| Classification domain | WHO 5th edition / ICC 2022 update | Key details | Evidence |
|---|---|---|---|
| Disease definition | Systemic mastocytosis (SM) | Rare clonal hematopoietic/mast cell neoplasm characterized by abnormal mast cell accumulation in extracutaneous organs; diagnosis integrates morphology, immunophenotype, molecular findings, and clinical features. Adult disease is usually systemic and clinically heterogeneous. | (pqac-00000001, pqac-00000002, pqac-00000004) |
| Broad subtype grouping | Non-advanced SM | Includes bone marrow mastocytosis (BMM), indolent SM (ISM), and smoldering SM (SSM); generally lacks overt organ damage from mast cell infiltration. | (pqac-00000001, pqac-00000003, pqac-00000004) |
| Broad subtype grouping | Advanced SM | Includes aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN; ICC often uses SM-AMN for associated myeloid neoplasm), and mast cell leukemia (MCL); defined by organ damage, high disease burden, or associated hematologic malignancy. | (pqac-00000001, pqac-00000003, pqac-00000004) |
| Major diagnostic criterion | WHO 2022 / ICC 2022 | Multifocal dense aggregates of mast cells (≥15 mast cells per aggregate) in bone marrow and/or other extracutaneous organs. ICC specifies tryptase- and/or CD117-positive mast cells in tissue sections. | (pqac-00000004, pqac-00000005, pqac-00000007) |
| Minor diagnostic criterion 1 | WHO 2022 / ICC 2022 | ≥25% atypical or spindle-shaped mast cells in marrow smears/infiltrates; ICC wording emphasizes spindle-shaped or atypical immature morphology in marrow or extracutaneous tissue. | (pqac-00000005, pqac-00000007) |
| Minor diagnostic criterion 2 | WHO 2022 / ICC 2022 | Activating KIT mutation present in bone marrow, blood, or extracutaneous tissue; recent criteria accept KIT D816V or another activating KIT mutation, not only codon 816. | (pqac-00000002, pqac-00000005, pqac-00000007) |
| Minor diagnostic criterion 3 | WHO 2022 / ICC 2022 | Aberrant mast-cell expression of CD25 and/or CD2 and/or CD30. A key 2022-2023 update is incorporation of CD30 as a minor criterion. | (pqac-00000002, pqac-00000005, pqac-00000007) |
| Minor diagnostic criterion 4 | WHO 2022 / ICC 2022 | Persistent baseline serum tryptase >20 ng/mL; does not count in SM with associated myeloid neoplasm in some settings, and should be interpreted with adjustment/caution in hereditary alpha-tryptasemia. | (pqac-00000004, pqac-00000005, pqac-00000007) |
| Diagnostic rule | WHO 2022 / ICC 2022 | Diagnosis requires 1 major + 1 minor criterion, or if no major criterion is present, at least 3 minor criteria. | (pqac-00000004, pqac-00000005, pqac-00000007) |
| KIT mutation frequency | Adult SM overall | KIT mutations are present in >90% of mastocytosis/SM cases overall; KIT D816V is the dominant driver. Recent reviews report ~85–90% or >90% in adult SM; another 2023 review states ~90% of SM. | (pqac-00000002, pqac-00000004, pqac-00000005, pqac-00000009) |
| BMM | WHO 2022 recognized subtype; also retained in current frameworks | Fulfills SM criteria, no skin lesions, no B-findings/C-findings, low disease burden, and no criteria for MCL or SM-AHN. Often suspected in severe anaphylaxis without skin lesions or unexplained osteoporosis/fracture. Prognosis is generally favorable/non-advanced. | (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000008) |
| ISM | WHO 2022 recognized subtype; retained in ICC-era practice | Most common adult SM subtype; usually bone marrow infiltration <20%, no associated hematologic disease, at most 1 B-finding and no C-findings. Typical manifestations are mediator-related symptoms such as flushing, pruritus, GI symptoms, anaphylaxis, and osteoporosis/osteopenia. Life expectancy is often near normal. | (pqac-00000001, pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000005) |
| SSM | WHO 2022 recognized subtype; retained in ICC-era practice | SM with ≥2 B-findings and no C-findings; reflects higher mast cell burden than ISM and higher risk of progression to advanced SM. Clinical burden may include organomegaly without dysfunction, high tryptase, and marrow mast-cell burden. Prognosis is intermediate between ISM and advanced SM. | (pqac-00000001, pqac-00000003, pqac-00000007) |
| ASM | WHO 2022 recognized subtype; retained in ICC-era practice | Defined by one or more C-findings indicating organ damage due to mast cell infiltration. Clinical features may include cytopenias, malabsorption, hepatosplenomegaly, ascites, pathologic fractures, and organ dysfunction. Prognosis is poor relative to non-advanced SM. | (pqac-00000003, pqac-00000004, pqac-00000005, pqac-00000007, pqac-00000009) |
| SM-AHN / SM-AMN | WHO uses SM-AHN; Pardanani 2023 and ICC-focused sources emphasize SM-AMN for associated myeloid neoplasm | SM coexists with another hematologic neoplasm, commonly myeloid. Clinical course and management are strongly influenced by the associated neoplasm; tryptase may be less specific diagnostically. Prognosis is generally poor and depends on both SM burden and associated neoplasm biology. | (pqac-00000003, pqac-00000004, pqac-00000005, pqac-00000007) |
| MCL | WHO 2022 recognized subtype; retained in ICC-era practice | Rare leukemic form with very high mast cell burden; may be aleukemic in some cases. Associated with severe systemic disease, rapid progression, and the worst prognosis among SM subtypes. | (pqac-00000001, pqac-00000003, pqac-00000004, pqac-00000009) |
| B-findings | WHO/ICC disease burden markers | Used mainly to distinguish ISM from SSM; reflect high mast-cell burden without overt organ damage. Examples include high marrow mast-cell burden and markedly elevated tryptase. | (pqac-00000004, pqac-00000007) |
| C-findings | WHO/ICC organ damage markers | Define aggressive disease/ASM when organ dysfunction is attributable to mast cell infiltration; examples include cytopenias, malabsorption/weight loss, liver dysfunction/portal hypertension/ascites, large osteolytic lesions/pathologic fractures, and hypersplenism. | (pqac-00000003, pqac-00000004, pqac-00000007) |
| Frequent symptom clusters across SM | Clinical phenotype summary | Recurrent anaphylaxis, flushing, pruritus/itching, urticaria/angioedema, abdominal pain, nausea, vomiting, diarrhea, syncope/presyncope, tachycardia, osteoporosis/osteopenia, and in advanced disease cytopenias and hepatosplenomegaly. | (pqac-00000005, pqac-00000007, pqac-00000008) |
| Important 2022-2023 classification updates | WHO 5th edition / ICC 2022 | Key refinements include recognition of BMM, addition of CD30 as a minor criterion, acceptance of any activating KIT mutation as a molecular minor criterion, continued integration of marrow morphology + immunophenotype + molecular testing, and refined B-/C-finding assessment for subtype assignment. | (pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000005, pqac-00000007) |
| Prognostic modifiers beyond subtype | Molecular risk stratification | Poor-risk co-mutations include ASXL1, RUNX1, SRSF2, and NRAS; multilineage KIT involvement and additional myeloid mutations are linked to progression and worse survival, especially in advanced SM. | (pqac-00000002, pqac-00000004, pqac-00000009) |


*Table: This table summarizes systemic mastocytosis classification, diagnostic criteria, KIT mutation patterns, subtype-defining features, and prognosis using recent WHO 2022 and ICC 2022/2023-aligned sources. It is useful as a compact reference for comparing non-advanced and advanced SM entities.*