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Aims: To characterize clinico-pathological features and clinical outcome of low grade triple negative early breast carcinomas. Material and methods: Between January 2005 and December 2006, 300 tumours were classified as triple negative (ER-ve, PR-ve, HER2 0/1+) out of 3000 patients treated for a breast cancer at the Institut curie. Patients with a low-grade (grade 1 and 2 according to Ellis and Elston) T1 and small T2 (< 3cm) breast carcinoma treated with surgery first were considered in our study. Immunohistochemistry was performed with ER, PR, Androgen Receptor (AR), HER2, Ki67, EGFR, CK5/6, CK14 and CK8/18 antibodies for all tumours; GCDFP15 for invasive lobular carcinomas (ILC) and invasive ductal carcinoma (IDC) with apocrine features, and CA15-3 to assess the inverted polarity if needed. Results: We identified 36 low-grade carcinomas out of 186 triple negative breast carcinomas (19%). Thirty-two tumours were grade 2 and four tumours grade 1 and associated with a low or a moderate mitotic score. Ki67 proliferation index was high (20%) in 22 cases (61 %) (median: 22%-mean: 29%). Thirty-one (86%) tumours showed a basal-like phenotype (EGFR+ or CK5/6+ or CK14 +). Interestingly, the five "nul" (non basal-like) triple negative tumours demonstrated a low proliferation index (Ki67 20%). All but one tumors expressed CK8/18. The tumour's size varied between 3 and 37 mm (mean = 17.2). Lympho- vascular invasion was present in 10 cases (27%). High and intermediate grade ductal carcinoma in situ component was associated in 28 cases (77%). Stroma was abundant and associated with a lymphocytic infiltrate in all cases. Various histological types were observed: 16 IDC (44%), 7 ILC (19%), 5 IDC with apocrine differentiation, 2 micropapillary, 1 papillary, 1 mucinous, 3 adenoid cystic and one low grade adeno-squamous carcinomas. Three out of 16 IDC showed a week nuclear positivity with AR. Five and six out of the seven ILC were positive for AR and GCDFP15 respectively. All carcinomas with apocrine differentiation were AR and CGDFP15 positive. Conversely, all micropapillary, papillary and mucinous carcinomas were AR negative. The mean age of patients was 61.6 years. Distant metastases occurred in five patients. Thirty-three (91 %) women were alive and 29 (80%) of them without evidence of cancer at 6 years of follow-up. Conclusion: Low grade invasive carcinomas represent 19% of the cases in our series of 186 triple negative early breast carcinomas and were diagnosed in patients older than 60 years. These cases were of various histological types, were all associated with a marked lymphocytic infiltrate and in the majority of the cases with high grade ductal carcinomas in situ. Despite a low mitotic activity, proliferation index was generally higher than 20% except for "nul" non-basal cases. However, patient's overall survival seemed to be better than that reported for high grade triple negative breast cancer. Histological types, proliferation and age should be taken into account for treatment decision in triple negative early breast carcinoma patients. [ABSTRACT FROM AUTHOR]

Introduction: Renal cell carcinoma (RCC) and breast carcinoma (BC) are frequent tumours, yet their co-occurrence in the same patient is a unique scenario. Few studies explored the characteristics of such patients without specific focus on pathological data. In this retrospective study, we aimed to describe the clinico-pathological features of RCC patients with a history of BC and compare them to a control cohort of RCC women free of previous BC., Methods: All adult women treated for BC at a high-volume cancer institution between 2007 and 2020 and who subsequently developed a RCC were retrospectively included. Their clinical and pathological characteristics were compared to an independent cohort of consecutive women undergoing percutaneous kidney tumour biopsy for localized kidney cancer in a second high-volume cancer institution., Results: A total of 113 patients were identified from 2 different institutions. We observed a lower rate of clear cell RCC in the Kidney-breast (KB) group compared to the Kidney-only (KO) group, suggesting a potential association between breast cancer and non-ccRCC. The KB group had a higher proportion of locally advanced tumours and high-grade lesions. Although recurrence-free survival favored the KO cohort, no significant difference was found in cancer-specific survival and overall survival rates between the groups. Noteworthy, patients in the KB group had a higher prevalence of family history of cancer., Conclusion: Our findings highlight the need for further research to elucidate the underlying mechanisms and clinical implications of RCC coexisting with breast carcinoma. Understanding the characteristics of this unique population can guide clinical strategies and improve patient outcomes., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Genomic classifiers such as the Genomic Prostate Score (GPS) could help to personalize treatment for men with intermediate-risk prostate cancer (I-PCa). In this study, we aimed to evaluate the ability of the GPS to change therapeutic decision making in I-PCa. Only patients in the intermediate NCCN risk group with Gleason score 3 + 4 were considered. The primary objective was to assess the impact of the GPS on risk stratification: NCCN clinical and genomic risk versus NCCN clinical risk stratification alone. We also analyzed the predictive role of the GPS for locally advanced disease (≥pT3+) and the potential change in treatment strategy. Thirty patients were tested for their GPS between November 2018 and March 2020, with the median age being 70 (45-79). Twenty-three patients had a clinical T1 stage. Eighteen patients were classified as favorable intermediate risk (FIR) based on the NCCN criteria. The median GPS score was 39 (17-70). Among the 23 patients who underwent a radical prostatectomy, Gleason score 3 + 4 was found in 18 patients. There was a significant correlation between the GPS and the percentage of a Gleason grade 4 or higher pattern in the surgical sample: correlation coefficient r = 0.56; 95% CI = 0.2-0.8; p = 0.005. In this study, the GPS combined with NCCN clinical risk factors resulted in significant changes in risk group.

The diagnosis, histomolecular classes of breast cancers (luminal A, luminal B, HER2-enriched, and basal-like), and accurate prediction of prognosis are commonly determined using morphological and phenotypical analyses in clinical practice worldwide. Therapeutic strategies are mostly based on the disease stage and molecular subclasses of breast cancer. Targeted therapies, such as anti-HER2s, poly-ADP ribose polymerase inhibitors or, to a lesser extent, phosphatidylinositol 3 kinase inhibitors, have substantially improved breast cancer patient prognosis over the past decades. Human epidermal growth factor receptor 2 (HER2) overexpression is widely determined based on immunohistochemistry, while next-generation sequencing (NGS) is currently employed to assess the presence of molecular alterations, including breast cancer gene 1 (BRCA1) and 2 or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, which are targets of these new approved therapies. In addition, next-generation sequencing (NGS) can aid the pathologist in challenging situations, such as a diagnostic workup for a metastatic carcinoma in lymph nodes of unknown origin, differential diagnosis of spindle cell tumourtumor in the breast between metaplastic carcinoma, malignant PT and sarcoma, o, as well as determining relatedness between primary breast cancers and recurrences. NGS offers a powerful tool that enables the pathologist to combine morphological analyses together with molecular alterations in challenging diagnostic situations., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer death in men worldwide. If local PCa presents a favorable prognosis, available treatments for advanced PCa display limiting benefits due to therapeutic resistances. Nucleolin (NCL) is a ubiquitous protein involved in numerous cell processes, such as ribosome biogenesis, cell cycles, or angiogenesis. NCL is overexpressed in several tumor types in which it has been proposed as a diagnostic and prognostic biomarker. In PCa, NCL has mainly been studied as a target for new therapeutic agents. Nevertheless, little data are available concerning its expression in patient tissues. Here, we investigated the expression of NCL using a new cohort from Mondor Hospital and data from published cohorts. Results were then compared with NCL expression using in vitro models. NCL was overexpressed in PCa tissues compared to the normal tissues, but no prognostic values were demonstrated. Nine genes were highly co-expressed with NCL in patient tissues and tumor prostate cell lines. Our data demonstrate that NCL is an interesting diagnostic biomarker and propose a signature of genes co-expressed with NCL.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Carbonic Anhydrase IX (CAIX) is a well-described enzyme in renal cell carcinoma, with its expression being regulated by the hypoxia-inducible factor 1 alpha, it is known for interfering with hypoxia processes. Renal carcinoma encompasses a broad spectrum of histological entities and is also described as a heterogeneous malignant tumor. Recently, various combinations of checkpoint inhibitors and targeted therapies have been validated to manage this disease. Reliable markers to confirm the diagnosis, estimate the prognosis, predict or monitor the treatment response are required. Molecular imaging developments allow a comprehensive analysis of the tumor, overcoming the spatial heterogeneity issue. CAIX, being highly expressed at the tumor cell surfaces of clear cell renal carcinoma, also represents a potential treatment target. In this manuscript we reviewed the current knowledge from the literature on the pathophysiological interactions between renal cell carcinoma and CAIX, the role of CAIX as a marker for diagnosis, prognosis, treatment monitoring and molecular imaging, and the potential target for therapeutic strategies.

Purpose: The optimal schedule for palliative external beam radiotherapy (EBRT) in patients with bladder tumors with hematuria unfit for surgery remains undefined. This study aimed to assess the clinical hemostatic efficacy and safety of two EBRT hypofractionated schedules., Methods: From February 2008 to October 2017, 31 patients were referred to our department for palliative hemostatic bladder irradiation. EBRT consisted of two schedules: "continuous" treatment (CRT) was delivered following consecutive 3-10 weekdays (3-6Gy/fraction (fr), to a total dose of 18-30Gy) (n=14); the "discontinuous" schedule (DRT) consisted of 23Gy in 4fr (6.5Gy/fr on days 1 and 3, followed by 5Gy/fr on days 15 and 17; n=12). The primary endpoint was the rate of hemostatic control (HC) at the end of the radiation course. Other endpoints included mid-term HC, toxicities and overall survival. Comparative analyses were performed by exact Fisher test with a cut-off of 0.05 for statistical significance., Results: The rate of HC at the end of EBRT was 92% (n=24) with no differences between CRT and DRT (100% vs 86%; p=0.48). The median follow-up was 6 months, HC was achieved in 15/26 (58%) patients at the last follow-up, without meaningful differences between CRT and DRT (50% vs 67%; p=0.45). Three and two patients developed acute grade ≤2 diarrhea in CRT and DRT groups, respectively., Conclusion: Our study suggests that both hypofractionated "continuous" and "discontinuous" EBRT are well tolerated and represent acceptable schedules for patients with limited life expectancy. DRT schedule could be preferred for departments' organization to increase the slots for the treatment of other referred patients for radiotherapy.

Nuclear factor of activated T cells 1 (NFAT1) expression has been associated with increased migratory/invasive properties of mammary tumor-derived cell lines in vitro. It is unknown, however, if NFAT activation actually occurs in breast cancer cases and whether the calcineurin/NFAT pathway is important to mammary tumorigenesis. Using a cohort of 321 diagnostic cases of the major subgroup of breast cancer, we found Cn/NFAT pathway activated in ER(-)PR(-)HER2(-) triple-negative breast cancer subtype, whereas its prevalence is less in other subgroups. Using a small hairpin RNA-based gene expression silencing approach in murine mammary tumor cell line (4T1), we show that not only NFAT1 but also NFAT2 and their upstream activator Cn are essential to the migratory and invasive properties of mammary tumor cells. We also demonstrate that Cn, NFAT1 and NFAT2 are essential to the tumorigenic and metastatic properties of these cells in mice, a phenotype which coincides with increased apoptosis in vivo. Finally, global gene expression analyses identified several NFAT-deregulated genes, many of them being previously associated with mammary tumorigenesis. In particular, we identified the gene encoding a disintegrin and metalloproteinase with thrombonspondin motifs 1, as being a potential direct target of NFAT1. Thus, our results show that the Cn/NFAT pathway is activated in diagnostic cases of breast cancers and is essential to the tumorigenic and metastatic potential of mammary tumor cell line. These results suggest that pharmacological inhibition of the Cn/NFAT pathway at different levels could be of therapeutical interest for breast cancer patients.

Dissemination of carcinoma cells requires the pericellular degradation of the extracellular matrix, which is mediated by membrane type 1-matrix metalloproteinase (MT1-MMP). In this article, we report a co-up-regulation and colocalization of MT1-MMP and atypical protein kinase C iota (aPKCι) in hormone receptor-negative breast tumors in association with a higher risk of metastasis. Silencing of aPKC in invasive breast-tumor cell lines impaired the delivery of MT1-MMP from late endocytic storage compartments to the surface and inhibited matrix degradation and invasion. We provide evidence that aPKCι, in association with MT1-MMP-containing endosomes, phosphorylates cortactin, which is present in F-actin-rich puncta on MT1-MMP-positive endosomes and regulates cortactin association with the membrane scission protein dynamin-2. Thus, cell line-based observations and clinical data reveal the concerted activity of aPKC, cortactin, and dynamin-2, which control the trafficking of MT1-MMP from late endosome to the plasma membrane and play an important role in the invasive potential of breast-cancer cells.