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Systemic Mastocytosis

Posted on April 15 2013

Systemic Mastocytosis
Case Study

Systemic Mastocytosis is frequently associated with somatic activating point mutations with KIT, with the most commonly observed mutation being the D816V gain-of function point mutation (occurring in >95% of mutated cases).  This mutation provides relative resistance to imatinib, the prototypical tyrosine kinase inhibitor.

History:

A 45 year old man presents with occasional episodes of sweating, diarrhea, tachycardia, flushing, and syncope over previous four years.  Laboratory data shows an increased tryptase level. A bone marrow biopsy was performed.

Microscopic Findings:

Bone marrow examination revealed few small paratrabecular lymphoid aggregates consisting of small unremarkable lymphocytes with admixed cells with spindle-shaped nuclei and well-defined cytoplasmic borders in a fibrotic stroma. The aggregates also contained an infiltrate of unremarkable eosinophils.  Aspirate smear morphology was unremarkable with no aggregates seen.

Special Studies:

Flow Cytometry
No aberrant immunophenotypic expression detected, no increased or aberrant mast cells (<0.1% of sample).

Immunohistochemistry
A CD117 stain was positive in the spindled cells consistent with mast cells, comprising less than 10% of the overall bone marrow cellularity.  A CD2 stain was positive in the mast cells.

Conventional Cytogenetics
Normal male karyotype 46,XY

Molecular
Kit (D816V) mutation testing by PCR – Insufficient nucleic acids to obtain valid result

Differential Diagnosis

Reactive mast cell infiltrate vs. systemic mastocytosis

Diagnosis

Normocellular marrow involved by systemic mastocytosis (comprising less than 10% of the marrow cellularity).

Educational comments:   

The diagnosis of systemic mastocytosis (SM) can be made when multifocal, dense infiltrates of mast cells are present in bone marrow or other extracutaneous organs.  Additionally, one of the following criteria must be met:

a) >25% of the mast cells are spindle-shaped or have atypical morphology

b) Detection of the D816V KIT mutation

c) Mast cells express CD2 and/or CD25

d) Serum total tryptase persistently exceeds 20 ng/mL

SM is frequently associated with somatic activating point mutations with KIT, with the most commonly observed mutation being the D816V gain-of function point mutation (occurring in >95% of mutated cases).  This mutation provides relative resistance to imatinib, the prototypical tyrosine kinase inhibitor.

Most patients with SM have indolent systemic mastocytosis (ISM), which requires an absence of cytopenias, hepatosplenomegaly, skeletal involvement, and GI mast cell infiltrates. These patients tend to have a benign course with survival similar to the general population.  Treatment in these patients is usually palliative and directed towards the symptoms. Advanced systemic mastocytosis has a more aggressive prognosis, and there are no current effective therapies for the majority of patients, although new tyrosine kinase inhibitors targeting the KIT kinase are being developed.

Due to the associated fibrosis often seen in SM, aspirate samples usually lack the neoplastic mast cells, and molecular testing is often limited to the formalin-fixed paraffin-embedded tissue.  In the current case, Kit (D816V) mutation testing was attempted on the paraffin block, and unfortunately, an insufficient amount of DNA was extracted to perform the assay.  However, sufficient criteria were met to establish a diagnosis of SM.

 

Fig. 1 H&E showing paratrabecular aggregate of “spindled” mast cells in a fibrotic background
H&E

Fig. 2 CD117 stain showing positivity in the mast cell infiltrate
CD117 Stain

Fig. 3 CD25 stain showing positivity in a pattern similar to CD117,
and therefore establishing aberrant expression in the mast cells
CD25 Stain

References:

Pardanani, A. Systemic mastocytosis in adults: 2012 update on diagnosis, risk-stratification and management. Am J Hematol. 2012 Apr;87(4):401-11

Sperr WR, Valent P. Diagnosis, progression patterns an prognostication in mastocytosis.  Expert Rev Hematol. 2012 Jun;5(3):261-74


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