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This review aims to synthesize the molecular pathophysiology and diagnostic framework for systemic mastocytosis.

July 10, 2026Open Access

Systemic Mastocytosis: Molecular Pathophysiology, WHO Diagnostic Framework, and KIT-Directed Targeted Therapies

CACaterina AlatiAzienda ospedaliera "Bianchi-Melacrino-Morelli"MGMaria Bruna GreveUniversity of Reggio Calabria GPGaetana PortoAzienda ospedaliera "Bianchi-Melacrino-Morelli"

Key Points

This review aims to synthesize the molecular pathophysiology and diagnostic framework for systemic mastocytosis.
Overview of the 2022 WHO classification and diagnostic criteria for systemic mastocytosis.
Discussion of underlying molecular mechanisms, including mutations in KIT and associated genes.
Exploration of emerging therapies targeting the KIT D816V mutation.
Identification of KIT D816V mutations in over 95% of systemic mastocytosis cases.
Formal diagnosis requires histological criteria, immunophenotyping, biochemical markers, and molecular confirmation.
Introduction of type I KIT inhibitors selectively targeting the D816V-mutant conformation has changed the treatment landscape.

Abstract

Background: Systemic mastocytosis (SM) is a clonal mast cell (MC) neoplasm driven by somatically acquired activating mutations in the KIT receptor tyrosine kinase (CD117), resulting in pathological accumulation of morphologically atypical MCs in extracutaneous organs. The KIT D816V substitution is detectable in over 95% of cases by high-sensitivity next-generation sequencing (NGS) or allele-specific PCR. This gain-of-function variant confers ligand-independent receptor autophosphorylation, leading to constitutive activation of downstream signaling cascades that promote MC progenitor survival, clonal expansion, and resistance to apoptosis. Co-occurring somatic mutations in TET2, SRSF2, ASXL1, CBL, and RUNX1, increasingly identified in the context of clonal hematopoiesis of indeterminate potential, are associated with more aggressive phenotypes and independently confer adverse prognostic impact. Results: The 2022 WHO classification delineates indolent forms from advanced-phase SM, aggressive SM, SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia, which produce progressive end-organ damage through both neoplastic tissue infiltration and uncontrolled mediator release. Formal diagnosis requires integration of histological criteria (multifocal bone marrow MC aggregates of ≥15 cells), immunophenotypic aberrancies (CD25, CD2, and/or CD30 coexpression on MCs by flow cytometry or immunohistochemistry), biochemical markers (baseline serum tryptase ≥ 20 ng/mL), and molecular confirmation of KIT D816V or equivalent pathogenic KIT mutation. The development of type I KIT inhibitors with selectivity for the D816V-mutant conformation has fundamentally restructured the therapeutic field of advanced SM. Conclusions: This review provides a thorough synthesis of SM pathobiology, WHO-defined diagnostic and classification criteria, validated prognostic tools, and the developing landscape of KIT-directed and combination therapies, with direct translational relevance for specialist practitioners managing this heterogeneous myeloid neoplasm.

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