Systemic Mastocytosis (SM)


Some of the characteristic features of systemic mastocytosis (SM) are considered to be major and minor criteria for the diagnosis. The major criterion is the presence of multifocal clusters of abnormal mast cells (MCs) in the bone marrow. The minor diagnostic criteria include an elevated serum tryptase level, abnormal CD25 expression in MCs, and presence of the KIT D816V mutation. The World Health Organization requires that either 1 major and 1 minor criterion or 3 minor criteria be present to establish a definitive diagnosis.1 Specific diseases that resemble SM, with similar pathophysiologic mechanisms, include mast cell activation syndrome (MCAS), idiopathic mast cell activation syndrome (IMCAS), and anaphylaxis; others, whose features overlap clinically with those of SM but without mast cell activation, are mentioned below.

Mast cell activation syndrome 

The signs and symptoms of MCAS involve the skin and the gastrointestinal, cardiovascular, respiratory, and neurologic systems. Symptoms include tachycardia, hypotension, syncope, pruritus, urticaria, angioedema, wheezing, stridor, dyspnea, vomiting, diarrhea, and abdominal pain.2 It is broadly accepted that patients with MCAS must have symptoms of chronic mast cell activation (MCA) that are aberrant, manifest in multiple organs, and are not explained by another disease.3 By definition, patients cannot meet all the criteria for SM. 

Idiopathic mast cell activation syndrome 

IMCAS is a rare cause of chronic abdominal pain in children and remains a diagnosis of exclusion. Four criteria must be met to establish a diagnosis of IMCAS. First, the patient must exhibit episodic symptoms that are consistent with MC mediator release and that affect 2 organ systems. There must be a degree of clinical responsiveness to antihistamines or agents that target mast cells, and there must be evidence of an increase in validated urinary serum markers of MCA. Finally, primary and secondary causes of MCA must be ruled out.4 

Anaphylaxis 

Anaphylaxis is an acute, life-threatening hypersensitivity disorder mediated by immunoglobulin E and characterized by a rapidly evolving, generalized, multisystem allergic reaction. Patients with anaphylaxis may have serum tryptase levels that are elevated during the acute event, and these may remain elevated for a few hours; however, patients with SM have persistently elevated levels of tryptase in the baseline state.1,5  

Disorders that do not involve MCA but whose symptoms clinically overlap with those of SM include the following:

Hereditary angioedema

This is an autosomal-dominant condition due to the lack or dysfunction of C1-esterase inhibitor protein. Manifestations include swelling of the upper airway, skin, and/or gastrointestinal tract that may be severe enough to lead to asphyxiation. Laryngeal edema in SM is rare. Abnormal C1-esterase inhibitor and complement studies confirm the diagnosis.6 These are typically normal in SM.  

Carcinoid syndrome

Carcinoid tumors are well-differentiated neuroendocrine tumors that secrete humoral factors such as prostaglandins and biogenic amines with vasodilating effects. Symptoms include flushing, wheezing, diarrhea, malabsorption, niacin deficiency, right-sided valvular disease, fatigue, and cognitive impairment. Elevation of 5-hydroxyindoleacetic acid in a 24-hour urine sample is diagnostic.7 

Pheochromocytoma

Flushing is a feature of both pheochromocytoma and SM; however, patients with pheochromocytoma present with paroxysmal episodes of hypertension rather than the hypotension seen in SM.8 

Bone metastatic disease

Destructive bone lesions may develop in patients with SM in the presence of massive MC infiltrates. These osteolytic lesions resemble disease metastatic to bone and should prompt further investigation in some circumstances.9 

Vasoactive intestinal peptide (VIP)–secreting tumors

Flushing and diarrhea are overlapping symptoms of VIP-secreting tumors and SM. Increased levels of VIP distinguish VIP-secreting tumors from SM.10 

References

1. 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

2. Mast cell activation syndrome (MCAS). American Academy of Allergy Asthma & Immunology. Accessed April 12, 2022.

3. Afrin LB, Ackerley MB, Bluestein LS, et al. Diagnosis of mast cell activation syndrome: a global “consensus-2.” Diagnosis (Berl). 2021;8(2):137-152. doi:10.1515/dx-2020-0005

4. Rechenauer T, Raithel M, Götze T, et al. Idiopathic mast cell activation syndrome with associated salicylate intolerance. Front Pediatr. 2018;6:73. doi:10.3389/fped.2018.00073

5. McLendon K, Sternard BT. Anaphylaxis. StatPearls [Internet]. Updated December 21, 2021. Accessed April 12, 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK482124/

6. Abdulkarim A, Craig TJ. Hereditary angioedema. StatPearls [Internet]. Updated July 12, 2021. Accessed April 12, 2022.

7. Pandit S, Annamaraju P, Bhusal K. Carcinoid syndrome. StatPearls [Internet]. Updated February 17, 2022. Accessed April 12, 2022.

8. Reisch N, Peczkowska M, Januszewicz, Neumann H. Pheochromocytoma: presentation, diagnosis and treatment. J Hypertens. 2006;24(12):2331-2339. doi:10:10.197/01.hjh.0000251887.00185.54

9. Bonifacio M, Zanotti R, Guardalben E, et al. Multiple large osteolytic lesions in a patient with systemic mastocytosis: a challenging diagnosis. Clin Case Rep. 2017;5(12):1988-1991. doi:10.1002/ccr3.1232

10. Zandee WT, Hofland J, de Herder WW. Vasoactive intestinal peptide tumor (VIPoma). EndoText [Internet]. Updated August 28, 2021. Accessed April 12, 2022.

Reviewed by Hasan Avcu, MD, on 4/16/2022.

READ MORE ON SM