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Virchows Arch (2002) 440:583–588 DOI 10.1007/s004280100458

O R I G I N A L A RT I C L E

Toni Valkovi´c · Frane Dobrila · Mauro Melato Franco Sasso · Clara Rizzardi · Nives Jonji´c

Correlation between vascular endothelial growth factor, angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma Received: 14 December 2000 / Accepted: 11 March 2001 / Published online: 16 May 2001 © Springer-Verlag 2001

Abstract Angiogenic and anti-angiogenic factors, secreted by tumor, inflammatory, and stromal cells play an important role in regulation of neovascularization. Among the most important of these is vascular endothelial growth factor (VEGF), a specific mitogen for endothelium, which increases vascular permeability and induces proteolytic enzymes necessary for vascular remodeling. Tumor-associated macrophages (TAMs) can express complex functions related to tumor biology, including growth, proliferative rate, stroma formation and dissolution, and neovascularization. The aim of this study was to define, using immunohistochemical analysis, the microvessel density (MVD), VEGF expression, and TAMs level in 97 human invasive ductal breast carcinomas not otherwise specified (NOS), investigate a possible relationship between them and then correlate their values with tumor grade, mitotic activity index (MAI), tumor size and lymph-node status. Statistical analysis showed a strong positive relationship between MVD and VEGF expression (P3 Positive lymph nodes

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Results The clinicopathological parameters of the 97 patients included in this study with the results of immunohistochemical analysis are summarized in Table 1. The microvessel density in the 97 cases of invasive ductal breast carcinomas ranged from 36/mm2 to 161/mm2 (median 85/mm2, SD 25.6). The hot spots occurred anywhere in the tumor but most frequently at the invasive edge of the tumor. Of the 97 breast carcinomas, 56 (57.7%) were in VEGF “–’’ group, 20 (20.6%) were in VEGF “–/+’’ group and 21 (21.6%) were in VEGF “+’’ group. Posi-

Fig. 1 Immunohistochemical staining for vascular endothelial growth factor (VEGF) in invasive breast carcinoma. A Positive vascular smooth muscle cells with surrounding negative tumor cells, ×10. B Tumor cells stained similarly to smooth muscle cells, ×10. C Strong expression of VEGF in tumor cells, ×40

tive tumoral and stromal (smooth muscle, endothelium, fibroblasts, and macrophages) cells showed diffuse cytoplasmic immunoreactivity, ranging in intensity from weak to strong (Fig. 1). Many tumors showed a heterogeneous distribution of VEGF staining, and tumor cells that stained for VEGF were observed more often in the invasive front than in the tumor center. With regard to TAMs, 27 (27.8%) tumors had no macrophages in the stroma, 18 (18.6%) had small foci, 31 (32%) had large foci, and 21 (21.6%) had diffuse infiltration of TAMs in the tumoral stroma (Fig. 2). Immunoreactivity was cytoplasmic, moderate or strong, granular or diffuse in nature. CD68-positive cells were observed in the stroma, very often on the invasive margins of the tumor or around the foci of necrosis. Furthermore, in the same specimen, we frequently noticed the concomitance between the “hot spot” and the areas of the highest TAM level and VEGF expression. The average values of MVD showed significant differences in the different VEGF groups of tumors. Namely, the mean value of MVD was 76.2 for VEGF “–’’; 102.2 for VEGF “–/+’’, and 94.2 for VEGF “+’’ group (P

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