Genetic differences between benign phyllodes tumors and fibroadenomas revealed through targeted next generation sequencing.

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.

Genomic characterisation of breast fibroepithelial lesions in an international cohort.

Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16-gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non-Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild-type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Granulomatous Mastitis and Factors Associated with Recurrence: An 11-Year Single-Centre Study of 113 Patients in Singapore.

BACKGROUND: Granulomatous mastitis (GM) is an inflammatory breast disease of unknown aetiology. It poses diagnostic and therapeutic challenges with myriad forms of clinical presentation, varying results to treatments and propensity to recur. This study aims to look at clinical and treatment factors that predispose to recurrence of GM. METHODS: We performed a retrospective review of 113 patients in our unit with histologically proven GM from 2006 to 2016. Demographic, clinical, treatment and outcomes data were collected and analysed. RESULTS: Eighty-nine patients were treated with antibiotics (78.8%), 79 (69.9%) with steroids and 23 (20.4%) patients underwent surgery. Twenty (17.7%) patients had recurrence. Patients who presented with inflammatory signs and symptoms had increased odds of having subsequent recurrence: skin changes (1.50), pain (2.00), fistula (4.39) and antibiotic treatment (6.65). Four patients (20%) with recurrence had positive bacterial cultures. All 4 grew Corynebacterium. Patients with Corynebacterium infection had a 2.64 times higher risk of recurrence. Surgery did not preclude recurrence. There was a 70% (7/10) penicillin resistance rate in our patients with positive cultures for Corynebacterium. CONCLUSION: Initial presentation with inflammatory signs and symptoms may confer increased risk of recurrence, warranting closer monitoring. Corynebacterium infection may play a part as a causative factor and risk factor for recurrence. Non-penicillin antibiotics should be considered as first-line antibiotics for patients presenting with inflammatory changes. Further prospective studies with larger patient populations might reveal information on the aetiology of GM and result in the development of a more standardized and effective treatment regimen.

HER2-low breast cancers: challenges in the interpretation of immunohistochemistry.

ABSTRACT: Overexpression of human epidermal growth factor receptor 2 (HER2) protein in breast cancers carries significant prognostic and therapeutic implications. Anti-HER2 blockade has shown to be a useful adjunct to surgery in treating HER2-positive tumours. Up till today, the HER2 immunohistochemistry (IHC) and in situ hybridisation (ISH) scoring algorithms are geared towards identifying HER2-positive cases. A recently published Phase III clinical trial (DESTINY-Breast04) has demonstrated that an antibody-drug conjugate (trastuzumab-deruxtecan) significantly reduced disease progression and death in patients with metastatic disease with IHC score 1+ or 2+ and without ISH amplification, defining a new category of cases known as HER2 low. At present, IHC scores 0, 1+ and 2+ show significant interobserver variability, and identifying HER2-low breast cancers may pose significant challenges with the current algorithms. More work is needed in this area to better define HER2-low breast cancers, target the appropriate group of patients and assess treatment efficacy.

Effect of pregnancy and lactation on a benign phyllodes tumour.

Phyllodes tumours occurring in pregnancy are very rare. While most cases presented as rapidly enlarging masses, we present a benign phyllodes tumour which had the most growth in the first half of pregnancy followed by gradual growth in the latter half of pregnancy and lactation, as characterised on ultrasound imaging. This is the first report, to the best of our knowledge, which has objective measurements of the lesion before, during and after pregnancy. It also highlighted the need for a vigilant approach to fibroepithelial lesions in pregnancy, instead of attributing the growth of these lesions solely to hormonal changes.

Invasive papillary breast cancer with Paget's disease: first reported association and literature review.

Invasive papillary carcinoma of the breast and Paget's disease are both rare entities. We report the first known case of invasive papillary carcinoma associated with Paget's disease in a woman who presented clinically with a nipple mass. While invasive papillary carcinoma has been reported to have an indolent course without need for overtreatment, our patient had unusual unfavourable histological features. Literature review of this rare subtype was performed.

Natural history of metaplastic squamous cell breast cancer: a case report and literature review on surgical management.

Metaplastic squamous cell breast cancer is an extremely rare subtype, accounting for less than 1% of all invasive breast cancers. As a result, there is sparse data in literature relating to its presentation and management. We report the first known case of metaplastic squamous cell breast cancer which was detected on screening mammogram and followed up as the patient delayed her treatment. This case highlights the aggressive natural behaviour of this subtype and importance of early treatment. The surgical management of this rare entity was reviewed.