Systemic Mastocytosis (SM)

The World Health Organization (WHO) has outlined the criteria for the diagnosis of systemic mastocytosis (SM). The diagnosis of SM can be established by the presence of either 1 major and 1 minor criterion or 3 minor criteria.¹

Major criterion:

The presence of multifocal dense infiltrates of mast cells (MCs) (≥15 MCs in aggregates) in bone marrow (BM) biopsies and/or sections of other extracutaneous organs. 

Minor criteria: 

• >25% of all MCs are atypical cells (type I or type II) on BM smears or are spindle-shaped in MC infiltrates on sections of visceral organs
• KIT point mutation at codon 816 in the BM or another extracutaneous organ
• MCs in the BM, blood, or another extracutaneous organ express CD2 and/or CD25
• Baseline serum tryptase level >20 ng/mL (in the case of an unrelated myeloid neoplasm, this item is not valid as an SM criterion)

The full systemic workup required for the diagnosis of SM includes the measurement of serum tryptase level, BM/involved extracutaneous organ biopsy, KITD816V mutation screening, MC immunophenotyping, and screening for FIP1L1–PDGFRA if there is blood eosinophilia.² 

Serum tryptase level

A persistently elevated level of tryptase (>20 ng/mL) is defined by the WHO as a minor criterion for SM. This measurement has limited utility in the presence of an associated myeloid neoplasm since elevated levels are seen with neoplasms like acute and chronic myeloid leukemias and myelodysplastic syndrome. Approximately 30% of patients with indolent SM have serum tryptase levels of <20 ng/mL.²

Bone marrow/extracutaneous organ biopsy

The diagnostic approach for SM begins with a BM biopsy, given that this site is almost always involved in adult mastocytosis. In SM, the presence of multifocal dense MC aggregates in the BM is pathognomonic. The WHO’s major diagnostic criterion for SM is dense infiltrates of ≥15 MCs aggregated in a BM biopsy and/or on sections of extracutaneous organs. Due to a lack of standardization in the histological diagnostic criteria for non-BM extracutaneous organ involvement, BM is the preferred specimen.² 

Analysis involves using standard dyes and immunohistochemical markers. Standard dyes have a limitation in that the characteristic MC aggregates may not be easily distinguished when there is extensive BM involvement of a second hematological neoplasm, hypogranular MCs, abnormal MC morphology, or significant reticulin fibrosis. The immunohistochemical marker tryptase is present in all stages of MC maturation and is the marker of choice for the detection of small and/or immature MC infiltrates. In addition, immunohistochemical detection of aberrant CD25 expression in BM MCs appears to be a reliable diagnostic tool in SM. It has the advantage of being able to detect abnormal MCs in all SM subtypes, including rare cases with a loosely scattered, interstitial pattern of MC involvement.² 

The presence of CD30 (Ki-1 antigen) may be observed since it is reported to be preferentially expressed in neoplastic MCs in some patients, although the prognostic implications are unclear.² 

Mast cell immunophenotyping

A minor criterion per the WHO classification system for SM is the abnormal expression of CD25 with or without CD2. Immunophenotyping is performed on BM specimens using immunostaining and immunophenotyping studies.² 

Molecular testing

Molecular studies are used to identify KITD816V mutations, a WHO minor diagnostic criterion. Screening for KIT mutations that do not involve D816 is not a standard clinical practice. Enhanced sensitivity of detection can be achieved by enriching lesional MCs via laser capture microdissection, cell sorting using magnetic beads or fluorescence-activated cell sorting (FACS), or highly sensitive polymerase chain reaction (PCR) techniques. Approximately 20% of patients with indolent SM lack MC clusters on BM biopsy, and approximately 30% have a serum tryptase level of <20 ng/mL. In these patients, molecular testing is a useful diagnostic tool and has a sensitivity of >90% for detecting morphologic atypia, aberrant CD25 and/or CD2 expression, or KITD816V mutations.²

FIP1L1–PDGFRA screening

Screening for FIP1L1–PDGFRA using either fluorescent in situ hybridization (FISH) or reverse transcriptase-PCR (RT-PCR) is warranted in patients who exhibit blood eosinophilia.² The FIP1L1–PDGFRA fusion gene is a pathogenic cause of hypereosinophilic syndrome, which should be ruled out in patients presenting with eosinophilia.³ 

References 

1. Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129(11):1420-1427. doi:10.1182/blood-2016-09-731893

2. Pardanani A. Systemic mastocytosis in adults: 2021 update on diagnosis, risk stratification and management. Am J Hematol. 2021;96(4):508-525. doi:10.1002/ajh.26118

3. Yamada Y, Cancelas JA. FIP1L1/PDGFRα-associated systemic mastocytosis. Int Arch Allergy Immunol. 2010;152(Suppl 1):101-105. doi:10.1159/000312134

Reviewed by Harshi Dhingra, MD, on 4/14/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.