W. Misdorp

Proposal of a 2-Tier Histologic Grading System for Canine Cutaneous Mast Cell Tumors to More Accurately Predict Biological Behavior

Currently, prognostic and therapeutic determinations for canine cutaneous mast cell tumors (MCTs) are primarily based on histologic grade. However, the use of different grading systems by veterinary pathologists and institutional modifications make the prognostic value of histologic grading highly questionable. To evaluate the consistency of microscopic grading among veterinary pathologists and the prognostic significance of the Patnaik grading system, 95 cutaneous MCTs from 95 dogs were graded in a blinded study by 28 veterinary pathologists from 16 institutions. Concordance among veterinary pathologists was 75% for the diagnosis of grade 3 MCTs and less than 64% for the diagnosis of grade 1 and 2 MCTs. To improve concordance among pathologists and to provide better prognostic significance, a 2-tier histologic grading system was devised. The diagnosis of high-grade MCTs is based on the presence of any one of the following criteria: at least 7 mitotic figures in 10 high-power fields (hpf); at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; at least 3 bizarre nuclei in 10 hpf; karyomegaly (ie, nuclear diameters of at least 10% of neoplastic cells vary by at least two-fold). Fields with the highest mitotic activity or with the highest degree of anisokaryosis were selected to assess the different parameters. According to the novel grading system, high-grade MCTs were significantly associated with shorter time to metastasis or new tumor development, and with shorter survival time. The median survival time was less than 4 months for high-grade MCTs but more than 2 years for low-grade MCTs.

Mast cells and canine mast cell tumours. A review

Summary This article reviews the literature on mast cells and tumours derived from mast cells in the dog. Mast cells play a central role in inflammatory and inunune reactions. Mast cells, normal and neoplastic, contain and release important biologically active substances: heparin, histamine, eosinophilic chemotactic factor and proteolytic enzymes. Mast cell tumours occur in the dog, particularly in the boxer and related breeds, in the skin and less frequently in the intestines. Cytology usually provides an accurate diagnosis, but histological examination adds further information concerning the histologic grade and the completeness of surgical therapy. Cutaneous mast cell tumours should be regarded as potentially malignant and therefore be removed widely (3 cm. margin). Local recurrence, regional and distant metastases together with paraneoplastic disorders may cause the death of the pet. Histologic grading (2 or 3 grades) and clinical staging together with kinetic parameters and breed (boxers have relatively benign tumours) are important prognostic parameters. Based on prognostic criteria, surgical treatment should be completed with adjuvant radiotherapy, corticosteroids and eventually with combined chemotherapy. A novel, promising therapy is the application of the receptor kinase inhibitor. The study of the pathogenesis of mast cell tumours received new impetus by the finding of mutations, deletions and duplications, in exons 11 and 12 of the C‐kit oncogene. Further study of physiological and oncological aspects of mast cells are favoured by the availability of mast cells isolated from spontaneous mast cell tumours and of cultured cell lines.

Canine Malignant Mammary Tumors. III. Special Types of Carcinomas, Malignant Mixed Tumors

Sixty-four metastasized canine malignant mammary tumors were studied. The most important types of canine mammary cancer are discussed. Mammary squamous cell carcinomas of different types are found more frequently in the dog than in man. Mucinous carcinoma, a very rare type in the dog, seems to be more malignant than its counterpart in man. Anaplastic carcinoma in the dog is a very malignant diffusely infiltrating and extensively metastasizing cancer. The malignant mixed tumors, although showing many resemblances to complex carcinomas, are discussed here as a separate group. Both categories of tumors seem to be extremely rare in man. Simple carcinomas are highly infiltrating tumors metastasizing frequently to the regional nodes and lungs; survival time is short. Complex carcinomas are generally less invasive than simple carcinomas, and lymphatic permeation is also less frequent, resulting in a lower percentage of affected nodes; the median survival time is relatively long. The sarcomas, growing mostly in an expansive way, tend to spread mainly to the lungs; survival time is short.

Canine mammary tumours: Protective effect of late ovariectomy and stimulating effect of progestins

Ovariectomy, even when performed at an advanced age, was found to be to some extent protective against mammary tumour development in dogs. Bitches treated with progestins had a slightly higher risk for mammary tumours (all types, benign and malignant) than controls. Progestin treatment did not increase the risk of mammary cancer. Benign tumours in (treated and untreated) dogs appeared earlier than malignant ones. Progestin treatment resulted in earlier appearance of both benign and malignant tumours than in controls. The ratio solitary/multiple mammary tumours was not significantly different between treated and untreated dogs.

Immunohistochemistry with keratin, vimentin, desmin, and alpha-smooth muscle actin monoclonal antibodies in canine mammary gland: normal mammary tissue

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.

Canine Malignant Mammary Tumours II. Adenocarcinomas, Solid Carcinomas and Spindle Cell Carcinomas

A preliminary classification of 130 canine mammary adenocarcinomas, 76 solid carcinomas, and nine spindle cell carcinomas, together with several subtypes, was constructed from pooled, selected (metastasized) material. Each tumour in this series was classified by subjective assessment of its quantitatively predominant histological picture. Many adenocarcinomas and solid carcinomas of simple type were infiltrative, and lymphatic permeation was often found. The complex types of adenocarcinomas and of solid carcinomas were expansive, and lymphatic permeation was rare. Some metastasized adenocarcinomas were well differentiated. The clinical signs, distribution of metastases and some preliminary data on the times of survival of dogs with various types of carcinomas are discussed.

Congenital tumours and tumour‐like lesions in domestic animals. 1. Cattle A review

Summary The literature on congenital tumours and tumour‐like lesions in calves was reviewed. Lesions were subdivided by their anatomical distribution and in addition also according to their histologic‐pathogenetic nature. As a result of the latter method, four main groups were formed covering most of the lesions described so far: malignant lymphomas, mesotheliomas, hamartomas and embryonic tumours. Most lesions were of mesenchymal structure, carcinomas being extremely rare. Some findings may point to early genetic events, for instance twin calves both affected with malignant lymphoma and related calves with congenital facial neurofibromatosis. An external factor, asbestos, is suspected to play a role in the genesis of peritoneal mesotheliomatosis. The effects of congenital tumours on their hosts were often considerable: death by generalization (malignant lymphomas), ascites (mesotheliomas) or the growth of large abdominal tumours (nephroblastomas, mixed tumours). The latter two conditions often caused dystocia.

Immunohistochemistry with keratin, vimentin, desmin, and alpha-smooth muscle actin monoclonal antibodies in canine mammary gland: benign mammary tumours and duct ectasias.

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.

Canine malignant mammary tumours. I. Sarcomas.

Forty-five canine mammary sarcomas that had metastasized were pooled from several institutes, studied, and classified. The classification was based on morphology and did not include any histogenetic interpretation. In addition, one case was studied by histochemical and electron microscopic methods. Canine mammary sarcomas often have multidifferentiation (bone, cartilage, and fat) which is not unusual in human mammary sarcomas. Sarcomas resembling (malignant) cystosarcoma phyllodes in women appear to be very rare in the dog. Canine fibrosarcomas had a morphological resemblance to ‘stromal’ sarcoma or ‘fibrosarcoma’ in the woman. Five sarcomas without infiltrative growth, anaplasia, or mitotic activity had metastasized. In dogs and women the lungs are often involved by metastases, but, unlike in the human, metastases in the regional lymph nodes are also relatively common in the dog. There is need for further studies on the histogenesis and biological behaviour of mammary sarcomas.

Congenital and hereditary tumours in domestic animals. 2. Pigs. A review

Summary The literature on congenital and hereditary tumours in pigs was reviewed. One hitherto unreported own case was added. Sporadic cases of congenital tumours included several types found in newborn piglets. Embryonic tumours (nephroblastoma, rhabdomyosarcoma) occurred either in newborn or in juvenile animals. Cardiac rhabdomyomas were provisionally classified as hamartomas. The hereditary tumours, melanomas and lymphomas, were reproducible by experimental matings. These tumours are particularly interesting as models to elucidate genetic and immunologic mechanisms of tumour diseases. Striking is the high degree of regression in porcine melanomas and the associated melanosis.