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The frequency of MET and HER2 amplification being detected by next generation sequencing (NGS) is increasing due to NGS being increasingly adopted for molecular profiling of cancers. However, the accuracy of NGS in detecting these gene amplifications remains uncertain due to conflicting reports in the scientific literature. We studied the accuracy of an amplicon-based large panel NGS assay in detecting MET and HER2 amplification in lung and breast cancers, respectively, by comparing it against conventional testing methods. Amongst 48 lung cancers, four of five cancers that were MET amplified on fluorescence in situ hybridisation (FISH) were classified as amplified on NGS while 42 of the remaining 43 non-amplified cancers were classified as non-amplified on NGS, giving a sensitivity of 80%, specificity of 97.7% and overall concordance of 95.8%. Of the 46 breast cancers tested, only six of the nine cancers that were HER2-positive on immunohistochemistry (IHC)/FISH were HER2-positive on NGS, while all the remaining HER2-negative cases were negative on NGS, giving a sensitivity of 66.7%, specificity of 100% and overall concordance of 93.5%. All the false-negative cases had low level gene amplification (MET:CEP7 or HER2:CEP17 FISH ratio of <3). The low sensitivity for HER2 amplification may be confounded by the small sample size and disproportionate number of cases with low level amplification. In summary, the NGS assay has good concordance with conventional testing methods but may be less sensitive in detecting low level gene amplification., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Breast fibroepithelial lesions, which are composed of biphasic epithelial and stromal proliferations, comprise the fascinating spectrum of fibroadenomas and phyllodes tumours. Common difficulties surrounding their diagnosis include distinguishing between cellular fibroadenomas and benign phyllodes tumours, grading phyllodes tumours, classifying fibroepithelial lesions in paediatric patients, and handling surgical margins. Recent molecular advances have provided insights into the pathogenesis of fibroepithelial lesions and may offer diagnostic, prognostic, and therapeutic information. In this review, we briefly revisit the pathological features of fibroadenomas and phyllodes tumours, discuss common diagnostic dilemmas and management implications, and examine their key molecular characteristics., (Copyright © 2022. Published by Elsevier Inc.)

Breast fibroepithelial lesions (FEL) are biphasic tumors which consist of benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). FAs and PTs have overlapping features, but have different clinical management, which makes correct core biopsy diagnosis important. This study used whole-slide images (WSIs) of 187 FA and 100 PT core biopsies, to investigate the potential role of artificial intelligence (AI) in FEL diagnosis. A total of 9228 FA patches and 6443 PT patches was generated from WSIs of the training subset, with each patch being 224 × 224 pixel in size. Our model employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction from the patches, and a recurrent neural network (RNN) component for whole-slide classification using activation values from the global average pooling layer in the CNN model. It achieved an overall slide-level accuracy of 87.5%, with accuracies of 80% and 95% for FA and PT slides respectively. This affirms the potential role of AI in diagnostic discrimination between FA and PT on core biopsies which may be further refined for use in routine practice., (© 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Primary breast carcinomas often present as ill-defined, infiltrative lesions which may contain calcifications, whereas metastatic cancers from non-mammary sites are often more well-circumscribed, sharply demarcated from the adjacent breast tissue and are usually not associated with calcifications, although there are exceptions. We report an atypical case of a lady with lung adenocarcinoma with pleural involvement, who presented with diffuse breast swelling with calcifications on imaging from metastatic lung adenocarcinoma, the first of its kind in the literature. We postulate that the pathophysiology of this was due to lymphatic spread of the tumour from the pleura resulting in retrograde lymphovascular congestion of the breast, resulting in swelling and dystrophic calcification.

Breast fibroepithelial lesions are biphasic tumors which comprise the common benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). This study analyzed 262 (42%) conventional FAs, 45 (7%) cellular FAs, and 321 (51%) benign PTs contributed by the International Fibroepithelial Consortium, using a previously curated 16 gene panel. Benign PTs were found to possess a higher number of mutations, and higher rates of cancer driver gene alterations than both groups of FAs, in particular MED12, TERT promoter, RARA, FLNA, SETD2, RB1, and EGFR. Cases with MED12 mutations were also more likely to have TERT promoter, RARA, SETD2, and EGFR. There were no significant differences detected between conventional FAs and cellular FAs, except for PIK3CA and MAP3K1. TERT promoter alterations were most optimal in discriminating between FAs and benign PTs. Our study affirms the role of sequencing and key mutations that may assist in refining diagnoses of these lesions.

Context.—: The role of liquid biopsy in cancer management has been gaining increased prominence in the past decade, with well-defined clinical applications now being established in lung cancer. Recently, the US Food and Drug Administration also approved the Therascreen PIK3CA RGQ polymerase chain reaction assay as a companion diagnostic assay to detect PIK3CA mutations in breast cancer for both tissue and liquid biopsies, bringing the role of liquid biopsy in breast cancer management to the fore. Its utility in other aspects of breast cancer, however, is yet to be clearly defined., Objective.—: To review the studies that looked at liquid biopsies in breast cancer and examine their potential for clinical application in the areas of early diagnosis, prognostication, monitoring disease response, detecting minimal residual disease, and predicting risk of progression or relapse. We focus mainly on circulating tumor cells and circulating tumor DNA., Data Sources.—: Peer-reviewed articles in PubMed., Conclusions.—: Liquid biopsies in breast cancers have yielded promising results, especially in the areas of monitoring treatment response and predicting disease progression or relapse. With further study, and hopefully coupled with continued improvements in technologies that isolate tumor-derived materials, liquid biopsies may go on to play a greater role in the breast cancer clinic.

Papillary neoplasms of the breast encompass a wide range of tumor types ranging from the benign intraductal papilloma to in situ and invasive papillary carcinomas. In this review, we considered each tumor entity listed under the Papillary Neoplasms category in the latest WHO Classification of Breast Tumors (5th edition), namely intraductal papilloma, papillary ductal carcinoma in situ, encapsulated papillary carcinoma, solid-papillary carcinoma, and invasive papillary carcinoma. We examined their pathological features, current issues pertaining to diagnosis and prognostication, as well as the latest molecular findings. We also briefly addressed adenomyoepithelioma and the newly included tall cell carcinoma with reversed polarity, highlighting areas where they overlap with papillary neoplasms.

Aims: This study aims to examine the molecular genetics of paediatric breast fibroepithelial tumours through the targeted sequencing of 50 genes., Methods and Results: Formalin-fixed paraffin-embedded tissues of fibroepithelial tumours diagnosed in a cohort of patients aged 18 years and below were subjected to next generation sequencing using the Haloplex Target Enrichment System. Twenty-five conventional and 17 juvenile fibroadenomas were studied, with MED12 mutations found in 53.8 and 35% of the tumours, respectively. There was also one benign fibroepithelial neoplasm with hybrid features of juvenile papillomatosis and infarcted benign phyllodes tumour-like areas. Most tumours did not have mutations in well-known cancer driver genes, none harboured TERT promoter mutations, while 25.6% (11 of 43) showed no mutations. Metachronous and synchronous tumours were found to have mutational heterogeneity with some containing mutations in MED12; other genes or no mutations were detected at all. Four of eight giant fibroadenomas (size 5 cm or larger) had no mutations detected, suggesting that there are other molecular mechanisms driving their growth. Tumours with MED12 mutations incidentally had a significantly higher stromal mitotic count compared with those without., Conclusion: While paediatric fibroepithelial lesions can have cellular stroma potentially raising concern for phyllodes tumour, their lack of TERT promoter and cancer driver mutations is reassuring. The absence of mutations in a significant proportion of tumours, especially the giant fibroadenomas, warrants investigation of pathogenetic mechanisms beyond those involving the 50 genes., (© 2018 John Wiley & Sons Ltd.)

Spindle cell lesions of the breast are among the less common entities encountered in breast pathology. They encompass a whole spectrum of benign reactive lesions to high grade malignant neoplasms. An accurate diagnosis is important to ensure that the patient receives the appropriate management. While this group of conditions broadly share the same basic morphology of a lesion composed of spindle cells, there are often recognizable differences on histology, which coupled with ancillary studies and correlation with the clinical and imaging findings, can help one to arrive at a specific diagnosis. On core biopsy however, spindle cell lesions pose significant interpretive challenges and a firm diagnosis is often not possible. We share our approach to this group of conditions, with a focus on the more common entities, highlighting their key clinical, imaging and pathological features., (Copyright © 2017 Elsevier Inc. All rights reserved.)