Childhood myelodysplastic neoplasm with increased blasts

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Refractory Cytopenia of Childhood.

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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.

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category Myeloid proliferations and neoplasms
Family Myelodysplastic neoplasms
Type Myelodysplastic neoplasms of childhood
Subtype(s) Childhood myelodysplastic neoplasm with increased blasts

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

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Signs and Symptoms EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

EXAMPLE: B-symptoms (weight loss, fever, night sweats)

EXAMPLE: Fatigue

EXAMPLE: Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE: Cytopenias

EXAMPLE: Lymphocytosis (low level)


editv4:Clinical Features
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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

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Finding Marker
Positive (universal) EXAMPLE: CD1
Positive (subset) EXAMPLE: CD2
Negative (universal) EXAMPLE: CD3
Negative (subset) EXAMPLE: CD4


editv4:Immunophenotype
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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)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: 3'ABL1 / 5'BCR EXAMPLE: der(22) EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add reference)

Yes No Yes EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).


editv4:Chromosomal Rearrangements (Gene Fusions)
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No


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)
  • 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[7][8][9]. 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[10][11].

Individual Region Genomic Gain / Loss / LOH

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Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7:1- 159,335,973 [hg38]

EXAMPLE:

chr7

Yes Yes No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8:1-145,138,636 [hg38]

EXAMPLE:

chr8

No No No EXAMPLE:

Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH
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Monosomy 7 is the most frequent cytogenetic abnormality of RCC patients, followed by trisomy 8 and other abnormalities, including complex karyotypes[12][13][14].

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns
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Monosomy 7 (CCHMC), trisomy 8 and other abnormalities, including complex karyotypes.

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Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


editv4:Gene Mutations (SNV/INDEL)
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  • Mutations are less common than in adult MDS with a different profile
  • Most frequent mutations: RAS/MAPK, SAMD9/SAMD9L, GATA2[15][16].

Other Mutations

No

Epigenomic Alterations

No

Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program
editv4:Genes and Main Pathways Involved
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  • 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

Genetic Diagnostic Testing Methods

Bone marrow minimal histological criteria for refractory cytopenia of childhood[17][18]. 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.

Familial Forms

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Additional Information

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References

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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. ↑ 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)
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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)
  11. ↑ 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)
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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)
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.

Notes

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