Abstract: The illustrated embodiment is an improvement in a method of optically analyzing tissue in vivo in an individual to obtain a unique spectrum for the tissue of the individual, the improvement including the steps of optically measuring the tissue of the individual to obtain a spectrum of an optical parameter, and identifying a spectral signature specific to a metabolic or physiologic state in the tissue of the individual with a unique spectrum for the tissue by considering only the spectral differences between a first metabolic or physiologic state of the tissue of the individual and one or more other metabolic or physiologic states of the tissue of the individual such that identification of the spectral signature is self-referencing with respect to intra-individual metabolic or physiologic variations. The method also includes separating benign and malignant lesions only using the shape or a characteristic of the spectrum.