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Pesquisa Veterinária Brasileira

Print version ISSN 0100-736XOn-line version ISSN 1678-5150

Pesq. Vet. Bras. vol.23 no.2 Rio de Janeiro April/June 2003

https://doi.org/10.1590/S0100-736X2003000200004 

Histopathological aspects of Bovine Enzootic Hematuria in Brazil

 

Aspectos histopatológicos da Hematúria Enzoótica Bovina no Brasil

 

 

Paulo Vargas PeixotoI, *; Ticiana do Nascimento FrançaII; Claudio S.L.BarrosIII; Carlos Hubinger TokarniaIV

IDepto Nutrição Animal e Pastagem, Instituto de Zootecnia, Universidade Federal Rural do Rio de Janeiro (UFRRJ), 23835-000 Seropédica, RJ, Brasil
IIDisciplina de Anatomia Patológica, Curso de Medicina Veterinária da Universidade Estácio de Sá, Estrada Boca do Mato 850, Vargem Pequena, Rio de Janeiro 22783-320, Brasil. E-mail: ticiana@uol.com.br
IIIDepto Patologia, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brasil. E-mail: claudioslbarros@uol.com.br
IVDepto Nutrição Animal e Pastagem, Instituto de Zootecnia, UFRRJ. E-mail: tokarnia@ufrrj.br

 

 


ABSTRACT

The bladder lesions of 59 cattle, from the States of Rio de Janeiro, São Paulo, Minas Gerais, Espírito Santo, Rio Grande do Sul, Santa Catarina, Paraná and Amazon, affected by Bovine Enzootic Haematuria (BEH), were studied histologically. The objective of this study was to describe and reclassify neoplastic and non-neoplastic alterations not yet reported, according to the more complete current nomenclature used in human medicine. There was an almost complete identity with alterations observed in the bladder of man. Due to the occurrence of two or more neoplasms in the same animal, differences in the methodology and in the concept of classification, a more precise comparison was not possible. Coexistence of different types of epithelial and/or mesenchymal tumour growth was frequently seen. Rare neoplasms or differentiations not previously described were found in the bladder of some animals affected by BEH. These were trabecular carcinoma with Paneth cells differentiation, mesonephroid adenoma, mesonephroid adenocarcinoma, "signet ring" cell carcinoma, plasmocytoid carcinoma, chromophobe cell carcinoma and nested type of transitional cell carcinoma. Haemangiosarcomas originating from haemangiomas were also observed. This study also revealed the occurrence of many tumors with anaplasia and pronounced infiltrative features, but which did not metastasize. The elucidation of the cause of this "barrier against metastases" and its relationship with chemical carcinogenesis induced by the ptaquiloside, the active principle of bracken fern (Pteridium aquilinum), could be of interest to future research on the control ofneoplasia in man and animals.

Index terms: Histopathology, Bovine Enzootic Hematuria, bladder tumors, Pteridium aquilinum, Brazil


RESUMO

Com o objetivo de descrever alterações neoplásicas e não-neoplásicas ainda não relatadas e, paralelamente, reclassificá-las de acordo com nomenclatura mais completa e atual utilizada em medicina humana, foram estudadas, histologicamente, lesões da bexiga de 59 bovinos com Hematúria Enzoótica (HEB), oriundos dos Estados do Rio de Janeiro, São Paulo, Minas Gerais, Espírito Santo, Rio Grande do Sul, Santa Catarina, Paraná e Amazonas.Verificou-se, em termos qualitativos, quase uma perfeita identidade com as lesões de bexiga observadas em seres humanos. Comparações mais exatas com relação à freqüência dessas alterações ficaram prejudicadas, dadas a ocorrência de duas ou mais neoplasias em um mesmo animal e as diferenças da metodologia empregada ou do conceito de classificação. Coexistência entre neoplasias diversas, epiteliais e/ou mesenquimais, foi vista com freqüência. Neoplasias ou diferenciações raras, ainda não descritas na bexiga de bovinos, como carcinoma trabecular com diferenciação em células de Paneth, adenoma e adenocarcinoma mesonefróides, carcinoma "signet ring" (anel de sinete), carcinoma plasmocitóide, carcinoma de células cromófobas e carcinoma transicional tipo ninhado foram observadas na bexiga de alguns animais com HEB. Foram verificados hemangiossarcomas proliferando a partir de hemangiomas.O estudo revelou, ainda, a ocorrência de diversos tumores com anaplasia e carácter infiltrativo acentuados, incapazes, porém, de metastizarem. O esclarecimento da(s) causa(s) dessa "barreira à metástase" e suas relações com a carcinogênese química induzida pelo ptaquilosídeo, o princípio ativo de Pteridium aquilinum, talvez possa ser de interesse em futuros estudos que visem combater o câncer no homem e nos animais.

Termos de indexação: Histopatologia, Hematúria enzoótica bovina, tumores de bexiga, Pteridium aquilinum, Brasil.


 

 

INTRODUCTION

Pteridium aquilinum (L.) Kuhn, a poisonous plant known as bracken fern, has been registered in almost all continents; it has a wide distribution in Brazil. This plant causes different pathological symptoms, mainly because it contains two different toxic principles: one radiomimetic carcinogenic compound, the norsesquiterpene ptaquiloside (Hirono et al. 1984) and a thiaminase type I (Evans et al. 1963, Evans 1976).

Depending on the period during which the plant is eaten and on the amount ingested (Tokarnia et al. 2000), the radiomimetic principle is responsible for three different clinical-pathological pictures, observed mainly in cattle: hemorrhagic diathesis (HD) (Sippel 1952, Evans et al. 1954, Naftalin & Cushnie 1954), bovine enzootic hematuria (BEH) (Heeschen 1959, Rosenberger & Heeschen 1960, Rosenberger 1965, Döbereiner et al. 1967) and carcinomas of the upper digestive tract (CUDT) (Döbereiner et al. 1967, Tokarnia et al. 1969, Pirie 1973).

The nature of the bladder tumors, associated with the ingestion of P. aquilinum, is quite peculiar. Epithelial tumors, aswell as mesenchymal tumors have been described, beside the strange capacity to induce different neoplasms in a same animal (Tokarnia et al. 2000).

Histological examination of new cases of bovine enzootic hematuria revealed several undescribed bladder neoplasms. The microscopic reexamination and reclassification of cases originating from previous publications (Döbereiner et al. 1967, Tokarnia et al. 1969) was also performed to standardize and update the diagnoses according to the most recent nomenclature.

The aim of this paper is to characterize and to describe histologically neoplastic and non-neoplastic bladder lesions of cattle, not yet reported in scientific papers on BEH. At the same time, previously described lesions have been reclassified adopting the more complete nomenclature currently used in human medicine. It is hoped that this will call attention to improvements in veterinary pathology.

 

MATERIAL AND METHODS

Local.The study was developed in the Section of Pathology, of the Convênio Embrapa/Universidade Federal of Rio de Janeiro (UFRRJ), located at Km 47, Seropédica, Rio de Janeiro.

Appraised cases. From 59 histologically-examined cases, 15 originating from Rio de Janeiro, São Paulo, Minas Gerais, Paraná, Amazônia, Espírito Santo, were seen during the routine work of the Section of Pathological Anatomy (Embrapa/UFRRJ), 8 cases during routine work of the Veterinary Pathology Section of the Federal University of Santa Maria (UFSM/Rio Grande do Sul), 17 cases, part of which were processed at UFSM/RS and another part at Embrapa/ UFRRJ originating from São Paulo, and 19 belonging to the studies published by Döbereiner et al. (1967) and by Tokarnia et al. (1969) (originating from Espírito Santo, Minas Gerais, Rio de Janeiro and Santa Catarina).

Material. Most of the analyzed material was stored in paraffin blocks or already prepared tissues sections. Some old tissue sections were discolored with acetic acid and stained again with hematoxilineosin (HE). The materials in paraffin blocks were cut 5 micrometers thick, stained with HE and submitted to histopathological examination. In some cases special colorations were made by PAS (Schiff's reagent), toluidine blue or Masson's trichrome stain for connective tissue. The tissue sections were examined by optical microscopy. Animals submitted to us for post-mortem examination, had their organs collected immediately after death. The fragments for histopathological study were fixed in 10% formalin and processed by the usual methods.

Methodology used for classification and counting of the tumors. As there is no recent and complete histological classification of the bladder tumors of domestic animals in the literature, this study was based on human medical classifications used by the Armed Forces Institute of Pathology of the United States of America (AFIP), elaborated by Murphy et al. (1994) and on the nomenclature of the book Ackerman's Surgical Pathology, used by Ordónez & Rosai (1996). These were compared with the International Histological Classification of Tumors of Domestic Animals of the World Health Organization (WHO), elaborated for bladder tumors by Pamukçu (1974). Some animals had more than one tumor. Neoplastic processes, visualized separately in a section, without physical proximity, were classified separately. When the tumors occupied small areas and were of different morphology, distinguishing themselves from most of the neoplasm, these areas were considered as differentiations and not as separate tumors.

 

RESULTS

The changes found in the bladder of the animals were divided into neoplastic and non-neoplastic; the last ones were subdivided into inflammatory, hyperplastic and metaplastic. The coexistence among them was almost constant, and the frequent simultaneous occurrence of several of them was observed in the same bladder, as can be seen in Tables 1-5 and Fig. 1-9. Due to these miscellaneous lesions, it was frequently difficult or impossible to establish which was the main alteration and the chronological order of emergence of these lesions, as the tumors and the metaplastic alterations seemed to arise, at the same time, on several sites of the mucous membrane. However, only a few bladder fragments were available from many animals. In some cases there was a clear "differentiation" of one type of tissue into another at the same location. For instance, foci of hyperplastic urothelium with "intestinal" or mesonephroid changes differentiated at the base into carcinoma "in situ" or into "intestinal" adenocarcinoma, sometimes already with a clear infiltrative tendency. In other animals, evident hyperplastic, metaplastic and/or neoplastic cellular proliferation, at areas distant from one to another was verified, which characterizes multicentric lesions with different types of differentiation. This was also observed in mesenchymal tissues, since part of the hemangiomas and hemangiosarcomas seemed to be related to or originated from focal or multifocal proliferation of small vessels morphologically of normal aspect. In fact, this last alteration was verified in many of the examinated bladders. In a consistant way, predominantly lymphocytic inflammatory infiltration, sometimes accompanied by plasmocytes, diffuse and/or in the form of lymphoid follicles, went with the phenomena of cellular proliferation, amid variable degrees of fibroplasia of the propria among the muscle fascicles (detrusor muscle) and even at the serosa. In summary, the diversity and the coexistence of the different histological alterationscan be seen in the tables.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DISCUSSION

The diversity of the neoplasms observed in bovines with BEH is surprising, especially when we consider the small variation in the occurrence of bladder tumors in other species of domestic animals. On the other hand, there is almost a perfect identity with the neoplastic processes that are found in the human bladder. Almost the only significant differences were in the frequency in some processes seen in the bladder of cattle with BEH compared to humans.

It is very likely that in human bladder tumors the variability is associated to the three embryonic segments that participate in the formation of the bladder, which are portions of the mesonephric ducts, the mesenchyma that surrounds the urogenital protuberance and the infra-umbilical portion of the abdominal wall (Murphy et al. 1994). In fact, embryo-genesis makes it easier to understand the reason for the presence of the neoplastic and metaplastic alterations identical to renal and intestinal tissues in the bladder of cattle and human beings. It would be interesting to verify the exact correlation between the different portions of the bladder (in agreement with the embryogenesis) and the frequency of the various types of neoplasm. In this study that aspect could not be considered because the whole bladder was only available in a few cases. Most of the received fragments were collected at random from several parts of the bladder, mainly from areas that presented macroscopic alterations; therefore areas of the bladder without evident macroscopic lesions, but with possible significant microscopic alterations, were excluded from this study. Even so, why one and the same carcinogenic agent can give origin to different neoplasms in the same animal, is still a mystery. Possibly there is a relationship between the period during which the plant is ingested and the amount of carcinogens contained in the plant in each outbreak. Pamukçu et al. (1967) mentions the largest frequency of transitional carcinomas in bovines that survived for longer time.

Regarding the incidence of the main neoplasms found in cattle with BEH in our study, it is not easy to make exact comparisons with the data found in the literature. First, because few authors mention the frequency of the different histological types. This comparison is also very difficult to make because, in many cases, the animals present two or more types of neoplasm. Another problem for the exact determination of the frequency of these neoplasms is the possible variation in the nomenclature used by different pathologists. This has also been mentioned by Murphy et al. (1994) in relation to bladder neoplasms in man. Lesions interpreted as "severe dysplasia" by some authors, were considered as neoplastic by others.

In a similar way, the methodology and/or the criteria used in the evaluation, also has influence on classification.For example in their studies Pamukçu et al. (1976) and McKenzie (1978) apparently included only animals with true neoplasms. In our survey, we also included animals with BEH that presented only non-neoplastic alterations. These were 22% of the total.

At this point we think it opportune to mention that BEH can also be caused by inflammatory and vascular alterations, without the presence of neoplasms (Rosenberger & Heeschen 1960, Muller et al. 1975, Nielsen & Moulton 1990, Tokarnia et al. 2000). For this reason we preferred to include cases in which neoplasms were not present. This should be taken into account in the interpretation of the results.

Nevertheless, some of the data found by us are more or less consistent with those in the literature. For instance, we found 44% of carcinomas of transition cells (CCT), a number close to the 32.5% of CCT observed in cattle and buffalos with BEH in Turkey (Pamukçu et al. 1976). Natural occurring transitional carcinomas, also were observed more frequently in the bladder of sheep (McCrea & Head 1981). Additionally we found 42.3% carcinomas "in situ". Similar proportions were also verified regarding transitional cell papillomas of (PCT), 17% and 16.9% in the studies of Pamukçu (1974) and in our series, respectively. Though, in another work, Pamukcu et al. (1976) verified 24% of PCT. In these studies adenomas were rare (3.5%); in our series they amounted to 10.1% of the tumors. But the number of epidermoid carcinomas (16.9%) observed by us was higher, and that of adenocarcinomas (8.4%) was slightly lower (excluding the mesonephroid adenocarcinoma), when compared with those reported by Pamukçu et al. (1976), which were 10.7% and 13.6%, respectively.

Transitional epithelium neoplasms (more or less differentiated) are frequent in animals (Pamukcu 1974, Pamukcu et al. 1976, Nielsen & Moulton 1990) and in man (Murphy et al. 1994, Ordónez & Rosai 1996). However, there are some differentiations described as rare or infrequent for humans (Murphy et al. 1994, Ordónez & Rosai 1996) not mentioned in the veterinary literature that occurred with more or less significant prevalence in our cases of BEH. For example, neoplastic and metaplastic processes with nephrogenic (mesonephroid) characteristics can be mentioned. Beside this we verified intermediate differentiation between urothelial hyperplasia, metaplasia, nephrogenic adenoma and adenocarcinoma. Other authors, however, do not mention or do not believe in the occurrence of nephrogenic adenocarcinomas even in man (Murphy et al. 1994).

Trabecular carcinoma with Paneth cell differentiation, mesonephroid adenoma, mesonephroid adenocarcinoma, "signet ring"cell carcinoma, plasmocytoid carcinoma, chromophobe cell carcinoma and nested type of transitional carcinoma, although rare in our study, have not yet been described in the bladder of cattle with BEH.

Regarding mesenchymal tumors, we observed a high number of vascular neoplasias (84.7%, being 25.4% hemangiosarcomas and 59.3% hemangiomas), a fact also observed in Australia (84.1%, McKenzie 1978). In cattle with BEH in Turkey, these indexes were lower (56.1% - Pamuku et al. 1976). In Japan angiomas (87.8%) were more frequently observed (Maeda 1978).

The coexistence of tumors with elements of epithelial and mesenchymal origin, as well as the concomitance of two or more types of tumors of the same origin, in only one animal, also complicates the attempt to determine the frequency of the neoplasms which occur in BEH. Pamukcu et al. (1976) verified the simultaneous occurrence of mesenchymal and epithelial tumors in 54% of cases of BEH, while we verified this in 30.5% and McKenzie (1978) in 15.7%. Maeda (1978) observed two or more tumor types in 54.5% of the bovines. Part of this discrepancy may be due to the criteria of classification or the methodology used. For instance, we made the computation on the total of the animals with BEH (59), however 13 of them (22%) presented only non-neoplastic alterations. If the computation would be made only on the animals with neoplasias, as apparently used by the authors mentioned above, the percentage in our study would rise to 39.1%.

In the cases of BEH with pure epithelial neoplasms (including here the cases with two or more epithelial neoplasms) we found a percentage of 33.8% (or 42.5%, leaving out of the calculation the non-neoplastic changes), against 35% (Pamukcu et al. 1976) and 15.7% (McKenzie 1978).

In respect to the mesenchymal tumors, a percentage of 9% (Pamukcu et al. 1976) and 15.2% (our study) again contrasts with the 68.4% found by McKenzie (1978). Although it is just a hypothesis, it may be that those discrepancies are due to the fact that the outbreaks of BEH described in that last paper were due to the ingestion of Pteridium esculentum (3 properties) or Cheilantes sieberi (4 properties), that could contain carcinogens with different activity/intensity from that of P. aquilinum.

The biological behavior of the alterations that occur in the bladder of animals with BEH is difficult to understand. For instance: neoplasias with severe anaplasia and evident infiltrative potentiality (infiltration in the detrusor muscle and even in the serosa), with vascular invasion, rarely are capable of metastasizing into regional lymph nodes and other organs. In man, metastases of transitional carcinoma usually are associated with tumorous invasion into the muscular wall and, have even been observed in regional lymph nodes of 14% of the patients with superficial neoplasias (Murphy et al. 1994). This point had already been mentioned by Tokarnia et al. (2000). The most logical explanation is that the local immunological reaction would impede the spread of the neoplasia. In fact, as reported by other authors (Rosenberger & Heeschen 1960, Döbereiner et al. 1967, Tokarnia et al. 1969, Smith & Beatson 1970), we also observed inflammatory infiltration, predominantly lymphocytic, diffuse or focal, with variable degrees of intensity. This inflammation accompanied several types of benign and maligne tumors, however it was more frequent and intense in more aggressive neoplasias. On the other hand, diffuse lymphocytic infiltration and formation of lymphoid foci also occurred in bladders without neoplastic processes. Therefore these findings do not allow a simple correlation between this type of inflammation and some metaplastic or specific neoplastic alterations or with a specific protective alteration against tecidual infiltration of the neoplasia or metastases. Still, we registered cases with unequivocal presence of neoplastic cells in vessels, without signs of distant metastases. The elucidation of the cause(s) of this "barrier against metastases" and their relationship with the chemical carcinogenesis induced by the ptaquiloside may be of interest in future studies that aim to combat cancer in man and animals.

Eosinophils were also seen in neoplasms, mainly squamous cell carcinomas or areas of squamous differentiation and their presence is correlated with the antigenicity of the keratin present in these tumors (Murphy et al. 1994). In one case, we observed eosinophilic infiltration of an hemangioma and also under the urothelium together with lymphocytic infiltration (29279). We can not explain the presence of the eosinophils in this case.

Regarding the nomenclature and classification of general pathology, the term metaplasia is used for malignant tumors (Nielsen & Moulton 1990, Ordónez & Rosai 1996). However as it defines the transition of a morphologically normal tissue into another, it does not seem logical to use it for neoplastic proliferations. The word differentiation seems to us more appropriate. On the other hand, small variations between the different classifications in nomenclature sometimes just reflect a preference for one or other term. For instance, the alteration denominated carcinoma "in situ" by us is classified by some authors as dysplasia degree IV. We opted for the first designation, in function of the marked anaplasia present in these alterations. We also preferred to use the term transitional or squamous carcinoma with areas of pseudo-glandular differentiation to the one of carcinoma of transitional cells with lumen similar to the gland, used by AFIP (Murphy et al. 1994), because we observed this alteration in transitional and squamous carcinomas, while Murphy et al. (1994) mention this only in transitional carcinomas, in which the "glandular" spaces are surrounded by epithelium with pseudo stratified appearance and the superficial cells differentiate into transitional epithelium. In our cases, the "gland" structures are formed following the necrosis of transitional and squamous tumorous cells.

Beside the intestinal metaplasia observed in part of the Brunn nests, that characterizes the so called Cystitis glandularis or intestinal mataplasia, we also verified, in a small number of cases, squamous, mesonephroid and mesonephroid type cell chromophobe metaplasia, in thesestructures, lesions not yet described in veterinary medicine. Still regarding metaplastic processes we also found foci of intestinal metaplasia, close to carcinomas, in areas of transitional hyperplastic epithelium (case 24581). There were also coexistence or intermediate phases between several types of metaplasia. An intermediate phase was observed between intestinal metaplasia and mesonephroid proliferation (case 24496), characterized by a bistratified metaplastic process, mostly with basal polar nuclei, cylindrical or basal nuclei perpendicular to each other, layer for layer. In several cases, the dysplastic changes occurred on different sites, at the same time. Beside this, we verified that parts of the carcinomas "in situ" were associated with the formation of multicentric epithelial neoplasms. These data corroborate with the statement of Nielsen & Moulton (1990) that the occurrence of the lesions is associated with the exhibition of different areas to the carcinogens.

We noted that part of the transitional carcinomas with spindle cell stroma and with pseudoglandular differentiation had a marked similarity with carcinomas of the uterus of cows. We had difficulty in the differentiation between sarcomatoid carcinoma, carcinosarcoma and carcinoma with spindle cell stroma, since the fusiform portion of these neoplasms closely resemble each other. The exact determination, in our opinion, is only possible through immunohistochemistry and/or electron microscopy, which can be accomplished in future studies.

In two cases, we found contiguous neoplasms, the so-called "collision of tumors"; in the first case (24581) a neoplasm of more invasive growth (transitional carcinoma) invaded the other (cavernous hemangioma) of more expansible growth. In the other case (V-274-90) a squamous carcinoma infiltrating a hemangiosarcoma was observed.

A well differentiated proliferation of blood vessels in the propria, diffuse or localized to greater or smaller degree, was observed in all animals. In some animals this process was accompanied by dysplasia and hyperplasia of vessels of the stroma and vessels of the bladder muscles, besides metaplastic alterations of the connective tissue surrounding those vessels, into mixoid connective tissue (cases 24582 and 28231).

Other processes were also found inside some vessels, such as the proliferation of endothelial cells of the intima of arteries, forming small "papillae" in the vascular lumen, or even of the media, with marked thickening of the vascular muscle layer (cases 24582 and V-276-90). Nielsen & Moulton (1990) refer to the occurrence of obliterant endarteritis and detachment of the vascular endothelium in the bladder of cattle affected by BEH. Ordónez & Rosai (1994) described similar lesions in the bladder of humans submitted to radiotherapy.

 

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Accepted for publication on February 5, 2003

 

 

* Autor para correspondência. E-mail: peixotop@ufrrj.br

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