Clinical and Epidemiologic Background (See Chapter 80)

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor in the adult liver. It ranks among the most frequent neoplasms—approximately 6% of all new cancer diagnosed worldwide with an estimated incidence of about 500,000 to a million new cases per year. It is a deadly malignancy and the third most frequent cause of cancer death among men, causing 600,000 deaths worldwide per year (McGlynn & London, 2005; Sherman, 2005; Parkin et al, 2005; Bruix et al, 2004).

One of the striking characteristics of HCC is the marked geographic variation in its frequency, which is mainly related to geographic distribution of chronic liver disease risk factors. East Asia and sub-Saharan Africa have a very high incidence, whereas Italy, Spain, and Latin America are at intermediate risk. A relatively low but increasing incidence is found in Western Europe, the United States, Canada, and Scandinavia. In these countries, the incidence rate is 50 times lower than in Southeast Asia (Bosch et al, 2004; Kahn et al, 2002; Seeff & Hoofnagle, 2006).

The association between cirrhosis and HCC has been well established. Indeed, 60% to 90% of HCC arises in cirrhotic livers. Conversely, approximately 1% to 3% of patients with cirrhosis will develop HCC annually (Colombo et al, 1991; Johnson & Williams, 1987; Zaman et al, 1985). Most of the epidemiologic variation in HCC prevalence is thought to reflect differences in etiologic risk factors for liver cirrhosis that encompasses a large group of environmental factors (El-Serag et al, 2008). The major known risk factors for HCC are hepatitis viruses (chronic hepatitis B and C; see Chapter 64), toxins (alcohol, aflatoxins), metabolic diseases (metabolic syndrome, α₁ antitrypsin deficiency, Wilson disease), hereditary hemochromatosis, and immune-related diseases (primary biliary cirrhosis, autoimmune hepatitis; see Chapter 70A). Given that the burden of chronic liver diseases is expected to rise along with increasing rates of alcoholism, hepatitis B and C infection, and fatty liver disease, it is expected that the incidence of HCC will also increase in the near future (Nordenstedt et al, 2010; El-Serag, 2008).

HCC is primarily a disease of older men, and its incidence generally increases with age. In Western Europe and the United States, most patients with HCC are between 50 and 75 years of age, although there are geographic differences. It occurs more frequently in men than women, with a male/female ratio ranging from 2 : 1 to 9 : 1, although the reason for this is not clear (El-Serag et al, 2008). Routine liver function tests are variably abnormal, often reflecting the underlying cirrhosis without a consistent pattern of alterations. Serum α-fetoprotein (AFP) is elevated in most symptomatic tumors, but small cancers are associated with lower or even normal levels. Thus serum AFP is not a reliable diagnostic test for HCC screening in patients with cirrhosis (Bruix & Sherman, 2005).

It is admitted that HCC usually occurs after a mean delay of 10 years following the onset of liver cirrhosis. This observation is highly consistent with the multistep process of liver cirrhosis that implies progressive malignant transformation of preneoplastic lesions, such as macroregenerative and dysplastic cirrhotic nodules. Because of the dismal prognosis of the disease, increasing emphasis has been placed on detecting early, asymptomatic HCC that is potentially curable.

Ultrasound (US) is a sensitive technique for identifying nodules larger than 1.5 cm and is thus often used for detection, whereas magnetic resonance imaging (MRI) is a more accurate procedure for liver mass characterization (Bolondi et al, 2005; see Chapters 13 and 17). Reliable and highly specific imaging criteria now allow confident diagnosis of HCC in cirrhotic patients so that liver biopsy can be avoided when hyperarterialization associated with early washout is present in dynamic imaging (Bruix & Sherman, 2005; Forner et al, 2008). Screening programs have thus been proposed to follow cirrhotic patients by repeat US. These programs have been successful in identifying small and asymptomatic HCCs in high-incidence areas such as Japan, China, and Alaska but have been less effective in regions where the tumor incidence is low (Sangiovanni et al, 2004).

Despite some progress in managing HCC, liver cancer still carries a dismal prognosis, which is partly explained by its late diagnosis and the clinical context of the patient, which may compromise potential therapeutic strategies. Prognosis is also related to the liver tumor itself, which is prone to early angioinvasion.

HCC is a peculiar tumor for several reasons. Indeed, its morphologic patterns are various, beyond the usual classification based on growth pattern and tumor differentiation. Furthermore, molecular pathogenesis of HCC is complex, involving different molecular pathways that may reflect both etiologic factors and underlying liver disease (Thorgeirsson & Grisham, 2002; Villanueva et al, 2007).

Gross Pathology

HCC can adopt a wide range of gross configurations, and several macroscopic classifications of varying complexity have been proposed, but their clinical relevance has not yet been proven. Tumor size ranges from less than 1 cm to more than 30 cm in diameter. At the time of diagnosis, mean size of HCC arising in a cirrhotic liver is usually less than those occurring in nonfibrotic liver. HCC tumors less than 2 cm are recognized as small or early HCC (International Working Party [IWP], 1995). Recently, small HCC have been subdivided into vaguely nodular and well-circumscribed HCC, two patterns with differences in prognosis; the vaguely nodular form has a better prognosis (International Consensus Group [ICG], 2009; Hytiroglou et al, 2007). Although the diagnosis of large HCC relies mainly on imaging modalities, biopsy is often requested for the diagnosis of these small nodular lesions. Upon gross examination, HCC may display a nodular, infiltrative, or diffuse macroscopic pattern (Okuda et al, 1984).

Nodular (Expanding) Hepatocellular Carcinoma

The nodular (expanding) pattern is the most common type of HCC, and it is typically seen in association with cirrhosis. This group of tumors is characterized by a sharp demarcation between the tumor mass and the compressed and partly atrophic surrounding parenchyma (Fig. 78.1). The presence of distorted hepatic vessels, including arteries, that form curved structures on the surface of the tumor mass or are visible on the cut surface support the concept of an expanding growth pattern. The nodule may be solitary or multiple across the liver, when these develop as a complication of cirrhosis. When nodules are multiple, small (<1 cm in diameter), and adjacent to the main tumor nodule, they are known as satellite nodules (Fig. 78.2).

FIGURE 78.1 Hepatocellular carcinoma developed on liver cirrhosis with an expanding growth pattern. The tumor is sharply demarcated from the surrounding parenchyma and limited by a fibrous capsule.

FIGURE 78.2 Hepatocellular carcinoma. The tumor is massively necrotic with minute satellite nodules in the vicinity (arrows).

In cases of multiple HCCs, nodules may represent either multifocal independent tumors or intrahepatic metastasis. Such a distinction is quite impossible based on pathologic study alone but could be addressed with surrogate molecular analysis (Paradis et al, 1998; Sakamoto et al, 1989). On cut section, nodular HCC is well delineated from nontumoral liver and circumscribed totally or partially by a fibrous capsule (Okuda et al, 1977). Capsule formation is considered to begin at a tumor diameter of at least 10 mm or greater, because no distinct capsule has been noted in lesions less than 10 mm (Nakanuma et al, 1986). The prognostic significance of capsule formation has not yet been definitively settled. HCC typically forms soft masses that vary in color from gray, light brown, or yellow-green, often punctuated by foci of hemorrhage or necrosis when the tumor reaches a significant volume (Fig. 78.3).

FIGURE 78.3 Hepatocellular carcinoma. The tumor forms soft masses with foci of hemorrhage or necrosis.

Infiltrative (Massive) Hepatocellular Carcinoma

The infiltrative (massive) pattern is usually characterized by a large, solitary mass that occupies a substantial portion of the liver. The lesion is poorly circumscribed with ill-defined, invasive borders (Fig. 78.4). This pattern has been associated more commonly with noncirrhotic livers (Smalley et al, 1988; Grando-Lemaire et al, 1999). On cut section, the tumor extends into and distorts the adjacent nontumor tissue, interdigitating with surrounding parenchyma. Vessels are incorporated into, not displaced by, the tumor mass so that tortuous vessels around the tumor are not so obvious (Okuda et al, 1982).

FIGURE 78.4 Hepatocellular carcinoma with an infiltrative growth pattern. The tumor is poorly circumscribed and extends into the surrounding parenchyma. No rim of compressed tissue or capsule is visible.

Diffuse Hepatocellular Carcinoma

The diffuse pattern is the least common type of HCC and represents a widespread infiltration by numerous small nodules that virtually replace the entire liver. In this pattern, tumor consists of several unconnected small tumors of roughly similar size. Multicentric origin or intrahepatic spread after portal vein invasion have been discussed as pathogenic mechanisms (Fig. 78.5; Nakashima & Kojiro, 1986).

FIGURE 78.5 Hepatocellular carcinoma with a diffuse pattern of growth. The liver is totally replaced by numerous small, round tumor nodules.

Limits of Gross Classification

This gross classification has limits, because categorization of a tumor within one single growth pattern may be difficult; for example, expanding HCC may show areas of infiltrative pattern. Furthermore, the reproducibility of this categorization among different pathologists has not been shown. Finally, besides the diffuse pattern, which is associated with a dismal prognosis, the differentiation between expanding and infiltrative patterns does not appear as a prognostic indicator in multivariate analysis.

In nodular, advanced, and infiltrative HCC, invasion of large veins is common even at gross examination. The portal vein is more often involved than hepatic veins, inferior vena cava, or right atrium (Fig. 78.6). Portal vein invasion may be associated with thrombosis, and vascular invasion should be determined with care at the initial gross examination (macrovascular invasion). In some instances, intravascular tumor plugs in the close periphery of a large tumor may be difficult to distinguish from satellite tumor nodules. Invasion of large bile ducts may produce biliary obstruction, and hemobilia might be occasionally found.

FIGURE 78.6 Invasion of a dilated large portal vein (large arrow) and a small vein (small arrow) by a tumoral thrombus in a cirrhotic liver close to a hepatocellular carcinoma.

Histopathology

Histopathologic evaluation is no more systematic, because dynamic imaging has high diagnostic accuracy for tumors larger than 3 cm. When imaging is not diagnostic, US-guided biopsy must be performed. This is often the case for HCC smaller than 2 cm, when biomarkers have low predictive values, and hyperarterialization may be incomplete or absent. For nodules smaller than 1 cm, biopsy is generally not recommended because of its limited performance. These diagnostic criteria have been endorsed by most international liver disease associations (Bruix & Sherman, 2005; Bruix et al, 2001). Nevertheless, despite the major advances in radiologic procedures, the definitive diagnosis continues to be based primarily on accurate examination and interpretation of histologic material for any small or atypical nodule.

Histopathologically, the diagnosis of HCC is based on the distinction between tumor cells and normal hepatocytes (Anthony, 1973). Therefore, the microscopic evaluation entails assessment of cytologic characteristics of tumor cells and evaluation of their architectural pattern.

Tumor cells may be seen in varying degrees of hepatocellular differentiation within a single tumor. Nuclei are usually basophilic and often irregular, with prominent nucleoli and a high nuclear/cytoplasmic ratio. In well-differentiated HCC, the tumor cells may closely resemble normal hepatocytes, with a polygonal shape, distinct cell membranes, and eosinophilic granular cytoplasm (Fig. 78.7). Bile canaliculi can often be seen by light microscopy or can be demonstrated by immunostaining. When dilated, they might contain bile pigment, a characteristic feature of hepatocellular differentiation. Accumulation of glycogen or fat in tumor cells may produce a clear-cell appearance (Fig. 78.8). Cytoplasmic fat droplets might be more common in small HCCs. Mallory-Denk bodies, hyaline globules, and eosinophilic or so-called ground-glass cytoplasmic inclusions may also be observed.

FIGURE 78.7 Well-differentiated hepatocellular carcinoma. Tumor cells are organized in large trabeculae and resemble normal hepatocytes with a polygonal shape, distinct cell membranes, and clear cytoplasm with a high nuclear/cytoplasmic ratio.

FIGURE 78.8 Hepatocellular carcinoma with a clear-cell pattern. Malignant tumor cells of various sizes are enlarged with a clear cytoplasm.

As the tumor evolves to a poorly differentiated phenotype with cell-to-cell heterogeneity, bizarre nuclei or giant tumoral cells may appear. Mitosis and apoptotic bodies can be observed (Fig. 78.9). Different degrees of cellular differentiation are usually present within a single large tumor, although small HCC tend to be more homogeneous.

FIGURE 78.9 Poorly differentiated hepatocellular carcinoma. The tumor is highly cellular with tumoral cells organized in large trabeculae with bizarre nuclei, mitosis, and apoptotic bodies.

Growth Patterns

The arrangement of the cells contributes to the variability in the microscopic appearance. On this basis, several types of tumor have been categorized, but it has not yet been fully established whether these variations reflect differences in behavior and influence prognosis (Qin & Tang, 2002). The three main architectural patterns of growth of HCC are trabecular; acinar, or pseudoglandular; and scirrhous.

Trabecular Growth

Trabecular growth occurs when tumoral hepatocytes are arranged in plates in varying thicknesses from 2 to more than 20 cells (see Fig. 78.7). This feature resumes the normal trabecular arrangement of liver plates. Neoplastic cells are organized along simplified sinusoids lined by flat endothelial cells with few or no Kupffer cells. Compared with normal liver plates, the reticulin framework is commonly sparse or absent (Fig. 78.10). A compact or solid pattern occurs when the trabeculae are closely aligned, and the sinusoids become compressed and unapparent.

FIGURE 78.10 Reticulin staining in hepatocellular carcinoma. The lower part of the figure displays fragmentation and rarefaction of the reticular framework.

Acinar (Pseudoglandular) Growth

The acinar, or pseudoglandular, pattern results either from glandlike dilation of the canaliculi between tumor cells, in which the lumens can contain bile, or central degeneration of trabeculae, in which the lumens contain mainly degenerative products with fibrin (Fig. 78.11). As with the trabecular pattern of growth, stroma is typically sparse. The lack of a desmoplastic stroma reaction is a helpful diagnostic clue, when other glandular malignant epithelial neoplasms, especially cholangiocarcinomas, are discussed. On occasion, large vascular lakes resembling peliosis can develop within the pseudoglandular formations.

FIGURE 78.11 Hepatocellular carcinoma with a pseudoglandular pattern. Hepatocytes display glandlike organization around dilated canaliculi between tumor cells.

Histologic Variants

Fibrolamellar Hepatocellular Carcinoma

This subset, which differs from other types of HCC in clinical features and prognosis, is the only variant with clinical significance. It was first delineated as a distinct entity in 1980 (Craig et al, 1980). In a population-based study, fibrolamellar HCC constituted 0.85% of all cases of primary liver cancer and 13.4% of all cases in patients younger than age 40 (El-Serag & Davila, 2004). The clinical presentation is similar to other HCCs, except that it occurs in young people with equal gender ratio and has no association with chronic liver disease, cirrhosis, or any other known predisposing risk factors.

On gross examination, fibrolamellar HCC is a firm, mostly well-defined but unencapsulated single nodule that can range from 5 cm to more than 20 cm (Saab & Yao, 1996). On cut section, the tumor is gray to brown with scalloped borders and a solid consistency (Fig. 78.12). Prominent fibrous septa subdivide the mass and may connect with a central zone of scarring. Such features may be confused with focal nodular hyperplasia. In addition, several reports in the literature describe fibrolamellar HCC spatially associated with focal nodular hyperplasia, although filiation between these two lesions has never been convincingly demonstrated (Saul et al, 1987). Calcifications may also be observed.

FIGURE 78.12 Fibrolamellar hepatocellular carcinoma. Large lobulated tumor is well delineated from normal surrounding liver.

The distinctive histologic features are fibrous stroma and large, eosinophilic tumor cells (Fig. 78.13; Berman & McNeill, 1988). The stroma comprises dense, fibrous bands of varying thickness organized around nests, cords, and sheets of neoplastic cells (Nerlich et al, 1992). The tumor cells are usually larger than normal hepatocytes and display abundant, granular, and deeply eosinophilic cytoplasm with prominent nucleoli. Bile pigment is common, and fat or glycogen accumulation is sometimes seen. Most fibrolamellar carcinomas are histologically low grade, mitoses are usually sparse, and nuclear pleomorphism and multinucleation are infrequent. Cytoplasmic inclusions of various types are common, including ground-glass pale bodies (Fig. 78.14), eosinophilic cytoplasmic globules of variable periodic acid-Schiff positivity, and rarely Mallory-Denk bodies. In contrast to most HCC, fibrolamellar HCC seems to abundantly express type 7 cytokeratin (CK) and, in some cells, biliary-type CK19 (Van Eyken et al, 1990).

FIGURE 78.13 Fibrolamellar hepatocellular carcinoma. The tumor is composed of large eosinophilic tumor cells organized in cords between dense, acellular fibrous bands.

FIGURE 78.14 Fibrolamellar hepatocellular carcinoma. A, Tumoral cells organized in trabeculae along fibrous septa. B, High magnification showing large eosinophilic tumor cells with intracytoplasmic ground-glass pale bodies. C, Intracytoplasmic pale bodies. D, Intracytoplasmic eosinophilic globules of various size.

Fibrolamellar HCC tends to be slow growing and frequently resectable with a better prognosis than other types of carcinoma. However, when adjustment is made for tumor stage, all series do not demonstrate this better prognosis. Successfully resected patients have good chance of long-term survival despite extrahepatic recurrences.

Other Morphologic Patterns of Hepatocellular Carcinoma

It is well known that HCCs that arise in hemochromatosis fail to show accumulation of stainable iron, and iron-free foci in siderotic macroregenerative nodules in human cirrhotic livers have been suggested to be a marker for incipient neoplastic lesions (Hirota et al, 1982; Deugnier et al, 1993). Some HCCs accumulate copper, which can be detected using histochemical methods. Accumulation of large amounts of copper and copper-binding protein (orcein-positive) has been found chiefly in the fibrolamellar variant of HCC (Lefkowitch et al, 1983).

There are some unusual instances in which HCC produces substances that occur in some rare metabolic disorders (e.g., black HCC in a patient without Dubin-Johnson syndrome; Roth et al, 1982). A granulomatous sarcoid-like reaction may be encountered within HCC, the granulomas being characterized by epithelioid cells, Langerhans-type giant cells, and varying numbers of lymphocytes (Nakashima & Kojiro, 1986). Massive lymphoid stroma may also circumscribe otherwise typical HCC.

Hepatocellular Carcinoma in Noncirrhotic Liver

HCC in noncirrhotic liver encompasses several entities. It may develop during the evolution of a chronic fibrosing liver disease at the stage of incomplete cirrhosis (septal fibrosis). This is especially common in the context of chronic hepatitis B (Lam et al, 2004). Because of the possible reversibility of cirrhosis, it is not known whether HCC in incomplete cirrhosis develops during an ongoing fibrogenesis or along with the reversion of cirrhosis. In this context, HCC does not show any specific morphologic criteria. HCC may also develop in strictly normal liver or in liver with mild changes, such as steatosis. This group includes the fibrolamellar variant of HCC, that arising from malignant transformation of liver cell adenoma (see below), and a group that develops in the context of other chronic liver disease, including nonalcoholic fatty liver disease (Paradis et al, 2009; Marrero et al, 2002).

Grading and Other Pathologic Prognostic Factors

Grading of HCC relies on the Edmondson and Steiner system, which subdivides HCC into four grades, from I to IV, on the basis of histologic and cytologic resemblance to normal liver (Edmonson & Steiner, 1954). This grading has been shown to correlate with the DNA content and cellular proliferation indices of the tumor (Grigioni et al, 1989). Grade I is the well-differentiated type, in which hepatocyte-like cells are arranged in thin trabeculae. Small HCC tends to be grade I, although these are often not uniform in their differentiation. Grade II HCC is composed of larger tumor cells with abnormal nuclei; glandular structures may also be present. In grade IV, neoplastic cells are much less differentiated, with hyperchromatic nuclei and loss of trabecular pattern. In fact, most HCC seen initially is grade II or III (Kenmochi et al, 1987). Therefore, and as for other carcinomas, the general tendency is to summarize the grading using a three-tiered system comprising well-, moderately, and poorly differentiated HCC.

Nonetheless, tumor grade is a weak independent predictor of the clinical course and conveys little prognostic information (Lai et al, 1979; Chuong et al, 1982). Furthermore, grading of HCC is often heterogeneous alongside the tumor so that liver biopsy might have limited performance for grading HCC. Consequently, the histologic grading of HCC is useful, but rather as a descriptive tool; its practical value is limited (Pawlik et al, 2007).

Besides grading, other histologic features of HCC, such as architectural pattern, have little or no independent prognostic value. However, several staging systems have been proposed for HCC (Llovet et al, 1999; Marrero et al, 2005). The main prognostic factors are related to general health status; tumor stage, specifically the number and size of nodules, presence of vascular invasion, and extrahepatic spread; liver function, defined by the Child-Turcotte-Pugh classification system and by serum bilirubin and serum albumin levels; and portal hypertension. Etiology has not been identified as an independent prognostic factor.

Size is a major prognostic factor: small or minute carcinomas have a better prognosis, although with larger cancers, the tumor size does not directly correlate with outcome. Presence of satellite nodules around the main tumor has been also recognized as a prognostic factor in several studies. Improved survival has been associated with tumors that are encapsulated or fail to invade surrounding hepatic parenchyma (Ohnishi et al, 1987; Arii et al, 2000; Sutton et al, 1988).

Macroscopic and microscopic vascular invasion are important histoprognostic criteria that deserve special mention. Vascular invasion is a known predictor of recurrence and survival, directly associated with histologic differentiation, degree, and size of the main nodule (Nathan et al, 2009; Pawlik et al, 2005). Characteristically, the prevalence of microscopic vascular invasion increases with tumor size, with up to 60% to 90% in nodules larger than 5 cm. Other histologic findings are not consistently correlated with outcome, although occasional series have reported a better prognosis with clear-cell HCC and tumors of low histologic grade.

Using microarray technology, recent studies have shown that a subset of adult HCC displays phenotypic traits of hepatoblasts. These tumors retent stem cells markers and express CK7 and CK19. Interestingly, worse survival was demonstrated for this subgroup (Lee et al, 2004). Although the significance of CK7 and CK19 expression in HCC is still unclear, it might represent a relevant prognostic factor, although a larger study with multidimensional analysis should be performed.

A major influence on clinical status of the patient is the presence or absence of cirrhosis, which thus becomes a leading indicator for survival. Therefore, simultaneous biopsy of nontumoral liver is of major importance and should be systematically performed for consideration in the therapeutic decision and to help the pathologist in the diagnosis of very well-differentiated HCC.

Molecular Genetics

From experimental hepatic carcinogenesis and epidemiologic studies, it appears that liver carcinogenesis follows a multistep process (see Chapter 8C). Although a few cases of HCC arise in normal liver, the vast majority of them develop from the stepwise pathway: normal liver progresses to fibrosis then to cirrhosis and finally to HCC. Therefore, cirrhosis is recognized as a precancerous lesion (IWP, 1995).

As a result of careful follow-up of cirrhotic patients and detailed pathologic analysis of cirrhotic explanted livers, relevant insights have been gained into the early pathogenesis of HCC. Data are less clear when associated molecular events are concerned; however, a consensus supports the idea that HCC results from cumulative genetic and epigenetic events (Thorgeirsson & Grisham, 2002). Although recurrent gene abnormalities have been reported in fully developed HCC, the early molecular events are far less unknown.

Several studies using different approaches have looked for early molecular abnormalities in regular cirrhosis. Several molecular markers have been evaluated in macronodules, and none of the oncogenes or tumor suppressor genes involved in advanced HCC have been repeatedly found altered in the precancerous lesions. By contrast, proliferation markers, neoangiogenesis, telomerase expression, allelic losses, and clonality have been studied with more consistent results. Interestingly, these studies convincingly demonstrate, using clonal analysis, that among cirrhotic micronodules that looked similar on light microscope, some are already monoclonal (neoplastic), and others are polyclonal (regenerative; Paradis et al, 1998, 2000). Telomerase, an enzyme that allows unrestricted cell proliferation and that is specifically expressed in cancer, can be detected in some but not all of these clonal micronodules without any remarkable histopathologic features (Oh et al, 2003). In the same orientation, and using cell-cycle markers, studies have shown that cirrhosis associated with HCC, or that will give rise to HCC, already expresses increased cell-cycle markers. Therefore even in regular cirrhosis with a bland histopathologic appearance, foci of neoplastic clonal proliferation of liver cells with a limitless capacity of proliferation clearly are already present.

Most genomic studies address advanced HCC, and several efforts have been made to provide molecular classification of HCC based on gene expression (Villanueva et al, 2007; Chuma et al, 2003). Global gene-expression profiling may be the most appropriate technology to unravel the pathogenesis of HCC and explore its heterogeneous origin (Lee et al, 2004; Wurmbach et al, 2007; Llovet et al, 2006; Hoshida et al, 2008). In fact, application of gene-expression profiling of HCC has identified subgroups of patients according to etiologic factors, different stages of the disease, recurrence, and survival (Villanueva et al, 2008; Ladeiro et al, 2008; Boyault et al, 2007). The diversity of these tumors is also found at the molecular level, and a large number of genetic and epigenetic alterations have been described, some of them specific of risk factors. Recently, several comprehensive studies have shown that a molecular classification of HCC can be drawn, linking the transcriptomic pattern of gene expression (Boyault et al, 2007), micro-RNA profiling (Ladeiro et al, 2008), promoter methylations, chromosome gains, and deletions (Xue et al, 2008) to mutation of oncogenes and tumor suppressor genes (de la Coste et al, 1998). Major classes of tumors emerging from these comprehensive analyses are also related to important carcinogenesis pathways, such as activation of ß-catenin (de la Coste et al, 1998), AKT/mTOR (Villanueva et al, 2008), or inactivation of TP53 and RB1. Whether this molecular subclassification may provide a clue to personalized, targeted treatment or to prognosis is under active investigation (Villanueva et al, 2008). Interestingly, using genome-wide expression profiling of formalin-fixed, paraffin-embedded tissues, a recent study demonstrated that a reproducible gene-expression signature correlating with survival was only described in liver tissue adjacent to the tumor in patients with HCC (Hoshida et al, 2008).

Macroregenerative Nodules

A macroregenerative nodule (MRN) is a tumor-like hepatocellular mass that can arise in the setting of cirrhosis. These lesions have increasingly been detected, the result of both improved radiographic imaging techniques and more widespread screening of cirrhotic patients. Most MRN are large, discrete nodules that range from 1 to 3 cm in diameter. There is no minimum size threshold for definition; MRNs have to be appreciated according to the size of background cirrhotic nodules, which may be twofold to threefold larger than cirrhotic nodules (Theise et al, 1992; Terada et al, 1993). Macronodules are often well demarcated and surrounded by condensed connective tissue. MRNs are common, and they have been found after careful inspection in about 10% of cirrhotic livers at autopsy or at transplantation (Theise et al, 1992; Furuya et al, 1988; Mion et al, 1996). Histologically, most MRNs are indistinguishable from the usual parenchymal nodules seen in cirrhosis: normal-appearing hepatocytes are arrayed in plates one or two cells thick, limited by a regular sinusoid lining and bounded by typical fibrous septa containing blood vessels, bile ductules, and varying degrees of inflammatory infiltration (Fig. 78.15).

FIGURE 78.15 Low magnification of a benign regenerative macronodule in a cirrhotic liver. The macronodule is well-demarcated from surrounding liver. Fibrous septa and portal tracts are still present within the macronodule.

Dysplastic Nodules

Dysplastic nodules (DNs) are sizable lesions arising in cirrhosis, and they differ from the surrounding liver parenchyma with regard to size, color, texture, and degree of bulging of the cut surface. Based on microscopic features, DNs are further subdivided into low grade (LGDN) and high grade (HGDN), the latter being closer to HCC in the spectrum of hepatocarcinogenesis (IWP, 1995; ICG, 2009). Briefly, LGDNs display features suggestive of a clonal cell population but lack architectural atypia, whereas HGDNs show cytologic and architectural atypia but insufficient for a diagnosis of malignancy.

The premalignant nature of DNs is supported by different clues, including the common association with HCC in resected and explanted end-stage cirrhotic livers (Theise et al, 1992; Furuya et al, 1988; Libbrecht et al, 2005; Sakamoto et al, 1991); the presence of hepatocellular cyto-architectural abnormalities, featuring a lesion on the way to HCC (Ferrell et al, 1992; Ganne-Carrie et al, 1996; Takayama et al, 1990); the morphologic evidence of neoangiogenesis under the form of unpaired arteries supporting the abnormally ongoing vascular supply (Roncalli et al, 1999; Park et al, 2000; El-Assal et al, 1998); the detection of both genetic and epigenetic changes, greater than those in the surroundings but less frequent and consistent than in HCC; and a natural history showing an increased risk for malignant transformation compared with control cirrhotic nodules (Maggioni et al, 2000; Kobayashi et al, 2006; Terasaki et al, 1998; Seki et al, 2000).

Among the various cytologic alterations that characterize DNs are enlarged, crowded, or irregular nuclei with patent nucleoli and an increased nuclear/cytoplasmic ratio. Atypical architectural findings involve expansile proliferative zones, sometimes located within an MRN (nodule-in-nodule formations); focal loss of associated reticulin framework; and foci of abnormal structural patterns that includes irregular thickening of hepatic plates (IWP, 1995; Fig. 78.16). According to Eastern pathologists, stromal invasion, defined as the presence of tumor cells invading into the portal tracts or fibrous septa, is the most relevant feature distinguishing HGDN from early HCC (International Consensus Group for Hepatocellular Neoplasia, 2009). The degree and extent of these features vary greatly among patients, thus forming a histologic continuum that stretches between ordinary MRNs and obvious hepatocellular carcinoma.

FIGURE 78.16 A macronodule with a nodule-in-nodule pattern of growth. An expansile proliferative basophilic zone is located within a macronodule.

Dysplastic nodules must be differentiated from dysplastic foci, microscopic changes incidentally recognized in cirrhotic tissue. According to histopathologic criteria, dysplastic foci are split into two groups: those with large-cell changes or those with small-cell changes. Although large liver cell change, previously called large liver cell dysplasia (Fig. 78.17) consists of abnormal but nonneoplastic hepatocytes that are predictors of HCC development; small liver cell dysplasia is composed of neoplastic cells that are direct precursors of HCC (Lee et al, 1997; Borzio et al, 1995).

FIGURE 78.17 Large liver cell changes. Cluster of abnormal large liver cells with dystrophic nuclei.

Small Hepatocellular Carcinoma

A “small” liver cancer is currently defined as HCC with a maximum diameter of less than 2 cm (Nakashima & Kojiro, 1986). However, the lack of a widely accepted definition has led to confusion, and HCCs smaller than 3 to 5 cm have also been included in this group by others. Small HCCs are usually clinically silent and are often discovered incidentally on explanted liver or at autopsy (Mion et al, 1996). Small HCCs are most often a well-differentiated lesion, sometimes still containing portal triads, growing without substantial destruction of the preexisting hepatic framework and seldom showing angioinvasion (Sakamoto et al, 1991).

Small HCCs have been subdivided into two different entities: those with indistinct margins, called vaguely nodular HCC, and those with distinct margins, called distinctively nodular HCC (ICG, 2009). Whereas vaguely nodular HCC is the earliest, most indolent, and least angioinvasive type of HCC, distinctively nodular HCC is thought to have already acquired an ability to invade the vessels and to metastasize (Hytiroglou, 2007; Kojiro & Roskams, 2005; Theise et al, 2002). Therefore small HCC with distinct margins seems to be a progressed cancer in spite of its small size. On the liver biopsy, the difference between these two entities cannot be appreciated, because it requires the notion of gross features, which are not recognizable in small fragments. Therefore the term well-differentiated HCC may be better used in the biopsy report.

Natural History of Premalignant Lesions and Diagnostic Challenges

Few prospective studies have been conducted in large series of histologically proven nonneoplastic nodules detected by US during surveillance programs in cirrhosis. Taken together, these studies have shown that only a minority of macroregenerative or dysplastic nodules became malignant, those transforming are mostly in the group of HGDN. Furthermore, 40% to 60% stabilized, and a few definitely disappeared during follow-up (Borzio et al, 2003; Kondo et al, 1990). Most of these nodules are 1 to 2 cm, so they seldom display a diagnostic pattern at imaging. Therefore histologic assessment is needed at baseline, and it is worth repeating when sampling is not adequate.

Whether HCC regularly develops from DNs in a low grade–high grade–small and early–small HCC sequence in individual patients is still unclear. This hypothesis is supported by the feature of so-called nodules in nodules, which have been mainly reported in the Eastern literature (Kojiro, 2004; Roncalli et al, 2004, 2007). However, HCC has also been found to originate from outside dysplastic nodules during the surveillance of cirrhotic patients, supporting the notion that HCC can also develop “de novo,” by skipping the gradual transition of the sequence (Borzio et al, 2003).

From a clinical point of view, correct classification of hepatocellular nodules, as well as the exact number of truly malignant nodules, is crucial in order to plan the most appropriate therapy. However, the diagnostic approach to these small nodular lesions is a challenge. The prevalence of HCC is closely dependent on the size of the lesion. Indeed, almost half of those lesions smaller than 1 cm are nonmalignant, whereas the large majority of lesions exceeding 2 cm are HCC, so that in the group of lesions greater than 2 cm, a diagnosis of nonmalignancy should suggest the suspicion of a diagnostic error. It has been well established that, in cirrhosis, the progression from nonmalignant nodules to dysplastic to early and advanced HCC is characterized by the progressive loss of the portal blood with a “de novo” arterial vascularization (Hayashi et al, 2002). However, in the group of lesions sized 1 to 2 cm, about 20% of small HCC is hypovascular, so that histology is required in most of these cases, either at baseline or during follow-up, to confirm the nature of the lesions (Forner et al, 2008).

In clinical practice, liver biopsy is today mostly performed to classify small hepatocellular nodules (Bruix & Sherman, 2005). Diagnosis has to be made on tiny and often fragmented material, and clinicians need a conclusive report as to whether lesions are benign or malignant. Nevertheless, the diagnosis is not always straightforward, and other techniques may be required in addition to standard staining. Fortunately, immunocytochemical tools useful to distinguish malignant from nonmalignant nodules within the group of well-differentiated hepatocellular lesions have been developed recently, such as glypican-3 antibody (Di Tommaso et al, 2007).

Focal Nodular Hyperplasia

FNH is ten times more common than HCA and is the second most common benign liver process after hemangioma. It is predominantly diagnosed in women 30 to 50 years of age. Most FNH is found incidentally, but some is revealed by clinical symptoms or biologic alterations such as pain, liver mass, or increased γ-glutamyltransferase (GGT) levels. However, complications such as rupture or bleeding are exceptional, and no evidence of malignant transformation has been reported. In contrast to HCA, the diagnosis of FNH is strongly suggested by imaging techniques, so that histopathologic examination is required for diagnosis in a minority of cases. When performed, fine needle biopsy of FNH can be difficult, because fibrous septa and thick abnormal arteries, the hallmarks of FNH, are usually missing (Fabre et al, 2002; Makhlouf et al, 2005).

On gross examination, FNH appears usually as a solitary, discrete, rounded mass, pale to beige, and well-delineated from background normal liver but without a defined fibrous capsule (Fig. 78.21). On cut surface, FNH displays a variegated and partly nodular organization, and frequently, but not always, a central stellate scar with radiating fibrous cords are also visualized at imaging (Wanless et al, 1985; Nguyen et al, 1999).

FIGURE 78.21 Focal nodular hyperplasia. A well-circumscribed nodular lesion with a central stellate scar and radiating fibrous cords.

The typical histopathologic features of classical FNH include fibrous septa, which contain large dystrophic arteries with a peripheral ductular reaction, and an absence of interlobular bile ducts (Fig. 78.22). Hepatocytes are usually unremarkable, arranged in normal or mildly thickened plates without cytologic atypia, lined by a well-preserved sinusoidal framework. Steatosis or cholestatic degeneration with Mallory-Denk bodies may be seen.

FIGURE 78.22 Focal nodular hyperplasia. Fibrous septa contain often large, dystrophic arteries with thick walls and thin, fibrous septa.

FNH has been divided into classic and nonclassic forms (Nguyen et al, 1999). In forms of FNH other than the classic one, the diagnosis may prove difficult, because some of the distinguishing pathologic features may be unapparent. Such forms consist of FNH without a central scar, a mixed hyperplastic and adenomatous form, FNH with massive steatosis, and a form with atypia of the large-cell type (Nguyen et al, 1999). Strong evidence has been found, based on clonal features and the angiopoietin gene-expression profile, that the previously so-called telangiectatic variant of FNH may, in fact, belong to the HCA group (see below; Paradis et al, 2004).

Immunohistochemistry may provide interesting information. Immunostaining with glutamine synthetase that shows focal positive hepatocellular areas, usually centered by hepatic veins and described as a maplike pattern, is highly consistent with the diagnosis of FNH and suggests a focal maintenance of lobular organization (Bioulac-Sage et al, 2009a). In addition, the perisinusoidal spaces in FNH exhibit an aberrant extracellular matrix associated with abnormal fibrillin-1 expression (Lepreux et al, 2004). Further study showed that the phenotype of endothelial cells lining the vascular channels in FNH differs from those in the remaining liver, associated with a downregulation of angiotensin I–converting enzyme/CD143 (Grantzdorffer et al, 2004).

FNH and FNH-like nodules are now well known to develop in the context of hepatic venous outflow obstruction, including Budd-Chiari syndrome (Maetani et al, 2002; Rangheard et al, 2002), and in other circulatory disorders of the liver such as portal vein thrombosis, portal vein agenesis, hereditary telangiectasia, and even in cirrhosis; this supports the concept of a vascular trigger in the pathogenesis of FNH (Kondo, 2001; Kondo et al, 2004; Bureau et al, 2004). Evidence supports that FNH is a hyperplastic reaction resulting from an arterial malformation related to increased arterial blood flow (Wanless et al, 1985).

Similar to HCA, FNH has been observed in association with the use of oral contraceptives, although the relationship remains controversial (Scott et al, 1984). FNH may occur together with HCA (Grange et al, 1987), and it has been found to be associated with a variety of nonhepatic tumors and tumorlike conditions, such as HCA, hemangioma of the liver, and several other tumors (e.g., in siblings with glioblastoma; Handra-Luca et al, 2006). The significance of these associations is unclear, but it suggests that the pathogenesis of FNH is probably heterogeneous.

Hepatocellular Adenomas

HCA is a rare, benign liver cell neoplasm strongly associated with oral contraceptive (OC) use and androgen steroid therapy (Coombes et al, 1978; Nime et al, 1979). Its estimated incidence is 0.1 per year per 100,000 in non-OC users and reaches 3 to 4 per 100,000 in long-tem OC users. HCA can also occur spontaneously or in association with underlying metabolic diseases, including type 1 glycogen storage disease, iron overload related to β-thalassemia, and diabetes mellitus. Therefore, HCA represents a heterogeneous group of tumors in which histopathologic features may vary according to the etiologic background (Bioulac-Sage et al, 2007b).

HCA is usually solitary, sometimes pedunculated, with size ranging from a few millimeters to 30 cm. Large subcapsular vessels are commonly observed with large superficial tumors (Fig. 78.23). On analysis of cut sections, the tumor is soft, white to brown, and well delineated with little or no fibrous capsule (Fig. 78.24). Heterogeneous areas of necrosis or hemorrhage may be observed, especially in larger tumors. Histologically, HCA consists of a proliferation of benign hepatocytes of normal size or slightly enlarged with a normal nuclear/cytoplasmic ratio. Hepatocytes are arranged in a trabecular pattern without any residual portal tracts; a pseudoglandular growth pattern is possible but rare. Small, thin, and unpaired vessels without other portal tract elements—including connective tissue, bile ducts, or ductular reaction—are usually found throughout the tumor (Fig. 78.25). The cytoplasm of hepatocytes may be normal, glycogen-rich, or fatty, and cellular atypia can be impressive, especially in patients who have taken steroids for many years. In that context, differential diagnosis with HCC may be difficult. Vascular changes are frequent and include sinusoidal dilation, peliosis, infarcts, and hemorrhage. These changes may leave edematous or fibrotic regions, often with hemosiderin-laden macrophages.

FIGURE 78.23 Hepatocellular adenoma. External view of a superficial tumor with large subcapsular and dilated vessels.

FIGURE 78.24 Hepatocellular adenoma. Soft, well-delineated tumor with little or no fibrous capsule and small, heterogeneous foci of hemorrhage.

FIGURE 78.25 Hepatocellular adenoma. Proliferation of benign hepatocytes of normal size with a normal nuclear/cytoplasmic ratio pushing the normal liver parenchyma (arrows).

Compared with patients with FNH, those with HCA are more likely to come to medical attention with symptoms such as spontaneous bleeding and hemorrhage, with an increased risk according to size for tumors larger than 5 cm in diameter (Dokmak et al, 2009). The risk for malignant transformation of HCA ranges between 4% to 10%, with a higher rate in males and in large HCA (Bioulac-Sage et al, 2007; Dokmak et al, 2009). In addition, recent evidence suggests that metabolic syndrome may favor development of HCC in a preexisting HCA (Paradis et al, 2009). Increased incidence of metabolic syndrome may partly explain the rising incidence of malignant transformation of HCA, especially in the male population (Farges et al, 2011).

Multiple HCA and so-called adenomatosis are not so rare (Fig. 78.26). Patients with multiple HCAs are predominantly female, but the use of OC appears to be less prevalent (Fléjou et al, 1985). Patients with glycogen storage disease type I are also at risk of developing multiple HCA (Labrune et al, 1997). Nevertheless, these tumors share the same clinical and imaging characteristics independent of their number (Dokmak et al, 2009; Lewin et al, 2006). In addition, a recent study supports that the risk of complications, including bleeding and malignant transformation, is similar to that in patients with solitary HCA, and it is not influenced by the number of tumors (Dokmak et al, 2009; Bioulac-Sage et al, 2009b). The three main morphologic patterns of liver adenomatosis have been described: 1) steatotic, 2) peliotic/telangiectatic, and 3) mixed (Lewin et al, 2006). To note, the proportion of steatotic HCA is higher, and presence of microadenomatous foci in the “nontumoral liver” is more often observed in patients with liver adenomatosis (Dokmak et al, 2009).

FIGURE 78.26 Adenomatosis. Multiple hepatocellular adenomas of various sizes are dispersed throughout the liver.

Molecular Classification of Hepatocellular Adenomas

Molecular comprehensive studies have recently garnered further insights into the structure of HCA, demonstrating some degree of molecular and histologic heterogeneity among the group of HCAs. Today, HCAs are subdivided into three main subtypes according to phenotypic and molecular features: 1) hepatocyte nuclear factor (HNF) 1α–mutated steatotic, 2) telangiectatic/inflammatory, and 3) β-catenin–mutated (Paradis et al, 2004; Rebouissou et al, 2008; Zucman-Rossi et al, 2006). In addition, a small group of HCA that does not display any specific morphologic or genotypic features remains unclassified.

The first group of HCA displays biallelic mutations of the TCF1 gene, inactivating the HNF-1α transcription factor. This homogeneous group is phenotypically characterized by marked steatosis and absence of cytologic abnormalities or inflammatory infiltrates (Fig. 78.27). Whereas both HNF-1α mutations are somatic in most cases, patients with inherited mutation in one allele of HNF-1α and an additional somatic mutation may develop HCA in the context of maturity-onset diabetes of the young type 3 (MODY3) and are predisposed to familial liver adenomatosis (Bluteau et al, 2002; Bacq et al, 2003).

FIGURE 78.27 Steatotic adenoma. Most liver cells display marked steatosis. Unpaired arteries are visible between tumoral cells, but no portal tract.

The second group of HCA displays β-catenin–activating mutations and is characterized by increased risk for malignant transformation into HCC. These HCAs are mostly encountered in male patients and frequently show significant cell atypias and pseudoglandular formations (Fig. 78.28; Zucman-Rossi et al, 2006).

FIGURE 78.28 Hepatocellular adenoma with β-catenin–activating mutations. Liver cells display marked atypia (A); β-catenin immunostaining (B) shows that some tumoral cells display abnormal cytoplasmic and nuclear staining.

The third group of HCA is the inflammatory/telangiectatic adenoma group. These tumors, previously called telangiectatic variant of FNH, are well-delineated, unencapsulated tumors with areas of vascular changes without any fibrous scar (Fig. 78.29; Paradis et al, 2004; Wanless et al, 1989; Bioulac-Sage et al, 2005). Histologically, the hepatocellular proliferation contains small clusters of arteries embedded in collagen, often associated with an inflammatory infiltrate (lymphocytes and macrophages) and occasionally with ductular proliferation. In addition, foci of sinusoidal dilation and peliotic changes are usually present, and mild or significant steatosis may also be observed within tumoral cells. Although commonly observed in women using OC, telangiectatic/inflammatory HCA is often reported in patients with increased body mass index (BMI) associated with inflammatory syndrome (increased C-reactive protein [CRP] or fibrinogen serum levels; Paradis et al, 2004). Interestingly, in approximately 60% of these lesions, the interleukin (IL)-6 signaling pathway was found to be activated in relation to mutations in the IL6ST gene that encodes the signaling coreceptor gp130. As a matter of fact, the gain-of-function somatic mutations in gp130 may result in the inflammatory phenotype of HCA, which would explain activation of the acute inflammatory phase observed in tumoral hepatocytes (Rebouissou et al, 2009).

FIGURE 78.29 Telangiectatic/inflammatory adenoma. Extended foci of sinusoidal dilation are visible at low magnification.

The fourth group includes HCAs without any characteristic morphologic features or any of the genetic abnormalities previously described.

Surrogate immunophenotypic markers related to the genetic abnormalities may be used for the classification of the main subtypes of HCA (Bioulac-Sage et al, 2007b). Indeed, expression of liver fatty acid binding protein (LFABP), a protein positively regulated by HNF-1α, is absent in steatotic HNF-1α–mutated HCA, whereas it is expressed in nontumoral liver. Similarly, telangiectatic/inflammatory HCA displays positive immunostaining with acute-phase inflammatory proteins, such as serum amyloid A (SAA) and CRP. Most β-catenin–mutated HCA presents abnormal and cytoplasmic and/or nuclear staining of β-catenin in tumoral hepatocytes, usually with a focal positivity restricted to a few isolated tumoral hepatocytes. Immunostaining with glutamine synthetase, a β-catenin–targeted gene, showing a strong and diffuse cytoplasmic staining increases the sensibility for diagnosis of β-catenin–mutated HCA.

In surgical series of HCA, steatotic and telangiectatic/inflammatory subtypes appear to be equally distributed, accounting for 85% of overall HCA, whereas β-catenin-mutated HCA is reported in 10% to 15%.

Epidemiology and Clinical Background (See Chapters 50A and 50B)

Cholangiocarcinoma (CC) is a malignancy with biliary differentiation that develops along the biliary tree. It is the second most frequent primary malignant tumor of the liver (5% to 15% of liver primary malignancies; Malhi & Gores, 2006; Welzel et al, 2006). CC is mainly observed in adults with a peak incidence between 60 and 70 years and a male/female ratio of 1.5 : 1 (Parkin et al, 2005). CC is classified according to the anatomic location, either intrahepatic (IH-CC) or extrahepatic (EH-CC; Welzel et al, 2006). CC within the intrahepatic bile ducts is referred to as peripheral cholangiocarcinoma, arising in the bifurcation of the common bile duct as hilar CC, or Klatskin tumor; those in the extrahepatic bile ducts are extrahepatic CC (Klatskin, 1965). The updated WHO classification divides CC into IH-CC, hilar CC, and EH-CC (Bosman et al, 2010).

Hilar tumors are the most common, accounting for 60% to 70% of CC; peripheral lesions and tumors located in the extrahepatic bile duct represent 5% to 10% and 20% to 30% of CC respectively (Malhi & Gores, 2006; Patel, 2006). Although hilar CCs are usually considered an IH-CC, their characteristics in terms of clinical presentation, morphology, and phenotype are closer to EH-CC.

Prevalence of CC shows a wide geographic distribution largely as a result of variations in regional environmental risk factors, with the highest incidence observed in Asian countries where parasitic infections—namely, Opisthorchis viverrini and Clonorchis sinensis—are endemic (Kim et al, 1989; Lim et al, 2006; Watanapa & Watanapa, 2002; see Chapter 45). Importantly, incidence of CC is rising in most countries, even in nonendemic areas. Such an increase is specifically observed for IH-CC, including hilar tumors, whereas incidence of EH-CC is stable or even decreased (Khan et al, 2002; Patel, 2001, 2006; Shaib et al, 2004).

Although several risk factors for CC are well established, most occur in patients without evident predisposing factors (Chapman, 1999). Primary sclerosing cholangitis (PSC) associated with ulcerative colitis is one of the most recognized risk factors (see Chapter 41). Indeed, patients with PSC display a 1.5% cumulative annual risk of developing CC, and 10% to 20% will eventually develop CC (Boberg et al, 2002). Fibropolycystic liver diseases that include choledocal cyst, Caroli syndrome, and congenital hepatic fibrosis are also common risk factors (Yamato et al, 1998; see Chapter 46); infections with parasitic liver flukes, such as Opisthorchis viverrini and Clonorchis sinensis, contribute to the high incidence of CC in Asia (Curado & Shin, 2007; Lim et al, 2006; see Chapter 45). Hepatholithiasis (see Chapters 39 and 44), cholelithiasis, cholangitis, chronic pancreatitis, and Thorotrast exposure are also risk factors (Chapman, 1999; Lipshutz et al, 2002). More recently, associations of CC with obesity, diabetes, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection, and alcoholic liver disease have been reported in large population databases (Shaib et al, 2005; Welzel et al, 2007).

Clinical symptoms at diagnosis are dependent on the anatomic location, the growth types of the CC, and the tumor-node-metastasis (TNM) stage (Malhi & Gores, 2006). Although IH-CC is usually discovered at a late stage, hilar CC and EH-CC usually are found earlier with cholestasis (Ebata et al, 2009). The prognosis of CC is dismal, partly related to its propensity to invade directly adjacent liver parenchyma and to spread along the portal pedicles. Presence of perineural and vascular invasion is frequent in the hilar tumors. In the intraductal growth type, tumor often spreads intraluminally along the ducts, and intrahepatic metastases develop in nearly all advanced cases. The incidence of metastases to regional lymph nodes is higher than in HCC. Blood-borne spread occurs later, particularly to the lungs (Jiang et al, 2009; Patel, 2001; Suzuki et al, 2002).

Pathology (See Chapter 47)

Most CC develops in noncirrhotic liver. The Liver Cancer Study Group proposed a classification of CC based on growth patterns, and three main types emerged: 1) mass forming, 2) periductal infiltrating, and 3) intraductal growing (  Yamasaki et al, 2003). These patterns are associated with different clinical evolution, the intraductal growing and the periductal infiltrating showing the best and worse prognoses, respectively (65% survival at 5 years vs. <5%; Jiang et al, 2009; Suzuki et al, 2002).

The mass-forming variation is the main type of IH-CC, accounting for approximately two thirds of cases. It is a solitary, nodular lesion developed in the liver parenchyma. The tumor is usually well delineated, not encapsulated, and gray to white with a firm and solid consistency (Fig. 78.30). In cases with large tumors, adjacent satellite tumoral nodules are commonly observed. The periductal infiltrating type spreads along the portal tracts with stricture of the involved ducts, potentially leading to obstructive dilation and cholangitis of the peripheral bile ducts (Fig. 78.31). The intraductal growing type is a polypoid or papillary tumor developed within dilatated bile duct lumen (Fig. 78.32). This type represents malignant progression of biliary papillomatosis or intraductal papillary neoplasm (IPN) of the bile duct (see below). These three patterns may overlap in the same tumor. Although most CC occurs in a background normal liver, recent reports suggest that independently to its origin, cirrhosis increases the risk 10-fold for patients to develop CC (Fig. 78.33; Shaib et al, 2005; Kobayashi et al, 2000).

FIGURE 78.30 Cholangiocarcinoma, mass-forming type. Well-circumscribed, unencapsulated tumor is gray to white with a fibrous aspect developed in normal liver.

FIGURE 78.31 Cholangiocarcinoma, periductal infiltrating type. On cut section, infiltrating tumor developed along the portal tract and led to narrowing bile duct and obstructive dilation of peripheral intrahepatic bile ducts.

FIGURE 78.32 Cholangiocarcinoma, intraductal growing type. On cut section, endoluminal papillary proliferation growing into the bile ducts in a normal liver.

FIGURE 78.33 Cholangiocarcinoma in cirrhotic liver. Gross macroscopy of a small, solitary, well-delineated, unencapsulated white tumor developed on a cirrhotic liver.

The next most common form is mixed mass forming and periductal infiltrating CC, observed in 25% of cases. The pure peri-infiltrating type and the intraductal growth pattern are seldom observed (Guglielmi et al, 2009). CC arising in the intrahepatic small bile ducts or ductules is usually the mass-forming type, whereas CC arising in the intrahepatic large bile ducts (hilar CC) may be any of the three types (Nakanuma et al, 2008).

Most CCs are adenocarcinomas with a prominent, fibrous stroma. CC can be graded as well-, moderately, or poorly differentiated adenocarcinoma according to morphology. Most CCs are well-differentiated tumors with a glandular or tubular pattern of growth, although micropapillary, acinar, or cordlike patterns also occur. Similar to their normal counterparts, tumor cells are small or medium sized, cuboidal or columnar, with small nuclei and nucleoli (Fig. 78.34). Cytoplasm is usually pale, slightly eosinophilic, and sometimes more abundant and clear. Mucus secretion may be highlighted by Alcian blue staining, though the amount is usually small. Less differentiated tumors may show cribriform formations and/or a cordlike pattern, and poorly differentiated cancers are characterized by marked cellular pleomorphism. Hilar and EH-CC are more often well differentiated compared with peripheral CC (Guedj et al, 2009). Presence of dense, hyaline, fibrous stroma is a key feature of CC. Usually, the center of the tumor is densely sclerotic and hypocellular with focal calcifications, whereas the periphery of the tumors is more cellular. CC frequently infiltrates into portal tracts, invading portal vessels, and perineural invasion is a frequent finding in hilar CC (Fig. 78.35; Guedj et al, 2009).

FIGURE 78.34 Cholangiocarcinoma: well-differentiated adenocarcinoma with a glandular pattern composed of small, cuboidal eosinophilic cytoplasm into a prominent fibrous stroma.

FIGURE 78.35 Histoprognostic factors of cholangiocarcinoma (CC): A, Gross macroscopy showing a mass-forming type of CC with satellite nodules. B, Lymph node metastasis (arrows). C, Vascular section invaded by carcinomatous glands (arrow). D, Perineural invasion with tumoral cells lining the nerve structure (arrows).

Several histologic variants have been reported, including adenosquamous and squamous carcinoma, mucinous carcinoma, signet-ring cell carcinoma, clear-cell carcinoma, mucoepidermoid carcinoma, lymphoepithelioma-like carcinoma, and sarcomatous CC.

Because CC originates from biliary epithelial cells, tumor cells display immunostaining with anti–CK7 and anti–CK19, carcinoembryonic antigen (CEA), and epithelial membrane antigen (EMA). The keratin profile is particularly useful for the differentiation of IH-CC from metastatic carcinoma derived from colorectal origin: CK7 is constantly expressed in CC, and CK20 is constantly expressed in metastatic colon carcinoma (Rullier et al, 2000). The diagnosis of IH-CC may be a challenging main diagnostic issue concerning the differential diagnosis between CC and metastatic carcinoma. In that setting, fine needle aspiration, and especially cytologic smears, have been shown as performant as core biopsy with a specificity of 100%, a sensitivity of 84%, and no false-positive cases of CC (Pupulim et al, 2008). In contrast, performance of biopsy is much more limited in cases of extrahepatic strictures. Additional approaches, including evaluation of ploidy and fluorescence in situ hybridization (FISH), have been shown to increase sensitivity up to 34% and specificity up to 98% (Kipp et al, 2004; Levy et al, 2008).

Biliary Cystadenoma

Biliary cystadenoma is an uncommon cystic neoplasm that accounts for less than 5% of all intrahepatic biliary cysts (Ishak et al, 1977; Van Roekel et al, 1982). The histogenesis of biliary cystadenoma remains uncertain, although an origin from embryonic foregut rests has been advanced (Akwari et al, 1990). Almost all of these tumors occur in middle-aged women, with a peak incidence in the fifth decade (Devaney et al, 1994).

Biliary cystadenomas are characteristically large (2.5 to 28 cm), multiloculated cysts without communication with the intrahepatic biliary system (Fig. 78.40). The tumor is solitary and spherical and contains white to yellow to brown mucinous or gelatinous material. Individual locules vary in size, and the internal surface is typically smooth with occasional trabeculations or papillations (Ishak et al, 1977). If solid areas are present, concern should be raised for an invasive component (Devaney et al, 1994; Buetow et al, 1995).

FIGURE 78.40 Cystadenoma. The tumor is cystic, solitary, and spherical with a smooth, white internal surface.

Histologically, the cysts are lined by a simple columnar to cuboidal epithelium with mucin-filled cytoplasm. On occasion, the epithelium may be pseudostratified or focally ulcerated, and goblet cells or squamous cells are sometimes seen. Nuclear atypias and mitoses are rare, and their presence should raise the possibility of complicating cystadenocarcinoma. Also recognized is a serous variant of biliary cystadenoma, which is distinguished by a single layer of glycogen-rich cuboidal cells similar to those seen in microcystic adenomas of the pancreas.

Underneath is an ovarian type stroma, which is absent in cases arising in men (Devaney et al, 1994). Typically, this stroma is densely cellular and composed of closely packed spindle cells reminiscent of ovarian stroma. This stroma stains with antibodies to estrogen and progesterone receptor, and growth can occur during hormone replacement therapy and pregnancy (Daniels et al, 2006). As dysplasia may be patchy, and invasive tumors may arise in as many as 25% of cystadenomas (Ishak et al, 1977), the gross specimens of cystic tumors need to be carefully examined for suspicious areas, and extensive sampling of the cyst should be performed.

Biliary Cystadenocarcinoma

This rare malignancy generally develops as a complication of a biliary cystadenoma, which may or may not demonstrate the distinctive mesenchymal stroma (Ishak et al, 1977; Wheeler & Edmondson, 1985b; Woods, 1981). Most patients are between 45 and 70 years of age, and men and women are equally affected. Cysts are generally multilocular and range in size from 5 cm in diameter to more than 20 cm. Although the gross appearance can be difficult to distinguish from a biliary cystadenoma, the suspicion of malignancy should be raised if areas of large, solid, thickening papillary masses are present (Ishak et al, 1977).

Histologically, cystadenocarcinomas are usually well-differentiated adenocarcinomas, often with an intracystic papillary component, and they are composed of malignant epithelial cells with varying degrees of nuclear stratification, pleomorphism, and hyperchromasia; often, the benign epithelium of the preexisting cystadenoma can be identified. Transitions can sometimes be discerned with varying degrees of epithelial dysplasia (Woods, 1981). The tumor infiltrates the underlying cyst wall, and vascular invasion and extension into adjoining hepatic parenchyma or adjacent organs are characteristic of malignancy. These tumors tend to grow slowly, but they eventually invade adjacent structures and metastasize to distant sites. In rare cases the carcinoma demonstrates adenosquamous, oncocytic, or spindle-cell (pseudosarcomatous) differentiation (Moore et al, 1984; Unger et al, 1987; Wolf et al, 1992).

Ciliated Hepatic Foregut Cysts

A ciliated hepatic foregut cyst is a rare lesion that is generally solitary and unilocular (Terada et al, 1990). This lesion is smaller than 3 cm and lined by a characteristic ciliated pseudostratified columnar epithelium with mucous cells and an underlying fibrous wall that contains abundant smooth muscle (Fig. 78.41; Vick et al, 1999a). Occasional cases of squamous carcinoma arising in a ciliated hepatic foregut cyst have been reported (Vick et al, 1999b). Because these features are similar to those seen in bronchial and esophageal cysts, an analogous origin from the embryonic foregut is suggested (Wheeler & Edmondson, 1984).

FIGURE 78.41 Ciliated hepatic foregut cyst. The cystic wall is lined by a characteristic ciliated pseudostratified columnar epithelium with an underlying fibrous wall.

Bile Duct Adenoma

Bile duct adenoma is an incidental finding, often discovered at surgery, because most develop superficially under the Glisson capsule (Gold et al, 1978; Allaire et al, 1988). It is an inconsequential lesion that may be mistaken for bile duct hamartoma or metastatic carcinoma (Govindarajan & Peters, 1984). Almost all bile duct adenomas are less than 1 cm in diameter, although cases up to 4 cm have been recorded (Govindarajan & Peters, 1984). The lesion typically appears as a discrete white nodule, usually solitary and subcapsular in location, with a firm consistency and unencapsulated margin. Histologically, bile duct adenoma is made of a compact proliferation of small ductules with small or inapparent lumens lined by cuboidal epithelium with slightly basophilic cytoplasm and bland, regular nuclei (Fig. 78.42). Mitoses, cytologic atypia, and nuclear pleomorphism are absent. Ductular structures are surrounded by a fibrotic, hyalinized stroma that can distort ductal structures, portal tracts are often entrapped within the tumor, and scattered inflammatory cells are sometimes seen. Malignant transformation has not been clearly documented.

FIGURE 78.42 Bile duct adenoma. Proliferation of small ductules with small or inapparent lumens lined by bland cuboidal epithelium with few inflammatory cells.

Biliary Microhamartoma

Biliary microhamartoma, also known as a von Meyenburg complex, is a developmental malformation resulting from the aberrant remodeling of the ductal plate. The lesion is relatively common; it occurs in about 3% of all autopsied patients and is generally found incidentally. Microhamartomas are often multiple, but when numerous, this raises the possibility of early autosomal dominant polycystic disease or congenital hepatic fibrosis (Desmet, 1992). The lesions appear as small, subcapsular white or green nodules that seldom exceed 0.5 cm in diameter, often located within or close to portal tracts. Microscopically, biliary microhamartomas are composed of numerous bile duct–like structures with an angulated or branching configuration with varying degrees of dilation. These structures are lined by a single layer of low columnar or elongated epithelium, and their lumens contain bile plugs or eosinophilic proteinaceous debris; ducts are embedded within a dense, fibrous stroma (Fig. 78.43). In rare cases, microhamartomas have been complicated by the development of cholangiocarcinoma (Burns et al, 1990; Honda et al, 1986).

FIGURE 78.43 Biliary microhamartoma. Focal proliferation of bile duct–like structures with an angulated or branching configuration and varying degrees of dilation embedded within a dense, fibrous stroma.

Hemangioma

Hemangioma is the most common primary tumor of the liver, with a prevalence in autopsy surveys that ranges from 0.4% up to 20% (Karhunen, 1986). This lesion is discovered in all ages and both sexes, although hemangiomas are more frequent in older age groups, and in most series they favor women (Bioulac-Sage et al, 2008).

Most hemangiomas are clinically silent and are discovered incidentally during radiologic examination, surgery, or autopsy. However, larger tumors can occasionally become clinically evident with abdominal discomfort, hepatomegaly, or a palpable abdominal mass (Schnelldorfer et al, 2010). Rare reports describe spontaneous rupture with hemoperitoneum or a bleeding diathesis with hypofibrinogenemia or platelet sequestration and consequent thrombocytopenia (Kasabach-Merritt syndrome; Gandolfi et al, 1991). Hemangiomas can be correctly identified in most instances by radiographic imaging (see Chapter 17). Needle biopsy is not necessary and is, in fact, contraindicated because of the risk of severe hemorrhage (Trastek et al, 1983).

Most hemangiomas are solitary lesions less than 4 cm in diameter (Fig. 78.44). Multiple tumors are seen in up to 25% of cases, and hemangiomas up to 30 cm have been recorded. The tumors can occur anywhere in the liver but are frequently located immediately beneath the hepatic capsule. The cut surface demonstrates a soft, dark red, spongy mass with blood-filled cavities and occasional foci of thrombosis, scarring, or calcification. Most are well demarcated from the surrounding liver. Histologically, hemangiomas are composed of dilated vascular spaces lined by flattened endothelial cells and supported by connective tissue septa. The septa consist of poorly cellular fibrous bands with varying degrees of myxoid change and scarring. Thick-walled blood vessels and scattered bile ducts are sometimes found in larger septa, and the vascular spaces are frequently the sites of thrombi in various stages of organization. Hemangiomas may also demonstrate involutional changes with extensive hyalinization, obliteration of the vascular channels, and sometimes calcification.

FIGURE 78.44 Hemangioma, low magnification. The lesion is made of vascular cavities, some filled with blood, and is well demarcated from the surrounding liver.

Infantile Hemangioendothelioma

Infantile hemangioendothelioma is a benign pediatric vascular proliferation of the liver (see Chapter 82). Although uncommon, it is nonetheless the predominant hepatic neoplasm of the first year of life, and only a few cases have been reported in adults. Most cases manifest clinically with hepatomegaly, diffuse abdominal enlargement, or a palpable abdominal mass. The prognosis is generally good, because the tumors usually undergo spontaneous involution and can completely regress (Dachman et al, 1983); however, a potentially life-threatening feature is not uncommon because of arteriovenous shunting through the tumor that may result in cardiac failure, with a reported mortality rate of about 25% (Vorse et al, 1983).

Infantile hemangioendothelioma typically appears as sharply defined but unencapsulated masses, ranging between 1 and 15 cm in diameter. On cut section, the lesion is well delineated with a gray-tan to pink color and a firm or spongy appearance. Central hemorrhage, necrosis, fibrosis, and calcification may be noted in larger lesions.

Histologically, the tumor is characterized by a proliferation of small, irregular vascular channels lined by a single layer of plump endothelial cells. These channels display small, often compressed lumens and contain varying quantities of red blood cells. The endothelial cells are uniform, with almost no mitoses. The fibrous stroma is composed of scattered fibroblasts and collagen fibers, and small bile ducts are scattered through the mass. The tumor generally grows by expanding into adjacent liver, although hepatic plates can sometimes be entrapped along its advancing edge.

Some hemangioendotheliomas may demonstrate atypical histologic features with atypical crowded and multilayered endothelial cells that show hyperchromatic nuclei and occasional mitoses. This atypical pattern has been referred to as type 2, in contrast with the more common type 1 pattern (Dehner, 1978). Most of the type 2 tumors pursue a benign course, but some exhibit more aggressive behavior with extensive local growth and, in some instances, metastases. Consequently such tumors have been considered by some investigators as a low-grade childhood form of angiosarcoma (Dehner & Ishak, 1971).

Mesenchymal Hamartoma

Mesenchymal hamartoma is a tumor-like lesion arising in young children, usually those younger than 2 years, although sporadic examples are described in adolescents and adults (see Chapter 82; Dehner, 1978; Gramlich et al, 1988). It is thought to represent a developmental anomaly, probably arising from the aberrant formation of primitive portal mesenchyme together with secondary degenerative changes (Siddiqui & McKenna, 2006). Although some cases are discovered incidentally, most are clinically evident because of their large size, causing progressive abdominal distension or a palpable abdominal mass (Srouji et al, 1978).

Mesenchymal hamartoma appears grossly as a solitary mass that ranges from 3 to 30 cm in diameter. Typically, the tumor is well demarcated from the adjacent liver, although an infiltrative border and satellite lesions are not so rare (Stocker & Ishak, 1983). On cut surface, the lesion is composed of multiple small cysts filled with clear or mucoid fluid, lined by a smooth surface, and surrounded by a myxoid tissue with fibrous bands (Dehner et al, 1975).

Histologically, mesenchymal hamartoma is characterized by the association of immature myxoid mesenchymal tissue, bile ducts, blood vessels, and mature hepatocytes. The mesenchymal component consists of elongated bland cells within an edematous myxoid stroma that contains varying amounts of collagen. Focally, this stroma undergoes cystic degeneration, yielding a lymphangiomatous appearance and giving rise to the grossly visible cysts. In addition, numerous thick-walled veins, foci of extramedullary hematopoiesis, and scattered bile ducts can be observed. The ducts often exhibit branching or cystically dilated lumina. Bile duct cells can be atrophic or hyperplastic, and small clusters of unremarkable hepatocytes that lack a lobular arrangement are interspersed within the tumor (Stocker & Ishak, 1983).

Angiomyolipoma

Angiomyolipoma (AML) is a rare tumor that occurs at a median age of about 45 years; it is predominant in women by a ratio of 5 : 1 (Goodman & Ishak, 1984; see Chapter 79A), and 10% of cases occur in the setting of tuberous sclerosis, usually associated with coexisting renal AML (Petrolla & Xin, 2008). Size ranges widely, from 1 cm in diameter to more than 20 cm. Tumors are usually single, but multiple tumors in the liver and multiorgan involvement have been described (Nonomura et al 1994, 1995). Only one malignant degeneration in a liver AML has been reported in the literature (Dalle et al, 2000).

Most AMLs are well circumscribed but not encapsulated (Fig. 78.45). AMLs have three key components: 1) tortuous vessels, 2) fat, and 3) myoid cells. Liver AMLs demonstrate solid growth with a variable amount of fat and myoid elements. Hematopoietic cells may also be seen in some cases. Myoid cells may be epithelioid or spindled. The fat component is typically mature, but lipoblast-like cells may be found. A hallmark of this lesion is the existence of tortuous, thick-walled vessels that are usually lacking in elastic lamina and are often rimmed by epithelioid myoid cells (Fig. 78.46; Tsui et al, 1999). The diagnosis of AML may be confirmed by immunohistochemistry, because myoid cells are reactive to HMB-45 (Sturtz & Dabbs, 1994).

FIGURE 78.45 Angiomyolipoma. A well-circumscribed, soft, white nodular lesion with foci of hemorrhage.

FIGURE 78.46 Angiomyolipoma, light microscopy. The lesion is composed of myoid cells with fat droplets and thick-walled vessels.

The histogenesis of AML is unclear, but recent studies suggest AML is a clonal proliferation that favors a neoplastic process (Flemming et al, 2000). Strong arguments suggest that the three cell types are derived from a single precursor cell in the perivascular space, the perivascular epithelioid cell (PEC; Tsui et al, 1999; Hornick & Fletcher, 2006). AMLs composed of a large number of epithelioid cells have been termed PEComas (perivascular epithelioid cell tumors; Bonetti et al, 1997).

Lipoma

Lipomatous tumors are rarely found in the liver. Most occur in adults as asymptomatic lesions, incidentally detected by radiographic imaging (Roberts et al, 1986). Typically, the tumors are solitary masses ranging from 1 to 20 cm. Microscopically, they are composed of mature adipose tissue, either pure or accompanied by a vascular, hematopoietic, or myeloid component. Depending on the constituents, the tumor is designated a pure lipoma, angiolipoma, or myelolipoma (Nishizaki et al, 1989; Peters et al 1983).

Coelomic fat ectopia consists of a rounded nodule of fat attached to the hepatic capsule, usually on the anterior diaphragmatic aspect of the right lobe (Komori et al, 2008). The histologic features accordingly entail mature adipose tissue with various degenerative changes, including calcification (Wheeler & Edmonson, 1985b).

Fibrous Tumors

Localized fibrous tumors of the liver have been reported under a variety of names, including fibroma, solitary fibrous mesothelioma, and benign mesothelioma. Similar to their pleural counterparts, these tumors arise from submesothelial connective tissue and form large masses, from 5 cm in diameter to more than 25 cm, that protrude from the hepatic surface (Komori et al, 2008). The histologic features entail interlacing bundles of bland spindle cells with variable cellularity and intermixed collagen fibers (Kim & Damjanov, 1983; Kottke-Marchant et al, 1989).

Other Benign Mesenchymal Tumors

Sporadic cases of hepatic leiomyoma, lymphangiomatosis, chondroma, hemangioblastoma, and myxoma have been recorded (Rojiani et al, 1991; Van Steenbergen et al, 1985; Fried et al, 1992; Santos et al, 2010).

Epithelioid Hemangioendothelioma

Epithelioid hemangioendothelioma is a low-grade malignant tumor of endothelial origin that can occur in several sites, including the liver. At diagnosis, most patients are in their fourth or fifth decade of life, and about 60% are women (Ishak et al, 1984). Unlike hepatic angiosarcoma, no strong etiologic associations or predisposing factors have been identified, although a relationship with long-term OC use has been suggested (Dean et al, 1985).

Epithelioid hemangioendothelioma tends to be an indolent and slowly growing tumor, but the natural history can vary considerably ( Woodal et al, 2008). Most patients have a prolonged survival, whereas others suffer rapid deterioration with early death from hepatic failure or extensive tumor spread (Dean et al, 1985; Dietze et al, 1989). Metastases commonly involve the lung, spleen, abdominal lymph nodes, omentum, and peritoneum. Even with metastatic disease, some patients can survive for many years, although the distinction between metastatic spread and multicentric disease is sometimes difficult to make (Mehrabi et al, 2006).

In about 80% of cases, the tumor is multifocal with involvement of both lobes by tumor nodules of various sizes. Nodules are white to tan and have a firm consistency (Fig. 78.47), and the background liver is generally normal (Ishak et al, 1984).

FIGURE 78.47 Epithelioid hemangioendothelioma, characterized by diffuse involvement of both lobes by white to tan tumor nodules of various sizes with a firm consistency.

Histologically the tumor comprises small groups of tumor cells surrounded by a distinctive and often abundant stroma of varying myxoid or sclerotic character. The neoplastic cells display abundant eosinophilic cytoplasm and large vesicular and hyperchromatic nuclei with variable nucleoli. These cells reveal their endothelial origin by displaying one or more intracytoplasmic vacuoles that represent intracellular vascular lumina. In addition, they can form small capillary-like lumina, which sometimes contain red blood cells (Makhlouf et al, 1999).

At the actively proliferating margin of the tumor, the neoplastic cells infiltrate the sinusoids, resulting in ductular transformation, atrophy, and eventual obliteration of the adjacent hepatic plates. The underlying lobular architecture is frequently preserved, and remnants of portal tracts can be identified. The tumor also invades the central veins, portal vein branches, and larger blood vessels. This intravascular growth appears as intraluminal papillary clusters or tuftlike projections (Bioulac-Sage et al, 2008). Infiltrating tumor cells are accompanied by a prominent stromal matrix that is initially fibrillar or hyaline, and an attendant mixed inflammatory infiltrate is often also present. Toward its center, the tumor ultimately becomes densely sclerotic, often with focal calcification, and the tumor cells can be difficult to discern (Weiss et al, 1986).

Angiosarcoma

Hepatic angiosarcoma is the most common primary sarcoma of the liver (Brady et al, 1977). Association with exposure to Thorotrast, vinyl chloride monomer, or inorganic arsenic compounds have been identified in 25% to 40% of angiosarcomas (Brady et al, 1977; Falk et al, 1981a; Kojiro et al, 1985; Sherman, 2009). Although these agents either have been discontinued or are under stricter controls, the prolonged latency period suggests that associated angiosarcomas will continue to be encountered for many years (Falk et al, 1981a). The peak incidence is in the sixth and seventh decades of life, and approximately 75% of the patients are men. Rare cases have been reported in children, most in association with infantile hemangioendothelioma (Strate et al, 1984).

The prognosis of patients with hepatic angiosarcoma is very poor. Most patients deteriorate rapidly and die within 6 months of diagnosis, usually from hepatic failure, extensive tumor burden, or tumor rupture. Distant metastases are noted in more than half the patients, most commonly to the lungs, regional lymph nodes, spleen, or bone marrow (Locker et al, 1979).

On gross examination, angiosarcomas typically appear as multiple gray or hemorrhagic masses scattered throughout both liver lobes (Fig. 78.48). The size varies greatly, between 0.1 and 5 cm, and tumors have a spongy consistency with irregular, ill-defined borders. Less often, the tumor is represented by a large solitary mass, typically more than 15 cm in diameter.

FIGURE 78.48 Angiosarcoma is a hemhorragic mass, ill limited from surrounding liver.

The histologic appearance is characterized by a proliferation of malignant endothelial cells with pale, ill-defined cytoplasm and enlarged pleomorphic and hyperchromatic nuclei (Fig. 78.49). The cells usually assume an elongated orientation, but they can also appear rounded or polygonal with conspicuous cytoplasm and prominent nucleoli. Mitoses, although in variable number, are often numerous and bizarre: in some cases the cells show evidence of phagocytic behavior (Bioulac-Sage et al, 2008; Ludwig & Hoffman, 1975).

FIGURE 78.49 Angiosarcoma, light microscope. Proliferation of malignant endothelial cells with pale, ill-defined cytoplasm and enlarged, pleomorphic, and hyperchromatic nuclei.

The tumor infiltrates preexisting vascular structures and eventually destroys the hepatic parenchyma. With early involvement, the malignant cells line the sinusoids and separate the hepatic plates. With progression, the hepatocytes atrophy and are ultimately replaced by fibrosis, and the sinusoids dilate, producing irregular pelioid-like vascular spaces of varying size. These spaces are lined by multilayered tumor cells, sometimes in a papillary arrangement, and contain blood and necrotic debris. Extramedullary hematopoiesis is often present (Kojiro et al, 1985). The tumor also invades central veins or portal vein branches, which can lead to luminal occlusion with subsequent hemorrhage, necrosis, and infarction.

In angiosarcomas associated with Thorotrast, vinyl chloride, and arsenic exposure, an initial precursor stage that precedes the development of overt tumor has been recognized, with hypertrophy and hyperplasia of endothelial cells together with reactive hepatocyte alterations (Tamburro et al 1984).

Undifferentiated (Embryonal) Sarcoma

Embryonal sarcoma of the liver is a highly malignant childhood neoplasm (Stocker & Ishak, 1978; see Chapter 82). It is the third most common hepatic malignancy in the pediatric population after hepatoblastoma and hepatocellular carcinoma. The peak incidence is between 6 and 10 years with an age range that extends from newborn infants to almost 30 years of age (Stocker & Ishak, 1983, 1978; Pachera et al, 2008). The prognosis of undifferentiated sarcoma is very poor. Death often occurs because of massive local tumor growth with direct extension into contiguous structures and even through the diaphragm.

On gross examination, the tumors are large, well-demarcated masses, usually 10 to 30 cm in diameter with a soft gelatinous consistency. Most of the tumors occupy the right lobe of the liver. The cut surface is variegated with areas of solid gray-white tumor interrupted by foci of cystic degeneration, hemorrhage, and necrosis (Stocker & Ishak, 1978).

Histologically, the tumors are composed of malignant spindle-shaped cells separated by myxoid stroma. The neoplastic cells are grouped into closely packed sheets or fascicles or scattered loosely in the stroma. They vary greatly in size and have pleomorphic, hyperchromatic nuclei; inconspicuous nucleoli; and poorly defined borders. Mitoses are often numerous and bizarre, and multinucleated tumor giant cells can be seen. A characteristic finding is the presence of periodic acid-Schiff–positive, diastase-resistant eosinophilic globules within tumor cells and in the extracellular stroma (Ma et al, 2008). The myxoid stroma dominates the less cellular portions of the tumor and harbors numerous thin-walled veins and often contains foci of extramedullary hematopoiesis. Areas of hemorrhage and necrosis are abundant, and bands of dense, hyalinized collagen are occasionally noted. The periphery of the tumor typically entraps bile ducts that are cystically dilated and lined by a cuboidal epithelium that often displays hyperplastic or atypical features. The tumor lacks histologic evidence of cellular differentiation, and its histogenesis remains uncertain (Lack et al, 1991). Embryonal sarcoma represents a primitive mesenchymal neoplasm capable of divergent differentiation (Choi et al, 2010).

Other Sarcomas

Most primary hepatic sarcomas occur in adults between 40 and 60 years of age who are seen with signs and symptoms indicative of a hepatic mass. These primary hepatic sarcomas should be distinguished from metastatic involvement by sarcomas of other organs and from sarcomatoid hepatocellular carcinoma (Kakizoe et al, 1987). The overall prognosis is poor, and most patients die within a year of diagnosis.

Hepatic sarcomas histologically resemble their soft-tissue counterparts. Among the types reported are fibrosarcoma, follicular dendritic cell sarcoma, desmoplastic nested single-cell tumor, malignant fibrous histiocytoma, hemangiopericytoma, osteosarcoma, malignant schwannoma, and dedifferentiated liposarcoma (Choi et al, 2010; Hill et al, 2005; Li et al, 2008; Kim et al, 1987; Lederman et al, 1987). Leiomyosarcomas are described arising within the hepatic parenchyma, from the ligamentum teres, and from the hepatic vein, where they have been associated with Budd-Chiari syndrome (Shamseddine et al, 2010; Kuma et al, 2008; Fong & Ruebner, 1974; Hilliard et al, 2005).

Kaposi sarcoma is seen primarily in the setting of the acquired immunodeficiency syndrome (AIDS). Histologically, the tumor is characterized by multifocal nodules composed of proliferated spindle cells with slit-like spaces that contain extravasated erythrocytes. These lesions are predominantly centered on portal tracts, but they also spread into and destroy the parenchyma (Bioulac-Sage et al, 2008; Friedman, 1988).

Hepatobiliary rhabdomyosarcoma is a rare neoplasm that usually arises from the common bile duct (Ali et al, 2009). Most patients are young children, with exceptional cases reported in adults (Stocker, 2001; Lack et al, 1981). Histologically the tumor resembles botryoid-type embryonal rhabdomyosarcomas that occur elsewhere in the body. Soft polypoid masses protrude into the ductal lumen and are covered by intact, ulcerated, or inflamed biliary epithelium. The tumor is composed of small hyperchromatic cells with variable eosinophilic cytoplasm and rare cross-striations. Beneath the biliary epithelium, the cells are densely packed and form a so-called cambium layer, whereas deeper in the tumor, they are separated by a loose myxoid stroma. The diagnosis is secured by immunohistochemical demonstration of desmin, muscle-specific actin, or myoglobin expression or with the ultrastructural finding of the characteristic myofilaments.

Neuroendocrine Tumor

Neuroendocrine tumors in the liver are almost always metastatic, and a primary lesion in the gastrointestinal tract or pancreas is usually identified (see Chapter 81B). In rare cases, however, primary hepatic endocrine tumors have been described in which no extrahepatic site of involvement can be identified (Sioutos et al, 1991; Miura & Shirasawa, 1988). Because of the normal presence of endocrine cells in biliary epithelium, an origin from intrahepatic bile ducts has often been suggested. Histologically, the tumor is composed of small, uniform tumor cells with regular round nuclei and moderate granular cytoplasm arranged in nests, cords, and pseudoglandular patterns. Dense core neurosecretory granules are found on immunostaining.

Other Tumors

Several examples of malignant rhabdoid tumors of the liver have been recognized. These tumors are highly aggressive neoplasms with a distinctive histologic appearance (Hunt & Anderson, 1990). Rare cases of primary hepatic germ-cell tumors of several types—including teratomas, yolk sac tumors, and choriocarcinoma—have been described. The combination of yolk sac tumor and hepatoblastoma has also been described (Cross & Variend, 1992); these tumors exhibit malignant behavior, although occasional long-term survival has been obtained with cancer chemotherapy.

Squamous carcinoma of the liver is uncommon, with most cases developing within simple hepatic cysts, in various forms of fibropolycystic liver disease, or in teratomas (Gresham & Rue, 1985). Adrenal rest tumor and pancreatic heterotopia have also been described and might be misleading (Wolf et al, 1990; Contreras et al, 1985).

Primary Hepatic Lymphoma

The liver may represent the sole site of involvement by malignant lymphoma, but these primary hepatic lymphomas are uncommon, although hepatitis C infection may be a risk factor (Santos et al, 2003).

On gross examination, most cases are characterized by a single large mass or, less often, by multiple discrete nodules (Anthony et al, 1990). Rarely, the liver is diffusely infiltrated without a well-defined mass lesion. The tumors are predominantly classified as non-Hodgkin lymphomas of diffuse large cell type, with occasional examples of small cleaved or uncleaved varieties such as mucosa-associated lymphoid tissue (MALT) tumors (Deshald et al, 2010; Doi et al, 2008). Most of the tumors are phenotypically of B-cell lineage, although occasional T-cell lymphomas have also been described (Noronha et al, 2005; Andreola et al, 1988). The neoplastic lymphocytes expand the portal tracts and invade into adjacent parenchyma from large infiltrative nodules. The lobules are otherwise little affected, although occasional cases, particularly with T-cell lymphomas, demonstrate sinusoidal infiltration (Farcet et al, 1990).

Secondary Involvement

All varieties of lymphomas, leukemias, and hematopoietic proliferations can secondarily affect the liver, usually as a manifestation of disseminated disease and often in conjunction with splenic involvement. As a general rule, the low-grade non-Hodgkin lymphomas tend to produce multiple portal-based infiltrates, whereas the intermediate- and high-grade types give rise to large, irregular tumor masses. Sinusoidal involvement is uncommon except with peripheral T-cell lymphomas (Farcet et al, 1990; Gaulard et al, 1986).

Hepatic involvement in Hodgkin disease can manifest as large, irregular masses or as small, diffusely distributed nodules. The characteristic infiltrate, which predominantly affects portal tracts, consists of a polymorphous collection of Reed-Sternberg cells or variants together with small lymphocytes, large mononuclear cells, plasma cells, eosinophils, and neutrophils in varying numbers (Dich et al, 1989).

Leukemias of both acute and chronic types tend to permeate the sinusoids with malignant cells, with involvement of the portal tracts additionally noted with the lymphoid varieties. Hepatic involvement is especially common and conspicuous in hairy cell leukemia (Zafrani et al, 1987).

Langerhans cell histiocytosis involves the liver in about 40% of cases (Iwai et al, 1988). The most important clinical manifestations include jaundice and portal hypertension, resulting in part from infiltration of large bile ducts to produce a sclerosing cholangitis-like picture.

The liver is commonly involved in generalized mastocytosis. Mast cells accumulate principally in the portal tracts and are accompanied by varying degrees of periportal fibrosis and, on occasion, cirrhosis.