Cancer Genetics and Cytogenetics 161 (2005) 78–81
Short communication
Acute myelogenous leukemia with tetrasomy 8 is a disease with a poor prognosis Panagiotis Tsirigotisa, Sotirios Papageorgioua, Danai Abatzisb, Sofia Athanatoub, Constantinos Girkasa, Vasiliki Pappaa, Constantinos Pangalosb, Efstathios Papageorgioua, John Dervenoulasa,*, Sotirios Raptisa a
Abstract
Second Department of Internal Medicine, Propaedeutic, Haematology Unit, University of Athens, “Attikon” Hospital, 1 Rimini Street, Haidari 124 62, Greece b Diagnostic Genetic Center, Athens, Greece Received 29 November 2004; accepted 21 December 2004
Tetrasomy 8 is an extremely rare chromosome abnormality, one that has been reported in only a few cases with myeloid malignancies. The majority of reported cases consist of acute myelogenous leukemias (AML) of monocytic lineage. In slightly more than half of the patients, tetrasomy 8 was the single cytogenetic abnormality. Fluorescence in situ hybridization revealed tetrasomy 8 and trisomy 8 concurrently in all but one of the bone marrow samples. The clonal relationship between trisomy 8 and tetrasomy 8 in these cases remains to be clarified. Patients with tetrasomy 8 have a poor prognosis, and only 1 out of 33 patients was free of disease 3 years after autologous bone marrow transplantation. Here, we report the case of a 25-year-old female patient with monocytic leukemia and tetrasomy 8. 쑖 2005 Elsevier Inc. All rights reserved.
1. Introduction Trisomy 8 is one of the most frequent numerical chromosomal abnormalities observed in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) [1]. In contrast, tetrasomy 8 is a rare cytogenetic abnormality reported in only a few cases with myeloid malignancies, mostly AML of monocytic lineage. Here we describe the case of a patient with AML-M5 and tetrasomy 8 as the sole chromosomal abnormality. 2. Case Report A 25-year-old woman was admitted to our department for evaluation of unexplained fatigue and easy bruising. Physical examination revealed pallor and petechiae of the lower extremities. Blood count findings were as follows: hematocrit, 21%; hemoglobin, 7g/dL; white blood cell count, 12 × 103/µL (neutrophils, 30%; lymphocytes, 5%; monocytes, 30%; blasts, 35%); and platelets, 40 × 103/µL.
* Corresponding author. Tel.: ⫹30-210-503-2305; fax ⫹30-2105326450. E-mail address:
[email protected] (J. Dervenoulas). 0165-4608/05/$ – see front matter 쑖 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2004.12.016
Aspiration and biopsy revealed hypercellular bone marrow, infiltrated by 80% blasts. Immunophenotypic analysis of the bone marrow aspirate with flow cytometry showed CD45, 99%; CD4, 96%; CD33, 18%; CD11c, 92%; CD11b, 80%; HLADR, 96%; CD34, 2%; CD117, 4%; CD15, 83%; and CD56, 94%. The above findings are compatible with the diagnosis of AML-M5 according to the French–American– British (FAB) classification [2]. The patient received induction chemotherapy with the combination of cytarabine, idarubicin, and etoposide (7 ⫹ 3 ⫹ 3), and she achieved complete morphological and cytogenetic remission after the first course of treatment. She subsequently received consolidation therapy with highdose cytarabine, but relapsed after 3 months. At writing, she was under salvage treatment for relapsed AML, while a search continued for a matched unrelated donor. 3. Cytogenetic and molecular cytogenetic analysis Bone marrow aspirate was inoculated into RPMI culture at 37⬚C for 24 hours. Harvesting of the cells and slide preparation were done according to standard methods. Chromosomes were banded with an RHG technique. Twenty metaphase spreads were analyzed and karyotyped, in accordance with ISCN 1995 [3]. All metaphases examined were
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abnormal, with tetrasomy 8 as the sole abnormality; no metaphase with trisomy 8 was found. The karyotype was 48,XX,⫹8,⫹8[20] (Fig. 1). Fluorescence in situ hybridization (FISH) was concurrently performed on interphase nuclei from bone marrow culture, on freshly prepared slides, according to the manufacturer’s instructions and the protocol described by Pinkel et al. [4]. The CEP 8 SpectrumGreen (α-satellite) DNA probe (Vysis, Downers Grove, IL) was used for hybridization. This probe hybridizes to the centromere of human chromosome 8 (band region 8p11.1~q11.1, locus D8Z2). Two hundred interphase cells were scored for signal patterns, using a fluorescence microscope. Four green signals were visualized in 85% of the nuclei examined, revealing the presence of tetrasomy 8; three green signals, showing trisomy 8, were seen in 15% of the nuclei (Fig. 2). The trisomy 8 clone was not detected under conventional cytogenetic analysis. 4. Discussion As noted, tetrasomy 8 is a rare genetic event in hematologic disorders and to date 33 cases have been reported over 25 years. The vast majority of the reported cases were acute myelogenous leukemias (25 AML patients); also reported were three cases of refractory anemia with excess blasts (RAEB) [5,6], two cases of chronic myelomonocytic leukemia (CMML) [7], one case of polycythemia vera (PV) [8], one case of myelofibrosis [9] and one case of acute lymphoblastic leukemia (ALL) in a child [10]. Clinical and laboratory
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features of 25 patients with AML are shown in Table 1 [11–24]; 17 were male and 8 were female, with a median age of 54 years (range 14–82). Note that the majority (68%) of the reported cases were associated with AML of monocytic lineage, implying a potential involvement of oncogenes located on chromosome 8 in monocytic leukemia. In slightly more than half of the cases (56%), tetrasomy 8 was the sole chromosomal abnormality. Trisomy 8 was undetectable with conventional cytogenetics in all but one of the reported cases. When some of the cases were further examined with FISH, using probes specific for the centromere region of chromosome 8, a concurrent trisomy 8 was noticed in almost all (94%) of the examined cases. The results of our study are in agreement with cases reported in the literature [11–24] and strongly support the hypothesis that tetrasomy 8 confers a high proliferative advantage at least in vitro, in comparison to either trisomy 8 or normal cells [25]. This hypothesis could also explain the highly aggressive nature of myeloid leukemias with tetrasomy 8. The clonal relationship between trisomy and tetrasomy 8 in the reported cases is unclear. Tetrasomy 8 can occur by either of two mechanisms: (a) two consecutive events of single nondisjunction of chromosome 8 or (b) a single event of double nondisjunction of chromosome 8. Because tetrasomy 8 was always accompanied by trisomy 8 clones, as mentioned above, the first mechanism is considered more likely [16,26]. Although half of the treated patients achieved complete remission of the leukemia, almost all patients had short duration of remission and died from disease recurrence. The
Fig. 1. Bone marrow metaphase showing tetrasomy 8 (arrows).
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Fig. 2. FISH analysis of the bone marrow cells using a chromosome 8–specific α-satellite DNA probe. (A) The three fluorescent spots indicate trisomy of chromosome 8. (B) The four spots indicate tetrasomy of chromosome 8.
median overall survival was 7 months, with only two patients surviving for more than 1 year. At writing, only one patient survives free from disease, 3 years after autologous peripheral blood stem cell transplantation. Although definite conclusions cannot be made from the analysis of these case reports, it seems that tetrasomy 8 is associated with a poor prognosis. The data gathered strongly support the need for more aggressive treatment of AML cases with tetrasomy 8. Perhaps the option of allogeneic stem cell transplantation could be strongly suggested at first complete remission in this subset of patients. The pathogenetic significance of tetrasomy 8 remains unclear. In cases with additional chromosome changes, amplification of certain genes may be responsible for the
Table 1 Clinical information for AML cases with tetrasomy 8 Clinical and laboratory features Demographics Male/Female Median age (range) FAB subtype M0 M2 M4/M5 M7 Cytogenetic data Patients without additional chromosomal abnormalities Patients with trisomy 8, standard cytogenetics testing Patients with trisomy 8, FISH analysis Treatment outcome Complete remission Patients surviving more than 1 year Patients surviving more than 2 years
No. of patients/no. Percentage with available data of total 17/8 54 years (14–82)
68% males
1/25 6/25 17/25 1/25
4% 24% 68% 4%
14/25
56%
1/25
4%
16/17
94.1%
6/11 2/18 1/18
54% 11% 5.5%
malignant transformation. Genes that may be involved in leukemogenesis located on chromosome 8, such as MYC [27] in 8q24, MOS [28] in 8q22, RUNX1T1 (alias ETO) [29], and others, should be further investigated. Collection of clinical and laboratory data from case reports will be useful for therapeutic management of these patients. References [1] Mitelman F, Johansson B, Mertens F, editors. Mitelman database of chromosome aberrations in cancer [Internet]. Accessed October 2004. Available from http://cgap.nci.nih.gov/Chromosomes/Mitelman. [2] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French–American– British Cooperative Group. Ann Intern Med 1985;103:620–5. [3] Mitelman F, editor. ISCN: an international system for human cytogenetic nomenclature. Basel: S. Karger, 1995. [4] Pinkel D, Gray JW, Trask B, van den Engh G, Fuscoe J, van Dekken H. Cytogenetic analysis by in situ hybridization with fluorescently labeled nucleic acid probes. Cold Spring Harbor Symp Quant Biol 1986;51:151–7. [5] Hagemeijer A, Hahlen K, Abels J. Cytogenetic follow-up of patients with nonlymphocytic leukemia. II. Acute nonlymphocytic leukemia. Cancer Genet Cytogenet 1981;3:109–24. [6] Flactif M, Lai JL, Deminatti MM, Fenaux P. A new case of isolated tetrasomy of chromosome 8 in a patient with therapy related myelodysplastic syndrome: confirmation by chromosome painting in metaphase and interphase nuclei. Cancer Genet Cytogenet 1993;65:175–6. [7] Ferro M, Vazquez-Mazariego Y, Ramiro S, Santiago M, GarciaSagredo J, Nunez R, Hernandez J, San Roman C. Trisomy/tetrasomy of chromosome 8 and i(8q) as the sole chromosome abnormality in three adult patients with myelomonocytic leukemia. Cancer Genet Cytogenet 2000;120:163–5. [8] Berger R, Bernheim A, Le Coniat M, Vecchione D, Flandrin G, Dresch C, Najean Y. Chromosome studies in polycythemia vera patients. Cancer Genet Cytogenet 1984;12:217–23. [9] Sole F, de Pablos JM, Woessner S, Perez MM, Jurado M, Espinet B, Grao P, Moratalla A, Esquivias J. Coexistence of tetrasomy 8 and trisomy 8 in a case with myeloid metaplasia with myelofibrosis. Cancer Genet Cytogenet 1997;94:147–50.
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