The subject disclosure provides systems and methods for determination of Area of Interest (AOI) for different types of input slides. Slide thumbnails may be assigned into one of five different types, and separate algorithms for AOI detection executed depending on the slide type. Slide types include ThinPrep® slides, tissue micro-array (TMA) slides, control HER2 slides with 4 cores, smear slides, and a generic slide. The slide type may be assigned based on a user input. Customized AOI detection operations are provided for each slide type. If the user enters an incorrect slide type, operations include detecting the incorrect input and executing the appropriate method. The result of each AOI detection operations provides as its output a soft-weighted image having zero intensity values at pixels that are detected as not belonging to tissue, and higher intensity values assigned to pixels detected as likely belonging to tissue regions.