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Original Article Idiopathic Bone Marrow Dysplasia of Unknown Significance (IDUS): Definition, Pathogenesis, Follow Up, and Prognosis

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Original Article Idiopathic Bone Marrow Dysplasia of Unknown Significance (IDUS): Definition, Pathogenesis, Follow Up, and Prognosis Am J Cancer Res 2011;1(4):531-541 www.ajcr.us /ISSN:2156-6976/ajcr0000047 Original Article Idiopathic bone marrow dysplasia of unknown significance (IDUS): definition, pathogenesis, follow up, and prognosis Peter Valent1.2, Eva Jäger3, Gerlinde Mitterbauer-Hohendanner3, Leonhard Müllauer4, Ilse Schwarzinger3, Wolfgang R. Sperr1,2, Renate Thalhammer3, Friedrich Wimazal5 1Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; 2Ludwig Boltzmann Cluster Oncology, Vienna, Austria; 3Department of Laboratory Medicine; 4Institute of Pathology, and 5Department of Obstetrics and Gynaecology, Medical University of Vienna, Austria. Received February 24, 2011; accepted March 11, 2011; Epub March 16, 2010; Published April 1, 2011 Abstract: Minimal diagnostic criteria for myelodysplastic syndromes (MDS) include constant cytopenia recorded for at least 6 months, dysplasia, and exclusion of other causes of cytopenia and dysplasia. However, there are patients with dysplastic bone marrow features with or without a karyotype, who have only mild if any cytopenia. This condition has been termed idiopathic dysplasia of unknown significance (IDUS). Out of a series of 1,363 patients with suspected MDS or mild cytopenia seen between 1997 and 2010, we have identified 10 patients with IDUS, and analyzed their clinical course and outcome as well as features potentially involved in disease-evolution. Follow-up ranged between 2 and 13 years. Progression to an overt myeloid neoplasm was observed in 4 patients: two progressed to frank MDS, one to chronic myelomonocytic leukemia, and one to a myelodysplastic/myeloproliferative neoplasm exhibiting 5q- and JAK2 V617F. Consecutive studies revealed that most IDUS patients have an adequate production of erythropoi- etin (EPO) and sufficient numbers of EPO-responsive erythroid progenitors, features rarely seen in MDS. The erythro- poiesis-promoting JAK2 mutation V617F was only detectable in one case. We hypothesize that the dysplastic clone in IDUS cannot manifest as frank MDS because i) the clone retains responsiveness against EPO, and ii) an adequate EPO-production counteracts anemia. Evolution of IDUS to low risk MDS may thus depend on the biological properties of the clone as well as patient-related factors such as EPO production. The latter often decreases with age and may thus explain why MDS often manifests in the elderly. Keywords: MDS, diagnostic criteria, IDUS, EPO, BFU-E Introduction WHO, it is often difficult to decide whether a patient with mild cytopenia is suffering from low Myelodysplastic syndromes (MDS) are hemato- risk MDS, from an unrelated hematopoietic or poietic stem cell disorders defined by a matura- non-hematopoietic disease, or has abnormally tion defect in myeloid progenitor cells, periph- low blood counts without an underlying disorder eral cytopenia, and clonal instability with en- [8]. In other patients, it may be difficult to dis- hanced risk to transform into acute myeloid criminate between MDS and a myelodysplastic/ leukemia (AML) [1-4]. In the past, i.e. before myeloproliferative (MDS/MPN) overlap neo- 2001, MDS have been classified according to plasm [8]. To overcome the problem of the criteria provided by the French-American-British “diagnostic interface”, minimal diagnostic crite- (FAB) cooperative study group [5]. In 2001 and ria for MDS have been discussed and proposed 2008, the World Health Organization (WHO) has by several working-groups [7-9]. In resulting extended the FAB classification and has intro- proposals, constant cytopenia was considered duced additional criteria for defining subvari- to be a pre-requisite for the definition of MDS [7 ants [6,7]. -9]. However, although solid criteria for the discrimi- There are two conditions that do not meet mini- nation of MDS-variants from each other have mal diagnostic criteria for MDS although cyto- been provided by the FAB group and by the penia or dysplasia is recorded: idiopathic cyto- Pathogenesis of IDUS penia of unknown significance (ICUS) and idio- #9, transient leukocytopenia, Pseudo-Pelger- pathic dysplasia of unknown significance (IDUS) Huet cells in the blood, and an elevated serum [8-10]. Both conditions may progress to frank tryptase level (29.1 ng ml-1) were known before MDS over time [8-10]. Therefore, once diag- bone marrow biopsy; this patient was referred nosed, these patients should have a hema- because of suspected mastocytosis or/and tologic follow up. MDS. At the time of diagnosis, the following in- vestigations were performed: a bone marrow Patients with IDUS are younger or older patients biopsy and aspiration, complete blood counts in whom clonal hematopoiesis is established and differential counts, serum chemistry includ- and may replace normal marrow, but blood ing tryptase and lactate dehydrogenase (LDH), counts still remain normal or near-normal over and erythropoietin (EPO). In addition, the num- years [11,12]. Although a hypothesis about cyto- bers of circulating and bone marrow-derived kine-regulation has been proposed, little is colony-forming progenitor cells (CFU-GM, BFU-E, known about the pathogenesis and factors that CFU-GEMM) were determined in a methylcellu- keep clonal hematopoiesis in an ‘IDUS-state’ lose assay according to published protocols without cytopenia and thus without transforma- [13,14]. Bone marrow cells were examined for tion to an overt MDS. It has been hypothesized signs of dysplasia on Wright-Giemsa stained that at least in some of these patients, the re- smears. The percentage of dysplastic cells sponse of clonal erythropoietic progenitor cells (erythroid, neutrophilic, megakaryocytic) as well as well as erythropoietin (EPO) production re- as cell atypia in the monocytic, eosinophilic, and main ‘normal’ or at least adequate over time, mast cell compartments, were recorded. The and that both factors act together to keep the percentage of ring sideroblasts was determined hemoglobin level within a normal or subnormal on Prussian blue-stained bone marrow smears. range, so that no frank anemia and thus no In addition, standard cytogenetic analysis and overt MDS develops [12]. However, this hy- FISH were performed. Flow cytometry was per- pothesis has not been tested formally, and no formed to determine the percentage of CD34+ data documenting EPO-responses have been cells in most cases, and abnormal expression of presented so far. In the present study, we have PI-linked antigens in patient #1 (suspected tested the ‘EPO-hypothesis’ in a cohort of pa- Coombs-negative hemolysis). Bone marrow sec- tients with IDUS. Independent of age, adequate tions were examined using standard histologic EPO production as well as a measurable re- and immunohistochemical parameters sponse of burst- or colony-forming erythropoietic [8,15,16]. Immunohistologic parameters in- progenitor cells to EPO could be documented in cluded CD34, tryptase, KIT, CD14, and one all cases with IDUS. platelet-related antigen (CD42 or CD61). The Gomori-stain was also applied in all cases. Mo- Patients and methods lecular analyses included PCR assays for the detection of JAK2 V617F (all patients) and KIT Identification of patients with IDUS D816V (in case of mast cell atypia). Further staging investigations included an ultrasound of In a series of 1,363 consecutive patients with the abdomen (size of liver and spleen), virus cytopenia of unknown etiology or/and sus- serology, and serum vitamin B12- and folate pected MDS seen in our department between concentrations. Follow-up paramters included a 1997 and 2010, we have identified 10 well complete blood count and serum chemistry. documented cases with IDUS. Of these 10 indi- Depending on the course, all parameters re- viduals, 7 were females and 3 were males corded initially (i.e. at first presentation) were (Table 1). At diagnosis, the age in this group repeated in the follow-up. In case of suspected ranged between 33 and 83 years (median: 69 disease-manifestation (MDS), bone marrow in- years). The follow-up ranged between 2 and 13 vestigations were repeated. All patients gave years. The patients’ characteristics are shown in written informed consent before bone marrow Table 1. Two illustrative cases are described biopsy and before blood samples were ana- below. lyzed. Investigations at diagnosis and in the follow Up Case Reports All individuals were referred because of sus- Case #1: An 83 year old female patient was pected MDS with or without cytopenia. In case referred because of mild macrocytic anemia in 532 Am J Cancer Res 2011;1(4):531-541 Pathogenesis of IDUS Table 1. Patients’ Characteristics and Outcome in the Follow-Up (FU) Case Age FU BFU-E CFU-GM WBC PLT Hb EPO MCV BM Dysplasia Outcome in FU No # f/m yrs yrs Karyotype /µl PB /µl PB G L-1 G L-1 d dL-1 U L-1 fL Gran Ery Mega (time to progress) #1 f 83 03 normal 275 11 6.40 231 11.1 31.2 103.5 + ++ - MDS/RARS (2 yrs) #2 f 74 08 5q- 53 98 5.40 385 11.0 71.5 104.6 - + + JAK2 V617F+ MDS/MPN-U (6 yrs) #3 m 63 11 normal 97 217 2.60 115 12.4 33.1 81.5 ++ - + CMML (6 yrs) #4 m 59 03 normal 412 69 6.00 198 11.3 89.5 109.1 - ++ - MDS/RARS (2 yrs) #5 m 67 04 normal 76 44 3.22 133 12.3 18.0 90.8 ++ + - IDUS #6 f 36 13 complex 110 106 4.67 143 12.8 n.a. 92.5 + ++ - IDUS #7 f 80 07 normal 219 189 6.05 195 11.4 55.5 98.2 - + - IDUS #8 f 33 07 normal 436 46 4.00 124 10.8** 27.0 87.6 - + + IDUS #9 f 69 02 n.a. 747 35 5.56 186 13.3 09.7 91.4 + - - IDUS #10 f 73 11 normal 173 39 2.90 136 11.5 10.0 83.1 - + - IDUS f, female; m, male; FU, follow-up; yrs, years; BFU-E, burst forming erythroid progenitor cells; CFU-GM, granulocyte-macrophage colony-forming progenitor cells; MDS, myelodysplastic syndrome; WBC, white blood count; PLT, platelet count; Hb, hemoglobin; MCV, mean corpuscular volume; PB, peripheral blood; BM, bone marrow; g, gram; L, liter; RARS, refractory anemia with ring sideroblasts; IDUS, idiopathic bone marrow dysplasia of unknown significance; CMML, chronic myelomonocytic leukemia; MPN, myeloproliferative neoplasm; n.a., not available.
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