Myelodysplastic Syndrome (Myelodysplasia): overview and statistic of MDS cancer

Medically reviewed: 8, January 2024

Myelodysplastic Syndrome (Myelodysplasia): overview

Myelodysplastic syndrome (MDS) or Myelodysplasia is a severe blood disease that is part of the cancer group and does not respond to therapy. The problem of the disease is the damage of the blood cell formation process: their growth and splitting.

Because of these anomalies, malignant structures are formed, and immature blasts are produced. Gradually, the amount of normal, mature cells in the body reduces. This syndrome is called “hidden leukemia” because of the buildup of blast cells in the blood.

The IPSS is a system for estimating the prognosis of patients with myelodysplastic syndrome, a disorder with various subtypes and clinical manifestations that affect the survival outcomes. The prognosis assessment requires a comprehensive evaluation of several factors, such as age, disease course, clinical signs, blast cell count in the bone marrow and peripheral blood, cytogenetic alterations, and the number of cytopenic lineage(s).

Additionally, some morphologic features, such as the occurrence of Auer rods, aberrant distribution of immature cells, and pseudo-Pelger-Huët anomalies, have prognostic implications.

Subsequent studies reveal that patients with MDS frequently have chromosomal changes that are associated with the prognosis, highlighting the significance of cytogenetic analysis. As the techniques and knowledge of this condition have advanced, new systems for diagnosis and prognosis have been devised. Among the suggested systems, the IPSS has demonstrated better performance in prognosis estimation than other systems.

Historical Background of Myelodysplasia

The myelodysplastic syndromes (MDS) are a group of blood disorders characterized by ineffective clonal blood production and a tendency for leukemia change. These diseases share a single or multiple lineage of peripheral blood shortage contrasted with normal or increased cellularity in the bone marrow.

Various chromosome changes resulting in cancerous clonal growth, along with the increased activity of cell destruction via an increase of removal or cell death, play important roles in the cause of these syndromes.

Indeed, the contradictory coexistence of abnormal “growth” and “death” characterizes myelodysplastic syndrome as one of the most hard to treat blood disorders.

The idea of MDS can be traced back to the start of the 20th century. In 1907, Luzzatto used the term “pseudo-aplastic anemia” to describe a patient who showed clinical signs similar to aplastic anemia, but whose bone marrow showed red blood cell increase.

In 1938, Rhoads and Barker examined 100 patients with anemia and named their disease state as “refractory anemia” (RA), a disorder characterized by abnormal red blood cell production. Similarly, Parkes-Veber reported on 3 patients with anemia who showed no signs of increased white blood cells in the blood, but who later 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 named as preleukemic anemia, thus recognizing the tendency of some cell types to go from RA to acute leukemia. In 1953, Block and colleagues described patients with abnormal blood production as preleukemic. Since then, many terms have been used to describe patients with abnormal blood production with a tendency for leukemia change. It was not until 1982 that Bennett and colleagues, of the French-American-British Work Group (FAB), created a classification of myelodysplastic syndrome.

The FAB classification of MDS categorizes the disease into 5 subtypes based on its clinical and morphologic characteristics:

• RA;
• RA with ringed iron deposits (RARS);
• RA with too many blasts (RAEB);
• RA with too many blasts changing (RAEB-T);
• chronic white blood cell and monocyte disease (CMML).

For more than 15 years, this classification system has served as a guide, helping doctors toward the right MDS diagnosis and giving a rough prognosis prediction.

Yet, despite its popularity, as advances in molecular biology, immunology, cytology, and genetics are increasingly being used in the diagnosis, grouping, staging, and prediction of prognosis for myelodysplastic syndrome, changes in the classification system have become necessary.

In 1988, the Morphologic, Immunologic, and Cytogenetic Study Group suggested a working classification for primary and therapy-related MDS (t-MDS) and introduced chromosome analysis to the diagnosis of myelodysplastic syndrome.

Greenberg and colleagues, in 1997, introduced an International Prognosis Scoring System (IPSS) after a review of 816 cases.

The system separates patients into different danger groups based on their clinical, morphologic and cytogenetic features, giving well-proven, more precise prognostic value compared with the FAB system.

More lately, the World Health Organization (WHO) created a new MDS classification system that changes a lot from the FAB system in some ways.

First, cytogenetic study has been seen as an important and independent method in the diagnostic and prognostic assessment of MDS.

Second, specific subtypes of myelodysplastic syndrome have been changed to better show their features: CMML has been changed as part of the MDS/blood production syndromes (MPS) group, while low blood cell count with multiple lineage low blood cell count (RCMD), unknown MDS (u-MDS), and 5q- syndrome have been added as new subtypes of myelodysplastic syndrome.

Similarly, RAEB-T is now seen as a leukemia rather than a subtype of MDS because its treatment and prognosis are similar to acute blood cell cancer (AML).

As time passes, more changes of the classification systems will likely happen, given the improved understanding of the cause, diagnosis, and treatment of MDS.

Myelodysplastic Syndromes Classification

The French-American-British Classification System

The FAB classification for MDS has 5 subtypes, distinguished by clinical and morphologic features.

It has been widely used and tested as a set of diagnosis and prognosis guidelines for more than 15 years. The features used to define MDS in this system include abnormal blood production, red blood cell production, white blood cell production, and platelet production, with the blast level in bone marrow and peripheral blood serving as a rough predictor for prognosis.

Other features, such as iron deposits around the nucleus of red blood cells, Auer rods, and high monocyte count help to distinguish subtypes, and also give prognostic values. Chromosome and immune cell studies are not included in this classification of MDS.

The French-American-British Classification of Myelodysplastic Syndrome

Refractory anemia

One typical feature of RA is low reticulocyte count with less than 5% blasts in the bone marrow. About 30% of all patients with myelodysplastic syndrome are in this group. Clinically, patients with RA have mild-to-moderate anemia only, but most have no symptoms. Other cell lines are less affected. Prognosis is good. RA is also common in all other subtypes of patients with MDS.

Refractory anemia with ringed sideroblasts

As the name suggests, the presence of ringed sideroblasts in more than 15% of red blood cells is the characteristic feature of this subtype. The ringed sideroblasts can be seen by Prussian blue-stained iron particles around the nucleus of the red blood cells. The clinical, morphologic features and prognosis of RARS are similar to RA. Leukemia change is rare.

Refractory anemia with excess blast

By definition, RAEB is marked by the presence of 5% to 20% bone marrow myeloblasts and 1% to 5% peripheral blood blasts. Clinical signs of low blood cell count in multiple lineages are severe and the chance to change into leukemia is high. Most patients have two or three chromosome abnormalities. Prognosis is bad.

Refractory anemia with excess blasts in transformation

This is the subtype with the worst prognosis: almost all patients change into leukemia if they have not already died from other problems. Peripheral blood and bone marrow have more than 5% and 20% myeloblasts, respectively. The presence of Auer rods in bone marrow cells is common, which also shows a bad prognosis and predicts leukemia change.

Chronic myelomonocytic leukemia

Unlike other subtypes of myelodysplastic syndrome, CMML is marked by high monocyte count (> 1000/mcL), along with low blood cell count in other lineages. The bone marrow in CMML looks like RAEB, with a blast cell level of less than 5%, but with high monocyte count. Indeed, there has been a discussion 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 been helpful, some limitations of the FAB system have been noted. Patients with abnormal blood production in the bone marrow with low blood cell count in multiple lineages but bone marrow blasts of less than 5% are not classified according to the FAB system. Therefore, this subtype, along with others, was suggested to be part of an “unclassified” subtype of myelodysplastic syndrome.

Also, the FAB system only has a rough prognosis-predicting function, mainly depending on blast cell level and the presence of Auer rods, but not chromosome analysis.

Chromosome change is now seen as the most important factor linked to cancer, including MDS, and is directly linked to the prognosis. For example, using the FAB system, patients with RA and RARS have better prognoses, but were found to have a high rate of chromosome 5q- or 20q- alone.

Other single or multiple chromosome changes are often seen in patients with RAEB and RAEB-T, which may explain the worse prognoses and the high chance for leukemia change. Patients with myelodysplastic syndrome with normal chromosome patterns tend to have better survival outcomes than do patients with chromosome changes. On the other hand, the WHO-suggested subtypes of MDS such as 5q- syndrome in adults and one chromosome 7 missing syndrome in children are mainly diagnosed by chromosome studies.

Other methods, such as immune cell typing and genetic analysis with methods such as shining light in the cell and seeing the color are helpful in the diagnosis of many blood disorders. Lastly, childhood MDS, t-MDS, and other myelodysplastic syndrome caused by other factors have specific types that are not well described by the FAB system. So, change of this system was needed.

International Prognosis Scoring System

Given the complexity of MDS subtypes and their different clinical pictures, the survival rate of patients with myelodysplastic syndrome  varies widely, requiring a clear prognosis evaluation. Factors affecting prognosis include age, natural course of the disease, clinical signs, blast cell level in the bone marrow and peripheral blood, chromosome changes, and the number of lineage(s) of low blood cell count.

Other abnormal findings, such as the presence of Auer rods, wrong location of immature cells, and pseudo-Pelger-Huët anomalies also give prognostic values.

Later studies show that chromosome changes are common in patients with MDS and directly relate to the prognosis, indicating the importance of chromosome study.

Over the years, new diagnostic and prognostic scoring systems have been created as the methods and knowledge of this disorder have improved. Among the suggested systems, the IPSS has shown better than other systems in prognosis prediction.

The IPSS was based on a global analysis of 816 patients with MDS. Single analysis on these patients showed that the most important prognostic factors are the percentage of bone marrow blasts present, chromosome changes, and the number of lineage(s) of low blood cell count.

It is from these factors that the scoring values are made. Using multiple analysis, patients with MDS were split into 4 risk groups according to their score values, and patients’ survival rates and leukemia change periods were described. By using this two-way method, IPSS reached an objective prognosis prediction value similar to those found in multiple studies; age grouping 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 exact diagnostic classification. Indeed, some studies found that the IPSS is limited in predicting prognosis in patients with long survival rates, as well as in some patients with RA.

Also, the prognosis of childhood MDS, t-MDS, or other myelodysplastic syndrome caused by other factors that are clinically different from primary MDS, are not well described by IPSS. Although 1 study from the MD Anderson Cancer Center, in Houston, Texas, found that the IPSS is suitable for patients with secondary MDS, its prognostic value in these patients still needs more investigation.

World Health Organization Classification

The WHO classification of cancer diseases of the blood and lymph tissues was first based on a suggested system of the Society for Blood Disease Study and the European Group of Blood Disease Study. The system splits blood disorders by lineage, as do other previous classifications, but with more focus on chromosome analysis and with changing of some unclear 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 kept as defined in the FAB system, while CMML and RAEB-T are changed into the MDS/MPS and AML groups, respectively. This change shows the discussion that has happened over the past few years about the assignment of CMML, which has growth features. Patients with CMML show RA with high monocyte count, such that abnormal blood production and growth happen together in their bone marrow.

Some authors have suggested that a white blood cell count lower than 12,000/mcL should be seen as MDS, while a white blood cell count higher than 12,000/mcL should be seen as MPS given its more clear growth features.

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 large percentage of patients with bone marrow abnormality show more than 1 lineage of low blood cell count and do not fit into any of the myelodysplastic syndrome subtypes of FAB classification, a new subtype called RCMD was adopted. Patients with RCMD have low neutrophil and platelet counts with blast levels less than 1% and less than 5% in blood and bone marrow, respectively.

Chromosome changes in patients with RCMD are similar to those with RAEB. AML change tendency is higher in patients with RCMD than in patients with myelodysplastic syndromes who do not have multilineage low blood cell count.

Chromosome 5 change, either alone or with other chromosome changes, is the most common change in patients with MDS. One third of these patients have a chromosome 5 long arm loss (q12-13q31-33, q12q23, and q23q32), causing 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 a single chromosome 5q loss, which was confirmed in later 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 resistant large red blood cell anemia with oval large red blood cells and one-lobed platelet cells. Bone marrow shows normal to increased cellularity in 75% of patients.

Although significant abnormal red blood cell, white blood cell, and/or platelet cell production are seen in bone marrow, the blast level is usually less than 5%. Clinically, patients with 5q- syndrome have RA that needs transfusion, with the extra problem of iron overload. Low platelet and neutrophil counts are not often seen. Enlarged spleen can happen in about 25% of the patients. The AML change rate is about 10% and the prognosis is good.

The WHO system defines patients with MDS features but who do not fit into any subtype of myelodysplastic syndrome as u-MDS. It is important to separate this subtype from patients who are before AML, are after chemotherapy, or have other blood disorders with MDS features because of the differences in survival, prognosis, and response to therapy.

Myelodysplastic Syndrome Disorders with Leukemic Chromosome Changes

RAEB-T, t-MDS, and other MDS-like disorders with leukemic chromosome changes are included in the AML group and should be treated as AML (acute blood cell cancer) according to the WHO classification system. It has been shown that RAEB-T, the FAB subtype with the worst prognosis, has a high chance of AML change, as well as a progression, prognosis, and response to chemotherapy similar to AML. Once RAEB-T is moved to the AML group, the MDS blast limit in bone marrow should be below 20% and the prognosis of MDS will become more good.

Patients with leukemic chromosome patterns but with abnormal blood production in multiple lineages clinically, before MDS, and/or t-MDS should be seen and treated as AML. Although these patients show abnormal blood production features, the disease progression to leukemia is quick and the prognosis is bad. Bone marrow transplantation or t-MDS, although technically not in the AML group by WHO, should be also treated as AML.

Other Types of Myelodysplastic Syndrome

Childhood myelodysplastic syndromes. Primary MDS mainly happen in older patients, with a middle age of 60-70 years, but they can also happen in children, from newborns to teenagers. The rate of childhood myelodysplastic syndrome is 3% to 9% of all children’s blood cancers. Since the clinical signs of adult and childhood MDS are similar, FAB criteria have been used to group childhood MDS. Most of the myelodysplastic syndrome subtypes in the FAB system have been seen in children.

However, RARS is rarely seen in children, while its counterpart with growth features, known as JMML, is more often seen.

One chromosome 7 missing is the most common chromosome change of childhood MDS, compared with chromosome 5q- in adults.

About 20% of children with MDS have other chromosome changes; the disorders are most often linked to Down’s syndrome and Pearson syndrome.

The leukemia change and the prognosis of adult and childhood MDS are similar.

Low cell myelodysplastic syndrome

Although bone marrow signs in MDS are mostly normal to increased, about 5% to 15% of patients with myelodysplastic syndrome have low cell bone marrow shape, showing a cellularity of less than 30% in general and less than 20% if the patient’s age is 60 years or older. The clinical signs are hard to separate from those linked to aplastic anemia. Chromosome changes, especially chromosome 7 loss, support the diagnosis of MDS. The disease progression and prognosis are similar to those with normal or increased myelodysplastic syndrome.

Myelodysplastic syndrome with scar tissue

First described by Sultan and colleagues, the rate of scar tissue is about 17% to 47% in all types of MDS. The signs of MDS with scar tissue include low blood cell count, small organ enlargement, bone marrow increased cellularity with significant scar tissue, and multiple lineage abnormality. Bone marrow blast count is less than 20%. Although a few studies have reported that therapy with steroids can reach complete recovery, the prognosis of myelodysplastic syndrome with scar tissue is not good.

Therapy-caused myelodysplastic syndromes

One long-term problem seen in cancer patients who got chemotherapy or radiation therapy is t-MDS. In a typical case, 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 getting secondary cancers, such as t-MDS.

More than 90% of patients with t-MDS have abnormal chromosome patterns. Studies have showed a link between:

• t-MDS caused by alkylating agents and the loss of chromosome 5 and/or chromosome 7;
• t-MDS caused by topoisomerase II inhibitors make balance changes between 11q23 and 21q22.

Overall, patients with t-MDS are more advanced, have abnormal blood production in multiple lineages, and are hard to treat because of the high resistance to therapy; thus, their prognosis is bad.

More than one third of patients with t-MDS cannot be grouped according to the FAB system, since they show low cellularity, high blast counts, and scar tissue. Previous exposures to chemotherapy and/or radiation with chromosome changes are important signs for t-MDS diagnosis. No clear treatment has been shown for t-MDS, since patients always change to AML within a short time. It seems that bone marrow transplantation is the only healing therapy for t-MDS, although the death rate remains high.