Cellular Classification
Clinical Classification

The myelodysplastic syndromes (MDS) are classified according to features of cellular morphology, etiology, and clinical presentation. The morphological classification of the MDS is largely based on the percent of myeloblasts in the bone marrow and blood, the type and degree of myeloid dysplasia, and the presence of ringed sideroblasts.[1] The clinical classification of the MDS depends upon whether there is an identifiable etiology and whether the MDS has been treated previously.

Work on the French-American-British (FAB) classification scheme for the MDS began in the late 1970s under the direction of the French-American-British Cooperative Group (see table below). The version published in 1982 was the first diagnostic classification scheme to clearly and reproducibly distinguish MDS from acute myelogenous leukemia (AML).[1] According to the FAB scheme, the percentage of bone marrow blasts required for the diagnosis of MDS ranges from less than 5% to as much as 29%. The FAB scheme is still frequently used by clinicians to categorize the MDS.

Several weaknesses were identified in the FAB classification of MDS. The inclusion of chronic myelomonocytic leukemia (CMML) was problematic; CMML is a disease that combines features of both MDS and chronic myeloproliferative disorders.[2] In addition, the FAB classification did not take cytogenetic findings into account. For example, the cytogenetically defined MDS subtype del(5q) represents a distinct clinical entity.[3]

In 1997, under the auspices of the World Health Organization (WHO), a working group of pathologists and clinicians from around the world agreed to a new cellular classification scheme for hematopoietic and lymphoid malignancies.[4] Significant changes to the FAB classification of these malignancies were made. For the classification of MDS, the new WHO classification lowered the threshold to 20% for the number of myeloblasts required to make the diagnosis of AML.[5] This arbitrary threshold value for blast percentage eliminated the cellular type, refractory anemia with excess blasts in transformation (RAEB-t), found in the FAB classification scheme. In the WHO cellular classification scheme, RAEB-t is no longer considered a distinct clinicopathologic entity; instead, RAEB-t is included within the broader category, AML with multilineage dysplasia, and identified as AML with multilineage dysplasia following a myelodysplastic syndrome.[6] (Refer to the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)

The elimination of RAEB-t from the WHO cellular classification scheme met some resistance. Some have argued that the biology of RAEB-t is distinct from AML and should be retained as a diagnostic category of MDS.[7,8] Others have emphasized the similar prognoses and responses to treatment for RAEB-t and AML with trilineage dysplasia.[9,10] The diagnosis of AML, which is based upon a threshold of 20% bone marrow or peripheral blood myeloblasts, does not represent a therapeutic mandate. The decision to treat must include other factors, such as patient age, prior history of MDS, clinical findings, disease progression, and most importantly, patient preference, in addition to the blast count. The same factors influence treatment options for patients with 30% or more myeloblasts in the blood or marrow. (Refer to the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)

The addition of refractory cytopenia with multilineage dysplasia (RCMD), myelodysplastic syndrome, unclassifiable (MDS-U), and the myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality completes the WHO cellular classification scheme for MDS. Finally, the WHO classification of MDS removed CMML from MDS and placed it in a new category, myelodysplastic syndromes and myeloproliferative diseases (MDS and MPD).[11] (Refer to the PDQ summary on Myelodysplastic and Myeloproliferative Diseases Treatment for more information.)

MDS cellular types and subtypes in either cellular classification scheme have different degrees of disordered hematopoiesis, frequencies of transformation to acute leukemia, and prognoses. All WHO cellular types and subtypes and the FAB cellular type, RAEB-t, are described in detail below.

Refractory anemia (RA)

In patients with RA, the myeloid and megakaryocytic series in the bone marrow appear normal, but megaloblastoid erythroid hyperplasia is present. Dysplasia is usually minimal. Marrow blasts are less than 5%, and no peripheral blasts are present. Macrocytic anemia with reticulocytopenia is present in the blood. Transformation to acute leukemia is rare, and median survival varies from 2 years to 5 years in most series. RA accounts for 20% to 30% of all patients with MDS.

Refractory anemia with ringed sideroblasts (RARS)

In patients with RARS, the blood and marrow are identical to those in patients with RA, except that at least 15% of marrow red cell precursors are ringed sideroblasts. Approximately 10% to 12% of patients present with this type, and prognosis is identical to that of RA. Approximately 1% to 2% of RARS evolve to AML.

Refractory anemia with excess blasts (RAEB)

In patients with RAEB, there is significant evidence of disordered myelopoiesis and megakaryocytopoiesis in addition to abnormal erythropoiesis. Because of differences in prognosis related to progression to a frank AML, this cellular classification is comprised of two categories, refractory anemia with excess blasts-1 (RAEB-1) and refractory anemia with excess blasts-2 (RAEB-2). Combined, the two categories account for approximately 40% of all patients with MDS. RAEB-1 is characterized by 5% to 9% blasts in the bone marrow and less than 5% blasts in the blood. Approximately 25% of cases of RAEB-1 progress to AML. Median survival is approximately 18 months. RAEB-2 is characterized by 10% to 19% blasts in the bone marrow. Approximately 33% of cases of RAEB-2 progress to AML. Median survival for RAEB-2 is approximately 10 months.

Refractory anemia with excess blasts in transformation (RAEB-t)

In the FAB classification, RAEB-t represents a panmyelosis in which 20% to 30% of marrow cells are blasts, and more than 5% blasts are seen in the blood. Auer rods may be seen. Sixty percent to 75% of patients develop overt acute leukemia, and median survival is 6 months or less. Approximately 25% of patients present with RAEB-t. In the WHO classification, RAEB-t is not a distinct clinical entity; rather, it is included within the broader category, AML with multilineage dysplasia, and identified as AML with multilineage dysplasia following a myelodysplastic syndrome.[6] (Refer to the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)

Refractory cytopenia with multilineage dysplasia (RCMD)

In patients with RCMD, bicytopenia or pancytopenia is present. In addition, dysplastic changes are present in 10% or more of the cells in two or more myeloid cell lines. There are less than 1% blasts in the blood and less than 5% blasts in the bone marrow. Auer rods are not present. Monocytes in the blood are less than 1 × 10⁹. RCMD accounts for approximately 24% of cases of MDS. The frequency of evolution to acute leukemia is 11%. The overall median survival is 33 months. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) represents another category of RMDS. In RCMD-RS, features of RCMD are present, and more than 15% of erythroid precursors in the bone marrow are ringed sideroblasts. RCMD-RS accounts for approximately 15% of cases of MDS. Survival in RCMD-RS is similar to that in primary RCMD.

Unclassifiable myelodysplastic syndrome (MDS-U)

The cellular subtype, MDS-U, lacks findings appropriate for classification as RA, RARS, RCMD or RAEB. Blasts in the blood and bone marrow are not increased.

Myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality

This MDS cellular subtype, the 5q- syndrome, is associated with an isolated del(5q) cytogenetic abnormality. Blasts in both blood and bone marrow are less than 5%. This subtype is associated with a long survival. Karyotypic evolution is uncommon. Additional cytogenetic abnormalities may be associated with a more aggressive MDS cellular subtype or may evolve to acute myeloid leukemia.

The clinical classification of MDS is used to determine disease prognosis and treatment strategy, and to define entry requirements for many MDS clinical trials.

De novo myelodysplastic syndrome

Most MDS cases occur de novo with no known cause.

Secondary myelodysplastic syndrome

The risk of developing MDS may be increased by exposure to a variety of agents including:[12-14]

• Tobacco smoke.
• Ionizing radiation.
• Organic chemicals (e.g., benzene, toluene, xylene, and chloramphenicol).
• Heavy metals.
• Herbicides.
• Pesticides.
• Fertilizers.
• Stone and cereal dusts.
• Exhaust gases.
• Nitro-organic explosives.
• Petroleum and diesel derivatives.
• Alkylating agents.
• Marrow-damaging agents used in cancer chemotherapy.

Patients with documented exposure to such agents are referred to as having secondary MDS or treatment-related MDS and constitute as many as 30% of all patients with MDS. Secondary MDS typically has a poorer prognosis than does de novo MDS.

Previously treated myelodysplastic syndrome

Previously treated MDS are de novo or secondary cases of MDS that have progressed despite previous treatment and, in many cases, are receiving additional treatment.

References

1. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982.  [PUBMED Abstract]
   
   
2. Vardiman JW, Pierre R, Bain B, et al.: Chronic myelomonocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 49-52. 
   
   
3. Mathew P, Tefferi A, Dewald GW, et al.: The 5q- syndrome: a single-institution study of 43 consecutive patients. Blood 81 (4): 1040-5, 1993.  [PUBMED Abstract]
   
   
4. Harris NL, Jaffe ES, Diebold J, et al.: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 17 (12): 3835-49, 1999.  [PUBMED Abstract]
   
   
5. Brunning RD, Matute E, Harris NL, et al.: Acute myeloid leukemia with multilineage dysplasia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 88-9. 
   
   
6. Brunning RD, Matutes E, Harrris NL, et al.: Acute myeloid leukemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 77-80. 
   
   
7. Huh YO, Jilani I, Estey E, et al.: More cell death in refractory anemia with excess blasts in transformation than in acute myeloid leukemia. Leukemia 16 (11): 2249-52, 2002.  [PUBMED Abstract]
   
   
8. Greenberg P, Anderson J, de Witte T, et al.: Problematic WHO reclassification of myelodysplastic syndromes. Members of the International MDS Study Group. J Clin Oncol 18 (19): 3447-52, 2000.  [PUBMED Abstract]
   
   
9. Estey E, Thall P, Beran M, et al.: Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90 (8): 2969-77, 1997.  [PUBMED Abstract]
   
   
10. Bernstein SH, Brunetto VL, Davey FR, et al.: Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: a Cancer and Leukemia Group B Study. J Clin Oncol 14 (9): 2486-94, 1996.  [PUBMED Abstract]
    
    
11. Vardiman JW: Myelodysplastic/myeloproliferative diseases: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 47-8. 
    
    
12. West RR, Stafford DA, Farrow A, et al.: Occupational and environmental exposures and myelodysplasia: a case-control study. Leuk Res 19 (2): 127-39, 1995.  [PUBMED Abstract]
    
    
13. Nisse C, Lorthois C, Dorp V, et al.: Exposure to occupational and environmental factors in myelodysplastic syndromes. Preliminary results of a case-control study. Leukemia 9 (4): 693-9, 1995.  [PUBMED Abstract]
    
    
14. Rigolin GM, Cuneo A, Roberti MG, et al.: Exposure to myelotoxic agents and myelodysplasia: case-control study and correlation with clinicobiological findings. Br J Haematol 103 (1): 189-97, 1998.  [PUBMED Abstract]
    
    

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