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Benign neoplasms of the liver are not uncommon as incidental findings at autopsy and are becoming increasingly important because modern radiologic imaging procedures are now able to detect small tumors, raising the question of whether such tumors are benign or malignant, primary or secondary.
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Hemangiomas are common incidental findings at surgery, radiologic examination, and autopsy. Histologically, they are composed of large endothelium-lined spaces filled with blood.
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Peliosis hepatis is a rare degenerative condition associated with multiple blood-filled spaces in the liver, many of which lack an endothelial lining. It may be associated with use of anabolic steroids. There is an increased incidence of peliosis in patients with acquired immunodeficiency disease (AIDS).
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Sclerosing Bile Duct Adenoma
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Bile duct adenoma is uncommon and usually presents as an incidental finding at surgery. It appears as a firm, gray-white nodule situated beneath the capsule. Over 90% are less than 1 cm in diameter. Histologically, bile duct adenoma is composed of irregular glands surrounded by collagen. Distinction from metastatic adenocarcinoma can be difficult.
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Liver cell adenoma is a rare benign neoplasm that occurs mainly in women taking oral contraceptives and athletes taking anabolic steroids; some tumors have regressed when these drugs were withdrawn.
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The tumors may be multiple and large and may have foci of hemorrhage and necrosis. Microscopically, liver cell adenomas are composed of cytologically benign hepatocytes arranged in thickened cords. Bile ducts and portal tracts are absent. The distinction from a well-differentiated hepatocellular carcinoma may be difficult.
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Clinically, patients may present with a mass, sudden pain due to infarction, or hemorrhage due to rupture through the liver capsule.
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Focal Nodular Hyperplasia
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Focal nodular hyperplasia is another mass lesion of the liver that has been etiologically related to oral contraceptives. It is not a true neoplasm; the mechanism by which it arises is unknown.
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Focal nodular hyperplasia most frequently presents as a solitary solid mass lesion, usually subcapsular, well circumscribed, and only rarely larger than 5 cm. On cut section, it is gray-white and typically has a central scar with bands of fibrosis radiating to the periphery.
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Microscopically, nodules of liver tissue are separated by fibrous bands in which portal tracts containing bile ductules can be identified. The lesion resembles a neoplasm grossly and localized cirrhosis microscopically.
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Malignant neoplasms may arise in the liver from (1) hepatocytes (hepatocellular carcinoma), (2) intrahepatic bile ductules (cholangiocarcinoma), and (3) mesenchymal elements such as blood vessels (angiosarcoma and hemangioendothelioma).
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Hepatocellular Carcinoma
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Hepatocellular carcinoma (sometimes inappropriately called hepatoma) has a marked geographic variation in incidence, being common in the Far East and certain parts of Africa (Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms; Table 43-3), where in some areas it is the most common type of cancer. It is uncommon in Western Europe and North America (about 8000 cases a year in the United States).
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The cause is unknown, but several factors have been implicated: (1) Aflatoxin, a product of the fungus Aspergillus flavus, which grows on improperly stored grain and nuts (including peanuts), is toxic to liver cells. It is present in high levels in grain in Africa and Asia, leading to the suggestion that chronic ingestion of aflatoxin may be at least partially responsible for the high incidence of liver cell carcinoma in these areas; (2) Hepatitis B virus infection is strongly suspected of causing hepatocellular carcinoma. African and Far East countries where hepatocellular carcinoma is common have high rates of hepatitis carriers, probably with vertical transmission of the virus from generation to generation; and (3) Hepatitis C virus infection is also associated with hepatocellular carcinoma.
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Over 80% of patients who develop hepatocellular carcinoma have cirrhosis of the liver. The increased cell turnover in regenerative nodules of cirrhosis is associated with cytologic abnormalities that have been interpreted as premalignant dysplastic changes. While all types of cirrhosis may be complicated by carcinoma, the association is greatest with hemochromatosis, virus-induced cirrhosis, and alcoholic cirrhosis.
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Grossly, hepatocellular carcinoma may present as a large solitary mass (Figure 43-9), as multiple nodules, or as a diffusely infiltrative lesion. Microscopically, the neoplasm is composed of abnormal liver cells of variable differentiation. The better differentiated tumors are composed of cells resembling liver cells arranged in cords separated by sinusoids (Figure 43-10). The cells have enlarged nuclei that show prominent nucleoli and hyperchromatism and may contain bile in the cytoplasm. The less well differentiated tumors have sheets of anaplastic cells. Invasion of hepatic venous radicles is a typical feature that permits differentiation from adenoma. It may be difficult to distinguish a poorly differentiated hepatocellular carcinoma from metastatic carcinoma. Rarely, venous involvement is so extensive as to produce Budd-Chiari syndrome. Even more rarely, a tumor thrombus extends along the hepatic vein into the inferior vena cava and up into the right atrium.
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Immunohistochemical stains may show the presence of alpha-fetoprotein (AFP) in the neoplastic cells. Hepatocellular carcinoma also secretes AFP into the blood; elevated levels are present in 90% of patients, making serum AFP assay an important diagnostic test. (Note: AFP levels may be slightly elevated in some cases of hepatitis and cirrhosis, as well as in some germ cell neoplasms of the gonads.)
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Hepatocellular carcinoma tends to metastasize early via lymphatics to regional lymph nodes and via the bloodstream to produce lung metastases. Metastases to other sites occur terminally.
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A rare variant, fibrolamellar carcinoma, has a better prognosis than the usual hepatocellular carcinoma. This occurs mainly in younger females, has no AFP elevation, and is usually a grossly encapsulated mass. The entity is defined by the presence of large polygonal cells with abundant eosinophilic cytoplasm separated by broad fibrous bands.
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Hepatocellular carcinoma should be suspected when a patient with known cirrhosis presents with any new symptom such as pain, loss of weight, fever, increasing liver size, or increasing ascites. About 20% of patients present with intraperitoneal hemorrhage. Rarely, hepatocellular carcinoma may secrete an ectopic hormone, causing hypoglycemia (insulin-like polypeptide), polycythemia (erythropoietin), or hypercalcemia (parathyroid hormone-like polypeptide).
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Surgical resection is rarely undertaken for the treatment of hepatocellular carcinoma, and chemotherapy and radiotherapy are not very effective. Progression is extremely rapid, and most patients are dead within 1 year. The median survival after diagnosis is 2 months; the 5-year survival rate is almost nil.
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Cholangiocarcinoma arises in the intrahepatic bile ductules. It is uncommon in the United States and Europe but has a relatively high incidence in the Far East, where infection with the liver fluke, Clonorchis sinensis, is thought to be a predisposing factor. Cholangiocarcinoma is not associated with cirrhosis.
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Grossly, cholangiocarcinoma presents features indistinguishable from those of hepatocellular carcinoma. Histologically, it is an adenocarcinoma that shows mucin secretion. The presence of cytoplasmic mucin permits differentiation from hepatocellular carcinoma, which does not secrete mucin. Marked sclerosis is common. Differentiation from metastatic adenocarcinoma is almost impossible on histologic grounds alone. Serum AFP levels are normal.
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The clinical presentation is with a liver mass. The progress of disease is often slow, but bloodstream spread ultimately occurs, and the prognosis is poor.
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Malignant Vascular Neoplasms
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Hepatic angiosarcoma is a highly malignant rare neoplasm that has been linked etiologically to polyvinyl chloride, which is used extensively in the plastics industry; and to Thorotrast, a thorium dioxide-containing radiographic dye that was used several decades ago. Thorium was deposited as refractile crystals in the portal tracts and acted as a carcinogen.
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Patients present with rapid liver enlargement. The tumor appears as a solid, often very large hemorrhagic mass composed histologically of intercommunicating vascular spaces lined by malignant endothelial cells.
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Epithelioid Hemangioendothelioma
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This rare malignant neoplasm of endothelial cells has a slower rate of progression than angiosarcoma. It produces a diffusely infiltrative mass with marked fibrosis. Metastases occur late, and death occurs 10–15 years after diagnosis.
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Metastases account for most neoplasms involving the liver. Virtually any malignant neoplasm in the body can metastasize to the liver; those from the gastrointestinal tract (via the portal vein), breast, and lung and malignant melanoma are most common.
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Metastatic carcinoma characteristically produces massive liver enlargement with multiple nodules (Figure 43-12). However, differentiation of hepatocellular carcinoma from metastatic carcinoma is sometimes very difficult. The following features are helpful: (1) Grossly, the nodules of metastatic carcinoma often show central necrosis and umbilication; (2) The presence of cirrhosis favors hepatocellular carcinoma; (3) The demonstration of AFP in tumor cells or in the blood is almost pathognomonic of hepatocellular carcinoma. (4) Invasion of hepatic veins favors hepatocellular carcinoma.
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If metastatic spread is from an adenocarcinoma, distinction from primary cholangiocarcinoma of the liver may be impossible unless a primary adenocarcinoma is found elsewhere in the body.
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Liver Neoplasms in Infancy
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Several rare neoplasms have been described as occurring in the liver in infancy.
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Infantile hemangioendothelioma is a benign neoplasm of endothelial cells characterized by anastomosing vascular spaces. It is often large and tends to shunt blood from the arterial to the venous side, acting as an arteriovenous fistula and leading to a hyperdynamic circulation; the usual presentation is heart failure in infancy.
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Mesenchymal hamartoma also produces a mass—often a large mass—in the liver. It is solid, with areas of cystic change; microscopically, mesenchymal hamartoma is composed of bile duct-like structures admixed with disorganized mesenchymal elements. It is benign. Surgical removal is curative.
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Hepatoblastoma is a malignant neoplasm composed of primitive cells that resemble fetal liver cells. Mesenchymal elements such as bone are present in most cases. AFP is present both in tumor cells and in the blood. This tumor commonly presents as marked liver enlargement in infancy. It has a poor prognosis.