Does Diffusely Infiltrating Lobular Carcinoma of the Breast Arise from Epithelial-Mesenchymal Hybrid Cells?

Classic diffusely infiltrating lobular carcinoma has imaging features divergent from the breast cancers originating from the terminal ductal lobular units and from the major lactiferous ducts. Although the term "invasive lobular carcinoma" implies a site of origin within the breast lobular epithelium, we were unable to find evidence supporting this assumption. Exceptional excess of fibrous connective tissue and the unique cell architecture combined with the aberrant features at breast imaging suggest that this breast malignancy has not originated from cells lining the breast ducts and lobules. The only remaining relevant component of the fibroglandular tissue is the mesenchyme. The cells freshly isolated and cultured from diffusely infiltrating lobular carcinoma cases contained epithelial-mesenchymal hybrid cells with both epithelial and mesenchymal properties. The radiologic and histopathologic features of the tumours and expression of the mesenchymal stem cell positive markers CD73, CD90, and CD105 all suggest development in the direction of mesenchymal transition. These hybrid cells have tumour-initiating potential and have been shown to have poor prognosis and resistance to therapy targeted for malignancies of breast epithelial origin. Our work emphasizes the need for new approaches to the diagnosis and therapy of this highly fatal breast cancer subtype.

Predictive Potential of RNA Polymerase B (II) Subunit 1 (RPB1) Cytoplasmic Aggregation for Neoadjuvant Chemotherapy Failure.

We aimed to investigate the contribution of co-translational protein aggregation to the chemotherapy resistance of tumor cells. Increased co-translational protein aggregation reflects altered translation regulation that may have the potential to buffer transcription under genotoxic stress. As an indicator for such an event, we followed the cytoplasmic aggregation of RPB1, the aggregation-prone largest subunit of RNA polymerase II, in biopsy samples taken from patients with invasive carcinoma of no special type. RPB1 frequently aggregates co-translationally in the absence of proper HSP90 chaperone function or in ribosome mutant cells as revealed formerly in yeast. We found that cytoplasmic foci of RPB1 occur in larger sizes in tumors that showed no regression after therapy. Based on these results, we propose that monitoring the cytoplasmic aggregation of RPB1 may be suitable for determining-from biopsy samples taken before treatment-the effectiveness of neoadjuvant chemotherapy.

Integration in emerging social networks explains academic failure and success.

Academic success of students has been explained with a variety of individual and socioeconomic factors. Social networks that informally emerge within student communities can have an additional effect on their achievement. However, this effect of social ties is difficult to measure and quantify, because social networks are multidimensional and dynamically evolving within the educational context. We repeatedly surveyed a cohort of 226 engineering undergraduates between their first day at university and a crucial examination at the end of the academic year. We investigate how social networks emerge between previously unacquainted students and how integration in these networks explains academic success. Our study measures multiple important dimensions of social ties between students: their positive interactions, friendships, and studying relations. By using statistical models for dynamic network data, we are able to investigate the processes of social network formation in the cohort. We find that friendship ties informally evolve into studying relationships over the academic year. This process is crucial, as studying together with others, in turn, has a strong impact on students' success at the examination. The results are robust to individual differences in socioeconomic background factors and to various indirect measures of cognitive abilities, such as prior academic achievement and being perceived as smart by other students. The findings underline the importance of understanding social network dynamics in educational settings. They call for the creation of university environments promoting the development of positive relationships in pursuit of academic success.

The Added Value of SOX10 Immunohistochemistry to Other Breast Markers in Identifying Cytokeratin 5-Positive Triple Negative Breast Cancers as of Mammary Origin.

AIMS: Triple-negative breast cancer (TNBC) represents a specific group that lacks the expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 and might also lack the expression other breast markers like GATA3, mammaglobin (MG), GCDFP15 (growth cystic disease fluid protein 15), and NYBR1; when this occurs, proving the breast origin of a metastasis is a challenging task. In the present study, we assessed the added value of SOX10 immunohistochemistry to known GATA3, MG, GCDFP15, and NY-BR-1 statuses in a series of CK5-positive primary TNBCs. METHODS: Tissue microarrays were made from the formalin-fixed and paraffin-embedded blocks of 120 TNBCs, and 3-4-mm-thick sections were immunostained for SOX10. The cut-off for a positive reaction was at least 10% of tumor cells staining. RESULTS: In our cohort, SOX10 positivity was seen in 82/119 cases, 61, 74, 76, and 82 all of which were GATA3, MG, GCDFP15, and NY-BR-1 negative, respectively. Of the SOX10 negative cases, 12 stained with at least another breast marker. Nevertheless, 25/119 (21%) cases remained negative with all markers assessed. DISCUSSION: SOX10 proved to be the most commonly positive breast marker in our CK5 expressing TNBCs, but the other markers also had some additive value to SOX10.

Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of residual breast cancer.

Background: Chemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes. It is not known, however, whether treatment with various chemotherapeutic agents with different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in residual cancer.Methods: One hundred and twenty breast carcinoma cases with residual disease that were treated with one of three types of pre-operative chemotherapy regimens were selected for the study. The percentage of StrTIL was evaluated in pretreatment core biopsies (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL). TIL changes (ΔStrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.Results: When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we detected significant StrTIL increase independently of the treatment applied. Based on distant metastases-free survival analysis, both post-StrTIL and ΔStrTIL was found to be independent prognostic factor in HR negative cases. Conclusions: Significant increase of StrTIL in the residual disease was observed in patients treated with the highly (platinum), moderately (cyclophosphamide) and marginally mutagenic chemotherapeutic agents (taxane, anthracycline). Increase in StrTIL in residual cancer compared to pretreatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

An intra- and interobserver reproducibility analysis of the Ki-67 proliferation marker assessment on core biopsies of breast cancer patients and its potential clinical implications.

OBJECTIVE: The Ki-67 proliferation index has received an important role in treatment tailoring and molecular classification of estrogen receptor-positive breast carcinomas. The aim was to analyze the reproducibility of assessing proliferation on the basis of Ki-67 immunohistochemistry. METHODS: Thirty core biopsy samples of breast cancer patients were analyzed after immunostaining with B56, SP6 and MIB-1 monoclonal Ki-67 antibodies. All samples were evaluated twice and independently by 3 pathologists, with each observer performing his daily routine practice. The ratio of Ki-67-positive cells was estimated with 5% accuracy. Correlation was calculated for the results of each investigator for all pairs of antibodies and for the results of each antibody for all pairs of investigators. Ki-67 scores were divided into categories of either 4 quarters or into 3 groups reflecting the St. Gallen consensus recommendations with 15 and 30% as cutoff values. The reproducibility of classifying the tumors into these categories was assessed with ĸ statistics. RESULTS: Altogether, 540 evaluations were made. Good to excellent correlation (Spearman's and Pearson's coefficient range 0.74-0.92 and 0.73-0.93, respectively) was noted for the pairwise comparison of antibodies by observer and of observers by antibody. The inter- and intraobserver reproducibility of the Ki-67 score classification into equal quarters (1-25, 26-50, 51-75 and 76-100%) or into 3 categories with cutoffs at 15 and 30% was fair to poor in the middle categories, but moderate to substantial in the low and high ranges. Interobserver differences in practice potentially impacted on less consistent classification. CONCLUSION: Our results indicate that the three different Ki-67 antibodies tested do not substantially influence the reproducibility of the estimated proliferation rates. Although reproducibility is better in the clinically more relevant distinction of high versus low proliferation, without standardization, the current practice of Ki-67 assessment in many laboratories does not allow proper and consistent therapeutic decision-making.

Increased axonal expression of nectin-1 in multiple sclerosis plaques.

Nectin-1 is a cell adhesion molecule that plays a role in interneuronal synapse formation, in axonal guidance during development and possibly in neuron-glia interactions. To better understand axonal changes in MS, nectin-1 expression was determined by immunohistochemistry in normal adult human cerebral white matter (n = 4) and in six MS plaques (three active and three inactive). The intensity of axonal nectin-1 expression was scored on a scale of 0 to 4+. In normal adult cerebral white matter, axons showed weak nectin-1 expression with a score of 1.25 ± 0.50. Axonal nectin-1 expression was significantly stronger within both active (score = 3.33 ± 0.289, p = 0.001) and inactive (score = 2.16 ± 0.29, p = 0.038) MS plaques than in normal white matter. Axons in white matter adjacent to MS plaques showed nectin-1 expression (score = 1.5 ± 0.50) that was not statistically different from normal controls (p = 0.542). These findings raise the possibility that increased expression of nectin-1 in MS lesions plays a role in the pathogenesis of MS through participation in axonal responses to injury and mediation of altered neuron-glia interactions relevant to myelination.

Can we improve breast cancer management using an image-guided histopathology workup supported by larger histopathology sections?

PURPOSE: Breast radiologists examine the entire breast in full-size images, while breast pathologists examine small tissue samples at high magnification. The diagnostic information from these complementary imaging approaches can be difficult to integrate for a more clinically relevant evaluation of malignancies spanning several centimetres. We have explored the advantages and disadvantages of imaging guided larger section pathology techniques compared with the standard 2 × 2.5 cm. small section technique. METHODS: We compared the ability of conventional small section histopathology with larger section histopathology techniques to examine surgical resection margins and full disease extent. We evaluated the pre-surgical imaging workup and use of microfocus magnification radiography of sliced surgical specimens in the histopathologic evaluation of disease extent and status of surgical margins. RESULTS: Image assisted large section histopathology of excised breast tissue enables comprehensive examination of an approximately tenfold larger contiguous tissue area than is provided by conventional small section technology. Attempting to cover the full area of each consecutive slice of resected tissue is more labour-intensive and expensive with the small section approach and poses challenges in reconstituting three-dimensional tumour architecture after morcellation and sectioning. Restricting histopathologic examination to a limited number of samples provides an incomplete evaluation of surgical margins. CONCLUSIONS: A considerably improved documentation of breast cancer and a more reliable assessment of tissue margins is provided by using larger sized histopathology samples to correlate with breast imaging findings. These in turn can enable more appropriate treatment planning, improved surgical performance, fewer recurrences, and better patient outcome. Uncertainty of surgical margin evaluation inherent to the standard small section technique can lead to inappropriate decisions in surgical management and adjunctive therapy. Progress in breast diagnosis and treatment will largely depend on whether histopathology terminology and technique will undergo a revolution similar to the one that has already occurred in breast imaging.

TRPS1 expression in cytokeratin 5 expressing triple negative breast cancers, its value as a marker of breast origin.

The lack of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 expression in breast cancer (BC) is the basis for the categorization of the tumour as triple negative breast carcinoma (TNBC). The majority of TNBCs are aggressive tumours with common metastases and decreased expression of markers that could help in identifying the metastatic lesion as of mammary origin. Breast markers, such as gross cystic disease fluid protein-15 (GCDPF-15), GATA binding protein 3 (GATA3), mammaglobin (MGB) and SOX10, are not uniquely specific to BC. Our aim was to evaluate trichorhinophalangeal syndrome type 1 (TRPS1) protein as a breast marker in a series of cytokeratin-5-expressing TNBC, mostly corresponding to basal-like TNBCs, previously characterized for the expression of other breast markers. One hundred seventeen TNBCs in tissue microarrays were immunostained for TRPS1. The cut-off for positivity was ≥ 10%. The reproducibility of this classification was also assessed. TRPS1 positivity was detected in 92/117 (79%) cases, and this exceeded the expression of previously tested markers like SOX10 82 (70%), GATA3 11 (9%), MGB 10 (9%) and GCDFP-15 7 (6%). Of the 25 TRPS1-negative cases, 11 were positive with SOX10, whereas 5 to 6 dual negatives displayed positivity for the other makers. The evaluation showed substantial agreement. Of the five markers compared, TRPS1 seems the most sensitive marker for the mammary origin of CK5-expressing TNBCs. Cases that are negative are most often labelled with SOX10, and the remainder may still demonstrate positivity for any of the 3 other markers. TRPS1 has a place in breast marker panels.

Multifocal and diffusely infiltrating breast cancers are highly fatal subgroups needing further improvement in diagnostic and therapeutic strategies.

Physicians treating breast cancer patients often wonder why this dreaded disease is still fatal in some women despite our best diagnostic and therapeutic efforts. Our own studies on prospectively documented cases spanning several decades have given us new insights for approaching this problem. By using imaging biomarkers to classify breast cancer subtypes according to their apparent site of origin, we found that a majority of breast cancer deaths (71%) occur in a minority of breast cancers (45%). Breast cancer deaths are significantly more likely to occur in women with multifocal acinar adenocarcinoma of the breast, AAB (13.1%), diffusely invasive breast cancers of ductal origin, DAB (24 %) and breast malignancies of mesenchymal hybrid cell origin, BCMO (33.7%) compared with women having unifocal invasive breast cancers (6.1%). Preventing more of these fatal events will require a re-evaluation of the current imperfect histopathologic terminology of breast cancer with special attention to the diffuse breast cancer subtypes, intensification of multimodality imaging and multidisciplinary management, as well as application of image guided large format histopathology.

The term "classic invasive lobular carcinoma" of the breast defines breast malignancies of vastly different nature.

PURPOSE: To describe in detail the special features of a previously unappreciated "classic invasive lobular carcinoma" which is confined to the terminal ductal lobular units (TDLUs) and differs considerably from the extensive classic invasive lobular carcinoma, and to suggest specific terminology. METHOD: All invasive breast cancer cases without associated microcalcifications diagnosed in our Institution with the histopathologic diagnosis of classic invasive lobular carcinoma during the years 1996-2019 (n = 560) formed the basis of this study. The cases were prospectively classified according to their imaging biomarkers (mammographic features) and followed up to Dec 31, 2021, to determine long-term patient outcome. An additional 2600 invasive breast cancer cases (diagnosed other than invasive lobular carcinoma) without associated microcalcifications served as a reference group. Detailed histopathologic analysis used large format (10x8 cm) thin section technique and staining methods including hematoxylin-eosin (H&E), E-cadherin, cytokeratin CK 5/6, a transmembrane glycoprotein (CD44) and anti-actin or anti-smooth muscle myosin heavy chain. RESULTS: The imaging biomarkers differentiated two separate disease subgroups, having the same histopathologic diagnosis, classic invasive lobular carcinoma. One of these has the imaging biomarker of extensive architectural distortion with no central tumour mass, occupies the extralobular mesenchyme and has a long-term survival of 56%. The other subgroup forms stellate or circular non-calcified tumour masses usually smaller than 20 mm, which appear to arise in the intralobular mesenchyme, and has a significantly better long-term survival of 84%. CONCLUSIONS: There is a striking difference between the subgross histopathology and the mammographic appearance (imaging biomarkers) of two breast malignancies having the same histopathologic diagnosis, "classic invasive lobular carcinoma". The large difference in the long-term outcome of these two tumour types is even more striking. Using the same specific term, "classic invasive lobular carcinoma", to describe these two separate entities can adversely affect management decisions.

Social network and household exposure explain the use of malaria prevention measures in rural communities of Meghalaya, India.

Malaria remains a global concern despite substantial reduction in incidence over the past twenty years. Public health interventions to increase the uptake of preventive measures have contributed to this decline but their impact has not been uniform. To date, we know little about what determines the use of preventive measures in rural, hard-to-reach populations, which are crucial contexts for malaria eradication. We collected detailed interview data on the use of malaria preventive measures, health-related discussion networks, individual characteristics, and household composition in ten tribal, malaria-endemic villages in Meghalaya, India in 2020-2021 (n=1,530). Employing standard and network statistical models, we found that social network and household exposure were consistently positively associated with preventive measure use across villages. Network and household exposure were also the most important factors explaining behaviour, outweighing individual characteristics, opinion leaders, and network size. These results suggest that real-life data on social networks and household composition should be considered in studies of health-behaviour change.

Imaging biomarkers are underutilised but highly predictive prognostic factors for the more fatal breast cancer subtypes.

PURPOSE: The development and refinement of breast imaging modalities offer a wealth of diagnostic information such as imaging biomarkers, which are primarily the mammographic appearance of the various breast cancer subtypes. These are readily available preoperatively at the time of diagnosis and can enhance the prognostic value of currently used molecular biomarkers. In this study, we investigated the relative utility of the molecular and imaging biomarkers, both jointly and independently, when predicting long-term patient outcome according to the site of tumour origin. METHODS: We evaluated the association of imaging biomarkers and conventional molecular biomarkers, (ER, PR, HER-2, Ki67), separately and combined, with long-term patient outcome in all breast cancer cases having complete data on both imaging and molecular biomarkers (n = 2236) diagnosed in our Institute during the period 2008-2019. Large format histopathology technique was used to document intra- and intertumoural heterogeneity and select the appropriate foci for evaluating molecular biomarkers. RESULTS: The breast cancer imaging biomarkers were strongly predictive of long-term patient outcome. The molecular biomarkers were predictive of outcome only for unifocal acinar adenocarcinoma of the breast (AAB), but less reliable in the multifocal AAB cases due to variability of molecular biomarkers in the individual tumour foci. In breast cancer of mesenchymal origin (BCMO), conventionally termed classic invasive lobular carcinoma, and in cancers originating from the major lactiferous ducts (ductal adenocarcinoma of the breast, DAB), the molecular biomarkers misleadingly indicated favourable prognosis, whereas the imaging biomarkers in BCMO and DAB reliably indicated the high risk of breast cancer death. Among the 2236 breast cancer cases, BCMO and DAB comprised 21% of the breast cancer cases, but accounted for 45% of the breast cancer deaths. CONCLUSIONS: Integration of imaging biomarkers into the diagnostic workup of breast cancer yields a more precise, comprehensive and prognostically accurate diagnostic report. This is particularly necessary in multifocal AAB cases having intertumoural heterogeneity, in diffuse carcinomas (DAB and BCMO), and in cases with combined DAB and AAB. In such cases, the imaging biomarkers should be prioritised over molecular biomarkers in planning treatment because the latter fail to predict the severity of the disease. In combination with the use of the large section histopathology technique, imaging biomarkers help alleviate some of the current problems in breast cancer management, such as over- and under-assessment of disease extent, which carry the risk of overtreatment and undertreatment.

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

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 (range 2-11) are most commonly needed to give a robust estimate of reproducibility. In addition, the number and experience of observers, the distribution of values around or away from the extremes, and outliers in the classification also influence the results. Due to the simplicity and the potentially relevant information it may give, we propose ONEST to be a part of new reproducibility analyses.

Predictive role of neostromal CD10 expression in breast cancer patients treated with neoadjuvant chemotherapy.

Background: The therapeutic strategy of invasive breast cancer is based on routine histopathological markers (estrogen-, progesterone receptor, HER2, Ki67) routinely evaluated in tumor cells. However, the assessment of cancer stroma could influence therapeutic strategies. Studies have shown that stromal expression of CD10, a zinc-dependent metalloproteinase, is associated with biological aggressiveness of the tumor. In the present retrospective study, we aimed to evaluate stromal CD10 expression and association between CD10 expression and response to neoadjuvant chemotherapy in invasive breast cancer. Methods: CD10 immunohistochemistry was performed on core biopsies taken before the neoadjuvant therapy. Stromal CD10 expression was determined and compared with well-known predictive and prognostic tissue markers as well as with the following groups defined according to the degree of tumor response: no regression, partial regression, and complete regression. Results: A total of 60 locally advanced invasive breast carcinomas of "no special type" were included. The proportion of CD10 positive tumors was significantly higher in the "no regression" group compared to "complete regression" group (p = 0.000). Stromal CD10 expression was found to be significantly associated with decrease in response to neoadjuvant chemotherapy. According to CD10 expression we did not find any difference in hormone receptor status, Ki67, tumor grade or neostromal area. Conclusion: Our data suggest that CD10 expression can serve as a predictive marker of the effect of neoadjuvant chemotherapy in breast cancer patients. Therefore, its inclusion into the routine assessment of biopsies to tailor tumor-specific therapeutic strategies merits consideration.

New trends in the surgical treatment of axilla in breast cancer / Új trendek az axilla sebészi kezelésében emlorák esetén

Oncosurgical treatment of breast tumors involves the removal of metastatic axillary lymph nodes. In the last 30 years, the diagnosis and treatment of axillary lymph nodes have also undergone significant changes. The introduction of sentinel lymph node biopsy in 1993 made axillary block dissection with high morbidity safely omitted in a significant proportion of patients, and similarly, the staging of breast tumors and thus oncology and complex treatment became significantly more accurate. Shortly after the introduction of sentinel lymph node biopsy, intraoperative examination of sentinel lymph nodes (e.g. imprint cytology) also appeared, which significantly reduced the number of surgeries performed in the two sessions, thereby significantly reducing patient burden and surgical costs. The results of our study indicate that axillary block dissection is required in the treatment of axilla in an ever-decreasing group of patients and this proportion will decrease further in the future, with the increasing use of alternative axillary radiotherapy. The imprint cytological examination of sentinel lymph nodes taking into account current guidelines, no longer provides demonstrable benefits and its routine use is not justified. According to the latest international recommendations, intraoperative examination of the sentinel lymph node may be indicated in connection with mastectomy (when postoperative radiotherapy is not planned) and after neoadjuvant treatment. Our results suggest that the detection of suspected lymph nodes during preoperative axillary ultrasound may predict the stage of the disease. Based on our research results confirm that in patients receiving neoadjuvant therapy, in addition to the preoperative size of the tumour (≤20 mm, P = 0.002), the preoperative size of the lymph node (≤15 mm, P = 0.04) may also be used to predict that the stage of the disease is N0-1.

ONEST (Observers Needed to Evaluate Subjective Tests) suggests four or more observers for a reliable assessment of the consistency of histological grading of invasive breast carcinoma: A reproducibility study with a retrospective view on previous studies.

Histological grade is one of the most important prognosticators of breast cancer which is available for nearly all cases. It also makes part of several multivariable analysis derived combined prognostic profiles despite concerns about its reproducibility. The aims included a reproducibility study of grading in the light of a recently described statistical approach, ONEST (Observers Needed to Evaluate Subjective Tests) and review earlier reproducibility studies in the light of the ONEST analysis. Nine pathologists reviewed 50 core needle biopsies and 50 slides from different excision specimens and recorded the scores for gland (tubule) formation, nuclear pleomorphism and mitotic activity as well as histological grade. Overall percent agreement, Fleiss kappa and the intraclass correlation coefficient (ICC) were used for the analysis of reproducibility. ONEST data and curves were generated from 100 random permutations of the participants. ONEST suggested a minimum of 4 observers for the reliable evaluation of reproducibility for both the scored components and grade in either type of specimen. Our results suggested moderate or moderate to good reproducibility of grading (kappa values of 0.51 for excisions, and 0.54 for biopsies and ICCs of 0.70 and 0.69, respectively) with gland formation being the most and nuclear pleomorphism the worst consistently evaluated feature. In studies with sufficient participants (at least 4) and non-pairwise comparisons in the analysis, the reproducibility of histological grading is fair to moderate, whereas studies with fewer participants or pairwise kappa analysis suggest moderate to almost prefect agreement of the results. ONEST is a valuable complementation of reproducibility analyses.

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.

Tumor topoisomerase II alpha status and response to anthracycline-based neoadjuvant chemotherapy in breast cancer.

OBJECTIVES: Individualized chemotherapy for breast cancer improves the outcome. Anthracyclines target the enzyme topoisomerase IIα (TOP2A). We set out to perform a retrospective study of the presence of gene abnormalities and the expression of TOP2A in a cohort of breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. METHODS: Forty-three patients with 45 breast cancers were treated with neoadjuvant docetaxel-epirubicin with/without capecitabine chemotherapy. The TOP2A status of the cancers, determined retrospectively by fluorescent in situ hybridization and immunohistochemistry, was analyzed in relation to the standard clinical and pathological data. RESULTS: Clinically and pathologically complete remission (pCR) was achieved in 15 (33.3%) and 9 (20%) cases, respectively. The TOP2A gene was amplified in 2 human epidermal growth factor receptor 2 (HER2)-positive cancers (8%), and 32 (84.2%) overall exhibited TOP2A expression in >15% of the cells. The expression of TOP2A exhibited a strong correlation with the expression of Ki67 (R = 0.743, p < 0.001), and was negatively correlated with estrogen receptors (ER; R = 0.404, p = 0.012) and progesterone receptors (R = 0.430, p = 0.007). The expression of TOP2A was not related to the amplification of the TOP2A gene or the HER2 status of the tumor. The proportions of Ki67- and TOP2A-positive tumor cells were significantly reduced after chemotherapy (56.1 ± 23.6 vs. 19.0 ± 27.7%, p = 0.004, and 41.0 ± 27.9 vs. 12.7 ± 24.8%, p < 0.001, respectively). The development of pCR was related to a high grade (p = 0.054), ER negativity (p = 0.027) and high TOP2A expression (p = 0.037). The expression of TOP2A was an independent predictor of pCR (OR = 1.460, for every 10% increase, 95% CI: 1.016-2.096, p = 0.041). After a median follow-up time of 31.0 months, neither relapse-free survival nor overall survival was related to the tumor response. CONCLUSIONS: TOP2A expression is a marker of the tumor's proliferation rate and sensitivity to anthracycline-based chemotherapy, and does not depend on the amplification of its gene.

"Gap in the shield" ­ imaging of the thyroid gland from the multidisciplinary perspective / "Rés a pajzson" - a pajzsmirigy modern képalkotó vizsgálata multidiszciplináris szemszögbol.

Összefoglaló. A pajzsmirigy az elso szervek közé tartozik, melyek megjelenítésében, betegségeinek felfedezésében az ultrahang-diagnosztikának fontos szerepe van. A pajzsmirigybetegségek a lakosság jelentos részét érintik, és a technika fejlodésével egyre több pajzsmirigyeltérés, göb kerül felfedezésre. A pajzsmirigy rosszindulatú folyamatainak nincs egy bizonyos specifikus jele, viszont az ultrahangkép alapján meghatározhatók a malignitásra gyanús eltérések. Erre az elmúlt években több összefoglaló rendszer is született. Jelen összefoglaló tanulmányunknak az a célja, hogy bemutassuk a pajzsmirigy ultrahangdiagnosztikájának fejlodését; összehasonlítsuk az egyes leletezési rendszereket, úgymint TIRADS, EU-TIRADS, K-TIRADS, melyek célja a feltehetoleg rosszindulatú göbök kiszurése, azonosítása a mindennapi rutinmunka során; vizsgáljuk a különbözo rendszerek kapcsolatát a patológia által használt Bethesda-pontrendszerrel. Az ultrahangvizsgálat megfelelo értékelése, a pontrendszerek ismerete segíthet a pajzsmirigygöb differenciáldiagnózisában, a követési frekvencia meghatározásában, csökkentheti az aspirációs citológiák számát, ezzel támogatva a klinikai döntéshozatalt. Orv Hetil. 2021; 162(14): 530-541. Summary. The thyroid gland was one of the first organs, the ultrasound (US) examination of which has played an important role. The thyroid diseases affect a large part of the population, and with the development of imaging technology, more and more thyroid abnormalities, nodules and malignant lesions are being discovered. There are no specific signs of thyroid cancer, but the suspicious signs could be determined by US. In recent years, several systems have been developed. The aim of our review is to demonstrate the development of US diagnostics of the thyroid gland; to compare the different reporting systems, such as TIRADS, EU-TIRADS, K-TIRADS, which should help to identify the questionable lesions in the daily routine work. We examine the relationship between the different US systems and the Bethesda point score used by pathologists. The literature review shows that the US examination supports the clinical decisions, helps to select, who should have a fine-needle biopsy, and allows to determine the frequency of follow-up. The number of unnecessary fine-needle biopsies could be reduced, too. Our paper is part of a bigger research, the ethical license number is 23/2020, University of Szeged. Orv Hetil. 2021; 162(14): 530-541.