Lilla Madaras

Expression of tight junction protein claudin-4 in Basal-Like breast carcinomas

Claudins (CLDN) are tight junction proteins which contribute to the paracellular transport and ionic permeability of various epithelia. In recent years they came into focus for their suggested role in carcinogenesis and possible role in cancer therapy. According to our previous studies, in breast tissue CLDN4 is also related to the level of cellular differentiation. Thirty-eight estrogen (ER) and progesterone receptor (PgR) negative, HER2/neu negative, but cytokeratin 5/6 positive basal-like—mainly grade 3—breast carcinomas were compared with twenty-one grade 1, twenty-five grade 2 and twenty grade 3 non-basal-like invasive breast carcinomas, in respect to their CLDN4 expression. The immunohistochemical reactions were evaluated both semiquantitatively and by morphometrical analysis. Statistically significant difference (p = 0.001) was observable regarding CLDN4 expression in the basal-like group as compared to grade 1 and 2 cancers. Further, CLDN4 expression was significantly higher (p = 0.017) in the basal-like compared with the non-basal-like grade 3 carcinomas. Our results suggest that basal-like carcinomas are a subset of breast cancer with high level of CLDN4 protein expression. The finding is in accordance with our former observation that CLDN4 is indeed related to cellular differentiation. This observation may be seen as a further proof that basal-like carcinomas represent a separable group amongst grade 3 breast carcinomas.

Leiomyosarcoma of the female breast.

Leiomyosarcomas of the breast are rare tumors. Less than 15 such cases have been reported in the literature so far. In this paper authors describe a case of leiomyosarcoma of a female breast presenting as a firm lobulated mass, mimicking a phylloid tumor radiographically. By fine needle aspiration biopsy, on the smears discohesive malignant looking cells were conclusive to a poorly differentiated invasive ductal carcinoma of the breast. The mastectomy specimen contained a lobulated mass, microscopically showing a partly epithelioid spindle cell tumor, immunoreactive for vimentin, desmin, smooth muscle actin antibodies, and negative for epithelial markers, hormone and growth factor receptors. Axillary lymph nodes were free of tumor. A primary leiomyosarcoma of the breast was diagnosed.

Trabecular angiomyolipoma mimicking hepatic cell carcinoma.

Hepatic angiomyolipomas are rare tumors, especially in comparison with those occurring in the kidney. Nevertheless, it is important to be aware of their existence, especially when occurring in the liver, where they might have different subtypes. Not infrequently they are composed of rather irregular cells with epithelioid appearance. In these cases hepatocellular carcinoma or the possibility of other malignant tumors has to be ruled out, with the aid of numerous immunohistochemical reactions. The authors present a case of a female patient, whose liver lesion was first diagnosed on cytological examination as a hepatocellular carcinoma. Based on the preoperative cytological diagnosis, a large liver lobe resection was performed. Histological examination found an angiomyolipoma of the above-mentioned type, and the final diagnosis was ascertained with the aid of vimentin, smooth muscle actin (SMA), and HMB-45.

Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy

BackgroundStudies have partly demonstrated the clinical validity of Ki-67 as a predictive marker in the neoadjuvant setting, but the question of the best cut-off points as well as the importance of this marker as a prognostic factor in partial responder/non-responder groups remains uncertain.MethodsOne hundred twenty patients diagnosed with invasive breast cancer and treated with neoadjuvant chemotherapy (NAC) between 2002 and 2013 were retrospectively recruited to this study. The optimal cut-off value for Ki-67 labeling index (LI) to discriminate response to treatment was assessed by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve estimation, log-rank test and cox regression analysis were carried out to reveal the association between Ki-67 categories and survival (DMFS = Distant metastases-free survival, OS = Overall survival).ResultsTwenty three out of 120 patients (19.2%) achieved pathologic complete remission (pCR), whereas partial remission (pPR) and no response (pNR) to neoadjuvant chemotherapy (NAC) was detected in 60.8% and 20.0%, respectively. The distribution of subtypes showed a significant difference in pathological response groups (p < 0.001). Most of the TNBC cases were represented in pCR group.The most relevant cut-off value for the Ki-67 distinguishing pCR from pNR cases was 20% (p = 0.002). No significant threshold for Ki-67 was found regarding DMFS (p = 0.208). Considering OS, the optimal cut-off point occurred at 15% Ki-67 (p = 0.006). The pPR group represented a significant Ki-67 threshold at 30% regarding OS (p = 0.001). Ki-67 and pPR subgroups were not significantly associated (p = 0.653). For prognosis prediction, Ki-67 at 30% cut-off value (p = 0.040) furthermore subtype (p = 0.037) as well as pathological response (p = 0.044) were suitable to separate patients into good and unfavorable prognosis cohorts regarding OS. However, in multivariate analyses, only Ki-67 at 30% threshold (p = 0.029), and subtype (p = 0.008) were independently linked to OS.ConclusionsNAC is more efficient in tumors with at least 20% Ki-67 LI. Both Ki-67 LI and subtype showed a significant association with pathological response. Ki-67 LI represented independent prognostic potential to OS in our neoadjuvant patient cohort, while pathological response did not. Additionally, our data also suggest that if a tumor is non-responder to NAC, increased Ki-67 is a poor prognostic marker.

Az emlődaganatok primer szisztémás kemoterápiára adott válasza az immunhisztokémiai fenotípus tükrében

The purpose of the study was to identify breast cancer subtypes by immunohistochemistry likely to respond to neoadjuvant chemotherapy and to analyze the used chemotherapy regimen and the range of response rates. Analysis of a collected database was performed. Ninety-two patients were identified in our files who received neoadjuvant chemotherapy between 1998 and 2009. We used immunohistochemical profiles (ER, PgR, HER2, Ki-67 and p53) of NCB, FNAB and surgical breast specimens to subclassify the tumors. Pathological response rates were assessed following surgical removal of tumors by using the Chevallier classification. DFS and OS was measured in 88 cases from the date of definitive surgery to the date of last follow-up or death. Pathological complete or near-complete remission (pCR = Chevallier I and II) was observed in 13 of 92 cases (14.1%). According to the preoperative characteristics of the 13 tumors achieving pCR, 9 of the cases were triple negative, one of 13 was ER-/HER2+ and three of 13 ER+/HER2+. Twenty-four of 92 patients received taxane based neoadjuvant chemotherapy, 30 of 92 anthracycline based neoadjuvant chemotherapy, 33 of 92 taxane + anthracycline regimen and 2 of 92 CMF regimen. In the taxane treated group of patients the pCR rate was 29.1%, in the anthracycline group 6.6% and in the taxane + anthracycline treated group 12.1%. Concerning DFS, significant difference was observed between the Chevallier III and IV groups (p=0.006), and less events were observed in the pCR group (not significant). pCR was associated with significantly better OS (p=0.050). It seems that even limited, routinely used immunohistochemical profiling of tumors is able to predict the likelihood of pCR to neoadjuvant chemotherapy. Patients with triple negative and HER2-positive cancers are likely to achieve pCR after neoadjuvant chemotherapy.

Immunohistochemical phenotype of breast carcinomas predicts the effectiveness of primary systemic therapy

The purpose of the study was to identify breast cancer subtypes by immunohistochemistry likely to respond to neoadjuvant chemotherapy and to analyze the used chemotherapy regimen and the range of response rates. Analysis of a collected database was performed. Ninety-two patients were identified in our files who received neoadjuvant chemotherapy between 1998 and 2009. We used immunohistochemical profiles (ER, PgR, HER2, Ki-67 and p53) of NCB, FNAB and surgical breast specimens to subclassify the tumors. Pathological response rates were assessed following surgical removal of tumors by using the Chevallier classification. DFS and OS was measured in 88 cases from the date of definitive surgery to the date of last follow-up or death. Pathological complete or near-complete remission (pCR = Chevallier I and II) was observed in 13 of 92 cases (14.1%). According to the preoperative characteristics of the 13 tumors achieving pCR, 9 of the cases were triple negative, one of 13 was ER-/HER2+ and three of 13 ER+/HER2+. Twenty-four of 92 patients received taxane based neoadjuvant chemotherapy, 30 of 92 anthracycline based neoadjuvant chemotherapy, 33 of 92 taxane + anthracycline regimen and 2 of 92 CMF regimen. In the taxane treated group of patients the pCR rate was 29.1%, in the anthracycline group 6.6% and in the taxane + anthracycline treated group 12.1%. Concerning DFS, significant difference was observed between the Chevallier III and IV groups (p=0.006), and less events were observed in the pCR group (not significant). pCR was associated with significantly better OS (p=0.050). It seems that even limited, routinely used immunohistochemical profiling of tumors is able to predict the likelihood of pCR to neoadjuvant chemotherapy. Patients with triple negative and HER2-positive cancers are likely to achieve pCR after neoadjuvant chemotherapy.

Comparison of breast cancer in young and old women based on clinicopathological features

The two far ends of the age at the diagnosis of breast cancer are the age of younger than 35, and that of older than 70. Most probably, these two groups of patients differ in many ways. The aim of our present study was to underline the fact that age at the diagnosis of breast cancer is indeed a prognostic factor. Between October 1995 and March 2009, 80 old and 51 young breast cancer patients were treated at the Department of Diagnostic Radiology and Oncotherapy, Semmelweis University, Budapest. The prognostic and predictive factors of the tumors were analysed together with the disease-free and overall survival data. There were statistically significant differences between the two groups concerning the menstrual and reproductive factors, histological characteristics and immunophenotype of the tumors. Tumor size, nodal status and the Nottingham Prognostic Index did not show statistically significant differences. A trend to a shorter disease-free survival, higher rate of distant metastases and disease-specific death was seen in the group of young patients, but it was not significant. Overall survival was significantly shorter in the group of young patients. Therefore, we can state that young patients have a more aggressive disease and worse outcome. There is an increased importance of self examination in these groups, since both age groups are beyond the age limits of the screening population in Hungary. The media and primary school education as well should be involved in educating women concerning this aspect. The individual follow-up of young patients with positive family history should also be established.

BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters?

Background: BRCA mutation-associated (BRCAmut) breast cancer represents a heterogeneous group displaying certain molecular features. Claudin-low breast cancers (CLBC) overlap with characteristics of BRCAmut tumors; therefore, we have investigated whether these are identical subtypes. Methods: Using public gene expression data, CLDN, CDH1, 9-cell line claudin-low predictor (9CLCLP) and PAM50 expression was evaluated in BRCAmut and BRCA wild-type (BRCAwt) breast cancer cases focusing on their possible overlap with the CLBC subtype. A separate formalin-fixed, paraffin-embedded (FFPE) cohort of 22 BRCAmut and 19 BRCAwt tumor tissues was used for immunohistochemical examination of AR, CD24, CD44, CK5/6, claudin-1, -3, -4 and -7, E-cadherin, EGFR, estrogen receptor (ER), EZH2, HER2, Ki67, p53, progesterone receptor (PgR) and vimentin expression. Results: In the data sets, CLDN1 (ROC = 0.785, p < 0.001), CDH1 (ROC = 0.785, p < 0.001), CLDN7 (ROC = 0.723, p < 0.001), CLDN3 (ROC = 0.696, p = 0.020) and CLDN4 (ROC = 0.685, p = 0.027) were expressed at higher level in BRCAmut than BRCAwt tumor tissue. The PAM50 subtype differed from the assigned immunohistochemistry (IHC)-based subtype in 30%. Based on accessible 9CLCLP predictor genes, BRCAmut breast cancer does not display the claudin-low phenotype. Utilizing FFPE samples, claudins were evidently expressed in both BRCAmut and BRCAwt cases. However, at the protein level, only claudin-3 expression was higher in BRCAmut tumors, while claudin-1, -4 and -7 and E-cadherin expression was lower compared to BRCAwt cases. A CD24low/CD44high phenotype was found in BRCAmut tumors upon comparison with BRCAwt cases (p < 0.001 and p = 0.001, respectively). Conclusions: There is a prominent correlation between the genes under focus herein and BRCA mutation status. BRCAmut tumors bear stem cell characteristics displaying a distinct cell adhesion molecule profile characterized by high expression of CDH1 and CLDN4 according to public gene expression data set analysis, and higher claudin-3 expression as detected by IHC; thus, BRCAmut breast carcinomas are not identical with the previously identified claudin-low subtype of breast cancer.

Proteomic Profiling of Breast Carcinomas Based on Claudin Expression Pattern.

INTRODUCTION. With the advent of molecular techniques, the UNC workgroup (Perou 2000) has identified at least five biologically distinct subtypes (luminal A, luminal B, Her2+, triple-negative, normal-like) with genomic characterization of human breast tumors. The same lab (Herschkowitz 2007) identified a new and rare molecular subtype of human breast cancer which is now being referred to as the claudin-low subgroup. In our study, we aimed to perform a thorough analysis of the claudin, beta-catenin and E-cadherin protein expression pattern in invasive ductal (IDCs) and lobular (ILCs) breast carcinomas of different grades, their corresponding lymph node metastases (LNMs) and normal adjacent tissues NATs). METHODS. Tissue microarrays of 98 samples (59 IDCs: 20 grade 3, 26 grade 2 and 13 grade 1; 39 ILCs: 8 grade 3, 24 grade 2 and 7 grade 1), their corresponding LNMs and NATs have been analyzed immunohistochemically for beta-catenin, claudin-1, -2, -3, -4, -5, -7 and E-cadherin expression. The stained slides were digitalized with a slide scanner and the reactions were evaluated semiquantitatively according to our previous practice (Kulka 2009). RESULTS. Based on our evaluation, we were able to conclude the following significant results: 1) There is a markedly different expression of beta-catenin, claudin-1, -3, -4 and -7 in normal and neoplastic tissues. 2) Claudin-1, -2 and E-cadherin are able to differentiate ductal and lobular invasive carcinomas. 3) In E-cadherin-negative IDCs beta-catenin and claudin-7 is expressed on lower levels than in the E-cadherin-positive IDCs. In E-cadherin-positive ILCs the beta-catenin, claudin-4 and -7 is expressed at higher levels than in E-cadherin-negative ILCs. 4) Claudin-1 and -2 protein expression in the molecular subtypes can also distinguish luminal subtypes from each other and the HER2+ and triple-negative group. 5) Claudin-3 and E-cadherin or claudin-4 and -7 are both able to separate a claudin-low subtype of tumors with confidence.This later subclass also expresses beta-catenin on a lower level than the others. 6) Hierarchical clustering of primary carcinomas based on claudin expression reflects proliferation rates of the primary tumors. 7) Beta-catenin, claudin-1, -2 can differentiate primary carcinomas and lymph node metastases. 8) Histological grade correlates with claudin-1, -4 and -7 expression. CONCLUSION. According to our observations, the expression of TJ molecules, especially claudins, are different in tumors compared to normal breast tissue. Also, we could identify a claudin-low tumor subtype based on the loss of claudin-4 and -7 expression. Certain claudins are also differently expressed in the lymph node metastases as demonstrated by immunohistochemistry. Claudin profile of breast tumors correlates with histopathological variables and most likely it reflects an important mechanism of cancer differentiation and progression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6123.

Successful treatment of three synchronous primary malignant tumours—reflection on surgical, pathological and oncological aspects and decision making

Abstract We report a case of a patient with triple synchronous primary malignancies (breast, colon, kidney) which has not been previously reported in the literature. A 70-year-old woman was diagnosed with invasive ductal carcinoma of the left breast with axillary lymph node metastasis. During the staging period, renal cell carcinoma on the left kidney and mucinous adenocarcinoma in the proximal colon were found. Since the breast tumour demonstrated favourable biology, aromatase inhibitor therapy had been started and simultaneous right colectomy and left nephrectomy was performed. Six months after the first diagnosis, left sector excision and axillary block dissection were performed. Adjuvant FEC chemotherapy was administered, followed by radiotherapy. During the 16-month follow-up period disease recurrence was not detected.