Childhood Cutaneous Mastocytosis: Revisited

Abstract

Cutaneous mastocytosis is a neoplasm characterized by the proliferation and accumulation of mast cells in the skin. There can be involvement of other organ systems as well. Cutaneous manifestations can vary from mastocytoma to maculopapular lesions to diffuse cutaneous form. There can be symptoms associated with mast cell mediators release like itching, flushing, hypotension, diarrhoea, abdominal pain, and anaphylaxis. Hence, the mainstay of treatment is avoidance of triggers causing these mediators to release, anti-histamines, topical/intra-lesional/systemic steroids, mast cell-targeted therapy, epinephrine, and omalizumab depending upon the severity of symptoms/signs. Childhood cases usually have a good prognosis except in a few cases, especially those with systemic involvement. Such situations might warrant cytoreductive therapy, polychemotherapy, or autologous stem cell transplantation. Here, we intend to review the English literature on childhood cutaneous mastocytosis.

Introduction

Mastocytosis is a hematopoietic neoplasm characterized by clonal proliferation and accumulation of phenotypically abnormal mast cells into one or more organ systems.[1] The most common organs involved are the skin, bone marrow, spleen, liver, lymph nodes, and gastrointestinal tract. Both children and adults can have the disease with some differences. It can be cutaneous or systemic mastocytosis. Both these forms can cause mast cell mediators-associated symptoms like itching, flushing, anaphylaxis, diarrhoea, abdominal pain, hypotension, and breathlessness.[2]

Paediatric patients usually develop cutaneous mastocytosis; systemic involvement is quite rare. Even if there is systemic involvement, it is most likely an indolent systemic type.[2,3] We planned a narrative review on cutaneous mastocytosis in children. A PubMed search was done using search strings: ‘childhood cutaneous mastocytosis’, ‘cutaneous mastocytosis’ AND ‘children’ or ‘childhood’, ‘mastocytoma’ or ‘maculopapular mastocytosis’ or ‘urticaria pigmentosa’ or ‘diffuse cutaneous mastocytosis’ AND ‘children’ or ‘infants’, ‘paediatric mastocytosis’ and ‘childhood cutaneous mastocytosis’ AND ‘systemic association’. Articles written in the English language and available as full text were considered. The required information from them was amalgamated together in this review.

History

In 1869, Nettleship and Tay were the first to describe mastocytosis. Urticaria pigmentosa term was coined by Sangster in 1878 because of the urticaria-like appearance of lesions.[4] Sezary and Chauvillon were the first to describe cutaneous mastocytosis in 1936. Organ system infiltration in a child with urticaria pigmentosa was described by Ellis in 1949.[5] In 1955, Degos described many variants and attempted the first classification of cutaneous mastocytoses.

Epidemiology

The exact prevalence of childhood mastocytosis is not known but it is slightly more/equally prevalent in adults, approximately 10–13/lakh population according to population-based studies.[6] The annual incidence is around 5–10 new cases/million population.[7]

The disease can involve all age groups including infants. Cutaneous mastocytosis is most common in children, representing 90% of the cases. Childhood mastocytosis occurs in <2 years of age in around 50% of cases, the majority of them occurring in the first 6 months of life.[7] Fifteen per cent of cases are congenital and around 10% of cases occur between 2 and 15 years of age. The disease affects all races with sex predilection, but few studies have shown slight male predominance.[2] Cases in twins/triplets and familial forms have also been described in the literature.[8]

The maculopapular variant is the commonest form of cutaneous mastocytosis. It includes urticaria pigmentosa and nodulo-plaque forms. Cutaneous mastocytosis shows a bimodal presentation with the majority of urticaria pigmentosa cases occurring below 2 years of age and mastocytomas develop commonly in children over 15 years.[9]

Classification

Degos (1955), some modifications later, WHO (2001), and a working conference on mastocytosis (2005) revised the classification of mastocytosis. WHO issued the latest classification of mastocytosis in 2019 as mentioned below:[10]

1. Cutaneous mastocytosis: Maculopapular, urticaria pigmentosa, mastocytoma, and diffuse cutaneous mastocytosis

2. Indolent systemic mastocytosis: Does not associate with haematological neoplasm

3. Systemic mastocytosis: It is associated with haematological malignancy through a clonal mechanism

4. Smouldering systemic mastocytosis

5. Systemic mastocytosis (aggressive form): It does not associate with mast cell leukaemia

6. Mast cell sarcoma: It shows a localized destructive growth pattern with no association with systemic mastocytosis

7. Mast cell leukaemia: This is an extremely rare form of systemic mastocytosis accounting for <1% of all cases of mastocytosis. Dense diffuse infiltration of atypical mast cells occurs in the bone marrow. Bone marrow aspirate shows >20% mast cells and mast cells form >10% of total peripheral white blood cells (classic form). However, a rare aleukemic variant can also occur in which mast cells form <10% of total cells. Thus, cytological analysis of both bone marrow and peripheral blood is needed to make the diagnosis. There is a leukemic spread of mast cells, frequently involving multiple organs like the liver, peritoneum, spleen, and bone. The treatment usually fails with a median survival of <6 months duration. The utility of combination chemotherapy and bone marrow transplantation needs further research.

Pathophysiology

Genetics and molecular profile: Mastocytosis is a clonal disorder with somatic mutations in the majority of cases. Activating mutations in the KIT gene are crucial in the pathogenesis of mastocytosis as mentioned in Flowchart 1 below.[11]

Flowchart 1.

Pathogenesis of mastocytosis

c-KIT mutation D816V in exon 17 is found in over 80% of adult mastocytosis cases, whereas this mutation is found in approximately one-third of childhood cases. Bodemer et al. in their multicentric French study revealed that 86% of childhood mastocytosis cases had different types of KIT mutations. In their study, mutations of codon 816 in exon 17 (D816I, D816V, and D816Y) were found in 42% of the children, out of which 36% of cases had D816V mutation. Fifty-eight per cent of the examined cases lacked mutation of codon 816. Other mutations were detected in exons 8 and 9. Phenotype–genotype and mutation-sporadic/familial form association was not found.[12] There can be a role of other genes than KIT in the pathogenesis of mastocytosis.[13]

Inheritance of mastocytosis is extremely rare with only a few incidences. Germline mutations in various regions of a KIT gene like F522C, R634W, S476I, etc., can cause a hereditary form of mastocytosis. Association with tuberous sclerosis[14] and gastrointestinal stromal tumours[15] has also been reported previously. Familial forms with autosomal dominant inheritance have shown increased serum tryptase levels, chronic disease course, and more extracutaneous involvement.[16] It has been shown that the presence of KIT mutations in the skin is not a predictor of the evolution of disease/systemic involvement.[2]

There is an induction of melanocytes causing hyperpigmentation. Increased interleukin-31 (IL-31) and IL-6 cause pruritus and severe disease in cases with mastocytosis, respectively.[17] Studies have shown that increased expression of the TRAF4 gene (a member of the tumour necrosis factor (TNF) receptor-associated factor family) and B3GAT1 gene (that encodes the enzyme 3-betaglucuronosyltransferase 1) leads to an increased incidence of allergies in some patients of mastocytosis.[18]

Role of mediators released by mast cells: The mediators are released in both IgE-dependent and -independent manner. The precise role of all the mediators (preformed and newly formed) in pathogenesis is not yet fully clear. Most read ones are tryptase, histamine, and prostaglandins. They are mentioned in Table 1.

Table 1.

Role of mediators released by mast cells

Mediator	Effect
Histamine[19]	Erythema, oedema, pruritus An absolute correlation of histamine level with mast cell load has not been found but one study showed that its high level is associated with high basal gastric acid production and severe bone involvement
Tryptase[20,21]	Higher in diffuse cutaneous form than urticaria pigmentosa. Useful in follow-up as its value decreases with time as the disease improves with time in childhood mastocytosis (correlates with SCORMA index). Systemic symptoms and the presence/absence of c-KIT mutation are not found to correlate with tryptase levels. Serum level helps in deciding the plan of management (discussed later).
Prostaglandin D2 (PGD2)[22]	Flushing, hypotension, pruritus
Oncostatin M[23]	Induces the growth of fibroblasts, osteoblasts, and microvascular endothelial cells
Chemokine ligand 2 (CCL2)[24]	Regulation of tissue remodelling and angiogenesis in systemic mastocytosis. Increased mast cells migration to skin and bone marrow due to chemokine receptor 2 (CCR2) and vascular cell adhesion molecule-1 (VCAM-1) upregulation

Clinical features

Cutaneous mastocytosis: It is the most common form of mastocytosis. Amongst children with mastocytosis, >90% have only skin involvement. The characteristic skin lesions are brown.

Criteria based on EU/US consensus group:[25]

1. Absence of signs/criteria of systemic mastocytosis and

2. Major criterion—Typical cutaneous mastocytosis lesions associated with Darier's sign and

3. Minor criteria—(one or both of the two)

   • Increased mast cell count in the lesional skin biopsy sample
   • Activating KIT mutation in lesional skin.

Darier's sign is oedema, pruritus, and urticarial/blistered appearance of lesional skin post 5–10 minutes of mechanical irritation due to mast cell mediators release, predominantly histamine. [Figure 1].

Figure 1.

Darier's sign with oedema and urticarial appearance of lesional skin post 5 minutes of mechanical irritation

Cutaneous mastocytosis can be of the following types:[26]

1. Maculopapular mastocytosis (MPM) (includes urticaria pigmentosa)

2. Mastocytoma

3. Diffuse cutaneous mastocytosis (DCM)

4. Telangiectasia macularis eruptiva perstans (TMEP)

5. Other rare variants.

Maculopapular mastocytosis (MPM)

It is the commonest form of cutaneous mastocytosis. In children, the onset is usually within the first 6 months of life. Two variants have been described as mentioned below in Table 2.[27,28]

Table 2.

Two variants of maculopapular mastocytosis (MPM)

Features	Monomorphic	Polymorphic
Frequency	More common in adults	Usually in children
Clinical	Small, discrete, red-brown, flat maculopapular monomorphic lesions predominantly showing central symmetrical distribution over the body with sparing of central face, palms, and soles	Large, brown-red, heterogenous in size, and with asymmetrical distribution. Lesions may be macular, papular, plaque-type, or nodular. Involvement of the head especially the lateral parts of the forehead, neck, and the extremities
Serum tryptase	Higher	Lower
Disease duration	Longer	Shorter
Spontaneous remission	Less frequent	More frequent
Prognosis	Poor in children, progression into adulthood. Rarely, it can progress into systemic mastocytosis	Good in children as lesions regress spontaneously in the majority of cases by puberty

This variant includes urticaria pigmentosa which presents hyperpigmented/brown macules, papules, and plaques predominantly over the trunk [Figure 2], arms, and legs.

Figure 2.

Hyperpigmented/brown macules, papules, and plaques over trunk, buttocks, arms, and thighs

Lesions in children might change with time, and nodules in infancy might change to papulo-plaques by 5–10 years of age. Blistering upon stroking if in infancy, can resolve by 2–3 years of age.[25] Scalp, mucosae, palms, and soles are less frequently involved and the lesions heal without scarring.

Flushing (36%), syncope, diarrhoea, and wheezing can occur in some cases of urticaria pigmentosa. Bone involvement and hepatosplenomegaly have also been reported.[26]

Differentials include pigmented nevi, histiocytosis, lentigines, and xanthomas.

Mastocytoma

This variant is less common than maculopapular mastocytosis and forms 10–30% of childhood cases of mastocytosis. It can be present at birth/infancy or early childhood. Sixty per cent of the cases are congenital with the majority developing within 3 months of life. Clinical presentation includes, up to 3, round to oval, reddish-brown, yellow, and pink macules or nodules, measuring 1–10 cm in diameter over the trunk and less commonly over other sites. The surface is smooth and has a peau d’ orange appearance. The lesions are similar to the maculopapular variant of mastocytosis but are single or less than 3 and larger in size. They may develop vesiculation on eliciting the Darier's sign. Usually, these lesions are of benign nature but rarely can cause flushing, abdominal colic, or hypotension.[29] Though most of the cases arise spontaneously, there are reports of the development of mastocytoma post-trauma/vaccination.

Usually, it has a benign course with a tendency to regress before puberty. Persistence for many years may lead to the development of MPM. If more than three lesions are present, then it is called maculopapular mastocytosis.[25]

Differential diagnoses are juvenile xanthogranuloma, connective tissue nevus, Spitz nevus, histiocytoma, bullous insect bite reaction, and naevocellular nevus.

Diffuse cutaneous mastocytosis (DCM)

A rare and most severe form constitutes 1–13% of cases of childhood cutaneous mastocytosis. There is diffuse infiltration of mast cells in the skin.

Two variants have been described as mentioned below:

• Vesiculobullous—Extensive blistering is present with/without haemorrhagic (because of heparin) component. Diffuse papules and nodules cause skin thickening and a doughy appearance. Blistering is more common in infancy while a leathery thick appearance is more common in the later stage of life.

• There can also be an erythroderma-like picture without vesiculation.

• Blistering occurs due to serine proteases released by mast cells, causing a split at the level of lamina lucida.[30]

• Differentials include epidermolysis bullosa, epidermolytic ichthyosis, autoimmune vesiculobullous disorders, and scabies.

• Pseudoxanthomatous—It is characterized by the presence of multiple, flat, yellow, papules, nodules, and plaques resembling xanthomatosis.[31]

Systemic symptoms and signs associated with the release of mast cell mediators are quite common in DCM like diarrhoea, cyanotic spells, wheezing, flushing, hypotension, nausea, vomiting, headache, dizziness, abdominal pain, and tachycardia.[32]

Telangiectasia macularis eruptiva perstans (TMEP)

It was first described by Parker in 1930. This variant is extremely rare in children. Red telangiectatic macules in a brown background are the described classical lesions.[33] MPM lesions may also coexist with TMEP. Trunk and extremities are the commonest sites of involvement while facial involvement is rare. Unlike other forms of cutaneous mastocytosis, Darier's sign is usually negative in such patients. Associated systemic features like flushing and abdominal colic are quite rare.

This form of mastocytosis is predominantly seen in the adult population, usually lacks systemic association, and has a refractory nature in terms of treatment response.

Other rare variants

Giant suprapubic and inguinal masses, anetoderma,[34] bullous, and blaschkoid are the other described variants.

Mast cell mediator-related symptoms: Symptoms range from an asymptomatic state to severe anaphylaxis. The type, severity, and frequency of these symptoms depend on the serum tryptase level and the extent of tissue involvement.[35]

• Cutaneous symptoms: Extensive blistering is suggestive of massive mast cell activation and hence their effects. The presence of flushing is a warning sign as it indicates a systemic vascular response to the mast cell mediators which can cause a hypotensive collapse in a few cases.[35]

  Symptoms due to extracutaneous involvement which include gastrointestinal complaints like vomiting, abdominal pain, diarrhoea, and reflux can occur in more than 50% of children with cutaneous mastocytosis due to the effect of mediators released by dermal mast cells, on the gastrointestinal tract.

  Other mediator-related symptoms include bone pain, headache, fatigue, and cognitive complaints.

  A study showed an association of mastocytosis with autistic disorder, pervasive neurodevelopmental disorder, and Asperger's disorder. The role of IL-6 and tumour necrosis factor α, released by mast cells, has been suggested in their pathogenesis.[36]

  Anaphylaxis: The risk of anaphylaxis is lower in childhood mastocytosis as compared to adults (<1–9% vs. 35–50%).[2] In adults, mediator-related symptoms including anaphylaxis may be associated with systemic mastocytosis, while in children, it represents extensive cutaneous involvement regardless of the absence/presence of organ system involvement.[37]

  The common elicitors of anaphylaxis in children are food, rubbing, heat, fever, and idiopathic, while in adults, Hymenoptera venom, drugs, and food are the commonest elicitors.[37]

Systemic mastocytosis

This is rare in children. The majority of children with systemic mastocytosis suffer from an indolent form with cutaneous involvement.[38] The same diagnostic criteria are followed as followed in adults. It is mentioned in Table 3.[11]

Table 3.

Diagnostic criteria of systemic mastocytosis

Major criterion	Histological demonstration of dense multifocal infiltrates of mast cells (at least 15 cells/aggregate) in the bone marrow biopsy and/or in sections of other extracutaneous organ(s)
Minor criteria	>25% of all mast cells are atypical cells (type I or type II) in bone marrow smears or are spindle-shaped in mast cells infiltrates detected on sections of visceral organs
	KIT point mutation at codon 816 in the bone marrow or other extracutaneous organ(s)
	Mast cells in bone marrow or blood or other extracutaneous organ(s) exhibit CD25 and/or CD2
	Baseline serum total tryptase level >20 ng/mL (in case of a concomitant myeloid neoplasm AHN (associated haematological neoplasm), an elevated tryptase does not qualify as systemic mastocytosis criteria Table 4: Symptoms-based treatment in mastocytosis on)

Diagnosis: 1 major+at least 1 minor OR in the absence of a major criterion, three minor criteria should be fulfilled to make the diagnosis of systemic mastocytosis

Skin biopsy

Precaution needs to be taken prior to taking a skin biopsy as friction/rub over the lesion can cause degranulation of mast cells leading to their low count/absence on histopathological evaluation. Local anaesthesia is to be given perilesional rather than into the lesion. A punch biopsy sample can be taken and sent in a formalin/normal saline vial.

Histology shows upper dermal perivascular, interstitial, and nodular infiltrate of mast cells. Sheets of mast cells can also involve the reticular dermis. In urticaria pigmentosa, mast cells have irregular shapes, there can be the presence of eosinophils, increased melanin in the basal layer, and melanophages in the papillary dermis.[39]

Special stains used to demonstrate mast cells are Giemsa, toluidine blue, and leder's stain. Giemsa and toluidine blue stain the metachromatic granules purple while leder's stain stains them red.[26]

Electron microscopy shows round and spindle-shaped cells staining positive with chymase and tryptase. The number of mast cells can be as high as 10 times of normal skin.[40]

Evaluation in children

The algorithm for paediatric mastocytosis is mentioned in Flowchart 2.[41]

Flowchart 2.

The algorithm for pediatric mastocytosis

Treatment

Avoidance of triggers like mechanical/physical stimuli, sudden temperature changes, infections, allergens, and drugs like NSAIDs, opioids, quinolones, muscle relaxants, and cough suppressants to prevent the release of mediators.[42] Gentle holding of the child especially if the lesions are widespread, avoidance of rubbing with a towel after bathing, and avoidance of any sort of trauma are some of the precautions that should be mentioned to the parents and relatives. However, NSAIDs can trigger the release of mediators (0–2% of children), but when systemic symptoms like pruritus and flushing are not controlled with anti-histamines then NSAIDs might be of help by inhibiting prostaglandin. Hence, their use should not be considered an absolute contraindication.

Anti-mediator and mast cell-targeted therapy are very important as symptom control is the mainstay of therapy and no intensive therapy is usually needed except if there is organ system involvement. Oral H1 antihistamines for controlling pruritus and flushing and H2 antihistamines for gastrointestinal complaints like abdominal pain, diarrhoea, and cramps are of great help. If H2 blockers fail, proton pump inhibitors can also be used for gastrointestinal complaints. In limited lesions of cutaneous mastocytosis, topical or intralesional steroid, and topical calcineurin inhibitors (causes mast cell apoptosis) can be used while in diffuse involvement, NB-UVB OR PUVA therapy and systemic corticosteroid therapy are available options. A surgical excision is also an option in solitary mastocytoma apart from topical therapy and active non-intervention. Symptoms-based treatment is mentioned in Table 4.[41]

Table 4.

Symptoms-based treatment in mastocytosis

Symptoms	Treatment
Pruritus, blistering	Second-generation H1 antihistamines (can updose up to four times)/leukotriene antagonists/sodium cromoglycate. Topical steroid/calcineurin inhibitors. Short-course oral corticosteroids can also be given if needed. Excision/intralesional steroid (mastocytoma) and PUVA/NBUVB therapy (DCM) is the other modalities
Flushing	Second-generation H1 antihistamines
Gastrointestinal	H2 antagonists, proton pump inhibitors
Neuropsychiatric	H1, H2 antagonists
Cardiovascular	H1, H2 antagonists
	Oral steroids, epinephrine if indicated
Osteopenia, osteoporosis	Calcium, vitamin D Bisphosphonates if indicated

Epinephrine autoinjectors can be used and the decision on the prescription of epinephrine to children is based on the course, symptoms, and subtype of cutaneous mastocytosis. Extensive skin lesions, highly elevated serum tryptase level, and a history of severe systemic symptoms or anaphylaxis are indications for prescribing epinephrine. The dose used is 0.01 mg/kg with the maximum dose being 0.5 mg.[43] Omalizumab (IgG monoclonal antibody) is a third-line therapy for mastocytosis, especially for severe recurrent anaphylaxis.[44] It inhibits IgE binding to high-affinity IgE receptors on mast cells and basophils. The dosing used is based on the control of symptoms. Serum tryptase and CD63 count may not decrease with omalizumab therapy even when the clinical improvement is quite evident. Targeted therapy/cytoreductive therapy in the form of tyrosine kinase inhibitors like imatinib, masitinib, multikinase inhibitors like midostaurin, polychemotherapy, and autologous stem cell transplantation is usually not indicated in childhood mastocytosis because of its indolent course. They can be used in advanced systemic mastocytosis cases.[45] Imatinib is used in aggressive cases with negative D816V KIT mutation. It can cause cardiotoxicity and growth retardation in children. Masitinib is more specific to c-KIT receptors than other tyrosine kinase inhibitors; hence, there is good clinical efficacy with minimal toxicity. Midostaurin has been rarely used in children and it can be used in both D816V KIT positive and negative cases. Side effects include nausea, vomiting, diarrhoea, and thrombocytopenia.

Vaccination: The proportion of hypersensitivity reactions to vaccines in patients with mastocytosis is similar to that of the normal population and they are generally mild and transient. In a child with a history of prior reaction to a vaccine, an altered schedule may be tried to identify the inciting antigen. For individuals with DCM or large body surface area involvement, single vaccine regimens should be considered. Vaccinations of these patients should be done in experienced centres and they should be observed for 1–2 hours post-vaccination.[21]

Prognosis

Childhood mastocytosis generally has a favourable prognosis due to the regression of disease by puberty in the majority (50–60%) of cases. If there is the persistence of disease beyond adolescence, about 10% progress to a systemic disease with a guarded prognosis. Urticaria pigmentosa, mastocytoma, and cutaneous disease without systemic involvement have a good prognosis. Solitary mastocytomas resolve spontaneously in the majority of cases.[10] In a study by Le et al., complete regression rates of mastocytomas and MPM were 10% and 1.9% per year, respectively. There was no evidence of complete regression in DCM and systemic mastocytosis.[46] The prognosis of DCM is uncertain because of the risk of life-threatening mast cells-related symptoms in infancy. The risk of their progression to systemic mastocytosis is not known due to the rarity of DCM.

In most patients with indolent systemic mastocytosis, the prognosis is good, whereas in cases of advanced systemic mastocytosis, the prognosis is poor.[47]

KIT mutation or immunophenotyping of mast cells (CD 20, 2, 25) does not correlate with the clinical form and the course of cutaneous mastocytosis.[2]

Conclusion

Mastocytosis is a disease characterized by increased accumulation and clonal proliferation of mast cells in the skin or/and other organ systems. Broadly classified as cutaneous and systemic mastocytosis. WHO classification of cutaneous mastocytosis includes maculopapular, urticaria pigmentosa, mastocytoma, and diffuse cutaneous mastocytosis. TMEP variant has not been incorporated in this classification of mastocytosis. Clinical signs can vary from solitary lesions to multiple hyperpigmented macules, papules, and plaques to diffuse infiltration of the skin, blistering, and xanthomatous lesions. Symptoms develop predominantly due to mast cell mediators release and include itching, abdominal colic, breathlessness, flushing, and neuropsychiatric symptoms. Hence, treatment focuses mainly on the prevention of their release, anti-histamines, epinephrine, omalizumab, topical and oral corticosteroids, NB-UVB phototherapy, and PUVA therapy. Necessary precautions should be taken while doing skin biopsies to prevent mast cell degranulation. Further studies are needed to delineate the clinical implications of various genetic alterations seen in c-KIT and other genes in the cases of childhood mastocytosis. Molecular characterization of the disease will be of utmost importance for the proper utilization of precision medicine in the form of targeted therapy. Overall good prognosis in paediatric cases of mastocytosis is a matter of great relief but still, proper long follow-up needs to be done for timely evaluation of systemic mastocytosis if suspicion of systemic disease arises or if the disease persists till adulthood.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.