Mastocytosis (overview) Q82.2

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Mast cell disease; Mastocytosis

History
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Nettleship, 1869

Definition
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Rare, clonal disease of the hematopoietic stem cell with development of clinically heterogeneous disease patterns characterized by mast cell accumulation in the skin and internal organs. In cutaneous mastocytosis, the proliferation of mast cells is restricted to the skin. In systemic mastocytosis, at least 1 extracutaneous organ is affected. Most patients show an activating point mutation of the KIT gene (KIT D816V). Both the expression of KIT (CD117) on the cell surface and the mutation are not specific for mastocytosis.

Classification
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Classification of mastocytosis (modified according to Golkar):

Classification of mastocytosis according to the type of systemic involvement:

  • Type Ia: Indolent mastocytosis without systemic involvement
  • Type Ib: Indolent systemic mastocytosis with systemic involvement (at least infestation of an extracutaneous organ, mostly KM)
  • Type II: Systemic mastocytosis associated with non-mastocytic myeloproliferative or myelodysplastic involvement
  • Type III: Lymphadenopathic mastocytosis with eosinophilia
  • Type IV: Mast cell leukemia (>20% atypical mast cells in KM)

Classification of mastocytosis according to C-kit mutation profile

  • Childhood mastocytosis
    • No activating mutation (most cases)
    • D816V activating mutation (few cases)
    • Non-activating mutation (most cases)
  • Adult mastocytosis
    • D816V activating mutation (most cases)
    • 560 activating mutation (few cases)
    • 820 activating mutation (few cases)
  • Familial mastocytosis
    • No activating mutation
    • No non-activating mutation

Occurrence/Epidemiology
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Very rare; incidence: about 0.3-1.0/100,000 inhabitants/year. In dermatological outpatient clinics the percentage is in the single-digit per mille range.

Etiopathogenesis
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The vast majority of adult patients with mastocytosis show a point mutation of the KIT gene in codon 816; other mutations are rarer, see below. functions of KIT s.there. This activating mutation of the pro-oncogene c-Kit codes for a mast cell growth factor receptor, also known as stem cell factor (SCF), which activates cellular proliferation and simultaneously prevents apoptosis of mast cells.

In juvenile mastocytosis, the activating c-Kit mutation is rarely found and only in cases characterized by a persistent and progressive course. In contrast, an inactivating c-kit mutation of cocon 839 is found.

Manifestation
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Bi- (or tri-) phasic age of disease:

  • In about 55% of all patients the first symptoms are found in infancy (< 2 years). About 90% of childhood mastocytoses manifest themselves within the first two years of life; 75% of these are urticaria pigmentosa, 20% mastocytomas, 5% diffuse forms).
  • In about 10% of all patients the first symptoms are found at the age of 2-15 years
  • In about 35% of all patients the initial symptoms are found in adulthood
  • m:f=1:4

Clinical features
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HV are almost always present in the indolent forms, but are often absent in mast cell leukemia. Skin lesions are considered a favourable prognostic sign. Papulo-macular skin lesions define the picture of urticaria pigmentosa and cutaneous mastocytomas. An important diagnostic sign is the"Darier sign" = immediate urticarial reaction after a lesion has been scratched.

Laboratory
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  • If systemic mastocytosis is suspected, tryptase is determined according to the guidelines (standard value: <20µg/l). If the value is exceeded, systemic mastocytosis is considered possible and a bone marrow biopsy and screening for further system involvement is sought. If the values are low, extensive diagnostic procedures are usually not necessary without compelling clinical indications. In a larger study, systemic mastocytosis was confirmed in 32% of patients with cutaneous mastocytosis in bone marrow histology. The mean tryptase value of the collective with system involvement was 43.9±39.93µg/l (3.74-173µg/l), without system involvement 19.63±13.31 µg/l (2.44-54 µg/l). Tryptase elevations > 20µg/l were detectable in 43% of patients with pure cutaneous mastocytosis. 28% of patients with systemic mastocytosis showed normal values. Thus the laboratory value "tryptase" does not seem to be a reliable parameter for the question of systemic involvement.
  • In addition, the determination of N-methylhistamine or 1,4-methylimidazole acetic acid in the collective urine can be performed.

Histology
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See below the different forms.

Diagnosis
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Program for adult mastocytosis (modified according to Langer and Wolff):
  • Basic program:
    • Skin function test: Urticarial dermographism (positive Darian sign for skin lesions)
    • Skin biopsy (Giemsa or toluidine blue staining; immunohistological examination with CD2, CD25 (see CD classification below); these are not expressed on normal mast cells)
    • Tryptase in serum (standard value <20µg/l; for valence see laboratory below)
    • Other: Blood count with differential blood count, platelets, coagulation status, CRP, electrophoresis, total IgE, skeletal scintigraphy
    • X-ray Thorax
    • Abdominal sonography (liver and spleen).
  • Extended basic programme (in case of justified suspicion of systemic mastocytosis):
    • Iliac crest biopsy
    • gastrointestinal examinations (endoscopy).
    • For specific differential diagnostic questions: excretion of histamine and its metabolites in 24-hour urine, 5-hydroxyindoleacetic acid excretion in 24-hour urine, catecholamine excretion in 24-hour urine
    • If necessary, genetic examination with detection of point mutations of the kit gene (see kit below).

Complication(s)
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Systemic involvement of mastocytosis (5-10% of cases): mast cell infiltration of at least one internal organ, with or without skin involvement. Most frequently affected are the skeletal system (osteolyses, osteofibrosis, especially in the skull and axial skeleton), bone marrow (anemia, leukocytosis, leukopenia, eosinophilia), lymph nodes, gastrointestinal tract (vomiting, cramps, diarrhoea), liver and spleen (hepato-, splenomegaly). The use of subtle examination techniques (several bone and liver biopsies) sometimes shows a higher involvement of internal organs in skin mastocytosis than generally assumed.

Notice! In cases of mastocytosis and insect venom allergy, specific immunotherapy (SIT) is urgently recommended for life.

Therapy
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Cave! Avoid histamine liberators (caffeine, aspirin, atropine, morphine, toxins, cold, heat, food).

External therapy
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Corticoid therapy under occlusion or intralesional injections are described for isolated mastocytomas.

Radiation therapy
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UVA1-irradiation (cold light) or PUVA-therapy, especially for urticaria pigmentosa and strong cutaneous involvement.

Internal therapy
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See below the respective clinical pictures.

  • Antihistamines possibly as a combination of H1 antagonists (e.g. once/day 1 Xusal tablet) and H2 antagonists (e.g. Tagamet 200-800 mg/day).
  • Disodium cromoglicic acid (e.g. Colimune 4 times 200 mg/day) especially in the case of gastrointestinal symptoms.
  • Ketotifen (e.g. Zaditen, 1-4 mg/day according to symptoms) simultaneously inhibits mast cell degranulation and is an H1-blocker.
  • Systemic glucocorticoids should only be used in severe cases.
  • Experimental: Masitinib; Masitinib is a drug in the group of protein kinase inhibitors (PKI), which is currently approved as a veterinary drug for a very specific type of tumor in dogs (mast cell tumors). Masi1tinib selectively inhibits the mutated form of c-kit tyrosine kinase in vitro. Such c-kit tyrosine kinase, which is permanently activated by mutations, plays a role in various proliferative processes, including mastocytosis. Masitinib also inhibits platelet growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR3). Results from a Phase III study are awaited (Lortholary O et al. 2017).

Progression/forecast
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The younger the patient and the lower the number of skin lesions, the more likely spontaneous remission is.

Solitary mastocytomas in infancy practically always regress spontaneously.

If the disease starts in adulthood, the risk of clinically manifest systemic involvement and long persistence is high.

Larger studies have shown the following prognoses for the entire population:

  1. 67%: regression
  2. 27%: Stabilization
  3. 2-9%: Progression with poor prognosis

Note(s)
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  • The designation of disseminated mastocytosis as " Urticaria pigmentosa" is historically influenced and should be abandoned. Neither is urticaria clinically impressive, nor is the "Urticaria pigmentosa" obligatory pigmented. The term "Teleangiectasia macularis eruptiva perstans" is used to describe a largely non-pigmented special form.
  • The designations "cutaneous or systemic mastocytosis" with its subforms or its classification according to types (I-IV) with indication of the respective mutation form or its absence are recommended.
  • Elevated levels of tryptase >11.4ug/l indicate mastocytosis. At these levels, the risk of an anaphylactic reaction under specific immunotherapy is 2x greater than at 4.25ug/l.

Literature
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  1. Anstey A, Lowe DG, Kirby JD, Horton MA (1991) Familial mastocytosis: a clinical, immunophenotypic, light and electron microscopic study. Brit J Derm 125: 583-587
  2. Ehrlich P (1879) contributed to the knowledge of granulated connective tissue cells and eosinophilic leukocytes. Arch Anat Physiol 3: 166-169
  3. Gobello T et al (2003) Medium versus high-dose ultraviolet A1 therapy for urticaria pigmentosa: a pilot study. J Am Acad Dermatol 49: 679-684
  4. Golkar L, Bernard JD (1997) Mastocytosis. Lancet 349: 1379-1385
  5. Grundmann SA et al (2011) Importance of serumtryptase for differentiation between systemic and cutaneous mastocytosis. Abstract CD 46th DDG-Dresden: P02/06
  6. James MP, Eady RAJ (1981) Familial urticaria pigmentosa with giant mast cell granules: a clinical, light, and electron microscopic study. Arch Derm 117: 713-718
  7. Lortholary O et al (2017) Masitinib for treatment of severely symptomatic indolent systemic ma stocytosis:
    arandomised, placebo-controlled, phase 3 study. Lancet 389:612-620.

  8. Nettleship E (1869) Rare forms of urticaria. BMJ 2: 323-324

  9. Nettleship E (1869) Chronic urticaria leaving brown stains: nearly two years duration. BMJ 2: 435
  10. Oku T, Hashizume H, Yokote R et al (1990) The familial occurrence of bullous mastocytosis (diffuse cutaneous mastocytosis). Arch Derm 126: 1478-1484
  11. Yarden Y et al (1987) Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO Journal 6: 3341-3351.

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Last updated on: 29.10.2020