Discussion
We describe a rare case of transformation of MDS to AMKL in a middle-aged male who did not respond to standard chemotherapy. Our patient presented with pancytopenia at diagnosis, which is consistent with most literature on AMKL, but in 30% of the cases, patients may present with leucocytosis5. Organomegaly in the form of hepatosplenomegaly and lymphadenopathy is commonly seen in AMKL unlike other subtypes of AML. AMKL is more frequently seen in children with an incidence of 3-10% whereas, only 1.2% of adult AML can be attributed to AMKL6.
On cytomorphology, megakaryoblasts are described as pleomorphic, medium-to-large in size which exhibit scanty cytoplasm, inconspicous nucleoli and cytoplasmic pseudopods. Megakaryoblasts show diffuse reaction on Periodic acid Schiff (PAS), non-specific esterase (NSE) and acid phosphatase cytochemistry7. On electron microscopy, megakaryoblasts express platelet peroxidase8.
AMKL may arise as de novo, or from a pre-existing myelodysplastic syndrome (MDS) such as seen in our case, in which, the latter has a worse prognosis. Megakaryoblasts often express Factor VIII, CD13, CD33, CD34, CD36, CD38, CD41 (Gp IIb/IIIa), CD42b (Gp Ib) and CD 61(Gp IIIa) on immunophenotyping analysis8. The tumour cells are negative for CD117, HLA DR and cMPO.
Common molecular abnormalities encountered in AMKL are mutations of the megakaryoblastic leukemia protein-1 (MKL-1), and GATA1 gene9. The tumour cells in AMKL are thought to overexpress multidrug resistant-1 gene (MDR-1) and P-glycoprotein (P-gp) which contribute to its poor prognosis9. Cytogenetic abnormalities are more frequently encountered in AMKL than in other subtypes of AML. They are trisomy 8, -7q, -5q and balanced reciprocal chromosomal translocations such as t(1;22), t(1;5) and t(8;17)9. Cytogenetic abnormality t(1;22) is commonly associated with AMKL in children, more extensive myelofibrosis and cytopenia10. The presence of t(9;22) abnormality may indicate the transformation of an underlying chronic myeloid leukemia (CML).
The differential diagnosis for AMKL is pure erythroid leukemia (PEL) and MDS-erythroleukemia. The World Health Organization (WHO) 2016 has reclassified PEL as the only subtype of de novo acute erythroid leukemia (AEL), and erythroleukemia into the MDS category11. PEL is defined as clonal proliferation of erythroid precursors >80% of all nucleated cells, of which at least 30% are proerythroblasts11. MDS-erythroleukemia often refers to progression of disease from pre-existing MDS. In both PEL and MDS-erythroleukemia, peripheral pancytopenia is common, with the marrow erythroblasts being medium-to-large in size, agranular and they exhibit deep basophilic cytoplasm. The neoplastic cells show reactivity with acid phosphatase, NSE and PAS cytochemistry. Erythroblasts usually express CD36 (early erythroid marker), glycophorin A/CD235a (late erythroid marker) and CD71 (transferrin receptor-1) but are negative for CD34 and HLA DR12. High frequency of TP53 mutations may indicate the importance of TP53 in the pathogenesis of the disease13. Presence of complex karyotype, AXL1, DNMT3a, 5q- and 7q- should prompt the possibility of MDS-erythroleukemia rather than de novo PEL. Prognosis of PEL and MDS-erythroleukemia is poor with a median survival of less than 6 months from diagnosis.
A combination chemotherapy regimen of daunorubicin, an anthracycline and cytarabine, an antimetabolite is used commonly as first line treatment in AMKL. However, the complete remission (CR) rate with this standard therapy is at 50%14. Those who achieve CR are only able to sustain as such for a brief period. Patients should be given the option of allogenic stem cell transplantation (Allo-SCT) at first remission but relapse rates post Allo-SCT are high. As of today, there are no novel agents to treat AMKL.