urinary bladder neoplasms induced by feeding bracken fern ... · the histologie appearance of the...

[CANCER RESEARCH 27 Part 1, 917-924, May 1967]

Urinary Bladder Neoplasms Induced by Feeding Bracken Fern(Pteris aquilina) to Cows1

A. M. PAMUKCU [1], S. K. GOKSOY [1], AND J. M. PRICE [2]

[/] Department of Pathological Anatomy, College of Veterinary Medicine, University of Ankara, Ankara, Turkey, andClinical Oncology, University of Wisconsin Medical School, Madison, Wisconsin 53706

Division of

SUMMARY

The chronic toxicity of bracken fern (Pteris aquilina) harvested near Bolu, Turkey, where bovine bladder tumors occurin a high incidence, was tested by feeding the plant to 18 cowsof native stock ranging from 1.5 to 4 years of age. The cowsweighed from 100 to 150 kg and were fed from 300 to 600 gmof dried or 400 to 1000 gm of fresh plant daily in an attempt tosimulate natural exposure in the field. Of 18 animals fed brackenfern, 10 developed neoplasms of the urinary bladder and 3 ofthese lesions were carcinomas. The 2 carcinomas which invadedthe muscular wall of the urinary bladder were found 2.6 and 3.3years after the initiation of feeding. The 8 animals which died oftoxicity without evidence of bladder neoplasms after a meanfeeding time of 163 days included 5 of the 7 animals fed thehighest dosage of bracken. Most of the animals which develojiedbladder lesions were fed bracken at a lower dietary level for amean period of 550 days (range, 276 to 1192 days). Ten controlanimals not exiiosed to bracken fern did not manifest any clinical symptoms during the experiment. The histologie appearanceof the neoplasms and other parameters of the study suggestthat this experiment has resulted in the production of lesionsthat are indistinguishable from the naturally occurring bovinebladder tumors which are a common feature of bovine enzootichematuria. These results provide further evidence for the presence of a carcinogenic substance in bracken fern.

INTRODUCTION

Although urinary bladder tumors were once common in thePacific Northwest of North America, they are now rarely seenin the United States (1). Bladder tumors are frequently foundin cattle in various parts of the world such as Turkey, Yugoslavia, Bulgaria, Panama, and Brazil (3, 20). The tumors arecommonly associated with a syndrome known as chronic enzootichematuria (17, 18). The pathologic features and clinical courseof these neoplasms (19) resemble human industrial and non-industrial bladder tumors (14).

The etiology of the naturally occurring bovine urinary bladdertumors remains obscure. Recently, a papilloma-like virus was

1This investigation was supported by Grant FG-TU-102 of theUnited States Department of Agriculture, Agricultural ResearchService, and by USPHS Research Grant No. CA-08254 from theNational Cancer Institute.

Received June 24, 1966; accepted December 29, 1966.

recovered from tumors of the bovine urinary bladder (16). Thebehavior of the infectious agent in test calves resembles thatof the bovine cutaneous papilloma virus. It may be a passengervirus and not related to the etiology of the bladder tumors. Thebladder tumors produced with this agent (16) and with thebovine cutaneous papilloma virus (2) were self-limiting.

Bracken fern (Pteris aquilina) has often been associated withthe occurrence of chronic hematuria (3, 19, 20, 23). Fatal poisoning of cattle with bracken fern has been reproduced by manyinvestigators by feeding either fresh fronds, sun-dried bracken,or powdered rhizomes mixed with an otherwise adequate diet(5, 20, 23) and with a fraction extracted from the bracken plantwith boiling ethanol (9). The bracken plant is known to containsubstances with radiomimetic activity. A high level of brackenin the diet of cattle caused a hemorrhagic syndrome in whichthere was panmyeloid bone marrow damage. Widespread pete-chial hemorrhages (6-8) were also seen in these animals.

Recently it has been found that, following the continuousfeeding of a low level of bracken in the ration over a period ofmany months, polypoid bladder lesions (23) and tumors havebeen observed in cattle (20). Georgiev et al. (12) obtained anextract from the urine of cattle fed hay from hematuria areaswhich, when introduced into the urinary bladder of dogs,produced changes similar to hemangiomas in a dog. When thesame extract was applied to the skin of white mice, papillo-mas were produced.

An extract of urine from cattle in the hematuria region ofBulgaria produced hematuria, capillary proliferations, andadenomatous proliferations in the bladder walls of calves, dogs,and rate, respectively, when surgically introduced into thebladders of these animals (11). When an acetone solution ofthis extract was applied to the skin of mice, papillomas developed. Some papillomas changed into epidermoid carcinoma andcarcinosarcoma (11). Similar resulte were obtained with anextract of urine from a healthy cow fed hay from the hematuriaarea in Bulgaria. When this extract was applied to the skin ofmice, it produced papillomas and carcinomas (10). By biologicteste, we were able to demonstrate that the acidic fraction ofurine from bracken-fed cattle contained one or more carcinogenic substances which induced a relatively high incidence ofcarcinoma (33%) in the transitional epithelium of the mousebladder (21).

Evans and Mason (4) reported the development of intestinaladenocarcinoma in rate fed bracken fern. A survey by Parkerand McCrea (22) for bracken poisoning of sheep on the North

MAY 1967 917

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A.M. Pamukcu, S. K. GÃ¶ksoy,and J. M. Price

TABLE 1The Amount of Bracken Fern Supplement Fed to the Four Groups of

Animals

GroupininIVNo. ofanimals7443Brackensupplement

(gm/animal/day)Dried600500400300Fresh1000600500400

Yorkshire Moors revealed that a number of older animals fromareas infested with bracken died of the same type of tumor asthat produced in rats fed a bracken diet [cited by Evans andMason (4)].

These results suggest that bracken fern may be one of thefactors responsible for the high incidence of bladder tumors inbovine species in those parts of the world where cattle receive acontinuous low level of bracken by eating the fresh plant or thedried plant which may be mixed with hay. It was felt worthwhile to investigate the possible carcinogenic activity of brackendirectly by feeding the plant to cattle. The results of the brackenfern feeding experiment are the subject of this report.

MATERIALS AND METHODS

Eighteen cows of native stock ranging from 1.5 to 4 years ofage and weighing from 100 to 150 kg were fed bracken fern(Pteris aquilina) obtained from the vicinity of Bolu, Turkey.The experimental animals were obtained from herds near Ankarawhere bovine bladder tumors do not occur. The animals werekept in a barn at Bolu near the source of the bracken. Althoughthe syndrome of acute bracken poisoning has not been observedin the region of Bolu, bladder tumors occur very frequently. Thebracken was harvested in July and was spread out to dry first inthe sun for a day and then in the shade. It was chopped in ahay cutter before being introduced into the diet. In the summer,chopped fresh green bracken was administered to the animals.The amounts of bracken fern supplement fed to the animals ineach of 4 experimental groups are shown in Table 1.

Fourteen additional cows of the same age and breed but notexposed to bracken fern were used as control animals. Twelveof the animals were fed hay and straw, collected from nonhema-turic areas, for a period of 4 years. Eight of these 12 controlswere autopsied at the end of the study. The other 4 animals inthis group are still under observation. All of the test animalsand the other 2 control animals received the same basic diet oftimothy and alfalfa hay and a standard dairy feed supplement(1% salt, 27% corn, 27% bran, 27% oats, and 18% linseed oilmeal). The calculated amount of chopiied bracken, either driedor fresh, was mixed with the basic diet given individually toeach test animal once a day. The feeding experiment was startedon June 1, 1961, and continued for more than 4 years.

The clinical signs and symptoms displayed by the test andcontrol animals were closely observed and recorded. Urine wasexamined for blood periodically. Blood cell counts and differential leukocyte counts were made. Necropsy was ijerformed on

each animal after it died or was killed. The urinary bladderswere distended postmortem with 10% formalin solution injectedinto the urethra. After the fixation of the bladder, a specimenwas taken for histologie examination. The paraffin sections werestained with hematoxylin and eosin. Special staining methodswere used when necessary, but all photomicrographs (Figs. 2-12) were from sections stained with hematoxylin and eosin. Theurinary bladders of all but 4 of the control animals were obtainedand examined for comparison with those of the test animals.

RESULTS

The development of manifestations of toxicity apj>eared to bedÃ©tendentupon the amount of bracken fern fed to each animal.Signs typical of poisoning api>eared in 3 animals (Cows 2, 3, and4) out of 7 in the 1st group in a j^eriod of 46 to 67 days after theadministration of 600 gm of dried or 1000 gm of fresh brackenper day. The animals in the 4th group, which received 300 gmof dried or 400 gm of fresh bracken daily, survived longer thandid the animals in the other 3 groups. However, the animals ineach group showed considerable individual variation in reactions to the toxic effects of bracken. For example, Cow 1, fed ahigh level of bracken fern, survived longer than did most of theanimals which received a smaller amount of bracken (Table 2).Three hundred gm of dried bracken per day appeared to be mostsuitable for the production of chronic toxicity and bladder neoplasms.

Clinical Findings. An early sign of chronic toxicity consisted of hematuria which began as microhematuria and thendevelo[)ed into macrohematuria, causing discoloration of theurine in a few cases. However, in 1 animal (Cow 8), macrohematuria became apparent without previous observation of microhematuria. In 8 cases (Cows 1, 5, 7, 11, 13, 14, 15, and 21), onlymicrohematuria was observed. Microhematuria associated withmacrohematuria was observed in 3 animals (Cows 6, 9, and 954).The duration of feeding had a great influence on the development and continuation of hematuria. The minimal period oftime required for producing microhematuria was 67 days ofbracken feeding. Hematuria was insidious in development andwas characterized by a slow and progressive increase with frequent intermissions of variable duration lasting from a few daysto several months. In the early stages of feeding of bracken, nosystemic disturbance of any kind was observed. There was norise in body temara ture or loss of weight.

Bracken poisoning was associated with hÃ©matologiechangesin 11 of the 18 animals. The main feature was a progressivediminution in the number of white cells and platelets in theperipheral blood. The changes reached maximum proportions afew days before the death of the animal (Table 2). The fall inthe total number of leukocytes was associated with a drasticdiminution in the number of polymorphs. The inversion of thenumbers of polymorphs and lymphocytes suggested that brackenfeeding severely damaged the bone marrow. These changes werecoincident with a fall in the numbers of the platelets in mostcases (Table 2). The blood changes apjieared not to be affectedby the duration of feeding. Cows 5, 6, 15, and 16 received brackenfor 302, 978, 327, and 276 days, respectively, and these 4 animals did not develo]) significant blood changes. In contrast withthe marked fall in the number of platelets and white cells, the

918 CANCER RESEARCH VOL. 27



Induction of Urinary Bladder Neoplasms

TABLE 2Leukocyte and Platelet Counts and Differential Leukocyte Counts of the Animals at a Late Stage of the Toxic

Keaction io Bracken Feeding

GroupNo.IIIIIIIVAnimalNo.1234578131415169111218621954Cell

countsWBC(lO'/cumm)10.07.17.37.88.03.05.02.93.07.210.01.71.31.51.00.03.54.9Platelets

(lO'/cumm)5.56.86.35.96.52.03.01.01.55.55.01.70.82.00.52.53.14.5Differentialleukocytecounts

(%)Poly-

mo rnho-nuclear26111024120000182600002885Lymphocyte5278806376100941001006806100100100100568590Mono-cyte666770600850000243Eosino-phil6546500005300001435Baso-phil000000000100000000Survival

time(days)3956752403021133602803503272769363743782189781541192Hematuria+â€”â€”â€”++++++-+++++++

number of red blood cells per cu mm remained within normallimits until severe macrohematuria and terminal hemorrhagesoccurred.

Toward the end of the experiment, a few animals exhibited aloss of condition and their hair became rough and staring. Fleshwas lost particularly from the hind quarters. Some cows did notshow any marked loss of condition. Body temperature rose toabout 107 to 108Â°Fin 9 of the 18 animals (Cows 7, 9, 11, 12,

13, 14,15,18, and 954) up to 12 days prior to death. Hemorrhagesfrom the nose and blood in the feces were observed in 6 of theseanimals with high body temperature (Cows 7, 11, 14, 15, 18,and 954). Diarrhea followed constipation in 2 animals (Cows 12and 18).

All the animals in the 4 groups fed bracken died with somesigns of bracken poisoning. Death was due to extensive internalhemorrhage or other manifestations of bracken poisoning.

The 14 animals not exposed to bracken fern did not manifestany clinical symptoms during the experiment. There were noblood changes or blood in the urine of these animals.

Postmortem Findings. The primary feature of brackenpoisoning was multiple hemorrhages throughout the carcass, buttheir degree and location varied. Hemorrhages were observed inthe subcutaneous tissues, in the fasciai planes, in the muscles,serosae, subserosae, mucosae, and submucosae. The subcutaneous tissue of the neck and the lumbar region of 3 animals (Cases1, 5, and 7) was grossly edematous and gelatinous in appearance.The mediastinum and subpleural tissue of the right lung of 1animal had a similar gelatinous appearance. Although they lost

weight, the animals were not very emaciated since subcutaneousand omental fat was present.

Hemorrhages were also noted in the alimentary tract, heart,gall bladder, nasal mucosa, tongue, larynx, trachea, lungs, andpancreas; in the capsule of the spleen but not in its substance;under the capsules and in the hili of lymph nodes; under thecapsules of the adrenal glands and thyroid; in the mammarygland, ovaries, uterus, cervix, and kidneys; in the aorta; externalto and in the dura mater and under the pia mater. No hemorrhages were observed in the brain itself, and there were no hemorrhages into the joint cavities.

By gross inspection, small white necrotic areas from pin-pointsize up to 5 cm in diameter were noted in the liver of 11 animals(Cows 1, 4, 5, 7, 11, 12, 13, 14, 15, 18, and 21). The subcapsularlesions tended to be triangular in section. In Cows 9 and 16, thelesions were yellow in color and were often near a portal vein.

In every cow fed bracken, there were multiple submucosalhemorrhages extending throughout the urinary tract from thecalyces of the kidneys to the urethra. The degree of hemorrhagevaried from pin-point lesions to confluent hemorrhages showing

almost complete infiltration of the submucosa. There was noobvious gross ulcÃ©ration.Pieris cuÂ¿uÃ¼inaalso caused hyperplasticand neoplastia changes in the epithelial and stromal layers ofthe urinary bladder in 10 of the 18 animals.

Tumors were observed macroscopically in only 3 animals(Cows 6, 9, and 954), and in 7 animals (Cows 1, 8, 11, 12, 13,15, and 16) more clearly microscopically (Table 3). The macro-

MAY 1967 919



A. M. Pamukcu, S. K. GÃ¶ksoy,and J. M. Price

TABLE 3Salient Features of Urinary Bladder Tumors Induced by Bracken Feeding and Survival Time of Animals

GroupNo.IIIIIIIVAnimalNo.18131516911126954Bracken

consumed(kg/animal)Fresh6000183(>189030304872Dried192180125134123285120114249292Survivaltime

(days)3953602803272769363743789781192Histologie

classification oftumorsEpithelialPapillomaPapillomaPapillomaPapilloma

andtransitionalcellcarcinomaPapillomaEpithelial

andstromalPapilloma

and capillaryhemangiomaTransitional

cell carcinoma andheman-gioendotheliomaCapillary

hemangiomaSquamouscell car

cinoma and hemangiomaStromalFibroma

scopic api>earance of tumors in these 3 cases (Cows 6, 9, and954) is described below.

Case 6. Hemangiomas were situated at various sites in themucosa of the urinary bladder as dark-red patches varying froma pinhead up to a few cm in diameter. They were of rather firmconsistency. The tumors were capillary hemangiomas (Fig. 12).

Case 9. Lesions in the bladder consisted of a vascular growthand multiple sessile nodules. The vascular tumor was located atthe trigone region of the bladder. It presented as a dark-red,sharply defined patch 1 by 3 cm in size. The tumor was of softconsistency, and blood could be expressed from it by pressure.Histologie examination revealed that the tumor was a hemangio-endothelioma. The multiple sessile nodules which were firm andgrayish white in color were distributed throughout the bladdermucosa. The surface epithelium was smooth. The nodules werefirmly attached to the mucosa and were histologically diagnosedas transitional cell carcinoma. The tumors were contiguousand infiltrated the submucosa. No metastasis was detected.

Case 954. The bladder contained a large blood clot. Lesions inthe bladder consisted of small congested patches of mucousmembrane, punctate hemorrhagic foci, papillomas, and domelikenodules distributed throughout the bladder (Fig. 1). The wallof the bladder was greatly thickened. The tumors infiltrated intothe muscular coat and reached the subserosa. The serosal surfaceof the bladder was nodular. No metastasis to the iliac lymphnodes or to distant organs was detected (Figs. 7-10).

Histologie findings. Microscopically, the main lesions werehemorrhages scattered throughout the various organs. Thepathologic changes in the livers consisted of centrilobularnecrosis, fatty degeneration, hemorrhagic or ischemie infarctsassociated with bacteria or fibrin, and occasionally infiltration

with small round cells and mononuclear cells in the portal triad,particularly in relation to infarcts. No fibrosis was found (Fig.2). The wedge-shaped hemorrhagic areas seen under the capsuleof kidneys were infarcts.

The histologie changes in the urinary bladders showed greatvariations (Figs. 3-6), including hy|x>rplastic, metaplastic, andneoplastic changes. The histology of the lesions (Figs. 7-9, 12)was similar to that described by others (17, 18) for the spontaneous Ijovine bladder cancers. The tumors of epithelial ormesenchymal origin developed in the urinary bladder of 10 ofthe 18 cows which survived for a prolonged jxriod of brackenfeeding. Of these tumors, 7 were benign, including transitionalcell papillomas, a fibroma, and capillary hemangiomas. Theremaining 3 tumors were found to be malignant neoplasms consisting of transitional or squamous cell carcinomas and a hemangi-oendothelioma (Table 3). A relatively high incidence of tumorsand a high degree of malignancy followed bracken feeding lastinglonger than 1 year. Two of the 3 carcinomas (Cases 9 and 954)developed in animals that survived more than 936 days andpenetrated the muscle wall (Figs. 9, 10), whereas the othercarcinoma (Case 11) developed in only 374 days and was confinedto the submucosa (Fig. 11). No gross or microscopic metastasiswas found in any of the animals.

The urinary bladders of the 10 control animals did not showany gross or microscopic changes. These 10 controls and the 4living controls did not have hematuria, blood changes, or othersigns or symptoms.

DISCUSSION

The hypothesis that bracken fern may be related to the etiologyof bovine urinary bladder tumors obtained its first experimental





support in the relatively long-term feeding trials by Rosenbergerand Heeschen (23) and Pamukcu (20). Recently, Evans andMason (4) produced intestinal adenocarcinoma in rats withbracken feeding. The effect of ingestion of bracken on theconstituents in the urine of cattle was studied by Doebereiner(3), who found no detectable differences with respect to contentof diazotizable aromatic amines or phenols. Biologic tests (10-12,21), however, have demonstrated that urine from cattle in thehematuria regions, from cows fed hay from the hematuriadistricts, or from cattle fed bracken fern contained some carcinogenic agent which induced tumors in the bladders of the calf,dog, rat, or mouse and tumors in the skin of mice. The presentstudies demonstrated that bracken contained one or more substances which induced a relatively high incidence of benigntumors and carcinomas in the bladders of 18 cows (Table 3).The development of malignant tumors in the transitional epithelium of the bovine bladder required a long period of feeding ofa low level of bracken. The carcinomas (Grade II) developed in2 cases (Cows 9 and 954) about 3 years after the initiation offeeding. The animals in each feeding group at different levels ofbracken in the diet showed considerable individual variation intheir reaction to the toxic effects of bracken. Ingestion of 300gm of dried bracken per day appeared to be relatively nontoxicand most suitable for producing chronic toxicity and neoplasmsin cows weighing from 100 to 150 kg. Toxicity in the animals wasassociated with an inversion of the numbers of polymorphs andlymphocytes. This inversion was coincident with the fall in thenumbers of thrombocytes in most cases. Platelet and differentialleukocyte counts might be used as a guide to monitor Â¡mendingserious acute toxicity.

The nature of the carcinogenic substance in bracken and inthe urine of cows fed bracken has not been determined. A varietyof chemicals, suchasastragalin, isoquercitrin, rutin (15), catechol-tannins, pteraquilin, sugar, starch, aliphatic nondrying oil, andmuch pectose mucin (13), have been identified in bracken; yetthere is no indication that these chemicals or their metabolitesmay be bladder carcinogens.

The results obtained in this study are in agreement with thefindings of others (10-12, 20, 21) who have presented evidence

for the carcinogenic activity of bracken fern. Although the number of animals in the present study was small, the histologiespectrum of the lesions resembles that found naturally occurringin cattle in the disease areas. Accordingly, it appears that theresults obtained in this study represent the first successfulattempt to produce the natural disease under laboratoryconditions.

REFERENCES

1. Brobst. D. F., and Olson, C. Neoplastic and ProliferativeLesions of the Bovine Urinary Bladder. Am. J. Vet. Res.,84: 105-111, 1963.

2. Brobst, D. F., and Olson, C. Histopathology of UrinaryBladder Tumors Induced by Bovine Cutaneous PapillomaAgent. Cancer Res., 25: 12-19, 1965.

3. Doebereiner, J. Chromatography of Urine from Cattle FedBracken Fern (Pteridium aquilinum (L.) KÃ¼hn).M.S. Thesis,University of Wisconsin, 1963.

4. Evans, I. A., and Mason, J. Carcinogenic Activity of Bracken.Nature, S08: 913-914, 1965.

5. Evans, W. C. Bracken Poisoning of Farm Animals. Vet.Record, 76: 365-369, 1964.

6. Evans, W. C., Evans, E. T. R., and Hughes, L. E. Studies onBracken Poisoning in Cattle. I. Brit. Vet. J., 110: 295-306,1954.

7. Evans, W. C., Evans, E. T. R., and Hughes, L. E. Studies onBracken Poisoning in Cattle. II. 1950 Bracken PoisoningExperiments (Lluest Farm). Brit. Vet. J., 110: 365-380, 1954.

8. Evans, W. C., Evans, E. T. R., and Hughes, L. E. Studies onBracken Poisoning in Cattle. III. Field Outbreaks of BovineBracken Poisoning. Brit. Vet. J., 110: 426-442, 1954.

9. Evans, W. C., Evans, I. A., Thomas, A. J., Watkins, J. E.,and Chamberlain, A. G. Studies on Bracken Poisoning inCattle. IV. Brit. Vet. J., 114: 180-198, 1958.

10. Georgiev, R., and Antonov, S. Ãœberdie Ã„tiologie der chronischen vesikalen HÃ¤maturie der Rinder. II. Mitteilung. Versuche zur Feststellung der Anwesenheit kanzerogenerMetaboliten im Harn gesunder KÃ¼heaus einem HÃ¤maturie-freien Gebiet bei FÃ¼ttsrung mit Heu aus HÃ¤maturiegebieten.Wien. Tieraerztl. Monatsschr., 6%:90-94, 1965.

11. Georgiev, R., Antonov, S., Vrigasov, A., Dimitrov, A., andGoranov, C. Ãœber die Ã„tiologie der chronischen vesikalenHÃ¤maturie der Rinder. I. Mitteilung. Zur Frage des karzino-matÃ¶sen Charakters der chronischen vesikalen HÃ¤maturie derRinder. Wien. Tieraerztl. Monatsschr., 51: 641-657, 1964.

12. Georgiev, R., Vrigasov, A., Antonov, S., and Dimitrov, A.Versuche zur Feststellung der Anwesenheit kanzerogenerStoffe im Harn der mit Heu aus HÃ¤maturiegebieten gefÃ¼ttertenKÃ¼he.Wien. Tieraerztl. Monatsschr., 50: 589-595, 1963.

13. Kwasniewski, V. Die Inhaltstoffe der Rhizome des Adlerfarns,Pteridium aquilinum (L.) KÃ¼hn. Arch. Pharm., 888: 307-311,1955.

14. Mostofi, F. K. Pathology of Cancer of Bladder. Acta UniÃ³Intern. Contra Cancrum, 18: 611-615, 1962.

15. Nakabayashi, T. Isolation of Astragalin and Isoquercitrinfrom Bracken, Pteridium aquilinum. Bull. Agr. Chem. Soc.Japan, 19: 104-109, 1955.

16. Olson, C., Pamukcu, A. M., and Brobst, D. F. Papilloma-likeVirus from Bovine Urinary Bladder Tumors. Cancer Res.,25: 840-849, 1965.

17. Pamukcu, A. M. Investigations on the Pathology of EnzooticBovine Haematuria in Turkey. Zentr. Veterinaermed., 2:409-429, 1955.

18. Pamukcu, A. M. Tumors of the Urinary Bladder in Cattle andWater Buffalo Affected with Enzootic Bovine Hematuria.Zentr. Veterinaermed., 4: 185-197, 1957.

19. Pamukcu, A. M. Tumors of the Urinary Bladder in Cattle,with Special Reference to Etiology and Histogenesis. Acta UniÃ³Intern. Contra Cancrum, 18: 625-638, 1962.

20. Pamukcu, A. M. Epidemiologie Studies on Urinary BladderTumors in Turkish Cattle. Ann. N. Y. Acad. Sci., 108:938-947,1963.

21. Pamukcu, A. M., Olson, C., and Price, J. M. Assay of Fractionsof Bovine Urine for Carcinogenic Activity after FeedingBracken Fern (Pteris aquilina). Cancer Res., 26: 1745-1753,

1966.22. Parker, W. H., and McCrea, C. T. Bracken (Pteris aquilina)

Poisoning of Sheep in the North York Moors. Vet. Ree.,77: 861-865, 1965. Cited by Evans and Mason (4).

23. Rosenberger, G., and Heeschan, W. Adlerfarn (Pterisaquilina)â€”die Ursache des sog. Stallrotes der Rinder (Haema

turia vesicalis bovis chronica). Deut. Tieraerztl. Wochschr.,67: 201-208, 19GO.

MAY 1967 921




FIG. 1. Case 954. Multiple hemangiomas and round tumor masses in the mucosa of the opened urinary bladder of a cow fed brackenfor 1192days.

FIG. 2. Case 954. Widespread centrilobular necrosis in the liver. X 115.FIG. 3. Case 6. Bladder showing solid ingrowths of epithelium into subepithelial tissue (Brunn's nest) and chronic inflammation of

the bladder wall. X 250.FIG. 4. Case 11. Moderate hyperplasia of transitional epithelium with some cells showing hydropic degeneration. Branched crypts

lined with transitional epithelium (cystitis glandularis). X 140.FIG. 5. Case 6. Marked hyperplasia of transitional epithelium wit h many cells showing hydropic degeneration and deep-seated branched

crypts lined with transitional epithelium. The distinction between hyperplasia and benign neoplasia is difficult with this type oflesion. X 140.

FIG. 6. Case 11. Transitional cell papilloma. X 95.FIG. 7. Case 954. Glandular metaplasia of enteric type and chronic inflammatory infiltration of the bladder wall. X 115.FIG. 8. Case 954. Squamous cell carcinoma. X 115.FIG. 9. Case 954. Squamous cell carcinoma infiltrating into the submucosa. X 115.FIG. 10. Case 954. From same section as Fig. 9. Note infiltration of cells of Squamous cell carcinoma into the bladder wall. X 115.FIG. 11. Case 11. Transitional cell carcinoma infiltrating into the wall of the bladder. X 250.FIG. 12. Case 0. Capillary hemangioma. X 250.





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MAY 1967 923




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CANCER RESEARCH VOL. 27



1967;27:917-924. Cancer Res A. M. Pamukcu, S. K. Göksoy and J. M. Price

) to CowsPteris aquilinaUrinary Bladder Neoplasms Induced by Feeding Bracken Fern (

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