Systemic Mastocytosis (SM)

Systemic mastocytosis is a rare hematological disease characterized by excessive proliferation of mast cells, a type of white blood cell produced in the bone marrow, throughout the body’s tissues and organs, including the skin, liver, lungs, digestive tract, bones, joints, and nerves.¹

Mast cells contain chemical inflammatory mediators such as histamine, heparin, growth factors, and cytokines, which are released during allergic reactions and immune responses to environmental triggers. These chemical mediators cause vasodilation of blood vessels and angiogenesis, producing the common symptoms of flushing and itching. More severe symptoms such as anaphylaxis, low blood pressure, vomiting, nausea, diarrhea, and abdominal cramping occur when mast cells release larger quantities of these mediators.² 

Diagnostic Criteria

In 2016, the World Health Organization (WHO) revised its classification of myeloid neoplasms, transferring systemic mastocytosis into its own disease category instead of a myeloproliferative neoplasm subgroup.³

Diagnosis of systemic mastocytosis depends on whether the specific major criterion plus 1 minor criterion OR at least 3 of the 4 minor criteria are met.^1-3

The major criterion is confirmation of multifocal infiltration of mast cells with a density of ≥15 mast cells in aggregates, located within the bone marrow and/or other extracutaneous organs upon biopsy.^3,4

The 4 minor criteria include^1-5:

• Confirmation of the KIT D816V gene mutation
• Elevated serum tryptase levels exceeding 20 ng/mL
• Pathognomonic mast cell infiltration found in biopsies of bone marrow or other extracutaneous organs where more than 25% of mast cells in the infiltrate exhibit spindle-shaped or atypical morphology OR more than 25% of mast cells in bone marrow aspirate smears are immature or atypical
• Abnormal expression of CD25, an immunohistochemical biomarker indicating neoplastic mast cell phenotype, with or without CD2

More than 80% of patients diagnosed with systemic mastocytosis exhibit a somatic (acquired) point mutation of the KIT gene at codon 816 that may be targeted by kinase inhibitors.⁴

When mast cells are activated, they release tryptase along with histamine and other mediators. Tryptase is selectively contained in the secretory granules within mast cells and not within other white blood cells like basophils. Therefore, elevated serum tryptase concentrations serve as significant indicators of mast cell activation.⁶

Mast cells originate from hematopoietic precursor cells within the bone marrow. Mast cell infiltration patterns within the bone marrow correlate with associated disease subtypes. One study evaluated the bone marrow of 57 individuals with systemic mastocytosis and 31 individuals with mast cell hyperplasia.⁷ They found 5 patterns of mast cell infiltration within the bone marrow:

• Type I: a diffuse interstitial infiltration
• Type II: a focal, dense infiltration
• Type III: a focal, dense infiltration with additional diffuse elements around focal infiltrates
• Type IV: a focal, dense infiltration with an even distribution of diffuse elements
• Type V: a diffuse, dense infiltration

Of the 31 individuals with mast cell hyperplasia, 29 demonstrated type I infiltration patterns. Type V patterns correlated significantly with mast cell leukemia. Most of the 57 individuals with systemic mastocytosis exhibited infiltration patterns II through V, with the most frequent being type IV (n=36).⁷ 

Another study compared 73 patients with systemic mastocytosis with 75 controls, 54 of whom had reactive bone marrow and 21 of whom had myelogenous neoplasms. The investigators observed that the mast cells of nearly all (72 of 73) individuals with systemic mastocytosis expressed CD25, regardless of disease subtype. In contrast, none of the individuals with reactive bone marrow or myelogenous neoplasms had mast cells expressing CD25. They concluded that CD25 reliably indicates the presence of neoplastic mast cells.⁵

Diagnosis of Disease Subtypes

Researchers have identified 5 disease subtypes within systemic mastocytosis, including indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). The latter 3 subtypes consist of more advanced cases of systemic mastocytosis.⁴

To obtain a diagnosis of a particular subtype of systemic mastocytosis, the WHO delineated 2 additional classification categories titled B-findings and C-findings.^3,4 

B-findings include³:

• Greater than 30% mast cell infiltration on bone marrow biopsy and total serum tryptase levels above 200 ng/mL
• Hepatomegaly without liver dysfunction, splenomegaly without hypersplenism, and/or lymphadenopathy
• Beginning signs of non-mast cell dysplasia or myeloproliferation with normal or mildly abnormal blood counts, but not enough to qualify for the diagnosis of an associated hematological neoplasm (AHN)

C-findings include³:

• Bone marrow dysfunction due to neoplastic mast cell infiltration as demonstrated by ≥1 cytopenia(s), including a platelet count of <100 x 10⁹/L, a hemoglobin count of <10 g/dL, and/or an absolute neutrophil count of <1.0 x 10⁹/L
• Palpable hepatomegaly with liver dysfunction, ascites, and/or portal hypertension
• Palpable splenomegaly with hypersplenism
• Malabsorption with concomitant weight loss caused by mast cell infiltration of the gastrointestinal system
• Skeletal impairment caused by large osteolytic lesions with or without pathological fractures 

Indolent systemic mastocytosis meets the criteria for systemic mastocytosis and requires no C-findings or evidence of AHN. If the bone marrow is involved but not the skin, this reflects an isolated bone marrow mastocytosis within the ISM classification. Typically, ISM reflects a low burden of mast cells.³ 

Smoldering systemic mastocytosis meets the criteria for systemic mastocytosis and requires 2 or more B-findings and no C-findings, demonstrating a high burden of mast cells.³ 

Aggressive systemic mastocytosis meets the criteria for systemic mastocytosis and 1 or more C-findings without evidence of MCL. Bone marrow dysfunction caused by neoplastic mast cell infiltration and palpable hepatomegaly with impairment of liver function classify as C-findings, while pathological fractures caused by osteoporosis do not qualify as a C- finding.³ 

Systemic mastocytosis with an associated hematological neoplasm meets the criteria for systemic mastocytosis as well as the WHO criteria for AHN.³ 

Mast cell leukemia meets the criteria for systemic mastocytosis along with diffuse, dense mast cell infiltration detected on bone marrow biopsy. Bone marrow aspirate smears exhibit more than 20% mast cells, most of which have atypical morphology and are immature. Diffuse infiltration can be seen in the bone marrow with more than 10% mast cells in peripheral blood white cells.³

References

1. Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Accessed April 11, 2022.
2. Genetic testing – mastocytosis skin; urticaria pigmentosa (cutaneous mastocytosis) – Gen KIT. Valencian Institute of Microbiology (IVAMI). Accessed April 11, 2022.
3. Pardanani A. Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management. Am J Hematol. 2019;94(3):363-377. doi:10.1002/ajh.25371
4. Nicolosi M, Patriarca A, Andorno A, et al. Precision medicine in systemic mastocytosis. Medicina (Kaunas). 2021;57(11):1135. doi:10.3390/medicina57111135
5. Sotlar K, Horny HP, Simonitsch I, et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol. 2004;28(10):1319-1325. doi:10.1097/01.pas.0000138181.89743.7b
6. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316(26):1622-1626. doi:10.1056/NEJM198706253162603
7. Krokowski M, Sotlar K, Krauth MT, Födinger M, Valent P, Horny HP. Delineation of patterns of bone marrow mast cell infiltration in systemic mastocytosis: value of CD25, correlation with subvariants of the disease, and separation from mast cell hyperplasia. Am J Clin Pathol. 2005;124(4):560-568. doi:10.1309/CX45R79PCU9HCV6V

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.