Diagnostic algorithm for HE incorporating 2016 WHO categories of eosinophilia-associated neoplasms. In patients presenting with HE, we recommend an initial work-up to rule out reactive (secondary) causes. If this work-up is negative, parallel or sequential testing for a primary (clonal) eosinophilia should be undertaken. Evaluation includes morphologic analysis of the peripheral blood and BM, immunohistochemistry (eg, CD117, tryptase, and CD25 in systemic mastocytosis), flow cytometric immunophenotyping to assess the presence of myeloid, B- and/or T-lymphocyte markers, and cytogenetic/molecular/genetic testing. As shown in the algorithm, this combination of clinicopathologic and molecular testing can help identify a specific neoplasm and the WHO category within which it resides (shown in blue-colored boxes). Idiopathic HES is a diagnosis of exclusion and requires the presence of organ damage. HES is considered a provisional diagnosis until a cause of HE is discovered. *The provisional variants ETV6-JAK2 and BCR-JAK2 are also included in this category. Figure modified from: Gotlib J, Cools J, Malone JM 3rd, et al. Blood. 2004;103(8):2879-2891.