Mastocytosis - Where are we now?
Updated: March 2017
Originally Posted: July 2011
Cem Akin, MD, PhD
Brigham and Women’s Hospital Mastocytosis Center, Boston, MA
Mariana Castells, MD, PhD
Brigham and Women’s Hospital Mastocytosis Center, Boston, MA
Pathogenesis:
The growth , differentiation and survival of mast cells depends on stem cell factor (SCF) which binds KIT (CD117), a receptor tyrosine kinase expressed on the surface of normal and clonal mast cells. SCF is expressed on fibroblasts, melanocytes and others cells of the connective tissue and mucosal membranes, which have similar homing patterns as mast cells. The interactions between SCF and KIT lead to the phosphorylation of KIT and intracellular signal transduction, promoting mast cell activation, proliferation and survival. Activating mutations of KIT lead to continuous phosphorylation and signal transduction and mediators release (1). The most common activating mutation in codon 816 located in exon 17 of KIT is a valine substitution for aspartate (D816V) and is found in over 90% of patients with systemic mastocyosis and in the skin biopsies of over 30% children with cutaneous mastocytosis (2). Another 30% of children with cutaneous mastocytosis may have KIT mutations outside of exon 17. Other mutations in genes such as SRSF2, RUNX1, TET2, and ASLX1 can be found mutated in addition to KIT in patients with advanced variants of systemic mastocytosis and are associated with poorer prognosis (3).
Epidemiology:
Mastocytosis is seen in all ethnic backgrounds. Estimated incidence is approximately 1:20,000 (4). It occurs in males and females in approximately equal ratios. A childhood onset form is distinguished from the adult onset form by its early appearance (usually within the first year of life) and good prognosis with spontaneous resolution by puberty. Most patients diagnosed in adulthood have evidence of systemic disease defined by presence of pathologic mast cells in a non-cutaneous tissue (usually bone marrow). These patients have persistent disease that do not spontaneously resolve.
Clinical manifestations:
All patients with pediatric onset disease and >70% of adult patients with systemic mastocytosis present with typical skin lesions (see below). In addition, most patients also have symptoms related to mast cell mediator release. Patients with advanced disease categories such as ASM or SM-AHN present with hematologic abnormalities including high or low WBS, anemia, thrombocytopenia and findings indicative of tissue dysfunction.
Mast Cell Mediators Related Symptoms:
Patients with cutaneous and systemic mastocytosis present with symptoms related to the tissue response to the release of mediators and to the local mast cell burden (5). Patients with systemic mastocytosis have a history of acute and chronic mast cell mediator-related symptoms and the indolent variant has a good prognosis and a normal life span. Patients with cutaneous mastocytosis can present with systemic symptoms due to the skin mast cells release of mediators with a systemic action. Symptoms include pruritus, flushing, syncope, gastric distress, nausea and vomiting, diarrhea, bone pain and neuropsychiatric symptoms, most of which can be controlled with medications (6). Anaphylaxis due to acute mast cell mediator release can be triggered by multiple factors and should be promptly address due to the potential for massive cardiovascular collapse and death. Efforts to link particular mast cell mediators to symptoms depend on the known actions of the mediator and the efficacy of the mediator-targeted medications. Mast cell mediators include preformed mediators such as histamine and proteases such as tryptase, chymase and carboxypeptidase and newly formed lipid products of membrane arachidonic acid such as prostaglandins, leukotrienes and platelet activating factor. Other mediators include cytokines such as TNFa, IL-6, IL1 b and chemokines. Osteoporosis due to mastocytosis is becoming increasingly acknowledged, can occur in up to 30% of patients with systemic mastocytosis and has been associated with the increase in urinary histamine excretion and the increased presence of serum IL-6. The presence of osteoporosis in young males should alert the treating physician to the possibility of a diagnosis of mastocytosis. Other skeletal findings include patchy or diffuse bone sclerosis and osteolysis (7). All patients with systemic mastocytosis should undergo a bone mineral density scan.
Patient perceptions of mastocytosis
A recent cross sectional comprehensive survey of over 400 patients with Mastocytosis done under The Mastocytosis Society based in the USA indicated that the symptoms most commonly associated with the disease included anxiety, flushing, itching, fatigue, brain fog, stomach pain, diarrhea, headaches, joint pain, lightheadedness and syncope (8). These symptoms were not correlated with mast cell mediator levels and cannot be attributed to a single mediator but were critical in decreasing the quality of life of these patients. Whether current medications can address these symptoms and provide relief that increases the quality of life should be studied in multi center clinical trials.
Hymenoptera Anaphylaxis and Mastocytosis
A new expression of mastocytosis has been recognized in the last 10 years in patients presenting with anaphylaxis during hymenoptera stings (9). These patients are now known to be at risk for clonal mast cell disorders including monoclonal mast cell syndrome (MMAS) and indolent systemic mastocytosis (10). These patients usually have little mast cell bone marrow burden and in some cases present without skin lesions and normal tryptase levels. Patients at risk include males presenting severe hypotension at the time of the sting and with baseline tryptase >25 ng/ml. Tryptase should be evaluated in all patients, males and females, presenting with hypotension during hymenoptera stings and at baseline 4-6 weeks later. Specific IgE for venom hymenoptera is found in over 80% of these patients but 20% remained negative by skin test and serum specific IgE. A newly discovered mast cell receptor MrgprX2 may in fact be the target of the direct action of the venom vasoactive amines but there is currently no evidence that mastocytosis patients have an increased expression of MrgprX2 (11). Minor components of hymenoptera venom may be responsible for the anaphylactic events and may not be included in the skin testing or immunotherapy reagents. Patients with no evidence for venom specific IgE are not candidates for immunotherapy. For patients with specific venom IgE, immunotherapy is indicated for life and has been shown to be protective for over 80% of these patients (12). Patients with mastoocytosis may have increased risk of systemic reactions during venom immunotherapy. Omalizumab has been used successfully in these patients to allow them to receive venom immunotherapy (13). Mast cell cytoreductive therapies in these patients are not generally indicated since their mast cell burden is low and the expression of the disease is typically limited to the sting events with few or no mast cell mediators-related symptoms at baseline.
Atopy, Food and Medication Allergy and Mastocytosis
The presence of atopy does not appear to be increased in patients with mastocytosis (14) and a recent report indicates that patients presenting with drug hypersensitivity reactions and drug induced anaphylaxis are not at increased risk for clonal mast cell disorders (15). Although the expression of anaphylaxis is increased in patients with mastocytosis due to specific and non specific triggers, hymenoptera venoms remain the most common offender. The pattern of aeroallergen and food sensitization and asthma in atopic patients with mastocytosis did not differ from that found in patients without mastocytosis but a comprehensive allergic workup (including skin prick testing, total and specific IgE) should be performed on selected patients based on history to elicit potential triggers.
Cutaneous Mastocytosis
A recent new classification of cutaneous mastocytosis in adults and children has been developed to better assess the systemic impact of skin lesions and their potential prognosis (16).
The term “Maculopapular cutaneous mastocytosis (MPCM)” has been recommended to replace “Urticaria Pigmentosa”, which is the most common skin presentation in both children and adults. MPCM is divided into monomorphic and polymorphic and it appears as tan colored to reddish-brown macules and can be slightly raised papules of similar size and shape (monomorphic) and different sizes and shapes (polymorphic). It usually occurs on the sun-protected areas of the upper and lower extremities, chest, abdomen and back. It is rare on the palms, soles, face, scalp and other sun-exposed areas in adults. Children may have scalp involvement. Darier's sign can be elicited (erythema and urticaria within minutes after persistent scratching or rubbing of affected skin). Monomorphic form is the most common in adults, and if present in children after puberty can signify the presence of systemic disease, and has a prognostic value. Children with cutaneous mastocytosis may experience blistering of the lesions up to 4 years of age. Telangiectasia macularis eruptive perstans (TMEP) is a rare form which can be associated with maculopapular mastocytosis and is characterized by tan to brown macules with the presence of telangiestasia. Due to the rarity of this form, it is no longer part of the classification of the skin disease.
Mastocytoma of the skin is less common than maculopapular forms and is usually present in children. There is a typical history of flushing when the lesion is rubbed or disturbed. These lesions spontaneously involute.
Diffuse cutaneous mastocytosis (DCM) is a rare form of the disease that present in children with diffuse thickening of the skin instead of individual maculopapular lesions. Skin biopsy shows high level of infiltration. Children with DCM are more prone to systemic mast cell activation symptoms including anaphylaxis, as well as localized symptoms such as flushing, itching and blistering.
Non clonal mast cell activation syndrome
Recent studies of patients with anaphylaxis and symptoms compatible with mast cell activation and mediator release have lead to the recognition of a non clonal mast cell activation syndrome (MCAS) (17, 18). These patients are predominantly females and the symptoms include abdominal pain, dermatographism, flushing, headache, poor concentration and memory, diarrhea, naso-ocular symptoms, asthma and anaphylaxis. Criteria proposed by an expert consensus group include the presence of symptoms in 2 unrelated organs, the evidence of mast cell mediators whether tryptase elevations, or 24 h urine methyl histamine or prostaglandins and the response to the mast cell controller medications. Patients need to be ruled out for diseases with similar symptoms which can masquarade as mast cell activation such as pheochromocytoma, carcinoid, VIP tumors and other connective tissue disorders.
Diagnostic criteria:
Cutaneous mastocytosis
Cutaneous mastocytosis is diagnosed by inspecting the characteristic skin lesions and confirmed by skin biopsy which shows increased numbers of mast cells in upper dermis especially around blood vessel (16). Patients with mastocytomas or diffuse cutaneous mastocytosis have a high degree of infiltration whereas patients with maculopapular cutaneous mastocytosis may have more subtle infiltrations. Subvariant designated as telengiectasia macularis eruptiva perstans in former classifications is no longer present in the current classification due to the rarity of the diagnosis and its frequent association with classic MPCM.
Systemic mastocytosis:
Systemic mastocytosis by definition is presence of disease in extracutaneous tissues and requires a biopsy of the involved tissue (19,20). The biopsy site is bone marrow in the majority of the patients. Gastrointestinal biopsies were occasionally used to reach the initial diagnosis although all of the patients with GI involvement also have bone marrow disease. Therefore, in a patient with suspected systemic mastocytosis, tissue of choice for biopsy is bone marrow.
WHO criteria to diagnose systemic mastocytosis are as follows (21). The major plus one minor or 3 minor criteria should be met to establish the diagnosis.
Major criterion: Multifocal clusters of mast cells containing >15 mast cells per cluster. Bone marrow biopsy should be stained for tryptase and CD117 to visualize mast cells.
Minor criteria:
1. Aberrant cytomorphology of the mast cells. Normal mast cells are round and fully granulated with a central nucleus. Mast cells in biopsy sections or aspirate smears in mastocytosis have an aberrant morphology including spindle shapes, cytoplasmic projections, hypogranulation, and oval, eccentric nucleus sometimes with bilobulation (22).
2. Aberrant expression of CD25 and/or CD2. Normal mast cells do not express these antigens. CD25 is more sensitive than CD2 as CD2 may be lost in advanced variant of mastocytosis. CD25 can be detected by immunohistochemistry in bone marrow biopsy sections or flow cytometry (23, 24).
3. Detection of a codon 816 KIT mutation. D816V gain of function mutation is seen in more than 90% of adults and approximately 30% of children in lesional tissue. The mutation may also be detectable in peripheral blood especially in those with advanced disease (25). Since this is a somatic mutation, assay sensitivity should be kept in mind when interpreting a negative result. Most commercially available allele specific PCR based assays have sensitivity of around 1% and may yield false negative results if allelic frequency in the sample is low. Therefore, lesional tissue such as bone marrow or skin have a higher yield of positive results than peripheral blood. Sequencing based assays (usually used in evaluating solid tumors with KIT mutations such as GISTs, are not routinely recommended for diagnosis of mastocytosis as their sensitivity is very low.
4. Baseline serum tryptase >20 ng/ml. Normal median serum tryptase is 5 ng/ml. Levels exceeding 20 ng/ml are seen in mastocytosis (26). However, patients with low grade involvement of bone marrow may have tryptase levels less than this threshold. Likewise, some patients without mastocytosis (e.g. recently described familial hyperalphatryptasemia) may have elevated tryptase levels (27).
Monoclonal mast cell activation syndrome: This has been introduced as a relatively recent concept to designate patients who present with mast cell activation symptoms (such as recurrent anaphylaxis) but have low level involvement with clonal mast cell disease and do not fully meet the criteria for SM. These patients must have a codon 816 KIT mutation and/or CD25 expression as a marker of clonality but lack skin lesions and their tryptase level is usually below 20 ng/ml (18).
Classification and prognosis:
Current classification of mastocytosis is shown in Table 1 (21).
Cutaneous mastocytosis: This category by definition refers to disease limited to skin. It should be differentiated from “mastocytosis in skin” which may be encountered in patients with adult onset skin lesions who also have systemic disease. Cutaneous mastocytosis is almost exclusively seen in children with early onset skin lesions. A bone marrow biopsy to look for systemic disease is generally not indicated in these children unless there is hepatosplenomegaly, unexplained lymphadenopathy, abnormal CBC with differential or persistently elevated tryptase levels greater than 20 ng/ml. Patients with cutenaous mastocytosis have a good prognosis with approximately 90% showing spontaneous resolution or significant improvement of skin lesions by adolescence.
Systemic mastocytosis: This category defines patients with extracuatenous mast cell collections who may also have skin lesions of mastocytosis. Most patients with adult onset skin lesions will have systemic mastocytosis. SM is divided into 5 different subcategories.
Indolent systemic mastocytosis: This is the most common category of SM. Patients with ISM have aberrant mast cell collections in their bone marrow, but have no evidence for another hematologic disease or tissue dysfunction. Mast cells in aspirate smears are usually <5%. Patients with ISM have a comparable life expectancy to general population but can be symptomatic with various mast cell mediator release symptoms. Risk of progression to an advanced variant is less than 5%.
Smoldering systemic mastocytosis: This is a new category denoting patients with high burden of mast cells but no evidence of an overt hematologic disorder or tissue dysfunction. 2 of the 3 “B-findings” should be present: 1. Tryptase >200 ng.ml or bone marrow infiltration >30%, 2. Presence of hepatomegaly or splenomegaly without hypersplenism or liver dysfunction, 3. Presence of mild dysplastic changes or hypercellular marrow without meeting a WHO category of another hematologic disorder such as MDS or MPN. Patients with SSM are thought to have a higher risk of progression to a more advanced category below.
Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN): Patients in this category have SM but also have another non-mast cell hematologic neoplasm (AHN) associated with it. AHN is usually of myeloid in nature. MDS and MPNs are common but occasionally lymphoproliferative disorders can also be seen. The SM component of SM-AHN may be indolent or aggressive. The prognosis is usually determined by the AHN.
Aggressive systemic mastocytosis: Patients in this category have high level of tissue mast cell burden and signs of tissue dysfunction designated as “C-findings”. One of the following C-findings must be present: 1. High grade marrow infiltration with cytopenias (ANC <1000/mL, Hgb <10 g/dl, platelets <100,000/mL), 2. Hepatomegaly with liver dysfunction (e.g. portal hypertension with ascites), 3. Splenomegaly with hypersplenism, 4. Malabsorption with hypoalbuminemia and weight loss, 5. Large osteolytic lesions (>2 cm) with pathologic bone fractures. Patients with ASM have a reduced life expectancy and are candidates for mast cell cytoreductive therapies.
Mast cell leukemia: This is the rarest and the most advanced form of SM. It is characterized by presence of >20% immature mast cells in bone marrow aspirate smears or >10% in peripheral blood. It carries a very poor prognosis. Patients with MCL are candidates for polychemotherapy, SCT or investigational treatments.
Mast cell sarcoma: This is a rare solid tumor with invasive features and malignant spread and carries a poor prognosis.
Well differentiated systemic mastocytosis: This is a rare histopathologic variant originally described in 2004 (28). Patients with WDSM may fall into any subvariant of SM. The majority of the patients have childhood onset disease that progresses to SM. This variant is characterized by mature appearing mast cells with minimal morphologic aberrancies. CD 25 or CD2 expression is absent, although CD30 is generally found aberrantly on the surface of the mast cells. Mast cells in WDSM usually lack D816V KIT mutations and may be sensitive to imatinib as opposed to those carrying D816V mutation (29).
Management:
There are 4 main principles of management:
1. Avoidance of mast cell activation triggers
2. Anti-mediator treatment
3. Mast cell cytoreductive therapies
4. Adjunctive treatments for the co-existing disease
Each patient may have a unique set of triggers that exacerbate mast cell activation symptoms. These include physical factors such as temperature changes, friction, exercise, fever, emotional stress, alcohol and drugs. NSAIDs and opioids are commonly incriminated although many patients can tolerate them. Hymenoptera stings can be life threatening in those who also developed IgE mediated sensitization to venoms. In contrast, IgE mediated food and environmental allergies are not seen in increased frequency in mastocytosis.
Anti mediator treatment commonly includes once or twice daily dosing of H1 and H2 antihistamines as well as leukotriene blockers, and cromolyn (30). Glucocorticoids are helpful in those with recurrent anaphylaxis or in patients with liver or gastrointestinal involvement. Aspirin therapy has been used by some authors to reduce flushing however patient’s tolerance to aspirin should be known before initiating this treatment. Omalizumab has been found to be useful in reducing anaphylactic symptoms in those who do not respond optimally to first line antimediator options stated above. Multiple doses of self-injectable epinephrine should be prescribed to all patients with SM even if they do not have any history of anaphylaxis, as the incidence of anaphylaxis has been reported to be as high as 50% in some cohorts.
Currently approved mast cell cytoreductive therapies include IFN-alpha and cladribine (31). Alpha IFN has a slow onset of action and has poor tolerability due to side effects such as flu like symptoms has fallen out of favor in recent years. Cladribne is a nucleoside analogue and is a non-specific poison of mast cells as well as other hematopoietic cells. It usually causes a rapid cytoreduction evidenced by decreased tryptase levels however has profound immunosuppression and cytopenias. Imatinib has been approved by FDA to be used for treatment of mastocytosis without or unknown codon 816 KIT mutation. Our experience is that most patients with SM in need of a cytoreductive therapy are not candidates for imatinib as they have a high incidence of codon 816 mutations. Investigational tyrosine kinase inhibitors such as midostaurin have recently yielded promising results in patients with ASM and MCL (32). Stem cell transplantation may have a role in selected patients with advanced disease (33). Treatment of associated conditions such as AHN and osteoporosis should be done according to the guidelines of these entities.
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Table 1.
Classification of mastocytosis
Cutaneous mastocytosis
Indolent systemic mastocytosis
Smoldering systemic mastocytosis
Systemic mastocytosis associated with a hematologic neoplasm
Aggressive systemic mastocytosis
Mast cell leukemia
Mast cell sarcoma
