Hepatic hemangiomas (also referred to as cavernous hemangiomas) are the most common benign neoplasms of the liver [2–8].

Estimates of the prevalence range from 0.4 to 10 % of the population, although one autopsy series specifically searching for hepatic lesions suggested a prevalence as high as 20 %. A 1.4–7 % prevalence has been reported in necropsy or surgical series [2–4].

The extensive use of noninvasive abdominal imaging modalities has led to an increased detection of asymptomatic lesions. In a series of 549 patients who underwent MRI for evaluation of focal hepatic lesions, 585 of 805, i.e., 72 %, resulted to be hemangiomas [3, 4].

Hepatic hemangiomas are usually small (<5 cm) and incidentally discovered during abdominal studies for unrelated causes. Lesions larger than 5 cm have been arbitrarily termed “giant hemangiomas.”

Hepatic hemangiomas may occur at all ages. However, 60–80 % of cases are diagnosed in patients who are in their fourth and fifth decade of life, and the average age of patients presenting with symptomatic lesions is approximately 45 years. Patients presenting for evaluation of hepatic hemangioma are predominantly female F:M ratio 2: 1 to 6: 1. In particular, female patients often have a younger age and present with larger tumors. History of multiparity seems to have a facilitating role. Hepatic hemangiomas can also occur in the infancy and have also been detected in a growing fetus.

The prevalence of hemangiomas in patients with focal nodular hyperplasia (FNH) resulted higher than in the general population. It has been suggested that both lesions may have common causative factors, including focal alteration of the hepatic blood supply that somehow facilitates the hyperplastic lesions f FNH [6].

The cause of hepatic hemangiomas is unknown, but they are considered to be vascular malformations or hamartomas of congenital origin. Enlargement occurs by ectasia rather than hypertrophy or hyperplasia.

No definite familial or genetic mode of inheritance has been described. However, a large family of Italian origin has been reported, in which three female patients in three generations had large hepatic hemangiomas. The exclusive presence of hemangiomas in females could be explained by sex-dependent differences in penetrance, by a different expression of a putative liver-hemangioma gene, or by an increase of gender-related growth factors or hormones [7, 8].

In particular, enlargement of existing hemangiomas has been reported during pregnancy. This again suggests a relationship with female hormonal factors such as an endogenous or exogenous exposure to estrogens or progesterone [7, 8].

Glinkova et al. reported that enlargement occurred over time in 23 % of patients receiving estrogen therapy as compared to only 10 % in of the control group. On the other hand, estrogen receptors have not been detected in all tumors, and tumor growth has also been demonstrated in the absence of estrogen therapy and in postmenopausal women [8].

As such, the risk associated with the use of contraceptives or pregnancy is poorly understood. In particular there is still insufficient evidence to conclusively link estrogens to the development or progression of hepatic hemangiomas.

Kasabach–Merritt syndrome was originally described as purpura associated with thrombocytopenia and “capillary hemangioma.” Recent studies have identified these lesions as tufted angioma or kaposiform hemangioendothelioma rather than typical hemangioma. It is a rare disease in which a vascular tumor leads to decreased platelet levels (consumption coagulopathy) and possible bleeding.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu–Osler–Weber disease, is an autosomal dominant genetic disorder that leads to abnormal blood vessel formation in the skin, in the mucous membranes, and often in the liver, lung, and brain. Five genetic types of HHT have been recognized. Three of them have been linked to particular genes. More than 80 % of all cases are due to germ line mutations in either the ENG gene, mapped at 9q34.1, or ACVRL1. A total of over 600 different mutations have been detected. In about 2 % of cases, mutations in the gene MADH4, have been found cause colonic polyposis in addition to HHT.

Histopathology: Macroscopically, hemangiomas may vary in size from a few millimeters to many centimeters. They are dark purple, soft, compressible lesions that are well demarcated and frequently surrounded by a thin capsule (blood-filled “cysts”).

Histologically, they consist of cavernous vascular spaces lined by endothelium and separated by connective tissue, totally lacking biliary or portal structures. By immunohistochemistry, the endothelium displays vascular as opposed to sinusoidal differentiation. Large tumors can have central thromboses, necrotic areas, or dystrophic calcifications.

Hepatic adenoma (HA) is a benign tumor usually occurring in an otherwise normal liver [9–15]. Solitary adenoma, usually associated with the use of contraceptives or anabolic steroids, should be distinguished from hepatic adenomatosis (multiple adenomas, usually 10 or more).

HAs consist of hepatocytes which are arranged in liver cell plates that are only mildly thickened or irregular. The tumor parenchyma is supplied by numerous arteries, which are not accompanied by bile ducts. Hepatocytes are of normal size.

The association between HA and contraceptives has long been established. The incidence of HA is approximately 0.1 per 100,000 in non-OCP users versus 4 per 100,000 in OCP users. Two-thirds of HA express estrogen and progesterone receptors, and enlargement or even rupture has been reported during pregnancy. Distribution in HA incidence is different across the world. Whereas a marked female predominance has been reported in Europe, North America, and South Asia, accounting for 91, 78, and 73 %, respectively, in China only 37 % of HA patients are female, and only 11 % of them have a personal history of OCP or anabolic steroid use.

A precise mechanism underlying the role of estrogen in the pathogenesis of HA has not yet been clarified. However, the exogenous estrogen exposure has been considered by most studies as a stimulating growth factor for HA. Furthermore, HAs are more common in females than in males, with a F:M ratio of 11:1. This gender discrepancy is likely due to a combination of unregulated estrogen stimulation on hepatocytes, with variable effects of estrogens on liver metabolism, immunity, and response to cell injury.

An increased risk of hepatic adenoma has also been noted with the use of androgen preparations, such as in aplastic anemia, hypogonadism, hypopituitarism, and other endocrine disorders. Furthermore, the widespread use of androgens by bodybuilders has also been reported to promote HA formation.

In addition to steroid use, other risk factors associated with HA include hereditary diseases such as glycogenosis (namely, type I and type III glycogen storage disease, where HAs predominantly affect male patients), galactosemia, hepatic iron overload related to beta thalassemia, and maturity-onset diabetes of the young type (MODY 3).

HAs are benign monoclonal tumors occurring essentially in young women taking oral contraceptives (OCs). They frequently bleed but rarely transform into hepatocellular carcinoma (HCC).

Several molecular features associated with HA have been described (See Chap. 2). Recurrent mutations were identified in the TCF1 (transcription factor 1) gene, encoding the hepatocyte nuclear factor 1 alpha (HNF1 alpha), in the CTNNB1 (catenin beta 1) gene coding for beta-catenin, and in the IL6ST (interleukin 6 signal transducer) gene, which encodes for the signaling coreceptor gp 130 and is important for the activation of the JAK/STAT pathway.

In particular, HNF1A is a key transcription factor involved in liver development. It controls hepatocyte differentiation as well as glucose and lipid metabolism. Transcriptomic analysis of H-HAs revealed the dysregulation of genes involved in glucose and lipid metabolism. The main features observed included repression of gluconeogenesis, activation of glycolysis, and stimulation of aberrant fatty acid synthesis. Moreover, in human H-HA, several oncogenic factors lead to mTOR activation, angiogenesis, cell cycle activation, and cell proliferation.

Pathological analysis showed that inactivating biallelic mutations of HNF1A define a very homogeneous subgroup of HA characterized by a marked steatosis. However, steatosis alone is insufficient to diagnose H-HA. In fact, it is also detected in more than 35 % of inflammatory and unclassified HAs. In particular, expression of liver fatty acid-binding protein (LFABP) is specifically downregulated in H-HAs and has been included in the panel of immunohistological markers used to classify H-HAs (100 % specificity and 100 % specificity).

Concerning beta-catenin-mutated HAs, genotype–phenotype correlation revealed striking hallmarks of these adenomas. First, few male subjects develop HAs. However, when it occurs, it is usually a beta-catenin-mutated adenoma. At the pathological level, these adenomas exhibit cholestasis and cell dysplasia. Interestingly, beta-catenin mutations are associated with a high risk of malignant transformation. Beta-catenin-mutated adenomas show strong overexpression of GLUL (coding for glutamine synthase) and LGR5 (coding for leucine-rich repeat-containing G-protein-coupled receptor 5), which are 2 beta-catenin target genes.

By immunohistochemistry, diagnosis of a beta-catenin-mutated adenoma is performed using beta-catenin and glutamine synthase immunostaining. Beta-catenin-mutated HA are characterized by a nuclear localization of beta-catenin and a strong homogeneous expression of glutamine synthase in the cytoplasm. This pattern is homogeneous and diffuse in beta-catenin-mutated Has and differs from the “maplike pattern” that is usually observed in FNH. Due to difficult interpretation, because beta-catenin is detectable only in a few nuclei, analysis of beta-catenin expression has to be combined with glutamine synthase staining, in order to increase detection sensitivity for beta-catenin activation.

Concerning “inflammatory adenomas,” IL6ST/gp130, STAT3, or GNAS were discovered as oncogenes activated by mutations in IHA. In tumors, each mutation is exclusive of the 2 others, and the 3 genes can explain more than 75 % of the overall IHAs. This suggests that other driver genes leading to JAK/STAT3 activation remain to be identified. Mutations in IL6ST/gp130, STAT3, or GNAS act by a similar mechanism called “oncogene-induced inflammation” that leads to constitutive STAT3 activation. Uncontrolled activation of the JAK/STAT pathway in tumor hepatocytes explains the inflammatory phenotype observed at both the histologic and clinical levels. Cytokines and chemokines induced by STAT3 and secreted by hepatocytes act as chemoattractants that promote tumor infiltration by lymphocytes. The origin of dystrophic artery and sinusoidal dilatation that is usually observed in the tumor is unknown, but a direct or indirect role of the release of inflammatory proteins by the mutated hepatocytes could be hypothesized. All of these data highlight that hepatocytes are major inflammatory cells and that inflammation is a key mechanism in liver tumorigenesis.