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Changing perceptions of pediatric mastocytosis

DII small banner By Warren R. Heymann, MD
Sept. 3, 2018

I have always been disquieted by mastocytosis. Its constellation of clinical presentations from childhood to adulthood, spectrum of systemic involvement, variable prognoses, and therapeutic challenges, never allow for complacency or certainty.

Even when the diagnosis is straightforward with an excellent prognosis, trouble can ensue. I will never forget eliciting the Darier sign on a toddler’s mastocytoma, witnessing his entire cutaneous surface turn crimson red from the massive histamine release. I’m not sure who was about to pass out first – the child, his parents, or me. (A word to the wise — skip the Darier sign on large mastocytomas).

This commentary will focus on pediatric mastocytosis.

According to Macri and Cook: “Mastocytosis is a disorder characterized by mast cell accumulation, commonly in the skin, bone marrow, gastrointestinal (GI) tract, liver, spleen, and lymphatic tissues. The World Health Organization (WHO) divides cutaneous mastocytosis into three main presentations. The first has solitary or few (less than or equal to 3) lesions called “mastocytomas.” The second involves multiple lesions ranging from less than 10 to greater than 100 which is referred to as “urticaria pigmentosa” (UP). The last presentation involves diffuse cutaneous involvement. Urticaria pigmentosa is the most common cutaneous mastocytosis in children, and it can form in adults as well. It is thought to be a benign, self-resolving condition that remits in adolescence. Unlike adult forms of mastocytosis, there is rarely any internal organ involvement in UP.” (1)

Based on a systemic review of 1747 cases of pediatric mastocytosis, although the majority of cases hold true to aforementioned tenets, the outcome may not be favorable. Méni et al report that lesions occurred before the age of 2 years in 90% of cases, and presented as urticaria pigmentosa (75%), mastocytoma (20%) or diffuse cutaneous mastocytosis (5%). The male-to-female ratio was 1:4. A KIT D816V mutation was detected in 34% of 215 tested patients. Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%. However, the outcome was fatal in 2.9% of patients. The authors assert that the development of aggressive forms several years after the onset of “benign” forms of pediatric mastocytosis (both mastocytoma and urticaria pigmentosa) confirms the importance of long-term follow-up for these patients. (2)
The c-kit gene encodes for Kit (CD117), a transmembrane receptor with intrinsic tyrosine kinase activity and pleotropic effects on multiple cell types. Upon binding to stem cell factor (SCF), dimerization of Kit results in intracellular tyrosine kinase activation. In adults, > 90% of patients with systemic mastocytosis have a somatic mutation of the c-kit gene in exon 17 resulting in D816V Kit. In pediatric mastocytosis multiple mutations to c-kit are found in several exons; approximately 40% of mutations are reported to be outside of exon 17. Despite the overall lower prevalence of the D816V mutation in pediatric patients, it is still the most frequently detected variation, reported in approximately 30% of pediatric mastocytosis patients. Evidence from small studies indicates that pediatric patients who harbor the D816V mutation may be more likely to have systemic rather than cutaneous mastocytosis at the time of diagnosis compared to patients with non-D816V mutations. (3)

Evaluation of children with mastocytosis depends upon the results of a thorough history and physical examination. With gastrointestinal symptoms, a barium study or endoscopy may be needed. Bone pain or fractures may warrant a skeletal survey or bone scan. Check for lymphadenopathy and hepatosplenomegaly. If there is a suspected abnormality, a liver ultrasound or CT scan is indicated. A complete blood count (CBC), serum tryptase level, LFTs, and KIT gene analysis can be obtained (although it is considered by some to be optional in the pediatric population). Bone marrow involvement is not very common in children with cutaneous mastocytosis, as opposed to adults, and a bone marrow biopsy is not usually recommended. (1)
Treatment revolves around avoiding triggers that cause mast cell degranulation (see reference 4 for a detailed list of drugs and anesthetics) and treating symptomatic patients (antihistamines; oral cromolyn sodium for GI symptoms). Although topical steroids and phototherapy (PUVA, narrow band UVB, UVA1) have been utilized, if patients are asymptomatic, given the overall good prognosis, I usually do not treat the skin at all (especially in this age of steroid phobia).

I might change my approach. Since 2005, when Lee et al reported the case of an 86 year-old man with telangiectasia macularis eruptiva perstans that responded to topical pimecrolimus (5) there have been just a smattering of reports utilizing calcineurin inhibitors (more for pimecrolimus than tacrolimus) for mastocytosis. Ma et al demonstrated that pimecrolimus decreases the density of murine cutaneous mast cells, and subsequent reduction of histamine production, by inducing mast cell apoptosis. (6) Mashiah et al performed a retrospective study 18 children with cutaneous mastocytosis (mastocytomas and urticaria pigmentosa) treated with topical pimecrolimus 1% (11 male, 7 female; age range 3-42 months) with CM were evaluated. Of the 146 treated lesions, 39 (26.7%) disappeared and 98 (67%) faded or developed postinflammatory hyperpigmentation. Of the 119 papular lesions, 24 (16.4%) showed partial flattening and 56 (47%) became macular. Darier sign became negative in 14 (82%) of 17 patients. No topical or systemic complications were observed. (7). Although this was not a randomized, prospective, controlled study, I will undoubtedly prescribe pimecrolimus in my next cutaneous mastocytosis encounter.

Point to remember: Pediatric cutaneous mastocytosis regresses in most, but not all cases. Topical calcineurin inhibitors, notably pimecrolimus, may have therapeutic value.

1. Macri A, Cook C. Urticaria pigmentosa (Cutaneous mastocytosis). StatPearls [Internet], Treasure Island (FL): StatPearls Publishing, 2018-2018 Feb 14.
2. Méni C, et al. Paediatric mastocytosis: A systematic review of 1747 cases. Br J Dermatol 2015; 172: 642-51.
3. Klaiber N, et al. Mastocytosis in children. Curr Allergy Asthma Rep 2017; 17: 80.
4. Hermans MAW, et al. Management around invasive procedures in mastocytosis: An update. Ann Allergy Asthma Immunol 2017; 119: 304-9.
5. Lee HW, et al. Two cases of telangiectasia macularis eruptive perstans demonstrated by immunohistochemistry for c-kit (CD 117). J Dermatol 2005; 32: 817-20.
6. Ma Z, et al. Pimecrolimus induces apoptosis of mast cells in a murine model of cutaneous mastocytosis. Int Arch Allergy Immunol 2010; 153: 413-8.
7. Mashiah J, et al. Topical pimecrolimus for paediatric cutaneous mastocytosis. Clin Exp Dermatol 2018; 43: 559-65.

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