Fibroepithelial lesions of the breast, comprising the fibroadenoma and phyllodes tumour, are a unique group of neoplasms that share histological characteristics but possess different clinical ...behaviour. The fibroadenoma is the commonest benign breast tumour in women, while the phyllodes tumour is rare and may be associated with recurrences, grade progression and even metastasis. The diagnosis of fibroadenoma is usually straightforward, with recognised histological variants such as the cellular, complex, juvenile and myxoid forms. The phyllodes tumour comprises benign, borderline and malignant varieties, graded using a constellation of histological parameters based on stromal characteristics of hypercellularity, atypia, mitoses, overgrowth and the nature of tumour borders. While phyllodes tumour grade correlates with clinical behaviour, interobserver variability in assessing multiple parameters that are potentially of different biological weightage leads to significant challenges in accurate grade determination and consequently therapy. Differential diagnostic considerations along the spectrum of fibroepithelial tumours can be problematic in routine practice. Recent discoveries of the molecular underpinnings of these tumours may have diagnostic, prognostic and therapeutic implications.
The fifth edition of the World Health Organization (WHO) “Blue Book” brings a comprehensive update on the terminology, epidemiology, pathogenesis, histopathology, diagnostic molecular pathology, and ...prognostic and predictive progress in genitourinary tumors. In this review, we presented a summary of the salient changes introduced in the WHO 2022 classification of tumors of the prostate and the urinary tract.
The 2022 World Health Organization (WHO) classification of the urinary and male genital tumors was recently published by the International Agency for Research on Cancer. This fifth edition of the WHO “Blue Book” offers a comprehensive update on the terminology, epidemiology, pathogenesis, histopathology, diagnostic molecular pathology, and prognostic and predictive progress in genitourinary tumors. In this review, the editors of the fifth series volume on urologic and male genital neoplasms present a summary of the salient changes introduced to the classification of tumors of the prostate and the urinary tract.
Self-DNA is present in the cytosol of many cancer cells and can promote effective immune rejection of tumor cells, but the mechanisms leading to the presence of cytosolic DNA are unknown. Here, we ...report that the cleavage of genomic DNA by DNA structure-specific endonuclease MUS81 and PARP-dependent DNA repair pathways leads to the accumulation of cytosolic DNA in prostate cancer cells. The number of nuclear MUS81 foci and the amount of cytosolic dsDNA increased in tandem from hyperplasia to clinical stage II prostate cancers and decreased at stage III. Cytosolic DNA generated by MUS81 stimulated DNA sensor STING-dependent type I interferon (IFN) expression and promoted phagocytic and T cell responses, resulting in type I and II IFN-mediated rejection of prostate tumor cells via mechanisms that partly depended on macrophages. Our results demonstrate that the tumor suppressor MUS81 alerts the immune system to the presence of transformed host cells.
•Presence of cytosolic DNA in prostate cancer cells depends on Mus81•Mus81 induces STING-dependent type I interferon expression•Immune rejection of prostate cancer cells relies on Mus81 and STING•Mus81 enhances innate and adaptive anti-cancer immune responses
The mechanisms leading to the presence of cytosolic DNA in cancer cells are unknown. Gasser and colleagues find that the DNA structure-specific endonuclease Mus81 promotes the shedding of genomic DNA into the cytosol of prostate cancer cells. Mus81 stimulates STING-dependent DNA sensor pathways and immune rejection of prostate cancer cells.
Molecular biomarkers have come to constitute one of the cornerstones of oncological pathology. The method of classification not only directly affects the manner in which patients are diagnosed and ...treated, but also guides the development of drugs and of artificial intelligence tools. The aim of this article is to organise and update gastrointestinal molecular biomarkers in order to produce an easy‐to‐use guide for routine diagnostics. For this purpose, we have extracted and reorganised the molecular information on epithelial neoplasms included in the 2019 World Health Organization classification of tumours. Digestive system tumours, 5th edn.
Breast lesions with a prominent myoepithelial cell component constitute a heterogeneous group of benign and malignant neoplastic proliferations. These lesions are often dual epithelial–myoepithelial, ...but may be purely myoepithelial cell in nature. Benign epithelial–myoepithelial lesions typically maintain the morphology and immunophenotype of the normal bilayer epithelial myoepithelial structures. However, the distinction between the two cell components is not always clear‐cut in malignant lesions in which the histogenesis of myoepithelial cells remains uncertain. Neoplastic biphasic epithelial–myoepithelial lesions of the breast include adenomyoepithelioma (AME), pleomorphic adenoma and adenoid cystic carcinoma. Four histological patterns of classical AME have been described: tubular, lobulated, spindle‐cell and adenosis variants. Overlapping patterns occur and some AMEs display an intraductal papillary pattern that may represent a fifth variant. AME can be benign or malignant. Classical AME may show atypical features, which are not sufficient for the diagnosis of malignancy (atypical AME). Atypical AME is recognised as a lesion of uncertain malignant potential with limited metastatic capability. Based on the histological features, we propose a classification of malignant AME (M‐AME) into three variants: M‐AME in situ, M‐AME invasive and AME with invasive carcinoma. In this review, we provide an overview of myoepithelial lesions of the breast focusing on the classification of AME to improve not only the consistency of reporting but also help to guide further management decision‐making.
HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC).
...Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH-) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH- status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS.
ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82-0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76-0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85-0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79-0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83-0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78-0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH- and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59-0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found.
HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.
Aims
Although rare, malignant sarcomatoid breast tumours without evidence of epithelial differentiation comprise a diagnostic challenge with management implications. Earlier studies have generally ...considered these to be primary breast sarcomas; however, supporting evidence is lacking and management remains variable. This study aimed to provide an evidence‐based approach to improve the consistency of diagnosis and management for such cases.
Methods and results
A large series (n = 140) of metaplastic breast carcinoma (MBC) diagnosed in Nottingham over 18 years was analysed. Only cases with available data on immunohistochemical expression of cytokeratins (CKs) were included. The prevalence and pattern of expression for various CKs were assessed and details of tumours negative for CKs were collected. A diagnostic approach based on our experience is provided. Forty‐seven cases (34%) showed foci of conventional type invasive breast carcinoma or ductal carcinoma in situ (DCIS), while 93 cases (66%) were diagnosed as MBC based on morphology and/or CK expression. Ninety‐seven cases (69%) were negative for one or more CKs, with 18 cases (13%) negative for five or more CKs. Eight cases (6%) lacked expression of all CKs tested. Further examination showed evidence of carcinomatous nature in five cases, and three were diagnosed as MBC following extensive diagnostic work‐up and based on our experience.
Conclusion
This study suggests that MBC represents a spectrum of neoplasms, with some lacking CK expression. Sarcomatoid neoplasms of the breast lacking evidence of carcinomatous morphology and CK expression may represent an extreme end of differentiation that can be considered as carcinomas rather than sarcomas for management purposes (following extensive work‐up).
Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on ...the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.
There is a quest for novel noninvasive diagnostic markers for the detection of breast cancer. The goal of this study is to identify circulating microRNA (miRNA) signatures using a cohort of Asian ...Chinese patients with breast cancer, and to compare miRNA profiles between tumor and serum samples.
miRNA from paired breast cancer tumors, normal tissue, and serum samples derived from 32 patients were comprehensively profiled using microarrays or locked nucleic acid real-time PCR panels. Serum samples from healthy individuals (n = 22) were also used as normal controls. Significant serum miRNAs, identified by logistic regression, were validated in an independent set of serum samples from patients (n = 132) and healthy controls (n = 101).
The 20 most significant miRNAs differentially expressed in breast cancer tumors included miRNA (miR)-21, miR-10b, and miR-145, previously shown to be dysregulated in breast cancer. Only 7 miRNAs were overexpressed in both tumors and serum, suggesting that miRNAs may be released into the serum selectively. Interestingly, 16 of the 20 most significant miRNAs differentially expressed in serum samples were novel. MiR-1, miR-92a, miR-133a, and miR-133b were identified as the most important diagnostic markers, and were successfully validated; receiver operating characteristic curves derived from combinations of these miRNAs exhibited areas under the curves of 0.90 to 0.91.
The clinical use of miRNA signatures as a noninvasive diagnostic strategy is promising, but should be further validated for different subtypes of breast cancers.
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