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Systemic mastocytosis

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Disease definition

A heterogeneous group of rare, acquired and chronic hematological malignancies related to an abnormal accumulation/proliferation of neoplastic mast cells (MCs) in one or several organs, mainly the bone marrow (BM), associated frequently with skin involvement.

ORPHA:2467

Classification level: Group of disorders

Prevalence: 1-5 / 10 000

Inheritance: Not applicable

Age of onset: All ages

ICD-10: C96.2

ICD-11: 2A21.0

UMLS: C0221013

MeSH: D034721

GARD: 8616

MedDRA: 10042949

Summary
Epidemiology

The prevalence in Europe is estimated between 1/7,700 and 1/10,400. Systemic mastocytosis (SM) preferentially affects Caucasians and there is no sex predominance.

Clinical description

SM is mainly observed in adults (average age at diagnosis is 60 years) and is very rare in the pediatric population. SM can be divided into five variants: indolent SM (ISM), smoldering systemic mastocytosis (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL), the later 3 variants being collectively termed advanced SM (advSM). In ISM, there are no signs of high mast cell burden (B-findings) and no organ dysfunction (C-findings). SSM is a slowly progressive SM with B-findings. By contrast, advSM variants are characterized by (multiple) C-findings.

Etiology

Most patients with SM present activating mutations in KIT, the receptor of the stem cell factor, in their neoplastic MCs. Of note, a recurrent KIT mutation (D816V; exon 17 of the KIT gene) located in the phosphotransferase domain of the receptor is detectable in most patients (> 80% of all SM patients), including those with advSM. Other less frequent mutations affect exons 2, 8, and 9 encoding for the extracellular domain or exons 13 and 14 encoding for Kinase Domain 1 of KIT. Whatsoever, the various KIT mutations encountered in SM result in uncontrolled activation of the receptor, making the migration, survival and activation of MCs independent of stem cell factor.

Diagnostic methods

Consensus criteria for the diagnosis of systemic mastocytosis established by the WHO include one major criterion - the presence of aggregates of at least 15 MCs identified in BM or other extracutaneous organ biopsies (usually revealed after tryptase staining of biopsies) - and four minor criteria: the presence of more than 25% of MCs with atypical morphology in BM smears (spindle-shaped, degranulated and/or multinucleated MCs); aberrant immunophenotype of MCs which frequently abnormally express non-mast cell markers (CD25 and/or CD2); presence of a point mutation in codon 816 of the KIT gene in BM; peripheral blood or other extracutaneous organs; and increased level of serum tryptase (above 20 ng/mL). For diagnosis of SM, at least the major and one minor criterion or at least three minor criteria are fulfilled. The disease is then categorized, as described above, according to the presence of B-findings and C-findings.

Differential diagnosis

Differential diagnoses of SM include all the other causes of mast cell activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy (most cases) or another reactive inflammatory disease process is present (and is considered to be the causative etiology); and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. As well, differential diagnoses include other forms of mastocytosis (cutaneous mastocytosis, mast cell sarcoma), endocrine disorders (adrenal tumors, VIPoma,, Zollinger-Ellison syndrome), some gastrointestinal pathologies, allergies, other myeloproliferative diseases that affect bone marrow, histiocytosis, hypereosinophilic syndrome and Waldenström macroglobulinemia.

Genetic counseling

SM is usually a sporadic disease, although a few familial cases have been reported so far, for which no genetic counseling is available.

Management and treatment

Management depends on the type of SM. Treatment of ISM and stable SSM is typically symptomatic (antihistamines, corticosteroids or disodium cromoglyylcate). For advanced SM treatment is symptomatic (antihistamines anti-H1 and H2) and antiproliferative with non-targeted (e.g interferon alpha) or targeted cytoreductive therapy with KIT tyrosine kinase inhibitors. Hydroxyurea (HU) is given in patients with SM-AHN. Allogeneic stem cell transplantation (allo-SCT) is rarely used and reserved for fit patients with very aggressive, life-threatening advSM and a suitable donor.

Prognosis

Prognosis depends on the type of SM.

Last update: July 2019 - Expert reviewer(s): Pr Michel AROCK
A summary on this disease is available in Français (2019) Español (2019) Deutsch (2019) Italiano (2019) Nederlands (2019) Suomi (2020.pdf) עברית (2020.pdf) Polski (2008.pdf) Русский (2019.pdf)
Detailed information
General public
Article for general public
Guidelines
Emergency guidelines
Français (2020.pdf) - Orphanet Urgences
Anesthesia guidelines
English (2020) - Orphananesthesia
Español (2020) - Orphananesthesia
Čeština (2020) - Orphananesthesia
Clinical practice guidelines
English (2015) - Hematology Am Soc Hematol Educ Program Logo ERN
Disease review articles
Review article
English (2019) - Am J Hematol
Patient-Centered Outcome Measures (PCOMs)
English (2023) - PROQOLIDTM

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