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©Ferrata Storti Foundation Haematologica 1998; 83:258-275 review Recent Advances in Myelodysplastic Syndromes Guest Editors: Miguel Angel Sanz, Guillermo Sanz & Teresa Vallespí Diagnosis, classification, and cytogenetics of myelodysplastic syndromes TERESA VALLESPÍ,* MICHÈLE IMBERT,º CRISTINA MECUCCI,# CLAUDE PREUDHOMME,@^ PIERRE FENAUX§^ *Servicio de Hematología, Hospital General Vall d’Hebrón, Barcelona, Spain; ºService d’Hématologie-Biologique, Hôpital Henri Mondor, Créteil, France; #Hematology and Bone Marrow Transplantation Unit, University of Perugia, Policlinico Mon- teluce, Perugia, Italy; @Laboratoire d’Hématologie A, Hôpital Calmette, Lille, France; §Service des Maladies du Sang, CHU, Lille, France; ^Unité INSERM U124, Lille, France ABSTRACT Background and Objective. The diagnosis of myelo- ognized as a new MDS subtype. Therapy-related MDS dysplastic syndromes (MDS) is essentially morpho- (t-MDS) should be classified according to the logical and based on the presence of dysplastic fea- involved agents. Finally, besides including chromo- tures in the peripheral blood and bone marrow. The somal abnormalities in the diagnosis (e.g., RAEB French-American-British (FAB) Cooperative Group with trisomy 8), several cytogenetic abnormalities proposed a classification based on easily obtainable such as deletion 5q and deletion 17p, associated to laboratory information. In spite of some limitations, specific clinical-morphological features, should be of the FAB criteria have been useful for a long time. help to identify new MDS syndromes. Currently, the recognition of other distinct morpho- ©1998 Ferrata Storti Foundation logical MDS subgroups such as hypocellular MDS and MDS with myelofibrosis, the increasing inci- Key-words: dyshemopoiesis, FAB subtypes, chromosome dence of MDS in children as well as that of therapy- changes, MDS related MDS, and the finding of specific chromoso- mal alterations associated with different morpho- logical features, reveal the insufficiency of this clas- he diagnosis of myelodysplastic syndrome sification. The aim of the present review is to exam- (MDS) requires a careful light microscopic ine some new aspects of the diagnosis, classifica- examination of optimally stained peripheral tion, and cytogenetics of MDS. T blood and bone marrow smears and trephine biop- Evidence and Information Sources. The authors of sy sections, with the diagnosis being based on the this review have been actively working and con- presence of dysplastic features of hematopoietic lin- tributing original papers on MDS for the last 15 eage. Abnormalities such as erythroblasts with abnor- years. They also organized or participated in the mal nuclear shape, ringed sideroblasts, degran- Fourth International Symposium on MDS (Barcelona, April 24-27, 1997). In addition, the present review ulation/hyposegmentation of granulocytes, large- critically examines relevant articles and abstracts degranulated platelets and micromegakaryocytes in published in journals covered by the Science Citation a patient with unexplained cytopenia are character- Index© and Medline©. istic features of MDS.1,2 State of the Art and Perspectives. Most of investi- In spite of some limitations, The French-American- gators working on MDS tend to integrate morpholo- British (FAB) Cooperative Group classification for gy and cytogenetics in the diagnosis and classifica- MDS3 has been useful for the last fifteen years. At tion of these disorders. FAB criteria remain useful present, the recognition of other distinct subgroups particularly for patients with not available cytoge- such as hypocellular MDS and MDS with myelofi- netic study. Refractory cytopenia with multilineage brosis, the increasing incidence of MDS in children dysplasia should be considered as a new MDS sub- as well as that of therapy-related MDS, and the find- type. Some authors propose considering all patients ing of specific cytogenetic abnormalities make nec- with more than 20% of blast cells in peripheral blood 1,2,4 or bone marrow as having acute leukemia. Chronic essary to review this classification. myelomonocytic leukemia with myeloproliferative Cytogenetic studies in MDS may have patho- features may be included among chronic myelopro- genetic, diagnostic, and prognostic implications. The liferative disorders. MDS with myelofibrosis is rec- cytogenetic study of bone marrow cells is mandato- ry in the diagnosis and classification of MDS, with Correspondence: Teresa Vallespí, MD, Servicio de Hematología, Hospi- the most frequent chromosome abnormalities being tal General “Vall d’Hebrón”, Passeig Vall d’Hebrón 129, 08035 del(5q), monosomy 7, trisomy 8 and complex kary- Barcelona, Spain. 5 Phone: international +34-3-2746205 • Fax: international +34-3- otype. Conventional cytogenetics methods are rou- 2746015. tinely used to detect karyotypic abnormalities in the Diagnosis, classification and cytogenetics of MDS 259 bone marrow cells of MDS patients. Nevertheless, oblasts (>15%) defines a subgroup of MDS (refrac- these techniques have several drawbacks, the most tory anemia with ring sideroblasts). Nevertheless, important being that cytogenetic analyses are limit- ringed sideroblasts may be found in other MDS sub- ed to metaphases.6 Fluorescent in situ hybridization groups, although in a lower proportion.14 (FISH) method, using chromosome-specific DNA probes, allows the detection of chromosomal abnor- Dysgranulopoiesis malities in interphase nuclei and metaphase chro- This is easily recognized in peripheral blood, with mosomes.7 FISH has been found to be particularly the most common findings being hypogranulation useful to determine the number of cells with a specific and hyposegmentation (i.e., Pelger-Huët-like anom- chromosomal abnormality and identify the origin of aly). In fact, a very good correlation between the aberrant or marker chromosomes.6-9 An additional degree of hypolobulation and/or hypogranulation in problem is the identification of the cell lineage bear- peripheral blood and that observed in bone marrow ing cytogenetic abnormalities. Combined immuno- has been found.15 Abnormal chromatin clumping is phenotyping and FISH techniques make possible to another morphological feature seen in MDS; it may identify the nature of the cell with chromosomal be associated with granulocytic hyperplasia in bone 9,10 aberrations and the number of lineage involved. marrow and leukocytosis. Granulocytes with a For all these reasons, conventional cytogenetic analy- nuclear hole (i.e., ring-shaped nuclei) may be pre- sis should be completed (but no replaced) in most sent. Persistent associated basophilia of the rim and cases by FISH and, occasionally, by combined FISH excess of azurophilic granulation or granules larger and immunophenotypic or cytochemistry analyses. than usual can also be found. Nuclear sticks can be Diagnosis seen particularly in cases of secondary MDS or ther- apy-related MDS.4 The diagnosis of MDS is essentially morphological and is based on the presence of dysplastic features in Dysmegakaryocytopoiesis peripheral blood and bone marrow (Table 1). Bone The most common dysplastic features in the mega- marrow dyspoiesis results in cytopenia probably due karyocytic lineage are the presence of micromega- to an increased apoptosis of the bone marrow dyshe- karyocytes, large mononuclear forms and megakary- 11 mopoietic cells. ocytes with multiple small nuclei. Megakaryocytes The most reliable features of MDS include the pres- with non-lobulated nucleus (i.e., large mononuclear ence of micromegakaryocytes in bone marrow, tri- forms) are typical of the 5q- syndrome. Platelets are lineage dysplasia, a high percentage of blasts cells, or also affected by the dyspoietic changes with a high cytogenetic abnormalities. Nutritional deficiencies, number of giant or degranulated platelets. drug-induced dyshematopoiesis, alcoholism, anemia of chronic diseases, and metabolic disturbances accompanying chronic renal and liver diseases should be excluded before accepting the diagnosis of MDS.2 Dyshemopoietic morphological features Table 1. Morphological features of MDS. (Figures 1-12) Dyserythropoiesis PB BM This is characterized by the presence of anisocyto- sis, prominent macrocytosis, basophilic stippling, Dyserythropoiesis Anisocytosis Multinuclearity poikilocytosis, nucleated red blood cells, and acan- Poikylocytosis Abnormal nuclear shape thocytosis in peripheral blood. In bone marrow, Macrocytosis Megaloblastoid changes dyserythropietic changes include megaloblastosis Basophilic stippling Cytoplasmic abnormalities and nuclear abnormalities (e.g., multinuclearity, Nucleated RBC Ringed sideroblasts nuclear fragments, bizarre nuclear shapes, abnormal mitosis, internuclear bridging12 and abnormal dense Dysgranulopoiesis* Pelger-Huët-like anomaly Clumping of chromatin chromatin); cytoplasmic abnormalities may include Degranulation Larger granules Howell-Jolly bodies, intense cytoplasmic basophilia, Hypersegmentation Ring-shaped nuclei defects in hemoglobinization and ghosted cytoplasm Nuclear sticks (erythroblasts with areas of unstained cytoplasm). Döhle bodies These erythroblasts with ghosted cytoplasm coexist- ing with coarse basophilic stippling (May-Grünwald- Dysthrombopoiesis Giemsa stain) seem to represent ringed siderob- Large platelets Micromegakaryocytes 13 Hypogranulation Large mononuclear forms lasts. Iron staining in bone marrow may show the Hypergranulation Multiple small nuclei presence of ringed sideroblasts that are the result of iron deposition in the mitochondria. This abnormal- *All dysgranulopoietic features can be
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