Systemic Mastocytosis (SM)

Systemic mastocytosis (SM) is a heterogeneous condition that was designated its own disease entity in 2016 by the World Health Organization (WHO). It is no longer considered a subgroup of myeloproliferative neoplasms (MPNs). SM results from the clonal proliferation and infiltration of neoplastic, morphologically and immunophenotypically abnormal mast cells (MCs) in one or more organ systems. The pathognomonic feature of SM is the presence of multifocal clusters of 15 or more abnormal MCs in bone marrow.¹

SM is differentiated from MPNs by KIT mutations, prominent eosinophilia, splenomegaly, marked elevation of serum B12, elevation of serum tryptase, and increased MCs in bone marrow in clusters. MPN is commonly associated with rearrangement of PDGFRA (FIP1L1-PDGFR) and PDGFRB (PRKG2-PDGFRB) and is sensitive to the tyrosine kinase inhibitor imatinib.¹ 

Gain-of-function mutations within KIT, usually the D816V mutation, are characteristic of most SM subtypes; they are present in more than 80% of all patients with SM and in more than 90% of those with typical indolent SM.² In the D816V mutation, an adenine-to-thymine base substitution (A>T) at nucleotide position 2468 results in a change from aspartic acid to valine at position 816 in the protein.

Type III KIT receptors are expressed on various hematopoietic progenitor cells, germ cells, melanocytes, and interstitial cells of Cajal in the gastrointestinal tract and play an important role in the development of these cell lineages. KIT expression is usually downregulated in the cells once maturation has been achieved except in MCs. In mature MCs, the interaction of surface KIT with its ligand plays a key role in MC proliferation, maturation, adhesion, chemotaxis, and survival. Gain-of-function mutations in KIT are associated with clonal proliferation. The most common gain-of-function mutation in the KIT tyrosine kinase domain is the D816V mutation; less common (<5%) mutations include V560G, D815K, D816Y, insVI815-816, D816F, D816H, and D820G. D816V results in an activating loop in the kinase domain and appears to cause ligand-independent autophosphorylation of KIT, inducing constitutive activation of the Stat5-PI3K-Akt signaling cascade.³ Most cases of SM are due to sporadic mutations in KIT.⁴ It is theorized that SM of childhood onset may be associated with germline mutations of KIT.¹ It is believed that other signal cascades cooperate with KIT D816V and/or KIT D816V downstream molecules to trigger the oncogenic growth of neoplastic MCs.² 

SM Symptoms & Pathophysiology

Symptoms of SM are related to the infiltration of abnormal MCs in cutaneous and extracutaneous tissues and MC degranulation, resulting in mediator release. The release of mediators such as histamine, leukotriene C4, prostaglandin D2, chemokines, cytokines, and heparin may manifest as allergic events, fluid extravasation leading to hypotension, hypersecretion of stomach acid, and increased tone of bronchiolar smooth muscles manifesting as wheezing. Headache, dizziness/lightheadedness, syncope/presyncope, and hypotension may also result. The release of histamine results primarily in flushing and gastric acid hypersecretion, which may cause gastroesophageal reflux disease, abdominal pain, bloating, and diarrhea.^5,6

The massive degranulation of MCs may lead to life-threatening episodes of anaphylaxis in response to certain triggers, such as Hymenoptera venom, physical and emotional stress, alcohol, spicy food, and medications. Common medication triggers are aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), narcotics, muscle relaxants, and radiocontrast material.⁶ 

The infiltration of various organs by MCs in SM, including bone, liver, spleen, and lymph nodes, gives rise to a variety of features.⁶ Bone marrow infiltration by MCs can result in cytopenias and osteolysis.⁶ Musculoskeletal symptoms, including bone pain, arthralgias and myalgias, are present in 31% of patients.⁵ Osteopenia or osteoporosis may develop in patients with bone involvement, predisposing them to pathologic bone fractures.⁷ Liver infiltration can result in hepatomegaly in 27% of patients with SM, in addition to elevated liver enzymes, impaired hepatic function, and portal hypertension.^5,6 Splenomegaly is present in 37% and hepatosplenomegaly in 21% of patients.⁵ MC infiltration of lymph nodes leads to lymphadenopathy, which is present in 21% of patients.^5,6 

References 

1. Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2021;96(4):508-525. doi:10.1002/ajh.26118

2. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420-1427. doi:10.1182/blood-2016-09-731893

3. Harir N, Boudot C, Friedbichler K, et al. Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade. Blood. 2008;112(6):2463-2473. doi:10.1182/blood-2007-09-115477

4. Systemic mastocytosis. Genetic and Rare Diseases Information Center (GARD). Accessed April 17, 2022.

5. 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

6. Mastocytosis. NORD (National Organization for Rare Disorders). Accessed April 17, 2022.

7. Systemic mastocytosis. MedlinePlus Genetics. Accessed April 17, 2022.

Reviewed by Hasan Avcu, MD, on 4/29/2022.

---

Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.