Affiliations of authors: S. B. Fox, K. C. Gatter (Department of Cellular Science), R. D. Leek, A. L. Harris (Molecular Oncology), Imperial Cancer Research Fund, University of Oxford, John Radcliffe Hospital, Oxford, U. K.; K. L. Chew, B. H. Mayall, Department of Laboratory Medicine and the Cancer Center, University of California, San Francisco, CA; D. H. Moore II, Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco.
Correspondence to: Stephen B. Fox, M.D., Anatomical Pathology, Canterbury Health, Christchurch Hospital, Christchurch, New Zealand (e-mail: sfox{at}chmeds.ac.nz).
Axelsson et al. (1) reported in this Journal that microvessel density (MVD) in 220 breast cancers did not provide prognostic information for metastasis-free or overall survival; this result was contrary to most published series (2). The study was designed to assess the reliability of MVD to predict the outcome for patients with breast cancer. MVD was measured by two observers who independently selected and scored the three most vascular fields. The maximum MVD was used for survival analysis (1).
Fox et al. (3) proposed, in a subsequent letter to this Journal, that these findings might be due to "the method of assessing tumor vascularity, the patient group studied, and their subsequent stratification," and suggested that the use of a Chalkley eyepiece graticule to quantify the hotspots (4) might help to reduce some confounding variables. In their response, Axelsson et al. (5) suggested that Fox et al. rescore the same tumors to "estimate differences in counting precision, assess the magnitude of observer bias, identify substantial differences among the methods, and determine the effects on prognostic power." In this correspondence, we report the outcome of this collaborative study.
Tumor sections from the original 220 factor VIII slides were reviewed. Fifty-one of these slides were considered unsuitable for reanalysis because of immunohistochemical fading (n = 23), high background staining (n = 5), a tumor area that was too small for assessment (n = 15), and paucity of invasive disease (n = 8). In the remaining 169 cases, angiogenesis was quantified by use of a 25-point Chalkley eyepiece graticule. The average of the three Chalkley counts for each tumor ranged from 2 to 11.7 (median = 5.67; mean = 5.87) and was comparable with other series using this technique (4).
Pearson correlation analysis and Kappa analysis based on tertiles assessed differences in
counting method and estimated bias between the two observers using MVD (B.-M. Ljung, K.
Axelsson) and between each observer and Chalkley count (Table 1).
There were significant associations between individual MVD scores (two-sided P<.001) and between each MVD and Chalkley count (two-sided P<.001); however,
the level of agreement in categorizing tumor vascularity was only fair, with the two MVD scores
showing the closest agreement. Although the correlation between MVD and Chalkley count was
not as strong as had been reported (4), these findings suggest that
Chalkley count is equivalent to MVD in assessing tumor angiogenesis but that there is a large
amount of residual variance among observers and between methods.
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Many of the confounding variables that could account for these findings have been extensively discussed in the original paper (1) and subsequent correspondence (3,5,7,8). We had hoped that the Chalkley count would reduce the subjective variability of MVD and lead to greater prognostic power. However, we must conclude that the assay itself is intrinsically unreliable or that the patients in this study had outcomes that were statistically significantly different from those reported in studies by others (2). If a group of patients has a disproportionate number of other poor prognostic features, then it would be hard to demonstrate the role of the new feature. Those patients in the poor prognostic group may have a reduction in survival for multiple reasons (e.g., size, grade, or lymph node status) that would mask the additional contribution of the new factor.
As has been suggested (3), standardized methodology should be used to analyze a series of patients in randomized trials and to investigate the interactions of factors. Agreement on the design of such a study has now been reached and is presented in a consensus paper (9); we suggest that these consensus guidelines be used to initiate a multicenter trial of the prognostic utility of tumor angiogenesis.
NOTE
Supported by Public Health Service grant P01CA44768 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
REFERENCES
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9 Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCullough P, et al. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 1996;32A:2474-84.[Medline]
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