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Background: Malignant melanoma of dogs is a highly aggressive neoplasm and is the 2nd most common digit tumor. Metastatic disease is a common sequela for which few effective treatment options exist. Studies show that xenogeneic tyrosinase DNA vaccination yields immune responses and prolongation of survival in dogs with oral malignant melanoma., Objectives/hypothesis: Describe clinical findings and tumor characteristics of a cohort of dogs with digit malignant melanoma, and evaluate the prognostic utility of a proposed staging system. Determine if a novel xenogeneic DNA vaccine is safe and potentially effective for treatment of dogs with digit melanoma., Animals: Fifty-eight dogs with digit malignant melanoma treated at the Animal Medical Center between 2004 and 2007., Methods: Retrospective, medical records review of dogs with digit melanoma treated with xenogeneic DNA vaccine., Results: Overall median survival time (MST) for dogs treated with loco-regional control and xenogeneic DNA vaccine was 476 days with a 1-year survival rate of 63%. MST for dogs presenting with metastasis was 105 days versus 533 days for dogs presenting without metastasis (P < .0001). Forty-eight percent of the dogs in the latter group were alive at 2 and 3 years. A proposed staging system proved prognostic with stages I-IV dogs surviving >952, >1,093, 321, and 76 days, respectively., Conclusions and Clinical Importance: The xenogeneic murine tyrosinase DNA vaccine was safe and appears effective when used in conjunction with local and regional disease control. The proposed staging system was prognostic in this study and future studies might benefit from utilizing this staging system., (Copyright © 2010 by the American College of Veterinary Internal Medicine.)

Gastrointestinal stromal tumors (GISTs), leiomyomas, and leiomyosarcomas are common mesenchymal neoplasms in the gastrointestinal (GI) tract of dogs. As previously diagnosed smooth muscle tumors of the canine GI tract are increasingly reclassified as GISTs, it becomes important to identify additional criteria that may assist in the diagnosis of these neoplasms, provide prognostic information, and offer targets for therapy. Examination of cluster of differentiation (CD), molecule expression (such as KIT [CD117] and CD34) as well as gross, histologic, and immunohistochemical features (such as tumor size, tumor location, mitotic index, AgNOR, and Ki67 labeling) in human GISTs has revealed new and valuable prognostic, diagnostic, and therapeutic information. In this study, GISTs were examined for the gross, histologic, and immunohistochemical features listed above. Forty-nine cases of canine gastrointestinal mesenchymal neoplasms from the Animal Medical Center (New York, NY) were categorized as GISTs (KIT positive), leiomyosarcoma/leiomyoma (KIT negative, smooth muscle actin [SMA], and/or desmin positive), or other (KIT, SMA, and desmin negative). A proportion (55%) of canine cases previously diagnosed as smooth muscle tumors were reclassified as GISTs according to KIT immunoreactivity. Statistical correlations with survival data were not possible because of insufficient follow-up data. However, there was a significant difference between mitotic index, AgNOR, and Ki67 scores depending on the location of the tumor (small vs large intestine). This study represents the first time CD34 immunoreactivity has been demonstrated in canine GISTs.

The prognosis of canine soft-tissue sarcomas (STS) has traditionally been based on histologic grading. We have recently demonstrated the prognostic value of cellular proliferation markers in canine STS. Another method of predicting the behavior of neoplasms is intratumoral microvessel density (IMD), which is a measure of tumor angiogenesis. The prognostic significance of IMD has been documented in many human neoplasms and in a limited number of canine and feline neoplasms. To evaluate the prognostic value of IMD in canine STS, we studied 57 STS and compared IMD with histologic features, histologic grade, cellular proliferation, metastatic propensity, and survival. Using immunohistochemistry, the STS were labeled with anti-factor VIII-related antigen (FVIII-RA) and anti-CD31 antibodies to determine 3 IMD parameters: mean microvessel density, high microvessel density, and microvessel area. Using FVIII-RA and CD31, increasing IMD was statistically associated with increasing histologic grade, necrosis scores, and mitotic scores. Higher FVIII-RA IMD values were significantly associated with higher median argyrophilic nucleolar organizing region (AgNOR) values (as previously investigated) and increased metastatic propensity. Fibrosarcomas appear to be the least vascularized of STS. There is no correlation between IMD and survival. Our results indicate that IMD is of prognostic value for histologic grade, histologic features, cellular proliferation (based on AgNOR), and metastatic propensity of canine STS, specifically when using FVIII-RA as the endothelial marker. Assessing histologic grading, cellular proliferation, and IMD of canine STS at the time of diagnosis could therefore provide better prognostic information for the veterinary clinician.

Introduction: Canine malignant melanoma (CMM) is an aggressive neoplasm treated with surgery and/or fractionated RT; however, metastatic disease is common and chemoresistant. Preclinical and clinical studies by our laboratory and others have shown that xenogeneic DNA vaccination with tyrosinase family members can produce immune responses resulting in tumor rejection or protection and prolongation of survival. These studies provided the impetus for development of a xenogeneic DNA vaccine program in CMM., Materials and Methods: Cohorts of three dogs each received increasing doses of xenogeneic plasmid DNA encoding either human tyrosinase (huTyr; 100/500/1500 mcg), murine GP75 (muGP75; 100/500/1500 mcg), murine tyrosinase (muTyr; 5 dogs each at 100/500 mcg), muTyr+/-HuGM-CSF (9 dogs at 50 mcg muTyr, 3 dogs each at 100/400/800 mcg HuGM-CSF, or 3 dogs each at 50 mcg muTyr with 100/400/800 mcg HuGM-CSF), or 50 mcg MuTyr intramuscularly biweekly for a total of four vaccinations., Results: The Kaplan-Meier median survival time (KM MST) for all stage II-IV dogs treated with huTyr, muGP75 and muTyr are 389, 153 and 224 days, respectively. Preliminarily, the KM MST for stage II-IV dogs treated with 50 mcg MuTyr, 100/400/800 mcg HuGM-CSF or combination MuTyr/HuGM-CSF are 242, 148 and >402 (median not reached) days, respectively. Thirty-three stage II-III dogs with loco-regionally controlled CMM across the xenogeneic vaccine studies have a KM MST of 569 days. Minimal to mild pain was noted on vaccination and one dog experienced vitiligo. We have recently investigated antibody responses in dogs vaccinated with HuTyr and found 2- to 5-fold increases in circulating antibodies to human tyrosinase., Conclusions: The results of these trials demonstrate that xenogeneic DNA vaccination in CMM: (1) is safe, (2) leads to the development of anti-tyrosinase antibodies, (3) is potentially therapeutic, and (4) is an attractive candidate for further evaluation in an adjuvant, minimal residual disease Phase II setting for CMM.

Antitumor immune responses can be elicited in preclinical mouse melanoma models using plasmid DNA vaccines encoding xenogeneic melanosomal differentiation antigens. We previously reported on a phase I clinical trial of human tyrosinase (huTyr) DNA vaccination of 9 dogs with advanced malignant melanoma (World Health Organization stages II-IV), in which we demonstrated the safety of the treatment and the prolongation of the expected survival time (ST) of subjects as compared to historical, stage-matched controls. As a secondary goal of the same study, we report here on the induction of tyrosinase-specific antibody responses in three of the nine dogs vaccinated with huTyr DNA. The antibodies in two of the three responders cross-react with syngeneic canine tyrosinase, demonstrating the ability of this vaccine to overcome host immune tolerance and/or ignorance to or of "self" antigens. Most interestingly, the onset of antibody induction in these three dogs coincides with observed clinical responses and may suggest a means to account for their long-term tumor control and survival.

Ten dogs with neuroendocrine carcinoma of the liver were selected for inclusion in the study. Clinical signs were anorexia (7), vomiting (5), polydipsia/polyuria (3), icterus (2), lethargy (2), weight loss (2), paresis (1), ataxia (1), weakness (1), collapse (1), and urinary tract infection (1). Hematologic and biochemical abnormalities included anemia (2/8), leukocytosis (4/8), high liver enzyme activity (serum alkaline phosphatase, 7/9; alanine transaminase, 7/9; aspartate transaminase, 8/9), and high total bilirubin (6/9). Grossly, the tumors were diffuse, involving all liver lobes in six dogs, and two dogs had various-sized nodules in addition to diffuse involvement. Histologically, there were eight tumors with solid or trabecular pattern (group A), one tumor with cords or rows of neoplastic cells (group B), and one tumor with multiple rosette-like structures (group C). Immunohistochemical studies revealed that all 10 neoplasms were positive for at least one of the endocrine markers used: neuron-specific enolase (NSE; 8/10), synaptophysin (5/10), and chromogranin-A (3/10). A panel of NSE, chromagranin-A, and synaptophysin detected 100% of the tumors in our series. Electron microscopy confirmed the diagnosis by the presence of intracytoplasmic neurosecretory granules in the two examined cases. Our results show that neuroendocrine markers commonly used in humans can be used for the diagnosis of hepatic neuroendocrine carcinoma in dogs, preferably a panel of synaptophysin, chromagranin-A, and NSE because chromogranin-A alone is not as useful in dogs as in humans.

Renal cysts in the cortex of a juvenile Belgian Malinois dog with acute renal failure were studied by means of light, scanning and transmission electron microscopy, immunohistochemistry for intermediate filaments, and binding for wheat germ agglutinin (WGA), peanut agglutinin (PNA), and Maclura pomifera agglutinin (MPA) lectins to determine the morphological and histochemical features of the epithelial cells of these cysts. The cysts were renal corpuscles with expanded urinary space. Glomerular tufts were small with poorly developed capillary loops and increased mesangial matrix. Continuity with the proximal tubule was evident in some cystic glomeruli. Two cell types lined Bowman's capsule. One was squamous with a central cilium and microvilli. The other had morphological and histochemical features of immature podocytes (parietal podocytes). These cells were round and protruded into the urinary space; they had thick cytoplasmic projections that resembled foot processes of podocytes, microvilli, and filtration slits. The parietal podocytes expressed vimentin and cytokeratins and had affinity for WGA as do normal immature podocytes. These features suggest that the parietal podocytes are derived by metaplasia of the parietal cells. The basement membrane of Bowman's capsule was irregularly thickened and showed multifocal glycosylation changes with lectin histochemistry (WGA, PNA, MPA) in areas adjacent to the parietal podocytes. Histologic and ultrastructural findings in this dog are consistent with glomerulocystic kidney disease. This is the second report of canine glomerulocystic kidney disease. Features are similar to those of the human counterpart, but it is unclear whether genetic defects cause the disease in the dog. The presence of parietal podocytes in all cysts suggests that abnormal differentiation may play an important role in the pathogenesis of this type of polycystic kidney disease.

Samples from rectal plasmacytoma in three adult dogs that were diagnosed by light microscopy and immunohistochemistry were examined by electron microscopy. The most common cell type had typical plasmacytoid features. A second cell type was a plasmacytoid giant cell with single or multiple eccentric nuclei, irregular nuclear membrane, abundant and dilated rough endoplasmic reticulum, and numerous electron-dense granules. The third cell type was a histiocytic giant cell that intermingled with plasmacytoid cells. All three tumors had abundant amyloid, mainly in the interstitium but also within histiocytic cells and less commonly in plasma cells or plasmacytoid giant cells. Extracellular and intracellular amyloid fibrils and the contents of membrane-bound electron-dense bodies of plasma cells reacted with antibody to lambda-light chain of immunoglobulins by immunogold staining.