What is myelodysplastic syndromes (MDS)?
Myelodysplastic syndromes, also known as MDS, are composed of various blood disorders that usually appear in older adults. MDS are clonal disorders affecting one or more blood cell lines, resulting in multiple types of cytopenia (a reduced blood cell count in different cell lines). Since myelodysplastic syndromes are composed of a heterogeneous group of diseases, the bone marrow can be either aplastic (not having many cells) or hypercellular (having too many cells). What is true in most MDS is that cells in the bone marrow share aberrant features and inadequate maturation, and this is why blood cell production becomes impaired.
Depending on the stage and type of disease, patients may experience different signs and symptoms and various cytogenic events. Genetics are variable, but the clinical presentation shares some features, especially anemia and thrombocytopenia. Thus, the workup is similar, and the differential diagnosis is sometimes difficult to make if we don’t have bone marrow biopsies.
This disease was initially considered an independent disease, and it was only included as a neoplastic disease after 2001. Back in 1976, the incidence was 1500 cases every year. Now, the myelodysplastic syndrome is diagnosed in up to 55,000 new patients every year. This rise is apparently due to improved diagnostic tests, an increase in the lifespan and the population of older adults.
86% of cases are diagnosed in older adults, the median age of diagnosis is 76 years old, and it is more common in males. However, there are cases of myelodysplastic syndrome in children and females, especially if they have risk factors.
Pathophysiology
Myelodysplastic syndromes result from clonal mutations in stem cells of the bone marrow. These mutations are caused either by genetic predisposition, exposure to certain substances, infections or radiation, or a combination of both. In some cases, myelodysplastic diseases are secondary to cancer treatment, especially in patients subject to radiation or alkylating agents.
The reduction of blood cell lines has various phases. In the early phase of the disease, it is caused by programmed cellular death. But as the myelodysplastic syndrome progresses, it may turn into leukemia, and the subsequent gene mutations cause a proliferation of aberrant cells in the bone marrow that takes the place of healthy cells and impairs their normal function.
Types of myelodysplastic syndrome
The subtypes of myelodysplastic syndrome, according to the classification by the World Health Organization updated in 2016 are as follows:
- Myelodysplastic syndrome with single-lineage dysplasia: Usually featuring one blood cytopenia or two.
- Myelodysplastic syndrome with multilineage dysplasia: It may have 2 or 3 cytopenias
- Myelodysplastic syndrome with ring sideroblasts: A type of anemia with a characteristic ring of granules.
- Myelodysplastic syndrome with isolated deletion of 5q: Caused by deletion of a chromosome arm. It features anemia and sometimes reduced platelet count.
- Myelodysplastic syndrome with excess blasts: A variable number of blood cytopenias with up to 20% blasts in peripheral blood.
- Unclassifiable myelodysplastic syndrome: Characteristics of MDS but not classifiable in any of the above groups.
Causes of Myelodysplastic syndrome
Myelodysplastic syndrome is an umbrella term, and its causes depend on each subtype or modality. There are three main genetic profiles in myelodysplastic syndrome. Patients can have a completely normal genetic profile, a slight and balanced chromosomal abnormality, or complex and mounting abnormalities consisting of 3 or more mutations.
When patients acquire a myelodysplastic syndrome as a result of aggressive cancer therapy, their chances of complex mutations are 50%. These patients have a worse prognosis and usually have more severe symptoms that may not respond successfully to treatment.
Myelodysplastic syndromes may also develop after the patient is exposed to certain chemicals, especially benzene, insecticides, fungicides, weed killers and other agricultural products. In some cases, viral infections can be an initial trigger in some patients. And even though heredity might be a risk factor because some familial incidences have been described, they are not the main cause of myelodysplastic syndromes.
Although rare, hereditary causes have been described, especially through mutations in the RUNX1 gene or the GATA2 gene. Another cause that has been described but not thoroughly investigated is a chronic immune stimulation in cases of treatment for autoimmune conditions, which is especially prevalent in genetically predisposed patients.
Signs and symptoms
In some cases, myelodysplastic syndromes are not clinically apparent for many years. The symptomatic myelodysplastic disease is sometimes preceded by sustained macrocytic anemia for many years and mild neutropenia or thrombocytopenia. The most prevalent signs and symptoms depend on the course of the disease, and are as follows:
1) Fatigue
Chronic fatigue is common in MDS. It results from anemia and increased metabolic rate due to chronic disease. Some patients have chronic heart failure and other cardiac causes of fatigue.
2) Skin rash
Hemorrhagic manifestations are common in MDS, and that include petechial spots, ecchymoses, and other symptoms.
3) Bleeding gums
It is another common hemorrhagic manifestation, and it is an alarm sign that there’s a significantly low platelet count.
4) Fever and infectious symptoms
There’s an increased risk of bacterial and fungal infections in patients with a reduced neutrophil count. Therefore, they usually display a type of low-grade fever that’s difficult to tract and other signs of infections such as dysuria and cough.
5) Enlarged organs
It is more common in patients with an overlapped myelomonocytic leukemia. These patients may have severe complications, such as spontaneous rupture of the spleen, and should be evaluated carefully.
Diagnosis of myelodysplastic syndromes
The diagnosis of the myelodysplastic syndrome should include a complete blood count and peripheral blood smears. When a myelodysplastic syndrome is suspected, a bone marrow study should be performed including cytogenetic studies to detect genetic mutations. All of these studies are useful to diagnose and stage the disease.
- Complete blood count: Usually has either anemia, thrombocytopenia or neutropenia in the early stage of the disease. In a late stage of the disease, it may show 2 or 3 deficient cell counts (bicytopenia or pancytopenia, respectively).
- Peripheral blood smear: Red blood cells in anemia are oval-shaped and dimorphic, which means there are 2 cell populations or more. In cases of neutropenia, the nucleus is either nonsegmented or segmented into 6 to 7 lobes. In platelets, there are usually hypergranular platelets or big fragments of megakaryocytes in the blood.
- Bone marrow studies: It is more commonly hypercellular with dysplastic changes, but it can be hypocellular with aplastic anemia, too. Bone marrow fibrosis is present and may be confused with myeloproliferative diseases. Erythroid cell precursors usually have ringed sideroblasts and may display two or more nuclei. White blood cell precursors are usually larger than usual (hyperplasia), with increased blasts.
- Cytogenetic studies: Identification of chromosome abnormalities include a 7q deletion, 5q deletion, trisomy 8, or monosomy 7
Other studies that might be useful, depending on each patient, include:
- Serum vitamin B-12 and folate in red blood cells
- Serum erythropoietin, especially before deciding to transfuse blood
- Thyroid-stimulating hormone
- HIV testing
Myelodysplastic syndrome prognosis
The myelodysplastic syndrome has various features depending on the patient and the severity of the disease. It is sometimes slow-progressing, but it can be very aggressive and cause many complications and cytopenias that increase the risk of mortality. In some cases, myelodysplastic syndrome turns into acute leukemia, and the patient needs urgent medical treatment to stabilize.
Prognosis can be calculated in patients depending on various factors, especially their hemoglobin levels, neutrophil and platelet count, the percentage of blasts in the bone marrow and the type of cytogenetic abnormalities. Patients with mild cytopenias, a normal karyotype and less than 10% blasts in the bone marrow have a 2-year survival rate or longer, and it is reduced as the severity of cytopenias and chromosomal abnormalities increase, and the percentage of blasts in the bone marrow is higher than 10%.
Treatment
Treatment for myelodysplastic syndrome depends on the blood count, the stage of the disease, the prognosis of the patient, and the expectations of the patients. The main therapeutic goal is to maintain appropriate levels of blood cell lines, which is why blood transfusions are commonly used as supportive therapy.
Therapy for myelodysplastic syndrome should be decided and monitored by a hematologist and may include aggressive measures such as stem cell transplantation and chemotherapy. This is usually performed in young patients and those with a higher risk.
Bone marrow stimulation with hematopoietic growth factors is recommended in patients with symptomatic anemia, and it is sometimes used along with iron supplementation. Drugs commonly used in myelodysplastic syndrome include topotecan or Hycamtin, lenalidomide, and hypomethylating agents. In some cases, it will be necessary to use immunosuppressive medications, when there’s an immune cause for pancytopenia.
References
Germing, U., Kobbe, G., Haas, R., & Gattermann, N. (2013). Myelodysplastic syndromes: diagnosis, prognosis, and treatment. Deutsches Ärzteblatt International, 110(46), 783.
Narayanan, S. (2017). Clinical, hematological, and cytogenetic profile of adult myelodysplastic syndrome in a tertiary care center. Journal of blood medicine, 8, 21.
Borjas-Gutiérrez, C., Domínguez-Cruz, M. D., & González-García, J. R. (2017). Cytogenetics of myelodysplastic syndromes and its impact as prognostic factor. Revista Médica del Instituto Mexicano del Seguro Social, 55(4), 481-489.
Germing, U., Schroeder, T., Kaivers, J., Kündgen, A., Kobbe, G., & Gattermann, N. (2019). Novel therapies in low-and high-risk myelodysplastic syndrome. Expert review of hematology, 12(10), 893-908.
Fuchs, O. (2019). Recent Developments in Myelodysplastic Syndromes.