An epidemiologic study of canine multiple primary neoplasma involving the female and male reproductive systems

The significance of canine multiple primary neoplasms involving the reproductive system and one or more additional anatomic sites was evaluated using data from the Alameda and Contra Costa County Animal Tumor Registry. Among the registry's data base of 35 015 histologically confirmed tumors, both sequential and simultaneous occurrences of histologically distinct benign and malignant tumors were identified. Retrospective analysis demostrated that there was a decreasing risk gradient for multiple tumors of the reproductive systems. The intact female had the highest risk followed in order by the spayed female and all male dogs. The incidence-based analyses also indicated a strong predilection for development of multiple tumors within both the female and the male reproductive systems. A four- to five-fold increase in observed numbers of mammary tumors and other histologically distinct reproductive tumors was found. Benign and malignant mammary tumors were strongly associated in their occurrence, and dogs with benign mammary neoplasms had a three-fold increased risk for subsequent development of histologically different malignant mammary tumors. These quantitative results were consistent with observations in man for malignancies and provide additional evidence that multiple primary malignant and benign neoplasms of the female and male reproductive systems are biologically associated.     

Immunohistochemical evaluation of MMP-2 and TIMP-2 in canine mammary tumours: a survival study

Canine mammary tumours (CMTs) are a very heterogeneous group of neoplasms with variable prognosis. Their aggressiveness is mainly due to their ability to invade locally and to metastasize. The degradation of extracellular matrix components is an important determinant of the invasive phenotype. The aims of this study were to analyse by immunohistochemistry and double immunofluorescence the expression of metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in eight normal canine mammary glands and 118 CMTs (24 benign, 94 malignant) and to investigate relationships with metastatic disease and survival.MMP-2 and TIMP-2 expression was higher in malignant tumours than in normal canine mammary tissue and benign tumours. The main difference between benign and malignant CMTs was the pattern of expression of both molecules: benign tumours presented TIMP-2 and MMP-2 immunoreactivity in the myoepithelial cells lining the basement membrane of tubuloalveolar structures, while malignant tumours showed mainly diffuse expression in neoplastic cells. In malignant tumours, increased TIMP-2 expression was significantly associated with the development of distant metastases, lower overall survival and lower disease-free survival. MMP-2 expression was not significantly associated to any of these parameters. These results suggest that the immunohistochemical expression of TIMP-2 is a useful prognostic factor in CMTs.     

Nontumoral, benign ad malignant stages of transformation of a diploid pig cell line. A review.

The PFT cell line originated from diploid endometrial cells and was subcultured more than 500 times. Nontumoral, benign and malignant transformation appeared at different stages. Four populations (F1, F2, F3 and F4) of cells were demonstrated sequentially by chromosomes analysis. These consisted of eight phenotypes corresponding to the sequential appearance of markers which included three chromosomal aberrations. The PFT malignant transformation in vitro is a progressive process through qualitatively different stages and may reflect neoplastic development in vivo. It is suggested that the benign and malignant transformations were under separate genetic control since they occurred after two chromosomal translocations on two different chromosomes. The spontaneous expression of a pig endogenous type-C virus which occurred concomitantly with the first translocation appeared to be related to oncogenesis.     

Expression of HER-2 and nuclear localization of HER-3 protein in canine mammary tumors: histopathological and immunohistochemical study

HER-2 and HER-3 are transmembrane receptor proteins that are considered to be important but poorly understood biomarkers in canine tumors. In this study, the expression and the localization of HER-2 and HER-3 were evaluated immunohistochemically in canine mammary tumors (n = 64; 12 benign, 52 malignant).HER-2 overexpression was identified in 2/12 (16.7%) benign and in 18/51 (35.3%) malignant cases. HER-3 was expressed in a non-nuclear localization in 11/12 (91.7%) benign and 18/52 (34.6%) malignant tumors. In contrast, HER-3 was expressed in the nucleus of neoplastic cells in 0/12 (0%) benign and 22/52 (42.3%) malignant tumors. Nuclear HER-3 expression was higher in neoplastic epithelial cells compared to myoepithelial cells, and positively correlated with high histological grade and lymphatic vessel invasion. These results suggest that nuclear HER-3 expression is significantly associated with tumor progression and metastasis and may serve as a useful prognostic biomarker in canine malignant mammary tumors.     

Molecular cloning of canine nm23 cDNAs and their expression in normal and tumor tissues

Two canine nm-23 cDNAs, designated as nm23-C1 and -C2, were isolated and characterized. Both have a putative open reading frame consisting of 459-bp encoding 152 amino acids and are highly similar to human, mouse and rat homologues. To understand the potential role of nm23-C1 and -C2 in the development of mammary gland tumors (MGT), we analyzed the mRNA expression in 14 MGT samples by RT-PCR. The samples were divided into categories according to their histopathology (benign/malignant) and metastasis. No significant difference in the mRNA expression levels of either nm23-C1 or -C2 were observed between the benign and malignant groups or the metastatic and non-metastatic groups. These results suggest that nm23-C1 and -C2 are not related to the establishment of malignancy and metastatic lesions in canine MGT cases.     

CONTRAST ENHANCED SONOGRAPHIC ASSESSMENT OF FEEDING VESSELS AS A DISCRIMINATOR BETWEEN MALIGNANT VS. BENIGN FOCAL SPLENIC LESIONS

Contrast‐enhanced sonography was conducted in 17 confirmed focal splenic lesions (five malignant, 12 benign). Relative echogenicity changes were used for subjective interpretation of lesion perfusion. A rapid influx of contrast agent, resulting in an increased relative echogenicity of the lesion, followed by a rapid clearance of contrast agent was referred to as early washin/early washout. There were 6/12 benign, and 3/5 malignant lesions characterized by early washin/early washout. Therefore, sensitivity, specificity, and accuracy for this parameter in differentiating malignant from benign lesions was 60%, 50%, and 53%, respectively. There were 2/12 benign, and 2/5 malignant lesions with persistent hypoperfusion throughout all phases. Therefore, sensitivity, specificity, and accuracy for malignancy using this criterion were 40%, 83%, and 71%, respectively. However, none of the benign and all malignant lesions were characterized by tortuous and persistently visible feeding vessels. This suggests that interpretation of splenic lesions cannot be performed accurately on the basis of echogenicity or persistent hypoperfusion, but that assessment of vascular tortuosity may be helpful in discriminating between a malignant vs. benign focal splenic lesion.     

Decorin concentrations in canine normal and neoplastic mammary gland tissues

In the present study, the concentration of decorin in canine normal and neoplastic mammary gland tissues was examined to understand the potential role of decorin in development and progression of canine mammary tumours. The homogenates of 48 mammary gland tumours (10 benign and 38 malignant) and 10 samples of normal canine mammary gland tissue were used in the study. The presence and quantification of decorin was examined in the homogenates using Western blot and specific canine ELISA. Western blotting confirmed the presence of decorin both in the normal mammary gland tissues and in the mammary gland tumours. The concentration of decorin was significantly higher (p < .05) in the benign tumours and non-metastatic malignant tumours than in the normal mammary gland. The concentration of decorin was significantly lower (p < .05) in the malignant tumours with metastasis to regional lymph nodes compared with benign tumours and non-metastatic malignant tumours. No significant differences were found in the level of decorin between the benign and the non-metastatic malignant tumours. Both the histological type of malignant tumours and the histological grade did not significantly affect the concentration of decorin. These findings suggest that neoplastic transformation in the canine mammary gland leads to increase in the decorin protein synthesis. The reducing decorin concentration in canine malignant mammary tumours appears to facilitate the metastatic spread of these tumours.     

Magnetic resonance imaging of focal splenic and hepatic lesions in the dog

Focal hepatic and splenic lesions in the dog are common, and approximately half of such lesions are malignant. Both incidentally discovered lesions and lesions in patients with known malignancies represent diagnostic dilemmas. Ultrasound often fails to characterize such lesions adequately. This uncertainty may result in unnecessary splenectomies and liver biopsies for benign lesions or noncurative surgery for advanced-stage malignancies. In humans, ultrasound largely has been supplanted by computed tomography and magnetic resonance imaging (MRI) for the characterization of focal hepatic and splenic lesions. The inherently high soft tissue contrast of MRI allows the differentiation of benign from malignant hepatic and splenic lesions in the human patients. In this prospective study, 35 focal lesions of either the spleen (n = 8) or the liver (n = 27) were characterized by MRI in 23 dogs. Lesions were presumptively classified as malignant or benign on the basis of MRI findings. Imaging results then were correlated with histopathologic (29) or cytologic (6) evaluation of the lesions. The overall accuracy in differentiating malignant from benign lesions was 94% (33 of 35 lesions). The overall sensitivity and specificity were 100% (95% CI, 78-100%) and 90% (95% CI, 68-99%), respectively. MRI classified malignant hepatic lesions as hepatocellular carcinoma (HCC) in all confirmed cases and correctly predicted the histologic grade of 5 HCC lesions. These results suggest that MRI is a useful modality for abdominal imaging in veterinary patients, and MRI accurately differentiated benign from malignant focal hepatic and splenic lesions in this sample of patients.     

RADIOGRAPHIC ASPECTS OF GASTRIC ULCERS IN DOGS

This paper is a retrospective analysis of the radiographic appearance of one benign and four malignant gastric ulcers in dogs. The benign gastric was diagnosed radiographically following gastric surgery and was healed at necropsy 28 months after diagnosis. Malignant gastric ulcers were confirmed at surgery and/or necropsy. None of the five ulcers penetrated the normally expected gastric contour. Mucosal fold pattern was either partially or completely effaced with all five ulcers. Undermining appeared to be present asymmetrically in the benign and one malignant ulcer, and symmetrically in one malignant ulcer. Tissue surrounding the ulcers joined the normal gastric wall very abruptly in three malignant ulcers. This transition was more gradual in the benign ulcer and was not identified in one malignant ulcer. None of these ulcers completely fit the criteria used in people to diagnose benign gastric ulcer. Prospective evaluation of more cases with a more thorough radiographic technique is needed     

The activity of matrix metalloproteinases (MMPS) and tissue inhibitors of metalloproteinases (TIMPs) in mammary tumors of dogs and rats

We conducted zymography for detecting the activity of matrix metalloproteinases (MMPs) and reverse zymography for the activity of tissue inhibitors of metalloproteinases (TIMPs) in canine spontaneous and rat 7, 12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor tissues. The activities of MMPs of canine mammary tumors were quite higher than those of the rat chemically induced tumors. The activities of MMPs were significantly higher in malignant tissues than in benign ones of canine tumors, whereas the activity of only MMP-2 was higher in both benign and malignant rat tumors compared to normal tissues. There were no differences of MMPs activities between benign and malignant rat tumors. The results of reverse zymography indicated that the activities of TIMP-1, -2 and -3 were strikingly higher in rat tumors than in canine tumors. The activities were higher in malignant tissues than in benign ones of dogs, and higher in tumor tissues than in normal mammary tissues of rats. The results of film in situ zymography for tissue localization of gelatinolytic activity showed that the digested area was more extended in malignant tumors than in benign ones of dogs. However, the area was similarly extended in both benign and malignant rat tumors. These results may indicate that the canine spontaneous malignant mammary tumors possess more aggressive nature than the rat chemically induced counterpart, resulting from the high level of MMPs and low level of TIMPs activities of the tumor tissues.     

Canine mammary gland tumours; a histological continuum from benign to malignant; clinical and histopathological evidence*

This study describes the clinical and histopathological findings in dogs with mammary gland tumours, and compares the histopathological and clinical evidence consistent with progression from benign to malignant to human breast cancer epidemiology. Clinical and histopathological data on 90 female dogs with 236 tumours was included. Dogs with malignant tumours were significantly older than dogs with benign tumours (9.5 versus 8.5 years), P = 0.009. Malignant tumours were significantly larger than benign tumours (4.7 versus 2.1 cm), P = 0.0002. Sixty‐six percent had more than one tumour, and evidence of histological progression was noted with increasing tumour size. Dogs with malignant tumours were significantly more likely to develop new primary tumours than dogs with benign tumours, P = 0.015. These findings suggest that canine mammary tumours progress from benign to malignant; malignant tumours may be the end stage of a histological continuum with clinical and histopathological similarities to human breast carcinogenesis.     

Cytosolic 20 alpha-hydroxysteroid dehydrogenase activity in spontaneous neoplasms in the dog and cat.

Steroid-producing tissues such as ovary, placenta, testis and adrenal gland and non-steroid-producing cells including lymphocytes are known to contain 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD). In the present study, we measured and partially characterized the 20 alpha-HSD in 11 neoplastic tissues surgically removed from dogs and a cat. The tissues were pathologically classified as 4 benign and 7 malignant. The enzyme activities in the cytoplasmic fraction were positive in 6 of the 7 malignant tissues and 2 of the 4 benign ones. Following DEAE chromatography analysis of 2 malignant tumour samples, multiple forms of enzyme activities with different electric charges were detected. Furthermore, 20 alpha-HSD activity in the cytosol fraction from malignant tumours was increased dramatically by passage through the DEAE column, suggesting that the enzyme is present in the cytosol as an inactive or sequestered form.     

Oral malignant melanomas and other head and neck neoplasms in Danish dogs - data from the Danish Veterinary Cancer Registry

Background

Head and neck cancers (HNC) are relatively common and often very serious diseases in both dogs and humans. Neoplasms originating in the head and neck region are a heterogeneous group. HNC often has an unfavourable prognosis and the proximity of the tissue structures renders extirpation of tumours with sufficient margins almost incompatible with preservation of functionality. In humans oral malignant melanoma (OMM) is extremely rare, but represents a particular challenge since it is highly aggressive as is the canine counterpart, which thus may be of interest as a spontaneous animal model.

Methods

Canine cases entered in the Danish Veterinary Cancer Registry (DVCR) from May 15th 2005 through February 29th 2008 were included in this study. Fisher''s exact test was used to compare proportions of HNC in dogs and humans as well as proportions of surgically treated cases of OMM and squamous cell carcinomas (SCC). Also the proportions of benign and malignant neoplasms of different locations in dogs were compared using Fisher''s exact test.

Results

A total of 1768 cases of neoplasias (679 malignant, 826 benign, 263 unknown) were submitted. Of all neoplasias HNC accounted for 7.2% (n = 128). Of these, 64 (50%) were malignant and 44 (34%) benign. The most common types of malignant neoplasia were SCC (18; 28% of malignant), OMM (13; 20% of malignant), soft tissue sarcoma (11; 17% of malignant) and adenocarcinoma (5; 11% of malignant). The most common types of benign neoplasms were adenoma (7; 16% of benign), polyps (6; 14% of benign) and fibroma (5; 11% of benign).

Conclusions

In the current study, the proportion of neoplasia in the head and neck region in dogs in Denmark was similar to other canine studies and significantly more common than in humans with a large proportion of malignancies. Spontaneous HNC in dogs thus, may serve as a model for HNC in humans.Canine OMM is a spontaneous cancer in an outbred, immune-competent large mammal population and could be a clinical model for OMM in humans.     

Flow cytometric evaluation of hemophagocytic disorders in canine

Background — Hemophagocytic macrophages in canine bone marrow are observed in malignant histiocytosis as well as benign hemophagocytic histiocytosis. Cytomorphologic evaluation alone may be inadequate to consistently differentiate between benign and malignant forms of hemophagocytic disorders. Objective — The purpose of this study was to evaluate the ability of flow cytometry and immunophenotyping to differentiate between benign and malignant types of hemophagocytic disorders in dogs. Methods — Blood smears and bone marrow differential cell counts were evaluated for 10 dogs with hemophagocytic disorders. Bone marrow samples were labeled with monoclonal antibodies to CD18, MCH class‐II, Thy‐1, CD14, CD3, and CD21. Using flow cytometry, forward‐angle versus side‐angle light scatter plots were analyzed and immunophenotypes were determined. Results — Scatter plots from 3 dogs with a necropsy diagnosis of malignant histiocytosis revealed 2 atypical cell clusters. One cluster contained cells of similar size or larger than immature myeloid cells and metamyelocytes. Cells in the other cluster were highly granular, with granularity similar to or greater than that of metamyelocytes. In bone marrow from dogs with malignant histiocytosis that was labeled with anti‐CD14 antibody, macrophages represented 29–48% of nucleated cells. Seven dogs had a clinical or histopathologic diagnosis of benign hemophagocytic syndrome. Three of the dogs had normal cell distribution in scatter plots. Two dogs had 2 abnormal cell clusters: 1 within the immature myeloid and metamyelocyte gates and the other with granularity similar to or greater than that of metamyelocytes. The remaining 2 dogs had an atypical cell population, mostly within the immature myeloid gate. For dogs with benign hemophagocytic syndromes, 6–17% of cells in the bone marrow were CD14 positive. Conclusions — The cellular distribution in scatter plots and the total number of macrophages in bone marrow may be useful in differentiating malignant histiocytosis from benign hemophagocytic syndromes in dogs.     

Signs of metastatic disease on thoracic radiographs of dogs suffering from mammary gland tumours: a retrospective study (1990-1998)

A mammary gland tumour (MGT) was clinically diagnosed in 136 dogs. Histologically 71% were malignant and 29% benign. Intrathoracic metastatic disease was noted or suspected radiographically in 13.5% of the dogs with malignant and in 2.5% of the dogs with benign MGT. Six dogs with malignant MGT were necropsied, 5 had pulmonary metastases but only 1 had radiographic signs of intrathoracic metastatic disease. We conclude that radiographs are not very sensitive for detection of early intrathoracic metastatic disease of MGT.     

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.     

Contrast harmonic imaging characterization of canine splenic lesions

Background: Although B-mode ultrasound is very sensitive for the detection of splenic lesions, its specificity is low. Contrast harmonic imaging is used successfully to differentiate benign from malignant liver lesions in humans and dogs.
Hypothesis: Contrast harmonic imaging could be useful to differentiate benign and malignant splenic lesions in dogs.
Animals: Sixty dogs (clinical patients) with splenic abnormalities detected during abdominal ultrasonography.
Methods: A prospective study was performed with a Philips ATL 5000 unit for contrast pulse inversion harmonic imaging (mechanical index: 0.08, contrast medium: SonoVue). Perfusion was assessed subjectively and quantitatively.
Results: Cytology or histology identified 27 benign (hyperplasia, extramedullary hematopoiesis, hematoma) and 29 malignant (hemangiosarcoma, malignant lymphoma, malignant histiocytosis, mesenchymal tumors without classification, mast cell tumors, and others) lesions and 4 normal spleens. Except for 1 benign nodule, extensive to moderate hypoechogenicity was only seen in malignant lesions during wash-in, at peak enhancement, and during wash-out ( P = .0001, odds ratios: 37.9 [95% CI 4.5–316.5], 66.4 [95% CI 8.0–551.1], and 36.9 [95% CI 4.4–308.4]). Although all but 1 benign lesion enhanced well and were mildly hypo-, iso-, or hyperechoic in comparison with the normal spleen during all blood pool phases, marked enhancement occurred both in benign as well as in malignant splenic lesions. Quantitative perfusion values did not differ significantly between benign and malignant lesions.
Conclusions and Clinical Importance: Moderate to extensive hypoechogenicity clearly identifies canine splenic malignant lesions. In nodules with marked enhancement, contrast harmonic ultrasound is of limited value and histology is needed.     

Vulvovaginectomy and perineal urethrostomy for neoplasms of the vulva and vagina

Vulvovaginectomy and perineal urethrostomy were performed in three dogs with extensive neoplasms of the vulva and vagina. One benign tumor (fibroleiomyoma) and two malignant tumors (transitional cell carcinoma and anaplastic spindle cell sarcoma) were diagnosed. Survival times were 9 weeks to 10 months. Urinary continence was preserved in all three dogs. The procedure may be curative for benign tumors or malignant tumors that have not yet metastasized; it is a palliative procedure for advanced malignancies.     

Vulvovaginectomy and Perineal Urethrostomy for Neoplasms of the Vulva and Vagina

Vulvovaginectomy and perineal urethrostomy were performed in three dogs with extensive neoplasms of the vulva and vagina. One benign tumor (fibroleiomyoma) and two malignant tumors (transitional cell carcinoma and anaplastic spindle cell sarcoma) were diagnosed. Survival times were 9 weeks to 10 months. Urinary continence was preserved in all three dogs. The procedure may be curative for benign tumors or malignant tumors that have not yet metastasized; it is a palliative procedure for advanced malignancies.     

Magnetic resonance imaging characterization of canine splenic lesions

Introduction:  Splenic lesions are a common finding in veterinary medicine and typically 1/2 to 2/3 of these lesions are malignant. Due to the limited accuracy of ultrasound, unnecessary exploratory surgeries/biopsies may be performed for benign lesions and treatment may be delayed for malignant ones. Splenic lesions are rare in people. MR imaging, with its inherently high soft tissue contrast, is efficacious in imaging the human spleen. We have previously demonstrated the efficacy of MRI to differentiate canine hepatic lesions. In that study 8 splenic lesions were all accurately characterized. This current study represents a further evaluation of splenic lesions.
Methods:  In this prospective study, 27 dogs with splenic lesions were accrued. Histopathological/cytological confirmation of lesions occurred either before or shortly after imaging. MRI clinicians were blinded to histopathology results. MR (General Electric, 1.5 Tesla) images using a variety of sequences were obtained before and after intravenous administration of gadolinium.
Results:  32 lesions (9 malignant, 23 benign) were evaluated in 27 dogs. Lesions were confirmed via histopathology (n = 20) or cytology (n = 12). Benign lesions included, EMH (n = 7), hematoma/hemorrhage (n = 5), lymphoid hyperplasia (n = 9), and hemangioma (n = 2). Malignant lesions included anaplastic sarcoma (n = 3), malignant histiocytosis (n = 2), hemangiosarcoma (n = 2), plasma cell tumor (n = 1) and adenocarcinoma (n = 1). The overall accuracy in differentiating benign from malignant lesions was 88%(29/32 lesions). The overall sensitivity and specificity were 100%(95% CI, 66–100) and 87%(95% CI 66–97).
Conclusions:  Based upon these results, MRI is both sensitive and specific in distinguishing between malignant and benign splenic lesions.