Evaluation of the routine use of E-cadherin immunohistochemistry in the typing of breast carcinomas: results of a randomized diagnostic study.

AIMS: Invasive lobular carcinoma (ILC) has distinct morphology and association with loss of E-cadherin function. It has special clinical and imaging features, and its proper recognition is important. Following a recent proposal, we tested the value of the routine use of E-cadherin immunohistochemistry (IHC) in recognizing ILC. METHODS AND RESULTS: Five pathologists with experience in breast pathology from four Hungarian institutions histotyped 1001 breast cancers from diagnostic core biopsies or excision specimens randomly assigned to haematoxylin and eosin (HE) diagnosis first, followed by E-cadherin IHC; or to immediate HE and E-cadherin-based diagnosis. Of 524 cases with HE diagnosis, 73(14%) were deemed uncertain. E-cadherin made the initial histological type change in 14/524 cases (2.7%), including three with confident HE-based type allocation. Use of E-cadherin immunostaining was considered useful in 88/477 cases (18%) with immediate dual assessment, and typing uncertainty went down to 5% (25/477 cases), but was not zero. Collective assessment of 171 uncertain, difficult, nonclassical cases resulted in consensus diagnosis in most cases, but 15 cases were still doubtful as concerns their proper histological type. CDH1 gene sequencing was attempted and successful in 13; pathogenic genetic alterations were identified in seven cases. CONCLUSIONS: The routine use of E-cadherin IHC decreases the uncertainty in typing and improves the typing accuracy at the cost of potentially redundant additional immunostains. Furthermore, this procedure does not exclude uncertainty due to E-cadherin-positive ILCs, which are occasionally difficult to confidently label as ILC, especially when the growth pattern is not classic.

Pathological Diagnosis, Work-Up and Reporting of Breast Cancer 1st Central-Eastern European Professional Consensus Statement on Breast Cancer.

This text is based on the recommendations accepted by the 4th Hungarian Consensus Conference on Breast Cancer, modified on the basis of the international consultation and conference within the frames of the Central-Eastern European Academy of Oncology. The recommendations cover non-operative, intraoperative and postoperative diagnostics, determination of prognostic and predictive markers and the content of cytology and histology reports. Furthermore, they address some specific issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, and some remarks about the future.

[Pathological diagnosis, work-up and reporting of breast cancer. Recommendations from the 4th Breast Cancer Consensus Conference]. / Az emlorák patológiai diagnosztikája, feldolgozása és kórszövettani leletezése. Szakmai útmutatás a IV. Emlorák Konszenzus Konferencia alapján.

There have been some relevant changes in the diagnosis and treatment of breast cancer to implement the updating of the 2016 recommendations made during the 3rd national consensus conference on the disease. Following a wide interdisciplinary consultation, the present recommendations have been finalized after their public discussion at the 4th Hungarian Breast Cancer Consensus Conference. The recommendations cover non-operative, intraoperative and postoperative diagnostics, the determination of prognostic and predictive markers and the content of the cytology and histology reports. Furthermore, it touches some special issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, some relevant points about the future. The most important changes include the integration of the TNM 8th edition, the WHO classification of breast tumors 5th edition, the ASCO/CAP HER2 assessment guidelines from 2018, and the Yokohama terminology for cytology reporting; a more detailed text on tumor-infiltrating lymphocytes and size determination after neoadjuvant therapy and a broader discussion of molecular tests.

[Evaluation of resection margins following breast conserving surgery for breast cancer. A multicentric retrospective study]. / Emlorák miatti szervmegtartó mutétek reszekciós széleinek vizsgálata. Multicentrikus retrospektív elemzés.

Introduction: Breast conserving surgery for breast cancer requires the analysis of surgical margins. If the tumor is not removed completely, additional treatments (reoperation, boost irradiation) are generally recommended. Aim: To analyze the information content of histopathology reports on surgical margins in consecutive cases of breast conservation for invasive female breast cancer, to evaluate the frequency of incompletely removed tumors and to estimate the rate of further treatments after incomplete removal. Method: Analysis of margin related data of consecutive histopathology reports from 8 Hungarian pathology units with locoregional treatment related data in case of unsafe margins. Results: 386 reports were analyzed after exclusions. 200 and 32 cases were identified as having unsafe margins according to the previous (<5 mm) and the new (0 mm) definition of unclear margin, respectively. Unsafe margins were more common with lobular carcinomas. Specimens with clear margins weighed more. Reoperations for unsafe margins were performed in 43/180 and 12/22 cases according to the previous and the new definitions, respectively. Only 75/137 patients without reoperation received boost irradiation of the tumor bed; information on boost radiotherapy was often missing. Residual cancer was identified in 15/43 reoperated patients, of whom 9 had >0 mm margin distance. Conclusions: Some pathology reports lack information on surgical margins. Unsafe margin rates decreased with the new definition. Residual cancer may be left behind in case of clear margins with no ink on tumor. Neither reoperation, nor boost radiotherapy is given to some patients with unclear surgical margins. Orv Hetil. 2019; 160(26): 1036-1044.

A long-term retrospective comparative study of the oncological outcomes of 598 very young (≤35 years) and young (36-45 years) breast cancer patients.

BACKGROUND: Breast cancer diagnosed in very young women (VYWBC; ≤35 years) and young women (YWBC; 36-45 years) tends to be heterogeneous. The current study aimed to compare the clinicopathological characteristics and long-term clinical outcomes between YWBC and VYWBC subgroups. PATIENTS AND METHODS: The institutional prospectively led database was retrospectively analysed from 2000 to 2014 at the National Institute of Oncology, Hungary. A total of 297 patients were assigned to the VYWBC group, and 301 patients were assigned to the YWBC group. RESULTS: The median follow-up period was 69 months for the VYWBC group and 79 months for the YWBC group. Significant differences were observed based on breast cancer subtype. The proportion of Triple-negative and ER-negative patients was higher in the VYWBC group than in the YWBC group (P = 0.00008). The incidence of distant metastasis was significantly higher in the VYWBC group (P = 0.01). Significant differences in the frequency of chemotherapy (P = 0.049) and endocrine therapy (P = 0.037) were observed between the two groups. The YWBC group exhibited significantly better overall survival (OS) and disease-free survival (DFS) rates than did the VYWBC group (P = 0.00005 and P = 0.00004, respectively). CONCLUSION: Breast cancers in VYWBC are biologically different from those in YWBC and tend to be more aggressive. Younger age was associated with worse OS and DFS. Young women with breast cancer should be subgrouped into VYWBC and YWBC populations, and these subgroups should be targeted by specialized clinical trials and further investigations.

Erratum: Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

This corrects the article DOI: 10.1038/ncomms14944.

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination.

[Breast cancer care quality analysis of the National Institute of Oncology in Hungary according to the requirements of European Society of Breast Cancer Specialists (EUSOMA)]. / A European Society of Breast Cancer Specialists (EUSOMA) eloírásainak megfelelo emlorákellátás minoségbiztosítási elemzése az Országos Onkológiai Intézetben.

INTRODUCTION: The European Society of Breast Cancer Specialists has created quality indicators for breast units to establish minimum standards and to ensure specialist multimodality care with the conscious aim of improving outcomes and decreasing breast cancer mortality. AIM: The aim of this study was to analyse the breast cancer care in the National Institute of Oncology according to the European Society of Breast Cancer Specialists requirements and in a large number of cases in order to present representative clinico-pathological data on the incidence of breast cancer in Hungary. METHOD: According to the European Society of Breast Cancer Specialists uniformed criteria clinico-pathological data of multimodality treated breast cancer cases were retrospectively analysed between June 1, 2011 and May 31, 2012. RESULTS: During the period of interest 906 patients underwent breast surgery for malignant or benign lesions. According to the European Society of Breast Cancer Specialists quality indicators the breast cancer care of the National Institute of Oncology is eligible. CONCLUSIONS: The diagnostic modalities and multimodality care of breast cancer of the National Institute of Oncology breast unit meets the critical mass and minimum standards of the European Society of Breast Cancer Specialists criteria. Orv. Hetil., 2016, 157(42), 1674-1682.

[Pathological diagnosis, work-up and reporting of breast cancer. Recommendations of the 3rd Hungarian Consensus Conference on Breast Cancer]. / Az emlõrák patológiai diagnosztikája, feldolgozása és kórszövettani leletezése. Szakmai útmutatás a III. Emlõrák Konszenzus Konferencia alapján.

There have been relevant changes in the diagnosis and treatment of breast cancer to implement the updating of the 2010 recommendations made during the 2nd national consensus conference on the disease. Following a wide interdisciplinary consultation, the present recommendations have been finalized after their public discussion at the 3rd Hungarian Consensus Conference on Breast Cancer. The recommendations cover non-operative and intraoperative diagnostics, the work-up of operative specimens, the determination of prognostic and predictive markers and the content of the cytology and histology reports. Furthermore, it touches some special issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, some relevant points about the future.

Serum estrone concentration, estrone sulfate/estrone ratio and BMI are associated with human epidermal growth factor receptor 2 and progesterone receptor status in postmenopausal primary breast cancer patients suffering invasive ductal carcinoma.

BACKGROUND: We investigated in postmenopausal women with primary breast cancer prior to surgical intervention whether, serum levels of different steroid hormones and hormonal precursors associated with tumor tissue estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. METHODS: We enrolled 1,042 patients suffering invasive ductal carcinoma undergoing surgical resection in the National Institute of Oncology, Hungary between 2003 and 2011. Serum parameters were measured by RIA/IRMA assays; tumor tissue ER, PR and HER2 status was assessed histologically. Patients were classified according to tumor receptor status. Case-case analysis subjects were categorized into four subgroups based on serum hormone concentrations in ER, PR and HER2 receptor-negative cases, respectively. RESULTS: Serum estrone sulfate and dehydroepiandrosterone sulfate levels correlated with each other and also with serum estrone and estradiol levels. According to case-case study the odds ratios in the highest quartile were 1.517 (p = 0.0305, Ptrend = 0.0394) for androstenedione, 1.495 (p = 0.0317, Ptrend < 0.0105) for estrone and 0.654 (p = 0.0273, Ptrend < 0.0151) for estrone sulfate/estrone ratio in PR+ vs. PR- tumors. Regarding HER2 status (HER2+ vs. HER2-), the odds ratios for estrone, estrone sulfate and estrone sulfate/estrone ratio were 0.530 (p = 0.0234, Ptrend = 0.0595), 2.438 (p = 0.0042, Ptrend < 0.0066) and 3.118 (p = 0.0001, Ptrend < 0.0001) in the highest quartile, respectively. Of note significantly increased BMI associates with PR+ and ER +/PR+ status while significantly decreased BMI was observed in HER2+ cases. CONCLUSIONS: Taken together, measurement of serum estrone and estrone sulfate concentrations prior to surgical intervention might support the individualization of regime in postmenopausal primary breast cancer patients.

Expression of miRNAs in adenoid cystic carcinomas of the breast and salivary glands.

Despite their similar histomorphologic appearance, adenoid cystic carcinomas of the breast and salivary glands (bACCs and sACCs, respectively) are clinically and pathologically diverse. We studied the expression levels of 18 microRNAs (miRNAs) in bACCs and sACCs and control normal breast and salivary gland tissues (bNs and sNs, respectively) by quantitative real-time polymerase chain reaction on formalin-fixed paraffin embedded tissues. miRNAs showing significant differences between the study groups were selected for target prediction. Increased expression of miR-17 and miR-20a was found in bACCs compared with bNs (p(miR-17) = 0.017 and p(miR-20a) = 0.024, respectively), while the expression level of let-7b and miR-193b was lower in sACCs compared with normal sNs (p let-7b = 0.032 and p(miR-193b) = 0.023, respectively). Expression of miR-23b and miR-27b differed between normal breast and normal salivary gland tissue (p(miR-23b) = 0.007 and p(miR-27b) = 0.024, respectively), but not between bACCs and sACCs. The potential target mRNAs CCND1 and BCL2 were identified as reported targets of let-7b, miR-193b, miR-17, and miR-20a. Expression of their corresponding proteins cyclin D1 and Bcl-2 was studied by immunohistochemistry. We found both proteins overexpressed in bACCs as well as sACCs in comparison with corresponding normal tissues. However, expression of cyclin D1 and Bcl-2 proteins was not significantly different between bACCs and sACCs or between bNs and sNs. Although no differences in miRNA levels were found between bACCs and sACCs, in both organs, miRNA expression level was highly different between tumor tissue and control tissue.

[Optimal treatment of the axilla after positive sentinel lymph node biopsy in early invasive breast cancer. Early results of the OTOASOR trial]. / Az axilla optimális kezelése pozitív orszemnyirokcsomó esetén korai invazív emlorákban. Az OTOASOR vizsgálat elozetes eredményei.

INTRODUCTION: Sentinel lymph node biopsy alone has become an acceptable alternative to elective axillary lymph node dissection in patients with clinically node-negative early-stage breast cancer. Approximately 70 percent of the patients undergoing breast surgery develop side effects caused by the axillary lymph node dissection (axillary pain, shoulder stiffness, lymphedema and paresthesias). AIM: The current standard treatment is to perform completion axillary lymph node dissection in patients with positive sentinel lymph node biopsy. However, randomized clinical trials of axillary dissection versus axillary irradiation failed to show survival differences between the two types of axillary treatment. The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment of the Axilla - Surgery or Radiotherapy) trial compares completion axillary lymph node dissection to axillary nodal irradiation in patients with sentinel lymph node-positive primary invasive breast cancer. METHOD: Patients with primary invasive breast cancer (clinically lymph node negative and less than or equal to 3 cm in size) were randomized before surgery for completion axillary lymph node dissection (arm A-standard treatment) or axillary nodal irradiation (arm B-investigational treatment). Sentinel lymph node biopsy was performed by the radio-guided method. The use of blue-dye was optional. Sentinel lymph nodes were investigated with serial sectioning at 0.5 mm levels by haematoxylin and eosin staining. In the investigational treatment arm patients received 50Gy axillary nodal irradiation instead of completion axillary lymph node dissection. Adjuvant treatment was recommended and patients were followed up according to the actual institutional guidelines. RESULTS: Between August 2002 and June 2009, 2106 patients were randomized for completion axillary lymph node dissection (1054 patients) or axillary nodal irradiation (1052 patients). The two arms were well balanced according to the majority of main prognostic factors. Sentinel lymph node was identified in 2073 patients (98.4%) and was positive in 526 patients (25.4%). Fifty-two sentinel lymph node-positive patients were excluded from the study (protocol violation, patient's preference). Out of the remaining 474 patients, 244 underwent completion axillary lymph node dissection and 230 received axillary nodal irradiation according to randomization. The mean length of follow-up to the first event and the mean total length of follow-up were 41.9 and 43.3 months, respectively, and there were no significant differences between the two arms. There was no significant difference in axillary recurrence between the two arms (0.82% in arm A and 1.3% in arm B). There was also no significant difference in terms of overall survival between the arms at the early stage follow-up. CONCLUSIONS: The authors conclude that after a mean follow-up of more than 40 months axillary nodal irradiation may control the disease in the axilla as effectively as completion axillary lymph node dissection and there was also no difference in terms of overall survival.

[Sentinel lymph node biopsy in pregnancy-associated breast cancer]. / Orszemnyirokcsomó-biopszia terhességi emlorákban.

The incidence of pregnancy-associated breast cancer is rising. Sentinel lymph node biopsy is the method of choice in clinically node negative cases as the indicated minimally invasive regional staging procedure. Some reports have linked radioisotope and blue dye required for lymphatic mapping to teratogenic effects, the idea of which has become a generalized statement and, until recently, contraindication for these agents was considered during pregnancy. Today, there are many published reports of successful interventions with low-dose 99mTc-labeled human albumin nanocolloid, based on dosimetric modeling demonstrating a negligible radiation exposure of the fetus. These results contributed to the seemingly safe and successful use of sentinel lymph node biopsy during pregnancy, though generally it can not replace axillary lymphadenectomy in the absence of high-quality evidence. The possibility of sentinel lymph node biopsy should be offered to pregnancy-associated early breast cancer patients with clinically negative axilla, and patients should be involved in the decision making following extensive counselling. This paper presents the successful use of sentinel lymph node biopsy with low-dose tracer during two pregnancies (in the first and third trimesters) and, for the first time in Hungarian language, it offers a comprehensive literature review on this topic. Orv. Hetil., 154(50), 1991-1997.

[Modern pathologic diagnostics in breast cancer]. / Az emlorák korszeru patológiai diagnosztikája.

The diagnosis of breast cancer is morphologically based. Pathologic parameters, such as tumor size, lymph node status, and histological grade are well accepted to guide treatment decisions in clinical practice. Estrogen receptor, progesterone receptor and HER2 status are also routinely assessed in today's pathology laboratories to provide further information on predictive and prognostic factors affecting patients' care. Newer molecular techniques, including gene-expression profiling have been widely used to study breast cancer and several molecular prognostic tests already available for clinical use stemmed from these scientific efforts. Authors review prognostically important aspects of the diagnostic pathology and the molecular classification of invasive breast cancer.

[Sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer]. / Orszemnyirokcsomó-biopszia neoadjuváns kemoterápiát igénylõ emlõrákoknál.

The indication of neoadjuvant chemotherapy has been recently extended; it is now applied not only in locally advanced breast cancer but in primarily resecable tumours as well, in order to promote breast conservation. Based on recent clinical results, the reconsideration of traditional lymph node dissection in axillary staging is timely in patients receiving neoadjuvant chemotherapy. Precise axillary staging needs surgical removal of lymph nodes. Based on prospective randomised trials, sentinel lymph node biopsy appears to be appropriate for axillary staging even in tumours requiring neoadjuvant treatment. The extended indication of sentinel lymph node biopsy raises several questions and problems. In the present paper the authors review the results and possible limitations of sentinel lymph node biopsy in relation to neoadjuvant chemotherapy.

[Challenges in oncologic plastic surgery of the breast]. / A modern emlosebészet onkoplasztikai kihívásai.

Breast screening programs along with advances in diagnostic methods and oncologic treatment have resulted in full recovery for a decisive number of patients diagnosed with early-stage breast cancer. The results of the ultra-radical-, followed by the breast conserving era pose new opportunities and challenges for the oncologic breast surgeon. The focus of oncoplastic surgery is not only on the tumor, but also on the female patient, allowing for individualized immediate breast reconstruction with acceptable esthetic result following radical tumor exstirpation. Modern procedures differ both in concept and technique from that of traditional breast surgery. This paper provides a comprehensive and detailed overview of reconstructive and oncoplastic breast surgery.

Estrogen receptor negative and progesterone receptor positive breast carcinomas-how frequent are they?

Estrogen receptor (ER) testing has become an important part of breast cancer reporting as the ER status is a predictor of hormonal treatment efficacy. Progesteron receptors (PR) are often tested in parallel, and the best response to hormonal manipulations can be expected in tumors positive for both receptors. The existence of breast cancers with an ER negative and PR positive phenotype is controversial. A series of cases with this phenotype were reevaluated to clarify the existence and the frequency of this entity. A total of 205/6587 (3.1%; range of the rate per department: 0.3-7.1%.) cases reported to have the ER-negative and PR-positive status by immunohistochemistry were collected from 9 Hungarian departments. After careful reevaluation of the tumor slides and control tissues with a 1% cut-off for positivity and restaining of the questionable cases, all but 1 of the reevaluable 182 cases changed their original phenotype. Most cases converted to dual positives (n = 124) or dual negatives (n = 31) or unassessable / questionable. ER-negative and PR-positive breast cancers are very rare if existing. Such a phenotype should prompt reassessment.

[Triple-negative breast carcinoma--rewiev of current literature]. / A tripla-negatív emlokarcinóma--irodalmi áttekintés.

Breast cancer is one of the most common malignancies in women. Approximately 15% of cases belong to the triple-negative breast cancer (TNBC) group, in which no estrogen/progesterone receptors, or HER2 expression is detected. The unfavorable prognosis of this group of patients, as well as the lack of effective targeted therapy makes TNBC the subject of intensive research. In the present study, we searched PubMed for publications from January 2007 to June 2009 with the following key-words in addition to "breast cancer" and "triple negative": "epidemiology" or "gene-profile" or "predictive" or "prognostic" or "therapy" or "review". A total of 513 publications were identified. Relevant references were also reviewed. Beyond the well-known facts that TNBC affects younger patients, and is more common among Afro- or Hispano-Americans with lower socioeconomic status, hormonal environment and obesity emerged as potential etiologic factors. TNBC is not a homogenous disease. It can be further sub-classified based on histomorphologic features and immunohistochemistry. Hereditary BRCA1 mutations as well as acquired BRCA1 disfunction are described to be common in TNBC. Previously, many investigators considered TNBC to be identical to a subgroup called basal-like breast cancer defined by gene expression micro-array technology, but in the light of more recent findings, this view is no longer accepted by most investigators. Several large studies provide evidence that triple negativity, per se, is an independent adverse prognostic factor, in spite of the fact that approximately 10% of TNBC patients have a good prognosis. The therapy of choice for TNBC is systemic chemotherapy. Promising novel targeted chemotherapeutic agents include PARP1 inhibitors, a new group of compounds exploiting the defective DNA repair machinery. Rubovszky G, Udvarhelyi N, Horváth Z, Láng I, Kásler M. Triple negative breast carcinoma - rewiev of current literature.

[Combined surgery and radiotherapy in the treatment of ductal carcinoma in situ of the breast: preliminary results of the Hungarian multicenter prospective randomised study]. / In situ duktális emlokarcinóma kombinált sebészi- és sugárkezelése: a magyarországi multicentrikus prospektív.

The aim of this work is to report the preliminary results of the Hungarian multicentric randomised DCIS study. Between 2000 and 2007, 278 patients with ductal carcinoma in situ (DCIS) treated by breast-conserving surgery were randomised according to predetermined risk groups. Low/intermediate-risk patients (n=29) were randomised to 50 Gy whole-breast irradiation (WBI) or observation. High-risk cases (n=235) were allocated to receive 50 Gy WBI vs. 50 Gy WBI plus 16 Gy tumour bed boost. Very high-risk patients (patients with involved surgical margins; n=14) were randomised to 50 Gy WBI plus 16 Gy tumour bed boost or reoperation (reexcision plus radiotherapy or mastectomy alone). Immunohistochemistry (IHC) was performed to detect the expression of potential molecular prognostic markers (ER, PR, Her2, p53, Bcl-2 and Ki-67). At a median follow-up of 36 months no recurrence was observed in the low/intermediate- and very high-risk patient groups. In the high-risk group, 4 (1.7%) local recurrences and 1 (0.4%) distant metastasis occurred. No patient died of breast cancer. In the high-risk group of patients, the 3- and 5-year probability of local recurrence was 1.1% and 3.1%, respectively. The positive immunostaining for Her2 (38%), p53 (37%) and Ki-67 (44%) correlated with a high nuclear grade. Significant inverse correlation was found between the expression of ER (77%), PR (67%), Bcl-2 (64%) and grade. Preliminary results suggest that breast-conserving surgery followed by radiotherapy yields an annual local recurrence rate of less than 1% in patients with DCIS. IHC of molecular prognostic markers can assist to gain insight into the biologic heterogeneity of DCIS.