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.