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Background Mammary phyllodes tumours (PT) are rare biphasic neoplasms but have important clinical significance. Both epithelial and stromal components participate in PT development. Despite a number of studies on stromal c-kit in PT, little is known about the role of its epithelial expression. Objective To further evaluate the stromal and epithelial expression of c-kit in a cohort of patients with PT. Method and results Expression of c-kit in both epithelial and stromal components was examined and correlated with histological features in PT. Stromal c-kit expression was associated positively with stromal cellularity (median expression=10.0, 30.0 and 50.0 from mild to severe cellularity; p=0.019). Conversely, a significant negative trend between epithelial c-kit expression with stromal pleomorphism (median expression=55.0, 30.0 and 2.5 from mild to severe pleomorphism; p=0.043) and mitosis (median expression=70.0 and 20.0 for low and high mitosis respectively; p=0.003); and a trend of negative correlation with increased PT grade was found. Despite these reverse associations, epithelial and stromal c-kit expressions were positively correlated with each other. Notably, the correlation of stromal c-kit expression with malignant histological features appeared to be stronger in cases with low epithelial c-kit expression but not in those with high epithelial c-kit expression. Conclusions This study demonstrated the association of epithelial c-kit expression with stromal histological features and stromal c-kit. Interestingly, epithelial c-kit expression affected the strength of the correlation of stromal c-kit with these histological features. These findings provide further evidence of the interaction between the epithelial and stromal components in PT. [ABSTRACT FROM AUTHOR]

Aims Columnar cell lesions are known as a link between normal breast and low grade neoplastic lesions in female, but have not been established in the male breast. This study evaluated the presence of ducts showing columnar cell-like features in the male breast. Methods Seventy-one consecutive surgical resections from men (6 invasive breast carcinoma of grade 3, 1 atypical ductal hyperplasia and 64 other lesions) were reviewed to identify foci of dilated ducts with columnar epithelial cells, and their morphological features including apical snouts, intraluminal secretions and calcifications were assessed. The expression of CK5/6 and estrogen receptor (ER) was evaluated immunohistochemically. Clinicopathological features including patients' age, histological diagnosis and gynaecomastoid hyperplasia were documented. Results Ducts showing columnar cell-like features were identified in 39 cases, morphologically as distended ducts with round or undulating outline. There was an outer layer of myoepithelial cells and an inner layer of columnar luminal cells showing apical snouts, but without intraluminal secretions or calcifications. Immunohistochemically, these columnar epithelial cells were negative for CK5/6 in 38/39 cases and all were ER heterogeneously positive. These changes were associated with older age, but their incidence did not differ whether they were associated with invasive breast carcinoma, atypical ductal hyperplasia and other lesions. Conclusions In the male breast, there is an entity sharing morphological features and immunohistochemical profile of columnar cell lesions. [ABSTRACT FROM AUTHOR]

The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type-specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions. [ABSTRACT FROM AUTHOR]

Basal-like breast cancer (BLBC) is the breast cancer subtype defined by gene profiling and generates keen clinical interest. Immunohistochemical panels using basal cytokeratins and epidermal growth factor receptor are widely adopted for its identification. Nonetheless, there are concerns about the risk for missing some true BLBCs. Both P-cadherin and vimentin have been proposed as BLBC markers, but their usefulness for BLBC classification has not been well documented. In this study, we evaluated by immunohistochemistry their expression in a large cohort of breast carcinoma. Cancers expressing vimentin or P-cadherin showed BLBC-related morphological features (high grade, presence of necrosis, and lymphocytic infiltration; P < .001 for all except P = .006 for vimentin with lymphocytic infiltration) and immunohistochemical profile (P < .001 for all markers tested except P = .007 for vimentin with human epidermal growth factor receptor 2). Concordantly, they were significantly associated with BLBC (P < .001 for both). Nonetheless, they did not appear to be good stand-alone BLBC markers. Compared with the commonly used reference panel, the specificity (95.9%) and sensitivity (43.1%) of coexpression of vimentin and P-cadherin were better than most single markers or their combinations tested. Moreover, their coexpression was significantly associated with basal features in non-BLBCs and worse disease-free survival in triple-negative breast cancers (hazard ratio, 2.232; P = .027). This raised the possibility that the vimentin and P-cadherin combination can be used to identify BLBC especially those that were missed by the commonly used basal cytokeratins and epidermal growth factor receptor panel. Together, P-cadherin and vimentin could be adjunctive to the commonly used immunohistochemical surrogates for BLBC identification. [ABSTRACT FROM AUTHOR]

Carcino-embryonic antigen-related cell adhesion molecule 6 (CEACAM6), one of the members of human carcino-embryonic antigens, is a multifunctional regulatory protein involved in various cellular processes in cancers. Its role in malignant transformation and the clinical significance has been extensively studied in colonic and pancreatic cancers. However, relatively few studies have been done on breast cancers. In the current study, CEACAM6 expression in two independent cohorts of invasive breast cancers were evaluated immunohistochemically and correlated with clinico-pathological features, biomarker profiles and patient survival. In the primary cohort, CEACAM6 expression was detected in 37.1 % (312/840) of primary invasive cancers. It was positively correlated with HER2 ( p < 0.001). Concordantly, HER2-OE subtype showed the highest CEACAM6 expression (62.7 %) among all molecular subtypes; whereas, other subtypes also showed substantial CEACAM6 expression (21.8–37.5 %). Interestingly, a significantly worse overall survival was found in high pN stage HER2 positive cancers with CEACAM6 positivity (log-rank = 4.452, p = 0.035) and this could be validated in an independent cohort. Additionally, HER2 signaling was found to induce SMAD3 phosphorylation and CEACAM6 expression in a cell line model. Likewise, in the primary tumors, a positive association was found between HER2 and SMAD3 phosphorylation in CEACAM6 positive cancers ( p = 0.012). Overall, CEACAM6 was widely expressed in different molecular subtypes, but highest and significantly in HER2-OE breast cancer. Within this group, CEACAM6 was associated with adverse high nodal stage patient outcome. Given the wide expression of CEACAM6 in all breast cancers, its roles as prognostic marker and therapeutic target warrant further evaluation. [ABSTRACT FROM AUTHOR]

Purpose: SETD2 is one of the key epigenetic regulatory genes involved in histone modifications. Its alterations were potentially oncogenic and commonly found in cancers. Interestingly, SETD2 is one of the most frequent mutated genes found exclusively in phyllodes tumor of the breast (PT). However, little has been done to further characterize SETD2 alterations in PT. Methods: In this study, we examined the alterations of SETD2 gene and protein expression in a large cohort of PTs. Their correlations with SETD2 downstream target, H3K36me3 expression, and clinicopathologic features in PT were also assessed. Results: SETD2 mutation was found in 15.9% of our cases and was mostly predicted to be damaging mutations. Interestingly, SETD2 mutations were associated with lower H3K36me3 expression, particularly those with damaging mutations (p =.041). Neither SETD2 mutations nor H3K36me3 expression was associated with PT grading and other clinicopathological features. By contrast, the SETD2 protein expression cannot reflect its mutation status and showed a different trend of clinicopathological correlations from H3K36me3. Conclusions: Our findings may suggest a potential involvement of epigenetic regulation via SETD2 alterations and downstream H3K36me3 on PT development. SETD2 mutations may occur early in the pathogenic process of PTs and its loss per se may not be sufficient for progression to malignancy. Exclusive alterations of SETD2 in PT can be used as markers for the diagnosis of fibroepithelial lesions. The association of H3K36me3 with SETD2 mutations may also indicate the value of evaluation of H3K36me3 expression in the diagnosis of fibroepithelial lesions. [ABSTRACT FROM AUTHOR]

Aims: Atypical ductal hyperplasia (ADH) of breast is increasingly diagnosed in core needle biopsy (CNB). As higher‐grade lesions were found in the excision in a substantial proportion of ADH on CNB, factors predicting risk of subsequent upgrade are clinically significant. This study aims to investigate relevant histopathological factors in CNB that could predict diagnostic upgrade at excision. Methods and results: One hundred and forty‐three cases of CNB with paired subsequent excision were evaluated for multiple clinicopathological parameters related to CNB sampling, ADH morphology, calcification and other co‐existing histological features, and which of these parameters were associated with diagnostic upgrade at subsequent excisions were determined. Forty‐eight cases (34.3%) were upgraded to malignancy, including 15 invasive cancers and 33 ductal carcinomas in situ (DCIS). An increased tissue area occupied by ADH (P = 0.026), a higher number of ADH foci (P = 0.004), the presence of solid pattern (P = 0.037) and older age (P = 0.012) were positively associated with upgrade, while negative associations were found with the presence of micropapillary pattern (P = 0.025), co‐existing columnar cell lesions (CCL) (P = 0.001) and the presence of calcifications (P = 0.009). Multivariate logistic regression analysis showed that the number of ADH foci (HR = 2.810, P = 0.013) was an independent positive predictor, while co‐existing CCL (HR = 0.391, P = 0.013) was an independent negative predictor for upgrade. Conclusions: Patients with ADH in CNB showing the presence of co‐existing CCL and a lower number of ADH foci have a lower risk of disease upgrade at excision, and are potential candidates for observation‐only management. [ABSTRACT FROM AUTHOR]

Aims: Phyllodes tumours (PTs) of the breast are uncommon fibroepithelial neoplasms with the potential to recur and metastasise. Apart from histological grading, the expression of biological markers and its relationship with tumour behaviour have been topics of interest. The phosphatidylinositol 3‐kinase (PI3K)–AKT pathway regulates diverse biological functions, and is one of the most frequently deregulated pathways in cancers. Little is known of PI3K–AKT pathway alteration in PT. We aim to investigate the alterations in different component of AKT pathway in PTs. Methods and results: This study investigated the expression of four biological markers involved in this pathway (PTEN, INPP4B, PI3KCA and pAKT) in 134 PTs by the use of immunohistochemistry. According to an immunoscore incorporating staining intensity and proportion, low epithelial INPP4B expression (P = 0.045) was associated with recurrence. A trend of association was found for low epithelial PTEN expression with recurrence (P = 0.090). Interestingly, low epithelial INPP4B expression was also associated recurred tumours (P = 0.043). Stromal PI3KCA expression (P = 0.016) and pAKT expression (P = 0.006) were found to be correlated with increased histological grade, but an opposite trend was seen for stromal INPP4B expression (P = 0.018). In addition, epithelial and stromal PTEN expression, PI3KCA expression and pAKT expression showed strong correlations with each other (P ≤ 0.001). Conclusions: These findings indicate that alterations in AKT pathway activation may correlate with malignant transformation and recurrence in PT. Low epithelial INPP4B/PTEN expression is associated with shorter recurrence‐free survival. These observations suggest that the pathway may play a crucial role in the biological behaviour and progression of PT, and assessing the expression of this pathway may be of value in diagnosis, grading, prognostication, and management. [ABSTRACT FROM AUTHOR]

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Purpose: Despite numerous studies on the utility of GATA-3 as breast cancer marker, its comparison with other breast markers, its concordance between primary and metastatic tumors and its expression in primary cancers from sites with frequent breast metastases remains unclear.Methods: To address these questions, totally 993 invasive breast cancers (IBC), 254 paired nodal metastases, 23 distant metastases, and 208 lung carcinomas were included. GATA-3 expression was analyzed by immunohistochemistry and compared to other breast markers [gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin (MGB)].Results: GATA-3 was expressed in 82.5% of IBC, predominantly in luminal (93.9%), and lower in non-luminal cancers [59.6% of HER2 overexpressing (HER2-OE) and 38.1% of triple negative breast cancer (TNBC) subtypes]. GATA-3 identified more IBC than GCDFP-15 (23.9%) and MGB (46.6%). However, MGB showed a comparable sensitivity for non-luminal cancers to GATA-3. Combining MGB and GATA-3 improved sensitivity for both HER2-OE (80.8%) and TNBC cases (55.4%). GATA-3 showed a high sensitivity for nodal metastases and distant metastases, with good concordance with primary tumors. GATA-3 was expressed in 1.0% of lung carcinomas, with sensitivity and specificity of 82.5 and 99.0% in differentiating IBC and lung carcinoma.Conclusions: GATA-3 expression was the highest in luminal breast carcinomas, and showed higher sensitivity than GCDFP-15 and MGB. However, in the poorly differentiated IBC, its utility was still limited. One should be aware of the possible GATA-3 expression in lung carcinomas. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockades are currently actively investigated in invasive breast cancers. Given the complexity of immune regulation, multiple inhibitory molecules within the immune checkpoint framework would be involved in tumor immune escape. Evaluation of the components within the framework is a prerequisite for not only identification of additional treatment targets and optimization of immunotherapeutic strategies but also understanding the prognostic value of these molecules. Methods and Results: We examined a recently described component, herpes virus entry mediator (HVEM), in a large cohort of invasive breast cancers using immunohistochemistry, and evaluated its clinical relevance. HVEM expression was associated with aggressive tumor features, namely high grade ( p < 0.001), high pT ( p = 0.001) and pN stage ( p = 0.008), and was most prevalently found in human epidermal growth factor receptor 2-overexpressed subtype (67%). Interestingly, a negative association with programmed death-ligand 1 ( p = 0.021) has been observed. The prognostic impact of HVEM depended on the level of tumor-infiltrating lymphocytes (TILs), with the worst outcome occurring in patients with low TIL, HVEM-positive tumors. Conclusion: HVEM plays significant oncogenic roles in breast carcinogenesis, and may also be a tumor-specific target. [ABSTRACT FROM AUTHOR]

Background. The presence of tumor infiltrating lymphocytes (TIL) is associated with favorable prognosis. Recent evidence suggested that not only their density, but also the spatial organization as tertiary lymphoid structures (TLS), play a key role in determining patient survival. Materials and Methods. In a cohort of 248 breast cancers, the clinicopathologic association and prognostic role of TLS was examined. Results. Tertiary lymphoid structures were associated with higher tumor grade, apocrine phenotype, necrosis, extensive in situ component, lymphovascular invasion (LVI), and high TIL. For biomarkers, TLS were associated with hormone receptors negativity, HER2 positivity, and c-kit expression. Tertiary lymphoid structures were significantly related to better disease-free survival (DFS) in HER2 positive (HER2+) breast cancers (log-ran = 4.054), which was not dependent on high TIL status. The combined TLS and TIL status was an independent favorable factor associated with DFS in those cases. Interestingly, tumor cell infiltration into the TLS was found in 41.9% of TLS positive cases. It was associated with LVI in HER2 negative (HER2-) TLS positive (particularly estrogen receptor positive [ER+] HER2-) cases. In the ER+ HER2- cases, tumor cell infiltration into TLS was also associated with increased pathologic nodal stage (pN) stage and nodal involvement. Conclusion. Tertiary lymphoid structures showed a similar relationship with clinicopathologic features and biomarkers as TIL. The presence of TLS, irrespective of TIL level, could be an important favorable prognostic indicator in HER2+ breast cancer patients. Given the significance of TLS in promoting effective antitumor immunity, further understanding of its organization and induction may provide new opportunities to improve the current immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity presents challenges in the management of cancer. To gain deeper insight in intratumoral heterogeneity at different levels and tumor sites for common biomarkers in breast cancers, this report examines seven cases of invasive breast cancer with multiple axillary nodal metastases and/or recurrences for immunohistochemical expression of estrogen receptors, progesterone receptors, human epidermal growth receptor 2, and Ki67 on all tissue blocks in both primary and metastatic tumors. [ABSTRACT FROM AUTHOR]

Purpose: Clinical trials showing programmed death (PD)-1-PD-ligand 1 (L1) axis as a promising therapeutic target in melanoma and non-small cell lung cancers have made the pathway a focus of recent attention. However, the data regarding PD-L1/PD-1 in breast cancer are inconsistent. Given the heterogeneity of breast cancers, the clinical relevance of PD-L1 and PD-1 tumor infiltrating lymphocytes (TIL) may vary according to subtypes of breast cancer. We aim to investigate PD-L1 expression in a large cohort of breast cancers and analyze its clinico-pathological as well as outcome relationship according to molecular subtypes. Also, we evaluate the relationship of PD-1 TIL and PD-L1 expression with patients' survival, particularly for breast cancers with high TIL. Methods and results: Immunohistochemical analysis of PD-L1 on tissue arrays for 1091 breast cancer patients and PD-1 TIL on 97 whole sections was performed. Associations of PD-L1 with luminal cancers ( p < 0.001) and features associated with that subtype [lower histologic grade, absence of necrosis, ER, PR, and AR expression ( p < 0.001)] were observed. However, in HER2+ breast cancers, PD-L1 was an independent poor prognostic indicator (DFS: HR = 1.866, p = 0.001; OS: HR = 1.517, p = 0.036). Interestingly, HER2+ cancers showed a lower PD-1 TIL level compared to the other high TIL cases ( p = 0.011). Cases with low PD-TIL but high PD-L1 expression showed the worst survival. This could be indicative of an active immune suppression by PD-L1 expression. Conclusions: Our data showed the relevance of PD-L1 expression in HER2+ breast cancer. A combined evaluation of PD-L1 and PD-1 TIL in the prognosis of breast cancer might also be of value in treatment prediction. [ABSTRACT FROM AUTHOR]

Background: Recent data have shown anterior gradient 2 (AGR2) to be a novel oncogene overexpressed in luminal breast cancers. However, many studies only focused on its relationship with treatment resistance, and the clinical relevance of AGR2 has not been widely evaluated. Methods: AGR2 expression in a cohort of breast cancer was correlated with the clinicopathologic features, biomarker expression, and patient survival. Results: AGR2 expression correlated with lower grade ( p = 0.002) and absence of necrosis ( p = 0.001) and was most highly expressed in luminal cancers ( p < 0.001). Correspondingly, AGR2 correlated positively with estrogen receptor, progesterone receptor, and androgen receptor ( p < 0.001) and negatively with epidermal growth factor receptor ( p = 0.002) and CK5/6 ( p < 0.001). AGR2 was an independent unfavorable disease-free survival prognostic factor in patients with hormone therapy (hazard ratio 2.537, p = 0.023). Interestingly, it was also an independent adverse disease-free survival prognostic factor in node-positive luminal cancers (hazard ratio 3.381, p = 0.016). AGR2 expression was higher in nodal metastasis than the corresponding primary tumors in luminal cancers ( p = 0.023). Conclusions: The prognostic impact of AGR2 expression could be related to treatment outcome in estrogen receptor-positive breast cancers and/or its metastasis-promoting effects. It could be an important tumor biomarker and negative prognostic factor potentially exploitable in clinical practice. [ABSTRACT FROM AUTHOR]

Aims Micro RNAs (miRs) have been shown to play important roles in tumour progression. Their expression pattern can be useful for cancer classification. However, little is known about miRs in mammary phyllodes tumours ( PT). Methods and results In this study, polymerase chain reaction ( PCR)-based miR profiling was performed in a small PT cohort to identify deregulated miRs in malignant PT. The purported roles and targets of these miRs were further validated. Unsupervised clustering of miR expression profiling segregated PT into different grades, implicating the miR profile in PT classification. Among the deregulated miRs, miR-21, miR-335 and miR-155 were validated to be higher in malignant than in lower-grade PT in the independent cohort by quantitative PCR (q PCR) ( P ≤ 0.032). Their expression correlated with some of the malignant histological features, including high stromal cellularity, nuclear pleomorphism and mitosis. Subsequent analysis of their downstream proteins, namely PTEN for miR-21/miR-155 and Rb for miR-335, also showed an independent significant negative association between miR and protein expression. Conclusions Differential expression of miRs in PT could be useful in diagnosis and grading of PT. Their deregulated expression, together with the altered downstream targets, implicated their active involvement in PT malignant transformation. [ABSTRACT FROM AUTHOR]

Aims To evaluate the prognostic significance of GATA-binding protein 3 ( GATA-3), gross cystic disease fluid protein-15 ( GCDFP-15) and mammaglobin ( MGB) in invasive breast carcinomas ( IBCs). Methods and results GATA-3, GCDFP-15 and MGB were expressed in 37.9% (370/976), 26.0% (254/978) and 35.3% (348/986) of this cohort of 1017 IBCs, respectively. GCDFP-15 was an independent favourable prognostic factor in all cases [disease-free survival ( DFS), hazard ratio ( HR) 0.587, P = 0.049; overall survival ( OS), HR 0.512, P = 0.049], as well as in oestrogen receptor ( ER)-negative ( DFS, HR 0.353, P = 0.012; OS, HR 0.310, P = 0.017) and HER2-positive ( DFS, HR 0.279, P = 0.036; OS, HR 0.235, P = 0.050) cases; it also refined the prognostication of molecular apocrine cancers. GATA-3 and MGB did not show any prognostic significance. Conclusions The commonly used breast carcinoma biomarkers vary in their prognostic implications. GCDFP-15 independently indicated a favourable prognosis, especially in ER-negative, HER2-positive and molecular apocrine cancers. GATA-3 and MGB were not associated with outcome. [ABSTRACT FROM AUTHOR]

Combined B-cell lymphoma 2 (Bcl2) and Ki67 expression for breast cancer prognostication has been proposed recently. However, the combinatorial relationship with patient outcome, clinico-pathologic features, and various biomarkers has not been fully explored. Bcl2 and Ki67 expression were examined in a large cohort of breast cancers. Differential Bcl2 and Ki67 combinatorial analysis, particularly in luminal cancers, were evaluated with respect to the clinico-pathologic features, biomarkers profile and outcome. Combined Bcl2/Ki67 phenotypes classified by Bcl2 and Ki67 cutoffs showed a better correlation with outcome. Multivariate analysis revealed this to be an independent prognostic factor in luminal cancers. Both Ki67 and Bcl2 contributed to the prognostic implications of different subgroups defined by Bcl2/Ki67 combination phenotypes with clinico-pathologic features and biomarkers profile. Ki67low/Bcl2high cases showed better DFS (HR = 2.17, P = 0.015) and OS (HR = 3.217, P = 0.015) compared to Ki67high/Bcl2low cases. Interestingly, Ki67low/Bcl2high cases also showed better outcome than other phenotypes in grade 2 cancers (log-rank = 4.844, P = 0.028) and TNM stage 2 cancers (log-rank = 8.161, P = 0.004). This classification by Bcl2/Ki67 combination phenotypes, together with PR expression, can also refine luminal A cancers prognostication. Not all PR low luminal A cases had poorer outcome compared to the PR high luminal A cases; poor prognosis was only limited to those with also low Bcl2 (log-rank = 23.568, P < 0.001 compared to PR high Bcl2 high cases). The combined Ki67/Bcl2 phenotyping was useful in luminal cancers prognostication. It also refined prognostication in intermediate groups (grade 2 and stage 2 cancers) of luminal cancers; and aided in further classification of luminal A cancers. [ABSTRACT FROM AUTHOR]

Aims Many immunohistochemical markers have been studied for differentiating papillary lesions. However, their differentiating power has not been evaluated comprehensively. Additionally, assessment of some markers will require the difficult task of identifying different cell types. In the current study, we aimed to devise a simple papillary panel which can aid in diagnosis irrespective of architectural pattern and cell type differentiation. Methods and results Immunohistochemical analysis of papillary lesions using myoepithelial markers [p63 and smooth muscle actin (SMA)], high molecular weight cytokeratins (HMWCKs: CK5, CK5/6, CK14 and 34βE12), hormone receptors (ER and PR) and neuroendocrine markers (chromogranin and synaptophysin) was performed. Among them, neuroendocrine markers showed high specificity but low sensitivity. HMWCK specificity was better than that for myoepithelial markers. Homogeneous staining pattern for hormonal receptors rather than their percentage positivity was more effective in identifying malignant lesions. Negative staining for two or more of HMWCKs, namely CK5/6, CK14 and 34βE12, achieved the best overall specificity and sensitivity of 87.8% and 94.1%, respectively, irrespective of the architecture. Their discriminatory power was validated with an independent cohort of core needle biopsies. Conclusions A marker panel with HMWCKs could be used in differentiating papillary lesions irrespective of architectural pattern or cell type differentiation. [ABSTRACT FROM AUTHOR]

Background: Histologic grade, TNM stage, and Nottingham Prognostic Index are traditional prognostic tools for breast cancer. 'IHC-molecular' classification of breast cancer can also identify patients at different recurrence risks and provides insight into cancer therapy. However, cancers in each group are heterogeneous. A model based on the comprehensive analysis of morphologic features and molecular subtype was constructed to predict recurrence and refine these traditional prognostic tools. Methods: Morphologic features including histologic grade, fibrotic focus, extensive intraductal component, lymphocytic infiltrate, lymphovascular invasion, tumor necrosis, tumor margin and TNM stage, and molecular subtypes approximated by immunohistochemistry were analyzed in 633 patients with invasive breast carcinoma (excluding those with HER2 targeted therapy). Significant independent predictors for recurrence included: high histologic grade ( p = 0.004), presence of lymphovascular invasion ( p = 0.004), fibrotic focus ( p = 0.020), mild lymphocytic infiltrate ( p = 0.013), high TNM stage ( p < 0.001), and HER2-overexpressing ( p = 0.004) and basal-like ( p < 0.001) molecular subtypes. A morphologic-molecular recurrence predictive model based on these features was useful in recurrence prediction, independent of treatment modalities, and was able to refine the traditional prognostic tools of histologic grade, TNM stage, and Nottingham prognostic index, particularly for intermediate-risk groups, and to refine the luminal group molecular subtypes. Such findings were reproducible with a validation cohort. Conclusion: TNM stage, histologic grade, lymphovascular invasion, fibrotic focus, mild lymphocytic infiltrate, HER2-overexpressing and basal-like molecular subtypes were important independent recurrence risk factors for breast cancer. This morphologic-molecular model was robust in recurrence prediction and refined recurrence risk stratified by the traditional prognostic parameters, independent of treatment modalities. [ABSTRACT FROM AUTHOR]

Background: Androgen receptor (AR), a nuclear steroid hormone receptor, is differentially expressed in breast cancer subgroups with distinct clinical implications. Methods: To investigate the clinical significance of AR in breast cancers more precisely, the expression of AR in a large cohort of breast cancer was correlated with clinicopathological features, biomarker expression, and patients' survival according to different molecular groupings in this study. Results: Higher AR expression was found in ER+ (57.8 %) than in ER− (24.7 %) cancers. In the ER+ cancers, AR expression was associated with favorable clinicopathological features, including lower grade ( p < .001), lower pT stage ( p < .001), and positivity for PR ( p < .001). It was an independent prognostic factor for longer disease-free survival, mainly in the HER2+ luminal B cancers (hazard ratio [HR] = 0.251, 95 % CI 0.065−0.972, p = .045). In ER− cancers, AR expression was associated with features distinct from basal-like breast cancer, and such features were found in molecular apocrine (MA) cancers. AR correlated with presence of extensive in situ component ( p = .006) and apocrine phenotype ( p < .001), HER2 ( p = .026), and EGFR ( p = .048), but negatively with c-kit ( p = .041), CK5/6 ( p < .001), CK14 ( p = .002), and αB-crystallin ( p = .038). However, AR expression was found only in 37.8 % of immunohistochemically defined MA. Of note, AR−MA appeared to have a trend of worse overall survival than AR+MA. Conclusions: AR expression was different in ER+ and ER− cancers and had different clinical implications. AR alone may not be a good marker for MA subtype. Its expression in MA may have substantial prognostic implication and as such warrants further validation. [ABSTRACT FROM AUTHOR]

Aims SOX2 is a key regulatory gene in embryonic stem cells. Although it has been implicated in cancer progression, its role in breast carcinoma is poorly understood. Materials and methods Fifty-seven ductal carcinomas in situ ( DCIS), 552 invasive breast carcinomas and 107 corresponding metastatic lymph nodes were evaluated immunohistochemically for the expression of SOX2. Its correlation with clinicopathological features, other biomarker profiles and patients' outcomes were analysed. Results SOX2 was detected in 19.0% (105 of 552) of invasive breast carcinomas and 12.3% (seven of 57) of DCIS. Expression correlated with larger tumour size ( P = 0.005) and higher grade ( P = 0.002). It was associated negatively with ER ( P = 0.015) and PR ( P = 0.046) expression, but positively with Ki67 index ( P = 0.013). Interestingly, it was also associated with neuroendocrine marker expression (synpatophysin and chromogranin/synaptophysin, P = 0.048 and 0.028, respectively). Expression appeared to be independent from that of common stem cell markers, namely CD44, CD24 and aldehyde dehydrogenase 1 ( ALDH1). Furthermore, a higher rate of expression was observed in metastatic lymph nodes than in the corresponding primary tumours ( P = 0.034). High SOX2 expression was correlated with poor disease-free survival (log-rank=9.489, P = 0.012) and was an independent prognostic factor ( HR=2.918, P = 0.015) in patients with high nodal stages. Conclusions In summary, SOX2 expression was related to adverse breast carcinoma profile and poor outcome in selected patient groups. [ABSTRACT FROM AUTHOR]

Aims To evaluate thyroid transcription factor-1 (TTF-1) expression in a large cohort of invasive breast carcinomas (IBCs) using two commercially available monoclonal antibody clones (8G7G3/1 and SPT24). Methods and results Nuclear and cytoplasmic TTF-1 expression was evaluated in 1132 primary IBCs and 208 primary pulmonary carcinomas using tissue microarray (TMA) sections. TTF-1 nuclear expression was detected in one of 1132 (0.09%) IBCs by 8G7G3/1. In pulmonary carcinoma, TTF-1 expression was detected in 149 (71.6%) and 147 (70.6%) cases by 8G7G3/1 and SPT24, respectively, with no significant difference being seen between the two clones ( P = 0.839), and there was good consistency between these two antibodies in differentiating breast and pulmonary carcinomas (kappa value 0.905; P < 0.001). Both clones showed high specificity but relatively low sensitivity. Cytoplasmic TTF-1 expression was detected in 44 IBCs by 8G7G3/1, and this particular expression pattern was an independent adverse prognostic factor. Conclusions Both TTF-1 antibodies (clones 8G7G3/1 and SPT24) were useful in differentiating breast from pulmonary carcinomas. Nuclear expression of TTF-1 was detected in IBCs by 8G7G3/1, but not by SPT24. Cytoplasmic expression of 8G7G3/1 was seen in IBC for the first time, and was an independent unfavourable prognostic factor. [ABSTRACT FROM AUTHOR]

The value for lymphocytic infiltration (LI) has been increasingly recognized for tumor assessment. In breast cancer, however, the overall significance of LI remains poorly defined, probably due to its heterogeneity. A large cohort of breast cancer was evaluated for the degree of LI and its association with traditional pathologic factors, biomarker expression, and cancer subtypes. The number of CD8 cytotoxic effector and FoxP3 regulatory T cell (Treg) was evaluated in those cases with high LI. High LI was associated with negative ER and PR but positive HER2 and EGFR expression ( p < 0.001 for all). In ER-positive cancers, high LI was associated with poor prognostic features including higher grade, the presence of necrosis, and lymphovascular invasion (LVI) ( p = 0.007 for LVI and <0.001 for the others). Conversely, LI correlated with smaller tumor size, a good prognostic feature ( p = 0.046) in HER2+ ER-cancers. These observations suggested LI may show opposite prognostic values in different breast cancer subgroups. Interestingly, when the phenotype of LI in these subgroups was evaluated, a strong positive association with intratumoral accumulation of Treg was found in ER-positive cancers ( p = 0.003, Rs = 0.319), while the opposite was observed in HER2+ ER-cancers ( p < 0.001, Rs = −0.427). Also, in ER-positive cancers, positive associations between peri- and intra-tumoral distribution were found with both CD8 and Tregs (CD8: p < 0.001, Rs = 0.547; Treg: p = 0.001, Rs = 0.460). Nonetheless, in HER2+ ER-cancers, such strong association was found with CD8 ( p < 0.001, Rs = 0.766) but not Tregs. The results may implicate a differential intratumoral migration of LI in different subtypes of breast cancer. In summary, the clinical value of LI in breast cancers could be subtype-dependent. In ER-positive cancers, high LI correlated with biologic parameters associated with poor prognosis, whereas in HER2 positive cancers, LI correlated with biologic parameters of favorable prognosis. [ABSTRACT FROM AUTHOR]

Background: Fibrotic focus (FF) has been observed in breast cancers and is suggested to be an important prognostic marker. However, most of these observations were reported by the same group of investigators with similar sample cohort. The relationship of FF and molecular subtypes as well as its associated prognosis has not been elucidated. Methods: In this study, 450 cases of breast carcinomas were evaluated for the presence of FF and its association with clinicopathologic parameters and biomarkers. Results: FF was found in 18.7 % of all consecutive cases. FF was associated positively with infiltrative margins ( p = 0.03) but negatively with extensive in situ component ( p < 0.001) and lymphocytic infiltration ( p < 0.001). It was positively associated with estrogen receptor ( p = 0.007) but negatively with human epidermal growth factor receptor 2 (HER2; p = 0.001), epidermal growth factor receptor ( p = 0.021), Ki-67 ( p = 0.001), and c-kit ( p = 0.009). Concomitantly, FF was seen more commonly in luminal A cancers ( p < 0.001) but less so in luminal B ( p = 0.045) and HER2-overexpressing cancers ( p = 0.011). Analysis on patient outcome (median 41 months, range 1-69 months) indicated that FF was an independent poor prognostic factor for disease-free survival (hazard ratio = 2.57; 95 % confidence interval = 1.267-5.214, p = 0.009), particularly in the luminal B subtype. Conclusions: The findings suggested that FF is associated with specific tumor morphology of an infiltrative, stellate pattern (typical invasive ductal carcinoma-not otherwise specified) rather than round, cellular mass with intense lymphocytic infiltrate (basal-like breast cancers). The poor prognostic implication of FF is additional and independent of other adverse prognostic indicators. [ABSTRACT FROM AUTHOR]

The significance of chemokines in cancer biology has been widely recognized in recent years. CX3CL1 is a unique subclass of chemokine with complex functions, including recruitment of anti-tumor leukocytes and promoting cancer survival, thus affecting cancer progression in both the directions. It is not clear how these different functions interact in breast cancers. This is further complicated by the heterogeneity of breast cancer, and differential association of CX3CL1 with different subgroups could be present. There is only limited knowledge of CX3CL1 expression profile, its relationship with different biological features, subtypes, and outcomes in breast cancers. In this study, CX3CL1 expression was examined in a large cohort of breast cancers by immunohistochemistry and its association with clinicopathological factors, biomarker expression, and impact on patients' survival was assessed. High CX3CL1 expression was detected in 33.3 % (252/757) of primary invasive cancers. In line with its chemo-attractant function, CX3CL1 expression correlated positively with increased tumor infiltrating lymphocytes (TIL) ( p = 0.005). In addition, CX3CL1 also correlated positively with adverse features in breast cancers, including lymph node involvement ( p = 0.007), high Ki67 ( p = 0.002), α-B crystallin expression ( p = 0.008), and luminal B (worse prognosis luminal cancers) subtype ( p = 0.024). Consistently, breast cancers with high expression of CX3CL1 were found to have a poorer overall survival (χ = 4.797, p = 0.029). Interestingly, the adverse effect of CX3CL1 on outcome appeared to be more prominent in cancers with low TIL. These findings indicated that CX3CL1 could also have a pro-tumor role in breast cancer, despite its previously suggested role in enhancing anti-tumor immunity. The results highlighted the complicated functions of CX3CL1 in breast carcinogenesis. Further studies are needed to clarify the relative contribution of these anti- and pro-tumor functions in order to understand the true prognostic and potential therapeutic values of CX3CL1. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 58-year-old woman who was presented with a mass in the forehead. It has been ruled out that the patient has metastatic poorly differentiated carcinoma after she undergone various tests including magnetic resonance imaging and positron emission tomography-computed tomography. A combined radiation and hormonal therapies was given to the patient.

A response from the author of the article related to a case of breast cancer in the previous issue is presented.

A letter to the editor is presented regarding the correlation of the tumoral lymphocytic infiltration (LI) in breast cancer with molecular subtypes and human epidermal growth factor receptor-2 overexpressing (HER2-OE) gene amplification.