Flow Cytometry in Clinical Cancer Research

The prognosis of patients with cancer is largely determined by the specific histological diagnosis, tumor mass stage, and host performance status. The management of neoplastic disease with the currently available treatment armamentarium may be further advanced if individual patients' risk factors could be better defined. Some of the determinants of tumor response seem to be expressed at the cellular level in terms of degree of tumor cell differentiation, growth kinetics, and hormone receptor expression, which are not readily appreciated by descriptive morphology. Quantitative cytology in the form of flow cytometry has greatly advanced the objective elucidation of tumor cell heterogeneity by using probes that discriminate tumor and normal cells and assess differentiate as well as proliferative tumor cell properties. Abnormal nuclear DNA content is a conclusive marker of malignancy and is found with increasing frequency in leukemia (23% among 793 patients), in lymphoma (53% among 360 patients), and in myeloma (76% among 177 patients), as well as in solid tumors (75% among 3611 patients), for an overall incidence of 67% in 4941 patients. The degree of DNA content abnormality varies according to disease type, with a predominant excess of 10 to 20% in the hematological cancers, whereas ploidy levels in solid-tissue neoplasms span the entire range from almost haploid to hyperoctaploid abnormalities, with near-triploid mean and median DNA content values. The proportion of cells in the S phase of the cell cycle increases with increasing DNA excess in a number of different solid tumors and in acute leukemia. This cytokinetic parameter permits discrimination of low-and high-grade malignant lymphomas. Several reports demonstrate increasing morphological immaturity to be associated with increasing DNA content abnormality and increasing S percentage, all of which adversely affect prognosis. Among phenotypic tumor cell markers, surface membrane antigens have been extensively studied in lymphoid and myeloid neoplasms by the use of hybridoma-generated monoclonal antibodies, which have recently also found in vitro and in vivo therapeutic application. Cellular RNA content is useful for the objective discrimination of acute leukemias and of multiple myeloma. Newer applications of flow cytometry concern studies in the areas of cytoenzymology and cellular pharmacology. Current research is dedicated to the identification of neoplastic marker probes for DNA-diploid disease (e.g., nucleolar antigen) and additional phenotypic (e.g., hormone receptors) and cytokinetic (e.g., cycle traverse rate, growth fraction) parameters. From a patient management perspective, a role for flow cytometry is emerging as a tool for diagnosis of cancer (abnormal DNA content), specific histopathological diagnosis (RNA for hematological cancers; surface markers for lymphoid and myeloid neoplasms), prognosis (adverse impact of aneuploidy and high S percentage), and treatment (cytokinetically oriented, monoclonal antibodies, drug pharmacology). The pace of past progress justifies the hope that cytometry may soon provide “fingerprinttype” information of an individual patient's tumor which, if proven prognostically relevant, may provide the basis for treatment selection in the future.