Nonleukemic T/B mixed phenotype acute leukemia with PHF6 and NOTCH1 mutations

A 24-year-old woman presented with cervical lymphadenopathy and a mediastinal mass. Complete blood count showed thrombocytosis (533 K/μL) and no other abnormality. Cervical lymph node biopsy showed sheets of immature mononuclear cells expressing TdT, CD19, CD79a, PAX5, CD3 and lacking MPO (panels A-F; hematoxylin and eosin stain [A], immunostains [B]; 40× objective, total magnification ×400). Flow cytometry showed blasts expressing TdT, cytoplasmic-CD3(strong), CD19(strong), cytoplasmic-CD79a and not expressing cytoplasmic-CD22, CD10, or MPO (panels G-I). Bone marrow showed 30% involvement by the same blast population. Cytogenetics showed gain of 9q, but fluorescence in situ hybridization was negative for BCR-ABL1 and MLL rearrangements. Mutational analysis revealed PHF6 Y105*, NOTCH1 V1576E, NRAS A59D, and TP53 Y236D pathologic mutations. Variants of unknown significance were identified in JAK3, SUZ12, and IL7R. Mutations in FLT3 and DNMT3A were not identified.

This is a case of nonleukemic T/B–mixed phenotype acute leukemia (MPAL) presenting with adenopathy and a mediastinal mass. T/B-MPAL usually presents in young adults as lymphadenopathy, with only rare nonleukemic cases described. This is the second reported case of T/B-MPAL with concurrent inactivating PHF6 and activating NOTCH1 mutations, both mutations which promote T-cell differentiation at the expense of B-cell differentiation. Overall, the genetic aberrations of T/B-MPAL are similar to early T-cell precursor acute lymphoblastic leukemia with common mutations in PHF6 and JAK-STAT pathway genes, however without mutations in FLT3, DNMT3A, WT1, or EZH2.