Systemic Mastocytosis (SM)

Systemic mastocytosis is a rare hematological disease impacting the immune system that is characterized by the overproliferation of mast cells, a type of white blood cell produced in the bone marrow. Mast cells accumulate in organs and tissues, including the skin, bones, joints, liver, nerves, digestive tract, and lungs.¹

Mast cells are granulocytes containing various chemical mediators such as histamine, cytokines, growth factors, and heparin. These chemical inflammatory mediators are released during an allergic reaction or immune system response to environmental triggers, causing widespread vasodilation and growth of new blood vessels, which results in skin flushing and pruritus. The release of larger quantities of these mediators may cause more serious symptoms such as anaphylaxis, low blood pressure, vomiting, nausea, diarrhea, and abdominal cramping.²  

General Subtypes

There are 5 disease subtypes within systemic mastocytosis³:

• Indolent systemic mastocytosis (ISM)
• Smoldering systemic mastocytosis (SSM)
• Aggressive systemic mastocytosis (ASM)
• Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) 
• Mast cell leukemia (MCL)

The latter 3 subtypes consist of more advanced cases of systemic mastocytosis. Specific criteria must be met to obtain an official diagnosis of a systemic mastocytosis subtype.³ 

Read more about systemic mastocytosis diagnosis

Nearly all (≥90%) patients with systemic mastocytosis carry detectable mutations in the KIT gene (KIT D816V), while patients with more advanced subtypes of systemic mastocytosis often carry additional variations in other genes, with a median quantity of 4 mutations.⁴ 

In addition to KIT D816V, investigators have identified 21 other genes containing 86 point mutations or insertions/deletions/duplications in patients with systemic mastocytosis. More commonly affected genes include ASXL1, RUNX1, CBL, SRSF2, and TET2. Less commonly observed mutations occur in the KRAS, NRAS, JAK2, EZH2, ETV6, and U2AF1 genes.⁴

Milder Subtypes

ISM and SSM are the milder subtypes of systemic mastocytosis, resulting in more generalized symptoms of fatigue, flushing, nausea, abdominal pain, diarrhea, acid reflux, nasal congestion, headaches, hypotension, and cognitive difficulties with memory or attention.⁵ 

Indolent Systemic Mastocytosis

ISM is the most frequently diagnosed systemic mastocytosis subtype, with a prevalence of 90% to 95%.^5,6 Patients diagnosed with ISM often manifest mast cell mediator-release symptoms at a younger age than those with other subtypes and demonstrate a normal life expectancy. They frequently present with skin lesions and gastrointestinal complaints, with a prevalence around 70% to 80%.^6,7 Additionally, patients with ISM have a decreased likelihood of constitutional symptoms or hepatosplenomegaly (<20%). Treatments for ISM focus on the management of osteoporosis and symptoms, as well as the prevention of anaphylaxis.⁷

Within the ISM classification, there is a subvariant—isolated bone marrow mastocytosis. Isolated bone marrow mastocytosis occurs in the absence of skin lesions, generally manifesting with a low burden of mast cells affecting only the bone marrow.⁷

Smoldering Systemic Mastocytosis

More organs are impacted in SSM with a greater severity than in ISM.⁵ Therefore, SSM is classified as a separate variant with a higher burden of mast cells. Patients diagnosed with SSM have a less favorable prognosis than those with ISM, as they are usually older at the time of diagnosis and have lower hemoglobin levels than the normal range for their age.⁷  

Advanced Subtypes

Aggressive Systemic Mastocytosis

While ISM was the most commonly reported subtype (46%) in a previous retrospective study, ASM was the third most common subtype diagnosed (12%).⁸ These patients exhibited general constitutional symptoms (60%), hepatosplenomegaly (50%), serum tryptase concentrations >200 ng/mL (40%), lymphadenopathy (30%), and hematological symptoms including severe anemia with hemoglobin levels <10 g/dL (24%), thrombocytopenia with platelet levels <100 x 10⁹/L (27%), and leukocytosis (41%).⁷ 

ASM correlates with osteoporosis/osteopenia and an increased risk of pathological fractures.⁵ Due to the aggressive nature of this subtype, these patients demonstrate decreased survival rates.^5,7

Systemic Mastocytosis With an Associated Hematological Neoplasm

In the aforementioned study, SM-AHN was the second most common subtype (40%). Patients in this category exhibit an associated hematological neoplasm of nonmast cell lineage. In the study, most patients exhibited an associated myeloid neoplasm (89%), while the associated hematological neoplasms for a small minority of the patients included lymphoma, myeloma, chronic lymphocytic leukemia, and primary amyloidosis.⁸ 

Many of the patients with SM-AHN, especially those with systemic mastocytosis with myeloproliferative neoplasms (SM-MPN), demonstrated notable eosinophilic levels ≥1.5 x 10⁹/L. Around 39% of the patients with elevated eosinophilic concentrations carried the FIP1L1–PDGFRA fusion gene.^7,9 

Mast Cell Leukemia

MCL is the rarest, most severe subtype with the worst prognosis within the systemic mastocytosis classifications.^5,7 In the previous study, MCL occurred in 4 of the 342 patients (1%).⁸ ASXL1, RUNX1, and SRSF2 gene mutations often lead to worse prognostic outcomes due to myeloid malignancies such as MCL.⁷ The median survival for these patients was around 2 months following diagnosis.^5,7

Mast Cell Bone Infiltration Patterns 

Following bone marrow biopsies, researchers noted that some specific mast cell bone marrow infiltration patterns corresponded to specific systemic mastocytosis subtypes. They identified 5 patterns of mast cell infiltration within the bone marrow¹⁰:

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

Most patients with systemic mastocytosis demonstrated infiltration patterns II through V, most frequently pattern IV. Pattern V correlated significantly with MCL. Patterns III and IV correlated with all systemic mastocytosis subtypes except MCL and SSM. Pattern I corresponded to mast cell hyperplasia, not a systemic mastocytosis subtype.¹⁰  

References

1. Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Accessed April 13, 2022.
2. Genetic testing – mastocytosis skin; urticaria pigmentosa (cutaneous mastocytosis) – Gen KIT. Valencian Institute of Microbiology (IVAMI). Accessed April 13, 2022.
3. Nicolosi M, Patriarca A, Andorno A, et al. Precision medicine in systemic mastocytosis. Medicina (Kaunas). 2021;57(11):1135. doi:10.3390/medicina57111135
4. Schwaab J, Schnittger S, Sotlar K, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013;122(14):2460-2466. doi:10.1182/blood-2013-04-496448
5. Systemic mastocytosis. MedlinePlus. Updated August 18, 2020. Accessed April 13, 2022.
6. Desmond DH, Carmichael MG. Systemic mastocytosis: the difficult patient with a rare disease. Case presentation and brief review. Hawaii J Med Public Health. 2018;77(2):27-29. 
7. 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
8. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113(23):5727-5736. doi:10.1182/blood-2009-02-205237
9. Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1–PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104(10):3038-3045. doi:10.1182/blood-2004-03-0787
10. 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

Reviewed by Hasan Avcu, MD, on 4/27/2022.

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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.