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Current approach to cutaneous mastocytosis in childhood.

Abstract

Mastocytosis is a heterogeneous disorder characterized by clonal proliferation and accumulation of mast cells in one of more organs which may lead to different clinical pictures. Pathological increase and activation of mast cells in various tissues can cause different clinical pictures. Cutaneous mastocytosis limited to the skin is the most typical clinical picture observed in children and systemic mastocytosis is very rare in the pediatric age group. The diagnosis of cutaneous mastocytosis is based on clinical findings, but is often delayed due to lack of clinical awareness of the disease and lack of its consideration in the differential diagnosis. This article focuses on the current diagnosis, management and treatment of cutaneous mastocytosis in children in order to increase awareness about this issue.

(Turk Pediatri Ars 2016; 51: 123-7)

Keywords: Child, cutaneous, mastocytosis

Introduction

Mastocytosis is a disorder characterized by clonal proliferation and accumulation of mast cells in one or more organs which may lead to different clinical pictures (1). It may be in the form of cutaneous mastocytosis with involvement of the skin alone or systemic mastocytosis with involvement of multiple organs.

Mastocytosis is defined in two main ways: cutaneous mastocyutosis characterized with cutaneous involvement and systemic mastocytosis characterized with involvement of the organs including liver, spleen, lymph nodes and/or bone marrow. However, a new classification was made by the World Health Organization in 2008 (Table 1) (2, 3).

Mastocytosis may be observed in all ethnic groups and age groups. In children, it is typically observed in the form of cutaneous mastocytosis and systemic mastocytosis is substantially rare (4). In adults, it is generally characterized with more serious systemic findings.

Pathogenesis

Mast cells are found in the skin and many tissues and lead to various clinical symptoms and signs by secreting many mediators when they are induced. The mediators secreted from the mast cells and their roles are shown in Table 2 (5). Abnormal accumulation of mast cells in tissues and the mediators they secrete are involved in the pathogenesis of mastocytosis. Both uncontrolled proliferation and defective apopytosis are responsible of accumulation of mast cells in tissues (6).

Mast cells originate from hematopoetic progenitor cells. Mast cell progenitors have been demonstrated in the bone marrow and peripheral blood (7, 8). It is thought that these cells migrate and differentiate and mature in various organs (9). The most important one among growth factors is "stem cell factor (SCF)". This factor is also named mast cell growth factor or KIT ligand. Mast cells develop from CD34+ progenitor cells by way of stem cell factor (10, 11). The effects of stem cell factor on mast cells and mast cell progenitors is mediated by KIT which is encoded by c-kit protooncogene and is a tyrosine kinase receptor for SCF (12). Stem cell factor and SCF-related KIT activation are essential for development and differentiation of mast cells. "Activating" mutations located in the kinaze region of the KIT protein lead to excessive development of mast cells and their progenitors (13). Among these mutations which lead to transformation of cells, Asp-816-Val mutation is observed commonly especially in adult patients with systemic mastocytosis (14-16).

Cutaneous mastocytosis

Cutaneous mastocytosis was reported in 1936 for the firts time by Sezary and Chauvillon (17). Although there is no clear data about the prevalence of cutaneous mastocytosis, it was reported to be 1/500 in children presenting to pediatric dermatology cinics in one study (18). It is clinically manifested as urticaria pigmentosa, diffuse cutaneous mastocytosis or solitary mastocytosis (2).

Urticaria pigmentosa is the most common form. It is generally manifested as a stable, red-brown lesions in the form of maculopapular plaque, nodule or bulla in any region of the body, scalp, face trunk and extremities in infancy (19). Pruritus of varying degrees accompanies the lesions (20). In cutaneous lesions, erythema and urticaria may develop around the lesion with physical trauma including rubbing and friction; this is called "Darier's sign" (21). Sudden blushing may develop in the lesions with hot bath, cold water or exercise (22). On histopathological examination of the cutaneous lesions, mast cell accumulation is observed along the papillary dermis and reticular dermis and inside the subcutaneous adipose tissue (23). Therefore, the incidence of atopic disease is increased compared to the general population (24).

Diffuse cutaneous mastocytosis is a rare type of mastocytosis which occurs in childhood. It is usually observed in adults. Lesions in the form of diffuse xanthogranulomas similar to yellow-orange subcutaneous nodules or diffuse red bullae are observed (19). Dermatographism mostly result in hemorrhagic bullae. Urticaria pigmentosa has a more severe course and may lead to life-threatening conditions by causing hypovolemic shock, mast cell leukemia, gastrointestinal hemorrhage and cachexy (25). Mast cell infiltration is observed around the blood vessels along the whole dermis (23).

Single or multiple brown nodules are observed in solitary mastocytoma. If these nodules are exposed to any trauma including friction, they may lead to xing and systemic symptoms including hypotension. Histologically, mast cell infiltration which shows extensions into the papillary and reticular dermis is observed in the subcutaneous tissue without cytological atypia (23).

Diagnosis

The diagnosis of cutaneous mastocytosis is made clinically and confrmed histopathologically. On histopathological examination of the cutaneous lesions, mast cell accumulation is found and the mast cells are differentiated by metachromatic staining by Giemssa and Toluidine dyes (26). SCORMA (SCORing MAstocytosis index) and serum triptase level should be evaluated in all pediatric patients with mastocytosis (27). The SCORMA index is a scoring system which is used in specifying the disease severity (Figure 1) (28). The flowchart which should be followed when there is a suspicion of mastocytosis is presented in Figure 2 (19).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Generally, bone marrow aspiration and biopsy are not recommended in children aged below 5 years with acute-onset cutaneous mastocytosis. However, it is beneficial to perform bone marrow aspiration and biopsy, if additional conditions including abnormal complete blood count, hepatosplenomegaly and lymphadenopathy are present. Bone marrow biopsy should be absolutely performed, if systemic mastocytosis is considered. Evaluation of bone marrow aspiration by way of flow-cytometry is diagnostic.

The diagnostic criteria for systemic mastocytosis specified by the World Health Organization in 2008 are presented in Table 3 (2).

Treatment

Generally, treatment is not needed in patients with isolated cutaneous mastocytosis. Patients and families should be informed that they should avoid excessively hot bath, sudden temperature changes, physical stimulation, hardly rubbing of the skin, stress, bee bite and drugs including aspirin, codeine, morphine, alcohol and radiocontrast substances containing iodide to prevent exacerbations (23). Education related with use of epinephrine autoinjector in case of sudden hypotension which is observed as a result of acute degranulation of mast cells should be given. In this case, corticosteroid and antihistaminic treatment may be administered additionally.

In children aged above 2 years, topical therapies may be given, if cosmetic problems are present. Closed dressing may be preferred, if the lesions cover 10% of the body. However, topical corticosteroid creams should be preferred, if the lesions cover more thanl0% of the body (29). One should be cautious in terms of secondary bacterial infections while using these creams. If pruritus, erythema and swelling occur, systemic H1 and H2 antihistaminics and cromolyn sodium may be helpful (29).

Treatment is controversial in diffuse cutaneous mastocytosis. If frequent hospitalization is required or life-threatenting reactions are observed, imatinib treatment may be tried. Imatinib mesilate is a type 2 kinase inhibitor. It induces cell growth and apopytosis by binding to adenosine 3 phosphate and the adjacent kinase domain. It may lead to cardiomyopathy and stunted growth in children. Other side effects include nausea, vomiting, diarrhea, increased liver enzymes, hypophosphatemia, edema, rush, granulocytopenia, anemia and thrombocytopenia. However, these side effects are observed rarely in children. The initial dose in children is 200 mg/[m.sup.2]/day. One should taper the dose to the dose which is sufficient to control the cutaneous lesions as soon as possible. Complete blood count, liver enzyme tests and growth rate should be absolutely checked (25).

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - Z.T., D.O.; Design - Z.T., D.O.; Supervision - Z.T., D.O.; Funding - Z.T., D.O.; Materials - Z.T., D.O.; Data Collection and/or Processing - Z.T., D.O.; Analysis and/or Interpretation - Z.T., D.O.; Literature Review - Z.T., D.O.; Writing - Z.T., D.O.; Critical Review - Z.T., D.O.; Other - Z.T., DO.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

References

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(2.) Horny HP, Metcalfe DD, Bennett JM, et al. Mastocytosis. In: Swerdlow SH, Campo E, Harris N, (eds). WHO classification of tumors of hematopoietic and lymphoid tissues. 4th edition. Lyon (France): International Agency for Research and Cancer (IARC), 2008.p.54-63.

(3.) Yavuz AS. Mastositoz. HematoLog (Turk Hematoloji Dernegi) 2012: 2-1.

(4.) Hartman K, Metcalfe DD. Pediatric mastocytosis. Hematol Oncol Clin North Am 2000; 14: 625-40. [CrossRef]

(5.) Bradding P, Feather IH, Wilson S, et al. Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol 1993; 151: 3853-65.

(6.) Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci USA 1995; 92: 10560-4. [CrossRef]

(7.) Kitamura Y, Yokoyama M, Matsuda H, Ohno T, Mori KJ. Spleen colony forming cell as common precursor for tissue mast cells and granulocytes. Nature 1981; 291: 15960. [CrossRef]

(8.) Rottem M, Okada T, Golff JP, Semere T, Metcalfe DD. Mast cells cultured from peripheral blood of normal donors and patients with mastocytosis originate from a CD34+/FceRIcell population. Blood 1994; 84: 2489-96.

(9.) Valent P. The riddle of the mast cell: c-kit ligand as missing link? Immunol Today 1994; 15: 111-4. [CrossRef]

(10.) Mitsui H, Furitsu T, Dvorak AM, et al. Development of human mast cells from umblical cord blood cells by recombinant human and murine c-kit ligand. Proc Natl Acad Sci USA 1990; 90: 753-9.

(11.) Valent P, Spanplochl E, SperrWR, et al. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor (SCF)/kit ligand (KL) in long term culture. Blood 1992; 80: 2237-45.

(12.) Galli SJ, Tsai M, Wershil BK. The c-kit receptor, stem cell factor and mast cells: what each is teaching us about the others. Am J Pathol 1993; 142: 965-74.

(13.) Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res 2001; 25: 519-28. [CrossRef]

(14.) Longley BJ, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-kit catalytic domain mutations in distinct forms of mastocytosis. Proc Natl Acad Sci USA 1999; 96: 1609-14. [CrossRef]

(15.) Akin C, Kirschenbaum AS, Semere T, Worobec AS, Scott LM, Metcalfe DD. Analysis of the surface expression of c-kit and recurrence of the c-kit Asp816-Val mutation in T cells, B cells and myelomonocytic cells in patients with mastocytosis. Exp Hematol 2000; 28: 140-7. [CrossRef]

(16.) Yavuz AS, Lipsky PE, Yavuz S, Metcalfe DD, Akin C. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single cell analysis of mutations in the c-kit gene. Blood 2002; 100: 661-5. [CrossRef]

(17.) Sezary ALCG, Chauvillon P. Dermographisme et mastocytose. Bull Soc Fr Dermatol Syph 1936; 43: 359-61.

(18.) Kiszewski AE, Duran-Mckinster C, Orozco-Covarrubias L, et al. Cutaneous mastocytosis in children: a clinical analysis of 71 cases. J Eur Acad Dermatol Venereol 2004; 18: 285-90. [CrossRef]

(19.) Ferrante G, Scavone V, Muscia MC, et al. The care pathway for children with urticaria, angioedema, mastocytosis. World Allergy Organ J 2015; 8: 5. [CrossRef]

(20.) Slavkovic-Jovanovic M, Jovanovic D, Petrovic A, Mihailovic D. Urticaria pigmentosa. A case report. Acta Dermatovenerol APA 2008; 7: 79-82.

(21.) Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children. Am J Clin Dermatol 2011; 12: 259-70. [CrossRef]

(22.) Azana JM, Torrelo A, Mediero IG, Zambrano A. Urticaria pigmentosa: a review of 67 pediatric cases. Pediatr Dermatol 1994; 11: 102-6. [CrossRef]

(23.) Carter MC, Metcalfe DD. Paediatric mastocytosis. Arch Child 2002; 86: 315-9. [CrossRef]

(24.) Muller U, Helbling A, Hunziker T, et al. Mastocytosis and atopy: a study of 33 patients with urticaria pigmentosa. Allergy 1990; 45: 597-603. [CrossRef]

(25.) Morren MA, Hopp A, Renard M, et al. Imatinib mesylate in the treatment of diffuse cutaneous mastocytosis. J Pediatr 2013; 162: 205-7. [CrossRef]

(26.) Valent P, Horny H-P, Li CY, et al. Mastocytosis (mast cell disease). World Health Organization (WHO) classification of tumors. Pathology and genetics. In: Jaffe ES, Haris NL, Stein H, Vardiman JW, (eds). Tumors of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, 2001: 291-302.

(27.) Lange M, Niedoszytko M, Renke J, Glen J, Nedoszytko B. Clinical aspects of paediatric mastocytosis: a review of 101 cases. J Eur Acad Dermatol Venereol 2013; 27: 97-102. [CrossRef]

(28.) Heide R, Beishuizen A, De Groot H, et al. Dutch National Mastocytosis Work Group Mastocytosis in children: a protocol for management. Pediatr Dermatol 2008; 25: 493-500. [CrossRef]

(29.) 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 cutaneous mastocytosis. Dermatology 2007; 214: 333-5. [CrossRef]

Zeynep Tamay, Deniz Ozceker

Division of Pediatric Immunology and Allergy, Department of Pediatric, Istanbul University Istanbul School of Medicine, Istanbul, Turkey

Address for Correspondence: Deniz Ozceker E-mail: denizozceker@gmail.com

Received: 26.01.2016 Accepted: 20.02.2016
Table 1. Classification of mastocytosis (adapted from the references
number 2 and 3)

1. Cutaneous mastocytosis
   a) Maculopapular type (urticaria pigmentosa) (the most
      common type with the best prognosis)
   b) Diffuse cutaneous mastocytosis
   c) Solitary mastocytosis
2. Indolent (Slowly progressing) systemic mastocytosis (good
   prognosis)
3. Systemic mastocytosis in association with a clonal hematological
   non-mast cell lineage disease (variable prognosis)
4. Aggressive systemic mastocytosis (poor prognosis)
5. Mast cell leukemia (MCL) (poor prognosis)
6. Mast cell sarcoma (poor prognosis)
7. Extracutaneous mastocytosis (good prognosis-rare)

Table 2. Mediators released from the mast cells and their roles (5)

Mediator   Functions

Histamine  Bronchoconstriction, tissue edema, increased vascular
           permeability, collagen synthesis, fbroblast
           growth, epithelial cell induction
Heparin    Anticoagulant, fbroblast activation, endothelial cell
           migration
Triptase   Degradation of respiratory allergens, IgE binding,
           increased TGF-[beta] secretion, increased heart rate,
           increse in constriction of smooth muscles in the respiratory
           tract
Chymase    Increase in mucus secretion, matrix degradation,
           increase in type 1 procollagen production, decrease
           in adhesion of T cells to respiratory muscles, IL-1[beta]
           activation
PGD2       Bronchospasm, increased tissue edema and mucus
           secretion, eosinophil, increase in Th2 cells and basophilic
           infiltration, activation of dentritic cells
LTC4/LTD4  Bronchospasm, increase in tissue edema and mucus secretion,
           increase in IL-13, increase in IL-4 secretion from
           eosinophils, mast cell induction

Table 3. Diagnostic criteria for systemic mastocytosis (2)

Diagnostic criteria for systemic mastocytosis (2008)

* Major;
  1. Multifocal mast cell infiltrates in tissue sections (groups
     composed of more than 15 mast cells in the bone marrow and/or
     extra cutaneous organs)
* Minor;
  1. Fusiform, immature or atypical mast cells in "tissue sections or
     bone marrow (>25%)
  2. Detection of KIT D816 V mutation (in the bone marrow, blood or
     tissue)
  3. CD2 and/or CD25 expression in mast cells
  4. A persistent triptase level of >20 ng/mL (if there is no myeloid
     clonal disease in association)

A diagnosis of systemic mastocytosis is made in presence of 1 major and
1 minor criterion or 3 minor criteria
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Author:Tamay, Zeynep; Ozceker, Deniz
Publication:Turkish Pediatrics Archive
Article Type:Report
Date:Sep 1, 2016
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