The Spectrum of Mast Cell Activation Syndromes

In 2016, the World Health Organization (WHO) updated their classification of mastocytosis, including three major subvariants of mastocytosis: 1) systemic,  2) cutaneous, and 3) localized mast cell tumors (i.e. mast cell sarcoma) [23]. In 2021, updated diagnostic criteria and classification of mast cell disorders were proposed [13].

2.1.1 Systemic mastocytosis (SM) 

The WHO criteria for SM state that a diagnosis can be made by fulfilling the major criterion plus one minor criteria or 3 minor criteria (Table 2) [13, 23, 24]. The major criterion for SM is the presence of multifocal dense mast cell infiltrates (>15 mast cells in aggregates) in bone marrow biopsies and/or other extracutaneous organs, such as the spleen, gastrointestinal tract, lymph nodes, and/or liver. Minor criteria include the  following: 1) > 25% of all mast cells are atypical or spindle-shaped; 2) KIT-activating KIT point mutation(s) at codon 816; 3) expression of CD2 and/or CD25 on mast cells in  bone marrow; and 4) baseline serum tryptase > 20 ng/mL [13, 23]. Proposed revisions entail adjusting sBT for HaT as discussed above, including CD30 (which has utility in identifying well-differentiated SM), and extending KIT mutation criteria to include other non-816 critical regions [13]. 

The activating KIT mutation, most commonly a gain-of-function point mutation at D816V, has been detected in > 80% of patients with SM, > 80% of those with indolent  systemic mastocytosis (ISM), and about 35% of pediatric cutaneous mastocytosis (CM) patients [25-28]. In addition to KIT mutational status being part of the WHO criteria, it is  also critical to evaluate for D816V KIT mutation to inform treatment, as this mutation is associated with drug resistance to imatinib and masatinib [20, 23, 29].  

SM has been further divided into ISM (subvariant of isolated bone marrow mastocytosis), smoldering systemic mastocytosis (SSM), and advanced systemic mastocytosis. Advanced SM can be sub-categorized into aggressive SM (ASM), systemic mastocytosis with an associated hematologic neoplasm (of non-mast cell lineage, SM AHN), and mast cell leukemia (MCL) [10, 13, 23, 30]. These subvariants have been diagnostically distinguished by strict criteria, as the prognosis and treatment for each is variable. Some of the differentiating criteria include the presence/absence of skin lesions and of B (significant organ involvement, supportive of increased mast cell burden) and C (organ dysfunction related to mast cell infiltration) findings. Patients with isolated bone marrow mastocytosis and ISM with lower tryptase levels are thought to have lower disease burden and better prognosis, typically having near normal lifespan [31]. A minority of patients with ISM (3%) and SSM (18%) will advance to develop to more advanced disease [10, 13, 20, 30].

There are also patients who may meet criteria for SM but also have another associated hematologic neoplasm, such as a myelodysplastic syndrome (MDS), lymphoma or leukemia [20]. Patients with SM-AHN tend to be more severely affected, with both bone marrow and tissue dysfunction; the prognosis is dictated by the underlying AHN, and patients may transform into mast cell leukemia (MCL) [10, 13, 23, 30]. Aside from bone marrow failure, other clinical manifestations include pathologic fractures, malabsorption, and liver failure. Patients who develop MCL have > 20% mast cells in the bone marrow or > 10% mast cells in the peripheral blood [10, 32]. Patients with MCL have an unfavorable prognosis with a median survival time of less than one year [2, 20, 23]. 

The majority of patients with SM present in adulthood. The typical clinical signs and symptoms of SM are similar to those of other MCAS, including episodic flushing, generalized pruritus, lightheadedness, presyncope, syncope, hypotension, tachycardia, abdominal pain and cramping, diarrhea, and headache [10, 33] (Table 1). As with other  MCAS, common triggers for these symptoms include heat, exercise, alcohol, envenomation, and stress [2, 33].  

When a patient presents with clinical signs and symptoms concerning for MCAS, a detailed history and physical exam is necessary. In evaluating for mastocytosis, the clinician should perform a thorough skin exam and determine if hepatosplenomegaly is present. If there are atypical skin lesions present and concern for potential CM, a skin biopsy should be performed and specific mast cell staining should be requested [34, 35]. Initial laboratory evaluation should include a complete blood count (CBC) with  differential, complete metabolic panel (CMP, including liver function tests), and a  baseline serum tryptase level [9, 30]. If the diagnosis of MCAS is met with fulfillment of the previously discussed criteria regarding recurrent symptoms, biochemical documentation of mast cell activation and favorable response to treatment, a bone marrow biopsy is warranted [2, 10, 17, 30]. Notifying the pathologist of suspected SM is imperative to ensure appropriate evaluation based on WHO diagnostic criteria (Table 2).  Pending bone marrow findings, additional studies may be necessary to evaluate for B or C findings suggestive of mast cell-related organ involvement. 

Treatment for SM is based on the WHO criteria-guided subvariant. Treatments focus on symptom control and decreasing mast cell activation and burden. Mast cell degranulation symptoms are managed with H1 & H2 anti-histamines, anti-leukotrienes, mast cell stabilizing agents, and epinephrine. Other symptoms, such as heartburn and osteoporosis, should also be treated with directed therapy. Inhibition of mast cell activation and mast cell cytoreduction therapies include tyrosine kinase inhibitors (imatinib, midostaurin, avapritinib), cladribine, corticosteroids, hydroxyurea,  chemotherapy, interferon-α, and even hematopoietic stem cell transplant [20, 23, 36, 37]. Imatinib has a limited role in SM treatment, as it targets the minority of patients without D816V mutation [20]. Midostaurin and avapritinib are both highly selective for D816V mutated KIT, and both are now FDA-approved for the treatment of ASM. Avapritinib has been FDA approved for the treatment of advanced SM since June 2021 and is the only drug FDA-approved for ISM [28, 36]. Additional clinical trials are ongoing to identify other therapies for SM [28]. 

2.1.2 Monoclonal mast cell activation syndrome (MMAS) 

Patients are diagnosed with monoclonal mast cell activation syndrome (MMAS)  when they meet criteria for MCAS but do not fully meet the WHO criteria for SM (they only fulfill one or two minor criteria) [13]. These patients may have pathologic findings on bone marrow examination, such as spindle shaped mast cells, and/or abnormal CD2,  CD25 and/or KIT mutations [13]; yield may improve if the bone marrow sample is enriched for mast cells rather than unfractionated [38]. MMAS bone marrow biopsies often lack mast cell aggregates, and patients may have normal or slightly elevated sBT [2, 10, 17]. An activating KIT mutation, usually D816V, is often detected in the bone marrow and may also be identified in the peripheral blood. If a KIT mutation is identified in the peripheral blood, a bone marrow biopsy is indicated [2, 9, 25, 27]. It has been shown that patients with MMAS have rates of severe anaphylaxis comparable to patients with ISM [39]. Given that the natural history of MMAS is unclear, monitoring tryptase, blood counts and organ function for emergence of B and/or C symptoms is important.