How I Diagnose Low-grade Myelodysplastic Syndromes

Alexa J. Siddon, MD; Robert P. Hasserjian, MD


Am J Clin Pathol. 2020;154(1):5-14. 

In This Article

Questions for the Experts

1. How did the WHO writers come up with the 10% cutoff for dysplasia in each of the cell lineages? Have you ever considered increasing the cutoff?

The cutoff of 10% dysplasia in any of the marrow lineages (erythroid, granulocyte, and megakaryocyte) is admittedly arbitrary, as more than 10% dysplasia can be seen in association with nonmyeloid neoplasms involving the bone marrow, in many nonneoplastic conditions, and even in healthy volunteers. Furthermore, interobserver variability in assessing morphologic dysplasia is also a significant confounding variable, even among experts. When morphologic dysplasia is borderline (near 10%) or only in one cell lineage, caution should be exercised in making a definitive diagnosis of MDS.

A 30% to 40% dysplasia cutoff has been proposed for megakaryocytes, which has been shown in some studies to improve the specificity of dysmegakaryopoiesis in diagnosing MDS; however, it is impossible to derive a perfect cutoff, since sensitivity will be lost with higher cutoffs.[10,30] The current 10% threshold for a diagnosis of dysplasia appears to be an acceptable minimal level and has withstood the historic "test of time." Nevertheless, it must be used with the recognition that many non-MDS causes of cytopenia may be associated with higher levels of dysplasia in one cell line (usually erythroid) and even occasionally in two cell lines.

2. Sometimes, my CD34 immunostain appears to stain megakaryocytes—what does that mean? Can it happen in normal bone marrow?

While CD34 is generally considered a marker of hematopoietic stem cells as well as endothelial cells and stromal cells[31,32] and can be used to help enumerate blasts in MDS cases with dry tap or a hemodilute aspirate, it has also been reported to stain megakaryocytes in myeloid neoplasms such as MDS (most common) Image 3, myeloproliferative neoplasms (MPN), and MDS/MPN, as well as in normal and reactive marrows.[33–36] Insuasti-Beltran et al[37] demonstrated that the presence of 30% or more strongly stained CD34-positive megakaryocytes can reliably differentiate between neoplastic myeloid neoplasms and benign conditions such as immune thrombocytopenia and autoimmune disease. Furthermore, high numbers of CD34-positive megakaryocytes in MDS correlate with a significantly lower platelet count than cases with fewer CD34-positive megakarytocytes[37] and have been shown to be an independent poor prognostic marker in MDS, being associated with more severe cytopenias, high-risk cytogenetics, increased blasts, and shorter overall survival.[35] Thus, a high number CD34-positive megakaryocytes (particularly if the latter exhibit clear dysplastic features) can help support a diagnosis of MDS.

Image 3.

Utility and pitfalls of CD34 immunostaining of bone marrow in myelodysplastic syndromes (MDS). A, CD34 stain of a case of fibrotic MDS with a dry tap in which the aspirate blast count was only 1%; the immunostain shows increased and clustered CD34-positive blasts, suggesting MDS with excess blasts-1 (×20). B, Prominent CD34 staining of megakaryocytes in MDS with multilineage dysplasia, including small, dysplastic forms (×20). C, Bone marrow from a patient with cytopenias due to human immunodeficiency virus (HIV) infection shows many small megakaryocytes, some of which are CD34 positive. In this case, the cytopenia was attributed to the HIV infection and not MDS; thus, CD34 staining of megakaryocytes must be interpreted with caution and does not necessarily indicate a myeloid neoplasm (×20).

3. Currently, there is no information in the WHO on how to incorporate NGS variants into the diagnosis of MDS. Are there instances where pathogenic variants can be diagnostic of MDS?

At the current time, mutations alone cannot be used to diagnose MDS in the absence of dysplasia or a defining cytogenetic abnormality. In healthy individuals with normal blood counts and with no history of hematologic malignancy, a somatic DNA variant is classified as CHIP. Patients with persistent and unexplained cytopenias but no significant morphologic evidence of dysplasia are considered with the group of CCUS.[29] It is noted that some comutational patterns and high mutation VAFs (discussed above) identify patients virtually certain to develop MDS, even in the absence of morphologic dysplasia on the initial bone marrow examination.[29] We use DNA somatic mutations to support a borderline pathogenic finding; for example, the presence of multiple mutations at high VAF could bolster a definitive diagnosis of MDS with single- or multilineage dysplasia when the number of dysplastic cells is near 10% and if other possible nonneoplastic causes of cytopenic have been excluded clinically. In addition, the presence of the SF3B1 mutation accompanied by ring sideroblasts strongly supports a neoplastic rather than nonneoplastic etiology of anemia. Conversely, the absence of mutations, even in the presence of more than 10% myelodysplasia, tends to argue against MDS and should lead to a careful search for other causes of cytopenia and dysplasia (such as a medication-induced cytopenia secondary dysplasia). That being said, 10% to 15% of patients with MDS are reported to lack detectable DNA variants by clinical NGS testing; thus, a lack of detectable mutations does not exclude a diagnosis of MDS if definitive morphologic features, such as unexplained excess of blasts and clear-cut dysplasia, are present. At the current time, a diagnosis of MDS should not be based solely on mutations, no matter how compelling the mutation profile may be. When we encounter such cases, we recommend close clinical follow-up and repeat bone marrow biopsy at a later date, by which time sufficient morphologic dysplasia may be present to establish a definitive diagnosis.