Stromal cells in phyllodes tumors of the breast are enriched for EZH2 and stem cell marker expression.
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.
Department of Pathology, University of California Davis, Sacramento, CA, USA.
Yanhong
Y
Zhang
Departments of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Adam L
AL
Liss
Departments of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Eugene
E
Chung
Departments of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Lori J
LJ
Pierce
Department of Pathology, University of Michigan, 4217 Comprehensive Cancer Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA. kleer@umich.edu.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. kleer@umich.edu.
Celina G
CG
Kleer
D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism; D003557:Phyllodes Tumor / Q000378:metabolism / Q000473:pathology*; D050697:Retinal Dehydrogenase; D017154:Stromal Cells / Q000378:metabolism
D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
ALDH1; Breast cancer; EZH2; Phyllodes tumors; Stem cell; Stromal cells