Angiogenesis is known to be important in metastasis, and microvasculature density, defined as vessels per unit area, has been reported to be a reliable prognostic indicator in early stage breast cancer (Weidner et al., 1992). It has been suspected that angiogenesis might be the necessary switch for progression from CIS to invasive carcinoma. However, increased angiogenic activity appears to be an even earlier event in progression. Preneoplastic mammary lesions induce an angiogenic response when transplanted into the anterior chamber of the eye (Brem et al., 1977, 1978).

In one study (Brem et al., 1978), fragments of human invasive breast cancers and CIS induced angiogenesis equally well (two thirds of the fragments were positive). Fragments from normal breast tissue, nonproliferative fibrocystic disease, fibroadenomas, and other benign lesions were not angiogenic. However, nearly one third of fragments from hyperplastic lesions were angiogenic.

Immunohistochemical studies have identified apparent angiogenic activity in ductular carcinoma in situ (DCIS) at an incidence similar to that found in hyperplastic lesions. Pure DCIS was associated with vascular cuffing detected by staining for factor VIII in 38% of cases (Guidi et al., 1994) and DCIS mixed with invasive carcinoma was associated with vascular cuffing in 23% of cases (Weidner et al., 1991).

Vascularity was found to increase sequentially with progression from normal to proliferative disease without atypia (PDWA) to atypical hyperplasia to DCIS (Heffelfmger et al., 1996). Furthermore, comedo DCIS was more highly vascularized than other types. These findings are somewhat at odds with an earlier study in which size of blood vessels increased around areas of hyperplasia and DCIS but new vessels were not apparent (Ottinetti and Sapino, 1988). The latter authors suggested that the expansion of the epithelial mass impeded blood flow causing stasis and vessel dilation, and was inconsequential because the phenomenon was detected in both DCIS and benign hyperplasias.

Both vascular concentration (number of vessels per µm² lesion field) and vascular density (vascular area per area of lesion field) were determined in a case control study of 24 cancer patients and 24 controls for whom benign biopsy specimens were available (Guinebretiere et al., 1994). All had been diagnosed as fibrocystic disease, but there were only four cases of atypical hyperplasia in each group.

Factor VIII staining of the most proliferative slide from each patient and quantitative image analysis revealed that both vascular density and vascular concentration correlated with subsequent development of invasive cancer. Thus, in this study, vascular parameters identified high risk fibrocystic disease without atypia.

Fred Raymond Miller
Advances in Oncobiology

References