Relationships between vascularization and proliferation in invasive breast cancer

Abstract

Studies on relationships between angiogenesis and tumour cell proliferation have provided conflicting results. This study has therefore investigated the relationships between the number and location of fully automatically identified CD31‐positive microvessels and interactively segmented mitoses and necrotic compartments by image processing. These features were studied in ten invasive breast cancers, in the ‘hot spots’ and in whole tumour sections. Microvessel and mitosis hot spots were topographically close or overlapping and were always located at the periphery of the tumour. The numbers of mitoses and microvessels per mm2 in the hot spot were strongly correlated with the respective numbers in the whole tumour section, as well as mutually. The ratio of mitoses in the hot spot to the whole tumour section was significantly higher than the corresponding microvessel ratio. Mitoses were preferentially located at a distance of 50–150 µm from microvessels. No significant difference was found between the average distance between mitoses and microvessels in the whole tumour sections and in the hot spot (79 vs. 72 µm), although considerable inter‐tumour differences were found (hot spot 43–101 µm, tumour 47–111 µm). The presence of necrotic areas correlated with the number of mitoses per mm2 and necrosis was in general observed at a distance of more than 150 µm from the microvessels, suggesting that necrotic areas have outgrown their vascular system. These results indicate the usefulness of image processing of whole tumour sections for the identification of proliferation and vascularization hot spots, which are strong prognostic factors in breast cancer. The results also support a close relationship between tumour necrosis and microvessels. Copyright © 1999 John Wiley & Sons, Ltd.

Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

“…The mean distance from microvessels to the epithelium was significantly higher for phyllodes tumors as compared with fibroadenomas, suggesting that the hypoxic microenvironment in the epithelial component of phyllodes tumors is caused by relatively distant microvessels. Most vessels in phyllodes tumors were within 150 μm of the epithelial basal membrane, however, which is a critical distance for necrosis [41]. Still, it is conceivable that rapidly growing stroma stretches the two-layered epithelium in such way that it's oxygen supply does not keep up, resulting in a state of mild hypoxia.…”

Early distant relapse in ?node-negative? breast cancer patients is not predicted by occult axillary lymph node metastases, but by the features of the primary tumour

“…This might at first seem counterintuitive. Increased angiogenesis, however, is associated with higher mitotic activity51 and reduced apoptosis52, leading to proliferation of tumour cells beyond their vascular supply.…”

Tumour vascularity and proliferation: clear evidence of a close relationship

“…The sheath of viable cells appears to remain as thick as diffusion allows exchange of nutrients, oxygen, and waste products by the crowded cell population; a thickness of 150 m was suggested by Belien et al 1 Tumour cells that proliferate beyond this diffusion limit undergo necrosis, which may be caused by ischaemic hypoxia and/or apoptosis. Peritheliomatous pattern necrosis is probably related to the comedotype necrosis found in most high-grade ductal carcinomas in situ (DCIS) of the breast.…”

“…In this issue of the Journal of Pathology, Belien et al 1 report that areas of highest intratumoural microvessel density (iMVD) are topographically close to, or even overlap, the areas of tumour with the most mitotic figures (i.e. 'hot spots'), and that both areas are almost always located at the periphery or growing front of the tumour.…”