Chapter 43. The Liver: II. Toxic & Metabolic Diseases; Neoplasms

Incidence & Pathogenesis

Chronic alcoholism is a major problem in almost every society (see also Chapter 12: Disorders Due to Chemical Agents). In developed countries, it has been estimated that about 10% of the population consume potentially harmful amounts of ethyl alcohol. The habit often begins in the teen years and continues throughout life. The incidence is increasing, and in developed countries chronic liver disease and accidents associated with alcoholism are among the 10 most common causes of death. Alcoholic liver disease is most common in middle-aged men, but there is an increasing incidence among women and in the young.

The greater the amount and the longer the duration of alcohol consumption, the greater the risk of liver disease. Most patients with chronic alcoholic liver disease have consumed about 150 g or more of ethyl alcohol daily for over 10 years (a standard 750 mL bottle of 80-proof whisky contains about 300 g of alcohol).

Not all heavy drinkers develop liver disease. About 50% of alcoholics have no detectable liver disease, 30% have alcoholic hepatitis, and 20% develop cirrhosis. Prediction of liver disease in individual cases is uncertain.

Alcohol is metabolized in the hepatocyte cytoplasm by the reduced nicotinamide adenine dinucleotide (NADH)-dependent enzyme alcohol dehydrogenase into acetaldehyde. Acetaldehyde or a related substance is believed to exert a toxic effect on liver cells. Malnutrition, which frequently coexists with alcoholism, may aggravate the liver injury.

Clinicopathologic Syndromes

Alcoholic liver disease may be manifested as fatty liver, alcoholic hepatitis, or alcoholic cirrhosis (Figure 43-1). These lesions may coexist.

Fatty Liver

(See Chapter 1: Cell Degeneration & Necrosis.) Fatty liver is a common early manifestation of alcohol injury. It is the result of decreased fatty acid oxidation, increased synthesis of triglycerides, and impaired secretion of lipoproteins by the liver cell. Fat accumulates first as small globules that coalesce, increasing in size and pushing the hepatocyte nucleus to one side.

Clinically, fatty liver causes diffuse liver enlargement. Liver function is normal even when there is severe fatty change. Fatty liver is reversible if the patient stops drinking at this stage.

Acute Alcoholic Hepatitis (Acute Sclerosing Hyaline Necrosis of the Liver)

Acute alcoholic hepatitis is characterized pathologically by (1) focal lytic necrosis of hepatocytes, causing an increase in serum enzyme levels; (2) cholestasis with jaundice; (3) neutrophilic infiltration of the sinusoids and around necrotic liver cells; (4) sclerosis around the central venule, initially as fine fibrils in the space of Disse and later as coarse fibrosis that may obliterate central veins; and (5) the presence of eosinophilic waxy alcoholic hyalin—Mallory bodies—in the cytoplasm of liver cells (Figure 43-2). Hyalin is a fibrillar material derived from the cell's cytoskeleton; it stains positively for cytokeratin and ubiquitin by the immunoperoxidase technique. Hyalin is not specific for alcoholic liver injury as it is also found in biliary cirrhosis, Indian childhood cirrhosis, Wilson's disease, and liver cell carcinoma.

Clinically, patients present with an acute onset of fever, jaundice, tender enlargement of the liver, and ascites, commonly after a recent bout of heavy drinking. With severe alcoholic hepatitis, encephalopathy and death may occur. Symptoms and most of the pathologic features resolve with cessation of drinking, but the fibrosis increases progressively with each episode.

Chronic Alcoholic Liver Disease

Chronic ingestion of alcohol is associated with progressive fibrosis in the centrizonal region of the liver and distortion of liver architecture by fibrous bands that may connect portal areas and central veins; this differs from cirrhosis in the absence of true regenerative nodules. Progression may slow or come to a halt if alcohol ingestion is discontinued.

Alcoholic Cirrhosis

See later discussions of Cirrhosis of the Liver and Alcoholic Cirrhosis.

Many drugs and other chemical substances cause liver damage by a variety of mechanisms (Table 43-1).

Predictable (Dose-Related) Toxicity

Agents in this group cause liver cell necrosis in all individuals at a predictable dose level. Acetaminophen, which is normally metabolized by the glutathione reductase system, is an example of this phenomenon. In overdosage, the glutathione becomes exhausted, and alternative metabolic pathways yield toxic products. Salicylates in high doses and cytotoxic anticancer drugs such as methotrexate also cause liver cell necrosis. Carbon tetrachloride and chloroform, which are used in industry, also cause liver cell necrosis (Figure 43-3).

Tetracycline in high intravenous dosages has been reported to cause acute microvacuolar fatty change in the liver, with liver failure and a high mortality rate.

Unpredictable (Idiosyncratic) Toxicity

Some hepatotoxic drugs cause liver injury in an unpredictable manner, usually unrelated to dose and in only a small percentage of susceptible individuals. Injury is manifested in a variety of ways.

Massive Hepatocellular Necrosis

Isoniazid, halothane, and methyldopa may cause submassive or massive liver necrosis, with acute liver failure. Lesser degrees of liver necrosis have been reported following exposure to other antituberculous drugs and antidepressants.

Isoniazid-induced necrosis is important because of the recommendation that this drug be used for chemoprophylaxis in all patients who give a positive tuberculin skin test. Massive necrosis occurs in only 0.1% of patients taking isoniazid; the risk is insignificant in individuals under 30 years of age and rises after that.

Halothane is an anesthetic agent that causes massive necrosis in a small number of patients. More than one exposure is usually necessary.

Cholestasis

Cholestasis is caused by anabolic steroids, oral contraceptives, phenothiazines, and oral antidiabetic drugs. Clinically, patients present with deep jaundice of the obstructive type. Liver biopsy shows cholestasis with minimal inflammation and necrosis. The bile ducts in the portal areas are normal, and radiologic studies show lack of dilation of the intrahepatic biliary system.

Acute Hepatitis

Acute hepatitis indistinguishable clinically and pathologically from viral hepatitis has been reported as a complication of isoniazid (in about 1% of patients taking the drug), phenytoin, and salicylates.

Fatty Change

Fatty change occurs as an idiosyncratic effect of methotrexate, valproic acid, and corticosteroids.

Chronic Hepatitis

Chronic hepatitis of a type that is very difficult to distinguish clinically and pathologically from viral and autoimmune chronic active hepatitis occurs with methyldopa and oxyphenisatin. The disease may progress to cirrhosis.

Granulomatous Hepatitis

Noncaseating epithelioid cell granulomas occur with a variety of drugs. Distinction from sarcoidosis is possible only by clinical means.

Mass Lesions

Mass lesions in the liver, including liver cell adenoma and focal nodular hyperplasia, have been attributed to oral contraceptives and anabolic steroids. A few cases of liver cell carcinoma have been reported in oral contraceptive users, but a causal relationship has not been established. Vinyl chloride and thorium dioxide (Thorotrast—a radiologic dye used in the past) are associated with angiosarcoma of the liver.

Malnutrition (kwashiorkor) is associated with fatty liver and nutritional cirrhosis. Indian childhood cirrhosis is now thought to be the result of malnutrition. The exact mechanism by which undernutrition causes cirrhosis is uncertain.

At the other extreme, obese patients treated with ileoileal bypass (no longer performed) developed liver disease characterized by fatty change and sclerosing hyaline necrosis very similar to alcoholic liver disease. The mechanism of liver injury after ileal bypass is uncertain.

The role of immunologic hypersensitivity in liver disease is difficult to evaluate. Immune injury probably contributes to the changes seen in viral hepatitis and in several types of drug-induced liver injuries. There is strong evidence that nonviral chronic active hepatitis and primary biliary cirrhosis are the result of injuries mediated by immune mechanisms.

Autoimmune Chronic Active Hepatitis (“Lupoid Hepatitis”)

Immune-mediated and viral chronic active hepatitis have identical clinical and pathologic features. Patients with autoimmune chronic active hepatitis have negative viral serologic tests. Anti-smooth muscle antibody and antinuclear antibodies are frequently present in the serum, and the lupus erythematosus (LE) cell test is positive (hence “lupoid” hepatitis). Immune-mediated chronic active hepatitis has no relationship to systemic lupus erythematosus.

In contrast to its viral counterpart, immune-mediated chronic active hepatitis occurs more frequently in women. The disease has a bad prognosis, progressing to cirrhosis in the majority of cases. Corticosteroids are sometimes of value in treatment.

Primary Biliary Cirrhosis

Primary biliary cirrhosis occurs predominantly (over 90% of cases) in middle-aged women. The exact cause is uncertain, but immunologic injury is strongly suspected. Primary biliary cirrhosis is associated with other immunologic diseases such as progressive systemic sclerosis and Sjögren's syndrome and is characterized by the presence in serum of several autoantibodies, the most specific of which is antimitochondrial antibody; when present in the serum in a titer in excess of 1:160, it is diagnostic of primary biliary cirrhosis.

Histologically, the diagnostic changes are in the portal tracts. Lymphocytes and plasma cells surround, infiltrate, and appear to actively destroy the walls of the bile ductules. Epithelioid cell granulomas with Langhans' giant cells occur in 30% of cases. Initial bile duct proliferation is followed by progressive destruction. In the final stage of the disease, bile ducts are absent from the portal tracts, which show marked fibrosis. Even in the terminal phase, primary biliary cirrhosis shows only moderate fibrosis. It does not show nodular regeneration of the liver and is therefore not a true cirrhosis despite its name.

Hepatic parenchymal changes are nonspecific and consist of cholestasis and Kupffer cell hyperplasia. Hyalin may be present in the peripheral zonal liver cells.

Clinically, patients present with slowly progressive biliary obstruction. The onset is insidious; pruritus is the most common first symptom, resulting from accumulation of bile salts in the blood. Serum alkaline phosphatase is elevated early, but jaundice occurs later, usually 6–18 months after onset. Most patients have elevated serum triglyceride and cholesterol levels, and many develop xanthomas in the skin. There is an increased risk of atherosclerosis. Portal hypertension and liver failure may occur 5–15 years after onset.

Cirrhosis of the liver is a pathologic entity characterized by (1) necrosis of liver cells, slowly progressive over a long period and ultimately causing chronic liver failure and death; (2) fibrosis, which involves both central veins and portal areas; (3) regenerative nodules, the result of hyperplasia of surviving liver cells; (4) distortion of normal hepatic lobular architecture; and (5) diffuse involvement of the whole liver. A regenerative nodule is an abnormal mass of liver cells without a normal cord pattern or central venule and surrounded completely by fibrosis (Figure 43-4).

Pathology

Grossly, the liver is enlarged in the early stages, but later it becomes smaller because of cell loss and fibrous contraction. It is much firmer than normal. Nodularity is the most characteristic feature (Figure 43-5). Depending on whether the nodules are more or less than 3 mm in size, cirrhosis is classified as macronodular, micronodular, or mixed.

Histologically, regenerative nodules are characteristic. They are composed of hyperplastic liver cells organized into irregular plates. Liver cells often show enlargement, with atypical nuclei—a picture sometimes called “dysplasia” because of the suspicion that such changes are a precursor of liver cell carcinoma.

The vasculature of the liver is greatly distorted. The fibrous bands obstruct the portal venous radicles and lead to abnormal fistulous communications between portal veins and hepatic arterioles, resulting in portal hypertension.

Clinical Features

Cirrhosis is manifested clinically by features of chronic liver failure and portal hypertension (Figure 43-6). Common presenting symptoms include hematemesis due to rupture of gastroesophageal varices and ascites. Cirrhosis is an irreversible and progressive disease that ultimately causes death. The rate of progression is variable.

Cirrhosis is a premalignant lesion. The risk of hepatocellular carcinoma is greatest in cirrhosis caused by hemochromatosis, virus-induced cirrhosis, cryptogenic cirrhosis, and alcoholic cirrhosis, in order of decreasing hazard.

Etiologic Types of Cirrhosis

(Table 43-2)

The terminology of this disorder is confusing and unsatisfactory. Characterizing cirrhosis as micronodular and macronodular according to the size of the nodules is of little value because the size of nodules does not correlate with etiology. The terms portal cirrhosis and Laennec's cirrhosis are no longer used; both denoted micronodular cirrhosis of the alcoholic type. The term postnecrotic cirrhosis should no longer be used because all forms of cirrhosis are associated with necrosis of liver cells and are therefore postnecrotic.

Cirrhosis is most usefully classified according to its causes. All etiologic classifications include a group called cryptogenic cirrhosis (cirrhosis of unknown cause). The incidence of cryptogenic cirrhosis depends on how diligently the cause is sought and how rigorous the criteria are for assigning specific causes to individual cases.

Cryptogenic Cirrhosis

Hepatic cirrhosis is said to be cryptogenic when complete evaluation of the patient has failed to identify a cause. Cryptogenic cirrhosis may include cirrhosis following immune-mediated chronic active hepatitis or following injury due to drugs or chemicals—because there is no way to identify these causes with certainty. Many patients with cirrhosis give a history of drug ingestion, but it is difficult to establish a causal role for the drugs.

Alcoholic Cirrhosis

Alcoholic cirrhosis is frequently associated with evidence of fatty change or acute alcoholic hepatitis. Alcoholic cirrhosis is typically a fatty micronodular cirrhosis (Figure 43-4). In patients who stop drinking, the nodules are not infrequently larger and fat is absent.

Alcoholic cirrhosis tends to have a slow rate of progression, particularly if the patient stops drinking. The disease is irreversible and causes death.

Virus-Induced Cirrhosis

Cirrhosis may follow chronic active hepatitis resulting from infection with hepatitis B and C viruses. Patients who present with cirrhosis may or may not give a history of hepatitis. Typically, virus-induced cirrhosis is macronodular. Features of chronic active hepatitis may coexist. Virus-induced cirrhosis tends to progress rapidly, with death due to chronic liver failure, portal hypertension, or hepatocellular carcinoma.

Cirrhosis caused by hepatitis B virus may be identified by the presence of hepatitis B (HB)sAg in the serum and in liver cells; orcein stains and immunoperoxidase stains for HBsAg are positive. A few cases of cirrhosis due to hepatitis B show coinfection with delta hepatitis that can be demonstrated by immunologic techniques. Patients with cirrhosis caused by hepatitis C have anti-hepatitis c virus (HCV) antibody in their serum.

Biliary Cirrhosis

Primary biliary cirrhosis causes portal fibrosis, but the changes fall short of the definition of true cirrhosis because regenerative nodules are usually absent (Figure 43-7).

Secondary biliary cirrhosis occurs in patients with prolonged large bile duct obstruction (gallstones, stricture, tumor, cholangitis). Marked cholestasis causes liver cell necrosis, and prolonged cholangitis leads to portal fibrosis (Figure 43-7). Biliary cirrhosis causes a fine nodularity (micronodules). Features of chronic liver failure and portal hypertension occur late.

Hemochromatosis

Hemochromatosis results from iron overload in the body as demonstrated by increased serum iron, ferritin, and saturation of iron-binding protein; increased iron stores in the bone marrow; and the presence of iron in liver cells.

Etiology

Hereditary Hemochromatosis

This is a familial disease with autosomal recessive inheritance of an abnormal gene located on chromosome 6 in close linkage with human leukocyte antigen (HLA)-A3. The disease occurs in homozygotes; heterozygotes show slightly elevated serum iron levels. The mechanism by which the abnormal gene causes iron overload is not certain but is believed to involve increased intestinal iron absorption.

Secondary Hemochromatosis

Secondary hemochromatosis is the occurrence of iron overload due to recognizable causes such as the following:

Increased Dietary Intake of Iron

This occurs in the Bantu tribe of Africa, who use iron cooking utensils (“Bantu siderosis”). The excessive use of iron-containing drugs and iron-rich wine and beer may also cause iron overload.

Iron Infusions

Usually in the form of repeated blood transfusions for patients with chronic anemias.

Liver Disease

Particularly alcoholic cirrhosis, which is associated with increased iron absorption. The resulting iron deposition in liver cells may contribute to further liver cell damage.

Chronic Hemolytic Anemias

Thalassemia is the most common cause of secondary hemochromatosis. Iron overload is due to repeated blood transfusions and stimulation of intestinal iron absorption by erythroid hyperplasia in the bone marrow.

Liver Changes in Hemochromatosis

Iron is deposited as hemosiderin in the cytoplasm of Kupffer cells and hepatocytes. Hemosiderin appears as golden brown granules in routine microscopic sections (see Chapter 1: Cell Degeneration & Necrosis). The Prussian blue stain for iron produces an intense blue color. The most accurate assessment of hepatic iron load is by quantitative assay of iron content in a liver biopsy. Patients with hereditary hemochromatosis show marked elevation of hepatic iron (> 10,000 μg/g of liver dry weight; normal is < 1000 μg/g of liver dry weight).

Accumulation of iron in hepatocytes causes cellular degeneration, functional impairment, and clinical disease. This occurs early in idiopathic hemochromatosis and later in secondary forms of hemochromatosis. The mechanism by which stored iron causes cell damage is uncertain. It is believed that free iron accumulates in the cytoplasm when the capacity for storage as ferritin and hemosiderin is exhausted. Free ferric iron undergoes reduction, causing abnormal electron transfers and the formation of toxic oxygen-based free radicals.

Initially, the liver is slightly enlarged. Over a long period of time, there is progressive loss of liver cells accompanied by fibrosis—leading to cirrhosis, which is commonly macronodular. Hepatic hemochromatosis progresses rapidly and may be complicated by hepatocellular carcinoma.

Changes in Extrahepatic Tissues

Iron deposition occurs in many other tissues: The pancreas, myocardium, skin, endocrine glands, and joints are commonly affected, producing the extrahepatic clinical manifestations of hemochromatosis (Figure 43-8). Increased pigmentation of the skin and pancreatic islet destruction result in bronze diabetes, which is an alternative name for hemochromatosis.

Wilson's Disease

Wilson's disease is an autosomal recessive disorder characterized by (1) defective excretion of copper into bile; (2) increase in total body copper, resulting from unchanged absorption in the face of decreased biliary excretion; (3) accumulation of copper in the cytoplasm of liver cells, complexed to an abnormal protein; (4) decreased ceruloplasmin level in plasma; and (5) increased “free” copper in plasma, causing increased urinary excretion of copper and deposition of copper both in cells and in connective tissue. The primary defect is in the liver cell and is corrected by liver transplantation.

Liver Changes in Wilson's Disease

Liver involvement is responsible for the dominant clinical features. Intracellular copper produces an injury manifested as a progressive microvacuolar fatty change and focal liver cell necrosis. It may present, usually in late childhood, as acute hepatitis clinically resembling viral hepatitis. With continuing liver cell necrosis, it progresses to fibrosis and finally to cirrhosis with chronic liver failure. Increased copper levels in the liver can be demonstrated biochemically. Histochemical methods (rubeanic acid stain) are not always positive because of the abnormal protein binding of the copper in liver cells.

Extrahepatic Changes in Wilson's Disease

Copper deposition in the brain involves the basal ganglia (particularly the lenticular nucleus), thalamus, red nucleus, and dentate nucleus of the cerebellum, all of which show atrophy, slight brown discoloration, and cavitation. Microscopically, the neurons are decreased in number, representing chronic cell necrosis. Reactive astrocytic proliferation is present. These changes produce clinical features of extrapyramidal dysfunction. Wilson's disease is also called hepatolenticular degeneration.

Deposition of copper in Descemet's membrane at the sclerocorneal junction is important for clinical diagnosis because it produces a characteristic greenish-brown ring (Kayser-Fleischer ring) at the corneal edge. This is not seen with the naked eye until a late stage of the disease but can be recognized early by slit-lamp examination. Copper deposition in the eye does not cause visual impairment.

Alpha1-Antitrypsin Deficiency

(See also Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases)

Severe α1-antitrypsin (α-antiprotease) deficiency occurs in homozygous PiZZ individuals and is a rare cause of cirrhosis, usually with onset during childhood. The abnormal gene results in hepatic synthesis of an abnormal α1-antitrypsin molecule that accumulates in the liver cell cytoplasm, appearing as eosinophilic globules. These globules are present in liver cells in the peripheral part of the lobule and stain positively with periodic acid-Schiff (PAS) stain. They also stain by immunoperoxidase methods using antibody against α1-antitrypsin. The demonstration of these globules establishes the diagnosis, which can be further confirmed by absence of α1-antitrypsin in the blood.

Galactosemia

Galactosemia is a rare inherited disease caused by deficiency of galactose-1-phosphate uridyl transferase. Galactose metabolites accumulate in the liver, causing injury. Affected patients present in early infancy following feeding of milk (which contains lactose, a disaccharide of glucose and galactose). Cholestasis, fatty change, and cirrhosis progress rapidly to liver failure. Galactosemia is also associated with cataracts and mental retardation.

Galactosemia is routinely looked for in neonatal screening tests. Diagnosis in a neonate followed by administration of a diet that contains no milk products prevents liver damage.

Benign Neoplasms

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.

Cavernous Hemangioma

Hemangiomas are common incidental findings at surgery, radiologic examination, and autopsy. Histologically, they are composed of large endothelium-lined spaces filled with blood.

Peliosis Hepatis

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).

Sclerosing Bile Duct Adenoma

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.

Liver Cell Adenoma

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.

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.

Clinically, patients may present with a mass, sudden pain due to infarction, or hemorrhage due to rupture through the liver capsule.

Focal Nodular Hyperplasia

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.

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.

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.

Malignant Neoplasms

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).

Hepatocellular Carcinoma

Incidence

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).

Etiology

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.

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.

Pathology

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.

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.)

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.

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.

Clinical Features

(Figure 43-11)

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).

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.

Cholangiocarcinoma

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.

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.

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.

Malignant Vascular Neoplasms

Angiosarcoma

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.

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.

Epithelioid Hemangioendothelioma

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.

Metastatic Neoplasms

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.

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.

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.

Liver Neoplasms in Infancy

Several rare neoplasms have been described as occurring in the liver in infancy.

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.

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.

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.