Written by: Prithviraj Bose, MD, UT MD Anderson Cancer Center
Description: The purpose of this PQI is to assist in the diagnosis of the advanced systemic mastocytosis patient by providing a diagnostic algorithm.
Background: Systemic mastocytosis (SM) is a myeloid neoplasm driven in ~95% of cases by an activating mutation, D816V, affecting exon 17 of the KIT gene, and characterized by the accumulation of neoplastic mast cells in a variety of extra-cutaneous organs (as opposed to cutaneous mastocytosis (CM), which generally affects children and is limited to the skin).1 The bone marrow is almost always involved, and patients can exhibit an array of symptoms involving multiple organ systems, such as spots, itching, flushing, fatigue, headache, dizziness, “brain fog”, nausea, vomiting, diarrhea and abdominal pain, among many others. Osteopenia and osteoporosis are common. Patients may report a wide range of triggers, stress being the most common, for their symptoms, believed to be a result of mast cell degranulation and mediator release. Anaphylaxis can occur and it is essential that patients have an epinephrine auto-injector in hand. SM is rare, with an annual incidence of 0.89/100,000 in a population study from Denmark.2
The diagnosis of SM is a pathologic one, typically based on examination of the bone marrow.3 Serum tryptase testing and peripheral blood testing for the KIT D816V mutation using a sensitive technique such as digital droplet or allele-specific oligonucleotide polymerase chain reaction (ddPCR or ASO-PCR) can provide extremely helpful clues to the diagnosis in the appropriate setting, and serve as the basis for referral to a hematologist for bone marrow biopsy. Importantly, myeloid mutation panels utilizing next-generation sequencing (NGS) platforms, may miss low (ex. <2-5%) mutant allele frequency KIT mutations.4 Well-differentiated SM, characterized by rounded, instead of spindled, mast cells is very rare but important to recognize because of the usual absence of KIT D816 mutations and hence, responsiveness to imatinib (imatinib is ineffective against the D816V and related mutations).5 A recent, single-institution study from Germany estimated the annual incidence and prevalence of advanced SM (AdvSM, see below) to be 0.8 and 5.2 per million inhabitants in the region, respectively.6 Survival in AdvSM has historically been poor; in a 2019 study by the European Competence Network on Mastocytosis, median survival was 5.7 years for patients with aggressive SM (ASM), 2.9 years for those with SM with an associated hematologic neoplasm (SM-AHN), and 1.9 years for those with mast cell leukemia (MCL).7
- Criteria for the diagnosis of systemic mastocytosis: the major criterion and ≥1 minor criteria or ≥3 minor criteria required for diagnosis8
- Major criterion:
- Multifocal dense infiltrates of mast cells (≥ 15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)
- Minor criteria:
- > 25% of all mast cells are immature or atypical on bone marrow aspirate smears or are spindle-shaped or atypical in mast cell infiltrates detected on biopsy sections of bone marrow or other extra-cutaneous organs
- Activating c-KIT point mutation at codon 816 in the bone marrow, blood or another extracutaneous organ
- Mast cells in bone marrow or blood or another extracutaneous organ express CD25 and/or CD2, in addition to normal mast cell markers
- Serum tryptase concentration > 20 ng/ml in the absence of an associated myeloid neoplasm
- SM Subclassification:8
- Indolent SM (ISM): 0-1 B findings and no C findings – life expectancy near-normal (though inferior to that of patients with CM), with a 5-10% risk of progression to more advanced forms
- Smoldering SM (SSM): ≥2 B findings in the absence of C findings – a condition with relatively high mast cell burden but without organ damage from infiltrating neoplastic mast cells
- Advanced SM (AdvSM): ≥1 C findings – organ damage attributable to mast cell infiltration AdvSM Subtypes:
- Aggressive SM (ASM)
- SM with an associated hematologic neoplasm (SM-AHN) *most common*
- AHN is usually myeloid, the most frequent ones being myelodysplastic/myeloproliferative (MDS/MPN) “overlap” syndromes such as chronic myelomonocytic leukemia (CMML)
- Finding of KIT D816V in a patient with another myeloid neoplasm should prompt a search for an occult SM that may have been obscured on histopathology by the AHN9
- Mast cell leukemia (MCL): presence of ≥20% mast cells on the bone marrow aspirate smear; in contrast, circulating mast cells are usually <10% (“aleukemic” MCL)
- Rarely a “chronic” variant of MCL, without C findings, may be encountered10
- B and C Findings8
- B findings (high mast cell burden but no organ damage)
- >30% infiltration of bone marrow cellularity by mast cells and serum total tryptase >200 ng/mL
- Signs of dysplasia or myeloproliferation in non-mast cell lineage(s), but criteria are not met for definitive diagnosis of an associated hematologic neoplasm with normal or only slightly abnormal blood counts
- Hepatomegaly without impairment of liver function
- Palpable splenomegaly without hypersplenism
- Lymphadenopathy on palpation or imaging
- C findings (organ damage caused by mast cell infiltration)
- Bone marrow dysfunction caused by neoplastic mast cell infiltration manifested by ≥1 cytopenia: absolute neutrophil count <1.0 × 109/L, hemoglobin level <10 g/dL, and/or platelet count <100 × 109/L
- Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
- Skeletal involvement, with large osteolytic lesions with or without pathological fractures (pathological fractures caused by osteoporosis do not qualify as a C finding)
- Palpable splenomegaly with hypersplenism
- Malabsorption with weight loss due to gastrointestinal mast cell infiltrates
- B findings (high mast cell burden but no organ damage)
- Major criterion:
Patient Centered Activities:
- Discuss the importance of testing for KIT and other mutations in the context of other diagnostic criteria
- Ensure patient has prescription for epinephrine auto-injector and proper knowledge of how to use
- Ensure bone health is not ignored/overlooked and patients are treated for osteopenia/osteoporosis
- Discuss diagnostic findings and counsel patients regarding treatment options (symptom-directed therapies for non-advanced SM, KIT-targeted and other cytoreductive therapies for advanced SM)
- Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O, et al. Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future. Cancer Res. 2017 Mar 15;77(6):1261-70.
- Cohen SS, Skovbo S, Vestergaard H, Kristensen T, Moller M, Bindslev-Jensen C, et al. Epidemiology of systemic mastocytosis in Denmark. Br J Haematol. 2014 Aug;166(4):521-8.
- Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001 Jul;25(7):603-25.
- Gotlib J, Gerds AT, Bose P, Castells MC, Deininger MW, Gojo I, et al. Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018 Dec;16(12):1500-37.
- Alvarez-Twose I, Matito A, Morgado JM, Sanchez-Munoz L, Jara-Acevedo M, Garcia-Montero A, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget. 2016 Jul 19;8(40):68950-63.
- Schwaab J, Cabral do O Hartmann N, Naumann N, Jawhar M, Weiss C, Metzgeroth G, et al. Importance of Adequate Diagnostic Workup for Correct Diagnosis of Advanced Systemic Mastocytosis. J Allergy Clin Immunol Pract. 2020 Oct;8(9):3121,3127.e1.
- Sperr WR, Kundi M, Alvarez-Twose I, van Anrooij B, Oude Elberink JNG, Gorska A, et al. International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study. Lancet Haematol. 2019 Dec;6(12):e638-49.
- Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53.
- Craig JW, Hasserjian RP, Kim AS, Aster JC, Pinkus GS, Hornick JL, et al. Detection of the KIT(D816V) mutation in myelodysplastic and/or myeloproliferative neoplasms and acute myeloid leukemia with myelodysplasia-related changes predicts concurrent systemic mastocytosis. Mod Pathol. 2020 Jun;33(6):1135-45.
- Valent P, Sotlar K, Sperr WR, Reiter A, Arock M, Horny HP. Chronic mast cell leukemia: a novel leukemia-variant with distinct morphological and clinical features. Leuk Res. 2015 Jan;39(1):1-5