Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma.

BACKGROUND Experimental evidence suggests that the growth of a tumor beyond a certain size requires angiogenesis, which may also permit metastasis. To investigate how tumor angiogenesis correlates with metastases in breast carcinoma, we counted microvessels (capillaries and venules) and graded the density of microvessels within the initial invasive carcinomas of 49 patients (30 with metastases and 19 without). METHODS Using light microscopy, we highlighted the vessels by staining their endothelial cells immunocytochemically for factor VIII. The microvessels were carefully counted (per 200x field), and their density was graded (1 to 4+), in the most active areas of neovascularization, without knowledge of the outcome in the patient, the presence or absence of metastases, or any other pertinent variable. RESULTS Both microvessel counts and density grades correlated with metastatic disease. The mean (+/- SD) count and grade in the patients with metastases were 101 +/- 49.3 and 2.95 +/- 1.00 vessels, respectively. The corresponding values in the patients without metastases were significantly lower--45 +/- 21.1 and 1.38 +/- 0.82 (P = 0.003 and P less than or equal to 0.001, respectively). For each 10-microvessel increase in the count per 200x field, there was a 1.59-fold increase in the risk of metastasis (95 percent confidence interval, 1.19 to 2.12; P = 0.003). The microvessel count and density grade also correlated with distant metastases. For each 10-microvessel increase in the vessel count per 200x field, there was a 1.17-fold increase in the risk of distant metastasis (95 percent confidence interval, 1.02 to 1.34; P = 0.029). CONCLUSIONS The number of microvessels per 200x field in the areas of most intensive neovascularization in an invasive breast carcinoma may be an independent predictor of metastatic disease either in axillary lymph nodes or at distant sites (or both). Assessment of tumor angiogenesis may therefore prove valuable in selecting patients with early breast carcinoma for aggressive therapy.

[1]  G. Pinkus,et al.  Are keratin proteins a better tumor marker than epithelial membrane antigen? A comparative immunohistochemical study of various paraffin-embedded neoplasms using monoclonal and polyclonal antibodies. , 1986, American journal of clinical pathology.

[2]  L. Liotta,et al.  The significance of hematogenous tumor cell clumps in the metastatic process. , 1976, Cancer research.

[3]  J. Folkman.  What is the evidence that tumors are angiogenesis dependent? , 1990, Journal of the National Cancer Institute.

[4]  Sandra R. Smith,et al.  An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. Srivastava,et al.  Neovascularization in human cutaneous melanoma: a quantitative morphological and Doppler ultrasound study. , 1986, European journal of cancer & clinical oncology.

[6]  J. Connolly,et al.  Suppression of tumor-forming ability and related traits in MCF-7 human breast cancer cells by fusion with immortal mammary epithelial cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S. Rosenberg,et al.  Isolation and characterization of actin and actin-binding protein from human platelets , 1981, The Journal of cell biology.

[8]  R. Fruchter,et al.  The significance of atypical vessels and neovascularization in cervical neoplasia. , 1981, American journal of obstetrics and gynecology.

[9]  L. Weiss.  Fundamental Aspects of Metastasis , 1977 .

[10]  Smith Ss,et al.  Mast cells in corneal immune reaction. , 1970 .

[11]  S. Brem,et al.  Angiogenesis as a marker of preneoplastic lesions of the human breast , 1978, Cancer.

[12]  J. Folkman,et al.  Angiogenic Activity as a Marker of Neoplastic and Preneoplastic Lesions of the Human Bladder , 1980, Annals of surgery.

[13]  D. Ingber,et al.  A heparin-binding angiogenic protein--basic fibroblast growth factor--is stored within basement membrane. , 1988, The American journal of pathology.

[14]  H M Jensen,et al.  Angiogenesis induced by "normal" human breast tissue: a probable marker for precancer. , 1982, Science.

[15]  S. Brem,et al.  Angiogenesis: a marker for neoplastic transformation of mammary papillary hyperplasia. , 1977, Science.

[16]  David R. Cox.  The analysis of binary data , 1970 .

[17]  D. Hanahan,et al.  Induction of angiogenesis during the transition from hyperplasia to neoplasia , 1989, Nature.

[18]  W. Clark,et al.  Biology of tumor progression in human melanocytes. , 1987, Laboratory investigation; a journal of technical methods and pathology.

[19]  A. Srivastava,et al.  The prognostic significance of tumor vascularity in intermediate-thickness (0.76-4.0 mm thick) skin melanoma. A quantitative histologic study. , 1988, The American journal of pathology.

[20]  Peter J. Polverini,et al.  Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene , 1989, Cell.

[21]  D M Gersten,et al.  The biology of cancer invasion and metastasis. , 1978, Advances in cancer research.

[22]  H. Dvorak,et al.  Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. , 1989, Biochimica et biophysica acta.

[23]  P. Polverini,et al.  Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages. , 1984, Laboratory investigation; a journal of technical methods and pathology.

[24]  L. Liotta,et al.  Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. , 1974, Cancer research.

[25]  S Friedman,et al.  Prognostic value of histologic grade nuclear components of Scarff‐Bloom‐Richardson (SBR). An improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas , 1989, Cancer.