Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Mast cell neoplasms
Systemic mastocytosis


Topic Completed: 1 May 2014

Minor changes: 24 June 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed search: systemic mastocytosis

Sheren Younes, M.D.
Nikhil Sangle, M.D.
Page views in 2020 to date: 1,386
Cite this page: Younes S., Sangle N. Systemic mastocytosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/bonemarrowsystemicmastocytosis.html. Accessed September 18th, 2020.
Definition / general
  • Heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MCs) in one or more organ systems
  • Mast cells are cytologically and immunophenotypically abnormal
  • See also Cutaneous mastocytosisis
Terminology
  • According to the WHO classification 2008, mastocytosis is classified into the following categories:
    • Cutaneous mastocytosis (CM)
    • Indolent SM (low mast cell burden with no skin lesions)
    • SM associated with clonal hematologic non mast cell lineage disease (MDS, MPN, AML or lymphoma) (SM-AHNMD)
    • Aggressive SM (meets criteria for SM, no evidence of mast cell leukemia or skin involvement)
    • Mast cell leukemia (mast cells > 20% of nucleated marrow cells, aleukemic if < 10% of WBC are mast cells)
    • Extracutaneous mastocytoma (unifocal mast cell tumor with nondestructive growth pattern)
    • Mast cell sarcoma (unifocal, destructive growth pattern with high grade cytological features)
Epidemiology
  • Uncommon
  • Affects males more than females
  • Bimodal age; affects pediatric age groups and adults
  • Bone marrow and bone involvement are present in up to 90% of SM cases, followed by other organs
Etiology
  • Mast cells are derived from CD34+, c-kit+, CD13+ hematopoietic cell precursor
  • C-kit:
    • Encoded by proto-oncogene at chromosome 4
    • Type III tyrosine kinase receptor at mast cell surface
    • SCF (general hematopoietic growth factor), and other factors play role in terminal differentiation of mast cells
    • Kit is dimerized by SCF, initiates signal transduction mechanisms, cell proliferation
    • In mastocytosis, kit mutation leads to SCF independent activation of kit
    • C-kit affects cell proliferation, maturation, adhesion, chemotaxis, and survival
    • The most common KIT mutation is KITD816V, other less common mutations are KITV1815, KITD816F, and KITD820G
    • Effect of mastocytosis on bone is both direct by the neoplastic growth itself, and indirect by the release of mediators including histamine, which promotes osteoblasts and heparin, and prostaglandin D2, which induces bone resorption by activation of osteoclasts (Age Ageing 1996;25:1)
Clinical features
  • Course is variable from benign self limited to aggressive
  • Spectrum of symptoms depending on type
  • Variable symptoms of diarrhea, weight loss, weakness, fractures or osteoporosis in 25%, arthralgia, flushing, bronchospasm
  • Most commonly affected sites are skin (urticaria pigmentosa) and bone marrow
  • Serum tryptase may predict bone marrow involvement (Haematologica 2008;93:120)
  • May be associated with clonally related second myeloid neoplasm (J Clin Pathol 2004;57:604), including primary myelofibrosis (J Mol Diagn 2008;10:58)
  • Symptoms related to mast cell degranulation: episodic blisters, flushing, diarrhea, abdominal pain, musculoskeletal pain, hypotension, peptic ulcers
  • Musculoskeletal symptoms: arthralgia, myalgia, bone pain, osteoporosis and fractures
  • Symptoms related to non mast cell clonal disorders in SM-AHNMD
  • Symptoms related to clonal involvement of organ systems by mast cells: cytopenias, lymphadenopathy, hepatosplemomegally
  • C-findings: cytopenia, pathological fracture, malabsorption, hypoalbuminemia, weight loss, hepatomegally and ascitis, splenomagally and hypersplenism
  • B findings:
    • BM MCs count >30% and / or tryptase > 200 ng/mL
    • BM hypercellularity
    • Dysmyelopoiesis without cytopenia
    • Organomegally without functional impairment
Diagnosis
  • Examine bone marrow with tryptase stain to confirm presence of abnormal (spindle shaped) mast cells, use flow cytometry of bone marrow to look for CD25+ (phenotypically abnormal) mast cells, mutation screening to find KIT D816V and to exclude other abnormalities (Haematologica 2008;93:6)
  • Mastocytosis is working diagnosis if:
    • bone marrow aggregates of morphologically abnormal mast cells are present or
    • when histology is equivocal, if KIT D816V or phenotypically abnormal (CD25+) mast cells are present
    • Other requirements: no BCR–ABL, no dyserythropoiesis, no granulocyte dysplasia, no monocytosis, no rearrangements of PDGFRA, PDGFRB or FGFR1
  • Clinical manifestations
  • Serum tryptase level
  • Radiographic investigations according to affected site
  • Histopathologic examination of tissue
  • Bone marrow biopsy, with immunohistochemistry
  • Flow cytometric evaluation of CD2 and CD25
  • Genetic / molecular studies for c-kit evaluation

Diagnostic criteria, based on WHO 2008:
  • Cutaneous mastocytosis (CM):
    • Urticaria pigmentosa (UP)-like lesions, start as reddish brown macules or papules, as early as 6 months of age, tend to show improvement, no systemic symptoms, no elevated serum tryptase, no bone marrow infiltration or hematologic abnormalities, no other organ infiltration
  • Systemic mastocytosis (SM): one major criterion, and at least one minor criterion
    • Major criteria:
      • Multifocal, dense, compact (≥ 15 mast cells constitute an aggregate), in bone marrow or other organs
    • Minor criteria:
      • < 25% of MCs in bone marrow sections have spindle shape / atypical morphology, or > 25% of MCs in BM smear are atypical or immature
      • KIT activating point mutation at codon D816, in bone marrow or other extracutaneous organs
      • CD25 or CD2 expression in addition to MCs usual antigens
      • Persistently elevated serum tryptase level
  • Indolent systemic mastocytosis (ISM): meets criteria of SM with less mast cell burden, may have associated skin involvement, B findings, but no C findings
  • Systemic mastocytosis with an associated clonal hematopoietic non mast cell lineage disease (SM-AHNMD): meets criteria of SM as well as other clonal hematopoietic non mast cell neoplasm
  • Aggressive systemic mastocytosis (ASM): meets the criteria of SM, typical C findings, does not meet mast cell leukemia criteria
  • Mast cell leukemia: > 20% mast cells in BM smears or > 10% in peripheral blood
  • Mast cell sarcoma (MSS): no evidence of SM criteria, but focal destructive infiltration by clonal mast cells, high grade cytology
  • Extracutaneous mastocytoma: no evidence of SM criteria, but focal nondestructive infiltration by clonal mast cells, low grade cytology
Laboratory
  • Serum tryptase > 20 ng/mL is a minor diagnostic criterion for SM
  • Histamine metabolites in 24 hour urine sample may be present, but are not sensitive nor specific
Radiology description
  • Rarely presents as skeletal disorder (Iowa Orthop J 1996;16:126)
  • Bone radiography: in cases associated with bone marrow infiltration, diffuse, poorly demarcated, sclerotic, and lucent areas involving the axial skeleton
  • Lytic changes, osteopenia, osteonecrosis and bone destruction, which may be associated with surrounding sclerosis
  • Osteosclerosis, increased trabeculation volume, increased cortical thickness, and narrowing of marrow spaces
  • Mixed pattern
  • Changes can be diffuse or focal
  • Changes can affect the axial or appendicular skeleton
  • Pathologic fractures (Skeletal Radiol 2012;41:887)
Prognostic factors
  • Age: pediatric patients show regression at puberty, no regression in adults
  • CM and ISM have favorable prognosis, ASM and MCL do not (Blood 2009;113:5727)
  • Poor prognostic features are late age of onset, weight loss, high LDH, high alkaline phosphatase, hypoalbuminemia, cytopenias, BM hypercellularity, organomegaly, organ dysfunction, atypical morphology of mast cells (Am J Med 1991;91:612, Blood 2009;113:5727)
Case reports
Treatment
  • Careful counseling
  • Avoidance of factors that trigger disease or exacerbation
  • Symptomatic treatment
  • May not be necessary if indolent
  • IFN alpha and cladribine if systematic
  • Usually resistant to imatinib (since the D816V mutation causes ligand independent activation of KIT tyrosine kinase) (Curr Allergy Asthma Rep 2007;7:248)
Microscopic (histologic) description
  • Bone marrow and different organs are infiltrated by mast cells (MCs) according to mastocytosis type
  • Bone marrow:
    • Compact foci of ≥ 15 MCs (round or spindled), within fibrohistiocytic matrix
    • Multifocal or disseminated
    • Perivascular or peritrabecular
    • Granulomatoid appearing infiltrate of mixed cellularity
    • Admixed eosinophils, plasma cells, lymphocytes, histiocytes
    • Prominent angiogenesis
    • Hematopoiesis and percentage of fat cells are variably affected according to mastocytosis type
    • ASM: more MCs, are more atypical, hematopoietic precursors are reduced
    • CM: BM is normal
    • ISM: hematopoiesis is normal
    • MCL: extremely hypercellular, compact infiltrate, markedly depleted hematopoietic precursors and fat cells
    • SM-AHNMD: an associated hematologic, non mast cell neoplasm is present, together with mastocytosis criteria
  • Other organs:
    • CM: dermis shows perivascular and periadnexal infiltration by mast cells, no epidermotropism
    • Dense compact infiltrate of MCs in liver, spleen, lymph nodes, GI
Microscopic (histologic) images

AFIP images

Systemic mastocytosis


Systemic mastocytosis


Involving bone marrow


Images hosted on other servers:

Mast cells

Toluidine blue+

CD117



Bone marrow biopsy:

Various images

Chymase staining


Bone marrow smear:

Various images

With an associated clonal hematological non mast cell lineage disease

Cytology description
  • From BM biopsy or peripheral blood
  • Mast cell number is increased in comparison to normal count, correlates with prognosis
  • > 20% of mast cells in BM smears or > 10% in peripheral blood is diagnostic of MCL
  • Mast cells normally are round to polygonal, with round to oval nuclei, cytoplasm is packed with basophilic granules
  • Variable atypia: hypogranulation, spindling, and oval eccentric nuclei that may be multilobed
Cytology images

Cytologic spectrum


Images hosted on other servers:

Giemsa stain

Positive stains
  • Tryptase: positive in all MCs, normal or neoplastic, granular, intracytoplasmic staining
  • CD117: membranous staining, together with tryptase help differentiating MCs from basophils
  • CD2: weak positive in neoplastic MCs, even stronger in surrounding reactive lymphocytes
  • CD25: positive in neoplastic MCs
  • Others of less diagnostic utility are: CD68, CD30, CD45, VEGF, and chymase
  • CD30 is preferentially positive in MCL and ASM more than ISM (Mod Pathol 2011;24:585)
  • Also Giemsa, toluidine blue, polychrome methylene blue, chloroacetate esterase (Leder), CD9, CD33,
Negative stains
Flow cytometry description
Molecular / cytogenetics description
Differential diagnosis
  • Mast cell hyperplasia: associated with solid tumors, may be massive, but no compact BM infiltration, diffuse interstitial pattern in bone marrow, round CD25 negative mast cells, molecular studies; (Am J Clin Pathol 2005;124:560)
  • Myeloid tumors with mast cell differentiation: generally lack SM diagnostic criteria
  • Tryptase positive AML
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