Evolving role of molecular imaging with PET in detecting and characterizing heterogeneity of cancer tissue at the primary and metastatic sites, a plausible explanation for failed attempts to cure malignant disorders

The diversity in cancer cell characteristics is an area of great interest in the practice of clinical oncology. By now, we know that tumors can be composed of different subpopulations of cells that can harbor very different characteristics (both in terms of genotype and phenotype), thereby exhibiting differential biologies including degrees of differentiation, growth rates, and response to various therapeutic interventions [1]. Intertumor heterogeneity across various malignancies and lesions (i.e., different biological characteristics between various lesions of the same malignancy or between different histological subtypes) has been relatively well described compared to intratumor heterogeneity (i.e., different biological characteristics within the subpopulations of neoplastic and non-neoplastic cells that successively evolve within a tumor mass) which, though recognized, has been relatively less well investigated probably due to paucity of available techniques and methodologies. This regional intratumoral heterogeneity is manifested at the cellular level by multiple subpopulations with different genetic and phenotypic characteristics. Several newer tools (e.g., laser capture microdissection) have been utilized to study this phenomenon on a cellular basis in an apparently homogeneous tumor [2, 3]. There is also tremendous temporal and spatial variation in the environment (and, therefore, environmental selection forces) that drive regional phenotypic evolution, largely as a result of variability of vascular density and blood flow. The prognostic significance of tumor heterogeneity has been emphasized in several malignancies, and in fact, grading systems have evolved in certain tumors based upon this characteristic [4–9]. To cite an example of its importance, in a study designed to determine genetic profiles of breast carcinoma cells, CD44+ cells had an active transforming growth factor beta (TGF-beta) pathway that correlated with decreased patient survival and poor prognosis compared to CD24+ cells [7]. It is important to note that heterogeneity is typically generated prior to clinical detection of the tumor, and that phenotypic diversity probably generally increases with tumor size, in parallel with the potential for genetic mutation to occur with each mitosis and the development of hypoxia, acidosis, ischemia, and necrosis.