PATHOLOGICAL AND BIOLOGICAL RELEVANCE OF CYTOPHOTOMETRIC DNA CONTENT TO BREAST-CARCINOMA GENETIC PROGRESSION

Correlating cytophotometrically detectable genetic alterations to even ts of known biological and pathological significance in breast carcino ma has been challenging, in large part owing to the difficulty in isol ating and analyzing premalignant (i.e., hyperplastic) or preinvasive ( i.e., in situ carcinoma) lesions. This problem may be addressed by usi ng histologically directed evaluation of intact, paraffin-embedded tis sue sections. Using image cytophotometry in preserved sections, we hav e identified clonal DNA content abnormalities (i.e., aneuploidy) in up to three-fourths of preinvasive breast carcinomas. Moreover, comparis on of ploidy determinations between residual in situ and corresponding invading neoplastic populations suggests that host invasion is accomp anied by measurable DNA content shifts in many cases. Image cytophotom etric DNA content abnormalities are also detectable in florid/atypical proliferative lesions, albeit less frequently (approximately 25% of c ases) and to a lesser extent (i.e., near-diploid) than in situ carcino mas. Taken together, these findings imply an association between clona l DNA content aberrations and histologic disease progression. Although the sensitivity of cytophotometric ploidy assessments in tissue secti ons is limited by nuclear sectioning artifact and overlap, the presenc e of genomic instability in precursor lesions is supported by evidence of individual chromosome aneuploidy, which can be demonstrated in tis sue sections by interphase cytogenetics with fluorescent, centromere-s pecific probes. Further, presence of intra-tumoral clonal DNA content heterogeneity is confirmed by cytogenetic studies showing co-existing near-diploid chromosome number modes in many tumors with hyperdiploid stemlines. Karyotypic stemline analyses imply polyploidization events are an important mechanism of clonal evolution leading to genetic hete rogeneity. Recent studies also demonstrate predictable relationships b etween cytophotometric and karyotypic alterations, as well as between cytophotometric ploidy and molecular level events. Therefore, we concl ude that cytopbotometrically detectable DNA content anomalies may prec ede unequivocal morphologic transformation in breast neoplasia. Moreov er, clonal DNA content evolution via endoreduplication may not only ac company biologically critical steps in histologic progression of breas t tumors, but may also be reflected in DNA histogram patterns. (C) 199 3 Wiley-Liss, Inc.