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

In children without Down syndrome who have acute megakaryoblastic leukemia (AMKL), inv(16)(p13q24)/<i>CBFA2T3::GLIS2</i> is the most frequent genetic aberration. Pediatric <i>CBFA2T3::GLIS2</i>-positive AMKL is strongly associated with a poor prognosis and a high cumulative incidence of relapse. One of the key laboratory signs of <i>CBFA2T3::GLIS2</i>-positive AMKL is the RAM immunophenotype, which looks very similar to that of solid-tumor bone marrow (BM) infiltration. For this reason, in cases of isolated extramedullary involvement of <i>CBFA2T3::GLIS2</i>-positive AMKL, excluding solid tumors may be challenging. We report a case of a girl with isolated extramedullary <i>CBFA2T3::GLIS2</i>-positive AMKL relapse, which was misdiagnosed as secondary Ewing sarcoma. The morphological differential diagnosis between Ewing sarcoma and AMKL presented significant challenges owing to their overlapping histological features (small, round blue-cell morphology and similar growth patterns). The tumor cells' immunophenotype completely mirrored that at the initial diagnosis of AMKL. Additional cytogenetic and molecular studies confirmed the presence of the <i>CBFA2T3::GLIS2</i> fusion, but no Ewing sarcoma-specific <i>EWSR1, FUS</i> and <i>CIC</i> fusion transcripts were found. Thus, extramedullary <i>CBFA2T3::GLIS2</i>-positive AMKL relapse was confirmed. The presented case demonstrates the difficulties in differential diagnosis between AMKL relapse and the development of a secondary tumor.