Extramedullary Relapse of CBFA2T3::GLIS2-Positive Megakaryoblastic Leukemia Mimicking Secondary Ewing Sarcoma: An Exemplary Case for the Diagnostic Trap

Acute megakaryoblastic leukemia (AMKL) is a heterogeneous form of acute myeloid leukemia (AML) and is significantly more common in children than in adults. In non-Down syndrome children with AMKL, inv(16)(p13q24)/CBFA2T3::GLIS2 is the most frequent genetic aberration. Pediatric CBFA2T3::GLIS2-positive AMKL is strongly associated with a poor prognosis and a high cumulative incidence of relapse. One of the key laboratory signs of CBFA2T3::GLIS2-positive AMKL is the RAM immunophenotype, which includes dim to negative CD45 and CD38 expression, extremely bright CD56 and a lack of HLA-DR on leukemic cells. This immunophenotype looks very similar to that of solid tumor bone marrow (BM) infiltration. For this reason, in cases of isolated extramedullary involvement of CBFA2T3::GLIS2-positive AMKL, excluding solid tumors may be challenging. The differential diagnosis between extramedullary AMKL relapse and secondary tumors is especially difficult. We report a case of a 3.5-year-old girl with isolated extramedullary CBFA2T3::GLIS2-positive AMKL relapse, which was misdiagnosed as secondary Ewing sarcoma. The morphological differential diagnosis between Ewing sarcoma and AMKL presents significant challenges owing to their overlapping histological features (small round blue cell morphology and similar growth patterns). The tumor cells immunophenotype was completely mirrored that at the initial diagnosis of AMKL. Additional cytogenetic and molecular studies confirmed the presence of the CBFA2T3::GLIS2 fusion, but no Ewing sarcoma-specific EWSR1 fusion transcripts were found. Thus, extramedullary CBFA2T3::GLIS2-positive AMKL relapse was confirmed. The patient’s clinical condition gradually worsened, and the patient died 5 months after diagnosis. The presented case demonstrates difficulties in the differential diagnosis between AMKL relapse and the development of a secondary tumor.