IV. Tumours of the Urinary Bladder

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

IV. Tumours of the urinary bladder

A. M. PAMUKCU 1

Tumours of the urinary bladder are uncommon in all domestic animals except cattle in certain regions. Where cattle eat bracken (Pteridium aquilinum) there is a high incidence of these tumours. Epithelial tumours are the most frequently encountered neoplasms in cattle and 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 occurrence animals developed urinary bladder tumours (includ- and nature of tumours of the urinary bladder in ing carcinomas) indistinguishable from those that animals other than man is that the information occur naturally in areas of the world where bracken obtained may help to clarify the etiology of the abounds. human disease. Unfortunately, careful studies of The tumours are rare in cattle living outside areas the subject are rarely made and most reviews of the of endemicity and relatively infrequent when bracken epidemiology of cancer in animals provide little is not eaten. Thus a prevalence of 0.1 % has been information about these tumours. One explanation reported in cattle in Kenya and 0.01 % in the USA. for this may be that the only lesions reported are Primary tumours of the urinary bladder are sel- large masses plainly visible at autopsy. Small mucosal dom reported in sheep, but this does not necessarily lesions in a viscus, such as the urinary bladder, may mean that they are rare. These animals are mostly not be noticed if the organ is not distended, bisected, killed for food at an early age, before they have and carefully examined. had a chance to develop such tumours. Recently Urinary bladder tumours have been studied in carcinoma of the urinary bladder was described in cattle more than in other domestic animals and a flock of aged merino wethers in Australia that had reports indicate that these tumours are common in had access to bracken for at least 18 months. certain parts of the world, reaching a prevalence as The high incidence of tumours in the sheep exam- high as 25% in slaughtered cattle over 2 years of ined, and the number showing clinical haematuria, age. These neoplasms are associated with a syn- suggested that 5-8 % of the flock probably had drome known as chronic enzootic haematuria. All bladder tumours. No information is available on breeds of cattle between the ages of 4 and 12 years the incidence of primary vesical tumours in goats. may be affected; the disease is rarely seen in younger Primary tumours of the urinary bladder occur animals. The tumours occur also in the domestic infrequently in dogs, comprising less than 1 % of water buffalo in Turkey, Formosa, and Indonesia. all canine neoplasms. The average age of the dogs They are found in the male as frequently as in the with these tumours was 9-10 years at the time of female in both species. diagnosis. The frequency of the tumours does not The occurrence of bovine urinary bladder tumours seem to be related to the sex or breed. Although in different parts of the world has often been linked little is known of the etiology of naturally occurring with the geographical distribution of bracken canine bladder tumours, a variety of chemicals can (Pteridium aquilinum). Studies have demonstrated produce urinary bladder neoplasia experimentally. clearly that such tumours are related to the ingestion Cats apparently have a very low incidence of blad- of this fern. When the plant was fed in small quanti- der tumours-only 14 cases have been reported in ties to cattle for a long period (mean: 550 days), the this species: 8 primary carcinomas of the bladder, 1 Department of Pathologic Anatomy, Faculty of 2 papillomas, 2 lymphosarcomas, 1 myxoma, and Veterinary Medicine, Ankara University, Ankara, Turkey. 1 leiomyoma. Vesical tumours are not usually

3166 - 43 - 44 A. M. PAMUKCU found in cats under 8 years of age. These animals HISTOLOGICAL GRADING seem to be more resistant to the development of Grading of carcinomas is of particular importance such tumours than are other domestic species that from the standpoint of prognosis. It is based solely are permitted to live most of their life span. This on the degree of anaplasia of the cells and not on resistance may be due to differences in metabolic the pattern of tumours, the cell type, or the extent pathways between species rather than to differences of invasion into the bladder wall. All carcinomas of tissue susceptibility. For example, it has been may be graded according to the following histo- shown that cats metabolize tryptophane-an essen- logical indications of cellular anaplasia: (1) increased tial amino acid-by a process that does not involve cellularity; (2) nuclear crowding; (3) disturbance of the production of large quantities of orthoamino- cellular polarity; (4) failure of differentiation from phenol metabolites. Consequently, unlike the dog, base to surface; (5) polymorphism; (6) irregularity rat, and man, the cat has an extremely low level of in the size of cells; (7) variation in the shape of such tryptophane metabolites in the urine. Certain nuclei and in chromatin pattern; (8) presence of of these metabolites have been implicated as etio- giant cells; and (9) displaced or abnormal mitotic logic agents in the genesis of human bladder cancer. figures. The presence of one or more of these Primary neoplasms of the urinary bladder are criteria is acceptable as evidence of anaplasia. Care infrequent in horses. So far, only 37 cases have been must be taken to exclude reactive or regenerative reported, nearly all of them in horses over 10 years conditions in which some of these features may be of age. The tumours were more common in males present. than in females. Tumours that demonstrate slight anaplasia are Urinary bladder tumours are exceedingly rare in designated as Grade I carcinoma (Fig. 3, 4). At the swine. One papilloma was found in the bladder of opposite extreme are tumours showing severe ana- an animal 6 months old. plasia, which should be classified as Grade III car- Because of the small number of such tumours cinoma (Fig. 6, 7). Any tumour that does not fit reported in cats, sheep, horses, and swine, this histo- readily into Grade I or Grade III is assigned to the logical classification will be based mainly on the intermediate grade, i.e., Grade II (Fig. 5). findings in cattle and dogs. However, reference will Sections used for grading should be of adequate also be made to other species in the explanatory size: usually a piece of tissue measuring about notes. 1.5 x 2.0 cm will show the full range of the tumour A wide variety of benign and malignant tumours pattern. Occasionally a definite variation in grade, occur in the urinary bladder. Epithelial tumours are as distinct from mere variation in structural pattern, the most common, accounting for approximately may be seen in the same histological section. The 82% (145 of 177 cases) and 77% (123 of 160 cases) grading should then be that of the most malignant of all primary bladder tumours in cattle and dogs, part of the growth. Consistency of grading can be respectively. Malignant epithelial tumours are more acquired only after considerable experience. frequently found than benign ones. Tumours of the The author acknowledges the collaboration of urinary bladder may be of primary or secondary Dr F. K. Mostofi in examining slides and reviewing origin. Primary tumours are the most common in the manuscript. The photographs were reproduced cattle and dogs, and most primary malignant tumours by courtesy of the Armed Forces Institute of Path- are of epithelial origin. ology, Washington, D.C., USA.

* * URINARY BLADDER 45

HISTOLOGICAL CLASSIFICATION AND NOMENCLATURE OF TUMOURS OF THE URINARY BLADDER I. EPITHELIAL TUMOURS II. NONEPITHELIAL TUMOURS A. PAPILLOMA A. MUSCLE TUMOURS B. ADENOMA B. VAscuLAR TUMOURS C. TRANSITIONAL CELL CARCINOMA C. FIBROBLASTIC TUMOURS D. VARIANTS OF TRANSITIONAL CELL CARCINOMA D. OTHER NONEPITHELIAL TUMOURS 1. With squamous metaplasia III. TUMOURS WITH COEXISTING EPI- 2. With glandular metaplasia THELIAL AND MESENCHYMAL ELEMENTS 3. With squamous and glandular metaplasia IV. SECONDARY TUMOURS E. SQUAMOUS CELL CARCINOMA F. ADENOCARCINOMA V. UNCLASSIFIED TUMOURS G. UNDIFFERENTIATED CARCINOMA VI. PROLIFERATIVE CHANGES

DESCRIPTION OF TUMOURS

I. EPITHELIAL TUMOURS (30 of 177 cases) of primary tumours of the bladder and, in dogs, for 14% (23 of 160 cases). It is no Normally the bladder is lined with 3-6 layers of known whether these tumours recur after surgica transitional epithelial cells.a Under certain condi- removal. tions the bladder mucosa may be in an unstable condition. The mucosa is often seen not to be B. Adenoma normal when examined cystoscopically, yet a definite This is a benign growth of glandular epithelium diagnosis of tumour cannot be made histologically. that occurs rarely in cattle and dogs. These aden- The condition may revert to normal, stabilize, or omas vary from solitary, cauliflower-shaped masses progress to a tumour. These changes are mainly of to multiple, pedunculated growths. Some aden- a proliferative nature (vide infra). omas are indistinguishable from papillary urothelial A. Papilloma (Fig. 1) tumours. Adenomas are composed of a large number of Bladder papillomas are defined as papillary tu- glandular structures separated from one another by mours that have delicate fibrovascular stroma cov- a variable amount of connective tissue. The epi- ered with transitional epithelium indistinguishable thelium forming the glands consists of a single from the normal bladder epithelium and not more layer of columnar cells. The amount of mucin in than six cells deep. The individual cells are slender the epithelial cells varies. In some there is only a and elongated; they are arranged parallel to one small amount situated in the cell substance nearest another and at right angles to the basement mem- the lumen, whereas in others there is an amount brane; they contain basal normal mitotic figures; large enough to produce goblet-type cells. Frequently and there is no evidence of invasion. Histological the glands are distended into thin-walled cystic diagnosis of papilloma is based on a complete spaces filled with mucin and desquamated cells. The absence of cellular anaplasia (vide infra). There is arrangement of the cells lining the glands is orderly a wide variation in their biological behaviour. In and mitotic figures are exceedingly rare. Adenomas cattle, papillomas account for approximately 17% do not invade the muscular layers of the bladder wall. They develop either from the preexisting glands a The term " urothelium " is used in some departments in the mucosa or from the transitional epithelium for this type of epithelium; likewise, transitional cell carcinoma is called " urothelial carcinoma ". through metaplastic changes. The most common 46 A. M. PAMUKCU adenomas in cattle and dogs are those of meta- cinomas are not reported separately from papillary plastic origin. Endometrial or nephrogenic aden- infiltrating carcinomas. Therefore, it is difficult to omas have not been reported in animals. give any figure for their frequency in animals. Such differentiation may have prognostic importance. C. Transitional cell carcinoma (Fig. 2-7) Papillary and infiltrating carcinoma resembles pap- Carcinomas account for nearly 80% of epithelial illary carcinoma in many respects. It also invades tumours of the bladder in cattle (115 of 145) and the stroma of its own stalk and lamina propria of in dogs (98 of 123). Transitional cell carcinomas are the bladder wall (Fig. 4, 5). Most of the transitional the most common; squamous cell carcinomas and cell carcinomas are papillary. They account for adenocarcinomas occur less frequently. The dia- nearly 55% of carcinomas in cattle and dogs. gnosis of malignancy is based on cellular anaplasia, However, very few adenomas, adenocarcinomas. invasion, or metastasis. Metastasis is a late pheno- and squamous cell carcinomas have papillary foci, menon in carcinoma of the bladder. Infiltrating carcinoma grows into the wall of the Transitional cell carcinoma of the bladder may bladder and usually appears as a flat, plaque-like be single or multiple. Multiple tumours are mostly lesion or as an ulcerated, infiltrated mucosal patch papillary and vary in size and appearance. Some are overlying a nodular growth. Microscopically, the almost microscopic, whereas others may completely tumour is composed of transitional cells forming fill the bladder with protuberant growths or may cohesive sheets, cords, or nests. The cellular borders extend over most of the mucosal surface. On the are sharp, but prickles cannot be demonstrated. basis of morbid anatomy, both gross and micro- Nuclear and cytoplasmic patterns vary widely. Ses- scopic, transitional cell carcinomas may be sub- sile infiltrating carcinomas carry a poorer prognosis divided into four kinds as indicated below. than papillary carcinomas (Fig. 6, 7). Infiltrating Nonpapillary andnoninfiltrating carcinoma, in which transitional cell carcinomas constitute nearly 21 % the tumour is confined to the surface, i.e., carcinoma of all primary carcinomas of the bladder in cattle. in situ (Fig. 2). This is defined as a neoplastic Transitional cell carcinomas often metastasize to entity in which the tumour cells are still within the the regional lymph nodes and the lungs in cattle epithelium of origin without invasion of the base- and dogs, although other organs, such as the liver, ment membrane. Although it is noninvasive and non- spleen, and kidneys, are involved in some instances. papillary, carcinoma in situ is found most often in the mucosa adjacent to well-formed carcinoma in D. Variants of transitional cell carcinoma the bladder. Its occurrence in association with Since the large majority of carcinomas of the definite carcinomas raises the question of its relation- bladder start as transitional cell carcinomas and ship with invasive as well as with papillary carcinoma. remain as such, they may be referred to simply as Carcinoma in situ is rarely found in cattle and dogs. " carcinomas ". However, a number of transitional It occurs mainly in association with nodular infiltrat- cell carcinomas exhibit areas of squamous cells or ing transitional cell carcinoma. glandular structure. It is best not to categorize such Papillary carcinoma grows into the lumen of the tumours as squamous, glandular, or metaplastic bladder and resembles the papilloma grossly, but its carcinomas, but to designate them as follows: base is relatively broader and the villi are confluent 1. With squamous metaplasia and clubbed or blunted. The growth may have a cauliflower-like pattern. Microscopically, the fronds 2. With glandular metaplasia of the papillary carcinoma have a thick epithelial 3. With squamous and glandular metaplasia coat. The covering epithelium shows an increase in cells, which are not uniform, are crowded together, E. Squamous cell carcinoma (Fig. 8, 9) and are irregularly stratified. Atypical nuclei, ana- Squamous cell carcinoma is usually not papillary, plasia, giant cells, and mitotic figures are character- although it may have papillary foci. The tumour istic (Fig. 3). In some tumours, squamous cells are may have firm, raised, and rolled edges and an observed among the transitional cells that dominate eroded centre. Microscopically, squamous cell car- the pattern ofthe papillary noninfiltrating carcinoma. cinoma of the bladder does not differ in histological The papillary carcinoma does not invade the stroma appearance from squamous carcinoma elsewhere in of its own stalks or the base of the growth. In the the body. The least well differentiated tumours can veterinary literature, papillary noninfiltrating car- be distinguished from transitional cell carcinoma Fig. 1. Papilloma (cow). Fig. 2. Carcinoma in situ (cow).

Fig. 3. Transitional cell carcinoma, papillary and Fig. 4. Transitional cell carcinoma, papillary and noninfiltrating, Grade I (dog). infiltrating, Grade I (cow). Fig. 5. Transitional cell carcinoma, papillary Fig. 6. Transitional cell carcinoma, infiltrating, Grade infiltrating, Grade lII(dog). Ill (dog).

Fig. 7. Transitional cell carcinoma, infiltrating, Grade Fig. 8. Squamous cell carcinoma (cow). Ill (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 51 because there is frank keratinization (Fig. 8, 9). The Adenocarcinomas not infrequently arise as a result most highly differentiated growths show the usual of glandular metaplasia of the transitional epi- pearls. Squamous cell carcinomas most often result thelium or normally located glands in the bladder from the epidermidalization of a papillary or trans- mucosa. Those of dysontogenic origin have not been itional cell tumour. They consist entirely of squa- studied in detail in animals. Most adenocarcinomas mous epithelial elements. Transitional cell carcin- reported in cattle fall into the metaplastic category. omas having areas of squamous metaplasia are not Primary adenocarcinomas are those with a glandular regarded as true squamous cell carcinomas. structure throughout. Transitional carcinomas, hav- This type of carcinoma is not infrequent in ani- ing foci of glandular metaplasia, are excluded from mals, and it accounts for approximately 70% (9 of the category of true adenocarcinoma. 115) and 14% (14 of 98) of all primary bladder Primary adenocarcinomas comprise 60/ (6 of 98) carcinomas in cattle and dogs, respectively. It occurs and 10% (12 of 115) of all primary carcinomas of in old male dogs more often than in bitches. How- the bladder in dogs and cattle, respectively. ever, a high incidence of squamous cell carcinoma G. Undifferentiated carcinoma (Fig. 11, 12) has been reported in horses (13 of 35 cases). This With some tumours, it is impossible to recognize was explained by the normal presence of squamous the cell type as belonging to any of the above- cell islands in the urinary bladder epithelium of the mentioned categories. Such tumours are designated horse. as " undifferentiated carcinoma ". The term " undif- Squamous cell carcinomas metastasize readily. In ferentiated" is used here in a histogenic sense to dogs, 9% of such tumours showed metastases. characterize a type of epithelium-not to indicate the degree of anaplasia of the tumour. This category F. Adenocarcinoma (Fig. 10) is not synonymous with anaplastic tumours. All adenocarcinomas of the bladder, with the exception of the mucinous varieties, resemble uro- II. NONEPITHELIAL TUMOURS thelial carcinomas. They present as localized areas of diffusely involved vesical mucosa, as flat ulcer- Nonepithelial bladder tumours comprise fewer ations, or as polypoid growths. When examined than 18% and 230% of all primary tumours in cattle grossly and microscopically, adenocarcinomas are and dogs, respectively. They may arise from prac- seen to fall into three patterns: papillary; papillary tically any tissue component of the bladder. They and infiltrating; and sessile and infiltrating. The two are classified according to the system described under last-mentioned patterns occur with equal frequency Tumours of the soft (mesenchymal) tissues (see in cattle. Histologically, the tumours are made up page 101). Nonepithelial tumours should be recorded of glands of variable sizes and shapes. These glands as recommended above for epithelial tumours, with are lined with mucous-secreting columnar or cuboidal observations on the pattern, tissue type, degree of cells. The amount of mucus in the glands varies con- anaplasia, organ or area involved, depth of penetra- siderably, and lakes of mucus lined with indistinct tion, and presence of lymphatic or blood vessel epithelial cells may be formed. invasion. The histological differentiation of primary and The most common nonepithelial tumours of the secondary adenocarcinoma may also be difficult. bladder are muscle tumours and vascular tumours The three most common adenocarcinomas that in dogs and cattle, respectively. involve the bladder secondarily are those of the A. Muscle tumours uterus, prostate, and rectum. Features helpful for Leiomyoma and leiomyosarcoma (Fig. 13) account differentiation include: (a) the presence of foci of for 12% (20 of 160) of all primary tumours in dogs. transitional epithelium, (b) areas of transition from Rhabdomyosarcomas occur infrequently in animals. normal to neoplastic epithelium, (c) an association So far, two cases have been reported in dogs. of proliferative changes in the adjoining epithelium, Muscle tumours are very rare in cattle. and (d) areas of carcinoma in situ. Adenocarcinomas Leiomyoma and leiomyosarcoma arise from the of the prostate are generally of the nonmucinous muscle of the bladder or are a growth of undifferen- type, whereas those of the bladder commonly pro- tiated mesenchyma that differentiates into muscle. duce mucin. Adenocarcinoma metastases may be Leiomyosarcomas are generally vascular and consist found in the lungs, prostate, and abdominal walls of elongated acidophilic cells arranged in sharply in dogs (3 of 6). intersecting bundles. The presence of cellular pleo- 52 A. M. PAMUKCU morphism, marked cellularity, tumour giant cells, by metastasis from distant primary tumours. Secon- and atypical mitotic figures helps to distinguish them dary tumours comprise 7.8 % of all urinary bladder from their benign counterparts, the leiomyomas. tumours (13 of 166) in dogs. In 7 of 13 cases, the B. Vascular tumours secondary tumour originated from carcinoma of the Angioendothelial tumours, such as haemangioma prostate. The remainder had metastasized from (Fig. 14), haemangiosarcoma (Fig. 15, 16) and malignant tumours of the heart, thyroid, bone, and haemangiopericytoma, occur often in the bovine lymphoid tissue. In lymphosarcoma, the wall of the bladder. They make up nearly 6% of all primary urinary bladder may be infiltrated, but secondary bladder tumours and are usually found in compound lymphosarcomas occur more frequently in the kid- tumours with primary epithelial tumours of the neys. The kidneys were involved in 10 of 52 cases bladder. Vascular tumours are found infrequently in (19.2%) of lymphosarcoma in dogs, whereas the dogs and cats. urinary bladder was involved in only 2 (3.8 %). Three The microscopic appearance of these tumours is cases of secondary lymphosarcoma have been ob- similar to that of vascular tumours found elsewhere served with generalized lymphosarcoma in cattle. in the body. Secondary tumours of the urinary bladder are seldom found in other animal species. C. Fibroblastic tumours in and dogs and can be These occur both cattle V. UNCLASSIFIED TUMOURS either benign or malignant. So far, fibroma (5 of 160), fibrosarcoma (4 of 160), and sarcoma (unclas- These are primary benign or malignant tumours sified) (4 of 160) have been reported in dogs as that cannot be placed in any of the categories primary bladder tumours. Such tumours have a described above. histological structure similar to those seen elsewhere in the body. VI. PROLIFERATIVE CHANGES D. Other nonepithelial tumours Proliferative changes usually result from cystitis. Primary malignant lymphomas of the bladder are They may be mistaken for bladder tumours macro- very rare. Only 8 cases have been reported: 2 in scopically as well as microscopically, but histological dogs, 2 in cats, and 4 in cows. However, secondary differentiation from bladder tumours does not cause involvement of the bladder in generalized lympho- any difficulty. The proliferative changes commonly sarcoma is not uncommon, and the histology is observed are listed below. similar to that observed in lymphosarcoma of the Von Brunn's nests. These are compact groups of lymph nodes. transitional epithelial cells lying in the lamina propria, with or without connexion to the surface III. TUMOURS WITH COEXISTING EPITHELIAL epithelium. AND MESENCHYMAL ELEMENTS Glandular metaplasia (glandular cystitis). This is These are defined as tumours composed of neo- characterized by mucus-containing columnar epi- plastic epithelial components and of mesenchymal thelial cells either on the surface or forming glands tissue, e.g., carcinosarcoma, carcinohaemangioma in the lamina propria. and carcinoleiomyosarcohaemangioma, adenohaem- Squamous metaplasia. Transitional epithelium angioma, adenocarcinohaemangioma, and papillo- shows squamous metaplasia and is replaced by haemangioma. Frequently, two or more different squamous cells with or without keratinization. There types of tumour have been recognized in the urinary is usually hyperplasia of the epithelium. bladders of cattle that have ingested bracken. These Cystic cystitis. These are groups of transitional types of tumour are very rare in other animal species. epithelial cells with central cavitation, sometimes cystic, lying in the lamina propria, with or without IV. SECONDARY TUMOURS connexion to the surface epithelium. Secondary involvement of the bladder occurs Papillary (polypoid) cystitis. This proliferative either by direct extension from malignant primary change is characterized by hyperplastic epithelium tumours of adjacent organs (chiefly the prostate, that covers thickened, finger-like projections of the rectum, and uterus), by implantation from primary lamina propria. The projections are aedematous, lesions located in the upper urinary tract, or, rarely, hyperaemic, and infiltrated with inflammatory cells.