The Provider Primer Series: Diagnostic criteria of systemic mastocytosis and all subvariants

World Health Organization Classification

  • Mastocytosis was classified by the WHO as a myeloproliferative neoplasm for a number of years. In 2016, the WHO placed mastocytosis into its own category, separate from myeloproliferative neoplasms.
  • In a paper summarizing changes to WHO classification of myeloid neoplasms and acute leukemias, the author stated that “mastocytosis…is no longer considered a subgroup of the MPNs due to its unique clinical and pathologic features, ranging from indolent cutaneous disease to aggressive systemic disease, and is now a separate disease category in the classification[i].”
Table 1: WHO Classification of Mastocytosisi
Category Subtype
Cutaneous mastocytosis (CM) Cutaneous mastocytosis (CM), including maculopapular cutaneous mastocytosis (MPCM, previously called urticaria pigmentosa); solitary mastocytoma of the skin; diffuse cutaneous mastocytosis*Author’s note: Telangiectasia macularis eruptiva perstans (TMEP) is considered a variant of maculopapular cutaneous mastocytosis (MPCM, previously called urticaria pigmentosa)
Systemic mastocytosis (SM) Indolent systemic mastocytosis (ISM)
Smoldering systemic mastocytosis (SSM)
Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)
Aggressive systemic mastocytosis (ASM)
Mast cell leukemia (MCL)
Mast cell sarcoma (MCS) Mast cell sarcoma (MCS)

 

Diagnostic criteria for subvariants of systemic mastocytosis

Table 2: Diagnostic criteria for indolent systemic mastocytosis[ii] 1 major and 1 minor criterion; or 3 minor criteria
Major Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ
Minor In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal. Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Baseline serum tryptase of 20 ng/ml or higher.

 

Table 3: Examples that meet minimum criteria for indolent systemic mastocytosis
Scenario 1:

1 major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ Minor criterion: Baseline serum tryptase of 20 ng/ml or higher.
Scenario 2:

major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous. Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 3:

1 major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ
Scenario 4:

1 major criterion, 1 minor criterion

Major criterion: Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25
Scenario 5:

3 minor criteria

Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Minor criterion: Baseline serum tryptase of 20 ng/ml or higher.
Scenario 6:

3 minor criteria

Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 7:

3 minor criteria

Minor criterion: Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Minor criterion:Baseline serum tryptase of 20 ng/ml or higher. Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal
Scenario 8:

3 minor criteria

Minor criterion: In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal Minor criterion:Baseline serum tryptase of 20 ng/ml or higher. Minor criterion: Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is essentially treated as two separate condition: systemic mastocytosis and an associated hematologic neoplastic condition. Accordingly, the diagnostic criteria for the systemic mastocytosis aspect of this diagnosis is the same as described here.

Table 4: Diagnostic criteria for smoldering systemic mastocytosis (2 or 3 B findings)[ii]
B findings Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Table 5: Examples that meet the criteria for smoldering systemic mastocytosis (2 or 3 B findings)
Scenario 1:

2 B findings

Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN
Scenario 2:

2 B findings

Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)
Scenario 3:

2 B findings

Meets criteria for systemic mastocytosis Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)
Scenario 4:

3 B findings

Meets criteria for systemic mastocytosis Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Table 6: Diagnostic criteria for aggressive systemic mastocytosis (1 or more C finding)[ii]
C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

Table 7: Examples that meet the minimum criteria for aggressive systemic mastocytosis (1 or more C finding) 
Scenario 1:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl)
Scenario 2:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Malabsorption evidenced by low albumin and weight loss
Scenario 3:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)
Scenario 4:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension
Scenario 5:

1 C finding

Meets criteria for systemic mastocytosis 1 or more B findings may be present, not a requirement Splenomegaly with hypersplenism

 

Table 8: Diagnostic criteria for mast cell leukemia[iii]
Meets criteria for systemic mastocytosis Mast cells compromise 20% of all nucleated cells in blood smears

 

Table 9: Examples that meet the minimum criteria for mast cell leukemia
Scenario 1 Meets criteria for systemic mastocytosis B findings may be present but are not required C findings may be present but are not required Mast cells compromise 20% of all nucleated cells in blood smears

 

[i] Arber DA, et al. (2016). The 2016 revisioin to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391-2405.

[ii] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10

[iii] Valent P, et al. (2014). Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol, 25(9), 1691-1700.