Pathogenesis

Unlike HCA, FNH does not develop as a result of oral contraceptive use; however, evidence suggests that FNH lesions may increase in size with contraceptive use or regress after cessation of therapy. The exact pathogenesis is not established for FNH, but FNH is thought to represent a hyperplastic or altered growth response to alterations in parenchymal blood flow that occur around preexisting vascular malformations.²⁶ The presence of numerous abnormal muscular vessels in FNH and the association of some of these lesions or similar hyperplastic foci with hemangiomas and the Budd-Chiari syndrome lend support to this theory. Another theory suggests that the lesions result from vascular occlusive events with the formation of collaterals and secondary reactive or ischemic changes.²⁷ Lesions caused by vascular occlusive events may be referred as “FNH-like lesions” (my preferred nomenclature) instead of FNH because they have different etiologic factors and because FNH-like lesions may not have all the typical features of FNH.

FNH has no known malignant potential, and despite its rare association with fibrolamellar HCC, most authorities think that the lesion does not progress to carcinoma. Instead, the association of FNH with fibrolamellar HCC may represent a hyperplastic response to increased vascularity, which is typical of carcinomas. The lesion formerly known as the “telangiectatic” type of FNH, which was originally associated with the multiple FNH syndrome,¹¹ is now recognized as the inflammatory variant of HCA (see Hepatocellular Adenoma, earlier).¹⁴

Pathologic Features

Similar to HCAs, FNH usually involves a solitary nodule, but it may be multifocal.^12,23 FNH has a nodular appearance, which may simulate the appearance of macronodular cirrhosis, and it tends to be lighter in color than the surrounding liver parenchyma. These lesions are often located near the liver capsule, which may impart a localized nodular appearance mimicking cirrhosis. Occasionally, FNH may be pedunculated. The edges of FNH are normally well demarcated from the normal liver parenchyma, but a fibrous capsule is usually absent. FNH may vary considerably in size. Most FNH lesions have a central fibrous scar, which consists of fibrovascular tissue, not dense scar tissue.

Microscopically, the classic type of FNH is composed of normal-appearing hepatocytes arranged in incomplete nodules and partially separated by fibrous tissue that extends outward from the central fibrous zone of the tumor. Variable numbers of bile ductular structures are normally seen in the fibrous stroma and particularly at the edge of the nodules. The cell plate architecture is similar to that of normal liver. However, the cell plates are usually wider (two to three cells thick), similar to regenerative nodules. The reticulin framework should be intact, but in some lesions, cell plates may have a more acinar appearance, may be wider than three cells (usually not thicker than five cells), and be separated by thin collagen bands. The hepatocytes in FNH may demonstrate increased levels of glycogen, fatty change, bile stasis, lipofuscin, iron pigment, copper or copper-associated protein, and Mallory bodies.¹² Foci of atypical hepatocytes containing larger nuclei and mild hyperchromasia, with or without conspicuous nucleoli, may be seen in some cases.

Another important diagnostic feature is the presence of medium- to large-sized, thick-walled muscular vessels, which often exhibit myointimal myxoid or fibromuscular hyperplastic changes (Figs. 55.6 and 55.7). These vessels are not considered components of a portal tract, because large ducts of similar caliber and portal veins are not associated with them. Portal tracts are absent in FNH except at the periphery of the lesion, although a bile duct of intermediate or large caliber may be found in the central fibrous zone in rare cases.²³ The sinusoids may be dilated, and Kupffer cells may be evident. Inflammatory cell infiltrates are relatively common and consist mainly of lymphocytes, although neutrophils and eosinophils may be seen, particularly around bile ductular structures. Rarely, granulomas are identified.

Immunohistochemistry demonstrates intense but patchy staining (i.e., maplike pattern) for glutamine synthetase^1,14 (Fig. 55.8), which is distinctly different from the centrizonal hepatocyte staining pattern of normal liver. For FNH-like lesions, portal zones may be seen within the lesion, the ductular reaction may be decreased or lacking, and the central scarlike zone may be absent.

Differential Diagnosis

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

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

Similar to HCA, FNH normally stains positively for hepatocellular markers, including the cytokeratin (CK) marker CAM 5.2 and the canalicular marker polyclonal CEA. The reticulin stain typically demonstrates an intact reticulin framework in FNH, as in HCA, but rare foci may also show cell plates three to five cells thick, and care must be taken not to mistake this finding for HCC.²⁸ A copper stain may demonstrate deposits in hepatocytes adjacent to fibrous bands.²⁸ CD34 often is positive in endothelial cells that line cell plates, although to a lesser extent than in many HCAs and HCCs, but in any one case, this marker is not reliable for distinguishing FNH from HCA or HCC.¹⁸ However, CD34 may still be useful for demonstrating lesional tissue in the sample. Staining for AFP is typically negative in FNH.

Treatment

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

Clinical Features

Macroregenerative nodules and low-grade dysplastic nodules occur in the setting of cirrhosis, with only a few exceptions, such as in the setting of chronic liver disease without fully developed cirrhosis.³¹ They are usually an incidental finding at autopsy or at the time of transplantation, but they may also be identified on radiographic studies. The serum AFP concentration is typically normal or within the low range expected for the underlying chronic liver disease or cirrhosis.

Pathogenesis

These nodules usually are considered benign lesions, but nodules with this histologic appearance have been associated with an increased incidence of HCC.³² Almost no previous studies of macroregenerative nodules have attempted to define the lesions as regenerative or clonal but instead have defined them as lacking features of high-grade dysplastic nodules or HCC on routine histologic examination. The literature may be somewhat contradictory, and it cannot be definitively stated whether regenerative nodules and clonal, low-grade dysplastic nodules have similar risks for HCC. These nodules are typically seen in cirrhosis related to HBV or HCV infection, alcohol consumption, or hemochromatosis, and they are less likely to be seen in primary biliary cirrhosis. The risk factors for development of macroregenerative nodules are similar to those for HCC.

Pathologic Features

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

Histologically, these nodules resemble cirrhotic nodules. They have an intact reticulin framework similar to that of normal liver, and the cell plates are usually one or two cells thick (Figs. 55.11 and 55.12). The hepatocytes typically have unremarkable cytology, although some focal variation in cell size and scattered large cell change similar to that seen in other cirrhotic nodules may be seen in large regenerative nodules. Low-grade dysplastic nodules are expected to have a more uniform population of hepatocytes because of their clonal nature, but many specific features of this type of clonal nodule have not been definitively established. Findings such as Mallory bodies, bile stasis, clear cell cytoplasmic changes, iron or copper deposits, a slight decrease in cell size,³³ and focal or diffuse fatty changes may be seen. Portal tracts are usually seen in the nodule, and bile ductular reaction may be prominent. Fibrous septa that extend into the nodule without a complete triad of duct, vein, and artery may be identified.³⁴

Differential Diagnosis

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

Studies of the vascularity of these nodules have shown that they have a large number of arteries unassociated with other components of a normal portal space. They are referred to as unpaired arteries. However, staining for CD34 or CD31, as a marker for sinusoidal capillarization, is usually similar to that seen in cirrhotic nodules; some peripheral staining is normally seen at the edge of the nodules.^35,36 The nodules are usually negative for AFP³⁷ and otherwise show a staining pattern similar to that expected in normal liver for cytokeratin and polyclonal CEA.

Treatment

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

Pathogenesis

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

Pathologic Features

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

Microscopically, when dysplastic changes are observed uniformly throughout a nodule, a designation of high-grade dysplastic nodule is warranted. A nodule containing one or more dysplastic foci is referred to as a dysplastic nodule (see Fig. 55.10). The atypical features of these lesions are not overtly severe enough to be diagnostic of HCC, but they are more atypical than expected in usual cirrhotic nodules. The nodule is often recognized by zones of small cell change (see Fig. 55.10) with an increased nucleus-to-cytoplasm ratio (i.e., increased nuclear density), which is defined as an increased number of hepatocyte nuclei per microscopic field compared with normal liver.³³ Large cell change, which is rarely a feature of high-grade dysplastic nodules, may be identified in a discrete zone of atypical cells rather than as enlarged nuclei scattered singly throughout the nodule.

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

Differential Diagnosis

High-grade dysplastic nodules are differentiated from overt HCC by several features (see Table 55.5). Those particularly helpful for diagnosing HCC include the mitotic figures in moderate numbers, trabeculae, cell plates greater than three cells thick, nuclear density more than two times normal, marked reduction in the reticulin framework, numerous unpaired arteries, and absence of portal tracts. High-grade dysplastic nodules are more likely to show an immunostaining pattern similar to that of HCC, such as sinusoidal staining with CD34 and rare positivity with GPC3 (see Hepatocellular Carcinoma and Its Variants).^19,38

Treatment

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

Pathogenesis

HCC develops during a long period and is probably a multistep process that involves various risk factors (e.g. chronic hepatitis), exposure to certain toxic or viral agents, and genetic alterations (see Chapter 44).⁴¹ The major etiologic association is cirrhosis, but HBV or HCV infection is also an independent predisposing factor. Patients with cirrhosis resulting from hemochromatosis or α₁-antitrypsin disease have an increased risk of HCC compared with patients with cirrhosis related to other causes (excluding HBV and HCV). Other risk factors include exposure to thorium dioxide (Thorotrast), aflatoxins, and estrogenic steroids.⁹ Stem or progenitor cells in the liver have the potential to differentiate into hepatocytic and biliary cell types, and they may play a role in the pathogenesis of primary liver tumors, particularly HCC, cholangiocarcinoma, or mixed HCC and cholangiocarcinoma,^42,43 but their exact role remains unclear.

Pathologic Features

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

The WHO¹ has described the four typical histologic patterns of HCC: trabecular, acinar, compact, and scirrhous. The trabecular (platelike) pattern is the most common (Fig. 55.14). In this variant, tumor morphology mimics the cell plate architecture of normal liver but has important differences. The cell plates in trabecular HCC are typically three or more cells thick, whereas the cell plates in normal or regenerative liver are normally only one or two cells thick. As in normal liver, tumor cell plates are lined by endothelial cells, but reticulin staining usually shows that the reticulin framework is absent or markedly decreased or distorted, with irregular or absent staining of the borders of the trabeculae (Fig. 55.15). Tumor cells often have features of a small cell change (see Figs. 55.14 and 55.15). Large cell change may be seen infrequently, except in high-grade tumors. Foci of small and large cell changes often are admixed. Kupffer cells are typically absent in HCC. Occasionally, the tumor cell plates (or trabeculae) may be separated by an increased amount of connective tissue instead of by endothelial cells (Fig. 55.16), and reticulin staining is usually increased in the bands of connective tissue. The thickened cell plates, which are separated by a prominent reticulin framework, often have a linear or ribbon-like arrangement. This pattern has been subclassified as an early form of scirrhous HCC, although the overall amount of fibrous tissue may not be as high as previously described.

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

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

The scirrhous pattern contains prominent, focal or diffuse areas of fibrosis and may be associated with any of the patterns previously described (Fig. 55.19). Differentiation of scirrhous HCC from fibrolamellar HCC (see Fibrolamellar Variant of Hepatocellular Carcinoma) is based on identification of the characteristic cytologic features of the latter and on the different clinical settings in which these two tumors occur. The term sclerosing hepatic carcinoma has been used for some of the HCCs and cholangiocarcinomas associated with hypercalcemia, but this form is not recognized as a distinct variant.⁴⁴

In all of these patterns, the cytologic features of HCC tend to resemble those of normal hepatocytes, but the degree of nuclear atypia varies, ranging from near normal to markedly abnormal (i.e., angular nuclei with clumped chromatin). The tumor cells often maintain their polygonal shape and have round vesicular nuclei and prominent nucleoli that exhibit features typical of hepatocytic differentiation. Intranuclear vacuoles (composed of cytoplasmic invaginations) and glycogenation of nuclei (another feature seen in normal liver) are fairly common in HCC tumors (Fig. 55.20). Small cell change is probably the most common atypical cytologic change, but a large cell change and giant or pleomorphic cells may be seen focally or diffusely (see Fig. 55.20). The amount of cytoplasm may vary, and it is often slightly more basophilic than in normal hepatocytes. The cytoplasm may have a granular appearance, or it may be exceptionally oxyphilic because of a large number of mitochondria. Cytoplasmic inclusions (e.g., Mallory bodies, globular acidophilic bodies) composed of proteins (i.e., albumin, fibrinogen, α₁-antitrypsin, or ferritin) may be seen (see Fig. 55.20).

Fat (Fig. 55.21), glycogen, or possibly water may be prominent in HCCs, providing the cells with a clear appearance. This has been described as the clear cell variant of HCC. If the entire tumor shows this type of clear cell change and it occurs in a noncirrhotic liver, it may be difficult to differentiate HCC from other types of clear cell tumors, such as metastatic renal cell carcinoma (see Differential Diagnosis). Other cytoplasmic changes seen much less frequently include pale bodies, which are round to oval, lightly eosinophilic or clear cytoplasmic structures most frequently seen in the fibrolamellar variant of HCC; ground-glass cells containing hepatitis B surface antigen, which is found in some patients with HBV infection⁴⁵; and dark brown to black pigment similar to that seen in the Dubin-Johnson syndrome. Rare forms of HCC that show a prominent spindle cell component or diffuse small cells (i.e., small cell type) have been described.

Differential Diagnosis

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

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

Hepatocyte antibody (i.e., clone OCH1E5.2.10 or HepPar-1 antibody) is relatively specific for hepatocellular differentiation. This antibody demonstrates a granular cytoplasmic pattern of some degree among tumors with hepatocytic differentiation.^48,49 Similar to polyclonal CEA, HepPar-1 is less sensitive for poorly differentiated HCCs, and it may also stain hepatoid variants of adenocarcinoma, many of which metastasize to the liver.^50,51 Another relatively specific hepatocyte marker is arginase 1, which may stain a slightly broader spectrum that extends to moderately or poorly differentiated HCCs.⁵²

CK8 and CK18 (in the CAM 5.2 stain) occur in tumors with hepatocellular differentiation. Staining with the AE1/AE3 antibody, which recognizes most keratin types except CK8 and CK18, is usually negative. However, because both of these cytokeratin stains react in most adenocarcinomas, CAM 5.2 should not be used in isolation. CK7 staining is commonly negative in HCCs, but it often focally stains small ductular-like hepatocytes or acinar structures in HCC and can be diffusely positive, especially in tumors with fibrotic stromal backgrounds. CK7 staining has also shown a relative lack of ductular reaction at the borders of HCC.⁴⁷ CK20 staining is usually negative (>95% of cases) except for rare isolated cellular staining, some of which may be caused by Mallory hyaline staining.

CD10 stains the bile canalicular cytoplasmic surface of hepatocytes. CD34 stains endothelium-lined trabeculae in HCC and can be used to highlight increased vascularity typical of this tumor type. GPC3, an oncofetal protein the concentration of which is elevated in the sera of many patients with HCC, can be helpful to distinguish benign from malignant hepatocellular neoplasms (Fig. 55.22) and HCC from many other tumor types, but it is not entirely specific for HCC.^19,20,22,53 Use of a combination of immunostains has been advocated to increase diagnostic accuracy of HCC, including use of GPC3 and CD34⁵⁴ and the triple combination of GPC3, heat shock protein (HSP70), and glutamine synthetase.⁵⁵

Prognosis and Treatment

The prognosis of patients with HCC is primarily related to the pathologic stage, including the presence or absence of lymph node and distant metastases, and to certain histologic features, such as vascular invasion, adequacy of the surgical resection margins (at least 1 cm), number and location of lesions, presence or absence of cirrhosis, and tumor size. The relation of histologic tumor grade, or subtype, of HCC to prognosis is not considered highly important by some authorities.⁶ However, almost all small, early HCCs are well differentiated and have a good prognosis, and HCCs with CK19 positivity have a poorer prognosis.^68,69 HCC tumors that arise in a noncirrhotic liver are associated with a better prognosis than those that arise in the setting of cirrhosis, as observed for the fibrolamellar variant of HCC.

Liver transplantation is an effective form of therapy for HCC tumors smaller than 5 cm (including multifocal, small HCCs no greater than 5 cm in aggregate diameter) and with no evidence of large vessel invasion. Alternative therapies, such as cryoablation, percutaneous ethanol injection, and transarterial chemoembolization, have been used in inoperable cases and may help to improve survival time.

Pathologic Features

Fibrolamellar HCC tumors are typically well circumscribed, nodular, yellow to brown tumors with extensive fibrosis. Rarely, a prominent central fibrous zone, as seen with FNH,⁷⁰ may be identified. Larger tumors may show foci of hemorrhage and necrosis. Satellite lesions are rare.

Microscopically, the cellular component of these tumors consists of clusters or sheets of tumor cells separated by dense bands of lamellar fibrous tissue (Fig. 55.23). The tumor cells are polygonal and exhibit eosinophilic and granular cytoplasm. The nuclei are usually large and contain prominent nucleoli. Other cytoplasmic features include pale bodies, which may contain fibrinogen and albumin, and d-PAS–positive bodies, which probably represent glycoprotein secretions. Other features that may be seen focally in the tumor include acinar structures, bile, multinucleated tumor cells, copper, fat, epithelioid granulomas, and peliosis hepatis.

Neuroendocrine markers (see Hepatocellular Carcinoma versus Neuroendocrine Tumor) may be focally positive, but they do not have any known clinical significance.⁶⁴ CD68, a marker for a transmembrane protein in lysosomes and endosomes that is used to highlight macrophages, is positive to a significant degree in fibrolamellar HCC compared with less intense, less frequent positivity in HCC in cirrhotic or noncirrhotic livers.⁷⁵ Fibrolamellar HCCs are typically positive for CK7.^76,77 Glandular differentiation (with mucin secretion) and areas of trabecular HCC have also been observed.⁷⁸ Stem cell–like staining has been described that is consistent with CK7 positivity and with CD133 positivity.⁷⁹ Staining for CK19 and epithelial cell adhesion molecule (EpCAM) is positive in approximately 30% of cases.⁷⁷

Differential Diagnosis

Clinically, fibrolamellar HCC should be differentiated from benign hepatocellular tumors (e.g., adenoma, FNH) that arise in patients of a similar young age group without cirrhosis, but the morphologic differences are usually easily distinguishable. Fibrolamellar carcinomas may be difficult to differentiate from other variants of HCC, particularly the scirrhous type (Table 55.9), but strict reliance on the characteristic cytologic and stromal features of fibrolamellar HCC tumors helps in this differential, as does the fact that fibrolamellar HCC should arise in a noncirrhotic liver.

Prognosis and Treatment

Some studies have suggested that patients with fibrolamellar HCC have a better prognosis than those with typical HCC tumors of a similar size when associated with cirrhosis.^70–73 However, later findings demonstrated that patients with HCC but without cirrhosis have a prognosis that is similar, stage for stage, to that of patients with fibrolamellar HCC.⁷⁸

Complete excision of the involved lobe is the preferred therapy. When tumor location precludes surgical resection, liver transplantation is an option. However, the outcome of this type of therapy is not considered favorable.

Pathologic Features

Bile duct adenomas are small (<2 cm in diameter), firm, white to gray-tan, well-circumscribed lesions. They are usually located directly underneath the liver capsule, but they may develop deep in the liver parenchyma, particularly in the setting of cirrhosis. They may be single or multiple.

Histologically, the ductules are usually uniform in size, are not dilated, and usually contain less intervening fibrous stroma than bile duct hamartomas (Figs. 55.26 and 55.27). However, the amount of collagen may vary considerably, depending on the age or size of the lesion, and focal, abundant, dense collagen may be seen in the center of the lesion. The ductules have a tubular or curvilinear shape and are lined by cuboidal cells with bland, round to oval nuclei. Most importantly, they do not show mitotic activity. Mucinous metaplasia of the epithelium is a common feature, and α₁-antitrypsin droplets and neuroendocrine differentiation are occasionally seen focally in the ductal cells. Residual portal tracts are often preserved in or very near the borders of the lesion, and small aggregates of lymphocytes may be seen, most often at the periphery.

Differential Diagnosis

Bile duct adenomas may be difficult to distinguish from metastatic adenocarcinoma, particularly on frozen section analysis. Bland cytologic features combined with the uniformity of the shape of the ductules and the lack of mitoses help to distinguish a bile duct adenoma from a metastatic adenocarcinoma (Tables 55.10 and 55.11).⁸³

On permanent sections, immunohistochemistry is quite helpful. For example, bile duct adenomas normally show preservation of SMAD4 (DPC4) staining and negativity for TAG72 (B72.3), mesothelin, and monoclonal CEA, in contrast to metastatic pancreatic adenocarcinomas, which show an absence of SMAD4 staining in as many as 55% of cases and positivity for TAG72, mesothelin, and monoclonal CEA.⁸³

Pathologic Features

MCNs typically are multilocular and contain a smooth or somewhat trabeculated epithelial lining. The cysts may contain serous, mucinous, gelatinous, and bloody or purulent material. MCNs do not communicate with the normal biliary tract. Large, polypoid projections or dense masses in the wall of the cysts often indicate areas of malignant transformation.

Microscopically, the cysts are typically lined by a single layer of epithelial cells, usually of the mucinous type, and the cells stain similar to biliary-type epithelium (i.e., CK7 and CK19 positive). The cells may be flat, cuboidal, or columnar (Fig. 55.28), and small papillary tufts may be seen along the inner surface of the cysts. Epithelial nuclei normally appear bland, are basally located, and have no mitotic activity. Features such as marked nuclear pleomorphism, loss of polarity, mitotic figures, and multilayering of the epithelium support the diagnosis of high-grade dysplasia and warrant extensive examination for invasive adenocarcinoma. Invasion of tumor cells into the stroma is the only reliable evidence of invasive carcinoma. The changes designating low-, intermediate-, or high-grade dysplasia that are detailed in Chapter 40 are essentially those described for MCN in the pancreas and pancreatic intraepithelial neoplasia.

Rarely, gastric, intestinal, and squamous metaplasia can be seen, and many of the lesions contain a component of chromogranin- or synaptophysin-positive endocrine cells.¹ The underlying stroma resembles that of the ovary in women, but this pattern may not be uniformly seen in the lesions. A layer of dense hyalinized stroma often separates or can replace the ovarian-like stroma from adjacent liver. The cyst walls may be lined focally by macrophages, calcifications, or scar tissue. Adenocarcinomas that arise in MCNs may have tubulopapillary histology and other typical features of invasive adenocarcinoma of the pancreatobiliary tree.⁸⁴

Differential Diagnosis

The primary cystic lesions in the differential diagnosis are simple biliary cysts. Simple cysts are often resected as a large, single cystic lesion that is not multiloculated, but these cysts can still be multifocal. All lack the ovarian-like stroma and typically have flatter, less mucinous-appearing epithelium. Differentiation from intraductal papillary neoplasia is based on the configuration of the papillary lesions and evidence of communication with the biliary tree in cases of intraductal papillary neoplasia. Other rare lesions in the differential include endometriosis, which has an endometrial stroma that may mimic the ovarian-like stroma of MCN but should also have significant evidence of intralesional hemorrhage and mural changes of pigmented macrophages. MCNs should not be confused with microcystic adenoma (i.e., serous cystadenoma). This lesion is most commonly seen in the pancreas (see Chapter 40), but it rarely can be seen in the liver. The cysts are much smaller in microcystic adenoma and are lined by nonmucinous, glycogen-containing (PAS-positive) epithelial cells.

Pathologic Features

The peripheral, hilar, and extrahepatic variants of cholangiocarcinoma are usually firm, white-tan lesions because of the amount of dense fibrous tissue in the tumor. In contrast, the intraductal papillary neoplasm variant is typically soft and polypoid or cauliflower-like, causing ductal dilation; they are typically multifocal.

Microscopically, the peripheral, hilar, and extrahepatic variants often have a significant amount of dense fibrous stroma. These tumors are usually well-differentiated adenocarcinomas, formed of tubular glands with only mild cytologic atypia. However, foci of marked atypia with an increased nucleus-to-cytoplasm ratio, prominent nucleoli, increased variation in nuclear size, and loss of polarity are often seen at least focally in the tumor (Fig. 55.30).

Features that support a diagnosis of carcinoma rather than a benign hyperplastic or reactive process include the formation of intracytoplasmic lumina and a cribriform pattern of growth. Multilayering of nuclei and intraluminal cellular debris are also features of malignancy, as are destruction and infiltration of portal tracts. Some cholangiocarcinomas spread into the portal bile ducts, which presumably is the result of pagetoid spread of tumor cells along the biliary system. This may be difficult to differentiate from high-grade intraepithelial neoplasia of the bile ducts (BilIN-3).⁹⁵ Some types of adenocarcinomas metastatic to the liver may show spread of tumor cells into the biliary system, mimicking BilIN-3.

Intraductal papillary neoplasms grow into the bile duct lumina as multifocal, papillary lesions. The papillae are lined by columnar epithelial cells and supported by a delicate fibrovascular stroma (Fig. 55.31). The tumor cell nuclei are round to oval and basally located without significant multilayering in the low-grade lesions. Cytoplasm is abundant and mucinous, but clear or oncocytic differentiation and intestinal metaplasia with goblet cell change may also be seen. Mitotic figures are typically uncommon. High-grade intraductal papillary neoplasias show evidence of cytologic features typical of BilIN-3.⁹⁵ Frank invasion of the stalk and underlying periductular tissues is a requisite for a diagnosis of invasive adenocarcinoma.

Differential Diagnosis

Immunoperoxidase and mucin histochemical staining may be used to differentiate intrahepatic cholangiocarcinoma from HCC (see Table 55.6). However, differentiation from metastatic adenocarcinoma may be difficult, particularly if there is no evidence of a primary tumor at another anatomic site. Adenocarcinomas composed of tall columnar cells with an adenomatous pattern, cribriforming, lack of intraepithelial mucin, and luminal necrotic debris suggest metastatic (colonic) carcinoma rather than primary cholangiocarcinoma, which usually shows a greater degree of intracellular mucin differentiation and is composed of glands lined by low columnar to cuboidal cells. CK7, CK19, and CK20 are useful to help differentiate primary from metastatic lesions. Cholangiocarcinomas are usually CK7 and CK19 positive, but most are CK20 negative. In contrast, metastatic colorectal adenocarcinomas are CK7 negative in as many as 90% of cases but are usually positive for CK19 and CK20.^58,59

Differentiation from benign ductular reactions may be difficult. Localized ductular reactions may occur in cirrhotic and noncirrhotic livers (e.g., bile duct adenomas) (see Table 55.10), but extensive ductular reactions may develop in cirrhotic livers that contain large zones of fibrosis. An extensive ductular reaction may form as a sequela of tumor ablation (Fig. 55.32). In this case, the changes are thought to represent a reaction to ischemic necrosis of cirrhotic nodules. Zones of parenchymal extinction maintain for the most part the background architecture of cirrhotic nodules, and a somewhat nodular grouping of ductules can usually be identified on microscopic examination at low magnification. Reactive ductules may appear atrophic (with flattened epithelium), they have a more uniform pattern of growth (e.g., in bile duct adenomas), and the native portal tracts are usually well preserved.

TP53 staining is not a good method for differentiating benign from malignant ductular lesions, because weak TP53 staining is a common feature of benign lesions. However, Ki67 (MIB1) staining that demonstrates a high proliferative rate of more than 30% offers a marker favoring malignancy.⁹⁶ For intraductal papillary neoplasias, the typical differential diagnostic consideration may be an MCN (discussed earlier).

Prognosis and Treatment

The prognosis for peripheral, hilar, and extrahepatic cholangiocarcinoma is dismal because the disease is usually advanced at the time of diagnosis, rendering surgical removal difficult or impossible. However, survival time may be increased when tumor-free surgical margins are attained.⁴

Intraductal papillary neoplasms, although histologically benign in most cases, are regarded clinically as borderline or low-grade malignant tumors because of their tendency to recur, their multicentricity, and their ability to undergo malignant transformation and rarely metastasize.³⁹ The tumor is associated with significant morbidity and mortality. Morbidity most often results from recurrent bouts of cholangitis, obstructive jaundice, sepsis, and hemobilia. The incidence of metastasis is much lower than for other forms of cholangiocarcinoma. Although most intraductal papillary neoplasms do not metastasize, the probability of achieving cure without liver transplantation is low because of the multicentric nature of the lesion. Tumor recurrence has been observed in the extrahepatic ducts.

Pathologic Features

Angiomyolipomas usually appear as variably colored tumors because of hemorrhage, necrosis, and adipose tissue in the lesions.^102,103 The size of these tumors varies considerably, but they are often large at the time of clinical presentation.

Angiomyolipomas are composed of a variety of tissue elements, including smooth muscle–like cells, blood vessels, and adipose and hematopoietic tissue. Smooth muscle–like differentiation is more prominent in liver angiomyolipomas than in renal tumors. The tumor consists of epithelioid or spindle-shaped cells, often surrounding blood vessels. Epithelioid cells have a round or polygonal shape with abundant eosinophilic cytoplasm (Fig. 55.34). Nuclei are typically large and round with prominent nucleoli, but their appearance can vary. The cytoplasmic contents are usually oncocytic and often condensed around the nucleus, leaving a clear zone directly underneath the cell membrane, resulting in an appearance like that of a spider web (Fig. 55.35).¹⁰³

Spindle cells have eosinophilic cytoplasm and small, oval nuclei. Trabeculae, usually composed of epithelioid cells, may be seen. The epithelioid or spindle cell component may predominate in any angiomyolipoma. Spindle cells often stain more strongly for smooth muscle actin, whereas epithelioid cells stain for HMB-45.¹⁰³ Desmin positivity has been observed in spindle cells.¹⁰³ Stains for keratin are typically negative. S100 staining is focally positive in angiomyolipomas, and it usually stains epithelioid and fat cells.¹⁰³

The vascular component is typically composed of thick-walled arterial or venous-like channels mixed with thin-walled, venous-like spaces. Adipose tissue consists of mature fat cells scattered throughout the tumor singly or in clusters or sheets of cells. However, in the liver, the fat component of angiomyolipomas may be scant or absent. Foam cells, containing fine droplets of lipid, often are seen. Peliotic spaces closely associated with areas of hemorrhage are common, and these spaces typically lack an endothelial lining. Dense lymphoid aggregates, composed of a mixture of T and B cells, may be prominent in some cases. Hemosiderin and melanin pigments are rare. Some hematopoietic elements, including megakaryocytes and erythroid and myeloid precursors, may be scattered in the tumor.

Differential Diagnosis

Most diagnostic problems arise when epithelioid smooth muscle–like cells predominate in the tumor. Epithelial cells with large, round nuclei and prominent nucleoli, particularly when there is abundant eosinophilic cytoplasm, may mimic HCC or HCA (Table 55.12). The formation of trabeculae containing epithelioid cells may closely mimic HCC.

Immunohistochemistry is helpful in identifying the tumor as an angiomyolipoma rather than HCC or adenoma by demonstrating positivity for HMB-45 and smooth muscle actin in the smooth muscle–like cells. A combination of spindle and epithelioid cells mimics metastatic melanoma, and HMB-45 positivity may add to diagnostic confusion. In this case, other melanoma markers may be useful. Rarely, inflammatory cells (usually mononuclear cells) may be prominent, mimicking inflammatory pseudotumor. Features that differentiate angiomyolipoma from other mesenchymal tumors, such as epithelioid hemangioendothelioma and angiosarcoma, are listed in Table 55.13.

Pathologic Features

The gross appearance of inflammatory pseudotumors varies considerably, especially if the lesion is large and contains foci of fibrosis, hemorrhage, and necrosis.¹⁰⁷ These tumors may vary considerably in size and may be solitary or multiple. They develop anywhere in the liver parenchyma but occur particularly in the porta hepatis.⁹⁸

Microscopically, inflammatory pseudotumors consist of a mixture of inflammatory and fibrous tissue, but the relative amounts of these components vary (Fig. 55.36). In inflammatory myofibroblastic tumors, the spindle cells are myofibroblasts and typically immunostain positively for smooth muscle actin.

The inflammatory component of both pseudotumor types often contains a polyclonal population of plasma cells,^105,106 but neutrophils, eosinophils, and lymphocytes (predominantly T cells) also may be seen. Some macrophages (often xanthomatous) may be seen, particularly in lesions related to cholangitis and bile duct injury. Sclerotic foci are common. Mitotic figures may be seen but are not normally numerous,¹⁰⁷ and abnormal mitotic figures are typically absent. Occasionally, granulomas or phlebitis (or some degree of venous obstruction) may be observed in patients with inflammatory pseudotumors.^105,106

Differential Diagnosis

Inflammatory pseudotumors should be differentiated from other types of sarcomas, such as angiosarcoma and metastatic GI stromal tumor. The sarcomas usually have cellular atypia and frequent mitotic figures and lack inflammatory cells.

Immunohistochemistry may be helpful. Angiosarcomas normally stain positively for vascular endothelial markers (including CD34), and metastatic GI tumors typically react with CD117 or CD34. Differentiation of an inflammatory myofibroblastic tumor from a follicular dendritic cell tumor may be difficult. However, the absence of plasma cells and the presence of pleomorphic tumor cells, as well as positive immunostaining for CD21, CD35, and R4/23 in the latter, help to distinguish between these two types of lesions.¹⁰⁹ Rarely, the inflammatory form of angiomyolipoma may mimic an inflammatory pseudotumor, but staining for HMB-45 in the background tumor cells can help to differentiate the former from the latter.¹⁰³

Pathologic Features

Angiosarcomas are often large, hemorrhagic tumors with indistinct borders and solid and cystic areas; the latter usually contain blood. Satellite nodules may be seen. They typically have a mixed histologic pattern showing sinusoidal, solid, papillary, and cavernous types of growth. The sinusoidal pattern is the most distinctive pattern in the liver. In this pattern, endothelial cells line both sides of the hepatic cell plates in a scaffold-like arrangement that dissects the plates, often resulting in sinusoidal dilation (Fig. 55.37). The tumor cells that line the cell plates are more numerous, more hyperchromatic, and larger than seen in normal endothelial cells. The sinusoidal pattern is more likely to be identified at the periphery of the tumor and may represent an early outgrowth of the tumor, which later transforms into the solid or papillary form. The solid pattern may have a fascicular, or whorled, appearance, or it may resemble fibrosarcoma. The papillary pattern consists of nodules of stroma lined by tumor cells that protrude into a lumen (Fig. 55.38). The cavernous pattern consists of large, blood-filled spaces and is most commonly seen in combination with the other patterns.

Differential Diagnosis

Key features that help differentiate angiosarcoma from other mesenchymal tumors are listed in Table 55.13. Endothelial markers, such as factor VIII, CD31, CD34, and FLI1 are typically positive in tumor cells, but the staining may be focal or patchy. Factor VIII may be the most sensitive and specific marker for this type of tumor.

Pathologic Features

Epithelioid hemangioendotheliomas are firm, white to yellow tumors that often have ill-defined borders. The tumor is usually multifocal, with involvement of the right and left liver lobes. Calcifications may add a gritty consistency to the tumor.

Microscopically, the tumor cells may be dendritic or epithelioid in appearance. The former are irregularly shaped, elongated, or stellate cells with long, branching processes. The cell cytoplasm may contain a vacuole that represents an intracellular “capillary” luminal space. Epithelioid tumor cells are rounder and contain more abundant cytoplasm than dendritic cells. These cells often form small papillations, or tufts, in thin-walled vascular spaces (Fig. 55.39). Both cell types are typically surrounded by a myxoid or fibrous stroma, and the dense stroma may be calcified.

The tumor tends to grow around and leave intact preexisting structures, such as portal tracts and residual hepatocytes. Bile ducts may be seen in the tumor, particularly at the periphery of the lesion. The tumor also has a predilection for invading large vascular structures, such as portal and central veins, mimicking the appearance of vascular thrombosis. Scattered inflammatory cells, such as lymphocytes and neutrophils, are often seen.

Differential Diagnosis

Differentiation of this lesion from adenocarcinoma (including cholangiocarcinoma) or HCC may be difficult on routine hematoxylin and eosin staining (Table 55.14). However, immunohistochemical staining for endothelial markers in tumor cells, such as CD34, CD31, factor VIII, and FLI1, helps to confirm the diagnosis. Care must be taken not to mistake focal keratin positivity in trapped hepatocytes or bile ducts as evidence of a carcinoma. Keratin may stain some tumor cells.¹¹³ Another diagnostic problem is differentiation of epithelial hemangioendothelioma from venous thrombosis or veno-occlusive disease, because tumor growth in large vessels may mimic an organizing thrombus. Table 55.13 compares this lesion with angiomyolipoma and angiosarcoma.

Prognosis and Treatment

Overall, the prognosis of patients with epithelioid hemangioendothelioma is better than for those with angiosarcoma, even if excision is incomplete or extrahepatic metastases are identified. Liver transplantation may be a reasonable treatment in unresectable cases.¹¹⁴

Pathologic Features

The pathologic features of Kaposi sarcoma in the liver are similar to those that occur at other sites. The tumor may be fibrous, hemorrhagic, and multifocal, and it often centers on portal tracts. Microscopically, the tumor consists of a spindle cell proliferation that forms slitlike spaces or, in larger lesions, a solid, fibrosarcomatous growth pattern (Fig. 55.40). Cellular pleomorphism and mitotic activity are minimal, and extravasation of erythrocytes, hemosiderin deposits, and small eosinophilic globules are common. One pattern typical of Kaposi sarcoma of the liver is growth of tumor cells into sinusoidal spaces, usually at the periphery of tumor nodules. Growth results in dilated channels containing erythrocytes that replace normal sinusoids, a feature that imparts a peliotic appearance to the liver (see Fig. 55.40). The tumor also tends to surround and infiltrate portal tracts but does not involve the hepatic artery and interlobular bile ducts.

Tumor cells are positive for endothelial markers (CD31, CD34), which are useful in differentiating Kaposi sarcoma from fibroblastic tumors. Positivity for human herpesvirus 8 is pathognomonic.¹¹⁵

Pathologic Features

Mesenchymal hamartomas may be solid or cystic. Tan cysts may contain translucent fluid or gelatinous material.^116,119 Cysts probably develop from degeneration of loose tumor mesenchymal tissue, and the tumors may enlarge through progressive accumulation of fluid in the cysts.

Histologically, mesenchymal hamartoma contains a mixture of epithelial and stromal components. The former consists of relatively normal-appearing hepatocytes and bile ducts, both of which are usually surrounded by some amount of myxoid or fibrous stroma (Fig. 55.41). The hepatocytes are cytologically unremarkable. They are often arranged in small clusters or larger groups but retain the normal cell plate architecture of the liver (Fig. 55.42). Bile duct structures are typically arranged in a branching pattern and associated with an acute inflammatory infiltrate. Cystic spaces, when present, may be lined by flattened to cuboidal epithelial cells surrounded by fibrous tissue (see Fig. 55.41). Occasionally, the cysts lack a distinct epithelial lining. The stroma contains increased numbers of small vascular structures, spindle cells, and inflammatory cells. Normal-appearing portal tracts are typically absent. Extramedullary hematopoiesis is often observed.

Pathologic Findings

Infantile hemangiomas are poorly circumscribed lesions that may be solid and cystic with hemorrhage. Hemorrhagic foci usually alternate with fibrotic (solid) areas. The tumors are typically multifocal.

The two histologic subtypes may be difficult to distinguish microscopically from one another. One type has a mixture of small vascular channels with irregularly shaped cavernous spaces (Fig. 55.43). Both types of vascular channels are lined by a single layer of endothelial cells. The vascular spaces are separated by a poorly developed stroma containing scattered collagen or reticulin fibers. Small bile ducts and hepatocytes may be identified in the stroma and are often accentuated near the periphery of the tumor (see Fig. 55.43). Focal areas of necrosis, hemorrhage, fibrosis, and calcifications are often seen. The second type contains endothelial cells with a more atypical cytologic appearance, including increased mitotic activity and more prominent nuclear hyperchromasia. Tumor cells in this type are arranged in a more complex budding or branching pattern.⁹⁸

Tumor endothelial cells stain with vascular markers, including CD34, CD31, and factor VIII. Stromal cells underlying the basement membrane of capillary structures are positive for α-smooth muscle actin (SMA) and a muscle actin–specific monoclonal antibody (HHF35), and they are negative for desmin. This immunoprofile suggests pericytes.¹²²

Prognosis and Treatment

Infantile hemangiomas are histologically benign tumors. However, because of the tumor’s multifocality and large size, the mortality rate is high, often as a result of cardiac or hepatic failure.¹²⁰ These tumors may regress. More often, surgical resection, embolization, hepatic arterial ligation, or chemotherapy or irradiation (or both) are used to prolong patient survival.¹²¹ Angiosarcomas may rarely arise in this lesion.¹¹⁰

Pathologic Features

Hepatoblastomas typically occur as a large, single mass in noncirrhotic livers. Their gross appearance varies, but the tumor is often multinodular and contains areas of hemorrhage and necrosis. Because distinct tumor nodules may contain different histologic components, generous tissue sampling is recommended. After chemotherapy, tumors often become quite necrotic, but the mesenchymal components, especially osteoid, remain prominent.¹²⁹

Microscopically, there are two main subtypes of hepatoblastoma. One consists of purely epithelial components, and the other consists of mixed epithelial and mesenchymal elements. The pure epithelial type usually has a combination of the embryonal and fetal patterns (Fig. 55.44). Rarely, a pure fetal subtype occurs. The mixed epithelial and mesenchymal subtype is usually composed of epithelial patterns admixed with spindle cell mesenchyme, and osteoid is a common finding (Fig. 55.45).

In the epithelial subtype, the embryonal pattern represents the more immature form. It consists of small tumor cells with round to oval nuclei and scant basophilic cytoplasm. The cells tend to form tubular, acinar, or ribbon-like structures (see Fig. 55.44). The fetal pattern represents a more mature form that more closely resembles fetal liver and has tumor cells arranged in plates or cords (see Fig. 55.44). Fetal tumor cells are typically smaller than normal hepatocytes, but they are slightly larger than embryonal tumor cells. Fetal cells show the cytoplasmic features of hepatocellular differentiation. Fetal tumor cells have a moderate amount of eosinophilic cytoplasm or clear cytoplasm that is caused by the presence of lipid or glycogen. Eosinophilic and clear cytoplasmic features often occur in the same tumor, resulting in a distinctive alternating pattern of pink and white (Fig. 55.46). Fetal cell nuclei are small and round, similar to normal fetal liver cells. In the embryonal and fetal patterns, mitotic figures are rare. Extramedullary hematopoiesis often is associated with the fetal component.

Less common hepatoblastomas include a small cell undifferentiated type, a macrotrabecular type, and a mixed type with teratoid features. The small cell type consists of sheets of small tumor cells without evidence of hepatocellular differentiation. These cells have scant cytoplasm, similar to that of neuroblastoma. One of the other patterns of hepatoblastoma should be identified to differentiate it from neuroblastoma.

The macrotrabecular type consists of wide trabeculae greater than 10 cells thick. Fetal and embryonal tumor cells form trabeculae, but a much less common pattern consists of large cells with abundant cytoplasm. This pattern may mimic HCC. Other patterns of hepatoblastoma and their occurrence in a noncirrhotic liver helps to distinguish the macrotrabecular variant of hepatoblastoma from HCC. Tumors with a minor macrotrabecular component should be classified according to the most predominant patterns.¹³⁰

The mixed-type of hepatoblastoma with teratoid features contains epithelial and mesenchymal components mixed with other tissue types, such as intestinal-type glands, squamous epithelium, melanin pigment, and other mesenchymal elements, including cartilage, skeletal muscle, and neural tissue.

Differential Diagnosis

Pure fetal hepatoblastoma may resemble HCA. However, fetal hepatoblastoma tumor cells tend to be smaller. Alternating pink and white cytoplasmic staining is not typically seen in HCAs. These tumor types also may be distinguished on the basis of clinical parameters. For example, HCAs do not generally occur before the patient is 5 years old, except in association with metabolic disorders such as glycogen storage disease. The serum AFP level is not normally elevated in adenoma cases. Clinical parameters also help to distinguish the macrotrabecular variant of hepatoblastoma from HCC, because the latter occurs primarily in the setting of preexisting liver disease or in association with an underlying metabolic disorder (usually in the setting of cirrhosis) in the pediatric population.

Hepatoblastomas immunostain positively for AFP in the embryonal component⁶³ and hepatocyte antibody and polyclonal CEA in the epithelial component, especially in fetal cells.⁴⁹ β-Catenin nuclear or cytoplasmic staining is often observed.¹³¹ Focal neuroendocrine staining with chromogranin A in the embryonal, fetal, and osteoid components has been reported.^63,132

Prognosis and Treatment

Prognosis is directly related to completeness of surgical excision and tumor stage.¹³⁰ The treatment of choice is complete surgical resection. However, chemotherapy is often used preoperatively to reduce tumor size or for treatment of residual and nonresectable tumors. Certain histologic subtypes (discussed earlier), such as the pure fetal type, have a better prognosis after complete resection¹²³ than the fetal and embryonal or the mixed patterns. Other histologic subtypes, such as the small cell and macro­trabecular variants, have been associated with worse outcomes.¹³⁰

Tumor-free margins are an important prognostic factor. However, vascular invasion has not been shown to have a significant effect on outcome.¹²³ Additional indicators of a poor prognosis are young age at presentation (<1 year), large tumor size, and involvement of adjacent vital organs.

Pathologic Features

Embryonal sarcomas are usually large, soft tumors with cystic (often multicystic) and solid areas and a white, shiny, or gelatinous mucoid surface. Areas of necrosis and hemorrhage are often observed.

Microscopically, embryonal sarcomas contain a mixture of stellate and spindle-shaped cells embedded in a myxoid stroma. The tumor cells have a granular or bubbly appearance and light pink cytoplasm and contain cytoplasmic globules that are d-PAS positive (Fig. 55.47). Globules may also be seen in the extracellular stroma. Other features include large, atypical tumor cells with hyperchromatic nuclei and multinucleation, dense collagen deposits, and numerous mitotic figures. Extramedullary hematopoiesis is often identified, and entrapped hepatocytes and ductules may be observed at the periphery of the tumor.

Embryonal sarcomas stain with vimentin, α₁-antitrypsin, and α₁-antichymotrypsin.^135,138 Staining for GPC3 expression is positive in this tumor, including the giant tumor cells.¹³⁹ The differential diagnosis includes angiosarcoma and rhabdomyosarcoma, but immunostaining for CD34 and myogenin is negative in embryonal sarcomas and helps to exclude these possibilities.¹³⁸