Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management

Abstract

Overview: Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs. Diagnosis: The major criterion is presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and presence of activating KIT mutations. Risk Stratification: Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients. Management: Treatment goals for ISM patients are primarily directed toward anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation. | DISEASE OVERVIEW AND PATHOGENESISSystemic mastocytosis (SM) results from a clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells (MC) that accumulate in one or more organ systems. 1,2 The sine qua non of mastocytosis is the presence of multifocal clusters of abnormal MC, which in contrast to normal MC are variable in appearance, ranging from round to fusiform variants with long, polar cytoplasmic processes, and may display cytoplasmic hypogranularity with

Granularity in disease classification impacts survival prediction in advanced systemic mastocytosis: A single institution study of 329 informative cases

“…SM remains an enigmatic disease that appears to be driven by KIT mutation but with markedly heterogeneous clinical and morphological presentation 10 . At one extreme are ICC‐defined MCL (i.e., WHO‐defined MCL with immature cytomorphology) 5 and mast cell sarcoma, 11,12 with median survival measured in weeks, while a near‐normal life expectancy is possible with ISM 13 .…”

“…SM remains an enigmatic disease that appears to be driven by KIT mutation but with markedly heterogeneous clinical and morphological presentation. 10 At one extreme are ICC-defined MCL (i.e., WHOdefined MCL with immature cytomorphology) 5 and mast cell sarcoma, 11,12 with median survival measured in weeks, while a nearnormal life expectancy is possible with ISM. 13 Both the ICC 1,2 and WHO 3 classification systems start with a broad classification scheme that distinguishes SM-Adv from ISM or SSM, based primarily on longterm clinical outcome and presence (SM-Adv) or absence (ISM/SSM) of at least one "C," as in "cytoreduction-requiring," finding; the latter includes (i) cytopenia (hemoglobin <10 g/dL, absolute neutrophil count <1 Â 10 9 /L, or platelet count <100 Â 10 9 /L) related to BM MC infiltration, (ii) palpable hepatomegaly with liver function test abnormalities or ascites or portal hypertension, (iii) palpable splenomegaly with thrombocytopenia, (iv) malabsorption with weight loss secondary to MC infiltration of the gastrointestinal system, and (v) large osteolytic lesions with or without pathological fractures.…”

Factor VII Deficiency in Systemic Mastocytosis with an Associated Myeloid Neoplasm

“…Systemic mastocytosis (SM) is a heterogeneous disease sustained by the clonal proliferation of abnormal mast cells (MC) that infiltrate the bone marrow and/or other extracutaneous organs [ 5 , 6 ].…”

Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease

“…Mastocytosis is a rare condition characterized by an abnormal accumulation of neoplastic mast cells (MCs) in various tissues, mostly including the skin, bone marrow (BM), spleen, liver, gastrointestinal tract, and lymph nodes [ 1 , 2 , 3 ]. In 2016, the World Health Organization (WHO) categorized the disease into three primary clinical variants: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and the locally aggressive disease known as MC sarcoma (MCS) [ 4 ].…”