Stromal cells in phyllodes tumors of the breast are enriched for EZH2 and stem cell marker expression

Abstract

Phyllodes tumors (PTs) of the breast are fibroepithelial neoplasms with stromal hypercellularity, which is the basis for their classification as benign, borderline, and malignant. The histologic diagnosis of PTs is often difficult, and the pathological features may not always predict clinical behavior. The pathobiology of PT remains poorly understood. Enhancer of Zeste 2 (EZH2) epigenetically regulates cell-type identity, cellular differentiation, and breast cancer stem cells. EZH2 exerts oncogenic functions in breast cancer and is associated with metastasis. We hypothesized that in PTs, EZH2 and the stem cell marker ALDH1 may be expressed in stromal cells and may be associated with their degree of differentiation. Forty PTs were histologically characterized at our institution following the World Health Organization criteria. We investigated the expression of EZH2 and ALDH1 by immunohistochemistry and recorded as percentage of positive epithelial and stromal cells. EZH2 was positive when over 10 % of cells exhibited nuclear staining; ALDH1 was positive when over 5 % of cells had cytoplasmic staining. Of the 40 PTs, 24 (60 %) were histologically benign, 8 (20 %) borderline, and 8 (20 %) malignant. Stromal EZH2 was significantly associated with the diagnosis of malignant PT, as it was detected in 1 of 24 (4 %) benign, 3 of 8 (37.5 %) borderline, and 5 of 8 (62.5 %) malignant tumors. Stromal EZH2 was significantly associated with stromal overgrowth (p = 0.01), atypia (p = 0.01), hypercellularity (p = 0.01), and mitoses (p = 0.02), all features of malignant PT. Stromal EZH2 and ALDH1 were significantly associated with grade of PT (p = 0.01 and p < 0.05 respectively). In conclusion, EZH2 and ALDH1 expression in the stroma of PT may mark malignant progression and may be helpful to distinguish histologically benign from borderline and malignant tumors in challenging cases. Our study also suggests that PTs contain mesenchymal stem cells, shedding light into the pathogenesis of these tumors.

Integrating single‐cell and spatial transcriptomes reveals COL4A1/2 facilitates the spatial organisation of stromal cells differentiation in breast phyllodes tumours

“…Once exposed to CAF‐like Stroma tA cells, or so‐called ‘reactive stroma’, EPs may have been further stimulated and underwent a mesenchymal transition. Previous studies have reported the expression of stem cell markers in the stroma 36,37 . In the present study, we observed that TEP cells expressed both EPs and mesenchymal markers, providing evidence of the presence of less differentiated cells in the stroma.…”

The significance of enhancer of zeste homolog 2 (EZH2) expression in spindle cell lesions of the breast

“…Our study results for PT were similar to the study reported by Zhang et al . that EZH2 expression was directly correlated with stromal cellularity, nuclear atypia, and the number of mitoses, as well as the overall grade of tumors 5 . Frequent high EZH2 expression in MBC with spindle cell features was also reported previously 4 .…”

“…Enhancer of zeste homolog 2 (EZH2) overexpression was demonstrated in various cancer types, including breast cancer, in which high EZH2 expression is associated with adverse clinicopathologic features and aggressive behavior 3 . Moreover, malignant phyllodes tumor (PT) and metaplastic breast carcinoma (MBC) with spindle cell morphology were also reported to overexpress EZH2 in previous studies 4,5 …”

Association of clinicopathological features and prognosis of TERT alterations in phyllodes tumor of breast

“…Recently, a role of histone methylation of TERT regulation has been demonstrated 24 . Of interest, stromal EZH2, an epigenetic modifier, was significantly associated with PT malignancy 25 . Additionally, TERT gene amplification was only reported in malignant PTs 7 .…”