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Background: Liver metastases (LM) are ultimately present in ~50% of all patients with metastatic breast cancer (BC). Metastatic seeding to the liver relies on the interaction between cancer cells and the host microenvironment, resulting into two main histopathological growth patterns (HGPs): the replacement HGP (metastasis mimics the liver architecture and exploits liver vasculature) and the desmoplastic HGP (presence of a fibrotic rim separating the hepatocytes from the tumor cells). While the prognostic value of these HGPs is established for colorectal cancer, with the desmoplastic HGP being associated with better prognosis, investigation is needed for BC. It has also been reported that patients with LM have a poorer response to immune checkpoints inhibitors. A systematic evaluation of the HGP and LM-associated immune infiltrates (stromal tumor infiltrating lymphocytes, sTIL) is currently lacking. In this study, we aimed at: (i) investigating HGPs and sTIL in LM from patients with BC, and, (ii) evaluating the association of these HGPs and sTIL with standard variables and outcome. Patients and methods: The study currently includes clinical data and samples from: 1) a retrospective cohort of 122 patients from 7 hospitals with surgically resected LMs (represented by 548 hematoxylin and eosin (H&E)-sections), further referred to as ‘surgical cohort’ and, 2) LMs from 2 institutional post-mortem tissue donation studies for a total of 23 patients (97 H&E-sections). All available H&E-sections were used to assess HGP and sTIL. HGPs were scored according to a standardized method (PMIDs: 35650276) and categorized per patient as pure-replacement (rHGP, i.e. 100% of the tumor-liver interface is replacement) or any-desmoplastic (dHGP, i.e. at least 1% of the tumor-liver interface is desmoplastic). sTIL are expressed as the percentage of stromal area covered by mononuclear immune cells at the metastasis-liver interface. Associations were assessed using Fisher exact and Wilcoxon tests. Univariable and multivariable Cox regression analyses stratified by center were used to evaluate the role of HGP on progression-free (PFS) and overall survival (OS). Results: In the surgical cohort, 54 (44%) of patients displayed a rHGP and 68 (56%) a dHGP. Intra-patient, meaning inter-slide, heterogeneity of the HGP was observed in 24/122 (20%) of the patients suggesting that scoring multiple slides is needed for accurate assessment of the HGPs. We did not find any statistically significant association between HGP and clinico-pathological data. Higher sTIL were associated with dHGP (p=.003), as well as with a higher histological grade (p= .087), estrogen receptor-positivity (p=0.062) and ductal histology (p= .08) of the primary tumor. rHGP was associated with worse PFS and OS, both at the univariable and multivariable level (Table). In the post-mortem cohort, we observed a higher frequency of rHGP patients (19/23 patients, 83 %) and significantly lower levels of sTIL in the rHGP patients as compared to the rHGP patients from the surgical cohort (p= .009). Conclusion: This study represents the largest study evaluating HGPs and immune infiltrates of LMs from patients with BC. Approximately half of the surgically resected LMs have a dHGP, which is associated with higher sTIL and a better prognosis. The results from the LMs from the post-mortem cohort suggest that a more advanced stage of the disease is associated with an increase in rHGP and with a more immunosuppressed environment. Table 1: Univariable and multivariable analyses Citation Format: Sophia Leduc, Maxim De Schepper, Peter Vermeulen, Giuseppe Floris, Elia Biganzoli, Vincent Donckier, Ali Bohlok, Marco Gerling, François Richard, Marion Maetens, Joris Jaekers, Baki Topal, Emily Latacz, Karen Van Baelen, Tatjana Geukens, Ha Linh Nguyen, Luc Dirix, Denis Larsimont, Sophie Van Kerckhove, Rui Caetano Oliveira, Janina Kulka, Valerio Lucidi, Yannick Meyer, Cornelis Verhoef, Eva Santos, Ferenc Salamon, Lilla Madaras, A. Marcell Szasz, Székely Borbála, Kristòf Dede, Jennie Engstrand, Carlos Fernandez Moro, Christine Desmedt. Histopathological and immune characterization of liver metastases from patients with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-06.

A molaterhesség a terhességi trophoblastbetegségek közé sorolt, rendkívül ritka kórkép. A kórkép patogenezise egyedülálló, hiszen az anyai daganat eredete maga a terhességi szövet. Előfordulását tekintve főleg a reproduktív korú nőket érinti. Esetbemutatásunkban egy 53 éves nőbeteg postmenopausalis vérzési rendellenességet okozó panaszainak hátterében igazolódott molaterhesség. A molaterhesség fokozott kockázattal járó veszélyállapot, mely esetén a mihamarabbi befejezés alapját a megfelelő diagnosztika adja. Kezdeti tünetei megtévesztőek lehetnek, ectopiás terhességet vagy inkomplett abortuszt, anovulációs vérzési rendellenességet utánozhatnak. Esetismertetésünk célja, hogy felhívja a figyelmet a molaterhesség atipikus megjelenésére; postmenopausalis nőbetegünk kapcsán áttekintjük a molaterhesség kezelésének alapelveit, és bemutatjuk egy sikeresen kezelt eset diagnosztikus és terápiás lépéseit. Orv Hetil. 2023; 164(7): 273–277.

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM. Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN, RAD51C, BRIP1, and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations.

Papillary lesions of the breast represent a heterogeneous group of lesions including benign papillomas, papillomas with focal epithelial atypia, fully fledged ductal carcinoma in situ (DCIS) or lobular neoplasia, papillary DCIS, encapsulated papillary carcinomas without or with invasion, solid papillary carcinomas, and invasive papillary carcinomas. A micropapillary pattern characterized by lack of fibrous stalks within the papillae is observed in micropapillary DCIS and invasive micropapillary carcinoma. In addition, a variety of other rare breast lesions reveals a papillary architecture such as tall cell carcinoma with reversed polarity (TCCRP) and mucinous cystadenocarcinoma, adenomyoepithelioma, and secretory carcinoma. In addition, benign lesions such as usual ductal hyperplasia, apocrine metaplasia, gynecomastia, and juvenile papillomatosis may show a papillary or micropapillary architecture. Fragments of a benign papilloma in a breast biopsy are considered a lesion of uncertain malignant potential (B3 in the European classification) and excision is mostly recommended. Although the knowledge about molecular pathology of papillary breast lesions has increased, there is not sufficient evidence for diagnostically useful molecular features, yet. The aim of this review is to provide an update on papillary and micropapillary lesions with emphasis on problematic areas for daily diagnostic work including biopsies. ispartof: VIRCHOWS ARCHIV vol:480 issue:1 pages:65-84 ispartof: location:Germany status: published

Although several antibodies are available for immunohistochemical detection of Ki-67, even the most commonly used MIB-1 has not been validated yet. Our aim was to compare 5 commercially available antibodies for detection of Ki-67 in terms of agreement and their ability in predicting prognosis of breast cancer. Tissue microarrays were constructed from 378 breast cancer patients' representative formalin-fixed, paraffin-embedded tumor blocks. Five antibodies were used to detect Ki-67 expression: MIB-1 using chromogenic detection and immunofluorescent-labeled MIB-1, SP-6, 30-9, poly, and B56. Semiquantitative assessment was performed by 2 pathologists independently on digitized slides. To compare the 5 antibodies, intraclass correlation and concordance correlation coefficient were used. All the antibodies but immunofluorescent-labeled MIB-1 (at 20% and 30% thresholds, P=.993 and P=.342, respectively) and B56 (at 30% threshold, P=.288) separated high- and low-risk patient groups. However, there were a significant difference (P values for all comparisons≤.005) and a moderate concordance (intraclass correlation, 0.645) between their Ki-67 labeling index scores. The highest concordance was found between MIB-1 and poly (concordance correlation coefficient=0.785) antibodies. None of the antibodies except Ki-67 labeling index as detected by poly (P=.031) at 20% threshold and lymph node status (P

We aimed to analyze to what extent expression of four cell cycle regulation markers-minichromosome maintenance protein (MCM2), Ki-67, cyclin A, and phosphohistone-H3 (PHH3)-predict response to primary systemic therapy in terms of pathological complete remission (pCR). In search of an accurate and reproducible scoring method, we compared computer-assisted (CA) and routine visual assessment (VA) of immunoreactivity. We included 57 patients with breast cancer in the study. The cell cycle markers were detected using immunohistochemistry on pre-therapy core biopsy samples. Parallel CA (validated by manual labeling) and standard VA were performed and compared for diagnostic agreement and predictive value for pCR. CA and VA results were dichotomized based on receiver operating characteristic analysis defined optimal cut-off values. "High" was defined by staining scores above the optimal cut-off, while "low" had staining scores below the optimal cut-off. The CA method resulted in significantly lower values for Ki-67 and MCM2 compared to VA (mean difference, -3.939 and -4.323). Diagnostic agreement was highest for cyclin A and PHH3 (-0.586 and -0.666, respectively). Regardless of the method (CA/VA) used, all tested markers were predictive of pCR. Optimal cut-off-based dichotomization improved diagnostic agreement between the CA and VA methods for every marker, in particular for MCM2 (κ = 1, p

Introduction To characterize breast tumors and metastases, fine-needle aspiration cytology (FNAB) can be a favorable first choice. However, the diagnostic accuracy of ancillary tests applied to FNAB samples is yet to be validated. Patients and Methods We examined 110 breast cancer patients' paired cytological and surgical resection specimens evaluated between 2005 and 2014. Comparison of ER and Her2 immunocytochemical (ICC) and immunohistochemical (IHC) staining and HER2 fluorescence in situ hybridization (FISH) was performed. Results Significant difference (p

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.

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.

Purpose We aimed to compare the immunohistochemical expression of PD-1, PD-L1 and CTLA-4 of pregnancy-related breast cancer (PRBC) and early onset non-PRBC (YWBC), and their prognosis prediction potential was correlated to that of conventional clinicopathological factors. Methods Twenty-one PRBC cases were paired with 21 YWBC in this matched case-control study. Immune-checkpoint markers (ICM) were evaluated with immunohistochemistry (IHC) on whole slides using the following antibodies: PD-1 (NAT-105), PD-L1 (28-8) and CTLA-4 (F-8). IHC score was defined as the percentage of positive cells, assessed separately among tumor cells, intratumoral lymphocytes and peritumoral lymphocytes. Results The optimal threshold of PD-L1 expression of tumor cells occurred at 10% for overall survival (OS, AUC = 0.847, p = 0.009), and at 1% for disease-free survival (DFS, AUC = 0.795, p = 0.010). For PD-L1 expression on intratumoral lymphocytes, the optimal cut-off was 1% (AUC = 0.763, p = 0.048). Considering PD-1, PD-L1 and CTLA-4 expression, no significant difference occurred between PRBC and YWBC (p > 0.05 for all comparisons). PD-1, PD-L1 expressed on peritumoral lymphocytes and CTLA-4 failed, but PD-L1 expressed on tumor cells and on intratumoral lymphocytes was suitable to distinguish patient cohorts with different OS and DFS (p ≤ 0.011 for all comparisons). Higher PD-L1 expression was associated with poor prognosis. PD-L1 expressed on tumor cells represented an independent association with OS (p = 0.023) and DFS (p = 0.032). Conclusions Our results suggest that PRBC and YWBC do not differ in the expression of PD-1, PD-L1 and CTLA-4. However, our findings emphasize the relevance of PD-L1 expression in early-onset breast cancer, as an independent negative predictor of prognosis.

In this study, the reproducibility of Ki-67 proliferation index (KIPI) was investigated by comparing the semi-quantitative (SQ) results of three assessors with those of digital image-analysis (DIA) methods. The prognostic significance of the two approaches was also correlated with clinical outcome. Tissue microarrays of duplicate 2 mm cores were constructed from representative areas of formalin-fixed and paraffin-embedded tumor blocks of 347 breast cancer patients. SQ evaluation of Ki-67 (MIB1 clone) immunostained slides was performed independently by three pathologists. DIA was completed using a fully automated histological pattern and cell recognition module for KIPI detection (DIA-1) and an adjustable module (DIA-2) with the possibility of manual corrections. To compare SQ and DIA evaluations intra-class correlation (ICC) and concordance correlation coefficients (CCC) were determined. The three SQ evaluations demonstrated a remarkable ICC (0.853). Significant difference and poor concordance occurred between SQ-1 and SQ-2 as well as between SQ-1 and SQ-3 (p ≤ 0.001, CCC ≤ 0.827 for both comparisons). Thus, the reference KIPI value (SQ-RV) was generated from the mean values of SQ-2 and SQ-3. SQ-RV and DIA-2 results showed substantial concordance (CCC = 0.963, at p = 0.754), while SQ-RV and DIA-1 values differed (p ≤ 0.001) at only moderate concordance (CCC = 0.906). In multivariate analysis, lymph node status and SQ-2 assessment were significantly associated with clinical outcome (p ≤ 0.012 for both comparisons). Our results confirm that KIPI is a significant prognostic marker in breast cancer, which can be can be reliably reproduced by using an adjustable DIA-2 image analysis module.

The name of the co-author of MD-05-001 (page S62) should be presented as 'S. Vari-Kakas' instead of 'I.i Vari-Kakas' in the authorship group. The name has been corrected in the authorship group shown above.

Pregnancy Associated Breast Cancer (PABC) manifests during pregnancy or within a year following delivery. We sought to investigate differences in management, outcome, clinical, histopathology and immunohistochemistry (IHC) characteristics of PABC and matched controls in a retrospective case control study. PABC and control patients were selected from breast cancer cases of women ≤45 years, diagnosed in the 2nd Department of Pathology, Semmelweis University, Budapest, Hungary between 1998 and 2012. Histopathology information on tumor type, grade, size, T, N, lympho-vascular invasion (LVI), Nottingham Prognostic Index (NPI), associated in situ lesions and IHC charcteristics: ER, PgR, HER2, Ki67, p53 were recorded, IHC-based subtype was assessed, clinical, management and outcome data were analysed. Thirty-one breast cancer cases were pregnancy related. Clinical management data did not differ in cases and controls. Histopathology of disease at presentation was not significantly different, but NPI assessed the PABC group as having poor, whereas controls as having intermediate prognosis. Associated in situ lesion was more often high grade Extensive Intraductal Carcinoma Component (EIC) in PABC. Triple negative and LuminalB prol tumors predominated in PABC. Disease-free and overall survival was inferior compared to controls. PABC patients with LuminalB prol and Triple negative tumors had inferior outcomes. On multivariate analysis inferior prognosis of PABC was associated with pregnancy. Our study has demonstrated inferior outcome of PABC. Difference in tumor biology is reflected by the predominance of triple negative and LuminalB tumors in PABC. The strength of the study is the analysis of complete pathology and IHC data.

Phenotypical change in metastatic breast carcinoma has widely been accepted as an inherent biological feature rather than technical fault. We analyzed the immunohistochemical phenotype and histopathological features of 25 primary breast carcinomas and 90 corresponding distant metastases in 23 organs retrospectively. Histological slides were reviewed for prognostic and predictive factors. Overall, metastases were more similar to each other and often differed from the primary tumor. We created a 3-step grouping system based on the localization of metastases. Regions: tumors metastasizing to the abdominal region were likely to lose ER (p = 0.002); we detected loss of PR in metastases to the thorax (p = 0.039) and abdomen (p < 0.001). Organ systems: loss of ER and PR was observed in metastases to the gastrointestinal system (p = 0.026 and p = 0.001, respectively), in the respiratory system only the loss of PR was significant (p = 0.05). Individual organs: the primaries were likely to lose the hormone receptors in liver metastases (ER p = 0.026; PR p = 0.004). In lung metastases only loss of PR was apparent (p = 0.049). We did not observe significant change in HER2 status, regarding Ki67 change occurred only in bone metastases compared to the primary (p = 0.048). 7/25 patients’ distant metastases had heterogeneous immunoprofiles. The later the metastasis was discovered the more likely it had a differing IHC profile compared to the primary tumor, patients who had longer OS had a higher chance to develop a discordant metastasis. Immunoprofile of metastases may differ from primary breast cancer and from each other, probably resulting in different response to therapy.

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.

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.

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.Az emlõrákkal kapcsolatos klinikopatológiai kutatások egyetemünkön a XX. század második felében a II. Sz. Patológiai Intézethez köthetõk. Napjainkban, az onkológiai ellátás fejlõdését követve, egyre inkább arra törekszünk, hogy olyan prediktív és prognosztikus markerek meghatározását végezzük el, amelyek lehetõvé teszik/tehetik az egyre inkább személyre szabott terápiás megközelítést. A mai molekuláris patológiai eljárások képesek lehetnek a tumor biológiai viselkedésének pontosabb felmérésére, lehetõvé téve a hatékonyabb terápiás választást mind neoadjuváns/adjuváns kezelés esetén, mind metasztatikus betegség esetén. Összefoglaló közleményünkben áttekintést nyújtunk a Semmelweis Egyetem II. Sz. Patológiai Intézetben elvégzett emlõrákkutatások fontosabb eredményeirõl a 2000–2015 periódusban.

To characterize breast tumors and metastases, fine-needle aspiration cytology (FNAB) can be a favorable first choice. However, the diagnostic accuracy of ancillary tests applied to FNAB samples is yet to be validated.We examined 110 breast cancer patients' paired cytological and surgical resection specimens evaluated between 2005 and 2014. Comparison of ER and Her2 immunocytochemical (ICC) and immunohistochemical (IHC) staining and HER2 fluorescence in situ hybridization (FISH) was performed.Significant difference (p 0.001) and moderate correlation (κ = 0.446) were noted between results of 97 paired ICC an IHC reactions for ER expression. ICC for ER status had a sensitivity of 75%, specificity of 100%, positive predictive value (PPV) of 100%, and negative predictive value (NPV) of 38.2%. Significant difference (p = 0.012) and moderate correlation (κ = 0.541) were found between results of 77 paired ICC an IHC reactions for Her2 expression. The Her2 ICC had a sensitivity of 54%, specificity of 95.4%, PPV of 66.7%, and NPV of 92.6%. The results of FISH carried out on 23 paired samples of FNAB and surgical specimens indicated perfect correlation (κ = 1.000) and no significant difference (p = 1.000). FISH performed on FNAB has sensitivity, specificity, PPV, and NPV of 100%.The correlation of ICC and IHC is moderate regarding ER and Her2 expression of the same tumor. FISH performed on FNAB samples is suitable to categorize primary and metastatic breast cancer in regard of HER2 gene amplification status and can be used as a predictive test in respect of therapies targeting HER2. Diagn. Cytopathol. 2016;44:466-471. © 2016 Wiley Periodicals, Inc.

Introduction: The molecular architecture of tight junctions (TJ) has been a subject of extensive studies in a number of malignancies. Among the TJ components, the members of the protein family claudins (CLDN) have been found to be differentially expressed correlating with histological grade (HG) in a number of tissues. Furthermore, the expression of these junctional proteins (JP) have recently been implied in the identification of the claudin-low subtype by gene expression analysis. Material and methods: 261 breast cancer specimens diagnosed between 1999 and 2002 were collected and evaluated histopathologically and immunophenotypically by a single specialist. Tissue microarrays were constructed using a TMA-builder instrument (Histopathology Ltd., Pecs, Hungary). To identify the eventual prognostic role of the TJ proteins CLDN3, −4 and −7, and adherent junction protein E-cadherin (ECDH) their immunohistochemical (IHC) expression was analysed by 3 investigators separately, and a consensus score was reached. The IHC results were compared to the patients' follow-up data applying Kaplan-Meier analysis supported by log-rank test. Furthermore, we aimed at identifying the worse prognosis tumour group based on clustering of the expression of the above mentioned JPs. Results: The expression of CLDN3 correlated with vascular invasion (VI)/p = 0.029/, necrosis (NC)/p = 0.001/, HG/p = 0.001/ and mitotic index (MI)/p = 0.022/. CLDN4 and CLDN7 correlated with NC/p = 0.001, p = 0.012, respectively/ and HG/p = 0.034, p = 0.001, respectively/, while ECDH correlated with HG/p = 0.001/ and MI/p = 0.001/. In single protein analysis, groups displaying gradually increasing CLDN3, −7 and ECDH/p = 0.017/expression (split at mean expression ± SD) showed a trend of bearing poorer prognostic features. CLDN4, on the other hand, showed different tendency: gradually increasing expression also correlated with worse relapse-free survival (RFS), while CLDN4 negative/low tumors had the poorest prognosis/p = 0.034/. In multiple protein analysis, groups were created using k-means clustering and the following cohorts were created - appearing in prognostic sequence starting with the longest RFS: ECDH-low groups with 1) low/n=31/ and 2) high/n=42/ CLDN3 expression; 3) CLDN7-low (CLDN3, -4 and ECDH-high) group/n=35/, 4) “all-high” expression group/n=70/; 5) CLDN3-low (CLDN4, -7 and ECDH-high) group/n=68/ and 6) “all-low” group/n=15/. The latter was characterised by the CLDN4-low feature as compared to the other groups. Conclusion: Expression of JPs can have prognostic relevance in breast carcinomas. The groups with low expression of ECDH have good prognosis, while gradually increasing JP expression outlines poor prognostic tumours. Strikingly the drop in all JPs expression - most likely resembling the claudin-low subtype - specifies the subgroup with the poorest outcome, which still remains an infrequent disease entity. Grant support: TÁMOP-4.2.2/B-10/1-2010-0013. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-08.

The optimal oncological result of radical prostatectomy (RP) is complete removal of the prostate gland and seminal vesicles with negative surgical margins. Preoperative diagnostic biopsies are examined and reported by the pathologist according to standardized rules. Staging of the disease is based on modern preoperative image analysis, most commonly multiparametric MRI. Pathological assessment and reporting of RP specimens is based on the International Society of Uropathology guidelines issued by the 2009 Consensus Conference. Positive surgical margin (PSM) is reported by the pathologist in approximately 1/3rd of RP cases. PSM increases the risk of biochemical, local and systemic progression. Pseudo-whole mount assessment of these specimens is the basis for radio-pathological correlation, thus providing quality control for preoperative MRI as well as assisting preoperative image analysis, sampling and diagnostic workup.A radikális prosztatektómia onkológiai szempontból akkor optimális, ha a prosztata és az ondóhólyagok teljes egészében, szabad (tumormentes) sebészi széllel kerülnek eltávolításra. A preoperatív diagnosztika egyik alappillére a ma már egyre inkább elterjedt, 12 szövethengert biztosító ún. extended biopszia, a minta értékelése standardizált szabályok szerint történik a patológus által. A preoperatív diagnosztika másik fontos tényezõje a modern képalkotás – mely a betegség stádiumának meghatározásához nélkülözhetetlen – amely napjainkban leggyakrabban a multiparametrikus MR-vizsgálat. A radikális prosztatektómia során eltávolított preparátum patológiai feldolgozása és értékelése az International Society of Urological Pathology (ISUP) 2009-es konszenzuskonferenciáján meghatározottak szerint történik. Pozitív sebészi szél elõfordulása – az egyre javuló mûtéti technikák ellenére – ma sem ritka, a patológus az esetek harmadában diagnosztizálja azt. A pozitív sebészi szél fokozza a biokémiai, lokális és szisztémás progresszió kockázatát. A radikális prosztatektómiás preparátum nagyblokkokban (pseudo-whole mount) történõ feldolgozása a radio-patológiai korreláció alapja, mely lehetõvé teszi az MR-vizsgálatok minõségbiztosítását, valamint az így szerzett tapasztalatok a preoperatív képalkotást, mintavételt és diagnosztikát is segíthetik.

Introduction: In cases of breast cancer, in addition to hormone receptor and Her2 status, proliferation markers (mitotic index, Ki-67 proliferation index = KIPI) also have therapeutic implications. The 2013 St. Gallen consensus guideline includes 14% cut-off point (20% by many experts) for KIPI to distinguish luminal A-like and luminal B-like subtypes, that might be associated with remarkable intra-/interobsever variability applied in daily pathological routine utilizing semiquantitative (SQ) "eye-balling" method. Objective: The comparison of conventional SQ method and digital image-analysis (DIA) processes for the detection of KIPI. Methods: Three hundred and forty-seven breast cancer patients' samples with 99.24 months median follow-up data were included in our study (ethical approval: IKEB #7/2008 and 7-1/2008). Tissue microarrays (TMA) were prepared from the representative paraffin-embedded tumor blocks. After performing Ki-67 (MIB1 clone, #0505 by iOT on Ventana Benchmark XT autostainer by Roche) immunoreaction, conventional evaluation of KIPI was performed by 3 breast pathologists independently (SQ1-3). Digital image analysis was supported by PatternQuant (Pannoramic Viewer v15.3 and QuantCenter 2.0, 3DHistech Ltd.) applying a fully automatic tumor tissue recognition module with KIPI detection (DIA-1), and an adjustable module (DIA-2) with the possibility of manual corrections to exclude false detections. Interobserver variability was estimated with intra-class correlation coefficient (ICC). Digital pathological methods were compared to the - currently gold standard - SQ determination of KIPI using SPSS 22 statistical program. Results: The three pathologists' SQ evaluations demonstrated a remarkable concordance (ICC=0.889; 95% CI= 0.834-0.922). A reference KIPI value (KIPI-RV) was derived from mean values of SQ2 and SQ3, since no significant difference was found between them (p=0.617). KIPI-RV and DIA-2 showed no significant difference (p=0.754), and excellent concordance (ICC=0.979; 95% CI=0.975-0.982). Significant difference has occurred between KIPI-RV and results of DIA-1 (p=0.001). Upon dichotomizing KIPI value at 14%, no significant difference was found between KIPI-RV and DIA-2 (p=0.262), while KIPI-RV and DIA-1 differed (p=0.006). For prognosis prediction, all three methods were able to perform statistically significant division of our patients into 2 cohorts with distinct DFS at 14% (p Conclusion: The DIA processes are objective methods in the evaluation of KIPI. The fully automated DIA-1 method differed most from SQ results. Digital image analysis adjusted by a pathologist (our DIA-2 method) reached high concordance with results of SQ. Further refinement and validation are needed to verify applicability of automatic tumor pattern recognition software in diagnostic practice. Our results confirm that SQ evaluation of KIPI is reliable. This study was supported by the research grant from Hungarian Society of Medical Oncology 2014 and research grant from Doctoral School of Ph.D. Studies, Semmelweis University 2014. Citation Format: Acs B, Madaras L, Kovacs KA, Tokes A-M, Kulka J, Szasz AM. Ki-67 proliferation index supported by digital quantitation in breast cancer: A comparative study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-02.

Patients at young age (≤ 35 years) diagnosed with breast cancer (BC) are considered to have poor prognosis. The aim of the present study was to retrospectively analyse clinicopathological characteristics and prognosis in a group of young BC patients. We included women diagnosed with invasive breast carcinoma younger than/or at the age of 35 years. Between 1999 and 2009, 107 women with early-onset BC were selected from the database of the 2nd Department of Pathology at Semmelweis University. For clinicopathological comparison, 55 women (36-45 years), 214 women (46-65 years), 110 women (66-75 years) and 58 women (76 ≤ years) were also included in the analysis. Family history, clinicopathological and follow-up data were analysed. The tissue specimens were reviewed for histological type, nuclear grade, and estrogen receptor (ER), progesterone receptor (PgR), Ki67 and HER2 status (IHC4). The mean age in the study group was 31.6 years at the time of diagnosis. Histology showed a high incidence of grade III tumours in this group of patients (67.9 %), while only four cases (3.8 %) were considered grade I. According to the immunohistochemical results, 35.3 % of the study cases were considered as Luminal B (LumB: either being higly proliferative or co-expressing HER2) and 33.3 % as triple negative breast carcinomas (TNBC). The detailed questionnaire related to family history was completed and received in 49/107 cases (45.8 %). Analysis of these data revealed an affected family history of breast or ovarian carcinoma in first and second degree relatives in 51.0 %. A high proportion (52.0 %) of TNBC was observed among young women with a family history of the disease. Survival analysis of the 107 patients showed that 25 (23.3 %) women died until 31 December 2012. No significant difference in survival was detectable considering the regimen of systemic treatment (p = 0.188). Regarding clinicopathological parameters, the immunophenotypes, grade, pT and pN values differred substantially between the age groups (p = 0.001, for all), and the shortest relapse-free survival was seen among the youngest BC patients. This analysis illustrates that breast cancer arising in young women is characterized by the presence of less favorable subtypes such as LumB and TNBC. The increased proportion of TNBC was especially remarquable in the group of patients presenting with family history of the disease. The fact that a high rate of death occurred and no significant difference in OS were notable regarding the scheme of systemic therapies (neoadjuvant vs. adjuvant) highlight the necessity of the development of new treatment strategies.

There is a reasonable heterogeneity in the morphological appearance and the immunohistochemical properties of distinct breast tumors. Furthermore, it is also known that cancer arising in young women have different prognosis than the ones developing in the elderly. We analyzed breast tumors of 41 young (35 years) and 33 older women (65 years) regarding histopathological properties and immunohistochemical reactions for ER, PgR, HER2 and Ki-67, as well as HER2 FISH. The longest diameters, thus largest available surface areas of the tumors were included in the evaluation. Different regions were marked for morphology and in all immunohistochemical reactions. The regions in the distinct tumors showing different pathological and immunohistochemical appearance were identical (p0.001). The number of morphologically different tumor regions were more frequent in tumors developing in the young (1.82 vs. 1.48 regions/tumor), and 53.6% of tumors with heterogeneous architecture were in young vs. 39.4% in the elderly. However, regarding HER2 staining, cancers in the young patients have shown greater variability among the different tumor areas (p=0.007). The origin of tumor cells predicting prognosis remains undetermined. Whether the analysis of the expression pattern of the whole tumor is conducted or the minute regions are separately examined and averaged, the same results can be achieved. With the development of molecular techniques and accurate prognostic and treatment information rendered to samples the question may be soon answered.

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.

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.

Adherent and tight junction molecules have been described to contribute to carcinogenesis and tumor progression. Additionally, the group of claudin-low tumors have recently been identified as a molecular subgroup of breast carcinoma. In our study, we examined the expression pattern of claudins, beta-catenin and E-cadherin in invasive ductal (IDCs) and lobular (ILCs) carcinomas and their corresponding lymph node metastases (LNMs). Tissue microarrays of 97 breast samples (60 invasive ductal carcinomas, 37 invasive lobular carcinomas) and their corresponding LNMs have been analyzed immunohistochemically for claudin-1, -2, -3, -4, -5, -7, beta-catenin and E-cadherin expression. The stained slides were digitalized with a slide scanner and the reactions were evaluated semiquantitatively. When compared to LNMs, in the IDC group beta-catenin and claudin-2, -3, -4 and -7 protein expression showed different pattern while claudin-1, -2, -3, -4 and -7 were differently expressed in the ILC group. Lymph node metastases developed a notable increase of claudin-5 expression in both groups. Decrease or loss of claudin-1 and expression of claudin-4 in lymph node metastases correlated with reduced disease-free survival in our patients. According to our observations, the expression of epithelial junctional molecules, especially claudins, is different in primary breast carcinomas compared to their lymph node metastases as demonstrated by immunohistochemistry. Loss of claudin junctional molecules might contribute to tumor progression, and certain claudin expression pattern might be of prognostic relevance.

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.

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.