متلازمة خلل التنسج النقوي

Myelodysplastic syndrome
الأسماء الأخرى	Preleukemia, myelodysplasia
Blood smear from a person with myelodysplastic syndrome. A hypogranular neutrophil with a pseudo-Pelger-Huet nucleus is shown. There are also abnormally shaped red blood cells, in part related to removal of the spleen.
التخصص	Haematology, oncology
الأعراض	None, feeling tired, shortness of breath, easy bleeding, frequent infections
البداية المعتادة	~ 70 years old
عوامل الخطر	Previous chemotherapy, radiation therapy, certain chemicals such as tobacco smoke, pesticides, and benzene, exposure to mercury or lead
الطريقة التشخيصية	Blood test, bone marrow biopsy
العلاج	Supportive care, medications, stem cell transplantation
الدواء	Lenalidomide, antithymocyte globulin, azacitidine
Prognosis	Typical survival time 2.5 years

متلازمة خلل التنسج النقوي (بالإنجليزية Myelodysplastic Syndrome) هو عبارة عن مرض من أمراض الدم، ويتصف المرض بأنه مجموعة من الأعراض التي تؤدي إلى هبوط كل من كريات الدم الحمراء والبيضاء والصفائح الدموية. تحدث الإصابة غالبا عند البالغين ونادرا حدوثها عند الأطفال أو تحت سن الخمسين، ومعدل عمر المريض عند الإصابة مابين 65-75 عاما. من العلامات المميزة لهذا المرض النشاط العالي لنخاع العظم لمحاولة تعويض النقص الحاصل في مكونات الدم. من مضاعفات المرض حدوث ابيضاض الدم النقوي الحاد ولكن هذا النوع من المضاعفات يحدث بنسبة ضئيلة.

Risk factors include previous chemotherapy or radiation therapy, exposure to certain chemicals such as tobacco smoke, pesticides, and benzene, and exposure to heavy metals such as mercury or lead. Problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts. Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood. The types of MDS are based on specific changes in the blood cells and bone marrow.

Treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. Certain people can be cured with chemotherapy followed by a stem-cell transplant from a donor.

About seven per 100,000 people are affected with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook 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. The typical survival time following diagnosis is 2.5 years. The conditions were first recognized in the early 1900s. The current name came into use in 1976.

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 العلامات والأعراض

Enlarged spleen due to myelodysplastic syndrome; CT scan coronal section, spleen in red, left kidney in green

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
• Neutropenia (low neutrophil count) – increased susceptibility to infection
• Thrombocytopenia (low platelet count) – increased susceptibility to bleeding and ecchymosis (bruising), as well as subcutaneous hemorrhaging resulting in purpura or petechiae

Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:

• 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 acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. However, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment. Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important factor in the person's medical history. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process.

 الأسباب

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). Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.

 Pathophysiology

MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy (therapy associated MDS, t-MDS). MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation. Other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into MDS.

MDS is thought to arise from mutations in the multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB), then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell.

While recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion, MDS patients rarely suffer injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to iron overload.

 الوراثة

The recognition of epigenetic changes in DNA structure in MDS has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine) of three (the third is lenalidomide) commercially available medications approved by the U.S. Food and Drug Administration to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia.

Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS.

 5q- syndrome

Since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, lenalidomide, a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome, and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion.

 Splicing factor mutations

Mutations in splicing factors have been found in 40–80% of cases with myelodysplastic syndrome, particularly in those with ringed sideroblasts.

 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, and confer a worsened prognosis in low-risk MDS. 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.

 GATA2 deficiency

GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations, in one of the two GATA2 genes. These autosomal dominant mutations cause a reduction, in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymph-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations is MDS that often progresses to acute myelocytic leukemia or less commonly chronic myelomonocytic leukemia.

 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.

 التشخيص

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.

A typical diagnostic investigation includes:

• Full blood count and examination of 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.
• Bone marrow examination by a hematopathologist: This is required to establish the diagnosis, since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia.
• Cytogenetics or chromosomal studies: This is ideally performed on the bone marrow aspirate. Conventional cytogenetics require a fresh specimen, since live cells are induced to enter metaphase to 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.
• Virtual karyotyping can be done for MDS, which uses computational tools to construct the karyogram from disrupted DNA. Virtual karyotyping does not require cell culture and has dramatically higher resolution than conventional cytogenetics, but cannot detect balanced translocations.
• Flow cytometry is helpful to identify blasts, abnormal myeloid maturation, and establish the presence of any lymphoproliferative disorder in the marrow.
• Testing for copper deficiency should not be overlooked, as it can morphologically resemble MDS in bone-marrow biopsies.

The features generally used to define a 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:
  1. Hypersegmented neutrophils (also seen in vit B₁₂/folate deficiency)
  2. Hyposegmented neutrophils (pseudo Pelger-Huet)
  3. Hypogranular neutrophils or pseudo Chediak-Higashi (large azurophilic granules)
  4. 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)
  5. Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
• Erythroid series:
  1. Binucleated erythroid precursors and karyorrhexis
  2. Erythroid nuclear budding
  3. Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
  4. Loss of e-cadherin in normoblasts is a sign of aberrancy.
  5. Periodic acid-Schiff (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)
  6. Ringed sideroblasts (10 or more iron granules encircling one-third or more of the nucleus) seen on 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):
  1. Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
  2. Hypersegmented (osteoclastic appearing) megakaryocytes
  3. Ballooning of the platelets (seen with interference contrast microscopy)

Other stains can help in special cases (PAS and napthol 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 atypical localization of immature precursors, which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles. This morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. Also, topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.

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 Differential diagnosis

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also, congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) have been recognized, Pearson's syndrome (sideroblastic anemia), Jordans anomaly – vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome, aminolevulinic acid enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines; however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity, and other poisons.

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).

 التبويب

 التبويب الفرنسي-الأمريكي-البريطاني (FAB)

In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976, and revised in 1982. It was used by pathologists and clinicians for almost 20 years. Cases were classified into five categories:

ICD-O	الاسم	الوصف
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.)

The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of 3–5 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 1 year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.

 منظمة الصحة العالمية

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. Most recently, the WHO has evolved a new classification scheme (2008) 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.

The list of dysplastic syndromes under the new WHO system includes:

النظام القديم	النظام الجديد
Refractory anemia (RA)	Refractory cytopenia with unilineage dysplasia (Refractory anemia, Refractory neutropenia, and Refractory thrombocytopenia)
Refractory anemia with ringed sideroblasts (RARS)	Refractory anemia with ring sideroblasts (RARS) Refractory anemia with ring sideroblasts – thrombocytosis (RARS-t) (provisional entity) which is in essence a myelodysplastic/myeloproliferative disorder and usually has 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 (RAEB)	Refractory anemias 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.
Refractory anemia with excess blasts in transformation (RAEB-T)	This category was eliminated; such patients are now considered to have acute 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.
Chronic myelomonocytic leukemia (CMML)	CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes.
	Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)
	Refractory cytopenia of childhood (dysplasia in childhood) – New in WHO classification 2008

Note : not all physicians concur with this reclassification, because the underlying pathology of this diseases is not well understood.

 انظر أيضاً

• Chloroma
• Myeloproliferative syndrome
• Clonal hematopoiesis

 وصلات خارجية

• متلازمة خلل التنسج النقوي at Curlie
• Fenaux, P., et al. (2014). [1] Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 25(suppl 3): iii57-iii69.

Classification	V · T · D ICD-10: D46. ICD-9-CM: 238.7 MeSH: D009190 DiseasesDB: 8604
External resources	eMedicine: med/2695 ped/1527 Patient UK: متلازمة خلل التنسج النقوي Orphanet: 52688