Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a rare group of hematologic neoplasms characterized by the clonal proliferation of hematopoietic stem cells accompanied by cytopenia and dysplasia in the peripheral blood, ineffective hematopoiesis in the bone marrow, recurrent genetic abnormalities, and a potential for the development of acute myeloid leukemia (AML). MDS usually occurs in older adults, manifesting as macrocytic to normocytic anemia of unclear origin. A slow increase in myeloblasts over many years can eventually lead to the development of AML. The clinical condition of cytopenia in MDS, which includes anemia, is refractory to therapy; it was once known as preleukemia because it progresses slowly over time.¹ 

Bone marrow and blood cell morphological abnormalities are characteristic of MDS. It is common to see megaloblastoid erythroid hyperplasia with macrocytic anemia and normal vitamin B12 and folate levels. Granulocytes in the circulation are frequently hypo- or hypergranular and may exhibit the pseudo-Pelger-Huet anomaly. Varying percentages of early, abnormal myeloid progenitors are found in the bone marrow. Micromegakaryocytes, which are abnormally small megakaryocytes, may be found in the bone marrow, and hypogranular or giant platelets may show up on blood smears.²

Histology of Bone Marrow in MDS

The established diagnostic criteria for MDS require the presence of a number of peripheral blood and bone marrow abnormalities rather than a single histopathologic characteristic. Supplementary diagnostic procedures often include immunophenotyping by flow cytometry, cytogenetic analysis by karyotyping and fluorescent in situ hybridization (FISH), and genetic profiling to check for pertinent somatic mutations.³

Myeloid Dysplasia

The defining morphological feature of MDS is dysplasia in one or more myeloid lineages. The cutoff for dysplasia across all lineages is 10%. Myeloid blast counts in the peripheral blood and/or bone marrow may rise in the presence of dysplasia, although they always remain below 20%. The dysplastic myeloid lineages are not always those that are cytopenic.⁴ 

It is recommended that a 500-cell differential count of all nucleated cells be performed in a bone marrow smear or trephine biopsy imprint as well as a 200-leukocyte differential count in peripheral blood to determine blast proportions in the bone marrow and blood. The blast count is expressed as a percentage of the total number of nucleated cells in the bone marrow, with nucleated erythroid cells always included, and as a percentage of leukocytes in the peripheral blood, with nucleated erythroid cells excluded.⁴

Read more about MDS testing

Cellular Characteristics

Nuclear changes such as budding, internuclear bridging, karyorrhexis, and multinuclearity are the main manifestations of dyserythropoiesis. Megaloblastoid alterations are frequent, although they are inadequate for establishing dyserythropoiesis. Ring sideroblasts, vacuolization, and abnormal periodic acid-Schiff (PAS) positivity (either diffuse or granular) are cytoplasmic characteristics.⁴ 

Characteristics of Dysgranulopoiesis

Nuclear hyposegmentation (pseudo-Pelger-Huet anomaly) or hypersegmentation, cytoplasmic hypogranularity, and pseudo-Chediak-Higashi granules are the main characteristics of dysgranulopoiesis.⁴ 

Read more about MDS pathophysiology

Megakaryocytic Dysplasia

Micromegakaryocytes, nuclei without lobes in megakaryocytes of all sizes, and numerous, widely separated nuclei are the hallmarks of megakaryocytic dysplasia. Bone marrow sections clearly show megakaryocytic dysplasia; biopsy (or clot) and aspirated specimens should also be examined.⁴ 

Read more about MDS diagnosis

Overall Characteristics of Bone Marrow Histology

General MDS findings in the bone marrow are enumerated below⁵:

• The bone marrow is usually hypercellular or normocellular (hypocellular in 10% of cases). Iron stores are frequently increased.
• All 3 lineages (erythroid, myeloid, and megakaryocytic) show dysplastic or disordered differentiation. 
• Myelofibrosis is noted in therapy-related MDS.
• Features in the erythroid lineage include hyperplasia; ringed sideroblasts (iron-laden mitochondria appearing as perinuclear granules with Prussian iron stain); megaloblastoid maturation of nuclei; abnormalities of nuclear budding (including polypoid outlines, nuclear hyperlobation, nuclear fragments, internuclear bridging, multinuclearity,  cytoplasmic vacuolization, and PAS-positive erythroblasts).
• Features in the myeloid lineage include the following: increase in myeloblasts to up to 20% of nonerythroid cells (>20% is considered AML); abnormally localized immature precursors (ALIPs, consisting of 3 to 5 aggregates or 6+ clusters of immature precursors away from trabeculae; in normal bone marrow, mature granulocytes extend from trabeculae or blood vessels toward central areas); neutrophils with reduced secondary granules or 2 lobes (pseudo-Pelger-Huet cells); toxic granules; Döhle bodies; Auer rods; irregular nuclear segmentation; increased basophils or monocytes; occasional monocytic nodules; and myeloid cells negative for myeloperoxidase (MPO) stain. 
• Features in the megakaryocytic lineage include clusters of megakaryocytes, single nuclear lobe, hypolobular or multiple separate nuclei, and micromegakaryocytes.

Read more about MDS guidelines

Histology of the Spleen in MDS 

An enlarged spleen, or splenomegaly, is uncommon in MDS. Histologic examination of the spleen may reveal plasmacytosis in the red pulp, erythrophagocytosis, extramedullary hematopoiesis, or marked expansion of the red pulp due to the proliferation of monocytes. Splenomegaly is usually due to dyspoiesis, not proliferation.⁵ 

References

1. Kayano H. Histopathology in the diagnosis of high-risk myelodysplastic syndromes. J Clin Exp Hematop. 2018;58(2):51-60. doi:10.3960/jslrt.18009. 
2. Myelodysplastic syndromes treatment (PDQ®)–health professional version. National Cancer Institute at the National Institutes of Health. Updated September 30, 2022. Accessed June 9, 2023.
3. Dotson JL, Lebowicz Y. Myelodysplastic syndrome. StatPearls [Internet]. Updated July 18, 2022. Accessed June 9, 2023. 
4. Myeloid proliferations and neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 5th ed. International Agency for Research on Cancer; 2022: chap 2. Accessed June 9, 2023.
5. Sangle N. WHO classification – MDS. PathologyOutlines.com. Accessed June 9, 2023.

Reviewed by Kyle Habet, MD, on 6/11/2023.

---

Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.