XIII. Tumours of the liver and biliary system V. PONOMARKOV 1 & L. J. MACKEY 2 In this histological classification of liver and gall bladder tumours the tumour types largely correspond to thosefound in man. The most common tumours in this group are liver cell adenoma, hepatocellular carcinoma, and cholangiocarcinoma.

Tumours of the liver and the intrahepatic biliary The etiology of naturally occurring liver tumours system are fairly common in most domestic animals, in domestic animals is unknown. Cirrhosis of the although absolute prevalence figures are generally liver in man is associated with liver cell carcinoma not available. The most common tumours appear to but, although cirrhosis is an important disease of the be liver cell adenoma, hepatocellular carcinoma, and dog, co-existing liver cell carcinomas have been cholangiocarcinoma. Benign tumours of the bile found only occasionally in cirrhotic dogs. Chronic ducts are infrequent and tumours of the gall bladder hepatic fibrosis is a major disease of sheep and are seldom recognized. The series of tumours on cattle, resulting from infestation by Fasciola hepa- which this classification is based includes examples tica, but again there is no evidence that this condi- from the dog, cat, ox, sheep, and pig but none from tion leads to subsequent neoplasia. No relationship the horse. The tumours occurred in both male and between aflatoxin and liver tumours has been shown female animals, but no information is available on in domestic animals. sex predisposition. Hepatoblastoma similar to the fetal type in man In many respects, liver tumours in animals resem- occurs in domestic animals, particularly in lambs. ble the corresponding neoplasms of man. However, Tumours of the extrahepatic bile ducts were not seen liver cell carcinomas of animals metastasized less in the present series and are probably rare. frequently than might have been predicted from the The material for this chapter was provided by the histological features. In general, little difference in Departments of Veterinary Pathology of the Univer- the histological characteristics of the tumours was sities of Edinburgh, Giessen, Glasgow, and London found among the animal species studied except that and by the Institute of Experimental and Clinical in cattle, cholangiocarcinoma was usually a more Oncology, Moscow. The authors acknowledge the scirrhous tumour than its canine counterpart and assistance of Mr K. W. Head, Professor E. Weiss, was more likely to show serosal dissemination over and Dr C. Appleby. the abdominal organs.

HISTOLOGICAL CLASSIFICATION AND NOMENCLATURE OF TUMOURS OF THE LIVER AND BILIARY SYSTEM Tumours of the liver C. HEPATOCELLULAR CARCINOMA (LIVER CELL CARCI- NOMA) I. EPITHELIAL TUMOURS D. CHOLANGIOCARCINOMA (INTRAHEPATIC BILE DUCT A. LIVER CELL ADENOMA (HEPATOCELLULAR ADE- CARCINOMA) NOMA) E. HEPATOBLASTOMA B. INTRAHEPATIC BILE DUCT ADENOMA (CYSTADE- NOMA) II. NON-EPITHELIAL TUMOURS 1 Pathologist, Cancer Research Centre, Moscow, USSR. Present address: International Agency for Research on A. HAEMANGIOMA Cancer, 69009 Lyon, France. 2 Senior Lecturer, Department of Veterinary Pathology, B. HAEMANGIOSARCOMA University of Glasgow, Veterinary School, Bearsden, Glas- gow G61 IQH, Scotland. C. FIBROSARCOMA

3429 -187 - BULL. WORLD HEALTH ORGAN., Vol. 53, 1976 188 V. PONOMARKOV & L. J. MACKEY

III. MISCELLANEOUS TUMOURS Tumours of the gall bladder

IV. HAEMATOPOIETIC AND LYMPHOID I. EPITHELIAL TUMOURS NEOPLASMS A. ADENOMA (PAPILLARY ADENOMA) V. UNCLASSIFIED TUMOURS B. ADENOCARCINOMA (PAPILLARY CARCINOMA) VI. SECONDARY TUMOURS II. TUMOUR-LIKE LESIONS

VII. TUMOUR-LIKE LESIONS A. CYSTIC HYPERPLASIA

DESCRIPTION OF TUMOURS

Tumours of the liver B. Intrahepatic bile duct adenoma (cystadenoma) (Fig. 3) I. EPITHELIAL TUMOURS This tumour is a well circumscribed, small, solitary nodule composed of epithelium-lined tubules with a A. Liver cell adenoma (hepatocellular adenoma) moderate amount of stroma. The epithelial cells are (Fig. 1, 2) cuboidal and may have clear cytoplasm. At the This is a well differentiated tumrur composed of margin of the lesion, there may be some infiltration cells that resemble normal hepatocytes, although by mononuclear cells. they are often larger and more varied in shape. The Biliary cystadenomas are rather more common. cytoplasm is often vacuolated and in some tumours They are multilocular cystic tumours composed of the amount of glycogen and fat stored gives the locules lined by epithelial cells. These cells are tumour a predominantly clear-celled appearance. similar to normal biliary epithelium but may appear The nuclei contain prominent nucleoli but mitotic flattened. The cysts are supported on a fibrous figures are rare. connective tissue stroma and contain a clear muci- Most liver cell adenomas show a predominantly nous fluid. trabecular or acinar pattern; mixed patterns may occur. Trabeculae are usually two or three cells thick C. Hepatocellular carcinoma (liver cell carcinoma) and are separated by fine endothelial sinusoids. (Fig. 4-8) Some adenomas have a solid structure without There is a wide range in the degree of differentia- acinar or trabecular differentiation. Very well differ- tion of individual tumours. In well differentiated entiated adenomas may be distinguishable from nor- carcinomas, the cells retain a close resemblance to mal liver tissue only by the absence of portal triads. normal liver cells: they are large and polygonal with The vascular element is seldom conspicuous in liver eosinophilic cytoplasm and have central vesicular cell adenomas of animals. nuclei with prominent nucleoli. The cytoplasm is Liver cell adenomas are not uncommon in young often granular but may be vacuolated or clear owing animals and in these cases, foci of extramedullary to the presence of glycogen and fat. In less well haematopoiesis are present. The latter feature is differentiated tumours, the cells show pleomorphism occasionally seen in tumours from adult animals. with a high mitotic rate and tend to have more Liver cell adenomas are usually found as well basophilic cytoplasm. Most carcinomas show a pre- demarcated, circumscribed, light-tan-coloured nod- dominantly trabecular structure. The trabeculae may ules. There is no invasion of adjacent liver tissue, be 2-3 or several cells thick and are separated by which is usually compressed by the tumour. If such endothelium-lined sinusoids. Acini or larger cystic tumours reach a large size, they tend to become spaces may occur within individual trabeculae. In fragile and rupture. Small adenomas may be ex- some tumours, the cells are arranged in short cords tremely difficult to distinguish from hyperplastic and groups with focal acinar differentiation; non- nodules; the latter are, however, usually multiple. mucinous PAS-positive material is often present Fig. 1. Liver cell adenoma, trabecular pattern (cow). Fig. 2. Liver cell adenoma, acinar pattern (sheep).

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Fig. 3. lntrahepatic biliary cystadenoma (dog). Fig. 4. Hepatocellular carcinoma, trabecular pattern (dog). 10 Fig. 5. Hepatocellular carcinoma, trabecular pattern Fig. 6. Hepatocellular carcinoma, trabecular pattern (cow). with focal acinus and cyst formation (cow).

Fig. 7. Hepatocellular carcinoma with clear cells (dog). Fig. 8. Hepatocellular carcinoma, poorly differentiated (cow). Fig. 9. Cholangiocarcinoma, moderately differentated Fig. 10. Cholangiocarcinoma, moderately differentiated (sheep). (cow).

Fig. 1 1. Hepatoblastoma, fetal type (sheep). Fig. 12. Haemangiosarcoma of the liver (dog). Fig. 14. Adenocarcinoma of the gall bladder (pig). Fig. 13. Carcinoid tumour of the liver (cow). Fig. 14. Adenocarcinoma of the gall bladder (pig). LIVER AND BILIARY SYSTEM 193

within the acini. More than one histological pattern E. Hepatoblastoma (Fig. 11) may occur in different parts of the same tumour. In Tumours resembling hepatoblastomas of the fetal poorly differentiated carcinomas, there may be no type in man occur occasionally in domestic animals, distinctive organization, the tumour cells simply particularly in lambs. Hepatoblastoma of the em- forming diffuse invasive sheets. Occasionally, foci bryonic type has not been encountered. These tu- may be seen where the tumour cells resemble biliary mours appear to be benign and are composed of rather than hepatic epithelium. However, these are cells resembling fetal hepatocytes; these are smaller not true combined hepatocellular and cholangiocar- than hepatocytes in adults and have granular or cinomas, since there is no evidence of mucin produc- vacuolated cytoplasm. The mitotic rate is low. The tion. cells are arranged in an orderly pattern of trabeculae Well differentiated carcinomas may be difficult to and micro-acini separated by sinusoids. Foci of distinguish from adenomas, because mitotic figures extramedullary haemopoiesis are always present are infrequent and in both cases the tumour cells within the tumour. Unlike most hepatoblastomas of retain a close resemblance to normal hepatocytes. man, there is little or no evidence of a non-epithelial Carcinomas do not always show obviously invasive component. The above cytological features distin- growth at the primary site even when metastasis has guish the condition from liver cell adenoma. occurred. They may reach a large size and cause extensive destruction of the normal liver before metastising. The usual sites for metastasis are the II. MESENCHYMAL TUMOURS the regional lymph nodes and lungs. A. Haemangioma D. Cholangiocarcinoma (intrahepatic bile duct carci- This is a benign, solitary or multiple, vasoforma- noma) (Fig. 9, 10) tive tumour. Capillary haemangiomas are composed of re- of small vascular channels lined with endothelial These tumours are composed epithelium In sembling biliary tract epithelium. The cells are cells and separated by a delicate fibrous stroma. cuboidal or columnar and have clear or, less often, cavernous haemangiomas, the vascular channels are granular eosinophilic cytoplasm. The cells are ar- generally larger and more varied in size. Individual ranged, at least in places, in a micro-acinar pattern. blood-filled spaces in the tumour may reach several In many instances there is a striking scirrhous centimetres in diameter. The lining endothelial cells reaction, giving the tumour its fibrous consistency. may be flattened and, in some places, desquamated. The histological appearance of individual tumours The vascular channels are supported by a fibrous varies according to the degree of differentiation: in stroma. In all haemangiomas, the cytological fea- well differentiated tumours, there is regular forma- tures tend to be regular and mitotic figures are rare. tion of small acini; in moderately differentiated B. Haemangiosarcoma (Fig. 12) cases, such acini are less well defined; and in poorly differentiated carcinomas solid cords of tumour cells This is a malignant tumour of endothelial cells, show only occasional lumen formation. Mucin pro- which form irregular, anastomosing, vasoformative duction is always demonstrable. Bile may be seen channels. The cells tend to be large, plump, and within the acini but not within the tumour cells. spindle-shaped, but frequently show marked pleo- Within predominantly acinar tumours areas showing morphism and an extremely high mitotic rate. Such a papillary structure may occur. In occasional cases, tumours are invasive and fragile with little support- mucin production is particularly marked and may ing stroma and are therefore liable to rupture and accumulate to form "lakes" within the tumour haemorrhage. The terms angiosarcoma and malig- tissue. In rare instances, the tumour may be of the nant haemangioendothelioma have been applied to adenosquamous type, in which foci of squamous this condition. differentiation occur in an adenocarcinoma. Cholangiocarcinomas form dense, white, firm C. Fibrosarcoma multinodular masses showing invasive growth within These tumours are similar to fibrosarcomas at the biliary tract and into the surrounding paren- other sites.a chyma. They commonly spread to the liver capsule, as well resulting in widespread serosal dissemination, a WEISS, E. Bulletin of the World Health Organization, 50: as metastasing to the lymphatic system and lungs. 101-110 (1974).

11 194 V. PONOMARKOV & L. J. MACKEY

III. MISCELLANEOUS TUMOURS ance, which do not form normal lobules but which may include small bile ducts. They often contain Carcinoid of the liver (Fig. 13) is a rare neoplasm in more fat than normal cells, giving them a vacuola- domestic animals. The tumour appears to originate ted appearance. Occasional mitotic figures and bi- from the cells with argentaffin properties in the bile nucleate cells may be found. duct epithelium and is composed of uniform cells Telangiectasis (Peliosis hepatis) consists of small, with hyperchromatic, round or oval nuclei. The cells blood-filled, vascular or sinusoidal spaces, which are typically arranged in small groups, separated often occur throughout the liver. It is particularly from each other by a delicate fibrous stroma. The common in cattle. The individual lesions vary from a cells within the groups are orientated towards the few millimetres to two centimetres in diameter. basement membrane to form pseudolobules. Mitotic Histologically, an endothelial lining is sometimes but figures are infrequent. Silver impregnation should be not always apparent. used to show the granules in the cytoplasm of carcinoid tumour cells to distinguish this tumour from cholangiocarcinoma. Tumours of the gall bladder I. EPITHELIAL TUMOURS IV. HAEMATOPOIETIC AND LYMPHOID NEOPLASMS adenoma) The liver is commonly involved in disseminated A. Adenoma (papillary malignancies of the haematopoietic and lymphoid Adenoma of the gall bladder is a simple tumour of systems and these conditions have been described mucus-secreting epithelium, which forms a nodule elsewhere., Very occasionally, lymphosarcoma and composed of acini separated by a delicate stroma. mast cell tumours may apparently involve only the The acini are lined with tall columnar epithelium liver with no demonstrable lesions at other sites. and they may be distended by mucin. Papillary adenoma is composed of papilliform structures cov- V. UNCLASSIFIED TUMOURS ered with cuboidal or columnar epithelium. The These are primary tumours of the liver that cannot stroma may be abundant and acini within the tu- be placed in any of the above categories. mour may show cystic dilation. Some tumours may show features of both simple and papillary adenoma. VI. SECONDARY TUMOURS B. Adenocarcinoma (papillary carcinoma) (Fig. 14) The liver is an extremely important site for metas- Malignant tumours of the gall bladder epithelium tases of primary tumours situated elsewhere. The are composed of mucin-secreting columnar epithe- great majority of malignant tumours originating in lium. Such tumours often show a papillary pattern in extrahepatic tissues may produce secondary tumours addition to the formation of acini. They may include in the liver. If the primary site is closely related to less well differentiated areas where the cells are less the liver anatomically or by vascular supply, metas- regularly arranged. The tumour is composed of tall tases to the liver may occur early, e.g., carcinoma of columnar cells that have basal nuclei, mucin contain- the pancreas. ing cytoplasm, and usually a low mitotic rate. The stromal connective tissue is often well vascularized VII. TUMOUR-LIKE LESIONS and may contain an infiltrate of mononuclear cells. Hyperplastic nodules occur as focal and often multiple lesions, and are extremely common in mid- II. TUMOUR-LIKE LESIONS dle-aged and old dogs. They are clearly circum- A. Cystic hyperplasia scribed, seldom more than 3 cm in diameter, often fatty in consistency, and are found in otherwise Cystic hyperplasia of the gall bladder epithelium normal livers. Multiple nodular hyperplasia of cir- causes diffuse thickening and may produce a honey- rhosis involves the entire liver, with the formation of combed structure. The individual cysts are lined with irregular nodules that vary in size and are separated tall, columnar, mucin-secreting epithelial cells of by fibrous tissue. Histologically, hyperplastic foci normal appearance. Infiltration of the stroma by consist of cords of hepatocytes of regular appear- lymphocytes is frequently seen. There may be prolif- eration of smooth muscle within the stroma. Accu- of mucin secretion causes individual cysts a JARRETr, W. F. H. & MACKEY, L. J. Bulletin of the mulation World Health Organization, 50: 21-34 (1974). to show different degrees of distention.