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The thin red line between cutaneous mastocytosis and well-differentiated systemic mastocytosis

Published Online: June 19, 2015

Mastocytosis is a heterogeneous group of disorders characterized by the accumulation of mast cells (MCs) in one or more organs. The World Health Organization (WHO) divides mastocytosis into two major subtypes depending on the specific organ/s involved. These include cutaneous mastocytosis (CM), where the skin is the only tissue involved, and systemic mastocytosis (SM), which is defined by the accumulation of MCs in the bone marrow (BM), which frequently results in BM MC aggregates (major criterion). In addition, BM MCs from SM patients often show abnormal morphology, express the CD25 surface antigen, and carry the D816V KIT mutation; these features, together with serum tryptase levels >20 µg/L, constitute the minor WHO diagnostic criteria for SM. Thus, the diagnosis of SM is made if the major criterion plus ≥1 minor criteria, or ≥3 minor criteria in the absence of the major criterion are fulfilled.

In recent years, a few reports have identified a sub-variant of SM termed well-differentiated SM (WDSM), which is characterized by mastocytosis skin lesions together with mature-appearing CD25-negative BM MCs often lacking the D816V KIT mutation, therefore mimicking normal mature BM MCs. This implies that, in absence of a significant BM MC tumor burden, the current WHO diagnostic criteria fail to correctly classify these patients as SM, thus being misdiagnosed with CM. These observations clearly support the need for refined additional diagnostic criteria for WDSM.      

In a recent study published in The Journal of Allergy and Clinical Immunology (JACI), I. Alvarez-Twose et al. described in detail the clinical, histopathological, cytomorphological, immunophenotypical, and molecular characteristics of the largest group of patients with WDSM reported so far (n=33). Based on their results, the authors propose specific diagnostic criteria for WDSM.

The authors found several unique features that were recurrently present in their cohort of patients, which could be used as specific minor criteria for WDSM. These features included: 1) adult women with a pediatric onset or familial aggregation in first-degree relatives, 2) clustering of BM MCs outside BM particles forming pairs or triplets of MCs, 3) aberrant expression by BM MCs of the CD30 antigen together with overexpression of cytoplasmic proteases by flow cytometry, and 4) mutations involving any region of the KIT gene (or a clonal pattern of inactivation of the chromosome X by the HUMARA assay). The authors concluded that patients with mastocytosis skin lesions in association with mature-appearing CD25-negative BM MCs who show BM MC aggregates together with at least one of these proposed minor criteria, or meet ≥3 of such minor criteria in the absence of BM MC aggregates, should be diagnosed with WDSM, even though the WHO criteria for SM are also fulfilled.

In summary, WDSM constitutes a biologically distinct rare subgroup of SM, which requires specific diagnostic criteria, to avoid being misdiagnosed as CM as per the current WHO criteria.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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