14 John M. Cullen North Carolina State University, USA This is a spontaneous nodular proliferation of hepatocytes of unknown cause. Nodular hyperplasia is a spontaneous lesion of unknown pathogenesis that occurs frequently in older dogs.1–3 Similar lesions have been reported in swine and cats, but nodular hyperplasia of hepatocytes is uncommon in domestic species other than dogs.4,5 In dogs, age is the major determinant for the occurrence of nodular hyperplasia, since there is no sex or breed predisposition. It first develops in dogs at about 6–8 years of age, and 70–100% of dogs have nodular hyperplasia by 14 years of age.1,2 The incidence in swine has been reported to be 4 per 100,000 animals, but this is probably a low estimate since the data are derived from a slaughterhouse study conducted in young pigs.4 There are no data to suggest nodular hyperplasia is a preneoplastic lesion in domestic animals or that it is associated with hepatic regeneration. Nodular hyperplasia of the liver does not produce clinical signs or adverse effects on liver function. Although the lesions are expansile and compress adjacent parenchyma, the extent of liver involvement is insufficient to be clinically relevant. Consequently, nodular hyperplasia of the liver is most often found as an incidental lesion during post‐mortem examinations or during surgery, when it is important to distinguish nodular hyperplasia from metastatic lesions. Nodular hyperplasia presents a diagnostic challenge for the ultrasonographer; it is difficult to distinguish these lesions from primary hepatic malignancies and from metastatic masses.6 The cytologic appearance of hepatocytes obtained by fine‐needle aspirates from areas of nodular hyperplasia can be virtually identical to that of normal hepatocytes.6 Hepatocytes from areas of nodular hyperplasia may contain abundant vacuoles of glycogen or lipid, but this is not distinctive, since such vacuoles can be found in normal hepatocytes. The size of the lesion can be helpful as nodules of hyperplasia are usually less than 3 cm in diameter. Larger masses are more likely to be a true neoplasm. Nodular hyperplasia of the liver appears as one or more randomly distributed masses that may be distinct or subtle.1–3 During post‐mortem examination nodular hyperplasia may be underestimated, since the areas of nodular hyperplasia that are contained within the hepatic parenchyma and have a color similar to normal liver may only be apparent when liver slices are rinsed. Nodules are usually multiple and may be too numerous to count. Often the nodules bulge from the capsular surface of the liver. The nodules on the capsular surface tend to blend smoothly with the adjacent liver tissue. Other nodules may be completely within the liver parenchyma. They are usually spherical to ovoid and well circumscribed, but without a fibrous capsule (Figure 14.1A). There is no increase in fibrosis within the nodules, and their consistency is usually softer than normal parenchyma. Hyperplastic nodules range from 2 mm to 3 cm in diameter. They may be paler than normal hepatic parenchyma, darker than normal hepatic parenchyma, or difficult to detect because of their similarity to normal parenchyma. Pale nodules, typically pale yellow to a pinkish tan, are composed of hepatocytes with an increase in cytoplasmic lipid or glycogen or a combination of both. Dark red nodules usually have an accumulation of sinusoidal blood. Nodules with several appearances may be found in a single liver. Since nodular hyperplasia is a symmetrical, expansile lesion, it cannot be distinguished from hepatocellular adenoma on the basis of gross pathological appearance alone. In most circumstances, the liver is otherwise normal, a key distinguishing feature from regenerative nodules. Figure 14.1 Non‐neoplastic hepatic nodules from dogs. (A) Natural and cut surface (inset) of a liver from a dog with two large areas of nodular hyperplasia and several smaller foci. These nodules are spherical to oval and well circumscribed, but unencapsulated. They may bulge from the natural or cut surface. The adjacent liver is usually normal. (B) A distinct border with the adjacent normal parenchyma characterizes the histologic appearance of nodular hyperplasia. A key feature is the retention of normal portal tracts within the nodule (present in this image), although they may be separated more than normal. Hepatocytes that make up the nodules may be vacuolated due to lipid or glycogen, as in this case. Note that the adjacent hepatic parenchyma is normal. (C) Regenerative nodules are prominent, raised, and spherical. They are always multiple and can range from a few millimeters in diameter to several centimeters. They are usually separated by damaged parenchyma or fibrous septa. (D) The histologic appearance of regenerative nodules differs from nodular hyperplasia as they rarely have more than one portal tract within the nodule. Adjacent hepatic parenchyma is damaged and often fibrotic. (E) Liver from a dog with hepatocutaneous syndrome. In the hepatocutaneous syndrome the liver has a characteristic confluent, multinodular appearance. Hepatocytes are typically vacuolated and often contain fat. The septa between the nodules can be formed from collapsed stroma, rather than abundant collagen. Inflammation is usually absent. There is confusion and frequent overlap in the literature regarding the accurate diagnosis of hepatic nodular hyperplasia, regenerative nodules, and hepatocellular adenomas in domestic species, particularly in dogs3 (Table 14.1). The term nodular hyperplasia should be reserved for those hepatic nodular lesions that have an increased number of cells and the hepatocytes in nodular hyperplasia are also often increased in size due to vacuolization with glycogen, lipid or both. A key feature is that these nodules retain hepatic lobular architecture (i.e., lobular structures are preserved and they are not present in the other types of nodules), although portal tracts may be more widely separated than those in normal parenchyma.1–3 Central veins may be less apparent than in normal parenchyma and sinusoids may be dilated (Figure 14.1B). The nodules are never encapsulated, although they compress adjacent hepatic parenchyma. There is never an increase in fibrous tissue within the nodule. Usually the adjacent hepatic parenchyma is normal in nodular hyperplasia and is always abnormal in regenerative nodules. Table 14.1 Identification of nodular lesions of the liver. These are generalizations that are characteristic of the lesions; exceptions are not listed Hepatocytes are arranged into plates 1–2 cells wide, although thicker plates predominate in the periportal regions of the lobules. Within the nodule, vacuolization, when present, can be diffuse or focal. Vacuolated hepatocytes contain lipid or glycogen, alone or in combination. Generally, hepatocytes in nodules of hyperplasia are enlarged because of increased cytoplasm or because of extensive vacuolization.1–3 The combination of cellular hypertrophy, vacuolization, and hyperplasia are responsible for the mass effect. Nuclei have a normal appearance, but they and their nucleoli are occasionally enlarged. There is an increase in binucleated hepatocytes.2 Mitotic figures are uncommon, but are more frequent in nodules than in normal liver. Extramedullary hematopoiesis may be present and hepatic stellate cells may be more prominent than in the adjacent parenchyma.2 The hepatic parenchyma immediately adjacent to the nodule may be atrophic due to compression. This lesion is spontaneous; it is not stimulated by a need for regeneration. A variant of nodular hyperplasia has been termed the micronodule because the nodules are smaller than a lobule and are not visible to the unaided eye.2 Micronodules, like nodular hyperplasia, expand and compress adjacent parenchyma and are composed of thickened plates of hepatocytes. An association with congestive heart failure has been noted in a large proportion of these cases. Therefore, micronodules may be generated in response to the atrophy or loss of centrilobular hepatocytes that can occur in right‐sided heart failure and could, therefore, also be considered a type of nodular regeneration. Another type of nodular but non‐neoplastic hepatic lesion results from hyperplasia of hepatocytes in damaged, usually fibrotic, livers. The gross appearance of the liver and the numerous nodules is so characteristic that they are easily distinguished from nodular hyperplasia and hepatocellular adenomas. Regenerative nodules arise from compensatory proliferation of viable hepatocytes in response to the destruction of hepatic parenchyma, most often following chronic hepatic injury as a component of cirrhosis (end‐stage liver)3 (Figure 14.1C). Often the original insult is unknown, but the response of some dogs to anticonvulsant drugs such as phenobarbital or phenytoin serves as an example.7–10 They are most common in dogs, but develop in other species on occasion. Regenerative nodules in dogs are unlikely to be related to nodular hyperplasia since regenerative nodules are not related to age and they arise from the proliferation of hepatocytes in response to hepatocyte injury and loss. They are distinguished from nodular hyperplasia by the moderate to marked lesions in the adjacent liver and the greater number of nodules. Also, there is usually only a single portal tract within each regenerative nodule, no matter how large it is. Because the lobular architecture is lost, there are no central veins, but only individual veins and bile ducts within the nodule (Figure 14.1D). Additionally, extramedullary hematopoiesis is not a feature of regenerative nodules. Regenerative nodules can be difficult to distinguish from hepatocellular adenomas on the basis of histology alone because both lesions lack normal lobular architecture. This is particularly problematic in needle biopsies when only the nodule has been sampled, although there are a few distinguishing features. Regenerative nodules are composed of hepatic plates that are no more than two cells thick, and adenomas may have thicker hepatic plates. Hepatocellular adenomas tend to form solitary lesions and usually do not arise in a background of hepatic injury and fibrosis so clinical data, particularly ultrasound evaluation or laparoscopy, can aid in the final diagnosis. A distinctive form of nodular regeneration occurs in dogs with hepatocutaneous syndrome (superficial necrolytic dermatitis) (Figure 14.1E). Affected livers in this syndrome have confluent nodules and the nodules are likely formed in an attempt at regeneration. However, the nodules in hepatocutaneous syndrome may have moderate to prominent glycogen and lipid vacuolization of hepatocytes that is more pronounced than that typically seen in nodular hyperplasia. Another difference between hepatocutaneous syndrome and typical nodular regeneration is found in the inter‐nodular septa. The septa are formed primarily by parenchymal collapse, with condensation of reticulin fibers and ductular proliferation, and only limited inflammation and new collagen synthesis. The presence of the typical skin lesion, a triad of basal cell hyperplasia, hydropic degeneration of the stratum spinosum keratinocytes, and parakeratosis with crust formation, is the definitive feature that identifies hepatocutaneous syndrome.11,12 Plasma amino acid levels are also low in this disorder. The cause of nodular hyperplasia is unknown. Idiopathic, age‐related hyperplasia is not limited to hepatocytes; it occurs in other glandular epithelial cells such as those in the prostate, exocrine pancreas, and adrenal cortex. This type of hyperplasia has been speculatively attributed to a local dysregulation of growth factors. Hepatic nodular hyperplasia in dogs does not appear to be a preneoplastic lesion as it is not induced by treatment with experimental carcinogens.1,13,14 This is a benign tumor of hepatocytes. Hepatocellular adenomas occur in dogs,15,16 cattle,17,18 sheep,17,19 cats,20,21 and pigs.22,23 In many of these reports, the diagnostic criteria that distinguish hepatocellular adenomas from nodular hyperplasia and hepatocellular carcinoma had not been well characterized and therefore the real prevalence of these lesions is difficult to extract from the literature. Most likely, hepatic adenomas have been grossly underdiagnosed given the lack of clear morphologic criteria for this diagnosis. Clearer criteria have been proposed for adenomas, carcinomas and non‐neoplastic nodules and these guidelines are followed in this chapter and in Table 14.1.3 Based on several older tumor surveys in dogs, the species that has been studied most extensively, benign hepatocellular neoplasms appear to occur less frequently, or are diagnosed less often, than their malignant counterpart.15,24,25 In one study in which hepatocellular adenomas were distinguished from carcinomas, hepatocellular carcinomas were more common (1%) than adenomas (0.4%).15 However, there were no hepatocellular adenomas reported in other surveys of canine hepatic neoplasms, suggesting diagnostic criteria used at the time were not similar to those used currently.24–26 Most hepatocellular adenomas are reported in older dogs. Due to their infrequent recognition and the lack of clear diagnostic criteria, there is insufficient data to determine incidence or if there are sex or breed predispositions. However, surveys of food animals conducted in slaughterhouses reported hepatocellular adenomas in young pigs and sheep.17 There are no recognized clinical signs or characteristic abnormalities in clinical pathology assessments associated with hepatocellular adenomas. Typically they occur as individual lesions or occasionally a second lesion is coexistent. Compression of adjacent structures could conceivably disrupt blood or bile flow through the affected region of the liver, but there are no reports of hepatic injury associated with hepatocellular adenomas. Given the significant functional reserve of the liver, hepatocellular adenomas would be unlikely to alter hepatic function. Hepatocellular adenomas are most frequently detected as incidental lesions at autopsy or are detected in live animals by ultrasound or other imaging examinations. Hepatocellular adenomas are most often solitary, but they can be multiple. They range from 2 to 12 cm in diameter and are usually roughly spherical masses due to their uniform expanding growth pattern. Typically, they are well demarcated due to compression of adjacent parenchyma (Figure 14.2A). Hepatocellular adenomas may bulge from the capsular surface or only be evident on the cut surface of the liver or they can be pedunculated. They are not fully encapsulated and their color varies from yellowish‐brown to the dark mahogany red of normal liver parenchyma. Lipid or glycogen accumulation imparts the lighter color to the paler lesions, which often have a soft and friable consistency compared to normal liver. Hepatocellular adenomas are never firmer than normal liver since they do not contain increased fibrous tissue. Usually, they have a uniform color and consistency on the cut surface, but may contain minor evidence of hemorrhage or necrosis. They are indistinguishable from nodular hyperplasia on gross examination, except when particularly large. Figure 14.2 Hepatocellular adenoma, dog. (A) Hepatocellular adenomas are typically discrete solitary masses ranging from 2 to 12 cm in diameter. They compress, but do not invade adjacent parenchyma. (B) Histologically, hepatocellular adenomas cause circumferential compression of adjacent liver tissue, can be partially encapsulated, as in this example, lack normal hepatic lobular architecture. Usually, only a single portal tract is present. Isolated bile ducts or vessels can be found. Hepatocellular trabeculae can be thicker than in normal parenchyma, but are typically uniform. Hepatocellular adenomas usually have a circular outline and are well demarcated from adjacent parenchyma by a circumferential zone of compression but they are not encapsulated (Figure 14.2B).3 A consistent feature of adenomas is a loss of normal lobular architecture within the tumor. Typically no more than one portal triad can be found and there are no evident central veins, although individual veins, arteries, and bile ducts may be found randomly through the mass. Any additional portal tracts probably result from entrapment of normal hepatic parenchyma in the mass of proliferating hepatocytes. Hepatocellular adenomas are composed of hepatocytes that form uniform trabeculae, 2–3 cells thick, but they are usually thinner and more uniform than the significantly thicker and more variable trabeculae of hepatocellular carcinomas. Sinusoids may be focally dilated and form prominent cystic spaces filled with blood or serum.3 The orientation of trabeculae is often distinctly different from the normal lobular orientation as the hepatic plates in hepatocellular adenomas tend to be arranged in a radial orientation that intersects the normal hepatic plates at right angles, accentuating the margins of the adenoma. Although there may be an accumulation of connective tissue (the reticulin fibers) at the interface of the adenoma and the normal liver, fibrosis and encapsulation are not a features of hepatocellular adenomas. At the margin of the adenoma, surrounding normal hepatocytes are typically compressed and atrophic, leading to disruption the normal hepatic lobular architecture. The atrophic hepatocytes may contain cytoplasmic lipid vacuoles or glycogen as well as an increase in lipofuscin. Typically, neither lipofuscin nor hemosiderin is found in the neoplastic hepatocytes but they may contain lipid or glycogen or a combination of the two. The cytological characteristics of hepatocytes from hepatocellular adenomas are similar to those of normal hepatocytes, but there are subtle differences. Hepatocytes from hepatocellular adenomas may have mild anisocytosis, basophilia of the cytoplasm, increased glycogen or lipid, hyperchromatic nuclei, anisokaryosis, and slightly more prominent nucleoli than normal hepatocytes.3 However, these changes are less prominent in adenomas than in carcinomas. Usually, all the cells in a particular adenoma have a similar appearance, but hepatocytes from other adenomas within the same liver may differ in their characteristics. Mitotic figures are absent or rare. All hepatocytes will stain immunohistochemically with HepPar‐1, an antibody that stains intermediate filaments in normal hepatocytes as well. Table 14.1 provides criteria to distinguish nodular hyperplasia, regenerative nodules, hepatocellular adenoma, and hepatocellular carcinoma. Many cases will follow these guidelines but there will always be problematic cases, especially in biopsy material with limited tissue. The most important differential diagnosis for hepatocellular adenoma is hepatocellular carcinoma and the most reliable criteria to distinguish these two tumors is evidence of invasion and metastasis. Hepatocellular adenomas may be partially encapsulated, have a symmetrical, well‐delineated, and expansile pattern of growth that distinguishes them from the invasive growth of hepatocellular carcinomas that may extend into adjacent parenchyma or vasculature.3 In biopsies it may be difficult to fully evaluate the presence of invasion, particularly if the interface of normal parenchyma and the neoplasm is not included in the sampled tissue. The hepatocytes that form hepatocellular adenomas are always well differentiated and readily recognized as hepatocytes. The architecture of the hepatic adenomas consist of plates or trabeculae that are usually no more than three cells in thickness and which form relatively uniform arrays, rather than the irregular and variable trabeculae that characterize carcinomas. Hemorrhage and necrosis are uncommon in adenomas and are a more typical finding in hepatocellular carcinomas. Hepatocellular adenomas can be difficult to distinguish from nodular hyperplasia of the liver by gross inspection. However, hepatocellular adenomas are usually individual, while nodular hyperplasia occurs more often as multiple lesions (Table 14.1). Larger nodules are more likely to be adenomas; certainly masses greater than 6 cm in diameter are not nodules of hyperplasia. Lobular architecture is the best single criterion to distinguish these lesions, particularly when both adenomas and nodular hyperplasia are present. When portal tracts are present throughout the lesion (although they may be separated to a greater degree than in the normal parenchyma) and hepatic plates retain normal arrangement, nodular hyperplasia is the appropriate diagnosis. Hepatocellular adenomas have an abnormal lobular architecture and a single portal tract at most. The presence of extensive hepatic damage and associated fibrosis in the adjacent liver and the absence of normal portal tracts support the diagnosis of nodular regeneration. These criteria can pose a particular diagnostic dilemma when evaluating needle biopsies in particular, since lobular architecture and the degree of fibrosis cannot be thoroughly evaluated. Correlating clinical data from imaging studies that detail how many nodules are present, size of nodules, and health of adjacent parenchyma can be helpful in these circumstances. Hepatocellular adenomas are benign tumors that grow by symmetrical expansion and never metastasize. They typically have a spherical shape, compress adjacent parenchyma uniformly but are not invasive. Size alone does not distinguish adenomas from carcinomas. Adenomas may have a pedunculated structure in some cases, which would be rare for a hepatocellular carcinoma. There is no known etiology for clinically relevant hepatocellular adenomas of domestic animals, although it is possible that chemical carcinogens may have a role in the development of these lesions. In experimental settings involving rodents, dogs, and swine, the liver is a frequent target of numerous artificial as well as naturally occurring chemical carcinogens that produce hepatocellular neoplasia.13,14,23,27–29 Several naturally occurring carcinogens, most notably aflatoxins and nitrosamines, produce hepatocellular carcinomas in experimental rodents and, as these substances can be food contaminants for large and small animals, any of these may contribute to hepatocellular neoplasia in a variety of domestic animals; however, few carcinogenicity studies have been carried out in domestic animals. Hepatocellular carcinoma occurs in all veterinary species, including cats,21,30,31 dogs,15,24,25,32 cattle,17,18,33,34 sheep,19,22 pigs,22,35 potbellied pigs,36 and horses.37–39 The historical failure to distinguish benign from malignant hepatocellular neoplasms in many reports creates a significant challenge in estimating tumor incidence. Surveys from abattoirs, which evaluate younger animals primarily in the United Kingdom, indicate that hepatocellular and biliary neoplasms are 4 times more common in cattle than sheep and nearly 18 times more common in cattle than pigs.22 These authors also reported that hepatic and biliary neoplasms account for 10% of all neoplasms in cattle, 31% in sheep, and 4% in pigs. In potbellied pigs that are kept as pets and live considerably longer than commercial pigs, the incidence of hepatocellular carcinoma can be quite high, with 29% of autopsied potbellied pigs reported to have hepatocellular carcinoma.40 The dog may have a higher incidence of hepatocellular carcinomas than most other species, based on several studies, but such reports may simply reflect a disproportionate interest in neoplasms of dogs.41 The incidence of hepatocellular carcinoma in dogs has been reported to be less than 0.5% of all autopsies15,32 and less than 1% of all neoplasms.24 In most surveys, hepatocellular carcinomas were more common than cholangiocellular tumors in dogs, ranging from approximately 35 to 60% of all primary hepatic tumors,15,25 but there are contradictory studies.24,42 Hepatocellular carcinomas are less common than cholangiocarcinomas in cats, ranging from 10 to 22% of primary liver tumors,20,21,30 although one study disputes these observations.43 Hepatocellular carcinomas in cattle are reported more often than cholangiocarcinomas in most studies,18,22,33,44 but not all.17 Hepatocellular tumors were found to be more frequent than biliary neoplasms in sheep17,19,22,44 and in the potbellied pig.36,40 Clearly, up to date surveys using contemporary diagnostic criteria are needed to establish the incidence of hepatocellular carcinomas in dogs and other species. In dogs the earliest onset of hepatocellular carcinoma occurs at 4–5 years of age, with the mean age approximately 10 years.15,25 There is no clear evidence of a gender‐related incidence25,45 and no breed predisposition has been identified.24–26,32,45 In one study in dogs, hepatocellular carcinoma was more frequent in males than in females, but not in another.32,45 In cats, the earliest age of onset was 2 years (ranging from 2 to 20 years of age) and the median age at diagnosis was 12 years.20 No breed‐associated risk for hepatocellular carcinoma has been identified in cats. The data on the age distribution of large animals with hepatocellular carcinoma is difficult to interpret with confidence. In older surveys, sheep less than 1 year of age17,19,22 and pigs less than 6 months old were reported to have hepatocellular carcinomas.17,22 These reports should be interpreted with caution as there have not been any more recent surveys to confirm this. Hepatocellular carcinoma in cattle was also reported at an early age in older studies, but this was not confirmed by more recent studies in which adult animals were primarily affected, although one animal in a group of 66 cattle with a primary hepatic tumor was a calf.18 In potbellied pigs the incidence of hepatocellular carcinomas increases with age.36,40 In dogs and cats, the clinical signs associated with hepatocellular carcinoma are nonspecific. They include anorexia, vomiting, ascites, lethargy, and weakness.15,25,32,46,47 Other less common signs include jaundice, diarrhea, and weight loss. During the physical examination of cats and dogs, hepatomegaly causing abdominal enlargement and a palpable mass in the cranial abdomen is often evident.15,47,48 There are no patterns of clinical chemistry abnormalities that suggest hepatocellular neoplasia over other diseases of the liver. Dogs with hepatocellular carcinoma frequently have mild increases in serum activities of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, and gamma glutamyltransferase.25,32,46,48,49 Increased levels of fasting bile acids alone or in combination with increased levels of serum alkaline phosphatase have been shown to be indicative of hepatic neoplasia, but did not distinguish primary neoplasia from metastatic disease or other hepatobiliary disease.49,50 Less often, other markers of hepatic damage such as serum lactate dehydrogenase and bilirubin may be increased. Since all of these laboratory test results may be altered in a variety of hepatic diseases, they cannot separate hepatocellular carcinoma from other primary hepatic or metastatic neoplasms in the liver. Slightly over half of the dogs with hepatocellular carcinoma have nonspecific hematological abnormalities such as leukocytosis and anemia.32 Hypoglycemia, reported in dogs and a horse, is an uncommon paraneoplastic effect of hepatocellular carcinoma.32,39,46,51–53 Affected animals may have seizures, presumably due to hypoglycemia or possibly hepatoencephalopathy, since hepatic metastases to the brain are not reported. The mechanism by which hepatocellular carcinomas affect this change in blood glucose levels has not been confirmed. Hypoglycemia is attributed to the release of an insulin‐like substance or, less likely, excessive glucose consumption by the neoplasm.52,53 A similar pathogenesis explains hypoglycemia in patients with plasma cell tumors and smooth muscle tumors. An uncommon paraneoplastic effect of hepatocellular carcinoma in cats can lead to alopecia.54 Serum alpha‐fetoprotein has been used as a marker for hepatocellular carcinoma in cattle, horses, and dogs but it is not specific.34,55–58 Immunohistochemical staining for alpha‐fetoprotein is frequently positive in canine hepatocellular carcinomas as well, but hepatocytes in end‐stage livers may also be positive 59 as can hepatoblasts in equine hepatoblastomas.37,60 Radiographic or imaging signs of hepatocellular carcinoma are also nonspecific. They include displacement of the stomach to the right ventral aspect of the abdomen and hyperechoic masses. Although ultrasound examination of the liver can readily detect masses within the liver, the technique cannot identify specific tumor types or separate hyperplastic lesions from neoplastic lesions.6,61,62 Ultrasound‐guided fine‐needle aspiration and/or biopsy is a necessary combination to establish correct diagnoses. Computed tomography scanning may be more useful as a means to identify hepatic masses and provide more detail to distinguish benign from malignant hepatocellular lesions, but debate continues in the field of radiology in this regard.63 Hepatocellular carcinomas have a range of appearances including massive, nodular, or diffuse forms.18,32 Of these, massive is the most common, at least in dogs and cattle, and the diffuse pattern is rare. 15,18 Massive hepatocellular carcinomas are usually a single neoplasm that involves one or contiguous liver lobes (Figure 14.3A). Cut surfaces often reveal multiple smaller nodules within the larger mass that have slightly different appearances. Figure 14.3 (A) This feline hepatocellular carcinoma is massive, nearly replacing the entire left lateral lobe. (B) The cut surface, as in this canine hepatocellular carcinoma, often reveals multiple smaller nodules within the larger mass that have different appearances and often will have areas of necrosis. Hepatocellular carcinoma can be found in all lobes of the liver, but the left lateral lobe is affected most often in dogs.32 Why one lobe of the liver would be affected more often than the others is not clear. Given the fact that the left lobe is one‐third to one‐half of the total mass of the liver in the dog, its greater volume compared to other liver lobes may account for the increased frequency of involvement if tumor development is a random event.64 Nodular hepatocellular carcinoma forms scattered nodules, often within multiple liver lobes. They vary from small, round, discrete lesions a few centimeters in diameter to large, diffuse masses that may be greater than 10 cm in diameter.22,32,42,47 These nodules resemble benign hepatocellular neoplasms by gross inspection and imaging studies. It is not clear if multifocal hepatocellular carcinomas arise from multicentric origin or if they arise from intrahepatic spread of a single malignancy. Without molecular analysis of specific mutations for each mass this issue will remain a topic of speculation. Diffuse hepatocellular carcinomas are characterized by minute indistinct masses spread throughout the liver parenchyma, affecting multiple lobes. Multiple hepatocellular carcinomas within the liver may arise from intrahepatic metastasis or multiple individual points of origin, but, as mentioned previously, it is not currently possible to distinguish between these possibilities. Larger masses usually have an uneven to multinodular surface and an irregular shape. Umbilication is not a typical feature of hepatocellular carcinomas but can occur. Carcinomas often protrude from the liver capsule and distort the profile of the liver. Hepatocellular carcinomas can have a discrete border, and can usually be distinguished from the adjacent normal liver parenchyma even in multinodular masses. Evidence of invasion into adjacent parenchyma is strong support for malignancy. Intravascular invasion is seen rarely macroscopically but, if present is an excellent indication of malignancy. Adhesions between the neoplasm and adjacent structures such as the diaphragm or body wall may be found, but are not common.15 The color and consistency of hepatocellular carcinomas vary considerably from one neoplasm to another but generally they are the color of normal liver and are soft to friable. However, regions within a single mass may have different characteristics due to necrosis or different patterns of vacuolization. The smaller neoplasms are more likely to be uniform and to resemble normal liver. Larger neoplasms frequently have a mottled appearance, with some areas resembling normal liver, while other sites are light gray to tan on the natural and the cut surface (Figure 14.3B). In some instances, lipidosis of the neoplastic lesion imparts a light tan to yellow appearance to the entire tumor. Focal, usually central, areas of dark red discoloration caused by hemorrhage and necrosis are common in larger tumors. Light gray to white areas, usually found within the central regions of the neoplasm, are caused by necrosis without associated hemorrhage. Hemorrhage and necrosis are uncommon in other liver nodules of hepatocellular origin. The friable and soft consistency of hepatocellular carcinoma is a useful diagnostic feature that distinguishes this neoplasm from the firm consistency of cholangiocarcinomas, which also are usually gray‐white or yellow‐brown. Since hepatocellular carcinomas are friable, rupture of the tumor with resultant hemoperitoneum or blood clots on the capsule is fairly common. However, hemoperitoneum is more common with hemangiosarcoma of the liver or spleen. The histological appearance of hepatocellular carcinomas varies considerably, depending on the degree of differentiation of the individual hepatocytes and the histological arrangement of the cells.15,32,42 This wide spectrum of histological appearance has led to different classification systems.32,65 The term hepatoma should be avoided as it is confusing. Although hepatoma has been used for many years and is still in use in human hepatic malignancies, the suffix “‐oma” suggests a benign neoplasm. Hepatoma should not be used to name a hepatic adenoma. Some nomenclature systems are complex, while others have fewer categories and a recent consortium has proposed using a simplified category as there is no known biologic significance to the different histologic appearances and hepatocellular carcinomas often contain more than one histologic pattern.3 Nevertheless, four major histologic patterns can be recognized: trabecular, pseudoglandular, solid, and an uncommon pattern termed scirrhous. In trabecular hepatocellular carcinomas, the trabecular histological arrangement bears some resemblance to normal liver. The neoplastic cells form trabeculae that vary considerable in width; in some sites they are thin, but they are markedly thickened in other sites (Figure 14.4A). It is characteristic to find trabeculae of neoplastic hepatocytes that are 5–10 cells thick and occasionally as many as 20 cells thick. Variability in hepatocellular trabeculae thickness is one of the criteria used to differentiate a well‐differentiated trabecular hepatocellular carcinoma from a hepatocellular adenoma. Adenomas have essentially uniformly thick trabeculae. Figure 14.4 Histologic patterns of hepatocellular carcinoma. (A) Trabecular pattern: This is composed of variably thick trabeculae formed by neoplastic hepatocytes separated by vascular channels of various widths. Some trabeculae in this case are two cells thick and in other regions the hepatocytes pile together to form variably thick trabeculae. Anisokaryosis and binucleation are present. (B) Solid pattern: Neoplastic hepatocytes form solid masses devoid of trabeculae or gland‐like structures. This example is characterized by prominent pleomorphism and occasionally multinucleate giant cell formation, typical of anaplastic hepatocellular carcinomas. (C) Clear cell pattern: This variant of the solid pattern consists of neoplastic cells with prominent vacuolization that may form trabecular or solid patterns. (D) Scirrhous pattern: This is rare and is characterized by multiple foci of ductular formation and an associated extracellular matrix. (E) IHC stain for cytokeratin 7 in a scirrhous hepatocellular carcinoma. The ductular epithelium, unlike the surrounding neoplastic hepatocytes or connective tissue, contains cytokeratin 7. (F) Histology of a pulmonary metastasis from a canine hepatocellular carcinoma is characterized by modest pleomorphism of neoplastic hepatocytes. It can be challenging to assess the potential for metastasis from the phenotype of the primary hepatocellular carcinoma. Little or no connective tissue stroma occurs, but necrosis may be found in the center of the wide trabeculae. In other cases, the neoplasm has widely dilated sinusoids, occasionally forming blood‐filled or serum‐filled cavernous spaces that separate trabeculae. Although the trabecular pattern is the most common histological form of the tumor in domestic animals, other patterns can occur.32,42 The pseudoglandular hepatocellular carcinoma is characterized by crude acini formed by neoplastic hepatocytes. The lumens may vary in size, and some may contain proteinaceous material, but never mucus. Solid sheets of neoplastic hepatocytes with no apparent pattern characterize the solid hepatocellular carcinoma (Figure 14.4B). Solid hepatocellular carcinomas are composed of neoplastic hepatocytes that lack obvious sinusoids and have a solid appearance. Often hepatocytes are pleomorphic. Individual masses frequently contain different histological patterns within different areas. This may be due to the proliferative advantages of subpopulations of neoplastic hepatocytes within the mass that expand over time. In some variants all neoplastic hepatocytes are prominently vacuolated and these are termed clear cell hepatocellular carcinomas (Figure 14.4C). An uncommon form of hepatocellular carcinoma, termed a scirrhous hepatocellular carcinoma, is characterized by dense connective tissue, within which there are multiple foci of ductular formations embedded within a larger mass of neoplastic hepatocytes66 (Figure 14.4D). The ductular structures stain immunohistochemically for cytokeratin 7 and 19, distinguishing them from adjacent neoplastic hepatocytes (Figure 14.4E). The cellular features of hepatocytes in hepatocellular carcinomas can be varied.3,32,37,42,65 Hepatocytes in well‐differentiated carcinomas closely resemble normal hepatocytes, with central, round nuclei and usually abundant and moderately eosinophilic cytoplasm. The cytoplasm, however, may be pale staining or even vacuolated if filled with glycogen or lipid. Some hepatocellular carcinomas may be entirely composed of vacuolated cells due to either glycogen or lipid. These are identified as a clear cell variant (Figure 14.4C). At the other end of the spectrum, poorly differentiated hepatocellular carcinomas have very pleomorphic hepatocytes (Figure 14.4B). The nuclei in these pleomorphic cells are variable in both size and shape; the nuclei or the cytoplasmic surface area of different cells may vary in diameter by threefold, and tumor giant cells can be found. However, in other regions the cytoplasm of the cells may be eosinophilic to light basophilic and greatly reduced in volume, resulting in an obviously increased nuclear‐to‐cytoplasmic ratio. This variability in cell and nuclear features is a useful criterion to distinguish carcinomas and adenomas. The neoplastic cell often lacks the square to polygonal shape of the sectioned normal hepatocyte. The cells may assume a round or, rarely, spindle shape. Nucleoli tend to be enlarged, irrespective of the general state of differentiation and can be multiple and be of different sizes. Individual hepatocyte giant cells with enlarged or multilobulated nuclei or multinucleated giant cells are sometimes found in the poorly differentiated neoplasms. Mitotic figures are common in poorly differentiated carcinomas and relatively uncommon in well‐differentiated carcinomas. Vascular invasion is not common but when present, clearly identifies the malignant varieties. Presumably, the majority of hepatocytes in most hepatocellular carcinomas will stain immunohistochemically with an antibody to HepPar‐1 that stains certain cytokeratins in normal and neoplastic hepatocytes, but this stain was not used in any of the historical evaluations of hepatocellular carcinomas in small or large animal species. Consequently, this is only an assumption. In some forms of poorly differentiated hepatocellular carcinomas aggregates of cells or the entire tumor may no longer stain with HepPar‐1.66 Consequently, these tumors should be stained for cytokeratin 19, as both canine and human hepatocellular carcinomas can express this phenotype as an indication of their progenitor cell origin and likely aggressive behavior.45 These latter variants with more than 5% of hepatocytes expressing cytokeratin 19 are more likely to metastasize than other types of hepatocellular carcinomas in dogs. Foci of extramedullary hematopoiesis are common, and iron‐containing Kupffer cells and macrophages may be present. Cytoplasmic pigments, such as lipofuscin, however do not occur. Ultrastructural study suggests that the sinusoidal lining cells in hepatocellular carcinomas of dogs differ from those found in normal liver. The typical fenestration of the normal sinusoidal endothelial cells is lost. Also, unlike the normal pattern for sinusoidal endothelial cells, there is deposition of basement membrane material beneath the endothelial cells in hepatocellular carcinomas.67 Another change in the vessels in hepatocellular carcinomas that is consistent with their conversion from sinusoids to a capillary‐like structure is the appearance of factor VIII–related antigen in the endothelial cytoplasm. This protein is usually expressed in the endothelial cells of most vessels, but not in normal hepatic sinusoids. Other changes in the sinusoids of hepatocellular carcinomas include increased alpha‐smooth muscle actin staining and/or a decrease in desmin staining of hepatic stellate cells (Ito cells). The non‐neoplastic liver parenchyma is usually histologically normal in small animals, horses, and ruminants with hepatocellular carcinoma.15,17,32 This is in contrast to the situation in humans, in which cirrhosis is a frequent prelude to hepatocellular carcinoma.68 Chemically induced liver cancer in pigs has been associated with hepatic fibrosis.23,29 Touch imprints and aspirates have limited utility in the diagnosis of well‐differentiated hepatocellular carcinoma. Hepatocytes from well‐differentiated hepatocellular carcinomas may resemble normal hepatocytes or hepatocytes from hepatocellular adenomas and nodular hyperplasia.69 Cells with a recognizable hepatocytic origin and with marked atypia, such as altered nuclear‐to‐cytoplasmic ratios, staining alterations, increased basophilia, and variation in the size of cells and nuclei, support a diagnosis of hepatocellular carcinoma. The possibility of metastatic epithelial neoplasms must always be considered when poorly differentiated cells are encountered in aspirates or imprints. Distinguishing well‐differentiated hepatocellular carcinomas from hepatocellular adenomas is the principal diagnostic challenge faced by the pathologist. Historically, it is likely too many adenomas were diagnosed as well‐differentiated hepatocellular carcinomas. Evidence of extrahepatic metastasis or tumor cell invasion into adjacent parenchyma or vasculature are the key easiest criteria for a diagnosis of malignancy, but they are often not present.3 If these features are not apparent the most useful features for a diagnosis of malignancy include a substantial degree of diffuse or regional pleomorphism of the hepatocytes, the presence of atypical or multinucleate hepatocytes, mitotic figures, multiple nucleoli, and prominent variation in the thickness and organization of the trabeculae (in trabecular carcinomas). Difficulty may arise in distinguishing a hepatocellular carcinoma with a pseudoglandular pattern from cholangiocarcinoma. In this case, a distinction can be made by examining the cytological characteristics as well as the general histological pattern. The neoplastic acini of pseudoglandular hepatocellular carcinomas may contain proteinaceous material, while cholangiocarcinomas are more likely to have PAS‐positive mucin within neoplastic acini.32,70 In addition, the cholangiocarcinomas usually have an extensive collagenous stroma compared to the modest or absent stromal elements in pseudoglandular hepatocellular carcinomas. At the ultrastructural level, biliary epithelial cells can be recognized by the presence of a basement membrane, a feature that is absent in hepatocytes. Special techniques have been used to characterize hepatocellular carcinomas and distinguish them from other neoplasms in animals. Immunohistochemistry may be useful to distinguish pseudoglandular hepatocellular carcinomas from biliary malignancies. Normal and neoplastic biliary epithelial cells can be distinguished from hepatocytes because they contain a distinct population of cytokeratins, including cytokeratin 7 and 19, and epithelial membrane antigen/mucus‐1. Normal and most neoplastic hepatocytes do not express these markers.16,30 Normal and neoplastic hepatocytes from cats can be stained with the monoclonal antibody HepPar‐1. In dogs, the situation is less clear as some hepatocellular carcinomas express HepPar‐1, but some poorly differentiated hepatocellular carcinomas with metastatic potential will no longer stain with this marker, but may stain with cytokeratin 19 in more than 5% of cells.45 Hepatocellular carcinomas in dogs have also been separated from cholangiocarcinomas on the basis of their immunohistochemical (IHC) staining patterns for oncofetal antigens.71 Within the set of cases examined, only the hepatocellular carcinomas could be stained for alpha‐fetoprotein, and only the cholangiocarcinomas contained carcinoembryonic antigen. However the application of this observation may require clarification and caution in dogs. Some canine hepatocytes in regenerative nodules stain for alpha‐fetoprotein59 and other studies indicate increases in serum alpha‐fetoprotein for both hepatocellular carcinoma and cholangiocarcinoma in dogs.55 Immunostaining of equine hepatoblastomas is also positive for alpha‐fetoprotein.37 Staining results of IHC should be interpreted with some caution and used as a component of the process of establishing a diagnosis, rather than a definitive feature. Hepatocellular carcinoma should also be distinguished from primary hepatic carcinoid on the basis of histological appearance and the use of silver impregnation stains that demonstrate secretory granules in carcinoid cells.72 IHC detection of various neurosecretory products, such as neuron‐specific enolase, S‐100, and chromogranin A in the cytoplasm of carcinoids is also a useful technique for identification of these tumors. Carcinoids do not react with HepPar‐1. The diagnosis of hepatocellular carcinoma has relied on a combination of gross size, infiltration and microscopic features. If metastasis was a required criterion there would be very few confirmed hepatocellular carcinomas. Hepatocellular carcinomas infiltrate the adjacent parenchyma and certainly can appear aggressive on histological examination. Pathologists, clinicians, and owners should realize that a diagnosis of hepatocellular carcinoma does not necessarily portend metastases and/or incipient euthanasia. It is more likely that hepatocellular carcinoma‐related morbidity results from expansive growth leading to local compression or necrosis and hemorrhage of the mass rather than tumor spread. Hepatocellular tumors that invade the adjacent hepatic tissue should be designated carcinoma. Invasion tends to occur by clusters of neoplastic cells and, rarely, as individual neoplastic cells; it does not occur uniformly around the periphery of the neoplasm and may occur only in a few areas. This feature necessitates examining multiple sections of questionably malignant tumors. Invasion of blood vessels and lymphatics occurs, but is rarely obvious within a single section; thus, vascular invasion should not be considered a necessary requirement for diagnosis of malignancy. Multiple tumor masses within the same or different lobes may be indicative of intrahepatic metastasis. However, it is difficult to ascertain with certainty if these arise from metastasis or are multiple sites of tumor origination. The published rates of metastasis for each species may be unreliable, as metastasis usually occurs late in the development of hepatocellular carcinomas and many large animal surveys are done in younger animals presented to abattoirs. Diagnosis of metastasis also depends on the effort expended to search for evidence of metastasis and abattoir studies are not as thorough as those conducted by diagnostic pathologists. The metastatic rate for hepatocellular carcinomas in dogs was reported to be less than 25% in one study, involving the lung, hepatic lymph nodes, and the peritoneum15 and 61% in another, involving local lymph nodes, lung, and peritoneum most often.32 In a collective survey of 54 hepatocellular carcinomas diagnosed using contemporary diagnostic standards3 from two university veterinary hospitals, only four cases with metastasis outside the liver were identified, representing less than 8% of the dogs with hepatocellular carcinoma. Two of these metastasized to the lung and the others were found in local lymph nodes or as omental implants. From this data it is apparent that extrahepatic metastasis is uncommon and this is similar to anecdotal reports from other veterinary pathologists. A small subset of canine hepatocellular carcinomas with hepatic progenitor cell characteristics do have an aggressive growth pattern and they may be identified by IHC staining that demonstrates cytokeratin 19 and glypican‐3 within the hepatocytes, and negative staining for HepPar‐1.66 The IHC features of these canine hepatocellular carcinomas resemble the staining pattern in similarly aggressive human hepatocellular carcinomas.45 All 17 of these canine tumors spread within the liver (N = 3) or produced extrahepatic metastases in local lymph nodes (N = 10), mesentery (N = 4), lung (N = 3), spleen (N = 3), and peritoneum, pancreas, or kidney (N = 1 each). This pattern of behavior is similar to that seen in humans with hepatocellular carcinoma, where the most frequent sites of metastasis involve the local lymph nodes and hematogenous spread is less common, but can involve the lung and a variety of other sites.73 It should be noted that some canine hepatocellular carcinomas that retain HepPar‐1 staining can also metastasize outside the liver. 74 It can be difficult to predict which canine hepatocellular carcinomas will metastasize as some tumors with only modest pleomorphism can metastasize (Figure 14.4F). Overall, the large majority of canine hepatocellular carcinomas are unlikely to develop clinically significant metastasis. Those that remain HepPar‐1 positive have a particularly low potential for metastasis. Those variants that are pleomorphic, with increased mitotic activity and have significant (>5%) cytokeratin 19 staining and are HepPar‐1 negative should be considered to have a higher risk of metastasis. In cats, metastasis of hepatocellular carcinoma seems to be more common than in dogs (Figure 14.5A,B). Metastasis is reported to occur at a rate of 28% (5/18) for cats with spread to the local lymph nodes most common (4), and the lung (1) and spleen (1) also involved.47 Figure 14.5 Pulmonary metastasis of hepatocellular carcinoma, cat. (A) Numerous light tan to pink metastatic nodules are evident in the lung. (Image courtesy of Stephanie Montgomery.) (B) IHC staining with hepatocyte‐specific antibody (HepPar‐1) confirms metastatic hepatocellular carcinoma in the lungs of the cat shown in (A). In cattle, a recent study indicated that 10% of 40 hepatocellular carcinomas metastasized, involving the local lymph nodes, lungs, and kidneys.18 Metastasis is reported with hepatocellular carcinoma in several other large animal species; however, most of these reports are older studies and whether tumors other than hepatocellular carcinoma were included is difficult to discern. Metastasis generally occurs late in the course of neoplastic development for all species. The primary neoplasm is large, while the metastases are small. Therefore, the resulting devitalization of the affected animal is usually due to the primary neoplasm and not to the metastasis. Hence, the prognosis is considered favorable for dogs with hepatocellular carcinoma that involves only one or two lobes and the tumor can be removed. Previous studies have indicated that surgical resection of affected lobes can prolong life by 1–3 years in dogs, and recurrence of the neoplasm is uncommon.48,75 However, given the age of these studies it is not clear if the tumors would all be considered malignant by contemporary diagnostic criteria. When present, metastatic sites in the lung are usually numerous and relatively small. The earliest metastatic foci are located in the capillaries of the alveolar wall, indicating a hematogenous spread. Hepatocellular carcinoma is also known to occasionally metastasize to a variety of other organs.17,32,45 The neoplasm also spreads by direct extension to the omentum and peritoneum. This occurs when neoplastic cells from a friable neoplasm are dispersed within the peritoneal cavity after rupture of the primary tumor. Poorly differentiated and pleomorphic neoplasms tend to metastasize more often than the more differentiated neoplasms.32,45 An extensive study that uses contemporary accepted histologic features combined with ancillary results of IHC is needed to clarify the incidence of hepatocellular carcinoma in animals and to characterize the biologic behaviors. At least for dogs and cats treatment regimens and prognosis will depend on accurate histologic diagnoses and correlation of these with clinical outcomes. For example, one of the earlier studies reports metastases in 16 of 18 dogs with either anaplastic or pleomorphic hepatocellular carcinoma.32 However, the image reported for pleomorphic hepatocellular carcinoma could represent a histiocytic lineage. IHC and additional techniques to confirm cell or tissue of origin are needed for poorly differentiated neoplasms. From the literature and my experience it seems reasonable to expect very few metastases at the time of initial diagnosis. Any metastases that eventually develop are unlikely to contribute to patient morbidity or mortality. Future studies need to employ the newer standards to classify tumors via H&E, with a standard battery of IHC and search thoroughly for metastases during the follow‐up periods studied. The etiology of the spontaneously occurring hepatocellular carcinoma in domestic animals is unknown, but chronic infections or chemical ingestion may play a role in tumor development. Some clues to the cause of liver cancer in domestic species may be provided by studies in humans and laboratory animals. Chronic viral infections of the liver caused by hepatitis B virus and hepatitis C virus are clearly associated with an increased risk of liver cancer in humans.76 More compelling evidence of the carcinogenicity of members of the hepatitis B virus family, Hepadnaviridae, is provided by studies in woodchucks.77 Woodchucks chronically infected with woodchuck hepatitis virus have a 100% risk of developing hepatocellular carcinoma. Metastases are reported in a minority of these animals allowed to live after initial diagnosis. The recent discovery of a hepatitis C‐like virus in dogs raises the possibility of a viral etiology of canine hepatocellular carcinoma. Viral growth in the liver appears to be limited and an association with the presence of the virus and hepatic disease has not been demonstrated.78 Solid evidence of chronic hepatic infections with viruses equivalent to those that cause hepatocellular carcinoma in humans is not evident in domestic animals as of yet.79 The role of chronic infections with bacteria, such as the Helicobacter spp. that have been shown to cause liver cancer in some strains of mice, has not been evaluated in domestic animals. A histologic difference between dogs with hepatocellular carcinoma and humans is the adjacent liver, which is relatively normal in dogs, in contrast to the cirrhotic changes and/or inflammatory and chronic lesions commonly seen in humans.
Tumors of the Liver and Gallbladder
EPITHELIAL NEOPLASMS OF THE LIVER
Nodular hyperplasia
Incidence
Clinical characteristics
Gross morphology
Histological features
Lesion
Clinical and gross features
Histologic features
Nodular hyperplasia
Common in older dogs, less common in cats. Asymptomatic. Single or multiple, usually only a few. Color can be similar to liver, darker or lighter. Adjacent hepatic parenchyma is normal
Non‐encapsulated
Lobular architecture retained
Uniform 2‐cell hepatic plates
Mild compression at margins of nodule
Hepatocytes in the nodule may be diffusely vacuolated (lipid or glycogen); adjacent parenchyma usually normal
Regenerative nodule
Common in dogs with chronic liver injury. Multiple to numerous; adjacent hepatic parenchyma is abnormal; often fibrotic. Clinical signs often present due to chronic liver injury
Non‐encapsulated, but surrounded by collapsed stroma and markedly injured liver
Loss of lobular architecture in nodule
Isolated vessels rather than portal tracts within parenchyma
Background of liver injury and repair
Hepatocellular adenoma
Seen in all species. Usually single or occasionally multiple. Color may be similar to normal liver, lighter or darker. Adjacent parenchyma usually normal. Well demarcated
Well‐demarcated, mostly non‐encapsulated
Loss of lobular architecture (portal tracts and bile ducts usually absent)
Hepatic plates or uniform trabeculae of well‐differentiated hepatocytes
Mitoses absent or rare
Cystic sinusoids possible
HepPar1 positive
Extensive vacuolization of neoplastic hepatocytes possible
Hepatocellular carcinoma
Seen in all species. Metastasis infrequent. Spread within the liver and to regional lymph nodes more frequent than spread to distant sites. Necrosis and hemorrhage can occur
Well‐demarcated with areas of invasion, and spread to lymphatic and distant intrahepatic sites
Well‐differentiated to markedly pleomorphic nuclei and hepatocytes (regional or diffuse distribution)
Loss of lobular architecture
Irregular thickness of trabeculae >4–5 hepatocytes thick
Hepatocytes are often small
Multinucleate cells
Mitotic figures can be abundant
Extramedullary hematopoietic foci are common
Regenerative nodules
Etiology
Hepatocellular adenoma
Incidence
Clinical characteristics
Gross morphology
Histological features
Differential diagnosis
Growth and metastasis
Etiology
Hepatocellular carcinoma
Incidence
Clinical characteristics
Gross morphology
Histological features
Differential diagnosis
Growth and metastasis
Etiology
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