Review Article

Breast Tumor Angiogenesis and Tumor-Associated Macrophages: Histopathologist's Perspective

Table 1

Summary of the selected studies in the last 10 years exploring the prognostic significance of VEGF and associated factors using immunohistochemistry in breast cancers.

PatientsAssessment of VEGF expressionPrognostic value of VEGF expression

98 stage II ductal breast cancers [26]Antibody: monoclonal anti-VEGF165
Scoring system: 0 = none, 1 = <33%, 2 = 33–66%, 3 = >66% positive tumor cells
VEGF had no prognostic significance for overall survival or disease-free survival

48 triple negative breast cancers not receiving systemic adjuvant treatment from 500 primary breast cancers using tissue microarrays [24]Antibody: polyclonal anti-VEGF
Scoring system: cytoplasmic staining intensity was scored from 0 to 3
High expression had score 3
VEGF had no prognostic significance for 5-year breast-cancer-specific survival

125 stage II node-positive invasive ductal carcinomas, NOS 25 stage II node-positive invasive lobular carcinomas [23]Antibody: polyclonal anti-VEGF-C
Staining was graded as strong, medium, or weak-to-absent expression
VEGF-C had no prognostic significance for overall survival or disease-free survival

172 primary breast cancer [25]Antibody: anti-VEGF-A
Scoring system: staining intensity was graded from 0 (negative) to 3 (strong intensity)
Positive cases had score 1–3
VEGF-A had no prognostic significance for recurrence-free survival

116 invasive ductal breast cancers [27]Antibody: anti-VEGF
Scoring system: positive cases had >10% positive tumor cell staining
VEGF-A had no prognostic significance for overall survival in multivariate analysis

52 infiltrating ductal carcinomas, 4 intraductal carcinomas, 3 mucinous adenocarcinomas,1 medullary carcinoma, 1 inflammatory breast carcinoma [38]Antibody: anti-VEGF-C, anti-VEGF-D
Scoring system: sum of staining intensity (0 = negative to 3 = strong) and percentage of positive cells (0 = 0%, 1 = 1–10%, 2 = 11–30%, 3 = 31–50%, 4 = 51–100%)
High-expression group had score 4–7
High expression of VEGF-C/D had poorer disease-free survival and overall survival

59 invasive ductal carcinomas, NOS 11 other types of invasive breast cancer [39]Antibody: polyclonal anti-VEGF-C
Scoring system: negative, 1+ (focal expression in <5%), 2+ (focal expression in 5–20%), 3+ (diffuse expression in >20%)
High-expression group had score above 2+
Shorter disease-free survival and overall survival for high expression of VEGF-C in univariate analysis

215 high-risk primary breast cancers with extensive axillary involvement [28]Antibody: monoclonal anti-VEGF
Staining intensity was graded from 0 to 3+
Positive cases are those having any tumor areas with positive staining
VEGF had no prognostic significance for overall survival or relapse-free survival

177 invasive breast cancers [40]Antibody: monoclonal anti-VEGF-A, anti-VEGF-D, polyclonal anti-VEGF-C
Scoring system: H score (multiplying percentage of positive carcinoma cells by the staining intensity graded 0 to 3)
High-expressing tumors had score above the median score
(1) Shorter overall survival for high expression of VEGF-A in univariate analysis
(2) Shorter overall survival and disease-free interval for high expression of VEGF-C in univariate and multivariate analyses
(3) No prognostic significance for VEGF-D
(4) Tumours with high expression of both VEGF-A and -C had significantly shorter overall survival

130 invasive ductal carcinomas, 30 invasive lobular carcinomas [41]Antibody: polyclonal anti-VEGF-B, monoclonal anti-VEGF-A (165, 189, 206 a.a.)
Scoring system: 0 (no or weak staining in <10%), 1 (weak-to-moderate staining in 11–20%), 2 (moderate-to-strong staining 21–50%), 3 (strong staining in >50%)
Positive cases had score above 2
(1) VEGF-A had no prognostic significance
(2) Unfavorable disease-free and overall survival for VEGF-B-positive cases in lymph node metastases cases

136 invasive ductal carcinomas, 31 invasive lobular carcinomas [42]Antibody: polyclonal anti-VEGF-C, polyclonal anti-VEGF-D
Scoring system: positive cases had at least 10% immunoreactive tumor cells
Poorer overall survival for VEGF-C-positive cases
VEGF-D had no prognostic significance
80 invasive ductal carcinomas, 15 ductal carcinomas in situ, 5 lobular carcinomas in situ, 14 invasive lobular carcinomas, 6 medullary carcinomas, 2 tubular carcinomas [43]Antibody: monoclonal anti-VEGF
Scoring system: 0 = none, 1+ = < 5%, 2+ = 5–50%, 3+ = >50% positive tumor cells
High reactivity cases had score above median value
Overexpression of VEGF had both unfavorable overall survival and disease-free survival

114 breast cancers [29]Antibody: monoclonal anti-VEGF165
Scoring system: staining intensity was graded from 0 (no staining) to III (most intense staining)
VEGF had no prognostic significance for disease-free survival or cancer survival

100 invasive ductal carcinomas, NOS, 19 invasive lobular carcinomas [30]Antibody: polyclonal anti-VEGF-C
Staining was graded as strong, medium, or weak expression
VEGF-C had no prognostic significance for overall survival or disease-free survival

323 invasive breast carcinomas [31]Antibody: monoclonal anti-VEGF
Scoring system: sum of staining intensity (0 = negative to 3 = strong) and percentage of positive cells (0 = 0%, 1 = 1–25%, 2 = 26–50%, 3 = >50%)
Positive cases had score 4–6
VEGF was not associated with incidence of relapse or death

181 invasive ductal carcinomas, 22 invasive lobular carcinoma, 8 invasive ductal and lobular (mixed) carcinomas, 5 ductal in situ carcinomas, 1 medullary carcinoma [32]Antibody: anti-VEGF-C
Scoring system: cytoplasmic staining was graded negative (negative), 1+ (10–39%), 2+ (40–69%), 3+ (>70%)
VEGF-C had no prognostic significance for disease-free survival

238 invasive breast cancers not receiving tamoxifen from 500 primary breast cancers using tissue microarrays [22]Antibody: polyclonal anti-VEGF
Scoring system: cytoplasmic staining intensity was scored from 0 to 3
High staining intensity group had score 3
VEGF had no prognostic significance for relapse-free survival

87 primary breast cancers [33]Antibody: polyclonal anti-VEGF-C
Scoring system: 0 (no staining or cytoplasmic staining in <10%), 1+ (faint cytoplasmic staining in >10%), 2+ (weak-to-moderate complete cytoplasmic staining in >10%), 3+ (strong complete cytoplasmic staining in >10%)
Positive cases had score 2+ or 3+
VEGF-C had no prognostic significance for disease-free survival or overall survival

224 invasive breast cancers using tissue microarrays [44]Antibody: polyclonal anti-VEGF
Scoring system: staining intensity was graded from 0 (negative) to 3 (intense intensity), and the percentage of positive cells was recorded (0 = 0%, 1 = <1%, 2 = 1–10%, 3 = 10–50%, 4 = 50–90%, 5 = >90%)
Positive cases are those having any positive staining
VEGF-A-positive cases had favorable disease-free survival at 10-year followup in multivariate analysis

207 invasive breast carcinomas [34]Antibody: polyclonal anti-VEGF-D
Scoring system: 0 = negative, 1 = weak focal staining, 2 strong focal/widespread moderate staining, 3 = strong widespread staining
Positive cases had score 2 or 3
VEGF-D had no prognostic significance for overall survival or relapse-free survival

96 invasive ductal carcinomas, 9 other invasive carcinomas [45]Antibody: monoclonal anti-VEGF-D
Scoring system: positive cases had more than 10% tumor cells with cytoplasmic staining
(1) Positive VEGF-D cases had poorer disease-free survival in univariate and multivariate analyses
(2) Positive VEGF-D cases had poorer overall survival in univariate analysis

228 invasive unilateral breast carcinomas [35]Antibody: monoclonal anti-VEGF (isoforms 121, 165 and 189)
Scoring system: positive cases had more than 1% immunoreactive tumor cells
VEGF had no prognostic significance for overall survival or relapse-free survival

114 invasive ductal carcinomas, 9 other invasive carcinomas [46]Antibody: polyclonal anti-VEGF-C
Scoring system: positive cases had more than 10% immunoreactive tumor cells
Positive VEGF-C cases had poorer disease-free survival and overall survival in univariate analysis
99 invasive ductal carcinomas, NOS [36]Antibody: anti-VEGF
Scoring system: positive cases had more than 10% tumor cells with membrane or cytoplasmic staining
VEGF had no prognostic significance for overall survival or relapse-free state

107 primary invasive breast carcinomas [47]Antibody: anti-VEGF-A, anti-VEGF-C, anti-VEGF-D
Scoring system: computer-assisted image analysis based on the percentage of immunostained surfaces and mean optical density
High-expression group had value equal to or higher than median
(1) High-VEGF-A-expression cases had worser disease-free survival
(2) VEGF-C or VEGF-D had no prognostic significance
(3) Cases with both low VEGF-A and VEGF-C expression had better disease-free survival

242 node-negative breast cancer [37]Antibody: polyclonal anti-VEGF isoforms 121, 165, 189, and 206
Scoring system: high-expression cases had >40% immunopositive tumor cells
VEGF had no prognostic significance for disease-free survival or overall survival

94 invasive breast cancer, 4 noninvasive cancer [48]Antibody: polyclonal anti-VEGF-C
Scoring system: positive cases had over 10% tumor cells stained positively
VEGF-C-positive group had poorer disease-free survival