Obtaining a skin sample through a biopsy is an invasive diagnostic method. This is not associated with a significant risk of wound healing disturbance per se. However, it is unnecessary for the diagnosis and classification of lymphedema. In case of suspicion of a malignant primary tumor on a chronic lymphedema (angiosarcoma), the adequate skin biopsy is essential, as well as when a retrograde lymphovascular tumor cell spread is suspected, e.g. on the chest wall after breast cancer (Lymphangiosis carcinomatosa cutis). There are three peculiarities in a full-body examination that “en passant” arouse differential diagnostic attention and indicate an immediate skin biopsy: 1. Persistent swelling of the lips (“macrocheilia”). 2. Long-standing lower leg ulcer. 3. Localized blue-black skin areas (flat spots at skin level or prominent) in all topographical skin regions, but especially to be noted on soles of the feet and big toe nail apparatus.