Solid Carcinoma of the Canine Mammary Gland: a Histological Type or Tumour Cell Arrangement?

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.

Relationship between PD-L1 expression and tumor-infiltrating lymphocytes in canine mammary tumor

Background: Studies pointed out that the tumor-infiltrating lymphocytes (TILs) have considerable importance in caninemammary tumor (CMT). On the other hand, cancer cells sometimes find ways to use immune checkpoint proteins as ashield to avoid being identified and attacked by the immune system as programmed death 1 ligand 1 (PD-L1). In this study,it was investigated the relationship between PD-L1 expression, stromal tumor-infiltrating lymphocytes (TILs) in caninemammary tumor (CMT), and the association with clinical and pathological characteristics of the tumors.Materials, Methods & Results: PD-L1 expression and TILs were assessed in 23 female dogs with CMT. The tumors weregrouped into simple carcinoma (CA, n = 8) and complex carcinoma (CC, n = 15). Stromal TILs were assessed using twothresholds as TILs-Low representing < 50% of infiltrate within stromal area and TILs-High representing ≥ 50% of stromalarea. Clinicopathological data of CMT was characterized according to key parameters, as well as survival rates. TILs evaluation within tumor stroma revealed that 65.2% (n = 15) of tumors had TILs-Low. PD-L1 expression and stromal TILs weresignificantly associated (P = 0.009). PD-L1 expression was observed in 39% (n = 9) of all tumors of which 17.4% (n = 4)were from CA group and 21.7% (n = 5) were from CC group. PD-L1 expression within TILs was observed in 39% (n =9) of the tumors. PD-L1 in malignant epithelium was present in all lymph node metastasis (n = 5). PD-L1 was associatedwith involvement of regional lymph nodes (P = 0.034). Survival curves demonstrated TILs-Low had higher (P = 0.010)overall survival (OS) compared with TILs-High, and PD-L1+ and PD-L1(P = 0.06) did not differed. The clinicopathological variables significantly correlated with OS by univariate analysis were the histological grade (P = 0.009), lymphnode involvement (P = 0.004), stromal...(AU)

Relationship between PD-L1 expression and tumor-infiltrating lymphocytes in canine mammary tumor

Background: Studies pointed out that the tumor-infiltrating lymphocytes (TILs) have considerable importance in caninemammary tumor (CMT). On the other hand, cancer cells sometimes find ways to use immune checkpoint proteins as ashield to avoid being identified and attacked by the immune system as programmed death 1 ligand 1 (PD-L1). In this study,it was investigated the relationship between PD-L1 expression, stromal tumor-infiltrating lymphocytes (TILs) in caninemammary tumor (CMT), and the association with clinical and pathological characteristics of the tumors.Materials, Methods & Results: PD-L1 expression and TILs were assessed in 23 female dogs with CMT. The tumors weregrouped into simple carcinoma (CA, n = 8) and complex carcinoma (CC, n = 15). Stromal TILs were assessed using twothresholds as TILs-Low representing < 50% of infiltrate within stromal area and TILs-High representing ≥ 50% of stromalarea. Clinicopathological data of CMT was characterized according to key parameters, as well as survival rates. TILs evaluation within tumor stroma revealed that 65.2% (n = 15) of tumors had TILs-Low. PD-L1 expression and stromal TILs weresignificantly associated (P = 0.009). PD-L1 expression was observed in 39% (n = 9) of all tumors of which 17.4% (n = 4)were from CA group and 21.7% (n = 5) were from CC group. PD-L1 expression within TILs was observed in 39% (n =9) of the tumors. PD-L1 in malignant epithelium was present in all lymph node metastasis (n = 5). PD-L1 was associatedwith involvement of regional lymph nodes (P = 0.034). Survival curves demonstrated TILs-Low had higher (P = 0.010)overall survival (OS) compared with TILs-High, and PD-L1+ and PD-L1– (P = 0.06) did not differed. The clinicopathological variables significantly correlated with OS by univariate analysis were the histological grade (P = 0.009), lymphnode involvement (P = 0.004), stromal...

Exploring Collagen Parameters in Pure Special Types of Invasive Breast Cancer.

One of the promising tools to evaluate collagen in the extracellular matrix is the second-harmonic generation microscopy (SHG). This approach may shed light on the biological behavior of cancers and their taxonomy, but has not yet been applied to characterize collagen fibers in cases diagnosed as invasive breast carcinoma (BC) of histological special types (IBC-ST). Tissue sections from 99 patients with IBC-ST and 21 of invasive breast carcinoma of no special type (IBC-NST) were submitted to evaluation of collagen parameters by SHG. Tissue microarray was performed to evaluate immunohistochemical-based molecular subtype. In intratumoral areas, fSHG and bSHG (forward-SHG and backward-SHG) collagen parameters achieved their lowest values in mucinous, papillary and medullary carcinomas, whereas the highest values were found in classic invasive lobular and tubular carcinomas. Unsupervised hierarchical cluster analysis and minimal spanning tree using intratumoral collagen parameters allowed the identification of three main groups of breast cancer: group A (classic invasive lobular and tubular carcinomas); group B (IBC-NST, metaplastic, invasive apocrine and micropapillary carcinomas); and group C (medullary, mucinous and papillary carcinomas). Our findings provide further characterization of the tumor microenvironment of IBC-ST. This understanding may add information to build more consistent tumor categorization and to refine prognostication.

Cytological Criteria for Predicting the Luminal Phenotype of Breast Carcinoma.

BACKGROUND: Specific cytological criteria for the luminal phenotype of breast carcinoma, despite it being the most common and having a better prognosis as well as targeted therapies under study, remain to be established. Using fine-needle aspiration cytology (FNAC), we aimed to identify the luminal phenotype through the evaluation of cytological criteria recognized in routine practice. METHODS: We correlated 169 FNACs of breast carcinomas with their tissue specimens, classified into phenotypes by immunohistochemistry (applying tissue microarray technology) as luminal A, luminal B, HER2 overexpression, and triple negative. All FNAC samples were blindly reviewed according to cellularity, cell cohesion, necrosis, nucleoli, and nuclear atypia. Fisher's exact test was used to test associations between the cytological criteria and phenotypes. RESULTS: The following phenotypes were obtained - luminal A: 107 (63.3%), luminal B: 39 (23.1%), HER2 overexpression: 8 (4.7%), and triple negative: 15 (8.9%). The luminal phenotype showed mild/moderate cellularity (40.4%) (OR = 7.12, 95% CI: 1.61-31.52), inconspicuous, present nucleoli (55.5%) (OR = 8.31, 95% CI: 2.36-29.19), and mild/moderate nuclear atypia (44.5%) (OR = 8.42, 95% CI: 1.90-37.25). CONCLUSION: The criteria that might indicate the luminal phenotype of breast carcinoma in FNAC were mild/moderate cellularity, inconspicuous, present, and nonprominent nucleoli, and mild/moderate nuclear atypia.

Fine needle aspiration cytology of lobular breast carcinoma and its variants.

OBJECTIVE: To identify associations between cytological criteria in fine needle aspiration (FNA) specimens and histological subtypes of lobular breast carcinoma (classical and other types). STUDY DESIGN: FNA cytology and mastectomy specimens from 72 cases of invasive lobular breast carcinoma were consecutively retrieved from the files of the Amaral de Carvalho Hospital, Jaú-São Paulo, Brazil. All cases were reviewed regarding five cytological criteria: cellularity, cellular cohesion, presence of inflammation, nucleoli and nuclear atypia. The χ2 test or Fisher's exact tests with 95% confidence intervals (CI) were used. RESULTS: The classical type showed lower initial cytological diagnosis of malignancy compared to the other variants (p=0.017; odds ratio (OR) 0.26, 95% CI 0.89-0.80). Moderate/intense cellular cohesion (p=0.011; OR 0.18, 95% CI 0.04-0.73) and mild atypia (p=0.000; OR 16.15, 95% CI 3.20-81.48) were significantly associated with the classical type of lobular breast carcinoma, while the absence of inflammation (p=0.082; OR 0.36, 95% CI 0.12-1.15) was marginally associated with the classical type. CONCLUSIONS: In cytology, the characterization of lobular carcinoma as malignant is difficult, especially the classical type. The association between cell cohesion and the classical type of lobular breast carcinoma may be one of the factors that complicate this diagnosis.

Expression of CK19 in invasive breast carcinomas of special histological types: implications for the use of one-step nucleic acid amplification.

BACKGROUND: The sentinel lymph node (SLN) is the first lymph node to receive the lymphatic drainage of a primary tumour; based on the knowledge that CK19 is positive in more than 95% of breast carcinomas, a molecular method for intraoperative diagnosis of SLN metastases (the one-step nucleic acid amplification (OSNA) assay) was developed. AIMS: To evaluate CK19 immunoreactivity in a series of special histological types of breast carcinoma in order to verify whether the OSNA assay can be used in all breast cancer cases independently of the histological type. METHODS: 116 samples of invasive breast carcinomas of special type were investigated for CK19 immunoreactivity in tissue microarrays (TMA); negative cases were evaluated in the entire tissue tumour tissue. RESULTS: Of the 116 cases, 88.9% were positive CK19. Micropapillary and apocrine carcinomas were all positive for CK19 in TMAs. The tubular (93%), mucinous (86%), medullary typical and atypical (84%), mixed carcinomas (83%) increased the rate of positivity for this marker to 100% after repeating the immunostain in whole tissue of negative TMA cases, because the expression of those cases was focal. CONCLUSION: Most breast cancer cases were positive for CK19, independent of the histological type; therefore the OSNA assay can be used in all breast cancer cases with a potential low rate of false negative for CK19 detection of micrometastasis. There is an important variation between the positivity assessed on TMAs and the entire tissue; these findings can be clinically relevant because in some cases CK19 is evaluated on core-needle biopsy prior to surgery.

Angiogenesis and breast cancer.

Angiogenesis is an essential step for breast cancer progression and dissemination. The development of new blood vessels in cancer setting (angiogenesis) is conducted by numerous physiological and pathological stimuli, where the main stimulus is hypoxia. The knowledge of different molecular pathways regulating angiogenesis is constantly growing. An increased and complex scenario of angiogenesis is nowadays available in breast cancer, specifically, and permits not only to understand most of the important phases of neoplastic growth but also offer an exciting perspective for new therapeutic proposals based on blocking new blood vessels sprouting. This review focused on historical and recent understanding of angiogenesis occurrence in breast cancer.

Cytological criteria to predict basal phenotype of breast carcinomas.

Breast carcinoma is a heterogeneous disease. It can be classified into phenotypes based on the expression of certain proteins, with distinct differences in prognosis. The basal phenotype is associated with worse prognosis and it still remains without specific treatment. However, there is currently no international consensus on the cytological criteria that could predict this phenotype. The purpose of the study was to evaluate the cytological criteria in fine-needle aspiration biopsy and to identify their association with the basal phenotype of breast carcinoma. Fine-needle aspiration biopsy specimens and tissue sections (mastectomy specimen) from 74 cases of high-grade invasive ductal breast carcinomas were consecutively retrieved from the files of three institutions. Breast carcinomas were studied using the tissue microarray technique, being classified into phenotypes: luminal A, luminal B, HER2 overexpression, and basal. The cytological criteria for all cases were reviewed blindly by two pathologists according to five cytological criteria: cellularity, cell pattern, presence of necrosis, nucleoli, and nuclear atypia. Exact Fisher test was used to test the association between cytological criteria and the phenotypes of breast carcinoma. Necrosis was present in 64.7% of basal breast carcinomas, and 31.1% of nonbasal breast carcinomas, and that result was statistically significant, showing an odds ratio (OR) of 3.80. The basal phenotype, compared with the luminal A, showed more necrosis (OR = 6.97), present/prominent nucleoli (OR = 8.18), and cellularity more frequently (OR = 18.03). Necrosis, as well as present/prominent nucleoli and abundant cellularity are criteria more frequently associated to the basal phenotype of breast carcinoma.

Possible Relationship between Basal-Like Breast Carcinoma and Age.

SUMMARY: INTRODUCTION: Estrogen receptor expression is lower in breast carcinoma of women ≤45 years compared to women ≥65 years of age, which may imply a higher frequency of basal-like breast carcinomas in younger women. This study evaluated whether there is any difference in the frequency of basal-like phenotype and estrogen receptor (ER)-/HER2- invasive breast carcinomas between women of these 2 different age groups. PATIENTS AND METHODS: A total of 151 women aged ≤45 years or ≥65 years with invasive breast carcinomas were evaluated using tissue microarray, and classified into the following phenotypes: luminal A (ER+/HER2-), luminal B (ER+/HER2+), HER2 overexpression (ER-/HER2+), and basal-like (ER-/HER2- and expressing at least 1 of the basal markers p63, CK5 and/or P-cadherin). RESULTS: ER-/HER2- carcinomas were twice as frequent in women aged ≤45 years (p = 0.0247). However, when the basal-like phenotype was compared with all the other phenotypes grouped together, no statistically significant difference was found (p = 0.0854). CONCLUSIONS: ER-/HER2- carcinomas were more frequent in younger women compared to all the other phenotypes grouped together. An international consensus will be necessary to establish which markers should be used to define basal-like phenotype.

Lymphangiogenesis: from the pig embryos to cancer: [review] / Linfangiogênese: de embriões de suínos ao câncer: [revisão]

The discovery and the comprehension of lymphatic vessels suffered several historical delays and setbacks. The inherent anatomical problems slowed down the precise identification of the lymphatic system during the development of medical science. Gasparo Aselli, an Italian surgeon and anatomist, was the first to describe the lymphatic vessels in 1627 (De Lacteibus sive Lacteis Venis). However, most original descriptions that report the morphology of the lymphatic system in different organisms were done during the 19th and the 20th centuries. The recent identification of specific lymphatic vasculature molecular markers allows a more accurate identification and characterization of the lymphatic system evolution in different organs, as well as its role in different pathological conditions, including cancer. This study summarizes the current understanding of lymphangiogenesis in tumour progression, as well as it presents a review of the promising data regarding the prognostic value of lymphatic density and the use of therapeutic lymphangiogenic molecules.

A descoberta dos vasos linfáticos e sua compreensão enfrentaram uma série de atrasos e dificuldades históricos. As inerentes dificuldades anatômicas retardaram a identificação precisa da rede vascular linfática durante o desenvolvimento da ciência médica. Gasparo Aselli, um anatomista e cirurgião italiano, foi o primeiro a descrever os vasos linfáticos, em 1627 (De Lacteibus sive Lacteis Venis). Entretanto, a maioria das descrições originais que relatam a morfologia do sistema linfático nos diferentes organismos foi realizada depois, entre os séculos XIX e XX. A recente identificação de marcadores moleculares específicos à vasculatura linfática permite agora identificação e caracterização mais acuradas da evolução da rede linfática nos vários órgãos e em diferentes situações, inclusive no câncer. Esta revisão resume o conhecimento sobre a linfangiogênese na progressão tumoral, bem como apresenta uma síntese dos dados mais promissores em relação ao valor prognóstico da densidade linfática e da utilização das moléculas linfangiogênicas como alvo terapêutico.

Induction of COX-2 expression by acrolein in the rat model of hemorrhagic cystitis.

AIM: Acrolein (ACR) is a urinary metabolite of cyclophosphamide (CPS) and ifosfamide (IFS), which has been demonstrated to be the causative agent of hemorrhagic cystitis (HC), induced by these compounds. In this study, we investigate the participation of cyclooxygenase-2 (COX-2) on ACR-induced HC. METHODS: Male Wistar rats (150-200g; six rats per group) were treated with distilled water or intravesical ACR and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters and COX-2 expression. RESULTS: COX-2 immunohistochemical expression was significant 12h after ACR administration mainly in subepithelial cells. ACR injection also alters some macroscopic and microscopic parameters in bladder of rats analyzed by Gray's criteria. CONCLUSIONS: COX-2 participates in the pathogenesis of ACR-induced HC first seen 12h after initial contact between ACR and urothelium.

Carcinoma de mama: novos conceitos na classificação: [revisão] / Breast cancer: new concepts in classification: [review]

O carcinoma de mama é a neoplasia maligna mais comum em mulheres. Estudos moleculares do carcinoma de mama, baseados na identificação do perfil de expressão gênica por meio do cDNA microarray, permitiram definir pelo menos cinco sub-grupos distintos: luminal A, luminal B, superexpressão do HER2, basal e normal breast-like. A técnica de tissue microarray (TMA), descrita pela primeira vez em 1998, permitiu estudar, em várias amostras de carcinoma, os perfis de expressão protéica de diferentes neoplasias. No carcinoma de mama, os TMAs têm sido utilizados para validar os achados dos estudos preliminares, identificando, desta forma, os novos subtipos fenotípicos do carcinoma de mama. Dentre os subtipos classicamente descritos, o grupo basal constitui um dos mais intrigantes subtipos tumorais e é freqüentemente associado com pior prognóstico e ausência de alvos terapêuticos definidos. A classificação histopatológica do carcinoma de mama tem pobre valor preditivo. Portanto, a associação entre o diagnóstico histológico com técnicas moleculares nos laboratórios de anatomia patológica, por meio do estudo imunoistoquímico, pode determinar o perfil molecular do carcinoma de mama, buscando melhorar a resposta terapêutica. Este estudo visou resumir os mais recentes conhecimentos em que se baseiam os novos conceitos da classificação do carcinoma de mama.

Breast cancer is the principal cause of death from cancer in women. Molecular studies of breast cancer, based in the identification of the molecular profiling techniques through cDNA microarray, had allowed defining at least five distinct sub-group: luminal A, luminal B, HER-2-overexpression, basal and " normal" type breast-like. The technique of tissue microarrays (TMA), described for the first time in 1998, allows to study, in some samples of breast cancer, distinguished by differences in their gene expression patterns, which provide a distinctive molecular portrait for each tumor and the basis for and improved breast cancer molecular taxonomy. Another important implication is that genetic profiling may lead to the identification of new target for therapy and better predictive markers are needed to guide difficult treatment decisions. Additionally, the current pathology classification system is suboptimal, since patients with identical tumor types and stage of disease present different responses to therapy and different overall outcomes. Basal breast tumor represents one of the most intriguing subtypes and is frequently associated with poor prognosis and absence of putative therapeutic targets. Then, the purpose of this review was to resume the most recent knowledge about the breast carcinoma classification and characterization.

Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats.

PURPOSE: Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). In this study, we investigated the participation of cyclooxygenase-2 (COX-2) upon ifosfamide-induced HC. METHODS: Male Wistar rats (150-200 g; six rats per group) were treated with saline, IFS (400 mg/kg, i.p.) and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters, and COX-2 expression. In other groups etoricoxib (selective COX-2 inhibitor), indomethacin (non-selective COX inhibitor), thalidomide (selective TNF-alpha inhibitor), pentoxifyllin (non-selective TNF-alpha inhibitor) were added 1 h before IFS administration. The classical protocol using three doses of Mesna was also evaluated and compared with two extra doses of etoricoxib or indomethacin. RESULTS: COX-2 was expressed significantly 24 h after IFS administration mainly in myofibroblasts and mast cells evaluated by immunohistochemistry. Treatment 1 h before IFS injection with etoricoxib, indomethacin, thalidomide, and pentoxifylline reduced COX-2 expression and some macroscopic and microscopic parameters in IFS-induced HC. Moreover, addition of etoricoxib or indomethacin with the last two doses of Mesna was more efficient than three doses of Mesna alone when evaluated microscopically. CONCLUSIONS: COX-2 participates in the pathogenesis of IFS-induced HC and the treatment with COX and TNF-alpha inhibitors reduced COX-2 expression. The addition of COX-inhibitors to the last two doses of Mesna represents a new therapeutic strategy of preventing HC.

[Breast cancer: new concepts in classification]. / Carcinoma de mama: novos conceitos na classificação.

Breast cancer is the principal cause of death from cancer in women. Molecular studies of breast cancer, based in the identification of the molecular profiling techniques through cDNA microarray, had allowed defining at least five distinct sub-group: luminal A, luminal B, HER-2-overexpression, basal and 'normal' type breast-like. The technique of tissue microarrays (TMA), described for the first time in 1998, allows to study, in some samples of breast cancer, distinguished by differences in their gene expression patterns, which provide a distinctive molecular portrait for each tumor and the basis for and improved breast cancer molecular taxonomy. Another important implication is that genetic profiling may lead to the identification of new target for therapy and better predictive markers are needed to guide difficult treatment decisions. Additionally, the current pathology classification system is suboptimal, since patients with identical tumor types and stage of disease present different responses to therapy and different overall outcomes. Basal breast tumor represents one of the most intriguing subtypes and is frequently associated with poor prognosis and absence of putative therapeutic targets. Then, the purpose of this review was to resume the most recent knowledge about the breast carcinoma classification and characterization.

Angiogenesis, haemostasis and cancer: new paradigms and old concerns / Angiogênese, homeostasia e câncer: novos paradigmas e velhos problemas

Neovascularization is a crucial phenomenon for the continuous growing of neoplastic cells and cancer progression. The growth of new blood vessels from pre-existing vessels (angiogenesis) occurs in several physiological and pathological conditions, including cancer, where it is critical for tumor-cells nutrition. Recently, new remarkable insights regarding angiogenesis and blood coagulation (key events in vascular biology) have been described. The serine protease thrombin, which plays a central role in blood coagulation cascade through its ability to cleave fibrinogen conducting to fibrin clot formation, is also known to be involved in embryogenesis, inflammation, wound healing, through its active role on vascular remodeling. Although the increased knowledge of factors regulating angiogenesis and coagulation led to the understanding that angiogenesis, homeostasis and carcinogenesis are three close team players, little is still known about how these pathways support each other in the process of angiogenesis in vivo. This review summarizes current understanding of blood coagulation cascade role in conducting angiogenesis and tumor progression, as well as provides an overview of the emerging anti-angiogenic and anti-coagulation therapies inducing tumor regression.

A neovascularização é um processo fundamental para a sobrevivência e a progressão das células neoplásicas malignas. O crescimento de novos vasos sanguíneos a partir de vasos já existentes, fenômeno designado como angiogênese, está envolvido em vários processos fisiológicos e patológicos, incluindo o crescimento tumoral, onde a angiogênese desempenha papel crítico na nutrição das células tumorais. Tal como a angiogênese, o sistema de coagulação sanguínea exerce importante função na biologia vascular. A trombina, uma serina protease, tem papel fundamental na cascata de coagulação, pela quebra enzimática do fibrinogênio e pela conseqüente produção de fibrina. Essa protease encontra-se também implicada em desenvolvimento embrionário, inflamação e cicatrização, processos nos quais a remodelação vascular está altamente ativa. Apesar de o crescente conhecimento de fatores reguladores da angiogênese e da coagulação demonstrar que a carcinogênese, a coagulação e a angiogênese são três close team players, ainda muito pouco se sabe sobre o modo como esses players comunicam-se e interagem no processo de angiogênese in vivo. Esta revisão sumariza os conhecimentos atuais quanto ao papel da cascata de coagulação na condução do processo angiogênico e do crescimento tumoral, bem como oferece uma visão geral sobre recentes terapias antiangiogênicas e anticoagulantes envolvidas na regressão tumoral.

Tissue microarrays for testing basal biomarkers in familial breast cancer cases.

CONTEXT AND OBJECTIVE: The proteins p63, p-cadherin and CK5 are consistently expressed by the basal and myoepithelial cells of the breast, although their expression in sporadic and familial breast cancer cases has yet to be fully defined. The aim here was to study the basal immunoprofile of a breast cancer case series using tissue microarray technology. DESIGN AND SETTING: This was a cross-sectional study at Universidade Estadual de Campinas, Brazil, and the Institute of Pathology and Molecular Immunology, Porto, Portugal. METHODS: Immunohistochemistry using the antibodies p63, CK5 and p-cadherin, and also estrogen receptor (ER) and Human Epidermal Receptor Growth Factor 2 (HER2), was per-formed on 168 samples from a breast cancer case series. The criteria for identifying women at high risk were based on those of the Breast Cancer Linkage Consortium. RESULTS: Familial tumors were more frequently positive for the p-cadherin (p = 0.0004), p63 (p < 0.0001) and CK5 (p < 0.0001) than was sporadic cancer. Moreover, familial tumors had coexpression of the basal biomarkers CK5+/ p63+, grouped two by two (OR = 34.34), while absence of coexpression (OR = 0.13) was associated with the sporadic cancer phenotype. CONCLUSION: Familial breast cancer was found to be associated with basal biomarkers, using tissue microarray technology. Therefore, characterization of the familial breast cancer phenotype will improve the understanding of breast carcinogenesis.

Tissue microarrays for testing basal biomarkers in familial breast cancer cases

CONTEXT AND OBJECTIVE: The proteins p63, p-cadherin and CK5 are consistently expressed by the basal and myoepithelial cells of the breast, although their expression in sporadic and familial breast cancer cases has yet to be fully defined. The aim here was to study the basal immunopro-file of a breast cancer case series using tissue microarray technology. DESIGN AND SETTING: This was a cross-sectional study at Universidade Estadual de Campinas, Brazil, and the Institute of Pathology and Mo-lecular Immunology, Porto, Portugal. METHODS: Immunohistochemistry using the antibodies p63, CK5 and p-cadherin, and also estrogen receptor (ER) and Human Epidermal Receptor Growth Factor 2 (HER2), was per-formed on 168 samples from a breast cancer case series. The criteria for identifying women at high risk were based on those of the Breast Cancer Linkage Consortium. RESULTS: Familial tumors were more frequently positive for the p-cadherin (p = 0.0004), p63 (p < 0.0001) and CK5 (p < 0.0001) than was sporadic cancer. Moreover, familial tumors had coexpression of the basal biomarkers CK5+/ p63+, grouped two by two (OR = 34.34), while absence of coexpression (OR = 0.13) was associ-ated with the sporadic cancer phenotype. CONCLUSION: Familial breast cancer was found to be associated with basal biomarkers, using tissue microarray technology. Therefore, characterization of the familial breast cancer phenotype will improve the understanding of breast carcinogenesis.

CONTEXTO E OBJETIVO: As proteínas p63, p-cad e CK 5 são expressas em células basais/mioepiteliais da mama. Entretanto a expressão dessas proteínas no câncer esporádico e familiar ainda não é bem conhecida. O objetivo do estudo foi estudar essas proteínas no câncer de mama, utilizando a técnica de tissue microarray, assim como ER e HER2. TIPO DE ESTUDO E LOCAL: Estudo transversal, realizado no Centro de Atenção Integral à Saúde da Mulher, Universidade Estadual de Campinas, Brasil, e no Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Portugal. MÉTODOS: O estudo analisou a expressão das proteínas p63, CK 5, p-cad, ER e HER2 numa série de 168 casos de câncer de mama. Os critérios utilizados para identificar as mulheres com alto risco foram os do Breast Cancer Linkage Consortium. RESULTADOS: A série de câncer familiar foi freqüentemente mais positiva para as proteínas basais p-cadherin (p = 0,0004), p63 (p < 0,0001) e CK 5 (p < 0,0001) que o câncer esporádico. A presença da co-expressão das proteínas basais CK 5+/p63+, agrupados dois a dois, foi associada com o fenótipo do câncer familiar (odds ratio, OR = 34,34), enquanto que sua ausência foi com o câncer esporádico (OR = 0,13). CONCLUSÕES: O câncer da mama familiar está associado aos marcadores de células basais proteínas p63, p-cad e CK 5, utilizando-se a técnica de tissue microarray. Por fim, parece legítima a interpretação destes resultados como mais uma evidência que suporta a hipótese da existência de células precursoras do câncer familiar da mama. O conhecimento dos perfis de expressão destas células, bem como das vias de sinalização envolvidas, beneficiarão o entendimento da carcinogênese mamária.

Fibrosmatose mamária / Breast fibromatosis

A fibromatose é uma lesão caracterizada por proliferação fibroblástica, sendo raramente encontrada na mama. Atinge habitualmente a fáscia ou aponeurose da parede abdominal. Aqui se relata um caso de mulher de 72 anos com nódulo mamário de crescimento rápido, mostrando ao exame físico um nódulo em mama direita mal delimitado, não aderente a plano superficial nem profundo, medindo 20 x 30 mm, apresentando aos exames de imagem características de benignidade. Foi indicada e realizada punção aspirativa por agulha fina (PAAF), cujo resultado apresentou células fusiformes atípicas. A paciente foi submetida à exérese de lesão com biópsia de congelação que não foi conclusiva, permanecendo a suspeita de malignidade. Somente após o exame histopatológico e estudo imuno-histoquímico, o diagnóstico foi estabelecido. Vale ressaltar que a apresentação clínica da fibromatose pode ser confundida com um carcinoma de mama.

The fibromatosis is a lesion characterized by fibroblastic proliferation that is rare in breast. This pathology is frequently found in abdominal wale fascia. We present a case in a 72 year-old woman with a breast nodule that has grown fast. Physical examination showed an ill-defined but freely movable mass at right breast, measuring 2 x 3 cm. Mammography and ultrassonography showed benign findings. Citopathology showed not typical spindle cells. Excisional biopsy of the nodule was performed and the histopathological examination and immunohistochemistry established the diagnosis. Clinical examination mimics breast cancer and for this reason the presence of an unusual breast lesion may include fibromatosis as differential diagnosis.

Basal-like Breast Carcinomas: Identification by P-cadherin, P63and EGFR Basal Cytokeratins Expression

Invasive breast carcinomas constitute a heterogeneous group of tumours, with different clinical behaviour and response to chemotherapy. These lesions, as determined morphologically, are thought to arise exclusively from the inner, luminal epithelial cell compartment of the terminal-duct lobular unit of the breast. Irrespective of the true histogenesis of breast carcinomas, ithas become increasingly clear that a small proportion of cancers exhibit a basal/myoepithelial phenotype as defined by immunohistochemical positivity for myoepithelial markers, meaning they express molecules normally seen in the basal/myoepithelial compartment of the normal breast. The purpose of this review is to resume the more recent knowledge about the use of a panel of basal molecular markers in “basal-like” breast carcinomas classification and characterization. This subtypecharacterization has a great importance, since it requires a more focused investigation of putative therapeutic targets. The existing therapies against estrogen receptor (ER) or HER-2 oncogene amplification would not be expected to be effective against basal breast carcinomas, since these tumours express neither of these proteins. In contrast, basal breast carcinomasusually express basal cell cytokeratins (like CK5/6), P-cadherin adhesion molecule, p53 family member p63, and the transmembrane tyrosine kinase receptor EGFR (epidermal growth factor receptor), which can be used as excellent markers for this line of mammary carcinogenesis, and become interesting therapeutic targets against these highly aggressive lesions.