Pathology of Unclassifiable Myelodysplastic Syndromes (MDS-U)

Before discussing the pathology of unclassifiable myelodysplastic syndromes (MDS-U), some background information is necessary.

The 2008 revision of World Health Organization (WHO) classification of myelodysplastic syndromes (MDS) recognized several clinicopathologic entities, defined by particular morphologic, cytogenetic, and clinical features. ^[1] However, a small minority of MDS cases could not be classified into any specific entity, because they bear features that are atypical, making their clinical significance uncertain. See the image below.

Pathology of unclassifiable myelodysplastic syndromes (MDS-U). Bone marrow biopsy section from a patient with myelodysplastic syndrome, unclassifiable (MDS-U) (pancytopenia and -7 cytogenetic abnormality). The biopsy is hypocellular with hemosiderin deposition secondary to multiple transfusions. Megakaryocytes are not dysplastic.

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Rather than attempting to force such unclassifiable cases into a specific MDS diagnostic group (that may carry particular prognostic or therapeutic implications), placing such cases in a separate group known as "MDS, unclassifiable," until sufficient data are available to better characterize their biologic features and clinical behavior is preferable. Thus, "myelodysplastic syndromes, unclassifiable" (MDS-U) encompasses cases of myelodysplasia (myeloid neoplasms characterized by ineffective hematopoiesis) that do not fulfill the criteria for any of the specific MDS entities. In the 2016 revised fourth edition classification of MDS-U, ^[2] minor changes were made to the diagnostic criteria of this disease subgroup compared to the original 2008 fourth edition classification. ^[1]

It is important to note that the MDS-U designation is not a wastebasket to be used for MDS cases in which the diagnostic workup is incomplete or some studies are suboptimal. Before the pathologist designates a case as MDS-U, any and all pertinent clinical, morphologic, immunophenotypic, or cytogenetic information that could enable classification as another MDS entity (or, indeed, another disease altogether) should be elicited. Moreover, the case must fuflill defining features of one of the three MDS-U subgroups in order to be assigned to this category.  

The 2016 revised World Health Organization (WHO) classification recognizes three distinct scenarios that form the unclassifiable myelodysplastic syndromes (MDS-U) group, as follows ^{[3, 4]} :

• Cases of myelodysplastic syndrome (MDS) with less than 5% bone marrow blasts that have 1% blasts in the peripheral blood, documented on at least two separate occasions

• Cases of MDS with dysplasia limited to one lineage (MDS with single lineage dysplasia [MDS-SLD], MDS with ring sideroblasts and single lineage dysplasia [MDS-RS-SLD]) that have pancytopenia (hemoglobin < 10 g/dL, absolute neutrophil count [ANC] < 1.8 x 10⁹/L [see the Absolute Neutrophil Count calculator], and platelet count < 100 x 10⁹/L)

• Cases presenting with persistent, unexplained cytopenia(s) that lack the diagnostic morphologic features of MDS but bear a specific clonal bone marrow cytogenetic abnormality (see the section on Immunophenotypic and Cytogenetic Features).

See also the following related Medscape Drugs and Diseases articles:

• Pathology of Acute Myeloid Leukemia With Myelodysplasia-Related Changes
• Pathology of Therapy-Related Myeloid Neoplasms
• Pathology of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
• Pathology of Acute Myeloid Leukemia Not Otherwise Specified
• Pathology of Myeloid Proliferations Related to Down Syndrome.

The incidence of unclassifiable myelodysplastic syndromes (MDS-U) is unknown; however, the incidence appears to represent only a small fraction of myelodysplastic syndrome (MDS) cases. In one case series, MDS-U, as defined by the 2008 World Health Organization (WHO) classification criteria, comprised only 3% of MDS cases lacking excess bone marrow blasts. ^[5]

This figure represented a much smaller proportion of cases than when the 2001 WHO classification criteria ^[6] were applied to the same cohort of cases, reflecting the more specific definition of MDS-U) in the 2008 versus the 2001 classification systems, as well as the broadening of the definition of certain other MDS entities. ^{[5, 7]} The relatively low proportion of MDS-U cases in the newer 2008 classification validates its use in assigning the vast majority of MDS cases to specific diagnostic groups with relatively defined biologic features and clinical behavior.

The clinical features of unclassifiable myelodysplastic syndromes (MDS-U) cases vary depending on the specific type. Common to all myelodysplastic syndrome (MDS) cases is that patients usually present with symptoms related to one or more cytopenias.

Although the clinical features of MDS-U are varied, obtaining a detailed clinical history and complete blood cell (CBC) count with differentials is critical to exclude other, specific types of MDS that may masquerade as MDS-U. If the patient’s history includes chemotherapy or radiation therapy, the case should be classified as therapy-related MDS (t-MDS), not MDS-U. Therapy-related MDS may present with cytopenias and a cytogenetic abnormality in the absence of significant dysplasia, mimicking MDS-U if the pertinent history is not elicited. ^[8]

The administration of exogenous growth factors such as granulocyte colony-stimulating factor (G-CSF) may transiently increase the peripheral blast count to a level of 1% (or higher). Thus, possible effects of growth factors should be excluded before diagnosing MDS-U on the basis of 1% peripheral blasts; ideally, a peripheral smear should be examined at least 1 week off exogenous growth factors.

Finally, patients with refractory cytopenia with unilineage dysplasia (RCUD) may develop pancytopenia due to the transient effects of drugs, toxins, infection, immune processes, or metabolic derangements. The pancytopenia should be shown to be persistent and unexplained (aside from ineffective hematopoiesis due to the MDS) before a case that would otherwise qualify as refractory cytopenias with underlying dysplasia is diagnosed as MDS-U.

Morphologic dysplasia in at least one lineage characterizes most types of unclassifiable myelodysplastic syndromes (MDS-U); cases with morphologic dysplasia are placed into the MDS-U category if they have discordant cytopenias (pancytopenia with dysplasia limited to one lineage) or peripheral blood blast count (1% blasts in the peripheral blood with no increase in blasts in the bone marrow) (see the images below).

Pathology of unclassifiable myelodysplastic syndromes (MDS-U). Bone marrow biopsy section from a patient with myelodysplastic syndrome, unclassifiable (MDS-U) (pancytopenia and -7 cytogenetic abnormality). The biopsy is hypocellular with hemosiderin deposition secondary to multiple transfusions. Megakaryocytes are not dysplastic.

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Pathology of unclassifiable myelodysplastic syndromes (MDS-U). Bone marrow aspirate smear from a patient with myelodysplastic syndrome, unclassifiable (MDS-U) (pancytopenia and -7 cytogenetic abnormality). Occasional late mitotic figures in erythroid elements are present, but no significant erythroid or myeloid dysplasia exists.

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In the latter case, examining well-prepared peripheral smears and obtaining an accurate blast count on at least 200 cells in the peripheral smear is important; in smears with marked leukopenia, examination of a concentrated buffy coat may be helpful in ensuring sufficient cells to perform an accurate count. ^[9] The possibility that the marrow aspirate may be hemodilute and the case actually represents myelodysplastic syndrome with excess blasts -1 or -2  with a nonrepresentative aspirate should be considered.

Cases with cytopenias that appear to lack significant morphologic dysplasia but bear a myelodysplastic syndrome (MDS)–defining cytogenetic abnormality should undergo careful examination of aspirate smears, peripheral blood, and bone marrow biopsy (the latter for megakaryocyte morphology, ideally examining at least 30 megakaryocytes) to ensure that morphologic dysplasia is not present in at least 10% of any lineage. Note that cases with a single cytopenia and dysplasia in a single but different lineage (such as anemia with dysplasia limited to the megakaryocytic lineage) are not classified as MDS-U; these cases are still considered within the spectrum of refractory cytopenia with unilineage dysplasia (RCUD).

In all cases of MDS-U the possibility of a myeloproliferative neoplasm (MPN) or myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) should be excluded. ^[10] The presence of persistent peripheral blood monocytosis (> 1 x 10⁹/L), thrombocytosis (≥ 450 x 10⁹/L), or leukocytosis (≥ 13 x 10⁹/L) in a case in which MDS-U is considered should be placed in the MDS/MPN category. Cases that exhibit "proliferative-type" megakaryocyte morphology (enlarged, hyperlobated, and hyperchromatic megakaryocytes), splenomegaly, and bone marrow fibrosis may represent cases of primary myelofibrosis, mimicking MDS due to cytopenias and even morphologic dysplasia of neutrophils and erythroid elements that may occur in the later stages of disease.

Immunophenotypes

No specific immunophenotype of unclassifiable myelodysplastic syndromes (MDS-U) exists. However, in cases with a hemodilute aspirate but with 1% peripheral blood blasts, CD34 staining of the bone marrow trephine biopsy may help disclose increased and/or clustered blasts. ^[11] If blasts appear to comprise at least 5% of the bone marrow biopsy cells by this method, a diagnosis of represent myelodysplastic syndrome (MDS) with excess blasts may be suggested rather than MDS-U.

Cytogenetics

Cytopenic patients lacking excess blasts or sufficient dysplasia in any lineage may be diagnosed with MDS-U if any of certain cytogenetic abnormalities is detected on bone marrow karyotype. The following abnormalities are considered diagnostic of MDS-U in such a situation ^[9] : -7, del(7q), -5, del(5q), i(17q), t(17p), -13, del(13q), del(11q), del(12p) or t(12p), del(9q), idic(X)(q13), t(11;16)(q23;p13.3), t(3;21)(q26;q22.1), t(1;3)(p36.3;q21.2), t(2;11)(p21;q23), inv(3)(q21q26.2), t(6;9)(p23;q34). However, many of these cytogenetic abnormalities can also be present in myeloproliferative neoplasm (MPN) and myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) entities.

The following image is an example of a cytogenetic analysis.

Pathology of unclassifiable myelodysplastic syndromes (MDS-U). Cytogenetic analysis from a patient with myelodysplastic syndrome, unclassifiable (MDS-U), showing an abnormal 45, XX, -7 karyotype in 15 of 20 metaphases. In a patient with unexplained cytopenia, this finding confirms a diagnosis of MDS-U even in the absence of significant dysplasia in any lineage.

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When considering a diagnosis of MDS-U based solely on a cytogenetic finding, other myeloid neoplasms must be carefully excluded by close examination of clinical data, such as the presence or absence of splenomegaly and a complete blood cell (CBC) count and differentials. JAK2 mutation analysis may also be helpful, because although JAK2 mutation is rare in MDS, it is relatively common in MPN and in some types of MDS/MPN. ^{[12, 13]} If the abnormality is present in all metaphases, a constitutional abnormality that may not be related to the cytopenia(s) should be considered.

Precautions

Note that some abnormalities that are frequently observed in MDS cases, +8, -Y, and del(20q), are not considered diagnostic of MDS if these represent sole abnormalities; these cytogenetic abnormalities have been identified in patients with immune disorders and may not necessarily indicate a clonal stem cell abnormality. ^{[14, 15]}  Aplastic anemia (AA) and immune thrombocytopenic purpura (ITP) are presumed to be immune-mediated processes that can exhibit cytogenetic abnormalities: trisomies of chromosome 6, 8, and 15; loss of the Y chromosome; as well as monosomy of chromosome 7 have been reported in aplastic anemia, and deletion of the long arm of chromosome 20 has been reported in ITP. ^{[15, 16]} Partly for these reasons, +8 and del(20q) abnormalities alone are considered insufficient to make a diagnosis of MDS-U.

However, the significance of a -7 abnormality (that is MDS-defining) in a hypoplastic marrow is less certain. Although some studies suggest that this abnormality confers a poor prognosis and lack of responsiveness to immunosuppression, supporting classification as MDS-U, some cases may still respond to immunosuppression, resembling aplastic anemia. ^{[14, 17]} Moreover, some cases of bona fide MDS respond to immunosuppression. ^[18]

Further study is needed to determine how best to classify and treat cases of hypoplastic marrow with cytogenetic abnormalities; these cases challenge our conceptualization of the distinction between MDS and aplastic anemia.

One particular scenario in which caution must be exercised is in patients with chronic myelogenous leukemia (CML) treated with tyrosine-kinase inhibitors (TKI). Such patients may develop cytogenetic abnormalities, including some that are considered MDS-defining, in remission from CML. Although these cases occasionally progress to MDS and acute myeloid leukemia (AML), in most instances they are transient. Thus, MDS-U should not be diagnosed if a cytogenetic abnormality develops on TKI therapy in the absence of significant dysplasia or increased blasts. ^[19]

A study by Wang et al found that the WHO 2008 criteria for atypical chronic myeloid leukemia (aCML) identify a subgroup of patients with features clearly distinct from unclassifiable myelodysplastic/myeloproliferative neoplasm. ^[20]

Cases of unclassifiable myelodysplastic syndromes (MDS-U) should be followed carefully and should be reclassified as one of the defined myelodysplastic syndrome (MDS) subtypes if appropriate criteria are met after the initial evaluation (see Overview). Among cases lacking morphologic dysplasia but with a cytogenetic abnormality, the presence of monosomy 7 appears to be associated with evolution to other types of MDS (eg, refractory cytopenia with multilineage dysplasia [RCMD]) or acute leukemia. ^{[17, 21]}

Cases of MDS-U that are placed into this category because of 1% peripheral blood blasts show a significantly poorer prognosis and higher incidence of transformation to acute myeloid leukemia (AML) than cases of refractory cytopenia with unilineage dysplasia (RCUD) or refractory cytopenia with multilineage dysplasia (RCMD), akin to refractory anemia with excess blasts-1 (RAEB-1). ^[22] Although it is recommended that only one or two cytopenias be allowed for patients with RCUD (thus requiring that cases with unilineage dysplasia but pancytopenia be classified as MDS-U), it is unclear if these patients have an inferior prognosis to RCUD patients. Further study is needed on this group of patients with MDS-U to determine their clinical behavior.