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F C Schmitt
Cytopathology 12/2011; 22(6):355-7. · 1.59 Impact Factor
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ABSTRACT: Tumour size is considered one of the most important determinants of clinical staging in cancer patients. The aim of this study was to assess the value of tumour size as an indicator of the differentiation of mammary neoplasias in female dogs. The tumour, nodes metastates (TNM) system, based on primary lesion size, the extent of its dissemination to regional lymph nodes and the presence or absence of distant metastases, was applied to 120 female dogs diagnosed with mammary neoplasias. Paraffin blocks from 38 cases were selected and studied by immunohistochemical staining for prognostic and predictive markers of breast cancer. The Kaplan-Meier survival curve was estimated for 110 female dogs. Larger tumours (T3) were mostly malignant and showed lower expression of progesterone receptor and higher expression of cellular proliferation markers. Global survival time was shorter in female dogs with large tumour masses. This study highlights the importance of tumour size as a prognostic indicator of mammary neoplasias in female dogs.
Veterinary and Comparative Oncology 12/2009; 7(4):230-5. · 1.56 Impact Factor
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ABSTRACT: Cell-cell adhesion is an elementary process in normal epithelial cellular architecture. Several studies have shown the role mediated by cadherins in this process, besides their role in the maintenance of cell polarity, differentiation and cell growth. However, during tumour progression, these molecules are frequently altered. In breast cancer, tumours that overexpress P-cadherin usually present a high histological grade, show decreased cell polarity and are associated with worse patient survival. However, little is known about how this protein dictates the very aggressive behaviour of these tumours. To achieve this goal, we set up two breast cancer cell models, where P-cadherin expression was differently modulated and analysed in terms of cell invasion, motility and migration. We show that P-cadherin overexpression, in breast cancer cells with wild-type E-cadherin, promotes cell invasion, motility and migration. Moreover, we found that the overexpression of P-cadherin induces the secretion of matrix metalloproteases, specifically MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. Further, we showed that soluble P-cadherin fragment is able to induce in vitro invasion of breast cancer cells. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-cadherin expressing breast tumours.
Oncogene 11/2009; 29(3):392-402. · 6.37 Impact Factor
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ABSTRACT: 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
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.
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.
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.
Journal of clinical pathology 08/2008; 61(7):856-62. · 2.43 Impact Factor
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ABSTRACT: In the last decade, new molecular techniques were introduced into pathology laboratories. Cytology also benefited from the innovations emerging from this new era. Molecular cytopathology (MCP) can be defined as molecular studies applied on all types of cytological specimens, namely gynaecology cytology, exfoliative non- gynaecology cytology and fine needle aspirates. The development of many new ancillary techniques has paralleled the emergence of clinical cytology as a major diagnostic specialty. Clinical applications of these techniques have been growing in the last decade. The widespread acceptance of liquid-based systems in gynaecological cytology emphasises the relation between cells and molecules. The increased use of morphology and molecular biology in human papillomavirus-induced lesions for example, showed the potential to optimise, in one single brushed sample, diagnosis and research. Cytology samples from serous effusions, the pulmonary tree, urine, and aspirations, among others, are now likely to be studied by different molecular techniques for diagnosis, prognosis, or even assessment of therapeutic targets. In this review, the main published results concerning the application of molecular techniques in different fields of cytopathology are highlighted, and their applications discussed.
Journal of clinical pathology 04/2008; 61(3):258-67. · 2.43 Impact Factor
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ABSTRACT: Metastases from ovarian serous papillary carcinoma to the breast and primary invasive micropapillary carcinoma of the breast are histologically similar. The distinction is clinically important to ensure appropriate management. Wilms' tumour-1 (WT1) and Ca125 are frequently expressed in serous papillary carcinomas, and uncommonly in unselected mammary carcinomas. One previous study found Ca125 expression in 69% of invasive micropapillary carcinomas. The aim was to assess the frequency of expression of WT1 and Ca125 in invasive micropapillary carcinoma.
Twenty-five of 34 invasive micropapillary carcinomas showed no nuclear expression of WT1. The remaining nine tumours showed weak to moderate immunoreactivity in 1-10% of nuclei. Six of these nine tumours also contained ductal carcinoma in situ, which expressed WT1 in five of the six. Membranous or cytoplasmic expression of Ca125 was found in seven tumours.
Nuclear WT1 expression is present in a minority of invasive micropapillary carcinomas and, when present, expression is focal. The frequency of expression of Ca125 was similar to the results in unselected mammary carcinoma. Thus, these markers are useful members of the immunohistochemical panel for the distinction of mammary invasive micropapillary carcinoma from ovarian serous papillary carcinoma.
Histopathology 01/2008; 51(6):824-8. · 3.08 Impact Factor
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ABSTRACT: Gastrointestinal stromal tumors (GISTs) are characterized by overexpression and mutations of c-Kit. Approximately 80% of c-Kit mutations occur in exon 11, being a response factor to imatinib (Gleevec) therapy. 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 51 mesenchymal tumors. We identified c-Kit mutations in 61% of GIST cases, in accordance with previously published ranges (30-90%). Nearly 95% (19/20) of c-kit-mutant tumors carried exon 11 mutations. Mutation analysis is possible in FNA cell blocks and can assist in the diagnosis and therapeutic decisions in GIST cases.
Minerva medica 09/2007; 98(4):385-8. · 0.90 Impact Factor
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ABSTRACT: The authors evaluated the accuracy of the fine needle aspiration cytology technique in the diagnosis of 77 canine mammary gland tumours using the same cytological and histological criteria currently applied to the diagnosis of human breast cancer.
The study was performed in 73 pure or mixed-breed female dogs submitted to surgical resections of 'mammary tumours'. All cytological smears were stained by routine May-Grunwald-Giemsa and Papanicolaou stains.
We obtained a correct cyto-histological correlation in 52/77 cases (67.5%) when all cytopathological examinations were considered, and in 52/56 cases (92.9%) when the inconclusive cases were excluded from the analysis.
Our results demonstrate that, because of the similarity of the cytological findings in the human and canine mammary gland tumours, it is possible to use the same cytological criteria applied in human pathology for the diagnosis of canine mammary gland tumours.
Cytopathology 07/2007; 18(3):191-6. · 1.59 Impact Factor
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N C Turner,
J S Reis-Filho,
A M Russell,
R J Springall,
K Ryder,
D Steele,
K Savage,
C E Gillett, F C Schmitt,
A Ashworth,
A N Tutt
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ABSTRACT: Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells. Breast cancers arising in carriers of germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers. We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age- and grade-matched controls, for downregulation of BRCA1. Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P=0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P=0.008). ID4, a negative regulator of BRCA1, was expressed at 9.1-fold higher levels in basal-like breast cancer (P<0.0001), suggesting a potential mechanism of BRCA1 downregulation. BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype. Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls (P<0.0001). The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer.
Oncogene 03/2007; 26(14):2126-32. · 6.37 Impact Factor
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J S Reis-Filho,
C Pinheiro,
M B K Lambros,
F Milanezi,
S Carvalho,
K Savage,
P T Simpson,
C Jones,
S Swift,
A Mackay,
R M Reis,
J L Hornick,
E M Pereira,
F Baltazar,
C D M Fletcher,
A Ashworth,
S R Lakhani, F C Schmitt
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ABSTRACT: Metaplastic breast carcinomas are reported to harbour epidermal growth factor receptor (EGFR) overexpression in up to 80% of the cases, but EGFR gene amplification is the underlying genetic mechanism in around one-third of these. In this study, EGFR gene amplification as defined by chromogenic in situ hybridization and protein overexpression was examined in a cohort of 47 metaplastic breast carcinomas. Furthermore, the presence of activating EGFR mutations in exons 18, 19, 20, and 21 was investigated. Thirty-two cases showed EGFR overexpression and of these, 11 (34%) harboured EGFR gene amplification. In addition, EGFR amplification showed a statistically significant association with EGFR overexpression (p < 0.0094) and was restricted to carcinomas with homologous metaplasia. Ten cases, five with and five without EGFR amplification, were subjected to microarray-based CGH, which demonstrated that EGFR copy number gain may occur by amplification of a discrete genomic region or by gains of the short arm of chromosome 7 with a breakpoint near the EGFR gene locus, the minimal region of amplification mapping to EGFR, LANCL2, and SEC61G. No activating EGFR mutations were identified, suggesting that this is unlikely to be a common alternative underlying genetic mechanism for EGFR expression in metaplastic breast carcinomas. Given that metaplastic breast carcinomas are resistant to conventional chemotherapy or hormone therapy regimens and that tumours with EGFR amplification are reported to be sensitive to EGFR tyrosine kinase inhibitors, these findings indicate that further studies are warranted to explore EGFR tyrosine kinase inhibitors as potential therapeutic agents for metaplastic breast carcinomas harbouring amplification of 7p11.2.
The Journal of Pathology 08/2006; 209(4):445-53. · 6.32 Impact Factor
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ABSTRACT: Recently, an immunohistochemical panel comprising antibodies against HER2, oestrogen receptor (ER), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6 was reported to identify basal-like breast carcinomas, as defined by cDNA microarrays. Our aim was to analyse a series of metaplastic breast carcinomas (MBCs) using this panel plus two other basal markers (CK14 and p63) and progesterone receptor (PR), to define how frequently MBCs show a basal-like immunophenotype.
Sixty-five cases were retrieved from the pathology archives of the authors' institutions and reviewed by three of the authors. Immunohistochemistry with antibodies for HER2, ER, EGFR, CK5/6, CK14 and p63 was performed according to standard methods. All but six cases (91%) showed the typical immunoprofile of basal-like tumours (ER- and HER2-, EGFR+ and/or CK5/6+). When CK14 and p63 were added to the panel, two additional cases could be classified as basal-like. The majority of MBCs lacked PR, except 4/19 (21%) carcinomas with squamous metaplasia.
Our results demonstrate that MBCs show a basal-like phenotype, regardless of the type of metaplastic elements. Moreover, as these neoplasms frequently overexpress EGFR (57%), patients with MBC may benefit from treatment with anti-EGFR drugs.
Histopathology 08/2006; 49(1):10-21. · 3.08 Impact Factor
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ABSTRACT: Hybrid capture is an easy and highly sensitive technique for screening population due to its capacity to detect malignant and premalignant lesions of the cervix. To evaluate its sensitivity, we investigated the frequency of high-risk human papillomavirus (HPV) infection and its correlation with glandular malignant lesions, analyzing a total of 113 cases of adenocarcinomas and related lesions. High-risk HPV was investigated using a hybrid capture II (HC2) assay. Samples were collected in two different ways: either brushed directly from surgical specimens before fixation or collected from the patients. We also investigated the frequency of HPV in squamous malignant lesions, 65 squamous cell carcinomas (SCC) and 66 in situ squamous cell carcinomas (ISSCC), to compare the occurrence of HPV for these lesions. The 113 glandular lesions comprised 62 invasive adenocarcinomas (IAC), 8 in situ adenocarcinomas (ISAC), 26 IAC plus SCC, and 17 adenosquamous cells carcinomas (ASCC). The HPV-positive reactions were as follows: 51 (82.2%) in IAC, 8 (100%) in ISAC, 25 (96.1%) in IAC plus SCC, and 14 (82.3%) in ASCC. HC2-positive results in the squamous malignant lesions were as follows: 58 of 63 (89.0%) for SCC and 94 of 103 (91.2%) for ISSCC. High-risk HPV infection was quite similar for glandular and pure squamous invasive malignant lesions, 82.2% and 89.0%, respectively, indicating that high-risk HPV is also highly prevalent in glandular lesions. Although hybrid capture proved to be an excellent adjunctive technique, we do not believe its results merit replacing the Pap smear as a screening tool.
International Journal of Gynecological Cancer 02/2006; 16(2):586 - 590. · 1.65 Impact Factor
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Revista Clínica Española 02/2006; 206(1):60-1; author reply 61. · 2.01 Impact Factor
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ABSTRACT: To study P-cadherin aberrant expression as a possible marker for cervical adenocarcinomas in cytological samples.
We studied P-cadherin immunoexpression in liquid-based cervical cytology samples of biopsy-proven cervical lesions.
We found a statistically significant correlation between P-cadherin expression and a cytological diagnosis of malignancy, either glandular or squamous (P < 0.0001). Twenty-two of 33 malignant cases showed P-cadherin membrane staining. None of the 30 benign cases tested showed membrane staining, but three of them displayed an aberrant nuclear P-cadherin expression.
We concluded that P-cadherin can be used to discriminate between malignant and benign cervical cytological specimens, but not to discriminate glandular from squamous lesions.
Cytopathology 04/2005; 16(2):88-93. · 1.59 Impact Factor
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ABSTRACT: The objective of the present investigation was to study the expression of c-erbB-2 and MIB-1 and try to associate them with morphological features of the cell such as nuclear pleomorphism, mitotic count and histological grade in a series of 70 canine mammary gland tumors, 22 of them benign and 48 malignant. Tumors were collected at the Veterinary Hospital of UFMG (Brazil) and the Veterinary Faculty of Porto University (Portugal). c-erbB-2 expression was determined according to the guidelines provided by the manufacturer of the HercepTest system and nuclear pleomorphism, mitotic count and histological grade according the Elston and Ellis grading system. The HercepTest is the FDA-approved in vitro diagnostic test marketed by Dako. It is a semi-quantitative immunohistochemical assay used to determine overexpression of HER2 protein (human epidermal growth factor receptor) in breast cancer tissue. MIB-1 expression was also evaluated in 28 malignant tumors. Seventeen (35.4%) of the malignant tumors were positive for c-erbB-2 expression, which was positively associated with nuclear pleomorphism (P < 0.0001), histological grade (P = 0.0017) and mitotic count (P < 0.05). Nuclear pleomorphism also showed a positive association with MIB-1 index (P < 0.0001). These results suggest that some of the biological and morphological characteristics of the tumor are associated in canine mammary gland tumors, as also reported for human breast cancer. It was also possible to show that the immunoexpression of c-erbB-2 can be a factor in mammary carcinogenesis. This fact opens the possibility of using anti-c-erbB-2 antibodies in the treatment of canine mammary tumors.
Brazilian Journal of Medical and Biological Research 12/2004; 37(11):1673-81. · 1.13 Impact Factor
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ABSTRACT: To study the immunoexpression and mutational status of c-KIT and PDGFRA in a series of benign and malignant phyllodes tumours of the breast.
Nineteen phyllodes tumours (13 benign and six malignant) were analysed by immunohistochemistry for the expression of c-KIT and PDGFRA. Direct sequencing of exons 9, 11, 13, and 17 of the c-KIT gene and exons 12 and 18 of PDGFRA was performed to check the mutational status of these two genes.
c-KIT expression was found in 12 of the 19 cases (six of the 13 benign cases and all six malignant ones) and PDGFRA expression was seen in two of the 19 cases (one benign and one malignant case); the 2415 C>T alteration in exon 17 of the c-KIT gene was found in two cases (both benign); the intronic insertion IVS17-50insT and the 2866 G>T alteration in the coding region of exon 18 of the PDGFRA gene were also found in two cases (one malignant and one benign). However, the activating mutations described for these genes in gastrointestinal stromal tumours were not present.
c-KIT expression is a frequent finding in phyllodes tumours, particularly in malignant cases; however, no activating mutations similar to those described for gastrointestinal stromal tumours were found. The PDGFRA does not seem to be an alternative pathway to tumour development in phyllodes tumours because neither expression nor activating mutations were noteworthy.
Journal of Clinical Pathology 10/2004; 57(10):1075-9. · 2.31 Impact Factor
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ABSTRACT: To investigate the possible role of E-cadherin in canine mammary tumours 20 benign and 40 malignant tumours were evaluated by immunohistochemistry in formalin-fixed paraffin wax-embedded samples. In all the benign tumours, E-cadherin was strongly expressed at the intercellular borders of epithelial cells, but it was less strongly expressed in 17 (43 per cent) of the malignant tumours. Furthermore, poorly differentiated carcinomas were less immunoreactive for E-cadherin than moderately and well differentiated carcinomas.
The Veterinary record 06/2003; 152(20):621-4. · 1.25 Impact Factor
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Histopathology 02/2003; 42(1):94-5. · 3.08 Impact Factor
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ABSTRACT: One of the limitations of fine needle aspiration biopsy (FNAB) of the breast is in distinguishing invasive carcinoma (IDC) from ductal carcinoma in situ (DCIS). It has been proposed that the presence of myoepithelial cells overlying epithelial malignant cell clusters suggests DCIS. However, the recognition of myoepithelial cells in aspirates may be difficult. The aim of this study was to investigate a new nuclear myoepithelial cell marker, p63, a p53 homologue nuclear transcription factor, in a series of breast FNABs in an attempt to distinguish IDC from DCIS.
Papanicolaou stained smears from eight cases of pure DCIS and 15 cases of pure IDC with a histologically confirmed diagnosis were submitted to immunocytochemical analysis using the antibody 4A4 against p63. Two pathologists evaluated the presence of p63 positive cells overlying malignant cell clusters and admixed with malignant cells. The frequency of p63 positive cells in DCIS and IDC was compared using Fisher's exact test.
p63 consistently stained the nuclei of myoepithelial cells, either overlying malignant cell clusters and/or admixed with malignant cells. p63 positive myoepithelial cells were seen in all DCIS cases and in nine of the 15 cases of IDC (p = 0.0375). In eight cases (three DCIS and five IDC), scattered p63+ epithelial malignant cells were seen.
Although p63 positive myoepithelial cells are found more frequently in DCIS cases, their presence cannot be used as a criterion to rule out invasion in breast FNABs because they are present in up to 60% of invasive cases.
Journal of Clinical Pathology 01/2003; 55(12):936-9. · 2.31 Impact Factor
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ABSTRACT: Foi elaborado um protocolo para exame anatomopatológico de tumores de mama em cães, constituído de três partes: requisição, exame clínico e laudo histopatológico. O exame clínico contém dados sobre a descrição macroscópica da lesão. O laudo histopatológico constituiu-se de campos para descrição microscópica pormenorizada das lesões e classificação da principal lesão observada. A elaboração do protocolo tem como objetivo estabelecer critérios para estudos e pesquisas sobre neoplasias mamárias em animais e auxiliar no diagnóstico e prognóstico de lesões mamárias.
Arquivo Brasileiro de Medicina Veterinária e Zootecnia. 01/2003;
