Prognostic value of S-Phase fraction in lymph-node-negative breast cancer by image and flow cytometric analysis

Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Spain.
Modern Pathology (Impact Factor: 6.19). 04/1997; 10(3):216-22.
Source: PubMed


Cellular DNA content and proliferation rates have been suggested as prognostic factors in breast carcinomas. A series of 271 lymph-node negative breast carcinoma patients without adjuvant therapy was reviewed (mean follow-up, 108 mo). Tumor cells from the same paraffin-embedded block tissue (Hedley's method) were analyzed by image analysis (IA) in Feulgen-stained smears and by flow cytometric analysis (FC). Clinicopathologic features, ploidy, S-phase fraction, and percentage of tumor cells with more than 5n DNA content (in diploid tumors, by IA) were related to outcome. The results of IA and FC were compared in 115 cases. Tumor size, histologic grade, desmoplasia and S-phase fraction were significant predictors of survival in multivariate analysis (Cox proportionate regression) (P < or = 0.03). Ploidy by the two methods showed agreement in 100 carcinomas (87%). Of the 15 discordant cases, FC detected 6 multiploid and 4 aneuploid-peridiploid. In contrast, IA detected more tetraploid carcinomas. Tumor size, histologic grade, desmoplasia, and S-phase fraction were independent predictors of long-term prognosis in our patients. Ploidy and percentage of tumor cells with more than 5n DNA content were not prognostic indicators. FC detected aneuploidy more frequently than did IA.

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    • "Peiro et al. also showed an agreement in ploidy by flow and image cytometry in 87%. However, flow cytometry detected aneuploidy more frequently than image cytometry [42]. The superposition of tumor cell populations by contaminating non-epithelial cells could be minimized with cytokeratin labeling of the epithelial cells. "
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    ABSTRACT: Flow cytometric assessment of DNA-ploidy and S-phase fraction in malignant tumors is compromised by the heterogeneity of cell subpopulations derived from the malignant and surrounding connective tissue, e.g., tumor, stromal and inflammatory cells. To evaluate the effect on quality of DNA cell cycle analysis and determination of DNA ploidy, cytokeratin labeling of epithelial cells was used for tumor cell enrichment in breast, ovarian, cervical and endometrial cancer prior to DNA analysis. In a prospective study, tumor cell subpopulations of 620 malignant tumors were labeled by a FITC-conjugated cytokeratin antibody (CK 5, 6, CK18 and CK 5, 6, 8 and CK 17, respectively) prior to flow cytometric cell cycle analysis. Compared to total cell analysis, detection rate of DNA-aneuploid tumors following cytokeratin labeling was increased from 62% to 76.5% in breast cancer, from 68% to 77% in ovarian cancer, from 60% to 80% in cervical cancer and from 30% to 53% in endometrial cancer. Predominantly in DNA-diploid tumors, a significantly improved detection of S-phase fraction of the tumor cells was shown due to the elimination of contaminating nonproliferating "normal cells". S-phase fraction following tumor cell enrichment was increased by 10% (mean) following cytokeratin staining in ovarian and endometrial cancer, by 30% in breast cancer and even by 70% in cervical cancer compared to total cell analysis. Thus, diagnostic accuracy of DNA-analysis was enhanced by cytokeratin labeling of tumor cells for all tumor entities investigated.
    Full-text · Article · Feb 2001 · Analytical cellular pathology: the journal of the European Society for Analytical Cellular Pathology
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    ABSTRACT: SUMMARY In order to establish the relationship between ploidy, S-Phase fraction and morphological features in breast carcinoma, 402 frozen specimens were studied. No rela- tionship could be found when ploidy and S-phase fraction were correlated with lymph node status and patient's age. Aneuploid lesions were larger than diploid tumors and usually did not express hormone receptors. Infiltrat- ing duct carcinoma (322/402) showed a higher rate of aneuploidy and S-phase fraction related to the increase of the histological grade, scores of tubule formation, nuclear pleomorphism and mitotic rate. In a multivariate regression analysis the nuclear pleomorphism and tu- moral size were the only independent variables and most powerful predictive for aneuploidy in infiltrating duct carcinomas. DNA pattern and S-phase fraction are variables that correlate with morphological features, providing more objective and reproducible information.
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    ABSTRACT: During the past decade, more than 300 articles, abstracts, and book chapters have been published about S-phase fraction (SPF) determined by DNA flow cytometry and its clinical utility for patients with breast cancer. However, the use of SPF for making treatment decisions for breast cancer patients remains controversial. After reviewing 273 published articles, we conclude: 1) Despite different techniques and cutpoints, correlations between SPF and other prognostic markers are relatively consistent across studies; higher SPF is generally associated with worse tumor grade, absence of steroid receptors, larger tumors, and positive axillary lymph nodes. 2) Higher SPF is generally associated with worse disease-free and overall survival in both univariate and multivariate analyses; SPF values from laboratories that have conducted validation studies can be used, in combination with other factors, to estimate the prognosis of patients with primary breast cancer. 3) There is considerable variability among laboratories regarding assay methodology, cell-cycle analysis techniques, and cutpoints for classifying and interpreting SPF; use of SPF values from different laboratories is problematic, and there remains a need for standardization of these processes and well-designed confirmation studies. We conclude that measurement of SPF does have clinical utility for patients with breast cancer, but standardization and quality control must be improved before it can be routinely used in community settings.
    No preview · Article · Feb 1998 · Breast Cancer Research and Treatment
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