Carcinoma da mama de tipo basal

Breast cancer presents as a heterogeneous disease, not only for the clinic and histology, but also in genetic expression profile. Studies using cDNA microarrays have recently led to the re-classification of invasive breast carcinomas, based on their molecular signature, into three main groups: luminal; HER2 (Human Epidermal Receptor 2) overexpressing, and basal-like. Although the latter group is the least prevalent it is the most agressive one, lacking a target based therapy, since their main characteristic is being negative for hormonal receptors or HER2. So, it is of paramount importance to try to unravel their histogenic origin and characterize their molecular and immunohistochemical profiles. EGFR (Epidermal Growth Factor Receptor), which is overexpressed in a high proportion of these carcinomas, is a potential therapeutic target, and clinical trials with inhibitors of its activity may represent important advances in basal-like breast carcinomas therapy.O cancro da mama apresenta-se como uma doença heterogénea, não só clínica e histologicamente, como também no seu perfil de expressão genética. A avaliação por cDNA microarrays permitiu re-classificar recentemente os carcinomas da mama invasivos, de acordo com uma assinatura molecular, em três grandes grupos: luminal; com sobre- expressão de HER2 (Human Epidermal Receptor 2 – receptor epidérmico humano 2) e o de tipo basal. Este último é dos três o menos prevalente mas o mais agressivo e aquele que não possui tratamento dirigido, uma vez que não expressa receptores hormonais ou HER2, que são actuais alvos terapêuticos no cancro da mama. Os carcinomas da mama de tipo basal têm sido tema de vários trabalhos de investigação que visam conhecer a sua origem histogenética, bem como a sua caracterização do ponto de vista molecular e imunohistoquímico. O EGFR (Epidermal Growth Factor Receptor – receptor do factor de crescimento epidérmico), que se encontra sobre-expresso numa elevada percentagem destes carcinomas, é um potencial alvo terapêutico, e ensaios clínicos utilizando fármacos inibidores da sua actividade podem representar importantes avanços na terapia dirigida dos carcinomas da mama de tipo basal.info:eu-repo/semantics/publishedVersio

Molecular analysis of c-Kit and PDGFRA in GISTs diagnosed by EUS

Gastrointestinal stromal tumors (GISTs) are characterized by overexpression and mutations of c-Kit. Approximately 80% of c-Kit mutations occur in exon H, being a response factor to imatinib (Gleevec) therapy. Mutations of platelet-derived growth factor receptor-a (PDGFRA) are observed in a subset of GISTs lacking c-Kit mutations. We aimed to assess whether c-Kit and PDGFRA mutation analysis of GISTs obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) could be routinely performed. Mutation analysis of c-Kit hotspot exons (9, 11, 13, and 17) and PDGFRA hotspot exons (12 and 18) was performed in aspirates of 33 GISTs and 18 non-GIST mesenchymal tumors. Of the GIST cases, 19 (58%) of 33 contained a mutation in exon 11, 1 (3%) in exon 9, and none in exons 13 and 17. No activating c-Kit mutations were identified in non-GIST cases. No PDGFRA mutation was detected. Mutation analysis is possible in these FNA cell blocks and can assist in the diagnosis and therapeutic decisions in GIST cases.Supported in part by NOVARTIS Oncologyinfo:eu-repo/semantics/publishedVersio

Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis

The distribution and significance of caveolin 1 (CAV1) expression in different breast cell types and role in breast carcinogenesis remain poorly understood. Both tumor-suppressive and oncogenic roles have been proposed for this protein. The aims of this study were to characterize the distribution of CAV1 in normal breast, benign breast lesions, breast cancer precursors, and metaplastic breast carcinomas; to assess the prognostic significance of CAV1 expression in invasive breast carcinomas; and to define whether CAV1 gene amplification is the underlying genetic mechanism driving CAV1 overexpression in breast carcinomas. Purpose: The distribution and significance of caveolin 1 (CAV1) expression in different breast cell types and role in breast carcinogenesis remain poorly understood. Both tumor-suppressive and oncogenic roles have been proposed for this protein. The aims of this study were to characterize the distribution of CAV1 in normal breast, benign breast lesions, breast cancer precursors, and metaplastic breast carcinomas; to assess the prognostic significance of CAV1 expression in invasive breast carcinomas; and to define whether CAV1 gene amplification is the underlying genetic mechanism driving CAV1 overexpression in breast carcinomas. Experimental Design: CAV1 distribution in frozen and paraffin-embedded whole tissue sections of normal breast was evaluated using immunohistochemistry, immunofluorescence, and immunoelectron microscopy. CAV1 expression was immunohistochemically analyzed in benign lesions, breast cancer precursors, and metaplastic breast carcinomas and in a cohort of 245 invasive breast carcinomas from patients treated with surgery followed by anthracycline-based chemotherapy. In 25 cases, CAV1 gene amplification was assessed by chromogenic in situ hybridization. Results: In normal breast, CAV1 was expressed in myoepithelial cells, endothelial cells, and a subset of fibroblasts. Luminal epithelial cells showed negligible staining. CAV1 was expressed in 90% of 39 metaplastic breast carcinomas and in 9.4% of 245 invasive breast cancers. In the later cohort, CAV1 expression was significantly associated with ‘basal-like’ immunophenotype and with shorter disease-free and overall survival on univariate analysis. CAV1 gene amplification was found in 13% of cases with strong CAV1 expression. Conclusions: The concurrent CAV1 amplification and overexpression call into question its tumor-suppressive effects in basal-like breast carcinomas

P-cadherin and cytokeratin 5: useful adjunct markers to distinguish basal-like ductal carcinomas in situ

Gene expression profiles of invasive breast carcinomas have identified a subgroup of tumours with worse prognosis, which have been called "basal-like". These are characterized by a specific pattern of expression, being estrogen receptor (ER) and HER2 negative, and frequently expressing at least one basal marker such as basal cytokeratins or epidermal growth factor receptor (EGFR). Previously, our group characterized basal-like tumours in a series of invasive breast carcinomas using P-cadherin (P-CD), p63 and cytokeratin 5 (CK5). Based on that study, we hypothesized that those high-grade basal-like invasive carcinomas might have a pre-invasive counterpart, which could be identified using the same approach. A series of 79 ductal carcinomas in situ (DCIS) were classified into distinct subgroups according to their ER, HER2 and basal markers expression. Luminal DCIS expressed ER and constituted 64.6% of the series; the HER2 overexpressing tumours did not express ER and represented 25.3% of the cases, whereas 10.1% lack the expression of ER and HER2 and expressed at least one basal marker (P-CD, CK5, CK14, p63, vimentin and/or EGFR). These basal-like DCIS were mostly high-grade, with comedo-type necrosis, and consistently showed expression of P-CD and CK5. In conclusion, DCIS with a basal-like phenotype represent a small percentage in our series, being P-CD and CK5, the most useful adjunct markers to distinguish this subset of carcinomas in situ of the breast.The authors thank Dr. Leda Viegas de Carvalho(M.D., Ph.D.), Santos, São Paulo, Brazil, who kindly provided casematerial used in this study.This study was supported by two research grants (Joana Paredes:SFRH/BPD/15319/2005; Nair Lopes: POCTI/CBO/45157/2002) andby a scientific project (POCI/BIA-BCM/59252/2004) both financedby the Portuguese Science and Technology Foundation

Immunohistochemical expression of VEGF-A and its ligands in non-neoplastic lesions of the breast sampling-assisted by dynamic angiothermography

The aim of this study was to investigate the expression of angiogenic markers, vascular endothelial growth factor A (VEGF-A) ligand and its receptors, VEGFR-1 and -2, in a series of biopsy-proven non-neoplastic lesions of the breast detected by dynamic angiothermography. We have also studied the vascular density demonstrated by CD31 immunoreactivity, in order to assess the potential of the imaging method to recognize lesions with an enhanced vascular network of clinical importance in routine breast examination. The lesions were classified as non-proliferative, proliferative without atypia and proliferative with atypia. VEGF was diffusely expressed in the epithelial cells of proliferative lesions in almost all cases. Similarly, VEGFR-1 and -2 also exhibited epithelial positive reactions in the majority of cases. VEGF-A and its receptors were also present in blood vessels. CD31 showed an increase in vascular proliferation at the periphery of proliferative epithelial lesions, but not in non-proliferative lesions. Our results, showing marked expression of VEGF by the epithelial proliferative lesions and neoangiogenesis at their periphery, confirm that these lesions can be detected by dynamic angiothermography.Grants from FIG

Breast carcinomas that co-express E- and P-cadherin are associated with p120-catenin cytoplasmic localisation and poor patient survival

Background: Changes in junctional catenin expression may compromise cadherin-mediated adhesion, increasing cell malignant properties such as invasive and metastatic abilities. Altered expression of alpha-, beta-, gamma- and p120-catenin has been reported to be associated with E-cadherin loss or decreased expression, in both breast carcinomas and breast cancer cell lines. Aims and Methods: To investigate the expression and subcellular localisation of p120- and beta-catenin in a series of human invasive breast carcinomas, and correlate it with biological markers and clinicopathological parameters. Results: Both catenins frequently exhibited a reduced membranous or cytoplasmic staining pattern. These alterations were significantly correlated with lack of both E-cadherin and oestrogen receptor-alpha expression. It was possible to associate the expression of beta-catenin with histological grade, tumour size and nodal status, suggesting a relevant role for this catenin as a prognostic factor. The majority of E- and P-cadherin co-expressing tumours were related to cytoplasmic expression of p120-catenin; in this group of breast carcinomas, patient survival was poor. Conclusion: Results indicate that p120-catenin cytoplasmic accumulation may play an important role in mediating the oncogenic effects derived from P-cadherin aberrant expression, including enhanced motility and invasion, particularly in tumours which maintain E-cadherin expression.This work was supported by three research grants (JP: SFRH/BPD/15319/ 2005; ALC: POCI/N/07.01.02/10/25/2005; ASR: POCI/BIA-BCM/59252/2004) and by a scientific project (POCI/BIA-BCM/59252/2004), all financed by the Portuguese Science and Technology Foundation. We are grateful to the Calouste Gulbenkian Foundation for the ‘‘Programa Gulbenkian de Estímulo à Investigação (FCG 55/05)’’

Pero Vaz de Caminha: an-interchange program for quality control between Brazil and Portugal

To start an interexchange program for quality control in cervical cytology and discuss conceptual criteria for diagnosis. Slides were selected in the archives of the 2 institutes and included cases with unsatisfactory, negative and positive results. Sets of slides were changed between the partners every 3 months. At the end of each year a senior cytopathologist was invited to discuss the major discrepancies found in the study.A total of 1,041 cases were analyzed. Full concordance was obtained in 74.4% (774) of cases and discrepancies in 25.6% (267 cases). Full agreement was achieved in 276 (39%) of 707 cases categorized as negative. In 421 negative cases from laboratory A, this concordance represents 65.5% and 96.5% for laboratory B, which submitted 286 negative cases. The main discordance was the high number of atypical squamous cells of undetermined significance cases: 3.1% for A and 128 (33.2%) for B. Samples with discrepancies related to the quality of the material was another controversial issue: of 16 cases from laboratory A, 6 (37.5%) unsatisfactory cases were the same and 10 (62.5%) different. Laboratory B presented 20 unsatisfactory cases, and 14 (70.0%) had other diagnoses. Low grade squamous intraepithelial lesion and high grade squamous intraepithelial lesion concordance ranged from 75% to 80%, and invasive carcinoma has 4 discordances (28.5%), 3 previously screened as high grade squamous intraepithelial lesion and 1 as atypical squamous cells of undetermined significance. The kappa value obtained was 0.65, indicating substantial agreement.Our results indicated that atypical squamous cells of undetermined significance diagnoses are the crucial point of controversies and concern the quality of routine diagnosis in cytopathology.(undefined

Correlação entre as expressões de P-caderina e de receptores de estrógeno no câncer da mama

Introdução: A manutenção da arquitetura dos tecidos adultos depende essencialmente da integridade estrutural e funcional das caderinas, uma superfamília de moléculas de adesão celular dependentes de cálcio, que medeiam normalmente a adesão intercelular homofílica e homotípica. A P-caderina é expressa pelas células mioepiteliais da glândula mamária normal, sendo aberrantemente expressa num pequeno subgrupo de carcinomas da mama. Vários estudos recentes têm demonstrado que a expressão desta proteína está significativamente correlacionada com tumores de alto grau histológico e negativos para os receptores de estrógeno (RE). Objetivos: Investigar a expressão da P-caderina e dos receptores de estrógeno (RE) em carcinomas da mama invasivos e correlacionar os resultados obtidos. Material e método: O padrão de expressão da P-caderina e dos RE foi estudado imunoistoquimicamente em 149 carcinomas invasivos da mama; seguidamente, correlacionou-se estatisticamente a expressão destas duas proteínas. Resultados: A P-caderina foi detectada nas células mioepiteliais do tecido mamário normal e em 46 de 146 (31,5%) casos de carcinoma invasivo da mama. A expressão da P-caderina correlacionou-se inversamente com a expressão dos RE, verificando-se que o subgrupo de tumores P-caderina positivos e RE negativos apresentava alto grau histológico e maior agressividade tumoral. Conclusão: Demonstrou-se que a P-caderina identifica um subgrupo de carcinomas da mama, que não expressa RE e que parece representar um estado mais avançado da progressão tumoral. Estes resultados levantam ainda a hipótese de que a expressão desta proteína possa ser regulada por uma via alternativa, independente de estrógeno.<br>Background: The maintenance of adult tissue architecture largely depends on structural and functional integrity of cadherins, a superfamily of Ca2+-dependent cell-cell adhesion molecules that usually mediate homophilic and homotypic intercellular adhesion. P-cadherin is expressed by myoepithelial cells of normal breast tissue, and is aberrantly expressed in a subset of breast carcinomas. In addition, recent studies have demonstrated that the expression of this protein in breast cancer is significantly correlated with high histological grade and negativity for estrogen receptors (ER). Objectives: To investigate the expression of P-cadherin and ER in invasive breast carcinomas and correlate the obtained results. Material and methods: The expression pattern of P-cadherin and ER was immunohistochemically studied in 149 invasive carcinomas of the breast; subsequently, the statistic correlation between ER and P-cadherin immunophenotypes was assessed. Results: P-cadherin was detected in myoepithelial cells of normal breast tissue and in 46 out of 146 (31.5%) cases of invasive breast carcinomas. P-cadherin expression showed a high inverse correlation with ER expression, and it was observed that the subset of P-cadherin positive and ER negative tumours were related to higher histological grade and more agressive behaviour. Conclusion: We demonstrated that P-cadherin identifies a subgroup of breast carcinomas, which lacks ER expression, and that seems to represent an advanced step of cancer progression. Our data suggests the hypothesis that an alternative estrogen independent pathway regulates P-cadherin expression