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66 Paul N. Brooks and Francis I. Roe

Cholangionia, Liver, Rat

Paul N. Brooks and Francis J. C. Roe

Synonyms. Bile duct adenoma ; biliary adenoma; Differential Diagnosisbile duct cystadenoma ; biliary cystadenoma.

Gross Appearance

The macroscopic appearance of cholangiomas isvariable. Usually, the neoplasms are observed asraised grayish-white areas of firm consistency.However, in the more cystic forms, cholangiomashave a spongy texture and, in the presence of ap-preciable associated vascular proliferation, theneoplasm is dark-red in color. Multilocular cysticforms have a more irregular surface than those inwhich there is no significant cyst formation.Macroscopic differentiation between hepatocel-lular neoplasms and those of bile duct origin canbe difficult and in many cases impossible.

Microscopic Features

Simple cholangioma is a generally uniform well-circumscribed neoplasm composed of acini ofuniform size. The acini are lined by a single layerof cuboidal cells having somewhat basophilic cy-toplasm and a round or oval nucleus, which is oc-casionally vesicular and contains one or two con-spicuous nucleoli. The nucleus is usually locatedat or toward the base of the cell. Simple cholan-giomas have a sparse vascular stroma and rarelycontain evidence of mitotic activity. Cholangio-mas can become large enough to cause consider-able distortion, but there is never invasive growth.The glandular acini may vary in size and shapeand the lining epithelium, which can range fromcolumnar to flattened, is occasionally multilay-ered (Figs. 50, 51).Cystic cholangioma is characteristically com-posed of dilated glandular acini lined by flat-tened, almost atrophic, epithelium. The stroma incystic forms is less well vascularized and containsmore fibrous tissue and collagen than that in the,simple cholangioma. Papillary structures are oc-casionally observed projecting into the lumen ofcystic acini and clumps of liver cells are common-ly seen between the cysts (Fig. 52).In the hemangiomatous cholangioma, the aciniare morphologically similar to those in simplecholangioma, but the stroma contains cystic,blood-filled spaces lined by endothelium (Fig. 53).

The morphological forms of cholangioma mustbe distinguished from other proliferative lesionsof bile duct, hepatocellular, and endothelial oni-gin. With the exception of some forms of hepato-cellular carcinoma, the morphology of hepatocel-lular and endothelial neoplasms is quite distinctand rarely confounds the differential diagnosis ofcholangioma.Occasionally, acinar structures are formed withinhepatocellular carcinomas and these can appearvery similar in morphology to the glandular aciniof cholangiomas. importantly, the morphology ofsuch hepatocellular carcinomas is variable. Themore solid areas of carcinoma, frequently demon-.strating evidence of invasion, will clarify diagno-sis. This distinction is more of a problem in thedifferential diagnosis of cholangiocarcinoma thancholangioma.Other proliferative lesions of bile duct origin arenonneoplastic bile duct proliferation (hyperpla-sia), cholangiofibrosis, and cholangiocarcinoma.Simple nonneoplastic bile duct proliferation is avariable lesion which occurs spontaneously inageing rats and as a result of exposure to hepato-toxins including carcinogens. Cells proliferate instrands, with the progressive formation of a lu-men giving the appearance of bile ducts. Prolifer-ation extends into the liver parenchyma and maybe associated with fibroblastic proliferation,which can lead to cirrhosis. Bile duct proliferationof this type is, unlike cholangioma, muitifocal andusually widespread throughout the affected liver.In more advanced lesions, the fibrous prolifera-tion is much greater than that usually observed inthe stroma of bile duct neoplasms.Cholangiofibrosis, regarded by many as a preneo-plastic lesion, has the characteristic appearance ofclumps of glandular structures surrounded bydense connective tissue. The glandular prolifera-tion is from bile ducts and the lesion can be singleor multiple, but usually has an initial periportaldistribution: The proliferation 'of connective tis-sue may be great enough to result in atrophy ofthe glandular elements. There is a marked pro-duction of mucus by the acini in cholangiofibro-sis, which is not a characteristic of the cholangio-ma (see p. 52, this volume).In contrast to cholangiomas, cholangiocarcino-

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Cholangioma, Liver, Rat 67

Fig. % Liver, rat. A well-circumscribed simple cholangio-ma i llustrating the acinar structure of the neoplasm and thedelicate connective tissue capsule. No invasive growth isevident. H and F, x 430

Fig.51. Cytologic detail or the same neoplasm (Fig.50) il-lustrating the single-celled cuboidal epithelial lining of theacini and sparse connective tissue stroma. H and E, x 1720

mas are made up from acini lined by atypical epi-_[helium, the cells of which frequently contain mu-cus. Cholangiocarcinomas have evidence of inva-sive growth which is never observed in the cholan-gioma.

Biologic Features

An early change in the process of chemical-in-duced carcinogenesis in the rat liver is the prolif-eration of bile ducts (Farber 1963; Schaffner andPopper 1961; Bannasch and Reiss 1971). Thisproliferation is considered to be a reparative le-sion rather than a direct cellular response to car-cinogenic agents (Bannasch and Reiss 1971), andthe initial bile duct proliferation does not repre-sent preneoplasia (Schauer and Kunze 1976).However, the long-term administration of carcin-

ogenic compounds can result in the formation ofadenomatous hyperplasia, which can progress tocholangioma (Schauer and Kunze 1976).Of greater significance in the development of chol-angiomatous neoplasms is cholangiolibrosis,which is regarded as irreversible (Farber 1963)and preneoplastic (Bannasch and Reiss 1971), al-though cholangiomas do not always pass throughcholangiofibrosis (Schauer and Kunze 1976).Bannasch and Reiss (1971) demonstrated the pro-gression of cholangiofibrosis to cholangioma fol-lowing the administration of N-nitrosomorpho-line.It is probable that cystic cholangiomas result fromthe accumulation of secretion following partial orcomplete obstruction of the biliary drainage: thisis supported by the appearance of the flattenedepithelium of the cystic acini. Such obstructioncould result either from internal epithelial prolif-

68 Paul N. Brooks and Francis J. Roe

Fig.52. Cystic cholangioma with prominent connectivetissue stroma. H and E, x 430

Fig.53. Hemangiomatous cholangioma demonstratingcystic, endothelial lined spaces in the stroma. H and E.x 1720

eration or from compression resulting from theexternal proliferation of connective tissue (Schau-er and Kunze 1976). Apart from the cystic appear-ance of the acini, this form of cholangioma ismorphologically similar to the simple cholangio-ma and presumably behaves in much the sameway. Cystic transformation of the simple cholan-gioma seems to be a likely means by which thecystic cholangioma can be formed, although thepossibility that some cystic forms arise de novocannot be excluded, and the appearance of is-lands of hepatocytes trapped between the cysticacini in some instances is support for a primarilyproliferative origin rather than a consequence ofcystic transformation of a preexisting simple chol-angioma.Where hemangiomatous areas are present withina cholangioma, there are no indications of a pri-mary proliferation of endothelial cells. Simple en-

dothelium-lined blood-filled spaces surround theglandular acini.'There is no evidence to suggest that, as a generalrule, either the simple or cystic forms of cholan-gioma progress to cholangiocarcinoma.

Comparison with Other Species

Cholangiomas are observed rarely in man and areusually only encountered as an incidental findingat autopsy. In the cat and dog, simple and cysticforms of the neoplasm exist with much the samemorphology as that described for the rat. In par-ticular, multilocular cystic forms demonstrate thesame pressure-related epithelial flattening, withoccasional papillomatous outgrowths, and col-lagenous septa! stroma.

Hemangiosarcoma, Liver, Rat 69

References

I3annasch P, Reiss W (1971) Histogenese und Cytogenesecho langiocellularer Tumoren bei Nitrosomorpholin-ver-gifteten Ratten. Zugleich ein Reitrag zur Morphogeneseder Cystenleber. Z Krebsforsch 76: 193-215

Farber E (1963) Ethionine carcinogenesis. Adv Cancer Res7: 383-474

Schaffner F, Popper H (1961) Electron microscopic studiesof normal and proliferated bile ductules. Am J Pathol38:393-411)

Schauer A. Kunze E (1976) Tumours (-tithe liver. In: Turu-sov VS (ed) Pathology of tumours in laboratory animals,vol Tumours of the rat, part 2. IARC Sci Publ no 6,Lyon, pp 41-72

Hem angiosarcoma, Liver, Rat

James A. Popp

Synonyms. Angiosarcoma; malignant hemangio-endotheliorna

Gross Appearance

The gross appearance is variable. Lesions may bebarely visible or up to 1 cm in diameter. They fre-quently bulge above the surface of the liver cap-sule, but are sometimes deeply embedded in theliver parenchyma and not visible on the capsularsurface. The lesion usually lacks a capsule andhas poorly defined borders. Perhaps the greatestvariability occurs in the color, usually red, red-d ish-brown, or black with a mottled appearance,and in the consistency of the lesion. The more cel-lular and less vascular areas may be white to lighttan. Hemangiosarcomas typically are soft and pli-able and ooze blood or blood-tinged fluid whensectioned. Cysts are common due either to greatlydilated vascular spaces or to areas of necrosiswhich subsequently fill with blood. Rupture ofcysts or friable vascular walls results in hemoperi-toneum or hemothorax from metastatic lesions inover 75% of rats dying of hemangiosarcoma(Ward et al. 1975). Hemangiosarcomas are fre-quently multicentric within the liver. Metastaticsites in other tissues have a gross appearance simi-lar to the primary lesion in the liver.

M icroscopic Features

Early developing and small hemangiosarcomasconsist of small areas (1 mm in diameter) in whichthe sinusoids are lined by numerous neoplasticendothelial cells that may be multilayered

(Fig. 54). The sinusoids are frequently dilated withunderlying atrophied hepatocytes. The neoplasticendothelial cells vary in both size and shape, withindividual large cells occasionally observed. Mi-totic figures may be relatively numerous even inthe smaller lesions.As the neoplasm enlarges, hepatocytes are nolonger found within it. Large sheets of neoplasticcells with little evidence of vascular formation areseen. However, in all or nearly all lesions somevessels can be identified even though they mayoccupy a small percentage of the lesion. The vas-cular channels may be large dilated cysts or thincapillary-sized openings in the neoplastic tissue.Individual cells of the larger lesions tend to bemore pleomorphic, assuming either a polyhedralor spindle shape in different areas of a single le-sion (Fig. 55). Large cells with large single nucleias well as abnormal mitotic figures and numerousmitotic cells are observed: multinucleated giantcells are rare. Necrotic areas are invariably foundin large lesions ( —1 cm in diameter) and frequent-ly contain hemorrhage.The border of all hemangiosarcomas, irrespectiveof size, is indistinct. Neoplastic cells may mergewith adjacent normal tissue or may actively in-vade the sinusoids of adjacent tissue. Encapsula-tion is never observed although a thin fibrouszone may be found along some edges associatedwith compression.

Ultrastructure

Limited information is available on the ultrastruc-tural features of hepatic hemangiosarcomas inrats. The large nuclei have an irregular outline but