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Background: Hepatic tumors of primary origin account for 0.6% to 2.9% of cases in canine species, less common than hepatic metastases. The hepatic tumors are divided into hepatocellular tumors, neuroendocrine tumors, bile duct tumors or cholangiocarcinomas, and mesenchymal tumors. Cholangiocarcinomas, are classified according to their origin, being intrahepatic, extrahepatic, or gallbladder type. Cholangiocarcinomas are considered rare in dogs and cats with a ratio of 29% to 71% compared to hepatocellular carcinomas, accounting for 9% of the hepatic tumors. The present study aims to describe a case of cholangiocarcinoma in a bitch, focusing on the diagnostic approach. Case: A 10-year-old castrated bitch Poodle was attended presenting hypoglycemia and seizure crisis. The patient had previous exams of hemogram and serum biochemical profile, showing a discrete increase of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), besides hypoglycemia. Previous ultrasound exam revealed the presence of a hepatic mass located between the right and square lobes, immeasurable, and significant splenomegaly. Abdominal palpation revealed the presence of immeasurable abdominal formation of undetermined origin. Abdominal computerized tomography (CT), glycemic curve, and insulin dosage were requested. Tomography exam showed an increase in hepatic volume with the presence of a heterogeneous formation in the right lateral lobe topography; increase in spleen dimensions and the presence of multiple nodules; and the presence of a nodule in the right lung, at the caudal thoracic region. The glycemic curve showed acute variations, and insulin dosage was between normal values. The animal was referred for surgery, as in abdominocentesis, it was observed the presence of hemorrhagic fluid, confirming active bleeding by ultrasonography. The owners chose for euthanasia. In the post-mortem evaluation the main lesion was confirmed of hepatic origin, with a massive, irregular, cavitary presentation, involving multiple hepatic lobes, and a single nodule was observed in the right caudal lobe of the right lung. Histopathological evaluation was considered inconclusive. Immunohistochemistry was performed and the association of the immunohistochemical profile with the morphological characteristics indicated diagnosis of cholangiocarcinoma. Discussion: The related symptomatology, in hepatic neoplasms, is generally considered non-specific, with reports of lethargy, vomiting, dyspnea, anorexia and weight loss, however, the dog in this study presented a unique manifestation of hypoglycemia and one episode of convulsive crisis resulting from it. The clinical manifestation observed was extremely unspecific making initial diagnosis difficult. The ultrasonographic examination was effective in evidencing the abdominal mass. In addition, abdominal CT was also performed, which confirmed the hepatic origin, detailing the macroscopic aspect. Biochemical analyses of ALT and AST showed a discrete increase. Biochemical changes may occur in dogs with hepatic neoplasms, although they are not specific. Functional pancreatic beta-cell tumors producing insulin are the most common cause of paraneoplastic hypoglycemia, although in the case the insulin dosage was within normal limits. In cases of nonislet cell tumor the mechanism is frequently associated with the production of insulin-like growth factor (IGF). In most cases the definitive diagnosis of cholangiocarcinoma can be obtained by histopathological examination, although in the present report the result obtained was inconclusive, requiring an immunohistochemical examination. Due to the aggressive and metastatic character of this neoplastic type, early detection becomes extremely important in order to maximize therapeutic chances, however, diagnosis may be difficult.

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Background: Secretory carcinoma is a rare histological type of breast neoplasm in humans and dogs that is characterized by the presence of intracellular and extracellular eosinophilic secretions. Case Description: In this case report, we describe the cytological, histological, and immunohistochemical characteristics of secretory mammary carcinoma in a 10-year-old mixed-breed female dog with nodal and bone metastases. The bitch had a history of claudication and a mass in the left humeral scapular region, which revealed osteolysis of the proximal humerus on radiography. Fine-needle aspiration cytology revealed numerous neoplastic cells arranged mostly in cohesive groups but sometimes isolated, that contained cytoplasmic vacuoles and had a moderate-to-high nucleus: cytoplasm ratio with frequent karyomegaly and evident nucleoli. Histologically, the neoplasm was organized in solid, tubular structures with luminal spaces filled with eosinophilic secretions and was composed of cells with clear cytoplasm and prominent vacuoles that pushed the nuclei to the periphery, resembling signet ring cells. The extracellular and intracytoplasmic material of the epithelial cells was positive for periodic acid-Schiff staining and immunoreactive for alpha-lactalbumin. Two chemotherapy sessions were performed, but 1 month after surgery, the clinical condition worsened, and euthanasia was elected, accounting for 133 days of survival after surgical removal of the tumor. Conclusion: The bitch presented with secretory mammary carcinoma with nodal and bone metastases, and histological and immunohistochemical characteristics were important for diagnosis. The morphological and immunohistochemical characteristics of this carcinoma were similar to those observed in humans. Mammary gland secretory carcinoma with bone metastasis must be included as a differential diagnosis among canine mammary gland carcinomas showing cellular morphological characteristics of intracytoplasmic vacuolization and eosinophilic secretion.

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Vasculogenic mimicry (VM) is the ability of highly aggressive cancer cells to form fluid-conducting channels that facilitate the nutrition and metastasis of cancer cells. Considering the importance of VM in the prognosis of canine mammary gland tumours, this study aimed to investigate global gene expression in two canine mammary carcinoma cell cultures associated with the capacity for VM in vitro. The cell lines were subjected to an in-vitro assay to form VM channels (3D culture). Each cell line was then used in 2D conditions as controls and we compared the global gene expression with that of the 3D cultures. A total of 1,217 differentially expressed genes (DEGs) (P <0.05, fold change >2.0 or <2.0) were observed in 3D conditions compared with 2D culture in the UNESP-CM9 cell line, of which 677 were upregulated genes and 540 were downregulated. In contrast, the UNESP-CM60 cell line had only one upregulated and two downregulated genes. Overall, we identified several genes and pathways involved in the development of VM and these molecular data will be useful for future studies aimed at identifying diagnostic and therapeutic targets for VM in canine mammary carcinoma.

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Canine malignant mammary neoplasms (CMMN) exhibit behavioral variability with the patient survival time depending on several prognostic factors. In the present study, 134 CMMN were selected and different immunophenotypes and their associations with clinical and pathological parameters were identified. The tumors were classified as follows: 46% of luminal B HER2-, 34% of luminal A, 13% of triple-negative, and 7% of luminal B HER2+. Shorter specific survival time were associated with larger tumor sizes (>3.0 cm, HR=1.94; P=0.0209), lymph node metastasis or distant metastasis (HR= 2.82; P <.0001), more aggressive histological types (HR= 7.15, P<0.0001), higher histological grades (HR= 12.97 P=0.011), angiolymphatic invasion (HR=4.68, P<0.0001) and luminal B HER2 - (HR= 3.27, P<0.0001) and luminal B HER2 + (HR= 7.14 P<0.0001) immunophenotypes. In patients with lymph nodal metastasis, shorter survival times were associated with luminal immunophenotype B HER2 + (P=0.003). However, in patients without metastasis, an increased risk of death was associated with the aggressive histological type. In conclusion, the classification in our study allowed us to identify subtypes with different prognoses in canine malignant mammary tumors. Factors such as clinical stage, histological type, luminal B HER2+ subtype, and angiolymphatic invasion were the most important prognostic factors.

Neoplasias mamárias malignas caninas (CMMN) apresentam variável comportamento biológico e o tempo de sobrevida depende de diversos fatores prognósticos. Neste estudo, foram selecionadas 134 CMMN, bem como identificados diferentes imunofenótipos e suas associações com parâmetros clínicos e patológicos. Os tumores foram classificados em: 46% luminal B HER2-, 34% luminal A, 13% triplo negativo e 7% luminal B HER2+. Menores taxas de sobrevida específica foram associadas a tamanhos de tumor maiores (> 3,0cm; HR = 1,94; P = 0,0209), metástases em nodais ou a distância (HR = 2,82; P <0,0001), tipos histológicos mais agressivos (HR = 7,15; P <0,0001), graus histológicos mais elevados (HR = 12,97; P = 0,011), invasão angiolinfática (HR = 4,68; P <0,0001) e aos imunofenótipos luminal B HER2- (HR = 3,27; P <0,0001) e luminal B HER2+ ( HR = 7,14; P <0,0001). Em pacientes com estágio avançado, menor sobrevida específica foi associada ao imunofenótipo luminal B HER2+ (P = 0,003). Entretanto, em estágio inicial, um risco aumentado de óbito foi associado a tipos histológicos agressivos. Em conclusão, a classificação utilizada no presente estudo permitiu identificar subtipos com diferentes prognósticos em CMMN. Estágio clínico, tipo histológico, subtipo luminal B HER2+ e invasão angiolinfática foram os fatores prognósticos mais importantes.

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Mammary neoplasms are the most frequently diagnosed tumours in female dogs and are classified into various histological types, including solid carcinomas. We proposed a subclassification of solid carcinomas based on morphological and immunohistochemical characteristics, and correlated the subtypes with prognostic factors. A total of 135 cases of solid mammary carcinoma were selected from 3,400 canine mammary neoplasms in the archives of the Laboratory of Comparative Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Brazil. Epidemiological and survival data were obtained, and immunolabelling for chromogranin A, pancytokeratin, cytokeratin 14, Ki67 and p63 was performed. Solid carcinomas were classified into six subgroups: malignant adenomyoepithelioma (68/135), carcinoma with solid pattern (22/135), malignant myoepithelioma (16/135), basaloid carcinoma (14/135), neuroendocrine carcinoma (10/135) and solid papillary carcinoma (5/135). Shorter survival time was associated with the presence of lymphatic invasion (P = 0.009) in the initial clinical staging (I-III). When considering all clinical stages (I-V), vascular invasion (P <0.001) and the presence of regional metastasis (P = 0.004) were important prognostic factors. Basaloid carcinoma and solid papillary carcinoma did not reach the median survival time for early-stage cases, and malignant myoepithelioma had the highest median survival in advanced stages. Carcinoma with a solid pattern was associated with a higher number of regional metastases. Distinguishing the various histological and immunophenotypic subtypes that exhibit a solid arrangement, using histological and immunohistochemical criteria, is essential for understanding the behaviour of these neoplasms and for the selection of more appropriate and specific therapies.

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Background: Primary pituitary carcinoma is rarely reported in dogs and only few reports describe its malignancy. In veterinary literature, primary pituitary carcinomas correspond up to 2.4% to 3.4% of intracranial neoplasms found in dogs andinformation regarding its biological behavior is quite limited. In humans, primary pituitary carcinomas represent less than1.0% of all tumors found in the pituitary gland. The proposed classification for pituitary carcinoma in humans and dogsdetermines that the tumor must have its origin in adenohypophyseal region and disseminated metastasis by cerebrospinalfluid or systemically to other organs must be observed. In dogs, a few reports have described primary pituitary carcinoma.The goal of this report was to describe clinical, tomographic, histopathological and immunohistochemistry features of abitch with primary pituitary carcinoma with adjacent invasion.Case: A 7-year-old female spayed Golden Retriever dog was assessed by general practice due progressive weight loss,muscular atrophy, lethargy, blindness, head pressing, and hyporexia for 21 days. Computed tomography (CT) showeda cerebral parenchyma with expansive extra-axial base formation, originating from sella turcica topography, measuringabout 2.0 cm dorsally, displacing the third ventricle, suggesting the diagnosis of pituitary neoplasia. The hormones thyroidstimulating hormone (TSH) and total thyroxine (T4) as well as stimulation ACTH test were unremarkable. After 7 days,neurological clinical signs progressed and unfortunately the patient died ten days later after hospitalization. A necropsyexam revealed pituitary gland with increased dimensions (2.5 x 2.0 cm). Histopathological fi ndings revealed tumor proliferation in pituitary gland. The neoplasm showed invasion to the nervous parenchyma and metastatic foci between the brainlobes. Immunohistochemistry was positive for keratin and neuron-specifi c enolase...

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The proteoglycan versican (VCAN) plays a complex role in cancer. The expression of this molecule has been related to invasion and progression in malignant mixed tumors, such as carcinoma in mixed tumors (CMT) of the canine mammary gland. In addition, its interaction with surface cell receptors EGFR, HER-2 and CD44 in malignant epithelial cells may be responsible for proliferation and cellular motility in early stages of cancer. We comparatively evaluated the expression of this proteoglycan and its receptors in in situ and invasive areas of simple carcinomas (SC) and CMT to investigate similarities and differences between these histological types. Immunohistochemistry was performed with anti-VCAN, anti-CD44, anti-EGFR and anti-HER-2 antibodies in 32 cases of SC or CMT. VCAN was highly expressed in stroma adjacent to invasive areas in SC and CMT. CMTs presented comparatively higher expression of VCAN in stroma adjacent to in situ and in invasive areas than in corresponding areas in SCs. In CMT, EGFR and HER-2 expressions were higher in situ compared to invasive areas. In contrast, increased CD44 and EGFR expression was found in invasive areas in SC compared to CMT. These results indicate that versican expression is similarly associated with invasiveness in SC and CMT, however higher levels were seen in CMT suggesting that the presence of myoepithelial proliferation in this tumor type participates in stromal composition and promoting an increase in the expression of versican.

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Regional lymph node status impacts survival in dogs with malignant mammary tumors. However, few studies have evaluated extracapsular extension and tumor implants in regional lymph node metastases in dogs with mammary carcinoma. Therefore, 84 cases of mammary carcinomas with metastases in inguinal and/or axillary lymph nodes from female dogs of different breeds and a total of 139 metastatic lymph nodes were evaluated by routine histological staining. Clinical and pathological characteristics of primary tumors as well as the presence of extracapsular extension and tumor implants in the lymph nodes were analyzed, in addition to survival. One to 5 lymph nodes were evaluated in each case. Extracapsular extension and tumor implants were present in 17.9% and 39.3% of cases, respectively. The simultaneous presence of extracapsular extension and tumor implants were associated with an increased risk of death (hazard ratio 10.46). In addition, "special type carcinomas", high histological grade (grade III), and presence of extracapsular extension associated with tumor implants were related to a worse prognosis and shorter survival times (p < 0.05). Based on these results, we highlight the importance of identifying extracapsular extension and tumor implants in dogs with metastatic mammary carcinomas, as they are associated with a higher risk of death and shorter survival.

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Feline mammary carcinomas (FMCs) are commonly characterized by high clinical aggressiveness and poor prognosis. FMCs share many features with the corresponding human disease, allowing the comparative investigation of tumour biology and therapeutic strategies, including multidrug resistance (MDR) mechanisms. Although transporting/binding proteins, including permeability glycoprotein (P-gp), lung resistance protein (LRP) and metallothionein (MT), are frequently associated with tumour aggressiveness and unresponsiveness to chemotherapy in human breast cancer, they have not been analysed in FMCs. We investigated the immunoexpression of P-gp, LRP and MT in FMCs and their correlation with clinicopathological parameters and overall survival (OS) time in 46 FMCs, with a median follow-up period of 289 days. These markers were co-expressed in 85% of tumours. P-gp was expressed in 93.4% of FMCs and was positively associated with tumour grade (P = 0.049). While unequivocally observed in all FMCs, LRP immunoexpression did not correlate with any clinicopathological parameters or OS. Expression of MT was significant in triple-negative basal- and normal-like molecular subtypes of FMCs (P = 0.023). The concurrent expression of MDR proteins indicates the potential existence of chemotherapy resistance-related mechanisms in FMCs. The positive association between P-gp and MT immunoexpression and aggressive phenotypes could open new therapeutic and translational strategies for FMCs.

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Mammary tumours are the first and third most incident neoplasm in women and cats, respectively. Approximately 85% of feline mammary gland tumours are malignant and aggressive, especially the triple-negative and HER-2+ molecular subtypes. Triple-negative basal-like feline mammary carcinomas (FMCs) are considered suitable models due to the clinical and morphological similarities with human basal-like triple-negative breast cancer (TNBC). In women, TNBC has a poor prognosis and is often associated with mutations in the tumour suppressor genes BRCA1 and BRCA2. In light of this, the aim of the present investigation was to screen somatic and germline variants of BRCA1 and BRCA2 in nine female cats bearing FMCs. Matched whole blood and FMC samples were obtained for genetic analysis. Additional tumour samples were obtained for histopathological and immunohistochemical evaluation. Genomic DNA was isolated and 27 exonic regions of BRCA1 and BRCA2 genes were amplified and screened by next-generation sequencing. A somatic variant with high functional impact was found in exon 11 of BRCA2 at a frequency of 4.34% in one FMC-bearing cat. Four germline variants with moderate impact were detected in three of the nine FMC-bearing cats and were restricted to exon 9 of BRCA1. It is concluded that the germline genetic variants found in one-third of FMC-bearing animals might be associated with a higher risk of hereditary mammary carcinogenesis.

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