Pediatric-onset mastocytosis is an uncommon disease. Although the resolution of disease is often stated to be approximately 50%, there are only a small number of studies on which this general conclusion is based.[3
] The present study represents the longest duration of follow-up in a pediatric population with cutaneous disease and in which the initial study included a bone marrow analysis.
The results of our study are highly encouraging for those dealing with children with cutaneous mastocytosis. In this follow-up study, 10 of 15 of patients had complete resolution of cutaneous disease and symptoms at follow-up approximately 20 years later (). This resolution of disease, based on cutaneous findings and symptom scores, occurred in the absence of use of topical or systemic steroids, PUVA or cytoreductive agents including imatinib. Thus reports, such as one recently published reporting cutaneous improvement after administration of imatinib[12
] should be viewed with caution, as the natural history of disease is improvement. This conclusion is reinforced by our observation that the remaining 5 patients in our study experienced a major or partial regression of disease on conservative therapy.
The bone marrow examination performed when children were first entered into the study was highly predictive of outcome. All patients who experienced disease resolution or major regression had essentially normal original pediatric marrow biopsies upon re-evaluation. Two patients had partial regression. One of these patients had DCM at original evaluation and this persisted and was present on follow-up. The initial marrow examination revealed some increase in mast cells which persisted and was present on repeat biopsy. However, no disease progression on repeat examination was found. The second patient had UP and a bone marrow examination was compatible with ISM at the time of the initial evaluation. A repeat marrow biopsy during the follow-up examination reported in this paper again revealed evidence of ISM; and the marrow findings appeared relatively unchanged from the initial bone marrow. Thus if an initial marrow did not show evidence of systemic disease, no evidence of systemic disease was found an average of 20 years later. If a marrow was positive for ISM, the disease persisted. We continue, based on this data, to recommend bone marrow studies only on children with evidence of systemic disease including organomegaly, elevated tryptase, or unexplained peripheral blood abnormalities.
The KIT D816V mutation is one of the minor diagnostic criteria for systemic disease.[7
] The one patient with persistent systemic disease was positive for this mutation. We do not know if other mutations [13
] were present in other individuals in this study, but if they were present, they did not prevent disease resolution.
Tryptase levels were not available in the late 1980’s, as the tryptase assay was reported and evaluated somewhat later for both the diagnosis of mastocytosis and anaphylaxis.[14
] However, on the follow-up repeat examinations, only two patients had tryptase levels above 20 ng/. One patient had persistent DCM, and it is known that such patients with extensive cutaneous disease may have elevated tryptase levels.[17
] The second patient was the patient with persistent ISM, whose tryptase level could be expected to be elevated.
The age of inception of pediatric-onset cutaneous mastocytosis has been reported to have prognostic implications. In previous studies, skin lesions characterized as hyperpigmented red brown macules or papules typically were reported to appear prior to two years of age. In five such studies with 180, 112, 71, 55 and 17 patients, disease-onset prior to age 2 years was seen in 78, 92, 98, 92, and 82%, respectively.[1
] In the majority of patients, these lesions were reported to fade or resolve by late adolescence or early adulthood. Fading or resolution of UP is also reported in some adults (around 20%), although bone marrow disease persisted.[18
] Similarly, patients entered into our study had disease onset by age 2 and most had disease resolution or improvement as discussed above.
Five patients had increased mast cells and three patients had spindle shaped mast cells on the initial bone marrow biopsy. One of these patients (patient 15) had complete resolution of clinical and constitutional symptoms at follow-up. Three of the remaining four patients were re-evaluated. One of these was the patient with continued systemic disease (patient 14), one had persistent DCM (patient 11) and one had continued UP. However, two other patients with continued UP (patients 1 and 4) had neither an increase in mast cells nor spindle shaped mast cells noted on original bone marrow examination. Thus, while the presence of increased mast cells and of spindle-shaped mast cells was more often observed in those with persistent disease, the association was not sufficient to predict outcome.
The etiology of most cases of pediatric cutaneous mastocytosis remains unknown. Such cases have, by association, been attributed to mutations and polymorphisms in KIT. But if or how such genetic rearrangements would cause disease that often resolves is unknown. This leaves open the possibility that some cases of cutaneous mastocytosis could involve a mechanism independent of KIT mediated signaling.
This study makes the important observations that patients with pediatric-onset mastocytosis often experience disease resolution by adulthood; and that a bone marrow examination, if read as positive for evidence of systemic disease, should lead to the possibility that disease may persist. This further documentation of the natural history of mastocytosis combined with evidence of the predictive nature of a bone marrow examination should help in counseling those dealing with childhood onset cutaneous mastocytosis; and help prevent the unwarranted use of more aggressive agents directed toward ablating the mast cell compartment.