Bull. Org. mond. Sant 11974. 50, 43-52Bull. Wld Hlth Org. J

IV. Tumours of the urinary bladderA. M. PAMUKCU 1

Tumours of the urinary bladder are uncommon in all domestic animals except cattle incertain regions. Where cattle eat bracken (Pteridium aquilinum) there is a high incidence ofthese tumours. Epithelial tumours are the most frequently encountered neoplasms in cattleand in dogs-the two species most studied. They are described under the following names:papilloma, adenoma, transitional cell carcinoma (with variants), squamous cell carcinoma,adenocarcinoma, and undifferentiated carcinoma.

An important reason for studying the occurrenceand nature of tumours of the urinary bladder inanimals other than man is that the informationobtained may help to clarify the etiology of thehuman disease. Unfortunately, careful studies ofthe subject are rarely made and most reviews of theepidemiology of cancer in animals provide littleinformation about these tumours. One explanationfor this may be that the only lesions reported arelarge masses plainly visible at autopsy. Small mucosallesions in a viscus, such as the urinary bladder, maynot be noticed if the organ is not distended, bisected,and carefully examined.

Urinary bladder tumours have been studied incattle more than in other domestic animals andreports indicate that these tumours are common incertain parts of the world, reaching a prevalence ashigh as 25% in slaughtered cattle over 2 years ofage. These neoplasms are associated with a syn-drome known as chronic enzootic haematuria. Allbreeds of cattle between the ages of 4 and 12 yearsmay be affected; the disease is rarely seen in youngeranimals. The tumours occur also in the domesticwater buffalo in Turkey, Formosa, and Indonesia.They are found in the male as frequently as in thefemale in both species.The occurrence of bovine urinary bladder tumours

in different parts of the world has often been linkedwith the geographical distribution of bracken(Pteridium aquilinum). Studies have demonstratedclearly that such tumours are related to the ingestionof this fern. When the plant was fed in small quanti-ties to cattle for a long period (mean: 550 days), the

1 Department of Pathologic Anatomy, Faculty ofVeterinary Medicine, Ankara University, Ankara, Turkey.

animals developed urinary bladder tumours (includ-ing carcinomas) indistinguishable from those thatoccur naturally in areas of the world where brackenabounds.The tumours are rare in cattle living outside areas

of endemicity and relatively infrequent when brackenis not eaten. Thus a prevalence of 0.1 % has beenreported in cattle in Kenya and 0.01 % in the USA.

Primary tumours of the urinary bladder are sel-dom reported in sheep, but this does not necessarilymean that they are rare. These animals are mostlykilled for food at an early age, before they havehad a chance to develop such tumours. Recentlycarcinoma of the urinary bladder was described ina flock of aged merino wethers in Australia that hadhad access to bracken for at least 18 months.The high incidence of tumours in the sheep exam-ined, and the number showing clinical haematuria,suggested that 5-8 % of the flock probably hadbladder tumours. No information is available onthe incidence of primary vesical tumours in goats.

Primary tumours of the urinary bladder occurinfrequently in dogs, comprising less than 1 % ofall canine neoplasms. The average age of the dogswith these tumours was 9-10 years at the time ofdiagnosis. The frequency of the tumours does notseem to be related to the sex or breed. Althoughlittle is known of the etiology of naturally occurringcanine bladder tumours, a variety of chemicals canproduce urinary bladder neoplasia experimentally.

Cats apparently have a very low incidence of blad-der tumours-only 14 cases have been reported inthis species: 8 primary carcinomas of the bladder,2 papillomas, 2 lymphosarcomas, 1 myxoma, and1 leiomyoma. Vesical tumours are not usually

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A. M. PAMUKCU

found in cats under 8 years of age. These animalsseem to be more resistant to the development ofsuch tumours than are other domestic species thatare permitted to live most of their life span. Thisresistance may be due to differences in metabolicpathways between species rather than to differencesof tissue susceptibility. For example, it has beenshown that cats metabolize tryptophane-an essen-tial amino acid-by a process that does not involvethe production of large quantities of orthoamino-phenol metabolites. Consequently, unlike the dog,rat, and man, the cat has an extremely low level ofsuch tryptophane metabolites in the urine. Certainof these metabolites have been implicated as etio-logic agents in the genesis of human bladder cancer.Primary neoplasms of the urinary bladder are

infrequent in horses. So far, only 37 cases have beenreported, nearly all of them in horses over 10 yearsof age. The tumours were more common in malesthan in females.

Urinary bladder tumours are exceedingly rare inswine. One papilloma was found in the bladder ofan animal 6 months old.Because of the small number of such tumours

reported in cats, sheep, horses, and swine, this histo-logical classification will be based mainly on thefindings in cattle and dogs. However, reference willalso be made to other species in the explanatorynotes.A wide variety of benign and malignant tumours

occur in the urinary bladder. Epithelial tumours arethe most common, accounting for approximately82% (145 of 177 cases) and 77% (123 of 160 cases)of all primary bladder tumours in cattle and dogs,respectively. Malignant epithelial tumours are morefrequently found than benign ones. Tumours of theurinary bladder may be of primary or secondaryorigin. Primary tumours are the most common incattle and dogs, and most primary malignant tumoursare of epithelial origin.

HISTOLOGICAL GRADING

Grading of carcinomas is of particular importancefrom the standpoint of prognosis. It is based solelyon the degree of anaplasia of the cells and not onthe pattern of tumours, the cell type, or the extentof invasion into the bladder wall. All carcinomasmay be graded according to the following histo-logical indications of cellular anaplasia: (1) increasedcellularity; (2) nuclear crowding; (3) disturbance ofcellular polarity; (4) failure of differentiation frombase to surface; (5) polymorphism; (6) irregularityin the size of cells; (7) variation in the shape ofnuclei and in chromatin pattern; (8) presence ofgiant cells; and (9) displaced or abnormal mitoticfigures. The presence of one or more of thesecriteria is acceptable as evidence of anaplasia. Caremust be taken to exclude reactive or regenerativeconditions in which some of these features may bepresent.Tumours that demonstrate slight anaplasia are

designated as Grade I carcinoma (Fig. 3, 4). At theopposite extreme are tumours showing severe ana-plasia, which should be classified as Grade III car-cinoma (Fig. 6, 7). Any tumour that does not fitreadily into Grade I or Grade III is assigned to theintermediate grade, i.e., Grade II (Fig. 5).

Sections used for grading should be of adequatesize: usually a piece of tissue measuring about1.5 x 2.0 cm will show the full range of the tumourpattern. Occasionally a definite variation in grade,as distinct from mere variation in structural pattern,may be seen in the same histological section. Thegrading should then be that of the most malignantpart of the growth. Consistency of grading can beacquired only after considerable experience.The author acknowledges the collaboration of

Dr F. K. Mostofi in examining slides and reviewingthe manuscript. The photographs were reproducedby courtesy of the Armed Forces Institute of Path-ology, Washington, D.C., USA.

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URINARY BLADDER 45

HISTOLOGICAL CLASSIFICATION AND NOMENCLATURE OF TUMOURSOF THE URINARY BLADDER

I. EPITHELIAL TUMOURS

A. PAPILLOMA

B. ADENOMA

C. TRANSITIONAL CELL CARCINOMA

D. VARIANTS OF TRANSITIONAL CELL CARCINOMA

1. With squamous metaplasia2. With glandular metaplasia3. With squamous and glandular metaplasia

E. SQUAMOUS CELL CARCINOMA

F. ADENOCARCINOMA

G. UNDIFFERENTIATED CARCINOMA

II. NONEPITHELIAL TUMOURS

A. MUSCLE TUMOURS

B. VAscuLAR TUMOURS

C. FIBROBLASTIC TUMOURS

D. OTHER NONEPITHELIAL TUMOURS

III. TUMOURS WITH COEXISTING EPI-THELIAL AND MESENCHYMAL ELEMENTS

IV. SECONDARY TUMOURS

V. UNCLASSIFIED TUMOURS

VI. PROLIFERATIVE CHANGES

DESCRIPTION OF TUMOURS

I. EPITHELIAL TUMOURS

Normally the bladder is lined with 3-6 layers oftransitional epithelial cells.a Under certain condi-tions the bladder mucosa may be in an unstablecondition. The mucosa is often seen not to benormal when examined cystoscopically, yet a definitediagnosis of tumour cannot be made histologically.The condition may revert to normal, stabilize, orprogress to a tumour. These changes are mainly ofa proliferative nature (vide infra).

A. Papilloma (Fig. 1)Bladder papillomas are defined as papillary tu-

mours that have delicate fibrovascular stroma cov-ered with transitional epithelium indistinguishablefrom the normal bladder epithelium and not morethan six cells deep. The individual cells are slenderand elongated; they are arranged parallel to oneanother and at right angles to the basement mem-brane; they contain basal normal mitotic figures;and there is no evidence of invasion. Histologicaldiagnosis of papilloma is based on a completeabsence of cellular anaplasia (vide infra). There isa wide variation in their biological behaviour. Incattle, papillomas account for approximately 17%

a The term " urothelium " is used in some departmentsfor this type of epithelium; likewise, transitional cell carcin-oma is called " urothelial carcinoma ".

(30 of 177 cases) of primary tumours of the bladderand, in dogs, for 14% (23 of 160 cases). It is noknown whether these tumours recur after surgicaremoval.

B. AdenomaThis is a benign growth of glandular epithelium

that occurs rarely in cattle and dogs. These aden-omas vary from solitary, cauliflower-shaped massesto multiple, pedunculated growths. Some aden-omas are indistinguishable from papillary urothelialtumours.Adenomas are composed of a large number of

glandular structures separated from one another bya variable amount of connective tissue. The epi-thelium forming the glands consists of a singlelayer of columnar cells. The amount of mucin inthe epithelial cells varies. In some there is only asmall amount situated in the cell substance nearestthe lumen, whereas in others there is an amountlarge enough to produce goblet-type cells. Frequentlythe glands are distended into thin-walled cysticspaces filled with mucin and desquamated cells. Thearrangement of the cells lining the glands is orderlyand mitotic figures are exceedingly rare. Adenomasdo not invade the muscular layers of the bladderwall. They develop either from the preexisting glandsin the mucosa or from the transitional epitheliumthrough metaplastic changes. The most common

A. M. PAMUKCU

adenomas in cattle and dogs are those of meta-plastic origin. Endometrial or nephrogenic aden-omas have not been reported in animals.

C. Transitional cell carcinoma (Fig. 2-7)

Carcinomas account for nearly 80% of epithelialtumours of the bladder in cattle (115 of 145) andin dogs (98 of 123). Transitional cell carcinomas arethe most common; squamous cell carcinomas andadenocarcinomas occur less frequently. The dia-gnosis of malignancy is based on cellular anaplasia,invasion, or metastasis. Metastasis is a late pheno-menon in carcinoma of the bladder.

Transitional cell carcinoma of the bladder maybe single or multiple. Multiple tumours are mostlypapillary and vary in size and appearance. Some arealmost microscopic, whereas others may completelyfill the bladder with protuberant growths or mayextend over most of the mucosal surface. On thebasis of morbid anatomy, both gross and micro-scopic, transitional cell carcinomas may be sub-divided into four kinds as indicated below.

Nonpapillary andnoninfiltrating carcinoma, in whichthe tumour is confined to the surface, i.e., carcinomain situ (Fig. 2). This is defined as a neoplasticentity in which the tumour cells are still within theepithelium of origin without invasion of the base-ment membrane. Although it is noninvasive and non-papillary, carcinoma in situ is found most often inthe mucosa adjacent to well-formed carcinoma inthe bladder. Its occurrence in association withdefinite carcinomas raises the question of its relation-ship with invasive as well as with papillary carcinoma.Carcinoma in situ is rarely found in cattle and dogs.It occurs mainly in association with nodular infiltrat-ing transitional cell carcinoma.

Papillary carcinoma grows into the lumen of thebladder and resembles the papilloma grossly, but itsbase is relatively broader and the villi are confluentand clubbed or blunted. The growth may have acauliflower-like pattern. Microscopically, the frondsof the papillary carcinoma have a thick epithelialcoat. The covering epithelium shows an increase incells, which are not uniform, are crowded together,and are irregularly stratified. Atypical nuclei, ana-plasia, giant cells, and mitotic figures are character-istic (Fig. 3). In some tumours, squamous cells areobserved among the transitional cells that dominatethe pattern of the papillary noninfiltrating carcinoma.The papillary carcinoma does not invade the stromaof its own stalks or the base of the growth. In theveterinary literature, papillary noninfiltrating car-

cinomas are not reported separately from papillaryinfiltrating carcinomas. Therefore, it is difficult togive any figure for their frequency in animals. Suchdifferentiation may have prognostic importance.

Papillary and infiltrating carcinoma resembles pap-illary carcinoma in many respects. It also invadesthe stroma of its own stalk and lamina propria ofthe bladder wall (Fig. 4, 5). Most of the transitionalcell carcinomas are papillary. They account fornearly 55% of carcinomas in cattle and dogs.However, very few adenomas, adenocarcinomas.and squamous cell carcinomas have papillary foci,

Infiltrating carcinoma grows into the wall of thebladder and usually appears as a flat, plaque-likelesion or as an ulcerated, infiltrated mucosal patchoverlying a nodular growth. Microscopically, thetumour is composed of transitional cells formingcohesive sheets, cords, or nests. The cellular bordersare sharp, but prickles cannot be demonstrated.Nuclear and cytoplasmic patterns vary widely. Ses-sile infiltrating carcinomas carry a poorer prognosisthan papillary carcinomas (Fig. 6, 7). Infiltratingtransitional cell carcinomas constitute nearly 21 %of all primary carcinomas of the bladder in cattle.

Transitional cell carcinomas often metastasize tothe regional lymph nodes and the lungs in cattleand dogs, although other organs, such as the liver,spleen, and kidneys, are involved in some instances.

D. Variants of transitional cell carcinomaSince the large majority of carcinomas of the

bladder start as transitional cell carcinomas andremain as such, they may be referred to simply as" carcinomas ". However, a number of transitionalcell carcinomas exhibit areas of squamous cells orglandular structure. It is best not to categorize suchtumours as squamous, glandular, or metaplasticcarcinomas, but to designate them as follows:

1. With squamous metaplasia2. With glandular metaplasia3. With squamous and glandular metaplasia

E. Squamous cell carcinoma (Fig. 8, 9)Squamous cell carcinoma is usually not papillary,

although it may have papillary foci. The tumourmay have firm, raised, and rolled edges and aneroded centre. Microscopically, squamous cell car-cinoma of the bladder does not differ in histologicalappearance from squamous carcinoma elsewhere inthe body. The least well differentiated tumours canbe distinguished from transitional cell carcinoma

46

Fig. 2. Carcinoma in situ (cow).Fig. 1. Papilloma (cow).

Fig. 3. Transitional cell carcinoma, papillary andnoninfiltrating, Grade I (dog).

Fig. 4. Transitional cell carcinoma, papillary andinfiltrating, Grade I (cow).

Fig. 5. Transitional cell carcinoma, papillaryinfiltrating, Grade lII(dog).

Fig. 7. Transitional cell carcinoma, infiltrating, GradeIll (cow).

Fig. 6. Transitional cell carcinoma, infiltrating, GradeIll (dog).

Fig. 8. Squamous cell carcinoma (cow).

Fig. 9. Squamous cell carcinoma, tentacular invasion Fig. 10. Adenocarcinoma (cow).(cow).

Fig. 11. Undifferentiated carcinoma, spindle cells (cow). Fig. 12. Undifferentiated carcinoma, small round cells(water buffalo).

Fig. 13. Leiomyosarcoma (cow). Fig. 14. Haemangioma (cow).

Fig. 15. Haemangiosarcoma (cow). Fig. 16. Haemangiosarcoma (cow).

URINARY BLADDER

because there is frank keratinization (Fig. 8, 9). Themost highly differentiated growths show the usualpearls. Squamous cell carcinomas most often resultfrom the epidermidalization of a papillary or trans-itional cell tumour. They consist entirely of squa-mous epithelial elements. Transitional cell carcin-omas having areas of squamous metaplasia are notregarded as true squamous cell carcinomas.

This type of carcinoma is not infrequent in ani-mals, and it accounts for approximately 70% (9 of115) and 14% (14 of 98) of all primary bladdercarcinomas in cattle and dogs, respectively. It occursin old male dogs more often than in bitches. How-ever, a high incidence of squamous cell carcinomahas been reported in horses (13 of 35 cases). Thiswas explained by the normal presence of squamouscell islands in the urinary bladder epithelium of thehorse.Squamous cell carcinomas metastasize readily. In

dogs, 9% of such tumours showed metastases.

F. Adenocarcinoma (Fig. 10)All adenocarcinomas of the bladder, with the

exception of the mucinous varieties, resemble uro-thelial carcinomas. They present as localized areasof diffusely involved vesical mucosa, as flat ulcer-ations, or as polypoid growths. When examinedgrossly and microscopically, adenocarcinomas areseen to fall into three patterns: papillary; papillaryand infiltrating; and sessile and infiltrating. The twolast-mentioned patterns occur with equal frequencyin cattle. Histologically, the tumours are made upof glands of variable sizes and shapes. These glandsare lined with mucous-secreting columnar or cuboidalcells. The amount of mucus in the glands varies con-siderably, and lakes of mucus lined with indistinctepithelial cells may be formed.The histological differentiation of primary and

secondary adenocarcinoma may also be difficult.The three most common adenocarcinomas thatinvolve the bladder secondarily are those of theuterus, prostate, and rectum. Features helpful fordifferentiation include: (a) the presence of foci oftransitional epithelium, (b) areas of transition fromnormal to neoplastic epithelium, (c) an associationof proliferative changes in the adjoining epithelium,and (d) areas of carcinoma in situ. Adenocarcinomasof the prostate are generally of the nonmucinoustype, whereas those of the bladder commonly pro-duce mucin. Adenocarcinoma metastases may befound in the lungs, prostate, and abdominal wallsin dogs (3 of 6).

Adenocarcinomas not infrequently arise as a resultof glandular metaplasia of the transitional epi-thelium or normally located glands in the bladdermucosa. Those of dysontogenic origin have not beenstudied in detail in animals. Most adenocarcinomasreported in cattle fall into the metaplastic category.Primary adenocarcinomas are those with a glandularstructure throughout. Transitional carcinomas, hav-ing foci of glandular metaplasia, are excluded fromthe category of true adenocarcinoma.Primary adenocarcinomas comprise 60/ (6 of 98)

and 10% (12 of 115) of all primary carcinomas ofthe bladder in dogs and cattle, respectively.G. Undifferentiated carcinoma (Fig. 11, 12)With some tumours, it is impossible to recognize

the cell type as belonging to any of the above-mentioned categories. Such tumours are designatedas " undifferentiated carcinoma ". The term " undif-ferentiated" is used here in a histogenic sense tocharacterize a type of epithelium-not to indicatethe degree of anaplasia of the tumour. This categoryis not synonymous with anaplastic tumours.

II. NONEPITHELIAL TUMOURS

Nonepithelial bladder tumours comprise fewerthan 18% and 230% of all primary tumours in cattleand dogs, respectively. They may arise from prac-tically any tissue component of the bladder. Theyare classified according to the system described underTumours of the soft (mesenchymal) tissues (seepage 101). Nonepithelial tumours should be recordedas recommended above for epithelial tumours, withobservations on the pattern, tissue type, degree ofanaplasia, organ or area involved, depth of penetra-tion, and presence of lymphatic or blood vesselinvasion.The most common nonepithelial tumours of the

bladder are muscle tumours and vascular tumoursin dogs and cattle, respectively.A. Muscle tumoursLeiomyoma and leiomyosarcoma (Fig. 13) account

for 12% (20 of 160) of all primary tumours in dogs.Rhabdomyosarcomas occur infrequently in animals.So far, two cases have been reported in dogs.Muscle tumours are very rare in cattle.Leiomyoma and leiomyosarcoma arise from the

muscle of the bladder or are a growth of undifferen-tiated mesenchyma that differentiates into muscle.Leiomyosarcomas are generally vascular and consistof elongated acidophilic cells arranged in sharplyintersecting bundles. The presence of cellular pleo-

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A. M. PAMUKCU

morphism, marked cellularity, tumour giant cells,and atypical mitotic figures helps to distinguish themfrom their benign counterparts, the leiomyomas.B. Vascular tumours

Angioendothelial tumours, such as haemangioma(Fig. 14), haemangiosarcoma (Fig. 15, 16) andhaemangiopericytoma, occur often in the bovinebladder. They make up nearly 6% of all primarybladder tumours and are usually found in compoundtumours with primary epithelial tumours of thebladder. Vascular tumours are found infrequently indogs and cats.

The microscopic appearance of these tumours issimilar to that of vascular tumours found elsewherein the body.C. Fibroblastic tumours

These occur in both cattle and dogs and can beeither benign or malignant. So far, fibroma (5 of160), fibrosarcoma (4 of 160), and sarcoma (unclas-sified) (4 of 160) have been reported in dogs asprimary bladder tumours. Such tumours have ahistological structure similar to those seen elsewherein the body.D. Other nonepithelial tumours

Primary malignant lymphomas of the bladder arevery rare. Only 8 cases have been reported: 2 indogs, 2 in cats, and 4 in cows. However, secondaryinvolvement of the bladder in generalized lympho-sarcoma is not uncommon, and the histology issimilar to that observed in lymphosarcoma of thelymph nodes.

III. TUMOURS WITH COEXISTING EPITHELIALAND MESENCHYMAL ELEMENTS

These are defined as tumours composed of neo-plastic epithelial components and of mesenchymaltissue, e.g., carcinosarcoma, carcinohaemangiomaand carcinoleiomyosarcohaemangioma, adenohaem-angioma, adenocarcinohaemangioma, and papillo-haemangioma. Frequently, two or more differenttypes of tumour have been recognized in the urinarybladders of cattle that have ingested bracken. Thesetypes of tumour are very rare in other animal species.

IV. SECONDARY TUMOURS

Secondary involvement of the bladder occurseither by direct extension from malignant primarytumours of adjacent organs (chiefly the prostate,rectum, and uterus), by implantation from primarylesions located in the upper urinary tract, or, rarely,

by metastasis from distant primary tumours. Secon-dary tumours comprise 7.8 % of all urinary bladdertumours (13 of 166) in dogs. In 7 of 13 cases, thesecondary tumour originated from carcinoma of theprostate. The remainder had metastasized frommalignant tumours of the heart, thyroid, bone, andlymphoid tissue. In lymphosarcoma, the wall of theurinary bladder may be infiltrated, but secondarylymphosarcomas occur more frequently in the kid-neys. The kidneys were involved in 10 of 52 cases(19.2%) of lymphosarcoma in dogs, whereas theurinary bladder was involved in only 2 (3.8 %). Threecases of secondary lymphosarcoma have been ob-served with generalized lymphosarcoma in cattle.

Secondary tumours of the urinary bladder areseldom found in other animal species.

V. UNCLASSIFIED TUMOURS

These are primary benign or malignant tumoursthat cannot be placed in any of the categoriesdescribed above.

VI. PROLIFERATIVE CHANGES

Proliferative changes usually result from cystitis.They may be mistaken for bladder tumours macro-scopically as well as microscopically, but histologicaldifferentiation from bladder tumours does not causeany difficulty. The proliferative changes commonlyobserved are listed below.

Von Brunn's nests. These are compact groups oftransitional epithelial cells lying in the lamina pro-pria, with or without connexion to the surfaceepithelium.

Glandular metaplasia (glandular cystitis). This ischaracterized by mucus-containing columnar epi-thelial cells either on the surface or forming glandsin the lamina propria.Squamous metaplasia. Transitional epithelium

shows squamous metaplasia and is replaced bysquamous cells with or without keratinization. Thereis usually hyperplasia of the epithelium.

Cystic cystitis. These are groups of transitionalepithelial cells with central cavitation, sometimescystic, lying in the lamina propria, with or withoutconnexion to the surface epithelium.

Papillary (polypoid) cystitis. This proliferativechange is characterized by hyperplastic epitheliumthat covers thickened, finger-like projections of thelamina propria. The projections are aedematous,hyperaemic, and infiltrated with inflammatory cells.

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