Importance of Classical Morphology in the Diagnosis of Myelodysplastic Syndrome
Rosangela Invernizzi, Federica Quaglia and Matteo Giovanni Della Porta
Department of Internal Medicine, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
Received: March 25, 2015
Accepted: April 23, 2015
Mediterr J Hematol Infect Dis 2015, 7(1): e2015035, DOI 10.4084/MJHID.2015.035
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Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders characterized by dysplastic, ineffective, clonal and neoplastic hematopoiesis. MDS represent a complex hematological problem: differences in disease presentation, progression and outcome have necessitated the use of classification systems to improve diagnosis, prognostication, and treatment selection. However, since a single biological or genetic reliable diagnostic marker has not yet been discovered for MDS, quantitative and qualitative dysplastic morphological alterations of bone marrow precursors and peripheral blood cells are still fundamental for diagnostic classification. In this paper, World Health Organization (WHO) classification refinements and current minimal diagnostic criteria proposed by expert panels are highlighted, and related problematic issues are discussed. The recommendations should facilitate diagnostic and prognostic evaluations in MDS and selection of patients for new effective targeted therapies. Although, in the future, morphology should be supplemented with new molecular techniques, the morphological approach, at least for the moment, is still the cornerstone for the diagnosis and classification of these disorders.
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell
disorders characterized by dysplastic, ineffective and neoplastic
hematopoiesis. The risk of evolution to acute myeloid leukemia (AML) is
variable, and the clinical outcome is greatly heterogeneous. Therefore,
MDS constitute a complex hematological problem that gives rise to
difficulties in diagnosis and therapeutic decision-making.
Since a single biological or genetic reliable diagnostic marker has not
yet been discovered for MDS, quantitative and qualitative dysplastic
alterations of bone marrow precursors and of peripheral blood cells are
still fundamental for diagnostic classifications.
While the detection of increased blast cells may facilitate the
diagnosis in advanced forms, in the early forms, especially with modest
morphological abnormalities, a correct diagnosis is based mainly on the
exclusion of other diseases. Some bone marrow failure syndromes can
indeed mimic the MDS,[3,4] and the formulation of a correct diagnosis is fundamental for both prognostic evaluation and therapeutic approach.
In this review the meaning of morphology in MDS is examined; World Health Organization (WHO) classification refinements and current minimal morphological criteria for defining dysplastic involvement are highlighted, and several problematic issues are discussed.
Diagnosis and Classification
Currently, the reference classification of MDS is still the WHO classification, published in 2001 and updated in 2008.[5-7]
This classification system is based on an integrated multidisciplinary
approach that uses all available information (morphology,
cytochemistry, immunophenotype, genetics, clinical aspects) to define
biologically homogeneous and clinically relevant entities, that can be
usefully applied in clinical practice. The WHO classification improved
the prognostic value of the former FAB classification,
by recognizing more specific categories on the basis of cytogenetic
findings as well as cellular morphology and allowed to evaluate more
accurately emerging therapies that target specific genetic
The suspicion of MDS arises on the basis of an abnormal blood count with evidence of different combinations of anemia, neutropenia, and thrombocytopenia in an appropriate clinical setting. Anemia is often macrocytic, associated with a significantly reduced reticulocyte count. Obviously, all causes of reactive cytopenia/dysplasia should be excluded as well as other clonal stem cell disorders and congenital abnormalities (Table 1). The minimal diagnostic criteria for MDS include the presence of bone marrow specific alterations, i.e. one or more of the following characteristics: dysplasia in at least 10% of at least one of the major hematopoietic lineages, at least 15% ring sideroblasts or 5-19% myeloblasts in bone marrow smears. Certain chromosomal abnormalities detected by conventional karyotyping or FISH in the presence of a refractory cytopenia, but no morphological evidence of dysplasia, are considered presumptive evidence for MDS (Table 2).[6,11,12] Since morphology alone is often insufficient to reach a final diagnosis, it should be integrated, but not replaced, by other investigations such as flow cytometry, molecular studies, in vitro culture of hematopoietic progenitors.[2,13,14] However, if multilineage dysplasia, chromosomal aberrations and proof of clonality are absent, the diagnosis may be difficult.
On the basis of the proportion of peripheral blood and bone marrow blasts, defined by a morphological examination, two broad categories of MDS are recognized: forms with <2% peripheral blood blasts and <5% bone marrow blasts (lower risk subtypes), including refractory cytopenias with unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), myelodysplastic syndrome-unclassified (MDS-U) and MDS associated with isolated del(5q), and forms characterized by at least 2% peripheral blood blasts and/or at least 5% bone marrow blasts (higher risk subtypes), including refractory anemia with excess blasts-1 (RAEB-1) and RAEB-2 (Table 3). Chronic myelomonocytic leukemia (CMML), characterized by persistent monocytosis, is placed into the category of myelodysplastic/myeloproliferative neoplasms together with atypical chronic myeloid leukemia (ACML), BCR-ABL1 negative, juvenile myelomonocytic leukemia (JMML) and refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T), which is still a provisional entity.[15,16]
|Table 1. Differential diagnosis.|
|Table 2. Recurrent chromosomal abnormalities and their frequency in MDS.|
|Table 3. WHO-2008 classification of MDS.|
The diagnosis of MDS is mainly based on morphological findings of peripheral blood and bone marrow.[17-20]
Morphological examination has several advantages: it is a simple,
technically easy, not expensive method, which gives quick results;
moreover, it has prognostic importance, and should be supplemented, but
not replaced, by other tests. The morphological examination requires
peripheral blood smear, bone marrow aspirate, and bone marrow trephine
Peripheral blood and bone marrow specimens should be collected before any definitive therapy. No case of MDS should be reclassified while the patient is on growth factor therapy. Since prolonged exposure to anticoagulants can cause artifacts, the slides for the assessment of dysplasia should be made from freshly obtained specimens. On bone marrow aspirate smears and/or biopsy touch preparations, MGG or similar staining and iron staining could possibly, but not necessarily, be supplemented by cytochemical dyes to identify bone marrow cells and maturation stages: myeloperoxidase and Sudan black detect myeloid cells by staining cytoplasmic granular contents and better identify Auer rods, periodic acid-Schiff detects lymphocytic cells and certain abnormal erythroid cells by staining cytoplasmic glycogen, esterases distinguish myelocytic from monocytic maturation stages. On bone marrow aspirates, the cellularity should be enough to perform a 500 cells differential count, whereas, on peripheral blood smears, a differential count of 200-cell leukocyte is recommended. The blood and marrow smears should be examined for the percentages of blasts, dysplastic cells and ring sideroblasts. At least 100 erythroblasts, 100 granulocytic cells, and 30 megakaryocytes should be evaluated.
Assessment of Blasts
Blasts have variable size, ovoid or irregularly outlined nuclei with loose chromatin pattern and variable number of nucleoli, basophilic cytoplasm, with the absence of an evident Golgi zone. They are defined as granular or agranular and may contain Auer rods, whose presence allows the automatic diagnosis of RAEB-2. Myeloblasts showing strongly basophilic cytoplasm could be misinterpreted as immature erythroid precursors. Erythroid precursors, however, have relatively mature clumped chromatin and are often larger than myeloblasts at early stages. Granular blasts should be distinguished from normal or dysplastic promyelocytes. Promyelocytes are usually characterized by a well recognizable Golgi zone; dysplastic promyelocytes, however, are often hyper- or hypogranulated and may present a less evident Golgi area than normal promyelocytes (Figure 1).
It is worth noting that in the forms with recurrent cytogenetic abnormalities, such as t(8;21)(q22;q22), inv(16)(p13.1q22) or t(16;16)(p13.1;q22) and t(15;17)(q22;q12) the diagnosis of AML should be made even with fewer than 20% bone marrow blasts. These forms are considered clinical-pathological-genetic entities with peculiar features.
Assessment of Monocytic Cells
Assessment of Dysplasia
The dysplastic abnormalities of the cell nucleus and/or cytoplasm to be taken into account are listed in Table 4 and illustrated in Figure 2. Whereas variable degrees of dyserythropoiesis are commonly observed in various hematological, as well as non-hematological disorders, the morphological abnormalities of the granulocytic and megakaryocytic series are more specific and significant for the diagnosis. However, no single morphological finding is diagnostic for MDS, that sometimes remains a diagnosis of exclusion.
|Table 4. Morphological features of myelodysplasia.[2,6]|
Dyserythropoiesis and Ring Sideroblasts
Erythroid Predominant MDS (MDS-E)
Several studies have addressed the impact of the single morphological abnormalities and the degree of dysplasia on prognosis, and grading systems have been proposed to increase the diagnostic accuracy of MDS.[26,29,37-39]
A Japanese-German study concerning patients with MDS without excess blasts, 5q-syndrome excluded, showed the adverse prognostic significance of three parameters: the presence of at least 10% of micromegakaryocytes, dysmegakaryocytopoiesis > 40% and dysgranulopoiesis >10%. The authors suggested using these threshold values for the identification of multilineage dysplasia. In a very detailed cytomorphological study on 3156 patients of the Düsseldorf register, no differences were observed in the frequency of dysplastic changes in relation to the WHO subtype of MDS and no single morphological abnormality had prognostic significance. Also, these authors recommended using 40% as a threshold value for dysmegakaryopoiesis.
On the other hand, dysplastic features may also be observed in the normal bone marrow, as reported by some authors in the late '90s.[41,42] A more recent work has shown dysgranulopoiesis >10% in 46% of the bone marrow aspirates from 120 healthy donors, with multilineage dysplasia in 26% of the subjects; however, the counting of cells with pseudo Pelger anomaly and micromegakaryocytes did not exceed 10% and total dysmegakaryopoiesis 40%. The concordance rate between the four investigators was modest in dysgranulopoiesis but poor in dyserythropoiesis and dysmegakaryopoiesis; raising the threshold from 10% to an arbitrary 20% for all lineages led to a higher concordance rate. In conclusion, the 10% cut-off for dyshematopoietic cells is questionable in patients without cytopenia and should be revised for future consensus recommendations. Interestingly, another study showed discordance in the morphological diagnosis between the reference and peripheral centers in 12% of 915 MDS cases referred to MD Anderson Cancer Center, with a majority reclassified as having higher-risk disease with implications for therapy selection and prognosis calculation. Finally, a Spanish group showed a poor reproducibility of the WHO criteria for cases with 5-9% marrow blasts or up to 1% circulating blasts as well as for the percentage of dysplastic erythroid cells.
It should be emphasized the possible role of the barriers that can hinder a correct diagnostic definition: poor quality of marrow specimen, lack of clinical information, lack of available cytogenetic results, inter-observer variability in the assessment of dysplasia. The application of well codified reproducible criteria could allow a more objective morphological evaluation, and thus a correct implementation of the WHO classification.
In conclusion, this morphological score improving the objectivity and reproducibility of microscopic analysis might be very useful in the work-up of patients with suspected MDS. On the other hand, prognostic systems including the evaluation of the degree of bone marrow dysplasia should be adopted for clinical decision-making.
|Table 5. Morphological score.|
|Table 6. Diagnostic value and inter-observer reproducibility of the morphological score in an independent cohort of patients (MDS and non-clonal cytopenias).|
Bone marrow biopsy also allows a better evaluation of megakaryocytes and may show the presence of aggregates or clusters of blasts, a typical finding in aggressive subtypes.[35,54] Moreover, it can provide material for additional diagnostic procedures, such as immunohistochemistry, in situ hybridization or molecular analysis.
Recommendations for Diagnosis
|Figure 3. Diagnostic algorithm.|
Newly Defined Entities
The term ICUS was first proposed by the IWGM-MDS at a meeting in
Lisbon in 2005, and subsequently used in the 2008 WHO classification
and by others. ICUS and idiopathic dysplasia of undetermined
significance (IDUS) are conditions in which the criteria for the
diagnosis of MDS are not satisfied, even if cytopenia or dysplasia is
present.[6,55-58] ICUS is
characterized by persistent primary cytopenia, in the absence of
morphological or cytogenetic abnormalities specific of MDS, whereas in
IDUS there are morphological and/or karyotypic dysplastic alterations,
casually observed, in the absence of cytopenia. In ICUS, cytopenia may
concern one or more hematopoietic lineages; therefore, the terms of
idiopathic anemia, neutropenia, thrombocytopenia, or bi/pancytopenia of
uncertain significance have been proposed. The groups of cases so far
described are numerically small, except the one obtained from the MDS
registry of Düsseldorf. In both ICUS and IDUS, a
neoplastic clone can be found already at diagnosis, and progression to
an overt MDS or another myeloid malignancy is possible after a variable
period. Thus, these conditions should be considered as a potential
pre-phase of myeloid neoplasms, and have to be closely monitored for
the unpredictable course.
Despite the WHO diagnostic and classification criteria, the morphological diagnosis of MDS is still often critical and requires considerable expertise. On the other hand, as more specific treatments are becoming available, an accurate diagnosis is increasingly important. Recently, the use of new molecular techniques, including gene expression profiling and analysis of point mutations, has allowed to detect, even in patients with normal karyotype, clonal abnormalities of considerable diagnostic and prognostic meaning.[61-64] However, although in the future morphology and cytogenetics should be integrated with the new molecular techniques to classify MDS, for the moment the morphological approach continues to be fundamental at least at the beginning of the diagnostic algorithm.
AcknowledgmentsThis work was supported by a grant from Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
- Cazzola M, Della Porta MG, Travaglino E, Malcovati L. Classification and prognostic evaluation of myelodysplastic syndromes. Sem Oncol 2011; 38:627-634. http://dx.doi.org/10.1053/j.seminoncol.2011.04.007 PMid:21943669. .
L, Hellström-Lindberg E, Bowen D, et al. diagnosis and treatment of
primary myelodysplastic syndromes in adults. Recommendations from the
European LeukemiaNet. Blood 2013; 122:2943-2964.
http://dx.doi.org/10.1182/blood-2013-03-492884 PMid:23980065 PMCid:PMC3811170. .
- Yamazaki H, Nakao S. Border between aplastic anemia and myelodysplastic syndrome. Int J Hematol 2013; 97:558-563. http://dx.doi.org/10.1007/s12185-013-1324-x PMid:23613266. .
- Gondek LP, DeZern AE. I walk the line: how to tell MDS from other bone marrow failure conditions. Curr Hematol Malig Rep 2014; 9:389-399. http://dx.doi.org/10.1007/s11899-014-0224-3 PMid:25079655. .
- Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100:2292-2302. http://dx.doi.org/10.1182/blood-2002-04-1199 PMid:12239137. .
SH, Campo E, Harris NL, et al. WHO classification of tumours of
haematopoietic and lymphoid tissues. IARC Press, Lyon, 2008.
- Vardiman JW, Thiele J, Arber DA et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937-951. http://dx.doi.org/10.1182/blood-2009-03-209262 PMid:19357394. .
- Bennett JM, Catovky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51:89-99. http://dx.doi.org/10.1111/j.1365-2141.1982.tb08475.x .
- Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol 2005; 23:7594-7603. http://dx.doi.org/10.1200/JCO.2005.01.7038 PMid:16186598. .
L, Germing U, Kuendgen A, et al. Time dependent prognostic scoring
system for predicting survival and leukemic evolution in the
myelodysplastic syndromes. J Clin Oncol 2007; 25:3503-3510.
http://dx.doi.org/10.1200/JCO.2006.08.5696 PMid:17687155. .
- Valent P, Horny HP, Bennett JM, et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: Consensus statements and report from a working conference. Leuk Res 2007; 727-736. http://dx.doi.org/10.1016/j.leukres.2006.11.009 PMid:17257673. .
- Platzbecker U, Santini V, Mufti GJ, et al. Update on developments in the diagnosis and prognostic evaluation of patients with myelodysplastic syndromes (MDS): Consensus statements and report from an expert workshop. Leuk Res 2012; 36:264-270. http://dx.doi.org/10.1016/j.leukres.2011.11.005 PMid:22137318. .
- Malcovati L, Della Porta MG, Lunghi M, et al. Flow cytometry evaluation of erythroid and myeloid dysplasia in patients with myelodysplastic syndrome. Leukemia 2005; 19:776-783. http://dx.doi.org/10.1038/sj.leu.2403680 PMid:15789068. .
- Bacher U, Haferlach T, Kem W, Weiss T, Scnittger S, Haferlach C. The impact of cytomorphology, cytogenetics, molecular genetics, and immunophenotyping in a comprehensive diagnostic workup of myelodysplastic syndromes. Cancer 2009; 115:4524-4532. http://dx.doi.org/10.1002/cncr.24501 PMid:19569249. .
- Orazi A, Germing U. The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 2008; 22:1308-1319. http://dx.doi.org/10.1038/leu.2008.119 PMid:18480833. .
- Cazzola M, Malcovati L, Invernizzi R. Myelodysplastic/myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2011; 2011:264-272. http://dx.doi.org/10.1182/asheducation-2011.1.264 PMid:22160044. .
- Goasguen JE, Bennett JM. Classification and morphologic features of the myelodysplastic syndromes. Semin Oncol 1992; 19:4-13. PMid:1736369. .
- Komrokji RS, Zhang L, Bennett JM. Myelodysplastic syndromes classification and risk stratification. Hematol Oncol Clin N Am 2010; 24:443-457. http://dx.doi.org/10.1016/j.hoc.2010.02.004 PMid:20359636. .
- Wang SA. Diagnosis of myelodysplastic syndromes in cytopenic patients. Hematol Oncol Clin N Am 2011; 25:1085-1110. http://dx.doi.org/10.1016/j.hoc.2011.09.009 PMid:22054736. .
- Giagounidis A, Haase D. Morphology, cytogenetics and classification of MDS. Best Practice Res Clin Haematol 2013; 26:337-353. http://dx.doi.org/10.1016/j.beha.2013.09.004 PMid:24507811. .
- Mufti GJ, Bennett JM, Goasguen J, et al. Diagnosis and classification of MDS: International Working Group on Morphology of MDS (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts. Haematologica 2008; 93:110-115. http://dx.doi.org/10.3324/haematol.13405 PMid:18838480. .
- Wang H, Wang XQ, Xu XP, Lin GW. Bone marrow blast level predicts prognosis in patients with refractory cytopenia with multilineage dysplasia. Eur J Haematol 2009; 83:550-558. http://dx.doi.org/10.1111/j.1600-0609.2009.01343.x PMid:19737310. .
- Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454-2465. http://dx.doi.org/10.1182/blood-2012-03-420489 PMid:22740453. .
S, Strupp C, Gattermann N, et al. Presence of peripheral blasts in
refractory anemia and refractory cytopenia with multilineage dysplasia
predicts an unfavourable outcome. Leuk Res 2008; 32:33-37.
http://dx.doi.org/10.1016/j.leukres.2007.02.021 PMid:17412418. .
- Goasguen JE, Bennett JM, Bain BJ, Vallespi T, Brunning R, Mufti GJ for the International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS). Morphologic evaluation of monocytes and their precursors. Haematologica 2009; 94:994-997.http://dx.doi.org/10.3324/haematol.2008.005421 PMid:19535346 PMCid:PMC2704310. .
- Matsuda A, Germing U, Jinnai I, et al. Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification. Leukemia 2007; 21:678-686. http://dx.doi.org/10.1038/sj.leu.2404571 . .
- Verburgh E, Achten R, Louw VJ, et al. A new disease categorization of low-grade myelodysplastic syndromes based on the expression of cytopenia and dysplasia in one versus more than one lineage improves on the WHO classification. Leukemia 2007; 21:668-677. http://dx.doi.org/10.1038/sj.leu.2404564 . .
- Buckstein R, Jang K, Friedlich J, et al. Estimating the prevalence of myelodysplastic syndromes in patients with unexplained cytopenias: a retrospective study of 322 bone marrows. Leuk Res 2009; 33:1313-1318. http://dx.doi.org/10.1016/j.leukres.2009.02.010 PMid:19282029. .
D, Chen Z, Xue Y, et al. The significance of bone marrow cell
morphology and its correlation with cytogenetic features in the
diagnosis of MDS-RA patients. Leuk Res 2009; 33:1029-1038.
http://dx.doi.org/10.1016/j.leukres.2009.02.011 PMid:19411106. .
R, Nilsson I, Widell S, Ost A. Diagnostic significance of dysplastic
features of peripheral blood polymorphs in myelodysplastic syndromes.
Leuk Res 1989; 13:173-178
- Goasguen JE, Bennett JM, Bain BJ, et al. Proposal for refining the definition of dysgranulopoiesis in acute myeloid leukemia and myelodysplastic syndromes. Leuk Res 2014; 38:447-453. http://dx.doi.org/10.1016/j.leukres.2013.12.020 PMid:24439566. .
- Cazzola M, Invernizzi R, Bergamaschi G, et al. Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood 2003;101:1996-2000. http://dx.doi.org/10.1182/blood-2002-07-2006 PMid:12406866. .
- Zhou J, Orazi A, Czader MB. Myelodysplastic syndromes. Semin Diagn Pathol 2011; 28:258-272. http://dx.doi.org/10.1053/j.semdp.2011.08.005 PMid:22195404. .
- Wang SA, Tang G, Fadare O, et al: Erythroid-predominant myelodysplastic syndromes: enumeration of blasts from nonerythroid rather than total marrow cells provides superior risk stratification. Mod Pathol 2008; 21:1394-1402. http://dx.doi.org/10.1038/modpathol.2008.142. .
- Valent P, Orazi A, Büsche G, et al. Standards and impact of hemathopathology in myelodysplastic syndromes (MDS). Oncotarget 2010; 1:483-496. PMid:21317447 PMCid:PMC3248141. .
- Cantù Rajnoldi A, Fenu S, Kerndrup G, van Wering ER, Niemeyer CM, Baumann I for the European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Evaluation of dysplastic features in myelodysplastic syndromes: experience from the morphology group of the European Working Group of MDS in Childhood (EWOG-MDS). Ann Hematol 2005; 84:429-433. http://dx.doi.org/10.1007/s00277-005-1034-4 PMid:15838669. .
- Matsuda A, Jinnai I, Yagasaki F, et al. Refractory anemia with severe dysplasia: clinical significante of morphological features in refractory anemia. Leukemia 1998; 12:482-485. http://dx.doi.org/10.1038/sj.leu.2400966 PMid:9557604. .
- Tassin F, Dewé W, Schaaf N, et al. A four-parameter index of marrow dysplasia has predictive value for survival in myelodysplastic syndromes. Leuk Lymph 2000; 36:485-496. http://dx.doi.org/10.3109/10428190009148396 PMid:10784393. .
- Matsuda A, Jinnai I, Miyazaki Y, Tomonaga M. Proposals for a grading system for diagnostic accuracy of myelodysplastic syndromes. Clin Leuk 2008; 2:102-106. http://dx.doi.org/10.3816/CLK.2008.n.012 . .
U, Strupp C, Giagounidis A, et al. Evaluation of dysplasia through
detailed cytomorphology in 3156 patients from the Düsseldorf Registry
on myelodysplastic syndromes. Leuk Res 2012; 36:727-734.
http://dx.doi.org/10.1016/j.leukres.2012.02.014 PMid:22421409. .
- Ramos F, Fernandez-Ferrero S, Suarez D, et al. Myelodysplastic syndrome: a search for minimal diagnostic criteria. Leuk Res 1999; 23:283-290. http://dx.doi.org/10.1016/S0145-2126(98)00166-0 . .
- Bain BJ. The bone marrow aspirate of healthy subjects. Br J Haematol 1996; 94:206-209. http://dx.doi.org/10.1046/j.1365-2141.1996.d01-1786.x PMid:8757536. .
- Parmentier S, Schetelig J, Lorenz K, et al. Assessment of dysplastic hematopoiesis: lessons from healthy bone marrow donors. Haematologica 2012; 97:723-730. http://dx.doi.org/10.3324/haematol.2011.056879 PMid:22180437 PMCid:PMC3342975. .
K, Jabbour E, Bueso-Ramos C, et al. Implications of discrepancy in
morphologic diagnosis of myelodysplastic syndrome between referral and
tertiary care centers. Blood 2011; 118:4690-4693.
http://dx.doi.org/10.1182/blood-2011-03-342642 PMid:21868570 PMCid:PMC4081364. .
- Senent L, Arenillas L, Lu-o E, Ruiz JC, Sanz J, Florensa L. Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes. Haematologica 2013; 98:568-575. http://dx.doi.org/10.3324/haematol.2012.071449 PMid:23065505 PMCid:PMC3659988. .
- Glauser TA, Sagatys EM, Williamson JC, et al. Current pathology practices in and barriers to MDS diagnosis. Leuk Res 2013; 37:1656-1661. http://dx.doi.org/10.1016/j.leukres.2013.10.007 PMid:24220584. .
- Della Porta MG, Travaglino E, Boveri E, et al. Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes. Leukemia 2015; 29:66-75. http://dx.doi.org/10.1038/leu.2014.161 PMid:24935723. .
- Lambertenghi-Deliliers G, Annaloro C, Oriani A, Soligo D. Myelodysplastic syndrome associated with bone marrow fibrosis. Leuk Lymphoma 1992; 8:51-55. http://dx.doi.org/10.3109/10428199209049817 PMid:1493471. .
- Tuzuner N, Cox C, Rowe JM, Watrous D, Bennett JM. Hypocellular myelodysplastic syndromes (MDS): new proposals. Br J Haematol 1995; 91:612-617. http://dx.doi.org/10.1111/j.1365-2141.1995.tb05356.x PMid:8555063. .
J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A.
European consensus on grading bone marrow fibrosis and assessment of
cellularity. Haematologica 2005; 90:1128-1132.
- Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica 2009; 94:264-268. http://dx.doi.org/10.3324/haematol.13755 PMid:19144661 PMCid:PMC2635414. .
Porta MG, Malcovati L, Boveri E, et al. Clinical relevance of bone
marrow fibrosis and CD34-positive cell clusters in primary
myelodysplastic syndromes. J Clin Oncol 2009; 27:754-762.
http://dx.doi.org/10.1200/JCO.2008.18.2246 PMid:19103730. .
- Buesche G, Teoman H, Wilczak W, et al. Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia 2008; 22:313-322. http://dx.doi.org/10.1038/sj.leu.2405030 PMid:18033321. .
- Orazi A, Czader MB. Myelodysplastic syndromes. Am J Clin Pathol 2009; 132:290-305. http://dx.doi.org/10.1309/AJCPRCXX4R0YHKWV PMid:19605823. .
- Wimazal F, Fonatsch C, Thalhammer R, et al. Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface. Leuk Res 2007; 31:1461-1468. http://dx.doi.org/10.1016/j.leukres.2007.03.015 PMid:17507091. .
P, Horny HP. Minimal diagnostic criteria for myelodysplastic syndromes
and separation from ICUS and IDUS: update and open questions. Eur J
Clin Invest 2009; 39:548-553.
http://dx.doi.org/10.1111/j.1365-2362.2009.02151.x PMid:19453651. .
P, Jäger E, Mitterbauer-Hohendanner G, et al. Idiopathic bone marrow
dysplasia of unknown significance (IDUS): definition, pathogenesis,
follow up, and prognosis. Am J Cancer Res 2011; 1:531-541.
PMid:21984971 PMCid:PMC3186051. .
- Valent P, Bain BJ, Bennett JM, et al. Idiopathic cytopenia of undetermined significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), and their distinction from low risk MDS. Leuk Res 2012; 36:1-5. PMid:21920601. .
- Schroeder T, Ruf L, Bernhardt A, et al. Distinguishing myelodysplastic syndromes (MDS) from idiopathic cytopenia of undetermined significance (ICUS): HUMARA unravels clonality in a subgroup of patients. Ann Oncol 2010; 21:2267-2271. http://dx.doi.org/10.1093/annonc/mdq233 PMid:20439346. .
- Bennett JM. Morphological classification of the myelodysplastic syndromes: how much more education of diagnosticians is necessary? Haematologica 2013; 93:490-491. http://dx.doi.org/10.3324/haematol.2013.084418 PMid:23543153 PMCid:PMC3659978. .
- Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol 2011; 29:504-515. http://dx.doi.org/10.1200/JCO.2010.31.1175 PMid:21220588 PMCid:PMC3969457. .
- Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478:64-69. http://dx.doi.org/10.1038/nature10496 PMid:21909114. .
- Cazzola M, Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood 2013; 122:4021.4034.. .
- Malcovati L, Papaemmanuil E, Ambaglio I, et al. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood. 2014; 124:1513-1521. http://dx.doi.org/10.1182/blood-2014-03-560227 PMid:24970933 PMCid:PMC4148773. .
- Van't Veer M, Haferlach T. Should clinical hematologists put their microscopes on eBay? Haematologica 2014; 99:1533-1534. http://dx.doi.org/10.3324/haematol.2014.114710 PMid:25271310 PMCid:PMC4181246. .
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