Mastocytosis: difficulties in diagnosis and features of treatment

In recent years, the increased incidence of mastocytosis has attracted attention. It seems that cases of cutaneous mastocytosis are often not diagnosed and are recorded as other chronic skin diseases. Even with a favorable prognosis of the disease in children, the standards for its treatment remain unresolved. 

Lydia Denisovna Kalyuzhnaya,

Dermatovenereologist,

Honored Worker of Science and Technology of Ukraine, Doctor of Medical Sciences, Professor.

Mastocytosis - diagnostic difficulties and treatment standards

In recent years, the increased incidence of mastocytosis has attracted attention. It seems that cases of cutaneous mastocytosis are often not diagnosed and are recorded as other chronic skin diseases. Even with a favorable prognosis of the disease in children, the standards for its treatment remain unresolved. Mastocytosis

Hyperpigmented macules with spontaneous transition to urticaria on the skin of a 2-year-old girl were first reported in 1869 (Nettlrship E. and Tay W). It is noteworthy that only 8 years later, in 1877, Paul Ehrlich discovered and described mast cells (mastocytes). The following year, A. Sangster described a patient with severe itching, urticaria, and pigmentation, and he called these manifestations “pigmented urticaria”. PG Unna was the first to claim that with skin rashes of urticaria pigmentosa, mastocytes react to irritating factors, and this gave the right to call the disease mastocytosis. And only 60 years later, JM Ellis first described a patient with systemic mastocytosis. Approximately 55% of patients develop mastocytosis within 2 years of age, 10% – The onset of the disease occurs between the ages of 2 and 15 years. With this pathology, gender preferences are not noted, and most patients do not have a family tendency. There is a report in the literature about 70 familial cases observed, including 15 monozygotic twins (with predominantly monozygotic twins being discordant in mastocytosis).
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Manifestations of mastocytosis can appear from birth to adulthood and be limited to the skin only (most children) or affect various organs such as the bone marrow, liver, spleen, lymph nodes (in adults).

Mastocytoma as a dull spot or nodule is seen mainly in children.

1. In children, the disease has a normal course and often presents with solitary or multiple reddish-brown macules (urticaria pigmentosa) that disappear by adolescence.
2. Adults with mastocytosis either have no rash or have red-brown spots and papules 2-5 mm in diameter on the skin. In adults, the disease lasts a lifetime.
3. Most adult patients present with persistent telangiectatic macules.
4. Rubbing the lesions often results in blisters on their surface (Daria's sign), which is more common in children and depends on the density of the mast cells in these lesions.
5. In early childhood, mastocytosis may cause blisters in addition to maculopapular rashes.
6. The disease may be asymptomatic or associated with the release of mast cell mediators resulting in pruritus, brighter rash, abdominal pain, diarrhoea, hypotension, and syncope.
8. Symptoms of Mastocytosis

Both children and adults with mastocytosis can experience a complex of symptoms, sometimes affecting not only skin lesions, but also other organs. Such a variety of symptoms in the form of various physiological effects is associated with the secretion of such inflammatory mediators by mast cells as histamine, eicosanoids, and cytokines. Complaints and manifestations range from itching and inflammation to abdominal pain, diarrhea, chills, dizziness and fainting. The absence of pulmonary symptoms is usually emphasized. Complaints of fever, night sweats, vomiting, weight loss, bone pain, epigastric complaints, and thinking problems often signal extracutaneous mastocytosis. Fatal outcome associated with a sharp release of mediators from mast cells is rare, but there are isolated reports of such cases in adults, as well as among children. Symptoms of mastocytosis may be exacerbated by exercise, heat, and local trauma. In addition, the use of alcohol, drugs, salicylates and other non-steroidal anti-inflammatory drugs, anticholinergics lead to an exacerbation of the symptoms of mastocytosis. Some systemic anesthetics can even trigger anaphylaxis.

Skin manifestations of mastocytosis in children

The course of cutaneous mastocytosis in children can have three clinical forms:

- solitary mastocytoma,

- urticaria pigmentosa,

- diffuse cutaneous mastocytosis.

In children, mastocytosis predominantly begins before the age of 2 years with the appearance of flat or slightly elevated rashes above the surrounding skin. Such rashes may turn red or transform into urticaria and blisters when rubbed, after a hot bath, as a result of the use of drugs and food that promote the release of histamine (Fig. 1). Mastocytosis in children is manifested by single reddish-brown or yellow-red spots and nodes (with mastocytoma) or various from reddish-brown to brown spots and papules (urticaria pigmentosa; Fig. 2, 3). Mastocytoma can be detected already at birth or develops in infancy, it accounts for 15-20% of childhood mastocytosis. Eruptions usually appear on the distal extremities, but can have a wide variety of localization (Fig. 4).

Skin manifestations of mastocytosis in adults

Mastocytosis in adults differs significantly from mastocytosis in children. In most cases, skin manifestations in adults consist of reddish-brown spots and papules up to 1 cm in diameter. The predominant localization of these rashes is on the trunk and proximal extremities, less often – on the face, distal extremities, palms and soles (Fig. 7). These rashes tend to spontaneously resolve, but reappear over time. A rarer form in adults is the telangiectatic patchy form. The density of mastocytes in mastocytoma and in children with urticaria pigmentosa exceeds the norm by 40-150 times, and in adults – 8 times. This explains the readiness of the skin in children to respond to external factors (Daria's sign).

Skeletal disorders are observed mainly in adult patients, rarely – in children, as a rule, these are findings during radiodiagnosis. The bones of the skull, spine and pelvic bones are predominantly affected. Among adult patients with systemic mastocytosis, over 50% have diffuse bone changes and only 2% – localized. The pathology is based on diffuse demineralization followed by osteosclerosis, which eventually turns into mixed changes in the form of osteoporosis with osteosclerosis. In adult patients with mastocytosis with non-decalcified iliac bone, an increased number of mast cells was found in the biopsy, which causes changes in the cortical and trabecular part of the bone. Such data have led to the hypothesis that mast cells and their mediators are directly responsible for the skeletal abnormalities in this disease. Splenomegaly is noted in 50–60% of adult patients. Patients with mastocytosis may have gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, and vomiting. Pain is triggered by alcohol, certain types of food, stress, and stimulation of mast cell mediators. Diarrhea in patients with this pathology is episodic. With systemic mastocytosis, there may be secondary gastritis and even peptic ulcers. Of the symptoms of a violation of the nervous system, one can note such as irritability, fatigue, headache, decreased attention and motivation, limited memory for upcoming events, inability to work effectively, difficulties in communicating with other people. It is believed that these symptoms are secondary and are caused by mast cell mediators.

Classification of mastocytosis

Mastocytosis is divided into 4 types (I–IV):

type I represents the largest group, including most children and a fairly large number of adult patients. This category of patients has skin rashes, but systemic changes may also occur. With a fairly calm course of this type of mastocytosis, one or more of the following signs may be noted:

an increase in the number of mast cells in the skin;

gastric and duodenal ulcers;

secondary malabsorption caused by infiltration of mast cells in the intestine with a corresponding release of mediators;

skeletal changes as a result of an increase in the number of mast cells and their mediators;
• hemodynamic instability in the form of hot flashes and fainting;
  Mast cell infiltration of the bone marrow, liver, spleen and lymph nodes.
  
  in type II, mastocytosis is associated with hematological diseases, when skin involvement is by no means necessary. Typically, these patients are affected by the liver, spleen and lymph nodes. We are talking about older patients, and the leading symptoms are fever, weight loss, general malaise, hot flashes, and gastrointestinal phenomena. Hematological associations include: polycythemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, idiopathic myelofibrosis, lymphoma, hypereosinophilic syndrome. There may also be secondary myeloblastic or myelomonocytic leukemia. Along with hematological changes in the material of the bone marrow, the number of mastocytes was increased. The prognosis in such cases depends on the severity of the hematological disease;
  
  type III mastocytosis is rare, characterized by the predominant absence of clinical symptoms from the skin. Mast cell infiltrates are located in the bone marrow, digestive tract, liver, spleen, and lymph nodes. A lethal outcome with such mastocytosis occurs after 2–4 years;
  
  Type IV mastocytosis (mastocytic leukemia) is also rare. In these cases, 10% of the nuclear cells in the blood are represented by mast cells. It should be noted that single mast cells in the blood are extremely rare, so their appearance should alert. Most of these patients have no skin manifestations. The clinical picture of this form is characterized by fever, weight loss, abdominal pain, diarrhea, nausea and vomiting. 
• Diagnosis of mastocytosis
The diagnosis of mastocytosis can be confirmed by the detection of mast cells in one or more organs. With mastocytosis of the skin, a mastocytic infiltrate is detected pathohistologically in the affected areas. The study is carried out by staining the preparation with toluidine blue (according to Giemsa and Leder) or by an immunohistochemical method using monoclonal antibodies to tryptase or CD117. In systemic mastocytosis, regardless of symptoms, an elevated serum level of alpha-tryptase is noted.

In patients with systemic mastocytosis or with widespread skin manifestations, the level of histamine and its metabolites in the daily urine is increased. It should be alarming that 18% of children with urticaria pigmentosa have mast cell infiltration in bone marrow biopsy. Undoubtedly, such patients should be given special attention in terms of eliminating precipitating factors and monitoring their condition until adolescence. It should be noted that in half of the sick children the process is resolved spontaneously in adolescence, and in a quarter – in an adult. Yet 5% of children still have systemic mastocytosis.

Treatment of mastocytosis

First of all, patients should be alert to factors leading to mast cell degranulation (alcohol, anticholinergics, aspirin and other non-steroidal anti-inflammatory drugs, drugs, polymyxin B). It should be emphasized that heat and friction of the elements of the rash can provoke the appearance of local and systemic symptoms and should be excluded from the daily life of such patients, if possible. It is necessary to warn people with this pathology about the risk of exacerbation when bathing in hot water, when rubbing the skin with a washcloth, when wearing tight clothes. Patients should avoid exposure to extreme ambient temperatures at all costs. By the way, in patients with mastocytosis, the use of anesthetics (including lidocaine) is also at risk.

Histamine receptor antagonists are effective in relieving symptoms, representing in fact a symptomatic therapy for exacerbations. There are reports of the effectiveness of PUVA therapy 4 times a week. The use of topical corticosteroids for 6 or more weeks relieves the sensation of itching for a long time (up to 12 months). In a situation of extremely sharp exacerbation, systemic corticosteroids are used, as well as an urgent adrenaline injection.

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