Mast Cell Disease

Mast Cell Disease
Carlos E. Bueso-Ramos, MD, PhD
Roberto N. Miranda, MD
L. Jeffrey Medeiros, MD
Key Facts
Clinical Issues
  • Multiple clinical variants; common variants are
    • Cutaneous mastocytosis
    • Indolent systemic mastocytosis
    • Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease
    • Aggressive systemic mastocytosis
  • Cutaneous mastocytosis is localized to skin
  • Systemic mastocytosis usually involves bone marrow
    • Less often: Spleen, lymph nodes, and liver ± skin
Microscopic Pathology
  • Lymph node
    • Mast cells usually present in interfollicular or diffuse pattern
    • Mast cells have clear/pale cytoplasm with abundant fine granules
    • Delicate sclerosis; eosinophils are common
Ancillary Tests
  • Mast cells have metachromatic granules: Giemsa(+), toluidine blue(+), chloroacetate esterase(+)
  • Immunophenotype: Tryptase(+), CD117/KIT(+), aberrant CD2(-/+), CD25(+/-)
  • ± activating KIT point mutation D816V
Top Differential Diagnoses
  • Mast cell hyperplasia
  • Acute myeloid leukemia with tryptase(+) blasts
  • Myeloid and lymphoid neoplasms with PDGFRA rearrangements
  • Nodal marginal zone B-cell lymphoma
Mast cell disease involving skin. Note macular or maculopapular brown skin lesions. The pigmentation is usually caused by an intraepidermal accumulation of melanin.
Cutaneous mastocytosis displaying an interstitial image and perivascular image mast cell infiltrate. This infiltrate in an adult should prompt staging to exclude systemic mastocytosis.
TERMINOLOGY
Abbreviations
  • Systemic mast cell disease (SMCD)
Synonyms
  • Systemic mastocytosis (SM)
Definitions
  • Neoplastic proliferation of mast cells (MC), usually involving cutaneous and extracutaneous sites
  • SMCD is often divided into clinicopathologic subtypes
    • Cutaneous mastocytosis (CM): Skin is sole site of disease
    • Systemic mastocytosis (SM): Involvement of at least 1 extracutaneous site
      • ± skin disease
CLINICAL ISSUES
Epidemiology
  • Age
    • Wide range; mean is 60 years
    • CM occurs mainly in children
      • ˜ 50% of affected children are < 6 months of age
  • Gender
    • Slight male predominance
Site
  • SM usually involves bone marrow (BM), spleen
    • Less frequently lymph node, liver, ± skin
  • CM is disease confined to skin
Presentation
  • Indolent to aggressive disease ± multiorgan involvement
  • Skin manifestations
    • CM refers to disease restricted to cutaneous sites
      • Urticaria pigmentosa (UP)/maculopapular CM
      • Macules or macules and papules with melanin pigmentation
      • Lesions may urticate when stroked (Darier sign)
      • Affects mainly children
    • Usually associated with pruritus, urticaria, and dermographism
    • ˜ 10% of patients with UP have SM; indolent > aggressive SM
      • Lesions in adults tend to appear as disseminated macules and papules
    • Diffuse CM
      • Diffuse thickening of skin
      • Almost exclusively in children
    • Solitary mastocytoma of skin
      • Single lesion without predilection for presenting site; mostly in infants
  • Constitutional symptoms
    • Fatigue, fever, weight loss
  • Musculoskeletal manifestations
    • Bone pain ± pathologic fractures
    • Arthralgias, myalgias
  • Mediator-related systemic events
    • Flushing, syncope, headache, anaphylaxis
    • Abdominal pain, diarrhea, nausea, and vomiting
    • Hypotension, tachycardia, respiratory symptoms
  • Splenomegaly more frequent than hepatomegaly or lymphadenopathy
Laboratory Tests
  • Serum tryptase persistently > 20 ng/mL is a minor diagnostic criterion
  • Hematologic manifestations
    • Anemia; hemoglobin (Hb) < 10 g/dL is a “C” finding
    • ± leukocytosis, eosinophilia, monocytosis
    • ± leukopenia; absolute neutrophil count (ANC) < 1.0 x 109/L is a “C” finding
    • Thrombocytosis or thrombocytopenia; platelet count < 100 x 109/L is a “C” finding
Natural History
  • CM is usually self-limited
  • Indolent SM is characterized by
    • Limited lesions, mild symptoms, prolonged course
  • Aggressive SM is characterized by
    • BM or multiorgan dysfunction (“C” findings)
Treatment
  • Osteoporosis often responds to bisphosphonates
  • Patients with SM usually have slowly progressive disease
    • Interferon-α, 2-chlorodeoxyadenosine
  • Patients with SM and rapidly progressive disease &/or mast cell leukemia
    • Polychemotherapy
    • Hematopoietic stem cell transplant
  • SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD)
    • Therapy mainly directed to AHNMD component
Prognosis
  • Excellent prognosis for patients with CM and indolent SM
  • Patients with aggressive SM have poor prognosis
  • Poor prognosis when associated with BM or organ dysfunction
Cutaneous Mastocytosis: Diagnostic Criteria
  • Skin lesions associated with typical clinical findings of UP
    • Less frequent diffuse CM or solitary mastocytoma
  • Typical histological infiltrates of mast cells in multifocal or diffuse pattern
  • Absence of features/criteria that establish diagnosis of SM
Systemic Mastocytosis: Diagnostic Criteria
  • Diagnosis requires 1 major criterion and 1 minor criterion, or at least 3 minor criteria
  • Tissue diagnosis based on examination of BM or extracutaneous organs
  • Major criterion
    • Multifocal, dense infiltrates of mast cells (≥ 15 mast cells per aggregate)
  • Minor criteria
    • > 25% of mast cells in infiltrate are spindle-shaped or have atypical morphology or
    • > 25% of mast cells in BM aspirate smears are immature or atypical
    • Detection of an activating point mutation at codon 816 of KIT (usually D816V) in BM, blood, or another extracutaneous organ
    • Mast cells in BM, blood, or other extracutaneous organs express CD2 &/or CD25
    • Serum total tryptase persistently exceeds 20 ng/mL
      • Except when there is associated clonal myeloid neoplasm
Criteria for Variants of Systemic Mastocytosis
  • All variants meet criteria for SM; in addition, distinctive features and subgroups are described
  • Extracutaneous mastocytoma
    • Unifocal mast cell tumor with low-grade cytology and without destructive growth pattern
    • No evidence of SM; no skin lesions
  • Indolent SM
    • No “C” findings; no evidence of SM-AHNMD
    • Subtype: BM mastocytosis
      • Absence of skin lesions
    • Subtype: Smoldering SM
      • ≥ 2 “B” findings and no “C” findings
  • SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD)
    • Meets criteria for AHNMD, which include
      • Myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, lymphomas, or other hematological neoplasm
      • Associated neoplasm meets criteria for distinct entity as defined in WHO classification
      • Poor prognosis
  • Aggressive SM
    • 1 or more “C” findings; no evidence of mast cell leukemia; usually without skin lesions
    • Subtype: Lymphadenopathic mastocytosis with eosinophilia
      • Progressive lymphadenopathy with peripheral blood eosinophilia
      • Often with extensive bone involvement and hepatosplenomegaly; usually without skin lesions
  • Mast cell leukemia
    • BM biopsy specimen showing diffuse, compact infiltration by atypical, immature mast cells
    • BM aspirate smears show 20% or more mast cells
    • Mast cells usually account for ≥ 10% of peripheral blood white cells
    • Usually without skin lesions
  • Mast cell sarcoma
    • Unifocal mast cell tumor with destructive growth pattern and high-grade cytology
    • No evidence of SM
“B” Findings
  • BM biopsy specimen showing > 30% infiltration by mast cells (focal, dense aggregates) &/or serum total tryptase level > 200 ng/mL
  • Signs of dysplasia or myeloproliferation in non-mast cell lineage(s)
    • But insufficient criteria for diagnosis of clonal hematopoietic non-mast cell neoplasm (AHNMD)
      • Normal or only slightly abnormal blood counts
  • Hepatomegaly without liver dysfunction &/or
    • Splenomegaly without hypersplenism &/or
    • Lymphadenopathy on palpation or imaging
“C” Findings
  • BM dysfunction manifested by 1 or more cytopenias (ANC < 1.0 x 109/L, Hb < 10 g/dL, or platelet count < 100 x 109/L)
    • But no obvious clonal hematological non-mast cell hematopoietic disorder
  • Palpable hepatomegaly with impairment of liver function, ascites, &/or portal hypertension
  • Skeletal involvement with large osteolytic lesions &/or pathological fracture(s)
  • Palpable splenomegaly with hypersplenism
  • Malabsorption with weight loss due to mast cell infiltrates in gastrointestinal tract
IMAGE FINDINGS
Radiographic Findings
  • Radiograph of bone and bone mineral density assessment show
    • Osteosclerosis in ˜ 80% of patients
    • Osteoporosis in ˜ 30% of patients; mixed osteolytic and osteosclerotic lesions
    • Rare vertebral fracture, osteolytic lesions
    • No skeletal alterations in ˜ 20% of patients
CT Findings
  • Loss of corticomedullary differentiation in bones of axial skeleton
  • Thickening of cortical bone in appendicular skeleton
    • Can mimic myelofibrosis and osteosclerosis
  • Increased fluorodeoxyglucose (FDG) uptake in cortical bone by FDG-PET/CT scan
MACROSCOPIC FEATURES
General Features
  • Cut surface of spleen reveals micronodules and fibrous streaks
  • Lymph nodes are firm
MICROSCOPIC PATHOLOGY
Cytologic Features
  • Medium-sized round, oval, or spindled cells
  • Abundant pale/clear cytoplasm and indented nuclei
Cutaneous Mastocytosis
  • Spindle-shaped mast cells in papillary dermis that may extend to reticular dermis
    • Usually perivascular or periadnexal
    • Lesions in adults reveal relatively fewer mast cells than lesions in children
  • Diffuse CM
    • Sheets of mast cells filling papillary and upper reticular dermis
  • Solitary mastocytoma of skin
    • Large aggregates or sheets of mast cells that may extend into subcutaneous tissue
    • Mast cells with abundant granular cytoplasm
Bone Marrow
  • Multifocal, compact infiltrates of ≥ 15 mast cells in BM biopsy or clot specimen
    • Major diagnostic criterion for SM
  • Monomorphic, spindle-shaped mast cells that affect or stream along bone trabeculae
  • Mast cells appear as oval to spindle cells with faintly visible granules filling cytoplasm
    • Oval, round, elongated, or bilobed nuclei
      • Clumped chromatin with indistinct nucleoli
  • Predominantly paratrabecular or perivascular
  • Reticulin fibrosis within mast cell clusters and thickening of adjacent bone
  • Variable mixture of lymphocytes, eosinophils, histiocytes, and fibroblasts
  • Rarely, compact infiltrates composed of round, hypergranular MC
    • Tryptase(+) round cell infiltration of BM (TROCI-BM)
  • BM aspirate smears
    • Mast cells are found within fair distance from particles
    • ≥ 20% mast cells in BM aspirate smears indicate mast cell leukemia
  • BM not affected by SM
    • Normal distribution of fat and hematopoietic precursors
    • If abnormal, hypercellularity requires exclusion of MPN, MDS, or MDS/MPN
      • Also exclude lymphoproliferative disorders, plasma cell myeloma, lymphoma
Spleen
  • Splenomegaly in 25-40% of patients
  • “C” finding, if associated with hypersplenism
  • Clusters of mast cells with sclerosis around Malpighian follicles
    • Often associated with fibrosis or eosinophils
  • Less frequently, diffuse infiltration of parenchyma with minimal sclerosis
Liver
  • “C” finding, if associated with liver dysfunction
  • Small mast cell clusters in periportal tracts or in sinusoids
  • Mast cell clusters associated with fibrosis or eosinophils
Lymph Node
  • Eosinophils are commonly associated with mast cells; may be numerous
  • Mast cell infiltrate can be centered on arterioles
  • Mast cell infiltrate may be accompanied by
    • Prominent vascular proliferation
    • Follicular lymphoid hyperplasia
  • Lymphadenopathic mastocytosis with eosinophilia is rare subtype (˜ 10%)
    • Prominent, rapid development of lymphadenopathy with mast cell infiltrate
    • Peripheral blood eosinophilia
    • Features may be similar to cases with rearrangements of PDGFRα
Bone
  • Osteosclerotic or osteolytic lesions can be found
  • “C” finding, when large osteolytic lesions or pathologic fractures present
  • Irregular remodeling of bone trabeculae
Gastrointestinal Tract Mucosa
  • Mast cells can infiltrate mucosa; a “C” finding when associated with malabsorption and weight loss
    • Diffuse or multifocal mucosal lesions throughout intestines
  • Gastric rugal hypertrophy or flattening of folds
Histochemical Stains Helpful for Diagnosis
  • Naphthol AS-D chloroacetate esterase
  • Giemsa and toluidine blue highlight metachromatic cytoplasmic granules
ANCILLARY TESTS
Histochemistry
  • Wright-Giemsa stain
    • Reactivity: Positive
    • Staining pattern
      • Cytoplasmic
  • Toluidine blue
    • Reactivity: Positive
    • Staining pattern
      • Cytoplasmic
Immunohistochemistry
  • Tryptase(+), CD117/CKIT(+)
    • Highly sensitive for detecting mast cells
    • Tryptase helpful for identifying multifocal, compact infiltrates of atypical mast cells
  • CD25(+/-), CD2(-/+)
    • Aberrantly expressed by neoplastic mast cells
  • CD43(+), CD68(+/-), chymase(+/-)
  • B-cell antigens(-), CD3(-), CD5(-), CD7(-), MPO(-)
  • CD15(-), CD21(-), CD30(-), CD34(-)
  • MIB1/Ki-67 usually low
Flow Cytometry
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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Mast Cell Disease

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