Systemic Mastocytosis (SM)

Systemic mastocytosis is a rare hematologic disease characterized by an abnormal proliferation of mast cells within the connective tissues of multiple organ systems. Mast cells are frequently located under the skin, near lymph and blood vessels, in nerves, in bones and joints, and in organs commonly exposed to pathogens, such as the lungs and digestive tract.1 

Mast cells are granulocytes containing inflammatory mediators such as histamine, heparin, cytokines, and growth factors; these are released during an allergic reaction or an immunologic response. Mediator release leads to vasodilation and angiogenesis, which often cause symptoms such as flushing and itching. The release of large quantities of mediators may result in abdominal cramping, nausea, vomiting, diarrhea, muscle pain, low blood pressure, and anaphylactic shock. Mast cells are part of the body’s immune system.2    

Etiology of Systemic Mastocytosis 

Although familial cases of systemic mastocytosis have been reported, in most cases the disease is not directly inherited but rather acquired after exposure to an environmental trigger. Somatic mutations occurring in an individual’s genetic makeup after conception, primarily in the KIT gene, result in an overproduction of mast cells, which accumulate within organs.3

The KIT proto-oncogene, located on the long arm of chromosome 4, encodes KIT protein, which serves as a transmembrane receptor for stem cell factor cytokines. Stem cell factor cytokines are ligands that bind intrinsic tyrosine kinases, thereby activating a signaling pathway responsible for cell proliferation, maturation, and differentiation; inhibition of apoptosis; and degranulation, adhesion, and motility of activated cells. KIT protein plays a vital role in the development of mast cells.4

KIT gene mutations constitutively activate the receptor protein, resulting in unregulated, independently activated stem cell factor ligand binding to the transmembrane receptor protein. Continuous ligand binding to the receptor results in constitutive activation of the signaling pathway and therefore mast cell proliferation.4.5 

Around 80% of individuals diagnosed with systemic mastocytosis exhibit somatic point mutations in codon 816 of the KIT gene.5 More than 90% of KIT gene mutations responsible for systemic mastocytosis arise in exon 17, although some mutations may occur in exons 8, 9, 10, and 11.4 Of these 80% of individuals with systemic mastocytosis, approximately 93% have mutations specifically occurring in exon 17 of codon 816 the KIT gene (D816V) which causes valine to be substituted for aspartic acid.4,5   

Mutations in genes other than KIT that affect cellular proliferation or the regulation of genes involved in cellular development may increase the severity of systemic mastocytosis and decrease patient survival rates. These genes include ASXL1, DNMT3A, RUNX1, SRSF2, CBL, EZH2, K/N-RAS, and TET2.5,6

mast cell
Credit: Getty images

Mast Cells

Mast cells are white blood cells that develop from hematopoietic precursor cells within the bone marrow.5,6 Because mast cells are produced in the bone marrow, they commonly proliferate within the bone marrow in specific patterns of infiltration that frequently correspond to disease subtypes. 

Subtypes of systemic mastocytosis, which vary in severity, include the following:

  • Indolent systemic mastocytosis, the most common subtype;
  • Smoldering systemic mastocytosis;
  • Aggressive systemic mastocytosis;
  • Systemic mastocytosis with an associated hematologic neoplasm, and 
  • Mast cell leukemia.6

Mast cells become activated in a widespread immune system response to an environmental trigger or in an allergic reaction. In systemic mastocytosis, the normal physiologic immune response is exaggerated by the increased accumulation of mast cells within tissues. Potential triggers to which individuals with systemic mastocytosis may be hypersensitive include temperature changes, exercise, insect stings, animal bites, vaccines, stress, anxiety, surgical interventions, friction, minor trauma, alcohol, and even certain ingested foods, especially spicy foods. Specific medications, such as nonsteroidal anti-inflammatories (NSAIDs), aspirin, muscle relaxants, opioids, and radiocontrast material used in imaging, may also trigger excessive immune system responses.6,7 Because of their excessive immune responses, often to non-noxious triggers, approximately half of individuals with a diagnosis of systemic mastocytosis are prone to having severe allergic reactions, including anaphylaxis.6 

The widespread release of chemical mediators from areas with activated mast cells causes an increase in blood flow to those areas, leading to inflammation and organ dysfunction. Excessive histamine release may result in the hypersecretion of gastric acid, which causes many of the dyspeptic and gastrointestinal symptoms seen in systemic mastocytosis.7 Researchers in one study estimated that approximately 70% to 80% of patients with systemic mastocytosis have gastrointestinal symptoms and abnormalities.8

The chemical mediators released by mast cells cause vasodilation and increase the flow of blood and fluid; widespread inflammatory immune responses may lead to an accumulation of fluid within the abdominal cavity (ascites), portal hypertension, lymphadenopathy, bone deterioration (osteolysis/osteoporosis) with an increased incidence of fracture, and flushing of the skin, among other symptoms.7


  1. Definition of systemic mastocytosis. National Cancer Institute. Dictionary of Cancer Terms. Accessed April 9, 2022.
  2. Definition of mast cell. National Cancer Institute. Dictionary of Cancer Terms. Accessed April 9, 2022.
  3. Systemic mastocytosis. National Center for Advancing Translational Sciences. Genetic and Rare Diseases Information Center (GARD). Accessed April 9, 2022.
  4. Genetic testing – mastocytosis skin; urticaria pigmentosa (cutaneous mastocytosis). Gen KIT. IVAMI. Accessed April 9, 2022.
  5. Nicolosi M, Patriarca A, Andorno A, et al. Precision medicine in systemic mastocytosis. Medicina (Kaunas). 2021;57(11):1135. doi:10.3390/medicina57111135
  6. Systemic mastocytosis. MedlinePlus Genetics. Accessed April 9, 2022. 
  7. Mastocytosis. NORD (National Organization for Rare Disorders). Accessed April 9, 2022. 
  8. Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000;14(3):579-623. doi:10.1016/s0889-8588(05)70298-7

Reviewed by Harshi Dhingra, MD, on 4/12/2022.