Consensus review of the clinical utility of dna flow cytometry in colorectal cancer

Abstract

It is estimated that in 1993 there will be > 155,000 new cases of adenocarcinoma of the colon and rectum in the United States (1). Surgical resectability offers the best chance of cure, and the results of surgical and pathologic staging are important factors in deciding whether the patient should be offered adjuvant chemotherapy in the case of colon cancer or combined chemotherapy and radiation therapy for patients with rectal cancer. Because there is significant variation in the rate of recurrence and overall survival within TNM stage categories, there is a need for additional, independent factors to better predict outcome in patients that have had a potentially curative surgical resection.To assess the available data on the possible clinical utility of DNA flow cytometry, a Consensus Conference was recently held. The aims of this work, which reports the conclusions from the ColodRectum Organ System Group that participated in the conference, are: (1) to analyze the current published literature regarding the clinical utility of flow cytometric measurements of DNA ploidy and cell proliferative activity (PA, based on %S or %S + G2M) as prognostic factors for recurrence and survival, and (2) to suggest guidelines and standards for future investigation of DNA ploidy and PA so that these measurements can be appropriately applied to specific colorectal cancer patient care situations.The majority of studies in the literature (2-23; Table 1) suggest that DNA ploidy has significant prognostic value. There are no reports demonstrating DNA aneuploidy as a favorable feature, but several reports (e.g., 3,7,14,18,19,20,21,24) have concluded that DNA ploidy provides no additional significant prognostic information, particularly when considered following multivariate analysis that includes traditional prognostic factors. With exceptions (e.g., 7,17,25), most studies suggest a trend toward an increasing frequency of DNA aneuploidy in higher Dukes stages and for tumors located in the left colon and rectum. Although there are exceptions, most of the published studies suggest that DNA ploidy and PA are unrelated to numerous clinical and pathologic observations in colorectal cancers (26). These include evaluation of age, tumor grade, infiltrative growth pattern, host inflammatory and desmoplastic response, presence of vascular invasion, carcinoembryonic antigen, or mutant p53 status. Fewer studies have examined the prognostic significance of PA. As summarized in Table 2, these series with one exception (7) have found PA to be a significant prognostic factor in colorectal cancer. These conclusions were reached despite the use of four different mathematical methods for S-phase modeling, some with debris subtraction and some without. This emphasizes the need for careful methodological description and, wherever possible, standardization of methods as described subsequently.Contradictory study results have been obtained following the use of a wide variety of technical and analytical methods, many of which may compromise the accurate det...

Systematic heterogeneity and prognostic significance of cell proliferation in colorectal cancer

“…Concerning S-phase fraction, results both with (Bauer et al, 1987;Witzig et al, 1991) and without (Enker et al, 1991) significant prognostic impact have been published; Therefore, according to the consensus by Bauer et al (1993) doubts remain as to whether the S-phase fraction can contribute to the prediction of outcome for patients with colorectal cancer. Cell kinetic studies of colorectal carcinoma using other cell cycle associated parameters are sparse.…”

Redefining the Significance of Aneuploidy in the Prognostic Assessment of Colorectal Cancer

“…Although diploid tumors have good prognoses in early stages, once distant metastases emerge, these tumors become highly malignant, suggesting the presence of an efficient mechanism of invasion and dissemination independent of aneuploidy. The previously reported association of diploid status with good prognosis, reviewed in Bauer et al (1993) and American Society of Clinical Oncology (1996), should be reexamined in light of our results. Furthermore, distinct molecular pathways are manifest in diploid tumors.…”

“…Abnormal nuclear DNA content (aneuploidy), as determined by flow cytometry, reflects net changes in the number of chromosomes (Offerhaus et al, 1992;Remvikos et al, 1988) and has been proposed as a marker with prognostic applications. Nevertheless, no general agreement has been obtained regarding the routine clinical usefulness of aneuploidy in colorectal cancer (American Society of Clinical Oncology, 1996;Bauer et al, 1993). Studies in large series of samples indicate a lack of association between ploidy and survival (Tang et al, 1995;Zarbo et al, 1997).…”

“…Tumors contain heterogeneous populations of cells and it is the aneuploidy heterogeneity, rather than the maximum degree of aneuploidy, that is associated with poorer outcome in different types of tumors (reviewed in Heppner and Miller, 1998). Thus, multiple sampling would be necessary to have an accurate estimation of the aneuploidy of the tumor (Bauer et al, 1993). However, this is time consuming, expensive, and probably unfeasible for routine clinical application.…”

“…However, this is time consuming, expensive, and probably unfeasible for routine clinical application. The analysis of the S-phase fraction may be a more powerful prognostic parameter than DI (Bauer et al, 1993), but the inaccuracy of its calculation in aneuploid paraffin samples because of the overlapping of subpopulations limits its utility.…”