|Year : 2019 | Volume
| Issue : 3 | Page : 99-102
De novo acute myeloid leukemia with t(8;21)(q22;q22) and monosomy 7
Harish Kumar1, Paresh Singhal1, Ajay Malik1, Sanjeevan Sharma2
1 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Hematology, Command Hospital (SC), Pune, Maharashtra, India
|Date of Web Publication||14-Nov-2019|
Dr. Paresh Singhal
Department of Pathology, Armed Forces Medical College, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
The t(8: 21)(q22;q22) is the most common cytogenetic abnormality, usually with a favorable risk, in acute myeloid leukemia (AML). This translocation is not only of diagnostic significance but also has impact on survival outcomes and therapeutic implications. However, patients with adverse outcome in this category of recurrent genetic abnormalities have additional cytogenetic/molecular aberrations with elevated white blood cells count, CD56 expression, and extramedullary manifestations. This case is reported with aim to describe an elderly female who had a sudden downhill clinical course in de novo AML-FAB class M2 in spite of t(8;21), which was associated with monosomy 7 as an additional chromosomal abnormality and absence of high risk clinically relevant genetic mutations.
Keywords: Acute myeloid leukemia, monosomy 7, t(8;21)
|How to cite this article:|
Kumar H, Singhal P, Malik A, Sharma S. De novo acute myeloid leukemia with t(8;21)(q22;q22) and monosomy 7. J Appl Hematol 2019;10:99-102
| Introduction|| |
Cytogenetic abnormalities occur in approximately 50%–60% of cases of acute myeloid leukemia (AML) and is one of the most important determinants in AML prognostic risk stratification. The t(8:21)(q22;22) is the most common cytogenetic abnormality seen in −10% of all children and adults, diagnosed with AML and confers a favorable prognosis. Total white blood cell (WBC) count, immunophenotyping, additional chromosomal abnormality (ACA), molecular profile, and extramedullary disease have been described in cases of AML with t(8:21) which may have impact on the prognostic outcome., We hereby report a clinicopathological presentation of an elderly patient, case of de novo AML harboring the t(8:21)(q22;22) and monosomy 7 as an ACA, who had a sudden downhill course in her clinical condition.
| Case Report|| |
Our patient was a 63–year-old female with no previous comorbidities presented with a week history of ecchymotic patches over bilateral thighs, arms, abdominal wall, neck, and chest wall, which were gradually progressive and associated with low-grade continuous fever. She was not on any regular medications. On herfirst visit, general examination revealed pallor, purpuric spots, and ecchymosis over multiple cutaneous regions. There was no organomegaly or lymphadenopathy. Systemic examination was essentially unremarkable.
Treatment, course, and outcome
Initially, the patient was managed conservatively and symptomatically. A week later of hospital admission, she developed gradually progressive dyspnea. Clinical examination revealed bilateral crackles. Computed tomography scan chest showed perihilar opacities with minimal pleural effusion but no perihilar lymphadenopathy. Arterial blood gas (ABG) analysis revealed respiratory alkalosis and metabolic acidosis. Further, the course was complicated by severe acute respiratory distress syndrome, and she remained hypoxemic and eventually put on noninvasive ventilation support. She had a sudden downhill trend and succumbed to her illness within 2 weeks of the initial diagnosis of AML in spite of administration of parenteral broad-spectrum antibiotics, antifungal, vigorous ionotropics, and ventilatory support. Specific chemotherapy could not be administered, in view of sudden deterioration of her clinical condition followed by death.
Full blood count showed bicytopenia with hemoglobin of 6.6 g/dl and significantly reduced platelet counts (10,000/mm3); however, white cell counts were elevated (29,800/cumm). Peripheral smear showed 32% blasts, having high N:C ratio, open nuclear chromatin, 3–4 nucleoli, and basophilic cytoplasm with few having slender Auer rods. Her coagulation parameters, kidney function tests, and liver function tests were within normal limits. The dengue serology (NS-1 antigen and IgM antibody) was also negative. ABG analysis was consistent with clinical findings.
Bone marrow examination
Bone marrow aspiration and biopsy were hypercellular for age infiltrated by blasts (51%) having similar morphology as described above. Neutrophils were hypolobated and hypogranular [Figure 1]a. Megakaryocytes and erythroid elements were reduced [Figure 1]c. The blasts were highlighted by CD34 and myeloperoxidase (MPO) on immunohistochemistry [Figure 1]b and [Figure 1]d.
|Figure 1: (a) Bone marrow aspirate showing large blasts with scant basophilic cytoplasm and hypolobated neutrophils (MGG, ×1000). (b) Bone marrow biopsy shows myeloperoxidase positivity by blasts and myeloid precursors (×400). (c) Bone marrow biopsy showing interstitial increase in blasts. (d) Myeloblasts are highlighted by CD34 (×400) on immunohistochemistry|
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Blast populations showed bright expression of CD33, cytoplasmic MPO, CD34, and moderate expression of CD13, CD117, human leukocyte antigen-DR, and CD56. The morphological and immunophenotypic features were consistent with AML with maturation, AML (FAB)-M2.
Cytogenetics and molecular studies
Chromosomes analysis was done using image processor and software Cytovision version 7.2 Build 147, Copyright Leica Microsystems (Gateshead) Ltd, Unit 7 Queens Park, Ground Floor, North Wing, Queens way North, Team Valley Trading Estate, Gateshead, NE 110Q D United Kingdom build 147 and reported according to the International System for Human Cytogenetic Nomenclature (version: 2016) at band level of 350–400. Unstimulated bone marrow blasts chromosomal analysis revealed two abnormal clones [Figure 2]a and [Figure 2]b. The larger clone had t(8;21) in 14 metaphases, whereas the smaller clone had monosomy 7, in addition to the t(8;21), in six metaphases. *The modal karyotype of the patient was 46, XX, t(8;21)(q22;q22)(14)/45, XX, idem,-7. The t(8;21) was further confirmed on interphase cells fiuorescence in situ hybridization by commercially availablein vitro diagnostics approved Dual Color Dual Fusion Probe. In addition, mutation analysis from genomic DNA was negative for FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, and c-KIT mutation in exon 8 and exon 17, by capillary electrophoresis on ABI 3500 XL genetic analyzer (Applied Biosystems) using GeneMapper version 5.
|Figure 2: (a) Clone-1, 46 chromosomes, bone marrow cytogenetics showing t(8;21) (Red arrows). 46, XX, t(8;21)(q22;q22) in larger clone of 14 metaphases. (b) Clone-2, 45 chromosomes, bone marrow cytogenetics showing monosomy 7 (Blue arrow). 45, XX, -7, t(8;21)(q22;q22) in smaller clone of 6 metaphases|
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| Discussion|| |
AML, like other human neoplasms, is a consequence of complex genetic mutations. Among various genetic abnormalities, the t(8;21) is one of the most common chromosomal aberrations, which is not only of diagnostic significance but also of prognostic and therapeutic relevance in myeloid neoplasms. The t(8;21) results in the formation of derivative chromosome 8 due to juxtaposition of RUNX1 gene (on chromosome 21) to RUNX1T1 gene (on chromosome 8). The fusion product(RUNX1-RUNX1T1)downregulates myeloid transcriptional factors which disrupts normal hematopoietic differentiation. In general, this subclass of core-binding factor (CBF)-AML has a good response to chemotherapy with a high remission rate and a relatively long median survival. Among CBF-AML patients with short survival, several adverse prognostic factors have been mentioned in medical literature including additional cytogenetic/molecular abnormalities, elevated WBCs count, CD56 expression, and extramedullary manifestations.,, Although the t(8;21) is commonly a sole abnormality, it may be associated with secondary aberrations, out of which monosomy of sex chromosomes is the most common one, followed by del(9q), +8, del(7q), +4, and other variants.,
In this report, our patient was an elderly female (63 years), which was higher from the median age of reported cases of AML with t(8;21). Cytogenetics analysis had shown loss of chromosome 7 as an ACA in a smaller clonal subset [Figure 2]. Monosomy 7 is a common numerical abnormality seen in myeloid neoplasms, which is associated with dismal outcome. Loss of chromosome 7, with t(8;21) is a rare phenomenon, whereas other authors have reported structural abnormalities of chromosome 7 including del(7q) or as a part of complex rearrangements.,,, In addition to this, other poor prognostic factors in our patient were leukocytosis and moderate positive expression of CD56.
Although our patient has a very short survival period, possibly due to acute respiratory failure, it is indeed difficult to understand the exact pathophysiology/mechanisms which would have resulted in early death. In addition, due to rarity of this duo combination of t(8;21) and an isolated monosomy 7, it is difficult to predict the survival outcome in patients of AML and also leaves a dilemma to comment on which of the chromosomal abnormality is a primary and which one is a secondary change/ACA. Hence, a large sample size may be required for understanding the clinical outcomes in such cases. We conclude and further reiterate the importance of conventional cytogenetics by karyotyping in all cases of AML, in addition to other molecular methods, as it would help in detecting ACA which could be missed by other ancillary techniques and thus can modify the survival outcomes in patient with even presence of known favorable cytogenetic risk factors and absence of high-risk mutations.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Confiicts of interest
There are no confiicts of interest.
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[Figure 1], [Figure 2]