Liver Cancer Research Paper

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Introduction

Hepatic tumors may either originate in the liver – from hepatocytes, bile duct epithelium, or mesenchymal tissue – or spread to the liver from primary malignant tumors in distant or adjacent organs. Tumors originating in the liver are either malignant or benign. Of the primary malignant tumors, the most common is hepatocellular carcinoma, with cholangiocarcinoma being the only other tumor that occurs with any frequency. Rare but important primary malignant tumors are hepatoblastoma and angiosarcoma. Benign hepatic tumors, with the exception of hemangiomas, are rare. They include hepatocellular adenoma, hemangioepithelioma, and the tumor-like lesion, focal nodular hyperplasia. In most parts of the world, secondary spread of cancers to the liver (hepatic metastases) is more common than primary malignant tumors.

Primary Malignant Tumors Of The Liver

Hepatocellular Carcinoma

Incidence And Geographic Distribution

Hepatocellular carcinoma is the fifth most common malignant tumor in men and the eighth in women, but is among the three most common tumors in many of the most populous regions of the world. Approximately 550 000 new cases of hepatocellular carcinoma occur globally each year, constituting 5.6% of all new cancers. Hepatocellular carcinoma ranks third in annual cancer mortality rates.

High incidences of the tumor occur in eastern and southeastern Asia, some of the western Pacific Islands, and sub-Saharan Africa, but the tumor is rare or uncommon in most industrialized countries. Intermediate incidences occur in some European and South American countries. Hepatocellular carcinoma is increasing in incidence in a number of industrialized countries, especially in Japan but to a lesser extent in parts of North America and Europe.

Gender Distribution

Men are generally more susceptible to hepatocellular carcinoma. Male predominance is, however, more obvious in populations at high risk for the tumor (mean ratio 3.7:1.0) than in those at low or intermediate risk (2.4:1.0).

The main determinant of this difference is the higher rate of chronic hepatitis B virus infection (the most important cause of hepatocellular carcinoma in countries with a high incidence of the tumor) and exposure to the fungal toxin, aflatoxin (another important cause of the tumor in countries with a high incidence of hepatocellular carcinoma) in males than females in populations at high risk for hepatocellular carcinoma. In industrialized countries, patients with hepatocellular carcinoma in the absence of cirrhosis have an approximately equal sex distribution.

Age Distribution

The incidence of hepatocellular carcinoma increases progressively with advancing age in all populations, although it tends to level off in the oldest age groups. However, in Chinese and even more in Black African populations, the age distribution is skewed toward a younger age. This phenomenon is most striking in Mozambique, where more than 50% of Shangaan men with the tumor are younger than 30 years of age. Hepatocellular carcinoma is rare in children.

Clinical Presentation

Patients with hepatocellular carcinoma are often unaware of its presence until the tumor has reached an advanced stage. Black Africans, in particular, usually seek treatment late in the illness. When far advanced, hepatocellular carcinoma generally presents with typical symptoms and physical signs, and diagnosis is then relatively easy. Before this late stage is reached, however, clinical recognition is often difficult. The tumor frequently coexists with longstanding cirrhosis, more so in industrialized countries. In these countries, the cirrhosis is usually symptomatic and when hepatocellular carcinoma supervenes the patient has few, if any, symptoms attributable to the tumor. If, in addition, the tumor is small (as it often is in the presence of cirrhosis), it may not be obvious on physical examination. One circumstance that should alert the clinician to the possibility that hepatocellular carcinoma has developed is a sudden and unexplained change in the patient’s condition: He or she may complain of abdominal pain or weight loss; ascites may worsen or become blood-stained or intractable; the liver may enlarge rapidly or develop a bruit or hepatic failure may supervene. In contrast, in Chinese and Black African populations at high risk of hepatocellular carcinoma, the symptoms, if any, of the coexisting cirrhosis are overshadowed by those of the tumor. Hepatocellular carcinomas are generally considerably larger in these populations and the patient’s symptoms and signs are accordingly more florid, and this facilitates clinical diagnosis.

The most common symptom is upper abdominal pain, which is usually a dull ache but may become intense in the later stages of the illness. Pain is usually accompanied by weakness, anorexia, and loss of weight. Jaundice is infrequent. Physical findings depend upon the stage of the disease at the time the patient is first seen. Early on there may be no abnormal findings or only evidence of cirrhosis. More often the tumor is advanced at the first visit. The liver is then almost always enlarged, sometimes massively so, especially in Black African and Chinese patients, and may be tender. The surface may be smooth or obviously nodular, and the texture is stony-hard or firm. An arterial bruit (or rarely a friction rub) may be heard over the liver. Ascites may be present and increases in severity with progression of the tumor and the spleen is sometimes slightly enlarged. Slight or moderate wasting may be evident at the time of the first visit. Thereafter, progressive wasting is the rule. Jaundice is unusual and mild early on but may appear or deepen with progression of the disease. Physical evidence of cirrhosis is common in patients in industrialized countries.

Atypical presentations of hepatocellular carcinoma are with obstructive jaundice; an acute abdominal crisis when the tumor ruptures causing acute hemoperitoneum; Budd-Chiari syndrome when it invades the hepatic veins and severe pitting edema of the lower limbs when the inferior venal cava is blocked by tumor; superior mediastinal syndrome when the superior vena cava is compressed by malignant lymph nodes in the mediastinum; bone pain in the presence of bony metastases; and respiratory symptoms when the right hemidiaphragm is markedly elevated or pulmonary metastases or a large pleural effusion are present. Hepatocellular carcinoma may also present with one or more of a number of paraneoplastic syndromes, including most often hypoglycemia, polycythemia, or hypercalcemia.

Diagnosis

Conventional tests of hepatic function do not distinguish hepatocellular carcinoma from other hepatic masses or from cirrhosis. Accordingly, they contribute little to the diagnosis of the tumor.

a-Fetoprotein is an a1-globulin that is normally present in high concentration in fetal serum but in only minute amounts thereafter. Reappearance of high concentrations of the globulin in the serum strongly suggests the diagnosis of hepatocellular carcinoma (or hepatoblastoma). This finding is especially true in populations with a high incidence of hepatocellular carcinoma: Approximately 90% of Chinese and Black African patients have raised serum levels and roughly 75% have diagnostically raised levels (greater than 500 ng/ml). These percentages are appreciably lower in populations with low or intermediate incidences of the tumor, and a-fetoprotein is consequently a less useful tumor marker in these populations. Raised serum levels range over six orders of magnitude, although figures of greater than 1 million are rare. Synthesis of a-fetoprotein by a tumor is permanent and age-related: The younger the patient, the more likely the serum value is to be raised and the higher the level attained. There is no gender difference in afetoprotein production provided the patients are matched for age. No obvious correlation exists between the serum concentration of a-fetoprotein and any of the clinical or biochemical features of the tumor or the survival time of the patient. Small, asymptomatic tumors are accompanied by appreciably lower serum levels of a-fetoprotein than are symptomatic tumors.

The reason why 500 ng/ml is taken as a diagnostic level of a-fetoprotein is that serum concentrations up to this level may be found in patients with acute and chronic hepatitis and cirrhosis. False-positive results may also occur in patients with tumors of endodermal origin and nonseminomatous tumors of the ovary or testis.

Pulmonary metastases may be seen on plain chest radiography, particularly often in Black African and Chinese patients. They are almost always multiple. The right hemidiaphragm may be abnormally raised and may lose its normally crescentic outline.

Ultrasonography detects the majority of hepatocellular carcinomas but does not distinguish this tumor from other solid lesions in the liver. Its advantages include safety, availability, and cost effectiveness, although it has the drawbacks of being nonstandardized and observerdependent. Approximately two-thirds of hepatocellular carcinomas are uniformly hyperechoic, with the remainder being partly hyperechoic and partly hypoechoic; small, early tumors are hypoechoic. Tumors located immediately under the right hemidiaphragm may be difficult to visualize. Ultrasonography with Doppler is useful for assessing the patency of the inferior vena cava, portal vein and its larger branches, and hepatic veins. Dynamic contrast-enhanced Doppler ultrasonography with intraarterial infusion of carbon dioxide microbubbles and intravenous-enhanced color Doppler ultrasonography, by characterizing hepatic arterial and portal venous flow in hepatic nodules, facilitates the differentiation between malignant and benign hepatic nodules.

Spiral (helical) computerized tomography and computerized tomography during arterial portography have greatly improved imaging of hepatocellular carcinoma. The images obtained are, however, not specific. Computerized tomography is particularly useful in defining the extent of the tumor within and beyond the liver, and showing the course, caliber, and patency of blood vessels. Because iodized poppy seed oil (Lipiodol) is concentrated and retained in hepatocellular carcinoma tissue, injection of this material at the end of hepatic arteriography can be used in conjunction with computerized tomography, performed after a suitable delay, to detect very small tumors.

Magnetic resonance imaging provides another means of distinguishing hepatocellular carcinoma from normal liver tissue. Many tumors have a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images. Gradient echo sequences and turbo spin-echo sequences have greatly reduced the time needed for magnetic resonance imaging. Furthermore, use of a contrast agent, such as gadopentetate dimeglumine and superparamagnetic iron oxide, increases the accuracy of magnetic resonance imaging, especially in detecting small hepatocellular carcinomas in cirrhotic livers and distinguishing small hepatocellular carcinomas from hemangiomas or dysplastic nodules uncovered in surveillance programs.

Hepatic digital subtraction angiography is helpful in recognizing small hypervascular hepatocellular carcinomas, but may miss early well-differentiated hypovascular tumors. Angiography is also essential in delineating the hepatic arterial anatomy when planning surgical resection, transplantation, bland or chemoembolization of the tumor, or infusion of cytotoxic drugs into the hepatic artery or its branches. Angiography with recirculation will also determine the patency of the hepatic veins.

Laparoscopy can be used to detect peritoneal and other extrahepatic spread, ascertain whether the nontumorous part of the liver is cirrhotic, and obtain a biopsy of the liver under direct vision.

Pathology

Definitive diagnosis of hepatocellular carcinoma depends upon demonstrating the typical histological features of the tumor. Samples suitable for diagnosis can usually be obtained by either percutaneous needle biopsy or fine-needle aspiration. Because there is a risk of local, regional, or systemic dissemination of the tumor cells by needling the liver, these procedures should be avoided as long as the tumor is thought to be operable.

Gross Appearance

Hepatocellular carcinoma may take three forms: nodular, massive, or diffuse. The nodular variety accounts for 75% of tumors and usually coexists with cirrhosis. It is characterized by numerous round or irregular nodules scattered throughout the liver, many of which are confluent. The massive type is more common in younger patients without cirrhosis. It is the type most likely to rupture. The diffusely infiltrating variety is rare: A large part of the liver is infiltrated homogeneously by indistinct tumor nodules, which may be difficult to distinguish from the cirrhotic nodules that are almost invariably present.

The portal vein and its branches are infiltrated by tumor in approximately 70% of cases seen at necropsy. The hepatic veins and bile ducts are invaded less often.

Microscopic Appearance

Hepatocellular carcinoma is classified histologically into well-differentiated, moderately differentiated, and undifferentiated (pleomorphic) varieties.

Well-differentiated Despite the aggressive nature and poor prognosis of the great majority of hepatocellular carcinomas, most tumors are well-differentiated. Trabecular and acinar (pseudoglandular) varieties occur. In the trabecular variety the malignant hepatocytes grow in irregular anastomosing plates separated by sinusoids lined by flat epithelial cells. The trabeculae resemble those of normal adult liver, although they are often thicker and are composed of several layers of cells. The malignant hepatocytes are polygonal with abundant slightly granular cytoplasm that is less eosinophilic than that of normal hepatocytes. The nuclei are large and hyperchromatic with prominent nucleoli. Bile production is the hallmark of hepatocellular carcinoma, regardless of the pattern. A variety of gland-like structures are present in the acinar variety. They are composed of layers of malignant hepatocytes surrounding the lumen of a bile canaliculus, which may contain impissated bile. The individual cells may be more elongated and cylindrical than in the trabecular variety.

Moderately differentiated Solid, scirrhous and clear-cell varieties occur. In the solid type, the cells are usually small. Pleomorphic multinucleated giant cells are occasionally present. The tumor grows in solid masses or cell nests. Central ischemic necrosis is common in the larger tumors. In the scirrhous type, the malignant hepatocytes grow in narrow bundles separated by abundant fibrous stroma. Duct-like structures are occasionally present.

In most tumors, the cells resemble hepatocytes, although occasionally the cells are clear cells.

Undifferentiated The cells are pleomorphic, varying greatly in size and shape. The nuclei are also extremely variable. Large numbers of bizarre-looking giant cells are present. Occasionally, the cells may be spindle-shaped, resembling sarcoma cells.

Extrahepatic metastases are present at necropsy in 40–57% of patients with hepatocellular carcinoma. They are more common (roughly 70%) in patients without coexisting cirrhosis than in those with cirrhosis (approximately 30%). The most frequent sites are the lungs (up to 50%) and regional lymph nodes (approximately 20%).

Fibrolamellar hepatocellular carcinoma typically occurs in young patients, has an approximately equal sex distribution, does not produce a-fetoprotein, is not caused by chronic hepatitis B or C viruses, and almost always arises in a noncirrhotic liver. It is more often amenable to surgical treatment and therefore generally has a better prognosis than typical hepatocellular carcinoma. It does not, however, respond to chemotherapy any better than other forms of the tumor. The hepatocytes are characteristically plump and deeply eosinophilic and are encompassed by abundant fibrous stroma composed of thin parallel fibrous strands that separate the cells into trabeculae or nodules. The cytoplasm is packed with swollen mitochondria, and in approximately half of the tumors contains pale or hyaline bodies. Nuclei are prominent and mitoses are rare.

Etiology And Pathogenesis

Hepatocellular carcinoma is multifactorial in etiology and complex in pathogenesis. A number of risk factors for the tumor have been identified. Chronic necroinflammatory hepatic disease, especially cirrhosis, is the most common causal association, especially in industrialized countries. All forms of cirrhosis may be complicated by tumor formation, although not with the same frequency. Constitutive proliferation of hepatocytes triggered by continuous cycles of hepatocyte necrosis and regeneration and DNA damage resulting from the generation of oxidative stress by the chronic necroinflammation are the main pathogenetic mechanisms.

The most common environmental risk factor for hepatocellular carcinoma is chronic hepatitis B virus infection. It is implicated in about 80% of the hepatocellular carcinoma that occurs at high frequency in eastern and southeastern Asia, the Pacific islands, and subSaharan Africa. Approximately 54% of patients with the tumor globally are infected with the virus. Chronic carriers of the virus are infected very early in life, either by perinatal or horizontal infection, and they are at very high risk of developing the tumor later in life. The virus is thought to be both directly and indirectly hepatocarcinogenic. Many of the patients who develop hepatocellular carcinoma have cirrhosis and this contributes to the carcinogenic process. However, hepatitis B virus DNA becomes integrated into host DNA and is thought to be directly oncogenic. The hepatitis B virus x gene appears to play a central role in the direct hepatocarcinogenicity of this virus. Possible mechanisms include direct disruption of cellular DNA, generation of chromosomal instability, suppression of the function of tumor suppressor genes, and increased transactivation of protooncogenes.

Chronic hepatitis C virus infection is an important risk factor in industrialized countries. Together with hepatitis B virus, it is estimated to be responsible for more than 80% of global hepatocellular carcinoma. Virtually every patient with hepatitis C virus-induced hepatocellular carcinoma has cirrhosis and this is thought to be the major contributor to hepatocarcinogenesis. However, evidence is accumulating that the core and NS5A proteins of the virus may be directly carcinogenic. Hepatitis B and C viruses have synergistic hepatocarcinogenic effects.

A fungal toxin, aflatoxin B1, is an important cause of the tumor in sub-Saharan Africa, China, and Taiwan. It contaminates certain staple foodstuffs, such as maize and ground nuts. High levels of dietary intake result in the accumulation of an electrophilic metabolite, aflatoxin B1-8,9-exo-epoxide that, together with its metabolite, forms adducts with host DNA that result in the inactivation of the p53 tumor suppressor gene and other genotoxic effects. Aflatoxin B1 and chronic hepatitis B virus infection have synergistic hepatocarcinogenic effects.

Iron overload of the liver is a cause of hepatocellular carcinoma in patients with one of two diseases. The first is an inherited disease, known as hereditary hemochromatosis, in which the iron overload results from an inherited predisposition to absorb too much iron from a diet with a normal iron content. The second disease, dietary iron overload in the African, results from the consumption of large quantities of a traditional beer, which is homebrewed in cast iron drums or pots and which therefore contains a high iron content. Excess hepatic iron in these conditions causes cirrhosis, but is also directly hepatocarcinogenic by producing oxygen reactive species and oxidative damage to cellular DNA and other organelles.

Recently, it has been realized that nonalcoholic steatohepatitis with its associated metabolic abnormalities of hyperglycemia, insulin resistance, hypertriglyceridemia as well as obesity and arterial hypertension, is a risk factor for hepatocellular carcinoma. The resulting cirrhosis contributes to the carcinogenic process, but in addition oxidative damage and other changes are incriminated.

A number of rare inherited abnormalities may be complicated by hepatocellular carcinoma. These are a1-;antitrypsin deficiency, glycogen storage disease, hereditary tyrosinemia, hereditary hypercitrullinemia, and acute intermittent porphyria.

Natural History And Prognosis

Symptomatic hepatocellular carcinoma carries a grave prognosis. The main reasons for this are the advanced stage of the disease when the patient is first seen and the presence of coexisting cirrhosis. The natural history of hepatocellular carcinoma in its florid form is one of rapid progression with increasing hepatomegaly, abdominal pain, wasting, and deepening jaundice. In Black African and Chinese populations, death often ensues within 4 months, although in industrialized countries the tumor generally runs a more indolent course with longer survival times.

Treatment

The treatment of hepatocellular carcinoma depends on the burden of disease, the presence or absence of cirrhosis, and the degree of hepatic dysfunction.

Surgical Resection

Surgical intervention offers the only chance of cure. For resection to be considered, the tumor must be confined to one hepatic lobe and be favorably located in that lobe, and ideally the nontumorous tissue should not be cirrhotic. Resection can, however, be considered if the cirrhosis is not severe and the tumor is either confined to the left lobe or, if present in both lobes, allows the surgeon to perform a segmentectomy or limited nonanatomic resection. The number of patients with resectable tumors is small in countries with a high incidence of hepatocellular carcinoma. Even after successful resection, there is a high recurrence rate of the tumor.

Transplantation

Transplantation can be performed in patients in whom the tumor is not resectable but is confined to the liver, or in whom advanced cirrhosis and poor liver function preclude resection. Even patients with reasonably good liver function may be better served by transplantation. Because of undetected spread before surgery, the rate of tumor recurrence is high.

Nonoperative Treatments

Small tumors not amenable to resection because they are multiple or inaccessible or because of severe liver dysfunction have been treated with a variety of intralesional techniques. Alcohol injection was used initially, but more recently radiofrequency ablation has been preferred. Arterial embolization or chemoembolization are additional palliative methods in selected patients. They are also used to reduce the size of the tumor in an attempt to make resection possible or to allow a more conservative resection.

Chemotherapy

A large number of anticancer drugs, including alkylating agents, antitumor antibiotics, antimetabolites, plant alkaloids, platinum derivatives, and procarbazine, have been tried alone and in various combinations, and by different routes of administration, in the treatment of hepatocellular carcinoma, but response rates have invariably been less than 20%. Because single agents have limited value in treating hepatocellular carcinoma, it is not surprising that combinations of these agents are also disappointing. Multidrug resistance is an important factor in the poor outcomes, and the development and testing of drugs that reverse this resistance is in progress. Biologic response modifiers tested to date have not proved to be of value.

Screening For Small Presymptomatic Tumors

Because symptomatic hepatocellular carcinoma is seldom amenable to surgical intervention and responds poorly to conservative modalities of treatment, there is a pressing need either to prevent the tumor or to diagnose it at a presymptomatic stage when surgical intervention is still possible. Mass screening of populations at high risk for the tumor is a daunting and expensive task with a relatively low yield. Long-term surveillance of individuals known to be at high risk (particularly those chronically infected with hepatitis B or C viruses) is more effective and can be costeffective. Ultrasound examination is used as the initial imaging screen in association with measurement of serum a-fetoprotein levels, usually performed at 6-month intervals.

Prevention

The only very effective means of preventing hepatocellular carcinoma at present is the use of hepatitis B virus vaccination. Universal incorporation of this vaccine into the Expanded Program of Immunization in countries in which infection with this virus is endemic and hepatocellular carcinoma common has already resulted in a more than tenfold decrease in viral carrier rates and a more than 70% reduction in the occurrence of hepatitis B-virus-induced hepatocellular carcinoma in the age cohorts that have received the vaccine.

Cholangiocarcinoma

Cholangiocarcinomas may originate from small intrahepatic bile ducts (peripheral cholangiocarcinoma), larger or hilar intrahepatic ducts (hilar cholangiocarcinoma) (when located at the bifurcation of the right and left main intrahepatic bile ducts, referred to as Klatskin tumor), or extrahepatic bile ducts (bile duct carcinoma).

Epidemiology And Etiology

The occurrence of peripheral cholangiocarcinomas shows geographical variation, although not to the same extent as hepatocellular carcinoma. The tumor occurs most often in Hong Kong, Canton and, most notably in northeastern Thailand where it is causally related to chronic infestation with the liver flukes, Clonorchis sinensis and Opisthorchis viverrini. Occasionally, cholangiocarcinoma is a late complication of the use of thorium dioxide (Thorotrast) as a radiographic contrast medium. Hilar cholangiocarcinoma may complicate longstanding sclerosing cholangitis, biliary atresia, Caroli’s disease, von Meyenberg complexes, or intrahepatic cholestasis.

Intrahepatic cholangiocarcinomas are more common in older age groups (average age at presentation, 50–60 years). The gender distribution is approximately equal.

Clinical Presentation

Peripheral cholangiocarcinomas seldom produce symptoms until the tumor is far advanced. The clinical features are then similar to those of hepatocellular carcinoma, except that jaundice may be more frequent, earlier, and deeper. In addition, the liver tends not to be as enlarged, a bruit is not heard, ascites is much less common, and fever and extrahepatic metastases are less frequent. The clinical picture of hilar cholangiocarcinoma is one of progressive obstructive jaundice, with or without weight loss.

Diagnosis

Apart from the higher serum bilirubin, alkaline phosphatase and g-glutamyl transpeptidase levels in peripheral cholangiocarcinoma, the results of liver biochemical tests are similar to those in hepatocellular carcinoma. aFetoprotein levels are rarely raised in cholangiocarcinomas. The appearances of peripheral cholangiocarcinoma on ultrasonography and computerized tomography are similar to those of hepatocellular carcinoma. Larger hilar tumors and the resulting ductular dilatation can also be seen with these imaging modalities and endoscopic retrograde or transhepatic cholangiography localizes their site. In peripheral cholangiocarcinoma, the marked desmoplastic reaction characteristic of this tumor causes the branches of the hepatic artery to appear scanty, stretched, and attenuated on hepatic arteriography.

Pathology

Cholangiocarcinomas are usually large and solitary tumors, but they may be multinodular. They arise in a noncirrhotic liver, although hilar tumors, when longstanding, can cause biliary cirrhosis. Hilar cholangiocarcinomas may take the form of a firm intramural tumor encircling the bile duct, a bulky mass centered on the duct and radiating into the surrounding hepatic tissue, or a spongy friable mass within the lumen of the duct. Microscopically, cholangiocarcinomas consist of acinar or tubular structures, resembling adenocarcinomas. Most are well-differentiated. The tumor cells provoke a variable but often extensive desmoplastic reaction.

Treatment And Prognosis

Peripheral cholangiocarcinoma carries a poor prognosis. Resection is rarely possible and the results of radiation therapy and chemotherapy are disappointing. Liver transplantation offers the only chance of cure. Hilar cholangiocarcinoma may be resectable, depending on size, position, and spread. For inoperable tumors, bile drainage must be established for relief of symptoms of cholestasis.

Hepatoblastoma

Epidemiology

Hepatoblastoma is the most common malignant hepatic tumor in children. It occurs almost exclusively in the first 3 years of life. Boys are affected twice as often as girls.

Clinical Presentation

The most common symptom is abdominal swelling, but others are failure to thrive, weight loss, and abdominal pain. The liver is almost always enlarged and firm with a smooth or nodular surface. Jaundice is uncommon. The tumor occasionally presents with isosexual precocity in boys.

Diagnosis

Serum a-fetoprotein levels are raised in 80–90% of patients. The tumor is seen as a nonspecific echogenic mass on ultrasonography or computerized tomography and an avascular mass on hepatic arteriography.

Pathology

Hepatoblastomas arise as malignant derivatives of incompletely differentiated hepatocyte precursors. They are classified into an epithelial type and a mixed epithelial and mesenchymal type. Two types of epithelial cells are present. The first resemble fetal hepatocytes and the second less differentiated embryonal cells. Mixed hepatoblastomas contain both types of cells.

Treatment And Prognosis

Hepatoblastoma is a rapidly progressive tumor, with the fetal variety carrying the worst prognosis. If solitary, the tumor may be resected or liver transplantation performed. Chemotherapy, with or without radiotherapy, may shrink the tumor to the point that it becomes operable. Neither chemotherapy nor radiotherapy is, however, curative.

Angiosarcoma

Epidemiology

This rare tumor occurs almost exclusively in adults in the sixth and seventh decades. Men are affected four times more often than women.

Etiology

In early reports, this tumor often arose as a late complication of radiographic examination with thorium dioxide. More recently, it has usually followed many years of exposure to vinyl chloride monomers in industry.

Clinical Presentation

The most common presenting symptom is upper abdominal pain, but other frequent complaints are abdominal swelling, malaise, anorexia, weight loss, and rapidly progressing liver failure. The liver is almost always enlarged and is usually tender, with an irregular surface. The patient is often jaundiced. Splenomegaly and ascites may be present.

Diagnosis

Evidence of declining hepatic function is frequently present. Radiopaque deposits of thorium dioxide may be visible in the liver and spleen. One or more masses may be seen on ultrasonography, and hepatic arteriography shows a blush and puddling during the middle of the arterial phase, except in the central region, which may be hypovascular.

Complications And Prognosis

Angiosarcomas grow rapidly and the prognosis is very poor.

Pathology

Angiosarcomas are usually multicentric. Their hallmark is blood-filled cysts, although solid tumor growth is also evident. The earliest change is the presence of hypertrophic sinusoidal lining cells in ill-defined loci. With progression, sinusoidal dilatation and disruption of hepatic plates occur and malignant cells become supported by collagen tissue. Enlarging vascular spaces lined by malignant cells cause the lesion to become cavernous.

Treatment

Operative treatment is usually precluded by the advanced state of the tumor. Even when surgery is performed the results are poor. The results of radiotherapy and chemotherapy are poor.

Hepatic Metastases

The liver is the organ most frequently targeted for metastatic spread of tumors. The reasons for this are the double blood supply to the liver and the presence of fenestrations in the sinusoidal endothelium that facilitate the penetration of malignant cells into the hepatic parenchyma.

Clinical Presentation

Hepatic metastases are often silent or their symptoms are overshadowed by those of the primary tumor. Likely symptoms are malaise, weight loss, or upper abdominal pain. The liver may be enlarged. The surface may be nodular and umbilication of nodules may be felt.

Pathology

Hepatic metastases are almost always multiple. They may be discrete or infiltrative. Subcapsular metastases are often umbilicated. The microscopic appearance duplicates that of the primary tumor.

Diagnosis, Treatment, And Outcome

The diagnosis is made by hepatic imaging, confirmed if necessary by needle biopsy or aspiration cytology.

The extent of replacement of liver tissue determines the patient’s prognosis. Metastases from colorectal cancer may be successfully resected, but otherwise there is little that can be done therapeutically.

Benign Tumors Of The Liver

Hepatocellular Adenoma

Epidemiology And Etiology

Hepatocellular adenoma is extremely rare in men, but is less rare in women taking oral contraceptive steroids, particularly with prolonged usage. Both types of synthetic estrogen and all forms of progestogens contained in contraceptive steroids have been incriminated, especially in preparations with a high hormonal potency.

Clinical Presentation

Hepatocellular adenomas may produce no symptoms and are then usually discovered coincidentally during upper abdominal imaging for other reasons. They may produce upper abdominal pain, which is mild unless hemorrhage into or infarction of the lesion has occurred. The liver may be enlarged and slightly tender. The most alarming presentation is with an acute abdominal crisis resulting from rupture of the tumor with consequent acute hem peritoneum. This is most likely to occur during pregnancy.

Diagnosis

Hepatic angiography is the most useful aid to diagnosis. One-half of the tumors are avascular with vessels seen to be draped over the tumor. Often nearly parallel vessels are seen entering the lesion from the periphery (spoke-wheel appearance).

Pathology

Hepatocellular adenomas are usually solitary and arise in a normal liver. They are usually 8–25 cm in diameter and are larger in women taking contraceptive steroids. Microscopically, hepatocellular adenomas may mimic normal liver tissue to an astonishing degree. They are composed of sheets or chords of normal-looking or slightly atypical hepatocytes. Kupffer cells are usually markedly reduced in number or are absent. There are few or no portal tracts or central veins.

Treatment And Prognosis

Because of the danger of rupture and the small risk of the adenoma undergoing malignant transformation, surgical resection is recommended. If the lesion is not resected, pregnancy, oral contraceptives, and estrogen-containing preparations should be avoided.

Cavernous Hemangioma

Epidemiology

Cavernous hemangioma is the most common benign hepatic tumor and is present in as many as 7% of necropsies. It is thought to be a congenital malformation or hamartoma. Cavernous hemangiomas are present at all ages but most commonly in the third, fourth, and fifth decades. They increase in size during pregnancy and with the taking of estrogen-containing preparations.

Clinical Presentation

The great majority are small and asymptomatic and are discovered by chance. Larger or multiple lesions produce symptoms. Upper abdominal pain is the most common complaint. Cavernous hemangiomas occasionally rupture. The only abnormal finding may be an enlarged liver. Cavernous hemangiomas in the liver are occasionally associated with hemangiomas in other organs.

Diagnosis

Blood-pool radionuclide scanning, bolus-enhanced computerized tomography, magnetic resonance imaging, and hepatic arteriography can be used in the diagnosis of cavernous hemangiomas. Because of the risk of bleeding, percutaneous biopsy should not be performed.

Pathology

Cavernous hemangiomas are usually solitary, although multiple lesions occur in 10% of patients. They are well-circumscribed but seldom encapsulated. Microscopically, they are composed of multiple vascular channels lined by a single layer of flat epithelium and supported by fibrous septa. The channels may contain thrombi.

Treatment

The great majority can safely be left alone. Large hemangiomas causing incapacitating pain should be resected.

Infantile Hemangioendothelioma

Epidemiology And Clinical Presentation

The importance of this tumor lies in the high incidence of congestive cardiac failure that occurs in infants with the tumor and the resulting 70% mortality rate. The cardiac failure results from arteriovenous shunting of blood in the tumor. Infantile hemangioendothelioma almost invariably presents in the first 6 months of life and is twice as common in girls. It often coexists with hemangiomas in other organs, especially the skin.

Small lesions are asymptomatic. The presence of a large tumor is recognized by the diagnostic triad of an enlarged liver, high-output cardiac failure, and multiple cutaneous hemangiomas. The size of the liver is disproportionate to the severity of cardiac failure.

Diagnosis

Hepatic arteriography is particularly helpful in diagnosis. Abnormal vessels arise from the hepatic artery and promptly opacify the liver, the characteristic picture of an arteriovenous shunt. Percutaneous biopsy is contraindicated because of the danger of bleeding.

Pathology

Infantile hemangioendotheliomas are characteristically multifocal and produce a nodular deformity of the whole liver. The nodules vary in size from a few millimeters to many centimeters. Microscopically the tumor is composed of layers of plump endothelial cells: a single layer is a type I pattern, multiple layers a type II pattern. Fibrous stroma may be prominent.

Treatment And Prognosis

The course of infantile hemangioendothelioma is characterized by growth during the early months, followed by gradual involution. If the child survives, the tumor involutes completely. Life-threatening aspects of the disorder are intractable congestive cardiac failure and, to a lesser extent, tumor rupture. The cardiac failure should be treated by conventional means. If this fails, embolization or ligation of the hepatic artery or surgical resection should be attempted.

Focal Nodular Hyperplasia

Focal nodular hyperplasia is a tumor-like lesion. It is a circumscribed, usually solitary lesion composed of nodules of benign hyperplastic hepatocytes surrounding a central stellate fibrous scar.

Epidemiology And Pathogenesis

Focal nodular hyperplasia occurs at all ages, but most patients present in the third and fourth decades. It is hormone-dependent and is seen more often in women. The cause is unknown, but an ischemic origin related to vascular malformation is possible.

Clinical Presentation And Diagnosis

Focal nodular hyperplasia is almost always asymptomatic. Mild pain may be felt, particularly with bleeding into or necrosis of the lesion.

The mass lesion seen on ultrasonography and computerized tomography is not specific for focal nodular hyperplasia, although the central scar may be seen and is a useful diagnostic pointer. The picture obtained with dynamic contrast-enhanced Doppler ultrasonography with intraarterial infusion of CO2 microbubbles is characteristic.

Pathology

Focal nodular hyperplasia presents as a firm, coarsely nodular light brown or yellowish gray mass of variable size with a dense central stellate scar and radiating fibrous septa that divide the lesion into lobules. The nodule may be small or extremely large. Microscopically, focal nodular hyperplasia closely resembles inactive cirrhosis.

Treatment

Large symptomatic or complicated lesions should be resected, usually by segmental resection or enucleation. Otherwise, focal nodular hyperplasia should be left alone. If the lesion is not resected, contraceptive steroids should be discontinued and pregnancy avoided. There is no convincing evidence that focal nodular hyperplasia is a premalignant condition.

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