Pathology of Myelodysplastic Syndrome With Single Lineage Dysplasia (MDS-SLD)

Myelodysplastic syndrome (MDS) with single lineage dysplasia (SLD), formerly known as refractory cytopenia with unilineage dysplasia (RCUD), is a category of MDS characterized by morphologic dysplasia in at least 10% of the early cells of a single myeloid lineage (red blood cells, white blodd cells, or megakaryocytes) with associated peripheral blood cytopenia. ^{[1, 2]}  Previously, depending on the types of cells involved, this condition included refractory anemia, refractory neutropenia and refractory thrombocytopenia.

An MDS, as defined by the World Health Organization (WHO), is a clonal hematopoietic stem cell disorder resulting in ineffective hematopoiesis that manifests as morphologic dysplasia in hematopoietic cells and peripheral cytopenias. ^{[1, 3]}  The 2016 revised WHO classification of MDS primarily relies on the degree of dysplasia and blast percentages for disease classification, in which specific cytopenias have a small impact on the classification and the manifested lineage(s) of significant morphologic dysplasia did not often correlate with the specific cytopenia(s) in individual MDS cases. ^[1]  Thus, RCUD is now MDS-SLD.

As with all types of MDS, MDS-SLD carries a risk of progression or transformation to acute myeloid leukemia. ^[2]  However, MDS-SLD is considered a low-risk MDS; cases often follow a prolonged and sometimes indolent clinical course.

Myelodysplastic syndrome (MDS) with single lineage dysplasia (SLD) is characterized by morphologic dysplasia of a single myeloid lineage with associated one or two peripheral blood cytopenia(s). ^[1]

The World Health Organization's (WHO's) defined thresholds for cytopenias (adopted from the Myelodysplastic Working Group criteria) is as follows (unchanged from 2008 classification) ^{[1, 3]} :

• Hemoglobin level less than 10 g/dL

• Absolute neutrophil count (ANC) less than 1.8 × 10³/μL

• Platelet count less than 100 × 10³/μL

Note that the the Revised International Prognostic Scoring System (IPSS-R) lowered the neutropenia prognostic threshold to 0.8 × 10³/μL. ^[1]

The 2016 revised WHO classification has defined the following peripheral blood and bone marrow findings as well as cytogenetics of MDS-SLD as follows ^[1] :

• Ring sideroblasts as a percentage of marrow erythroid elements: Less than 15%, or below 5% in the presence of SF3B1 mutation

• Bone marrow, less than 5% blasts; peripheral blood, blasts below 1%; no Auer rods 

• Cytogenetics by conventional karyotype analysis: Any, unless all criteria for MDS with isolated del(5q) are fulfilled

However, morphologic and cytogenetic findings alone are considered diagnostic. In the bone marrow, at least 10% of a given myeloid lineage should be affected. However, note that dysplasia exceeding 10% may occur in healthy individuals as well as in nonneoplastic causes of cytopenia. ^[1]

Cases demonstrating Auer rods and/or increased numbers of myeloblasts (>5% in bone marrow) are not included in this group (see Refractory Anemia with Excess Blasts). As with all forms of MDS, other causes of myeloid dyspoiesis should be excluded before assigning the diagnosis of MDS-SLD. ^[1]

In general, myelodysplastic syndrome (MDS) has an incidence of 5 new MDS diagnoses per 100,000 people, with men affected more than women. ^[4]  In Western nations, the incidence is 22-45 per 100,000 people older than 70 years, whereas Asian countries (eg, Japan, China, Korea, India, Thailand,Turkey) report MDS at younger ages (median: 40-50 years). ^[4] The differences between these regions may be due in part to environmental pollutions and/or other factors (eg, uncontrolled pesticide use).

The epidemiologic features of MDS with single lineage dysplasia (SLD) (MDS-SLD) are similar to those of most types of MDS. The average age of patients at presentation is approximately 65-70 years. In contrast with other forms of MDS, there is no gender predilection. ^{[5, 6]}

Exposure to agricultural chemicals and a history of smoking confer an increased risk of the development of refractory anemia (RA) and RA with ring sideroblasts. ^[7]  The precise incidence and prevalence of MDS-SLD have not been well established.

Clinical features of myelodysplastic syndrome (MDS) with single lineage dysplasia (SLD) are often nonspecific and are generally related to the corresponding cytopenia (ie, bleeding associated with thrombocytopenia; fatigue and exercise intolerance associated with anemia). In many cases, the patient is asymptomatic and cytopenia is identified during routine evaluation.

The morphologic features of the peripheral blood and bone marrow (see the images below) are currently the gold standard for the diagnosis of myelodysplastic syndrome (MDS). The presence of hypoplasia does not exclude a diagnosis of MDS with single lineage dysplasia (SLD), because hypoplastic forms are not uncommon, accounting for approximately 10% of confirmed cases of MDS. Importantly, morphologic changes identical to those of dysplasia may occur as an artifact of poor preservation or as a result of inadequate storage during transport of samples; extra caution is advised when evaluating suboptimal specimens.

Peripheral blood

Evaluation of the peripheral blood smear demonstrates one or more cytopenias. When affected, the erythroid lineage is characterized by a macrocytic or normocytic anemia with variation in red cell size and shape (anisopoikilocytosis). Platelets may vary in size; giant forms may be present. Dysplasia of the granulocyte lineage may be assessed on the peripheral blood smear; hypolobated nuclei and hypogranularity are the most common features.

Bone marrow

The bone marrow is normocellular to hypercellular; at least 10% of a lineage demonstrates dysplastic features. In addition to nuclear and cytoplasmic atypia, the erythroid series may show megaloblastoid features (ie, dyssynchronous maturation of nucleus and cytoplasm and/or disproportionately large cell size relative to the corresponding normal stage of development); such megaloblastoid features are indistinguishable from those seen in vitamin B12 or folate deficiency. Ring sideroblasts may be present; however, if they account for fewer than 15% of erythroid precursors, a diagnosis of refractory anemia with ring sideroblasts is more appropriate.

A report by Gong et al indicated that evaluation of bone marrow imprints provided a more accurate means of diagnosing refractory cytopenia with unilineage dysplasia (RCUD) (now known as MDS-SLD) than does analysis of trephine biopsy sections. ^[8] In a study of 3781 patients, the investigators found that, using routine cytochemical staining, bone marrow imprints provided greater diagnostic accuracy than the biopsy sections did for RCUD, refractory cytopenia with multilineage dysplasia, megaloblastic anemia, acute myeloid leukemia, refractory anemia with excess blasts, and lymphoplasmacytic lymphoma. The report also found that for these conditions, the diagnostic accuracy of bone marrow imprints was not statistically different than that of aspirate smears. ^[8] The morphologic features of erythroid, granulocytic, and megakaryocytic dysplasia are presented in Table 1.

Table 1. Morphologic Features of MDS-SLD (Open Table in a new window)

Staining

Immunohistochemical studies are not necessary in most cases of myelodysplastic syndrome (MDS) with single lineage dysplasia (SLD). However, staining for CD34, a relatively specific hematopoietic stem cell marker in bone marrow, may be used to localize immature precursors and to exclude higher-grade forms of MDS. ^[9] Importantly, CD34 is not lineage specific, and some myeloblast populations do not express CD34; interpretation of staining patterns should not be performed in isolation.

Flow cytometry

The use of flow cytometry in the diagnosis of myelodysplasia has progressively evolved from identifying myeloblast populations to recognizing aberrant immunophenotypic patterns of myeloid and erythroid maturation. Because the diagnosis of MDS is complicated by the lack of morphologic specificity, there is an ever-increasing body of literature supporting the application of flow cytometry to fill diagnostic gaps. ^[10]

Aberrant antigenic patterns may be identified on the blast populations, including expression of CD7 (a T-cell–associated antigen) and/or CD56 (a natural killer [NK]-cell–associated antigen). Myeloid maturation patterns may also be assessed; evidence suggests that a limited panel of markers, including glycophorin A, CD71 (transferrin receptor), CD105 (endoglin), cytosolic ferritin subunits, and mitochondrial ferritin, may be used to accurately assess for erythroid dysplasia and to identify ringed sideroblasts. ^{[11, 12]}

Approximately 50% of cases of refractory anemia (RA) have a demonstrable cytogenetic abnormality, most often involving chromosomes 5 or 7. ^[5] Although abnormalities in RA are limited to a small number of chromosomes, proper characterization is prognostically significant. ^[13] Too few cases of refractory neutropenia (RN) or refractory thrombocytopenia (RT) have been reported to definitively establish cytogenetic associations.

Myelodysplastic syndrome (MDS) with single lineage dysplasia (SLD) is considered a low-grade form of MDS; the median survival is prolonged—on the order of 5 years. ^[5] There is some disagreement as to the likelihood of the subsequent development of acute myeloid leukemia, ^{[1, 2]} although the risk appears to be low (1-2%). ^{[5, 14, 15]}

The widely accepted International Prognostic Scoring System (IPSS) was introduced by the Myelodysplastic Syndrome Working Group in 1997. The IPSS stresses the importance of cytogenetic findings. It has been successfully used to stratify patients on the basis of the percentage of bone marrow myeloblasts; karyotypic abnormality; and cytopenia. ^[13]  The revised IPSS (IPSS-R) lowered the neutropenia prognostic threshold to 0.8 × 10³/μL. ^[1]

Incorporating associated laboratory findings, the classification system previosly separated patients into five risk groups, which represented an increasing likelihood of progression to acute leukemia and decreasing survival (see Tables 2 and 3). ^[13] The majority of patients with a World Health Organization (WHO) diagnosis of the former RCUD (now MDS-SLD) fall into the low-risk and intermediate-1–risk groups. The prognostic value of a proposed WHO Prognostic Scoring System (WPSS), which considers the impact of transfusion requirements and morphologic classification, has previously also been established. ^[16]

Table 2. International Prognostic Scoring System: Prognostic Variables* (Open Table in a new window)

Table 3. International Prognostic Scoring System: Risk Groups* (Open Table in a new window)

The IPSS-R has updated/expanded its MDS cytogenetic risk groups, prognostic score values, prognostic risk categories/scores, and prognostic risk category clinical outcomes. These can be found at the MDS Foundation.