Mastocytosis in Children: A Protocol for Management

Authors


Address correspondence to Professor Dr. Arnold P. Oranje, Department of Dermatology and Venereology, Erasmus MC, University Medical Center, Post Box 2040, 3000 CA Rotterdam, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands, or e-mail: arnold.p.oranje@inter.nl.net.

Abstract

Abstract:  Mastocytosis is characterized by an increased number of mast cells with an abnormal growth and accumulation in one or more organs. In most children mastocytosis is limited to the skin (cutaneous mastocytosis) and often transient as compared with that in adults in whom mastocytosis is usually progressive and systemic. Generally, we recognize three more common forms of cutaneous mastocytosis: maculopapulous mastocytosis (formerly urticaria pigmentosa), mastocytoma of skin, and diffuse cutaneous mastocytosis. Childhood mastocytosis can further be divided into cutaneous mastocytosis (nonpersisting and persisting) and systemic mastocytosis (extremely rare). An approach to management using a set protocol is described in table form. In most cases of mastocytosis, only yearly checkups are necessary and no treatment is required; preventive recommendations are warranted in those individuals with systemic disease and constitutional symptoms. Symptomatic therapy is advised in only a minority of cases. This article is meant as a guideline for physicians involved in the care of children with mastocytosis and their parents.

Mastocytosis is defined as a heterogenous group of disorders with an abnormal accumulation of mast cells (MCs) anywhere in the body. All forms of mastocytosis are rare. Mastocytosis has many variants, which share several clinical features (1–3). The course of mastocytosis is varied and depends on the subtype and on the age of onset (4–6). In children, mastocytosis is commonly cutaneous (CM) and often transient when compared with that in adults, in whom the disease usually is progressive and systemic (2,6). However, all variants of mastocytosis may be diagnosed in children. A considerable body of evidence that many forms of mastocytosis are caused by point mutations in the genes coding for growth factor receptor c-kit (2,7–9). Genetic findings also indicate several different pathogenetic forms of mastocytosis. Adult patients and minor subsets of pediatric mastocytosis express activating mutations of the c-kit receptor, whereas in most cases of childhood-onset mastocytosis such mutations were not reported (10). The heterogeneity of c-kit mutations may have contributed to difficulties in characterizing genotype–phenotype correlations of the disease (11).

Traditionally, mastocytosis has been classified on the basis of clinical presentation. In 2001 a consensus classification based on the behavior/course of the disease rather than its clinical description was proposed and approved by the World Health Organization (12). In this consensus, classification mastocytosis is divided into three major groups consisting of CM, systemic mastocytosis (SM), and the extremely rare localized extracutaneous MC neoplasms not described in children (13). In children, mastocytosis is mostly cutaneous and transient. Therefore, for childhood mastocytosis we prefer a classification of five subgroups of increasing severity and morbidity as shown in Table 1. First, CM is distinguished from SM on the basis of criteria shown in Table 2. Second, the severity of the systemic subtype is defined on the basis of investigations of skin lesions, bone marrow, peripheral blood, and serum tryptase levels, as well as the functions of the liver, the spleen, the lymph nodes, and other organs. The skin lesions may be clinically classified as shown in Table 3. In February 2007 additional broad-based thorough recommendations for the standardization of the recognized subtypes and workup of mastocytosis were reported by Valent et al (8). In that article, mastocytosis in adults is considered systemic until proved otherwise. In children this is not the case unless persistently high (or rising) serum tryptase levels and other signs of SM are encountered.

Table 1. Mastocytosis Classification (12)
CategoryDiagnosticsCharacteristic findings
  1. *SM criteria: criteria for establishing the diagnosis of systemic mastocytosis (see Table 2); †AHNMD: associated clonal hematologic illness of an origin other than the mast cell line; ‡reduced organ function: ascites, disturbed liver function and/or portal hypertension (liver), hypersplenism (spleen), malabsorption with hypalbuminemia and loss of weight (gastrointestinal tract); osteolytic centers and/or osteoporosis with fractures (skeleton). MDS, myelodysplastic syndrome; MPS, myeloproliferative syndrome; AML, acute myeloid leukemia; NHL, non-Hodgkin lymphoma; SM, systemic mastocytosis; WHO/FAB, World Health Organization/French American British study group.

Cutaneous mastocytosisSM criteria*Not present
Skin lesionsPresent (mast cell infiltrates in biopsy)
Bone marrow (not required in most cases)No mast cell infiltrates
Peripheral blood profileNormal
Serum tryptase<20 μg/L
Indolent systemic mastocytosisSM criteria*Fulfilled
Skin lesionsGenerally present
Bone marrowMultifocal mast cell infiltrates;
<20% mast cells in smears
Peripheral blood profileNormal or slightly deviating
Serum tryptase>20 μg/L
Liver/spleen/lymph nodesSometimes enlarged
Systemic mastocytosis with a AHNMD†SM criteria*Fulfilled
Bone marrow and peripheral blood profileBesides multifocal mast cell infiltrates MDS, MPS, AML of NHL (WHO/FAB criteria)
Aggressive systemic mastocytosisSM criteria*Fulfilled
Skin lesionsOften absent
Bone marrowMultifocal mast cell infiltrates;
<20% mast cells in smear; no AHNMD†
Peripheral blood profileAbnormal (leukocyte count <1.0 × 109/L, Hb <6.2 mmol/L, and/ of thrombocyte count <100 × 109/L)
Liver/spleen/lymph nodesEnlarged
Organ functionReduced‡
Mast cell leukemiaSM criteria*Fulfilled
Skin lesionsAbsent
Bone marrowDiffuse uncontrolled mast cell growth
≥ 20% mast cells in smear
Peripheral blood profile≥ 10% mast cells (in aleukemic variants)
<10% mast cells
Organ functionReduced
Table 2. Criteria for Establishing the Diagnosis of Systemic Mastocytosis (12)
Major criteriaMultifocal infiltrates of mast cells (>15 close to each other) observed in bone marrow biopsies and/or mast cells stained for tryptase in biopsies from other extracutaneous organs.
Minor criteria>25% spindle-shaped mast cells in infiltrates in biopsies from bone marrow or other extracutaneous organs or presence of >25% atypical mast cells in bone marrow aspirates.
Demonstration of the c-kit point mutation on codon 816 in bone marrow, blood or other extracutaneous organs.
CD117 (c-kit receptor) positive cells, which are also positive for CD2 and/or CD25.
Serum tryptase is >20 μg/L.
Table 3. Descriptive Classification of Skin Lesions in Cutaneous Mastocytosis and Indolent Systemic Mastocytosis Based on Valent et al (12) and Hartmann et al (14)
ManifestationPrevalenceAgeRemission partialSystemic mastocytosisRemarks
  1. The term Telangiectasia macularis eruptiva perstans has not been recognized by the WHO (2001).

Diffuse cutaneous mastocytosisVery rareInfantsIn 3rd–5th year of life UnknownOften with bleeding, blister formation, and severe initial systemic manifestations
Nodular form (one or several mastocytomas)FrequentBefore 3rd monthGenerally, before pubertyNo 
Maculo papular form, subdivided intoPlaque variant (large papular lesions) Infants, often before 1–2nd monthAbout 50% before puberty Formerly urticaria pigmentosa
Medium-size maculopapular (smaller maculae)Most common form Children and adultsLittle in children, seldom in adultsFrequently in adultsSometimes hardly visible
Formerly urticaria pigmentosa
Telangiectatic cutaneous mastocytosisVery rareVery rare in children FrequentlySometimes hardly visible

Generally, we recognize three more common forms of childhood CM: maculopapular mastocytosis (urticaria pigmentosa), mastocytoma of skin, and diffuse cutaneous mastocytosis (DCM). Telangiectasia macularis eruptive perstans has not been recognized by the WHO. SM is usually indolent and is extremely rare in children (5).

This protocol forms a practical guideline for the diagnosis, the evaluation, and the treatment of mastocytosis in children. It is primarily intended for dermatologists, allergists, and pediatricians.

Recommendations on History, Examination, Diagnostics, Therapy, and Follow-Up

History

History should include the following topics:

  • • Duration of the disease. Is there an increase/decrease in the number of lesions?;
  • • Factors provoking mediator release;
  • • Increase/decrease in the activity of the lesions in time;
  • • Itch (attacks/periodic/chronic);
  • • Mastocytosis in family;
  • • Heat;
  • • Exertion;
  • • Showers;
  • • Stress; and
  • • Certain foods.

Physical Examination

Physical examination should include:

  •  Inspection of whole skin;
  •  Examine Darier sign in suspected lesions;
  •  Classify skin profile using; and
  •  SCORMA (see Appendix“SCORMA”).

Diagnostics

Diagnostics are limited to the following:

  •  Skin biopsy from the lesion; and
  •  Skin biopsy from nonlesional skin only on indication (high clinical suspicion of DCM).

Interpretation of Skin Biopsies

  • 1Histologic findings and MC counts confirm clinical diagnosis of CM; absence of the characteristic findings and the number of MCs do not exclude the diagnosis in dermatologic patient population.

Bone Marrow

  • 1Generally not required; and
  • 2 Bone marrow investigation should only be performed in symptomatic pediatric cases with suspected hematologic disease or suspected SM. Only serum tryptase levels that are clearly elevated (>20 μg/L) are not enough to undertake investigations of bone marrow.

Therapy

Therapy in isolated CM may be omitted.

Cutaneous mastocytosis with cosmetic complaints only:

  •  Generally no therapy; and
  •  Topical therapy in children older than 2 years (15).
    • –  Confined to about 10% of the body surface area: corticosteroid cream with occlusive dressing and
    • –  More than 10% of the body surface area: corticosteroid cream (one part vs. three parts) 25% diluted under wet-wrap occlusion (optional) for 3 to 6 weeks.

Cutaneous mastocytosis with complaints of itch, redness, and swelling:

  •  Avoid foods, which according to the anamnesis provoke the lesions; and
  •  Systemic therapy, consisting of combination of H1- and H2-blocker (and oral sodium cromoglycate).

Follow-Up

Follow-up in isolated CM is recommended:

Checkup once a year, and telephone consultation once every 6 months. The symptoms in SM may vary considerably and depend on the extent and the site of MC accumulations in an organ. Most of the complaints are caused by the mediators (histamine, leukotrienes, prostaglandins, interleukins, platelet-activating factors, and tryptase) released from MCs. The mediator-related symptoms may be fainting, hypotensive shock, diarrhea with abdominal pain, heartburn, severe bone pain, flushes, and headache. It should be noted that extensive skin involvement alone may also induce these symptoms.

When in doubt on the extent of mastocytosis, the workup should be broadened.

History should also include the following topics:

  •  Attacks of flushing;
  •  Attacks of syncope;
  •  Attacks of heart palpitations;
  •  Abdominal cramps or pain (attacks/periodic/chronic);
  •  Diarrhea (attacks/periodic/chronic);
  •  Pyrosis (heartburn);
  •  Reaction to drugs (aspirin, NSAID, codeine, and opiates);
  •  Reaction to narcosis;
  •  Reaction to i.v. radiograph contrast fluids or MRI-contrast media;
  •  Reaction to wasp and bee stings;
  •  Anaphylactoid/anaphylactic reaction;
  •  Bone-pain; and
  •  General symptoms:
    • – Weight loss,
    • – Nausea,
    • – (Severe) headache,
    • – Fever/feverish feeling,
    • – General depression, and
    • – Fatigue.
  •  Physical examination (preferably in cooperation with a pediatrician) should also include:
    • – Length;
    • – Weight;
    • – Organomegaly; and
    • – Other investigations on indication (e.g., constitutional symptoms).
  •  Indications for screening for SM in the absence of CM are:
    • –  Unexplainable abdominal pain with diarrhea;
    • –  Unexplainable bone pain;
    • –  Unexplainable flushes;
    • –  Unexplainable itch;
    • –  Occurrence of an anaphylactic reaction/shock;
    • –  Organomegaly (liver, spleen, or lymph nodes);
    • –  Unexplainable (pan)thrombocytopenia; and
    • –  Combinations of the above.

Diagnostic procedures should include:

  • 1 Determination of serum tryptase levels; if clearly elevated (>20 μg/L) proceed to step 2;
  • 2 Skin biopsy (see addendum);
  • 3 Abdomen ultrasound;
  • 4 Peripheral blood analysis (thrombocytopenia, leukocytosis, differential cell count); and
  • 5 In cases with organomegaly, lymphadenopathy or abnormalities in the peripheral blood: crista biopsy and bone marrow aspirate (16).

In tissue/smear specimen:

  • –  Morphology of MCs and MC counts;
  • –  Immunologic staining (CD2 and CD25 on CD117 positive MCs);
  • –  Tryptase staining of the MCs; and
  • –  Determination of proto-oncogene c-kit mutation (codon 816).

Preventive measures in systemic and extensive CM in children are strongly recommended:

Prevention of anaphylactic/anaphylactoid reactions in general

  •  Eliminate allergen(s)/provoking factor(s), if known
  •  Avoid alcohol, aspirin, NSAIDs, codeine, opiates, polymyxin B, and intravenous radiograph contrast fluids and MRI-contrast media, unless (recently) known tolerance;
  •  2x Epinephrine auto injector; for instructions see http://www.anafylaxis.net;
  •  H1 + H2 blockers at maximum dose (on indication: e.g., high frequency);
  •  Aspirin or NSAID at high dose (on indication: e.g., high frequency and insufficient effect of H1 + H2 blockade; see remark);
  •  “Medical alert” card or chain (see Appendix: Example of text “medical alert” and information letter in English);
  •  Information letter in English for vacations abroad; and
  •  Hyposensitization for wasp or bee sting allergy is contraindicated.

Remark:

Aspirin and NSAID should be started only at a very low dose, gradually increased under strict monitoring of circulation! [pediatric intensive care (ICP/ICC)].

Prevention of anaphylactoid reactions with anesthetics:

  •  See Appendix“preventive measures”

Prevention of anaphylactoid reactions to radiograph contrast fluids or MRI-contrast media:

  •  See Appendix“preventive measures for radiograph contrast fluids or MRI-contrast media”

Therapy in SM in children is symptomatic:

  • –  Anti-mediator drugs (H1 blockers) such as anti-histamines: clemastine, ketotifen, and cromoglycic acid;
  • –  H2 receptor blockers such as ranitidine particularly for heartburn;
  • –  Aspirin for flushes, tachycardia, or fainting; (warning: hypotensive crisis during use of aspirin);
  • –  Adequate intake/formation of vitamin D;
  • –  Adequate calcium intake; and
  • –  Adrenaline auto injector.

Follow-up in SM should include at least:

  •  Anamnesis (annually);
  •  Physical examination (annually);
  •  Laboratory tryptase (annually);
  •  Abdomen ultrasound (once annually); and
  •  Additional diagnostics depending on the complaints.

Discussion

This article is intended as a guideline for physicians who are involved in pediatric mastocytosis care. Difficulties may arise in establishing the diagnosis despite the mild course of the disease in the majority of the children. In cutaneous forms, especially in the macular subtypes the number of MCs may be low after the Giemsa staining, Leder staining, or tryptase staining (18). When the number of MCs is low, the staining for c-kit usually results in a higher number of MCs, whereas the other stains are too insensitive. Anti-c-kit (CD117) staining has a high specificity and a high sensitivity for MCs in paraffin sections. This staining is against c-kit membrane receptor. It stains MCs even after they have degranulated (25).

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On the rare occasion when systemic involvement is highly suspected, a multidisciplinary approach in which careful monitoring of mediator-related symptoms, organ function, growth as well as hematologic and bone marrow analysis are performed is imperative.

Preventive measures with respect to wasp stings and anesthesia are only necessary in cases with (subjective) symptoms and clearly elevated serum tryptase levels. We developed the SCORMA index which has proved useful in cases in which obtaining repeated blood samples such as that in children with mild symptoms is problematic (23). The SCORMA index scoring system shows a good correlation with serum tryptase levels (submitted) and provides information on eventual disease improvement or aggravation (24).

Acknowledgment

Dr. B. Tank is thanked for valuable suggestions and correcting the English.

Appendix

Skin Biopsy Procedure Indications

  •   • Suspicion of CM; and
  •  Demonstrated SM in the absence of suspected abnormalities for CM.

Procedure

  •    Local anesthetics with low histamine liberating potential such as lidocaine or bupivacaine;
  •  3 to 4 mm punch biopsy from suspected lesion;
  •  3 or 4 mm punch biopsy from inner-side of left lower arm; and
  •  Send in biopsies on physiologic saline-drenched gauze.

Processing of Biopsy

  •    Routine Giemsa staining;
  •  Tryptase staining (else Tolnidine blue staining, if possible);
  •  Immunophenotyping;
  •  Mast cell counts; and
  •  Mutation in proto-oncogene c-kit.

Evaluation

  •    Counts (17):
    • – Healthy controls: max. 58 MCs/mm2;
    • – Nonlesional skin from CM: min. 68 MCs/mm2;
    • – Nonlesional skin from SM: min. 30 MCs/mm2;
    • – Lesional skin from CM: min. 64 MCs/mm2; and
    • – Lesional skin from SM: min. 335 MCs/mm2.

Remark

In children, 10× higher values are still normal. The number of cells probably depends on the age, site of the biopsy and staining. Therefore, the numbers mentioned above are with reservation. Preventive measures for children with CM should be considered when use of narcotics or anesthesia are planned (18).

Considerations when planning a procedure include:

  •  Intradermal skin testing with drugs to be used in anesthesia (19);
  •  Reducing anxiety, preoperative sedation (oral diazepam);
  •  Minimize the number of pharmacologic agents; and
  •  Use a relaxing agent with low potential of histamine liberation.

Suggested measures in children with large or unknown disease burden on the day of operation:

  •  Prednisolone i.v., bolus 2 mg/kg, followed by 1 mg/kg prior to the procedure; and
  •  Clemastine 3 dd 0.05 mg/kg orally.
  • Peri-operative period

  •  Isofluran (or others based on the experience of the attending anesthetist); and
  •  Keep adrenaline at hand.
  • Postoperative period

  •  Paracetamol/acetaminophen.

Aspirin, NSAIDs, codeine, opiates, atropine, polymyxin B, and procaine (warning: mouthwashes, eardrops, and nose ointments) are contraindicated.

No relevant systematic data are available in the literature on the pharmacologic pretreatment of patients with mastocytosis. From a theoretical point of view combined H1- and H2-blockers may be useful because these drugs have been reported to reduce unprovoked attacks (20). Unexpectedly, NSAIDs when given continuously were also shown to reduce attacks in some patients (21). However, NSAIDs also may induce attacks when given without careful up dosing and are thus not considered to be safe as a pretreatment regimen. Anti-IgE (omalizumab) has been shown to reduce attacks in mastocytosis patients (22). Pretreatment with anti-IgE probably will only be effective after several weeks of treatment and only in situations where IgE-mediated processes occur.

Two possible schemes are proposed based on these considerations. Scheme 1 may be used as a default and scheme 2 may be used in patients with a delayed intestinal resorption or preoperatively. If clemastine is not available, it may be replaced with another injectable drug. Obviously, anti histamines may be continued in mastocytosis patient already on maintenance treatment.

Pretreatment Scheme 1

  • T = −13 hours

    • Prednisolone 0.5 mg/kg orally;

    • Cetirizine 10 mg orally; and

    • Ranitidine 150 mg orally.

  • T = −7 hours

    • Prednisolone 0.5 mg/kg orally.

  • T = −3 hours

    • Prednisolone 0.5 mg/kg orally;

    • Cetirizine 10 mg orally; and

    • Ranitidine 150 mg orally.

  • T = 0 hour

    • Radio contrast.

Cetirizine: Children older than 6 years 10 mg orally, children 1 to 5 years 2.5 mg orally.

Ranitidine: Children 2 mg/kg orally.

Pretreatment Scheme 2

  • T = −13 hours

    • Prednisolone 0.5 mg/kg orally;

    • Clemastine 2 mg orally; and

    • Ranitidine 150 mg orally.

  • T = −7 hours

    • Prednisolone 0.5 mg/kg orally.

  • T = −1 hours

    • Prednisolone 0.5 mg/kg i.v. and Clemastine 2 mg/kg i.v. (slow i.v. injection)

    • Ranitidine 50 mg i.v. (in 20 mL, slow i.v. injection)

  • T = 0 hour

    • Radio contrast.

Clemastine: Children older than 12 years 2 mg orally or i.v., children 6 to 12 years 1 mg orally or i.v.

Ranitidine: Children orally 4 mg/kg; intravenously 1 mg/kg (in 20 mL, slow i.v. injection).

Acute Treatment of an Anaphylactoid/Anaphylactic Reaction in Children

  •    Eliminate cause (e.g., stop infusion with a provoking substance);
  •  Clemastine 0.05 mg/kg i.v.;
  •  Adrenaline (1:1000) 0.01 mg/kg i.m. or 0.1 mL in 10 mL NaCl 0.9% slowly i.v. under monitoring of cardiac rhythm in about 6 minutes; and
  •  Prednisolone 1 mg/kg i.m. or i.v.

Finally, observation during at least 8 to 10 hours.

SCORMA Index

We need an alternate method for monitoring the severity of childhood mastocytosis because obtaining blood samples from children should be avoided as much as possible (23,24). That was the main reason why we developed a scoring system comparable with already existing methods for monitoring the severity of atopic dermatitis. We also use this system for monitoring the severity of the disease in adults.

The extent of the skin abnormality is evaluated in the first part (A). This is filled in the SCORMA form. The marked area then represents the percentage of exposed skin. In multiple mastocytoma of skin, each lesion is 1% of the affected skin. In DCM, by definition, almost the whole of the skin is affected, thus 100%. The intensity of the disorder is dealt with in part B. Hereby, a lesion of a typical form, size, and color representing the majority of the lesions is examined. A lesion which is not affected by sunlight such as that on the back is preferred. This lesion is then judged on pigmentation/erythema, vesiculation, elevation, and Darier sign. Each item is scored from 0 to 3, whereby 0 is for an absent item and 3 represents the most severity. The 5 subjective symptoms such as provocative factors, flushing, diarrhea, itch, and local bone pain, which may occur in mastocytosis are dealt with in part C. The patient may score these symptoms from 0 to 10 (using the visual analog scale), whereby 0 is for absence and 10 is for continuous presence. The formula: A/5 + 5B + 2C/5 is used to calculate the final SCORMA score. The value of the SCORMA score then lies between 5.2 and 100.

Note: this system was validated by a group of dermatologists practicing in greater Rotterdam, The Netherlands (23).

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