Mastocytosis (overview) Q82.2

Rare, clonal disorders of hematopoietic stem cells with development of clinically heterogeneous clinical pictures characterized by mast cell proliferation in internal organs and/or (more rarely) only in the skin (cutaneous mastocytoses).

In cutaneous mastocytosis, mast cell proliferation is restricted exclusively to the skin. Cutaneous mastocytosis predominantly affects children.

In systemic m astocytosis, at least 1 extracutaneous organ is affected. It may present with or without skin manifestations. Maculopapular skin manifestations affect a high percentage of indolent systemic mastocytosis. They are largely absent in aggressive systemic mastocytosis and completely absent in (very rare) mast cell leukemia. Most patients have an activating point mutation of the KIT gene (KIT D816V). Both cell surface expression of KIT(CD117) and the mutation are not specific for mastocytosis.

Thediagnosis of "systemic mastocytosis" is made based on 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.

Secondary criteria

• Detection of atypical spindle-shaped mast cells (≥25% of all mast cells): histologically in the BM or in other extracutaneous organs or cytologically 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

Classification of mastocytoses (modified after Golkar):

• Cutaneous mastocytoses (CM/ 85-90% of cases):
  • Mastocytoma(s):
    • cutaneous mastocytoma
    • Multiple cutaneous mastocytomas
    • Diffuse cutaneous mastocytosis
  • Maculopapular cutaneous mastocytosis (Urticaria pigmentosa) = disseminated mastocytosis; 5 mastocytomas = Urticaria pigmentosa.
    • Adult cutaneous mastocytosis (maculopapular CM = MPCM)
      • Maculopapular cutaneous mastocytosis (classic type = MPCM)
      • Teleangiectasia macularis eruptiva perstans
    • Cutaneous mastocytosis of childhood
      • Maculopapular cutaneous mastocytosis (Urticaria pigmentosa) (classic type = MPCM)
      • Teleangiectasia macularis eruptiva perstans (extremely rare in childhood)
    • Special forms (old nomenclature):
      • Urticaria pigmentosa haemorrhagica
      • Exanthematic urticaria pigmentosa
      • Urticaria pigmentosa bullosa
      • Urticaria pigmentosa xanthelasmoidea
• Systemic mastocytoses
  • Indolent systemic mastocytosis (ISM) Skin lesions in 80% of cases
  • Smoldering systemic mastocytosis (SSM)
  • Isolated bone marrow mastocytosis without skin involvement
  • Systemic mastocytosis with associated haematological neoplasia (SM-AHN)
  • Aggressive systemic mastocytosis (ASM) - skin rarely affected!
  • Mast cell leukemia (< 1% of cases including the very rare mast cell sarcoma).
  • Mast cell sarcoma
  • Extracutaneous mastocytoma (benign mast cell tumor)

Classification of mastocytoses according to the type of systemic involvement:

• Type Ia: indolent mastocytosis without systemic involvement
• Type Ib: Indolent systemic mastocytosis with systemic involvement (at least involvement of one extracutaneous organ, usually BM)
• 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 BM)

Classification of mastocytoses according to C-Kit mutation profile

• Mastocytosis of childhood
  • 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

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.

The majority of adult mastocytosis patients show a point mutation of the KIT gene in codon 816. Rarer are other mutations (see under Functions of KIT). This activating mutation of the pro-oncogene c-Kit encodes a mast cell growth factor receptor, also called stem cell factor (SCF), which activates cellular proliferation while preventing 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 at codon 839 is frequently found in juvenile mastocytosis.

Bi- (or tri-) phasic age of onset:

• In about 55% of all patients, the initial symptoms are found in infancy (< 2 years of age). In childhood mastocytoses, about 90% manifest within the first two years of life; of these, 75% as maculopapular mastocytosis, 20% as mastocytomas, 5% as diffuse forms).
• In about 10% of all patients, the first symptoms occur at the age of 2-15 years.
• In about 35% of all patients the first symptoms occur in adulthood.

m:f=1:4

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.

If systemic mastocytosis is suspected, tryptase is determined according to guidelines (standard value: <20µg/l). If the value is exceeded, systemic mastocytosis is considered possible and a bone marrow biopsy and screening for further systemic involvement is aimed for. At low levels, extensive diagnostic testing is usually not performed without compelling clinical evidence. In a larger study, bone marrow histology confirmed systemic mastocytosis in 32% of patients with cutaneous mastocytosis.

The tryptase mean value of the collective with systemic involvement was 43,9±39,93µg/l (3,74-173µg/l), without systemic 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 the 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, N-methylhistamine or 1,4-methylimidazole acetic acid can be determined in the collected urine.

• 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).

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.

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

See below the respective clinical pictures.

• Antihistamines if necessary as a combination of H ₁ antagonists (e.g. 1 tablet Xusal 1 time/day) and H ₂ antagonists (e.g. Tagamet 200-800 mg/day).
• Disodium cromoglicic acid (e.g. Colimune 4 times 200 mg/day) especially for gastrointestinal symptoms.
• Ketotifen (e.g. Zaditen, 1-4 mg/day according to symptoms) simultaneously inhibits mast cell degranulation and is an_{H1 blocker}.
• Only in severe cases systemic glucocorticoids should be used.

• Experimental: Masitinib; Masitinib is a drug in the protein kinase inhibitor (PKI) group that has been approved to date as a veterinary drug for a very specific type of tumor in dogs (mast cell tumors). Masitinib 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-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR3). The results of a phase III trial are awaited (Lortholary O et al. 2017).

The younger the patient and the smaller the number of skin lesions, the more likely spontaneous remission.

Solitary mastocytomas in infancy practically always regress spontaneously.

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

In a non-classified overall population, larger studies yielded the following prognoses:

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

The designation of disseminated mastocytosis as " urticaria pigmentosa" is historically influenced and should be abandoned. Neither is urticaria clinically apparent, nor is "urticaria pigmentosa" obligatorily pigmented. The term "teleangiectasia macularis eruptiva perstans" is used to describe a largely non-pigmented special form of cutaneous mastocytosis.

It is recommended to use the names "cutaneous or systemic mastocytosis" with its subtypes or its classification by types (I-IV) with indication of the respective mutation form or its absence. It must be borne in mind that a large proportion of maculopapular mastocytoses (i.e. urticaria pigmentosa of the older nomenclature) are to be classified as systemic mastocytoses. As such, they should be included in a follow-up program.

Elevated levels of tryptase >11.4ug/l indicate mastocytosis. At these levels the risk of an anaphylactic reaction under specific immunotherapy is 2 times higher than at a level of 4.25ug/l.

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