Formaldehyde fixation impairs or totally destroys the immunoreactivity of many antigens and epitopes. The negative effect of formaldehyde fixation can be reversed successfully with enzymatic digestion for some markers while not for others. Non- enzymatic epitope unmasking techniques have been recently introduced to improve the immunoreactivity of many antigens in formaldehyde fixed tissues. Heat-Induced Epitope Retrieval (HIER) in EDTA buffer has been found to improve the reactivity of many antibodies in formal-fixed tissues.