Questions of reproducibility and efficacy of histologic malignancy grading relative to alternative proliferation index measurements for outcome prediction remain unanswered. Microsections of specimens from the Cooperative Breast Cancer Tissue Resource (CBCTR) were evaluated by seven pathologists for reproducibility of grade and classification. Nuclear figure classification was assessed using photographs. Grade was assigned by the Bloom-Richardson method, Nottingham modification. Proliferation index was evaluated prospectively by deoxyribose nucleic acid precursor uptake with thymidine (autoradiographic) or bromodeoxyuridine (immunohistochemical) labeling index using fresh tissue from 631 node-negative breast cancer patients accessioned at St Luke's Hospital. A modified Nottingham-Bloom-Richardson grade was derived from histopathologic data. Median post-treatment observation was 6.4 years. Agreement on classification of nuclear figures (N ¼ 43) was less than good by kappa statistic (j ¼ 0.38). Grade was moderately reproducible in four trials (N ¼ 10,10,19, 10) with CBCTR specimens (j ¼ 0.50-0.59). Of components of Bloom-Richardson grade, agreement was least for nuclear pleomorphism (j ¼ 0.37-0.50), best for tubularity (j ¼ 0.57-0.83), and intermediate for mitotic count (j ¼ 0.45-0.64). Bloom-Richardson grade was a univariate predictor of prognosis in node-negative St Luke's patients, and was improved when mitotic count was replaced by labeling index (low, mid, or high). When labeling index was added to a multivariate model containing tumor size and vessel invasion, grade was no longer a significant predictor of tumor-specific relapse-free or overall survival. Mitotic index predicted best when intervals were lowered to 0-2, 3-10, and 410 mitotic figures per ten 0.18 mm 2 highpower fields. We conclude that Nottingham-Bloom-Richardson grades remain only modestly reproducible. Prognostically useful components of grade are mitotic index and tubularity. The Nottingham-BloomRichardson system can be improved by lowering cutoffs for mitotic index and by counting 20-30 rather than 10 high-power fields. Measurement of proliferation index by immunohistochemically detectable markers will probably give superior prognostic results in comparison to grade.

Part I of this study [Spratt JS, Meyer JS, Spratt JA: J Surg Oncol 60:137-146, 1995] reviewed the early reports of investigators, predominantly mathematical biologists and statisticians considering the mathematical laws that would describe the growth of a neoplasm. Included were cytokinetic measurements of the mitotic index, thymidine labeling index, bromodeoxy-uridine labeling index, and the relation of these indices to the potential tumor volume doubling time. The actual doubling time of benign and malignant colonic neoplasms were reported. This second part provides the cumulative observations on the actual doubling times of pulmonary metastases, primary pulmonary cancers, skeletal sarcomas, melanomas, a chemodectoma, tumors of maxillary antrum, testicular cancers, prostate cancer, and the relation between the accumulation of multiple primary cancers and growth rates. The most complete data set is for breast cancer concluding that the cancer growth curve is a decelerating curve with great natural variance. Understanding of the rates of growth of human cancers is essential for understanding the spectrum of cancer behavior observed clinically.

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The purpose of this article is to consolidate data collected from a variety of sources that have permitted calculations of the rates of growth of human neoplasms. These sources include Fischel State Cancer Hospital (Columbia, MO); Mallinckrodt Institute of Radiology, (St. Louis, MO); Roentgen Diagnostic Institute, Allmanna Sjukhuset (Malmo, Sweden); University of Louisville (Louisville, Kentucky); University of Heidelberg (Heidelberg, Germany); and St. Luke's Hospital (St. Louis, MO). Included in the data are laboratory measurements of cell replication rates. All gross measurements were made either on imaging studies or with a centimeter scale for surface or palpable neoplasms. Data have been reported for breast and pulmonary cancers and metastases of many types, melanomas, skeletal sarcomas, benign and malignant colonic neoplasms, and isolated cases of less frequent neoplasms. Related cytokinetic measurements by tritriated thymidine labelling, bromodeoxyuridine labelling, S-phase fraction from DNA flow cytometric analysis, and mitotic indices are discussed. The various mathematical formulae applicable to the analysis of the collected data and the determination of rates and patterns of growth are included. Also considered are the clinical implications of these data and the importance of ever better knowledge on the cytokinetics of human cancer. Prior studies on the evolution of insight into this field are cited and discussed. The authors conclude that a more accurate quantification of the growth rates of human cancer is essential for understanding the biological variance of human cancers seen clinically.

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