Standards of Genetic Testing in the Diagnosis and Prognostication of Systemic Mastocytosis in 2022: Recommendations of the EU-US Cooperative Group

Systemic Mastocytosis and Other Entities Involving Mast Cells: A Practical Review and Update

“…Sensitivity enhancement can be achieved by enriching for neoplastic mast cells via laser capture microdissection, magnetic bead-based or flow cytometry-based cell sorting [ 18 , 23 , 24 ], or application of highly sensitive polymerase chain reaction (PCR) techniques, including digital droplet PCR (ddPCR) and allele-specific quantitative PCR (ASO-qPCR), reaching sensitivity as deep as 0.01% VAF [ 25 , 26 ]. Measurement of KIT D816V by ddPCR can be used to assess response to TKI treatment and disease progression in KIT D816V-mutated ISM or SSM patients [ 9 , 27 ].…”

“…HαT = hereditary alpha-tryptasemia; SM = systemic mastocytosis. The KIT gene is located on chromosome 4q12, comprises 21 exons, and is composed of four domains (extracellular, transmembrane, juxtamembrane, and an intracellular tyrosine kinase domain that contains a hydrophilic insert of approximately 80 amino acid residues); the extracellular domain consists of five immunoglobulin-like subunits, and the protein kinase domain is interrupted by a hydrophilic insert sequence of about 80 amino acids [9][10][11]. In wild-type KIT, the ligand stem cell factor (SCF) attaches to KIT via the second and third immunoglobulin domains [12], thereby triggering KIT autophosphorylation and dimerization and downstream activation of several pathways; however, KIT D816V mutations induce ligand-independent activation of KIT and aberrant mast cell proliferation [13].…”

“…Since the addition of the KIT-activating point mutation(s) at codon 816 or other critical regions of the KIT gene to the minor SM criteria [6], the unique WDSM features can be recognized, especially that a substantial percentage of reported WDSM cases (lack exon 17 KIT mutations and harbor KIT mutations primarily in exons [8][9][10][11] show excellent response to treatment with imatinib [28,31,36,[38][39][40][41][42]. Given that well-differentiated morphology of mast cells can be detected in all subtypes of SM (rarely observed in BMM, SSM, and MCL) [6], it has been proposed to add WDSM as a morphologic variant to all classical SM subtypes, e.g., SSM-WDSM for smoldering SM with well-differentiated morphology [8,36].…”

Recent Developments in the Field of Mast Cell Disorders: Classification, Prognostication, and Management

“…The recommended techniques are described in the current issue of this journal. 35 In other patients, including some with MC leukemia and most SM cases with a well-differentiated MC morphology, other mutations in codon 816, mutations in other codons of KIT, or no KIT mutation may be found. In these patients, sequencing of the entire coding region of KIT is recommended.…”

“…In these patients, sequencing of the entire coding region of KIT is recommended. 14,35 WP5 was dedicated to flow cytometry. A novel flow-cytometryebased diagnostic marker is CD30, which is specifically expressed on BM MCs in SM, including most patients with a well-differentiated MC morphology.…”