Childhood MDS and Refractory Cytopenia of Childhood

Question 1

What is the incidence of MDS in children ?

Answer 1

• it can occur but is not common (< 5% of hematopoietic neoplasms patients < 14)
• some cases are secondary to cytotoxic therapy for another neoplasm or
  
  • inherited bone marrow failure syndromes or
  • acquired severe aplastic anemia
• GATA2 germline mutations
  
  • present in 7% of all primary MDS cases
  • absent in secondary MDS cases

Question 2

What are the clinical and morphologic features

of children with MDS ?

Answer 2

• many similarities in morphology, genetics and clinical presentation with some exceptions:
  
  • MDS-RS and del 5q are rare in kids
  • isolated anemia is rare in children
    
    • more likely to present with neutropenia and thrombocytopenia
  • hypocellular bone marrows are more likely

Question 3

What are the designations of MDS in children ?

Answer 3

• PB 2-19% blasts, BM 5-19% blasts = MDS-EB (similar to adult cases)
  
  • differentiating between EB-1 and EB-2 in kids may not be as important
  • some of these cases even with blasts up to 29% have MDS related dysplasia and cytogenetics
    
    • these tend to behave more like MDS rather than AML
• kids with any of the gene rearrangements that are AML defining (core-binding factor)
  
  • diagnosed as AML regardless of blast count
• Kids have more RAS pathway, transcription factor and epigenetic modifier mutations

Question 4

What is the definition of refractory

cytopenia of childhood ?

Answer 4

• provisional MDS entity
• persistitent cytopenia
• BM < 5% blasts
• PB <2%
• dysplasia

Note: must have an excellent biopsy to evaluate for this…80% of children will have considerably hypocellular marrows.

IMP: difficult to differentiate from aplastic anemia

Question 5

What is the epidemiology and etiology of

RCC ?

Answer 5

• RCC is the most common subtype of childhood MDS
  
  • 50% of all cases
• diagnosed in all age groups
• affects boys and girls with equal frequency
• underlying cause may be a germiline mutation

Note: generally the spleen, liver, and lymph nodes are not sites of initial manifestation.

Question 6

What are the clinical features of

RCC ?

Answer 6

• most common: malaise, bleeding, fever and infection
  
  • lymphadenopathy due to local or systemic infection
  • hepatosplenomegaly is not a feature
  • 20% of cases have no signs or symptoms
• anemia and thrombocytopenia are frequent
  
  • 25% of cases have severe neutropenia

Question 7

What are the microscopic findings

on the peripheral blood smear in RCC ?

Answer 7

• anisopoikilocytosis and macrocytosis
• polychromasia may be seen
• platelets with giant forms and anisocytosis
• neutropenia
  
  • pseudo pelger huet, hypogranularity to agranular cytoplasm
• blasts <2%

Question 8

What are the microscopic findings on the aspirate smears

in RCC ?

Answer 8

• dysplasia in 2 myeloid lineages in at least 10% of the cells
• erythroid dysplasia is typicaly seen
  
  • there is a predominance of left shifted erythroblasts
  • patchy immature erythroid islands (>20 cells, KEY FINDING)
• myeloblasts <5% of total cellularity
  
  • granulopoiesis is decreased
  • clusters of blasts are not a feature of RCC
• Megakaryocytes are usually absent to only very few
  
  • micromegas indicate RCC
  • IHC is mandatory to identify them
• No RS or increased reticulin should be seen

Question 9

What is necessary to establish the

diagnosis of RCC ?

Answer 9

• at least two bone marrow biopsies at least >2 weeks apart from different locations are required
  
  • this is because excess fatty tissue and hypocellularity may hide characteristic features and mimic an aplastic anemia

Question 10

What is the differential diagnosis

of RCC ?

Answer 10

• non-clonal causes
  
  • viral infection, drugs, autoimmune, nutritional deficiencies, metabolic diseases
• acquired aplastic anemia
• inherited bone marrow failure syndrome
• PNH

Question 11

What are some differences that point

towards an aplastic anemia vs. RCC ?

Answer 11

Aplastic Anemia

• adipocytosis with sparsely scattered myeloid cells
• no significant erythroid islands
• no increased erythroblasts
• no granulocytic or megakaryocytic dysplasia
  
  • esp. micromegas

good comparison table p. 119

Question 12

What is the genetic profile

of RCC ?

Answer 12

• genetic changes largely remain unknown
• GATA2 deficiency
  
  • seen in 5% of cases
  • can be associated with monosomy 7 or trisomy 8
• Monosomy 7 is the most common aberration seen in RCC

Question 13

What are the prognostic and predictive factors in RCC ?

Answer 13

• karotype has the most important factor for predicting progression to advanced MDS
• Monosomy 7 also shows higher risk of progression
• patients with trisomy 8 or normal karyotype
  
  • show more stable, protracted course of disease
• stem cell transplant is the only cure
• select patients may benefit from immunosuppressive therapy
  
  • bone marrow failure appears to be mediated in part by cytotoxic T cells