C-kit expression in canine mucosal melanomas

The c-kit receptor is responsible for transmission of promigration signals to melanocytes; its downregulation may be involved in malignant progression of human melanocytic neoplasms. Expression of this receptor has not been examined in normal or neoplastic melanocytes from dogs. In this study, 14 benign dermal and 61 malignant mucosal melanocytic tumors were examined for c-kit (KIT) expression. Sites of the mucosal melanomas were gingiva (not further specified; n = 30), buccal gingiva (n = 6), soft palate (n = 4), hard palate (n = 5), tongue (n = 7), lip (n = 6), and conjunctiva (n = 3). Melan A was expressed in all 14 dermal melanocytomas and in 59 of 61 (96.7%) tumors from oral or conjunctival mucosa, confirming melanocytic origin. C-kit receptor expression was strong and diffuse throughout the cytoplasm in all 14 dermal melanocytomas and was identified in basilar mucosal melanocytes over submucosal neoplasms (27 of 61, 44.3%), junctional (neoplastic) melanocytes (17 of 61, 27.9%), and, less commonly, neoplastic melanocytes of the subepithelial tumors (6 of 61, 9.8%). KIT expression anywhere within the resected melanomas correlated with significantly longer survival. These results suggest that c-kit receptor expression may be altered in canine melanomas and may have potential as a prognostic indicator for mucosal melanomas.     

A matched observational study of canine survival with primary intraocular melanocytic neoplasia

A retrospective histopathologic study was performed to evaluate the effect of primary intraocular melanocytic neoplasia on canine survival. Tumor size, location within the globe, extent of infiltration, and mitotic index were analyzed for their potential to predict survival. A total of 244 cases of dogs with melanocytic tumors submitted to the Comparative Ocular Pathology Laboratory of Wisconsin from 1988 to 1998 were evaluated. Histopathologic criteria (mitotic index, cytologic features of anaplasia) were used to differentiate 188 benign melanocytomas from 56 malignant melanomas. Signalment evaluation of age, sex, and breed revealed similarities in both tumor populations, with the majority of tumors discovered in 9-year-old, female/spayed, mixed-breed dogs. A greater percentage of left eyes (66%) vs. right eyes (47%) was found in the melanoma population, but an equal distribution was found in the melanocytoma population (48% and 52%, respectively). The majority of tumors arose from the anterior uveal tract (79% in the melanocytoma and 95% in the malignant melanoma populations). The German Shepherd breed was predisposed in the limbal distribution. At the time of enucleation, most tumors had invaded the sclera, but did not show extrascleral extension (51% in the melanocytoma and 61% in the malignant melanoma populations). Survival analysis showed a significant difference in survival between control and malignant melanoma populations ( P  = 0.0081) and was suggestive of a difference between the melanocytoma and melanoma populations ( P  = 0.031). Tumor extension, tumor size, and mitotic index were not found to be reliable predictors of survival.     

Congenital and acquired melanocytomas (benign melanomas) in eighteen young horses.

In a retrospective study, cutaneous melanocytic tumors from 18 horses, less than 2 years old, were examined histopathologically and clinical follow-up requested. Melanocytomas (benign melanomas) occurred in a variety of breeds and in horses of varied coat color. The age of the horses at the time of biopsy ranged from 3 weeks old to 2 years old. Four melanocytomas were congenital, 11 melanocytomas were acquired by 1 year of age, and three were acquired prior to 2 years of age. Of the 18 horses, five were male, and 13 were female. All tumors were solitary and located on the legs or trunk; none were in the perineal region. Ulceration of the overlying epidermis was common. Tumors were generally localized and were not encapsulated. The tumors had a variety of cell patterns ranging from sheets, to streams, or nests of melanocytes. Cellular morphologic findings also ranged from epithelioid, to a mixture of epithelioid and spindle cells or to a spindle pattern. The nuclei were large and euchromatic, especially in the epithelioid cells. Several tumors had moderate cellular pleomorphism and binucleate cells. Mitotic activity was generally low (less than 1/high-powered field), but was readily detected (1-2/high-powered field) in bleached sections of four cases. Melanin pigmentation varied from mild to heavy. Melanophages were admixed with the tumor cells or in the adjacent tissue. Follow-up information was obtained on 15/18 horses and revealed that 14/15 horses were free of recurrence following excision. One neoplasm, that was poorly demarcated and had a spindle cell pattern, was not completely resected and continued to grow. These melanocytic tumors in young horses are distinct from melanomas in aged horses in their location, epithelial involvement, and age of horses affected. The majority of these tumors appear to be benign and share features of melanocytic nevi of human beings.     

Histologic features and clinical outcomes of melanomas of lip, haired skin, and nail bed locations of dogs.

Outcomes, signalments, and the relationship of histologic features with the outcome of melanomas located in lip, nail bed, and haired skin of dogs were reviewed. These melanomas were diagnosed as benign or malignant based on histologic features. Melanomas of the lip arose from mucous membrane in most cases. 32 dogs with lip melanomas that had histologic features of malignancy, 22 died because of the tumor within 1 year and 10 were tumor free for at least 1 year following removal. Of 10 dogs with melanomas with benign histologic features on the mucous membrane of the lip, 9 were tumor free for at least 1 year. Of 4 dogs with benign appearing tumors of the haired skin of the lip, 3 were tumor free for at least 1 year. Melanomas with histologic features of malignancy occurred in many locations of haired skin, and 11 of 24 dogs were tumor free for at least 1 year. All nail bed melanomas had histologic features of malignancy and all invaded the third phalanx, but 6 of 14 dogs were tumor free for at least 1 year after amputation of the digit. Among these dogs, the 1-year survival rates for tumors classified as malignant by histologic features were 69% for lip, 46% for haired skin, and 43% for nail bed. However, the clinical outcome of an individual malignant tumor could not be predicted accurately by any specific histologic features.     

Cyclooxygenase-2 expression is related with localization, proliferation, and overall survival in canine melanocytic neoplasms

A direct relationship has been firmly established between cyclooxygenase-2 (COX-2) expression and malignant behavior in human melanoma. This report examines the relationship between COX-2 expression and tumor location, mitotic and proliferative indices, degree of T CD3(+) lymphocyte infiltration, overall survival, and frequency of recurrence and metastasis of 57 melanocytic tumors (25 oral and 32 cutaneous). COX-2 was highly or moderately expressed in 88% of oral neoplasms (22 of 25), whereas for their cutaneous counterparts, COX-2 expression was low or insignificant in 75% of cases (24 of 32). High and moderate COX-2 expression levels were observed in 73% of melanocytic tumors with a mitotic index ≥ 3 per 10 high-power fields (26 of 36), whereas in 81% of tumors with a mitotic index < 3 (17 of 21), expression was mild or absent. There were 41 cases with known clinical outcomes; of those showing high, moderate, and mild COX-2 expression, 83.3% (10 of 12), 37.5% (3 of 8), and 25% (2 of 8) died, respectively, whereas 100% of animals showing no COX-2 expression (13 of 13) were still alive at the last follow-up. COX-2 expression was statistically correlated with tumor location, mitotic and percentage Ki-67 proliferative indices, and overall survival, frequency of neoplastic recurrence and metastasis. Regression analysis also showed disease-specific predictive value for COX-2 expression for subjects with melanocytic neoplasms. Additionally, only high COX-2 expression showed significant differences in overall survival, in comparison with moderate, mild, or absent expression. These results suggest that high COX-2 expression may be considered a prognostic biomarker and potentially as a target for therapeutic and preventive strategies in canine melanocytic neoplasms.     

Primary renal neoplasms of the dog.

Of 48 canine primary renal neoplasms found in the files of the Armed Forces Institute of Pathology, 36 were of tubular cell origin (five adenomas and 31 carcinomas), six of transitional cell origin (two papillomas and four carcinomas), two were nephroblastomas and four were nonepithelial. With the exception of nephroblastomas, renal neoplasms occurred in dogs older than 5 years and were most common in males. No breed predilection was apparent. Eight of the neoplasms were classified by histologic criteria as benign and 40 as malignant. Seventeen of the malignant neoplasms had metastasized. The neoplasms of tubular cell origin contained solid, tubular and papillary patterns, often mixed within the same tumor.     

Proliferation activity in oral and cutaneous canine melanocytic tumours: correlation with histological parameters,location, and clinical behaviour

A total of 62 canine melanocytic tumours (10 melanocytomas and 52 primary malignant melanomas) were investigated to compare the accuracy of prognosis provided by MIB-1 proliferation index (MIB-1-PI) with classical histological criteria and location. MIB-1-PI was assessed by means of quantitative image analysis of sections immunostained with MIB-1 monoclonal antibody. Tumour location, histological cell type, stromal or lymphatic vessel invasion, maximum tumour thickness, and presence of inflammation or necrosis were recorded for each case. Thirty-eight dogs were submitted to a 1-year follow-up and the clinical outcome of the disease determined. MIB-1-PI in melanocytomas differed significantly from that detected in primary malignant melanomas (P=0.0001). A significant difference in MIB-1-PI was revealed between oral and cutaneous malignant melanomas (P=0.015), and between presence and absence of lymphatic vessel invasion (P=0.05). MIB-1-PI was not correlated with the other parameters. In univariate analysis, only tumour location (oral vs cutaneous), presence of lymphatic vessel invasion, and MIB-1-PI were associated with decreased overall survival (P=0.0001,P=0.0144, and P=0.0489, respectively). In conclusion, the results of our study confirm that the assessment of the MIB-1-PI may be of additional prognostic value for dogs with primary malignant melanomas.     

Equine Melanocytic Tumors: A Retrospective Study of 53 Horses (1988 to 1991)

A study of 57 cutaneous melanocytic tumors from 53 horses revealed 4 distinct clinical syndromes: melanocytic nevus, dermal melanoma, dermal melanomatosis, and anaplastic malignant melanoma. Melanocytic nevus and anaplastic melanoma each had histopathologic features that distinguished them from dermal melanoma and dermal melanomatosis. Dermal melanoma and dermal melanomatosis were histologically similar but could be differentiated by their clinical features. Melanocytic nevi were diagnosed in 29 horses with an average age of 5 years; they were solitary, superficial masses that occurred in both grey and nongrey horses, and in which surgical excision was generally curative. Dermal melanomas were diagnosed in 20 horses with an average age of 13 years; all horses of known coat color were grey. Eight horses with an average age of 7 years had 1 or 2 discrete dermal melanomas. Follow-up information was available for 6 horses; metastases occurred in 2 horses, and surgical excision was apparently curative in 4 horses. Dermal melanomatosis was diagnosed in 12 grey horses with an average age of 17 years; all 6 of these horses evaluated had internal metastases. In 2 aged nongrey horses with anaplastic malignant melanoma, the tumors metastasized within 1 year of diagnosis. Two tumors with features of both melanocytic nevus and dermal melanoma remained unclassified.     

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.     

Immunohistochemical characterization of tumor cells and inflammatory infiltrate associated with cutaneous melanocytic tumors of Duroc and Iberian swine

The immunophenotype of tumor cells and inflammatory infiltrate associated with cutaneous melanocytic lesions (29 melanocytomas, two malignant melanomas, and 23 residual lesions) from 54 adult Iberian and Iberian x Duroc pigs were examined using a panel of nine antibodies. All neoplastic cells were vimentin+, cytokeratin-, and alpha-1-antitrypsin- and the majority were S100+, whereas all pigmented macrophages were vimentin+, cytokeratin-, and S100- and most expressed alpha-1-antitrypsin. Regressing tumors were characterized by zones with low density of neoplastic cells accompanied by heavy infiltration of CD3+ T lymphocytes, whereas zones with high density of neoplastic cells showed very low numbers of CD3+ T lymphocytes. The infiltrate of CD79a+ B cells and IgG, IgM, and IgA plasma cells was low. The majority of lymphocytes of the peri- and intratumoral infiltrate were major histocompatibility complex class II+, but neoplastic cells did not express class II antigen. The 17 residual lesions examined were composed of macrophages containing abundant melanin pigment and low to moderate numbers of CD3+ T lymphocytes. The results of the present study suggest that the local cellular immune response plays a crucial role in the host response that induces regression of cutaneous melanomas and melanocytomas of the Iberian and crossbred Iberian x Duroc pigs.     

Thyroid neoplasms in a colony of beagle dogs

The histologic, clinicopathologic, and epidemiologic features of spontaneous thyroid neoplasms were evaluated in a control population of Beagle dogs. The mean age of thyroid tumor-bearing dogs (16.2 years) as significantly higher than non-tumor-bearing dogs (13.6 years). Thirteen benign and 18 malignant tumors were identified, with the incidence of both tumors increasing rapidly near the mean age of 16.2 years for tumor-bearing dogs. The age-specific incidence of tumors was 1.1% per year at 8 to 12 years, increasing to 4.0% per year by 12 to 15 years and 67% over 17 years of age. Numbers of malignant tumors were greater than benign tumors at an earlier age. Approximately 44% of the malignant tumors metastasized but only 22% resulted in death of the dog. There was no difference in tumor incidence when compared according to sex, if total tumor numbers were considered or if tumors were separated into benign and malignant categories. The age at death of tumor-bearing dogs was not increased significantly by the surgical resection of the thyroid tumors. Of dogs with thyroid tumors, 15% had clinical diagnoses of hypothyroidism, and no dogs with thyroid tumors had diagnoses of hyperthyroidism.     

Canine ocular tumors following ciliary body ablation with intravitreal gentamicin

Iridociliary tumors are the second most common primary ocular tumor in dogs and are usually benign. A review of the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) database in 2009 suggested a potential correlation between malignant iridociliary epithelial tumors and ciliary body ablation by intravitreal gentamicin injection for the treatment of glaucoma. The purpose of this case series was to determine whether there is evidence of such a correlation in the COPLOW collection. Mining of the COPLOW database revealed that a significant number (39.5%) of canine globes with a history of ciliary body ablation were subsequently diagnosed with primary ocular tumors at enucleation, most commonly iridociliary epithelial tumors and melanocytic tumors. It is possible that neoplasia was present but unrecognized at the time of ciliary body ablation. These tumors had a higher than expected incidence of malignancy. These cases underscore the importance of reserving ciliary body ablation with gentamicin for disease‐free eyes.     

Prognosis after surgical excision of canine melanomas.

One hundred and thirty-four dogs from which melanomas had been excised were studied until death or for at least 2 years after surgery. Seven of 49 (14%) intraoral and lip tumours and 52 of 85 (61%) skin tumours were histologically benign; in spite of this, three of seven (43%) "benign" oral and four of 52 (8%) "benign" skin lesions led to the eventual death of the host. Thirty eight of 42 (90%) dogs with a histologically malignant melanoma of the lip or oral cavity died because of the tumour but only 15 of 33 (45%) with malignant skin melanomas died. Six of 59 (10%) dogs with a tumour of mitotic index 2 or less died from the tumour 2 years after surgery compared to 19 of 26 (73%) dogs having a tumour with a mitotic index of 3 or more.     

Perianal malignant melanoma in a dog

Melanocytic tumors are relatively common in dogs and most often occur in the oral cavity, lip, skin, digit, and eye. There are notable differences in the behavior of these tumors, depending on their anatomical location. The majority of oral melanomas and two-thirds of melanomas arising from the digit are malignant, whereas most of melanomas originating from the haired skin are benign. The anus and perianal areas are very uncommon sites for melanocytic tumors in domestic animals except horses, and most of those tumors in horses are malignant. To our knowledge, perianal malignant melanoma has not been reported in the dog and its prognosis is unknown.     

The histologic and epidemiologic bases for prognostic considerations in canine melanocytic neoplasia

The laboratory records from 384 dogs with a diagnosis of either melanoma or melanocytoma were selected for study. Significant negative determinants of patient survival for melanocytic tumors were: 1) metastasis, 2) mitotic index (MI), 3) nuclear atypia, 4) tumor score, 5) increasing size/volume, 6) the presence of deep inflammation, and/or 7) intralesional necrosis. In addition to these attributes, age was a significant determinant for tumors of the skin. For the feet and lips, 8) age and 9) junction activity negatively impacted survival. Mathematic models were constructed based on these significant determinants to predict the postsurgical outcome of melanocytic neoplasia. Melanocytic oral neoplasms comprised 19% (73/384) of the neoplasms; 92% of these were classified as malignant in the biopsy report, but malignant behavior (i.e., metastasis or recurrence) was observed in only 59% of cases. The prognostic model for oral tumors based on nuclear atypia provided the most accurate (89%) prediction of overall behavior. Melanocytic tumors of the feet and lips were also 19% (73/384) of the total population. Seventy-four percent were reported malignant, whereas only 38% actually demonstrated malignant behavior. The prognostic models based on both MI or nuclear atypia had an overall correct behavioral classification of 81%. Melanocytic tumors in the skin comprised 59% (227/384) of study specimens. Although 39% were reported as malignant, only 12% exhibited malignant behavior. A satisfactory predictive model that employed MI could not be constructed, but one using nuclear atypia gave an overall correct classification in 93.3% of the cases.     

Evaluation of angiogenesis in canine mammary tumors by quantitative platelet endothelial cell adhesion molecule immunohistochemistry

Angiogenesis was evaluated by immunohistochemistry for platelet endothelial cell adhesion molecule (CD31) in a series of benign and malignant canine mammary neoplasms. Computer image analysis was used to measure the intratumoral microvessel density (number of microvessels per square millimeter) and the area and perimeter of immunolabeled vascular structures. A higher intratumoral microvessel density and lower values for area and perimeter were found in malignant neoplasms compared with benign tumors and among the malignant tumors, in less differentiated phenotypes and in more anaplastic histological types (solid and squamous carcinomas), most of which had metastasized. These findings are consistent with an increase in angiogenesis in multistage neoplasia. Therefore, in more anaplastic malignant neoplasms, numerous but small and often malformed new vessels can be identified. The correlation of angiogenesis data with differentiation grade and histological type of mammary neoplasms is consistent with the findings in human medicine and demonstrates that angiogenesis can also have a prognostic value in veterinary medicine.