Systemic Mastocytosis Workup

Updated: May 09, 2017
  • Author: Koyamangalath Krishnan, MD, FRCP, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Workup

Laboratory Studies

The peripheral blood picture can show anemia, thrombocytopenia, and leukocytosis. The most common abnormality found in the peripheral blood is anemia (45%). In some patients with systemic mastocytosis, the following abnormalities can be observed in peripheral blood:

  • Eosinophilia
  • Basophilia
  • Thrombocytosis
  • Monocytosis

Total serum tryptase levels of 20 ng/mL or higher in a baseline serum sample that is associated with a ratio of total–to–beta-tryptase ratio greater than 20:1 is suggestive of systemic mastocytosis. [8] More than 50% of patients reveal a high tryptase level using the cut-off value of 11.5 ng/mL. However, a normal serum tryptase level does not exclude the diagnosis of systemic mastocytosis. [26]

Measurements of urinary N -methyl imidazole are useful in some patients with systemic mastocytosis.

Lueke et al developed an assay for measurement of urinary leukotriene E4 (LTE4) and confirmed that median urine LTE4 concentrations were significantly higher in patients with systemic mastocytosis (median 97 pg per mg creatinine versus 50 pg/mg cr.; P<0.01), with 48% sensitivity and 84% specificity for the disorder. These authors incorporated LTE4 into a panel of urinary biomarkers to provide a screening tool for systemic mastocytosis. [27] Additional biomarker results and accuracy were as follows:

  • N-methyl histamine (NMH): >200 ng/mL – Clinical sensitivity 71%
  • 11ß-prostaglandin F2α (BPG): >1000 ng/mL  – Clinical sensitivity  53%  

 

 

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Imaging Studies

Some imaging studies may be necessary in patients with systemic mastocytosis in order to identify the extent and stage of the disease, as follows:

  • Patients with abdominal pain may require GI radiography, ultrasonography, or liver-spleen computed tomography (CT) scanning
  • Skeletal surveys and bone CT scanning may be necessary in patients with suspected bone involvement.
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Other Tests

Cytogenetic data indicate that about 20% of patients with systemic mastocytosis have an abnormal karyotype. These include trisomy 8; monosomy 7; del (13q); del(5q); trisomy 10, 6, and 19; del(20q); and trisomy X. Cytogenetic abnormalities are more often seen with aggressive systemic mastocytosis (ASM) and systemic mastocytosis with associated hematological non–mast cell disorder (SM-AHNMD) than with indolent systemic mastocytosis. [7]

Molecular testing for KIT D816V mutation is universally positive, whereas JAK2 V617F is rarely positive (4%).

The mast cell clone is CD117 positive and CD25 and/or CD2 positive.

Bone marrow mast cells reveal 54% CD2 positivity and 93% CD25 positivity on flow cytometry, whereas on immunohistochemistry CD2 positivity is 17% and CD25 positivity is 100%. [7]

Expression of CD25 on mast cells is seen in systemic mastocytosis but is not noted in reactive states of mast cell hyperplasia. [28]

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Procedures

The following procedures may be indicated in patients with systemic mastocytosis:

  • When GI symptoms are present, perform GI procedures (eg, barium studies, endoscopy) to help confirm the diagnosis
  • Patients with hepatomegaly can show evidence of mast cell infiltration on liver biopsy specimens
  • Skin biopsy may be warranted in patients with skin manifestations
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Histologic Findings

Marrow cellularity ranges from normocellular to markedly hypercellular changes. Erythropoiesis is usually complete without any significant changes. Eosinophilia is a common finding from bone marrow histology. Hypocellular bone marrow and myelofibrosis are usually observed in late stages of systemic mastocytosis. Focal mast cell lesions in the bone marrow are found in approximately 90% of affected adult patients. A bone marrow smear is shown below.

Bone marrow aspirate, Romanowsky stain, high-defin Bone marrow aspirate, Romanowsky stain, high-definition magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a bone marrow smear from a patient with systemic mastocytosis. Several mast cells are present in this photograph. These mast cells are larger than normal mast cells and have more irregularly shaped nuclear outlines and less densely packed mast cell granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

A typical mast cell has a spindle-shaped nucleus and fine eosinophilic granules visualized at high magnification. These cells are likely to return positive findings upon Giemsa staining. Other stains used to identify mast cells are toluidine blue, chloroacetate esterase, aminocaproate esterase, and tartrate-resistant acid phosphatase. Examples are shown in the images below.

Bone marrow aspirate, toluidine stain, low magnifi Bone marrow aspirate, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cells. This is a toluidine blue stain of a bone marrow smear from a patient with marrow involvement by systemic mastocytosis. Five mast cells are present in this field. The mast cell granules are metachromatic with the toluidine blue reaction. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
Bone marrow biopsy, toluidine stain, low magnifica Bone marrow biopsy, toluidine stain, low magnification. Diagnosis is mastocytosis, and morphology is abnormal mast cell infiltrate. This is a toluidine blue stain of a bone marrow biopsy from a patient with systemic mastocytosis. The mast cells are metachromatic with toluidine blue and contain numerous purple granules. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

The peripheral blood picture can show anemia, leukopenia, thrombocytopenia, and lymphopenia. The most common abnormality found in the peripheral blood is anemia. Eosinophilia, leukocytosis, basophilia, thrombocytosis, and monocytosis can be observed in some patients.

Spleen and lymphoid tissue involvement is an important manifestation in systemic mastocytosis. Mast cell infiltrates in the spleen can cause nodular areas that could be confused with lymphomas. A biopsy sample from the spleen can reveal findings similar to a myeloproliferative disorder or hairy cell leukemia. Histopathology of the spleen can show two types of involvement: (1) diffuse infiltration of the red pulp and sinuses and (2) focal infiltration of the white pulp.

Lymph node biopsy can show mast cell infiltrates, particularly in the paracortex. Follicles and medullary involvement can be observed in some cases. Lymph node biopsy samples are shown below.

Lymph node biopsy. Diagnosis is mastocytosis, morp Lymph node biopsy. Diagnosis is mastocytosis, morphology is mast cell infiltrate, and the organ is the lymph nodes. This is a lymph node biopsy from a person with systemic mastocytosis. The mast cells have a characteristic perifollicular distribution. Courtesy of the American Society of Hematology Slide Bank. Used with permission.
Lymph node biopsy, chloroacetate esterase stain. D Lymph node biopsy, chloroacetate esterase stain. Diagnosis is mastocytosis, and morphology is mast cell infiltrate. This is a portion of a lymph node biopsy from a patient with systemic mastocytosis. The mast cells are chloroacetate esterase positive, which is characterized by an orange granular appearance. Courtesy of the American Society of Hematology Slide Bank. Used with permission.

Diagnostic criteria

Major diagnostic criteria for systemic mastocytosis are as follows:

  • Dense infiltrates of mast cells can be seen in bone marrow or other extracutaneous tissues
  • Mast cells should be seen in aggregates of 15 or more
  • Tryptase immunohistochemistry or metachromatic staining (eg, Giemsa, toluidine blue) should be used to confirm the presence of mast cells; immunohistochemical staining for mast cells is more reliable than metachromatic staining

Major criteria may be absent in early disease. In this situation, the minor criteria are used to make the pathological diagnosis. Three of the following four minor criteria are required to make the diagnosis:

  • Atypical mast cell morphology in 25% or more of the mast cells
  • Expression of CD2, CD25, or both in addition to normal mast cell markers
  • Serum/plasma tryptase levels greater than 20 ng/mL
  • A codon-816 c- kit mutation in peripheral blood, bone marrow, or involved tissue

Types of mastocytosis

The World Health Organization classification includes the following types of mastocytosis:

  • Cutaneous mastocytosis
  • Indolent systemic mastocytosis (systemic mast cell disease)
  • Systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease
  • Aggressive systemic mastocytosis
  • Mast cell leukemia
  • Mast cell sarcoma
  • Extracutaneous mastocytoma
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Staging

A classification for mastocytosis provided by Metcalfe in 1991 includes four categories. [29]

Category I is indolent mastocytosis, with the following subcategories:

  • Category IA is associated with skin involvement
  • Category IB is associated with systemic involvement, with or without skin involvement

Category II is associated with a hematopoietic disorder, as follows:

  • Category IIA is a dysmyelopoietic disorder
  • Category IIB encompasses myeloproliferative disorders
  • Category IIC is acute nonlymphocytic leukemia
  • Category IID is malignant lymphoma
  • Category IIE is chronic neutropenia

Category III is associated with mast cell leukemia.

Category IV is associated with lymphadenopathic mastocytosis with eosinophilia (aggressive mastocytosis).

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Bone Marrow Biopsy

Bone marrow aspiration and biopsy is essential for the diagnosis of systemic mastocytosis. [30] Histologic findings provide both major and minor diagnostic criteria.

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