VHL and neoplasm: In tumors in which VHL is the only driver event, metastatic evolution is rare, whereas cases with multiple drivers are associated with metastatic development; the sequence and the intratumor distribution of these additional drivers, either clonal (present in all tumor cells) or subclonal (present in all tumor cells) or subclonal (present in only a part of tumor cells) is a key determinant of tumor evolution, thus if the driver events in addition to VHL loss occur clonally the metastatic spread is slower [178].