Abstract: Due to potential sampling errors (due to small tissue samples not necessarily directly from the developing tumor) and limited optical resolution (˜1 micron), cancer may be missed or detected too late for optimal treatment, or conservative interpretation of indeterminate findings could lead to unnecessary surgery. The novel technology herein—Spatial-domain Low-coherence Quantitative Phase Microscopy (SL-QPM)—can detect structural alterations within cell nuclei with nanoscale sensitivity (0.9 nm) (or nuclear nano-morphology) for “nano-pathological diagnosis” of cancer. SL-QPM uses original, unmodified cytology and histology specimens prepared with standard clinical protocols and stains. SL-QPM can easily integrate in existing clinical pathology laboratories. Results quantified the spatial distribution of optical path length or refractive index in individual nuclei with nanoscale sensitivity, which could be applied to studying nuclear nano-morphology as cancer progresses.