Refractory Cytopenia of Childhood

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.


Primary Author(s)*

Xiaoli Du, Ph.D; Teresa A. Smolarek, Ph.D, FACMG

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.

Cancer Category/Type

Myelodysplastic Syndrome

Cancer Sub-Classification / Subtype

Refractory Cytopenia of Childhood

Definition / Description of Disease

Refractory Cytopenia of Childhood (RCC) is a low-grade MDS most common in childhood, which is characterized by <2% blood blasts and <5% bone marrow blasts and persistent cytopenia[1]. Since more than 80% RCC has a hypocellular bone marrow, it is important to distinguish RCC with aplastic anemia from other bone marrow failure disorders[2]. Aplastic anemia is an autoimmune-mediated disorder, while RCC is caused by a clonal stem cell defect with the potential to progress to an advanced disease. The presence of micromegakaryocytes is a strong indicator of RCC. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment[3].  

Synonyms / Terminology

Refractory Cytopenia of Childhood (RCC)

Epidemiology / Prevalence

RCC accounts for 50% of all cases of MDS[3] [4][5].

  • Most common childhood MDS
  • No significant sex predilection

Clinical Features

The clinical symptoms are usually related to cytopenia such as anemia, bleeding tendency, and infection. However, approximately 20% of patients have no clinical symptoms or signs[6].

  • Hemoglobin concentration: <10 g/dL AND
  • Platelet count: <150 x109/L

Sites of Involvement

Peripheral blood and bone marrow

Morphologic Features

The main morphologic features of the peripheral blood smear and bone marrow are for the diagnosis of RCC[3].

Categories Morphologic Features
Peripheral blood Anisopoikilocytosis and macrocytosis; neutropenia with pseudo-Pelger-Huet nulei, hypogranularity or agranularity,
Bone marrow aspirate/biopsy Erythropoiesis: immature erythroid precursors, nuclear budding, multinuclearity, internuclear bridging;

Graulopoiesis: pseudo-Pelger-Huet nulei, hypogranularity or agranularity, macrocytic bands; Megakaryopoiesis: absent or very few, however, micromegakaryocyte is crucial for the diagnosis.

Immunophenotype

CD61, CD41, von Willebrand factor are useful to help detect the micromegakaryocyte. No increase of CD34 staining should be observed, which indicates the progression of high grade MDS[3].

Chromosomal Rearrangements (Gene Fusions)

No

Characteristic Chromosomal Aberrations / Patterns

Monosomy 7 (CCHMC), trisomy 8 and other abnormalities, including complex karyotypes.

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Genomic Gain/Loss/LOH

Monosomy 7 is the most frequent cytogenetic abnormality of RCC patients, followed by trisomy 8 and other abnormalities, including complex karyotypes[7][8][9].

Gene Mutations (SNV/INDEL)

  • Mutations are less common than in adult MDS with a different profile
  • Most frequent mutations: RAS/MAPK, SAMD9/SAMD9L, GATA2[10][11].

Other Mutations

No

Epigenomics (Methylation)

No

Genes and Main Pathways Involved

  • RAS/MAPK: involved in MAPK tyrosine Kinase pathway
  • SAMD9/SAMD9L: involved in regulating the growth and proliferation and differentiation of cells
  • GATA2: involved in regulating transcription of genes related with the development and proliferation of hematopoietic and endocrine cell lineages

Diagnostic Testing Methods

Bone marrow minimal histological criteria for refractory cytopenia of childhood[12][13]. Refractory cytopenia of childhood is defined as persistent cytopenia with <5% blasts in bone marrow and <2% blasts in peripheral blood. The criteria of dysplasia must be fulfilled in ≥2 cell lineages or ≥10% of cells within one cell lineage on bone marrow aspirate smears. See table:

Cellularity Erythropoiesis Granulopoiesis Megakaryopoiesis
Variable A few clusters of ≥20 erythroid precursors.

Arrest in maturation, with increased number of proerythroblasts.

Increased number of mitoses.

No minimal diagnostic criteria. Unequivocal micromegakaryocytes;

immunohistochemistry is obligatory (CD61, CD41, CD42b);

other dysplastic changes in variable numbers.

In addition, RCC must be differentiated from aplastic anemia, bone marrow failure syndromes, infection, nutritional deficiencies, and metabolic diseases.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Diagnosis: <2% blood blasts and <5% bone marrow blasts and persistent cytopenia
  • Prognosis: In RCC, patients with monosomy 7 have a higher probability of progression[14][15][16]. Patients with trisomy 8 or a normal karyotype are unlikely to progress to advanced MDS.
  • Therapeutic: Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for RCC patients. This treatment is suitable for patients with monosomy 7 or a complex karyotype in the early stage of the process. Some of the RCC patients benefit from immunosuppressive therapy, although it is unclear whether the immunosuppressive therapy has the risk of relapse long-term[17][18].

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  1. ↑ Hasle, H.; et al. (2003-02). "A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases". Leukemia. 17 (2): 277–282. doi:10.1038/sj.leu.2402765. ISSN 0887-6924. PMID 12592323. Check date values in: |date= (help)
  2. ↑ Niemeyer, Charlotte M.; et al. (2011). "Classification of childhood aplastic anemia and myelodysplastic syndrome". Hematology. American Society of Hematology. Education Program. 2011: 84–89. doi:10.1182/asheducation-2011.1.84. ISSN 1520-4383. PMID 22160017.
  3. ↑ 3.0 3.1 3.2 3.3 Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.
  4. ↑ Passmore, S. Jane; et al. (2003-06). "Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival". British Journal of Haematology. 121 (5): 758–767. doi:10.1046/j.1365-2141.2003.04361.x. ISSN 0007-1048. PMID 12780790. Check date values in: |date= (help)
  5. ↑ Germing, Ulrich; et al. (2012-06). "Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Düsseldorf Registry on myelodysplastic syndromes". Leukemia Research. 36 (6): 727–734. doi:10.1016/j.leukres.2012.02.014. ISSN 1873-5835. PMID 22421409. Check date values in: |date= (help)
  6. ↑ Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
  7. ↑ Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
  8. ↑ Niemeyer, Charlotte M.; et al. (2011). "Classification of childhood aplastic anemia and myelodysplastic syndrome". Hematology. American Society of Hematology. Education Program. 2011: 84–89. doi:10.1182/asheducation-2011.1.84. ISSN 1520-4383. PMID 22160017.
  9. ↑ Gupta, Ruchi; et al. (2018-10). "Prevalence of Chromosome 7 Abnormalities in Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Single Center Study and Brief Literature Review". Indian Journal of Hematology & Blood Transfusion: An Official Journal of Indian Society of Hematology and Blood Transfusion. 34 (4): 602–611. doi:10.1007/s12288-018-0941-1. ISSN 0971-4502. PMC 6186231. PMID 30369728. Check date values in: |date= (help)
  10. ↑ Schwartz, Jason R.; et al. (2017-11-16). "The genomic landscape of pediatric myelodysplastic syndromes". Nature Communications. 8 (1): 1557. doi:10.1038/s41467-017-01590-5. ISSN 2041-1723. PMC 5691144. PMID 29146900.
  11. ↑ Wlodarski, Marcin W.; et al. (2016-03-17). "Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents". Blood. 127 (11): 1387–1397, quiz 1518. doi:10.1182/blood-2015-09-669937. ISSN 1528-0020. PMID 26702063.
  12. ↑ Arber DA, et al., (2016). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J Editors. IARC Press: Lyon, France, p106-109.
  13. ↑ Iwafuchi, Hideto (2018). "The histopathology of bone marrow failure in children". Journal of clinical and experimental hematopathology: JCEH. 58 (2): 68–86. doi:10.3960/jslrt.18018. ISSN 1880-9952. PMC 6413145. PMID 29998978.
  14. ↑ Passmore, S. Jane; et al. (2003-06). "Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival". British Journal of Haematology. 121 (5): 758–767. doi:10.1046/j.1365-2141.2003.04361.x. ISSN 0007-1048. PMID 12780790. Check date values in: |date= (help)
  15. ↑ Pui, Ching-Hon; et al. (2004). "Childhood and adolescent lymphoid and myeloid leukemia". Hematology. American Society of Hematology. Education Program: 118–145. doi:10.1182/asheducation-2004.1.118. ISSN 1520-4391. PMID 15561680.
  16. ↑ Kardos, Gabriela; et al. (2003-09-15). "Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7". Blood. 102 (6): 1997–2003. doi:10.1182/blood-2002-11-3444. ISSN 0006-4971. PMID 12763938.
  17. ↑ Hasegawa, Daisuke; et al. (2009-12). "Treatment of children with refractory anemia: the Japanese Childhood MDS Study Group trial (MDS99)". Pediatric Blood & Cancer. 53 (6): 1011–1015. doi:10.1002/pbc.22121. ISSN 1545-5017. PMID 19499580. Check date values in: |date= (help)
  18. ↑ Yoshimi, Ayami; et al. (2014-04). "Comparison of horse and rabbit antithymocyte globulin in immunosuppressive therapy for refractory cytopenia of childhood". Haematologica. 99 (4): 656–663. doi:10.3324/haematol.2013.095786. ISSN 1592-8721. PMC 3971075. PMID 24162791. Check date values in: |date= (help)

Notes

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