Approach

Diagnosis of MDS requires a detailed medical history and physical exam, and pathologic assessment of the peripheral blood and bone marrow.

MDS is a heterogeneous disease with varying presentations. Patients are often asymptomatic at presentation, and MDS is suspected following a routine blood test showing cytopenia (most commonly anemia).[47]​ Some patients present with symptoms related to cytopenia (e.g., fatigue, infections, bruising).

History and physical exam

Median age at diagnosis is 70-75 years, but the disease can occur at any age and should be considered in younger patients who have had prior exposure to chemotherapy or radiation therapy, or who have a congenital disorder (e.g., Fanconi syndrome, Bloom syndrome, Down syndrome).[9][10]​​​​​[15][16]​​​​​[18][26][27]​​​​[36][37][48][49]

History should include a careful assessment of prior exposure to chemotherapy and/or radiation therapy; prior infections or bleeding episodes; presence of comorbid conditions; family history of hematologic disorders; nutritional status (nutrient deficiencies); alcohol use; and exposure to toxic chemicals.[11][15]​​​​

A careful physical exam is required which may identify signs and symptoms related to cytopenias, such as pallor, fatigue, exercise intolerance, infections (usually bacterial), bruising, and bleeding (petechiae, purpura).

Autoimmune disorders (e.g., vasculitis, connective tissue disease, inflammatory arthritis) are reported in approximately 25% of MDS patients.[6]​​​​[7]​​[8]

Splenomegaly, hepatomegaly, and lymphadenopathy rarely occur in MDS. They can occur in chronic myelomonocytic leukemia (CMML), a myeloid neoplasm with pathologic and molecular features that overlap with MDS.[1]

Initial testing

The initial tests should be a complete blood count (CBC) with differential, and a peripheral smear. The CBC will show one or more cytopenias (most commonly anemia) that are sustained (e.g., >4 months).[11][15]​​[16]​​ Peripheral blood smear will show cytopenias and dysplasia (e.g., hypogranular and hypolobulated granulocytes [pseudo-Pelger-Huet anomaly]).[16] ​

Additional laboratory tests include reticulocyte count, red blood cell folate, serum vitamin B12, and iron studies (serum iron, total iron-binding capacity, ferritin).[11][15]​​[16]​​ These should be carried out to exclude other causes of cytopenias. Reticulocyte count is often low in MDS.[50]

Testing for viral infection (e.g., HIV; hepatitis B, C, and E; cytomegalovirus; parvovirus) can be carried out if there are risk factors for prior exposure.[11][15]​​[16]​​​ HIV infection can cause dysplastic bone marrow changes that are similar to those seen in MDS.[51]

[Figure caption and citation for the preceding image starts]: Blood film showing normal neutrophil (right) and dysplastic neutrophil with agranular cytoplasm and hypolobated nucleusImage used with permission from BMJ 1997;314:883 [Citation ends].com.bmj.content.model.Caption@1307bc51

Bone marrow evaluation

Bone marrow aspiration (with iron stain) and core biopsy are required for morphologic, cytogenetic, mutational, and flow cytometric analyses.[15][47]​​​​ These investigations confirm the diagnosis of MDS, and guide risk stratification and management.[15][47][52]​​​​

A diagnosis of MDS can be made in a patient with persistent cytopenia in the presence of one of the following three criteria: significant bone marrow dysplasia (≥10% in one or more of three major bone marrow lineages); blasts in the peripheral blood and/or bone marrow (<20%); or a clonal cytogenetic abnormality or somatic mutation.​[1][2][11]​ Biologic features are more important than a strict blast cutoff value.[15]

Patients with blasts ≥20% should be assessed for acute myeloid leukemia. See Acute myeloid leukemia.​

[Figure caption and citation for the preceding image starts]: Large mononuclear megakaryocyte in bone marrow of patient with MDS-del(5q)Image used with permission from BMJ 1997;314:883 [Citation ends].com.bmj.content.model.Caption@3edcc7a1

Genetic testing

Genetic testing for MDS-associated cytogenetic abnormalities (e.g., -5, del(5q), -7, del(7q), del(11q), del(12p), -17, del(17p), del(20q)) and somatic mutations (e.g., DNMT3A, TET2, ASXL1, TP53, SF3B1) informs the diagnosis and prognostic risk stratification.[11][15]​​​​ The presence of certain cytogenetic abnormalities or somatic mutations (e.g., -7/del(7q), del(5q), and SF3B1) may establish a diagnosis without dysplasia.[1][2]​​​​​ 

Genetic testing may be carried out on peripheral blood if bone marrow testing is not possible.

Patients with significant dysplasia who do not have a clonal cytogenetic abnormality or somatic mutation should undergo further evaluation to exclude a nonmalignant cause of dysplasia.

Do not perform MDS-related fluorescence in situ hybridization (FISH) panels on bone marrow samples obtained for cytopenias if an adequate conventional karyotype is obtained.[11]​[15]​[53]​ MDS-related FISH panels are expensive tests which are only indicated if standard cytogenetics (with ≥20 metaphases) cannot be obtained.[11]​[15]​[53]​

Subsequent testing

Once a diagnosis is established, the following additional tests may be useful in certain situations.

  • Serum erythropoietin levels: can be measured to guide treatment with erythropoiesis-stimulating agents.[15][16][54]​ Serum erythropoietin is usually elevated in MDS except in concurrent renal failure, in which case it is low.

  • Lactate dehydrogenase: has prognostic value and can be measured to inform risk stratification and management.[15][16]​​ Elevated lactate dehydrogenase is associated with poorer outcomes.[55][56]

  • HLA typing: useful if the patient is a candidate for hematopoietic stem cell transplantation, or if extensive platelet transfusions are needed or anticipated.[54]

  • Flow cytometry: can contribute to the diagnosis (by identifying dysplastic features and blasts) and prognostication. May be used (alongside STAT3 mutation testing) for the evaluation of a concurrent paroxysmal nocturnal hemoglobinuria clone, and possible large granular lymphocytic leukemia.[3][15]

Use of this content is subject to our disclaimer