Myelodysplastic syndrome
Myelodysplastic syndrome | |
---|---|
Other names | Preleukemia, myelodysplasia antithymocyte globulin, azacitidine[3] |
Prognosis | Typical survival time 2.5 years[3] |
A myelodysplastic syndrome (MDS) is one of a group of
Risk factors include previous
Treatments may include
About seven per 100,000 people are affected by MDS; about four per 100,000 people newly acquire the condition each year.[4] The typical age of onset is 70 years.[4] The prognosis depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells.[3] The average survival time following diagnosis is 2.5 years.[4] MDS was first recognized in the early 1900s;[5] it came to be called myelodysplastic syndrome in 1976.[5]
Signs and symptoms
Signs and symptoms are nonspecific and generally related to the blood cytopenias:
- Anemia (low RBC count or reduced hemoglobin) – chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain[6]
- Neutropenia (low neutrophil count) – increased susceptibility to infection[7]
Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:[10]
- Neutropenia, anemia, and thrombocytopenia
- Splenomegaly or rarely hepatomegaly
- Abnormal granules in cells, abnormal nuclear shape and size
- Chromosome abnormality, including chromosomal translocations and abnormal chromosome number
Although some risk exists for developing
Cause
Some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Xylene and benzene exposures have been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bombs in Hiroshima and Nagasaki during World War II).[12] Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.[13]
Pathophysiology
MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as
MDS is thought to arise from
Although recognition of leukemic transformation was historically important (see
Genetics
The recognition of
Some authors have proposed that the loss of
DNA damage
5q- syndrome
Since at least 1974, the deletion in the long arm of
Splicing factor mutations
Mutations in splicing factors have been found in 40–80% of people with MDS, with a higher incidence of mutations detected in people who have more
IDH1 and IDH2 mutations
Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in 10–20% of patients with myelodysplastic syndrome,[25] and confer a worsened prognosis in low-risk MDS.[26] Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state.[26]
GATA2 deficiency
GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic
Transient myeloproliferative disease
Transient myeloproliferative disease is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia.[29][27][30]
Diagnosis
The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from anemia, thrombocytopenia, and leukopenia is important.[citation needed]
A typical diagnostic investigation includes:
- blood film: The blood film morphology can provide clues about hemolytic anemia, clumping of the platelets leading to spurious thrombocytopenia, or leukemia.
- Blood tests to eliminate other common causes of cytopenias such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, kidney failure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy: Age-appropriate cancer screening should be considered for all anemic patients.
- hematopathologist: This is required to establish the diagnosis since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia.[31]
- bone marrow aspirate. Conventional cytogenetics require a fresh specimen since live cells are induced to enter metaphaseto allow chromosomes to be seen.
- Interphase fluorescence in situ hybridization testing, usually ordered together with conventional cytogenetic testing, offers rapid detection of several chromosome abnormalities associated with MDS, including del 5q, −7, +8, and del 20q.
- balanced translocations.
- lymphoproliferativedisorder in the marrow.
- Testing for copper deficiency should not be overlooked, as it can morphologically resemble MDS in bone-marrow biopsies.[33]
The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis, dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts.
Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
- Granulocytic series:
- Hypersegmented neutrophils (also seen in vit B12/folate deficiency)
- Hyposegmented neutrophils (pseudo Pelger-Huet)
- Hypogranular neutrophils or pseudo Chediak-Higashi (large azurophilic granules)
- Auer rods – automatically RAEB II (if blast count < 5% in the peripheral blood and < 10% in the bone marrow aspirate); also note Auer rods may be seen in mature neutrophils in AML with translocation t(8;21)
- Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
- Erythroid series:
- Binucleated erythroid precursors and karyorrhexis
- Erythroid nuclear budding
- Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
- Loss of normoblastsis a sign of aberrancy.
- PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin-fixed bone-marrow biopsy). Note: one can see PAS vacuolar positivity in L1 and L2 blasts (FAB classification; the L1 and L2 nomenclature is not used in the WHO classification)
- Perls' Prussian blue iron stain (>15% ringed sideroblasts when counted among red cell precursors for refractory anemia with ring sideroblasts)
- Megakaryocytic series (can be the most subjective):
- Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
- Hypersegmented (osteoclastic appearing) megakaryocytes
- Ballooning of the platelets (seen with interference contrast microscopy)
Other stains can help in special cases (PAS and naphthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.
On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may show
Differential diagnosis
Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores,
All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes, and platelets or their progenitor cells, megakaryocytes).[citation needed]
Classification
World Health Organization
In the late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, the WHO developed a new classification scheme that is based more on genetic findings, but morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related.[citation needed]
The list of dysplastic syndromes under the new WHO system includes:
Myelodysplastic syndrome | Description |
---|---|
Refractory cytopenia with unilineage dysplasia | Refractory anemia, Refractory thrombocytopenia .
|
Refractory anemia with ringed sideroblasts (RARS)
|
Thrombocytosis (RARS-t) (provisional entity) which is in essence a JAK2 mutation (janus kinase) – New WHO classification 2008
|
Refractory cytopenia with multilineage dysplasia (RCMD) | Includes the subset Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). RCMD includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. |
Refractory anemia with excess blasts I and II
|
RAEB was divided into RAEB-I (5–9% blasts) and RAEB-II (10–19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia.
|
5q- syndrome
|
Typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification. |
Myelodysplasia unclassifiable | Seen in those cases of megakaryocyte dysplasia with fibrosis and others. |
Refractory cytopenia of childhood (dysplasia in childhood) | – |
Note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood.
Myelodysplastic syndrome unclassified
The WHO has proposed a criterion for diagnosis and classification of MDS that may apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features:[citation needed]
- Rare cases with less than 5% blast will present with RAMD.
- Occasionally, cases of MDS present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to the single lineage. The terms refractory neutropenia and refractory thrombocytopenia have sometimes been used to describe these cases. A diagnosis of MDS in patients with neutropenia or thrombocytopenia without anemia should be made with caution.
- Patients with RA or RAEB occasionally present with thrombocytosisinstead of the usual cytopenia.
Management
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML.
The IPSS scoring
Agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS:
- Lenalidomide: Effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS[45]
- combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).[46]
Chemotherapy with the
Iron levels
Iron overload can develop in MDS as a result of the RBC
For patients requiring many RBC transfusions,
Prognosis
The outlook in MDS is variable, with about 30% of patients progressing to refractory AML. The median survival time varies from years to months, depending on type. Stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly.[50]
Indicators of a good prognosis: Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern
Indicators of a poor prognosis: Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section; completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern
Karyotype prognostic factors:
- Good: normal, -Y, del(5q), del(20q)
- Intermediate or variable: +8, other single or double anomalies
- Poor: complex (>3 chromosomal aberrations); chromosome 7 anomalies[51]
The IPSS is the most commonly used tool in MDS to predict long-term outcome.[52]
Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype.
The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of three to five years, although long-term remission is possible if a bone-marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than one year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated diseases. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997.[52] This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.
Genetic markers
Although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased the understanding of prognostic molecular factors for this disease. For example, in low-risk MDS, IDH1 and IDH2 mutations are associated with significantly worsened survival.[26]
Epidemiology
The exact number of people with MDS is not known because it can go undiagnosed and no tracking of the syndrome is mandated. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year.[53]
The typical age at diagnosis of MDS is between 60 and 75 years; a few people are younger than 50, and diagnoses are rare in children. Males are slightly more commonly affected than females.[citation needed]
History
Since the early 20th century, some people with acute myelogenous leukemia were begun to be recognized to have a preceding period of anemia and abnormal blood cell production. These conditions were lumped together with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al.[54] The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.[citation needed]
French-American-British (FAB) classification
In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This
ICD-O
|
Name | Description |
---|---|---|
M9980/3 | Refractory anemia (RA)
|
characterized by less than 5% primitive blood cells ( myeloblasts ) in the bone marrow and pathological abnormalities primarily seen in red cell precursors
|
M9982/3 | Refractory anemia with ring sideroblasts (RARS) | also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater of red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts" |
M9983/3 | Refractory anemia with excess blasts (RAEB)
|
characterized by 5–19% myeloblasts in the marrow |
M9984/3 | Refractory anemia with excess blasts in transformation (RAEB-T)
|
characterized by 5–19% myeloblasts in the marrow (>20% blasts is defined as acute myeloid leukemia) |
M9945/3 | Chronic myelomonocytic leukemia (CMML), not to be confused with chronic myelogenous leukemia or CML | characterized by less than 20% myeloblasts in the bone marrow and greater than 1*109/L monocytes (a type of white blood cell) circulating in the peripheral blood.
|
(A table comparing these is available from the Cleveland Clinic.[56])
People with MDS
- Michael Brecker, musician[57]
- President of Panama[58]
- Roald Dahl, author
- Nora Ephron
- Joe Farrell, musician
- Pat Hingle, actor[59]
- John Kirby, attorney
- Joe Morgan, baseball player
- Paul Motian, musician[60]
- James W. Nance
- Robin Roberts, newscaster
- Carl Sagan, astrophysicist[61]
- Susan Sontag, author[62]
- Fred Willard
- Nina Foch Actress
See also
- Chloroma– type of tumor made of leukemic cells
- Clonal hematopoiesis
- Myeloproliferative syndrome
References
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External links
- Myelodysplastic syndrome at Curlie
- Fenaux, P., et al. (2014). Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up † Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 25(suppl 3): iii57–iii69.