Angiogenesis in mammary Paget disease: histopathological analyses of blood vessel density and angiogenic factors

Author:

Akishima-Fukasawa Yuri,Honma Naoko,Ogata Hideaki,Akasaka Yoshikiyo,Mikami Tetuo

Abstract

Abstract Background We examined the vascularity of mammary Paget disease histologically to confirm the increased blood flow observed previously by clinical imaging. The relationships among blood vessel density (BVD), histopathological parameters of blood flow in the nipple, and the expression of angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor A (VEGFA) were examined. Methods We calculated the average CD34-positive BVD and podoplanin (D2–40)-positive lymphatic vessel density (LVD) and the proportion of proliferating of endothelial cells in 14 Paget disease, 3 dermatitis biopsy, and 14 age-matched control cases. As a parameter related to blood flow in the nipple, the total CD34-positive blood vessel lumen area relative to the entire nipple area was measured in each Paget disease and control case using an automated image analysis system. Immunohistochemical expression of bFGF and VEGFA in Paget cells was also examined. Results The average BVD and LVD were significantly higher in the Paget disease cases than in the dermatitis (p = 0.003) and control (p < 0.001) cases. The proportion of proliferating endothelial cells was also increased in the Paget disease cases. The ratio of the CD34-positive blood vessel lumen area to nipple area was also significantly higher in the Paget disease than control cases (p = 0.003). The average BVD was correlated with the average LVD (r = 0.734, p < 0.001) and ratio of the blood vessel lumen area to nipple area (r = 0.692, p < 0.001). Immunohistochemical expression of bFGF was strong in all Paget disease cases, with a significantly higher expression score in the Paget disease than dermatitis (p = 0.003) and control (p < 0.001) cases. The bFGF, but not VEGFA, expression score, was strongly correlated with the average BVD (r = 0.818, p < 0.001) and ratio of the blood vessel lumen area to nipple area (r = 0.503, p = 0.006). Conclusion These results provide direct histopathological evidence of a marked increase in nipple blood flow in Paget disease detected by clinical imaging. bFGF is considered to play a pivotal role in angiogenesis in mammary Paget disease.

Funder

Japan Society for the Promotion of Science

Initiative for Realizing Diversity in the Research Environment of Toho University

Publisher

Springer Science and Business Media LLC

Subject

General Medicine,Histology,Pathology and Forensic Medicine

Reference14 articles.

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2. Xu X, Shao N, Qiao D, et al. Expression of vascular endothelial growth factor and basic fibroblast growth factor in extramammary Paget disease. Int J Clin Exp Pathol. 2015;8:3062–8.

3. Ikeda DM, Helvie MA, Frank TS, et al. Paget disease of the nipple: radiologic-pathologic correlation. Radiology. 1993;189:89–94.

4. Lim HS, Jeong SJ, Lee JS, et al. Paget disease of the breast: mammographic, US, and MR imaging findings with pathologic correlation. Radiographics. 2011;31:1973–87.

5. Kim HS, Seok JH, Cha ES, et al. Significance of nipple enhancement of Paget’s disease in contrast enhanced breast MRI. Arch Gynecol Obstet. 2010;282:157–62.

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