Mast cells belong to the family of ´white blood cells´ (leukocytes). These cells originate from progenitors that are primarily produced in our bone marrow. Mast cells were first discovered and described by Paul Ehrlich in 1876. In contrast to other leukocytes, (normal) mast cells are not found in the peripheral blood, but are located in the tissues in various organs, such as the lung, skin or the gastrointestinal tract, where these cells reside for many months or even years.
Like most white blood cells, mast cells belong to the immune system that help us to defend against bacteria and other microbes. As part of an alarm system, mast cells can respond very rapidly to foreign attacks of microbes by releasing potent vasoactive and defense-related molecules into the tissues in local areas. These mediators are released from mast cells during allergic reactions. Depending on the underlying pathologies, type of allergies and other factors, the resulting symptoms may be mild, moderate or severe, and may sometimes result in the clinical picture of severe anaphylaxis.
One of the most important chemical mediators of mast cells is histamine, which can cause tissue swelling (edema), itching, flushing, and redness of our skin, but also headache, nausea, dizziness, or diarrhea. Histamine can also augment other gastrointestinal problems and are often involved in ulcerative diseases, like gastric ulcer. Finally, histamine is a ´neuroactive´ mediator and can influence the blood pressure. Apart from histamine, mast cells also produce numerous other chemical substances, proteolytic enzymes and cytokines.
"Mastocytosis was first described by Nettleship and Tay as a "rare form of urticaria" in the British Medical Journal in 1869. It then took until 1949 when Ellis discovered involvement of internal organs in mastocytosis in an autopsy case and thus systemic mastocytosis. About ten years earlier, the term mastocytosis had been created. In 1957, a first description of mast cell leukemia was presented. During the last few decades, the knowledge of scientists about mastocytosis has increased dramatically.
A first classification of the disease was introduced by Karl Lennert in the mid-70ths of the past century. In 1991, a first consensus classification was proposed by Dean Metcalfe. Between 1991 and 2000, a number of relevant cellular, molecular, and biochemical abnormalities specific for mastocytosis were discovered. In these studies, it turned out that the accumulating mast cells in patients with mastocytosis are always monoclonal (= neoplastic) in nature.
In the year 2000, the consensus classification was refined and updated by a US/EU consensus group (coordinator: Peter Valent) by introducing disease-specific criteria. In the year 2001, the WHO adopted both the criteria and the classification as official WHO classification of mastocytosis. Subsequent validation studies confirmed the value of the WHO classification and since then, this classification and the related criteria are regarded the diagnostic gold standard. The WHO classification of mastocytosis and the criteria were further validated and were refined in 2008 and 2016. In 2012, the consensus group presented a global classification of all mast cell disorders. This classification includes mast cell hyperplasia (a reactive increase in normal mast cells), cutaneous and systemic mastocytosis, myelomastocytic leukemia, and mast cell activation syndromes. This classification and the WHO classification of mastocytosis are still valid and global standards today.
Mastocytosis is a disease that is characterized by abnormal expansion and accumulation of mast cells in i) the skin, ii) in internal organs, or iii) in both the skin and internal organs. As a result, mastocytosis is diagnosed on the basis of a histologically confirmed increase and accumulation of too many mast cells (extra mast cells) in these organs. Both children and adults can develop mastocytosis.
In general, mastocytosis can be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In patients with CM, mast cell accumulation is only or primarily found in the skin. To diagnose CM, a biopsy of affected skin is often performed. The pure cutaneous form of mastocytosis is usually diagnosed in (early) childhood. By contrast, most patients in adulthood are diagnosed to have SM. Since most adult patients with SM have typical skin lesions, these patients are often regarded as suffering from CM and often labeled with the incorrect diagnosis of urticaria pigmentosa (UP). Since the bone marrow is almost always involved in these patients (but not in those with pure CM), the diagnosis of SM is usually established in these cases when a biopsy of the bone marrow is performed. Therefore, it is important to recommend a bone marrow biopsy in all adult patients with mastocytosis. In the rare patients without skin lesions, it may take a longer time until the doctors consider SM as a potential diagnosis, and thus it may take a longer time until the final diagnosis SM is established. Again, it is important that the physician recommends a bone marrow investigation in these cases.
Both CM and SM are regarded as neoplastic disorders of stem and progenitor cells of the mast cell lineage. In contrast to reactive mast cell hyperplasia (increased mast cell numbers in inflammation, infections, toxic reactions or cancer), mast cells in CM and in SM are monoclonal in nature, which means that all these cells are initially derived from one abnormal (mutated) stem cell. The monoclonal nature of the disease leads to an enhanced differentiation, survival and abnormal accumulation of mast cells in one or more organ systems.
The monoclonal nature of mast cells in mastocytosis is best documented by demonstrating the presence of a point mutation in the KIT proto-oncogene. In the vast majority of patients with SM, neoplastic cells display the somatic KIT mutation D816V (Asp-816-Val). In these patients, the mutation is detected in the bone marrow and in lesional skin (urticaria pigmentosa lesions). In many patients with SM, the KIT mutation D816V can also be detected in circulating blood leukocytes when a highly sensitive PCR test is applied. In most childhood patients with CM or SM, mast cells also express KIT mutations. However, unlike in SM of adults, a number of different KIT mutations can be detected in children with CM or SM. KIT D816V is only detected in a smaller subset of these cases.
The natural clinical course of mastocytosis is variable depending on age, organs involved, subtype of disease, other co-existing disorders (like allergies or other clonal hematologic disorders), and response to initial therapy. The majority of all patients with CM and indolent SM (ISM) have a normal life-expectancy. In pediatric mastocytosis (CM in most cases), the disease often (but not always) resolves during, shortly before, or shortly after puberty.
Mastocytosis is a non-contagious disease of mast cells and their progenitor cells. In a vast majority of all cases, no other family members are affected or will develop mastocytosis during lifetime. Familial mastocytosis is an extremely rare disorder with an estimated frequency of less than 1:100 among all patients with mastocytosis. In addition, a number of genetic patterns and constellations may be associated with a slightly increased risk to develop CM or SM. One of these variations is hereditary alpha tryptasemia (HAT=HaT). This condition is defined by an elevated basal serum tryptase level and an increased copy number of the gene encoding for alpha tryptase (TPSAB1). HAT is found in about 5% of the general populations in the Western World (EU/US) and in approximately 15-20% of all patients with SM.
The WHO defines the following variants of mastocytosis (update 2016):
- Cutaneous Mastocytosis (CM)
- Indolent Systemic Mastocytosis (ISM)
- Bone Marrow Mastocytosis (BMM)
- Smoldering Systemic Mastocytosis
- SM with Associated Hematologic Neoplasm (SM-AHN)
- Aggressive Systemic Mastocytosis (ASM)
- Mast Cell Leukemia (MCL)
- Mast Cell Sarcoma (MCS)
Cutaneous mastocytosis usually develops in early childhood, whereas in adulthood, almost all patients are diagnosed with a systemic form (variant) of mastocytosis (SM). Most adult patients have indolent SM (ISM) and in a majority of these cases, skin involvement is found. All other sub-variants of SM (such as SSM, SM-AHN, ASM, or MCL) are rarely diagnosed. Patients with ISM, bone marrow mastocytosis (BMM), a rare provisional sub-variant of ISM, and CM in adulthood (like in childhood CM) have an excellent prognosis regarding survival. However, in contrast to childhood CM, CM in adults is a persistent disease without spontaneous regression. CM in adults is a rare condition, whereas childhood CM is the most frequent form of mastocytosis. Most pediatric patients with CM have a benign and often self-limited clinical course. The disease often regresses spontaneously before, during or shortly after puberty. Children usually do not develop aggressive disease variants in the follow up.
There are also some unique aspects and clinical presentations in the skin lesions that can develop in childhood mastocytosis. For example, blistering of skin lesions is only seen in pediatric mastocytosis, usually in the first 3 years of life. A diffuse infiltration of the skin is also seen almost exclusively in children and is then leading to the diagnosis of diffuse cutaneous mastocytosis (DCM). DCM is a rare disease and the same holds true for mastocytomas of the skin, which are solid benign mast cell tumors. In general, the prognosis of childhood mastocytosis is excellent. The following variants of CM have been described by the WHO:
- Maculopapular Cutaneous Mastocytosis (MPCM) = Urticaria Pigmentosa (UP)
- MPCM with polymorphic (often asymmetrical) infiltration pattern
- MPCM with monomorphic small-sized (usually symmetrical) infiltration pattern
- Diffuse Cutaneous Mastocytosis (DCM)
- Mastocytoma of Skin
The following courses have been described in childhood CM: i) spontaneous regression (frequently seen), ii) persistence of CM into adulthood (rare), and iii) persistence into adulthood with ‘transition’ to SM (rare). Evolution to a ‘high-grade’ mast cell disease (aggressive SM or MCL) is extremely rare.
At the time of diagnosis, the clinical course in childhood CM is unpredictable. However, in most cases with DCM and mastocytomas in the skin, the disease resolves spontaneously. In patients with childhood MPCM there is also a clear tendency to complete regressions. However, definitive regression is only seen in a subset (estimated 60-80%) of these patients. It is difficult to predict the course in these patients. However, recent data suggest that the morphologic aspect of the skin lesions is of prognostic value: in particular, the skin lesions disappear in almost all patients with polymorphic (often asymmetrical) skin infiltration patterns, whereas in most cases with monomorphic skin lesions (that often show symmetrical distribution like in adults) the skin lesions may persist into adulthood. The clinical course in pediatric MPCM is independent of other factors, like age, gender, mutations in KIT, and basal serum tryptase levels. Even the demonstration of KIT D816V in lesional skin cannot predict the clinical course as full regressions are also seen in such cases.
The natural clinical course of SM is also variable. Most patients are adults at diagnosis and have ISM with a good prognosis and normal or near-normal life expectancy. Advanced SM variants are rarely diagnosed. These variants include aggressive SM (ASM), SM with an associated hematologic (non-mast cell-lineage) neoplasm (SM-AHN) and MCL. In these patients, the prognosis is grave. Especially in patients with MCL, where mast cells can often be found in the peripheral blood, the disease has an unfavorable prognosis with short survival despite intensive therapy. In the past few years, however, the advent of new, better treatment concepts (including KIT tyrosine kinase inhibitors and stem cell transplantation = SCT) has led to a considerable improvement of the prognosis and survival of patients with advanced SM (ASM, SM-AHN and MCL). In most patients with MCL and many with ASM, skin lesions are absent. In addition, in several of these cases, KIT D816V is not detectable.
In patients with SM-AHN, both the SM component and the AHN component of the disease have to be classified. In these cases, the SM portion of the disease may be an ASM or ISM depending on clinical presentations. The AHN is often a myeloid neoplasm, such as a myeloid leukemia, a myelodysplastic syndrome (MDS), a myeloproliferative neoplasm (MPN) or a MDS/MPN overlap disorder. The most prevalent type of AHN is chronic myelomonocytic leukemia (CMML). In patients with acute myeloid leukemia (AML) the prognosis is grave although complete remission may be achieved with poly-chemotherapy and/or SCT if such therapies can be offered. In some of these cases, long-term survival has been described.
Localized extra-cutaneous mast cell tumors (mastocytoma, mast cell sarcoma) are very rare. The natural clinical course and prognosis of extracutaneous mastocytomas is good. However, based on its rarity, this form of a mast cell disease has been eliminated in the 2016 update of the WHO classification. Most cases reported are localized in the lungs. The disease is benign without known clinical impact. By contrast, mast cell sarcoma, also an extremely rare tumor, often transforms into MCL and has a very unfavorable prognosis (similar to MCL). Only a few patients achieve a durable remission despite radiation and chemotherapy, and long-term survival has only been reported in a very few cases.
One important aspect in disease-heterogeneity of mastocytosis are clinically relevant mediator-related symptoms requiring symptomatic treatment (SY). This group of patients (variants of CM or SM) are labeled with the appendix ´SY´ in the diagnosis. Relevant symptoms can occur in any (sub)variant of CM (CMSY) and SM (SMSY), and can represent a major clinical problem. Mediator-induced symptoms range from mild and tolerable to severe and repeated life-threatening episodes of hypotension and anaphylactic shock (see below).
However, it is also worth noting that in many patients with CM or SM, no mediator-related symptoms are recorded, even when followed for a longer time period. This is an important point as also in these asymptomatic patients, prophylactic anti-mediator-type therapies are usually recommended because even after a long symptom-free interval, major and sometimes life-threatening, mediator-induced symptoms can occur and may be more dangerous in untreated cases. Such life-threatening events can in part be prevented or at least mitigated by use of prophylactic mediator-targeting drugs.
In each case, the doctor will first perform a careful physical examination, including a thorough inspection of the skin surface. The diagnosis of mastocytosis is based on a histological examination of the affected organ as well as additional laboratory tests and other investigations that are often performed in front of a biopsy (pre-invasive tests). These pre-invasive tests can help the physician to predict the likelihood of SM, especially when no skin lesions are detectable. These initial pre-invasive screens encompass routine laboratory parameters, including blood chemistry, blood counts and a basal serum tryptase level. A substantially increased basal tryptase level is always an indication for more investigations and a complete staging, and in many cases, an SM will indeed be diagnosed. However, an increased basal tryptase level is not specific for SM, but is also found in patients with other myeloid neoplasm and also in individuals carrying extra copy numbers of the alpha tryptase gene, also known as hereditary alpha tryptasemia (HAT=HaT). This genetic variation is associated with an increased prevalence of (and predisposition for) severe hypersensitivity reactions in patients who are suffering from an allergic disease or other reactive conditions and is also frequently documented in patients with SM (15-20%). The HAT test is a relatively simple test (PCR) but is currently offered in only a very few specialized centers worldwide. However, we assume that the HAT test will soon be available in more specialized centers.
In recent years, highly sensitive technologies (PCR-based) for the detection of KIT D816V in peripheral blood leukocytes have been developed. These assays are already used routinely to examine blood leukocytes in patients with suspected SM in specialized centers. When such mutation screen shows a positive test result in an adult patient, a bone marrow examination is recommended. In addition, a bone marrow study is recommended for (adult) patients with suspected SM and otherwise unexplained, relevant (and persistent) blood count abnormalities and/or when the basal serum tryptase level is clearly (and persistently) elevated (over 30 ng/ml) and is not explained by any other pathology or genetic variation (including HAT) or mast cell activation.
A skin biopsy is recommended in all adults with suspected mastocytosis and typical skin infiltrates: macules or maculopapular lesions that become red and sometimes swollen upon mechanical irritation (the so-called Darier´s sign). In children with very typical skin lesions, the physician may not take a skin biopsy. However, in adults, a skin biopsy should always be performed. In addition, a bone marrow biopsy and thorough investigation of bone marrow cells is always recommended in adults with typical skin lesions. By contrast, in children a bone marrow biopsy is usually not required since most patients have a normal serum tryptase level and the likelihood of SM is very low.
The histology of the skin and/or the bone marrow may show typical mast cell infiltrates (diagnostic criteria) leading to the diagnosis of (systemic or cutaneous) mastocytosis. In addition, the histology may reveal diagnostic information about the subtype of the disease. In the bone marrow aspirate, additional information can be obtained regarding the morphology of the (neoplastic) mast cells, their immunophenotype, and the presence of the KIT mutation D816V. In addition, a bone marrow investigation may reveal or exclude the presence of an associated hematologic (non-mast cell lineage) neoplasm (AHN).
A certain number of diagnostic criteria have to be fulfilled to arrive at the diagnosis SM. The WHO classification discriminates between major and minor criteria to diagnose SM with certainty (SM criteria). These criteria include the histology of the bone marrow or of another extra-cutaneous organ (major SM criterion), abnormal (spindle-shaped and hypogranulated) mast cell morphology (minor SM criterion), expression of CD2 and/or CD25 in bone marrow mast cells (minor SM criterion), presence of an activating KIT mutation at codon 816 in the bone marrow or in another extracutaneous organ (minor SM criterion), and an elevated serum tryptase level >20 ng/ml (minor SM criterion: this criterion is not valid if the patient is suffering from another myeloid neoplasm). If at least one major SM criterion and one minor SM criterion or at least three minor SM criteria are fulfilled, the diagnosis SM can be established. These criteria represent the global standard since 2001. In addition, there are disease-related criteria that define the smoldering state (B-Findings) and SM-induced organ damage in patients with an advanced SM (C-Findings).
Definition of B-Findings in patients with SM:
B-Findings are indicative of a huge mass of neoplastic mast cells and of multi-lineage involvement of the neoplastic process (involvement of additional hematopoietic cell lineages, not only mast cells). B-Findings include i) a high mast cell infiltration grade in the bone marrow biopsy section (>30% by histology and immunohistochemistry) and (plus) a high serum tryptase level (>200 ng/ml), ii) a hypercellular bone marrow with signs of myeloproliferation, bone marrow cell dysplasia, and iii) organomegaly (lymphadenopathy or splenomegaly). Importantly, B-Findings are not associated with organ damage by definition. Rather B-Findings are indicative of a smoldering state and an uncertain clinical course. When 2 or 3 B-Findings are documented, the diagnosis smoldering SM (SSM) is established. In a subset of patients, SSM progresses into an advanced form or SM, such as ASM or MCL. However, overall, the prognosis in patients with SSM is favorable as most patients have a stable disease course.
Definition of C-Findings in patients with SM:
C-Findings are always associated with the presence of an advanced form of SM and are usually also indicative of the need to administer intensive cytoreductive or targeted drug therapies to bring the SM-related disease process under control. C-Findings are thus indicative of a clinically relevant organ damage that is caused by a local neoplastic mast cell infiltration that replaces the normal organ. The organ damage may be irreversible. C-Findings are only detectable in advanced forms of SM (ASM, ASM-AHN, MCL) by definition. Any organ system may be involved. C-Findings include, among others, a decreased production and number of blood cells (due to a loss of bone marrow function), resulting in anemia (with weakness and dyspnea), leukopenia (with neutropenic infections and fever), and/or thrombocytopenia (decreased blood platelet counts with or without bleedings), (otherwise unexplained) weight loss, a decreased production and/or loss of albumin (hypalbuminemia), liver damage with ascites and increased liver enzymes (especially alkaline phosphatase), malabsorption (clinically relevant damage of the gastrointestinal tract and its ability to digest and take up nutrients) or huge bone lesions resembling osteolyses (caused by a mast cell infiltrate) with pathologic fractures (fractures occurring after minimal injuries or just spontaneously). It is important that the etiology of the C-Findings is investigated in detail and that the physicians and pathologists are sure that the clinical symptoms are derived directly (primarily) from the pathologic mast cell infiltrate but not from any other reason or comorbidity. Therefore, it is important that the physician asks for a pathologic report with histologic and immunohistochemical evidence of a local huge mast cell infiltrate before labeling the symptomatology as C-Finding and establishing the diagnosis of an advanced SM. In patients with advanced SM, one or more C-Findings may be recorded. It is important to know that one C-Finding alone is sufficient to establish the diagnosis of an advanced SM. Please Note:
B-Findings = Borderline Benign
C-Finding/s = Consider Cytoreduction or Chemotherapy
(or Targeted Drugs or SCT)
Symptoms that are caused by mast cell mediators must neither be regarded as B-Findings nor as C-Findings.
Mast cell leukemia (MCL) is usually accompanied by B-Findings and C-Findings and has a poor prognosis. Diagnostic criteria of MCL include SM criteria and the presence of ≥20% mast cells in the bone marrow smear (independent of the infiltration grade of mast cells in the bone marrow histology). Circulating mast cells may or may not be detected. In those patients in whom mast cells account for ≥10% of peripheral blood leukocytes, the diagnosis of classical MCL is appropriate. By contrast, in patients with <10% circulating mast cells, the aleukemic variant of MCL is diagnosed. In most patients with MCL, C-Findings are detectable. If this is not the case, the diagnosis is chronic MCL. Thus, MCL can be split into:
- Chronic Classical MCL
- Acute Classical MCL
- Chronic Aleukemic MCL
- Acute Aleukemic MCL
Finally, MCL may develop from another form of mastocytosis, such as ASM, ASM-AHN or mast cell sarcoma (secondary progression). In these patient, the diagnosis secondary MCL is appropriate. In the remaining cases, a primary form of MCL is diagnosed.
Symptoms of mastocytosis can occur from biologically active mediators that are released from mast cells (= mediator-related symptoms = SY) or from a malignant local infiltration and expansion of neoplastic mast cells in various organ systems (usually leading to C-Findings = organ damage). Mast cells produce and release a large number of biologically active mediators, including vasoactive mediators, coaguloactive substances, and immunoregulatory molecules, such as histamine, heparin, tryptases, prostaglandins, cytokines or chemokines. These mediators can cause a number of more or less specific symptoms, including headache, fatigue, bone pain, nausea, itching, urticarial, flushing, diarrhea, abdominal discomfort and cramping, an ulcerative disease of the stomach, hypotension, and even severe anaphylactoid reactions with shock. These symptoms can occur in any variant of mastocytosis and at any time during the course of disease. Usually, mast cell activation and the related symptoms are initiated by certain triggers (of mast cell activation). A number of different triggers are known to provoke mast cell activation in patients with CM and SM. One important type of underlying conditions are concomitant IgE-dependent (or IgE-independent) allergic and hypersensitivity reactions, other reactive disease processes and predisposing (genetic) conditions, such as a hereditary alpha tryptasemia (HAT). Therefore, the clinical presentations and symptomatology are highly variable in patients with CM and SM. In some patients, symptoms are very mild, whereas in others, symptoms are severe and require continuous therapy with anti-mediator-type drugs (these patients are then labeled as CMSY or SMSY) and sometimes even immediate therapy, especially in case of severe anaphylaxis. CM and SM patients have a particularly high risk to develop severe anaphylactic reactions when they suffer from multiple (concomitant) IgE-dependent allergies, and the risk may further increase when these patients are also HAT carriers. In these patients, anaphylactic reactions may be life-threatening and, in many cases, a so-called mast cell activation syndrome (MCAS) is diagnosed (see below).
An anaphylactic shock results from a sudden and massive release of vasoactive and inflammatory mediators from mast cells. In small children, unresponsiveness and flaccidity may be the only signs of an anaphylactic episode. Older children and adults may feel dizzy or become unconscious due to a drop in the blood pressure. Other signs are variable and may include headache, itching, sneezing, dyspnea (shortness of breath), nausea, tachycardia, swelling of the tongue and lips, flushing and abdominal pain. Triggers leading to anaphylaxis may be known or are immediately recognized, but may also remain unknown or are difficult to identify. In the case of a suspected severe anaphylaxis, immediate help should be provided and a professional emergency team should be organized as soon as possible. It is also recommended that the patients or/and parents (especially in case of a known allergy against bee or wasp venom) familiarize themselves with the use of epinephrine injectors and keep these injectors accessible at all times. As soon as the patient is admitted at a hospital, emergency measures will be initiated – and among other laboratory tests, a serum tryptase level should be determined.
The skeletal system, especially the bones, are often affected in patients with SM and may show a number of disease-related abnormalities. The most frequently recorded pathologies are osteosclerosis, osteopenia, and osteoporosis. Although the etiology is not entirely clear, experts believe that several different mediators released from mast cells can contribute to the bone loss seen in patients with SM. In patients with advanced SM, focal lesions may be detected. In rare cases, huge osteolyses with or without pathological fractures are seen. Osteoporosis is more frequently diagnosed in ISM and SSM than in patients with advanced SM. When osteoporosis is severe, these patients may also develop pathological fractures (fracture of bone after minimal or no injury), especially when no adequate therapy is administered or is initiated at a late time point. Additional risk factors for the development of severe osteoporosis are physical inactivity, vitamin-D deficiency, and long-term therapy with glucocorticosteroids. Although female patients may have a slightly higher risk, severe galloping osteoporosis can develop both in female and male patients with SM. Therefore, repeated measurements of the bone mineral density (osteodensitometry, T-score) are recommended in all patients with SM and also in those with a long-lasting CM in adults.
MCAS is a severe recurrent reaction of our body to certain triggers that lead to a massive release of mast cell-derived mediators. Typically, patients with MCAS present with symptoms of anaphylaxis involving two or more organ systems. In almost all cases, severe hypotension and anaphylactic shock are recorded. In contrast to the diagnosis ´anaphylaxis´, the diagnosis MCAS has to be based on solid confirmation that mast cells are essentially involved in the hypersensitivity reaction. Therefore, serum tryptase measurements are usually performed in these patients. Indeed, the most specific indication of a mast cell-related event is the demonstration of a substantial increase in the serum tryptase level over the individual´s baseline. The diagnostic threshold that has been proposed by the consensus group (and has been validated successfully) is an increase to over 120% + 2 ng/ml tryptase compared to the symptom-free interval (baseline tryptase value). Such baseline value is either known or must be obtained after (at least one day after) resolution of all symptoms. Finally, the diagnosis MCAS is based in the observation that the patient benefits from and recovers after specific therapies (drugs directed against mast cell mediators or mast cell stabilizers). The diagnosis of MCAS can be established when all three criteria of MCAS are fulfilled: i) clinical signs of a severe systemic mast cell-dependent reaction, usually in form of anaphylaxis, ii) increase in serum tryptase according to the 20%+2 equation and iii) response to specific therapies.
MCAS can be divided into 3 categories (variants) based on the underlying etiology. A primary form of MCAS is almost exclusively diagnosed in patients with CM or SM. The mast cells in these patients are always monoclonal cells and usually KIT-mutated (therefore also: monoclonal or clonal MCAS = MMAS). In rare patients with MCAS, clonal KIT D816V+ mast cells are found but the criteria for CM and SM are not fulfilled. Still these patients are also classified as suffering from primary/clonal MCAS – and several of these patients develop overt CM or SM in the follow up. In other patients with MCAS, an underlying IgE-dependent or IgE-independent allergy or another reactive disease process (that leads to mast cell activation) can be detected. This form of MCAS is termed secondary (or reactive) MCAS. Patients with CM or SM may also develop a mixed form of MCAS (primary MCAS plus secondary MCAS). These patients are often suffering from severe or even life-threatening episodes of anaphylaxis, especially when they are also carriers of a so-called hereditary alpha tryptasemia (HAT). When no clonal mast cells (no CM or SM), no IgE-dependent allergy and no other reactive underlying disorders or conditions are found, the diagnosis of an idiopathic MCAS is appropriate.
There are a number of different ways and strategies to treat mastocytosis. The form of treatment and drugs recommended depend on the type of mastocytosis, presence of additional diseases (co-morbidities) and response to therapy in individual patients.
A very important (maybe the most important) therapeutic strategy is prophylaxis which should be performed in all patients. In principle, two prophylactic strategies are followed:
1. Prophylactic avoidance of all known or suspected triggers of severe mediator-related symptoms and anaphylactic reactions. The patients are usually able to learn what factors and conditions (substances, drugs, allergens, food, stress, certain temperatures, vibration, alcohol, toxins, venom, others) can or may provoke such reactions, and they will then try everything possible to avoid exposure as much as possible. In addition, there are some classical triggers of anaphylaxis in mastocytosis patients that have to be avoided at all time (examples: bee or wasp venom or aspirin). Finally, patients with mastocytosis are often advised to avoid histamine-rich food and histamine-rich beverages.
2. Prophylactic therapy with histamine receptor (HR) targeting drugs. In particular, patients with mastocytosis are always advised to take both, HR1 blocker and HR2 blocker on a continuous basis. Although this basic prophylaxis may not always prevent the patient from severe mediator-related symptoms, the HR1/HR2 blockage may mitigate the intensity of the reactions to a degree and thus may help the patient to survive critical anaphylactic events. In addition, life-long therapy with HR blocker can prevent the occurrence of certain histamine-dependent diseases such as gastric ulcerative disease. Another important prophylactic therapy is supplementation with vitamin-D in order to avoid vitamin-D deficiency-related pathologies, such as osteoporosis. Especially in patients who have a high risk of osteoporosis (e.g., in cases with osteopenia, corticosteroid therapy or immobilized patients) prophylactic therapy with vitamin-D is recommended.
Two important aspects are anesthesia and unrecognized (unknown) allergies. In the case of a known (identified) allergy, the allergen (allergen source) should strictly be avoided. In front of a surgery, the involved physicians (surgeons, anesthesiologists) should be informed about the presence of mastocytosis and about the presence of concomitant allergies. Based on this information the perioperative management can be adjusted to the individual situation in each case. Some centers recommend preoperative intra-cutaneous drug testing (provocation tests) in patients with mastocytosis in order to learn whether and how the patient would react. In each patient with mastocytosis, preoperative management should include administration of HR1 and HR2 blocking drugs and sometimes also corticosteroids (in high-risk patients, e.g. in those with known IgE-dependent allergies, MCAS in their case history, previous events during surgery). Further information regarding anesthesia in patients with mastocytosis are available in the reference link (´literature´) in this homepage and in the PubMed (= major scientific medical database): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi.
In symptomatic patients with CM or SM, the physician is also recommending continuous HR1 and HR2 blocker to control disease activity. HR1 antagonists are drugs that are used to treat vascular instability (hypotension), itching, hiving, and flushing. HR1-targeting drugs can also bring some relief to gastrointestinal symptoms. HR2 antihistamines are drugs that can counteract gastrointestinal symptoms associated with mastocytosis, including reflux with indigestion, cramping, diarrhea, and ulcerative disease. In addition to HR-targeting drugs, a number of other drugs are also used in patients with mastocytosis to ameliorate mediator-related symptoms. These drugs include the so-called mast cell stabilizers (like cromolyn sodium), glucocorticosteroids which are also acting as mast cell stabilizer, and ketotifen, which also acts as a HR1 blocker. These drugs are often used when the conventional HR blocker fail to control disease activity.
Another anti-mediator-type drug is epinephrine which helps during most severe anaphylactic reactions with hypotension and shock. This drug needs to be applied in severe anaphylaxis with hypotension and shock as soon as possible. All mastocytosis patients should carry emergency medicines with them, including at least two epi-pen auto-injectors; and the patients and their relatives should be trained how to use and apply the pen in case of an emergency situation.
In each case, the treatment of mediator-related symptoms needs to be individualized by a physician who will do so according to the symptoms reported by patients and response to initial therapy. In general, the treatment is aimed at controlling symptoms with HR1 and HR2 antihistamines alone without other drugs. However, if required the doctor will prescribe additional drugs such as a corticosteroid, proton pump inhibitor, or others to keep the disease activity under control. Basic therapy in SM also includes prophylactic and specific therapy of osteopenia and osteoporosis both of which are seen in female and male patients. Prophylactic measures include supplementation with vitamin-D, exercise (to avoid immobilization), and aiming for corticosteroid-sparing therapies if possible. When the T score (bone density-related parameter) is below -2 and thus indicative of an imminent osteoporosis, an interventional therapy with a bisphosphonate should be started to avoid overt osteoporosis. The same holds true for patients who have overt osteoporosis. When therapy with bisphosphonates fails, RANKL inhibitors can be prescribed as an attempt to stop the osteoporosis-process.
Cytoreductive therapies and targeted drugs: A number of different cytoreductive and targeted drugs can be applied to counteract the increase and expansion of neoplastic cells in patients with advanced SM, including aggressive SM (ASM) and mast cell leukemia (MCL). These drugs include, among others, interferon-alpha (IFN-A), cladribine (2CdA), cytosine arabinoside (ARA-C), hydroxyurea, and drugs directed against KIT D816V, the main driver of disease evolution in SM. These KIT-targeting drugs can exert a remarkable and sometimes even long-lasting anti-neoplastic activity in patients with ASM or MCL. Midostaurin (PKC412) was the first KIT-targeting tyrosine kinase inhibitor (TKI) that received approval (by FDA and EMA) for the treatment of patients with advanced SM, including ASM and MCL (in the year 2017). Midostaurin is able to suppress the growth of neoplastic KIT D816V+ mast cells and is also able to counteract activation (and IgE-mediated histamine release) in normal and neoplastic mast cells. In line with this notion, many patients respond quite well to this drug. However, only a few patients enter complete remissions and the number of patients with advanced SM who relapse under treatment with midostaurin is relatively high. During the past few years, a number of additional drugs targeting KIT have been developed. Several of these drugs have shown a particularly strong effect on KIT D816V. One of these drugs is avapritinib, a KIT inhibitor that is currently tested in clinical trials – and will soon be approved for treatment of advanced SM in the US and in the EU.
In patients with rapidly galloping advanced SM, including MCL or patients with an associated aggressive leukemia, poly-chemotherapy with or without subsequent hematopoietic stem cell transplantation (SCT) may be required. All these treatments, including therapies with KIT-targeting drugs (TKI) and chemotherapy (+/- SCT), should only be applied by specialists in hematology/oncology and who are experienced in the field of mast cell neoplasms or stay in close contact with an experienced Center of Excellence (of the ECNM or of the American Initiative on Mast Cell Disorders = AIM) that can support and guide the physician in establishing treatment plans.
An important aspect is that despite the increase knowledge about the disease and availability of novel treatment options, advanced SM is still an incurable neoplasm in most cases. Therefore, the potential benefits of intensive therapies have to weighed against the risk of side effects and the quality of life in each individual patient. Another important point is that some of the intensive therapies introduce a mutagenic event and thus may contribute to disease progression in the future. Therefore, these treatments should not be offered to patients with indolent SM (ISM) or smoldering SM (SSM).
In some of the patients with advanced SM, glucocorticosteroids are recommended, for example in older patients with ASM who are suffering from liver damage with ascites but no other visible C-Findings. Usually, however, corticosteroids are applied together with interferon-alpha (IFN-A) or other anti-neoplastic drugs. Both, the corticosteroids and IFN-A are regarded as endogenous substances (made by our body) and therefore are considered to be less toxic and not mutagenic when compared to conventional cytoreductive agents. However, it is noteworthy that corticosteroids are acting as immunosuppressive drugs.
Additional treatment options in patients with mastocytosis: These include surgical excision of mastocytomas, surgery of the spleen = splenectomy (i.e. removal of the spleen) in case of a massively enlarged organ with consecutive severe cytopenia (lack of blood cells) or PUVA-therapy (Psoralen plus Ultraviolet A light) to mitigate/control massively infiltrated skin and the related skin-symptoms. Usually, repetitive cycles of PUVA are required to bring skin problems under control and treatment responses are transient in most patients. In children, PUVA is not recommended based on the potential threat (risk of secondary neoplasms).
While the overall risk to acquire the SARS-CoV-2 virus apparently is not increased in patients with mastocytosis, certain conditions may enhance the risk of infected patients to develop a severe pneumonia. These factors include certain co-morbidities affecting the cardiovascular or bronchopulmonary system, chemotherapy, and immunosuppressive drugs. Therefore, such therapies have to be carefully evaluated on a ´case-by-case´ basis during a COVID-19 infection. By contrast, other treatments, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mastocytosis should follow the general and local guidelines in the COVID-19 pandemic. This holds also true regarding vaccination against SARS-CoV-2. In general, all patients with mastocytosis should be vaccinated with recognition of the individual risk, especially when the patients are suffering from severe mediator-related symptoms and/or a concomitant allergic diseases is known. So far, the vaccines approved by health authorities appear to be rather safe. However, severe anaphylactic reactions have been reported in individual patients. Therefore, high-risk patients regarding anaphylaxis should only be vaccinated under controlled conditions and premedication, following local guidelines.