Approach Considerations
Blood studies used in the diagnosis of systemic mastocytosis incude the following:
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Complete blood cell count
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Measurement of serum tryptase
The following imaging studies may be necessary to identify the extent and stage of the disease:
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Gastrointestinal (GI) radiography, ultrasonography, and liver-spleen computed tomography scanning in patients with abdominal pain
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Skeletal surveys and bone computed tomography (CT) scanning in patients with suspected bone involvement
Diagnostic procedures are as follows:
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Bone marrow aspiration and biopsy with cytogenetic testing is essential
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GI procedures (eg, barium studies, endoscopy) are indicated for patients with GI symptoms
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Liver biopsy can show mast cell infiltration in patients with hepatomegaly
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Skin biopsy may be warranted in patients with cutaneous manifestations
The World Health Organization has established diagnostic and classification criteria for systemic mastocytosis.
Laboratory Studies
The complete blood cell count 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:
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Eosinophilia
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Basophilia
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Thrombocytosis
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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. [9] More than 50% of patients have 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. [37]
Measurements of urinary N-methylimidazole are useful in some patients with systemic mastocytosis. Donker et al reported that this marker had 95% accuracy for predicting bone marrow involvement in patients with clinical findings suggestive of indolent systemic mastocytosis. [38]
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. [39] Additional biomarker results and accuracy were as follows:
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N-methyl histamine (NMH): > 200 ng/mL – Clinical sensitivity 71%
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11ß-prostaglandin F2α (BPG): > 1000 ng/mL – Clinical sensitivity 53%
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:
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Patients with abdominal pain may require GI radiography, ultrasonography, or liver-spleen computed tomography (CT) scanning
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Skeletal surveys and bone CT scanning may be necessary in patients with suspected bone involvement.
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 hematologic non–mast cell disorder (SM-AHNMD) than with indolent systemic mastocytosis. [8]
Molecular testing for KIT D816V mutation is universally positive, whereas JAK2 V617F is rarely positive (4%). In the absence of the typical KIT D816V mutation, a search for other mutations by sequencing the entire KIT gene should be considered, as this can influence the choice of treatment. [40]
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%. [8]
Expression of CD25 on mast cells is seen in systemic mastocytosis but is not noted in reactive states of mast cell hyperplasia. [41]
Procedures
Bone marrow aspiration and biopsy is essential for the diagnosis of systemic mastocytosis. [42]
When GI symptoms are present, perform GI procedures (eg, barium studies, endoscopy) to help confirm the diagnosis. Interpretation of GI biopsies is difficult because mast cells are normally abundant in these tissues; in contrast to mast cell numbers, however, expression of CD25 on GI mast cells is a useful diagnostic marker for presence of systemic mastocytosis. [43]
Patients with hepatomegaly can show evidence of mast cell infiltration on liver biopsy specimens.
Skin biopsy may be warranted in patients with skin manifestations.
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.
Systemic mastocytosis. 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.
Systemic mastocytosis. 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.
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.
Systemic mastocytosis. 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.
Systemic mastocytosis. 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
In 2022, revised criteria for diagnosing systemic mastocytosis were released by the World Health Organization (WHO) [10] . Additionally, a clinical advisory committee (CAC) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world released the International Consensus Classification (ICC) of systemic mastocytosis. [44] The two classifications have significant concurrence although they are not identical. The WHO classification for diagnosis of systemic mastocytosis requires the presence of a major criterion plus one minor criterion, or the presence of three minor criteria; ICC requires the presence of the major criterion or at least three minor criteria. [44, 10]
Diagnostic Criteria for Systemic Mastocytosis (Open Table in a new window)
| Criteria | WHO | ICC |
|---|---|---|
| Major Criterion | Presence of multifocal and dense infiltrates of mast cells in bone marrow or in other extracutaneous tissues. Mast cells should be seen in aggregates of 15 cells or more. | Presence of multifocal dense infiltrates of tryptase- and/or CD117 positive mast cells detected in bone marrow or in other extracutaneous tissues. Mast cells should be seen in aggregates of 15 cells or more. |
Minor Criteria |
Spindle shape or atypical mast cell morphology (type I or type II) in 25% or more of the mast cells in biopsy sections of bone marrow or other extracutaneous organs | Spindle shaped or atypical immature morphology in more than 25% of mast cells in biopsy sections of bone marrow or other extracutaneous organs |
| Minor Criteria | Presence KIT-activating KIT point mutation(s) at codon 816 or in other critical regions of KIT in bone marrow or another extracutaneous organ |
Presence of KIT D816V mutation or other activating KIT mutation in bone marrow, peripheral blood, or other extracutaneous organs |
| Minor Criteria | Expression of CD25 and/or CD2 and/or CD30 in addition to normal mast cell markers |
Expression of CD25 and/or CD2 and/or CD30 in addition to normal mast cell markers |
| Minor Criteria | Serum/plasma total tryptase levels persistently greater than 20 ng/mL | Serum tryptase level persistently greater than 20 ng/mL. In cases of SM-AMN an elevated tryptase does not count as a SM minor criterion. |
Types of mastocytosis
The WHO classifies systemic mastocytosis into subtypes, depending on the presence of typical clinical findings (B and C findings). B findings, which refer to organ involvement without organ failure, are as follows [10] :
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Elevated grade of mast cell infiltration - Bone marrow biopsy showing >30% infiltration by mast cells (focal, dense aggregates) and/or serum total tryptase level >200 mg/mL and/or KIT D816V VAF ≥10% in bone marrow or peripheral blood leukocytes
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Dysmyelopoiesis - Signs of myelodysplasia or myeloproliferation in non–mast cell lineage(s) but insufficient criteria for definitive diagnosis of an associated hematologic neoplasm , with the blood picture normal or only slightly abnormal.
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Organomegaly on palpation or imaging - Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/or lymphadenopathy.
C findings, which refer to organ involvement with organ dysfunction, are as follows:
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Cytopenias – Bone marrow dysfunction manifested by one or more cytopenia (neutrophil count [ANC] < 1 × 10 9/L, hemoglobin < 10 g/dL, or platelets < 100 × 10 9/L) with no obvious non–mast cell hematopoietic malignancy.
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Palpable hepatomegaly with elevated liver enzyme levels, ascites, and/or portal hypertension.
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Skeletal involvement with large osteolytic lesions and/or severe osteoporosis and pathologic fractures.
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Palpable splenomegaly with hypersplenism.
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Malabsorption with hypoalbuminemia and weight loss due to gastrointestinal mast cell infiltrates.
WHO subtypes of systemic mastocytosis are as follows [10] :
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Bone marrow mastocytosis (BMM) – Diagnostic criteria include the presence of less than two B findings and the absence of C findings. Bone marrow aspirate smears show < 20% mast cells.
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Indolent systemic mastocytosis (ISM) – This is the most common form of systemic mastocytosis. No C findings are present. ISM follows a stable or slowly progressing clinical course and carries a good prognosis in most patients.
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Smoldering systemic mastocytosis (SSM) – Diagnostic criteria include the presence oftwo or more B findings and the absence of C findings.
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Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) – Diagnostic criteria include the presence of aclonal hematologic non–mast cell lineage disorder (eg, myelodysplastic syndrome [MDS], myeloproliferative neoplasm [MPN], acute myeloid leukemia [AML], lymphoma)
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Aggressive systemic mastocytosis (ASM) – Diagnostic criteria include the presence of C findings, with no features of mast cell leukemia.
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Mast cell leukemia (MCL) – Bone marrow biopsy shows a diffuse infiltration, usually compact, by atypical, immature mast cells. Bone marrow aspirate smears show ≥20% mast cells.
SM-AHN, ASM, and MCL are collectively referred to as advanced systemic mastocytosis.
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Systemic mastocytosis. 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.
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Systemic mastocytosis. 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.
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Systemic mastocytosis. 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.
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Systemic mastocytosis. 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.
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Systemic mastocytosis. 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.
Tables
| Criteria | WHO | ICC |
|---|---|---|
| Major Criterion | Presence of multifocal and dense infiltrates of mast cells in bone marrow or in other extracutaneous tissues. Mast cells should be seen in aggregates of 15 cells or more. | Presence of multifocal dense infiltrates of tryptase- and/or CD117 positive mast cells detected in bone marrow or in other extracutaneous tissues. Mast cells should be seen in aggregates of 15 cells or more. |
Minor Criteria |
Spindle shape or atypical mast cell morphology (type I or type II) in 25% or more of the mast cells in biopsy sections of bone marrow or other extracutaneous organs | Spindle shaped or atypical immature morphology in more than 25% of mast cells in biopsy sections of bone marrow or other extracutaneous organs |
| Minor Criteria | Presence KIT-activating KIT point mutation(s) at codon 816 or in other critical regions of KIT in bone marrow or another extracutaneous organ |
Presence of KIT D816V mutation or other activating KIT mutation in bone marrow, peripheral blood, or other extracutaneous organs |
| Minor Criteria | Expression of CD25 and/or CD2 and/or CD30 in addition to normal mast cell markers |
Expression of CD25 and/or CD2 and/or CD30 in addition to normal mast cell markers |
| Minor Criteria | Serum/plasma total tryptase levels persistently greater than 20 ng/mL | Serum tryptase level persistently greater than 20 ng/mL. In cases of SM-AMN an elevated tryptase does not count as a SM minor criterion. |
