- What is Myelodysplastic Syndrome
- Historical Background of Myelodysplasia
- Classification of Myelodysplastic Syndromes
- International Prognosis Scoring System
- World Health Organization Classification
- Reclassification of Myelodysplastic Syndrome Subtypes
- New Subtypes of Myelodysplastic Syndromes
- Karyotypically Leukemic Myelodysplastic Syndrome Disorders
- Miscellaneous Myelodysplastic Syndrome Subtypes
What is Myelodysplastic Syndrome
Myelodysplastic syndrome (MDS) is a severe hematologic disease that belongs to the group of oncopathologies and is not amenable to therapy. At the heart of the ailment lies the disruption of the process of reproduction of blood cells: their development and division.
As a result of such anomalies, oncological structures are formed, and immature blasts are formed. Gradually, the number of normally functioning, mature cells in the body decreases. This syndrome is called “dormant leukemia” due to the accumulation of blast cells in the blood.
Historical Background of Myelodysplasia
The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective clonal hematopoiesis and a tendency for leukemia transformation. These diseases share a mono- to multilineage of peripheral cytopenia contrasted with normo- to hypercellularity in the bone marrow.
Various cytogenetic abnormalities resulting in neoplastic clonal proliferation, coupled with the hyperactivity of cellular destruction via an increase of clearance or apoptosis, play important roles in the pathogenesis of these syndromes.
Indeed, the paradoxic coexistence of abnormal “growth” and “death” characterizes MDS as one of the most difficult hematologic disorders to treat.
The concept of MDS can be traced back to the beginning of the 20th century. In 1907, Luzzatto used the term “pseudo-aplastic anemia” to describe a patient who demonstrated clinical features similar to aplastic anemia, but whose bone marrow showed erythroid hyperplasia.
In 1938, Rhoads and Barker analyzed 100 patients with anemia and defined their disease state as “refractory anemia” (RA), a disorder characterized by dyserythropoiesis. Similarly, Parkes-Veber reported on 3 patients with anemia who showed no signs of peripheral blood leukocytosis, but who eventually developed leukemia.
- FAB, French-American-British;
- MDS, myelodysplastic syndromes;
- MIC, Morphologic, Immunologic, and Cytogenetic;
- IPSS, International Prognosis Scoring System;
- WHO, World Health Organization
These and other cases were summarized by Hamilton-Paterson in 1949 and were defined as preleukemic anemia, thus recognizing the tendency of certain cell types to progress from RA to acute leukemia. In 1953, Block and colleagues described patients with hematopoietic dysplasia as preleukemic. Since then, multiple terms have been used to describe patients with dyshematopoiesis with a tendency for leukemia evolution. It was not until 1982 that Bennett and colleagues, of the French-American-British Work Group (FAB), devised a classification of MDS.
The FAB classification of MDS consists of 5 subtypes based on the clinical and morphologic features of the disease:
- RA with ringed sideroblasts (RARS);
- RA with excess blasts (RAEB);
- RA with excess blasts in transformation (RAEB-T);
- chronic myelomonocytic leukemia (CMML).
For more than 15 years, this classification system has served as a roadmap, guiding physicians toward the appropriate MDS diagnosis and affording a rough prognosis prediction.
Yet, in spite of its popularity, as advances in molecular biology, immunology, cytology, and genetics are increasingly being used in the diagnosis, subgrouping, staging, and prediction of prognosis for MDS, adjustments in the classification system have become necessary.
In 1988, the Morphologic, Immunologic, and Cytogenetic Study Group proposed a working classification for primary and therapy-related MDS (t-MDS) and introduced cytogenetic analysis to the diagnosis of MDS.
Greenberg and colleagues, in 1997, introduced an International Prognosis Scoring System (IPSS) following a review of 816 cases.
The system divides patients into different risk groups based on their clinical, morphologic and cytogenetic features, providing well-tested, more accurate prognostic value compared with the FAB system.
More recently, the World Health Organization (WHO) devised a new MDS classification system that differs significantly from the FAB system in a number of ways.
First, cytogenetic study has been identified as an important and independent technique in the diagnostic and prognostic evaluation of MDS.
Second, specific subtypes of MDS have been reclassified to better reflect their characteristics: CMML has been reclassified as part of the MDS/myeloproliferative syndromes (MPS) group, while refractory cytopenia with multilineage cytopenia (RCMD), unclassifiable MDS (u-MDS), and 5q- syndrome have been added as new subtypes of MDS.
Similarly, RAEB-T is now considered a leukemia rather than a subtype of MDS because its treatment and prognosis are similar to acute myeloid leukemia (AML).
As time goes on, further adjustments of the classification systems will likely occur, given the improved recognition of the pathophysiology, diagnosis, and treatment of MDS.
Classification of Myelodysplastic Syndromes
The French-American-British Classification System
The FAB classification for MDS consists of 5 subtypes, differentiated by clinical and morphologic features.
It has been widely tested and used as a set of diagnosis and prognosis guidelines for more than 15 years. The features used to define MDS in this system include dyspoiesis, dyserythropoiesis, dysgranulopoiesis, and dysmegakaryocytopoiesis, with the blast level in bone marrow and peripheral blood serving as a rough predictor for prognosis.
Other features, such as ringed sideroblasts, Auer rods, and monocytosis help to differentiate subtypes, and also confer prognostic values. Cytogenetic and immunophenotypic studies are not included in this classification of MDS.
The French-American-British Classification of Myelodysplastic Syndromes
- Refractory anemia.
One typical feature of RA is reticulocytopenia with less than 5% blasts in the bone marrow. About 30% of all patients with MDS fall in this group. Clinically, patients with RA present with mild-to-moderate isolated anemia, but most are asymptomatic. Other cell lines are less affected. Prognosis is favorable. RA is also common in all other subtypes of patients with MDS.
- Refractory anemia with ringed sideroblasts.
As the name implies, the finding of ringed sideroblasts in more than 15% of erythroblasts is the characteristic feature of this subtype. The ringed sideroblasts can be identified by Prussian blue-stained iron granules surrounding the nucleus of the erythroblasts. The clinical, morphologic features and prognosis of RARS are similar to RA. Leukemia transformation is rare.
- Refractory anemia with excess blast.
By definition, RAEB is characterized by the presence of 5% to 20% bone marrow myeloblasts and 1% to 5% peripheral blood blasts. Clinical symptoms of multilineage cytopenia are profound and the tendency to transform into leukemia is high. Most patients carry dual or triple cytogenetic abnormalities. Prognosis is unfavorable.
- Refractory anemia with excess blasts in transformation.
This is the subtype with the poorest prognosis: almost all patients transform into leukemia if they have not already died from other complications. Peripheral blood and bone marrow show greater than 5% and 20% myeloblasts, respectively. The presence of Auer rods in bone marrow cells is common, which also indicates a poor prognosis and predicts leukemia transformation.
- Chronic myelomonocytic leukemia.
Unlike other subtypes of MDS, CMML is characterized by monocytosis (> 1000/mcL), accompanied by other lineage cytopenia. The bone marrow in CMML resembles RAEB, with a blast cell level of less than 5%, but with monocytosis. Indeed, there has been a debate over whether CMML is a subtype of MDS or actually belongs to the group of MPS.
Limitations of the French-American-British system
Although it has proved useful, certain limitations of the FAB system have been noted. Patients with bone marrow dyshematopoiesis with multilineage cytopenia but bone marrow blasts of less than 5% fail to be categorized according to the FAB system. Accordingly, this subtype, along with others, was proposed to be part of an “unclassified” subtype of MDS.
Furthermore, the FAB system only carries a rough prognosis-predicting function, mainly depending on blast cell level and the presence of Auer rods, but not cytogenetic analysis.
Chromosomal aberration is now considered the most important factor associated with tumorigenesis, including MDS, and is directly linked to the prognosis. For example, using the FAB system, patients with RA and RARS have more favorable prognoses, but were found to have a high frequency of isolated chromosome 5q- or 20q-.
Other isolated or multiple chromosome abnormalities are frequently seen in patients with RAEB and RAEB-T, perhaps accounting for the poorer prognoses and the high risk for leukemia transformation. Patients with MDS with normal karyotypes tend to have better survival rates than do patients with chromosome aberrations. By contrast, the WHO-proposed subtypes of MDS such as 5q- syndrome in adults and monosomy 7 syndrome in children are diagnosed mainly by cytogenetic studies.
Other techniques, such as immunophenotyping and genetic analysis with techniques such as fluorescence in situ hybridization are useful in the diagnosis of many hematologic disorders. Finally, childhood MDS, t-MDS, and other secondary MDS have specific entities that are not well defined by the FAB system. Therefore, modification of this system was necessary.
International Prognosis Scoring System
Given the complexity of MDS subtypes and their diverse clinical pictures, the survival rate of patients with MDS ranges broadly, necessitating a clear prognosis evaluation. Factors determining prognosis include age, natural history of the disease, clinical features, blast cell level in the bone marrow and peripheral blood, cytogenetic abnormalities, and the number of lineage(s) of cytopenia.
Other pathologic findings, such as the presence of Auer rods, abnormal localization of immature precursors, and pseudo-Pelger-Huët anomalies also confer prognostic values.
Later investigations indicate that chromosomal abnormalities are prevalent in patients with MDS and directly link to the prognosis, suggesting the importance of cytogenetic study.
Over the years, new diagnostic and prognostic scoring systems have been developed as the methodology and understanding of this disorder have improved. Among the proposed systems, the IPSS has proved superior to other systems in prognosis prediction.
The IPSS was derived from a global analysis of 816 patients with MDS. Univariate analysis on these patients indicated that the most important prognostic factors are the percentage of bone marrow blasts present, cytogenetic abnormalities, and the number of lineage(s) of cytopenia.
It is from these factors that the scoring values are defined. Using multivariate analysis, patients with MDS were divided into 4 risk groups according to their score values, and patients’ survival rates and leukemia evolution periods were described. By using this dual method, IPSS achieved an objective prognosis prediction value comparable to those found in multiple studies; age stratification has improved its accuracy.
Limitations of the International Prognosis Scoring System. Although this system has proven prognostic value, the IPSS is most effective when combined with a more precise diagnostic classification. Indeed, some studies found that the IPSS is limited in predicting prognosis in patients with extended survival rates, as well as in some patients with RA.
Moreover, the prognosis of childhood MDS, t-MDS, or other secondary MDS subtypes that are clinically different from primary MDS, are not accurately described by IPSS. Although 1 study from the MD Anderson Cancer Center, in Houston, Texas, found that the IPSS is applicable to patients with secondary MDS, its prognostic value in these patients still requires further investigation.
World Health Organization Classification
The WHO classification of neoplastic diseases of the hematopoietic and lymphoid tissues was initially derived from a proposed system of the Society for Hematopathology and the European Association of Hematopathologists. The system divides hematologic disorders by lineage, as do other previous classifications, but with more emphasis on cytogenetic analysis and with reassignment of some controversial disorders.
There are 3 main differences between the WHO classification and the FAB system, which are summarized below.
Reclassification of Myelodysplastic Syndrome Subtypes
The RA, RARS, and RAEB subtypes are maintained as defined in the FAB system, while CMML and RAEB-T are reclassified into the MDS/MPS and AML groups, respectively. This change reflects the debate that has existed over the past few years regarding the assignment of CMML, which has proliferative features. Patients with CMML show RA with monocytosis, such that dysplasia and proliferation coexist in their bone marrow.
Some authors have suggested that a white blood cell count lower than 12,000/mcL should be considered MDS, while a white blood cell count higher than 12,000/mcL should be considered MPS given its more obvious proliferative features.
Instead, the WHO classification system placed CMML, along with juvenile myelomonocytic leukemia (JMML), and chronic myeloid leukemia (CML), into the independent MDS/MPS grouping.
RAEB-T was excluded completely from the WHO’s classification of MDS because of its high leukemia evolutionary tendency and its similar prognosis and treatment to AML. Thus, the blast level limit for MDS in the WHO classification system is 20% or less instead of the FAB’s limit of 30% or less.
New Subtypes of Myelodysplastic Syndromes
RCMD, 5q- syndrome, and u-MDS are accepted as new subtypes of MDS in the WHO classification system. Since a substantial percentage of patients with bone marrow dysplasia show more than 1 lineage of cytopenia and fail to fit into any of the MDS subtypes of FAB classification, a new subtype termed RCMD was adopted. Patients with RCMD present with significant neutropenia and thrombocytopenia with blast levels less than 1% and less than 5% in blood and bone marrow, respectively.
Chromosomal abnormalities in patients with RCMD are similar to those with RAEB. AML transformation tendency is higher in patients with RCMD than in patients with MDS who lack multilineage cytopenia.
Chromosome 5 abnormality, either in isolated form or in complexes with other chromosomal aberrations, is the most common abnormality in patients with MDS. One third of these patients have a chromosome 5 long arm deletion (q12-13q31-33, q12q23, and q23q32), resulting in the loss of function of several important genes such as those that code for the cytokines and kinases, granulocyte-macrophage colony-stimulating factor (GM-CSF), CSF-1 (M-CSF), interleukin (IL)-3, endothelial cell growth factor (ECGF), and c-fms (CSF-1 receptor).
In 1974, Van den Berghe and colleagues described 5q- syndrome in patients with an isolated chromosome 5q deletion, which was confirmed in subsequent studies as a unique disorder among MDS subtypes.
5q- syndrome is more common in women than in men, in a ratio of 2:1. Morphologically, patients with 5q- syndrome show refractory macrocytic anemia with oval macrocytes and monolobulated megakaryocytes. Bone marrow shows normal to increased cellularity in 75% of patients.
Although significant dyserythropoiesis, dysgranulopoiesis, and/or dysmegakaryocytopoiesis are seen in bone marrow, the blast level is usually less than 5%. Clinically, patients with 5q- syndrome present with transfusion-dependent RA, with the additional complication of iron overload. Thrombocytopenia and neutropenia are not commonly seen. Splenomegaly can occur in about 25% of the patients. The AML transformation rate is about 10% and the prognosis is favorable.
The WHO system defines patients with MDS features but who fail to fit into any subtype of MDS as u-MDS. It is important to differentiate this subtype from patients who are pre-AML, are post chemotherapy, or have other hematologic disorders with MDS characteristics because of the differences in survival, prognosis, and response to therapy.
Karyotypically Leukemic Myelodysplastic Syndrome Disorders
RAEB-T, t-MDS, and other MDS-like disorders with leukemic chromosome abnormalities are included in the AML group and should be treated as AML (acute myeloid leukemia) according to the WHO classification system. It has been shown that RAEB-T, the FAB subtype with the poorest prognosis, has a high tendency of AML evolution, as well as a progression, prognosis, and response to chemotherapy similar to AML. Once RAEB-T is moved to the AML category, the MDS blast limit in bone marrow should be below 20% and the prognosis of MDS will become more favorable.
Patients with leukemic karyotypes but with multilineage dysplasia clinically, pre-MDS, and/or t-MDS should be considered and treated as AML. Although these patients exhibit dysplastic features, the disease progression to leukemia is fast and the prognosis is poor. Bone marrow transplantation or t-MDS, although technically not included in the AML group by WHO, should be also treated as AML.
Miscellaneous Myelodysplastic Syndrome Subtypes
Childhood myelodysplastic syndromes. Primary MDS occur mainly in elderly patients, with a median age of 60-70 years, but they can also occur in children, from neonates to adolescents. The incidence of childhood MDS is 3% to 9% of all pediatric hematologic malignancies. Since the clinical features of adult and childhood MDS are similar, FAB criteria have been used to categorize childhood MDS. Most of the MDS subtypes in the FAB system have been reported in children.
However, RARS is rarely found in children, while its counterpart with proliferative features, known as JMML, is more commonly seen.
Monosomy 7 is the most frequent cytogenetic anomaly of childhood MDS, compared with chromosome 5q- in adults.
Approximately 20% of children with MDS have other chromosomal abnormalities; the disorders are most commonly associated with Down’s syndrome and Pearson syndrome.
The leukemic evolution and the prognosis of adult and childhood MDS are similar.
Hypocellular myelodysplastic syndromes. Although bone marrow features in MDS are mostly normal to hypercellular, about 5% to 15% of patients with MDS have hypocellular bone marrow morphology, demonstrating a cellularity of less than 30% in general and less than 20% if the patient’s age is 60 years or older. The clinical features are difficult to distinguish from those associated with aplastic anemia. Cytogenetic abnormalities, especially chromosome 7 deletion, favor the diagnosis of MDS. The disease progression and prognosis are similar to those with normo- or hypercellular MDS.
Myelodysplastic syndromes with myelofibrosis. Initially described by Sultan and colleagues, the incidence of myelofibrosis is about 17% to 47% in all types of MDS. The features of MDS with myelofibrosis include pancytopenia, minimal organomegaly, bone marrow hypercellularity with significant fibrosis, and multiple lineage dysplasia. Bone marrow blast count is less than 20%. Although a few studies have reported that therapy with steroids can achieve complete remission, the prognosis of MDS with myelofibrosis is not favorable.
Therapy-related myelodysplastic syndromes. One long-term complication seen in cancer patients who received chemotherapy or radiation therapy is t-MDS. In a typical scenario, patients with Hodgkin’s diseases treated with mechlorethamine, vincristine, procarbazine, and prednisone or radiation therapy have relative risk of 2.2 to 3.3 after 15 years of developing secondary malignancies, such as t-MDS.
More than 90% of patients with t-MDS carry abnormal karyotypes. Studies have showed a link between:
- t-MDS induced by alkylating agents and the deletion of chromosome 5 and/or chromosome 7;
- t-MDS induced by topoisomerase II inhibitors produce balance translocations between 11q23 and 21q22.
Overall, patients with t-MDS are more progressive, have multilineage dysplasia, and are difficult to treat because of the high resistance to therapy; thus, their prognosis is poor.
More than one third of patients with t-MDS cannot be classified according to the FAB system, since they exhibit hypocellularity, elevated blast counts, and fibrosis. Previous exposures to chemotherapy and/or radiation with cytogenetic aberrations are important indices for t-MDS diagnosis. No definitive treatment has been demonstrated for t-MDS, since patients invariably convert to AML within a short period. It appears that bone marrow transplantation is the only curative therapy for t-MDS, although the mortality rate remains high.