Carcinoma prostático em gato - relato de caso e revisão de literatura / Prostatic carcinoma in a cat - case report and literature review / Carcinoma prostático en un gato - reporte de caso y revisión de la literatura

A neoplasia prostática em gatos é rara e pouco descrita na literatura. Não é um tumor andrógeno dependente, e a castração não ajuda na prevenção ou no tratamento. Técnicas ultrassonográficas e radiográficas evidenciarão compressão uretral ou retal na posição da neoplasia, e para diagnóstico definitivo deve-se realizar exame histopatológico. Não há protocolo terapêutico eficaz estabelecido, e o tratamento cirúrgico não costuma ser efetivo no controle da evolução do quadro, já que é de caráter maligno, agressivo e com altas taxas de metástases. Relata-se o caso de um gato macho, castrado, sem raça definida, de pelo curto, 10 anos, com histórico de disquesia, fezes em fita, hematuria e normorexia. O diagnóstico presuntivo foi realizado por meio de ultrassonografia; no entanto, devido à caracteristica obstrutiva apresentada pela neoplasia, assim como ao prognóstico de reservado a ruim em relação às alternativas terapêuticas, optou-se pela eutanásia, e não foi evidenciada nenhuma metástase.(AU)

Prostatic neoplasia in cats is rare and poorly described in the literature. It is not an androgen dependent tumor, and castration does not help in prevention or treatment. Ultrasonographic and radiographic techniques will show urethral or rectal compression in the position of the neoplasm, and for a definitive diagnosis. histopathological examination must be performed. There is no effective therapeutic protocol established, and surgical treatment is not usually effective in controlling the evolution of the condition, since it is malignant, aggressive and has high rates of metastases. The patient in this report is a 10-year-old male, neutered, mixed- breed, short-haired cat, with a history of dyschesia, ribbon-like stools, hematuria and normorexia. The presumptive diagnosis was performed by ultrasound; however, due to the obstructive characteristic presented by the neoplasm, as well as the poor prognosis in relation to the therapeutic alternatives, euthanasia was chosen, and no metastasis was evidenced.(AU)

La neoplasia prostática en gatos es rara y está pobremente descrita en la literatura. No es un tumor dependiente de andrógenos, y la castración no ayuda en la prevención ni en el tratamiento. Las técnicas ultrasonográficas y radiográficas mostrarán compresión uretral o rectal en la posición de la neoplasia, y para un diagnóstico definitivo se debe realizar un examen histopatológico. No existe un protocolo terapéutico eficaz establecido, y el tratamiento quirúrgico no suele ser eficaz para controlar la evolución del cuadro, ya que es maligno, agresivo y presenta altas tasas de metástasis. El paciente de este reporte es un gato macho de 10 años. castrado, mestizo, de pelo corto, con antecedentes de disquesia, heces en cinta. hematuria y normorexia. El diagnóstico presuntivo se realizó por ecografia; sin embargo, debido al carácter obstructivo que presentaba la neoplasia, así como al mal pronóstico en relación a las alternativas terapéuticas, se optó por la eutanasia y no se evidenció metástasis.(AU)

Expression and prognostic significance of vascular endothelial growth factor-A (VEGF-A) and its receptor in canine prostate cancer.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) and its receptor, VEGF receptor-2 (VEGFR-2), represent a complex family of angiogenic molecules consisting of different ligands and receptors. Due to the importance of VEGF-A/VEGFR-2 signaling in tumor proliferation and angiogenesis, this study aimed to evaluate the protein and gene expression levels of VEGF-A and VEGFR-2 in canine prostate cancer (PC). METHODS: We analyzed VEGF-A and VEGFR-2 expression in 87 PC samples by immunohistochemistry and quantitative-polymerase chain reaction. PC samples were graded according to the Gleason score and the immunohistochemical staining for VEGF-A and VEGFR-2 was quantified using a selected threshold from the ImageJ Software. Microvascular density was assessed by cluster of differentiation 31 staining and counting the number of positive vessels. Additionally, the homology of VEGF-A and VEGFR-2 between humans and dogs was assessed, followed by the construction of a protein structure homology model to compare the tertiary structures of these proteins in both species. RESULTS: Negative to weakly positive expression levels of VEGF-A and VEGFR-2 were observed in the epithelial cells of the normal prostate (NP) and prostatic hyperplasia samples. In contrast, the canine proliferative atrophy and PC samples exhibited higher VEGF-A (p < .0001) and VEGFR-2 (p < .0001) compared to NP. Moreover, positive correlations between the expression levels of VEGF-A and VEGFR-2 (Spearman's coefficient (r) = .68, p = .013) and the expression levels of VEGF-A and VEGFR-2 proteins (r = .8, p < .0001) were also observed in the NP samples. Additionally, the patients with PC exhibiting higher VEGFR-2 expression levels experienced a shorter survival period (p = .0372). Furthermore, we found an association between the microvascular density and overall survival. Dogs with a higher number of vessels showed a shorter survival time. We further demonstrated that the VEGF-A and VEGFR-2 exhibited high homology between humans and dogs, and identified their protein structures in both species. CONCLUSIONS: In conclusion, VEGFR-2 appears to be an independent prognostic factor in animals with PC. VEGF-A and VEGFR-2 are highly conserved between humans and dogs, which can be investigated further in future cross-species studies to explore their therapeutic applications.

Hypertrophic osteopathy and bone metastases in a dog with prostatic carcinoma / Osteopatia hipertrófica e metástases ósseas em um canino com carcinoma prostático

Prostatic carcinomas in are aggressive neoplasms and bone metastases may occur; however, hypertrophic osteopathy associated with that condition is poorly documented. A ten-year-old, neutered male, mixed breed dog had a history of lameness and volume increase in the left pelvic limb. On radiographic examination, a lytic bone mass was observed in the left metatarsus, as well as a diffuse proliferative periosteal reaction in several bones of the appendicular skeleton, in addition to radiopaque nodular structures in all lung lobes. A presumptive diagnosis of primary bone neoplasia with pulmonary metastases and hypertrophic osteopathy was established and chemotherapy treatment was started. However, there was no satisfactory clinical response, and euthanasia was ellected. At necropsy, there was moderate enlargement of the prostate gland. The gland was firm and whitish, with a multilobulated aspect. Several similar masses were observed in the right kidney, lungs, mediastinal lymph nodes, and multiple bones of the appendicular skeleton. These bones also presented evident diffuse periosteal reaction. Histological examination revealed a metastatic prostatic carcinoma with bone involvement and hypertrophic osteopathy. This report is an unusual case of metastatic prostatic carcinoma in association with hypertrophic osteopathy and concomitant bone metastases.(AU)

Os carcinomas prostáticos em cães são neoplasmas agressivos e as metástases ósseas podem ocorrer, entretanto a associação com osteopatia hipertrófica é pouco relatada. Um canino, macho, sem raça definida de 10 anos de idade, com histórico de claudicação e aumento de volume em membro pélvico esquerdo, apresentou no exame radiográfico uma massa óssea, lítica em metatarso esquerdo, bem como reação periosteal proliferativa difusa em diversos ossos do esqueleto apendicular além de estruturas nodulares, radiopacas em todos os lobos pulmonares. Realizou-se o diagnóstico presuntivo de neoplasia óssea primaria com metástases pulmonares e osteopatia hipertrófica e iniciou-se o tratamento quimioterápico. Todavia, não houve resposta clínica satisfatória, optando-se pela eutanásia. Na necropsia foi constatado aumento de volume moderado da próstata, com aspecto multilobulado, ao corte firme e brancacento. Diversas massas similares foram observadas no rim direito, pulmões, linfonodos mediastínicos e em vários ossos do esqueleto apendicular, além de evidente reação periosteal difusa. A avaliação histológica revelou um carcinoma prostático metastático com envolvimento ósseo, bem como osteopatia hipertrófica pulmonar. Esse relato é um caso incomum de carcinoma prostático metastático devido a associação com osteopatia hipertrófica pulmonar e as metástases ósseas concomitantes.(AU)

Achados clínicos, histopatológicos, laboratoriais e imagens de adenocarcinoma prostático em cães / Clinical, laboratory, histopathological and image findings of prostatic adenocarcinoma in dog

Prostate neoplasms are the main reproductive disorders affecting neutered dogs, being the adenocarcinoma the most common and developing signs of urinary and/or gastrointestinal tract. This tumor develops spontaneously in dogs, being malignant, very invasive and unresponsive to castration. Due the recent increase in reports and a high interference in the animals' quality of life, the objective of this study was to report a case of prostatic adenocarcinoma in an eight-year-old SRD dog with metastasis in bladder, peritoneum and mesentery. The animal presented dehydration, fever, difficulty for walking, severe pain, abdominal enlargement, apathy, hyporexia, hypodipsia and tenesmus. Rectal examination, identified a firm mass and incongruous in prostatic membrane. Two months before an orchiectomy was performed due a prostatomegaly. At the time, an ultrasound identified irregular prostate with cavity formations, spleen with hypoechogenic formation and bladder with hyperechogenic formation attached to the wall. Radiography was requested and fecaloma was observed. Thus, enterotomy and prostatectomy were required. In surgery, nodulations were identified in mesentery, peritoneum and spleen, in addition to a hemorrhagic focus and a palpable mass in the bladder. The prostate was attached to bone tissue, making the removal impossible. The animal was euthanized and prostatic histopathology identified acinar adenocarcinoma. Histological samples of peritoneum, mesentery and bladder presented metastasis. The treatment of this conditionis not feasible with a delayed diagnosis due to its high aggressiveness and metastatic capacity. Such report demonstrates the importance of digital rectal examination and ultrasound exams, even in castrated animals for a nearly diagnosis of these neoplasms.(AU)

Achados clínicos, histopatológicos, laboratoriais e imagens de adenocarcinoma prostático em cães / Clinical, laboratory, histopathological and image findings of prostatic adenocarcinoma in dog

Prostate neoplasms are the main reproductive disorders affecting neutered dogs, being the adenocarcinoma the most common and developing signs of urinary and/or gastrointestinal tract. This tumor develops spontaneously in dogs, being malignant, very invasive and unresponsive to castration. Due the recent increase in reports and a high interference in the animals' quality of life, the objective of this study was to report a case of prostatic adenocarcinoma in an eight-year-old SRD dog with metastasis in bladder, peritoneum and mesentery. The animal presented dehydration, fever, difficulty for walking, severe pain, abdominal enlargement, apathy, hyporexia, hypodipsia and tenesmus. Rectal examination, identified a firm mass and incongruous in prostatic membrane. Two months before an orchiectomy was performed due a prostatomegaly. At the time, an ultrasound identified irregular prostate with cavity formations, spleen with hypoechogenic formation and bladder with hyperechogenic formation attached to the wall. Radiography was requested and fecaloma was observed. Thus, enterotomy and prostatectomy were required. In surgery, nodulations were identified in mesentery, peritoneum and spleen, in addition to a hemorrhagic focus and a palpable mass in the bladder. The prostate was attached to bone tissue, making the removal impossible. The animal was euthanized and prostatic histopathology identified acinar adenocarcinoma. Histological samples of peritoneum, mesentery and bladder presented metastasis. The treatment of this conditionis not feasible with a delayed diagnosis due to its high aggressiveness and metastatic capacity. Such report demonstrates the importance of digital rectal examination and ultrasound exams, even in castrated animals for a nearly diagnosis of these neoplasms.

Carcinoma prostático felino / Feline prostatic carcinoma

Background: Prostatic cancer is a rare condition in cats but should be included as a differential diagnosis whenever middleaged cats present lower urinary tract signs, such as dysuria and hematuria. Abdominal ultrasound can indicate the disease,but fine-needle aspiration cytology and histopathology are necessary to establish the neoplastic origin and the therapeuticplan. Because of the limited data, no standard-of-care treatment or prognostic information exists in cats with prostate carcinoma. This report describes the clinical signs, diagnosis and surgical approach in a case of prostatic carcinoma in a cat.Case: A 6-year-old, intact male, domestic short-haired cat was presented with a 3-day history of dysuria, hematuria, inappetence, constipation, lethargy and prostration. On physical examination, the cat was in a very poor general conditionand abdominal palpation revealed firm mass located caudally to the urinary bladder. The urinary bladder presented highrepletion degree, while the large bowel was distended and presented soft faecal content. Blood count, serum biochemistryand urinalysis showed neutrophilic leukocytosis, hypoalbuminemia and high creatinine level, and severe hematuria, respectively. Abdominal ultrasound showed a mass located in the prostatic area with hypoechogenic and slightly heterogeneousparenchyma, measuring 3.3 x 3.0 cm. Echo-guided trans-abdominal fine-needle aspiration of the prostate was performed.Microscopically, the cells were round with basophilic cytoplasm, and had round to ovoid nuclei, dense chromatin andprominent nucleoli. Some cells were binucleated and mild anisocytosis and marked anisokaryosis were documented. Thesefindings were compatible with malignant prostatic neoplasia. After initial clinical stabilization, the patient underwent anexploratory laparotomy for tumor resection...(AU)

Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer.

Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of TP53, MDM2 and ZBTB4 were evaluated in an independent set of cases by qPCR. PC cases presented genomic complexity, while PIA samples had a small number of CNAs. Recurrent losses covering well-known tumor suppressor genes, such as ATM, BRCA1, CDH1, MEN1 and TP53, were found in PC. The in silico functional analysis showed several cancer-related genes associated with canonical pathways and interaction networks previously described in human PC. The MDM2, TP53, and ZBTB4 copy number alterations were translated into altered expression levels. A cross-validation analysis using The Cancer Genome Atlas (TCGA) database for human PC uncovered similarities between canine and human PCs. Androgen-receptor-negative canine PC is a complex disease characterized by high genomic instability, showing a set of genes with similar alterations to human cancer.

Association between decreased expression of estrogen receptor alpha, androgen receptor and phosphatase and tensin homolog immunoexpression in the canine prostate / Associação entre diminuição da expressão dos receptores de estrógeno alfa e andrógeno, e imunoexpressão de fosfatase e tensina homóloga na próstata canina

Canine prostate gland is a hormonal dependent organ and its imbalance of estrogen and androgen receptor expressions are directly associated with the development of different diseases. Due to the lack of information regarding the behavior of the aforementioned receptors in canine prostate cancer (PC), this study aimed to identify estrogen receptor alpha (ERα), androgen receptor (AR), Ki67 and phosphatase and tensin homolog (PTEN) protein expressions in canine PC by immunohistochemistry. We found nuclear expression of ERα and AR in the epithelial cells of normal canine samples and a loss of protein expression in PC samples. Normal samples showed Ki67 expression in a few basal cells and the PC samples showed the highest mean of positive cells (253.1). Canine prostate cancer showed a high proliferative index, which was associated with independence of hormonal actuation. PTEN showed positive nuclear and cytoplasmic expression in normal canine samples and a loss in PC. Loss of ERα, AR and PTEN indicated that canine PC exhibits the same immunohistochemical phenotype as in human patients with PC resistant to hormonal therapy. Therefore, canine PC should be considered as a model to study human PC resistant to hormonal therapy.(AU)

A glândula prostática canina é um órgão dependente de hormônio, e o desequilíbrio na expressão dos receptores de estrógeno e andrógeno estão diretamente associados com o desenvolvimento de diferentes doenças. Devido à falta de informação sobre o comportamento desses receptores no câncer prostático canino (PC), este estudo tem por objetivo identificar a expressão proteica através da técnica de imuno-histoquímica do receptor de estrógeno alfa (REα), receptor de andrógeno (RA), Ki67 e fosfatase e tensina homóloga (PTEN). Foi encontrado nas células epiteliais prostáticas normais caninas a expressão nuclear de REα e RA, e perda de expressão proteica nas amostras de PC. As amostras normais apresentaram expressão de Ki67 em poucas células basais e as amostras de PC apresentaram a maior média de células positivas (253,1). O câncer de próstata canino apresentou uma taxa alta de proliferação, o qual foi associado com a atuação independente de hormônio. As amostras de próstatas caninas normais revelaram marcação nuclear e citoplasmática da proteína PTEN e perda nas amostras de PC. A perda de REα, RA e PTEN indicam que as amostras de PC exibem o mesmo fenótipo imuno-histoquímico de pacientes humanos com câncer prostático resistente a terapia hormonal. Sendo assim, o PC canino deve ser considerado um modelo para estudos de câncer prostático humano resistente a terapia hormonal.(AU)

Association between decreased expression of estrogen receptor alpha, androgen receptor and phosphatase and tensin homolog immunoexpression in the canine prostate / Associação entre diminuição da expressão dos receptores de estrógeno alfa e andrógeno, e imunoexpressão de fosfatase e tensina homóloga na próstata canina

Canine prostate gland is a hormonal dependent organ and its imbalance of estrogen and androgen receptor expressions are directly associated with the development of different diseases. Due to the lack of information regarding the behavior of the aforementioned receptors in canine prostate cancer (PC), this study aimed to identify estrogen receptor alpha (ERα), androgen receptor (AR), Ki67 and phosphatase and tensin homolog (PTEN) protein expressions in canine PC by immunohistochemistry. We found nuclear expression of ERα and AR in the epithelial cells of normal canine samples and a loss of protein expression in PC samples. Normal samples showed Ki67 expression in a few basal cells and the PC samples showed the highest mean of positive cells (253.1). Canine prostate cancer showed a high proliferative index, which was associated with independence of hormonal actuation. PTEN showed positive nuclear and cytoplasmic expression in normal canine samples and a loss in PC. Loss of ERα, AR and PTEN indicated that canine PC exhibits the same immunohistochemical phenotype as in human patients with PC resistant to hormonal therapy. Therefore, canine PC should be considered as a model to study human PC resistant to hormonal therapy.(AU)

A glândula prostática canina é um órgão dependente de hormônio, e o desequilíbrio na expressão dos receptores de estrógeno e andrógeno estão diretamente associados com o desenvolvimento de diferentes doenças. Devido à falta de informação sobre o comportamento desses receptores no câncer prostático canino (PC), este estudo tem por objetivo identificar a expressão proteica através da técnica de imuno-histoquímica do receptor de estrógeno alfa (REα), receptor de andrógeno (RA), Ki67 e fosfatase e tensina homóloga (PTEN). Foi encontrado nas células epiteliais prostáticas normais caninas a expressão nuclear de REα e RA, e perda de expressão proteica nas amostras de PC. As amostras normais apresentaram expressão de Ki67 em poucas células basais e as amostras de PC apresentaram a maior média de células positivas (253,1). O câncer de próstata canino apresentou uma taxa alta de proliferação, o qual foi associado com a atuação independente de hormônio. As amostras de próstatas caninas normais revelaram marcação nuclear e citoplasmática da proteína PTEN e perda nas amostras de PC. A perda de REα, RA e PTEN indicam que as amostras de PC exibem o mesmo fenótipo imuno-histoquímico de pacientes humanos com câncer prostático resistente a terapia hormonal. Sendo assim, o PC canino deve ser considerado um modelo para estudos de câncer prostático humano resistente a terapia hormonal.(AU)

p-mTOR, p-4EBP-1 and eIF4E expression in canine prostatic carcinoma.

The mTOR/4E-BP1/eIF4E pathway plays important roles in the neoplastic transformation process and in tumour growth. In men, the mTOR/4E-BP1/eIF4E pathway was described as altered in different tumours, including prostate cancer (PC). Apart from humans, the dog is the only species that develops PC with high frequency and is considered a good model for comparative oncology initiatives. Due to limited information on this pathway in canine tumours, this study aimed to investigate mTOR, 4E-BP1 and eIF4E gene and protein expression in canine PC, as well as in metastatic and normal prostatic tissues, and to evaluate the correlations between gene/protein expression and Gleason score (GS) in PC. A total of 35 formalin-fixed paraffin-embedded (FFPE) samples, including 13 of normal prostatic tissue, 17 PC samples and 5 metastasis samples, were evaluated by immunohistochemistry and qPCR. mTOR gene mutation in the kinase domain was also investigated. We identified higher p-mTOR and eIF4E protein levels in canine PC with higher GS values (≥ 8) and a significant positive correlation in expression between these proteins. eIF4E overexpression was observed in metastasis relative to expression in normal samples. Our data suggest that p-mTOR and eIF4E expression is positively correlated with GS in canine PC, similar to the pattern in humans. More studies of the mTOR/4EBP1/eIF4E pathway should be performed to identify possible correlations of the proteins involved with clinical and pathologic findings in canine PC and the roles of these proteins as therapeutic targets for the treatment of canine PC.

Análise histopatológica qualitativa de um fibrossarcoma em rato Wistar após o tratamento com a tansulosina: relato de caso / Qualitative histopathological analysis of a Wistar rat fibrosarcoma after treatment with tamsulosin: case report

A tansulosina é um dos medicamentos mais prescritos no mundo para o tratamento da hiperplasia prostática benigna. Ela se liga aos receptores α-1-adrenérgicos impedindo a contração do músculo liso no estroma da próstata, consequentemente melhorando a micção. Existem alguns efeitos adversos ligados ao tratamento com a tansulosina. Entretanto, ainda não foi relatado na literatura o desenvolvimento de um fibrossarcoma após a utilização deste medicamento. O fibrossarcoma é um tipo de neoplasia maligna que ocorre no tecido conjuntivo. Geralmente é um tipo deneoplasia infiltrada, que pode ser encapsulada. O objetivo deste estudo foi identificar os componentes histopatológicos e o perfil de progressão de uma neoplasia em um animal Wistar tratado com a tansulosina. Foi utilizado um animal macho Wistar, que foi gavado com tansulosina 0,4mg/Kg/dia durante 21 dias. Após o 21ª dia o animaldesenvolveu uma massa tumoral foi sacrificado seis dias depois. Após dissecção do animal foi coletada da massa tumoral e o material foi fixado em formaldeído a 3,7% respeitando um tempo mínimo de 24 horas. A massa tumoral foi clivada em quatro pedaços e dividida em zonas: Zn1, Zn2, Zn3 e Zn4. Foram realizadas técnicas de histoquímicas para identificação das estruturas: Tricrômico de Masson, Picro Sirius Red, Azul de Toluidina e Fucsina-resorcina de Weigert com prévia oxidação. Ainda existem poucas evidências para corroborar se o tratamento farmacológico com a tansulosina tenha sido responsável pelo desenvolvimento do fibrossarcoma. Contudo, mais estudos serão feitos para identificar a origem e a progressão dessa neoplasia neste animal.(AU)

Tansulin is one of the most commonly prescribed drugs in the world for the treatment of benign prostatic hyperplasia. It binds α-1-adrenergic receptors preventing smooth muscle contraction in prostate aroma, thereby improving urination. There are someadverse effects linked to treatment with tamsulosin. However, it has not been reported in the literature or development of a fibrosarcoma after the use of this drug. The fibrosarcoma is a type of malignant neoplasm that occurs in connective tissue. It may be a type of infiltrated neoplasia that can be encapsulated. The aim of this study was to identify the histopathological components and the progression profile of a neoplasia in a tamsulosin treated Wistar animal. A male Wistar animal was used, which was removed with tamsulosin 0.4mg / kg / day for 21 days. After the 21st day the animal developed a tumor mass was sacrificed six days later. After dissecting the animal, the tumor mass was collected and the material was fixed in 3.7% formaldehyde, respecting a minimumtime of 24 hours. A tumor mass was divided into four pieces and divided into zones: Zn1, Zn2, Zn3 and Zn4. Histochemical techniques were performed to identify structures:Massons trichrome, Picro Sirius Red, Toluidine Blue and Weigert Fuchsin-resorcin with prior oxidation. There are still few that corroborate the pharmacological treatment withtamsulosin, being responsible for the development of fibrosarcoma. However, further studies will be done to identify the origin and progress of this neoplasia in this animal.(AU)

Carcinoma prostático felino / Feline prostatic carcinoma

Background: Prostatic cancer is a rare condition in cats but should be included as a differential diagnosis whenever middleaged cats present lower urinary tract signs, such as dysuria and hematuria. Abdominal ultrasound can indicate the disease,but fine-needle aspiration cytology and histopathology are necessary to establish the neoplastic origin and the therapeuticplan. Because of the limited data, no standard-of-care treatment or prognostic information exists in cats with prostate carcinoma. This report describes the clinical signs, diagnosis and surgical approach in a case of prostatic carcinoma in a cat.Case: A 6-year-old, intact male, domestic short-haired cat was presented with a 3-day history of dysuria, hematuria, inappetence, constipation, lethargy and prostration. On physical examination, the cat was in a very poor general conditionand abdominal palpation revealed firm mass located caudally to the urinary bladder. The urinary bladder presented highrepletion degree, while the large bowel was distended and presented soft faecal content. Blood count, serum biochemistryand urinalysis showed neutrophilic leukocytosis, hypoalbuminemia and high creatinine level, and severe hematuria, respectively. Abdominal ultrasound showed a mass located in the prostatic area with hypoechogenic and slightly heterogeneousparenchyma, measuring 3.3 x 3.0 cm. Echo-guided trans-abdominal fine-needle aspiration of the prostate was performed.Microscopically, the cells were round with basophilic cytoplasm, and had round to ovoid nuclei, dense chromatin andprominent nucleoli. Some cells were binucleated and mild anisocytosis and marked anisokaryosis were documented. Thesefindings were compatible with malignant prostatic neoplasia. After initial clinical stabilization, the patient underwent anexploratory laparotomy for tumor resection...

Análise histopatológica qualitativa de um fibrossarcoma em rato Wistar após o tratamento com a tansulosina: relato de caso / Qualitative histopathological analysis of a Wistar rat fibrosarcoma after treatment with tamsulosin: case report

A tansulosina é um dos medicamentos mais prescritos no mundo para o tratamento da hiperplasia prostática benigna. Ela se liga aos receptores α-1-adrenérgicos impedindo a contração do músculo liso no estroma da próstata, consequentemente melhorando a micção. Existem alguns efeitos adversos ligados ao tratamento com a tansulosina. Entretanto, ainda não foi relatado na literatura o desenvolvimento de um fibrossarcoma após a utilização deste medicamento. O fibrossarcoma é um tipo de neoplasia maligna que ocorre no tecido conjuntivo. Geralmente é um tipo deneoplasia infiltrada, que pode ser encapsulada. O objetivo deste estudo foi identificar os componentes histopatológicos e o perfil de progressão de uma neoplasia em um animal Wistar tratado com a tansulosina. Foi utilizado um animal macho Wistar, que foi gavado com tansulosina 0,4mg/Kg/dia durante 21 dias. Após o 21ª dia o animaldesenvolveu uma massa tumoral foi sacrificado seis dias depois. Após dissecção do animal foi coletada da massa tumoral e o material foi fixado em formaldeído a 3,7% respeitando um tempo mínimo de 24 horas. A massa tumoral foi clivada em quatro pedaços e dividida em zonas: Zn1, Zn2, Zn3 e Zn4. Foram realizadas técnicas de histoquímicas para identificação das estruturas: Tricrômico de Masson, Picro Sirius Red, Azul de Toluidina e Fucsina-resorcina de Weigert com prévia oxidação. Ainda existem poucas evidências para corroborar se o tratamento farmacológico com a tansulosina tenha sido responsável pelo desenvolvimento do fibrossarcoma. Contudo, mais estudos serão feitos para identificar a origem e a progressão dessa neoplasia neste animal.

Tansulin is one of the most commonly prescribed drugs in the world for the treatment of benign prostatic hyperplasia. It binds α-1-adrenergic receptors preventing smooth muscle contraction in prostate aroma, thereby improving urination. There are someadverse effects linked to treatment with tamsulosin. However, it has not been reported in the literature or development of a fibrosarcoma after the use of this drug. The fibrosarcoma is a type of malignant neoplasm that occurs in connective tissue. It may be a type of infiltrated neoplasia that can be encapsulated. The aim of this study was to identify the histopathological components and the progression profile of a neoplasia in a tamsulosin treated Wistar animal. A male Wistar animal was used, which was removed with tamsulosin 0.4mg / kg / day for 21 days. After the 21st day the animal developed a tumor mass was sacrificed six days later. After dissecting the animal, the tumor mass was collected and the material was fixed in 3.7% formaldehyde, respecting a minimumtime of 24 hours. A tumor mass was divided into four pieces and divided into zones: Zn1, Zn2, Zn3 and Zn4. Histochemical techniques were performed to identify structures:Masson’s trichrome, Picro Sirius Red, Toluidine Blue and Weigert Fuchsin-resorcin with prior oxidation. There are still few that corroborate the pharmacological treatment withtamsulosin, being responsible for the development of fibrosarcoma. However, further studies will be done to identify the origin and progress of this neoplasia in this animal.

Immunoexpression of cell cycle regulators in canine prostate with proliferative lesions / Imunoexpressão de reguladores do ciclo celular em próstatas caninas com alterações proliferativas

Immunostaining of p21, p27, p53, cyclin D1, c-myc was evaluated in normal canine prostate and prostate with proliferative disorders to verify the interaction between these regulators of cell cycle progression. From 106 samples of canine prostate obtained from a TMA block, 15 were considered normal, 16 diagnosed as benign prostatic hyperplasia (BPH), 30 as proliferative inflammatory atrophy (PIA), 20 as prostatic intraepithelial neoplasia (PIN), and 25 as prostatic carcinoma (PC). There was positive correlation between p21 and p27 for number of stained cells and staining intensity in all conditions and between c-myc and p53 in prostates with PIN. Considering the number of labeled cells, there was positive correlation between p21 and p53 in the normal prostate. Relative to the intensity of staining, there was positive correlation between p21 and p53 in prostate tissue with PIN and between p27 and c-myc in prostates with PIA. A negative correlation between c-myc and cyclin D1 was also identified in the glands with PIN, considering the number of labeled cells, and between p27 and c-myc in the prostates with PC for staining intensity. In conclusion, the expression of p21, p27, p53, cyclin D1 and c-myc varies according to type of proliferative lesion in canine prostate. Taken together, the results indicate low growth potential of the canine PC in the presence of p21 and p27 overexpression, cyclin D1 low expression and regular expression of c-myc, even with the expression of p53 mutant type. Further, it was possible reaffirm the premalignant potential of PIA and PIN in canine prostate.(AU)

A imunomarcação de p21, p27, p53, ciclina D1 e c-myc foi avaliada na próstata canina normal e com desordens proliferativas para verificar quanto a interação desses reguladores na progressão do ciclo celular. Um total de 106 amostras de próstata canina foi obtido a partir de um bloco de TMA, sendo 15 normais, 16 hiperplasia prostática benigna (HPB), 30 atrofia inflamatória proliferativa (PIA), 20 neoplasia intraepitelial prostática (PIN), e 25 carcinoma prostático (PC). Foi encontrada diferença na imunomarcação de p21, p27, ciclina D1 e p53 no epitélio acinar em relação aos diagnósticos. Houve correlação positiva entre p21 e p27 para as variáveis número de células marcadas e intensidade de imunomarcação em todos os diagnósticos (normal, HPB, PIA, PIN e PC), e entre c-myc e p53 nas próstatas com PIN. De acordo com o número de células marcadas, houve correlação positiva entre p21 e p53 na próstata normal. De acordo com a intensidade de imunomarcação houve correlação positiva entre p21 e p53 no tecido prostático com PIN e entre p27 e c-myc em próstatas com PIA. Foi observada correlação negativa entre c-myc e ciclina D1 nas glândulas com PIN, considerando o número de células marcadas, e entre p27 e c-myc na próstata com PC, para a variável intensidade de imunomarcação. Conclui-se que a expressão de p21, p27, p53, ciclina D1 e c-myc varia na próstata canina de acordo com o tipo de lesão proliferativa. Em conjunto, os resultados indicam baixo potencial de crescimento dos carcinomas da próstata canina quando há superexpressão de p21 e de p27, baixa expressão de ciclina D1 e expressão normal de c-myc, mesmo com expressão de p53 tipo mutante. Ainda, considerando o imunofenótipo semelhante nas glândulas com PIA, PIN e PC no que se refere aos reguladores da progressão do ciclo celular, reitera-se o potencial pré-maligno da PIA e PIN na próstata canina.(AU)

Deregulation of E-cadherin, ß-catenin, APC and Caveolin-1 expression occurs in canine prostate cancer and metastatic processes.

Prostate cancer is a heterogeneous disease with high levels of clinical and gene heterogeneity, consequently offering several targets for therapy. Dogs with naturally occurring prostate cancer are useful models for molecular investigations and studying new treatment efficacy. Three genes and proteins associated with the WNT pathway (ß-catenin, APC and E-cadherin) and Caveolin-1 (CAV-1) were evaluated in canine pre-neoplastic proliferative inflammatory atrophy (PIA), prostate cancer and metastatic disease. The APC gene methylation status was also investigated. As in human prostate cancer, cytoplasmic and nuclear ß-catenin, which are fundamental for activating the canonical WNT pathway, were found in canine prostate cancer and metastasis. Membranous E-cadherin was also lost in these lesions, allowing cellular migration to the stroma and nuclear localization of ß-catenin. In contrast to human prostate tumours, no APC downregulation or hypermethylation was found in canine prostate cancer. The CAV-1 gene and protein overexpression were found in canine prostate cancer, and as in humans, the highest levels were found in Gleason scores ≥8. In conclusion, as with human prostate cancer, ß-catenin and E-cadherin in the WNT pathway, as well as Caveolin-1, are molecular drivers in canine prostate cancer. These findings provide additional evidence that dogs are useful models for studying new therapeutic targets in prostate cancer.

Immunoexpression of cell cycle regulators in canine prostate with proliferative lesions / Imunoexpressão de reguladores do ciclo celular em próstatas caninas com alterações proliferativas

Immunostaining of p21, p27, p53, cyclin D1, c-myc was evaluated in normal canine prostate and prostate with proliferative disorders to verify the interaction between these regulators of cell cycle progression. From 106 samples of canine prostate obtained from a TMA block, 15 were considered normal, 16 diagnosed as benign prostatic hyperplasia (BPH), 30 as proliferative inflammatory atrophy (PIA), 20 as prostatic intraepithelial neoplasia (PIN), and 25 as prostatic carcinoma (PC). There was positive correlation between p21 and p27 for number of stained cells and staining intensity in all conditions and between c-myc and p53 in prostates with PIN. Considering the number of labeled cells, there was positive correlation between p21 and p53 in the normal prostate. Relative to the intensity of staining, there was positive correlation between p21 and p53 in prostate tissue with PIN and between p27 and c-myc in prostates with PIA. A negative correlation between c-myc and cyclin D1 was also identified in the glands with PIN, considering the number of labeled cells, and between p27 and c-myc in the prostates with PC for staining intensity. In conclusion, the expression of p21, p27, p53, cyclin D1 and c-myc varies according to type of proliferative lesion in canine prostate. Taken together, the results indicate low growth potential of the canine PC in the presence of p21 and p27 overexpression, cyclin D1 low expression and regular expression of c-myc, even with the expression of p53 mutant type. Further, it was possible reaffirm the premalignant potential of PIA and PIN in canine prostate.

A imunomarcação de p21, p27, p53, ciclina D1 e c-myc foi avaliada na próstata canina normal e com desordens proliferativas para verificar quanto a interação desses reguladores na progressão do ciclo celular. Um total de 106 amostras de próstata canina foi obtido a partir de um bloco de TMA, sendo 15 normais, 16 hiperplasia prostática benigna (HPB), 30 atrofia inflamatória proliferativa (PIA), 20 neoplasia intraepitelial prostática (PIN), e 25 carcinoma prostático (PC). Foi encontrada diferença na imunomarcação de p21, p27, ciclina D1 e p53 no epitélio acinar em relação aos diagnósticos. Houve correlação positiva entre p21 e p27 para as variáveis número de células marcadas e intensidade de imunomarcação em todos os diagnósticos (normal, HPB, PIA, PIN e PC), e entre c-myc e p53 nas próstatas com PIN. De acordo com o número de células marcadas, houve correlação positiva entre p21 e p53 na próstata normal. De acordo com a intensidade de imunomarcação houve correlação positiva entre p21 e p53 no tecido prostático com PIN e entre p27 e c-myc em próstatas com PIA. Foi observada correlação negativa entre c-myc e ciclina D1 nas glândulas com PIN, considerando o número de células marcadas, e entre p27 e c-myc na próstata com PC, para a variável intensidade de imunomarcação. Conclui-se que a expressão de p21, p27, p53, ciclina D1 e c-myc varia na próstata canina de acordo com o tipo de lesão proliferativa. Em conjunto, os resultados indicam baixo potencial de crescimento dos carcinomas da próstata canina quando há superexpressão de p21 e de p27, baixa expressão de ciclina D1 e expressão normal de c-myc, mesmo com expressão de p53 tipo mutante. Ainda, considerando o imunofenótipo semelhante nas glândulas com PIA, PIN e PC no que se refere aos reguladores da progressão do ciclo celular, reitera-se o potencial pré-maligno da PIA e PIN na próstata canina.

Investigation of c-KIT and Ki67 expression in normal, preneoplastic and neoplastic canine prostate.

BACKGROUND: c-KIT expression has been related to bone metastasis in human prostate cancer, but whether c-KIT expression can be similarly classified in canine prostatic tissue is unknown. This study assessed c-KIT and Ki67 expression in canine prostate cancer (PC). c-KIT gene and protein expression and Ki67 expression were evaluated in forty-four canine prostatic tissues by immunohistochemistry, RT-qPCR and western blot. Additionally, we have investigated c-KIT protein expression by immunoblotting in two primary canine prostate cancer cell lines. RESULTS: Eleven normal prostates, 12 proliferative inflammatory atrophy (PIA) prostates, 18 PC, 3 metastatic lesions and two prostate cancer cell cultures (PC1 and PC2) were analysed. The prostatic tissue exhibited varying degrees of membranous, cytoplasmic or membranous/cytoplasmic c-KIT staining. Four normal prostates, 4 PIA and 5 prostatic carcinomas showed positive c-KIT expression. No c-KIT immunoexpression was observed in metastases. Canine prostate cancer and PIA samples contained a higher number of Ki67-positive cells compared to normal samples. The median relative quantification (RQ) for c-KIT expression in normal, PIA and prostate cancer and metastatic samples were 0.6 (0.1-2.5), 0.7 (0.09-2.1), 0.7 (0.09-5.1) and 0.1 (0.07-0.6), respectively. A positive correlation between the number of Ki67-positive cells and c-KIT transcript levels was observed in prostate cancer samples. In the cell line, PC1 was negative for c-KIT protein expression, while PC2 was weakly positive. CONCLUSION: The present study identified a strong correlation between c-KIT expression and proliferative index, suggesting that c-KIT may influence cell proliferation. Therefore, c-KIT heterogeneous protein expression among the samples (five positive and thirteen negative prostate cancer samples) indicates a personalized approach for canine prostate cancer.

Alterations in PTEN, MDM2, TP53 and AR protein and gene expression are associated with canine prostate carcinogenesis.

The PTEN, AR, MDM2 and p53 protein network plays a central role in the development of many human cancers, thus eliciting the development of targeted cancer therapeutics. Dogs spontaneously develop tumours, and they are considered a good model for comparative oncology initiatives. Due to the limited information on these proteins in canine tumours, this study aimed to investigate gene and protein alterations in PTEN, AR, MDM2 and p53 in canine prostate cancer (PC). Protein expression was evaluated by immunohistochemistry (15 normal, 22 proliferative inflammatory atrophy (PIA) and 19 PC samples) and Western blotting (2 normal prostate tissue, 2 BPH, 2 PIA samples and 2 PC samples) and gene expression by RT-qPCR (10 normal, 10 PIA and 15 PC samples) of formalin-fixed tissue. We identified nuclear and cytoplasmic expression of PTEN and p53 in all samples, with only nuclear staining found for MDM2 and AR. Our results revealed high expression of MDM2 in PC and PIA samples compared to normal samples, whereas PTEN, P53 and AR expression was down-regulated in PC compared to normal tissue. All tumour samples (n=19) showed loss of nuclear PTEN expression, and all cancer mimickers showed positive nuclear staining. Therefore, nuclear PTEN staining could be a good diagnostic marker for differentiating between malignant lesions and mimickers. Canine prostate carcinogenesis involves increased expression of MDM2 in association with decreased expression of PTEN, p53 and AR, such as occurs in hormone refractory PC in men. Thus, dogs may be an important model for studying advanced stage PC.

Role of adhesion molecules and proliferation hyperplasic, pre neoplastic and neoplastic lesions in canine prostate.

E-cadherin and beta-catenin are component of adherens junctions in epithelial cells. Loss of these proteins have been associated with progression of prostatic diseases. We performed immunohistochemistry for E-cadherin, beta-catenin and Ki-67 on canine prostatic lesions. We analyzed the expression of these antibodies in benign prostatic hyperplasia (BPH, n = 22), in pre neoplastic lesions Prostatic Intra-epithelial Neoplasia (PIN), n = 3 and Prostatic Inflammatory Atrophy (PIA), n = 7 and prostate carcinoma (PC, n = 10). In this study, a membranous expression of E-cadherin and beta-catenin and nuclear expression of Ki-67 antigen were demonstrated. The proliferative index was statistically different between carcinomas and BPH and carcinomas and pre-neoplastic lesions. Like in men, the reduction of E-cadherin and increase of Ki-67 expression in neoplastic lesions in dog prostate may be related to the carcinogenic process in this gland.

Overexpression of vimentin in canine prostatic carcinoma.

Canine prostatic tumours exhibit similarities to those of man and may represent a useful model system to explore the mechanisms of cancer progression. Tumour progression to malignancy requires a change from an epithelial phenotype to a fibroblastic or mesenchymal phenotype. Vimentin expression is associated with the invasive phenotype of human prostate cancer cells. The aim of the present study was to characterize immunohistochemically the expression of vimentin by canine prostatic carcinomas. Primary carcinomas and metastatic tumour foci both showed vimentin expression. This finding suggests that the acquisition of the epithelial-mesenchymal transition phenotype in canine prostatic carcinoma may be characterized by the presence of mesenchymal intermediate filament (vimentin) that could lead to a higher likelihood of metastasis.