since then has been defined by the presence of more than 10 adenomas, involving both hepatic lobes, in the absence of glycogen storage diseases, prolonged use of steroids, or resolution with steroid cessation [28]. It is estimated that adenomatosis affects both men and women, and, unlike HA, is correlated with a higher risk of impaired liver function, manifested as an increase in serum alkaline phosphatase and GGT levels [27] and also with a higher risk of bleeding. Instead, the malignant degeneration does not correlate with the number of lesions. There are two different patterns of adenomatosis: (1) the massive pattern, which is defined by the existence of larger lesions, up to 10 cm, that often result in gross hepatomegaly with deformed contour of the liver and (2) the multifocal pattern, which is characterized by smaller lesions, with diameter less than 4 cm, that rarely deform the liver, but has a tendency to progress fast and become symptomatic [29]. The etiology of hepatic adenomatosis is suspected to be linked to congenital or acquired abnormalities of hepatic vasculature. In a study of 15 patients with adenomatosis, 5 had abnormalities in hepatic vasculature: congenital absence of portal vein, portal venous thrombosis with cavernous modification, and intrahepatic portosystemic shunts [1, 30].

The conditions that predispose to adenomatosis and evolution of the disease are poorly understood, since the medical literature reports only information in regard to individual cases or small case series, but some similarities with the HA are evident: the tendency toward hemorrhage (especially in adenomas larger than 4 cm) and the risk of malignant transformation. Adenomas in hepatic adenomatosis may be of inflammatory, hepatocyte nuclear factor 1 alpha mutated, or beta-catenin mutated subtype.
