Pathology of Refractory Cytopenia With Unilineage Dysplasia
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Refractory cytopenia with unilineage dysplasia (RCUD) is a category of myelodysplastic syndrome (MDS) characterized by morphologic dysplasia of a single myeloid lineage with associated peripheral blood cytopenia. An MDS, as defined by the World Health Organization (WHO), is a clonal hematopoietic stem cell disorder resulting in ineffective hematopoiesis.
As with all types of MDS, RCUD carries a risk of progression or transformation to acute myeloid leukemia. However, RCUD is considered a low-risk MDS; cases follow a prolonged and sometimes indolent clinical course.
Types of refractory cytopenia with unilineage dysplasia (RCUD) include the following:
Refractory neutropenia with unilineage dysplasia
Refractory anemia with unilineage dysplasia
Refractory thrombocytopenia with unilineage dysplasia
Refractory cytopenia with unilineage dysplasia (RCUD) represents a heterogeneous group of myelodysplastic syndromes (MDSs) characterized by morphologic dysplasia of a single myeloid lineage with associated peripheral blood cytopenia. This category of MDS includes refractory anemia (RA), refractory neutropenia (RN), and refractory thrombocytopenia (RT); specific diagnoses are made on the basis of the morphologically abnormal lineage present in the bone marrow. [1]
Although the dysplastic lineage most commonly corresponds to the identified cytopenia, discordant findings (eg, neutropenia with megakaryocyte dysplasia) do not preclude the diagnosis of RCUD. Cases with bicytopenias and unilineage dysplasia are also included in this group; data suggest that such features portend a worse prognosis. [2]
The World Health Organization (WHO), adopting criteria from the Myelodysplastic Working Group, has defined thresholds for cytopenias as follows:
Hemoglobin level less than 10g/dL
Absolute neutrophil count (ANC) less than 1.8 x 103/μL
Platelet count less than 100 x 103/μL
However, morphologic and cytogenetic findings alone are considered diagnostic. In the bone marrow, at least 10% of a given myeloid lineage should be affected.
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 RCUD.
The epidemiologic features of refractory cytopenia with unilineage dysplasia (RCUD) are similar to those of most types of myelodysplastic syndrome (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. [3, 4]
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. [5] The precise incidence and prevalence of RCUD have not been well established; however, RA represents the majority of cases of RCUD.
Clinical features 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 refractory cytopenia with unilineage dysplasia (RCUD), 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.
Evaluation of the peripheral blood smear demonstrates 1 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.
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 provides a more accurate means of diagnosing RCUD than does analysis of trephine biopsy sections. 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. [6] The morphologic features of erythroid, granulocytic, and megakaryocytic dysplasia are presented in Table 1.
Table 1. Morphologic Features of Refractory Cytopenia With Unilineage Dysplasia (Open Table in a new window)
Lineage
Nuclear Atypia
Cytoplasmic Atypia
Other
Erythroid
Binucleation
Budding/lobulation
Fragmentation/karyorrhexis
Single or multiple cytoplasmic vacuoles
Megaloblastoid changes
Megakaryocyte
Hypolobate or hyperlobate nuclei
Multiple, segregated nuclei (“pawn ball” nuclei)
Dyssynchronous maturation of nucleus and cytoplasm
Micromegakaryocytes
Clustering
Abnormal paratrabecular localization
Granulocyte
Hypolobation (pseudo– Pelger-Huet anomaly)
Hypersegmentation
Hypogranulation Hypergranulation (pseudo–Chediak-Higashi granules)
Macrocytosis or microcytosis
Immunohistochemical studies are not necessary in most cases of refractory cytopenia with unilineage dysplasia (RCUD). 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 myelodysplastic syndrome (MDS). [7] Importantly, CD34 is not lineage specific, and some myeloblast populations do not express CD34; interpretation of staining patterns should not be performed in isolation.
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. [8]
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. [9, 10]
Approximately 50% of cases of refractory anemia (RA) have a demonstrable cytogenetic abnormality, most often involving chromosomes 5 or 7. [3] Although abnormalities in RA are limited to a small number of chromosomes, proper characterization is prognostically significant. [11] Too few cases of refractory neutropenia (RN) or refractory thrombocytopenia (RT) have been reported to definitively establish cytogenetic associations.
Refractory cytopenia with unilineage dysplasia (RCUD) is considered a low-grade form of myelodysplastic syndrome (MDS); the median survival is prolonged—on the order of 5 years. [3] There is some disagreement as to the likelihood of the subsequent development of acute myeloid leukemia, although the risk appears to be low (1-2%). [3, 12, 13]
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. [11]
Incorporating associated laboratory findings, the classification system separates patients into 4 risk groups, which represent an increasing likelihood of progression to acute leukemia and decreasing survival (see Tables 2 and 3). The majority of patients with a World Health Organization (WHO) diagnosis of RCUD 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 also been established. [14]
Table 2. International Prognostic Scoring System: Prognostic Variables* (Open Table in a new window)
Prognostic Variables
Score 0
Score 0.5
Score 1
Score 1.5
Score 2
Bone marrow blasts (%)
< 5%
5-10%
11-19%
20-30%
Karyotypeΐ
Good
Intermediate
Poor
Cytopenias
0-1
2-3
*Adapted from Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. Mar 15 1997;89(6):2079-88.
ΐ Karyotype: Good: normal, -Y, del(5q), del(20q); Poor: complex (>3 abnormalities) or chromosome 7 abnormalities; Intermediate: all other abnormalities.
Table 3. International Prognostic Scoring System: Risk Groups* (Open Table in a new window)
Risk Group
Cumulative Score
Approximate Median Survival (years)
Low risk
0
6
Intermediate–1 risk
0.5-1
3.5
Intermediate–2 risk
1.5-2
1
High risk
≥2.5
0.5
*Adapted from Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. Mar 15 1997;89(6):2079-88.
Brunning RD, Orazi A, Germing U, et al. Myelodysplastic syndromes. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. chap 5.
Verburgh E, Achten R, Louw VJ, et al. A new disease categorization of low-grade myelodysplastic syndromes based on the expression of cytopenia and dysplasia in one versus more than one lineage improves on the WHO classification. Leukemia. 2007 Apr. 21(4):668-77. [Medline].
Germing U, Strupp C, Kuendgen A, et al. Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes. Haematologica. 2006 Dec. 91(12):1596-604. [Medline].
Matsuda A, Germing U, Jinnai I, et al. Differences in the distribution of subtypes according to the WHO classification 2008 between Japanese and German patients with refractory anemia according to the FAB classification in myelodysplastic syndromes. Leuk Res. 2010 Aug. 34(8):974-80. [Medline].
Strom SS, Gu Y, Gruschkus SK, Pierce SA, Estey EH. Risk factors of myelodysplastic syndromes: a case-control study. Leukemia. 2005 Nov. 19(11):1912-8. [Medline].
Gong X, Lu X, Wu X, et al. Role of bone marrow imprints in haematological diagnosis: a detailed study of 3781 cases. Cytopathology. 2010 Dec 3. [Medline].
Della Porta MG, Malcovati L, Boveri E, et al. Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J Clin Oncol. 2009 Feb 10. 27(5):754-62. [Medline].
Truong F, Smith BR, Stachurski D, et al. The utility of flow cytometric immunophenotyping in cytopenic patients with a non-diagnostic bone marrow: a prospective study. Leuk Res. 2009 Aug. 33(8):1039-46. [Medline].
Loken MR, van de Loosdrecht A, Ogata K, Orfao A, Wells DA. Flow cytometry in myelodysplastic syndromes: report from a working conference. Leuk Res. 2008 Jan. 32(1):5-17. [Medline].
Della Porta MG, Malcovati L, Invernizzi R, et al. Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome. Leukemia. 2006 Apr. 20(4):549-55. [Medline].
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15. 89(6):2079-88. [Medline].
Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005 Oct 20. 23(30):7594-603. [Medline].
Breccia M, Latagliata R, Cannella L, et al. Refractory cytopenia with unilineage dysplasia: analysis of prognostic factors and survival in 126 patients. Leuk Lymphoma. 2010 May. 51(5):783-8. [Medline].
Park MJ, Kim HJ, Kim SH, et al. Is International Prognostic Scoring System (IPSS) still standard in predicting prognosis in patients with myelodysplastic syndrome? External validation of the WHO Classification-Based Prognostic Scoring System (WPSS) and comparison with IPSS. Eur J Haematol. 2008 Nov. 81(5):364-73. [Medline].
Lineage
Nuclear Atypia
Cytoplasmic Atypia
Other
Erythroid
Binucleation
Budding/lobulation
Fragmentation/karyorrhexis
Single or multiple cytoplasmic vacuoles
Megaloblastoid changes
Megakaryocyte
Hypolobate or hyperlobate nuclei
Multiple, segregated nuclei (“pawn ball” nuclei)
Dyssynchronous maturation of nucleus and cytoplasm
Micromegakaryocytes
Clustering
Abnormal paratrabecular localization
Granulocyte
Hypolobation (pseudo– Pelger-Huet anomaly)
Hypersegmentation
Hypogranulation Hypergranulation (pseudo–Chediak-Higashi granules)
Macrocytosis or microcytosis
Prognostic Variables
Score 0
Score 0.5
Score 1
Score 1.5
Score 2
Bone marrow blasts (%)
< 5%
5-10%
11-19%
20-30%
Karyotypeΐ
Good
Intermediate
Poor
Cytopenias
0-1
2-3
*Adapted from Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. Mar 15 1997;89(6):2079-88.
ΐ Karyotype: Good: normal, -Y, del(5q), del(20q); Poor: complex (>3 abnormalities) or chromosome 7 abnormalities; Intermediate: all other abnormalities.
Risk Group
Cumulative Score
Approximate Median Survival (years)
Low risk
0
6
Intermediate–1 risk
0.5-1
3.5
Intermediate–2 risk
1.5-2
1
High risk
≥2.5
0.5
*Adapted from Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. Mar 15 1997;89(6):2079-88.
Yuri Fedoriw, MD Assistant Professor, Associate Director of Hematopathology, Director of Analytical Hematology, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine
Yuri Fedoriw, MD is a member of the following medical societies: American Society for Clinical Pathology
Disclosure: Nothing to disclose.
Cherie H Dunphy, MD, FCAP, FASCP Professor of Pathology and Laboratory Medicine, Diector of Hematopathology and Hematopathology Fellowship, Associate Director, Core, Flow Cytometry, and Special Procedures Laboratories, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine
Cherie H Dunphy, MD, FCAP, FASCP is a member of the following medical societies: American Society for Clinical Pathology, College of American Pathologists, International Academy of Pathology, North Carolina Medical Society, Children’s Oncology Group
Disclosure: Nothing to disclose.
Pathology of Refractory Cytopenia With Unilineage Dysplasia
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