The etiology of hemangiomas is unknown, although usage of steroids, female sex hormones, and pregnancy have been postulated to be related to the growth of hepatic hemangiomas.¹, ², ³

Hepatic hemangioma is the most common primary mesenchymal tumor of the liver.⁴ The reported incidence ranges from 0.4% to 7.4%.⁴,⁵ It occurs more often in women with a female-to-male ratio of about 3:1.⁶ Hemangiomas are often incidentally discovered on imaging, at surgery, or at autopsy.⁷ Occasional cases of massive hemangiomas or thrombosed hemangiomas can be associated with abdominal discomfort and thrombocytopenia.⁴ Hemangiomas arise sporadically as
solitary masses in most cases, but there can be multiple hemangiomas in rare conditions such as Von Hippel-Lindau syndrome or systemic hemangiomatosis syndromes.⁸,⁹

Hepatic hemangiomas are usually solitary, but rarely can be multiple. The sizes can range from a few millimeters to up to 30 cm. Grossly, hemangiomas appear as red-brown or red-blueish, well-demarcated lesions with a spongy cut surface (Fig. 26.1). Some long-standing cases may contain white fibrotic areas.

Hepatic hemangiomas are uniformly well-circumscribed lesions and may be of three types. The first and most common type is cavernous hemangioma. Much less common hepatic hemangiomas include capillary hemangiomas and anastomosing hemangiomas.

Cavernous hemangiomas. Cavernous hemangiomas are characterized by widely dilated vascular channels with fibrous walls lined by a single layer of flattened inconspicuous endothelial cells devoid of cytological atypia (Fig. 26.2). They are sharply demarked from the surrounding liver parenchyma on gross examination but often have an “infiltrative growth” at their edges on histology.¹⁰ Liver acini or portal tracts are absent within the lesion. Mitotic figures are absent. The lumens of vascular channels are usually filled with blood, but recently formed thrombi or organized thrombi are often seen as well. Some cavernous hemangiomas may undergo partial or complete sclerosis and thrombosis with calcification, and these lesions are known as sclerosed hemagiomas.

The term giant cavernous hemangioma is commonly used when tumors are >4 cm or 5 cm. The giant cavernous hemangiomas have similar histologic features to smaller cavernous hemangiomas. Some giant cavernous hemangiomas can have poorly defined
borders with a vascular proliferation composed of small aggregates of dilated vessels with smaller sizes compared with the main tumor. This finding has been named “hemangiomatosis.”¹⁰ However, this feature is not unique to large hemangiomas and can also be focally seen at the edges of small cavernous hemangiomas.

Capillary hemangioma. Capillary hemangioma is very rare in liver, with just a handful of case reports.¹¹ The morphology of hepatic capillary hemangioma is the same as those arising in the soft tissues. The lesion may have a fibrous capsule and consists of capillary-sized proliferating vessels arranged in a lobular configuration (Fig. 26.3). The endothelial cells are plump without atypia. Sometimes the plump cells may be confluent and obscure the vascular channels. Immunostains can be used to confirm the vascular nature of the tumor.

Anastomosing hemangioma. Anastomosing hemangioma is a relatively rare and recently recognized variant of hepatic hemangioma, which is generally well circumscribed and is characterized by a nonlobular, interanastomosing, sinusoidal proliferation of capillary-sized vessels¹² (Fig. 26.4). The interanastomosing pattern may raise concern for well-differentiated angiosarcoma, but mitotic figures and multilayering of the neoplastic endothelial cells are absent. The endothelial cells of anastomosing hemangioma may be slightly prominent with a “hobnail” appearance, but lack nuclear hyperchromatism and irregularity. Some cases have intermixed features of conventional cavernous hemangioma. Other useful clues to the diagnosis of anastomosing hemangioma are small thrombi, mature adipose tissue, and extramedullary hematopoiesis.¹², ¹³, ¹⁴

Immunostains are not routinely used for diagnosing typical cases, but they may be helpful to confirm the endothelial phenotype of the lesional cells in small biopsy specimens or sclerosed hemangiomas. The endothelial cells lining hemangiomas are positive for all vascular markers, including CD31, CD34, von Willebrand factor, ERG, and FLI1.

Epithelioid hemangioendothelioma is caused by WWTR1-CAMTA1 gene fusions in ˜90% of cases.²¹, ²², ²³ An unusual vasoformative neoplasm containing the YAP1-TFE3 fusion gene has been reported as a variant of epithelioid hemangioendothelioma, but more likely represents a distinct entity.²⁴

Epithelioid hemangioendothelioma is often incidentally discovered, and lung or other metastases may be present at the time of diagnosis.²⁵,²⁶ Some patients present with ascites and portal hypertension because of venous occlusion by tumor.²⁷,²⁸ There is a slight female predominance, with a female-to-male ratio of 3:2. The mean age at diagnosis is 41.7 years (range: 3 to 86 years).²⁵,²⁶

Epithelioid hemangioendothelioma is characteristically multifocal and forms ill-defined bilobar tan nodules (Fig. 26.7). The nodule sizes may range from a few millimeters to several centimeters. Some tumor nodules may appear white and firm, often mimicking metastatic carcinoma. Calcifications may also be present.

Epithelioid hemangioendothelioma frequently encircles bile ducts and hepatocytes, and shows a propensity for portal vein and central vein invasion.²⁵,²⁹ Histologically, epithelioid hemangioendothelioma is characterized by cords, chains, and single file arrays of small, bland endothelial cells growing in a distinctive myxoid to fibrous stroma²⁵,²⁹,³⁰ (Fig. 26.8). In the liver, the matrix in the center of the lesion often has
a “burnt out,” fibrotic appearance (Fig. 26.9). At the peripheral of the lesion, the tumor cells tend to grow along hepatic sinusoids. Although the underlying hepatic acinar architecture is preserved, the liver cell plates become gradually atrophic, and eventually disappear and are replaced by tumor. Careful inspection shows scattered tumor cells with intracytoplasmic “blisters” or “vacuoles,” containing red blood cells sometimes, representing primitive vascular lumen formation. In some cases, the neoplastic cells may be obscured by the accompanying inflammatory infiltrate.²⁹

The vascular markers CD31, CD34,²⁹ von Willebrand factor, ERG, and FLI1 are positive in the neoplastic cells and in this morphological context confirms the diagnosis (Fig. 26.10). Anomalous cytokeratin expression may be present, leading to confusion with adenocarcinoma, in particular cholangiocarcinoma.³⁰ Taking advantage of the identification of the genetic driver of epithelioid hemangioendothelioma, nuclear expression of carboxyl-terminus CAMTA1 can be used to support the diagnosis of epithelioid hemangioendothelioma.³¹,³²

Approximately 90% of cases of epithelioid hemangioendothelioma are characterized by the recurrent fusion gene WWTR1-CAMTA1 which is the genetic driver of the tumor. Detection of this fusion transcript by RT-PCR confirms the diagnosis of epithelioid hemangioendothelioma.²¹,²³

Most angiosarcomas develop without a clear etiology.³⁵ A minor fraction of hepatic angiosarcomas arise in a background of occupational vinyl chloride exposure.³⁵,³⁶ Thorotrast exposure was historically a risk factor for hepatic angiosarcoma, but is no longer in use.³⁷

Hepatic angiosarcoma is the third most common primary liver malignancy, after hepatocellular carcinoma and cholangiocarcinoma, but still only accounts for 2% to 3% of all primary liver malignancies.³⁸ Angiosarcomas usually arise in middle-aged or elderly adults.³⁹,⁴⁰ The clinical presentation of hepatic angiosarcoma is nonspecific. Patients may present with abdominal pain, weight loss, hepatomegaly, liver failure, or thrombocytopenia.⁴⁰ Catastrophic intra-abdominal bleeding occurs in about one-fourth of all cases.³⁸

Angiosarcomas form large hemorrhagic tumor masses with solid and cystic blood containing areas and ill-defined borders (Fig. 26.11). Satellite masses may be present. It can involve either lobe or the entire liver.

Angiosarcoma is a remarkably protean tumor that shows a widely variable appearance from tumor to tumor, and even within a single tumor. Angiosarcoma may display sinusoidal, papillary, cavernous/peliotic, or solid architectural patterns. The cytology also varies widely, from minimal atypia, often with a “hobnail” appearance, to severely anaplastic. Growth along the sinusoids of the hepatic plate, the so-called “sinusoidal pattern” (Fig. 26.12), may be particularly subtle; in such cases, the endothelial cells often show minimal atypia and frequently have spindled morphology. The presence of endothelial cell multilayering is a valuable clue to the diagnosis of angiosarcoma in cases with sinusoidal growth. The cavernous or peliotic pattern of hepatic angiosarcoma may also be quite treacherous because these lesions consist of relatively well-formed, large blood filled spaces lined by malignant endothelial cells with minimal atypia. Angiosarcoma can also purely consist of spindle cells with abundant extracellular matrix that mimics other sarcomas. Occasionally, the solid areas of angiosarcomas can undergo necrosis and cavitation, leaving a cavity filled with blood, fibrin, and necrotic debris that has only small rim of viable malignant cells. Thankfully, many hepatic angiosarcomas are much more obvious, consisting of a proliferation of obviously malignant endothelial cells forming papillary (Fig. 26.13), sieve-like, spindled, or solid formations (Fig. 26.14). Some angiosarcomas may show almost exclusively epithelioid morphology, mimicking carcinoma, mesothelioma, or a high-grade lymphoma (Fig. 26.15). In such cases, the presence of occasional intracytoplasmic lumen formation and the presence of small, peripheral zones of more typical
vasoformative growth are valuable clues to the correct diagnosis. Mitotic figures, including atypical mitotic forms, are usually easily identified in hepatic angiosarcoma, but may on occasion be difficult to identify. Mitotic activity is not required for the diagnosis of angiosarcoma, particularly when infiltrative growth is present.⁴

Hepatic angiosarcoma in children may have Kaposiform areas consisting of spindle cells, sometimes containing PAS-positive intracytoplasmic globules. Thorotrast-associated angiosarcoma may have brown-gray Thorotrast granules, which can be present either free or within macrophages. A precursor lesion consisting of endothelial hypertrophy and hyperplasia has been described in cases related to Thorotrast, vinyl chloride, and arsenic exposure.⁴¹,⁴²

Angiosarcomas are variably positive for vascular markers (CD31, CD34, factor VIII, ERG, and FLI1) (Fig. 26.16). Overall, the frequency of positivity of vascular markers in angiosarcomas is as follows: 40% to 90% of cases are positive for factor VIII, 60% to 90% are positive for CD34, 30% to 100% are positive for CD31, and nearly 100% are positive for ERG and FLI1.⁴³, ⁴⁴, ⁴⁵, ⁴⁶ An important diagnostic pitfall is the expression of cytokeratins.⁴⁷ Cytokeratin expression is seen in about 30% to 50% of cases (Fig. 26.17), in particular those showing epithelioid morphology, emphasizing the need to apply a panel of immunohistochemical stains in this differential diagnostic setting. Rare angiosarcomas also express synaptophysin and/or chromogranin, mimicking neuroendocrine tumors.⁴⁸

Recent studies have described recurrent genetic abnormalities in skin and visceral angiosarcomas. Angiosarcomas of the liver have not been specifically studied but the findings of these studies deserve mention. CIC mutations or rearrangements have been found in approximately 10% of angiosarcomas,⁴⁹ and PLCG1, PTPRB, and KDR mutations have each been noted in another 10%.⁴⁹ These alterations are mutually exclusive. Recurrent NUP160-SLC43A3 fusion genes have been identified in approximately 35% of angiosarcomas.⁵⁰ This fusion gene was mutually exclusive of KDR mutations. The relevance of these findings to primary hepatic angiosarcomas is unclear at this time.