Janina Kulka | Semmelweis University (original) (raw)

Papers by Janina Kulka

Research paper thumbnail of ONEST (Observers Needed to Evaluate Subjective Tests) Analysis of Stromal Tumour-Infiltrating Lymphocytes (sTILs) in Breast Cancer and Its Limitations

Cancers

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopath... more Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers ...

Research paper thumbnail of Klinikopatológiai szemléletű emlőrákkutatások

In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis U... more In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis University had been mostly linked to the 2nd Department of Pathology. Nowadays, following the rapidly improving treatment modalities in breast cancer there is an increasing need for defining new predictive and prognostic markers. The modern molecular pathological approach helps tremendously in mapping the biological behavior of individual cases of breast cancers and meanwhile, it is one of the prerequisites of a more efficient treatment both in neoadjuvant and adjuvant settings, as well as in metastatic disease. We provide a brief review of the relevant results we have obtained in breast cancer research between 2000 and 2015

Research paper thumbnail of A progeszteronreceptor kifejeződésének kórjóslati értéke a HER2-negatív Luminalis-B altípusú emlődaganatokban

A szerzők egyenlő mértékben járultak hozzá a közleményhez.

Research paper thumbnail of Investigating the Prognostic Relevance of Tumor Immune Microenvironment and Immune Gene Assembly in Breast Carcinoma Subtypes

Cancers

We hypothesized that different BC subtypes are characterized by spatially distinct tumor immune m... more We hypothesized that different BC subtypes are characterized by spatially distinct tumor immune microenvironment (TIME) and that immune gene assembly of metastatic (Met) and non-metastatic (Ctrl) BCs vary across subtypes. Peritumoral, stromal and intratumoral TIL was assessed on 309 BC cases. Hot, cold and immune-excluded groups were defined, and the prognostic role of this classification was assessed. CD4+/CD8+ positivity was analyzed in 75 cases in four systematically predefined tumor regions. Immune gene expression of Met and Ctrl HER2-negative BCs was compared by using NanoString nCounter technology. The amount of TIL infiltration varied greatly within all BC subtypes. Two-third of the cases were cold tumors with no significant survival difference compared to hot tumors. A lower CD4+/CD8+ ratio at the stromal internal tumor region was significantly associated with longer distant metastasis-free survival. The differentially expressed immune genes between Met and Ctrl varied acros...

Research paper thumbnail of Mucocele-like Lesion

Research paper thumbnail of Pseudoangiomatous Stromal Hyperplasia

Encyclopedia of Pathology, 2019

Research paper thumbnail of Invasive Micropapillary Carcinoma

Research paper thumbnail of s response to reviews Title : The potential prognostic value of connexin 26 and 46 expression in neoadjuvant-treated breast cancer

Research paper thumbnail of Complexity of the response evaluation during primary systemic therapy of breast cancer

Journal of Clinical Oncology, 2014

ABSTRACT Precise and standardized response evaluation enables clinicians to tailor primary system... more ABSTRACT Precise and standardized response evaluation enables clinicians to tailor primary systemic therapy (PST). Breast cancer patients underwent (18)F-fluoro-deoxy-glucose positron emission tomography and computerized tomography (FDG-PET/CT) before and after PST. Response was assessed by maximal Standardized Uptake Value (SUVmax); morphological changes and Ki-67 labeling index (LI). In parallel response assessment was performed by European Organization for Research and Treatment of Cancer (EORTC); PET Response Criteria in Solid Tumors (PERCIST); World Health Organization (WHO); Response Evaluation Criteria in Solid Tumors (RECIST); Chevallier and Sataloff classifications, and by a novel Ki-67 score. Accuracy of different scoring systems was evaluated. In the 42 enrolled patients, SUVmax, size, and Ki-67 LI decreased significantly on PST. Significant differences between patients with versus those without pathological complete response were observed for pre-treatment Ki-67 LI and SUVmax and for post-treatment Ki-67 LI, SUVmax and size. Change in Ki-67 LI was the best predictor of pathological complete response. Correlation patterns of the directly measured metabolic, morphological, and proliferation responses differed from those determined by scoring methods. During PST, FDG-PET/CT enables for robust assessment of treatment efficacy, but more reliable scoring systems are still needed for more precise response evaluation. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Research paper thumbnail of Comparison of Predictive Immunohistochemical Marker Expression of Primary Breast Cancer and Paired Distant Metastasis using Surgical Material: A Practice-Based Study

Journal of Histochemistry & Cytochemistry, 2016

Parallel studies of primary breast carcinomas and corresponding distant metastases samples reveal... more Parallel studies of primary breast carcinomas and corresponding distant metastases samples reveal considerable differences. Our aim was to highlight this issue from another perspective and provide further data based on 98 patient samples: 69 primary breast carcinoma and 85 distant metastases from bone, central nervous system (CNS) and lung (56 paired). Two independent series of immunohistochemical reactions with different antibodies for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (Her2), along with HER2 fluroscence in situ hybridization (FISH) were performed on tissue microarrays to classify breast carcinoma and distant metastases samples into Luminal A, Luminal B-proliferating, Luminal B-HER2+, HER2+ and triple negative (TNBC) surrogate breast cancer groups. Correlation and agreement between the two assessments of ER and PgR were fair-to-moderate, and almost perfect for HER2 and Ki67. There was 40% discordance concerning immunoph...

Research paper thumbnail of Morphological and pathological response in primary systemic therapy of patients with breast cancer and the prediction of disease free survival: a single center observational study

Croatian Medical Journal, 2016

To identify breast cancer subtypes likely to respond to primary systemic therapy (PST or neoadjuv... more To identify breast cancer subtypes likely to respond to primary systemic therapy (PST or neoadjuvant therapy) and to assess the accuracy of physical examination (PE) and breast ultrasonography (US) in evaluating and predicting residual size of breast carcinoma following PST. Methods 116 patients who received at least two cycles of PST between 1998 and 2009 were selected from a prospectively collected clinical database. Radiological assessment was done by mammography and US. Prior to PST, tumors were subclassified according to core biopsy (NCB) and/or fine-needle aspiration-based immunohistochemical profiles of NCB. Pathological response rates were assessed following the surgeries by using Chevallier classification. Tumor measurements by PE and US were obtained before and after PST. Different clinical measurements were compared with histological findings. Disease-free survival (DFS) was assessed. Results Pathological complete remission (pCR = Chevallier I/II) was observed in 25 patients (21.5%), 44% of whom had triple negative histology, 28% Her2 positive and 76% had high-grade tumor. Of 116 patients, 24 received taxanebased PST, 48 combined taxane + anthracycline treatment, 8 trastuzumab combinations, 21 anthracycline-based treatments, and 15 other treatments. In the taxane treated group, the pCR rate was 30%, in the taxane + anthracycline group 25%, in the anthracycline group 9.5%, and in trastuzumab group 37.5%. After PST, PE and US were both significantly associated with pathology (P < 0.001 and P = 0.004, respectively). Concerning OS, significant difference was observed between the Chevallier III and IV group (P = 0.031) in favor of Chevallier III group. In the pCR group, fewer events were observed during the follow-up period. Conclusions Our results show that even limited, routinely used immunohistochemical profiling of tumors can predict the likelihood of pCR to PST: patients with triple negative and Her2-positive cancers are more likely to achieve pCR to PST. Also, PE is better correlated with pathological findings than US.

Research paper thumbnail of Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers

Virchows Archiv, 2016

Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and di... more Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100 % agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

Research paper thumbnail of Response evaluation after primary systemic therapy of Her2 positive breast cancer – an observational cross-sectional study

Croatian Medical Journal, 2015

Aim To evaluate (I) trastuzumab-containing primary systemic therapy (PST) in human epidermal grow... more Aim To evaluate (I) trastuzumab-containing primary systemic therapy (PST) in human epidermal growth factor receptor 2 (Her2) overexpressing breast carcinomas.; (II) compare the patients who achieved and those who did not achieve pathological complete remission (pCR), and (III) analyze the accuracy of different clinical-imaging modalities in tumor response monitoring. Methods 188 patients who received PST between 2008 and 2014 were reviewed and 43 Her2 overexpressing breast cancer patients (28 Luminal B/Her2-positive and 15 Her2-positive) were enrolled. 26 patients received mostly taxane-based PST without trastuzumab (Group 1) and 17 patients received trastuzumab-containing PST (Group 2). We compared the concordance between pCR and complete remission (CR) defined by breast-ultrasound, CR defined by standard 18F-fluoro-deoxy-glucose positron emission tomography and computerized tomography (FDG-PET/CT) criteria (Method 1) and CR defined by a novel, breast cancer specific FDG-PET/CT criteria (Method 2). Sensitivity (sens), specificity (spec), and positive (PPV) and negative predictive values (NPV) were calculated. Results Ten patients (38.5%) in Group 1 and eight (47%) in Group 2 achieved pCR. pCR was significantly more frequent in Her2-positive than in Luminal B/Her2-positive tumors in both Group 1: (P = 0.043) and Group 2: (P = 0.029). PET/CT evaluated by the breast cancer specific criteria (Method 2) differentiated pCR from non-pCR more accurately in both groups (Group 1:

Research paper thumbnail of Pathological non-response to chemotherapy in a neoadjuvant setting of breast cancer: an inter-institutional study

Breast Cancer Research and Treatment, 2014

To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the a... more To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the adjuvant setting. Sixteen pathologists of the European Working Group for Breast Screening Pathology reviewed the core biopsies of breast cancers treated with NAC and recorded the clinico-pathological findings (histological type and grade; estrogen, progesterone receptors, and HER2 status; Ki67; mitotic count; tumor-infiltrating lymphocytes; necrosis) and data regarding the pathological response in corresponding surgical resection specimens. Analyses were carried out in a cohort of 490 cases by comparing the groups of patients showing pathological complete response (pCR) and partial response (pPR) with the group of non-responders (pathological non-response: pNR). Among other parameters, the lobular histotype and the absence of inflammation were significantly more common in pNR (p \ 0.001). By ROC curve analyses, cutoff values of 9 mitosis/2 mm 2 and 18 % of Ki67-positive cells best discriminated the pNR and pCR ? pPR categories (p = 0.018 and \ 0.001, respectively). By multivariable analysis, only the cutoff value of 9 mitosis discriminated the different response categories (p = 0.036) in the entire cohort. In the Luminal B/HER2-subgroup, a mitotic count \9, although not statistically significant, showed an OR of 2.7 of pNR. A lobular histotype and the absence of inflammation were independent predictors of pNR (p = 0.024 and \0.001, respectively). Classical morphological parameters, such as lobular histotype and Electronic supplementary material The online version of this article (

Research paper thumbnail of Claudin-1, -3 and -4 proteins and mRNA expression in benign and malignant breast lesions: a research study

Introduction We compared levels of protein and mRNA expression of three members of the claudin (C... more Introduction We compared levels of protein and mRNA expression of three members of the claudin (CLDN) family in malignant breast tumours and benign lesions. Methods Altogether, 56 sections from 52 surgically resected breast specimens were analyzed for CLDN1, CLDN3 and CLDN4 expression by immunohistochemistry. mRNA was also analyzed using real-time PCR in 17 of the 52 cases. Results CLDNs were rarely observed exclusively at tight junction structures. CLDN1 was present in the membrane of normal duct cells and in some of the cell membranes from ductal carcinoma in situ, and was frequently observed in eight out of nine areas of apocrine metaplasia, whereas invasive tumours were negative for CLDN1 or it was present in a scattered distribution among such tumour cells (in 36/39 malignant tumours). CLDN3 was present in 49 of the 56 sections and CLDN4 was present in all 56 tissue sections. However, CLDN4 was highly positive in normal epithelial cells and was decreased or absent in 17 out of 21 ductal carcinoma grade 1, in special types of breast carcinoma (mucinous, papillary, tubular) and in areas of apocrine metaplasia. CLDN1 mRNA was downregulated by 12-fold in the sample (tumour) group as compared with the control group using GAPDH as the reference gene. CLDN3 and CLDN4 mRNA exhibited no difference in expression between invasive tumours and surrounding tissue. Conclusions The significant loss of CLDN1 protein in breast cancer cells suggests that CLDN1 may play a role in invasion and metastasis. The loss of CLDN4 expression in areas of apocrine metaplasia and in the majority of grade 1 invasive carcinomas also suggests a particular role for this protein in mammary glandular cell differentiation and carcinogenesis.

Research paper thumbnail of Sentinel lymph node biopsy in staging small (up to 15 mm) breast carcinomas. Results from a European multi-institutional study

Pathology & Oncology Research, 2007

Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early b... more Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated.

Research paper thumbnail of Correlations of Differentially Expressed Gap Junction Connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with Breast Cancer Progression and Prognosis

PLoS ONE, 2014

Background and Aims: Connexins and their cell membrane channels contribute to the control of cell... more Background and Aims: Connexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers. Materials and Methods: Meta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models. Results: The expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo-and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other's prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively. Conclusion: Differential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers.

Research paper thumbnail of In breast cancer patients sentinel lymph node metastasis characteristics predict further axillary involvement

Virchows Archiv, 2014

The aim of the study was to correlate various primary tumor characteristics with lymph node statu... more The aim of the study was to correlate various primary tumor characteristics with lymph node status, to examine sentinel lymph node (SLN) metastasis size and non-SLN axillary involvement, to look for a cut-off size/number value possibly predicting additional axillary involvement with more accuracy and to examine the relationship of SLN metastasis size to overall survival. Of 301 patients who underwent SLN biopsy, 75 had positive SLNs. The size of the metastases was measured. For different size categories, association with the prevalence of non-SLN metastases was assessed. Associations between metastasis size and tumor characteristics and overall survival (OS) were studied. The prevalence of axillary lymph node (ALN) involvement was not significantly different between cases with micrometastasis or macrometastasis in SLNs (p = 0.124). However, for metastases larger than 6, 7, and 8 mm, the prevalence of ALN involvement was significantly higher (p = 0.046, 0.022, and 0.025). OS was significantly lower in SLN-positive than in SLN-negative cases (p = 0.0375). Primary tumor size larger than 20 mm was associated with a significantly higher incidence of SLN metastasis (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and primary tumor size over 26 mm was associated with additional positive non-SLN (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Higher mitotic index (≥ 7) in primary tumors was significantly (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) associated with ALN involvement in SLN-positive cases, whereas higher Ki67 labeling index was not significantly correlated with SLN or ALN involvement. Lymphovascular invasion (LVI) in primary tumors was significantly correlated with SLN positivity (p…

Research paper thumbnail of The expression of five different claudins in invasive breast carcinomas: Comparison of pT1pN1 and pT1pN0 tumors

Pathology - Research and Practice, 2005

The evaluation of the role of claudins (CLDNs) in breast carcinogenesis has recently begun. We in... more The evaluation of the role of claudins (CLDNs) in breast carcinogenesis has recently begun. We investigated the expression of CLDNs 1, 2, 3, 4, and 7 in pT1pN0 and pT1pN1 invasive ductal breast carcinomas. Tissue arrays of 30-30 pT1pN0 and pT1pN1 invasive ductal breast carcinomas of different grades were constructed, and the expression of CLDN 1, 2, 3, 4, and 7 proteins was analyzed using standard and immunofluorescent immunohistochemistry. The results were evaluated by light and confocal microscopy. Regarding CLDN 1, 4, and 7 expressions, differences were noted between normal and tumor cells and also between tumors of different grades, while no remarkable differences were noted between pT1pN0 and pT1pN1 tumors. CLDNs 1 and 7 were found to be downregulated in tumor cells compared to the normal epithelium, while CLDN 4 expression was decreased in grade 1 tumors. CLDN 7 protein was abundant in normal epithelia, and the staining decreased in grade 3 tumors. There were no differences between normal and neoplastic cells regarding CLDN 2 and 3 expressions. As a preliminary result, our observations suggest that the analyzed CLDNs do not promote tumor metastasis. On the basis of our findings, it seems that CLDN 1, CLDN 4, and CLDN 7 may rather have an important role in tumorigenesis or in cell-to-cell adhesion.

Research paper thumbnail of Expression of Claudin-1, -2, -3, -4, -5 and -7 Proteins in Benign and Malignant Canine Mammary Gland Epithelial Tumours

Journal of Comparative Pathology, 2008

Claudins are tight junction proteins expressed by epithelial and endothelial cells. The present s... more Claudins are tight junction proteins expressed by epithelial and endothelial cells. The present study has evaluated the expression of claudin-1,-2,-3,-4,-5 and-7 in 115 hyperplastic and neoplastic lesions of the canine mammary gland and compared this expression with that of normal mammary epithelium. The lesions studied included lobular hyperplasia (n ¼ 15), simple adenoma (n ¼ 20), non-infiltrating carcinoma in situ (n ¼ 20) and infiltrating carcinomas of histological grades I, II and III (n ¼ 20 of each). There was strong expression of claudin-1,-3,-4,-5 and-7 by epithelia within examples of lobular hyperplasia and simple adenoma, and strong expression of claudin-3 and-4 by non-infiltrating carcinomas and all three grades of infiltrating carcinoma. By contrast, there was reduced expression of claudin-5 and-7 by non-infiltrating and infiltrating carcinomas and the expression of these two molecules was inversely correlated with histological grade. Claudin-1 was expressed focally within carcinoma in situ, but this molecule was not detected in any invasive carcinoma. Claudin-2 was weakly expressed within areas of lobular hyperplasia and by simple adenomas, but was not expressed by any carcinoma cells. These results suggest that loss or reduction of expression of claudin-1,-2,-5 and-7 may lead to cellular disorientation, detachment and invasion in canine mammary neoplasia.

Research paper thumbnail of ONEST (Observers Needed to Evaluate Subjective Tests) Analysis of Stromal Tumour-Infiltrating Lymphocytes (sTILs) in Breast Cancer and Its Limitations

Cancers

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopath... more Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers ...

Research paper thumbnail of Klinikopatológiai szemléletű emlőrákkutatások

In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis U... more In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis University had been mostly linked to the 2nd Department of Pathology. Nowadays, following the rapidly improving treatment modalities in breast cancer there is an increasing need for defining new predictive and prognostic markers. The modern molecular pathological approach helps tremendously in mapping the biological behavior of individual cases of breast cancers and meanwhile, it is one of the prerequisites of a more efficient treatment both in neoadjuvant and adjuvant settings, as well as in metastatic disease. We provide a brief review of the relevant results we have obtained in breast cancer research between 2000 and 2015

Research paper thumbnail of A progeszteronreceptor kifejeződésének kórjóslati értéke a HER2-negatív Luminalis-B altípusú emlődaganatokban

A szerzők egyenlő mértékben járultak hozzá a közleményhez.

Research paper thumbnail of Investigating the Prognostic Relevance of Tumor Immune Microenvironment and Immune Gene Assembly in Breast Carcinoma Subtypes

Cancers

We hypothesized that different BC subtypes are characterized by spatially distinct tumor immune m... more We hypothesized that different BC subtypes are characterized by spatially distinct tumor immune microenvironment (TIME) and that immune gene assembly of metastatic (Met) and non-metastatic (Ctrl) BCs vary across subtypes. Peritumoral, stromal and intratumoral TIL was assessed on 309 BC cases. Hot, cold and immune-excluded groups were defined, and the prognostic role of this classification was assessed. CD4+/CD8+ positivity was analyzed in 75 cases in four systematically predefined tumor regions. Immune gene expression of Met and Ctrl HER2-negative BCs was compared by using NanoString nCounter technology. The amount of TIL infiltration varied greatly within all BC subtypes. Two-third of the cases were cold tumors with no significant survival difference compared to hot tumors. A lower CD4+/CD8+ ratio at the stromal internal tumor region was significantly associated with longer distant metastasis-free survival. The differentially expressed immune genes between Met and Ctrl varied acros...

Research paper thumbnail of Mucocele-like Lesion

Research paper thumbnail of Pseudoangiomatous Stromal Hyperplasia

Encyclopedia of Pathology, 2019

Research paper thumbnail of Invasive Micropapillary Carcinoma

Research paper thumbnail of s response to reviews Title : The potential prognostic value of connexin 26 and 46 expression in neoadjuvant-treated breast cancer

Research paper thumbnail of Complexity of the response evaluation during primary systemic therapy of breast cancer

Journal of Clinical Oncology, 2014

ABSTRACT Precise and standardized response evaluation enables clinicians to tailor primary system... more ABSTRACT Precise and standardized response evaluation enables clinicians to tailor primary systemic therapy (PST). Breast cancer patients underwent (18)F-fluoro-deoxy-glucose positron emission tomography and computerized tomography (FDG-PET/CT) before and after PST. Response was assessed by maximal Standardized Uptake Value (SUVmax); morphological changes and Ki-67 labeling index (LI). In parallel response assessment was performed by European Organization for Research and Treatment of Cancer (EORTC); PET Response Criteria in Solid Tumors (PERCIST); World Health Organization (WHO); Response Evaluation Criteria in Solid Tumors (RECIST); Chevallier and Sataloff classifications, and by a novel Ki-67 score. Accuracy of different scoring systems was evaluated. In the 42 enrolled patients, SUVmax, size, and Ki-67 LI decreased significantly on PST. Significant differences between patients with versus those without pathological complete response were observed for pre-treatment Ki-67 LI and SUVmax and for post-treatment Ki-67 LI, SUVmax and size. Change in Ki-67 LI was the best predictor of pathological complete response. Correlation patterns of the directly measured metabolic, morphological, and proliferation responses differed from those determined by scoring methods. During PST, FDG-PET/CT enables for robust assessment of treatment efficacy, but more reliable scoring systems are still needed for more precise response evaluation. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Research paper thumbnail of Comparison of Predictive Immunohistochemical Marker Expression of Primary Breast Cancer and Paired Distant Metastasis using Surgical Material: A Practice-Based Study

Journal of Histochemistry & Cytochemistry, 2016

Parallel studies of primary breast carcinomas and corresponding distant metastases samples reveal... more Parallel studies of primary breast carcinomas and corresponding distant metastases samples reveal considerable differences. Our aim was to highlight this issue from another perspective and provide further data based on 98 patient samples: 69 primary breast carcinoma and 85 distant metastases from bone, central nervous system (CNS) and lung (56 paired). Two independent series of immunohistochemical reactions with different antibodies for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (Her2), along with HER2 fluroscence in situ hybridization (FISH) were performed on tissue microarrays to classify breast carcinoma and distant metastases samples into Luminal A, Luminal B-proliferating, Luminal B-HER2+, HER2+ and triple negative (TNBC) surrogate breast cancer groups. Correlation and agreement between the two assessments of ER and PgR were fair-to-moderate, and almost perfect for HER2 and Ki67. There was 40% discordance concerning immunoph...

Research paper thumbnail of Morphological and pathological response in primary systemic therapy of patients with breast cancer and the prediction of disease free survival: a single center observational study

Croatian Medical Journal, 2016

To identify breast cancer subtypes likely to respond to primary systemic therapy (PST or neoadjuv... more To identify breast cancer subtypes likely to respond to primary systemic therapy (PST or neoadjuvant therapy) and to assess the accuracy of physical examination (PE) and breast ultrasonography (US) in evaluating and predicting residual size of breast carcinoma following PST. Methods 116 patients who received at least two cycles of PST between 1998 and 2009 were selected from a prospectively collected clinical database. Radiological assessment was done by mammography and US. Prior to PST, tumors were subclassified according to core biopsy (NCB) and/or fine-needle aspiration-based immunohistochemical profiles of NCB. Pathological response rates were assessed following the surgeries by using Chevallier classification. Tumor measurements by PE and US were obtained before and after PST. Different clinical measurements were compared with histological findings. Disease-free survival (DFS) was assessed. Results Pathological complete remission (pCR = Chevallier I/II) was observed in 25 patients (21.5%), 44% of whom had triple negative histology, 28% Her2 positive and 76% had high-grade tumor. Of 116 patients, 24 received taxanebased PST, 48 combined taxane + anthracycline treatment, 8 trastuzumab combinations, 21 anthracycline-based treatments, and 15 other treatments. In the taxane treated group, the pCR rate was 30%, in the taxane + anthracycline group 25%, in the anthracycline group 9.5%, and in trastuzumab group 37.5%. After PST, PE and US were both significantly associated with pathology (P < 0.001 and P = 0.004, respectively). Concerning OS, significant difference was observed between the Chevallier III and IV group (P = 0.031) in favor of Chevallier III group. In the pCR group, fewer events were observed during the follow-up period. Conclusions Our results show that even limited, routinely used immunohistochemical profiling of tumors can predict the likelihood of pCR to PST: patients with triple negative and Her2-positive cancers are more likely to achieve pCR to PST. Also, PE is better correlated with pathological findings than US.

Research paper thumbnail of Consistency in recognizing microinvasion in breast carcinomas is improved by immunohistochemistry for myoepithelial markers

Virchows Archiv, 2016

Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and di... more Microinvasion is the smallest morphologically identifiable stage of invasion. Its presence and distinction from in situ carcinoma may have therapeutic implications, and clinical staging also requires the recognition of this phenomenon. Microinvasion is established on the basis of several morphological criteria, which may be difficult and not perfectly reproducible among pathologists. The aim of this study was to assess the consistency of diagnosing microinvasion in the breast on traditional haematoxylin and eosin (HE) stained slides and to evaluate whether immunohistochemistry (IHC) for myoepithelial markers could improve this. Digital images were generated from representative areas of 50 cases stained with HE and IHC for myoepithelial markers. Cases were specifically selected from the spectrum of in situ to microinvasive cancers. Twenty-eight dedicated breast pathologists assessed these cases at different magnifications through a web-based platform in two rounds: first HE only and after a washout period by both HE and IHC. Consistency in the recognition of microinvasion significantly improved with the use of IHC. Concordance rates increased from 0.85 to 0.96, kappa from 0.5 to 0.85, the number of cases with 100 % agreement rose from 9/50 to 25/50 with IHC and the certainty of diagnosis also increased. The use of IHC markedly improves the consistency of identifying microinvasion. This corroborates previous recommendations to use IHC for myoepithelial markers to clarify cases where uncertainty exists about the presence of microinvasion. Microinvasive carcinoma is a rare entity, and seeking a second opinion may avoid overdiagnosis.

Research paper thumbnail of Response evaluation after primary systemic therapy of Her2 positive breast cancer – an observational cross-sectional study

Croatian Medical Journal, 2015

Aim To evaluate (I) trastuzumab-containing primary systemic therapy (PST) in human epidermal grow... more Aim To evaluate (I) trastuzumab-containing primary systemic therapy (PST) in human epidermal growth factor receptor 2 (Her2) overexpressing breast carcinomas.; (II) compare the patients who achieved and those who did not achieve pathological complete remission (pCR), and (III) analyze the accuracy of different clinical-imaging modalities in tumor response monitoring. Methods 188 patients who received PST between 2008 and 2014 were reviewed and 43 Her2 overexpressing breast cancer patients (28 Luminal B/Her2-positive and 15 Her2-positive) were enrolled. 26 patients received mostly taxane-based PST without trastuzumab (Group 1) and 17 patients received trastuzumab-containing PST (Group 2). We compared the concordance between pCR and complete remission (CR) defined by breast-ultrasound, CR defined by standard 18F-fluoro-deoxy-glucose positron emission tomography and computerized tomography (FDG-PET/CT) criteria (Method 1) and CR defined by a novel, breast cancer specific FDG-PET/CT criteria (Method 2). Sensitivity (sens), specificity (spec), and positive (PPV) and negative predictive values (NPV) were calculated. Results Ten patients (38.5%) in Group 1 and eight (47%) in Group 2 achieved pCR. pCR was significantly more frequent in Her2-positive than in Luminal B/Her2-positive tumors in both Group 1: (P = 0.043) and Group 2: (P = 0.029). PET/CT evaluated by the breast cancer specific criteria (Method 2) differentiated pCR from non-pCR more accurately in both groups (Group 1:

Research paper thumbnail of Pathological non-response to chemotherapy in a neoadjuvant setting of breast cancer: an inter-institutional study

Breast Cancer Research and Treatment, 2014

To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the a... more To identify markers of non-response to neoadjuvant chemotherapy (NAC) that could be used in the adjuvant setting. Sixteen pathologists of the European Working Group for Breast Screening Pathology reviewed the core biopsies of breast cancers treated with NAC and recorded the clinico-pathological findings (histological type and grade; estrogen, progesterone receptors, and HER2 status; Ki67; mitotic count; tumor-infiltrating lymphocytes; necrosis) and data regarding the pathological response in corresponding surgical resection specimens. Analyses were carried out in a cohort of 490 cases by comparing the groups of patients showing pathological complete response (pCR) and partial response (pPR) with the group of non-responders (pathological non-response: pNR). Among other parameters, the lobular histotype and the absence of inflammation were significantly more common in pNR (p \ 0.001). By ROC curve analyses, cutoff values of 9 mitosis/2 mm 2 and 18 % of Ki67-positive cells best discriminated the pNR and pCR ? pPR categories (p = 0.018 and \ 0.001, respectively). By multivariable analysis, only the cutoff value of 9 mitosis discriminated the different response categories (p = 0.036) in the entire cohort. In the Luminal B/HER2-subgroup, a mitotic count \9, although not statistically significant, showed an OR of 2.7 of pNR. A lobular histotype and the absence of inflammation were independent predictors of pNR (p = 0.024 and \0.001, respectively). Classical morphological parameters, such as lobular histotype and Electronic supplementary material The online version of this article (

Research paper thumbnail of Claudin-1, -3 and -4 proteins and mRNA expression in benign and malignant breast lesions: a research study

Introduction We compared levels of protein and mRNA expression of three members of the claudin (C... more Introduction We compared levels of protein and mRNA expression of three members of the claudin (CLDN) family in malignant breast tumours and benign lesions. Methods Altogether, 56 sections from 52 surgically resected breast specimens were analyzed for CLDN1, CLDN3 and CLDN4 expression by immunohistochemistry. mRNA was also analyzed using real-time PCR in 17 of the 52 cases. Results CLDNs were rarely observed exclusively at tight junction structures. CLDN1 was present in the membrane of normal duct cells and in some of the cell membranes from ductal carcinoma in situ, and was frequently observed in eight out of nine areas of apocrine metaplasia, whereas invasive tumours were negative for CLDN1 or it was present in a scattered distribution among such tumour cells (in 36/39 malignant tumours). CLDN3 was present in 49 of the 56 sections and CLDN4 was present in all 56 tissue sections. However, CLDN4 was highly positive in normal epithelial cells and was decreased or absent in 17 out of 21 ductal carcinoma grade 1, in special types of breast carcinoma (mucinous, papillary, tubular) and in areas of apocrine metaplasia. CLDN1 mRNA was downregulated by 12-fold in the sample (tumour) group as compared with the control group using GAPDH as the reference gene. CLDN3 and CLDN4 mRNA exhibited no difference in expression between invasive tumours and surrounding tissue. Conclusions The significant loss of CLDN1 protein in breast cancer cells suggests that CLDN1 may play a role in invasion and metastasis. The loss of CLDN4 expression in areas of apocrine metaplasia and in the majority of grade 1 invasive carcinomas also suggests a particular role for this protein in mammary glandular cell differentiation and carcinogenesis.

Research paper thumbnail of Sentinel lymph node biopsy in staging small (up to 15 mm) breast carcinomas. Results from a European multi-institutional study

Pathology & Oncology Research, 2007

Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early b... more Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated.

Research paper thumbnail of Correlations of Differentially Expressed Gap Junction Connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with Breast Cancer Progression and Prognosis

PLoS ONE, 2014

Background and Aims: Connexins and their cell membrane channels contribute to the control of cell... more Background and Aims: Connexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers. Materials and Methods: Meta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models. Results: The expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo-and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other's prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively. Conclusion: Differential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers.

Research paper thumbnail of In breast cancer patients sentinel lymph node metastasis characteristics predict further axillary involvement

Virchows Archiv, 2014

The aim of the study was to correlate various primary tumor characteristics with lymph node statu... more The aim of the study was to correlate various primary tumor characteristics with lymph node status, to examine sentinel lymph node (SLN) metastasis size and non-SLN axillary involvement, to look for a cut-off size/number value possibly predicting additional axillary involvement with more accuracy and to examine the relationship of SLN metastasis size to overall survival. Of 301 patients who underwent SLN biopsy, 75 had positive SLNs. The size of the metastases was measured. For different size categories, association with the prevalence of non-SLN metastases was assessed. Associations between metastasis size and tumor characteristics and overall survival (OS) were studied. The prevalence of axillary lymph node (ALN) involvement was not significantly different between cases with micrometastasis or macrometastasis in SLNs (p = 0.124). However, for metastases larger than 6, 7, and 8 mm, the prevalence of ALN involvement was significantly higher (p = 0.046, 0.022, and 0.025). OS was significantly lower in SLN-positive than in SLN-negative cases (p = 0.0375). Primary tumor size larger than 20 mm was associated with a significantly higher incidence of SLN metastasis (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), and primary tumor size over 26 mm was associated with additional positive non-SLN (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Higher mitotic index (≥ 7) in primary tumors was significantly (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) associated with ALN involvement in SLN-positive cases, whereas higher Ki67 labeling index was not significantly correlated with SLN or ALN involvement. Lymphovascular invasion (LVI) in primary tumors was significantly correlated with SLN positivity (p…

Research paper thumbnail of The expression of five different claudins in invasive breast carcinomas: Comparison of pT1pN1 and pT1pN0 tumors

Pathology - Research and Practice, 2005

The evaluation of the role of claudins (CLDNs) in breast carcinogenesis has recently begun. We in... more The evaluation of the role of claudins (CLDNs) in breast carcinogenesis has recently begun. We investigated the expression of CLDNs 1, 2, 3, 4, and 7 in pT1pN0 and pT1pN1 invasive ductal breast carcinomas. Tissue arrays of 30-30 pT1pN0 and pT1pN1 invasive ductal breast carcinomas of different grades were constructed, and the expression of CLDN 1, 2, 3, 4, and 7 proteins was analyzed using standard and immunofluorescent immunohistochemistry. The results were evaluated by light and confocal microscopy. Regarding CLDN 1, 4, and 7 expressions, differences were noted between normal and tumor cells and also between tumors of different grades, while no remarkable differences were noted between pT1pN0 and pT1pN1 tumors. CLDNs 1 and 7 were found to be downregulated in tumor cells compared to the normal epithelium, while CLDN 4 expression was decreased in grade 1 tumors. CLDN 7 protein was abundant in normal epithelia, and the staining decreased in grade 3 tumors. There were no differences between normal and neoplastic cells regarding CLDN 2 and 3 expressions. As a preliminary result, our observations suggest that the analyzed CLDNs do not promote tumor metastasis. On the basis of our findings, it seems that CLDN 1, CLDN 4, and CLDN 7 may rather have an important role in tumorigenesis or in cell-to-cell adhesion.

Research paper thumbnail of Expression of Claudin-1, -2, -3, -4, -5 and -7 Proteins in Benign and Malignant Canine Mammary Gland Epithelial Tumours

Journal of Comparative Pathology, 2008

Claudins are tight junction proteins expressed by epithelial and endothelial cells. The present s... more Claudins are tight junction proteins expressed by epithelial and endothelial cells. The present study has evaluated the expression of claudin-1,-2,-3,-4,-5 and-7 in 115 hyperplastic and neoplastic lesions of the canine mammary gland and compared this expression with that of normal mammary epithelium. The lesions studied included lobular hyperplasia (n ¼ 15), simple adenoma (n ¼ 20), non-infiltrating carcinoma in situ (n ¼ 20) and infiltrating carcinomas of histological grades I, II and III (n ¼ 20 of each). There was strong expression of claudin-1,-3,-4,-5 and-7 by epithelia within examples of lobular hyperplasia and simple adenoma, and strong expression of claudin-3 and-4 by non-infiltrating carcinomas and all three grades of infiltrating carcinoma. By contrast, there was reduced expression of claudin-5 and-7 by non-infiltrating and infiltrating carcinomas and the expression of these two molecules was inversely correlated with histological grade. Claudin-1 was expressed focally within carcinoma in situ, but this molecule was not detected in any invasive carcinoma. Claudin-2 was weakly expressed within areas of lobular hyperplasia and by simple adenomas, but was not expressed by any carcinoma cells. These results suggest that loss or reduction of expression of claudin-1,-2,-5 and-7 may lead to cellular disorientation, detachment and invasion in canine mammary neoplasia.