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 Table of Contents  
Year : 2016  |  Volume : 41  |  Issue : 2  |  Page : 106-110

Acute myeloid leukemia, M1 with trisomy 1, 8, and 21: a case report of a rare complex karyotype

1 Clinical Pathology Department, National Research Center, Ain Shams University, Cairo, Egypt
2 Clinical Hematology Unit, Internal Medicine Department, Ain Shams University, Cairo, Egypt
3 Cytogenetics Unit, Genetic Diagnostic Center, Ain Shams University, Cairo, Egypt
4 Clinical Pathology Department, Ain Shams University, Cairo, Egypt

Date of Submission09-Jan-2016
Date of Acceptance17-Jan-2016
Date of Web Publication15-Jul-2016

Correspondence Address:
Mohamed T. H. Sallam
Lotfi El-Sayed Street, Abassia, Cairo 11566
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-1067.186415

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Introduction Acute myeloid leukemia (AML) is a heterogenous disorder that results from a block in the differentiation of hematopoietic progenitor cells along with uncontrolled proliferation. Cytogenetics represents the most valuable predictor for a poor outcome in patients with AML, and the cytogenetic profile of AML at diagnosis consistently remains a highly influential prognostic factor. Of these cytogenetic aberrations, patients with complex karyotype anomalies show very low complete remission rates and short leukemia-free and overall survival.
Case presentation We report a case of AML in a 50-year-old female patient who presented with morphologic and immunophenotypic features of AML-M1. The patient's karyotyping and fluorescence in-situ hybridization of cultured bone marrow cells revealed a unique complex karyotype: 49, XX, +1, +8, +21. The patient's condition deteriorated rapidly and she died shortly after induction from fatal infectious complications.
Conclusion Reports of trisomy 1 in AML are rare, and, to the best of our knowledge, the present case is the only one reported with the occurrence of trisomy 1 in addition to trisomy 8 and 2. Treatment outcomes of complex karyotype AML patients receiving chemotherapy are very poor; the yet unreported complex karyotype observed in this case seems to be correlated with an adverse prognosis. Single case reports as well as large scale studies are necessary to provide further insights on karyotypic changes taking place in human malignancies.

Keywords: acute myeloid leukemia, chromosomal abnormalities, complex karyotype, fluorescence in-situ hybridization

How to cite this article:
Abdelrahman AH, Hasan EA, Abdelgawad SM, Sallam MT. Acute myeloid leukemia, M1 with trisomy 1, 8, and 21: a case report of a rare complex karyotype. Egypt J Haematol 2016;41:106-10

How to cite this URL:
Abdelrahman AH, Hasan EA, Abdelgawad SM, Sallam MT. Acute myeloid leukemia, M1 with trisomy 1, 8, and 21: a case report of a rare complex karyotype. Egypt J Haematol [serial online] 2016 [cited 2020 Feb 22];41:106-10. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/106/186415

  Introduction Top

Acute myeloid leukemia (AML) comprises a group of hematologic malignancies with variable outcomes and is characterized by a clonal proliferation of myeloid precursors with a reduced capacity to differentiate into more mature cellular elements. As a result, there is an accumulation of leukemic blasts in the bone marrow, peripheral blood, and occasionally in other tissues, with a variable reduction in the production of normal red blood cells, platelets, and mature granulocytes [1].

Cytogenetics has become necessary for the diagnosis of AML according to the 2008 revision of the WHO classification of tumors of hematopoietic and lymphoid tissues [2]. Cytogenetic analyses complemented with molecular methods, and mutation detection are useful for guiding treatment, monitoring residual disease, and for providing prognostic information toward clinical outcomes [3]. The presence of cytogenetic abnormalities with favorable and unfavorable prognostic significance is the strongest predictor of outcome in AML cases.

Complex karyotype is defined as the presence of three or more (in some studies ≥5) chromosome abnormalities [4],[5],[6],[7],[8]. The modal chromosome number is hypodiploid (i.e. ≤45 chromosomes) in the majority, between 55 and 75%, of the patients. Approximately one-fourth of patients have a hyperdiploid karyotype (i.e. comprising ≥47 chromosomes), whereas the karyotype of the remaining patients is pseudodiploid (i.e. the chromosome number is equal to 46 but the karyotype contains clonal chromosome abnormalities) [9],[10],[11]. This pattern of ploidy is in part a reflection of the fact that whole chromosome losses are more frequent compared with whole chromosome gains in this group of patients.

With regard to the whole-chromosome gains, which in contrast to chromosome losses can be reliably detected by means of G-banding alone, trisomy 8 is by far the most frequent; it is present in 10-25% of patients. Other recurrent trisomies observed in 5-10% of patients include +9, +10, +11, +13, +21, and +22 [9],[10],[11].

We present a de-novo AML case with trisomy 1, trisomy 8, and trisomy 21.

  Case presentation Top

A 50-year-old female patient presented with fever (39°C) for 10 days, nocturnal sweat, fatigue, and lethargy. Physical examination showed no hepatosplenomegaly or lymphadenopathy. Peripheral blood counts showed hemoglobin 10.0 g/dl, platelets 102 × 10 9 /l, and leukocytes 15.5 × 10 9 l with 63% blast cells, 12% neutrophils, 1% monocytes, and 24% lymphocytes. Bone marrow aspirate showed a markedly hypercellular marrow with 91% blasts. The blasts were large in size with open nuclear chromatin showing prominent nucleoli ([Figure 1]). Cytochemistry for myeloperoxidase was positive, whereas blast cells were negative for chloroacetate esterase stain. Therefore, the patient was diagnosed as having AML FAB M1.
Figure 1 Bone marrow aspirate Giemsa stained smears ×1000 showing cluster of large-sized blasts with irregular nuclear contours, fine chromatin with 1-3 nucleoli, and relatively abundant cytoplasm with rare azurophilic granules.

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Immunophenotypic analysis using flow cytometry revealed that the blasts were positive for CD34, HLADR, CD13, CD33, CD117, CD7, and myeloperoxidase but negative for CD14, CD15, CD61, glycophorin A, CD10, CD3 (surface and cytoplasmic), CD5, CD4, CD8, CD19, CD20, and CD22 ([Figure 2]).
Figure 2 Blast immunophenotype, flow cytometry histograms. Blast cells expressing myeloid immunophenotypic markers with aberrant expression of CD7

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Conventional cytogenetics was performed at the time of diagnosis. The bone marrow cells were grown in RPMI 1640 (Sigma, Schnelldorf, Germany) supplemented with 20% (v/v) fetal bovine serum. Following overnight incubation in the presence of colcemid (10 μl/8 ml of culture), the cultures were exposed to hypotonic solution (0.075 mol/l KCl) and fixed with methanol: acetic acid (3: 1). The slides were prepared using the air-dry method and stained with GTG-banding. Twenty metaphases were analyzed and karyograms were prepared using the Cytovision computer-assisted karyotyping system (Applied Imaging, Newcastle Upon Tyne, UK). Karyotypes were described according to the International System for Human Cytogenetic Nomenclature criteria [12]. The remaining fixed cell pellets were stored at − 20°C for further fluorescence in-situ hybridization (FISH) studies. Chromosome analysis of the bone marrow cells showed 49, XX, +1, +8, +21[16]/46, XX[4] ([Figure 3]). We considered trisomy 21 to be acquired when the patient showed no phenotypic characteristics of Down syndrome, such as developmental retardation, brachycephaly, epicanthal folds, and speckled iris.
Figure 3 GTG-banded bone marrow karyotype showing trisomy 1, 8, and 21.

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FISH analysis was performed on interphase cells from the patient's bone marrow cells. In all, 200 interphase nuclei were counted for each hybridization assay. We used spectrum red-conjugated and spectrum green-conjugated Vysis dual-color, dual-fusion, locus-specific identifiers (LSI) AML1/ETO probes (Abbott Molecular/Vysis, Des Plaines, Illinois, USA) to exclude AML-M2 subtype (used according to the manufacturer's recommendations). The LSI AML1 probe was labeled with spectrum green and the LSI ETO probe was labeled with spectrum orange. Three-green, three-orange signal pattern was detected on separate chromosomes in about 90% of cells, but with no yellow fusion signals in all cells, indicating AML1/ETO fusion negative result ([Figure 4]).
Figure 4 Interphase fluorescence in-situ hybridization (FISH) with AML1/ETO probe showed three-green and three-orange signal pattern with no yellow fusion signals, indicating the absence of AML1/ETO fusion.

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Trisomies +1, +8, and +21 were confirmed using the probes CEP 1 (1p11.1-q11.1), CEP 8 (8p11.1-q11.1), and LSI 21 (21q22.13-q22.2), respectively (spectrum orange labeled, supplied by Abbott Molecular/Vysis). The FISH probes detected trisomies in 90% of the cells ([Figure 5]).
Figure 5 Interphase fluorescence in-situ hybridization (FISH) with CEP 1 (1p11.1-q11.1), spectrum orange labeled showing three red signals indicating trisomy 1 (a representative figure of the CEP probes used).

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  Discussion Top

Trisomy 8 is the most frequent numerical aberration in AML, occurring at a frequency of 10-15% [13]. Reports have suggested that AML patients with trisomy 8 have poor outcomes and are not responsive to cytarabine-based therapy [14],[15]. Although some studies have reported that trisomy 8 confers an independent prognostic risk in AML [16], a German AML cooperative group study reported that prognosis in the presence of trisomy 8 appeared to be dependent on the other associated clonal cytogenetic changes. In a large retrospective study by Borthakur et al. [17], they reviewed the cytogenetic findings in 2187 AML patients. Trisomy 8 was detected in 211 (10%) patients, of which 64 (30%) had isolated trisomy 8, 45 (21%) had trisomy 8+≤2 additional cytogenetic abnormalities, and 102 (49%) had trisomy 8+≥3 additional abnormalities. They found shorter event-free survival among patients with isolated trisomy 8 compared with those with diploid CG. In contrast, patients with trisomy 8+≥3 abnormalities had outcomes comparable to the nontrisomy 8 CG group. They concluded that noncomplex CG trisomy 8 is associated with worse clinical outcome in patients with AML than in those with diploid CG and its inclusion in intermediate risk group may need reconsideration. The most adverse impact appears to be from lower remission rates among patients with trisomy 8+≤2 additional abnormalities and of 60 years or older. This is consistent with the adverse prognosis of our patient where the patient died shortly after starting induction chemotherapy.

Trisomy 21 represents the second most frequent trisomy after trisomy 8, being found, as a sole change or together with other aberrations, in ~6% of all cytogenetically abnormal AML [17],[18],[19]. In a previous study of more than 2000 AML cases, +21 was particularly common in subtypes M0 and M1 [20]. Trisomy 21 rarely occurs as an isolated anomaly (only 19-26% of +21 AML cases) but is frequently noted to occur concomitantly with other chromosomal aberrations, including trisomy 8 or complex karyotype in 38% of the cases and deletion 7 in 9% of the cases [5],[6],[21],[22],[23]. When present as a sole aberration or in combination with favorable cytogenetic anomalies, trisomy 21 is associated with a favorable outcome in AML patients. Thus, isolated trisomy 21 and trisomy 21 with favorable anomalies, which have traditionally been classified as intermediate-risk, may actually behave more like favorable-risk cytogenetics in non-DS AML patients, but specific analyses evaluating outcomes in non-DS trisomy 21 AML patients are lacking [24].

In AML, trisomy 1 as sole karyotyping abnormality is a rare finding. Very few reports on the occurrence of trisomy 1 as a part of complex karyotypes in AML were published [25],[26],[27]. The exact incidence or prognostic impact of trisomy 1 in AML is still unclear.

Complex karyotype in AML patients has been always regarded as a poor prognostic indicator, especially in patients treated with conventional induction and consolidation chemotherapy. Among older adults above the age of 60 years, who constitute the majority of patients with a complex karyotype, only 10-44% of those who harbor three or more abnormalities achieve a complete remission (CR), and even lower (7-26%) in those with five or more abnormalities. Almost all patients achieve a CR relapse. CR durations are short, with a median of 6-8 months, and the probabilities or remaining in CR at 3 years are between 0 and 11%, and at 5 years between 0 and 9% [7],[8],[28],[29]. Our patient died shortly after induction and never achieved CR to conventional AML therapy, which is consistent with the poor response rates reported in AML patients with complex chromosomal aberrations.

We report a case of de-novo AML with complex karyotype trisomies 1, 8, and 21. This is the first report of the simultaneous occurrence of these three trisomies in AML.


Authors' contributions : Amany H. Abdelrahman: the chief cytogenetics and FISH analysis investigator, paper writing; Essam A. Hasan: clinical examination and treatment protocols; Sarah M. Abdelgawad: cytogenetics and FISH techniques, paper writing; Mohamed T.H. Sallam: hematopathology and flow cytometric diagnosis, paper writing, helped in cytogenetics and FISH techniques.

Patient's consent: Written informed consent was obtained from the patient for anonymous publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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