Systemic Mastocytosis Variants, including B and C findings and Mast Cell Leukemia

Systemic mastocytosis (SM) consists of a group of rare, heterogeneous disorders involving growth and accumulation of abnormal mast cells (MC) in one or multiple extracutaneous (non-skin) organ systems (Table 1). Standard technique can be used to obtain an iliac crest bone marrow (BM) biopsy and aspirate smear for diagnosis. Aspirated BM should be allocated for flow cytometry to assess for the presence of mast cells with aberrant phenotype (i.e., co-expression of CD25). Immunohistochemistry for KIT, mast cell tryptase, and CD25 should be performed on sections of the biopsy.^1-5

RECENT UPDATES IN DIAGNOSIS

A new diagnostic algorithm has been proposed by the European Competence Network on Mastocytosis for evaluating patients with suspected mastocytosis.⁶ Recommendations for KIT mutation analysis, including in peripheral blood, have also been recently published.⁷

Table 1. Major Variants of Systemic Mastocytosis⁸

*SM-AHN is the recently updated term from the 2016 WHO classification of mastocytosis;⁹ a lymphoproliferative disorder or plasma cell dyscrasia may rarely be diagnosed with SM.

WHO: World Health Organization; BM: bone marrow; MC: mast cell; MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; MDS/MPN: myelodysplastic syndrome/ myeloproliferative neoplasm overlap disorders; AML: acute myeloid leukemia.

Table 2. B and C Findings⁸

* Must be attributable to the MC infiltrate.

INDOLENT SYSTEMIC MASTOCYTOSIS

The majority of adult patients fit into this category, fulfilling the criteria for indolent systemic mastocytosis (ISM).^{2, 10-12} The bone marrow, gastrointestinal tract, skeletal system, nervous system and skin may be affected. Some patients may have enlarged livers and spleens and lymphadenopathy. Mediator-related symptoms are common, but the grade of bone marrow infiltration is low (usually less than 5 percent) with the bone marrow fulfilling the criteria for SM and 80-90% of the patients exhibiting a positive D816V KIT mutation. In most patients the serum tryptase concentration exceeds 20 ng/mL, but a normal level of tryptase does not rule out either mastocytosis or another mast cell activation disorder. Treatment usually includes mediator-targeting drugs, including antihistamines, but does not usually require cytoreductive agents, although there are exceptions.

Isolated bone marrow mastocytosis (BMM) is a variant of indolent SM.¹² BMM is characterized by the absence of skin lesions, lack of multiorgan involvement, and an increased incidence of anaphylaxis.¹³

Well differentiated SM (WDSM) first described in 2004¹⁴, is reported in the literature as a rare variant that fulfills the major criterion for SM and continues to be studied by researchers.^15-17 WDSM is distinguished from pediatric cutaneous mastocytosis by its inclusion in the systemic category, despite that 91% of patients with WDSM have childhood onset of disease, with familial involvement in 39%. There is a heterogeneous presentation of lesions, maculopapular, nodular and diffuse cutaneous, that may involve a large percentage of the skin.¹⁷ Severe mast cell symptoms can occur and the variant may persist into adulthood in a low percentage of cases. The mast cells often do not express CD25 or CD2 that are part of the minor World Health Organization (WHO) criterion for SM, but may have CD30. Also, roughly 90% of WDSM patients don’t have the KIT D816V or other exon 17 KIT mutations.¹⁷ Bone marrow analysis identifies mast cells in WDSM patients as notably large, round, mature-appearing mast cells with the absence of the spindle-shaped mast cells typically seen in SM.¹⁵ Baseline serum tryptase levels in these patients are usually lower than what is frequently detected in SM, except in a variable percentage of children at onset. Imatinib mesylate has been used in some patients with severe cases of WDSM, since these patients do not usually carry the KIT D816V mutation, which causes resistance to imatinib.¹⁸

SMOLDERING SYSTEMIC MASTOCYTOSIS

Smoldering systemic mastocytosis (SSM) was recently moved out of the WHO ISM category and into its own category under SM.⁹ In SSM, two or more B findings, but no C findings (Table 2) are found and there is a greater possibility that the disease will progress to a more aggressive variant.

ADVANCED SYSTEMIC MASTOCYTOSIS VARIANTS⁸

SM with an Associated Hematologic Neoplasm (SM-AHN)

SM-AHN is the recently updated term for SM-AHNMD from the 2016 WHO classification of mastocytosis.⁹ These patients fit the criteria for SM and they fit the WHO criteria for myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), MDS/MPN overlap disorder, or acute myeloid leukemia (AML), with or without skin lesions.^{8, 19, 20} Patients are treated for both the SM component and for the associated hematologic neoplasm.

Aggressive Systemic Mastocytosis

In this rare variant, aggressive systemic mastocytosis (ASM) patients fit the criteria for SM, with or without skin lesions, and also meet criteria for one or more C findings (Table 2).⁸ Patients with ASM often require chemotherapy.

Mast Cell Leukemia²¹

In this rare variant, mast cell leukemia (MCL) patients fit the criteria for SM, and a bone marrow aspirate smear shows that 20% or more of the cells are mast cells, or 10% or more mast cells are seen in circulating blood.^{8, 21, 22} The mast cells have malignant features. A 2014 international consensus proposal recommends that MCL be separated into acute and chronic²³ subvariants based on whether or not C findings (Table 2) are present.²¹ In addition, it recommends a distinction between a primary form of MCL and a secondary form that evolves from an existing mast cell neoplasm, such as ASM or mast cell sarcoma. There is a prognostic pre-phase identified in patients with ASM with 5-19% mast cells in bone marrow smears, associated with rapid progression. It has been proposed that this condition be called “ASM in transformation to MCL” (ASM-t). Prognosis can be variable based on the form of disease; life expectancy has been extended, in some cases, due to advances in cytoreductive therapy.²⁴ It is important to note that myelomastocytic leukemia (MML), which is a differential diagnosis, is not regarded by mast cell disorder specialists as a subvariant of MCL or SM and should be considered a secondary condition.²¹