Updated Diagnostic Criteria and Classification of Mast Cell Disorders: A Consensus Proposal

Abstract

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.

Figure 1.

Expression of CD30 in neoplastic mast cells in systemic mastocytosis. (A), Flow cytometric detection of CD30 on neoplastic MC in patients with SM. BM cells were obtained from a control patient (no known BM disease; upper left image), patients with indolent SM (ISM: upper middle and right panels), and patients with advanced SM, namely 1 with ASM with an AHN (ASM-AHN: lower left image), 1 with ASM (lower middle histogram), and 1 with MCL by multicolor flow cytometry on a FACSCanto (Becton Dickinson). MC were identified as CD117⁺⁺/CD45⁺/CD34⁻ cells and stained with a phycoerythrin-labeled monoclonal antibody against CD30 (BerH8 from BD Biosciences; blue histograms). The isotype-matched control antibody (black open histogram) is also shown. (B), Immunohistochemical detection of CD30 in neoplastic MC. BM biopsy sections from patients with ISM, ASM, and MCL (as indicated) were stained with a monoclonal antibody against CD30 (Ber-H2 from Dako, Glostrup, Denmark) by an indirect immunoperoxidase staining technique as reported. The 2 images at the bottom show the nonaffected BM in 2 patients with ISM (control). Images were prepared using an Olympus DP21 camera connected to an Olympus BX50 microscope equipped with 60×/0.90 UPlan-Apo objective lens (Olympus, Hamburg, Germany) and processed with Adobe Photoshop CS2 software version 9.0 (Adobe Systems, San Jose, CA) as described. All patients gave written informed consent before BM samples were obtained and analyzed. AHN = associated hematologic neoplasm; ASM = aggressive SM; BM = bone marrow; ISM = MC = mast cells; MCL = MC leukemia; SM = systemic mastocytosis.