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E. Hellström-Lindberg et al.
Scope and limitations of this review
While definitions and classifications of MDS until 2001 included chronic myelomonocytic leukemia, in the 2008 WHO classification this former MDS subtype was trans- ferred to a novel entity of mixed MDS/MPN.2 MDS and MDS/MPN share several pathogenic features but also dis- play important differences. Clinical trials that constitute the basis for therapeutic recommendations have often enrolled both MDS and MDS/MPN patients. In this review, we will focus on the current WHO diagnosis of MDS but discuss MDS/MPN when relevant for the con- text.
An area with relevance for MDS are variants of clonal hematopoiesis, defined as the presence of somatic myeloid mutations in the absence of diagnostic criteria for MDS or any other blood cancer.3 Clonal hematopoiesis will be discussed herein as a differential diagnosis of MDS.
The review focuses on adult MDS. However, knowl- edge about germline conditions potentially predisposing to MDS has vastly increased over these past years, leading baseline investigation of patients with potential MDS to include evaluation of potential germline conditions.4
Classification systems
Historical perspective including the French-American- British classification
Morphological depiction of the disease spectrum has been difficult due to the somewhat subjective nature of defining marrow dysplasia and the patients’ variable clin-
Table 1. Morphological manifestations of dysplasias (WHO 5.01 and 6.02).*
Dyserythropoiesis
Nuclear
Nuclear budding Internuclear bridging Karyorrhexis Multinuclearity Megaloblastoid changes
Cytoplasmic
Ring sideroblasts
Vacuolization
Periodic acid-Schiff positivity
Dysgranulopoiesis
Small or unusually large size
Nuclear hyposegmentation (pseudo-Pelger-Huet) Nuclear hypersegmentation
Decreased granules – agranularity Pseudo-Chédiak-Higashi granules
Döhle bodies
Auer rods
Barr bodies
Dysmegakaryopoiesis
Micromegakaryocytes Nuclear hypolobation Multinucleation
• Dysplasia may also be visible in peripheral blood films when dysplastic
cells are released from the bone marrow
ical courses. Since its initial description as ‘preleukemia’ in 1953 a multiplicity of terminologies have been used to describe this entity (Table 2). The French-American-British (FAB) morphological classification in 1982 helped to pro- vide a consensus approach to grouping patients.5 MDS emerged as a separate entity in the FAB classification, which recognized one group with an excess of blasts but not fulfilling the criteria for acute leukemia, and, as indi- cated above, another group with increased monocytosis termed chronic myelomonocytic leukemia, now charac- terized as an MDS/MPN.
World Health Organization classification
In 2001, the WHO proposed an alternative classification for MDS which was subsequently updated in 2008 and in 20161 and currently identifies six MDS entities based on marrow morphology and cytogenetics (Table 3).4,6 The denominator used for determining blast percentage was recently redefined to include all nucleated bone marrow cells as opposed to only non-erythroid cells. The division between MDS and AML is a continued area of debate. The clinical outcomes of MDS patients are not only relat- ed to the quantity of blasts, but also to a differing pace of disease related to distinctive biological and molecular fea- tures compared with those of de novo AML.1,7,8 The National Comprehensive Cancer Network (NCCN) prac- tice guidelines for MDS (also discussed by the WHO) allow for patients with 20% to 29% blasts AND a stable clinical course for at least 2 months to be considered as having either higher-risk MDS or AML.9 Individuals with FLT3 or NPM1 mutations are more likely to have AML than MDS.10 Future challenges will include methods to further stratify patients’ clinical courses more effectively, using biological features (e.g., mutations) as adjuncts to morphology.
Demographics and clinical presentation
The incidence of MDS was previously based on large regional registries. The Düsseldorf Registry described 216 patients diagnosed between 1996 and 2005, correspon- ding to an incidence of 4.15 cases per 100,000 popula-
Table 2. Chronology of the terminology for myelodysplastic syndromes.
Monocytosis
Term Year
Preleukemia 1953
Refractory anemia with ringed sideroblasts 1956 Refractory normoblastic anemia 1959 Smoldering acute leukemia 1963 Chronic erythremic myelosis 1969 Preleukemic syndrome 1973 Subacute myelomonocytic leukemia 1974 Chronic myelomonocytic leukemia 1974 Hypoplastic acute myelogenous leukemia 1975 Refractory anemia with excess myeloblasts 1976 Hematopoietic dysplasia 1978 Subacute myeloid leukemia 1979 Dysmyelopoietic syndrome 1980 Myelodysplastic syndromes 1982
Author
Block et al.
Bjorkman
Dacie et al.
Rheingold et al. Dameshek
Saarni and Linman Sexauer et al. Miescher and Farquet Beard et al.
Dreyfus
Linman and Bagby Cohen et al. Streuli et al. Bennett et al.
No specific morphology but persistent monocytosis ≥1 x 109/L with monocytes accounting for ≥10% of leukocytes
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haematologica | 2020; 105(7)