Systemic mastocytosis Q82.2

A form of mastocytosis in which, in addition to the (usually) typical skin symptoms, systemic reactions such as flushing, dizziness, nausea, abdominal cramps, gastric ulceration, tachycardia, fever, respiratory problems, etc. occur. Furthermore, liver and spleen enlargement are found in about 70% of cases, often on the basis of fibrosing changes. Osseous involvement such as osteolysis and mast cell infiltrates of the bone marrow are not uncommon. The most aggressive form of systemic mastocytosis is mast cell leukemia.

A cutaneous manifestation (according to the old nomenclature: urticaria pigmentosa) is found in systemic mastocytosis, especially in indolent systemic mastocytosis (ISM). It is completely absent in mast cell leukemia.

The diagnosis of "systemic mastocytosis" is made on the basis of the 2016 WHO classification criteria. To diagnose SM, either one major criterion and at least one of four minor criteria or three minor criteria must be met.

Main criterion

• Histologic evidence of multifocal, compact infiltrates of mast cells (≥15) in the BM or in an extracutaneous organ.

Ancillary criteria

• Evidence of atypical spindle-shaped mast cells (≥25% of all mast cells); histologic in the BM or in other extracutaneous organs or cytologic in the BM smear
• Detection of a KIT D816 point mutation in peripheral blood, KM, or other extracutaneous organs.
• Detection of the surface marker CD2 and/or CD25 on mast cells in KM, peripheral blood, or other extracutaneous organ
• Serum tryptase level persistently ≥ 20μg/l.

Systemic mastocytosis is present when the major criterion (multifocal dense mast cell aggregation of 15 or more cells in the bone marrow and/or other extracutaneous organ(s)) and at least one minor criterion, or in the absence of a major criterion, three of the four minor criteria are met.

Classification and subtyping is according to the current WHO classification from 2016.

Cutaneous mastocytosis (CM)

• Cutaneous mastocytoma (findings in young children)
• Maculopapular cutaneous mastocytosis (MPCM = Urticaria pigmentosa of the old nomenclature)

Systemic mastocytosis (SM)

• Indolent SM (ISM)
• Smoldering SM (SSM)
• SM with associated haematological neoplasia (SM-AHN)* ⁺
• Aggressive SM (ASM⁾⁺
• Mast cell leukemia (MCL⁾⁺
• Mast cell sarcoma+

⁺ In clinical practice, the term "advanced SM (AdvSM)" has become the generic term for ASM, SM-AHN and MCL.

Systemic mastocytosis with associated hematologic neoplasia (SM-AHN): The hematologic neoplasia associated with rare SM-AHN is of myeloid origin in >95% of patients (SM-MDS; SM-CMML; SM-CEL; more rarely SM-AML). It reflects multilineage involvement of the KIT D816V mutation. The basis for subtyping is the extent of organ involvement and dysfunction.

Detectable somatic mutations, e.g. in the genes SRSF2, ASXL1 and RUNX1, among others, have now assumed increasing importance for phenotype, treatment response and prognosis (Valent P et al. 2017; Jawhar M et al. 2019).

SM is a rare disease. Epidemiological figures on incidence and prevalence are imprecise. ISM is thought to have an incidence around 1/100,000, while "advanced systemic mastocytosis (AdvSM)" is thought to have an incidence around 1-2/1 million population. In AdvSM, men are more frequently affected than women.

Mastcells: Mast cells are derived from CD34 -positive bone marrow progenitor cells. These immature mast cell volcano cells enter the connective tissue of skin and mucous membranes of their end organs (skin, bronchial mucous membranes, mucous membranes of the GI tract) via the blood vessels. Mast cells express the tyrosine kinase receptor KIT(CD117), which in turn binds stem cell factor (SCF). SCF is a growth factor. It is essential for proliferation and differentiation of mast cells. In the tissue of their end organs, the immature cells differentiate into mature mast cells. Mutations that lead to a defect of SCF or KIT result in mast cell deficiency with different effects.

Activation of mast cells: Mast cells can be activated by various stimuli, such as allergens, food components, infections, drugs, physical stimuli, insect venom. This stimulation usually leads to a controlled release of mast cell mediators. These include biogenic amines such as histamine, heparin, tryptase, chymase, cytokines such as TNF-alpha, chemokines and prostanoids. However, in rare cases, uncontrolled release of mast cell mediators may occur with flushing, urticaria, or angioedema (see also under mast cell). An extreme and uncontrolled release of mast cell mediators occurs in the so-called mast cell activation syndrome with severe life-threatening conditions, e.g. hypotension/anaphylactic shock. In contrast to these mediator-mediated symptoms, AdvSM often results in direct impairment of organ function due to mast cell infiltration itself and, in some cases, associated inflammation.

KIT mutation: Thus, an activating KIT D816 mutation (>95% KIT D816V in exon 17) is detectable in 80-95% of SM patients. The mutation leads to SCF-independent receptor activation with clonal expansion and accumulation of tissue mast cells. In childhood mastocytosis, mutations are also found in 50% of cases. However, in other regions of the KIT gene (exons 8, 9, 11).

KIT D816V mutation and mutation burden: KIT D816V mutation is detectable in mast cells in the vast majority of patients with ISM and SSM and in many patients with advancedSM without AHN. In general, quantitative KIT D816V mutation load correlates with mast cell load in KM. In AdvSM, especially in SM-AHN, and in SSM, the KIT D816V mutation is detectable in mast cells, but also in non-mast cell fractions (e.g., myeloid progenitor cells, monocytes, eosinophils, and others). In these cases, the KIT D816V mutation is always detectable in peripheral blood as well, and the KIT D816V mutation load in peripheral blood can reach levels of 50% and above.

Other mutations: In 60-80% of patients with AdvSM, additional somatic mutations are detectable in addition to KIT D816V. The most commonly affected genes are TET2, SRSF2, ASXL1, RUNX1, JAK2, CBL, N/KRAS, EZH2, IDH1/2 and SF3B1. Detection of at least one mutation in the SRSF2, ASXL1, RUNX1 (S/A/R) gene panel has a significant impact on phenotype, treatment response, progression and prognosis. Genetic studies have shown that the somatic mutations often represent an early event, while the KIT D816V mutation represents a rather late event in the disease evolution of multimutated AdvSM patients (Jawhar M et al. 2016).

In adults, ISM manifests most frequently between the ages of 20 and 40, and AdvSM between the ages of 60 and 70.

The skin changes in systemic mastocytosis correspond to the clinical picture of " maculopapular cutaneous mastocytosis".

The kinetic symptoms of systemic mastocytosis are flushing, diarrhoea, rhinitis, circulatory collapse, bone pain and pruritus in varying degrees. Much less common are tachycardia, headache, fever, or weight loss. Systemic mastocytosis is associated with liver and spleen enlargement, anemia, osteoporosis, and fracture tendency, depending on the severity and pattern of involvement.

Itis important to note an increased risk of anaphylaxis, e.g. after insect bites or reactions to drugs!

In connection with a systemic mastocytosis, a relevant eosinophilia may occur. This can be reactive, e.g. in the context of allergies and intolerances, or clonal. In addition to eosinophilia, monocytosis is often found. This combination is associated with a poor prognosis; prognosis-relevant somatic mutations such as SRSF2, ASXL1 and RUNX1 can often be detected in these cases. In SM-CEL, concomitant myelofibrosisis often found.

Urticarial dermographism (positive Dariers sign in skin lesions).

Basic program (see also mastocytosis): Tryptase in serum (see on the value of the tryptase value under mastocytosis/laboratory).

BB, coagulation, CRP, electrophoresis, total IgE

Skeletal scintigraphy, chest x-ray, sono-abdomen

If necessary, bone marrow biopsy, gastrointestinal endoscopy.

If necessary, genetic examination with detection of point mutations of the c-Kit gene (see kit below).

Mast cell hyperplasia

Immunocytoma: mast cell hyperplasia may mimic well-differentiated round cell SM

Myeloid neoplasms: Eosinophilia-associated myeloid neoplasms

Myelomastocytic leukemia (MML): as MCL, except that 10% mast cells in the BM smear or blood smear are sufficient to make the diagnosis of MML.

Histiocytoses

In case of acute circulatory symptoms with impending shock, see Shock, anaphylactic. Otherwise, symptomatic therapy according to the clinical symptoms (see Table 1). Antihistamines, possibly as a combination of H ₁ antagonists, e.g. levocetirizine (1 tablet Xusal 1 time/day) and H ₂ antagonists, e.g. cimetidine (Tagamet 200-800 mg/day), have a positive effect on itching and flushing symptoms. The choice of mildly sedating antihistamines such as clemastine (e.g. Tavegil) may be useful in some cases, especially in children. If unsuccessful, try therapy with ketotifen (e.g. Zaditen 1-4 mg/day). Disodium cromoglicic acid (e.g. Colimune 4 times/day 200 mg p.o.) especially in cases of gastrointestinal symptoms.

Glucocorticoids are not a permanent solution because of their side effects and are reserved for severe cases (e.g. bullous forms in children). If necessary, prednisolone (e.g. Decortin H) in medium dosage for 2-3 weeks, then reduce to the lowest possible maintenance dose. Especially in case of extensive systemic disorders (e.g. resorption disorders) they may be helpful. In systemic, connatal mastocytoses, good effects have been described with interferon alfa-2a (Roferon A 1 million IU s.c. 3 times/week).

KIT inhibitors: Midostaurin: the only drug approved in Germany for the treatment of AdvSM (ASM, SM-AHN and MCL). The effect is independent of previous therapies and KIT mutation status. Significant reduction of KM mast cell infiltration, serum tryptase, splenomegaly and KIT D816V mutation load as well as improvement of C-findings. The response rate is 60% and can last for several months, sometimes years. However, primary resistance or early progression are also observed. In the long term, an improvement in survival seems to be associated with the absence of pathogenetically relevant, somatic additional mutations (e.g. SRSF2, ASXL1, RUNX1), the achievement of a conventional response and with a >25% reduction in KIT D816V mutation load after 6 months.

Patients with ISM are characterized by a normal life expectancy. The median life expectancy of AdvSM is usually months to a few years. Patients with MCL ± AHN have the worst prognosis. Most recently, several unfavorable prognostic factors independent of the WHO classification have been identified. From a molecular point of view, a "S/A/R gene panel" consisting of three (SRSF2/ASXL1/RUNX1) prognostically essential genes can be used, in which a mutation per se as well as the number of mutations are associated with an aggressive clinical presentation as well as reduced survival.

Therapy of systemic mastocytosis

Criteria for systemic mastocytosis (cited in Wagner N et al. 2018). Systemic mastocytosis is present if one main criterion and at least 1 secondary criterion or 3 secondary criteria are met!

Major criteria

• multifocal dense mast cell aggregates of 15 or more cells in bone marrow and/or other extracutaneous organ(s) confirmed by tryptase immunohistochemistry or other special staining

Minor criteria

• 25% of the mast cells in the infiltrate in extracutaneous organs or blood have an atypical or spindle cell morphology
• Detection of a KIT mutation in codon 816 in bone marrow, blood or other extracutaneous tissue
• Coexpression of KIT with CD2 and/or CD25 expression of mast cells in the bone macula, blood or other extracutaneous organs
• Serumtryptase >20ng/ml

A 52-year-old female patient had been suffering from itching of varying severity for about 10 years, responding only moderately well to antihistamines (pruritus sine materia!). In the last 2 years she was treated several times as an emergency outpatient and inpatient because of anaphlactic reactions. The cause was once a wasp sting, the second time the intake of an ACE inhibitor (anaphylaxis several weeks after the start of therapy!) and another time the intake of a painkiller.

Findings: The skin findings were completely unremarkable. The serum showed a clearly elevated tryptase level of 50 μg/l. The bone marrow biopsy now ordered showed clear evidence of systemic mastocytosis with infiltration of CD25-positive mast cells and KIT mutation.

1. Arber DA et al. (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms
   and acute leukemia. Blood 127:2391-405.

2. Akin C (2014) Mast cell activation disorders. J Allergy Clin Immunol Pract 2:252-257.

3. Bohm A et al (2010) In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V. Exp Hematol 38:744-755.

4. Deb A et al (2003) Images in clinical medicine. Systemic mastocytosis. N Engl J Med 349: e7

5. Delling G et al. (2001) Histological characteristics and prevalence of secondary osteoporosis in systemic mastocytosis. A retrospective analysis of 158 cases. Pathologist 22: 132-140

6. Erben P et al (2014) The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol 93:81-88

7. Dollner R et al (2013) Non-allergic, mastocytosis-associated rhinitis. Clin Exp Allergy 43:406-412.

8. Ellis JM (1949) Urticaria pigmentosa: a report of a case with autopsy. Arch Pathol 48: 426-435

9. Gasior-Chzan B et al (1992) Systemic mastocytosis treated with histamine H1 and H2 receptor antagonists. Dermatology 184: 149-152

10. Haustein UF, Bedri M (1997) Bullous mastocytosis in a child. Dermatologist 48: 127-129
11. Jackson Roberts II L et al (1991) Pharmacologic aspects of mast cell disease. J Invest Dermatol 96: 19S-25S

12. Jawhar M et al. (2016) Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia 30:136-143.

13. Jawhar M et al. (2017) The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematologica 102:1035-1043.

14. Jawhar M et al. (2019) MARS: mutation-adjusted risk score for advanced systemic mastocytosis. J Clin Oncol 37:2846-2856.

15. Jawhar M et al. (2019) KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis. Leukemia 33:1124-1134.

16. Koide T et al (2002) Systemic mastocytosis and recurrent anaphylactic shock. Lancet 359: 2084

17. Kluin-Nelemans HC et al (2003) Cladribine therapy for systemic mastocytosis. Blood 102: 4270-4276
18. Krahl J et al (1999) Systemic connatal mastocytosis with universal skin involvement. Dermatologist 50: 893-896

19. Lubke J et al (2019) Inhibitory effects of midostaurin and avapritinib on myeloid progenitors derived from patients with KIT D816V positive advanced systemic mastocytosis. Leukemia 33:1195-1205.

20. Metcalfe DD (1991) The treatment of mastocytosis: An overview. J Invest Dermatol 96: 55S-59S.

21. Naumann N et al (2018) Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis. Genes Chromosomes Cancer 57:252-259.

22. Valent P et al (2003) Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 122: 695-717

23. Valent P et al (2017) Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future. Cancer Res 77:1261-1270.

24. Valent P et al (2017) Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood 129:1420-1427.

25. Wagner N et al. (2018) Mastocytosis - pathogenesis, clinical manifestation and treatment.J Dtsch Dermatol Ges 16:42-57.

26. Woodward T (2003) Systemic mastocytosis. Curr Treat Options Gastroenterol 6: 35-38.