Morphologic Deciphering of Hematopoietic Cell Vacuolization: Lessons From VEXAS Syndrome and Other Etiologies

Vacuoles in hematopoietic cell precursors have garnered significant attention in recent years due to their association with a newly characterized clonal hematopoiesis with acquired mutations of ubiquitin like modifier activating enzyme 1 (ubiquitin-activating enzyme E1, UBA1) gene associated with clinical systemic autoinflammatory manifestations, known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. The cytomorphologic hallmark of this rare disorder is vacuolization involving the granulocytic and erythroid precursors. While affected vacuolated cells are seen in most patients, the mere presence of such is not entirely specific for VEXAS syndrome; therefore, an aggregate of clinicopathologic correlates is needed to help distinguish VEXAS syndrome from morphologic mimics and prompt appropriate confirmatory genetic testing. Vacuolated hematopoietic cells could be seen in varied reactive conditions and neoplastic and nonneoplastic hematologic disorders and affect different lineages and cell types. This article aims to review the spectrum of vacuolated hematopoietic cells and their disease-association including VEXAS syndrome, among others.