An imaging system compensates for mask frame misalignment with non-mask frames in an image sequence of patient anatomy. The system includes an image data processor. The image data processor determines a compensation zoom factor for individual image frames of an image sequence of an object of interest in response to data indicating distance between the object and a radiation detector for the individual image frames. The processor then associates individual zoom factors with corresponding individual image frames of the image sequence. The individual zoom factors associated with corresponding individual image frames of the image sequence are stored in a repository. An individual determined zoom factor is applied to align an associated corresponding image frame with a mask frame to provide an aligned image frame. Data representing an image difference frame, comprising a difference between data representing the aligned image frame and a mask frame, is determined. A user interface generates data representing a display image presenting the image difference frame.