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WHO Classification of Tumours
Overview: Refractory cytopenia with unilineage dysplasia


Refractory cytopenia with unilineage dysplasia (RCUD) is intended to encompass those myelodysplastic syndromes (MDS) which present with a refractory cytopenia with unilineage dysplasia and includes refractory anaemia (RA), refractory neutro計enia (RN) and refractory thrombocyto計enia (RT). Although refractory anaemia with ring sideroblasts is also characterized by unilineage dysplasia, it is considered as a distinct entity of its own. Refractory bicytopenia may be included in the RCUD category if accompanied by unilineage dysplasia. It is recommended that refractory pancytopenia with unilineage dysplasia be placed in the category of myelodysplastic syndrome, unclassifiable (MDS-U). The recommended level for dysplasia is ≥10% in the cell lineage affected. The recommended levels for defining cytopenias are haemoglobin <10g/dL, absolute neutro計hil count (ANC) <1.8x109/L and platelet count <100x109/L
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Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88




Click to access Pubmed
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88



. However, values above these levels do not exclude MDS if definitive morphologic and/or cyto茆enetic evidence of MDS is present. The type of cytopenia in the majority of cases will correspond to the type of unilineage dysplasia, e.g. anaemia and erythroid dysplasia, although discordance between type of cytopenia and cell lineage dysplasia may be observed
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Verburgh E, Achten R, Louw VJ, Brusselmans C, Delforge M, Boogaerts M, Hagemeijer A, Vandenberghe P, Verhoef G (2007)
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 21: 668-77



. Some of the cases previously classified as MDS-U may be included in this category, e.g. RN, RT.

All non-clonal causes for the dysplasia must be explored and excluded before the diagnosis of MDS is established. These include, but are not limited to, drug and toxin exposure, growth factor therapy, viral infections, immunologic disorders, congenital disorders, vitamin deficiencies and possible essential element deficiencies, such as copper deficiency

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Gregg XT, Reddy V, Prchal JT (2002)
Copper deficiency masquerading as myelodysplastic syndrome.
Blood 100: 1493-5



. Excessive zinc supplementation has also been reported to be associated with severe cytopenia and dysplastic changes
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Irving JA, Mattman A, Lockitch G, Farrell K, Wadsworth LD (2003)
Element of caution: a case of reversible cytopenias associated with excessive zinc supplementation.
CMAJ 169: 129-31



. If a clonal cytogenetic abnormality is not present, there should be a period of observation of six months from initial examination before a diagnosis of MDS is established unless more definitive morpho衍ogic or genetic evidence emerges during the observation period.

The presence of peripheral blood (PB) blasts essentially excludes a diagnosis of RCUD although in an occasional case a rare blast may be identified: patients with the findings of RCUD and 1% blasts in the PB and <5% in the bone marrow (BM) on two successive evaluations should be placed in the category of MDS-U because of the uncertain biology of this constellation of findings. Patients with 2-4% blasts in the PB and <5% blasts in the BM should be classified as refractory anaemia with excess blasts-1 (RAEB-1) if other criteria for MDS are present. The number of cases with these findings is very low and these patients should be carefully observed for increasing BM blast percentage

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Knipp S, Strupp C, Gattermann N, Hildebrandt B, Schapira M, Giagounidis A, Aul C, Haas R, Germing U (2008)
Presence of peripheral blasts in refractory anemia and refractory cytopenia with multilineage dysplasia predicts an unfavourable outcome.
Leuk Res 32: 33-7



.

Refractory cytopenia with unilineage dysplasia should not be equated with "Idiopathic cytopenia of undetermined significance" (ICUS) which lacks the minimal morphologic or genetic criteria requisite for a diagnosis of MDS and should not be considered as such

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Wimazal F, Fonatsch C, Thalhammer R, Schwarzinger I, Mllauer L, Sperr WR, Bennett JM, Valent P (2007)
Idiopathic cytopenia of undetermined significance (ICUS) versus low risk MDS: the diagnostic interface.
Leuk Res 31: 1461-8



.

> Synonym
Refractory anaemia.

> Epidemiology
Refractory cytopenia with unilineage dysplasia comprises 10−20% of all cases of MDS

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Germing U, Strupp C, Kuendgen A, Isa S, Knipp S, Hildebrandt B, Giagounidis A, Aul C, Gattermann N, Haas R (2006)
Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes.
Haematologica 91: 1596-604




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Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, Passamonti F, Arcaini L, Maffioli M, Bernasconi P, Lazzarino M, Cazzola M (2005)
Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making.
J Clin Oncol 23: 7594-603



. It is primarily a disease of older adults; the median age is around 65−70 years. There is no significant sex predilection. The vast majority of RCUD cases are RA. Refractory neutro計enia and refractory thrombocytopenia are rare and extreme caution should be used in making either of these diagnoses.

> Sites of involvement
The PB and BM are the principal sites of involvement.

> Clinical features
In RCUD, the presenting symptoms are related to the type of cytopenia. The cyto計enias are refractory to haematinic therapy, but may be responsive to growth factors

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Howe RB, Porwit-MacDonald A, Wanat R, Tehranchi R, Hellstr闣-Lindberg E (2004)
The WHO classification of MDS does make a difference.
Blood 103: 3265-70



.

> Variants
There are three morphologic and clinical variants of RCUD
9980/3 Refractory anaemia (ICD-O code 9980/3)
9991/3 Refractory neutropenia (ICD-O code 9991/3)
9992/3 Refractory thrombocytopenia (ICD-O code 9992/3)

> Immunophenotype
In refractory anaemia aberrant immuno計henotypic features of erythropoietic precursors can be found by flow cytometry analysis

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Della Porta MG, Malcovati L, Invernizzi R, Travaglino E, Pascutto C, Maffioli M, Gall A, Boggi S, Pietra D, Vanelli L, Marseglia C, Levi S, Arosio P, Lazzarino M, Cazzola M (2006)
Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome.
Leukemia 20: 549-55



. There are no data on RN and RT.


> Genetics
Cytogenetic abnormalities may be observed in up to 50% of cases of refractory anaemia

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Germing U, Strupp C, Kuendgen A, Isa S, Knipp S, Hildebrandt B, Giagounidis A, Aul C, Gattermann N, Haas R (2006)
Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes.
Haematologica 91: 1596-604



. Several different acquired clonal chromosomal abnormalities may be observed, and although useful for establishing a diagnosis of RA, they are not specific. The abnormalities generally associated with RA include del(20q), +8 and abnormalities of 5 and/or 7. The number of reported cases of RN and RT is too low to allow for generalizations, although del(20q) has been reported in RT
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Gupta R, Soupir CP, Johari V, Hasserjian RP (2007)
Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation.
Br J Haematol 139: 265-8




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Sashida G, Takaku TI, Shoji N, Nishimaki J, Ito Y, Miyazawa K, Kimura Y, Ohyashiki JH, Ohyashiki K (2003)
Clinico-hematologic features of myelodysplastic syndrome presenting as isolated thrombocytopenia: an entity with a relatively favorable prognosis.
Leuk Lymphoma 44: 653-8



.

> Postulated cell of origin
Haematopoietic stem cell.

> Prognosis and predictive factors
The clinical course is protracted; the median survival of patients with RA in one series was approximately 66 months and the rate of progression to AML at 5 years was approximately 2%

Click to access Pubmed
Germing U, Strupp C, Kuendgen A, Isa S, Knipp S, Hildebrandt B, Giagounidis A, Aul C, Gattermann N, Haas R (2006)
Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes.
Haematologica 91: 1596-604



. In another study, the median survival for patients over 70 years of age with RA, RARS and MDS with del(5q) was not significantly different from the non-affected population
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Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, Passamonti F, Arcaini L, Maffioli M, Bernasconi P, Lazzarino M, Cazzola M (2005)
Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making.
J Clin Oncol 23: 7594-603



. Approximately 90−95% of patients with RA have low or intermediate International Prognostic Scoring System (IPSS) scores
Click to access Pubmed
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88




Click to access Pubmed
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J (1997)
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood 89: 2079-88



. Approximately 80−85% have good to intermediate cytogenetic profiles
Click to access Pubmed
Germing U, Strupp C, Kuendgen A, Isa S, Knipp S, Hildebrandt B, Giagounidis A, Aul C, Gattermann N, Haas R (2006)
Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes.
Haematologica 91: 1596-604




Click to access Pubmed
Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, Passamonti F, Arcaini L, Maffioli M, Bernasconi P, Lazzarino M, Cazzola M (2005)
Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making.
J Clin Oncol 23: 7594-603



. Most patients with RT have low IPSS scores and 90% of the patients live more than two years
Click to access Pubmed
Sashida G, Takaku TI, Shoji N, Nishimaki J, Ito Y, Miyazawa K, Kimura Y, Ohyashiki JH, Ohyashiki K (2003)
Clinico-hematologic features of myelodysplastic syndrome presenting as isolated thrombocytopenia: an entity with a relatively favorable prognosis.
Leuk Lymphoma 44: 653-8



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Richard D. Brunning
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Richard D. Brunning
Department of Laboratory Medicine and Pathology
University of Minnesota
Minneapolis
USA




Robert Paul Hasserjian
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Robert Paul Hasserjian
Department of Pathology
Massachusetts General Hospital
Boston
USA




Anna Porwit
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Anna Porwit
Department of Pathology
Karolinska University Hospital
Stockholm
Sweden




John M. Bennett
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John M. Bennett
Departments of Medicine and Pathology
University of Rochester Medical Center and the James P. Wilmot Cancer Center
Rochester
USA




Attilio Orazi
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Attilio Orazi
Department of Pathology and Laboratory Medicine
Weill Medical College of Cornell University
New York
USA




Jrgen Thiele
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Jrgen Thiele
Institute of Pathology
University of Cologne
Cologne
Germany




Eva Hellstr闣-Lindberg
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Eva Hellstr闣-Lindberg
Department of Medicine, Division of Hematology
Karolinska University Hospital
Stockholm
Sweden