An 8 year old male with a fever and cough
Maggie Yell, MD, Olukemi Esan, MD
An 8 year old male presents with fever and cough. Physical examination shows diffuse bruising across the body, petechiae on both distal lower extremities, and lateral conjunctival hemorrhage of the right eye. No hepatosplenomegaly is noted. A complete blood count shows mildly elevated white blood cells, normocytic anemia, and thrombocytopenia. The prothrombin time (PT) and international normalized ratio (INR) are mildly elevated. The partial thromboplastin time (aPTT) is within normal limits. D dimer level is markedly elevated and fibrinogen is within normal limits. A peripheral smear, bone marrow biopsy, flow cytometry, and cytogenetics/fluorescence in situ hybridization (FISH) studies are performed.
Laboratory Tests and Results
Image 1. Wright Stain. 500x. The peripheral smear shows large atypical cells with irregular nuclei, prominent nucleoli and moderate basophilic cytoplasm.
Image 2. Wright Stain. 1000x. The bone marrow aspirate shows more of these large atypical cells with irregular nuclei, prominent nucleoli and moderate basophilic cytoplasm. Occasional cells have coarse granules.
Image 3. H &E stain. 40x. The bone marrow core is hypercellular with extensive infiltration of these atypical cells.
Image 4. Flow cytometry shows an 80% population within the blast gate. These atypical blasts express: CD34, CD33, CD13 (variable), CD117 (dim), CD2, HLA-DR, CD71, CD58 and cMPO.
Fluorescence in situ hybridization (FISH) and cytogenetics studies were positive for t(15;17) PML-RARα.
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This patient’s bone marrow and peripheral blood showed numerous blasts characterized by large, ovoid to bilobed irregular nuclei, prominent nucleoli and moderate basophilic cytoplasm. Very rare blasts with numerous Auer rods were identified. On flow cytometry, these atypical myeloblasts express: CD34, CD33, CD13 (variable), CD117 (dim), CD2, HLA-DR, CD71, CD58 and cMPO. Fluorescence in situ hybridization (FISH) and cytogenetics studies were positive for t(15;17) PML-RARα. These findings are that of acute promyelocytic leukemia, microgranular variant.
The microgranular variant of acute promyelocytic leukemia (APL) is a rare entity that was first mention by Golomb et al in 1980. When studied on electron microscopy, the blast cells were noted to have granules typical of promyelocytes, but much smaller and variable in number. For this reason, the entity was termed “acute promyelocytic leukemia, microgranular variant.”2,3 Microgranular APL accounts for 10-25% of all APL, while APL accounts for 5-10% of all acute myeloid leukemias.3,4 This distribution of microgranular variant APL is similar in both adult and pediatric populations. 5
The presentation is variable and diagnosis of microgranular variant APL is challenging due to its non-specific morphological and cytochemical features.4,6 Similar to typical APL, risk of early death due to disseminated intravascular coagulation may occur if diagnosis is delayed. However, unlike typical APL, the microgranular variant usually presents with leukocytosis.3
Microscopically, the blast cells have folded nuclei and prominent nucleoli. The cytoplasm has faint or fine granules with no or minimal Auer rods. Flow cytometry usually shows expression of CD13, CD33, CD64, CD117 and shows lack of expression for CD34 and HLA-DR.3 Similar to typical APL, the chromosomal abnormality is a result of a reciprocal translocation of the retinoic acid receptor alpha (RARα) gene on 17q21 and promyelocytic leukemia (PML) gene on 15q22. The result of t(15;17) is a fusion gene product,PML-RARα.3,4,6
Prior to modern treatment, microgranular APL had a worse clinical course and prognosis than that of typical APL due to early hemorrhagic death.5 Currently, typical APL and microgranular APL have a similar clinical course and outcome. Microgranular APL is treatable and curable if treated early and appropriately with all-trans retinoic acid (ATRA) with the addition of arsenic trioxide (ATO).3
Variations in presentation and immunophenotypic findings such as leukopenia and CD34 expression, have been described.3 Other genetic abnormalities such as ins(17;15) have also been described.6 Immunophenotypic findings such as CD2 has been associate with a shorter duration of complete remission and shorter overall survival. Expression of CD56 has also been associated with an increased risk of relapse after ATRA-anthracycline therapy.3 Translocations such as t(5;17) and t(11;17) have been found to have poor response to ATRA.6
The patient was started on ATRA and ATO and showed no residual leukemia on her day 30 induction chemotherapy bone marrow biopsy.
- Swerdlow SH. WHO classification of tumours of haematopoietic and lymphoid tissues. 2008;2.
- Golomb HM, Rowley JD, Vardiman JW, Testa JR, Butler A. "Microgranular" acute promyelocytic leukemia: A distinct clinical, ultrastructural, and cytogenetic entity. Blood. 1980;55(2):253-259.
- McDonnell MH, Smith Jr. ET, Lipford EH, Gerber JM, Grunwald MR. Microgranular acute promyelocytic leukemia presenting with leukopenia and an unusual immunophenotype.Hematology/Oncology and Stem Cell Therapy. 2017;10(1):35-38.
- Zhang L, Samad A, Pombo-de-Oliveira MS, et al. Global characteristics of childhood acute promyelocytic leukemia. Blood Rev. 2015;29(2):101-125.
- Rovelli A, Biondi A, Cantù Rajnoldi A, et al. Microgranular variant of acute promyelocytic leukemia in children. J Clin Oncol. 1992;10(9):1413-1418.
- Guan H, Liu J, Guo X, Wu C, Yu H. Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature. Exp Ther Med. 2015;10(3):1009-1012.