Clinical Features

In the past, hepatocellular adenomas (HCAs) were considered rare tumors that developed almost exclusively in young women during their reproductive years and only rarely occurred in men or children. However, the incidence is increasing, mostly because of the obesity epidemic, and lesions are seen in older women (40 to 50 years) and in men.

Most patients have an abdominal mass, but some also have abdominal pain, discomfort, or nausea. Radiographically, most HCAs exhibit an enhanced vascular pattern. A significant proportion manifest with hemoperitoneum. Lesions larger than 5 cm in diameter usually are associated with a higher risk of hemorrhagic complications, and resection is typically recommended for these lesions. The serum alkaline phosphatase level may be elevated, but serum α-fetoprotein (AFP) levels are usually normal or only minimally elevated.

Pathogenesis

HCAs have historically developed as a result of oral contraceptive or anabolic steroid use. However, low-dose estrogens are now widely used, and the incidence of HCAs related to oral contraceptives may be decreasing. Some HCAs associated with oral contraceptive use regress after cessation of the drugs, but others do not.

Other risk factors for the development of adenomas include obesity (and probably the metabolic syndrome) and metabolic disorders, especially the carbohydrate metabolic disorders such as glycogen storage diseases I and IV, galactosemia, tyrosinemia, and familial diabetes mellitus. The consensus of the International Working Party is that a diagnosis of HCA should not be assigned for a lesion that arises in a cirrhotic liver unless regression is evident when the stimulus is removed or unless one of the risk factors is discernable. HCCs may arise within HCAs (see Chapter 44 ).

Genetic and molecular analyses have resulted in the subclassification of HCA into four major groups ( Table 55.3 ) (see Chapter 44 ). The first group demonstrates hepatocyte nuclear factor 1α (HNF1A) inactivation mutations that are somatic or germline. These tumors are characterized by steatosis, and they tend to occur in younger patients, some of whom have diabetes. Patients frequently have a history of familial adenomatous polyposis. The second major group of HCAs has β-catenin mutations. Tumors in this group tend to occur more in males, may have more cytologic abnormalities, exhibit a focal acinar pattern, and are less steatotic. This group is more frequently associated with the development of HCC. The third group known as inflammatory HCAs (previously known as telangiectatic or variant HCA and originally described as telangiectatic focal nodular hyperplasia ) is characterized by sinusoidal dilation, inflammatory infiltrates, and a focal ductular reaction. The fourth group consists of the remaining HCAs, which are heterogeneous, lack HNF1A or β-catenin mutations, atypical histologic features, and a telangiectatic pattern of growth.

Pathologic Features

Adenomas may be single or multifocal, and when they are multifocal (>10 lesions), the condition is referred to as hepatocellular adenomatosis . In most cases, these tumors occur in histologically normal or almost normal livers. Adenomas usually are round tumors that tend to bulge on cut section. They are soft and typically somewhat lighter in color than the surrounding liver parenchyma, but their appearance may vary if necrosis or hemorrhage exists. The inflammatory variants can be very ill defined and are notable only in some cases by an increased congestive appearance, some bulging, or bogginess of the parenchyma. HCAs usually lack significant fibrosis or nodularity, although these features are rarely present. Normally, HCAs are not encapsulated and can have an irregular, ill-defined border, especially in the inflammatory forms. Rarely, HCAs may have a slate gray to black color caused by large amounts of lipofuscin pigment, which is sometimes referred to as black adenoma .

Microscopically, HCAs are composed of a relatively uniform population of hepatocytes arranged in cell plates one to three cells thick ( Fig. 55.1 ). The cell plates usually have a slightly more irregular pattern than those in normal liver. A key feature of HCAs is that the reticulin framework of the cell plates is intact or only focally decreased ( Fig. 55.2 ). The tumor cells are usually similar in size to normal hepatocytes, although they may be slightly smaller or larger. However, the nucleus-to-cytoplasm ratio of adenoma cells is usually the same as for normal hepatocytes. The cytoplasm of tumor cells may be eosinophilic or clear, or it may contain fat droplets, bile stasis, lipofuscin pigment, or Mallory hyaline (rare). The HNF1A-inactivated HCA has a diffuse fatty change, and these lesions also show lack of staining for liver-type fatty acid binding protein 1 (LFABP1) ( Fig. 55.3 ). Other mild variations in cellular morphology, such as multinucleated tumor cells, or rare atypical or pleomorphic hepatocytes may also be seen, but they are usually focal and few in number. Regardless of the cellular morphology, mitotic figures are typically absent or rare in HCAs.

Inflammatory variant of hepatocellular adenoma. The size of the hepatocytic cells is almost normal, and the cell plate architecture is intact, although in this variant, sinusoidal dilation is prominent. Clusters of small arteries occur in a small fibrous stromal area ( center ) and are associated with mild mixed inflammatory infiltrates and a ductular reaction at the periphery. This zone should not be confused with normal portal zones.

Hepatocyte nuclear factor 1α–inactivated variant hepatocellular adenoma (HCA) as stained with reticulin. HCAs typically have an intact reticulin framework. The small acinar change can be seen focally and may be somewhat more prominent in this variant.

Hepatocyte nuclear factor 1α–inactivated variant hepatocellular adenoma shows a negative staining pattern for liver-type fatty acid binding protein 1; normal liver is positive. Note the irregular edge of the lesion.

Variations in architecture, such as the formation of acini (i.e., pseudoglands or glandlike structures composed of hepatocytes) may be seen but are typically limited in number. However, this can be a more prominent feature in the HNF1A-inactivated variant and acinar structures may contain bile. Alterations in the sinusoids may appear compressed, resulting in a somewhat uniform and solid appearance of the tumor. Alternatively, peliosis hepatis and sinusoidal dilation may be identified in some adenomas, particularly the inflammatory variant (see Fig. 55.1 ). Large arterial vessels often are prominent in all forms, and multiple, small arteries in clusters surrounded by mild inflammatory cell infiltrates are common features of the inflammatory variant. The inflammatory variant exhibits diffuse immunostaining for inflammatory proteins, including C-reactive protein (CRP) and serum amyloid A (SAA) ( Fig. 55.4 ).

In an inflammatory variant of hepatocellular adenoma, immunostaining for serum amyloid A typically shows a diffuse cytoplasmic pattern of granular staining. The small arterial zones do not show staining.

Kupffer cells may be seen in these adenomas, but fewer are identified than in normal liver. Rarely, a partial capsule exists, showing foci of tumor cells that merge with adjacent liver parenchyma at sites where the capsule is absent (see Fig. 55.3 ). A bile ductular reaction is typically absent, but in the inflammatory type, a ductular reaction at the periphery of the arterial foci may simulate portal tracts. Portal tracts are occasionally found within HCAs at the border of the lesions. Areas of infarction and hemorrhage are relatively frequent findings, especially in larger lesions.

The mutated β-catenin variant demonstrates focal positive hepatocellular nuclear immunostaining for β-catenin ( Fig. 55.5 ) and diffuse staining for glutamine synthetase. This type is most likely associated with anabolic steroid use and is more likely to show nuclear atypia, peliosis hepatis, or a prominent acinar (pseudoglandular) pattern. However, it is controversial whether some of these lesions represent well-differentiated HCCs. It is prudent to consider anabolic steroid–related lesions with atypia as well-differentiated hepatocellular neoplasms of uncertain malignant potential, and most authorities recommend resection of all β-catenin–mutated lesions, regardless of size.

In a mutated β-catenin variant, the immunostain for β-catenin demonstrates focal positive nuclear staining.

Differential Diagnosis

The main differential diagnoses for HCA are focal nodular hyperplasia (FNH) and well-differentiated HCC (see Table 55.4 ). Adenomas normally have a relatively uniform cell population that resemble normal liver, lack mitotic activity, reveal cell plates less than three cells thick, and have an intact reticulin framework lining the cell plates. These features help to distinguish this lesion from well-differentiated HCC. If a lesion shows more than rare cytologic atypia or focal loss of reticulin pattern, particularly in a male patient or older woman, a diagnosis of well-differentiated HCC or well-differentiated hepatocellular neoplasm of uncertain malignant potential should be considered.

HCAs stain positively for hepatocellular markers, such as the cytokeratin marker CAM 5.2 and the canalicular marker polyclonal carcinoembryonic antigen (CEA). Adenomas often show CD34 positivity in the endothelial cells that line the cell plates, similar to that seen in HCC. This marker cannot be used reliably to distinguish HCA from HCC. Staining for AFP is typically negative in HCAs, but because it is often negative in well-differentiated HCC, use of this marker is not typically helpful. Staining for glypican 3 (GPC3), an oncofetal protein, is negative in typical HCAs, and it is more often positive in HCCs than AFP staining. However, GPC3 is less useful in distinguishing very-well-differentiated HCCs from HCA, because the two may have similar (negative) staining patterns.

For differentiation of HCA from FNH, isolated arteries in small clusters with limited periarterial stroma, the lack of fibrous bands or central fibrous zone, and lack of nodularity are the most helpful features supporting a diagnosis of adenoma. Ductular reaction at the edge of the fibrous or hepatocyte zones is more prominent in FNH, but some degree of ductular reaction is typically seen in inflammatory HCAs. Acinar formation in HCA must not be confused with bile ductules.

Immunohistochemistry can be helpful to distinguish HNF1A-inactivated HCAs and inflammatory variants of HCA from FNH. Staining for LFABP1 is negative in the former (see Fig. 55.3 ), and staining for SAA or CRP is diffusely positive in the latter (see Fig. 55.4 ). Staining of SAA and CRP can be seen in FNH, but it should be focal rather than diffuse. Glutamine synthetase immunostaining in FNH produces a different pattern of staining (discussed later) than that seen in HCAs, which show no significant staining, limited perivenular staining, or diffuse strong staining (e.g., in β-catenin–mutated HCAs).

Treatment

Surgical excision is justified, particularly for large lesions (>5 cm), because of the risks of tumor growth, life-threatening hemorrhage, the rare development of HCC, and because it is difficult to differentiate an HCA from a well-differentiated HCC. Liver transplantation may be considered for patients with adenomatosis.

Clinical Features

FNH is a benign, non-neoplastic lesion most commonly encountered in young women, although significant numbers are seen in men. Classic FNH is often an incidental finding, but it may also come to clinical attention because of its large size (which rarely results from hemorrhage). Some patients have abnormal liver function test results, such as elevated γ-glutamyltranspeptidase activity.

Nodules similar to FNH nodules have been described adjacent to hemangiomas. Some patients with multiple FNH syndrome have at least two FNH lesions associated with one or more other lesions, such as hepatic hemangioma, an arterial structural defect, vascular malformation, meningioma, or astrocytoma. Nodules with FNH-like changes are commonly seen in Budd-Chiari syndrome and in hereditary hemorrhagic telangiectasia (i.e., Rendu-Osler-Weber disease). Many refer to these lesions as “regenerative nodules” or as FNH-like lesions.

Pathogenesis

Unlike HCA, FNH does not develop as a result of oral contraceptive use; however, evidence suggests that FNH lesions may increase in size with contraceptive use or regress after cessation of therapy. The exact pathogenesis is not established for FNH, but FNH is thought to represent a hyperplastic or altered growth response to alterations in parenchymal blood flow that occur around preexisting vascular malformations. The presence of numerous abnormal muscular vessels in FNH and the association of some of these lesions or similar hyperplastic foci with hemangiomas and the Budd-Chiari syndrome lend support to this theory. Another theory suggests that the lesions result from vascular occlusive events with the formation of collaterals and secondary reactive or ischemic changes. Lesions caused by vascular occlusive events may be referred as “FNH-like lesions” (my preferred nomenclature) instead of FNH because they have different etiologic factors and because FNH-like lesions may not have all the typical features of FNH.

FNH has no known malignant potential, and despite its rare association with fibrolamellar HCC, most authorities think that the lesion does not progress to carcinoma. Instead, the association of FNH with fibrolamellar HCC may represent a hyperplastic response to increased vascularity, which is typical of carcinomas. The lesion formerly known as the “telangiectatic” type of FNH, which was originally associated with the multiple FNH syndrome, is now recognized as the inflammatory variant of HCA (see Hepatocellular Adenoma, earlier).

Pathologic Features

Similar to HCAs, FNH usually involves a solitary nodule, but it may be multifocal. FNH has a nodular appearance, which may simulate the appearance of macronodular cirrhosis, and it tends to be lighter in color than the surrounding liver parenchyma. These lesions are often located near the liver capsule, which may impart a localized nodular appearance mimicking cirrhosis. Occasionally, FNH may be pedunculated. The edges of FNH are normally well demarcated from the normal liver parenchyma, but a fibrous capsule is usually absent. FNH may vary considerably in size. Most FNH lesions have a central fibrous scar, which consists of fibrovascular tissue, not dense scar tissue.

Microscopically, the classic type of FNH is composed of normal-appearing hepatocytes arranged in incomplete nodules and partially separated by fibrous tissue that extends outward from the central fibrous zone of the tumor. Variable numbers of bile ductular structures are normally seen in the fibrous stroma and particularly at the edge of the nodules. The cell plate architecture is similar to that of normal liver. However, the cell plates are usually wider (two to three cells thick), similar to regenerative nodules. The reticulin framework should be intact, but in some lesions, cell plates may have a more acinar appearance, may be wider than three cells (usually not thicker than five cells), and be separated by thin collagen bands. The hepatocytes in FNH may demonstrate increased levels of glycogen, fatty change, bile stasis, lipofuscin, iron pigment, copper or copper-associated protein, and Mallory bodies. Foci of atypical hepatocytes containing larger nuclei and mild hyperchromasia, with or without conspicuous nucleoli, may be seen in some cases.

Another important diagnostic feature is the presence of medium- to large-sized, thick-walled muscular vessels, which often exhibit myointimal myxoid or fibromuscular hyperplastic changes ( Figs. 55.6 and 55.7 ). These vessels are not considered components of a portal tract, because large ducts of similar caliber and portal veins are not associated with them. Portal tracts are absent in FNH except at the periphery of the lesion, although a bile duct of intermediate or large caliber may be found in the central fibrous zone in rare cases. The sinusoids may be dilated, and Kupffer cells may be evident. Inflammatory cell infiltrates are relatively common and consist mainly of lymphocytes, although neutrophils and eosinophils may be seen, particularly around bile ductular structures. Rarely, granulomas are identified.

Focal nodular hyperplasia contains abnormal muscular vessels and lacks associated bile ducts of similar size.

Focal nodular hyperplasia has a muscular vessel with irregular wall thickness and a ductular reaction that typically occurs at the junction of the stroma and parenchymal nodules.

Immunohistochemistry demonstrates intense but patchy staining (i.e., maplike pattern) for glutamine synthetase ( Fig. 55.8 ), which is distinctly different from the centrizonal hepatocyte staining pattern of normal liver. For FNH-like lesions, portal zones may be seen within the lesion, the ductular reaction may be decreased or lacking, and the central scarlike zone may be absent.

Glutamine synthetase immunostain of focal nodular hyperplasia demonstrates increased overall staining in a pattern described as maplike, resulting in focal strong cytoplasmic staining of hepatocytes not limited to the perivenular zones as seen in normal liver specimens.

Differential Diagnosis

FNH may resemble HCA or normal liver in small biopsy samples. One of the most important distinguishing features of FNH is the bile ductular reaction ( Table 55.4 ), but it must not be mistaken for the ductular reaction in the inflammatory variant of HCA. Because of the patchiness of the bile ductular reaction, a large-core needle biopsy or a wedge biopsy may be necessary for this feature to be identified. The finding of large blood vessels with abnormal hyperplastic features and usually surrounded by at least a moderate amount of connective tissue may be helpful, because the blood vessels in HCA tend to have a more normal configuration and lack significant perivascular connective tissue stroma.

The use of immunohistochemical stains can help to differentiate FNH from HCA. SAA and CRP typically are diffusely positive in inflammatory HCA but show very limited or no focal staining in FNH. Staining for glutamine synthetase in FNH should be intense and extensive compared with the patchy perivenular staining or lack of staining in HCA. The exception is the β-catenin–mutated variant of HCA, which may show diffuse intense staining of glutamine synthetase.

Similar to HCA, FNH normally stains positively for hepatocellular markers, including the cytokeratin (CK) marker CAM 5.2 and the canalicular marker polyclonal CEA. The reticulin stain typically demonstrates an intact reticulin framework in FNH, as in HCA, but rare foci may also show cell plates three to five cells thick, and care must be taken not to mistake this finding for HCC. A copper stain may demonstrate deposits in hepatocytes adjacent to fibrous bands. CD34 often is positive in endothelial cells that line cell plates, although to a lesser extent than in many HCAs and HCCs, but in any one case, this marker is not reliable for distinguishing FNH from HCA or HCC. However, CD34 may still be useful for demonstrating lesional tissue in the sample. Staining for AFP is typically negative in FNH.

Treatment

Surgical resection is usually unnecessary unless the lesion is pedunculated or very large, in which case there is a risk for torsion and hemorrhage, or for abdominal pain and distress. Excision of FNH is justified if the lesion cannot be differentiated from HCC or HCA with confidence.

Nomenclature

In cirrhosis, benign nodules larger than typical cirrhotic nodules have been referred to by various names, including large regenerative nodule and macroregenerative nodule. Low-grade dysplastic nodules are thought to represent a clonal proliferation of hepatocytes. However, because the gross and microscopic features of large regenerative nodules and low-grade dysplastic nodules are often indistinguishable, the following description applies equally to both lesions.

Many clinicians do not try to distinguish large regenerative nodules from low-grade dysplastic nodules, because clonality studies may be the only valid method for doing so. In clinical practice, these terms are used interchangeably to describe a nodule that is distinct from the surrounding cirrhotic liver but lacks the cytologic or architectural abnormalities characteristic of high-grade dysplastic nodules. I prefer the term macroregenerative nodule for these lesions and reserve the dysplastic label for high-grade lesions.

For similar-appearing nodules in noncirrhotic livers, the International Working Party recommends the term multiacinar regenerative nodules . They tend to occur in the setting of Budd-Chiari syndrome or portal vein thrombosis or as a sequela of hepatocyte necrosis with regeneration. These lesions may be similar to FNH and be designated as FNH-like lesions, (see Focal Nodular Hyperplasia ). Large regenerative nodules and multiacinar regenerative nodules represent a reactive process rather than a clonal preneoplastic lesion.

Clinical Features

Macroregenerative nodules and low-grade dysplastic nodules occur in the setting of cirrhosis, with only a few exceptions, such as in the setting of chronic liver disease without fully developed cirrhosis. They are usually an incidental finding at autopsy or at the time of transplantation, but they may also be identified on radiographic studies. The serum AFP concentration is typically normal or within the low range expected for the underlying chronic liver disease or cirrhosis.

Pathogenesis

These nodules usually are considered benign lesions, but nodules with this histologic appearance have been associated with an increased incidence of HCC. Almost no previous studies of macroregenerative nodules have attempted to define the lesions as regenerative or clonal but instead have defined them as lacking features of high-grade dysplastic nodules or HCC on routine histologic examination. The literature may be somewhat contradictory, and it cannot be definitively stated whether regenerative nodules and clonal, low-grade dysplastic nodules have similar risks for HCC. These nodules are typically seen in cirrhosis related to HBV or HCV infection, alcohol consumption, or hemochromatosis, and they are less likely to be seen in primary biliary cirrhosis. The risk factors for development of macroregenerative nodules are similar to those for HCC.

Pathologic Features

Macroregenerative nodules or low-grade dysplastic nodules are larger than typical cirrhotic nodules. The generally accepted lower limit is between 0.8 and 1 cm in diameter, and the higher limit is less than 3 cm in the greatest diameter. These nodules tend to bulge on cut section. The edges of the nodules are usually round and sharply circumscribed, and they may be more deeply bile stained or paler than typical cirrhotic nodules.

Histologically, these nodules resemble cirrhotic nodules. They have an intact reticulin framework similar to that of normal liver, and the cell plates are usually one or two cells thick ( Figs. 55.11 and 55.12 ). The hepatocytes typically have unremarkable cytology, although some focal variation in cell size and scattered large cell change similar to that seen in other cirrhotic nodules may be seen in large regenerative nodules. Low-grade dysplastic nodules are expected to have a more uniform population of hepatocytes because of their clonal nature, but many specific features of this type of clonal nodule have not been definitively established. Findings such as Mallory bodies, bile stasis, clear cell cytoplasmic changes, iron or copper deposits, a slight decrease in cell size, and focal or diffuse fatty changes may be seen. Portal tracts are usually seen in the nodule, and bile ductular reaction may be prominent. Fibrous septa that extend into the nodule without a complete triad of duct, vein, and artery may be identified.

In a macroregenerative or low-grade dysplastic nodule, the cytology of the cells is similar to that seen in normal liver, and the cell plate architecture is preserved.

Reticulin stain of a macroregenerative nodule demonstrates intact cell plate architecture.

Differential Diagnosis

The size of this nodule is important for differentiating it from typical cirrhotic nodules. Rarely, a nodule with this histologic pattern lacks portal structures, but this does not warrant a diagnosis of adenoma in a cirrhotic liver without one of the risk factors for adenoma. Features that differentiate these nodules from high-grade dysplastic nodules and small, well-differentiated HCCs are outlined in Table 55.5 .

Studies of the vascularity of these nodules have shown that they have a large number of arteries unassociated with other components of a normal portal space. They are referred to as unpaired arteries . However, staining for CD34 or CD31, as a marker for sinusoidal capillarization, is usually similar to that seen in cirrhotic nodules; some peripheral staining is normally seen at the edge of the nodules. The nodules are usually negative for AFP and otherwise show a staining pattern similar to that expected in normal liver for cytokeratin and polyclonal CEA.

Treatment

Therapy for macroregenerative nodules varies because most lesions are found incidentally on excision or explantation. For lesions that have not been excised, clinical follow-up for an increase in size or other features that suggest malignant transformation is recommended.

Clinical Features

High-grade dysplastic nodules, previously known as borderline nodules , almost always occur in cirrhotic livers. The serum AFP level is usually normal or within the range typical of chronic liver disease or cirrhosis. The lesions may enhance on radiographic imaging, but lesions less than 1 cm in diameter tend to fall below the limits of radiographic resolution.

Pathogenesis

High-grade dysplastic nodules, which typically occur in the setting of cirrhosis, are considered a premalignant change in the carcinogenic pathway to HCC. Various pathologic features and molecular features support this theory (see Chapter 44 ).

Pathologic Features

High-grade dysplastic nodules essentially have the same gross features as large regenerative or low-grade dysplastic nodules, although some may appear less circumscribed or have an irregular border.

Microscopically, when dysplastic changes are observed uniformly throughout a nodule, a designation of high-grade dysplastic nodule is warranted. A nodule containing one or more dysplastic foci is referred to as a dysplastic nodule (see Fig. 55.10 ). The atypical features of these lesions are not overtly severe enough to be diagnostic of HCC, but they are more atypical than expected in usual cirrhotic nodules. The nodule is often recognized by zones of small cell change (see Fig. 55.10 ) with an increased nucleus-to-cytoplasm ratio (i.e., increased nuclear density), which is defined as an increased number of hepatocyte nuclei per microscopic field compared with normal liver. Large cell change, which is rarely a feature of high-grade dysplastic nodules, may be identified in a discrete zone of atypical cells rather than as enlarged nuclei scattered singly throughout the nodule.

Other common features of high-grade dysplastic nodules include focal zones of cell plates that measure as much as three cells thick, a focal decrease in the reticulin framework, and mild dilation of sinusoids. These nodules may also contain foci of Mallory bodies, fat, clear cell change, cytoplasmic basophilia, rare mitoses, bile, and portal tracts. The nodules may contain iron deposits. High-grade dysplastic lesions tend to lack iron deposits, which are more common in low-grade nodules. The borders of these nodules may be irregular, and focal acini (pseudoglands) may be seen.

Differential Diagnosis

High-grade dysplastic nodules are differentiated from overt HCC by several features (see Table 55.5 ). Those particularly helpful for diagnosing HCC include the mitotic figures in moderate numbers, trabeculae, cell plates greater than three cells thick, nuclear density more than two times normal, marked reduction in the reticulin framework, numerous unpaired arteries, and absence of portal tracts. High-grade dysplastic nodules are more likely to show an immunostaining pattern similar to that of HCC, such as sinusoidal staining with CD34 and rare positivity with GPC3 (see Hepatocellular Carcinoma and Its Variants ).

Treatment

Most authorities recommend excision or ablation of high-grade lesions because they are thought to represent the early stage of a malignant process. Sampling by small-core biopsies may miss the areas of tissue diagnostic of HCC, which may be found focally in high-grade dysplastic nodules.

Clinical Features

HCC is the most common primary malignant tumor in the liver. In approximately 85% of cases in the United States, HCC occurs in the setting of cirrhosis. The incidence of HCC varies by geographic location, with a low incidence in Europe and North America (2 to 7 cases per 100,000 persons) and a high incidence in eastern Asia and southern Africa (30 cases per 100,000 persons). The incidence of HCC generally increases with age, but the mean age of occurrence depends on the specific geographic location. For example, in North America, the mean age at diagnosis is approximately 60 years, but in Africa, the average age is approximately 35 years. In Taiwan, the mean age of occurrence ranges from 40 to 60 years. HCC is three times more common among men than women, and worldwide, it is the fifth most common type of malignancy in men and the eighth most common in women.

The presenting symptoms vary, but many patients are completely asymptomatic or have mild abdominal pain. Other signs of HCC include weight loss, jaundice, ascites, malaise, and fever. Late serious complications of large HCC tumors include rupture with hemorrhage and disease that is metastatic most often to the abdominal cavity or lungs.

Many patients with cirrhosis are diagnosed by imaging or an elevated serum AFP level. Lesions smaller than 1.5 cm in diameter usually do not enhance on radiographic angiography, and HCC may be more echogenic or less echogenic than adjacent normal liver parenchyma. Almost two thirds of patients with large HCC tumors have a high serum AFP level (>1000 ng/mL). Tumors smaller than 2 to 3 cm in diameter are unlikely to be associated with an elevated serum AFP level. A serum AFP level of less than 500 ng/mL may be seen in many types of liver disorders. Elevation of AFP levels to between 500 to 1000 ng/mL suggests HCC but is not specific. Other types of malignancies, such as some types of tubal gut adenocarcinomas, ovarian tumors, and germ cell tumors, may also have markedly elevated AFP levels.

Pathogenesis

HCC develops during a long period and is probably a multistep process that involves various risk factors (e.g. chronic hepatitis), exposure to certain toxic or viral agents, and genetic alterations (see Chapter 44 ). The major etiologic association is cirrhosis, but HBV or HCV infection is also an independent predisposing factor. Patients with cirrhosis resulting from hemochromatosis or α ₁ -antitrypsin disease have an increased risk of HCC compared with patients with cirrhosis related to other causes (excluding HBV and HCV). Other risk factors include exposure to thorium dioxide (Thorotrast), aflatoxins, and estrogenic steroids. Stem or progenitor cells in the liver have the potential to differentiate into hepatocytic and biliary cell types, and they may play a role in the pathogenesis of primary liver tumors, particularly HCC, cholangiocarcinoma, or mixed HCC and cholangiocarcinoma, but their exact role remains unclear.

Pathologic Features

In the United States, most HCC tumors arise in cirrhotic livers. The liver of a patient with HCC may be more bile stained or paler than a nontumorous liver, and it may have irregular borders or satellite nodules. Rarely, the entire lesion is composed of multiple nodules similar in size to typical cirrhotic nodules ( Fig. 55.13 ). Large vein invasion and a fibrous capsule may be identified, particularly in association with large tumors. Small HCCs (<2 cm in diameter) usually lack vascular invasion, necrosis, and hemorrhage.

In a cirrhosis-like hepatocellular carcinoma, the tumor cell foci are yellow, and the cirrhotic nodules are green.

The WHO has described the four typical histologic patterns of HCC: trabecular, acinar, compact, and scirrhous. The trabecular (platelike) pattern is the most common ( Fig. 55.14 ). In this variant, tumor morphology mimics the cell plate architecture of normal liver but has important differences. The cell plates in trabecular HCC are typically three or more cells thick, whereas the cell plates in normal or regenerative liver are normally only one or two cells thick. As in normal liver, tumor cell plates are lined by endothelial cells, but reticulin staining usually shows that the reticulin framework is absent or markedly decreased or distorted, with irregular or absent staining of the borders of the trabeculae ( Fig. 55.15 ). Tumor cells often have features of a small cell change (see Figs. 55.14 and 55.15 ). Large cell change may be seen infrequently, except in high-grade tumors. Foci of small and large cell changes often are admixed. Kupffer cells are typically absent in HCC. Occasionally, the tumor cell plates (or trabeculae) may be separated by an increased amount of connective tissue instead of by endothelial cells ( Fig. 55.16 ), and reticulin staining is usually increased in the bands of connective tissue. The thickened cell plates, which are separated by a prominent reticulin framework, often have a linear or ribbon-like arrangement. This pattern has been subclassified as an early form of scirrhous HCC, although the overall amount of fibrous tissue may not be as high as previously described.

Trabecular type of hepatocellular carcinoma. A, The cell plate architecture shows the formation of trabeculae and somewhat dilated sinusoids. The trabeculae are lined by endothelial cells. Bile stasis and the small cell change are evident. B, The cell plates are three cells thick or wider in most of this tumor. The small cell change can be seen.

Reticulin stain of a trabecular type of hepatocellular carcinoma shows complete loss of the reticulin framework, which is normally visible as black strands of subendothelial connective tissue. The cell plates are relatively thin, and pseudoglands (i.e., acinar structures) are evident.

Variant of the trabecular type of hepatocellular carcinoma. A, The tumor trabeculae are separated by relatively thin fibrous bands. Extensive Mallory hyaline is in many of the tumor cells. B, Reticulin stain shows increased staining along the thin, fibrous septa that separate tumor trabeculae. The tumor cell plates tend to line up in a side-by-side (ribbon-like) pattern.

The acinar (pseudoglandular) pattern of HCC is less common than the trabecular pattern. This variant is defined by glandlike spaces (i.e., acini) that are lined by hepatocytic tumor cells ( Fig. 55.17 ). The acinar structures are formed by dilation or expansion of bile canaliculi, and they often contain bile or proteinaceous material. Less frequently, the spaces develop as a result of central necrosis of trabeculae and contain protein, cellular debris, or macrophages. The formation of glandlike spaces can lead to a misdiagnosis of adenocarcinoma. The acinar pattern is frequently admixed as a minor component with the trabecular pattern (see Fig. 55.15 ).

Hepatocytes of a pseudoglandular (acinar) type of hepatocellular carcinoma form glandlike structures that contain proteinaceous debris. They also contain bile (not shown).

The compact (solid) pattern of HCC is a relatively uncommon variant characterized by dense aggregates of tumor cells that seem to lack endothelial cell–lined trabeculae or cell plates ( Fig. 55.18 ), and it is more common in poorly differentiated HCC. However, careful examination with endothelial cell markers often reveals compressed trabeculae. Loss of the reticulin framework is typically seen in solid and crowded cellular zones.

In a solid type of hepatocellular carcinoma, the tumor cells are arranged in sheets without definable cell plates or trabeculae.

The scirrhous pattern contains prominent, focal or diffuse areas of fibrosis and may be associated with any of the patterns previously described ( Fig. 55.19 ). Differentiation of scirrhous HCC from fibrolamellar HCC (see Fibrolamellar Variant of Hepatocellular Carcinoma ) is based on identification of the characteristic cytologic features of the latter and on the different clinical settings in which these two tumors occur. The term sclerosing hepatic carcinoma has been used for some of the HCCs and cholangiocarcinomas associated with hypercalcemia, but this form is not recognized as a distinct variant.

In a scirrhous type of hepatocellular carcinoma, the tumor nests are separated by fibrous connective tissue.

In all of these patterns, the cytologic features of HCC tend to resemble those of normal hepatocytes, but the degree of nuclear atypia varies, ranging from near normal to markedly abnormal (i.e., angular nuclei with clumped chromatin). The tumor cells often maintain their polygonal shape and have round vesicular nuclei and prominent nucleoli that exhibit features typical of hepatocytic differentiation. Intranuclear vacuoles (composed of cytoplasmic invaginations) and glycogenation of nuclei (another feature seen in normal liver) are fairly common in HCC tumors ( Fig. 55.20 ). Small cell change is probably the most common atypical cytologic change, but a large cell change and giant or pleomorphic cells may be seen focally or diffusely (see Fig. 55.20 ). The amount of cytoplasm may vary, and it is often slightly more basophilic than in normal hepatocytes. The cytoplasm may have a granular appearance, or it may be exceptionally oxyphilic because of a large number of mitochondria. Cytoplasmic inclusions (e.g., Mallory bodies, globular acidophilic bodies) composed of proteins (i.e., albumin, fibrinogen, α ₁ -antitrypsin, or ferritin) may be seen (see Fig. 55.20 ).

Clear cell variant of hepatocellular carcinoma shows a prominent cytoplasmic clear cell change. An occasional intranuclear vacuole ( lower arrow ), focally enlarged pleomorphic nuclei, and eosinophilic cytoplasmic globules ( upper arrow ) can be seen.

Fat ( Fig. 55.21 ), glycogen, or possibly water may be prominent in HCCs, providing the cells with a clear appearance. This has been described as the clear cell variant of HCC. If the entire tumor shows this type of clear cell change and it occurs in a noncirrhotic liver, it may be difficult to differentiate HCC from other types of clear cell tumors, such as metastatic renal cell carcinoma (see Differential Diagnosis ). Other cytoplasmic changes seen much less frequently include pale bodies, which are round to oval, lightly eosinophilic or clear cytoplasmic structures most frequently seen in the fibrolamellar variant of HCC; ground-glass cells containing hepatitis B surface antigen, which is found in some patients with HBV infection ; and dark brown to black pigment similar to that seen in the Dubin-Johnson syndrome. Rare forms of HCC that show a prominent spindle cell component or diffuse small cells (i.e., small cell type) have been described.

Staining of a hepatocellular carcinoma with a prominent fatty change shows fat droplets in the tumor cell cytoplasm.

Differential Diagnosis

Immunostains may help to distinguish HCC from other tumors in the liver. Most diagnostic problems consist of differentiating adenoma or FNH from well-differentiated HCC, poorly differentiated adenocarcinoma (metastatic or primary) from HCC, and HCC from other primary or metastatic neoplasms. Well-differentiated HCC may be differentiated from large regenerative or low-grade dysplastic nodules and high-grade dysplastic nodules by the features listed in Table 55.5 .

AFP is a reasonably specific marker for HCC. However, the staining tends to be patchy or absent in as many as 50% of HCCs. It is typically absent in small, well-differentiated HCCs. Polyclonal CEA, which highlights bile canaliculi, is another highly specific marker for hepatocellular differentiation, but it tends to stain only moderately differentiated to well-differentiated lesions. This stain also delineates the outer cell membranes of adenocarcinomas, which may mimic a canalicular pattern on tangential sectioning.

Hepatocyte antibody (i.e., clone OCH1E5.2.10 or HepPar-1 antibody) is relatively specific for hepatocellular differentiation. This antibody demonstrates a granular cytoplasmic pattern of some degree among tumors with hepatocytic differentiation. Similar to polyclonal CEA, HepPar-1 is less sensitive for poorly differentiated HCCs, and it may also stain hepatoid variants of adenocarcinoma, many of which metastasize to the liver. Another relatively specific hepatocyte marker is arginase 1, which may stain a slightly broader spectrum that extends to moderately or poorly differentiated HCCs.

CK8 and CK18 (in the CAM 5.2 stain) occur in tumors with hepatocellular differentiation. Staining with the AE1/AE3 antibody, which recognizes most keratin types except CK8 and CK18, is usually negative. However, because both of these cytokeratin stains react in most adenocarcinomas, CAM 5.2 should not be used in isolation. CK7 staining is commonly negative in HCCs, but it often focally stains small ductular-like hepatocytes or acinar structures in HCC and can be diffusely positive, especially in tumors with fibrotic stromal backgrounds. CK7 staining has also shown a relative lack of ductular reaction at the borders of HCC. CK20 staining is usually negative (>95% of cases) except for rare isolated cellular staining, some of which may be caused by Mallory hyaline staining.

CD10 stains the bile canalicular cytoplasmic surface of hepatocytes. CD34 stains endothelium-lined trabeculae in HCC and can be used to highlight increased vascularity typical of this tumor type. GPC3, an oncofetal protein the concentration of which is elevated in the sera of many patients with HCC, can be helpful to distinguish benign from malignant hepatocellular neoplasms ( Fig. 55.22 ) and HCC from many other tumor types, but it is not entirely specific for HCC. Use of a combination of immunostains has been advocated to increase diagnostic accuracy of HCC, including use of GPC3 and CD34 and the triple combination of GPC3, heat shock protein (HSP70), and glutamine synthetase.

Hepatocellular carcinoma shows focal glypican 3 immunostaining in a moderately differentiated portion of the tumor.

Hepatocellular Carcinoma versus Adenocarcinoma

Differentiating primary or metastatic adenocarcinoma from HCC in noncirrhotic livers is a common problem in tumor pathology ( Table 55.6 ). MOC (monoclonal antibody)-31 is one of the more reliable and consistent markers of adenocarcinoma. It stains most adenocarcinomas (membranous pattern) and stains HCC in less than 20% of cases. Because MOC-31 may also stain benign hepatocytes in cirrhosis, a routine morphology investigation should be correlated with interpretation of this marker.

Table 55.6

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