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WHO Classification of Tumours
Overview: Myelodysplastic syndromes/neoplasms


The myelodysplastic syndromes (MDS) are a group of clonal haematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective haematopoiesis, and increased risk of development of acute myeloid leukaemia (AML)
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Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1982)
Proposals for the classification of the myelodysplastic syndromes.
Br J Haematol 51: 189-99




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Cazzola M, Malcovati L (2005)
Myelodysplastic syndromes--coping with ineffective hematopoiesis.
N Engl J Med 352: 536-8




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Vardiman JW (2003)
The new World Health Organization classification of myeloid neoplasms: Q&A with James W. Vardiman, MD.
Clin Adv Hematol Oncol 1: 18, 21



. There is an enhanced degree of apoptosis which contributes to the cytopenias
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Bowen D, Culligan D, Jowitt S, Kelsey S, Mufti G, Oscier D, Parker J, (2003)
Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes.
Br J Haematol 120: 187-200



. The thresholds for cytopenias as recommended in the International Prognostic Scoring System (IPSS) for risk stratification in the MDS are haemoglobin <10g/dL, absolute neutrophil count (ANC) <1.8x109/L and platelets <100x109L
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Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88




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Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88



. Values above these thresholds are, however, not exclusionary for a diagnosis of MDS if definitive morphologic and/or cytogenetic findings are present
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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



. The dysplasia may be accompanied by an increase in myeloblasts in the peripheral blood (PB) and bone marrow (BM) but the number is <20%, which is the requisite threshold recommended for the diagnosis of AML. It is important to recognize that the threshold of 20% blasts in the PB or BM for the distinction of AML from MDS does not represent a therapeutic mandate for treating patients with 20% blasts as acute leukaemia. A treatment decision to manage the patient as AML or MDS must be based on several factors ­including age, prior history of a myelodysplastic syndrome, overall clinical assessment and tempo of the process, which are the same determinant factors for patients with =30% blasts. Although progression to AML is the natural course in many cases of MDS, the percentage of patients who progress varies substantially in the various subtypes; a higher percentage of MDS with increased myeloblasts transforms to AML
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Germing U, Strupp C, Kuendgen A, Aivado M, Giagounidis A, Hildebrandt B, Aul C, Haas R, Gattermann N (2006)
Refractory anaemia with excess of blasts (RAEB): analysis of reclassification according to the WHO proposals.
Br J Haematol 132: 162-7




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Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, Passamonti F, Arcaini L, Maffioli M, Bernasconi P, Lazzarino M, Cazzola M (2005)
Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making.
J Clin Oncol 23: 7594-603



. Although the majority of MDS are characterized by progressive BM failure, the biologic course in some patients, e.g. refractory anemia with unilineage dysplasia (RA) and refractory anemia with ring sideroblasts (RARS), is prolonged and indolent with a very low incidence of evolution to AML
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Germing U, Strupp C, Kuendgen A, Aivado M, Giagounidis A, Hildebrandt B, Aul C, Haas R, Gattermann N (2006)
Refractory anaemia with excess of blasts (RAEB): analysis of reclassification according to the WHO proposals.
Br J Haematol 132: 162-7




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Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C, Cazzola M (2007)
Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes.
J Clin Oncol 25: 3503-10




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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



.

Epidemiology
Myelodysplastic syndromes occur principally in older adults with a median age of 70 years, with a non-age corrected annual incidence of 3-5/100 000 persons but rising to >20/100 000 among those over the age of 70 years

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Aul C, Gattermann N, Schneider W (1992)
Age-related incidence and other epidemiological aspects of myelodysplastic syndromes.
Br J Haematol 82: 358-67




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Germing U, Strupp C, Kündgen A, Bowen D, Aul C, Haas R, Gattermann N (2004)
No increase in age-specific incidence of myelodysplastic syndromes.
Haematologica 89: 905-10



. Approximately 10 300 incident cases of MDS were diagnosed in 2003 in the USA
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Ma X, Does M, Raza A, Mayne ST (2007)
Myelodysplastic syndromes: incidence and survival in the United States.
Cancer 109: 1536-42



. There is a male predominance. Therapy-related myelodysplastic syndromes are discussed in Chapter 6.

Clinical features
The majority of patients present with symptoms related to cytopenia(s); most of the patients are anaemic and transfusion-dependent. Less frequent are neutropenia and/or thrombocytopenia. Organomegaly is infrequently observed.

Etiology
Primary or de novo MDS occurs without a known history of chemotherapy or radiation exposure. Possible etiologies for primary MDS include benzene exposure at levels well above the minima allowed by most government agencies, cigarette smoking, exposure to agricultural chemicals or solvents and family history of haematopoietic neoplasms

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Strom SS, Gu Y, Gruschkus SK, Pierce SA, Estey EH (2005)
Risk factors of myelodysplastic syndromes: a case-control study.
Leukemia 19: 1912-8



. Some inherited haematological disorders, such as Fanconi anaemia, dyskeratosis congenita, Shwachmann-Diamond syndrome and Diamond-Blackfan syndrome are also associated with an increased risk of MDS.

Morphology
The morphological classification of MDS is principally based on the percent of blasts in the BM and PB, the type and degree of dysplasia and the presence of ring sideroblasts

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Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1982)
Proposals for the classification of the myelodysplastic syndromes.
Br J Haematol 51: 189-99



. The cytopenias generally correspond to the dysplastic lineage, but discordance may be present (Table 5.01)
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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



. To determine the blast percentage in the BM, a 500-cell differential of all nucleated cells in a smear or trephine imprint is recommended and in the PB, a 200-leukocyte differential. In severely cytopenic patients, buffy coat smears of PB may facilitate performing the differential.

The characteristics of the dysplasia are relevant when distinguishing between the various types of MDS and may be important in predicting biology. In addition, some cytogenetic abnormalities are associated with characteristic dysplastic features, e.g. isolated del(5q) and hypo­lobated and non-lobated megakaryocyte nuclei and del(17p) with hypolobated neutrophil nuclei

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Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M, Lepelley P, Wattel E, Fenaux P (1995)
Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations.
Leukemia 9: 370-81



.

Assessment of the degree of dysplasia may be problematic depending on the quality of the smear preparations and the stain. Poor quality smears may result in misinterpretation of the presence or absence of dysplasia particularly in assessing neutrophil granulation. Because of the critical importance of recognition of dysplasia to the diagnosis of an MDS, the necessity of high quality slide preparations cannot be overemphasized. Slides for the assessment of dysplasia should be made from freshly obtained specimens; specimens exposed to anticoagulants for more than two hours are unsatisfactory.

As a general precaution, no patient should be diagnosed as having MDS without knowledge of the clinical and drug history and no case of MDS should be reclassified while the patient is on growth factor therapy, including erythropoietin. In addition, cytopenia(s) in the absence of dysplasia should not be interpreted as an MDS. A presumptive ­diagnosis of MDS may be made in the absence of dysplasia if certain cytogenetic abnormalities are present (See Genetics). Persistent cytopenia without dysplasia and without one of the specific cyto­genetic abnormalities considered as presumptive evidence of MDS should be viewed as the recently described "idiopathic cytopenia of undetermined significance" (ICUS), and the patient’s haemato­logic and cytogenetic status should be carefully monitored

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Wimazal F, Fonatsch C, Thalhammer R, Schwarzinger I, Müllauer L, Sperr WR, Bennett JM, Valent P (2007)
Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface.
Leuk Res 31: 1461-8



.

In an attempt to more accurately predict clinical behaviour, cases of MDS without an increase in blasts are recognized as manifesting either unilineage or multilineage dysplasia. In refractory anemia (RA) and refractory anemia with ring sideroblasts (RARS), the dysplasia is generally confined to the erythroid lineage. Unilineage dysplasia may also occur in the neutrophils, refractory neutropenia (RN), and megakaryocytes, refractory thrombocytopenia (RT), but these processes are much less frequent than unilineage dysplasia involving the erythroid cells. In refractory cytopenia with multilineage dysplasia (RCMD) with or without ring sideroblasts, significant dysplastic features are recognized in two or more of the major myeloid cell lineages. The recommended requisite percentage of cells manifesting dysplasia to qualify as significant is ≥10%

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Rosati S, Mick R, Xu F, Stonys E, Le Beau MM, Larson R, Vardiman JW (1996)
Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome.
Leukemia 10: 20-6



in the erythroid precursors and granulocytes. Significant megakaryocyte dysplasia is defined as ≥10% dysplastic megakaryocytes based on evaluation of at least 30 megakaryo­cytes in smears or sections. Future studies may result in modification of this recommendation
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Matsuda A, Germing U, Jinnai I, Iwanaga M, Misumi M, Kuendgen A, Strupp C, Miyazaki Y, Tsushima H, Sakai M, Bessho M, Gattermann N, Aul C, Tomonaga M (2007)
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 21: 678-86



. Micromegakaryocytes and multinucleate megakaryocytes are the most reliable dysplastic findings in the megakaryocyte series
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Matsuda A, Germing U, Jinnai I, Iwanaga M, Misumi M, Kuendgen A, Strupp C, Miyazaki Y, Tsushima H, Sakai M, Bessho M, Gattermann N, Aul C, Tomonaga M (2007)
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 21: 678-86




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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



.

Although the majority of patients with MDS and unlineage dysplasia present with a single cytopenia, this revised classification allows for bicytopenia in refractory cytopenia with unilineage dysplasia (RCUD) and RARS (Table 5.02). The majority of patients with RCMD have =2 cytopenias

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Rosati S, Mick R, Xu F, Stonys E, Le Beau MM, Larson R, Vardiman JW (1996)
Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome.
Leukemia 10: 20-6



.

Characteristics of dysplasia
Dyserythropoiesis is manifest principally by alterations in the nucleus including budding, internuclear bridging, karyorrhexis, multinuclearity and megaloblastoid changes; cytoplasmic features include ring sideroblasts, vacuolisation and periodic acid-Schiff positivity, either diffuse or granular (Table 5.03). Dysgranulopoiesis is characterized primarily by nuclear hypolobation (pseudo Pelger-Huët) and hypersegmentation, cytoplasmic hypo­granularity, pseudo Chediak-Higashi granules and small size. Megakaryocyte dysplasia is characterized by micro-megakaryocytes with hypolobated nuclei, non-lobated nuclei in megakaryocytes of all sizes, and multiple, widely-separated nuclei. Megakaryocytic dysplasia may be more readily appreciated in BM sections than smears and both types of specimens should be evaluated.

The characteristics of the dysplasia may be relevant in predicting biology of a myelodysplastic disorder and the relationship to specific cytogenetic abnormalities, e.g. 5q- syndrome

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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



. Unilineage dysplasia is observed in RCUD and RARS. Multilineage dysplasia involving two or three of the myeloid cell lines is more frequently observed in the high-grade MDS and is used to distinguish RCMD from RCUD
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Rosati S, Mick R, Xu F, Stonys E, Le Beau MM, Larson R, Vardiman JW (1996)
Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome.
Leukemia 10: 20-6



. Similarly, the presence of multilineage dysplasia is used to separate RARS from RCMD with ring sideroblasts, the latter of which has a similar clinical course to RCMD. An increased number of ring sideroblasts, occasionally >15% of the erythroid precursors, may be observed in refractory anemia with excess blasts (RAEB). The defining criteria of RAEB-1 or RAEB-2 dictate the classification in such cases. The relationship between cytopenias, type of dysplasia, and classification is summarized in Table 5.02.

The significance of the Auer rod in myeloid disorders has historically been somewhat uncertain. For several decades its detection was viewed as virtually diagnostic of AML. There was no specificity applied to it with the introduction of the concept of MDS by the FAB group. In the revised FAB classification of 1982 it was viewed as evidence of a high-grade MDS, refractory anaemia with excess of blasts in transformation, (RAEB T), irrespective of the blast percentage in the PB or BM

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Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1982)
Proposals for the classification of the myelodysplastic syndromes.
Br J Haematol 51: 189-99



. In the prior WHO Classification of the MDS it was considered as evidence of RAEB-2 or CMML-2 in the context of MDS or MDS/MPN regardless of the blast percentage. This concept is retained in the present classification. Cases of MDS with <5% blasts in the BM and <1% in the PB may rarely have Auer rods. These cases have been reported to be associated with an adverse prognosis
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Willis MS, McKenna RW, Peterson LC, Coad JE, Kroft SH (2005)
Low blast count myeloid disorders with Auer rods: a clinicopathologic analysis of 9 cases.
Am J Clin Pathol 124: 191-8



.

Differential diagnostic considerations
A major problem in the diagnosis of MDS is the determination whether the presence of myelodysplasia is due to a clonal disorder or is the result of some other factor. The presence of dysplasia is not in itself definitive evidence of a clonal disorder.

There are several nutritional, toxic and other factors which may cause myelodysplastic changes, including but not limited to vitamin B12 and folic acid deficiency, essential element deficiencies and exposure to heavy metals, particularly arsenic and several commonly used drugs and biologic agents

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Bowen D, Culligan D, Jowitt S, Kelsey S, Mufti G, Oscier D, Parker J, (2003)
Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes.
Br J Haematol 120: 187-200



. The antibiotic cotrimoxazole may cause marked neutrophil nuclear hypolobation indistinguishable from the changes observed in MDS. In some patients on multiple drugs it may be difficult to identify the causative agent of the neutrophil changes
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Kennedy GA, Kay TD, Johnson DW, Hawley CM, Campbell SB, Isbel NM, Marlton P, Cobcroft R, Gill D, Cull G (2002)
Neutrophil dysplasia characterised by a pseudo-Pelger-Huet anomaly occurring with the use of mycophenolate mofetil and ganciclovir following renal transplantation: a report of five cases.
Pathology 34: 263-6




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Taegtmeyer AB, Halil O, Bell AD, Carby M, Cummins D, Banner NR (2005)
Neutrophil dysplasia (acquired pseudo-pelger anomaly) caused by ganciclovir.
Transplantation 80: 127-30



.

Congenital haematological disorders such as congenital dyserythropoietic anaemia must also be considered as a cause of dysplasia when it is confined to the erythroid cells. Parvovirus B19 infection may be associated with erythroblastopenia with giant megaloblastoid erythroblasts; the immunosuppression agent myco­phenolate mofetil may also be associated with erythroblastopenia. Chemotherapeutic agents may result in marked dysplasia of all myeloid cell lineages. Granulocyte colony-stimulating factor result in morphologic alterations in the neutrophils, including marked hypergranularity and striking nuclear hypolobation

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Schmitz LL, McClure JS, Litz CE, Dayton V, Weisdorf DJ, Parkin JL, Brunning RD (1994)
Morphologic and quantitative changes in blood and marrow cells following growth factor therapy.
Am J Clin Pathol 101: 67-75



; blasts may be observed in the PB and may reach levels of 9-10% and rarely higher in patients with no evidence of AML or MDS. The BM blast percentage is generally normal, but may be increased as well. Paroxysmal nocturnal haemoglobinuria may also present with features similar to MDS. As a result of all these possibilities, it is extremely important to be aware of the clinical history including exposure to drugs or chemicals and consider non-clonal disorders as possible etiologies when evaluating cases with myelodysplasia, particularly those cases with no increase in blasts. Repeated BM biopsies, including cytogenetic studies, over a period of several months may be necessary in difficult cases.

Histopathology
The value of the BM biopsy in MDS is well established

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Orazi A (2007)
Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases.
Pathobiology 74: 97-114



. It may aid in confirming a suspected diagnosis by excluding ­reactive conditions in which dyshaemato­poietic changes may also be observed; it can also increase the diagnostic accuracy and helps in refining the IPSS score
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Verburgh E, Achten R, Maes B, Hagemeijer A, Boogaerts M, De Wolf-Peeters C, Verhoef G (2003)
Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes.
J Clin Oncol 21: 273-82



. Assessment of BM cellularity and stromal reactions, e.g. fibrosis, are additional important diagnostic features of the biopsy. The BM in MDS is usually hypercellular or normocellular; the cytopenias result from the ineffective haematopoiesis.

Histologically, aggressive MDS may be characterized by the presence of aggregates (3-5 cells) or clusters (>5 cells) of blasts in BM biopsies usually localized in the central portion of the BM away from the vascular structures and endosteal surfaces of the bone trabeculae. These are frequently present in RAEB. The blasts can also be identified by immunohistochemistry with antibody to CD34, an antigen expressed in progenitor cells and early precursor BM cells in the majority of cases. Anti-CD34 can be used to demonstrate pathologic accumulations of blasts both singly and in clusters in aggressive subtypes of myeloid neoplasms

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Soligo D, Delia D, Oriani A, Cattoretti G, Orazi A, Bertolli V, Quirici N, Deliliers GL (1991)
Identification of CD34+ cells in normal and pathological bone marrow biopsies by QBEND10 monoclonal antibody.
Leukemia 5: 1026-30



. With some fixatives, CD34 will also immuno­react with megakaryocytes in MDS. Immunohistologic analysis with anti-CD34 may be especially useful in cases of MDS with fibrosis or hypocellular marrows as well as therapy-related cases to assess blast percentage. In these instances the presence of fibrosis or fatty changes in the BM may make accurate characterization of the process very difficult.

Hypoplastic MDS
In a minority of the cases of MDS, approximately 10%, the BM is hypocellular. These cases have been referred to as hypoplastic MDS. This group, which has no independent prognostic significance per se, may lead to difficulties in the differential diagnosis with aplastic anaemia

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Greenberg PL, Young NS, Gattermann N (2002)
Myelodysplastic syndromes.
Hematology Am Soc Hematol Educ Program : 136-61




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Orazi A, Albitar M, Heerema NA, Haskins S, Neiman RS (1997)
Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anemia by CD34 and PCNA immunostaining of bone marrow biopsy specimens.
Am J Clin Pathol 107: 268-74



. In addition, anti-thymocyte globulin and other therapies used for aplastic anaemia have been used with some degree of success in this subgroup
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Bowen D, Culligan D, Jowitt S, Kelsey S, Mufti G, Oscier D, Parker J, (2003)
Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes.
Br J Haematol 120: 187-200




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Lim ZY, Killick S, Germing U, Cavenagh J, Culligan D, Bacigalupo A, Marsh J, Mufti GJ (2007)
Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin.
Leukemia 21: 1436-41




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Young NS (2006)
Pathophysiologic mechanisms in acquired aplastic anemia.
Hematology Am Soc Hematol Educ Program : 72-7




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Young NS, Calado RT, Scheinberg P (2006)
Current concepts in the pathophysiology and treatment of aplastic anemia.
Blood 108: 2509-19



. It is also important when considering the diagnosis of hypoplastic MDS to exclude toxic myelopathy and auto­immune disorders.

MDS with myelofibrosis
Significant degrees of myelofibrosis are observed in approximately 10% of the cases of MDS. These cases have been referred to as MDS with fibrosis

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Lambertenghi-Deliliers G, Orazi A, Luksch R, Annaloro C, Soligo D (1991)
Myelodysplastic syndrome with increased marrow fibrosis: a distinct clinico-pathological entity.
Br J Haematol 78: 161-6



. Most of the cases with fibrosis have excess of blasts and an aggressive clinical course. Such cases may erroneously be considered low-grade MDS if only the blast count determined from the BM aspirate, which is usually diluted with PB, is evaluated. In the fibrotic group, as in other cases of MDS with inadequate aspirates, the blast determination requires a BM biopsy and immunohistochemical studies for CD34 may prove invaluable.

Immunophenotyping
Published studies on immunophenotyping by flow cytometry in MDS have focused on several strategies, including determining the size and immunophenotype of the blast population and assessing the maturation pattern of the myeloid cell population. More specifically, these studies included immunophenotyping of CD34+ cells, application of scoring systems, and pattern recognition strategies using multicolor analysis and comparison with normal/ reactive PB and BM.

There is generally good correlation between the percentage of blasts as determined by morphologic examination of routine smear or imprint or immunohistologic preparations and percentage of CD34+ cells determined by flow cytometry (FC). However, in some cases there may be significant discordance due to significant myelofibrosis and haemodilute samples. As a result, FC percentages of CD34+ cells cannot replace differential counts on smears. However, FC may be informative if abnormal phenotypes of CD34+ cells are detected; this could be additional evidence of dysplasia. In addition, an emerging pathological population of CD34 or CD117 cells in low-grade MDS could suggest evolution of the disease

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Ogata K, Kishikawa Y, Satoh C, Tamura H, Dan K, Hayashi A (2006)
Diagnostic application of flow cytometric characteristics of CD34+ cells in low-grade myelodysplastic syndromes.
Blood 108: 1037-44



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Maturation patterns of erythropoietic, granulocytic, and monocytic differentiation in the normal/reactive BM, as well as the immunophenotype of the mature cells in PB have been thoroughly described using four-color FC. Erythroid abnormalities as determined by the pattern of expression of H-ferritin, CD71 and CD105 in glycophorin A (GPA) positive nucleated cells reportedly can predict morphological erythroid dysplasia with 98% sensitivity

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Della Porta MG, Malcovati L, Invernizzi R, Travaglino E, Pascutto C, Maffioli M, Gallì A, Boggi S, Pietra D, Vanelli L, Marseglia C, Levi S, Arosio P, Lazzarino M, Cazzola M (2006)
Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome.
Leukemia 20: 549-55



. Aberrant maturation patterns in granulopoiesis could predict morphological dysplasia and abnormal cytogenetics in approximately 90% of cases
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Kussick SJ, Wood BL (2003)
Four-color flow cytometry identifies virtually all cytogenetically abnormal bone marrow samples in the workup of non-CML myeloproliferative disorders.
Am J Clin Pathol 120: 854-65



. Thus, flow cytometry results correlate well with morphology and cytogenetics in MDS. However, in cases with borderline dysplasia by morphology and no cytogenetic abnormalities, FC results are highly suggestive for MDS only if there are three or more aberrant features in erythropoietic, granulocytic or monocytic maturation; single aberrant features by FC are not significant. Cases with inconclusive morphologic and cytogenetic findings and three or more aberrant features by flow cytometry should be reevaluated over several months for definitive morpho­logic or cytogenetic evidence of MDS.

Genetics
Cytogenetic and molecular studies have a major role in the evaluation of patients with MDS in regard to prognosis, determination of clonality

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Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88




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Olney HJ, Le Beau MM (2007)
Evaluation of recurring cytogenetic abnormalities in the treatment of myelodysplastic syndromes.
Leuk Res 31: 427-34



, and the recognition of cytogenetic, morphologic, and clinical correlates. Clonal cytogenetic abnormalities are observed in ~50% of MDS cases. Myelodysplastic syndromes associated with an isolated del(5q) occur primarily in women, are characterized by megakaryocytes with non-lobated or hypo­lobated nuclei, refractory macrocytic anaemia, normal or increased platelet count, and a favourable clinical course, and are recognized as a specific type of MDS in this classification. The occurrence of 17p loss is associated with MDS or AML with pseudo Pelger-Huët anomaly, small vacuolated neutrophils, TP53 mutation and unfavourable clinical course; it is most common in therapy-related MDS
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Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M, Lepelley P, Wattel E, Fenaux P (1995)
Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations.
Leukemia 9: 370-81



. Complex karyotypes (≥3 abnormalities) typically include chromosomes 5 and/or 7 [-5/del(5q), -7/del(7q)], and are generally associated with an unfavourable clinical course. Several other cytogenetic findings appear to be associated with characteristic morphologic abnormalities such as isolated del(20q) with involvement of erythroid cells and megakaryo­cytes, and abnormalities of chromosome 3 [inv(3)(q21q26.2) or t(3;3)(q21;q26.2)], which are associated with MDS and AML with increased abnormal megakaryocytes
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Brunning RD, McKenna RW
Tumors of the bone marrow
Armed Forces Institute of Pathology: Washington, D.C. 1994




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Gupta R, Soupir CP, Johari V, Hasserjian RP (2007)
Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation.
Br J Haematol 139: 265-8




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Kurtin PJ, Dewald GW, Shields DJ, Hanson CA (1996)
Hematologic disorders associated with deletions of chromosome 20q: a clinicopathologic study of 107 patients.
Am J Clin Pathol 106: 680-8



.

Some clonal cytogenetic abnormalities occuring in MDS are not definitive evidence for this disorder in the absence of morphological criteria, e.g. -Y, +8 or del(20q) as the sole abnormality. The other abnormalities listed in Table 5.04 in the presence of a refractory cytopenia, but no morphologic evidence of dysplasia, are considered presumptive evidence for MDS. It is recommended that these patients be followed carefully for emerging morphological evidence of MDS. FISH provides increased sensitivity in monitoring such patients, once a recurring abnormality has been identified.


Postulated cell of origin
Haematopoietic stem cell.

Prognosis and predictive factors
The morphological subtypes of MDS can be generally categorized into three risk groups based on duration of survival and incidence of evolution to AML. The low-risk groups are RCUD and RARS. The intermediate-risk groups are RCMD with or without ring sideroblasts and RAEB-1. Patients with RAEB-2 constitute the high-risk group. It should be noted that patients with bicytopenia in RCUD and RARS have been reported to have a shorter survival than patients with one cytopenia

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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



. Patients with one cytopenia in the context of RCMD had a longer survival than patients with two cytopenias
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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



.

The importance of cytogenetic studies as a prognostic indicator in MDS has been recognized and codified by the International Myelodysplastic Syndrome Working Group

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Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88



. Three major risk categories of cytogenetic findings have been defined: i) good risk —normal karyotype, isolated del(5q), isolated del (20q) and -Y; ii) poor risk —complex abnormalities, i.e., ≥3 abnormalities, or abnormalities of chromosome 7; and iii) intermediate risk —all other abnormalities.

A scoring system for predicting survival and evolution to AML based on percent BM blasts, type of cytogenetic abnormalities, and degree and number of cytopenias has been proposed by this group (Table 5.05)

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Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88




Click to access Pubmed
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88



. Four risk groups based on this scoring system are recognized: low, 0; INT (intermediate)-1, 0.5-1.0; INT-2, 1.5-2.0; and high, ≥2.5. In general, the higher-risk groups are related to higher BM blast percentage, more unfavourable cytogenetic findings and more severe degree of cytopenia.

Consideration of age improves predictability of survival; patients younger than 60 years of age have improved survival in the individual risk categories compared with patients older than 60 years.

The cytogenetic subgrouping of the IPSS system also has an independent value in predicting the outcome of allogeneic stem cell transplantation in patients with MDS

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de Witte T, Oosterveld M, Muus P (2007)
Autologous and allogeneic stem cell transplantation for myelodysplastic syndrome.
Blood Rev 21: 49-59



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> Related Topics
Acute myeloid leukaemia (AML) with myelodysplasia-related changes
Therapy-related myeloid neoplasms
Introduction: Myeloid Neoplasms









Richard D. Brunning
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Richard D. Brunning
Department of Laboratory Medicine and Pathology
University of Minnesota
Minneapolis
USA




Attilio Orazi
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Attilio Orazi
Department of Pathology and Laboratory Medicine
Weill Medical College of Cornell University
New York
USA




Ulrich Germing
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Ulrich Germing
Department of Hematology/Oncology and Clinical Immunology
Heinrich Heine University
Düsseldorf
Germany




Michelle M. Le Beau
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Michelle M. Le Beau
Cancer Cytogenetics Laboratory
University of Chicago
Chicago
USA




Anna Porwit
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Anna Porwit
Department of Pathology
Karolinska University Hospital
Stockholm
Sweden




Irith Baumann
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Irith Baumann
Institute of Pathology
Bayreuth Clinic
Bayreuth
GERMANY




James W. Vardiman
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James W. Vardiman
Department of Pathology
University of Chicago Medical Center
Chicago
USA




Eva Hellström-Lindberg
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Eva Hellström-Lindberg
Department of Medicine, Division of Hematology
Karolinska University Hospital
Stockholm
Sweden





Atypical erythroid precursor in bone marrow smear from a patient with parvovirus B19 infection
Atypical erythroid precursor in bone marrow smear from a patient with parvovirus B19 infection

Dyserythropoiesis in bone marrow smear from a man with arsenic poisoning
Dyserythropoiesis in bone marrow smear from a man with arsenic poisoning

Bone marrow smear from a patient receiving folic acid antagonists for breast cancer
Bone marrow smear from a patient receiving folic acid antagonists for breast cancer

Congenital dyserythropoietic anaemia.
Congenital dyserythropoietic anaemia.

Bi-lobed neutrophil in blood of patient on G-CSF
Bi-lobed neutrophil in blood of patient on G-CSF

Blast in a blood smear from a patient on G-CSF.
Blast in a blood smear from a patient on G-CSF.

Dysgranulopoiesis in RCMD
Dysgranulopoiesis in RCMD

Dysgranulopoiesis in RCMD
Dysgranulopoiesis in RCMD

Abnormal localization of immature precursors in bone marrow biopsy.
Abnormal localization of immature precursors in bone marrow biopsy.

A focus of immature cells in RAEB-2. CD34
A focus of immature cells in RAEB-2. CD34

Myelodysplastic dyserythropoiesis
Myelodysplastic dyserythropoiesis

Dysplastic megakaryocytes
Dysplastic megakaryocytes

Neutrophil with a non-lobated nucleus (pseudo Pelger-Huët)
Neutrophil with a non-lobated nucleus (pseudo Pelger-Huët)

Binucleate megakaryocyte in refractory neutropenia
Binucleate megakaryocyte in refractory neutropenia

Bone marrow biopsy from RAEB with myelofibrosis. Note micromegakaryocytes.
Bone marrow biopsy from RAEB with myelofibrosis. Note micromegakaryocytes.

MDS with myelofibrosis. Reticulin stain
MDS with myelofibrosis. Reticulin stain