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Mastocytosis: A disease of Mast Cells

 

What are Mast Cells ?

Mast cells belong to the family of ´white blood cells´ most of which are produced in our bone marrow. The mast cell was first discovered and described by Paul Ehrlich in 1876. In contrast to most other bone marrow-derived cells, mast cells are not found in the peripheral blood, but are located in the tissues where they reside for many months or even years. Like most white blood cells, mast cells belong to the immune system that helps in the body´s defence against bacteria and other microbes. As part of an alarm system, mast cells can respond very rapidly to foreign attacks of microbes by releasing potent vasoactive and defence-related molecules into the tissues in local areas. These chemical mediators are released from mast cells systemically in our body during a severe allergic reaction which may result in the clinical picture of anaphylaxis. One of the most important chemical mediators of mast cells is histamine, which can cause tissue swelling (edema), itching, flushing, and redness of our skin, but also headache, nausea, dizziness, or diarrhoea. Histamine can also augment other gastrointestinal problems or be involved in ulcerative diseases of the gastrointestinal tract (like gastric ulcer). Finally, histamine is a ´neuroactive´ mediator and can influence the blood pressure. Apart from histamine, mast cells also produce numerous other chemical substances and cytokines.

 

Who Discovered Mastocytosis ?

Mastocytosis was first described by Nettleship and Tay as a "Rare form of Urticaria" in the British Medical Journal in 1869. It then took until 1949 when Ellis discovered involvement of internal organs in mastocytosis in an autopsy case. About ten years earlier, the term mastocytosis had been created. In 1957, a first description of mast cell leukemia was presented. During the last few decades, the knowledge of scientists about mastocytosis has increased dramatically. A first classification of the disease was introduced by Lennert in the mid-70ths of the past century. In 1991, a first consensus classification was proposed by Metcalfe. Between 1991 and 2000, many relevant cellular, molecular, and biochemical defects resulting in mastocytosis were discovered. It turned out that at least in systemic variants of mastocytosis, the accumulating mast cells are monoclonal (= neoplastic) in nature. In the year 2000, the consensus classification was refined and updated by introducing a catalog of disease-criteria. In the year 2001, the WHO adopted both the criteria and the classification. Based on the notion that mast cells derive from myelopoietic progenitor cells and mastocytosis often behaves as a myeloproliferative disorder, the WHO has introduced mastocytosis as a clonal hematopoietic disease in their classification of blood cell disorders.

 

What is Mastocytosis ?

Mastocytosis is a disease that is characterized by abnormal growth and accumulation of mast cells in i) the skin, ii) in internal organs, or iii) in both skin and internal organs. As a result, mastocytosis is a disorder with presence of too many mast cells (extra mast cells) in a person's body. Both children and adults can develop mastocytosis. Traditionally, mastocytosis is classified as being either cutaneous mastocytosis (CM) or systemic mastocytosis (SM). In cutaneous mastocytosis, mast cell accumulation is only found in the skin. To diagnose CM, a biopsy of affected skin has to be performed. The pure cutaneous form of mastocytosis is usually diagnosed in (early) childhood. By contrast, most patients in adulthood are diagnosed to have systemic mastocytosis. Most of the adult patients have typical skin lesions commonly termed urticaria pigmentosa. Since the bone marrow is almost always involved in these patients (but not in those with CM), the diagnosis of systemic mastocytosis in adults is usually established by a biopsy of the bone marrow. In the rare patients without skin lesions, it may take a longer time until the doctors consider a systemic mast cell disease as a diagnosis, and thus it may take a longer time until the final diagnosis SM can be established.

Systemic mastocytosis (SM) is a disease that arises on the basis of i. enhanced development of mast cells from their progenitor cells in one or more organs and (plus) ii. enhanced accumulation of these mast cells in the respective tissue(s). In contrast to a reactive mast cell hyperplasia (increase in mast cells during an inflammation, cancer, or fibrosis), mast cells in systemic mastocytosis (SM) are monoclonal in nature, i.e. derived from a single abnormal (= neoplastic) cell (clone). In cutaneous pediatric mastocytosis, the nature of mast cell-accumulation has not yet been entirely clarified. In some of these patients, mast cells also appear to be monoclonal in nature.

Monoclonality of mast cells in mastocytosis can be documented best by demonstrating the presence of a point mutation in the c-kit proto-oncogene. In the majority of all patients with systemic mastocytosis, the somatic c-kit mutation D816V (Asp-816-Val) is detected in the bone marrow, and often also in lesional skin (where mast cells reside in macules). In a smaller group of patients with systemic mastocytosis, the mutation can also be found in circulating (peripheral) white blood cells. By contrast, in cutaneous mastocytosis, the c-kit mutation D816V is usually not detectable in any organ. 

The natural clinical course of mastocytosis is variable depending on age, organs involved, subtype of disease, other co-existing disorders (like allergies or other clonal myeloid disorders), and the response to therapy. The majority of all patients have a normal life-expectancy. In pediatric mastocytosis (cutaneous mastocytosis in most cases), the disease often (but not in all cases) resolves during, shortly before, or shortly after puberty.

 

Is Mastocytosis a Hereditary or Contagious Disorder ?

Mastocytosis is a non-contagious disease of mast cells and their progenitor cells. In the vast majority of all cases, no other family members are affected or will develop mastocytosis during life. Familial mastocytosis is an extremely rare disorder with an estimated frequency of less than 1:1,000 among all patients with mastocytosis.


Subtypes of Mastocytosis

There are number of different subtypes (variants and subvariants) of mastocytosis. The WHO discriminates between the following major disease-categories (see PubMed):

 

  • Cutaneous Mastocytosis (CM)

  • Indolent Systemic Mastocytosis (ISM)

  • SM with Associated Clonal Hematologic Non-Mast Cell-Disease (SM-AHNMD)

  • Aggressive Systemic Mastocytosis (ASM)

  • Mast Cell Leukemia (MCL)

  • Mast Cell Sarcoma

  • Extracutaneous Mastocytoma

 

Cutaneous mastocytosis usually develops in early childhood, whereas in adulthood the mast cell disease usually turns out to be a systemic variant of mastocytosis. Most adult patients have indolent systemic mastocytosis = ISM. All other subvariants of mastocytosis (SM-AHNMD, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, extra-cutaneous mastocytoma) are rarely diagnosed.  

Most pediatric patients with CM have a benign and often self-limited clinical course. The disease often regresses spontaneously during puberty (see above). Aggressive disease variants usually do not develop in children.

There are some unique aspects in skin lesions developing in childhood mastocytosis. For example, blistering of skin lesions are only seen in pediatric mastocytosis. Diffuse cutaneous involvement (= Diffuse Cutaneous Mastocytosis) also occurs exclusively in children. The same holds true for Mastocytomas of Skin, which are solid benign mast cell tumors. In general, the prognosis of childhood mastocytosis is very good. The following subvariants of CM have been described:

- Urticaria Pigmentosa (UP) = Maculopapular Cutaneous Mastocytosis

- Diffuse Cutaneous Mastocytosis (DCM)

- Mastocytoma of Skin

At the time of diagnosis, the natural clinical course of CM in children is unpredictable. The following can be found: i. spontaneous regression (frequently seen), ii. persistence of CM into adulthood (very rare), and iii. persistence into adulthood with ´evolution´ to SM (rare). Evolution to a ´high-grade´ mast cell disease (aggressive mastocytosis or mast cell leukemia) has not been reported so far.

The natural clinical course of systemic mastocytosis (SM) is also variable. Most patients are adults at diagnosis and have ISM with a good prognosis and normal or near-normal life expectancy. Aggressive disease variants are rarely diagnosed. These categories include mast cell leukemia and aggressive systemic mastocytosis. In these patients, the prognosis is grave. Especially in patients with mast cell leukemia, where mast cells can be found in the peripheral blood, the disease has an unfavorable outcome. In almost all of these patients, skin lesions are absent.

In SM-AHNMD, both the SM component and the AHNMD component of the disease have to be subclassified. The SM may be ASM or ISM depending on clinical presentations. The AHNMD often is a myeloid leukemia or a myelodysplastic syndrome (MDS). The prognosis in patients with AHNMD often depends on the type of AHNMD. In case of an acute (myeloid) leukemia, the prognosis is unfavorable.

Localized (non-cutaneous) mast cell tumors (mastocytomas, mast cell sarcoma) are also rare. The natural clinical course and prognosis of mastocytomas is good. By contrast, mast cell sarcoma, an extremely rare tumor, often evolves into mast cell leukemia and has an unfavorable prognosis (similar to mast cell leukemia).

An important aspect in disease-heterogeneity of mastocytosis are mediator-related symptoms (SY). These symptoms can occur in any subvariant of CM and SM, and can represent a major clinical problem. The respective symptoms can range from mild and tolerable to repeated life-threatening episodes of hypotension and shock (see below).  

 

How is Mastocytosis Diagnosed ?

In each case, the doctor will first perform a careful physical examination including a thorough inspection of the skin surface. The diagnosis of mastocytosis is based on a histological examination of the affected organ as well as pre-invasive (done before biopsy) and post-biopsy tests. Common preinvasive tests are routine laboratory parameters and the serum tryptase level, a special screen-test for patients with mastocytosis. For these examinations, the doctor asks the patient to donate a few mililiters of peripheral venous blood. If the serum tryptase level is elevated, the likelihood of systemic mastocytosis is high (although elevated serum tryptase is not absolutely specific for SM). A skin biopsy is recommended in all cases of suspected mastocytosis and visible skin infiltrates (macules, maculopapular lesions). A bone marrow biopsy is required in suspected systemic mastocytosis. In adult-onset disease, a thorough bone marrow examination is always recommended. In children, the bone marrow biopsy is not required in most cases – i.e. most patients have a normal tryptase level so that the likelihood of SM is very low.

The histology of the skin or the bone marrow (or both) can show typipcal mast cell infiltrates leading to the diagnosis of (systemic or cutaneous) mastocytosis. In addition, the biopsy (histology) can give information about the subtype of the disease. From the bone marrow aspirate, additional important information is obtained including the mast cell phenotype, presence of a c-kit mutation, or presence of an unrelated clonal hematologic non mast cell lineage disease (AHNMD).    

The WHO Consensus Classification discriminates between major and minor criteria to diagnose Systemic Mastocytosis with certainty (SM criteria, see: see PubMed). These criteria include the histology of the bone marrow or of another extracutaneous organ (major), abnormal mast cell cytology (minor), expression of CD2 and/or CD25 on bone marrow mast cells (minor), presence of c-kit mutation at codon 816 in the bone marrow or in another extracutaneous organ (minor), and an elevated serum tryptase level, i.e. >20 ng/ml (minor). If one major and one minor or at least three minor criteria are fulfilled, the diagnosis SM can be established. Details regarding the classification and diagnostic criteria have been published by the WHO. see: classification and ICD-code).

 

What are the Symptoms in Mastocytosis ?

Symptoms of mastocytosis can occur from

i.  Release of chemical mediators from mast cells = mediator-related symptoms (SY)       

or from

ii. Aggressive infiltration of organs/tissues by mast cells with consecutive impairment of organ function


Mediators and chemical compounds produced and released by mast cells include a number of vasoactive, coaguloactive, and immunoregulatory molecules such as histamine, heparin, tryptases, prostaglandins, cytokines, interleukins, and many more. These mediators can cause headache, osteoporosis, bone pain, nausea, itching, diarrhoea, abdominal discomfort and cramping, an ulcerative disease of the stomach, hypotension, and even severe anaphylactoid reactions with shock. These symptoms can occur in any type of mastocytosis, and at any time during the course of disease. In some patients, symptoms are very mild, whereas in others, they are severe and require continuous medicines and sometimes immediate therapy, i.e. in anaphylaxis.

What is anaphylaxis: anaphylaxis results from massive and sudden release of  mediators from mast cells. In small children, unresponsiveness and flaccidity may be the only signs. Older children and adults may feel light-headed due to a drop of the blood pressure. Other signs include breathing problems, dizziness, swelling of the tongue and lips, flushing, and severe hypotension. Triggers leading to anaphylaxis may not be very obvious although sometimes anaphylaxis may follow bee or wasp stings. It is therefore recommended that the patients or/and parents familiarize themselves with the use of epinephrine injectors and keep them accessible at all times.

What are B-Findings: B-Findings (hypercellular bone marrow, dysplasia, organomegaly, high mast cell infiltration grade in the bone marrow, high serum tryptase level) are reflective of involvement of several myeloid cell lineages in the disease process (spread of the defect into various bone marrow lineages) or a massive increase in the number of mast cells without impairment of organ function (= no C-Finding). B-Findings reflect a borderline (smouldering) state with uncertain clinical course for the future, whereas C-Findings are always an alarming sign and a possible indicator for required therapy using cytoreductive agents.

What are C-Findings: Usually, mast cell infiltrations in the bone marrow or in other organs do not impair the physiologic function of the organ. Such impairment of organ function by mast cell infiltration is only seen in the rare aggressive variants of mastocytosis (aggressive systemic mastocytosis,  mast cell leukemia, mast cell sarcoma, some patients with SM-AHNMD).

Respective clinical findings are termed C-Findings. They include a decrease in blood cells resulting from an impaired bone marrow function (anemia: weakness, shortness of breath, headache, .. or leukocytopenia: neutropenic infections, thrombocytopenia: bleeding), fractures of bones caused by local mast cell infiltrates (osteopenia and osteolysis), wheight loss, or other clinical symptoms. In patients with aggressive mast cell disorders, one or more C-Findings may be detected.

Effects of mediators are neither called B- nor C-Findings. 

Note:    B-Findings = Borderline Benign

            C-Findings = Consider Cytoreduction or Chemotherapy

 

How is Mastocytosis Treated ?

There are three important ways of treating mastocytosis: i. prophylaxis and avoidance of triggering factors, ii. anti-mediator-drugs, and iii. cytoreductive therapies.

In many patients with mastocytosis, no symptoms occur - and thus no therapy may be required. Prophylactic anti-histamines has been proposed for such patients in some textbooks. In fact, prophylactic antihistamines may help to prevent histamine-related symptoms and disorders (like ulcerative stomach disease) even if no such symptoms have occurred before.

Another important aspect is the identification and avoidance of triggering factors = factors that may induce a severe anaphylactoid reaction. Because mastocytosis is a very heterogenous disease with divergent responses to triggering agents (i.e., what may trigger a reaction of mast cells in one person, may be harmless to someone else), it is very important for the patient to identify all potential triggers and to avoid them. Triggers can include allergens, insects, food, specific ingredients, environmental factors, friction, and also emotional stress. Once a patient is aware of the specific triggers that cause mast cells to degranulate, avoiding those triggers becomes part of the treatment plan.

The following list provides a summary of most frequently reported triggers in mastocytosis:

  • Drugs - examples: amphotericin B, quinine, anaesthetics such as   tetracaine, procaine, morphin, or methylparaben preservative, codein, d-tubocurarine, metocurine, etomidate, thiopental, acetyl-salicylic acid (aspirin), succinylcholine, enflurane

  • Insect- and other venoms (bee, wasp, snake, jellyfish, ...)

  • Physical: Exercise, Heat, Cold, Friction, Sunlight

  • Alcohol

  • Foods and food additives / preservatives: hot foods, spicy foods

  • Emotional stress

  • Some bacterial and viral infections

  • Allergens (all kinds of)

Two important aspects are anaesthesia and allergy. In case of a known allergy, the (suspected) allergen must be strictly avoided. Before surgery, the doctors (i.e. both the surgeon and anaesthesiologist) should know that you are suffering from mastocytosis. The anesthesia should be adjusted to the presence of mastocytosis in each case. A preoperative intradermal skin test to predict the patients who may develop reactions to the respective drug has been recommended by some authors.


A number of anti-mediator-type drugs are prescribed for patients with mastocytosis. The most commonly used drugs are anti-histamines i.e. histamine receptor antagonists. Two major groups of antihistamines are available, i.e. H1 and H2 receptor antagonists.

H1 antihistamines are drugs that are used to treat the symptoms of itching, hiving, and flushing. It can also bring some relief to gastrointestinal symptoms. Examples of H1 antihistamines are hydroxyzine, cetirizine, loratadine, or diphenhydramine.

H2 antihistamines are drugs that relieve gastrointestinal symptoms associated with mastocytosis. These are ulcer or reflux medications. Examples of H2 antihistamines include ranitidine and famotidine.

In addition to antihistamines, a number of other drugs are also used in patients with mastocytosis to ameliorate mediator-related symptoms. These drugs include glucocorticosteroids, so called mast cell stabilizers (like cromolyn sodium – may be used to treat diarrhea), or ketotifen, which is also a potent H1 antihistamine.

Another antimediator-type drug is epinephrine which helps during most severe anaphylactoid reactions with hypotension and shock. According to recommendations in several textbooks, all mastocytosis patients should carry emergency medicines with them including an epi-pen. An epi-pen is used in case of emergency to treat a patient who is in anaphylactic shock. For more information concerning the Epipen see: Epipen Auto-Injector® http://www.allerex.ca/epi.htm.

In each case, the treatment of mediator-related symptoms needs to be individualized by a physician who will do so according to the symptoms reported by patients. In general, the treatment is aimed at controlling symptoms with H1 and H2 anti-histamines alone (without other drugs). However, if required the doctor will prescribe additional drugs such as a corticosteroid, proton pump inhibitor, or others.

Use of cytoreductive drugs: A number of cytoreductive drugs are used to counteract growth of neoplastic mast cells in patients with aggressive mastocytosis or mast cell leukemia. These drugs are not prescribed in patients with indolent systemic mastocytosis or cutaneous mastocytosis. Cytoreductive drugs include interferon-alpha, cladribine (2CdA), cytosin arabinoside, hydroxyurea, and many more. In very severe cases, polychemotherapy may be required. All these drugs should be prescribed only by an experienced hematologist/oncologist who knows mastocytosis and is familiar with respective therapies. Despite increased knowledge about mastocytosis and the development of new therapies, mastocytosis remains an incurable disease. Therefore, the benefit of a cytoreductive therapy has to be balanced against side effects and the overall quality of life in each patient. Another important issue is the mutagenic potential of some of the cytoreductive drugs. Therefore, the use of these agents in indolent mastocytosis should be avoided.

Corticosteroids are sometimes used to manage C-Findings in patients with aggressive mastocytosis (in those with malabsorption or ascites). Usually, the glucocorticoid is combined with interferon-alpha. Corticosteroids and interferon-alpha act cytoreductive on mast cells, but are not considered to be mutagenic agents because almost the same molecules are produced in our bodies (at low baseline production rates).

Special forms of therapy: These include surgery of mastocytomas, surgery of the spleen (i.e. removal of the spleen in case of a massively enlarged organ with consecutive cytopenia or another clinical problem), or the use of bi-phopsphonates (in case of severe osteoporosis or osteopenia). PUVA (psoralen plus ultraviolet A) is often used to fade pigmented skin lesions. Usually, repetitive cycles of PUVA are required since treatment responses are merely transient in most patients.

Finally, it is important for the patient and for the doctors to have good communication and to work cooperatively on the goal to achieve the best possible control of disease.


Appendix - Anesthesia Information for Patients and Doctors:

For information about perioperative considerations and anaesthesia in patients with mastocytosis look up the published literature: link ´Literature´ in this homepage & PubMed (major scientific database): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi