# Clinico-Haematological Profile of Acute Megakaryoblastic  Leukaemia: Report of Five Cases

Authors: Sunita Sharma; Anita Nangia; Sonal Jain Malhotra; Shashi Narayan; Aparna Harbhajanka; Sarika Singh
Journal: Advances in Hematology
 (2009)

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## Abstract

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia. Although known as a distinct entity for a very long time, because of lack of distinct clinical features and morphological criteria, it is difficult to diagnose this variant correctly. We herein present the clinical, morphological, cytochemical, and immunocytochemical features of five cases of AMKL. Certain morphological features such as presence of abnormal platelet count, giant platelets, and cytoplasmic blebbing in blasts were found to be important pointers towards the diagnosis. However, none of the features were found to be consistent and thus morphological diagnosis has to be confirmed by cytochemistry and immunocytochemistry.


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## Body

## 1. Introduction

Acute megakaryoblastic leukemia (AMKL) is a rare entity and accounts for 3–5% of all acute myeloid
leukemia [1]. Although described in literature for more than 70 years [2], the
clinical profile and morphological criteria for its diagnosis remain ill
defined. It can be confused with acute lymphoblastic leukemia ALL-L1/acute myeloid
leukemia AML-M0. It may arise de novo or may be secondary to chemotherapy, or
progress from myeloproliferative neoplasm (MPN) and/or myelodysplastic syndrome
[1, 3–5]. It has a bimodal peak of distribution (in adults and children 1-2
years of age). Children with Down's syndrome have a particularly higher
incidence of AMKL [6]. Here we describe five cases of AMKL with variable
clinicohaematological presentations and discuss the diagnostic difficulties
faced in arriving at a definitive diagnosis.


## 2. Materials and Methods

All acute megakaryoblastic leukemias diagnosed in the Department of Pathology of Lady Hardinge Medical College,
New Delhi, in the period 1997 to 2007, were included in the study. A total of five cases were
retrieved. The clinical history and other details were taken from the case
files.Wright's
stained peripheral smears and bone marrow aspirate (BMA) smears were examined.
Bone marrow biopsy was available in only one case.Cytochemistry, including myeloperoxidase (MPO), Sudan black B (SBB), periodic
acid Schiff (PAS), and nonspecific esterase (NSE), was available in all the cases.Immunophenotyping
was done in 4 out of 5 cases. In 3/4 cases, immunocytochemistry was done by APAAP
technique using DAKO antibodies (Figure3) and in the fourth case flow cytometry results
were available.


## 3. Results

Clinical and haematological profiles of our 5 cases are summarized in
Tables1 and 2.Table 1
Clinical features and hematological parameters.
FeaturesCase ICase IICase IIICase IVCase VAge/sex6 years/M20 years/F1.5 years/M2 years/M22 years/MC/FPallor, easy bruisabilityPallor, dyspnea, gum bleeds, malena, hematemesisFever, petechiaeFever, epistaxis, seizuresFeverDown's syndrome———+—Hepatomegaly+—+—+Splenomegaly+—+—+Lymphadenopathy——+——Hb (g/dL)10.74.94.85.19.4WBC (×109/L)403017.57.17.9Plt count (×109/L)304801460203Table 2
Morphology, cytochemistry and immunocytochemistry.
Case ICase IICase
IIICase IVCase VMorphologyPeripheral smear*Red cellsNormocytic NormochromicPresentPresentPresentPresentPresent with tear drop cells*Blasts (%)18%40%4%5%25%*Blast morphology(i) agranular blue cytoplasm with cytoplasmic blebbingPresentPresentPresentPresent (some blasts were granular)Present(ii) Giant plateletsPresentAbsentAbsentAbsentPresent(iii) Platelet buddingPresentPresentAbsentAbsentPresentBone marrow aspiration/biopsy*Hypercellular marrow showing megakaryoblasts, micromegakaryocytes,
promegakaryocytes (full range of differentiation)Present with clustering mimicking metastasisPresentPresentDiluted BMA & Biopsy showed blasts with  clustering and
increased reticulin fibresPresent*Blast (%)25%45%56%25% (biopsy)28%CytochemistryPASPositivePositiveNegativePositivePositiveNSEPositive, fluoride resistantPositive, fluoride resistantPositive, fluoride resistantPositive, fluoride resistantPositive, fluoride resistantMPO/SBBNegativeNegativeNegativeNegativeNegativeImmunocytochemistryLymphoid markers  (CD5, 7,19, 20)NegativeNegativeNegativeNegativeNegativeMyeloid markers (CD13,33)NegativeNegativeNegativeNegativeEquivocalCD61 (Gp Illa)PositivePositivePositivePositiveNDMost of the cases were males (M:F = 4:1). Out of the 5 cases, two were adults while the
other three were in the pediatric age group (1.5 years to 6 years).Four out
of the five cases had an acute onset illness and presented with symptoms of
marrow infiltration while the fifth patient had a long history of 3 years
duration which is described separately.One patient out of these 4 cases had features
suggestive of Down's syndrome (Case IV). Hepatosplenomegaly and lymphadenopathy
were observed in two and one patient, respectively (Table1).All the four cases were anemic. Leucocytosis
was noted in 3 while one case showed thrombocytosis (Case II). Giant platelets
were present in Case I only.Peripheral
blood blast count was in the range of 4% to 40%. The blasts were large, 3-4
times the size of a small mature lymphocyte with moderate to abundant agranular
basophilic cytoplasm. The nuclei were round to oval with fine to stippled chromatin
& 1-2 prominent nucleoli. Few blasts in all the cases showed cytoplasmic
blebbing  (Figure1). Platelet budding was observed in 3/4 cases (Figure 2).Figure 1
Megakaryoblast with cytoplasmic blebbing (1000X).Figure 2
Megakaryoblast with platelet budding (1000X).Figure 3
CD61
positivity in blast (200X).Bone
marrow aspirate smears were cellular in three out of four cases showing blasts
ranging from 25% to 56% of all nucleated cells with morphology similar to that
seen in the peripheral blood along with presence of micromegakaryocytes and
promegakaryocytes. In one of the cases, blasts showed clustering mimicking
metastases (Case I). In the fourth case (Case IV), repeated attempts of BMA
yielded diluted marrow. Bone marrow biopsy in this case showed blasts with
clustering and increased reticulin fibers (Grade III).The fifth case (Case V) had a long duration illness and presented with weakness and
abdominal distension for 3 years.This
patient had massive splenomegaly, 7 cm below costal margin and mild
hepatomegaly. The patient was anemic with a normal total leukocyte count and
platelet count. Peripheral smear showed a leukoerythroblastic blood picture
with presence of tear drop cells and 25% blasts. Bone marrow aspirate revealed
28% blasts. These blasts had morphology and cytochemical findings similar to those
of the other cases (Table2). Based on these findings, a diagnosis of acute megakaryoblastic
leukemia arising as acute transformation of myeloproliferative neoplasm (primary myelofibrosis) was made. Bone marrow biopsy and immunophenotyping
was suggested. However, the patient left against medical advice and was lost to
follow up.


## 4. Discussion

AMKL is a rare leukemia, accounting for 7–10% of childhood
AML [7] and 1-2% of adult AML [8, 9] and confers a poor prognosis. Patients
with Down's syndrome have an increased incidence of AMKL and have a good
prognosis [6, 10]. AMKL can arise de novo or as a secondary event post
chemotherapy or progress from myeloproliferative neoplasm or myelodysplastic
syndrome [1, 3–5]. In our study, one patient was possibly secondary to MPN (primary myelofibrosis).It is difficult to diagnose this variant solely on the basis of morphology. However,
there are features like clustering of blasts, presence of cytoplasmic blebbing,
and platelet budding which may be useful in clinching the diagnosis [7]. In our
study these features were present in majority of the cases thus emphasizing
their importance. Cytochemistry is not very helpful although necessary to rule
out other leukemias. Bone marrow fibrosis if present is a very important
feature and is seen in a high proportion of cases [6]. In a study conducted at
M. D. Anderson Cancer Centre including 37 cases of AMKL, bone marrow fibrosis
was present in 62% of the cases [11], although in our study, bone marrow biopsy
was available in only one case which showed fibrosis. Immunophenotyping is
necessary to confirm the diagnosis which could be performed in 4 out of the 5
cases.Thrombocytosis
was present in one patient who was a 22-year-old female while the other adult
patient had a normal platelet count. All the three pediatric patients were
thrombocytopenic. This observation is similar to that seen in other studies [12],
thus emphasizing the fact that AMKL can be categorized as either
undifferentiated or differentiated, with more differentiated ones occurring in
adults [13].


## 5. Conclusion

AMKL is a rare leukemia. It is important to correctly diagnose this variant in view of
its prognostic implications. Although immunophenotyping is the gold standard,
it is not available in all the centers. Careful search for features like
cytoplasmic blebbing, platelet budding, bone marrow fibrosis, clustering of
blasts, and cytochemical positivity for nonspecific esterase which is fluoride
resistant can help in correctly diagnosing a significant number of AMKL.



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