Miscellaneous Liver Tumors and Tumor-like Lesions

Incidence and Demographics

Cavernous hemangioma is the most common benign liver tumor in adults. It is more frequently found in middle-aged women.

Clinical Manifestations

The majority of patients with hemangiomas are asymptomatic; the lesions are often found incidentally at laparotomy or autopsy. Patients with large cavernous hemangiomas may experience abdominal pain, which may be related to recurrent or intermittent intratumoral thromboses, infarction, stretching of the Glisson capsule, or pressure on adjacent organs. Rarely, a vascular hum may be heard over the lesion. Enlargement of hemangiomas during pregnancy and in patients taking estrogens has been reported.

Spontaneous rupture of hemangiomas, although sporadically reported in the literature, including in pregnancy, is relatively rare. Other rare complications of hemangiomas include microangiopathic hemolytic anemia and consumption coagulopathy (Kasabach-Merritt syndrome), as well as erythrocytosis due to secretion of erythropoietin by the tumor.

Radiologic Features

The diagnosis of hemangioma is based on imaging studies, in particular contrast-enhanced computed tomography (CT), which shows immediate homogeneous filling of the lesion during the arterial phase. The tumor is isodense to large blood vessels on CT, often with peripheral enhancement. Magnetic resonance imaging of hemangiomas usually shows a heterogeneous appearance caused by thrombi and scarring of the lesion.

CT-guided or ultrasound-guided fine-needle aspiration biopsies of hemangiomas, although usually safe in intraparenchymal lesions, are unnecessary in many instances. In peripheral or pedunculated lesions, biopsy may be complicated by bleeding.

Gross Pathology

Hemangiomas are well demarcated, single or multiple lesions, ranging in size from a few millimeters to more than 20 cm in greatest diameter. They are located either deep within the liver parenchyma or in the periphery of liver, from which they often project from the surface. They may infrequently be pedunculated. On gross examination, hemangiomas are sharply demarcated round or wedge-shaped lesions. The cut surface is dark red and spongy with cystic or honeycomb patterns ( Fig. 36.1 ). Areas of thrombosis, scarring, and, occasionally, calcification suggest regressive changes in older hemangiomas. Often, this occurs to the extent that the entire lesion may be sclerosed, resulting in the so-called sclerosed hemangioma. Mast cells have been implicated in the regression and development of fibrosis in these lesions.

Microscopic Pathology

Cavernous hemangiomas are composed of vascular channels of various sizes, which are lined by flattened endothelial cells with scant cytoplasm ( eSlide 36.1 ). Variable amounts of fibrous tissue separate the vascular channels ( Fig. 36.2 ); many strands are thin, delicate, and fibrous, whereas others are thick scars resulting from organized thrombi ( Fig. 36.3 ). Fresh and organizing fibrin thrombi may also be seen.

Although most of the smaller cavernous hemangiomas are well demarcated from the surrounding liver with a distinct fibrous interface, some may show entrapment of bile ducts or foci of hepatic parenchyma. In Zimmermann’s series of giant cavernous hemangiomas, defined as those larger than 4 cm, four distinct interface patterns were observed: fibrous interface (pattern A), the most common; interdigitating interface (pattern B); compression interface (pattern C); and irregular or “spongy” interface (pattern D).

In large cavernous hemangiomas, lesional dilated vascular channels may extend into the adjacent parenchyma as far as 2 cm beyond the confines of the main tumor; these are referred to as hemangioma-like vessels . This finding is of little or no consequence, and these structures should not be confused with low-grade angiosarcomas. None of the patients studied had recurrences or developed clinical complications following excision, and there was no evidence that these lesions represented low-grade malignancy or risk factors for clinically significant, locally recurrent disease.

Other less frequently encountered histologic subtypes of hemangioma are capillary hemangioma and anastomosing hemangioma. Capillary hemangioma, composed of numerous small vascular channels lined by plump endothelial cells, is similar to lobular capillary hemangioma (pyogenic granuloma) of the skin. The anastomosing type is formed by interconnecting vascular channels in a sinusoidal-like pattern and is lined by plump endothelial cells. Both types may mimic infantile hemangioendothelioma or angiosarcoma, but no mitosis, necrosis, or nuclear pleomorphism are observed.

Incidental focal nodular hyperplasia may be found in or adjacent to a hemangioma, underscoring the role of abnormal vascularity in its etiopathogenesis ( Fig. 36.4 ). This finding in a small-needle biopsy may mimic concurrent cirrhosis.

Differential Diagnosis

The differential diagnosis of hemangioma is mainly metastatic tumor, because hemangiomas are usually found incidentally during evaluation for metastatic disease of other organs. In many cases, imaging studies are sufficient to differentiate hemangioma from solid metastatic tumors. Hemangioma may be confused with other benign or low-grade vascular lesions, such as peliosis hepatis, hereditary hemorrhagic telangiectasia, or low-grade angiosarcoma, on biopsy ( Table 36.1 ).

Treatment and Prognosis

Prognosis is excellent. Surgical resection is often performed for large, rapidly expanding, or symptomatic lesions, or when coagulopathy occurs.

Brief Historical Overview

In 1982, Enzinger and Weiss described a histologically distinct group of vascular tumors of endothelial origin with a clinical course intermediate between benign hemangioma and angiosarcoma. Dail and Liebow described a similar tumor in the lung in 1975, which they called an intravascular bronchioloalveolar tumor (IVBAT) .

Incidence and Demographics

The average patient with epithelioid hemangioendothelioma is middle-aged, and two thirds of affected patients are women. The etiology of the lesion is unknown; no associated or predisposing factors have been identified. Its suggested association with oral contraceptives has not been supported by case-controlled studies. A few cases have been reported in vinyl chloride workers, but the significance of this association is unknown.

Clinical Manifestations

Patients with epithelioid hemangioendothelioma may present with abdominal pain, a mass, or nonspecific symptoms such as weight loss and malaise. Involvement of major hepatic vein branches or terminal hepatic venules may obstruct hepatic venous outflow, resulting in sinusoidal obstruction or Budd-Chiari syndrome. It is not uncommon for epithelioid hemangioendothelioma to be found incidentally. Because of its dense stroma, epithelioid hemangioendothelioma rarely undergoes spontaneous rupture.

Radiologic Features

Imaging shows either a single mass or, more commonly, multiple masses of varying sizes that are avascular and calcified, and which sometimes involve the entire liver. On ultrasonography, epithelioid hemangioendotheliomas may be seen as hypoechoic or isoechoic lesions with a peripheral hypoechoic rim and may be easily mistaken for metastatic carcinoma. On CT, epithelioid hemangioendothelioma may be seen as a hyperdense lesion. On magnetic resonance imaging, the tumor signal is low on T1-weighted images and moderately high on T2-weighted images.

Gross Pathology

Grossly, the tumors are gray-white and firm to hard, with ill-defined borders. The cut surface is often gritty because of the presence of dystrophic calcification. The gross appearance may be indistinguishable from intrahepatic cholangiocarcinoma ( Fig. 36.5 ). The uninvolved liver is usually normal.

Microscopic Pathology

Epithelioid hemangioendothelioma characteristically shows a zonal pattern of cellularity ( eSlide 36.2 ). The periphery or the advancing front of the tumor is more cellular than the center and tumor cells are seen infiltrating the surrounding liver parenchyma ( Fig. 36.6 ). The tumor cells invade the sinusoids, using them as a scaffold, resulting in atrophy and eventually obliteration of the hepatic trabecula. As the lesion enlarges, the stroma becomes more abundant and appears myxoid or cartilaginous. The center of the lesion may undergo necrosis and eventually becomes hypocellular, sclerotic, and sometimes calcified ( Fig. 36.7 ). The underlying lobular architecture remains preserved, and remnants of portal tracts are easily identifiable ( Fig. 36.8 ). Tufts of tumor cells can be seen in portal vein branches and hepatic venules ( Fig. 36.9 ), simulating vascular invasion by carcinoma.

There are two types of tumor cells in epithelioid hemangioendothelioma: dendritic and epithelioid cells. Dendritic cells are spindle or stellate shaped. Their nuclei are vesicular with small nucleoli. Epithelioid cells are rounded and have eosinophilic cytoplasm with round nuclei containing eosinophilic nucleoli. Intracytoplasmic vacuoles, often containing red blood cells, can be identified. These pathognomonic cells have a “signet ring” appearance but contain red blood cells rather than mucin and represent attempts by the tumor cells to form small capillary-like intracellular lumina.

The tumor demonstrates evidence of endothelial differentiation by immunohistochemistry and electron microscopy. Endothelial markers, such as ERG, factor VIII–related antigen, CD31, CD34, and Ulex europaeus are positive. Podoplanin, which is immunoreactive to D2-40 antibody, is positive in epithelioid hemangioendothelioma of the liver but not in other hepatic vascular tumors. Although some tumor cells may be focally reactive to cytokeratins (CKs), CK mainly highlights entrapped nonneoplastic hepatocytes and bile ductules. It is possible to find Weibel-Palade bodies by electron microscopy, which confirms endothelial differentiation of epithelioid hemangioendothelioma.

Differential Diagnosis

Small biopsies from hypocellular areas of epithelioid hemangioendothelioma are difficult to interpret and should not be confused with cirrhosis or a benign fibrosing process. The main differential diagnoses include intrahepatic cholangiocarcinoma, angiosarcoma, and sclerosed hemangioma ( Table 36.2 ).

Treatment and Prognosis

Epithelioid hemangioendothelioma is a low-grade malignancy with a 5-year survival rate of almost 50%, which is significantly better than most primary hepatic malignancies. Although complete surgical resection is the treatment of choice, epithelioid hemangioendothelioma is nearly always multifocal, and in many instances the results of resection have been dismal. In patients with multifocal disease, liver transplantation offers long-term disease-free survival. Extrahepatic disease should not be an absolute contraindication for liver transplantation in patients with severe liver dysfunction. Metastases occur in 30% to 45% of cases, but these are also conducive to long-term survival if the lesions are resectable. Prognosis and tumor recurrence appear to depend on tumor cellularity.

Incidence and Demographics

Angiosarcoma is a rare tumor; nonetheless, it is the most common sarcoma arising in the liver and represents approximately 1% of primary malignant tumors. Patients are usually older, with peak incidence between the sixth and seventh decades of life and a male-to-female ratio of 3:1.

Although the etiology of angiosarcoma is unknown in the majority of cases, the most common associations are exposure to vinyl chloride, arsenic, pesticides, anabolic steroids, and thorium dioxide (Thorotrast). The latter is a radioactive contrast medium that was used from the 1920s to the 1950s. The latent period from initial exposure to the insulting agent and development of tumor varies from 10 to more than 50 years. Other etiologic agents or causal conditions include copper sulfate, phenelzine, radiation, chemotherapeutic agents, and hemochromatosis.

Clinical Manifestations

Patients usually present with abdominal pain, fatigue, jaundice, and weight loss. Hepatomegaly with or without splenomegaly and thrombocytopenia are common findings. Portal hypertension is uncommon in early stages, but some patients exposed to vinyl chloride may develop portal hypertension before the onset of angiosarcoma. Rupture and acute hemoperitoneum have been reported.

Radiologic Features

Angiography and contrast-enhanced CT of the liver are the best diagnostic tools. The findings include nonhomogeneous contrast uptake by a hypervascular tumor or a tumor with peripheral hypervascularity and central hypovascularity. Accumulation of radiopaque Thorotrast may be seen in the liver, spleen, and lymph nodes on a plain radiograph.

Gross Pathology

Angiosarcoma forms numerous variably sized nodules that are soft, spongy, hemorrhagic, and poorly defined. In many instances, the entire liver is involved. Blood-filled cavernous areas may thrombose leading to necrosis and fibrosis. The presence of chalky material is typical of cases associated with exposure to Thorotrast. Nonneoplastic liver may show cirrhosis or fibrosis, particularly in patients who have been exposed to Thorotrast and vinyl chloride.

Microscopic Pathology

The tumor is hemorrhagic with blood-filled cavernous spaces in some areas and solid hypercellular areas or necrosis in others ( Figs. 36.10 to 36.12 ). Tumor cells are usually pleomorphic with spindle or epithelioid morphology. Bizarre hyperchromatic and multinucleated cells are commonly seen. Mitoses vary in a number in different areas but are usually easily identifiable. The tumor infiltrates extensively along the hepatic sinusoids, causing gradual atrophy and effacement of the liver trabecula. Areas of extramedullary hematopoiesis and hemophagocytosis may be present. Well-differentiated tumors may often show only plump, mildly atypical endothelial cells that line cords of hepatocytes or resemble cavernous hemangiomas. Epithelioid angiosarcoma may show sheets of tumor cells with eosinophilic cytoplasm and mildly pleomorphic nuclei. When present, Thorotrast can be recognized as granular, gray, refractile, nonbirefringent, extracellular material within histiocytes.

Angiosarcoma, similar to other vascular tumors, demonstrates evidence of endothelial differentiation by immunohistochemistry and electron microscopy. Immunoreactivity to endothelial markers (ERG, CD31, CD34, factor VIII–related antigen, U. europaeus lectin) occurs in the vasoformative foci but may be absent or weak in poorly formed vascular or spindle cell areas.

Differential Diagnosis

Imaging studies are invaluable in making the diagnosis preoperatively, because biopsies may result in major bleeding. Metastatic angiosarcoma is morphologically indistinguishable from primary hepatic angiosarcoma.

Well-differentiated angiosarcoma may only show subtle endothelial cell atypia and may be mistaken for hepatocellular carcinoma if the tumor cells infiltrate or line thickened hepatocyte cords. Solid spindle cell areas may resemble sarcomatoid carcinoma or other rare sarcomas, such as fibrosarcoma or leiomyosarcoma. See Table 36.3 for differential diagnosis of vascular spindle cell tumors.