Acute promyelocytic leukemia with a rare TBL1XR1::RARA fusion and distinctive morphologic and phenotypic attributes

Acute promyelocytic leukemias (APL) with variant translocations involving the RARA gene at 17q21.2 with non-PML partners constitute a rare and diverse subset of APLs, accounting for approximately 5% of total cases. Variant APLs present considerable diagnostic challenges, as standard testing methodologies targeting the PML::RARA fusion protein are unrevealing, leading to a lack of diagnosis.

We present the case of a 54-year-old patient with APL harboring a TBL1XR1::RARA fusion, an exceptionally rare APL variant that showed distinctive morphologic, phenotypic, and clinical attributes. Unlike conventional APL, the neoplastic promyelocytes lacked pathognomonic Auer rods and bilobed nuclei and were accompanied by marked granulocytic dysplasia and significant monocytosis. Phenotypically, the blasts were negative for CD117 and showed an associated expanded monocyte population with aberrant CD56 and CD23 expression, features highly uncharacteristic of classic APL. Cytogenetic analysis and targeted PCR yielded negative results for PML::RARA fusion; however, the break-apart probe analysis tested positive for a RARA rearrangement, ultimately facilitating an accurate diagnosis. The patient did not respond to all-trans retinoic acid (ATRA) and succumbed to the disease 24 days after the initial presentation.

This case brings to light the diagnostic challenges posed by variant APLs that may demonstrate divergent morphologic and phenotypic features and carry translocations that render the routine PML::RARA fusion-based methodologies futile. Accurate diagnosis requires a high index of suspicion and a comprehensive multifaceted diagnostic strategy that encompasses morphologic assessment, immunophenotypic analysis, RARA break-apart probe analysis supplementing traditional fusion probe techniques, conventional karyotyping, and advanced molecular fusion testing.