Review and Updates on Systemic Mastocytosis and Related Entities

Abstract

Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by KIT mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. The new ICC classifies SM slightly differently. The diagnosis of SM requires the integration of bone marrow morphologic, immunophenotypic, and molecular findings, as well as clinical signs and symptoms. Moreover, understanding the wide range of clinical presentations for patients with mast cell disorders is necessary for accurate and timely diagnosis. This review provides an updated overview of mast cell disorders, with a special emphasis on SM, including the latest approaches to diagnosis, prognostic stratification, and management of this rare disease.

Keywords: KIT; WHO 5th Edition Classification of Haematolymphoid Tumours (WHO 5th edition); classification; diagnosis; hereditary alpha-tryptasemia (HαT or HAT); mast cell activation syndrome (MCAS); molecular; systemic mastocytosis (SM); the International Consensus Classification (2022 ICC); treatment.

Figure 1

Representative illustration of KIT gene (top) and protein (bottom) with mastocytosis-associated mutations. Listed are all reported KIT variants identified in mastocytosis (modified from [8]). Bolded mutations are known to constitutively activate KIT, qualifying as oncogenic variants and a minor criterion for SM. ^ Denotes KIT mutations found in germline configuration in familial cases, mainly in CM. Variants are arranged by affected exons of KIT cDNA, which align to KIT protein functional domains. Ig = Immunoglobulin, JM = juxtamembrane domain, TKD = tyrosine kinase domain, and TM = transmembrane domain.

Figure 2

Aggressive systemic mastocytosis. Aspirate smears show areas with numerous hypogranular and/or spindle-shaped MCs (A; 200×). The marrow shows multifocal interstitial and paratrabecular aggregates of MCs, as well as a few small areas of residual trilineage hematopoiesis (B; 20×). One highlighted MC aggregate (C) shows expression of CD117 (D), tryptase (E), CD25 (F), and CD2 (weak, partial; (G)). CD3 (H) is negative in MCs. (C–H) are all at 100× magnification.

Figure 3

Systemic mastocytosis with an associated myelodysplastic syndrome with increased blasts-1 (SM-MDS-IB-1). (A,B) One of multiple MC aggregates (A, 100×; B, 400×). (C) Aspirate smear (Wright–Giemsa stain) shows erythroid dysplasia with nuclear budding and irregularity (black arrows) and increased blasts (red arrows). Immunohistochemistry (100×) shows MC aggregates to be positive for: CD117 (D), mast cell tryptase (E), CD25 (F), and CD30 (G). CD61 immunostaining highlights dysplastic megakaryocytes (H), and CD34 immunostaining highlights ~5% blasts (I).

Figure 4

Atypical mast cells (Wright–Giemsa stain, 1000×). (A) Spindle shaped (type I) mast cell, (B) bilobed promastocyte (type II; black arrow), and (C) metachromatic blasts (black arrows).