Mastocytosis

Abstracts

A mastocitose é caracterizada pelo acúmulo patológico e ativação de mastócitos nos tecidos e órgãos. Embora a classificação da mastocitose e seus critérios diagnósticos sejam bem aceitos, há necessidade de estabelecer parâmetros para aplicação de testes diagnósticos, avaliação clínica e respostas aos tratamentos. O objetivo deste trabalho é fazer uma revisão extensa da literatura, oferecendo conhecimento global sobre os mecanismos etiopatológicos e isiopatológicos, dando especial ênfase à diagnose, classificação e tratamento da mastocitose, promovendo a educação médica continuada.

Mastocitose; Mastocitose cutânea; Mastocitose sistêmica; Urticaria pigmentosa

CONTINUING MEDICAL EDUCATION

Mastocytosis

Luciana Cirillo Maluf^I; Jefferson Alfredo de Barros^II; Carlos D’Aparecida dos Santos Machado Filho^III

^IResident physician at the Department of Dermatology - Faculdade de Medicina do ABC - Santo Andre (SP), Brazil

IIMaster in Health Sciences at the Faculdade de Medicina do ABC. Instructor at the Department of Dermatology at the Faculdade de Medicina do ABC – Santo Andre (SP), Brazil

^IIIPhD from the Universidade Federal de São Paulo. Head of the Department of Dermatology - Faculdade de Medicina do ABC - Santo Andre (SP), Brazil

^{Mailing Address}

ABSTRACT

Mastocytosis is characterized by pathologic accumulation and activation of mast cells in tissues and organs. Although the classification for mastocytosis and diagnostic criteria are well accepted, there remains a need to define standards for the application of diagnostic tests, clinical evaluations, and responses to treatment. The objective of this article was to make an extensive literature review, providing comprehensive knowledge about the etiopathological and pathophysiological mechanisms, with a special emphasis on diagnosis, classification and treatment of mastocytosis, promoting continued medical education.

Keywords: Mastocytosis; Mastocytosis, Cutaneous; Mastocytosis, Systemic; Urticaria Pigmentosa

INTRODUCTION

Mastocytosis is a rare condition characterized by proliferation and subsequent accumulation of mast cells^1,2,3 in the skin and/or other organs and tissues, especially in the bone marrow and gastrointestinal tract.^3,4

This condition can be subdivided into: cutaneous (CM) and systemic mastocytosis (SM). CM is more frequent during childhood and it usually presents an early onset (up to the first year of age).⁵ In adults, it generally emerges in patients in their third or fourth decades of life. SM, on the other hand, is characterized by the accumulation of mast cells in other organs and tissues, usually emerges in patients older than 30 years of age and it can be progressive or even fatal.¹ Some articles show a prevalence in males, others in females, or equally in both sexes.^1,6

In the past decades there has been progress in the study of its etiopathogenesis with recognition of specific gene mutations.^7,8,9,10 Due to advance knowledge in some areas, such as oncogenesis and mast cell growth and differentiation, pathological hyperplasia of these cells has been better understood and elucidated, although not totally clarified. ^4,10,11

The relation between primarily cutaneous mastocytosis and that presenting hematological abnormalities since the onset is still not well understood. ⁹

BACKGROUND

In 1869, Nettleship and Tay described a clinical picture in a 2-year-old child with typical lesions of mastocytosis as a rare type of urticaria.^5,12,13,14 Mast cells in the connective tissue were first described by Paul Ehrlich, in 1877. He used aniline dye to stain these cells in purple red color, a phenomenon called metachromasia, and noticed the great amount of granules inside the cells1^2,15. Unna showed mast cells in skin lesions of urticaria pigmentosa (UP)¹⁶; and, in 1949, systemic mastocytosis was recognized by Ellis while finding mast cell in the necropsy of a child with diffuse chronic infiltration.¹²

LITERATURE REVIEW

Human mast cells originate from pluripotential cells (CD34+) in the bone marrow and through the bloodstream migrate to a specific tissue where they undergo full maturation by acquiring a large amount of granules within the cell and assuming the definitive morphology.^4,7,10 The evolution of mast cell seems to be determined by a sequence of molecules adhered to their surface and characterized by family genetics.⁷ Regulation of the number of mast cells and their differentiation are under the control of factors produced both in the bone marrow and by the influence of local cells (e.g., fibroblasts) adjacent to them.⁷ Fibroblasts contribute to differentiation and local maturation at the expense of the so-called stem cell factor (SCF; also called c-kit ligand^7,9), nerve growth factor and other mechanisms.^4,15 As in maturation and differentiation, other factors are responsible for regulating apoptosis in mast cells including growth factors, tumor necrosis factor alpha (TNF-α) receptors, immunoglobulin E (IgE), toll-like receptors and bcl 2 proteins.¹⁷

Progenitor cells of mast cells, in the process of cell development, express a tyrosine kinase receptor (c-kit) specific for the c-kit ligand. With this interaction, mast cell growth and differentiation take place.^8,9,15

The precursors CD34+, c-kit and CD13- develop in mast cells in the presence of a specific growth factor.^4,15 These progenitors were also seen in the peripheral blood, thus suggesting the existence of a distinct group of cells in addition to lymphocytes and mononuclear cells.¹⁵

Mast cells tend to be located in the perivascular tissues and in sentinel sites for the prompt response to noxious stimuli and allergens. Along with basophils (leukocytes originated in the bone marrow with dense granules of different sizes18), they express high affinity for FceRI (IgE receptors), which promote their degranulation when activated.^11,12,15

Mast cell activation and degranulation may also occur after other stimuli, such as opiates, components of the complement cascade, neuropeptides (vasoactive intestinal peptide, calcitonin gene-related peptide and substance P), anionic superoxide, radiographic contrast, low density lipoproteins, histamine release factors, chemokines, pathogenic bacteria, parasites, enterotoxin B, changes in osmolarity, etc. It was shown that interleukin 1 (IL-1), catecholamines and intercellular interactions (e.g., mast cell-fibroblast) can activate a mast cell and express its cytokines.¹⁵ Ionizing radiations also lead mainly to the release of tryptase and consequent degranulation of dermal mast cells¹⁹. Another study revealed that the main triggering factors in children are: food, followed by insect poisons and drugs.²⁰ Bussman et al. described mechanical manipulation of mastocytoma as another stimulus inducing mast cell degranulation a couple of hours later, leading to systemic symptoms and transient increase of serum tryptase.²¹

Pre-formed mediators released by mast cells include histamine, proteoglycans (heparin, chondroitin sulfate E), serotonins, proteases (tryptase, chymase, β-glucuronidase, cathepsin G, etc), some cytokines (TNF-α) and fibroblast growth factor. Newly formed products include: lipid mediators (prostaglandin D2 and leukotriens, generated from arachidonic acid), thromboxanes, ^5,12-hydroxy-eicosatetraenoic acid, nitrogen and oxygen radicals, cytokines and chemokines. Release of these products promotes inflammation, thus causing vasodilation, cell recruitment and adhesion, remodeling and fibrosis, as well as angiogenesis.¹⁵

The human mast cells are also able to express pleiotropic cytokines and growth factors, such as TNF-α, macrophage colony-stimulating factor, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-16, MIP-1α (macrophage inflammatory protein-1a), MIP-1β (macrophage inflammatory protein-1β), MCP-1 (monocyte chemoattractant protein-1) , vascular endothelial growth factor, among others.^4,15

Cheng et al, in 2007, showed for the first time a type II transmembrane protease - matriptase, distributed in the human epithelium in the overall population, but its expression is related to the progression of diseases/tumor cells derived from the epithelium. Matriptase of cancer cells in several tumor lines can be activated by trypsin, suggesting a simultaneous activation in extracellular proteolysis. In this study, biopsies revealed positive matriptase in mast cells and it was also found in mast cell neoplasms.²²

In tissues, mast cells differentiate into two subgroups: mucosal mast cells (MMC) and connective tissue mast cells (CTMC) based on their structures, biochemistry and functions.^4,15 MMC predominantly express tryptase and are usually close to the T-helper 2 lymphocyte cells. Patients with allergies and parasites show a high count of MMC; on the other hand, in HIV-positive patients, this number is decreased due to the sole dependence on the T-helper lymphocyte.⁴ CTMC, however, mainly express tryptase, chymase, carboxypeptidase and cathepsin G. They are more common in the gastrointestinal tract, skin, synovia and subcutaneous tissue. Their proliferation is seen in fibrosis and it is relatively unchanged in patients with allergies, parasites or HIV4 (Chart 1).

Mast cells are involved in the pathogenesis of some diseases including asthma, rheumatoid arthritis, atherosclerosis, interstitial cystitis, intestinal inflammatory disease, progressive systemic sclerosis, chronic graft-versus-host disease, fibrosing diseases, sarcoidosis, asbestosis, ischemic cardiopathy, keloids and malignancies, among others¹⁵. Certain diseases, such as acute infections, cardiovascular diseases and cancers induce the release of mast cell mediators which offer protection to the body; and other mediators act as potent inflammatory agents in urticaria, angioedema, bronchospasm and cardiovascular collapse causing extreme injury to the body. Several patients suffer from the mediator-dependent clinical symptoms.²³ Even so, this balance in the ethiopatological mechanism of mastocytosis is still not well established.^24,25

PATHOPGENESIS

The receptor tyrosine kinase (c-kit) and the stem cell factor (SCF) are considered essential for the growth and differentiation of mast cells. Defects in the c-kit or in the SCF gene would bring deficiencies in the mast cells; likewise, other mutations in the c-kit proto-oncogene would cause an increased mean lifespan of these cells and their progenitors. This is the case of a mutation in the c-kit D816V, frequently detected in patients with systemic mastocytosis.^{4, 9, 13, 23} A recent study showed the existence of tyrosine kinases Lyn and Fyn, which regulate the signal of mast cell transduction inhibiting and stimulating degranulation, respectively.¹¹

In humans, some studies demonstrated that mutations in the c-kit and increased levels of this proto-oncogene are associated with development of mastocytosis^{7, 15}. The c-kit ligand has several biological effects in mast cells including differentiation, growth and localization, induction of hyperplasia and production of its mediators¹⁵.

According to the type of mastocytosis, progressive increased number of mast cells and their progenitors may or may not be present; however, little is known about the factors interfering in the pathogenesis of each variant of this disease. Pathogenesis of cutaneous mastocytosis, generally self-limited in children, is still not well understood. There is still some doubt whether monoclonal accumulation of mast cells in the skin is present.⁹ In urticaria pigmentosa, for example, the disease is restricted to the skin; there is no mutation in the c-kit in a considerable number of patients and there is no evidence of systemic involvement of bone marrow, according to the World Health Organization (WHO) criteria.^1,9 Since few patients present mutations in the c-kit, there remains a hypothesis according to which, if mutation in the codon 816 of c-kit occurs, there would be a probable programming, so that the disease would become systemic and persistent.⁹ However, a study carried out in 2008 reported that the expression of DC25+ in cutaneous mast cells of adults with urticaria pigmentosa (UP) had a predictive value for SM, although it is not known if it is associated with a pre-existing indolent systemic disease. This marker, when detected in high expressions, may provide a hint for the presence of bone marrow neoplasm.²⁶

In SM there was evidence of monoclonal mast cell growth and mutation of codon D816V of proto-oncogene from c-kit, which was detectable in most patients.^4,9,13,23,27 Increased evidence of mutation of proto-oncogene c-kit D816V was observed in groups of patients with recurrent symptoms of the disease without cutaneous lesions and with apparently normal bone marrow biopsies. ²⁸

Molecular pathophysiology of mastocytosis is better understood, with updated classification based on different cell growth factors and on oncogenic abnormalities.²⁹

CLASSIFICATION

The WHO criteria are the most commonly used for classification and diagnosis of mastocytosis. (Chart 2)^1,2,913,23

As to the CM, the subcategories are based on the dermatological examination, skin pathological examination and in the absence of diagnostic criteria for SM. According to the WHO criteria, the following variants were defined: maculopapular cutaneous mastocytosis (urticaria pigmentosa - UP), diffuse cutaneous mastocytosis and mastocytoma. (Chart 3) ^1,23 There are some less common subtypes, such as nodular type, plaque type and telangiectasis type (telangiectasia macularis eruptiva perstans - TMEP).^1,9

However, classification of cutaneous mastocytosis is still controversial and new classifications have been suggested.¹⁴

Grattan and Black adopted the clinical classification developed by Tranis et al. and modified by Metcalfe, through which mastocytosis is divided into four categories related to the prognosis: indolent form, preferably with cutaneous involvement and a very good prognosis, to aggressive forms with reserved prognosis. (Chart 4).³⁰ Other authors, such as Prendiville and Krol, used a modified classification of the WHO criteria. (Chart 5). ³¹

Most cases of CM present maculopapular rash. The typical physical finding is the Darier sign, with lesion fractioning causing urticaria formation^6,9,23. Cutaneous blisters may be observed, particularly in a patient with diffuse involvement.⁹ Pruritus is the most frequent symptom.^4,6 In children, the clinical picture usually shows spontaneous remission before puberty and progression to SM is not frequent.^{9, 23}

UP, the most common form of mastocytosis^4,6,31, usually appears between the three and nine months of age.31 The disease usually remains confined to the skin.4 Lesions are numerous, red-brownish, and can manifest as maculae, papules and, sometimes, as nodules or plaques distributed mainly on the trunk^4,31 (Figure 1a-b). The lesion may be round or oval and its size may vary between one millimeter to some centimeters. Dermographism is present in 1/3 of patients.³² Clinical manifestations differ according to the age group: in adults the lesions are characterized by red-brownish maculae or slightly elevated papules, and vary between 3 and 4 mm in diameter, with symmetrical but random distribution, concentrated mainly on the trunk and thighs. Palms, soles, face and scalp are usually spared.⁵ Involvement in children is usually more extensive, with lesions more hyperpigmented than erythematous and varying between 5 and 15 mm. The trunk is the most affected region while the face and scalp are rarely affected. The lesions have more distinctive border and rarely merge or present in a diffuse pattern.⁵ Bone involvement and hepatosplenomegaly are rare but can be found due to mast cell hyperplasia in these organs.³¹ A subvariant is the non-pigmented plaque form, which occurs more among children.¹

Mastocytoma presents as a nodule with a red-brownish, pink or yellow color. Its surface is usually smooth, but it can be rugged as an orange peel. Lesions are round or oval, varying between 1 and 5 cm31 and they may reach a diameter larger than 15 cm⁴. The lesions might be single or present as a maximum of five isolated mastocytomas.⁴ They emerge at birth or, more commonly, during childhood⁴ and correspond to 10-15% of cases of CM.³¹ There are few symptoms associated with the single lesion and, when present, they usually include generalized pruritus, urticaria and blisters; systemic symptoms are rarely found. New lesions rarely emerge two months after the initial lesion.³¹ No bone marrow and/or visceral involvement has been seen; the prognosis is good with spontaneous remission in almost all patients.¹⁴

Diffuse CM is rare. The skin is frequently thickened, lichenified and has a softened texture with a large number of yellowish papules. Initial manifestations usually occur at the age of three months with sudden emergence of a sero-sanguineous blister; it evolves with skin thickening and its surface becomes evenly erythematous.4 Systemic symptoms coincide with degranulation events in mast cells and include: flushing, hemorrhage, hypotension, diarrhea, dyspnea and even shock.^4,31 In children, anaphylaxis occurs only in clinical settings with diffuse cutaneous involvement; in adults, however, it has a higher incidence.³³

In TMEP, lesions are hyperpigmented maculae or usually extensive erythematous-brownish lesions, telangiectasias and preferably located in the trunk.4,5,31 This condition is more common in youths and adults, and it is rare in children.¹³ It occurs in less than 1% of patients with CM, usually in adult, middle-aged women.⁵ Some authors classify TMEP as a subvariant of UP in adults; others describe this clinical manifestation characterizing it by a small number of large lesions (>1 cm) which are slightly pigmented with maculae telangiectasis, presenting a minimum or absent number of mast cells in the pathological examination.¹

There are several clinical manifestations of CM; a case of cutaneous anetoderma was reported as an uncommon type of presentation.²¹ Another clinical variant was described as pustules associated with systemic symptoms, leading to misdiagnosis of chronic urticaria or idiopathic anaphylaxis.29 Xanthelasma-like lesion was also reported in CM.³⁴34

Systemic mastocytosis may or may not be associated with malignancy and it rarely occurs in childhood.³¹ Its diagnosis is based on major and minor criteria of the WHO classification: 1 major and 1 minor or 3 minors. (Chart 6)^1,2,9,35,36

After a conference in 2005, there was a new attempt for a consensus to standardize the classification of mastocytosis and to facilitate its diagnosis, management, treatment and patient’s follow-up. According to this classification, it was necessary to differentiate the pre-diagnosis of cutaneous mastocytosis ("mastocytosis in the skin" - MIS) from a definitive diagnosis of mastocytosis based on the criteria of systemic mastocytosis and then classify it as CM or SM.²³

HISTOPATHOLOGY

A normal mast cell presents a round or oval nucleus and a cytoplasm with granules; no nucleolus is seen. A typical UP lesion reveals the presence of mast cells in the entire dermal papilla extending and coming into the reticular dermis. In a patient with mastocytoma, the mast cells have an abundant cytoplasm and fill the papillary and reticular dermis, and it can reach the deep dermis and the subcutaneous cell tissue. There is no cellular atypia. In diffuse mastocytosis there is infiltration of mast cells in the papillary dermis and in high reticular dermis. In the nodular, plaque or infiltrated lesions, the microscopy is usually similar to that of a solitary mastocytoma.¹

Giemsa dye and toluidine blue staining show the metachromatic granules in mast cells ^1,8 (Figure 2).

DIAGNOSIS

In disease investigation, one must first analyze the clinical picture through history and physical examination of the patient. In suspected disease, it is necessary to carry out a pathological examination of the lesion to confirm the diagnosis. Complementary laboratory tests may be requested to search systemic involvement.⁸

Complete blood count must also be ordered at the beginning of the investigation and at short intervals when systemic involvement is suspected.8 Other exams will be necessary according to the clinical manifestation: ultrasound of the abdomen in suspected cases of systemic mastocytosis; bone densitometry in case of bone pain in adult patients⁸; myelogram is necessary if some abnormalities, such as anemia, persistent leukocytosis, unexplained eosinophilia, bone pain, hepatosplenomegaly or lymphadenomegaly are present.⁸ In the absence of cutaneous lesions, patients with suspected mastocytosis should undergo a biopsy and a bone marrow aspiration for diagnosis and characterization of the disease subtype.⁷ The 24-hour urine examination with measurement of 5-hydroxyindoleacetic acid and metanephrines helps ruling out the possibility of carcinoid tumor or pheochromocytoma during investigation of mastocytosis.⁷ Increased levels of histamine, both in urine and plasma, help in the diagnosis of systemic mastocytosis with diffuse involvement, especially when gastrointestinal symptoms are present. Measurement of mediators released by the mast cells may also be helpful to show disease activity. ³¹

Cytochemical assessment and immunohistochemistry are helpful to differentiate the mast cell from other granule-containing cells, and biochemical measurement of the products (histamine, prostaglandin D2, tryptase, heparin and its metabolites) released by mast cells is considered more confirmatory than diagnostic.³² Flow cytometry with identification, enumeration and characterization of a mast cell by means of immunophenotyping has been the method of choice in the last decade.^23,37

Serum measurement of tryptase is generally < 20 ng/ml in patients with CM.⁹ However, some studies show that the interpretation of serum tryptase during childhood is more difficult than in adults due to the hypothesis of a relationship between the amount of granules in the mast cells and the child’s body volume, and the volume of affected skin over the total are different between the two age groups. Even so, serum monitoring should be performed, since it may suggest bone marrow involvement.^8,23 If increased, an ultrasound scan of the abdomen, bone densitomety and exams to locate bone pain (if present) must be requested.8 In a patient with mastocytosis, once the serum measurement of tryptase is high, it remains permanently above the normal levels.³⁸

From a clinical picture suggestive of mastocytosis, in addition to the pathological examination of the skin, one must also examine, if possible, the presence of positive matriptase, since this is a new resource for diagnosing the disease.²²

Follow-up exams will only be ordered if any of the initial exams is abnormal. In the setting of clinical suspect of systemic mastocytosis, a complete blood count must be obtained every year to assess the cell count, together with sodium, potassium, calcium and magnesium levels and serum tryptase levels.⁸

TREATEMT

The treatment consists of symptom relief, mainly pruritus, in addition to avoiding the factors that trigger degranulation of the mast cells^2,23,32,33: friction, sudden change in temperature, physical exercise, emotional stress, general anesthesia, alcoholic beverage, non-steroid anti-inflammatory drugs, narcotics, radiographic contrasts, some drugs (polymyxin B, dextran)^2,32,33 and ionizing radiation.¹⁹

These patients are also more sensitive to animal poisons, and they may suffer anaphylaxis; therefore, they should be well instructed about their disease, the triggering factors, and the possible risks as well as what to do in case of an emergency. They should carry some medications, such as epinephrine, corticoids and antihistamines.^32,33 Most subtypes of the disease have a benign course, and the drugs are administered in order to decrease or avoid the mast cell activation.⁴

Antihistamines are used to alleviate pruritus, and treatment duration depends on the clinical picture.³² Antagonists of histamine receptors H1 can control these symptoms. Gastrointestinal manifestations can be controlled with antagonists of H2 receptors, thus avoiding gastric acidity and ulcers.⁴ Some reports state that the proton pump inhibitors are better than H2 antagonists in these cases.³² Patients with diarrhea also benefit from the H2 antagonists, with or without sodium cromoglycate (a membrane stabilizer). This can also offer benefits in cases of flushing, pruritus and central nervous system manifestations⁴, in addition to muscular pain.³²

Doxepin has the advantage of being an H2 antagonist that is more active than the H1 antagonists. However, in general the non-sedating antihistamines are used as first line treatment.³²

Ketotifen, another membrane stabilizer, proved to decrease pruritus in patients with UP, although it did not show advantages over hydroxyzine. ^4,32

Phototherapy with UVA rays isolatedly or in combination with psoralens (PUVA) can be used in adolescents or adults when skin manifestations are resistant to previous treatments.4 However, there have been reports of disease recurrence after treatment discontinuation.³²

In cases with bullous lesions, one must pay attention to local care and prevention of infections.⁴ However, extensive blisters must be treated in the unit of major burns, taking into account the possibility of cutaneous and gastrointestinal bleeding.³²

In cases of anetoderma, there are reports of good response with PUVA therapy21. Some authors have also mentioned phototherapy with UVA-139, which is used with good results in cases of urticaria pigmentosa.⁴⁰

Telangiectasias and UP could also be treated with Ndyag laser with improvement of lesions but without destruction of mast cells.³² Pulsed dye laser is also suggested for the treatment of TMEP, which tends to be chronic and recurrent, by reducing the urticaria-like reaction and the lesions.⁴¹ Patients with poor absorption may need oral prednisone, although this drug may increase the bone involvement caused by the mast cells.⁴

Children are usually treated with symptomatic drugs. ⁴² For single and symptomatic mastocytomas, the first line treatment is occlusive topical steroids4 which helps control pruritus and decrease the lesions. ³² Heide et al. demonstrated the occlusive use of diluted 0.05% fluticasone propionate.43 However, one must be careful about skin atrophy secondary to this drug. ³² If the patient does not show any improvement, total exeresis of the lesion can be accomplished.⁴ Children with mastocytosis and a history of anaphylaxis and anaphylactic shock must be advised about self-medication and administration of injectable norepinephrine as Epi-Pen, if necessary.^2,4

Aspirin is a powerful histamine modulator, thus favoring the treatment of patients with relapsing episodes of flushing, and its introduction must be carried out while the patient is still at hospital under surveillance; it must be associated with an H1 antagonist and never administered isolatedly.⁴

Although the majority of cytoreductive agents (those that are able to promote a decrease in the number of leukocytes44) is effective in SM, they also decrease the symptoms of CM; however, the more frequent initial recommendation for cutaneous forms and indolent mastocytosis is to provide orientation and information about the disease, its risks and triggering factors, as well as administration of symptomatic drugs.⁴⁵In vitro experiments, however, showed that mast cells with a mutation in the c-kit D816V were resistant to the tyrosine kinase inhibiting agent named imatinib; therefore, new generations of this drug class are necessary. ⁴⁶ Studies carried out with retinoids show their inhibitory effect on the cell grow and mast cell apoptosis, thus being considered antitumor agents.⁴⁷

There is no consensus as to the treatment of systemic mastocytosis; several drug treatments can be used. Cytoreductive agents (especially chemotherapy) are usually reserved for mastocytosis with a progressive clinical course and with documented organ involvement showing mast cell infiltration.⁴⁸ First-line and second-line cytostatic and cytoreductive agents are commonly used, such as alpha interferon, 2-chlorodeoxyadenosine (cladribine; 2-Cda) and others.^47,48

Treatment of aggressive systemic mastocytosis must be carefully planned searching for diagnosis of systemic mastocytosis with or without hematopoietic involvement.² In aggressive systemic mastocytosis with blood abnormalities and in mast cell leukemia, alpha interferon can be successfully used. Chemotherapy and bone marrow transplant can be helpful in patients with associated blood abnormalities and splenectomy may prolong patient's life.⁴ The use of systemic corticoids has also been described.³² In its isolated form, aggressive systemic mastocytosis can be effectively fought with cyclosporine associated with methylprednisolone.³²

Mastocytosis is a typical example for the emerging pharmacogenetic field, which will predict the results of drugs based on the genetic structure of each patient in combination with the subtype of the disease.¹8 Much is known nowadays about specific gene defects in these patients; however, some genetic and molecular abnormalities are still being identified with a potential for drug treatment in the future.^2,36

PROGNOSIS:

Mastocytosis in children has a favorable prognosis, usually with spontaneous involution.^32,42 Most mastocytomas show spontaneous remission^21,32 and 50% of maculopapular cutaneous mastocytosis (UP) show clinical improvement during adolescence.³²32

According to a study carried out by Kiszewski et al., UP has a good prognosis with spontaneous cure in 80-90% of cases^14,21; visceral and/or bone marrow involvement is rare and benign.¹⁴ A higher potential for spontaneous remission is considered when the disease responds to drug treatments.²³

Prognosis of diffuse mastocytosis is variable since the blister tends to disappear; urticaria and hyperpigmentation tend to persist and neonatal involvement may be lethal. The organs and bone marrow are frequently affected. 14 Adults and children with diffuse skin involvement have a higher risk of developing severe anaphylaxis, although it is rare. The latter is more frequent in SM.³³ The presence of blisters and mutation in the proto-oncogene c-kit are suggestive of a more reserved prognosis.³² On the contrary, the prognosis of systemic mastocytosis is dependent on the disease subtype and its association with hematological diseases.^1,48

DISCUSSION

Mastocytosis can occur at any age. Knut Brockow et al. observed that 65% of patients with cutaneous mastocytosis were children and that 80% of lesions started before the first year of age.30 Additionally, 25% of cases were congenital.⁵ In adults, CM usually started in individuals in their 30’s and 40’s with no preference for either gender.^1,5 However, mastocytosis in childhood is rare and underdiagnosed, and it is more frequently seen in dermatology.⁴⁹

In approximately 80% of patients with mastocytosis only the skin is affected. In the remaining patients with the systemic form, the bone marrow is almost always affected, and biopsy is a necessary procedure for diagnostic confirmation. Peripheral blood rarely shows circulating mast cells. Other frequently affected organs include musculoskeletal system, gastrointestinal tract, spleen, lymph nodes and liver50; however, any tissue may suffer infiltration by these cells. Skin lesions occur in more than 50% of patients with systemic mastocytosis, usually the indolent type.¹

As to cutaneous mastocytosis, UP is the most common form, followed by mastocytoma and lastly, diffuse CM.^14,42 Darier sign is present in more than 90% of cases and it is considered a clinical diagnosis; however, a negative sign does not rule out the disease. Systemic signs such as hepatomegaly and splenomegaly are more frequent in diffuse CM, as well as pruritus, lymphadenopathy and diarrhea.¹⁴ Transient blisters may be seen both in UP and in mastocytoma; a genetic factor is present in approximately 1/6 of the cases of UP, while there is no family history in the cases of mastocytoma.⁴²

Anaphylaxis is more frequent in adult women with the systemic disease; SM is also more prevalent in this age group than in childhood. ^2,33,51 Studies show that recurrent anaphylaxis and with no apparent cause may be due to mastocytosis^20,27,28,52 and the main triggering factors in childhood should always be ruled out.²⁰ Anaphylaxis may also be triggered by a stress test/physical exercise.⁵³ A case of anaphylaxis following subdural and general anesthesia was described, and its cause was investigated by means of intradermal tests and measurement of serum tryptase. Tests were negative for the drugs used and after 12 weeks serum trypsin levels remained high with a suspect of mastocytosis.³⁸

The prevalence of other coexisting allergic diseases with mastocytosis is similar to that in found in the general population.⁵¹ Systemic form is more frequent in adults than in children.^2,23

Peter Valent et al. reported that, in the majority of pediatric cases and in most cases of indolent mastocytosis in adults, the diagnosis is suggested by the skin lesion and it is confirmed by the pathological examination. In children, bone marrow biopsy is performed only if signs of visceromegaly or significant abnormalities of the peripheral blood are present.2 However, in adults, the diagnosis includes bone marrow study.² In contrast to indolent SM, the aggressive form and the growth of hematopoietic non-mast cells frequently show urticaria pigmentosa-like lesions.² They highlight the importance of serum tryptase levels, since in most patients with SM those levels are > 20 ng/mL.^2,23 However, serum tryptase may be increased in other hematological disorders and, transiently, in a severe allergic reaction, thus it is not an exclusive finding in SM. Therefore, its measurement should be repeated within a few weeks, when the patient presents an episode of hypotension (anaphylactoid) and, if it remains high, a myelogram and/or a bone marrow biopsy should be performed. Otherwise, bone marrow study is already requested to diagnose or to rule out SM or other myeloid neoplasm.²

SM is considered persistent with cloning of myelomastocytic progenitors, and in most individuals it is possible to detect mutation D816V in the c-kit.^{2 23} CD25+ marker in cutaneous mast cells in adults with UP may be an indication of systemic disease, and this must be investigated and stratified. ^26,27

Additionally, there is a subgroup of SM with mutations found both in mast cells and in cells not belonging to the hematopoietic cell line. In this sense, SM is considered by the WHO as a separate group of myeloproliferative disorders within the hematopoietic neoplasms.²

Although knowledge about the disease has been substantial, it is still necessary to standardize the diagnostic means at medical sites all over the world so that larger multicenter studies can be carried out.⁵⁴

REFERENCES

Conflict of interest: None

Financial funding: None

How to cite this article: Barros JA, Maluf LC, Machado Filho CD. Mastocitose. An Bras

Dermatol. 2009;84(3):213-25.

• 1. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization Classification of Tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001. p.293-302
• 2. Valent P, Sperr WR, Schwartz LB, Horny HP. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non- mast cell hematopoietic neoplasms. J Allergy Clin Immunol. 2004;114:3-12
• 3. Fraitag-Spinner S. Mastocytoses cutanés. Ann Dermatol Venereol. 2007;134:589-92
• 4. van Gysel D, van Shaik RHN, Oranje AP. Mastocytosis. In: Harper J, Orange AP, Prose N, editors. Textbook of pediatric dermatology. 2nd ed. Cambridge (MA): Blackwell; 2006. v.1. p.703-17
• 5. Brockow K. Urticária pigmentosa. Immunol Allergy Clin North Am. 2004;24:287316
• 6. Akoglu G, Erkin G, Cakir B, Boztepe G, Sahin S, Karaduman A, et al Cutaneous mastocytosis: demographic aspects and clinical features of 55 patients. J Eur Acad Dermatol Venereol. 2006;20:969-73
• 7. Metcalfe DD. The mastocytosis syndrome. Freedberg IM, Eisen AZ, Wolf K, Austen KF, Lowell AG, Katz SI, Fitzpatrick TB, editors. Dermatology in general medicine. 6th ed. New York: McGraw-Hill; 2003. v.2, p.1902-8
• 8. Grattan CEH, Black AK. Urticaria and mastocytosis. In: Burns T, Breathnach S, Cox. N, Griffiths C, editors. Rooks textbook of dermatology. 7th ed. Oxford: Blackwell Science; 2004. v.3. p.31-7
• 9. Valent P, Akin C, Sperr WR, Mayerhofer M, Fodinger M, Fritsche-Polanz R, et al Mastocytosis: pathology, genetics, and current options for therapy. Leuk Lymphoma. 2005;46:35-48
• 10. Henz BM. Exploring the mast cell enigma: a personal reflection of what remains to be done. Exp Dermatol. 2008;17:91-9
• 11. KopeÄ A, Panaszek B, Fal AM. Intracelular signaling in IgE-dependent mas cell activation. Arch Immunol Ther Exp. 2006;54:393-401
• 12. Parker RI, MetCalfe DD. Basophils, mast cells, and systemic mastocytosis. In: Hoffman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, et al, editors. Hematology: basic principles and practice. 4th ed. Philadelphia: Elsevier; 2005. p.911-25
• 13. Akin C. Clonality and molecular pathogenesis of mastocytosis. Acta Haematol. 2005;114:61-9
• 14. Kiszewski AE, Duran-Mckinster C, Orozco-Covarrubias L, Gutierrez-Castrellon P, Ruiz-Maldonado R. Cutaneous mastocytosis in children: a clinical analysis of 71 cases. J Eur Acad Dermatol Venereol. 2004; 18:28590
• 15. Krishnaswany G, Ajitawi O, Chi DS. The human mastcell: an overview. Methods Mol Biol. 2006;315:13-34
• 16. MetCalfe DD. Regulation of normal and neoplasic human mast cell development in mastocytosis. Trans Am Clin Climatol Assoc. 2005;116:185-204
• 17. Gerabeulet A, Hartmann K, Mekori YA. Mast cell apoptosis. Methods Mol Biol. 2006;315:407-23
• 18. Carneiro J, Junqueira LC. Células do sangue. In: Histologia Básica. 8 ed. Rio de Janeiro: Guanabara Koogan; 1995. p.191-204
• 19. Albrecht M, Müller K, Köhn FM, Meineke V, Meyerhofer A. Ionizing radiation induces degranulation of human mast cells and release of tryptase. Int J Radiat Biol. 2007;83:535-41
• 20. Ott H, Lehmann S, Wurpts G, Merk HF, Viardot-Helmer A, Rietschel E, Baron JM. Anaphylaxis in childhood and adolescence. Hautarzt. 2007;58:1032-40
• 21. Bussmann C, Hagemann T, Hanfland J, Haidl G, Bieber T, Novak N. Flushing and increase of serum tryptase after mechanical irritation of a solitary mastocytoma. Eur J Dermatol. 2007;17:332-4
• 22. Cheng MF, Jin JS, Wu HW, Chiang PC, Sheu LF, Lee HS. Matriptase expression in the normal and neoplastic mast cells. Eur J Dermatol. 2007;17:375-80
• 23. Valent P, Akin C, Escribano L, Hartmann K, Brockow K, Castells M, et al Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37:435-53
• 24. Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy North Am. 2006;26:465-85
• 25. Guillén EJ, Vargas RMA, Mendoza ME, Zepeda OB, Sienra MJJ, Del Rio NBE. Urticaria and angioedema. Ver Alerg Mex. 2007;54:54-65
• 26. Hollmann TJ, Brenn T, Hornick JL. CD25 expression on cutaneous mast cells from adult patients presenting with urticaria pigmentosa is predictive of systemic mastocytosis. Am J Surg Pathol. 2008;32:139-45
• 27. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, Metcalfe DD. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis. Blood. 2007:2331-3
• 28. Greenhawt M, Akin C. Mastocytosis and allergy. Curr Opin Allergy Clin Immunol. 2007;7:387-92
• 29. Kong JS, Teuber S, Hallett R, Gershwin ME. Mastocytosis: the great masquerader. Clin Rev Allergy Immunol. 2006;30:53-60
• 30. Metcalfe DD. Classification and diagnosis of mastocytosis: current status. J Invest Dermatol. 1991;96:2s4s
• 31. Prendiville JS, Krol AL. Mastocytosis. In: Schachner LA, Hansen RC. Pediatric dermatology. 3rd ed. St Louis (Mo): Mosby: 2003. p.753-9
• 32. Almahroos M, Kurban AK. Management of mastocytosis. Clin Dermatol. 2003; 21:274-7
• 33. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. 2008;63:226-32
• 34. Chraibi H, Belgnaoui F, Benessahraoui M, Mirrane H, Mansouri F, Hassam B. Mastocytose xanthelasmoidea de l'adulte. Ann Dermatol Venereol. 2008;135:87-8
• 35. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007; 74:121-32
• 36. Akin C, Valent P, Escribano L. Urticaria pigmentosa and mastocytosis: the role of immunophenotyping in diagnosis and deteminig response to treatment. CurrAllergy Asthma Rep. 2006;6:282-8
• 37. Escribano L, Garcia Montero AC, Núñez R, Orfao A, Red Española de Mastocitosis. Flow cytometric analysis of normal and neoplastic mast cell: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. 2006;26:535-47
• 38. Eussell WJ, Snith WB. Pseudoanaphylaxis. Anaesth Intensive Care. 2006;34:801-3
• 39. Comte C, Picot E, Peyron JL, Dereure O, Guillot B. UVA-1 phototherapy: properties and indications. Ann Dermatol Venereal. 2007;134:407-15
• 40. Tuchinda C, Kerr HÁ, Taylor CR, Jacobe H, Bergamo BM, Elmets C, et al UVA1 phototherapy for cutaneous diseases: an experience of 92 cases in the United States. Photodermatol Photoimmunol Photomed. 2006; 22: 247-53
• 41. Rose RF, Daly BM, Sheeha-Dare R. Treatment of an unusual solitary mast cell lesion with the pulsed dye laser resulting in cosmetic improvement and reduction in the degree of urticarial reaction. Dermatol Surg. 2007;33:851-3
• 42. Ben-Amitai D, Metzker A, Cohen HA. Pediatric cutaneous mastocytosis: a review of 180 patients. Isr Med Assoc J. 2005;7:320-2
• 43. Heide R, de Waard-van der Spek FB, den Hollander JC, Tank B, Oranje AP. Efficacy of 25% diluted fluticasone propionate 0.05% cream as wet-wrap treatment in coutaneous mastocytosis. Dermatology. 2007;214:333-5
• ⁴⁴
  abrale.org.br [homepage]. Leucemia na Infância, março 2006 [acesso 18 Ago 2008]. Disponível em: http://www.abrale.org.br/apoio_profissional/artigos/ leucemia_infancia.php
• 45. Pardanani A, Akin C, Valent P. Pathogenesis, clinical features and treatment advanceds in mastocytosis. Best Pract Res Clin Haematol. 2006;19:595-615
• 46. Hungness SI, Akin C. Mastocytosis: advances in diagnosis and treatment. Curr Allergy Asthma Rep. 2007;7:248-54
• 47. Ohashi E, Miyajima N, Nakagawa T, Takahashi T, Kagechika H, Mochizuki M, et al Retinoids induce growth inhibition and apoptosis in mast cell tumor cell lines. J Vet Med Sci. 2006;68:797-802
• 48. Pardanani A. Systemic mastocytosis: bone marrow pathology, classification, and current therapies. Acta Haematol. 2005;114:41-51.
• 49. Renke J, Lange M. Mastocytosis in childhood. Przegl Lek. 2006;63:551-3
• 50. Santos JB, Montenegro L, Guimarães PB, Corrêa P, Carvalho SC, Duque Z. Urticária pigmentosa em adulto com apresentação clínica exuberante. An Bras Dermatol. 2006;81(Supl 3):S332-5
• 51. González OD, de la Hoz CB, Núñez LR, Sánchez ML, Cuevas AM, Diéguez MC, et al Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis. Clin Exp Allergy. 2007;37:1547-55
• 52. Webb LM. Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. 2006;97:39-43
• 53. Psaltis PJ, Dundon BK, Leong DP. Acute anaphylaxis following exercise stress testing. Intern Med J. 2007;37:343-4
• 54. Valent P. Diagnostic evaluation and classification of mastocytosis. Immunol Allergy Clin Noth Am. 2006;26:353-547

Publication Dates

• Publication in this collection
  07 Aug 2009
• Date of issue
  July 2009

History

• Received
  17 Feb 2009
• Accepted
  17 Feb 2009