Liquid biopsy for predictive mutational profiling of solid cancer: The pathologist's perspective.

The pathological diagnostics of cancer - based on the histological features - is today increasingly completed by molecular profiling at variable depth in an almost evident fashion. Predictive information should cover potential therapeutic targets and/or major resistance mechanisms the nature of which is subject of alteration during the course of the treatment. Mutational profiling recently became technically available by the analysis of circulating free DNA obtained following non-invasive peripheral blood or body fluid sampling. This "liquid biopsy" approach reflects the general status considering the actual tumor burden, irrespective of the intratumoral distribution and anatomical site. However, the dynamics of the liquid compartment relies on tissue-related processes reflected by histological variables. The amount and composition of free DNA seems to be influenced by many factors, including the stage and anatomical localization of the cancer, the relative mass of neoplastic subclones, the growth rate, the stromal and inflammatory component, the extent of tumor cell death and necrosis. The histopathological context should be considered also when analysis of cfDNA is about to replace repeated tumor sampling for molecular follow-up.