Diagnostic algorithm for the workup of leukocytosis. If increased blasts are present, then evaluation for an acute leukemia or precursor neoplasm should begin with BM examination including appropriate ancillary studies. If myeloid cells are present, the leukocytosis should be stratified into neutrophilia, monocytosis, basophilia, or eosinophilia; more than one type of leukocytosis may be present. Most monocytoses are reactive in nature. However, if reactive causes have been excluded, a persistent monocytosis of more than 3 months or the findings of dysplasia, blast cells, or significant left shift should trigger a BM examination to evaluate for malignancy. Neutrophilia should prompt examination for left shift, signs of activated neutrophils, basophilia, dysplasia, and degree of leukocytosis. Most neutrophilias are reactive in nature. A WBC count < 50 × 109/L, but usually < 30 × 109/L, is typical. Signs of activated neutrophils, mild left shift, and an absence of basophilia all suggest a reactive process. A marked leukocytosis of > 50 × 109/L, marked left shift, dysplasia, or basophilia should prompt a BM examination to evaluate for a myeloid malignancy. Basophilia, although rare, is most suggestive of a MPN, especially CML. PCR for BCR-ABL1 and JAK2 mutational studies can be performed in blood, but a BM examination with cytogenetic studies should also be performed. Most eosinophilias are reactive in nature and these should be evaluated as outlined by Gotlib.30 Once reactive eosinophilias are excluded, myeloid and lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, and FGFR1 should be searched for by performing a BM examination, cytogenetic studies, and FISH or PCR for the PDGFRA mutation. If a lymphocytosis is present, the lymphoid cells should be examined for pleomorphism or monomorphism. A pleomorphic lymphocytosis favors a reactive lymphocytosis. Correlation with clinical findings is necessary; a monospot test for EBV or viral serologies can also be performed. If monomorphic lymphocytosis is present, a lymphoproliferative disorder should be searched for using flow cytometric immunophenotyping. Depending on these results, select molecular genetic tests will be helpful. A BM biopsy or extramedullary tissue biopsy may be necessary for a final diagnosis of lymphoma. CBC indicates complete blood cell count; MPN, myeloproliferative neoplasm; MPN eos, myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1; and FL, follicular lymphoma.