Systemic Mastocytosis (SM)

Systemic mastocytosis (SM) is a heterogenous group of disorders characterized by diffuse and/or focal infiltration of neoplastic mast cells in various organs, including the bone marrow, spleen, liver, and gastrointestinal (GI) tract.¹ In a large study of 342 patients with SM, the most common clinical characteristics were urticaria pigmentosa (41%), cutaneous symptoms including pruritus, flushing, urticaria, and angioedema (53%), GI symptoms (65%), constitutional symptoms including weight loss, fever, chills, and night sweats (42%), mediator-related symptoms (47%), idiopathic and recurrent anaphylactoid reactions (17%), musculoskeletal symptoms including bone pain, arthralgia, and myalgia (31%), hepatomegaly (27%), splenomegaly (37%), hepatosplenomegaly (21%), and lymphadenopathy (21%).²

Gastrointestinal symptoms include nausea, vomiting, dyspepsia, dysphagia, diarrhea, constipation, abdominal pain/cramping, bloating, flatulence, early satiety, heartburn, GI tract bleeding, malabsorption, and steatorrhea. Mediator-related symptoms include headache, dizziness/lightheadedness, syncope/presyncope, hypotension, anaphylaxis, palpitations/tachycardia, bronchoconstriction/wheezing, and peptic ulcer disease.² 

Cutaneous manifestations are common in SM. Darier’s sign is a form of dermatographism that is associated with SM due to the presence of mast cells in affected skin. Patients with cutaneous involvement such as urticaria pigmentosa may develop urticaria and/or erythema over a region that was lightly scratched, and this is considered a positive Darier’s sign. Unlike other forms of dermatographism, Darier’s sign refers to urtication that is limited to the involved areas of skin and spares uninvolved skin. It is challenging to make a diagnosis of SM in the absence of cutaneous symptoms.³ In this situation, SM should be considered in patients with recurrent unexplained anaphylaxis, flushing, osteoporosis, GI ulcerative disease, or chronic abdominal cramping.⁴ 

The World Health Organization (WHO) organizes SM into 5 distinct categories. Patients who meet the WHO diagnostic criteria (either the major criterion and 1 minor criterion or at least 3 minor criteria) receive a definitive diagnosis of SM. In addition, the WHO has established “B” and “C” findings to determine the subtypes (or variant forms) of the disease.⁴ “B” findings are found in 49% of patients with SM, and “C” findings are present in 23% of patients.² 

“B” findings include the following⁴: 

1. Bone marrow biopsy showing >30% infiltration by mast cells (focal, dense aggregates) and/or a total serum tryptase level of >200 mg/mL. 
2. Signs of dysplasia or myeloproliferation in nonmast cell lineage(s) but insufficient criteria for definitive diagnosis of a hematopoietic neoplasm with normal or only slightly abnormal blood counts.
3. Hepatomegaly without impairment of liver function, palpable splenomegaly without hypersplenism, and/or lymphadenopathy on palpation or imaging.

“C” findings include the following⁴:

1. Bone marrow dysfunction due to neoplastic mast cell infiltration which manifests as 1 or more cytopenia(s) (absolute neutrophil count <1 × 10⁹/L, hemoglobin <10 g/dL, and/or platelets <100 × 10⁹/L) 
2. Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension.
3. Skeletal involvement with large osteolytic lesions and/or pathologic fractures.
4. Palpable splenomegaly with hypersplenism.
5. Malabsorption with weight loss due to GI mast cell infiltrates.

Patients with indolent SM (ISM) meet the WHO criteria for SM and exhibit no “C” findings. Patients with SM plus 2 or more “B” findings are considered to have smoldering SM (SSM). In a patient with SM and concomitant clonal hematologic nonmast cell lineage disorders such as myeloproliferative disorder, acute myeloid leukemia, or lymphoma, a diagnosis of SM with an associated hematologic neoplasm (SM-AHN) is made. Patients with SM plus “C” findings and no features of mast cell leukemia (MCL) are considered to have aggressive SM (ASM). Features of MCL include a bone marrow biopsy with diffuse infiltration, usually compact, by atypical, immature mast cells. Additionally, bone marrow aspirate smears show ≥20% mast cells. Patients with these features plus SM diagnostic criteria are considered to have MCL.⁴ 

Indolent SM is the most prevalent form of SM in adults and presents at an earlier age than ASM or SM-AHN, with a median age of onset of 49 years.⁴ Approximately 75% of patients with ISM have cutaneous symptoms, and 71% have gastrointestinal symptoms. Mast cell mediator-related symptoms are seen in 69% of patients, constitutional symptoms are seen in 19%, and splenomegaly, hepatomegaly, and lymphadenopathy are present in 17%, 14%, and 14%, respectively.² 

Systemic mastocytosis-AHN presents at a later age, usually in the sixth decade of life, and is less likely to present with skin findings, which are present in only 30% of patients. Constitutional symptoms are common (62%), along with GI symptoms (57%), and splenomegaly, hepatomegaly, and lymphadenopathy in 57%, 38%, and 29% of patients, respectively. Mediator-related symptoms are present in 28% of patients.²

Aggressive SM is a clinically severe form of SM. Common manifestations include GI symptoms (63%), cutaneous symptoms (49%), and splenomegaly, hepatomegaly, and lymphadenopathy in 44%, 39%, and 27% of patients, respectively. “B” findings were present in 54% of patients and require “C” findings to meet the definition of ASM.²

References

1. 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

2. 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

3. Galen BT, Rose MG. Darier’s sign in mastocytosis. Blood. 2014;123(8):1127. doi:10.1182/blood-2013-11-538355

4. 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

Reviewed by Harshi Dhingra, MD, on 4/24/2022.

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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.