NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Baba AI, Câtoi C. Comparative Oncology. Bucharest: The Publishing House of the Romanian Academy; 2007.

Cover of Comparative Oncology

Comparative Oncology.

Show details



Liver carcinogenesis can offer the possibility to study the pathological phenomenon of malignant transformation of cells. Hepatocyte changes, that precede malignant transformation, have suggested the gradual development of changes up to a physiological point of adaptation, changes that can finally be precursors of malignant transformation. Liver carcinogenesis has offered the possibility to explain the appearance and development of neoplasms by chronic evolutions and transformations of cells, confirming the multifactorial concept.

Liver carcinogenesis is a multistage process, and the similarity of precancerous and preneoplastic lesions even in the case of extremely different agents in terms of origin and mode of action should be remarked. In addition to this, the hepatic cell has limited possibilities of response. The hypotheses regarding the pathogenesis of liver carcinoma, which represents an attractive subject due to the almost ideal experimental possibilities, have concerned many laboratories and researchers. Thus, FARBER (1986) has defined some general principles regarding the pathogenesis of liver carcinoma.

The liver has a great capacity to adjust and adapt to the almost permanent strain to which it is submitted. Some of these responses can be involved in the phases of the carcinogenic process. It seems that the liver, through its possibilities of adaptive response, through its plasticity, allows for the understanding of the initiation and development of the neoplastic process. The cited author suggests the perception of the malignant process rather as a model of predictable physiological response than as an abnormality. The acceptance of this point of view leads to the conclusion that disease is the result of continuous successive adaptations that, at a certain point, determine disadaptations. The author experimentally proves, by chemical and/or food carcinogens, that the development of a liver neoplasm occurs in two main sequences:

  • - proliferation of benign foci based on “spontaneous” growths, without malignant evolution;
  • - extremely slow evolution of these proliferations, with gradual evolution towards hepatocellular cancer [18].

At first, persistent benign proliferations occur under the form of foci, clonal nodules. The evolution of these nodules may follow different routes: some nodules remain as benign formations, others regress, and liver cells have all the characteristics of adult cells.

Under circumstances that perpetuate hepatocyte changes, hepatocyte carcinoma develops from the nodules. Studies have demonstrated that neoplastic type cell proliferations can take place inside benign nodules, i.e. the formation of nodules within nodules [19].

Benign proliferation in foci or persistent hepatocyte nodules represents the first autonomous proliferation. This aspect can be considered the first step in the formation of true cancer, which may be regarded as an introductory stimulating process. It should be mentioned that in preneoplastic proliferation, nodules are derived from a single cell, clonal nodules.

Liver nodules formed by hepatocytes that are biochemically and biologically changed possess a totally distinct phenotype. These changed hepatocytes have a constitutive resistance to the cytotoxic effects of xenobiotic agents; cells are able to survive to toxic doses of environmental agents, even to CCl4, which are lethal for control animals [20]. At the same time, these hepatocytes are capable of responding to carcinogenic agents, by the rapid generation of hepatocyte nodules. The existence of a cellular type that manifests spontaneous or autonomous proliferation is not yet known. The only mechanism known so far, in the liver, uses the resistance phenotype, which is induced in the initial phase by numerous different carcinogens, for selection by differential inhibition. This principle of differential resistance has been suggested as a possible mechanism in the selective growth of changed, supposedly initiated hepatocytes, in the development of liver cancer in humans.

The formation of persistent benign proliferations in foci, the key of lesions from which hepatic cancer develops, is the product of the classic concept of carcinogenesis in two stages: initiation and promotion.

The initiation of cancer development, i.e. the induction of resistance in some hepatocytes, is a two-stage process.

In a first stage, potentially irreversible cellular changes occur, probably in the DNA. In the liver, as well as in other organs or tissues, initiation only takes place if there is a cell proliferation right after the chemical or biochemical change. Thus, the biochemical lesion will be repaired and no initiation will occur. It is possible that the hepatic cell lesion may be essential for cancer development with any agent, including viruses. In the case of carcinogenic chemical agents, the initiated hepatocytes are or include an unusual common cell, which has subsequently obtained the resistance phenotype. In initiated hepatocytes, a gene or a group of genes appear, which are closed or open in order to generate a new biochemical model in the cell.

Promotion is a process by which a tissue or organ with initiated cells develops proliferations in foci (nodules, papillomas, polyps, etc.), of which some or more act as precursors for the following stages in the carcinogenic process. In the liver, hepatocyte groups appear, which may develop, forming preneoplastic nodules, although only some of them evolve into cancer. There are attempts to catalogue biochemical, molecular, genetic, immunological or biophysical changes induced by a certain agent, in the hope of clarifying the mechanism of promotion. Cells seem to require a certain number of cell divisions, before a new model of genetic expression manifests. This model could be characteristic of the cancer process, where similar cells generate new proliferations in foci, with a different biological behavior [17].

The stage of progression is little understood, both from the point of view of the mechanism and the phenomenon. The progression stage would be the process in which one or more proliferations in foci (papillomas, polyps and nodules) undergo a slow cellular evolution towards a malignant neoplasm [37].

The majority of hepatocyte nodules appearing during promotion and selection evolve, and part of them show spontaneous cell proliferations. The rate of spontaneous cell proliferation increases, after a postinitiation phase reaching 4, then 8%, while hepatocytes around these nodules have a growth rate of approximately 0.4%. Concomitantly, hepatocyte death occurs, in a proportion of approximately 3%. This phenomenon is present in the nodule-to-cancer sequence, as well as in cancer proper. Another property of persistent nodules is the generation of nodules and the transplantation of hepatocytes in the spleen. These hepatocytes slowly grow in the spleen, without producing cancer.

Precancer nodules maintain a balance between cell destruction and cell growth. There is a homeostatic mechanism that acts in the liver in order to keep the number of cells constant. This homeostatic balance is lost with the appearance of malignization. The key factor in the precancer-cancer sequence may be the deregulation between cell death and cell proliferation, rather than cell proliferation.

The possible mechanisms of progression in cancer are, on the one hand, cell death as a triggering or as a consequence of cell proliferation, and, on the other hand, the production of factors of growth and stimulation of oncogenic expression. The general major mechanisms towards an increasingly malignant behavior could be the continuous proliferation of the small hepatocyte population in persistent nodules, without being accompanied by a loss of new generations, which leads to cellular evolution by mutation and selection or by clonal evolution.

Liver carcinogenesis can be explained by the adaptive hypothesis. Thus, initiated hepatocytes develop forming foci/nodules in an inhibitory or toxic environment. It has been found that following the action of toxic substances, hepatocytes resistant to these substances occur, and, moreover, cells with cross, simultaneous resistance to several toxic agents can appear. This determines the analogy with the resistance of cancer cells to multiple anticancer drug preparations. It is suggested that hepatocytes from nodules represent a new stage of differentiation adapted to hostile conditions. So, many of the early events in carcinogenesis are genetically programmed and are part of a normal physiological model of adaptation to some xenobiotic agents [16].

FARBER (1986) proposes the following possible scheme, in the action of two suspect factors in the development of liver cancer in man:

Image ch9fu1

The cited author emphasizes the need for a gradual analysis of the carcinogenic process, which would offer new study possibilities and open the way for the understanding of the modalities and mechanisms of cancer development.

Liver and biliary tumors are relatively frequent in animals, being especially found in dogs, cats, cattle and sheep. The literature reports a higher incidence of primary tumors compared to secondary ones. The structure of hepatobiliary tumors, in animals, is similar to that in humans, so that the same classifications should be used.

The classification proposed by PONOMARKOV and MACKEY (1976), slightly changed by KELLY (1993), is to a large extent accepted by the literature. The cited authors suggest the following classification:

  1. epithelial liver tumors: hepatocellular adenoma, intrahepatic duct adenoma; hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma;
  2. non-epithelial tumors: hemangioma; hemangiosarcoma; fibrosarcoma;
  3. mixed tumors;
  4. hematopoietic and lymphoid neoplasms;
  5. unclassified tumors;
  6. secondary tumors;
  7. tumor-like lesions.
  1. epithelial gallbladder tumors: papillary adenoma, papillary carcinoma.
  2. tumor-like lesions: cystic hyperplasia.

Histological Classification Of Tumors of the Liver and Gallbladder (Head et al. 2003)

Tumors of the Liver

  1. Epithelial Tumors
    • 1.1 Benign
      • 1.1.1 Hepatocellular adenoma
      • 1.1.2 Biliary adenoma (cholangioma, cholangiocellular adenoma)
        • Biliary cystadenoma
    • 1.2. Malignant
      • 1.2.1 Hepatocellular carcinoma
      • 1.2.2 Bile duct carcinoma (cholangiocarcinoma, biliary carcinoma, cholangiocellular carcinoma)
        • Biliary cystadenocarcinoma
      • 1.2.3 Hepatocholangiocarcinoma
      • 1.2.4 Hepatoblastoma
  2. Neuroendocrine Tumors
    • 2.1 Carcinoid (neuroendocrine carcinoma)
  3. Mesenchymal Tumors
    • 3.1 Benign
      • 3.1.1 Myelolipoma
      • 3.1.2 Hemangioma
    • 3.2 Malignant
      • 3.2.1 Hemangiosarcoma
      • 3.2.2 Others
  4. Tumors of Hematopoietic and Related Tissues
    • 4.1 Lymphoma (lymphosarcoma, malignant lymphoma)
    • 4.2 Myeloid neoplasms
      • 4.2.1 Histiocytic sarcoma/malignant histiocytosis
    • 4.3 Mast cell tumor
  5. Unclassified Tumors
  6. Secondary Tumors
  7. Tumorlike Tumors
    • 7.1 Nodular hepatocellular hyperplasia
    • 7.2 Regenerative hepatocellular hyperplasia
    • 7.3 Vascular hamartoma
    • 7.4 Telangiectasis (pelosis hepatis)
    • 7.5 Biliary hamartoma

Tumors of the Gallbladder

  1. Epithelial Tumors
    • 1.1 Benign
      • 1.1.1 Gallbladder adenoma
      • 1.1.2 Leiomyoma
    • 1.2 Malignant
      • 1.2.1 Gallbladder carcinoma
  2. 2. Tumorlike Lesions
    • 2.1 Cystic hyperplasia of the gallbladder (adenomatosis, adenomatous polyposis)

The liver tumors found with a higher incidence in animals are hepatocellular adenomas, hepatocellular carcinomas and cholangiocarcinomas. Biliary adenomas are infrequent, and gallbladder tumors are exceptional, in domestic animals. The rarity of liver neoplasms in horses can be underscored; there is no sex or breed predisposition; it seems that the incidence of liver neoplasms increases with age.

A number of toxic oncogenic factors are incriminated in the etiology of liver cancer, viroses, mycotoxins, substances used in agriculture, toxic agents from plants and other factors with slow, chronic action and/or combinations of these risk factors. If liver cirrhosis as well as viral hepatitis are associated in man with liver neoplasms, these factors are less involved in animals.

It is difficult to establish a direct connection between a certain pathogenic action and the appearance of liver cancer. However, there is undeniable evidence supporting the relation between the appearance of a certain cancer type and the action of the same carcinogenic agent.

Aflatoxins are unanimously recognized as hepatic carcinogenic factors [13]. The first report dates from 1959, by ADAMEŞTEANU, JITUC and COTIGA, the authors demonstrating the appearance and development of biliary adenomas in ducklings fed on food that contained aflatoxins. In 1972, ADAMEŞTEANU et al. showed that in cattle, aflatoxin passes through the placental filter, and newborn calves present adenomatous bile duct proliferations and centrilobular fibrosis. In swine, hepatocellular carcinomas were successfully induced by the administration of aflatoxins in very small amounts, which metastasized in the lymph nodes and abdominal organs [27].

Experiments in rats receiving food supplemented with 50 mg/kg aflatoxins have determined the development of hepatocellular carcinomas in a period of 19 months, with a higher incidence in males [12].

The action of aflatoxins, especially aflatoxin B1, in the liver is expressed by a high nucleic acid production; aflatoxins react non-specifically with hepatic macromolecules. This could be explained by the capacity of aflatoxin B1 to induce multiple lesions in liver cells [27].

Hepatic parasites with a higher incidence in some animal species, such as Fasciola hepatica and Dicrocelium lanceolatum in ruminants, Eimeria cuniculi in the bile ducts of young rabbits or other parasites with erratic location in the liver, have not been proved to be liver neoplasm initiators. In dogs and cats, liver infestation with Clonorchis simensis or Opistorchis felineus has been shown to be related to the appearance of liver neoplasms [36]. The first report of the connection between a parasite and the appearance of liver neoplasms dates from 1906 and belongs to BORREL, who remarks the presence of liver sarcomas in rats parasitized with Cysticercus fasciolaris. DUNNING and CURTIS (1946) demonstrate the formation of peritoneal sarcomas in 90% of rats intraperitoneally injected with a saline suspension of cysticercus triturate. In fact, this parasite has also been detected in the liver of humans that consume raw or less boiled fish. Researches have proved the presence of biliary adenomas in over 76% of people infected with this parasite. In humans, these hepatic adenomas can change into cholangiocarcinomas. The mode of action of the Clonorchis simensis parasite on the structures of bile ducts and the pathogenesis of cholangiocellular carcinoma are not clarified. The purely irritating action of the parasite on the biliary epithelium cannot be exclusively supported because, as it has been mentioned, there are other hepatobiliary parasites that do not induce cancer (Fig. 9.16).

Fig. 9.16. Reactive bile duct hyperplasia.

Fig. 9.16

Reactive bile duct hyperplasia.

Chemical substances such as benzene derivatives, as well as environmental pollutants, have been experimentally shown to be potentially carcinogenic. Some chemical products, used as insecticides or antiparasitic agents have proved to have oncogenic properties, being in particular hepatocarcinogenic [4, 5, 37].

The incidence of various neoplasm types varies depending on species, less on breed, but advanced age is a risk factor. In cattle, neoplasms have the following incidence, in decreasing order: hepatocellular carcinomas; adenomas; cholangiocarcinomas; biliary adenomas, followed by vascular and other tumors [9]. In cats, at over 10 years of age, biliary adenomas have the highest incidence, followed by biliary adenocarcinomas [33, 35], with the mention that incidence is higher in females than in males [6, 38].


9.2.1. Hepatocellular adenoma

Hepatocellular adenoma or hepatoma frequently occurs as a single nodular, sometimes pedunculated formation of large sizes, reaching over 15 cm in diameter. Color is lighter than that of the rest of the parenchyma, it can be light brown or yellowish, frequently icteric. Hepatoma is well delimited from the normal parenchyma, sometimes by a connective capsule.

Microscopically, cells are not significantly differentiated from the normal aspect, being arranged in short cords, irregular tubes or pseudoacini, containing small fat drops, which causes hepatocytes to be enlarged and rounded. The nuclei of these cells are large, vesicular, and the fine chromatin is disseminated uniformly, with obvious nucleoli. Mitoses are absent, but 2–3 nucleoli frequently appear. Kupffer cells are large, sometimes mobilized and loaded with hemosiderin (Fig. 9.1 and 9.2.).

Fig. 9.1. Hepatocellular adenoma, trabecular type.

Fig. 9.1

Hepatocellular adenoma, trabecular type.

Fig. 9.2. Hepatocellular adenoma, acinar type.

Fig. 9.2

Hepatocellular adenoma, acinar type.

Hepatocellular adenomas seem to be correlated with the development of hepatocellular carcinomas [15, 37]. The structure characteristic of the liver lobe is absent, and the portobiliary space, bile ducts and centrilobular venules are not detected. Due to this changed structure, the bile cannot be eliminated, accumulating intra- and extracellularly. Hematopoietic foci may be noted in cattle and sheep hepatomas. The lesion can be found in dogs and cats, farm animals that are affected at a younger age, as well as in experimental animals, spontaneous or induced [18, 24].

9.2.2. Biliary adenoma (cholangioma, cholangiocellular adenoma)

Benign duct bile tumors, cholangiocellular adenomas or cystadenomas, appear as usually multiple, well circumscribed nodular formations, with a cavernous aspect and little bile. Some formations appear as compact nodules. Cholangiocellular adenoma is found in old dogs and in cats.

Histologically, cystadenomas are formed by bile ducts with anarchic arrangement, prismatic or atrophied epithelium due to the mucoid bile content. The connective stroma is generally fine, possibly with fibrosis images. Compact adenomas have a predominantly epithelial structure, and cystic adenomas present microcysts full of seromucous and/or bile fluid. Some congenital formations are supposed to have a bile content, and mucosal formations could be of tumoral nature (Fig. 9.3.).

Fig. 9.3. Cholangiocellular adenoma.

Fig. 9.3

Cholangiocellular adenoma.

Bile duct adenoma has not been proved to be a precursor of cholangiocellular carcinoma, without this possibility being completely excluded.

9.2.3. Hepatocellular carcinoma

Hepatocellular carcinomas have been reported in dogs and cats, in cattle and sheep, exceptionally in other animals. The incidence of hepatocarcinoma in animals is close to that in humans, and in dogs it seems to be even higher [29].

In USA, hepatocellular carcinoma is estimated at 0.8% of all tumors diagnosed in cattle and up to 11 % in sheep [28]. Higher percentages are mentioned in Great Britain, hepatocellular carcinoma being estimated at 20% of all killed sheep, 4% in cattle, and 3% in swine.

In dogs, PATNAIK et al. (1980) mention that of 12245 necropsies, different types of primary liver neoplasms were diagnosed in 100 subjects. The authors mention the presence of 55 hepatocellular carcinomas, 24 cholangiocellular carcinomas and 2 cases of mixed neoplasms, hepatocellular carcinoma and cholangiocarcinoma. The subjects with liver neoplasms were aged over 10 years. Hepatocellular carcinomas, as well as primary liver sarcomas, were more frequent in males, while cholangiocarcinoma had a higher incidence in females. There are also observations remarking the absence of a correlation with animal sex and breed.

In goats, hepatocellular carcinomas associated with pheochromocytoma and leiomyoma are reported [25]. Hepatocellular carcinomas have been diagnosed in race horses, with the development of metastases by venous and lymphatic route, in the liver, kidney and skeletal musculature [22].

Macroscopically, the neoplasm appears as a single or multiple nodular formation; sometimes, around a large tumor that can exceed 25 cm in diameter, other smaller tumors appear, disseminated throughout the whole hepatic parenchyma. Hepatocellular carcinoma has distinct margins, it is more or less circumscribed, in section its surface is red-cherry, yellow-greenish, with necrotic or necrotic hemorrhagic foci. Sometimes, the neoplasm is encapsulated, and the connective tissue penetrates the tumor mass under the form of septa. The neoplasm may be accompanied by liver cirrhosis, without a causal relation between the two pathological processes. Macroscopy detects the invasion of portal vessels in the large veins and the vena cava, which can reach the spleen and the stomach. Metastases are frequent in the lung.

Microscopy differentiates trabecular hepatocellular carcinomas and clear cell hepatocellular carcinomas, with variable arrangements.

Trabecular hepatocellular carcinoma is characterized by the arrangement of hepatocytes in parallel cords forming irregular thickened trabeculae that are 5 to 10 cell thick and occasionally as much as 20 cell thick [42], the groups of cords being delimited by a fine connective stroma. Hepatocytes are large, with slightly rounded shapes, the cytoplasm is fine granular, poorly acidophilic, with 1–2 large vesicular nuclei and obvious nucleoli. Mitotic forms are rare; in contrast, neoplastic cells can be frequently detected in the vein lumen (Fig. 9.5).

Fig. 9.5. Hepatocellular carcinoma, trabecular type.

Fig. 9.5

Hepatocellular carcinoma, trabecular type.

In some old dogs with hepatocellular carcinomas, we found rectangular crystalloid intranuclear inclusions that distorted the nucleus, displacing the nucleolus towards the nuclear membrane. The association of these crystalloid inclusions with hepatocellular neoplasms could suggest the evolution of hepatic viruses, possibly involved at a certain point in the appearance and/or evolution of carcinoma.

Trabecular hepatocellular carcinoma can present an acinar arrangement (Fig. 9.4), in which case cystic formations may arise.

Fig. 9.4. Hepatocellular carcinoma, acinar type.

Fig. 9.4

Hepatocellular carcinoma, acinar type.

Clear cell hepatocellular carcinoma is more frequent in dogs, but it has also been reported in cows and buffalo cows. Microscopically, the focus is delimited by the aspect and shape of neoplastic cells and the compression exerted by the tumor on the adjacent parenchyma. Neoplastic cells are large, round, oval or with variable shapes. The cytoplasm is clear or fine granular, and nuclei are non-uniform, from round, oval to multilobated, with monstrous aspect, sometimes 2–3 in a cell. Nucleoli are obvious, intensely acidophilic, there can be 1–2 or even more nucleoli in a nucleus. Cells are grouped in irregular formations, mimicking acinar structures or short cords. Sinusoid capillaries are compressed by large neoplastic cells that in their majority have no lumen, and bile ducts are rare and disseminated non-uniformly in the tumor mass. The connective component of hepatocellular carcinomas in the neoplastic mass is poorly represented (Fig. 9.79.9).

Fig. 9.7. Hepatocellular carcinoma, clear cells type.

Fig. 9.7

Hepatocellular carcinoma, clear cells type.

Fig. 9.8. Hepatocellular carcinoma, scirhous type.

Fig. 9.8

Hepatocellular carcinoma, scirhous type.

Fig. 9.9. Hepatocellular carcinoma, vascular invasion.

Fig. 9.9

Hepatocellular carcinoma, vascular invasion.

Poorly differentiated hepatocellular carcinoma or solid hepatocellular carcinoma, characterized by marked cell pleomorphism, has been mentioned in cows [34]; we found it in a 7-year-old sheep. Macroscopically, the liver was 4–5-fold larger than normal and slightly umbilicated, white-gray nodules with rosette-shaped margins appeared on the surface, as well as in section. Portal lymph nodes were enlarged and with a greasy aspect in section.

Microscopically, the neoplasm was formed by small, hyperchromatic, highly polymorphic cells, along with large polyhedral cells and vesicular nuclei. Cells had an anarchic arrangement, without being grouped in cords or acini, and the connective component was poorly represented (Fig. 9.6). Tumor giant cells may occur in poorly differentiated hepatocellular carcinoma.

Fig. 9.6. Hepatocellular carcinoma, poorly differentiated.

Fig. 9.6

Hepatocellular carcinoma, poorly differentiated.

9.2.4. Bile duct carcinoma (cholangiocarcinoma, biliary carcinoma, cholangiocellular carcinoma)

Cholangiocarcinoma has an incidence differentiated by species, the neoplasm being found in decreasing order in: dogs, cats, sheep, cattle and horses [23, 24, 28].

Macroscopically, cholangiocellular carcinoma appears as a multiple tumor, with no predilection for a certain lobe. The tumor appears as umbilicated nodules of high consistency, making the liver surface irregular. Tumors are not delimited by a fibrous capsule, margins are poorly delimited, with a rosette-like appearance, having a round or oval shape. In the multinodular form, tumors ranging from 0.5 to 4 cm in diameter are scattered throughout all the liver lobes. The cut surface of the tumors varies from white to gray-white to yellow-brown. Areas of necrosis, characterized by softening of the tissue and reddish discoloration can be found in the central regions of nodular tumors as well as in focal areas of large single neoplasms [42].

Histologically, the neoplasm is formed by cuboid or columnar epithelial bile duct cells, with fine granular cytoplasm and large, globular, vesicular nuclei. Cells are arranged in acini or under the form of more or less obvious, regular, canaliculi. An abundance of mitotic figures is a distinctive feature of bile duct carcinoma. Sometimes, neoplastic cells form extensive cell bands, with anarchic arrangement. PAS-positive mucous secretion and, rarely, bile content may be identified in acinar or tubular structures. In the case of the tubular arrangement of prismatic cells, papilliferous proliferations may be noted, formed by large prismatic cells. The connective stroma is well represented, infiltrating the tumor mass, delimiting and grouping neoplastic cells; sometimes the tumor has a scirrhous aspect. Cholangiosarcomas are difficult, sometimes impossible, to differentiate from secondary tumors of pancreatic origin. The presence of mucus secretion and the intrasinusoidal penetration of neoplastic cells is a characteristic of the biliary origin [24] (Fig. 9.109.12.). Typically, tumor cells invade the surrounding hepatic parenchyma at multiple sites. Foci of hepatic necrosis are also common in the adjacent parenchyma, but there is no evidence of cirrhosis in most cases [42].

Fig. 9.10. Bile duct adenocarcinoma - well differentiated.

Fig. 9.10

Bile duct adenocarcinoma - well differentiated.

Fig. 9.11. Cholangiocelluar carcinoma, moderately differentiated.

Fig. 9.11

Cholangiocelluar carcinoma, moderately differentiated.

Fig. 9.12. Cholangiocellular carcinoma.

Fig. 9.12

Cholangiocellular carcinoma.

Biliary cystadenocarcinoma, a malignant biliary epithelial neoplasm characterized by multiple cystic spaces of variable size. The histological characteristics of this variant include the formation of cysts of variable volume lined with single to multiple layers of neoplastic biliary epithelium. Cysts frequently contain abundant mucinous secretion. Papillary projections extend into the lumen of the cysts [42].

Hepatocholangiocarcinoma, a malignant tumor with the histological and cytological characteristics of both hepatocellular and bile duct carcinoma; these are rare tumors [42].

Cholangiocarcinomas metastasize more frequently in the spleen, kidneys, lymph nodes, sometimes in the thyroid, adrenal glands, bone marrow, intestinal wall, etc. Metastasis routes are transperitoneal, lymphatic and hematogenous.

9.2.5. Hepatoblastoma

Hepatoblastoma is more rarely found in domestic animals, being only reported in sheep, with a different structure from that in humans. The neoplasm is formed by fetal type hepatocytes, small eosinophilic cells, with granular or vacuolated cytoplasm, arranged in cords or acini. Extramedullary hematopoietic foci are frequently observed [34]. Equine hepatoblastomas occur more often in young animals and have a more invasive growth pattern and evidence of metastasis. Embryonal cells have very small amounts of basophilic cytoplasm and uniformly sized hyperchromatic nuclei. They typically form acini, tubules, and rosettes [42].

9.2.6. Hemangioma

Hemangioma is a benign tumor of vascular origin, having variable sizes that can reach several centimeters in diameter. In most cases, nodules are multiple, more rarely solitary. Nodules can be prominent on the liver surface or they are found in the depth of the parenchyma, having a cherry color, with abundant blood flow in the section.

Histologically, hemangiomas are composed of capillaries lined by endothelium and separated by a fine connective stroma [28, 40].

In our personal cases, hemangioma is found in old dogs and cats. Differential diagnosis is required with macular telangiectasia, in cattle.

9.2.7. Hemangiosarcoma

Hemangiosarcoma is a malignant tumor, being known as angiosarcoma or hemangioendothelioma. The neoplasm is poorly delimited, has an infiltrative growth, and in section there is little connective stroma, which makes it particularly fragile. It has been reported in the liver of dogs and cats.

Histologically, endothelial proliferations with large fusiform or rounded cells, with numerous mitoses and pleomorphism appear. The microscopic aspect establishes positive diagnosis [11, 24].

Myelolipoma, a benign neoplasm composed of myeloid tissue and mature adipose tissue; there is usually more myeloid tissue than adipose tissue in the growth. Variable mature and immature cells of the granulocytic, erythrocytic, and megakaryocytic series compose the myeloid component. The lesion has been reported in domestic cats and captive wild Felidae as an incidental finding [42].

9.2.8. Sarcoma

Sarcoma, as a primary liver tumor, appears sporadically, but is not particularly uncommon. The tumor is large, solitary, arising in the interstitial connective tissue of the liver. Macroscopically, the neoplasm has all the known characteristics of sarcoma, and the following histological types are differentiated: round cell, fusocellular and mixed sarcoma, more rarely with myxomatous character, with chondroid or bone metaplasias [28].

Other forms of neoplasms have been identified in the liver, hematopoietic, lymphoid tumors, unclassified tumors and tumors metastasized from other organs.

Lymphoma (lymphosarcoma, malignant lymphoma), solitary primary lymphoma in the liver has rarely been reported in animals. Metastatic lymphoma is the most common secondary neoplasm found in the liver. Neoplastic lymphocytes initially accumulate within the portal tracts or within the connective tissue surrounding the central vein [42].

Diagnosis. In addition to classical investigations (clinical, radiological examination), the clinical diagnosis of liver neoplasms could be completed by the measurement of serum alpha-fetoprotein concentrations. Serum alpha-fetoprotein concentrations are significantly higher in dogs with liver neoplasms (liver cell carcinoma; cholangiocarcinoma) [26]. Alanine transaminase activity increases significantly in dogs with hepatocellular carcinoma [32, 39].

9.2.9. Tumorlike lesions

Nodular hepatocellular hyperplasia

Hyperplastic nodules are relatively frequent in old dogs, but they have also been reported more rarely in swine. In dogs, there is no sex predisposition, and hyperplastic nodules are not characteristic as preneoplastic forms. Usually, multiple nodules are found, disseminated in all hepatic lobes, developing against a background of generalized fibrosis. Nodules have diameters varying from 2 mm to 3 cm or more.

Macroscopically, hyperplastic nodules are differentiated from the adjacent liver tissue by either a lighter color, due to the high lipid and glycogen content of hepatocytes, or by a darker color, due to the stasis from sinusoid capillaries. Sometimes, nodules have the same color as the rest of the liver, however, in section they can be distinguished from the adjacent tissue after mild washing or blood removal, due to the compression and atrophy exerted on the normal parenchyma. Sometimes they can bulge at the liver surface, at other times they are only found in the parenchyma.

Microscopically, hepatocytes are apparently unchanged, but they are enlarged, sinusoids are dilated, the lobular structure is generally maintained, the radial orientation of the cords from the centrilobular vein remains, which makes difficult the identification of these nodules [8, 24]. Hyperplastic nodules compress the normal adjacent liver parenchyma. Hyperplastic nodules formed by Ito cells, ceroid pigment and macrophages have been observed, which are called lipogranulomas, being reported in dogs [8].

Hyperplastic nodules are difficult to differentiate histologically from hepatocellular adenoma or even adenocarcinoma.

Cystic hyperplasia appears as a consequence of the hypertrophy of mucous glands from the the gallbladder and large bile duct wall. The lesion has been more frequently found in dogs, but also in ruminants with inflammations and chronic parasitism. Nodules may be sessile or polyploid, with mucous content, and epithelial hyperplasia that delimits microcysts is microscopically found.

Regenerative hepatocellular hyperplasia (Fig. 9.13), nodular hepatic lesions that result from hyperplasia of hepatocytes in damaged, usually fibrotic livers. Nodules of regenerative hyperplasia are distinct from nodular hyperplasia. Regenerative nodules occur in some species, most often dogs, as a result of chronic injury. Regenerative nodules can be difficult to distinguish from hepatocellular adenomas on the basis of histology alone, although there are a few distinguishing features. Regenerative nodules are composed of hepatic plates. Hepatocytes in nodules of regenerative hyperplasia may be focally or diffusely vacuolated, with glycogen or lipid within the vacuoles. Hepatocellular adenomas are more likely to be solitary and usually do not arise in a background of hepatic injury and fibrosis [42].

Fig. 9.13. Regenerative hepatocellular hyperplasia.

Fig. 9.13

Regenerative hepatocellular hyperplasia.

Vascular hamartoma, a developmental anomaly characterized by abnormal proportions or mixing of normal vascular tissue. In cattle, vascular hamartoma has been described as an entity distinct from hemangioma. Vascular hamartomas are characterized by the presence of abundant stroma, aberrant blood vessels with papillary infoldings, the presence of arteries and veins, and the loss of hepatic parenchyma in affected sites [42].

Telangiectasis is a cavernous ectasia of groups of sinusoids that occurs in all species but is particularly common in cattle; the affected areas are dark red, irregular in shape but well circumscribed, and ranging from pinpoints to many centimeters in size. In bovine livers that bear early telangiectases, there are usually small foci of mononuclear cells that are intimately associated with a few degenerate hepatocytes in the center of the cluster.

Telangiectasis in the liver of cats is quite common in older animals; the cavities are rather more frequent in the subcapsular zone and rarely exceed 2–3 mm in size [24].

Peliosis hepatis. This term has been used for a long time to designate focal, blood-filled spaces in human liver; these lesions are of unknown cause and were originally described in tuberculous patients and, more recently, in association with therapy by various steroids. One form of sinusoidal dilatation in cattle is named peliosis, specifically to differentiate it from bovine telangiectasis. This form, unlike telangiectasis, begins as a diffuse periportal sinusoidal dilatation and develops in cattle poisoned by plants of the Pimelea genus. These changes are also found in these animals in spleen and in other organs with sinusoidal microcirculation. In the late stages of the intoxication by Pimelea, the liver may resemble a huge, blood-filled sponge. The animals eventually die of a combination of hemodilutional anemia and circulatory failure [24].

Biliary hamartoma, a nonneoplastic mass of bile ducts set in a fibrous stroma. These lesions may occur in cats or dogs as a result of abnormal embryonic ductal plate development either alone or in association with cystic lesions in the kidney. The lesion has been described in abattoir-slaughtered lambs [42].


9.3.1. Adenoma

Macroscopically, adenoma appears under the form of nodules of variable sizes, ranging from several millimeters to 0.5–1 cm in diameter, on the gallbladder surface. Nodules are shiny, fragile, with a slightly rough surface, yellow to red or gray.

The tumor is found in old dogs, sometimes accompanied by lithiasis; in cats and minks, the tumor has a moderate incidence, while in other species it occurs extremely sporadically.

Microscopically, mucous acini are detected, formed by columnar or cuboid epithelial cells, with scant connective stroma. Adenomas may have a papilliferous character, when epithelium is cubic or prismatic, lying on abundant connective stroma (Fig. 9.14). Acini can undergo cystic dilations with mucoid substance accumulations. Cystic variants of these neoplasms are called papillary cystadenomas [41, 42].

Fig. 9.14. Gallbladder adenoma.

Fig. 9.14

Gallbladder adenoma.

9.3.2. Gallbladder carcinoma

Adenocarcinoma is a malignant tumor of the gallbladder epithelium, having the character of a papilliferous carcinoma. Neoplastic formations can affect a smaller or larger area of the gallbladder mucosa. Neoplasms tend to extend, they are soft, cauliflower-like.

Microscopically, both papilliferous and acinar proliferations are found. Cells are tall, prismatic, pleomorphic, with irregular arrangement, basal nuclei, the cytoplasm contains mucin. The connective stroma is well represented, typical of a scirrhous carcinoma, intensely vascularized and frequently infiltrated with mononuclear cells. We mention among our personal cases the presence of an adenocarcinomatous neoplasm, in a cow aged over 10 years, in which the tumor was more developed at the level of the gallbladder neck (Fig. 9.15) [41, 42].

Fig. 9.15. Gallbladder carcinoma.

Fig. 9.15

Gallbladder carcinoma.

9.3.3. Tumorlike lesions

Cystic hyperplasia of the gallbladder (adenomatosis, adenomatous polyposis), with thickening of the entire mucosa of the gallbladder, has been reported in pregnant ewes and dogs treated with hormones; elderly dogs with multiple endocrine neoplasms may develop a few small cysts. The affected mucosa is gray-white and has a diffusely thickened, sponge-like consistency imparted by numerous 1- to -3 mm cysts within the hyperplastic mucosa. Cysts are lined with a single layer of tall columnar epithelial cells with abundant apical cytoplasmic mucus typical of the normal gallbladder epithelium. Epithelial cells may be cuboidal and occasionally foci of squamous metaplasia can be identified. Hyperplastic epithelium may form papillary projections that extend from the mucosa into the lumen of the gallbladder [42].


Adameşteanu C, Jiduc A, Cotiga C. Aflatoxina. Mh. Vet. Med. 1959;23:730–734.
Adameşteanu I, Adameşteanu C, Baba AI, Danielescu N, Moldovan NA, Rotaru O. Leberzirrhose bei neugeborene kälbern durch plazentare Ubertragung von Aflatoxin. Dtsch. Tieratztl. Wschr. 1974;6:141–144. [PubMed: 4596268]
Anderson WA, Monlux AW, Davis CL. Epithelial tumors of the bovine gallbladder. A report of eighteen cases. Am. J. Vet. Res. 1958;19:58–65. [PubMed: 13498237]
Ansay M. La carcinogenese chimique. Ann. Méd. Vét. 1976;120:456–463.
Baba AI, Cătoi C, Băşea I, Prică A. Studiul morfologic al tumorilor hepatice la animale. Rev. Rom. Med. Vet. 1995;5(3, Supl):86.
Barsanti JA, Higgins RJ, Spano JS. Adenocarcinoma of the extrahepatic bile duct in a cat. J. Small Anim. Pract. 1976;17:599–605. [PubMed: 979176]
Becker FF. Hepatoma - nature’s model tumor. A review. Am. J. Pathol. 1974;74:179–210. [PMC free article: PMC1910723] [PubMed: 4358463]
Bergman JR. Nodular hyperplasia in the liver of the dog: An association with changes in the Ito cell population. Vet. Pathol. 1985;22:427–430. [PubMed: 4049672]
Bettini G, Marcato PS. Primary hepatic tumours in cattle. A classification of 66 cases. J. Comp. Pathol. 1992;107 (1):19–34. [PubMed: 1331208]
Bohn FK. Tumore im Leberberaich beim Hund. Prakt. Tierarztl. 1984;4:346–348.
Buligescu L, Ribet A. Bolile ficatului, căilor biliare şi pancreasului. Medicală; Bucureşti: 1981. pp. 848–873.
Cullen JM, Ruebner BH, Hsieh LS, Hyde DM, Hsieh DP. Carcinogenicity of Dietary Aflatoxin M1 in Male Fischer Rats Compared to Aflatoxin B1. Cancer Research. 1987;47:1913–1917. [PubMed: 3102052]
Edds GT. Acute Aflatoxicosis. J. Am. Vet. Med. Assoc. 1973;4:304–309. [PubMed: 4631238]
Fabry A, Benjamini SA, Angleton GM. Nodular hyperplasia of the liver in the beagle dog. Vet. Pathol. 1982;19:109–119. [PubMed: 7072085]
Farber E. Some emerging general principles in the pathogenesis of hepatocellular carcinoma. Cancer Surveys. 1986;5(4):695–718. [PubMed: 3040241]
Farber E. The biochemistry of preneoplastic liver: a common metabolic pattern in hapatocyte nodules. Can. J. Biochem. Cell. Biol. 1984a;62:486–494. [PubMed: 6380687]
Farber E. Perspectives in cancer research. The multistep nature of cancer development, Cancer Research. 1984b;44:4217–4223. [PubMed: 6467183]
Farber E. Pre-cancerous steps in carcinogenesis: their physiological adaptive nature. Biochimica and Biophysica Acta. 1984c;738:171–180. [PubMed: 6394048]
Farber E, Erikcon LC, Roomi MW, Cameron RC, Hayes MA. Chemical carcinogenesis: hepatocyte nodules with a special phenotype as a common step at the crossroads. Toxical Path. 1984;12:288–290. [PubMed: 6515281]
Farber E, Sarma DSR. Biology of disease: hepato–carcinogenesis: hepatocarcinogenesis, a dynamic cellular perspective. Labor. Invest. 1987;56:4–22. [PubMed: 3025514]
Johnson SE. Diseases of the Liver. In: Ettinger, Feldman, editors. Textbook of Veterinary Medicine Disease of the Dog and Cat. II. W.B. Saunders Company; Philadelphia: 1995. pp. 1338–1340.
Kanemaru T, Oikawa M, Yoshihara T, Kaneko M, Kiryu K, Satoh H. Necropsy Findings of Hepatocellular Carcinoma in a Racehorse. Exp. Rep. Equine Hlth. Lab. 1978;15:8–17.
Kijima H, Watanabe H, Iwafuchi M, Ishihara N. Histogenesis of Gallbladder Carcinoma from Investigation of Early Carcinoma and Microcarcinoma. Acta Pathol. Jpn. 1989;39 (4):235–244. [PubMed: 2741703]
Kelly WR. Hyperplastic and Neoplastic Lesions of Liver and Bile Ducts. In: Jubb, Kennedy, Palmer, editors. Pathology of Domestic Animals. ed.4. Vol. 2. Academic Press; New–York: 1993. pp. 402–406.
Lairmore MD, Knight AP, De Martini JC. Three primary neoplasms in a goat hepatocellular carcinoma, phaeochromocytoma and leiomyoma. J. Comp Path. 1987;97:267–271. [PubMed: 3038970]
Lowseth LA, Gillett NA, Chang IY, Muggenburg BA, Boecker BB. Detection of serum α–fetoprotein in dogs with hepatic tumors. J. Am. Vet. Med. Assoc. 1991;199 (6):735–741. [PubMed: 1720115]
Mainigi KD, Sorof S. Carcinogen Protein Complexes in Liver during Hepatocarcinogenesis by Aflatoxin B1. Cancer Research. 1977;37:4304–4312. [PubMed: 922723]
Moulton JE. Tumors in Domestic Animals. 2. Univ. California Press; Berkely: 1978. Tumors of the Pancreas, Liver, Gallbladder and Mesothelium; pp. 273–287.
Nobel TA, Klopfer U, Perl S, Nyska A. Neoplasm of domestic animals in Israel, 1969–1979. Refuah Vet. 1979;36:23–26.
Patnaik AK, Hurvitz AI, Lieberman PH. Canine Hepatic Neoplasm: A Clinicopathologic Study. Vet. Pathol. 1980;17:553–564. [PubMed: 7404966]
Patnaik AK. Canine hepatocellular carcinoma. Vet. Pathol. 1981;18:561–570.
Patnaik AK, Hurvitz AI, Lieberman PH. Canine hepatocellular carcinoma. Vet. Pathol. 1981;18:427–438. [PubMed: 6266116]
Patnaik AK. A Morphologic and Immunocytochemical Study of Hepatic Neoplasm in Cats. Vet. Pathol. 1992;29:405–415. [PubMed: 1413408]
Ponomarkov V, Mackey LJ. Tumours of the liver and biliary system. Bull. World Health Organ. 1976;53:187–194. [PMC free article: PMC2366507] [PubMed: 1086149]
Post G, Patnaik KA. Nonhematopoietic hepatic neoplasms in cats: 21 cases (1983–1988) J. Am. Vest Assoc. 1992;201 (7):1080–1082. [PubMed: 1330999]
Santos JA, Lopes MAF, Schott AC, Santos EA, Porfirio LC, Passos L. Colangiocarcinomas em gatos com parisitisimo de dutos biliares por Platynosomum fastosum. Pesq. Vet. Bras. 1981;1:31–36.
Sarma DSR, Rao PM, Rajalakshmi S. Liver tumour promotion chemicals: models and mechanisms. Cancer Surveys. 1986;5(4):781–798. [PubMed: 3304621]
Schmidt RE, Langham RF. A survey of feline neoplasms. J. Am. Vet. Med. Assoc. 1967;151:1325–1328.
Strombeck DR. Clinicopathologic features of primary and metastatic neoplastic disease of the liver in dogs. J. Am. Vet. Med. Assoc. 1978;173:267–269. [PubMed: 211107]
Theilen GH, Madewell BR. Veterinary Cancer Medicine. Lea & Febiger; Philadelphia: 1987. Tumors of the Digestive Tract; pp. 524–534.
Baba AI. Oncologie comparată. Acad. Române; Bucureşti: 2002.
Head KW, Cullen JM, Dubielzig RR, Else RW, Misdorp W, Patnaik AK, Tateyama S, Van Der Gaag I. Histological Classification of Tumors of the Alimentary System of Domestic Animals. Second Series. X. WHO, Armed Forces Institute of Pathology; Washington, D.C: 2003.

List of Figures 9.1-9.16

  • Fig. 9.1 Hepatocellular adenoma, trabecular type. *)
  • Fig. 9.2 Hepatocellular adenoma, acinar type. *)
  • Fig. 9.3 Cholangiocellular adenoma.
  • Fig. 9.4 Hepatocellular carcinoma, acinar type.
  • Fig. 9.5 Hepatocellular carcinoma, trabecular type.
  • Fig. 9.6 Hepatocellular carcinoma, poorly differentiated.
  • Fig. 9.7 Hepatocellular carcinoma, clear cells type.
  • Fig. 9.8 Hepatocellular carcinoma, scirhous type.
  • Fig. 9.9 Hepatocellular carcinoma, vascular invasion.
  • Fig. 9.10 Bile duct adenocarcinoma - well differentiated.
  • Fig. 9.11 Cholangiocelluar carcinoma, moderately differentiated.
  • Fig. 9.12 Cholangiocellular carcinoma.
  • Fig. 9.13 Regenerative hepatocellular hyperplasia.
  • Fig. 9.14 Gallbladder adenoma.
  • Fig. 9.15 Gallbladder carcinoma. *)
  • Fig. 9.16 Reactive bile duct hyperplasia.



Courtesy of W.H.O.

Copyright © 2007, The Publishing House of the Romanian Academy.
Bookshelf ID: NBK9548


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...