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.

Radiopathological characteristics and outcomes of phyllodes tumor of the breast in Malaysian women.

Phyllodes tumor or cystosarcoma phyllodes is a rare fibroepithelial neoplasm which arises from the periductal stroma of the breast. They are classified as benign, borderline, and malignant based on the histologic features. However, all phyllodes tumor (PT) subtypes are regarded as having malignant potential and correct diagnosis is important for surgical management and optimal care. This study is a retrospective review of 76 women diagnosed as PT with highlights on the imaging characteristics, pathology, and surgical treatment over a 7-year period in a tertiary medical center of urban population in Malaysia. There were 45 benign, 16 borderline, and 15 malignant PT. The median age for benign PT was 43, borderline 48.5, and malignant 42 years. The Malay ethnic group constitute 52.6% of cases, with 27.6% and 18.4% in Chinese and Indian ethnic groups, respectively. On mammograms, most benign (64.3%) and 33.3% of malignant PT showed high-density lesions. Calcifications were only seen in 2 benign PT. On ultrasound, 86% of benign PT was well-circumscribed whilst 50.0% of malignant PT had irregular outline. Cystic spaces were seen in 40.0% of malignant and 9.5% of benign PT. 80% of malignant PT lesions were heterogenous. Malignant PT demonstrates tumor heterogeneity, cystic spaces, and posterior acoustic enhancement on ultrasound. Half of malignant PT showed regular borders on ultrasound and appear well circumscribed on mammogram. A total of 46 patients had wide local excision or excision biopsy whilst 30 underwent mastectomy as primary treatment. The majority of the borderline and malignant PTs in our study (75.0% and 85.7% respectively) and only 5 out of the 43 (11.6%) benign PT underwent mastectomy. There were 2 tumor recurrence in the benign PT group and 1 case in the borderline and malignant group respectively.

Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience.

Taking cognizance of the purported variation of phyllodes tumours in Asians compared with Western populations, this study looked at phyllodes tumours of the breast diagnosed at the Department of Pathology, University of Malaya Medical Centre over an 8-year period with regards to patient profiles, tumour parameters, treatment offered and outcome. Sixty-four new cases of phyllodes tumour were diagnosed during the period, however only 30 (21 benign, 4 borderline and 5 malignant) finally qualified for entry into the study. These were followed-up for 4-102 months (average = 41.7 months). Thirteen cases (8 benign, 3 borderline, 2 malignant) were Chinese, 9 (all benign) Malay, 7 (4 benign, 1 borderline, 2 malignant) Indian and 1 (malignant) Indonesian. Prevalence of benign versus combined borderline and malignant phyllodes showed a marginally significant difference (p=0.049) between the Malays and Chinese. Patients' ages ranged from 21-70 years with a mean of 44.9 years with no significant difference in age between benign, borderline or malignant phyllodes tumours. Except for benign phyllodes tumours (mean size = 5.8 cm) being significantly smaller at presentation compared with borderline (mean size = 12.5 cm) and malignant (mean size = 15.8 cm) (p<0.05) tumours, history of previous pregnancy, breast feeding, hormonal contraception and tumour laterality did not differ between the three categories. Family history of breast cancer was noted in 2 cases of benign phyllodes. Local excision was performed in 17 benign, 2 borderline and 3 malignant tumours and mastectomy in 4 benign, 2 borderline and 2 malignant tumours. Surgical clearance was not properly recorded in 10 benign phyllodes tumours. Six benign and all 4 borderline and 5 malignant tumours had clearances of <10 mm. Two benign tumours recurred locally at 15 and 49 months after local excision, however information regarding surgical clearance was not available in both cases. One patient with a malignant tumour developed a radiologically-diagnosed lung nodule 26 months after mastectomy, was given a course of radiotherapy and remained well 8-months following identification of the lung nodule.

Low local recurrence rates in young Asian patients with phyllodes tumours: less is more.

BACKGROUND: Phyllodes tumours are increasingly being discovered incidentally in young patients after excision of a seemingly innocuous breast lump. The clinical course of this group of patients has not been well-described, especially in the Asian population. METHODS: A retrospective review of 44 consecutive patients below 25 years of age undergoing surgery for phyllodes tumours at our institution from 1992 to 2010 was conducted. Clinico-pathological data, local recurrence rates and margin involvement were recorded. RESULTS: The majority of the patients had benign lesions treated with simple enucleation, and there were no local recurrences documented after a mean and median length of follow-up of 47.6 and 29.5 months, respectively. CONCLUSION: We conclude that in young Asian patients who present with benign phyllodes tumours, simple excision, followed by close follow-up is sufficient, regardless of surgical margin status.

Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression.

Phyllodes tumors of the breast are rare fibroepithelial neoplasms with a potential for recurrence. Current histological classification is not always predictive of clinical behavior. The aim of this study was to identify genetic changes associated with the development of borderline and malignant phyllodes tumors in an Asian population, and to assess if genetic data supported the categorization of these tumors into the existing three grades of benign, borderline, and malignant. Expression profiling of 21 phyllodes tumors (6 benign, 10 borderline, 5 malignant) was performed using Affymetrix U133Plus 2.0 GeneChips(®). Gene expression among benign, borderline, and malignant tumors was compared and a 29 gene list was able to classify them according to their histologic grade. Among these 29 genes are those responsible for matrix formation, cell adhesion, epidermis formation, and cell proliferation. Comparative genomic microarray analysis showed that the most common chromosomal alteration associated with borderline and malignant tumors was 1q gain, and an increasing number of chromosomal changes was noted with increasing histological grade. Upregulation of HOXB13 was seen in malignant relative to borderline phyllodes tumors and further investigated by immunohistochemistry in a corresponding set of formalin-fixed, paraffin-embedded tumors. HOXB13 protein overexpression was found to be correlated with stromal hypercellularity and atypia (P = 0.03, P = 0.039, respectively) and may be implicated in the development of malignant phyllodes tumors.