Smoldering systemic mastocytosis (ORPHA:158775)
A rare, slowly progressive form of systemic mastocytosis (SM) characterized by gradual accumulation of neoplastic mast cells in the visceral organs. Patients typically present with splenomegaly, hypercellular marrow and, in most cases, urticaria pigmentosa-like skin lesions.
Epidemiology
The prevalence and incidence is unknown.
Clinical description
The age of onset of smoldering systemic mastocytosis (SSM) is in adulthood, with patients tending to be slightly older than those with isolated SM (ISM). The disease is defined by the presence of at least two B-findings, indicative of a high mast cell (MC) burden, and no C findings (organ dysfunction). There is a pronounced MC infiltration (>30% in bone marrow (BM) biopsy), organomegaly and tryptase levels above 200 ng/ml. The clinical course is characterized by slow progression without signs of aggressive disease or an associated hematologic neoplasm (AHN). Patients may remain stable for years or may progress into a more advanced variant (aggressive SM (ASM), mast cell leukemia (MCL) or SM with an AHN).
Etiology
Although the etiology of SSM is not fully understood, an activating mutation of KIT, usually KIT D816V, is found in the MCs of virtually all SSM cases. This mutation probably accounts for the abnormal accumulation of MCs in organ(s)/tissue(s). Multilineage KIT D816V involvement is constantly found in SSM patients.
Diagnostic methods
Diagnosis of SSM is achieved by first establishing a diagnosis of SM, based on the WHO consensus criteria. The disease is then categorized according to the presence of B-findings and C-findings. For SSM, at least two B-findings (but no C-findings) should be present.
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, indolent SM, aggressive SM), endocrine disorders (adrenal tumors, VIPoma, gastrinoma), and some gastrointestinal pathologies. Waldenström disease should also be distinguished.
Management and treatment
In stable SSM patients, symptomatic treatment may be the only therapy. Avoidance of known triggers, prophylactic prescription of an epi-pen, and medications such as antihistamines, antileukotrienes, cromolyn sodium, omalizumab and aspirin may all have a role in the prevention or treatment of MC-mediated symptoms. Regular follow-up and assessment for transformation to more aggressive disease variants is required. Serum tryptase, which may be used to assess disease response, may be evaluated biannually to monitor disease activity and appropriately adjust therapy. In patients who progress to more advanced variants of the disease, introduction of targeted or non-targeted cytoreductive therapy may be discussed. Whilst favorable results have been seen with the current targeted and non-targeted treatment, a consensus on treatment in patients with SSM has not been reached.
Prognosis
Some SSM patients may remain stable for years, while others may progress to more advanced variants of the disease (ASM or MCL), with a poorer prognosis. In general, the prognosis of SSM regarding progression-free survival and overall survival is better than that of ASM or MCL, but poorer than in typical ISM.

                            Last update: 
                            August 2019


                            - Expert reviewer(s): 
                            Pr Michel AROCK