Indolent systemic mastocytosis (ORPHA:98848)
A rare, usually benign, chronic, form of systemic mastocytosis (SM) characterized by an abnormal accumulation of neoplastic mast cells (MCs) mainly in the bone marrow (BM) but also in other organs or tissues such as preferably the skin.
Epidemiology
Indolent SM (ISM) represents 90% of all cases of SM for which the prevalence in Europe is estimated between 1/7,700 and 1/10,400.
Clinical description
ISM mainly affects adults and typically presents with skin lesions (ISM+), usually in the form of urticaria pigmentosa (UP), while only a few patients have no skin lesions (ISM-). In addition, ISM patients frequently suffer from MC mediator-related symptoms, including pruritus, flushing, syncope, headache and gastro-intestinal (GI) events (vomiting, diarrhea, abdominal pain). Isolated BM mastocytosis (BMM) is a provisional subcategory of ISM typically characterized by absence of cutaneous lesions of ISM and normal to slightly elevated basal tryptase levels. In most patients with BMM, the KIT D816V allele burden in the peripheral blood is low. A BM smear typically reveals small-sized clusters and aggregates of MCs. In both ISM and BMM, patients have a high risk to develop severe anaphylactic reactions to various exogenous substances (triggers/allergens) such as insect bites. Presentation of severe osteoporosis or even spontaneous fractures is also possible.
Etiology
Although the etiology of ISM is not fully understood, an activating mutation of KIT, usually KIT D816V, is found in the MCs of virtually all ISM cases. This mutation probably accounts for the abnormal accumulation of MCs in organ(s)/tissue(s). In some cases, the mutation is found primarily in the neoplastic MC compartment; in other cases, the mutation may be detected in other mature BM and peripheral blood cells such as basophils, eosinophils, neutrophils, as well as B- and T-lymphocytes. Furthermore, precursors of erythroid and myeloid cells as well as CD34+ progenitors may carry the KIT D816V mutation, suggesting the involvement of a pluripotent stem cell.
Diagnostic methods
SM diagnosis is established using the WHO consensus criteria and is subsequently categorized according to the presence of B-findings and C-findings. In ISM and BMM there are neither B-findings, nor C-findings.
Differential diagnosis
Differential diagnoses include all the other forms of SM as well as other causes of MC activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy or another reactive inflammatory disease process is present; and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. Additional differential diagnoses include other forms of mastocytosis (pure cutaneous mastocytosis, mast cell sarcoma), endocrine disorders (adrenal tumors, VIPoma, gastrinoma), some gastrointestinal pathologies. In ISM-, the differential diagnosis is BMM. It should also be possible to distinguish Waldenström disease.
Management and treatment
Indolent SM patients, as well as those with BMM, usually only require symptomatic treatments. The main objective is to reduce the symptoms of MC activation, such as pruritus, flushes and gastrointestinal cramps. In case of pruritus or skin manifestations, antihistamines H1 (anti-H1) are used. For GI tract manifestations, anti-H2 are effective and can be combined with anti-H1, with di-sodium cromoglycate or with leukotriene inhibitors. Corticoids can suppress antihistamines recalcitrant symptoms. Epinephrine is indicated for hypotension, which may be spontaneous or observed after an insect bite. Patients should be trained to self-administer injectable epinephrine. Of note, some SM patients may suffer from bee or wasp venom allergy. In these patients, specific immunotherapy should be administered lifelong to ensure protection. For patients with SM and osteoporosis, biphosphonates are recommended with adequate supplementation of calcium and vitamin D.
Prognosis
The evolution of ISM and of BMM is slow and benign. The prognosis is generally good and life expectancy is similar to that of the general population. However, some of these patients may finally progress to SSM, SM-AHN, ASM or even MCL; multilineage KIT D816V involvement is probably the most important prognostic criterion for progression of ISM to more advanced SM subtypes.

                            Last update: 
                            October 2019


                            - Expert reviewer(s): 
                            Pr Michel AROCK