Reconsidering cytoreductive therapy in high-risk pediatric mastocytosis: From diffuse cutaneous to smoldering systemic disease

Abstract

Pediatric mastocytosis is usually benign and self-limiting, but diffuse cutaneous forms carry a higher risk of fatal anaphylaxis and/or underlying systemic disease. Cytoreductive treatment can modify the prognosis in these patients.

Mastocytosis is a clonal disorder of mast cell progenitors that is generally caused by somatic gain-of-function mutations in the KIT gene, leading to pathologic accumulation and activation of mast cells. It is classified into cutaneous and systemic forms, with systemic mastocytosis (SM) further subdivided into bone marrow, indolent, smoldering, and advanced variants. Cutaneous mastocytosis (CM) predominates in pediatric patients and usually follows a benign course with spontaneous resolution during adolescence. Conversely, SM typically affects adults and tends to persist lifelong.^1,2

Pediatric mastocytosis usually manifests as maculopapular CM (MPCM), diffuse CM (DCM), or mastocytoma (≤3 lesions). Whereas MPCM is common and mostly benign, DCM is a rarer, more severe variant marked by extensive skin involvement and (often) systemic symptoms with elevated serum tryptase levels, raising concern about more aggressive disease phenotypes.³ Systemic forms, including smoldering and aggressive SM, are unusual but possible in children.¹

A recent retrospective cohort study at Necker Children's Hospital (Paris, France) analyzed 33 cases of pediatric DCM over nearly 3 decades. The study highlighted the fact that patients with DCM had significantly higher baseline serum tryptase levels (mean 47.5 μg/L vs 7.4 μg/L in MPCM), greater anaphylaxis prevalence (12.1% vs 2.4%), and a stronger association with aggressive SM (12.1% vs 0.9%). KIT D816V mutation was consistently present in aggressive SM cases. Importantly, 21.2% of patients with DCM received early systemic therapy (imatinib, midostaurin, or sirolimus), which was generally effective and well tolerated. The study concluded that DCM differs significantly from MPCM, with a higher risk of severe anaphylaxis and systemic progression, suggesting targeted cytoreductive therapy in select cases.⁴ In this case report, we discuss the potential role of early cytoreductive therapy in high-risk pediatric patients, emphasizing pediatric cases representing 2 endotypes of mastocytosis. Both patients described in this report were first evaluated during infancy (before age 1 year), a period during which bone marrow biopsy is often avoided owing to procedural risks and limited feasibility, thus underscoring the clinical challenges in early risk stratification.

Case reports

Patient 1

A male infant developed hyperpigmented, bullous maculopapular lesions at age 2 months that was initially misdiagnosed as atopic dermatitis (Fig 1). The lesions rapidly progressed to widespread thickened plaques with intense pruritus and recurrent flushing. The patient’s initial serum tryptase level was 34 ng/mL (normal <11.4 ng/mL), rising to 86.9 ng/mL over 12 months. The patient was first evaluated at our center before age 1 year, when bone marrow biopsy was considered high-risk and therefore not performed. Apart from elevated tryptase levels, the patient exhibited no other clinical or laboratory findings suggestive of systemic disease. Despite symptomatic treatment with H1 and H2 antihistamines, the patient continued to experience systemic episodes. At age 1 year, he developed severe irritability, diarrhea, flushing, and lethargy. The anaphylactic reaction was ineffectively treated with 2 doses of epinephrine—one administered via autoinjector at home and the other administered in the emergency room. His condition progressed to fatal cardiopulmonary arrest.

Fig 1.

Anterior trunk (A) and posterior trunk (B) of patient 1 at age 10 months.

Peripheral blood testing for the KIT mutation was requested; unfortunately, the patient died before molecular analysis could be performed. This case reflects features described in the Necker Children's Hospital cohort, namely, early infancy onset, bullous eruption in 27.2% of cases, a high baseline tryptase level, and severe systemic symptoms. In the reported cohort, systemic cytoreductive therapies were initiated in some patients.⁴ Our case raises critical questions as to whether early cytoreductive therapy could have altered the disease outcome.

Patient 2

A 2-year-old girl with diffuse erythematous brown lesions (Fig 2) since birth experienced recurrent flushing, diarrhea, and multiple anaphylaxis episodes. Her serum tryptase level was higher than 200 ng/mL, and she exhibited hepatosplenomegaly suggestive of systemic involvement. The patient was first evaluated at our center during infancy (before age 1 year), when bone marrow biopsy was deferred owing to age-related procedural risks. Biopsy samples of the skin and gastrointestinal tract obtained via endoscopy showed infiltration by abnormal mast cells expressing CD2 and CD25. Peripheral blood PCR detected the KIT D816V mutation. Bone marrow biopsy was not performed. Instead, the diagnosis was supported by extracutaneous mast cell infiltration documented on gastrointestinal biopsy, detection of the KIT D816V mutation in peripheral blood, marked hepatosplenomegaly, and persistently elevated serum tryptase levels exceeding 200 ng/mL, all of which are findings consistent with smoldering SM. Treatment with midostaurin, a multitargeted tyrosine kinase inhibitor, resulted in improvement of the patient’s skin lesions (Fig 2), reduced systemic symptoms, and decreased tryptase levels (from >200 ng/mL to 88 ng/mL), consistent with the effective responses reported in the Necker Children's Hospital cohort.⁴ The patient has been followed for 2 years while undergoing treatment. Midostaurin was administered at a dose of 30 mg/m² twice daily. No severe adverse events were observed, and treatment was accessed through a medical emergency request. This case exemplifies the potential benefits of cytoreductive therapy in pediatric patients with systemic involvement.

Fig 2.

Anterior trunk (A) and posterior trunk (C) of patient 2 at age 23 months (before midoustarin) and anterior trunk (B) and posterior trunk (D) at age of 32 months (when the patient had been taking midoustarin for 9 months).

Discussion

Both of our cases illustrate the clinical spectrum of pediatric mastocytosis, in which diffuse cutaneous disease may be associated with markedly elevated serum tryptase levels, severe anaphylaxis, and evidence of systemic involvement. Importantly, whether systemic disease represents true progression over time or was already present but unrecognized at initial presentation often remains unclear. Diagnosing SM in children is particularly challenging, as reliable markers beyond organomegaly, laboratory abnormalities suggestive of systemic involvement, and elevated serum tryptase level are limited. Moreover, invasive procedures such as bone marrow biopsy are frequently deferred during infancy, thus increasing reliance on clinical severity and biochemical markers to guide risk assessment and management decisions.³

Our first case, which was characterized by markedly elevated serum tryptase level in the absence of confirmed systemic involvement, highlights a common clinical dilemma: in real-world settings—particularly in cases in which molecular diagnostics are delayed or unavailable—risk stratification often relies primarily on clinical presentation, laboratory findings, and serum tryptase levels. Our second case supports the use of cytoreductive therapy in select clinical scenarios, demonstrating significant clinical improvement during midostaurin therapy, including prevention of recurrent anaphylaxis and marked improvement of systemic symptoms. This case also illustrates how molecular testing and extracutaneous biopsies, beyond bone marrow evaluation, can play a pivotal role in establishing the diagnosis of systemic disease in children. In pediatric patients, bone marrow biopsy is required in only a minority of cases and should be reserved for situations with a high index of suspicion for SM based on integrated clinical, biochemical, and molecular assessment (Table I).

Table I.

Clinical, biochemical, and molecular features suggesting higher risk of systemic involvement or severe outcomes in pediatric mastocytosis

Domain	Features suggesting higher risk	Clinical relevance
Cutaneous involvement	DCM; extensive skin involvement; bullous lesions; erythroderma	Associated with higher mast cell burden and increased risk of severe mediator-related symptoms
Age at presentation	Onset during infancy (especially when aged <1 y)	Period of higher vulnerability; invasive diagnostic procedures often deferred
Mediator-related symptoms	Recurrent severe flushing; hypotension; gastrointestinal symptoms; recurrent or severe anaphylaxis	Suggest systemic mast cell activation and higher risk of life-threatening events
Serum tryptase level	Persistently elevated baseline levels (>20 ng/mL); extreme elevations (>100 to 200 ng/mL)	Surrogate marker of mast cell burden; associated with systemic disease and severe anaphylaxis
Laboratory abnormalities	Cytopenias; abnormal liver function test results; hypoalbuminemia	May suggest extracutaneous organ involvement
Organomegaly	Hepatomegaly and/or splenomegaly	Strong indicator of possible SM
Molecular findings	KIT D816V mutation detected in peripheral blood	Associated with systemic involvement; may guide further diagnostic workup
Histology beyond skin	Gastrointestinal or other extracutaneous biopsy samples showing mast cell infiltration	Supports diagnosis of systemic disease when bone marrow biopsy is deferred
Response to therapy	Poor control with symptomatic treatment alone	May justify consideration of cytoreductive therapy in select cases

Bone marrow biopsy should be reserved for pediatric patients with a high index of suspicion for SM based on an integrated assessment of clinical severity, biochemical markers, and molecular or extracutaneous histologic findings.¹

In conclusion, pediatric DCM differs from MPCM by virtue of a more aggressive course and risk of systemic disease. The present cases underscore the need for heightened vigilance and reconsideration of treatment paradigms. Cytoreductive therapies, although traditionally reserved for advanced SM, may benefit select pediatric patients with high-risk DCM or smoldering SM. Further studies are urgently needed to establish safety, efficacy, and treatment guidelines in this vulnerable population.

Disclosure statement

This work was supported by CNPq (grant no. 408685/2024-7).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.