Mastocytosis and related disorders

Mastocytosis represents a heterogeneous group of disorders characterized by an abnormal accumulation of mast cells in one or more organ systems. Mastocytosis is further divided into different subtypes according to the sites of involvement, laboratory findings, and degree of organ impairment. Cutaneous mastocytosis is diagnosed in the presence of skin involvement and absence of extracutaneous disease, and is most commonly seen in the pediatric population. Systemic mastocytosis, the disease form most commonly seen in adults, is characterized by the presence of multifocal, compact (dense) mast cell aggregates in the bone marrow or other extracutaneous organs. The mast cells may display atypical, often spindle-shape morphology and/or aberrant CD2 and/or CD25 expression. Elevation of serum tryptase and/or presence of KIT D816V mutation are other common findings. Systemic mastocytosis is further divided into different subtypes based on a combination of clinical features and laboratory findings. Recent studies have indicated that CD30 is frequently expressed in aggressive systemic mastocytosis and mast cell leukemia but infrequently in indolent systemic mastocytosis, and may be a useful marker for distinguishing these subtypes of systemic mastocytosis from one another. A group of related myeloid disorders, collectively termed myelomastocytic overlap syndromes, may pose diagnostic difficulty because of their significant clinical and pathologic overlap with systemic mastocytosis, and these will also be discussed in this review.     

Decreased tryptophan and increased kynurenine levels in mastocytosis associated with digestive symptoms

The main metabolism pathway of tryptophan is protein formation, but it can also be metabolized into serotonin and kynurenine. Indoleamine 2,3‐dioxygenase (IDO) is the enzyme that catalyzes the degradation of tryptophan into kynurenine. Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in various tissues with 57% of patients having gastrointestinal involvement. We studied tryptophan metabolism in mastocytosis patients displaying or not gastrointestinal features and healthy subjects (n = 26 in each group). Mastocytosis patients with digestive symptoms displayed significantly increased kynurenine level and IDO activity as compared to healthy controls and mastocytosis patients without digestive symptoms. This could be linked to mast cell‐mediated digestive inflammation among patients with mastocytosis. This work is the first focusing on kynurenine pathway in a mast cell disease and could help to understand the pathogenesis of digestive features in mastocytosis as well as in other mast cell‐mediated diseases.     

Mast cells in mastocytosis and allergy – Important player in metabolic and immunological homeostasis

The role of mast cell (MC) activity in pathophysiology is complex and challenging and its clinical effects are difficult to predict. Apart from the known role of MCs in basic immunological processes and allergy, underlined is their importance in bone mineralization and in regulation of autoimmune reactions. Mast cell mediators, especially those released from mast cells in degranulation, but also those released constitutively, are important both in metabolic and immunological processes. Mastocytosis is a heterogeneous group of disorders characterized by accumulation of MC in one or more organs. There are scientific data indicating that mastocytosis patients are at increased risk of osteoporosis in the systemic form of the disease and children with cutaneous mastocytosis have a higher rate of hypogammaglobulinemia. Moreover, the origin of osteoporosis in patients with allergy is no longer considered as linked to steroid therapy only, but to the mast cell mediators’ activity as well. There are indications that osteoporosis symptoms in this group of patients may develop independently of the cumulative steroids’ dose. Thus, the influence of mast cells on metabolic and immunologic processes in allergic patients should be investigated. The assessment of mast cell activity and burden in mastocytosis may be used to guide clinical management of patients with allergy.     

Mastocytosis and allergy

PURPOSE OF REVIEW: To illustrate features of allergy in mastocytosis. RECENT FINDINGS: The rates of atopy in patients with mastocytosis have generally been found to be similar to those of the normal population, although the incidence of anaphylaxis is much higher in mastocytosis. Introduction of objective pathologic criteria by the WHO for the diagnosis of mastocytosis has greatly facilitated the workup of patients with suspected mastocytosis, and has led to identification of mast cell disease in a subset of patients with anaphylaxis. There is increasing evidence that an activating c-kit mutation (D816V) exists in a subset of patients with recurrent mast cell activation symptoms who have normal-appearing bone marrow biopsies in routine evaluations without skin lesions. The genetic deficiency of alpha tryptase has not been found to influence serum tryptase levels in patients with mastocytosis. SUMMARY: Pathologic mast cell activation is a key finding in both allergic diseases and mastocytosis, albeit caused by entirely different mechanisms. Mastocytosis should be suspected in patients with recurrent anaphylaxis, who present with syncopal or near-syncopal episodes without associated hives or angioedema.     

Mastocytosis and Hymenoptera venom allergy

PURPOSE OF REVIEW: Mastocytosis is a rare disease characterized by increased mast cells in skin and/or internal organs. We evaluate the impact of mastocytosis on diagnosis and treatment of Hymenoptera venom allergy. RECENT FINDINGS: Patients with Hymenoptera venom allergy who suffer from mastocytosis develop life-threatening sting reactions more often than those who do not. When patients with Hymenoptera venom allergy were systematically examined for mastocytosis, it was found to be represented to an abnormally high extent. Most patients with mastocytosis tolerate venom immunotherapy with no or only minor systemic symptoms. Venom immunotherapy was found to be marginally less effective in patients with mastocytosis than in those without evidence of mast cell disease (defined as absent cutaneous mastocytosis combined with a serum tryptase concentration of <11.4 microg/l). Several deaths from sting reactions were reported in patients with mastocytosis after venom immunotherapy was stopped. These patients should have venom immunotherapy for the rest of their lives. SUMMARY: Patients suffering from mastocytosis and Hymenoptera venom allergy are at risk from a particularly severe sting anaphylaxis. They need optimal diagnosis and treatment. In patients presenting with Hymenoptera venom allergy, screening tests by measurement of serum tryptase concentration, and a careful skin examination, are highly recommended.     

Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22–49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti‐inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation.     

Mastocytosis, classification, biological diagnosis and therapy

In mast cell (MC) disorders (mastocytosis), clinical symptoms are caused by the release of chemical mediators from MCs, the pathologic infiltration of neoplastic MCs in tissues, or both. Cutaneous mastocytosis is a benign disease in which MC infiltration is confined to the skin. In pediatric cases cutaneous mastocytosis might regress spontaneously. Systemic mastocytosis (SM) is more frequently diagnosed in adults and is a persistent (clonal) disease of bone marrow-derived myelomastocytic progenitors. The somatic c-kit mutation D816V is found in the majority of such patients. The natural clinical course in SM is variable. Whereas most patients remain at the indolent stage for many years, some have aggressive SM (ASM) at diagnosis. Other patients have an associated clonal hematologic none MC lineage disease (AHNMD). MC leukemia (MCL) is a rare disease variant characterized by circulating MCs and fatal disease progression. Two important diagnostic clues in SM are an increased serum tryptase level and the presence of abnormal mast cells in the bone marrow. The current review provides an overview of mastocytosis and its subvariants, the new classification of these diseases, a practical guide for the biological diagnosis and advances and future directions in therapy of these pathologies.     

Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms

In mast cell (MC) disorders (mastocytosis), clinical symptoms are caused by the release of chemical mediators from MCs, the pathologic infiltration of neoplastic MCs in tissues, or both. Cutaneous mastocytosis is a benign disease in which MC infiltration is confined to the skin. In pediatric cases cutaneous mastocytosis might regress spontaneously. Systemic mastocytosis (SM) is more frequently diagnosed in adults and is a persistent (clonal) disease of bone marrow-derived myelomastocytic progenitors. The somatic c-kit mutation D816V is found in the majority of such patients. The natural clinical course in SM is variable. Whereas most patients remain at the indolent stage for many years, some have aggressive SM (ASM) at diagnosis. Other patients have an associated clonal hematologic non-MC lineage disease (AHNMD). MC leukemia (MCL) is a rare disease variant characterized by circulating MCs and fatal disease progression. The diagnoses of ASM, SM-AHNMD, and MCL might be confused with a variety of endocrinologic, vascular, or immunologic disorders. It is therefore of particular importance to be aware of the possibility of an underlying (malignant) MC disease in patients with unexplained vascular instability, unexplained (anaphylactoid) shock, idiopathic flushing, diarrhea, headache, and other symptoms that might be mediator related. An important diagnostic clue in such cases is an increased serum tryptase level. The current review provides an overview of mastocytosis and its subvariants and a practical guide that might help to delineate mastocytosis from unrelated systemic disorders.     

Recent advances in mastocytosis research. Summary of the Vienna Mastocytosis Meeting 1998.

The term mastocytosis denotes a heterogenous group of disorders characterized by abnormal growth and accumulation of mast cells in one or more organs. Cutaneous and systemic variants of the disease have been described. Mast cell disorders have also been categorized according to other aspects, such as family history, age, course of disease, or presence of a concomitant myeloid neoplasm. However, so far, generally accepted disease criteria are missing. Recently, a number of diagnostic (disease-related) markers have been identified in mastocytosis research. These include the mast cell enzyme tryptase, CD2, and mast cell growth factor receptor c-kit (CD117). Several gain-of-function-mutations in the kinase domain of c-kit appear to occur in mastocytosis supporting the clonal (neoplastic) nature of the disease. Also, certain point mutations appear to be associated with distinct variants of mastocytosis, i.e. Asp-816-->Val with a subset of sporadic persistent (systemic) mastocytosis (mostly adults), and Gly-839-->Lys with (a subset of) typical pediatric (mostly cutaneous) mastocytosis. Another potential indicator of mast cell neoplasm is the T-/NK-cell-associated marker CD2. This antigen (LFA-2) is abnormally expressed on neoplastic mast cells in cases of systemic mastocytosis or mast cell leukemia, but not found on normal mast cells. The mast cell enzyme tryptase is increasingly used as a serum- and immunohistochemical marker to estimate the actual spread of disease (burden of neoplastic mast cells). The clinical significance of novel mastocytosis markers is currently under investigation. First results indicate that they may be useful to define reliable criteria for the delineation of the disease.     

Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients

BACKGROUND: Systemic mastocytosis (SM) is a condition typically characterized by an increased number of mast cells in the bone marrow or in skin areas known as urticaria pigmentosa. Patients may present with flushing, itching, gastrointestinal symptoms, arrhythmias, headaches and osteoporosis. Some patients experience systemic symptoms indicative of SM in the absence of a positive bone marrow or skin biopsy, and are known as 'clinical mastocytosis', but are herein referred to as suspected of having systemic mastocytosis. Serum tryptase has been increasingly used as a biochemical marker of mastocytosis, but is not always elevated. OBJECTIVE: To investigate the association of serum levels of two key mast cell mediators, interleukin-6 (IL-6) and tryptase, to each other and with disease severity in patients with mastocytosis. METHODS: Patients responded to an announcement from the Systemic Mastocytosis Society (USA) and submitted frozen serum samples, but the precise diagnosis made by their own health providers was not known until after the assays were completed. There were 9 suspected systemic mastocytosis (SuSM), 3 cutaneous mastocytosis (CM), 11 indolent systemic mastocytosis (ISM), and 3 aggressive systemic mastocytosis (ASM). Five normal volunteers (3 females/2 males) also submitted samples, as did 33 cardiac patients without coronary artery disease. For 2 days prior to and during the collection period, mastocytosis patients were asked to abstain from any over-the-counter or food products containing biogenic amines, as well as drugs prescribed for this condition. Serum levels of IL-6 and tryptase were measured using established assays. RESULTS: Twenty-six patients (14 females/12 males) submitted serum samples. There were 9 cases of SuSM (6 females/3 males) in whom tryptase values were borderline normal; IL-6 values were slightly elevated with one being high. In 3 cases of CM (2 females/1 male), both tryptase and IL-6 were slightly elevated. In patients with ISM (5 females/6 males), only 6/11 had any tryptase elevated significantly as compared to 9/11 with elevated serum IL-6. Three patients with ASM had significant elevations of both IL-6 and tryptase. The most consistent finding was that of IL-6 elevations in 7/7 patients (3 females/4 males) who reported symptoms of osteoporosis and/or bone pain (1 SuSM, 3 ISM, 3 ASM) in the absence of any coexisting condition involving bone pathology. CONCLUSION: Serum IL-6 is elevated in mastocytosis patients and correlates with severity of symptoms and the presence of osteoporosis. High serum IL-6 may not only signify disease progression, but may also participate in the pathophysiology of mastocytosis.     

Systemic mastocytosis associated with acute myeloid leukemia: case report and implications for disease pathogenesis

Mastocytosis may be associated with clonal nonmast cell lineage hematologic diseases, including myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia. Here we present a patient with the simultaneous diagnosis of mastocytosis and an acute myeloid leukemia, M2 subtype in the French-American-British classification, with t(8;21) carrying a population of immature mast cell precursors, and discuss this presentation in the context of a potential pathogenetic cellular link between this leukemia and mastocytosis.     

Mastocytosis: state of the art.

Mastocytosis is a neoplastic disease involving mast cells (MC) and their CD34+ progenitors. Symptoms in mastocytosis are caused by biological mediators released from MC and/or the infiltration of neoplastic MC in various organs, the skin and the bone marrow being predominantly involved. A WHO consensus classification for mastocytosis exists, which is widely accepted and includes three major categories: (1) Cutaneous mastocytosis (CM), a benign disease in which MC infiltration is confined to the skin, is preferentially seen in young children and exhibits a marked tendency to regress spontaneously. (2) Systemic mastocytosis (SM) which is commonly diagnosed in adults and includes four major subtypes: (i) indolent SM (ISM, the most common form involving mainly skin and bone marrow); (ii) a unique subcategory termed SM with an associated non-mast cell clonal hematological disease (SM-AHNMD); (iii) aggressive SM usually presenting without skin lesions, and (iv) MC leukemia, probably representing the rarest variant of human leukemias. (3) The extremely rare localized extracutaneous MC neoplasms, either presenting as malignancy (MC sarcoma) or as benign tumor termed extracutaneous mastocytoma. Diagnostic criteria for mastocytosis are available and are widely accepted. SM criteria include one major criterion (multifocal compact tissue infiltration by MC) and four minor criteria: (1) prominent spindling of MC; (2) atypical immunophenotype of MC with coexpression of CD2 and/or CD25 (antigens which have not been found to be expressed on normal/reactive MC); (3) activating (somatic) point mutations of the c-kit proto-oncogene usually involving exon 17, with the imatinib-resistant type D816V being most frequent, and (4) persistently elevated serum tryptase level (>20 ng/ml). To establish the diagnosis of SM, at least one major and one minor criterion, or at least three minor criteria, have to be fulfilled. The natural clinical course of mastocytosis is variable. Most patients, in particular those with CM and ISM, remain in an indolent stage over many years or even decades, while others, in particular those with aggressive SM, SM-AHNMD, or mast cell leukemia, show a progressive course, usually with a fatal outcome.     

Contemporary Challenges in Mastocytosis

Mastocytosis denotes a wide range of disorders characterized by having abnormal growth and accumulation of mast cells. Mast cells contain histamine and other inflammatory mediators, which have diverse actions within the body, and play crucial roles in acquired and innate immunity. The diverse actions of these inflammatory mediators can lead to puzzling symptoms in individuals with mastocytosis. These symptoms can include flushing, pruritis, nausea, vomiting, abdominal pain, diarrhea, vascular instability, and headache. These clinical features generally divide into cutaneous and systemic manifestations, giving rise to the two divisions of mastocytosis: cutaneous mastocytosis (CM) and systemic mastocytosis. CM has a highly favorable clinical prognosis. Systemic mastocytosis has a range of severity, with the milder forms often remaining chronic conditions, while the severe forms have rapid complex courses with poor prognoses. Generally, treatment is aimed at avoiding mast cell degranulation, inhibiting the actions of the constitutive mediators released by mast cells and, in severe cases, cytoreductive and polychemotherapeutic agents. Behavioral intervention includes avoidance of triggers, such as heat, cold, pressure, exercise, sunlight, and strong emotions. Treatment for released histamine and other inflammatory mediators includes H1 antihistamines, H2 antihistamines, proton pump inhibitors, anti-leukotriene agents, and injectible epinephrine (for possible anaphylaxis). For severe cases, treatment includes cytoreductive agents (interferon alpha, glucocorticoids, and cladribine) and polychemotherapeutic agents (daunomycin, etoposide, and 6-mercaptopurine). For very specific and severe cases, tyrosine kinase inhibitors, imatinib and midostaurine, have shown promise.     

Mastocytosis and fibrosis: role of cytokines

Mastocytosis is a rare stem cell disorder characterized by abnormal growth and accumulation of mast cells in one or more organ systems. Clinical heterogeneity is a hallmark of mastocytosis. Recent observations of activating mutations in c-kit may help to understand the abnormal growth of mast cells in mastocytosis. However, this mutation alone does not explain the entire clinical heterogeneity of the disease. Reticulin fibrosis is also commonly associated with systemic mastocytosis. Mast cells are known to be the source of fibrogenic cytokines, including platelet-derived growth factor, transforming growth factor-beta (TGF beta) and basic fibroblast growth factor (bFGF). Immunohistochemical studies show a close correlation between the mast cell expression of bFGF and the reticulin fibrosis of mastocytosis lesions. The study of cytokine receptor expression also demonstrates that the TGF beta receptor I (RI)-negative cases of mastocytosis are prognostically less favorable than the TGF beta RI-positive cases. This finding may be related to the fact that the TGF beta R complex functions as a tumor suppressor gene in neoplastic cells.     

Mastocytosis

Mastocytosis is defined by a pathological increase in mast cell numbers in tissues. Recent clinical observations on rare manifestations highlight the diversity of this disease. The diagnosis is now aided by new surrogate markers. At the molecular level, recent studies have reinforced the role of activating mutations in KIT in the etiology of mastocytosis. These findings provide a conceptual basis for the development for new therapeutic strategies.     

Histopathological and immunohistochemical aspects of mastocytosis

The diagnosis of mastocytosis is based on histological evidence of a focal increase in tissue mast cells. Immunohistochemical staining with antitryptase antibodies is strongly recommended in all cases of suspected mastocytosis because mast cell infiltrates may be small and scanty. Mastocytosis may be difficult to distinguish from other hematological malignancies, in which an increase in mast cells is frequently seen. The expression of the T cell-associated antigen CD2 has been shown to be exclusively found on neoplastic mast cells in mastocytosis. The demonstration of expression of vascular endothelial growth factor by mast cells is consistent with the finding of angiogenesis which is commonly seen in tissue infiltrates of mastocytosis.     

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator‐related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator‐related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25–30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of ‘occult’ mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow‐up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations.     

The faces of mast cell disease: bone marrow infiltrates in 3 patients with systemic mastocytosis

The clinical spectrum of mast cell disease ranges from relatively innocuous and histologically subtle urticarial skin lesions to an aggressive and fatal leukemic form of mast cell proliferation. Not surprisingly, mast cell infiltrates may show significant microscopic heterogeneity, particularly in the bone marrow, the most common site of involvement in systemic mastocytosis (SM). Herein, 3 cases are presented to illustrate the clinical and morphologic heterogeneity of mast cell disease: the first patient, with long standing urticaria pigmentosa, developed anemia and thrombocytopenia; the second patient presented with a pathologic fracture; and the third patient was suspected to have refractory anemia. Upon bone marrow examination, all 3 patients showed mast cell infiltration with distinct morphologic features and all met the WHO criteria for aggressive systemic mastocytosis. Histochemical methods continue to play a role in the identification of mast cells, with some limitations depending on the degree of differentiation of the mast cells and tissue processing methods. Immunohistochemistry has contributed to the identification of mast cells. Coexpression of CD117 and CD25, as well as expression of the more specific immunohistochemical marker tryptase, is seen in systemic SM. The latter may also be employed as a serum marker in the diagnosis and follow-up of patients with SM. The mast cells, in the majority adults with SM, have somatic point mutations of KIT.     

Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L)

In an attempt to identify novel diagnostic markers for mast cell (MC)-proliferative disorders, serial bone marrow (bm) sections of 22 patients with mastocytosis (systemic indolent mastocytosis, n = 19; mast cell leukemia [MCL], n = 1; isolated bm mastocytosis, n = 2) were analyzed by immunohistochemistry using antibodies against CD2, CD15, CD29, CD30, CD31, CD34, CD45, CD51, CD56, CD68R, CD117, HLA-DR, bcl-2, bcl-x(L), myeloperoxidase (MPO), and tryptase. Staining results revealed expression of bcl-x(L), CD68R, and tryptase in neoplastic MCs (focal dense infiltrates) in all patients. Mastocytosis infiltrates were also immunoreactive for CD45, CD117 (Kit), and HLA-DR. In most cases, the CD2 antibody produced reactivity with bm MCs in mastocytosis, whereas in control cases (reactive bm, immunocytoma, myelodysplastic syndrome), MCs were consistently CD2 negative. Expression of bcl-2 was detectable in a subset of MCs in the patient with MCL, whereas no reactivity was seen in patients with SIM or bm mastocytosis. Mastocytosis infiltrates did not react with antibodies against CD15, CD30, CD31, CD34, or MPO. In summary, our data confirm the diagnostic value of staining for tryptase, Kit, and CD68R in mastocytosis. Apart from these, CD2 may be a novel useful marker because MCs in mastocytosis frequently express this antigen, whereas MCs in other pathologic conditions are CD2 negative.