Myeloperoxidase Deficient Acute Promyelocytic Leukemia: Report of Two Cases

Acute promyelocytic leukemia (APL) is characterized by the presence of ‘abnormal promyelocytes’ which show variable morphology but a characteristic strong myeloperoxidase (MPO) positivity on cytochemistry and immunohistochemistry (IHC). The characteristic morphology and cytochemistry is often considered as a strong evidence to make a morphological diagnosis of APL and often enough to prompt a haematologist to start all-trans-retinoic acid (ATRA), before a confirmatory molecular diagnosis arrives. We herein describe two cases of classical APL having an absent/reduced MPO activity.

Case 1

A 6-year-male child presents with history of ecchymosis and pallor. His complete blood count revealed pancytopenia (hemoglobin—82 gm/L, leukocyte count—4.1 × 10⁹/L and platelet count—19 × 10⁹/L). There were 40% abnormal promyelocytes in peripheral blood and 79% in bone marrow with occasional faggot cells. The findings were highly suspicious of APL, but the promyelocytes were negative for MPO on cytochemistry, IHC and flowcytometry (Fig. 1). However, reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated the presence of bcr1 isoform of PML-RARA fusion transcript confirming the diagnosis of APL.

Fig. 1.

Case 1: a Abnormal promyelocytes showing multiple Auer rods (MGG stain, ×1000); b Myeloperoxidase cytochemical stain showing negativity in abnormal promyelocytes. A neutrophil with positive reaction can be seen. Inset shows MPO negative Auer rods as negative linear shadows (haematoxylin counterstain, ×1000); c MPO immunostain on trephine biopsy depicting absence of staining in majority of the cells (hematoxylin counterstain, ×1000). d–i Flow cytometry showing classical immunophenotype suggestive of APL (CD34^Neg, HLA-DR^Neg, CD13^{Heterogeneous pos}, CD33^{Bright pos}) but with lack of high side scatter and negativity for MPO. The cells were negative for CD15 (not shown) and CD56 (Inset shows findings from the cells stained only for CD45)

Case 2

A 10-year-old male child presented with fever, pallor, gum hypertrophy and hepatosplenomegaly. Hemogram revealed leucocytosis and bicytopenia (Hb—111gm/L leukocyte count—73.9 × 10⁹/L, platelet count—43 × 10⁹/L). There were 95% abnormal promyelocytes in peripheral blood and 94% in bone marrow. The morphology was suspicious of APL, but MPO cytochemical stain was only weakly positive in approximately 20% of promyelocytes despite repeated attempts; and after excluding technical issues. Flowcytometric findings were not classical of APL (Fig. 2). A morphological diagnosis of APL could not be offered. However, RT-PCR for PML-RARA fusion transcript showed positivity for bcr3 isoform.

Fig. 2.

Case 2: a Abnormal promyelocytes showing cleaved nucleus and granulated cytoplasm. Auer rods were not seen (MGG stain, ×1000); b Myeloperoxidase stain showing weak positivity (haematoxylin counterstain, ×1000); c Trephine biopsy showing sheets of immature myeloid cells. d–i Flow cytometry showing absence of high side scatter, autofluorescence, CD34^Pos, HLA-DR^Pos, CD13^Pos, CD33^Pos, CD177^Pos, CD56^neg and MPO^Neg immunophenotype. The cells were also positive for CD9—not shown (Inset shows findings from the cells stained only for CD45)

A morphological diagnosis of APL can be challenging in cases with variant morphology. However, a strong MPO cytochemical reaction is often the clue to its diagnosis even such cases. MPO negativity often leads to an alternate diagnosis like monocytic leukemias. However, one of the pitfalls of relying on this simple cytochemical stain/IHC is an inherent MPO deficiency seen very rarely in the population. This together with atypical flow cytometric findings can lead to a wrong diagnosis.

Cui et al. [1] have described two cases of adult APL (both microgranular variant) with absent or reduced MPO activity. A third case was described by Heiblig et al. [2] where an extensive molecular analysis revealed germline heterozygous MPO gene mutation. Uniparental disomy of 17q chromosome, where the MPO gene is located, has resulted in a homozygous MPO deficiency. MPO enzyme deficiency is a rare autosomal recessive condition resulting from missense mutations and predisposes individuals to candida infections [3–5]. The absent/reduced MPO activity in our cases may be due to the same mechanism or due to some other unknown mechanisms.

The cases are being reported due to the extreme rarity of MPO negative APLs. The cases reinforce the dictum that morphological evaluation continues to be important; and PML-RARA or its equivalent should be tested in all patients even with the slightest morphological suspicion.

Compliance with Ethical Standards

Conflict of interest

All authors declare that they do not have any conflict of interest.

Ethical Statement

This article does not contain any studies with human participants or animals performed by any of the authors. The article does not include any identifying information of any individual.