ERG and CD31 expression in acute megakaryoblastic leukemia and myeloid sarcoma: A diagnostic pitfall

Following a case report in which acute megakaryoblastic leukemia (AMKL) presenting as a soft tissue mass was misdiagnosed as composite hemangioendothelioma due to ERG and CD31 co-expression, we investigated whether this vascular marker co-expression is an isolated phenomenon or a reproducible feature of AMKL and other myeloid neoplasms, with particular relevance to distinguishing extramedullary myeloid neoplasms from vascular tumors. We studied 11 AMKL, 17 myeloid sarcoma (MS), 10 acute myeloid leukemia (AML), 40 chronic myeloproliferative neoplasms (10 each of essential thrombocythemia, chronic myeloid leukemia [CML], primary myelofibrosis, polycythemia vera), 17 myelodysplastic neoplasms (MDS), and 20 non-neoplastic bone marrow samples. ERG and CD31 extent and intensity were evaluated separately in blasts and mature megakaryocytes, and H-scores were analyzed using Kruskal-Wallis and Mann-Whitney U tests with Benjamini-Hochberg correction; ROC-derived cut-offs are presented as exploratory. ERG expression in AMKL blasts was frequent (10/11) and typically extensive, with significantly higher H-scores than MS and AML blasts (p = 0.007 and p = 0.028). ERG was also expressed in most MS cases (12/17). CD31 expression in AMKL blasts did not differ from MS or AML (p = 0.87). In megakaryocytes, ERG was significantly higher in AMKL than in controls combined (p = 0.001), reaching significance against all individual groups except CML and MDS, while CD31 was uniformly expressed. ERG/CD31 co-expression in AMKL and, to a lesser extent, MS constitutes an under-recognized pitfall mimicking vascular neoplasms in extramedullary presentations. Rather than a stand-alone AMKL marker, awareness of this pattern is essential to avoid misinterpretation as angiosarcoma or epithelioid hemangioendothelioma.