Several other substances, including C-reactive protein, erythropoiesis-associated antigen, and factor XIII, are also said to be characteristic of hepatocellular carcinoma, but their sensitivity and specificity have not been widely examined.^141,160 Of lesser diagnostic utility is immunoreactivity for albumin, alpha-1-antitrypsin, alpha-1-chymotrypsin, ferritin, fibrinogen, and transferrin receptor, as these antigens are variably found in other tumors. Hepatitis B surface and core antigens can be detected in occasional hepatitis B-associated cases, but care must be taken to exclude trapped nonneoplastic hepatocytes.^{181,247,264,268} A small proportion of hepatocellular carcinomas immunostain for epithelial membrane antigen, HMB-45, neuron specific enolase, S-100 protein, tissue polypeptide antigen, and epithelial cell markers such as Leu-M1, tumor-associated glycoprotein-72 (B72.3), and glycoprotein BCA-225 (CU-18); positivity for these antigens thus tends to exclude, but not completely eliminate, hepatocellular carcinoma from consideration.^{141,160,178,195,256,274}

Cytopathologic and ultrastructural aspects. The same architectural and cytologic features seen in histologic specimens are also found with fine-needle aspiration cytology. In most cases a trabecular architecture can be discerned; cohesive clusters of malignant cells either contain branching sinusoidal vessels or are ensheathed by a thin endothelial layer. The clusters can fragment on smears, however, and cell blocks are therefore a useful adjunct in identifying the structural arrangements. As in histologic sections, the polygonal tumors cells have abundant eosinophilic cytoplasm and central round nuclei with coarsely granular chromatin and conspicuous nucleoli. Bile pigment can be noted, and on occasion, multinucleated tumor cells are seen.^{100,186,217,219}

With fine-needle aspiration biopsy, the diagnosis of the usual moderately-differentiated hepatocellular carcinoma is generally straightforward. Difficulties arise, however, with both poorly-differentiated and well-differentiated tumors, which can be indistinguishable from metastatic carcinoma and hepatocellular adenoma, respectively. An additional problem is presented by finding occasional cells with severe atypia in a background of normal-appearing hepatocytes, since this appearance can be seen with liver cell dysplasia in cirrhotic nodules as well as with low-grade hepatocellular carcinomas.⁹⁸

Ultrastructural features of hepatocellular carcinoma parallel those of normal liver cells. Bile canaliculi are the most distinctive finding, and the presence of peroxisome and absence of a distinct basement membrane are suggestive of hepatocellular differentiation.^235,239 These changes do not, however, distinguish between benign and malignant hepatocellular tumors.

In general, the histologic features in hepatocellular carcinoma wield little independent prognostic power. The major exception is fibrolamellar carcinoma, a distinct clinicopathologic variant that, as discussed below, is associated with a more favorable prognosis.^112,279 The outcome is instead governed primarily by the stage of the tumor and clinical status of the patient, the two principal factors that determine whether curative resection can be accomplished.^206,231,263

Among the morphologic contributors to tumor stage is size. Small or minute carcinomas with a maximum diameter variously defined as between 3 cm and 5 cm manifest a better prognosis, although with larger cancers the tumor size does not directly correlate with outcome.^{157,159,222,263} Improved survival has also been associated with tumors that are encapsulated or fail to invade surrounding hepatic parenchyma, although these are uncommon in most Western experience.^{139,159,167,170,216,226} Among resected tumors, an expected prognostic indicator is whether or not the surgical margin is tumor-free.^139,191

A major influence on clinical status of the patient is the presence or absence of cirrhosis, which thus becomes a leading indicator of survival. Among patients without cirrhosis, the two-year survival rate is approximately 25%, but it falls to under 5% in patients with cirrhosis.^200,260,263 This more favorable prognosis is independent of the presence of fibrolamellar carcinomas, which account for about 10% of the noncirrhotic cases. Other histologic findings are not consistently correlated with outcome, although occasional series have reported a better prognosis with clear cell carcinomas and tumors of low histologic grade.^189,197,260

The diagnosis of hepatocellular carcinoma rests on the identification of two fundamental features, cytologic malignancy and hepatocellular differentiation. In most cases these features are readily affirmed, and rendering a definitive histologic diagnosis then poses no great obstacle. Problems arise, however, when the two features are scant, focally distributed, or inadequately sampled. If cytologic malignancy is not clearly evident, the carcinomas can be difficult to distinguish from hepatocellular adenomas or macroregenerative nodules; if hepatocellular differentiation is not easily recognized, the distinction with cholangiocarcinoma or metastatic carcinoma becomes a concern.

Hepatocellular adenomas are generally composed of regular, bland cells in a sheet-like arrangement, and trabecular architecture, mitoses, cytologic atypia of more than minor degree, and vascular and parenchymal invasion are absent. This same histologic picture can be seen in areas of well-differentiated hepatocellular carcinoma, but even in those cancers that possess little cytologic atypia, areas of trabecular growth can often be identified. Although a definitive histologic diagnosis is not always possible, carcinoma should also be suspected when the tumor exhibits more than minor nuclear abnormalities or occurs in patients other than young women on oral contraceptives.

Macroregenerative nodules in cirrhotic livers are usually histologically benign, but they can sometimes demonstrate atypical cytologic or architectural features. These changes mimic those of hepatocellular carcinoma, but they generally do not attain the level of overt malignancy. When a trabecular growth pattern, pronounced nuclear atypia, vascular invasion, or infiltrative growth is present, a diagnosis of carcinoma is clearly warranted. Atypical macroregenerative nodules are, however, borderline lesions, and the precise line of demarcation between a severely atypical nodule and a well-differentiated carcinoma is difficult to define.

Cholangiocarcinomas and metastatic adenocarcinomas are typically characterized by gland formation, prominent desmoplastic stroma, and intracytoplasmic mucin. These features permit distinction from the usual hepatocellular carcinoma, although there is some histologic overlap with hepatocellular carcinomas that exhibit acinar architecture or stromal sclerosis. Other metastatic tumors are composed of eosinophilic cells in cords or sheets and thus more closely mimic hepatocellular carcinoma; the offenders include poorly-differentiated squamous carcinomas, some breast, lung, and pancreatic carcinomas, and neuroendocrine carcinomas such as carcinoid or islet cell tumors.²²⁰

The diagnostic strategy in these cases entails the search for compelling evidence of hepatocellular differentiation, such as bile pigment, bile canaliculi, trabecular growth, and compatible immunostaining patterns. An additional clue is provided by the tumor borders, since the potentially confusing cancers tend to infiltrate in a sinusoidal rather than pushing or merging configurations. In the absence of confirmed hepatocellular differentiation, a poorly differentiated tumor cannot be definitely categorized as a hepatocellular carcinoma and is apt instead to be metastatic in origin.

Liver cell dysplasia has been categorized into large and small cell types.²⁷⁶ The large dysplastic cells possess abundant cytoplasm in addition to enlarged nuclei, and the nuclear-cytoplasmic ratio is consequently normal or modestly increased. Small dysplastic cells, on the other hand, are smaller in size, with decreased basophilic cytoplasm and a moderately increased nucleus; the nuclear-cytoplasmic ratio is accordingly increased (Figure 15-29). The small cell type, although the beneficiary of less study, has been considered by some to be a better precancerous candidate than the large cell variety.^151,276

The nuclear aberrations seen in hepatocellular dysplasia vary in their degree and distribution. Based on the severity of the atypia, low and high grades of dysplasia can be distinguished.²⁶⁷ Whether this distinction carries biologic or prognostic significance is, however, not yet known. In many cases, the dysplastic cells are grouped in small, poorly demarcated foci, but they can also occupy entire cirrhotic nodules or occur as isolated single cells. Some investigators restrict the diagnosis of liver cell dysplasia to cases with multiple or prominent foci of involvement, although these quantitative issues have received little directed attention.^115,116

Dysplastic liver cells are noted in only a small fraction of normal livers, but they are found in approximately 20% to 45% of cirrhotic livers and up to 80% of cases of hepatocellular carcinoma associated with cirrhosis.^{91,116,127,168,276} Although dysplasia has been described in cirrhosis of virtually all causes, a strong relationship with the hepatitis B virus has often, but invariably, been noted. Even in the absence of cirrhosis or hepatocellular carcinoma, as many as 20% of patients with chronic hepatitis B infection demonstrate liver cell dysplasia on liver biopsy.^{84,152,241,248} A relatively high prevalence has also been reported with chronic non-A, non-B hepatitis, presumably representing hepatitis C virus infection.¹⁹²

The concept that liver cell dysplasia is a premalignant lesion is supported by circumstantial and sometimes conflicting evidence. The lesion is strongly associated with cirrhosis and hepatitis B infection, the two major predisposing factors of hepatocellular carcinoma. In addition, a chronologic sequence from cirrhosis to dysplasia to carcinoma is suggested by some studies, although it is contradicted by others.^91,116 Dysplastic cells possess certain morphometric similarities to hepatocellular carcinoma cells and, by flow cytometric analysis, exhibit an abnormal DNA content with aneuploidy in about 40% of cases.^{151,246,249,267} Phenotypically, however, the cells appear to more closely resemble normal than malignant hepatocytes, although inconsistent results are reported.^151,248,271 Finally, in prospective studies liver cell dysplasia has been identified as an independent risk factor for development of hepatocellular carcinoma.⁹⁹

Although its premalignant potential remains controversial, liver cell dysplasia should be specifically looked for in liver biopsy specimens and its presence recorded. Because the natural history of dysplasia is poorly understood, the appropriate management of affected individuals is unclear and subject to continued debate. On the basis of currently available information, these patients should nevertheless be considered to be at a higher than normal risk of developing hepatocellular carcinoma; periodic screening with radiologic imaging and serum alpha-fetoprotein determinations would seem prudent, as with other high risk patients.^88,248

The fibrolamellar variant of hepatocellular carcinoma merits a separate discussion because of its distinctive clinical and pathologic features (Table 15-3). It was first delineated as a distinct entity in 1980, although cases were recognized before that time, and accounts for 5% or less of all hepatocellular carcinomas.^286,288 The tumor has acquired several synonyms that all underscore the histologic hallmarks; these names include eosinophilic hepatocellular carcinoma with lamellar fibrosis, hepatocellular carcinoma of polygonal cell type with fibrous stroma, fibrolamellar oncocytic hepatoma, and oncocytic hepatocellular tumor.^238,284,290

The tumor occurs primarily in young patients 5 to 35 years of age with a mean age of about 25 years, and represents up to half of the hepatocellular carcinomas occurring in this age group.^136,188 Older patients are not exempt, however, and cases in octogenarians have been reported.²⁹⁶ Men and women are affected equally with a minor female predominance noted in some series. Over 90% of fibrolamellar carcinomas arise in noncirrhotic livers. No particular predisposing factors have been recognized, however, and there is no clear association with hepatitis B infection, oral contraceptive use, or alcohol abuse.^143,288

The clinical presentation is similar to other hepatocellular carcinomas. Abdominal pain, malaise, and weight loss are commonly accompanied by mild to moderate abnormalities of serum transaminases, alkaline phosphatase, and bilirubin levels. Jaundice is infrequent, but has accompanied bile duct invasion by tumor in some reported instances.^283,289 Serum alpha-fetoprotein levels are elevated in less than 10% of cases and rarely exceed 200 ng/ml. Other notable biochemical markers have been identified, including increased levels of vitamin B₁₂, vitamin B₁₂ binding capacity, neurotensin, and carcinoembryonic antigen, although these are not specific for fibrolamellar carcinoma.^298,301,304

By radiographic imaging the tumor is seen as a well-demarcated and usually homogeneous mass, appearing hyperechogenic with ultrasound and hypodense with unenhanced computed tomography. The most useful clues to the diagnosis include calcification, which is unusual in most hepatocellular carcinomas, and indications of a central scar; this latter finding can cause confusion with focal nodular hyperplasia. Angiography demonstrates a hypervascular mass with radiating vessels and, at times, early arteriovenous shunting to the portal veins.^291,307

One of the most striking features of fibrolamellar carcinoma is its relatively indolent behavior, high resectability rate, and correspondingly favorable prognosis. The overall five-year survival is estimated at 35%, distinctly better than that seen with the usual hepatocellular carcinoma.³⁰¹ Once adjustments are made for tumor stage, however, all series do not demonstrate this advantageous outcome.^296,317 At the time of diagnosis the tumor is often localized, and surgical resection can be accomplished in 50% to 75% of cases. This high frequency reflects not only the nature of the tumor, but also the young age of the patients and absence of underlying cirrhosis.^296,301 Successfully resected patients have an excellent chance of long-term survival; five-year survival rates are estimated at 56% with disease-free intervals of up to 21 years reported.^188,301

With advanced or recurrent local disease, an aggressive surgical approach, including liver transplantation, has sometimes been effective and, on occasion, has resulted in prolonged survival.^286,296,302 Patients with distant metastases, usually to abdominal lymph nodes, peritoneum, or lungs, are not operative candidates and have been treated with various cancer chemotherapeutic regimens with partial responses noted in occasional patients.²⁹³ Even these patients appear to have a better prognosis than those with usual hepatocellular carcinoma; the comparative median survivals are 24 months versus only 3 months.²⁹³

Pathologic Features ^286,288

Fibrolamellar carcinomas are firm, well-defined but unencapsulated masses that range from 5 cm to over 20 cm in diameter. A single tumor is present in most cases, and the left lobe is more commonly involved than the right, the opposite of the usual hepatocellular carcinoma. On cut section the tumor possesses a gray to brown hue, a scalloped border, and a solid consistency (Figure 15-30). Prominent fibrous septa subdivide the mass and, at times, connect with a central zone of scarring and occasional calcification, producing a gross appearance reminiscent of focal nodular hyperplasia.³⁰⁰ The background liver is usually unremarkable.

The defining histologic features of fibrolamellar carcinoma are the distinctive fibrous stroma and large eosinophilic tumor cells. The stroma comprises lamellar collagenous bands of varying density and thickness that are arrayed around nests, cords, and sheets of the neoplastic cells (Figure 15-31). These bands consist of collagen types I, III, and V with abundant fibronectin and contain various blood vessels, occasional small bile ducts, and on occasion, a scattering of mononuclear inflammation cells.^294,297 Focal calcification is sometimes noted.

The polygonal tumor cells are usually larger than normal hepatocytes and possess abundant, granular, and deeply eosinophilic cytoplasm (Figure 15-32). In other respects the cells resemble those of other hepatocellular carcinomas with well-defined cell borders, rounded vesicular nuclei, and conspicuous nucleoli. Bile pigment is commonly noted, and fat or glycogen accumulation sometimes seen. Although the cells are usually arranged in a compact pattern, a trabecular or acinar architecture is occasionally noted.

Most fibrolamellar carcinomas are histologically low-grade; mitoses are usually sparse, and nuclear pleomorphism or multinucleation is infrequent. Cytoplasmic inclusions of various types are commonly seen, including ground-glass pale bodies, eosinophilic cytoplasmic globules of variable PAS-positivity, and rarely, Mallory bodies.^261,285 Copper and copper-binding protein are additionally present in many cases.^295,306

The tumor cells commonly express immunoreactive alpha-1-antitrypsin, fibrinogen, C-reactive protein, and ferritin, both diffusely in the cytoplasm and within cytoplasmic inclusions, but alpha-fetoprotein is characteristically absent.^285,287,304 Polyclonal antibodies to carcinoembryonic antigen decorate bile canaliculi and intracellular lumina, and variable reactivity is noted with antibodies against cytokeratins.^164,304,305 By electron microscopy the tumor cells are packed with swollen mitochondria, accounting for their oncocytic appearance, and contain canalicular-like intercellular spaces and cytoplasmic inclusions of flocculent or electron-dense appearance.^{239,287,290,306} In some cases, a suggestion of neuroendocrine differentiation has been provided by immunostaining for neuron specific enolase and the ultrastructural demonstration of neurosecretory granules.²⁹⁹

In general, the histologic features of fibrolamellar carcinoma are characteristic and readily recognizable, even, for example, fine-needle aspiration specimens.³⁰³ However, the changes need not be uniformly distributed; they can vary in degree and extent and are sometimes missing from areas of the tumor.^285,296 Exactly what proportion of the tumor is required to show fibrolamellar histology for an express diagnosis has not been defined, and how this heterogeneity correlates with clinical attributes and patient outcome is a yet unanswered question. Consequently the distinction from usual hepatocellular carcinoma can be problematic. In some cases an equivocal label of hepatocellular carcinoma with fibrolamellar features is unavoidable.

Focal nodular hyperplasia shares certain architectural alterations with fibrolamellar carcinoma, including a multinodular appearance and radiating fibrous bands. The fibrous septa in focal nodular hyperplasia, however, contain bile ductular structures and inflammatory cells, and the cytologic atypia of the carcinoma is missing. The two lesions can nonetheless coexist, leading some to suggest that fibrolamellar carcinoma originates in focal nodular hyperplasia.^286,290,306 This suggestion, however, has received little corroboration.^292,300

Both sclerosing hepatocellular carcinoma and metastatic carcinomas to the liver exhibit a prominent fibrous stroma, but the desmoplasia typically lacks a multilaminated arrangement. In addition, metastatic tumors do not demonstrate evidence of hepatocellular differentiation.

Hepatoblastoma is the malignant hepatocellular neoplasm of infants and young children. Although the most common primary liver tumor of childhood, accounting for some 45% of the total, it is nonetheless rare. The annual incidence in the United States is estimated at only one case per million children under 15 years of age.³⁴²

The cause of hepatoblastoma is unknown, and few predisposing factors have been identified. Anecdotal cases have been linked to the fetal alcohol syndrome or maternal use of oral contraceptives, and one epidemiologic study implicated maternal exposure to industrial products such as paints, petroleum derivatives, and metals used in welding or soldering.³⁰⁹ Familial cases are rarely recorded.³³²

Almost all cases of hepatoblastoma occur during the first three years of life, although unusual examples are described in older children or detected at birth.^320,326 Boys are affected approximately twice as often as girls. The tumor has been associated with numerous other disorders, including the Beckwith-Wiedeman syndrome, familial adenomatous polyposis, Wilms' tumor, glycogen storage disease, and various congenital anomalies such as hemihypertrophy, cleft palate, and macroglossia.^{319,321,324,337}

The clinical presentation involves hepatomegaly or a growing abdominal mass accompanied by anorexia, weight loss, failure to thrive, and abdominal discomfort. Jaundice is an uncommon feature, and rarely an abdominal crisis is precipitated by rupture of the tumor with hemoperitoneum. In some cases unusual paraneoplastic manifestations are seen, including isosexual precocity resulting from human chorionic gonadotropin elaboration by tumor, osteopenia, cysthathioninuria, and thrombocytosis.^326,331

Routine liver function tests are variably abnormal, but are of little diagnostic assistance. An increased serum alpha-fetoprotein level occurs in found in over 75% of cases, with extreme values of over 1,000,000 ng/ml sometimes noted. The degree of elevation provides no prognostic information, but the levels can serve as rough indicators of tumor burden, falling with resection of the tumor and increasing with recurrence or metastasis.^331,337 Radiographic imaging studies including ultrasonography, computed tomography, and angiography are helpful in distinguishing hepatoblastomas from other pediatric abdominal tumors and in providing preoperative assessment of the extent of the tumor.³²⁹

Hepatoblastoma is an aggressive neoplasm that invades locally and eventually spreads to regional lymph nodes, lungs, adrenal glands, brain, and bone marrow. Surgical resection is the primary means of treatment, and the outcome depends largely on whether complete extirpation can be accomplished. The long-term survival among patients with curative resection and adjuvant chemotherapy ranges from 50% up to 90%.^317,327,326 Unfortunately only about half the cases fall into this favorable group, although in some instances preoperative chemotherapy has reduced tumor size sufficiently to permit resection of initially inoperable cases.³¹² The outcome is dismal for patients with residual or unresectable tumors, recurrent disease, or distant metastasis; the two-year survival rates are typically under 20%.³¹⁰ Treatment options in these patients are few; cancer chemotherapy, liver transplantation, and resection of isolated pulmonary metastases have prolonged survival in selected instances.^312,313,325 Death generally results from hepatic failure, metastatic spread, or tumor rupture.

Pathologic Features ^{277,320,337,341}

Hepatoblastomas are typically solitary masses, well-circumscribed and occasionally encapsulated, that range from 5 cm to 25 cm in maximum diameter. Most are located in the right lobe. The cut surface has a bulging, vaguely lobulated contour and a variable tan to light brown to gray-white appearance with a occasional foci of hemorrhage, cystic degeneration, necrosis, or calcification (Figure 15-33). Bile staining is sometimes noted. The background liver is usually unremarkable.

Histologically hepatoblastoma parallels the developing liver and is thus composed predominantly of immature epithelial cells resembling fetal or embryonic hepatocytes, sometimes with an admixed mesenchymal component. Two general histologic patterns of hepatoblastoma are thus recognized: a pure epithelial type and a mixed epithelial-mesenchymal type.³²⁰ The epithelial variety is typically the most common, accounting for about 60% of cases in most series.^310,326 The prevalence of the mixed type depends on the extent of tumor sampling; some have asserted that a mesenchymal element might be found in all hepatoblastomas with sufficient searching, although this has never been substantiated.^316,335,341

The epithelial component is represented by either fetal-type or embryonal-type cells or a combination of the two. Fetal-type cells are smaller than normal hepatocytes and have a uniform monotonous appearance with abundant polygonal cytoplasm, round regular nuclei, and inconspicuous nucleoli (Figure 15-34). Nuclear pleomorphism is minimal, and mitoses are few. The cells are organized in thin irregular plates that are two cells in thickness, contain bile canaliculi (sometimes with bile plugs), and are separated by endothelial-lined sinusoids. In compact areas of the tumor, however, the sinusoids can become indistinct and a sheet-like arrangement is seen. Foci of extramedullary hematopoiesis are a common finding. Some fetal cells display a lucent cytoplasm due to glycogen and fat accumulation; these pale cells tend to segregate from those with denser cytoplasm, producing a distinctive alternating arrangement of light and dark zones that is readily visible on low power examination (Figure 15-35).

The embryonal-type cells are more primitive in appearance. They are small, darkly staining, angular cells with compact cytoplasm and poorly defined outlines (Figure 15-36). The nuclei are relatively large and exhibit dense coarse chromatin and prominent nucleoli. Unlike fetal-type cells, no glycogen, fat, or bile accumulates in the cytoplasm. Scattered mitoses are regularly noted, and foci of necrosis are occasionally seen. The cells are typically grouped into loose sheets or organized into a variety of architectural arrays including ribbons, acini, rosette-like structures, cribriform configurations, and papillary formations that can simulate yolk-sac tumor.³²⁶ Extramedullary hematopoiesis is uncommon. Focal squamous or ductular (tubular) differentiation can be detected in some instances, and multinucleated tumor giant producing human chorionic gonadotropin have been noted in cases manifesting with isosexual precocity.^308,330,331 Fetal-type and embryonal-type cells often coexist in a given tumor, and transitions between the two are frequently present.

In addition to the two major requisite patterns, other epithelial types are also described. The small cell undifferentiated or anaplastic type consists of small uniform cells similar to those of neuroblastoma with scanty cytoplasm, hyperchromatic nuclei, and frequent mitoses (Figure 15-37).^317,323 These poorly cohesive cells grow in sheets or nests, occasionally accompanied by a mucoid stroma, and infiltrate and incorporate adjacent nonneoplastic hepatocytes and bile ducts.^322,326 Because the term anaplastic in pediatric pathology often denotes the presence of enlarged, bizarre nuclei, this variant is better referred to as the small cell undifferentiated type.³¹⁷

The macrotrabecular type is distinguished by broad trabeculae, ten or more cells in thickness, that are composed of fetal-type cells, embryonal-type cells, or a population of larger cells similar to those of hepatocellular carcinoma.³¹⁶ Those cases hepatocellular carcinoma-like cases have also been referred to as maturing or differentiated hepatoblastomas.³¹¹

The mixed hepatoblastomas combine the epithelial component with an element of mesenchymal-derived tissues. Usually this consists of osteoid-like material, sometimes focally calcified, or primitive spindle cells occurring in fasciculated or loose myxoid arrangements (Figure 15-38).³⁴¹ Rarely, trabecular bone formation or cartilaginous or rhabdomyoblastic differentiation is identified. Unusual cases demonstrate teratoid features with divergent differentiation including ganglion cells, melanocytes, neuroepithelial-type tubules, respiratory or intestinal-lined epithelial cysts, and various other mature tissues.^314,328

By immunohistochemical examination, hepatoblastomas express a wide variety of antigens, including the common markers of hepatocellular differentiation. The distribution of the antigens often reflects the types of histologic components present. Alpha-fetoprotein, alpha-1-antitrypsin, alpha-1-chymotrypsin, and ferritin are frequently noted, especially in the fetal-type cells, and cytokeratins of both hepatocellular type (Moll numbers 8 and 18) and "biliary" type (Moll numbers 7 and 19) can be identified.^308,336,339 In addition, the epithelial cells can express immunoreactivity for certain neuroendocrine markers such as chromogranin, serotonin, and somatostatin and various extracellular matrix proteins including laminin, fibronectin, and collagen types III, IV, and V.^333,334 The small undifferentiated cells can express both cytokeratins and vimentin and occasionally mark with S-100 protein.

Of particular interest, the cells associated with the osteoid material immunostain for cytokeratins, epithelial membrane antigen, and other markers of a hepatocellular lineage; this suggests that the osteoid represents a product of multipotential epithelial cells rather than osteoblasts, a conclusion additionally supported by animal model studies utilizing cultured liver epithelial cells.^308,338 Carcinoembryonic antigen can be detected in foci of ductular differentiation, and human chorionic gonadotropin can be found in multinucleated giant cells.^308,330

The most important predictor of outcome is the tumor stage at presentation.^310,311 Once stage is taken into account, the various histologic subtypes becomes less important prognostic indicators, although the issue is complicated by the relative infrequency of hepatoblastoma. Nonetheless, tumors of pure fetal-type histology tend to have the best prognosis; when completely resected, the two-year survival rate approaches 90%.^310,317,341 Improved survival has also been associated with the absence of mitoses and the presence of differentiated mesenchymal elements, although there is less consensus among studies.^310,317 Tumors with small cell undifferentiated features, on the other hand, typically behave in an aggressive manner, and in a few studies, this has also been true of the macrotrabecular type.^{315,316,323,326}

The prognostic implications of DNA content, cytogenetic abnormalities, or oncogene amplification have received little attention.^310,318

The histologic diagnosis of hepatoblastoma, with its distinctive variegated and sometimes biphasic appearance, is often straightforward. In some cases the characteristic changes can be noted with fine-needle aspiration cytology.³⁴⁰ Among the important differential considerations is hepatocellular carcinoma, which tends to be a more aggressive neoplasm with an overall poorer prognosis.³²⁰ The age of the affected patient provides one clue to the distinction; although there are exceptions, hepatocellular carcinoma generally occurs in children over five years of age, whereas hepatoblastoma is typically found in younger children under the age of three years. Histologically hepatocellular carcinoma exhibits larger, more pleomorphic tumors cells arranged in trabeculae that are usually several cells, rather than two, in thickness. Eosinophilic cytoplasmic globules are commonly noted, but extramedullary hematopoiesis is not present.

Hepatoblastomas, particularly those with a predominant small cell undifferentiated component, must also be distinguished from other childhood neoplasms involving the liver, including neuroblastoma, embryonal rhabdomyosarcoma, germ cell tumors, and leukemias or lymphomas. This distinction rests on identifying definite evidence of hepatocellular differentiation, as manifest by the presence of characteristic fetal-type cells or an appropriate immunohistochemical profile. Adequate sampling of the tumor is an obvious prerequisite.

The bile duct adenoma is an uncommon, and even less often reported, tumor that generally represents an incidental finding at laparotomy or surgery.^21,344,351 Also referred to as benign cholangioma or cholangioadenoma, it is an inconsequential lesion most notable for being mistaken for metastatic carcinoma.

Most bile duct adenomas are identified in adults older than about 40 years of age, and men and women are affected approximately equally. The lesions typically appear as discrete white masses, usually solitary and subcapsular in location, with a firm consistency and unencapsulated margin. Almost all are less than one cm in diameter, although cases up to four cm have been recorded.^344,351

Histologically they are characterized by a compact proliferation of small round ductular structures within a fibrotic stroma (Figure 15-39). The ductules have small or inapparent lumens and are lined by cuboidal epithelium with slightly basophilic cytoplasm and bland, regular nuclei. Mitoses, cytologic atypia, and nuclear pleomorphism are absent. The density of the supporting stroma varies; in cases with more prominent stromal hyalinization, the ductules can appear distorted or atrophic. On occasion, portal tracts are entrapped within the tumor, and scattered inflammatory cells are sometimes seen. Malignant transformation has not been clearly documented.^344,349,351

Bile duct adenoma is distinguished from primary or metastatic adenocarcinomas by its innocuous cytologic features and lack of vascular or parenchymal infiltration. Biliary microhamartomas are also characterized by the localized proliferation of bile ductular-like structures, but these differ by their angulated profiles and dilated, often bile-containing lumens.

Biliary microhamartomas, also known as von Meyenberg complexes, represents a developmental malformation resulting from the aberrant construction or remodeling of embryonic bile ducts. These lesions therefore fall into the spectrum of fibropolycystic diseases of the liver and can thus occur in conjunction with congenital hepatic fibrosis, autosomal dominant polycystic disease, or Caroli's disease (Chapter 14). In fact, biliary microhamartomas are considered the precursor lesion of autosomal dominant polycystic disease and constitute the basic histologic unit of congenital hepatic fibrosis.^{1,347,355,361}

Most often, however, the lesions are sporadic abnormalities found incidentally at autopsy or abdominal surgery. In some cases, hepatic ischemia is incriminated as the predisposing event.³⁶⁰ The exact prevalence of biliary microhamartomas is not precisely established and is clearly subject to the thoroughness of sampling, but is estimated at about 3% of all autopsied patients.

The microhamartomas can be solitary, but they are more often multiple. In particular, the presence of numerous, widely scattered lesions should raise the possibility of early autosomal dominant polycystic disease or congenital hepatic fibrosis. Typically the lesions appear as subcapsular white or green masses, seldom exceeding 0.5 cm in diameter, and are either within or closely apposed to portal tracts. Grossly the lesions can be mistaken for metastatic carcinoma or granulomatous foci.

Microscopically, biliary microhamartomas are composed of numerous disorderly bile duct-like structures embedded within a dense fibrous stroma (Figure 15-40). The ducts commonly display an angulated or branching configuration, and varying degrees of dilatation, eventually leading to cyst formation, can be noted. Lining these structures is a simple layer of low columnar to attenuated epithelium; the lumens contain bile plugs or eosinophilic proteinaceous debris.

In rare cases, microhamartomas have been complicated by the development of cholangiocarcinoma.^345,346,352

Biliary Papillomatosis

Biliary papillomatosis is an extremely rare condition characterized by the multicentric proliferation of adenomatous epithelium within the large bile ducts.^{350,357,359,365} Primarily a disease of middle age or older adults, the disorder manifests with features of biliary obstruction including abdominal pain, jaundice, and fever. Men are affected about twice as often as women. Treatment is difficult because of the wide distribution and progressive nature of the lesions, and consequently the prognosis is very poor. In most instances death follows within four years of diagnosis with bacterial cholangitis and sepsis, hepatic failure, or complicating carcinoma as major causes. Rare localized cases can be treated by partial hepatectomy, although recrudescent lesions can develop in the remaining liver.^359,365

Grossly the neoplasm is characterized by soft pink to tan papillary excrescences that vary from a few mm to several cm in diameter and reside anywhere in the large intrahepatic or extrahepatic bile ducts. These excrescences consists of columnar biliary epithelium supported by a delicate, branching fibrovascular core. The tall epithelial cells possess pale mucin-filled cytoplasm and basal nuclei. Although often cytologically benign, the cells can display greater degrees of nuclear atypia; in situ or invasive carcinoma is occasionally noted.³⁵⁸

Biliary cystadenoma is an uncommon multiloculated cystic neoplasm that arises in the liver parenchyma, or less commonly, in the extrahepatic biliary tract or gallbladder. Only about 100 cases of this tumor have been reported, and it accounts for less than 5% of all intrahepatic biliary cysts.^353,356 The histogenesis of biliary cystadenoma remains uncertain, although an origin from embryonic foregut rests has been advanced.^343,366

The tumor predominantly occurs in middle-aged women. Over 85% of affected patients are female, and the age range extends from 20 to 65 years with a peak incidence in the fifth decade. The typical clinical presentation involves abdominal discomfort, pain, or swelling or a palpable abdominal mass, and the duration of symptoms can range from a few weeks up to 17 years. Occasional cases are complicated by biliary obstruction as manifested by jaundice or the appearance of bacterial cholangitis; rupture of the tumor or compression of the vena cava or hepatic veins is rarely noted.^343,364 Radiographic imaging studies including ultrasonography and computed tomography are helpful in distinguishing biliary cystadenomas from other hepatic cysts.^343,348,363

Complete surgical excision is the treatment of choice. Although partial resection or marsupialization have been performed in some cases, the tumors can recur; these procedures should be reserved for cases in which total extirpation is not possible.³⁴³

Biliary cystadenomas are characteristically large multiloculated cysts analogous to mucinous cystadenomas of the pancreas (Figure 15-41). Generally solitary and spherical, they can range from 2 cm to over 25 cm and contain white to yellow to brown fluid of clear, opaque, mucinous, or gelatinous character. Individual locules vary in size, but usually display uniform diameters in any given tumor, and the internal surface is typically smooth with occasional trabeculations or papillations.^354,366

Histologically, the locules are lined by a simple columnar to cuboidal epithelium with basal nuclei and pale, mucin-filled cytoplasm (Figure 15-42). These cells, in addition to epithelial mucins, contain immunoreactive cytokeratins, carcinoembryonic antigen, and epithelial membrane antigen.³⁶² On occasion, the epithelium can be pseudostratified, attenuated, or focally ulcerated, and goblet cells or squamous cells are sometimes seen. Nuclear atypia and mitoses are rare, however, 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.³⁵³

Underlying the epithelium is a fibrous stroma of 1 to 3 mm thickness. At its most distinctive, this stroma is densely cellular and composed of closely packed spindle cells reminiscent of ovarian stroma (Figure 15-43); this mesenchymal stroma is peculiar to cystadenomas occurring in women. In men, by contrast, the tumors typically exhibit an undistinguished subepithelial band of hyalinized connective tissue.³⁶⁶ The stroma can contain varying components of smooth muscle, fat, benign glands, and inflammatory cells. Surrounding the stromal layer is a zone of dense collagen with scattered blood vessels, nerves, and bile ducts together with occasional hemosiderin deposits and foamy macrophages.

Biliary cystadenomas should be distinguished from the various types of nonneoplastic hepatic cysts (see Chapter 14). Although the particular features of these cysts vary, they all tend to be unilocular in nature and lack a mesenchymal stroma. The more critical distinction involves the development of cystadenocarcinoma, which is noted in as many as 25% of cystadenomas.^354,366 Because of this risk, the gross specimens of cystic tumors need to be careful examined for suspicious areas, and extensive sampling of the cyst should be performed.

Carcinomas can originate at any point along the intrahepatic or extrahepatic biliary tract from the small peripheral bile ducts to the ampulla of Vater. These neoplasms are typically referred to as cholangiocarcinomas, bile duct carcinomas, or cholangiocellular carcinomas, although some restrict the name cholangiocarcinoma to the intrahepatic variety alone.^1,399

Overall, intrahepatic cholangiocarcinomas account for between 7% and 25% of primary hepatic malignancies. On a worldwide basis, they are consistently less common than hepatocellular carcinoma, with prevalence figures ranging from three-times to twenty-times lower.³⁸⁶ Based on their primary location, the tumors can be divided into two main categories, peripheral and hilar types. Peripheral cholangiocarcinomas arise from the smaller intrahepatic bile ducts and represent from 50% to 70% of the total, whereas the less common hilar cholangiocarcinomas develop from the major bile ducts at the hepatic hilum, including the right and left hepatic ducts.^1,389 Tumors originating from the larger intrahepatic bile ducts are sometimes designated separately as major duct cholangiocarcinomas, but since they are otherwise similar to the neoplasms of the hilar region, the two can conveniently be considered together. These hilar cholangiocarcinomas are often eponymously referred to as Klatskin tumors and share many clinicopathologic features with extrahepatic bile duct carcinomas.³⁸³

Most cases of intrahepatic cholangiocarcinoma demonstrate no particular underlying factor, but several uncommon predisposing conditions are well recognized. All forms of fibropolycystic disease of the liver have been associated with cholangiocarcinoma, including congenital hepatic fibrosis, Caroli's disease, autosomal dominant polycystic disease, choledochal cysts, and as noted above, biliary microhamartomas.^{345,375,378,379,394,405} Another important group of associated disorders involves chronic inflammatory processes of the bile ducts such as primary sclerosing cholangitis, recurrent pyogenic cholangitis and hepatolithiasis, and parasitic infections with Clonorchis and Opisthorchis.^{382,384,387,396,406} Other cases have been associated with simple hepatic cysts, exposure to Thorotrast, and therapy with anabolic or contraceptive steroids.^{369,380,395,398,409} In contrast to hepatocellular carcinoma, cirrhosis or hepatitis B infection are infrequently present.

Intrahepatic cholangiocarcinoma is generally a disease of older adults; the mean age is about 65 years and most patients are between 50 years and 70 years of age. Men and women are affected almost equally, with a modest male predominance occasionally noted. In patients with the peripheral variant, the clinical presentation is similar to that of hepatocellular carcinoma; the tend to be clinically silent and symptoms of abdominal pain, malaise, anorexia, and weight loss occur late in the course. Patients with hilar cholangiocarcinomas typically manifest earlier with evidence of biliary obstruction including progressive jaundice, epigastric pain, and pruritus.^367,373,404

The routine liver function tests are variably and nonspecifically abnormal. The serum alkaline phosphatase level is frequently elevated, as with many mass lesions, and the serum bilirubin occasionally increased. Serum alpha-fetoprotein is notably undetectable in almost all cases, but the carcinoembryonic antigen is occasionally increased.

Ultrasonography and computed tomography are helpful in detecting the tumor and demonstrating the dilatation of proximal bile ducts seen with hilar carcinomas. Cholangiography by either endoscopic or percutaneous routes is the procedure of choice for establishing the location and extent of the neoplasm; the appearances range from intraluminal polypoid masses to luminal stenosis that is focal, multifocal, or diffusely distributed.^390,404,408

At the time of diagnosis, most intrahepatic cholangiocarcinomas are at an advanced stage with extensive intrahepatic involvement or invasion of adjacent local structures. Distant metastases are also seen, usually to regional lymph nodes, lungs, and peritoneal surfaces. As a consequence, the overall prognosis is dismal; progressive deterioration and death from liver failure or sepsis results in a mean survival of less than one year.³⁷³ In rare instances, the tumor growth is more indolent, and more prolonged survival can be seen.³⁴⁹

Approximately 20% of patients have localized tumors that can be surgically resected for cure. The outcome is better for this selected group with reported three-year survival rates of about 55% for peripheral carcinomas and 25% for hilar carcinomas.^374,376 The treatment of patients with advanced disease is largely palliative, since chemotherapy and radiotherapy have little effectiveness and liver transplantation is associated with a high risk of recurrence.^370,393,408

Pathologic Features ^{272,389,399,407}

On gross examination, cholangiocarcinoma generally appears as a grey-white mass, ranging from 2 cm to over 15 cm in diameter, with firm consistency and infiltrative margins (Figure 15-44). Central necrosis is occasionally noted, but hemorrhage and tumor rupture are uncommon. Portal and hepatic venous invasion, although less common than with hepatocellular carcinoma, can also be identified.

The gross configuration varies somewhat between peripheral and hilar cholangiocarcinomas. Peripheral tumors commonly present as solitary masses, but multiple or diffusely distributed nodular patterns can also occur. With hilar cholangiocarcinomas, several macroscopic patterns can be seen: a dense infiltrative mass centered on the hepatic hilum and extending into hepatic parenchyma, an ill-defined sclerotic annular mass encircling a large bile duct, or a polypoid mass protruding into the lumen of a large duct.¹

Histologically, the typical cholangiocarcinoma is a well to moderately differentiated adenocarcinoma characterized by duct-like glandular or acinar structures (Figure 15-45). The tumor cells are usually cuboidal or low columnar and resemble biliary epithelium with basophilic or clear cytoplasm, uniform round nuclei, and inconspicuous nucleoli. Intracytoplasmic mucin is an almost universal feature, although the quantity is frequently sparse; a combination of neutral and acid mucins (primarily sulfomucins) is generally found, just as with normal biliary epithelial cells.³⁷⁷ Bile production is not a feature. A dense fibrous stroma is characteristically noted and, at times, dominates the histologic picture.

Additional histologic variants of cholangiocarcinoma are also described, incorporating the full spectrum of adenocarcinomas as seen at other sites. These include poorly differentiated carcinomas with pleomorphic tumors, abortive gland formation, and often sparse fibrous stroma; mucinous carcinomas with abundant extracellular mucin; papillary carcinomas with arborescent fibrovascular stalks; and signet-ring carcinomas with individually infiltrating mucin-laden tumor cells (Figure 15-46). An unusual version demonstrates a trabecular appearance with double-layered cords of cells resembling cholangioles and has been referred to as cholangiolocellular carcinoma.³⁹⁷

In rare case, squamous differentiation is present and the tumors designated as mucoepidermoid, adenosquamous, or even pure squamous carcinomas.^368,392,403 A cystic component is noted with some of these cases, and the distinction between cholangiocarcinoma, cystadenocarcinoma, and carcinoma arising in a developmental cyst can be difficult in advanced cases and is sometimes arbitrary.

Cholangiocarcinomas tend to invade blood and lymphatic vessels, infiltrate along perineural and periductal spaces, and permeate the portal tracts (Figure 15-47). Growth along the lumens of large bile ducts can also be identified, especially with hilar tumors.³⁸² With infiltration into the adjacent parenchyma, the tumor typically extends along the sinusoids, separating and compressing the hepatic plates. In general, a specific site of biliary origin cannot be demonstrated, but in some cases, neighboring bile ducts exhibit varying degrees of epithelial dysplasia (Figure 15-48).^385,387,400 A progression from hyperplasia to dysplasia to carcinoma has thus been suggested. In other instances a origin from intrahepatic biliary glands has been postulated.⁴⁰²

A leading differential problem is distinguishing cholangiocarcinoma from metastatic adenocarcinoma, especially from such primary sites as the pancreas, breast, or extrahepatic biliary tract. Unfortunately the two tumors can be histologically and immunohistochemically identical, and the distinction is thus based solely on clinical and radiographic findings. A firm diagnosis of cholangiocarcinoma can be rendered only when the possible metastatic sites have been appropriately excluded. As a general rule, cholangiocarcinomas more often display perineural infiltration, free extracellular mucin, and marked heterogeneity of neoplastic cells within a single gland, but these are not specific features.⁴⁰⁷

Other benign and malignant hepatic neoplasms occasionally pose difficulties in differential diagnosis. Bile duct adenomas are distinguished by their small size, lack of cytologic atypia, and incidental nature. Most hepatocellular carcinomas demonstrate trabecular architecture, distinctive cytologic features, and a paucity of fibrous stroma, features not generally seen with cholangiocarcinomas. The distinction is more difficult, however, with hepatocellular carcinomas that exhibit focal pseudoglandular differentiation or are of the sclerosing variant; in this circumstance, identifying definite evidence of biliary epithelial differentiation, such as mucin production or appropriate immunohistochemical staining, is the solution. Rare cases of combined hepatocellular-cholangiocarcinoma are nonetheless recognized and are discussed below. Epithelioid hemangioendothelioma is a well-known imitator of cholangiocarcinoma, but it demonstrates immunoreactivity for endothelial markers and lacks mucin secretion.

Reactive epithelial alterations of bile ducts and proliferated bile ductules can also mimic the appearance of well-differentiated cholangiocarcinoma. Although the nuclei of the reactive ducts are enlarged and hyperchromatic, they tend to display an overall monotony an a delicate chromatin granularity. Moreover, the underlying histologic context often provides a clue, since cirrhosis or stromal inflammation is usually a prominent background feature. The carcinomas, on the other hand, exhibit severe cytologic atypia with marked variation in nuclear size and intraglandular bridging, strongly immunostain with carcinoembryonic antigen, and, at their most overt, demonstrate perineural invasion.^388,393

This rare malignancy generally develops as a complication of an antecedent biliary cystadenoma, which may or may not demonstrate the distinctive mesenchymal stroma.^{354,366,411,420} In other cases the preexisting lesion consists of a developmental cyst or, more often, cannot be positively identified.^409,415,417

Most patients are between 45 and 70 years of age, and men and women are affected about equally. The clinical features are otherwise broadly similar to those of biliary cystadenoma with abdominal pain or an abdominal mass being the predominant complaints. In general, the diagnosis requires histologic examination of the resected cystic mass, although radiographic imaging and fine-needle aspiration cytology can sometimes provide the diagnosis.^343,413,416 In one case, however, fine-needle aspiration was followed by peritoneal dissemination of the carcinoma.⁴¹²

The tumors tend to grow slowly, but they eventually invade adjacent structures and metastasize to distant sites. Overall, however, the prognosis is better than with the usual cholangiocarcinoma. Patient survival at two years is about 50%, and in some individuals, cures have apparently followed complete excision of localized tumors.^354,366,415

The cysts are generally multilocular, range from 5 cm to over 20 cm in maximum diameter, and may involve either the right or left lobes. Although the gross appearance can be difficult to distinguish from biliary cystadenomas, the suspicion of malignancy should be particularly heightened if blood-tinged fluid, areas of solid thickening, or large papillary masses are present. Nonetheless, any hepatic cyst should be extensively sampling with at least one section per cm diameter.

Histologically, cystadenocarcinomas are usually well-differentiated adenocarcinomas, often with an intracystic papillary component, and are composed of malignant epithelial cells with varying degrees of nuclear stratification, pleomorphism, and hyperchromasia (Figure 15-49). The tumor infiltrates the underlying cyst wall, and vascular invasion and extension into adjoining hepatic parenchyma or adjacent organs can be noted. In rare cases the carcinoma demonstrates adenosquamous, oncocytic, or spindle-cell (pseudosarcomatous) differentiation.^{410,414,418,419}

Within the background the benign epithelium of the preexisting cystadenoma can often be identified. Transitions can sometimes be discerned between this epithelium and the overt carcinoma in the form of varying degrees of epithelial dysplasia.⁴²⁰ Immunohistochemical studies are not useful, however, in distinguishing the benign and malignant foci.³⁶²

Hemangiomas are generally regarded as the most common primary tumor of the liver, with a prevalence in autopsy surveys ranging from 0.4% up to 20%.^1,33 The lesions occur at all ages and in both sexes, although they are more frequent in older age groups and, in most series, favor women.⁴³⁵

The vast majority of hemangiomas are small, clinically silent, and discovered incidentally during radiologic examination, surgery, or autopsy. However, larger tumors with diameters exceeding 5 cm can occasionally become clinically evident; typical manifestations include vague abdominal discomfort or pain, hepatomegaly, or a palpable abdominal mass.^434,460 Large or symptomatic hemangiomas are more common among women. Since the lesions can enlarge with pregnancy or administration of oral contraceptives or estrogens, the possibility that they are hormonally responsive has been advanced.⁴⁶⁷ Rare reports describe spontaneous rupture with hemoperitoneum or a bleeding diathesis from hypofibrinogenemia or platelet sequestration and consequent thrombocytopenia.^434,460

Hemangiomas can be correctly identified in most instances by the characteristic appearance on radiographic imaging with ultrasonography or computed tomography. In equivocal cases, magnetic resonance imaging, arteriography, or hepatic scintigraphy with labeled red blood cells might be required.^434,465 Needle biopsy is not necessary for the diagnosis and is, in fact, contraindicated because of the risk of severe hemorrhage.⁴⁶⁰ Fine-needle aspiration, however, has been safely performed.^423,425 Since the tumors remain stable in size and free of complications, only the symptomatic lesions require surgical resection or other ablative therapy.^434,455,460

Most hemangiomas are solitary lesions less than 4 cm in diameter. Multiple tumors are seen in 10% to 25% of cases, and diameters of up to 30 cm have been recorded. The tumors can occur anywhere in the liver, but are frequently located immediately beneath the hepatic capsule. Pedunculation is rare. The cut surface demonstrates a soft, dark-red, spongy mass with blood-filled cavities and occasional foci of thrombosis, scarring, or calcification. Some hemangiomas occur in conjunction with focal nodular hyperplasia.^47,52

Histologically, hemangiomas are composed of dilated, variably-sized vascular spaces lined by flattened endothelial cells and supported by connective tissue septa (Figure 15-50). Most are well-demarcated from the surrounding liver, but occasional lesions extend irregularly into adjoining parenchyma. The septa consist of delicate, poorly cellular fibrous bands with varying degrees of myxoid change and scarring (Figure 15-51). Thick-walled blood vessels and scattered bile ducts are found in the larger septa. The vascular spaces are frequently the sites of thrombi in various stages of organization. End-stage hemangiomas demonstrate involutional changes with extensive hyalinization, obliteration of the vascular channels, and sometimes calcification or ossification. Even in these advanced lesions, the underlying vascular architecture can usually be detected. Superimposed central necrosis can give rise to the so-called solitary necrotic nodule.^422,459

Hepatic hemangiomas are readily recognized tumors, and their distinctive cavernous appearance readily distinguishes them from other benign vascular disorders. Blood-filled spaces, for example, are also a characteristic feature of peliosis hepatis, but fibrous septa are not seen. In hereditary hemorrhagic telangiectasia, the dilated vascular channels are located within portal tracts and along the periportal parenchyma and are accompanied by aberrant portal vessels.^446,463 Although focal areas of infantile hemangioendothelioma can resemble hemangioma, other regions show the characteristic small vascular proliferation.

Infantile hemangioendothelioma is the pediatric contribution to the benign vascular proliferations of the liver. Although uncommon, it is nonetheless the predominant hepatic neoplasm of the first year of life and accounts for approximately 15% of all primary liver tumors in the pediatric population.^1,341 Almost 90% of the patients are under six months of age at diagnosis, with about half the cases being recognized during the first postnatal month.^426,429 Few patients are older than one year of age, and cases are rarely reported in adults. Girls are affected about twice as often as boys.

Small tumors can be asymptomatic, but the majority of cases manifest clinically with hepatomegaly, diffuse abdominal enlargement, or a palpable abdominal mass. A dramatic and potentially life-threatening feature of many cases is high-output cardiac failure resulting from arteriovenous shunting through the tumor.^421,462 Coincidental cutaneous hemangiomas are noted in approximately 50% of cases, and additional sites such as the lung, gastrointestinal tract, pancreas, and thymus can also be involved. Uncommon complications include massive hemoperitoneum from rupture of the tumor or severe thrombocytopenia resulting from platelet sequestration by the tumor.⁴²¹

Increased serum bilirubin levels are found in occasional instances, and the serum alpha-fetoprotein sometimes elevated, reflecting the young age of the patients. Anemia can also develop and, on occasion, has a microangiopathic component.⁴²⁹ Radiographic imaging is helpful in determining the hepatic origin and vascular nature of the mass, with angiography being the most useful procedure for defining the extent of the tumor and guiding possible surgical approaches.^426,445

Patients with uncomplicated hemangioendotheliomas have a good prognosis; the tumors tend to undergo spontaneous involution after six to eight months and can completely regress.⁴²⁶ Despite this favorable natural history, however, the development of cardiac failure or hepatic insufficiency portends a poorer outcome with a reported mortality rate of about 25%.⁴⁴⁵ Treatment thus entails medical management of the cardiovascular disturbances together with specific therapy directed at removing or obliterating the neoplasm. Surgical resection can be employed for localized tumors, and a variety of alternative approaches such as corticosteroid administration, transarterial embolization, hepatic artery ligation, and liver transplantation can be used in other cases.^421,445,462

The tumors can be single or multiple; the right lobe is favored by the solitary variants, whereas the multifocal tumors are usually scattered among both lobes. Typically they appear as sharply-defined but nonencapsulated masses, ranging between 0.2 to 15 cm in diameter, and on cut surface demonstrate a variable gray-tan to pink, firm or spongy, appearance. Central hemorrhage, necrosis, fibrosis, or yellowish areas of calcification can be noted in larger lesions. The vascular nature of the tumor may not be evident on gross examination.^427,429

Histologically the tumor is characterized by a proliferation of small, irregularly shaped vascular channels that are lined by a single layer of plump endothelial cells (Figure 15-52). These channels display small, often compressed lumens and contain varying quantities of red blood cells and occasional foci of extramedullary hematopoiesis. The endothelial cells are uniform in appearance with regular round nuclei, little nuclear pleomorphism, and almost no mitoses. They display immunoreactivity for endothelial cells markers include Ulex europaeus I lectin.⁴⁶⁶ The supporting fibrous stroma is composed of scattered fibroblasts and collagen fibers and variably displays a myxoid quality. Small bile ducts are scattered through the mass (Figure 15-53). The tumor generally grows in an expansile fashion, expanding into adjacent liver, although hepatic plates can sometimes be entrapped along its advancing edge.

These distinctive changes are best seen along the periphery of tumor. Toward the center the vascular spaces tends to enlarge and dilate, and the amount of stroma increases (Figure 15-54). On occasion, a cavernous configuration is adopted, and the appearance mimics that of hepatic hemangioma. The endothelial cells in these zones exhibit enhanced immunostaining for factor VIII-related antigen and vimentin, features that imply maturation of the tumor cells.⁴⁶⁶ In addition, the central region can harbor various regressive changes including hemorrhage, necrosis, thrombosis, fibrosis, and dystrophic calcification (Figure 15-55).

Some hemangioendotheliomas demonstrate atypical histologic features, involving either small foci widespread areas. The vascular spaces are larger and more irregular or tortuous. The endothelial lining is crowded and multilayered with pleomorphic cells demonstrating hyperchromatic nuclei and occasional mitoses. This atypical pattern has been referred to type 2, as contrasted with the more common type 1 pattern, although a definite separation between the two types is not always possible.^427,429 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 they have been considered by some investigators as a low-grade childhood form of angiosarcoma.⁴⁴⁸ Whatever the designation, the presence of endothelial pleomorphism, budding, or atypia in an infantile hemangioendothelioma should be specifically noted by the pathologist, although the clinical outcome cannot be confidently predicted by the histologic features.³⁴¹

Several reports describe the development of angiosarcoma months to years following a diagnosis of infantile hemangioendothelioma, in some instances even after clinical regression.^341,442,458 Although some of these cases have histologically resembled adult-type angiosarcoma, metastases have rarely been noted, and the distinction from type 2 hemangioendotheliomas is not always clear. Solid sarcomatous areas, vascular and sinusoidal permeation, and marked pleomorphism are more typical of angiosarcoma than type 2 hemangioendothelioma, but there is considerable histologic overlap, and the two conditions are sometimes indistinguishable.^427,448

Other differential considerations include hemangioma and mesenchymal hamartoma. Although infantile hemangioendotheliomas can focally resemble hemangiomas, especially in the central portions of the tumor, the more characteristic small vascular proliferation along the periphery enables the distinction. Mesenchymal hamartomas can exhibit vascular proliferation, but these vessels lack the irregular thin-walled character of the vessels in hemangioendothelioma and the distinctive primitive mesenchymal stroma is diffusely present.

Mesenchymal hamartoma is an uncommon tumor-like lesion seen primarily in young children. One of the more common benign tumors of this age group, it represents approximately 6% of all pediatric hepatic neoplasms.³⁴¹ The pathogenesis of the lesion is not known, but it is thought to represent a developmental anomaly, probably originating from the aberrant formation of primitive portal mesenchyme together with secondary degenerative changes.^428,435

Most cases occur in children less than two years of age, although sporadic examples are described in adolescents and adults.^431,432,437 A modest male predominance is usually noted. Although some cases are discovered incidentally, most are clinically evident because of progressive abdominal distension or a palpable abdominal mass; abdominal pain, respiratory distress, and failure to thrive are sometimes present.^430,456,457 Radiographic imaging studies including ultrasonography and computed tomography confirm the presence of a large multicystic hepatic mass.⁴⁵³

Surgical resection of the mass is generally recommended, although a good long-term outcome has also followed incomplete excision or marsupialization. Even with partial removal, recurrence disease or malignant transformation has not been reported.^430,457

The tumor appears grossly as a solitary mass, usually located in the right lobe and ranging from 3 cm to 30 cm in diameter. Occasional cases are pedunculated. On cut surface the lesion is typically composed of multiple cysts with diameters varying between a few mm and several cm. These cysts are filled with clear or mucoid fluid, lined by a smooth or ragged surface, and surrounded by a mixture of yellow-gray myxoid tissue with white fibrous bands. Necrosis, calcification, and hemorrhage are generally absent. Typically the tumor is well-demarcated from the adjacent liver, although an infiltrative border or satellite lesions are sometimes present.^444,457

Histologically mesenchymal hamartoma is characterized by a disorganized combination of immature mesenchymal tissue, bile ducts, blood vessels, and hepatocytes. The mesenchymal component consists of innocuous stellate cells dispersed within an edematous myxoid stroma containing varying amounts of collagen (Figure 15-56). Focally this stroma accumulates fluid and undergoes cystic change, yielding a lymphangiomatous appearance and giving rise to the grossly visible cysts. Scattered through the stroma are numerous thick-walled veins, foci of extramedullary hematopoiesis, and scattered bile ducts. The ducts often exhibit branching or cystically dilated profiles and are enclosed by a cuff of mesenchymal tissue; the epithelium can be atrophic, hyperplastic, or inflamed (Figure 15-57). Small clusters of unremarkable hepatocytes lacking a lobular arrangement are interspersed within the tumor. At the periphery of the mass, small portal-based tumor nodules occasionally extend into the adjoining liver.^435,444,457

Lipomatous tumors of several varieties are rarely found in the liver. Most occur in adults as asymptomatic lesions, incidentally detected by radiographic imaging, with isolated cases manifesting with abdominal pain from intratumoral hemorrhage.⁴⁵¹ Typically the tumors are solitary masses ranging from 1 cm to 20 cm. Histologically they are composed of mature adipose tissue, either alone or accompanied by a vascular, hematopoietic, or spindled or epithelioid smooth muscle component. Depending on the constituents, the various permutations can be designated as pure lipoma, angiolipoma, myelolipoma, angiomyelolipoma, and angiomyomyelolipoma.^{436,447,449,450,454}

An additional lipomatous tumor is the so-called hepatic pseudolipoma or coelomic fat ectopia. This lesion consists of a rounded nodule of fat attached to the hepatic capsule, usually on the anterior diaphragmatic aspect of the right lobe, and probably represents a detached appendix epiploica that has become affixed to the liver. The histologic features accordingly entail mature adipose tissue with various degenerative changes including calcification.^440,464 All of the lipomatous tumors should be distinguished from focal fatty change, a discrete area of exaggerated hepatocellular fat accumulation.⁴²⁴

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 to over 25 cm in diameter that protrude from the hepatic surface. The histologic features entail interlacing bundles of bland spindle cells with variable cellularity and intermixed collagen fibers.^441,443

Sporadic cases of hepatic leiomyoma, lymphangiomatosis, chondroma, hemangioblastoma, and myxoma are recorded.^{1,433,435,438,439,452,461}

Hepatic angiosarcoma, although the most common primary sarcoma of the liver, is nonetheless a rare neoplasm. It accounts for only about 2% of all malignant hepatic tumors seen at autopsy, with only an estimated 25 to 30 cases occurring annually in the United States.^1,474,483

The tumor is notorious for its striking etiologic associations. Exposure to Thorotrast, vinyl chloride monomer, or inorganic arsenical compounds is identified in 25% to 40% of cases.^{87,477,502,508} Although these agents either have been discontinued or are under stricter controls, the prolonged latency period -- ranging up to several decades -- means that associated angiosarcomas will continued to be encountered for many years.^483,486 Other agents infrequently implicated include oral contraceptives and other estrogens, anabolic steroids, and cupric sulfate.^89,492,516

Clinical features. The peak incidence is in the sixth and seventh decades of life, and approximately 75% of the patients are men. Rare cases are reported in children, most in association with infantile hemangioendothelioma.^442,448,458 The clinical presentation entails abdominal pain, weight loss, weakness, and fatigue together with hepatomegaly or a palpable abdominal mass. Some cases manifest with an acute abdomen due to rupture of the tumor or with hematologic complications such as thrombocytopenia, microangiopathic hemolytic anemia, or disseminated intravascular coagulation.^495,517

Radiographic imaging procedures are generally useful in demonstrating the presence of a hepatic mass, but the most helpful study is angiography, which shows a characteristic vascular blush with pooling of contrast.⁴⁷⁷ In Thorotrast-associated cases, deposits of radiopaque material are found in the liver, spleen, and lymph nodes. Open biopsy is generally required for histologic diagnosis since percutaneous liver biopsy can be complicated by uncontrollable bleeding and death.⁵⁰⁸

The prognosis of patients with hepatic angiosarcoma is very poor. Most patients deteriorate rapidly and die within six months of diagnosis, usually from hepatic failure, extensive tumor burden, or tumor rupture. Distant metastases, most commonly to the lungs, regional lymph nodes, spleen, or bone marrow, are noted in over half the patients.^467,508 Because of the advanced stage of the disease at diagnosis, surgical resection is not usually a therapeutic option. Rare cases have responded to cytotoxic chemotherapy or irradiation, but the survival advantage is limited and the results are mixed.⁵¹⁷

Pathologic features. On gross examination, angiosarcomas typically appear as multiple gray or hemorrhagic masses scattered throughout both liver lobes. These masses vary greatly in size, ranging between 0.1 cm and 5 cm in diameter, and have a spongy consistency and irregular, ill-defined borders. Blood-filled cavities reminiscent of peliosis hepatis can also be seen. Less often the tumor is represented by a large solitary mass, typically over 15 cm in diameter. The nonneoplastic liver is often normal, but can be fibrotic or cirrhotic, particularly in cases associated with Thorotrast, vinyl chloride, or arsenic exposure.^495,502

The histologic appearance is characterized by a proliferation of malignant endothelial cells with pale ill-defined cytoplasm and enlarged, pleomorphic, and hyperchromatic nuclei (Figure 15-58). The cells usually assume an elongated configuration, but they can also appear rounded or polygonal with conspicuous cytoplasm and prominent nucleoli. Mitoses, although a variable feature, are often numerous, and bizarre or multinucleated tumor cells are sometimes noted. In some cases the cells show evidence of phagocytic behavior.^{1,495,502,510,519}

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 (Figure 15-59). The surviving hepatocytes can undergo hyperplasia, sometimes with formation of cholestatic rosettes; the resulting trabecular pattern can be mistaken for hepatocellular carcinoma. With progression the hepatocytes atrophy and are ultimately replaced by fibrosis and the sinusoids dilate, producing irregular pelioid-like vascular spaces of varying size (Figure 15-60). These spaces are lined by multilayered tumor cells, sometimes in a papillary arrangement, and contain blood and necrotic debris. Extramedullary hematopoiesis is often present.^495,502

In addition the tumor cells can assemble into solid nodules or sheets, producing compact spindle-cell foci that simulate fibrosarcoma or areas of clustered epithelioid cells reminiscent of poorly differentiated carcinoma (Figure 15-61). The tumor also invades central veins or portal vein branches. This can lead to luminal occlusion with subsequent hemorrhage, necrosis, and infarction.

Immunohistochemical markers of endothelial cells, including factor VIII-related antigen and Ulex europaeus I lectin, are almost always positive, but the staining can be weak and can be absence in poorly differentiated areas of the tumor.^485,487,511 Weibel-Palade bodies are the characteristic ultrastructural feature.⁵¹⁹

Differential diagnosis. Although angiosarcoma has a characteristic appearance, the histologic diagnosis can be difficult in small or nonrepresentative biopsy specimens. Solid areas of tumor growth without vasoformative areas can be mistaken for other sarcomas or carcinomas, and immunohistochemical stains might be necessary to define the tumor differentiation. The appearance of hepatocyte trabeculae in some tumors can mimic hepatocellular carcinoma, but the malignant cytologic features of the endothelial cells, as opposed to the hepatocytes, permits the distinction. In other instances prominent sinusoidal proliferation of tumor cells and accompanying fibrosis can be confused with a variety of infections and inflammatory processes as well as with leukemic infiltration. Again, immunohistochemistry is helpful in equivocal cases.

At times the distinction between angiosarcoma and other vascular neoplasms becomes a problem. The benign tumors lack the malignant cytologic features and invasive nature of angiosarcoma. Epithelioid hemangioendothelioma is distinguished by its characteristic stroma and the presence of epithelioid and dendritic tumor cells with intracytoplasmic vascular lumina, although some cases show overlapping features.⁴⁸⁰ Metastatic angiosarcoma to the liver cannot be differentiated from primary hepatic angiosarcoma of histologic grounds.⁵¹⁰

Epithelioid Hemangioendothelioma

A distinctive low-grade malignant tumors of endothelial origin, epithelioid hemangioendothelioma can occur in several sites including the lungs, soft tissues, and bone as well as the liver.

Clinical features. Although the age range extends from teenagers to octogenarians, most patients are in their fourth or fifth decades of life. About 60% of the patients are women.^480,496 Unlike hepatic angiosarcoma, no strong etiologic associations or predisposing factors have been identified, although a relationship with long-term oral contraceptive use has been suggested.^467,478

The tumor may be asymptomatic and discovered incidentally, but the usual clinical presentation involves abdominal pain or discomfort, hepatomegaly, weight loss, fever, or jaundice. In rare cases an acute abdominal crisis results from rupture of the tumor, or the Budd-Chiari syndrome is produced by obstruction of the hepatic veins.⁴⁷⁶ Radiographic studies typically demonstrate multifocal masses, occasionally graced by focal calcification, and the tumor is characteristically hypovascular by hepatic angiography.^476,478

Epithelioid hemangioendothelioma tends to be an indolent and slowly growing tumor, but the natural history can vary considerably. Most patients have a slowly progressive clinical course with prolonged survival, whereas other suffer rapid deterioration with early death from hepatic failure or extensive tumor spread. The overall five-year survival is approximately 30%.^478,480,496 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 problematic.⁵⁰⁰

Surgical resection and liver transplantation have been apparently curative in some cases.^500,512,522 The response to cancer chemotherapy, radiotherapy, and arterial embolization has generally been disappointing.^478,498

Pathologic features. In about 80% of cases the tumor is multifocal with involvement of both lobes by tumor nodules ranging from 0.1 cm to over 10 cm in diameter. These nodules are white to tan and have a firm, sometimes gritty, consistency. The background liver is generally normal, although cases with underlying cirrhosis or nodular regenerative hyperplasia have been recorded.⁴⁹⁶

Histologically the tumor comprises small groups of tumor cells surrounded by a distinctive and often generous stroma of varying myxoid or sclerotic character (Figure 15-62). The neoplastic cells display abundant eosinophilic cytoplasm and large vesicular and hyperchromatic nuclei with variable nucleoli (Figure 15-63). These cells have been divided into two types: a dendritic type with irregular stellate processes and an epithelioid type with a rounded cytoplasmic profile.^495,496 Both types, but particularly the dendritic cells, divulge their endothelial nature either 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. These various findings can be mistaken for the signet-ring cells and glands of adenocarcinoma, but the cells of epithelioid hemangioendothelioma are immunoreactive for factor VIII-related antigen and Ulex europaeus I lectin, possess Weibel-Palade bodies, and are negative with immunostains for cytokeratins or carcinoembryonic antigen.^{478,496,500,521} Mitoses are present but are usually not conspicuous.

At the actively proliferating margin of the tumor, the neoplastic cells infiltrate the sinusoids, resulting in ductular transformation, atrophy, and eventual obliteration of the hepatic plates (Figure 15-64). The underlying lobular architecture is frequently preserved, and remnants of portal tracts can be identified. The tumor also invades the central veins, portal veins branches, and larger blood vessels. This intravascular growth appears as intraluminal papillary clusters or tuftlike projections, simulating vascular invasion by carcinoma, and sometimes causes complete luminal occlusion (Figure 15-65).⁴⁸⁰ Infiltrating tumor cells are accompanied by a prominent stromal matrix that is initially fibrillar or hyaline, and an attendant mixed inflammatory infiltrate is often additionally present. With evolution of the lesion, the stroma becomes more abundant, gains acid mucopolysaccharides, and acquires a myxoid or even chondroid appearance (Figure 15-66). Toward its center the tumor ultimately becomes densely sclerotic, often with focal calcification, and the tumor cells can be difficult to discern.^480,496

Differential Diagnosis. With its diverse histologic appearances, epithelioid hemangioendothelioma can mimic several different conditions. Confusion with cholangiocarcinoma or metastatic adenocarcinoma arises because of the epithelioid and sometimes signet-ring appearance of the neoplastic cells and the sclerotic stroma. The distinction is based on the preservation of the lobular architecture, the absence of mucin or other epithelial markers, and the presence of endothelial differentiation. The combination of myxoid stroma and epithelial-like cells has also resulted in some cases of epithelioid hemangioendothelioma being considered variants of malignant mixed tumors of the liver.^481,509

Other vascular neoplasms are also in the differential diagnosis. Both epithelioid hemangioendothelioma and angiosarcoma infiltrate sinusoids and intrahepatic veins, but epithelioid hemangioendothelioma is distinguished by its distinctive stroma, preserved lobular structure, and lesser degrees of cytologic atypia and parenchymal destruction.⁴⁹⁶ Infantile hemangioendothelioma usually lacks cellular pleomorphism and sinusoidal infiltration and occurs in a special clinical setting.

Finally, because of its obliterative venous changes, epithelioid hemangioendothelioma can be mistaken for venoocclusive disease. Recognizing the presence of malignant cells within the occlusive stroma is the key to the distinction.⁴⁸²

Undifferentiated (embryonal) sarcoma of the liver is an unusual but highly malignant childhood neoplasm.⁵²⁴ Also known as mesenchymal sarcoma, malignant mesenchymoma, and fibromyxosarcoma, it is the third most common hepatic malignancy in the pediatric population, following hepatoblastoma and hepatocellular carcinoma, and accounts for about 6% of such tumors.³⁴¹

The tumor occurs primarily in older children and adolescents; the peak incidence is between 6 and 10 years with an age range that extends from newborn infants to almost 30 years of age.⁵²⁴ A slight male predominance is noted. The usual clinical presentation involves an abdominal mass or abdominal pain of short duration. In exceptional cases jaundice or dyspnea resulting from intracardiac spread of the tumor has brought the patient to medical attention.^489,504

The prognosis of undifferentiated sarcoma is very poor. The majority of patients die within one year of diagnosis, and the overall survival rate is only about 20%.^507,524 Death often occurs because of massive local tumor growth with direct extension into contiguous structures and even through the diaphragm. Often the tumor is fatal before distant metastases develop, but secondary involvement of the pleura, lungs, peritoneum, and bone is occasionally noted.⁵⁰⁴ More encouraging survival results have been provided by recent studies that demonstrate long-term survival following complete surgical excision with or without preoperative or adjuvant chemotherapy.^{493,494,523,529}

On gross examination, the tumors are large, well demarcated masses, usually 10 cm to 30 cm in diameter, with a soft gelatinous consistency. The cut surface is variegated with areas of solid gray-white tumor interrupted by foci of cystic degeneration, hemorrhage, and necrosis. Most of the tumor occupy the right lobe of the liver.⁴⁹⁵

Histologically, the tumors are composed of malignant spindle-shaped or stellate cells separated by acid mucopolysaccharide-rich myxoid stroma (Figure 15-67). 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. By light microscopy no specific differentiating features are seen. Mitoses are often plentiful, and bizarre and multinucleated tumor giant cells can be seen (Figure 15-68). A characteristic finding is PAS-positive, diastase-resistant eosinophilic globules within tumor cells as well as scattered in the extracellular stroma.⁵²⁴ These globules variably immunostain for alpha-1-antitrypsin, alpha-1-chymotrypsin, and albumin, but they are consistently negative for alpha-fetoprotein.^{468,489,499,529} Although their exact nature is not certain, a origin from tumor cell degeneration or apoptosis has been suggested.^499,529

The myxoid stroma, which dominates the less cellular portions of the tumor, harbors numerous thin-walled veins and often contain foci of extramedullary hematopoiesis (Figure 15-69). Areas of hemorrhage and necrosis are frequent, and bands of dense hyalinized collagen are occasionally noted. The periphery of the tumor typically entraps bile ducts and hepatocytes and is surrounded from the compressed normal parenchyma by a fibrous pseudocapsule. The entrapped bile ducts are cystically dilated and lined by a cuboidal epithelium that often displays hyperplastic or atypical features (Figure 15-70).⁵²⁴ Because of these cytologic alterations, the ducts have sometimes been regarded as a component of the tumor, but their absence in areas away from the tumor periphery and in metastatic foci contradicts this contention.^504,529

By definition, the tumor lacks histologic evidence of cellular differentiation, and its histogenesis remains uncertain. Although ultrastructural and immunohistochemical studies support a mesenchymal origin, they do not generally demonstrate a consistent pattern of differentiation.^504,507,523 In occasional cases, however, evidence of fibroblastic, myofibroblastic, lipoblastic, leiomyoblastic, rhabdomyoblastic, or epithelial differentiation has been demonstrated.^{471,489,491,499,507,515,518} The tumor has therefore been proposed to represent a primitive mesenchymal neoplasm capable of divergent differentiation, and a close relationship to malignant fibrous histiocytoma has been suggested.^471,499

The differential diagnosis primarily centers around two other hepatic tumors characterized by spindled cells embedded in a myxoid stroma, embryonal rhabdomyosarcoma and mesenchymal hamartoma. Rhabdomyosarcoma involving the liver occurs as a polypoid tumor arising from large ducts in the hepatic hilum, rather than as a solid tumor mass within the parenchyma, and tends to affect younger patients under three years of age. Evidence of rhabdomyoblastic differentiation is a required feature and can include distinct cytoplasmic cross-striations, the arrangement of the cells into a subepithelial cambium layer, and the presence of immunoreactive desmin and muscle-specific actin. Mesenchymal hamartoma is distinguished by the lack of cytologic anaplasia and the lesser degree of cellularity. Some investigators have nonetheless regarded mesenchymal hamartoma as the benign counterpart of undifferentiated (embryonal) sarcoma, although this is disputed.⁵²⁴

Other malignant mesenchymal tumors are rarely described in the liver. These primary hepatic sarcomas should be distinguished from metastatic involvement by sarcomas of other organs; the retroperitoneum is, in particular, a primary site that is easily overlooked.⁴⁸⁵ In addition, the possibility of sarcomatoid hepatocellular carcinoma needs to be excluded by appropriate sampling and immunohistochemical studies.¹⁶⁶

Most primary hepatic sarcomas occur in adults between 40 and 60 years of age who present with signs and symptoms indicative of a hepatic mass. The overall prognosis is poor with most patients dying within a year of diagnosis; in some cases complete surgical resection has resulted in long-term survival.⁴⁸⁵

These tumors histologically resemble their more familial soft tissue counterparts (Figure 15-71). Among the types reported are fibrosarcoma, malignant fibrous histiocytoma, hemangiopericytoma, osteosarcoma, malignant schwannoma, and dedifferentiated liposarcoma.^{1,469,470,472,495,497,501,506,528,530} Leiomyosarcomas are described arising within the hepatic parenchyma, from the ligamentum teres, and from the hepatic vein, where they have been associated with the Budd-Chiari syndrome.^{473,475,484,513,527}

Kaposi's sarcoma is seen primarily in the setting of the acquired immunodeficiency syndrome (AIDS). Up to a third of patients with cutaneous disease also have hepatic involvement, but the diagnosis is seldom made before autopsy. Histologically, the tumor is characterized by multifocal nodules composed of proliferated spindle cells with slit-like spaces that contain extravasated erythrocytes (Figure 15-72). These lesions are predominantly centered on portal tracts, but they also spread into and destroy the parenchyma.^488,490,520

Hepatobiliary rhabdomyosarcoma is an rare neoplasm that usually arises from the common bile duct, although an origin from the hepatic ducts or liver has been recorded on occasion. Most patients are young children under five years of age, with exceptional cases reported in adults.^494,503,514 Progressive biliary obstruction is the chief clinical manifestation. The prognosis is generally poor, but favorable results have been obtained with combined modality therapy entailing surgical resection followed by chemotherapy and radiotherapy.³⁴¹

Histologically the tumor resembles botryoid-type embryonal rhabdomyosarcomas occurring 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 the ultrastructural finding of the characteristic myofilaments.⁴⁷⁹

Inflammatory Pseudotumor ^{534,537,538,547,550,552,559}

Inflammatory pseudotumors of the liver, as with other organs, are unusual nonneoplastic masses of mysterious etiology. They occur in both children and adults and clinically manifest with abdominal pain together with various systemic manifestations including low-grade fever, weight loss, leukocytosis, anemia, and elevated erythrocyte sedimentation rate. Although the cause is unknown, a yet unidentified infectious process is often considered to be the initiating factor.^538,547,552 Most lesions are treated with surgical resection, but some case have been noted to regress spontaneously; recurrences have not been reported.^534,537

The masses are often solitary and range between 2 cm and 25 cm in diameter. They have a variable histologic appearance consisting of proliferated fibroblasts and myofibroblasts, lymphocytes (sometimes with lymphoid follicles), plasma cells, eosinophils, and neutrophils. Fibrosis or granulation tissue-like zones can be conspicuous, particularly in the central portions of the mass. Multinucleated or foamy macrophages, phlebitis, and granulomas are sometimes noted.^537,552,559 A misdiagnosis of sarcoma is possible if close attention is not paid to the overall inflammatory context and the absence of cytologic anaplasia.⁵³⁴

Malacoplakia, a lesion broadly related to inflammatory pseudotumor, has also been reported in the liver.⁵⁵⁶

Carcinoid tumors in the liver are almost always metastatic in nature, and a primary source somewhere in the gastrointestinal tract or pancreas is usually identified. In rare cases, however, primary hepatic carcinoid tumors are described in which no extrahepatic site of involvement can be identified.^{220,531,533,551,558,566} Because of the normal presence of endocrine cells in biliary epithelium, an origin from intrahepatic bile ducts has often been suggested.

Most patients are middle-aged adults who come to medical attention because of a large hepatic mass, although on occasion the tumor has been hormonally active and produced an endocrine syndrome.⁵³¹ As with other carcinoid tumors, an indolent low-grade clinical course with prolonged survival following surgical resection is the rule.⁵³³

The histologic features are as expected; small uniform tumor cells with regular round nuclei and moderate granular cytoplasm are arranged in nests, cords, and pseudoglandular patterns (Figure 15-73). A less differentiated appearance is noted in some cases, prompting a designation of neuroendocrine carcinoma.⁵⁶⁹ Dense core neurosecretory granules are found on electron microscopic examination, and positive immunostaining for neuron specific enolase, chromogranin, and cytokeratin is regularly noted with variably positivity for serotonin, insulin, pancreatic polypeptide, and gastrin.^533,558,566

The combination of carcinoid tumor with hepatocellular carcinoma or cholangiocarcinoma has been noted in unusual cases.^532,535 In addition, evidence of neuroendocrine differentiation can be detected in some standard hepatocellular or biliary neoplasms, even in the absence of histologic features suggesting carcinoid tumor.^274,299

On rare occasions hepatic neoplasms exhibit more than one distinct type of differentiation. The best recognized example is the combined hepatocellular-cholangiocarcinoma, in which evidence of hepatocellular differentiation -- including trabecular pattern, bile production, and alpha-fetoprotein expression -- is coupled with features of biliary epithelial differentiation -- including mucin production, gland formation, and appropriate immunohistochemical markers.^541,543 Some of these cases these appear to be continuous but independent tumors, whereas others are more intimately associated, sometimes exhibiting transitions between the two types. In general the biologic behavior of these tumors parallels that of pure hepatocellular carcinoma. These combined neoplasms should not be confused with examples of hepatocellular carcinoma showing acinar or pseudoglandular growth patterns.

The combination of carcinoma, usually hepatocellular carcinoma, and a sarcomatous component is sometimes found. The malignant mesenchymal element in most of these cases consists of a poorly differentiated spindle-cell neoplasm, and the tumor represents an example of sarcomatoid hepatocellular carcinoma.^166,182 In exceptional tumors, the hepatocellular carcinoma is accompanied by a specifically differentiated sarcoma, such as osteosarcoma, chondrosarcoma, or rhabdomyosarcoma. These very rare neoplasms have been referred to as carcinosarcomas, malignant mixed tumors, or adult hepatoblastomas; although their clinicopathologic features are poorly defined, most are highly malignant and rapidly fatal.^{153,176,185,549,561}

Several examples of malignant rhabdoid tumor of the liver have been recognized. These tumors, as at other sites, are highly aggressive neoplasms with a distinctive histologic appearance: rounded cells with abundant cytoplasm, eosinophilic inclusions, vesicular nucleoli, and prominent nucleoli. Positive immunostaining for cytokeratins and vimentin is characteristically noted.^542,548,554

Rare reports describe primary hepatic germ-cell tumors of several types, including teratomas, yolk sac tumors, and choriocarcinoma. The combination of yolk sac tumor and hepatoblastoma has been described, but the distinction between teratoma and teratoid hepatoblastoma is sometimes problematic.^328,540 With the exception of mature teratomas in children, these tumors exhibit malignant behavior, although occasional long-term survival has been obtained with cancer chemotherapy.^{1,545,546,553,564,565,567}

Squamous carcinoma of the liver is uncommon, with most cases developing within simple hepatic cysts, various forms of fibropolycystic liver disease, or teratomas. Occasionally a squamous component complicates an adenocarcinoma to produce the rare mucoepidermoid or adenosquamous carcinoma of the liver.^{536,544,560,562}

Solitary necrotic nodules are subcapsular masses composed of acellular necrotic tissue enclosed by a hyalinized fibrous wall. The pathogenesis of the lesion is disputed, with divergent proposals suggesting that they represent sclerosed hemangiomas, the residua of traumatic injury, or remnants of parasitic infections. Their chief importance lies in their possible confusion with metastatic carcinoma on gross examination.^{422,459,557,563}

Primary hepatic pheochromocytoma, adrenal rest tumor, and pancreatic heterotopia have also been described.^1,539,568 A singular report describes two infants with a sinusoidal infiltrate of small neuroblastoma-like cells in the absence of other tumor.⁵⁵⁵

Primary Hepatic Lymphoma ^{572,584,588,605,609,614,616}

On occasion, the liver represents the sole or major site of involvement by malignant lymphoma. These primary hepatic lymphomas are uncommon, with fewer than 100 reported cases, but their numbers have increased with greater recognition and appreciation of the diagnosis. In addition, such tumors are acknowledged as one of the complications of the acquired immunodeficiency syndrome (AIDS).^578,612,601

The typical patient is a middle-aged man. The age range stretches from 7 to 80 years, but the bulk of the patients are between 40 and 60 years of age, and men account for about 80% of cases.^602,603 The principal manifestations include abdominal pain, hepatomegaly, or a palpable abdominal mass; fever, night sweats, and weight loss are common, but jaundice or other indicators of hepatic dysfunction are infrequently seen. Laboratory studies reveal variable and nonspecific liver function test abnormalities, including elevated serum aminotransferase and alkaline phosphatase levels.

The prognosis is similar to that of other isolated extranodal lymphomas with an overall five-year survival rate of approximately 50%. The most favorable outcome is noted in patients with disease that is amenable to surgical resection, typically followed by adjuvant chemotherapy or radiotherapy.^582,614 Some patients with nonresectable tumors nonetheless experience long-term survival with intensive multiagent cancer chemotherapy, although other suffer a rapidly progressive course with early death.^572,605

On gross examination, most cases are characterized by a single large mass or, less often, multiple discrete nodules. Rarely the liver is diffusely infiltrated without a well-defined mass lesion. The tumors are predominantly classified as non-Hodgkin's lymphomas of diffuse large cell type, with occasional examples of small non-cleaved or cleaved varieties. Most of the tumors are phenotypically of B-cell lineage, although occasional T-cell lymphomas are also described.^571,572,588 The neoplastic lymphocytes, interspersed with variable numbers of small lymphocytes and macrophages, expand the portal tracts and invade into adjacent parenchyma to form large infiltrative nodules. The lobules are otherwise little affected, although occasional cases, particularly with T-cell lymphomas, demonstrate sinusoidal infiltration.⁵⁸⁸

The histologic appearances can be difficult to interpret with liver biopsy specimens, and misdiagnoses of carcinoma or inflammatory processes have been noted in most large series.^572,584 Benign inflammatory conditions can be excluded by the malignant appearance and aggressive nature of the infiltrate, and immunohistochemical staining is invaluable in securing the correct diagnosis.⁶¹⁸

All varieties of lymphomas, leukemias, and akin hematopoietic proliferations can secondarily affect the liver, usually as a manifestation of disseminated disease and often in conjunction with splenic involvement. Hepatic involvement seldom gives rise to clinically evident liver dysfunction, although on occasion, a picture of fulminant hepatic failure is noted.^{574,580,598,621} At autopsy, hepatic involvement is noted in approximately 50% of patients with Hodgkin's or non-Hodgkin's lymphoma, but the prevalence in needle biopsy specimens is about 5% to 15%.^{573,593,595,596} Epithelioid granulomas appear as a background feature in some 10% to 20% of cases, regardless of the histologic type of the involvement.^{570,575,594,610,611}

Non-Hodgkin's lymphoma. As a general rule, the low-grade non-Hodgkin's lymphomas tend to produce multiple portal-based infiltrates, whereas the intermediate- and high-grade types give rise to large irregular tumor masses (Figure 15-74). Sinusoidal involvement is uncommon except with peripheral T-cell lymphomas, but can be conspicuous when a leukemic phase has supervened.⁵⁹³ Little or no accompanying hepatocyte injury or necrosis is noted, distinguishing this circumstance from acute hepatitis.

Histologically the cellular infiltrate corresponds to that seen in the lymph nodes. The large cell varieties can usually be recognized by their cytologic atypia and numerous mitoses, but the small cell types can be difficult to distinguish from reactive or inflammatory portal infiltrates. The dense monomorphic appearance and aggressive nature of the lymphocytic population are the main diagnostic clues (Figure 15-75). Appropriate immunophenotyping studies may be necessary in equivocal cases.⁶¹⁸ Pure canalicular cholestasis of unknown etiology can sometimes develop with non-Hodgkin's lymphomas.⁶¹⁹

Hepatic involvement is also occasionally noted with mycosis fungoides.⁶⁰⁷

Hodgkin's disease. Hepatic involvement in Hodgkin's 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 (Figure 15-76). In patients with established Hodgkin's disease, the presence of Reed-Sternberg variants is sufficient to indicate hepatic involvement, but the classic Reed-Sternberg cells are more strictly required for a de novo diagnosis.^573,593,596 Finding marked portal expansion by inflammatory infiltrates, portal edema, acute cholangitis, or a predominance of atypical lymphomas should prompt a careful search for more diagnostic features.⁵⁸⁵

A variety of nonspecific hepatic findings can also be noted in patients with Hodgkin's disease whether the liver is involved or not. These include mononuclear portal infiltrates, focal hepatocyte necrosis, lobular lymphoid aggregates, and sinusoidal dilatation in addition to epithelioid granulomas.^{573,577,599,615} Pure canalicular cholestasis is occasionally noted, and in some cases is accompanied by bile duct damage and destruction with the development of chronic cholestatic changes.^{579,591,598,600}

Leukemias. 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.⁶¹³ Attention to the cytologic appearances is the basis to confirming the diagnosis, although cytochemical and immunohistochemical stains can aid in the distinction.

Hepatic involvement is especially common and conspicuous in hairy cell leukemia.^608,620 Both portal and sinusoidal infiltration are usually present, and the presence of a string-of-beads pattern of involvement, often with angiomatoid or pseudopelioid lesions formed from clusters of leukemic cells, is a characteristic feature (Figure 15-77).⁶⁰⁴

Langerhans' cell histiocytosis (histiocytosis X). Multisystem Langerhans' cell histiocytosis involves the liver in about 40% of cases.^583,587 The most important clinical manifestations include jaundice and portal hypertension; these result in part from infiltration of large bile ducts to produce a sclerosing cholangitis-like picture.^592,597,617 The histologic features include the portal-centered infiltration of the distinctive Langerhans' cells with their large grooved nuclei and abundant cytoplasm. Their identification is aided by the ultrastructural identification of Birbeck granules or the immunohistochemical demonstration of positivity for S-100 protein or, in frozen sections, for CD 1 (OKT-6). These cells can be sparse or absent in the portal infiltrates of some cases, and a nonspecific population of lymphocytes and eosinophils is instead seen. Eventually a biliary cirrhosis can evolve, and liver transplantation might be required.^581,606

Other Hematologic Tumors. 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.^589,590 On occasional, hepatic infiltration occurs in sinus histiocytosis with massive lymphadenopathy.^576,583 In addition, a solitary plasmacytoma of the liver has also been reported.⁵⁸⁶

Malignant tumors are by far the most common form of hepatic malignancy. Accounting for over 95% of the total, they greatly outnumber primary neoplasms except in patients with cirrhosis, where the relative rates are more equal.⁶³³ In autopsy series, liver metastases are noted in about 40% of patients with malignant tumors, the sites of origin including virtually every organ in the body.^1,634 The more frequent offenders include carcinomas of the lung, pancreas, colon, and breast in adults, and neuroblastoma, Wilms' tumor, and rhabdomyosarcoma in pediatric patients.^1,633,634 Although the source of the tumor is often known when metastases are biopsied, carcinomas of the pancreas, stomach, and lung are particularly notorious for being occult primary neoplasms.

Early metastases are clinically silent, but most patients will have developed symptoms by the time the involvement is detected.⁶²³ The usual manifestations include upper abdominal pain, anorexia, and fatigue; in occasional cases jaundice develops either because of biliary obstruction or extensive parenchymal replacement. Percutaneous needle biopsy or fine-needle aspiration biopsy is diagnostic in over 80% of cases with widespread involvement, and the yield is greater when the procedure is under radiographic or laparoscopic guidance.^{626,627,630,631}

The presence of hepatic metastases generally portends a dismal prognosis, with few patients surviving more than one year. Surgical resection is indicated, however, in selected situations. With metastatic colorectal carcinoma, long-term palliation and occasional cures have been obtained with operative extirpation, especially when three or fewer metastatic foci are present. These patients experience a five-year survival rates of about 25%.^628,632 Resection of metastatic carcinoid tumors can also produce dramatic symptomatic palliation, although it rarely leads to cure. With a few exceptions, the results with most other metastatic tumors are poor.⁶²⁹

Grossly, metastatic tumors in the liver are almost always multiple, but they can appear as solitary nodules, confluent masses, or small diffusely infiltrative lesions that can mimic cirrhosis (Figure 15-78).^1,622 The size range varies considerably. Typically these tumors are gray to yellow nodules, sometimes complicated by central necrosis, umbilication, or cystic change, and they can occur anywhere within the parenchymal mass.^624,636,637 A coarsely scarred appearance reminiscent of hepar lobatum can follow treatment of metastatic breast carcinoma with chemotherapy.⁶³⁵

In general, metastatic tumors maintain the histologic features seen in their primary location. Within the liver they involve the portal tracts and their vascular structures and invade the parenchyma, leading to atrophy or destruction of the hepatic plates (Figure 15-79). A desmoplastic response is common with metastatic adenocarcinomas, especially those from the pancreas or breast, and the overall picture cannot be distinguished from cholangiocarcinoma. Many metastatic tumors tend to infiltrate the sinusoids, unlike the usual hepatocellular carcinoma. Extensive sinusoidal invasion is particularly noted with poorly differentiated carcinomas, in some cases without the formation of a large discrete mass. Other tumors such as small-cell undifferentiated carcinoma and melanoma can grow within the hepatic plates and replace the liver cells; the resulting trabecular appearance can be mistaken for hepatocellular carcinoma.

The liver adjacent to the metastatic focus often show bile ductular proliferation, portal tract edema with neutrophil infiltration, focal sinusoidal dilatation and congestion, along with various nonspecific reactive changes. The combination of portal alterations is reminiscent of biliary obstruction, and although not diagnostic, its presence in a biopsy specimen should lead to a continued search for metastases or other mass lesions.⁶²⁵