A comparative analysis of anatomopathological features and COX-2 expression of mammary neoplasms with malignant mesenchymal components in female dogs / Análise comparativa das características anatomopatológicas e expressão de COX2 em neoplasias mamárias com componentes mesenquimais malignos em cadelas

ABSTRACT: Canine mammary neoplasms with malignant mesenchymal components, such as carcinosarcomas and sarcomas, belong to an uncommon and histologically heterogeneous group. Little is known about the biological behavior of these histogenic variants. This study aimed to compare the clinicopathological characteristics and the COX-2 immunohistochemical expression of different histologic subtypes of carcinosarcomas and sarcomas. Samples of 23 carcinosarcomas and 15 sarcomas from the mammary glands of female dogs were studied. Medical records were reviewed to obtain clinical data. Subsequently, histology microscope slides were analyzed to assess for mesenchymal subtypes, necrosis, vascular invasion, histologic grades, and lymph node metastasis. Immunohistochemistry was used to assess the COX-2 expression. The malignant mesenchymal proliferation was categorized into osteosarcomas (23/40), fibrosarcomas (5/40), liposarcomas (6/40) and chondrosarcomas (4/40). The osteosarcomatous differentiation was the most predominant type among the sarcomas and carcinosarcomas and was associated with vascular invasion (P=0.010) and lymph node metastases (P=0.014). High COX-2 expression was detected in 14.3% of the carcinosarcomas (carcinoma and/or sarcoma cells) and 27.3% of the sarcomas. The carcinosarcomas and sarcomas had similar clinical and pathological characteristics and developed as large tumors, with intratumoral necrosis and a predominance of high histologic grades, although the frequency of vascular invasion and lymph node metastasis was low. Osteosarcoma subtypes presented more aggressive characteristics than non-osteosarcoma subtypes.

RESUMO: Neoplasias mamárias caninas com componentes mesenquimais malignos, como carcinossarcomas e sarcomas, são um grupo de neoplasias pouco frequentes e histologicamente heterogêneas e pouco se sabe sobre o comportamento biológico das variantes histogênicas. O objetivo desse estudo é comparar as características anatomopatológicas e a expressão imunoistoquímica de COX-2 de diferentes subtipos histológicos de carcinossarcomas e sarcomas. Foram estudados 23 carcinosarcomas e 17 sarcomas da glândula mamária de cadelas. Os prontuários médicos foram revisados para obtenção de dados clínicos. Posteriormente, as lâminas histológicas foram avaliadas para acessar os subtipos mesenquimais, necrose, invasão vascular, grau histológico, metástase linfonodal. A imunoistoquímica foi realizada para avaliar a expressão de COX-2. Os tipos encontrados de proliferação mesenquimal maligna foram osteossarcoma (23/40), fibrossarcoma (7/40), lipossarcoma (6/40) e condrossarcoma (4/40). A diferenciação osteossarcomatosa foi predominante entre os sarcomas e carcinossarcomas e foi associado com invasão vascular (P=0,006) e metástase linfonodal (P=0,014). Uma expressão alta de COX-2 foi detectada em 14,3% dos carcinossarcomas (células carcinomatosas e/ou sarcomatosas) e 27,3% dos sarcomas. Os carcinossarcomas e sarcomas apresentaram características clínicas e patológicas semelhantes e se desenvolveram como tumores grandes, com necrose intratumoral e predomínio de alto grau histológico, mas com baixa frequência de invasão vascular e metástase distante. Os subtipos osteossarcomatosos apresentaram características mais agressivas quando comparados com subtipos não osteossarcomatosos.

Consensus Regarding the Diagnosis, Prognosis and Treatment of Canine and Feline Mammary Tumors 2019

The aim of this paper is to discuss and update criteria that can guide the diagnosis, prognosis and treatment of canine and feline mammary neoplasms. It was elaborated during the IV Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment of the Canine and Feline Mammary Neoplasia, held on April 29th and 30th, 2019 in Belo Horizonte MG, Brazil, sponsored by the Laboratory of Comparative Pathology of the Federal University of Minas Gerais (UFMG), with the support of the Brazilian Association of Veterinary Pathology (ABPV) and Brazilian Association of Veterinary Oncology (ABROVET). Academics from several regions of Brazil were present and contributed to this work.(AU)

Consensus Regarding the Diagnosis, Prognosis and Treatment of Canine and Feline Mammary Tumors – 2019

The aim of this paper is to discuss and update criteria that can guide the diagnosis, prognosis and treatment of canine and feline mammary neoplasms. It was elaborated during the IV Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment of the Canine and Feline Mammary Neoplasia, held on April 29th and 30th, 2019 in Belo Horizonte – MG, Brazil, sponsored by the Laboratory of Comparative Pathology of the Federal University of Minas Gerais (UFMG), with the support of the Brazilian Association of Veterinary Pathology (ABPV) and Brazilian Association of Veterinary Oncology (ABROVET). Academics from several regions of Brazil were present and contributed to this work.

Tumor-associated macrophage is correlated with survival and SOCS protein expression in canine mammary carcinoma / Correlação do infiltrado macrofágico com a sobrevida e a expressão da proteína SOCS no carcinoma mamário canino

The inflammatory infiltrate in the tumor microenvironment, particularly in mammary tumors, has aroused great interest in oncology, to play different roles in the progression or tumor regression dependent on the types and cell subsets involved. The present study aimed to evaluate (1) the occurrence and intensity of macrophage infiltration in the mammary carcinoma microenvironment, (2) the expression of SOCS1 and SOCS3 proteins in tumor associated macrophages, (3) any association between these parameters and tumor development, as well as survival rates in female dogs. Twenty-two female dogs diagnosed as carcinoma arising in a mixed tumor (CMT) by histopathology were divided into two groups following mastectomy: dogs without metastasis (CMT(-)=11) and those with metastasis (CMT(+)=11). The following parameters were analyzed: tumor size, lymph node metastasis, clinical stage, histological grade, distribution and intensity of inflammatory infiltrate, tumor macrophage quantification by immunohistochemical analysis of SOCS1 and SOCS3 expression, and immunophenotyping of peripheral blood leukocytes by flow cytometry. Dogs with the higher proportions of macrophages in the inflammatory infiltrate (≥400/tumor) also had higher survival rates in comparison with dogs with less macrophages. Immunostaining revealed higher proportions of SOCS3-positive macrophages in dogs without lymph node metastasis, while SOCS1-positive macrophages were predominant in dogs with metastasis (p<0.05). Multivariate analysis found associations between survival rate and clinical staging (p=0.025), histological grade (p=0.007), and the expression of MHC-CI in circulating monocytes (p=0.018)...(AU)

O infiltrado inflamatório no microambiente tumoral, particularmente nos tumores mamários, tem despertado grande interesse na oncologia, por desempenhar diferentes funções na progressão ou regressão tumoral, dependendo dos tipos e subtipos celulares envolvidos. O presente estudo teve como objetivo avaliar: (1) a ocorrência e a intensidade do infiltrado macrofágico no microambiente do carcinoma mamário; (2) a expressão das proteínas SOCS1 e SOCS3 nos macrófagos associados ao tumor; (3) qualquer associação relacionada ao prognóstico entre estes parâmetros e o desenvolvimento tumoral, assim como a taxa de sobrevida. Vinte e duas cadelas diagnosticadas com carcinoma em tumor misto (CTM) por exame histopatológico foram divididas em dois grupos após a mastectomia: cadelas sem metástase (CTM(-)=11) e cadelas com metástase (CTM(+)=11). Foram analisados os seguintes parâmetros: tamanho do tumor, metástase para linfonodo, estadiamento clínico, grau histológico, distribuição e intensidade do infiltrado inflamatório, quantificação dos macrófagos tumorais por análise imuno-histoquímica da expressão de SOCS1 e SOCS3, e imunofenotipagem dos leucócitos (monócitos e linfócitos) do sangue periférico por citometria de fluxo. Cadelas que apresentavam maiores proporções de macrófagos no infiltrado inflamatório (≥400/tumor) também tiveram maior taxa de sobrevida em comparação àquelas com menos macrófagos. A imunomarcação revelou maiores proporções de macrófagos SOCS3-positivos em cães sem metástase para linfonodo, enquanto que macrófagos SOCS1-positivos foram predominantes naqueles com metástase (p<0,05). A análise multivariada identificou associações entre a taxa de sobrevida e o estadiamento clínico (p=0,025), grau histológico (p=0,007) e a expressão de MHC-CI em monócitos circulantes (p=0,018)...(AU)

Tumor-associated macrophage is correlated with survival and SOCS protein expression in canine mammary carcinoma / Correlação do infiltrado macrofágico com a sobrevida e a expressão da proteína SOCS no carcinoma mamário canino

The inflammatory infiltrate in the tumor microenvironment, particularly in mammary tumors, has aroused great interest in oncology, to play different roles in the progression or tumor regression dependent on the types and cell subsets involved. The present study aimed to evaluate (1) the occurrence and intensity of macrophage infiltration in the mammary carcinoma microenvironment, (2) the expression of SOCS1 and SOCS3 proteins in tumor associated macrophages, (3) any association between these parameters and tumor development, as well as survival rates in female dogs. Twenty-two female dogs diagnosed as carcinoma arising in a mixed tumor (CMT) by histopathology were divided into two groups following mastectomy: dogs without metastasis (CMT(-)=11) and those with metastasis (CMT(+)=11). The following parameters were analyzed: tumor size, lymph node metastasis, clinical stage, histological grade, distribution and intensity of inflammatory infiltrate, tumor macrophage quantification by immunohistochemical analysis of SOCS1 and SOCS3 expression, and immunophenotyping of peripheral blood leukocytes by flow cytometry. Dogs with the higher proportions of macrophages in the inflammatory infiltrate (≥400/tumor) also had higher survival rates in comparison with dogs with less macrophages. Immunostaining revealed higher proportions of SOCS3-positive macrophages in dogs without lymph node metastasis, while SOCS1-positive macrophages were predominant in dogs with metastasis (p<0.05). Multivariate analysis found associations between survival rate and clinical staging (p=0.025), histological grade (p=0.007), and the expression of MHC-CI in circulating monocytes (p=0.018). Higher SOCS3 expression in activated macrophages within the inflammatory infiltrate were considered indicative of an antitumor immune response, improved clinicopathological parameters and longer survival, whereas SOCS1-related activation was associated with tumor progression, metastasis development and reduced survival in female dogs with mammary carcinomas.(AU)

O infiltrado inflamatório no microambiente tumoral, particularmente nos tumores mamários, tem despertado grande interesse na oncologia, por desempenhar diferentes funções na progressão ou regressão tumoral, dependendo dos tipos e subtipos celulares envolvidos. O presente estudo teve como objetivo avaliar: (1) a ocorrência e a intensidade do infiltrado macrofágico no microambiente do carcinoma mamário; (2) a expressão das proteínas SOCS1 e SOCS3 nos macrófagos associados ao tumor; (3) qualquer associação relacionada ao prognóstico entre estes parâmetros e o desenvolvimento tumoral, assim como a taxa de sobrevida. Vinte e duas cadelas diagnosticadas com carcinoma em tumor misto (CTM) por exame histopatológico foram divididas em dois grupos após a mastectomia: cadelas sem metástase (CTM(-)=11) e cadelas com metástase (CTM(+)=11). Foram analisados os seguintes parâmetros: tamanho do tumor, metástase para linfonodo, estadiamento clínico, grau histológico, distribuição e intensidade do infiltrado inflamatório, quantificação dos macrófagos tumorais por análise imuno-histoquímica da expressão de SOCS1 e SOCS3, e imunofenotipagem dos leucócitos (monócitos e linfócitos) do sangue periférico por citometria de fluxo. Cadelas que apresentavam maiores proporções de macrófagos no infiltrado inflamatório (≥400/tumor) também tiveram maior taxa de sobrevida em comparação àquelas com menos macrófagos. A imunomarcação revelou maiores proporções de macrófagos SOCS3-positivos em cães sem metástase para linfonodo, enquanto que macrófagos SOCS1-positivos foram predominantes naqueles com metástase (p<0,05). A análise multivariada identificou associações entre a taxa de sobrevida e o estadiamento clínico (p=0,025), grau histológico (p=0,007) e a expressão de MHC-CI em monócitos circulantes (p=0,018). A maior expressão de SOCS3 nos macrófagos ativados foi considerada indicativa de uma resposta imune antitumoral, melhores parâmetros clínicos e maior taxa de sobrevida, ao passo que a ativação relacionada com SOCS1 foi associada à progressão tumoral, desenvolvimento de metástase e redução na taxa de sobrevida em cadelas com carcinoma mamário.(AU)

Consensus regarding the diagnosis, prognosis and treatment of canine mammary tumors: benign mixed tumors, carcinomas in mixed tumors and carcinosarcomas

Mammary neoplasms are the most frequent tumors in female dogs. Of these neoplasms, benign mixed tumors (BMTs) and carcinomas in mixed tumors (CMTs) represent a large proportion of small animal oncology diagnoses. Together with carcinosarcomas (CSs), these three neoplastic entities are characterized by the proliferation of benign or malignant epithelial, myoepithelial, and mesenchymal cells, depending on their histological types. This histological heterogeneity, in addition to their molecular heterogeneity, confers these tumors with distinct biological behavior, which results in the need for different clinical and therapeutic approaches. The present consensual document elucidates the oncological issues related to the diagnosis, prognosis, and treatment of BMTs, CMTs, and CSs of the canine mammary gland.

Consensus regarding the diagnosis, prognosis and treatment of canine mammary tumors: benign mixed tumors, carcinomas in mixed tumors and carcinosarcomas

Mammary neoplasms are the most frequent tumors in female dogs. Of these neoplasms, benign mixed tumors (BMTs) and carcinomas in mixed tumors (CMTs) represent a large proportion of small animal oncology diagnoses. Together with carcinosarcomas (CSs), these three neoplastic entities are characterized by the proliferation of benign or malignant epithelial, myoepithelial, and mesenchymal cells, depending on their histological types. This histological heterogeneity, in addition to their molecular heterogeneity, confers these tumors with distinct biological behavior, which results in the need for different clinical and therapeutic approaches. The present consensual document elucidates the oncological issues related to the diagnosis, prognosis, and treatment of BMTs, CMTs, and CSs of the canine mammary gland.(AU)

Consensus for the Diagnosis, Prognosis and Treatment of Canine Mammary Tumors 2013

The purpose of this paper is to establish criteria that could guide the diagnosis, prognosis and treatment of caninemammary neoplasias. It was elaborated during the Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment ofthe Canine Mammary Neoplasia, held on November 6th and 7th, 2010 in Belo Horizonte – MG, Brazil. Academics fromseveral regions of Brazil were present and contributed to this work. After three years, a new discussion was foundnecessary in order to address important questions: 1 - Have Brazilian DVMs applied the consensus? 2 - What were the maindifficulties in applying the consensus? 3 - What were the obtained results? 4 - What were the main differences among thevarious oncology services/groups? 5 - How could the criteria be improved and uniformed? A spreadsheet that allowed datacollection and an abstract was submitted by each oncology service/group from various parts of the country. Based on theabstracts we identified the main differences in diagnosis and therapeutic conducts among the groups. These differences haveguided the discussions of the II Mammary Pathology Meeting and the publication of a second consensus that has beenrevised and updated. The II Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment of the Canine mamaryNeoplasia, was held on December 9th, 10thand 11th, 2013 in Belo Horizonte – MG, sponsored by the Laboratory ofComparative Pathology of the Federal University of Minas Gerais (UFMG), with the support of the Brazilian Associationof Veterinary Pathology (ABPV) and Brazilian Association of Veterinary Oncology (ABROVET). Academics from severalregions of Brazil were present and contributed to this work.

Consensus for the Diagnosis, Prognosis and Treatment of Canine Mammary Tumors 2013

The purpose of this paper is to establish criteria that could guide the diagnosis, prognosis and treatment of caninemammary neoplasias. It was elaborated during the Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment ofthe Canine Mammary Neoplasia, held on November 6th and 7th, 2010 in Belo Horizonte MG, Brazil. Academics fromseveral regions of Brazil were present and contributed to this work. After three years, a new discussion was foundnecessary in order to address important questions: 1 - Have Brazilian DVMs applied the consensus? 2 - What were the maindifficulties in applying the consensus? 3 - What were the obtained results? 4 - What were the main differences among thevarious oncology services/groups? 5 - How could the criteria be improved and uniformed? A spreadsheet that allowed datacollection and an abstract was submitted by each oncology service/group from various parts of the country. Based on theabstracts we identified the main differences in diagnosis and therapeutic conducts among the groups. These differences haveguided the discussions of the II Mammary Pathology Meeting and the publication of a second consensus that has beenrevised and updated. The II Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment of the Canine mamaryNeoplasia, was held on December 9th, 10thand 11th, 2013 in Belo Horizonte MG, sponsored by the Laboratory ofComparative Pathology of the Federal University of Minas Gerais (UFMG), with the support of the Brazilian Associationof Veterinary Pathology (ABPV) and Brazilian Association of Veterinary Oncology (ABROVET). Academics from severalregions of Brazil were present and contributed to this work.(AU)

Consensus for the Diagnosis, Prognosis and Treatment of Canine Mammary Tumors

The purpose of this paper is to establish criteria that could guide the diagnosis, prognosis and treatment of canine mammary neoplasias. It was elaborated during the Mammary Pathology Meeting: Diagnosis, Prognosis and Treatment of the Canine Mammary Neoplasm, held on November 6th and 7th, 2010 in Belo Horizonte ­ MG, Brazil, sponsored by the Laboratory of Comparative Pathology ­ UFMG, with the support of the Brazilian Association of Veterinary Pathology (ABPV) and Brazilian Association of Veterinary Oncology (ABROVET). Academics from several regions of Brazil were present and contributed to this work.(AU)

Expressão da COX-2 nos carcinomas mamários de cadelas / Expression of COX-2 in canine mammary tumors

Na cadela, a freqüência dos tumores mamários espontâneos é duas a três vezes superior à observada na mulher. A identificação de marcadores tumorais é um método valioso para predizer o comportamento da neoplasia e determinar o prognóstico da doença. Alguns trabalhos relacionam a elevada expressão da ciclooxigenase-2 (COX-2) ao aumento da capacidade proliferativa das células neoplásicas, diminuição da taxa apoptótica, e neovascularização, fatores que indiscutivelmente ampliam o potencial metastático das células tumorais, representando um prognóstico extremamente desfavorável. Foram selecionadas e acompanhadas 30 cadelas apresentando neoplasia mamária atendidas do HOSPMEV-UFBA no período de agosto/2007 a Junho/2008. Foi realizado o esta¬diamento clínico, classificação e graduação histológica e imunomarcação para COX-2. A partir do diagnóstico histopatológico, os animais foram divididos em dois grupos: carcinoma evoluindo em tumor misto benigno (CATMB) e outros carcinomas (CA). Foi observada uma freqüência signi¬ficativamente maior de CATMB. A comparação da imunomarcação ainda que maior no segundo grupo, não apresentou diferença estatisticamente significativa. A COX-2 apresentou correlação significativa e positiva com tamanho tumoral (p=0,042) e envolvimento linfonodal (p=0,005). A maior taxa de sobrevida global foi observada em cadelas cujos tumores apresentavam menor quantidade de células positivas para COX-2. Com base nos resultados observados podemos concluir que a COX-2 apresenta-se como um marcador potencial para câncer de mama da cadela trazendo perspectivas para desenvolvimento de novas terapias anti-tumorais

In the female dog, the frequency of the spontaneous mammary tumors is two to three times higher than that observed in women. The identification of tumors markers is a valuable method for predicting the behavior of the tumor and determine the prognosis of the disease. Some studies relate the high expression of ciclooxigenase-2 (COX-2) to the increase of the proliferation capacity of the cancer cells, decrease apoptosis and angiogenesis, factors which undoubtedly increased the metastatic potential of tumors cells, representing an extremely poor prognosis. Were selected and monitored 30 female dog with mammary cancer attended the UFBA HOSPMEV-in period of August/2007 to June/2008. Were carried clinical tumor evolution, classification and histological grade and immunoreactive for COX-2. From the histopathologic diagnosis, the animals were divided into two groups: carcinomas develop in benign mixed tumor (CATMB) and other carcinomas (CA). There was a significantly higher frequency of CATMB. A comparison of immunoreactive even higher in the second group, showed no statistically significant difference. COX-2 showed significant and positive correlation with tumor size (p = 0.042) and lymph node involvement (p = 0005). The highest rate of overall survival was observed in bitches whose tumors had fewer cells positive for COX-2. Based on the observed results can conclude that the COX-2 is a potential marker for breast cancer the dog bringing new prospects for development of anti-tumor therapy

Expressão da COX-2 nos carcinomas mamários de cadelas / Expression of COX-2 in canine mammary tumors

Na cadela, a freqüência dos tumores mamários espontâneos é duas a três vezes superior à observada na mulher. A identificação de marcadores tumorais é um método valioso para predizer o comportamento da neoplasia e determinar o prognóstico da doença. Alguns trabalhos relacionam a elevada expressão da ciclooxigenase-2 (COX-2) ao aumento da capacidade proliferativa das células neoplásicas, diminuição da taxa apoptótica, e neovascularização, fatores que indiscutivelmente ampliam o potencial metastático das células tumorais, representando um prognóstico extremamente desfavorável. Foram selecionadas e acompanhadas 30 cadelas apresentando neoplasia mamária atendidas do HOSPMEV-UFBA no período de agosto/2007 a Junho/2008. Foi realizado o esta¬diamento clínico, classificação e graduação histológica e imunomarcação para COX-2. A partir do diagnóstico histopatológico, os animais foram divididos em dois grupos: carcinoma evoluindo em tumor misto benigno (CATMB) e outros carcinomas (CA). Foi observada uma freqüência signi¬ficativamente maior de CATMB. A comparação da imunomarcação ainda que maior no segundo grupo, não apresentou diferença estatisticamente significativa. A COX-2 apresentou correlação significativa e positiva com tamanho tumoral (p=0,042) e envolvimento linfonodal (p=0,005). A maior taxa de sobrevida global foi observada em cadelas cujos tumores apresentavam menor quantidade de células positivas para COX-2. Com base nos resultados observados podemos concluir que a COX-2 apresenta-se como um marcador potencial para câncer de mama da cadela trazendo perspectivas para desenvolvimento de novas terapias anti-tumorais(AU)

In the female dog, the frequency of the spontaneous mammary tumors is two to three times higher than that observed in women. The identification of tumors markers is a valuable method for predicting the behavior of the tumor and determine the prognosis of the disease. Some studies relate the high expression of ciclooxigenase-2 (COX-2) to the increase of the proliferation capacity of the cancer cells, decrease apoptosis and angiogenesis, factors which undoubtedly increased the metastatic potential of tumors cells, representing an extremely poor prognosis. Were selected and monitored 30 female dog with mammary cancer attended the UFBA HOSPMEV-in period of August/2007 to June/2008. Were carried clinical tumor evolution, classification and histological grade and immunoreactive for COX-2. From the histopathologic diagnosis, the animals were divided into two groups: carcinomas develop in benign mixed tumor (CATMB) and other carcinomas (CA). There was a significantly higher frequency of CATMB. A comparison of immunoreactive even higher in the second group, showed no statistically significant difference. COX-2 showed significant and positive correlation with tumor size (p = 0.042) and lymph node involvement (p = 0005). The highest rate of overall survival was observed in bitches whose tumors had fewer cells positive for COX-2. Based on the observed results can conclude that the COX-2 is a potential marker for breast cancer the dog bringing new prospects for development of anti-tumor therapy(AU)