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
|ISM (Indolent systemic mastocytosis)|
|WHO criteria for SM met, MC burden low, +/- skin lesions, no C findings, no evidence of AHN|
|Bone marrow mastocytosis|
|ISM with BM involvement, but no skin lesions|
|SSM (Smoldering systemic mastocytosis)|
|WHO criteria for SM met, typically with skin lesions, with 2 or more B findings, but no C findings.|
|Advanced Disease Variants|
|SM-AHN (SM with an associated hematologic neoplasm)*|
|Meets criteria for SM and also criteria for an AHN (MDS, MPN, MDS/MPN, AML), or other WHO-defined myeloid hematologic neoplasm, +/- skin lesions.|
|ASM (Aggressive systemic mastocytosis)|
|Meets criteria for SM with one or more C findings. No evidence of MCL, +/- skin lesions.|
|MCL (Mast cell leukaemia)|
Meets criteria for SM. BM biopsy shows a diffuse infiltration, usually compact, by atypical, immature MCs. BM aspirate smears show 20% or more MCs.
Typical MCL: MCs comprise 10% or more of peripheral blood white cells. Aleukemic MCL: < 10% of peripheral blood white cells are MCs. Usually without skin lesions.
*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 leukaemia.
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 fulfils 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 leukaemia (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 leukaemia (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 leukaemia (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
- Horny HP, Valent P. Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res. 2001 Jul;25(7):543-51. http://www.ncbi.nlm.nih.gov/pubmed/11377679
- 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. http://www.ncbi.nlm.nih.gov/pubmed/17537151
- Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74(2):121-32. http://www.ncbi.nlm.nih.gov/pubmed/17587883
- Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. 2006 Aug;26(3):535-47. http://www.ncbi.nlm.nih.gov/pubmed/16931292
- Alvarez-Twose I, Morgado JM, Sanchez-Munoz L, Garcia-Montero A, Mollejo M, Orfao A, et al. Current state of biology and diagnosis of clonal mast cell diseases in adults. Int J Lab Hematol. 2012 Oct;34(5):445-60. http://www.ncbi.nlm.nih.gov/pubmed/22551157
- Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K, et al. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014 Oct;69(10):1267-74. http://www.ncbi.nlm.nih.gov/pubmed/24836395
- Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32. http://www.ncbi.nlm.nih.gov/pubmed/25650093
- Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, et al. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood. 2013 Mar 28;121(13):2393-401. http://www.ncbi.nlm.nih.gov/pubmed/23325841
- Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. http://www.ncbi.nlm.nih.gov/pubmed/27069254
- Valent P. Mastocytosis: a paradigmatic example of a rare disease with complex biology and pathology. Am J Cancer Res. 2013;3(2):159-72. http://www.ncbi.nlm.nih.gov/pubmed/23593539
- Carter MC, Metcalfe DD, Komarow HD. Mastocytosis. Immunol Allergy Clin North Am. 2014 Feb;34(1):181-96. http://www.ncbi.nlm.nih.gov/pubmed/24262698
- Pardanani A. Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. Am J Hematol. 2016 Nov;91(11):1146-59. http://www.ncbi.nlm.nih.gov/pubmed/27762455
- Zanotti R, Bonadonna P, Bonifacio M, Artuso A, Schena D, Rossini M, et al. Isolated bone marrow mastocytosis: an underestimated subvariant of indolent systemic mastocytosis. Haematologica. 2011 Mar;96(3):482-4. http://www.ncbi.nlm.nih.gov/pubmed/21193416
- Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004 Apr 15;103(8):3222-5. http://www.ncbi.nlm.nih.gov/pubmed/15070706
- Torrelo A, Alvarez-Twose I, Escribano L. Childhood mastocytosis. Curr Opin Pediatr. 2012 Aug;24(4):480-6. http://www.ncbi.nlm.nih.gov/pubmed/22790101
- Fried AJ, Akin C. Primary mast cell disorders in children. Curr Allergy Asthma Rep. 2013 Dec;13(6):693-701. http://www.ncbi.nlm.nih.gov/pubmed/24150753
- Alvarez-Twose I, Jara-Acevedo M, Morgado JM, Garcia-Montero A, Sanchez-Munoz L, Teodosio C, et al. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J Allergy Clin Immunol. 2016 Jan;137(1):168-78 e1. http://www.ncbi.nlm.nih.gov/pubmed/26100086
- Alvarez-Twose I, Gonzalez P, Morgado JM, Jara-Acevedo M, Sanchez-Munoz L, Matito A, et al. Complete response after imatinib mesylate therapy in a patient with well-differentiated systemic mastocytosis. J Clin Oncol. 2012 Apr 20;30(12):e126-9. http://www.ncbi.nlm.nih.gov/pubmed/22370312
- Stoecker MM, Wang E. Systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease: a clinicopathologic review. Arch Pathol Lab Med. 2012 Jul;136(7):832-8. http://www.ncbi.nlm.nih.gov/pubmed/22742558
- Wang SA, Hutchinson L, Tang G, Chen SS, Miron PM, Huh YO, et al. Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. Am J Hematol. 2013 Mar;88(3):219-24. http://www.ncbi.nlm.nih.gov/pubmed/23440662
- Valent P, Sotlar K, Sperr WR, Escribano L, Yavuz S, Reiter A, et al. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol. 2014 Sep;25(9):1691-700. http://www.ncbi.nlm.nih.gov/pubmed/24675021
- Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013 Feb 21;121(8):1285-95. http://www.ncbi.nlm.nih.gov/pubmed/23243287
- 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. http://www.ncbi.nlm.nih.gov/pubmed/25443885
- Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. http://www.ncbi.nlm.nih.gov/pubmed/27355533