Biomedical subjects
Publications and source records attributed to W Misdorp.
Dermatophytosis is the most common equine skin disease. Mycotic-like lesions that do not disappear are suspected of being sarcoids. The clinical symptoms and therapeutic interventions for both affections are discussed. A short review of the differential diagnoses is presented.
A review of research in veterinary oncology, as executed in Amsterdam and Utrecht, is presented. Also an inquiry into the cooperation between oncologist, pathologist and practitioner is discussed. It is concluded that microscopic tumour diagnosis is practized at too low a scale (+/- 30%). Veterinary oncology has significance both from the veterinary and the comparative (model) point of view. Etiologic-pathogenetic and biologic-therapeutic aspects are studied in a multidisciplinary way. Intercellular communication, growth factors and intercellular matrix are items of present and future research. Molecular-genetic research is in progress. Prevention of mammary tumours by ovariectomy (dog, cat) and of malignant lymphoma (cat) by fighting FeLV seems promising.
Epidermal growth factor (EGFR), oestrogen (ER), and progestin (PR) receptor concentrations were determined by radioligand binding assay in non-affected mammary tissues (n = 13) and benign (n = 11) and primary/locally recurrent malignant proliferative mammary lesions (n = 45) and metastases (n = 19) in 65 female dogs. The number of specimens expressing EGFR was not significantly different among these tissues, but EGFR concentration was lower in metastases (P = 0.02) than in benign or primary/locally recurrent malignant lesions not mixed with non-affected mammary tissue. The presence of non-affected mammary tissue in primary cancer specimens was noticed as a factor that may influence results of receptor measurements. No relation was found between the expression of EGFR and that of ER or PR in non-affected or in tumorous mammary tissues. It was concluded that in the dog mammary gland EGFR expression is not associated with conditions of steroid receptor absence of biological agressiveness of neoplastic growth.
Duct ectasias (n = 2) and different types of benign canine mammary tumours (n = 19) were studied immunohistochemically with monoclonal antibodies (MoAbs) directed against various human keratin types (K), alpha-smooth muscle actin, vimentin, and desmin. In the duct ectasias and in most tumours the epithelial structures revealed an inner and outer cell layer. The inner cell layer was characterized by labelling with K 7, 8, 18, 19 and mostly also with K 4 and/or K 10 MoAbs. The outer cell layer was almost invariably labelled by K 14, K 14 and 17, and a-smooth muscle actin MoAbs. The labelling patterns of both duct ectasias and tumours corresponded largely to the patterns observed in normal mammary gland tissue, although a more distinct heterogeneity was seen. Tumours histomorphologically assumed to be of a myoepithelial origin did not show immunohistochemical features of myoepithelial cells. The myoepithelial nature of the vast majority of spindle-shaped cells present in the adenomas of the complex type and in the fibroadenomas of the benign mixed type could not be confirmed immunohistochemically. These cells, however, unequivocally expressed vimentin, suggesting proliferation of stromal cells in these tumours, which in the fibroadenomas of the benign mixed type may show metaplasia to bone or cartilage. In the duct ectasias and in some tumours, a fraction of elongated stromal cells, probably representing myofibroblasts, was labelled with the alpha-smooth muscle actin MoAb.
Ten malignant canine mammary gland tumours and five metastases from three of these tumours were studied immunohistochemically with monoclonal antibodies (MoAbs) directed against different human keratin types (K), alpha-smooth muscle actin, vimentin, and desmin. In all tumours the neoplastic epithelium was rather homogeneously labelled with the keratin MoAbs RCK 102 (K 5 and 8) and CAM 5.2 (K 8). The adenocarcinomas (n = 5), the solid carcinomas (n = 2), and the carcinosarcoma (n = 1) showed heterogeneous labelling with the MoAbs specific for luminal cell antigens in the normal canine mammary gland, i.e., K 18, K 7 and K 19 MoAbs. These cells were also immunoreactive with K 4 and K 10 MoAbs. The spindle cell carcinomas (n = 2), however, did not react with these MoAbs. All tumours except one adenocarcinoma were characterized by the absence of immunoreactive labelling with the alpha-smooth muscle actin MoAb. In the solid carcinomas this was associated with the absence of labelling with one or both basal cell specific keratin MoAbs, i.e., 8.7 (K 14 and 17) and RCK 107 (K 14), respectively. In contrast, the other malignant tumours showed marked labelling of neoplastic epithelium with these MoAbs. Another remarkable finding was the labelling of a limited to moderate number of neoplastic epithelial cells with the vimentin MoAb. The presence of such labelling patterns in canine mammary gland tumours may be indicative of malignancy. Metastatic tumour tissues had a labelling pattern largely similar to that of the primary tumour, although also loss of reactivity for some keratin MoAbs was seen.
Normal canine mammary gland tissue was studied immunohistochemically with monoclonal antibodies (MoAbs) directed against various human keratin types, vimentin, desmin, and alpha-smooth muscle actin. Both ductal and alveolar luminal cells were immunoreactive with MoAbs recognizing respectively human keratins no. 7, 8, 18 and 19. In addition, some ductal luminal cells were labelled with a keratin 4 and a keratin 10 MoAb. Basal/myoepithelial cells were immunoreactive only with MoAbs directed against keratin 14, keratins 14 and 17, and alpha-smooth muscle actin. The vimentin MoAb merely labelled solitary loose intraluminal cells representing macro-phages or sloughed epithelial cells. These findings correspond largely to observations made in human breast tissue.
Expression of keratins (cytokeratins, CK) known to be suitable markers for different types of epithelial differentiation was analyzed in specimens of feline mammary tissue. A panel of specific anti-CK monoclonal antibodies (MAb) was used to determine CK distribution pattern in normal feline tissues (n = 3), and in benign (n = 18) and malignant (n = 20) feline mammary tumors. In selected tumors, the CK distribution pattern was also determined by biochemical methods. A MAb specific for alpha-smooth muscle actin was used to discriminate between myoepithelial cells and luminal epithelial cells. In normal mammary gland tissues, 6 MAb reacted exclusively, either with myoepithelial cells or with luminal epithelial cells. Luminal epithelial cells reacted with MAb specific for CK typical of simple epithelia, whereas myoepithelial cells reacted with MAb specific for CK in basal cells of stratified epithelia. A similar distribution of CK was detected in specimens from benign tumors, except that CK4 was not detected in normal mammary gland tissues and was detected in some ducts in specimens with adenosis. Almost all tumor cells in specimens from malignant tumors reacted with MAb specific for CK typical of simple epithelia. Concomitant expression of CK typical of stratified epithelia was detected in small or large subpopulations of tumor cells in 70% of carcinomas. Cytokeratins typical of basal cell layers and typical for suprabasal layers of inner stratified epithelia were detected. Cytokeratins typical of stratified epithelia were always found in areas of squamous metaplasia, but also were found in adenocarcinomal cells surrounding these areas.(ABSTRACT TRUNCATED AT 250 WORDS)
Ovarian steroid hormones and their synthetic derivatives may enhance mammary tumorigenesis in dogs and cats. In toxicity studies of synthetic progestagens a dose-related effect has been observed in the dog, with low-dose exposure sometimes being protective against mammary tumour development. There is some evidence that steroid dependence, as reflected by the presence of steroid receptors (that are nearly always present in normal mammary tissue and benign mammary tumours), is decreased in advanced stages of malignant disease, both in the dog and cat. However, this difference in steroid receptor expression between benign and malignant conditions is not related to any significant alterations in the concentration of receptors for epidermal growth factor. Progestagens have been suggested to promote mammary tumorigenesis in the dog by their induction of growth hormone overproduction; however, there is no conclusive evidence that this effect is necessary for mammary tumour induction. Basal levels of growth hormone and of prolactin were found to be similar in tumour-bearing dogs and age-matched controls.
Mammary carcinoma in the cat has a poor prognosis. Because of metastasis and local malignity, these tumours are of relevance not only to veterinary practice but also to comparative research as a model to study possible therapies and the aetiology and pathogenesis of the disease. Little is known about the development of mammary tumours in humans and companion animals. A case-control study was carried out to learn more about the role of endogenous and exogenous sex hormones. In the cat, ovariectomy (RR 0.36) had a clear protective effect against the development of mammary carcinoma, whereas regular administration of progestogens clearly increased the risk of carcinoma development (RR 2.81). Our results show that with regard to the evidence of mammary carcinoma, oestrus prevention by ovariectomy is to preferred to the administration of progestogens.
Immunohistochemical staining was performed on seven canine and 10 feline soft tissue tumours histologically diagnosed as malignant fibrous histiocytomas (MFHs) or MFH-like tumours, and eight other histologically specified tumours (non-MFH). This was done to determine if commercially available antibodies that are used routinely in human diagnostic pathology for MFHs would express the same immunohistochemical patterns in canine and feline MFHs and MFH-like tumours. The antibodies were directed against human alpha 1-anti-trypsin (AT), human alpha 1-anti-chymotrypsin (ACT), human lysozyme, bovine S-100 protein and human desmin. AT did not show any immunoreactivity in the tissues investigated. Except for one MFH, all canine MFHs and other soft tissue tumours with a 'histiocytic' character stained for lysozyme and not for S-100. Six out of seven canine MFHs and MFH-like tumours stained positive for desmin as did most non-MFH sarcomas. Most of the canine and feline MFHs and MFH-like tumours were positive for ACT. These findings for ACT staining in canine and feline MFHs and MFH-like tumours are in agreement with the findings in human MFHs. The immunohistochemical results of canine MFHs and MFH-like tumours were different from those in cats. Feline MFHs differed from canine MFHs for both lysozyme and desmin staining.
From a single spontaneous feline mammary carcinoma, two subpopulations of epithelial tumor cells have been isolated. The variant cells were established as cell lines designated K248C and K248P. DNA ploidy analysis showed that the two cell lines represented cell populations already present in the original tumor. Chromosome analysis confirmed the feline origin of K248C and K248P and demonstrated that in addition to unique marker chromosomes characteristic for each cell line, both cell lines had several marker chromosomes in common. These data suggest that the two cell populations arose from a hypothetical single ancestor which diverged during tumor progression. The K248C and K248P cell lines differed from one another with respect to their tumorigenicity in athymic mice and epidermal growth factor (EGF) receptor content. The K248C cells were highly tumorigenic as indicated by a short latency period and high take rate. The K248P cells were poorly tumorigenic. Southern blot analysis revealed that the K248C cells contained an amplified EGF receptor gene that was accompanied by elevated levels of EGF receptor RNA and protein. The K248C cells were growth inhibited in vitro at EGF concentrations that stimulated growth of K248P cells. The amplification of the EGF receptor gene could be detected only in DNA derived from K248C cells at high passage numbers and not in DNA derived from the original tumor and K248C cells at low passage numbers. These data suggest that amplification of the EGF receptor gene occurred during establishment of the K248C cell line.
UNLABELLED: Thirty cows of the Dutch Friesian and the Maas-Rijn-Ijssel breed with histologically confirmed ocular squamous cell carcinoma were treated by repeated intralesional injection of live bacillus Calmette-Guérin (BCG) (n = 14) or a BCG cell-wall vaccine (n = 16). Complete regression of the primary tumour was observed in 64% and 57% of the animals respectively. In the 2-year follow-up period there was no recurrence of primary tumours. This sharply contrasts with the recurrence frequency (40%-50%) after complete remission induced by a single intralesional injection with BCG, observed in an earlier study. In 1 animal a new primary tumour developed. At necropsy metastases were present in 33% of the treated animals: in 3 of 17 animals that showed complete regression of the primary tumour and in 7 of 13 animals with partial regression or progressive disease. This did not differ significantly from results obtained after a single treatment (27%). Delayed-type hypersensitivity to M. bovis purified protein derivative (PPD) was more persistent in animals showing regression of the primary tumour than in non-responding animals. Of the animals with a positive PPD response 6 months after treatment, 79% showed tumour regression. Regression was observed in only 28% of the animals not responding to PPD after the same period of time. IN CONCLUSION: (a) recurrence of the primary tumour was not observed after repeated BCG treatment; (b) the frequency of metastases was not decreased compared to results obtained with a single treatment; (c) regression was correlated with a positive delayed-type hypersensitivity reaction to PPD (P less than 0.05) 6 months after treatment; (d) no significant differences were observed when the clinical results of treatment with live BCG and the BCG cell wall vaccine were compared.
The capacity of steroidal regulatory influence on benign and malignant mammary tissue in cats was investigated. Estrogen, progestin, and (in some cats) androgen receptor levels in the cytosol were measured by a multiconcentration dextran-coated charcoal method in non-affected mammary tissue (NAMT) and in benign and malignant mammary lesions from 34 cats. Receptor levels less than 5 fmol/mg protein were considered negative. Since 3 out of 4 NAMT samples had low-positive estrogen receptor and progestin receptor levels, we considered specimens in which tumour cells were intermeshed with NAMT separate from "pure" tumour specimens. The variation in estrogen receptor expression between the different tissues was moderate, there being 9/17 malignant lesions (without NAMT) estrogen receptor+ as compared with 6/6 benign lesions (without NAMT) (p less than 0.05). The variation in progestin receptor expression was greater (p less than 0.02), with only 5/17 malignant lesions-(without NAMT) progestin receptor+ as compared with 6/6 benign lesions (without NAMT). The difference in progestin receptor levels between these 2 groups was also statistically significant. In 5 cats metastases were also assayed and 2 had a low-positive estrogen receptor level, whereas 1 had a low-positive progestin receptor level. Two of 9 malignant lesions (without NAMT) had positive androgen receptor levels. Comparison of the steroid receptor expression of human and feline mammary cancer indicates that estrogen receptor and progestin receptor levels are lower in the latter. This may indicate that loss of steroid hormone dependency occurs at an earlier stage of the disease in feline mammary cancer than in human breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
There is no unanimity of opinion in the literature on the existence of a, possibly dose-related, mammary tumourigenic effect of progestagens in mammals. The present report comprises three studies. In the first it was established that long-term low-dose administration of a progestational compound (lynestrenol) protected beagle dogs against mammary tumours, whereas high doses were associated with an increased risk of mammary tumours, including carcinomas. In the second, a case-control field study in dogs, it was observed that administration of low doses of progestagens to prevent estrus resulted in a slightly increased risk of benign mammary tumours but not of carcinomas. The third study, a case-control field study in cats, revealed that progestagens used for estrus prevention or treatment of dermatological problems considerably increased the risk of mammary carcinoma if given regularly, but not if given irregularly. The results of these three studies indicate a dose-related tumourigenic effect of progestagens for the development of mammary tumours in dogs and cats. Similar results have been reported for rats and non-human primates. These observations in animals may require further studies on the risk of progestagen use in man and on the mechanism of the tumourigenic action of progestagens.
In response to the need for appropriate models for monoclonal antibody guided detection and therapy of human breast cancer, we developed an allogeneic host-tumor model by injecting K248C and K248P cells into cats. A comparison between the K248C- and K248P-induced tumors with respect to biological behavior and histological appearance was made throughout the study. Allotransplantation of tumor cells was performed both in newborn cats and fetal cats between days 42 and 51 of gestation, but only tumor cells injected by the latter approach resulted in tumor growth in all animals injected. Both tumor cell lines gave rise to progressively growing tumors at the site of injection, metastatic spread of tumor cells to various organs, and death from progression 2-4 months after birth. The predominant histological appearance of the K248C and K248P allografts resembled the cribriform and tubulo-papillary growth patterns, respectively, of the original tumor from which the two cell lines were derived. Autopsy of 1-day kittens showed that metastasis started already in the fetus in the short period between injection of tumor cells and birth. Three predominant patterns of metastases were identified: the pulmonary/pleural type, the abdominal type, and the soft tissue type. A lower incidence of metastases was found in bones and brain. The K248C allografts formed significantly more metastases of the abdominal type than K248P tumors (p less than 0.05). No difference in survival was observed between animals with K248C or K248P allografts. The difference in take rate and latency period between K248C and K248P in athymic mice does not seem to be present in the feline host. The similarity of the present model to spontaneous feline and human mammary carcinoma is discussed.
The essence of the cell-matrix interaction in tissues is that cells influence the composition of the extracellular matrix but that, on the other hand, components of the matrix are also involved in the regulation of growth and differentiation of the cells. Interaction is also found to occur in tumours though in a different way, so that infiltration and metastasis and the occurrence of scirrhous carcinomas are the result. Canine and feline mammary tumours are interesting objects for the study of this interaction since fibroadenomatous changes, in which connective tissue is the predominating tissue, is a common finding in cats only, whereas mixed and complex mammary tumours, producing matrix components of varying type, are common tumours in dogs.
Flow cytometric DNA analysis was performed on biopsies from 9 nonmalignant and 111 malignant (primary and metastatic) feline mammary lesions. In our series, 46.3% of the primary mammary carcinomas appeared to be aneuploid, whereas all but one benign breast lesion were diploid. The degree of aneuploidy in carcinomas was low, with a relatively high number of primary tumors (12 of 82) displaying hypodiploidy. Aneuploidy was not found to be correlated with any specific histological tumor type, vascular invasion, tumor size, or histological malignancy grade or with the separate components thereof. Comparison of the ploidy in primary and metastatic tumors from the same cases revealed a remarkable stability, both in time and location of appearance of the metastases. It is concluded that with respect to DNA ploidy feline mammary carcinoma has more in common with canine mammary carcinoma than with human mammary carcinoma. Further prospective studies are necessary to clarify the implications of aneuploidy in feline mammary carcinoma for tumor behavior and prognosis.
Naturally occurring cancer in companion animals parallels cancer in man more closely than does experimentally induced cancer in inbred laboratory animals. In dogs and cats, as in man, a role for immune responses is indicated in the development of tumors. A survey is presented based on the literature and our own studies concerning the immunological and immunotherapeutic aspects of canine and feline mammary neoplasia. In dogs bearing mammary neoplasms, circulating immune complexes appear to play a negative role in the generation of effective antitumor immune responses. The functional role of peripheral blood lymphocytes and tumor-infiltrating lymphocytes in dogs and cats with mammary tumors is not yet fully established. No tumor antigen responsible for humoral or cellular responses has yet been identified. Extracorporeal perfusion of serum of dogs with mammary tumors and subcutaneous administration of mitomycin- and neuraminidase-treated autologous tumor cells are associated with improved prognosis. The opposite was true for i.v. treatment with BCG or Corynebacterium parvum vaccine in our study, in contrast to a previous report. A number of other treatment modalities in cats and dogs with mammary carcinomas failed to induce tumor regression. Canine and feline mammary carcinomas are good candidates for modern immunotherapeutic approaches.