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What Is Aggressive Mastocytosis?

Aggressive Mastocytosis

Mastocytosis is a rare disorder characterized by abnormal accumulations of mast cells in the skin, bone marrow, and internal organs (liver, spleen, gastrointestinal tract and lymph nodes). Cases beginning during adulthood tend to be chronic and involve the bone marrow in addition to the skin, whereas, during childhood, the condition is often marked by skin manifestations with no internal organ involvement and can often resolve during puberty.

In most adult patients, mastocytosis tends to be persistent, and may progress into a more advanced category in a minority of patients. Mastocytosis can be classified to a specific type depending on the patient’s symptoms and overall presentation.

Synonyms of Mastocytosis

  • systemic mast cell disease
  • systemic mastocytosis

Subdivisions of Mastocytosis

  • cutaneous mastocytosis
  • indolent systemic mastocytosis
  • systemic mastocytosis with clonal hematologic non-mast cell lineage disease
  • systemic smoldering mastocytosis
  • aggressive systemic mastocytosis
  • mast cell leukemia
  • mast cell sarcoma

Signs & Symptoms

Cutaneous mastocytosis

The skin is the only site of involvement in cutaneous mastocytosis. Urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis) lesions are small, brownish, flat or elevated spots that may be surrounded by reddened, itchy skin when scratched and is known as Darier’s sign. These lesions tend to be more apparent on areas of skin exposed to pressure or rubbing. When skin lesions begin during childhood, the skin tends to be the only affected organ. Blistering of the skin lesions is seen exclusively in children younger than four years of age.

Based on clinical appearance, prognosis, and disease course, cutaneous mastocytosis can be further categorized into the following: maculopapular cutaneous mastocytosis, mastocytoma, and diffuse cutaneous mastocytosis. Maculopapular cutaneous mastocytosis and mastocytoma are the most common forms, compared to diffuse cutaneous mastocytosis which is rarer.

What Is Aggressive Mastocytosis?

 A mastocytoma is a single lesion that is usually found early in life and resolves spontaneously with age. Diffuse cutaneous mastocytosis (DCM) is seen in children and is the most severe form of cutaneous mastocytosis. The skin is diffusely thickened and discolored, generally without individual distinct lesions. Additional symptoms associated with DCM include itching, blistering, decreased blood pressure (hypotension), diarrhea, gastrointestinal bleeding, reddening of the skin (flushing), and anaphylactic shock.

Indolent systemic mastocytosis

Systemic mastocytosis is the main form of mastocytosis observed in adults whereas it is rarer in children. Systemic disease is defined by demonstration of pathologic accumulation of mast cells in a tissue other than skin (most commonly bone marrow). Indolent systemic mastocytosis is generally associated with low mast cell burden, and presence of mediator-related symptoms. Most patients also have maculopapular skin lesions.

Some patients may present with an enlarged liver or spleen and the gastrointestinal tract may also be affected. Life expectancy in ISM is comparable to general population with low risk of progression to a more advanced form.

Systemic smoldering mastocytosis

This variant of systemic mastocytosis is characterized by high mast cell burden as evidenced by high level of tryptase (>200 ng/ml) and high degree of bone marrow involvement with mast cells (>30%), splenomegaly with or without mild abnormalities in production of other blood cells. Patients with SSM may have a higher likelihood of progressing to an advanced disease category below.

Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease

Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease affects approximately one-fifth of all systemic mastocytosis cases. Myeloproliferative and myelodysplastic disorders are the most common diseases associated with this form and often patients do not display urticaria pigmentosa-like skin lesions.

Aggressive systemic mastocytosis

In aggressive systemic mastocytosis, there is an impairment or loss of organ function (usually liver, gut, bone or bone marrow) due to mast cell infiltrates.

Mast cell leukemia

Mast cell leukemia is an aggressive hematological malignancy characterized by circulating mast cells greater than 10% or immature mast cells in bone marrow aspirates greater than 20%. This condition is rare; however, it is associated with the worst prognosis among all mastocytosis varieties.

Mast cell sarcoma

A mast cell sarcoma is a single tumor composed of abnormal mast cells invading the tissue. This condition is very rare and often is not associated with additional skin involvement. More aggressive forms of mastocytosis, mast cell leukemias and mast cell sarcomas are very rarely encountered.

The severity of the symptoms associated with mastocytosis may vary from mild to life-threatening. In general, symptoms occurring in mastocytosis are mainly due to the release of chemicals from the mast cells and thus produce symptoms associated with an allergic reaction.

Flushing and gastric acid hypersecretion due to mast cell-associated histamine release are common symptoms. Heartburn, stomach aches, abdominal discomfort and diarrhea may occur. The liver, spleen and lymph nodes may become enlarged in some patients; therefore regular follow-up is necessary. Bones affected by mastocytosis may become softened (osteoporosis) and deteriorate, although some new bone growth may occur with thickening of the outer portions or spongy inner areas of the bones. In aggressive systemic mastocytosis, a decrease in blood cells (cytopenia), break-down of bones (osteolysis), swelling of the lymph nodes (lymphadenopathy), swelling of the liver (hepatomegaly), impaired liver function, ascites or portal hypertension, and malabsorption, may also occur.

Massive chemical release from the mast cells (degranulation) may lead to life-threatening episodes of anaphylaxis (anaphylactic shock). The most common triggers include, but are not limited to, certain foods, insect stings, physical stress (heat, cold, mechanical irritation of the skin), emotional stress, alcohol, and medications, including aspirin and non-steroidal anti-inflammatory drugs (NSAIDS), narcotics, muscle relaxants, radiocontrast material, among others.

These are similar in nature to severe allergic reactions and may involve decreased blood pressure (hypotension), increased heart rate and loss of consciousness. Recent studies have found that up to 10% of patients with severe allergic reactions to bee stings may have mastocytosis. Additional non-specific symptoms that can be seen with mastocytosis include pain, nausea, headache, and/or malaise. Patients with an associated hematologic disorder may have symptoms of that disorder such as fatigue and weight loss.

Causes

Genetic alterations (mutation) resulting in the over-activation of the receptor for mast cell growth factor (KIT) have been identified in the abnormal mast cells in almost all adult-onset mastocytosis and approximately 80% of children in skin lesions. The most common c-kit mutation in mastocytosis is D816V and is believed to cause the abnormal proliferation and accumulation of mast cells in tissues. Approximately >90% of adults and 40% of children also express this mutation whereas another 40% of children have mutations involving other areas of KIT.

Prognostic significance of the type of mutation in childhood disease is yet to be determined. The mutations are somatic in nature and therefore are not passed on to the next generation in most patients.

The release of mediators produced by mast cells, such as histamine, heparin, chemokines, cytokines, leukotrienes and prostaglandin D2, among other cellular mediators, results in symptomatic episodes. Histamine is a natural chemical released during an allergic event that causes itching, wheezing, dilation of blood vessels, and hypersecretion of stomach acid.

Diagnosis

Findings on blood studies may include the following:

  • Anemia (45% of patients)
  • Thrombocytopenia
  • Leukocytosis
  • Some patients have eosinophilia, basophilia, thrombocytosis, and monocytosis
  • The combination of anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts (>5%) portends a poor prognosis

Measurement of serum tryptase may reveal the following:

Total serum tryptase levels of 20 ng/mL or higher in a baseline serum sample with a total–to–beta-tryptase ratio greater than 20:1

Serum tryptase levels of 11.5 ng/mL or higher (the cut-off value used in more recent studies) are found in more than 50% of patients

The following imaging studies may be necessary to identify the extent and stage of the disease:

  • GI radiography, ultrasonography, and liver-spleen computed tomography scanning in patients with abdominal pain
  • Skeletal surveys and bone CT scanning in patients with suspected bone involvement
  • Diagnostic procedures are as follows:
  • Bone marrow aspiration and biopsy are essential
  • GI procedures (eg, barium studies, endoscopy) are indicated for patients with GI symptoms
  • Liver biopsy can show mast cell infiltration in patients with hepatomegaly
  • Skin biopsy may be warranted in patients with cutaneous manifestations

The major diagnostic criterion for systemic mastocytosis is the presence of dense infiltrates of mast cells in bone marrow or other extracutaneous tissues. Mast cells should be seen in aggregates of 15 or more.

Major criteria may be absent in early disease. In this situation, the minor criteria are used to make the pathologic diagnosis.

Three of the following four minor criteria are required to make the diagnosis:

  • Atypical mast cell morphology in 25% or more of the mast cells
  • Expression of CD2 and/or CD25 in addition to normal mast cell markers
  • Serum/plasma tryptase levels greater than 20 ng/mL
  • A codon-816 c- kit mutation in peripheral blood, bone marrow, or involved tissue

Types of mastocytosis (World Health Organization criteria) are as follows:

Cutaneous mastocytosis

Indolent systemic mastocytosis (systemic mast cell disease)

Systemic mastocytosis with associated clonal hematologic non–mast cell lineage disease

Aggressive systemic mastocytosis

Mast cell leukemia

Mast cell sarcoma

Extracutaneous mastocytoma

Management

Therapy for systemic mastocytosis is primarily symptomatic; no therapy is curative. Treatment modalities include the management of the following:

Anaphylaxis and related symptoms

Pruritus and flushing

Intestinal malabsorption

Agents for symptomatic relief include the following:

Epinephrine is used in acute anaphylaxis

H1 and H2 receptor blockers are used to control anaphylactic symptoms

Corticosteroids have been used to control malabsorption, ascites, and bone pain and to prevent anaphylaxis

Cromolyn is helpful for decreasing bone pain and headaches and for improving skin symptoms

Patients with osteopenia that does not respond to therapy may receive a trial of interferon alfa-2b

First-generation histamine H1 antagonists (eg, diphenhydramine, hydroxyzine) have been used to treat pruritus and flushing

Histamine H2 antagonists and proton pump inhibitors have been used to treat gastric hypersecretion and peptic ulcer disease

Aspirin can be used when H1 and H2 receptor blockers do not prevent vascular collapse

Mast cell stabilizers (eg, ketotifen) have been used to treat pruritus and whealing

Leukotriene antagonists (eg, zafirlukast, montelukast) have been used

Cromolyn is helpful for decreasing bone pain and headaches and for improving skin symptoms

Psoralen ultraviolet A therapy may provide transient relief of pruritus and may cause fading of skin lesions

Anticholinergics have been used in the treatment of diarrhea

Disodium cromolyn has been used in the treatment of abdominal cramping and diarrhea

Chemotherapy has not been particularly successful in the management of systemic mastocytosis, but the following regimens have been tried :

Interferon-alfa may be beneficial, especially in patients with aggressive systemic mastocytosis

2-Chlorodeoxyadenosine (cladribine [Leustatin])

Thalidomide in advanced disease

Imatinib mesylate (Gleevec) in patients who do not have mutations of the codon 816 on the c- kit gene and carry the wild-type kit, or who carry the FIP1L1-PDGFRA rearrangement [10]

Midostaurin (Rydapt) is approved by the FDA for aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL), collectively referred to as advanced systemic mastocytosis

Related Disorders

Symptoms of the following disorders can be similar to those of mastocytosis. Comparison may be useful for a differential diagnosis:

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is associated with an abnormal immune response to the natural bacteria in the gastrointestinal tract. Patients may experience weight loss, abdominal cramping and pain, nausea and vomiting, fatigue and irregular bowel movements. Diagnosis of IBD is often based on symptoms which can include increased heart rate (tachycardia), decreased red blood cell count (anemia) leading to fatigue, dehydration, and fever.

There are various tests and imaging studies that can be done to confirm a diagnosis and can include: complete blood count, serologic testing, stool studies, nutritional evaluation, colonoscopy, abdominal ultrasound and other gastrointestinal imaging studies.

Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) is a gastrointestinal disorder associated with abdominal discomfort, altered bowel patterns, and, in some cases, inflammation of the gastrointestinal tract. Patients with IBS may experience heartburn, nausea and vomiting, presence of clear or white mucus, abdominal pain, as well as presence of constipation or diarrhea.

Patients may also experience abdominal distention, which can be confirmed on an abdominal CT scan. Specific criteria on diagnosis IBS exists based on the frequency and duration of patient’s symptoms. Criteria for IBS diagnosis requires that patients have had recurrent abdominal pain or discomfort at least three days per month during the past three months associated with two or more of the following: relieved by defecation; onset associated with change in stool frequency; and/or onset associated with change in stool form or appearance. In order to establish a diagnosis of IBS, a physical exam and laboratory and radiographic studies may be performed to rule out any other causes.

Malabsorption

Malabsorption is inclusive of any condition associated with abnormalities occurring during digestion and/or absorption of food nutrients. Patients may experience diarrhea and weight loss; however, more characteristic symptoms are often based on the specific cause.

Various tests can be performed to identify the cause and can include blood tests, electrolytes and chemistry panel, and serologic testing. However, no specific test exists for malabsorption. Treatment for malabsorption consists of correcting any nutritional deficiencies as well as treating the causative condition.

Myeloproliferative Disease

Myeloproliferative diseases are a group of disorders associated with proliferation of one or more distinct cell lines. Patients can experience fatigue, weight loss, abdominal discomfort, easy bruising or bleeding, infections, as well as other symptoms. A specific diagnosis can be based on laboratory studies (i.e. complete blood counts, leukocyte alkaline phosphatase score, polymerase chain reaction assay, serum uric acid level, red blood cell mass) and bone marrow biopsies, which would reflect a change in blood cell counts. Management of the myeloproliferative disease depends on the specific cause. Patients with chronic myelogenous leukemia can be treated with a number of chemotherapeutic agents. In comparison, treatment is targeted at supportive care for patients with polycythemia vera, essential thrombocythemia, and myelofibrosis. Chronic eosinophilic leukemia is characterized by increased eosinophils carrying genetic alterations in blood and bone marrow and is often associated with increased mast cells.

Urticaria

Urticaria is a condition of the skin associated with red, elevated patches of the skin that can be itchy and irritating to touch and more commonly referred to as hives. Urticaria is often an isolated event not associated with other systemic symptoms or findings. Often times urticaria is self-limiting and of short-duration. Skin lesions can last for 20 minutes up to three hours disappear and then reappear within a 24-48 hour period.

New-onset urticaria is often associated with an identifiable cause such as direct contact and can be identified from the patient’s history. Often times, urticaria can be confused with other dermatologic conditions. However, based on the characteristic appearance of urticaria (i.e. itchy red raised skin lesions) a diagnosis can be made. Treatment of urticaria often includes antihistamine agents.

Endocrine disorders

Endocine tumors such as carcinoid, pheocromocytoma and medullary throid cancer can cause flushing. Postmenapausal flushing is usually brief in duration and is associated with sweating.

Monoclonal mast cell activation syndrome

These patients have symptoms of mast cell activation including recurrent anaphylaxis but no evidence of cutaneous mastocytosis. Their bone marrow biopsy shows 1 or 2 minor criteria for systemic mastocytosis, but does not fulfill the complete World Health Organization (WHO) criteria (See diagnosis section below).

Idiopathic mast cell activation syndrome

Patients with this disorder have episodic symptoms of systemic mast cell activation associated with elevated mast cell mediators such as tryptase, and urinary histamine or prostaglandin metabolites, respond favorably to treatment with mast cell mediator blocking drugs and have no diagnostic findings of cutaneous or systemic mastocytosis. Other disorders with similar symptoms such as allergic diseases should be ruled out before this diagnosis is considered.

Standard Therapies

Treatment

Currently, there is no curative treatment for mastocytosis. Treatment of mastocytosis is primarily directed at controlling the symptoms caused by the release of mast cell mediators. H1 and H2 antihistamines are therefore cornerstones of the treatment to relieve symptoms. Cromolyn sodium can be especially effective for the treatment of some gastrointestinal symptoms, decreasing bone pain, treating headaches and some of the skin manifestations.

Mast-cell stabilizers such as ketotifen can be used to treat some of the skin involvement. Leukotriene antagonists can also be used to improve symptoms in patients. Proton-pump inhibitors can be used to treat the increased acid production in the stomach. Bisphosphonates can be used if osteoporosis or significant osteopenia is present. PUVA (psoralen plus ultraviolet A radiation) treatment may cause temporary attenuation of the urticaria pigmentosa lesions. Steroids may be necessary in patients unresponsive to other therapy or with more advanced disease.

Self-injectable epinephrine should be prescribed to all patients and can be administered in cases of severe anaphylactic episodes and all patients are advised to carry epinephrine self-injectors. This therapy should always be followed by evaluation of the patient in a medical facility.

Associated hematologic disorders should be treated by a blood specialist (hematologist). In patients with advanced systemic mastocytosis, therapies to reduce mast cell numbers are considered. These include cladribine and interferon alpha. Stem cell transplantation can be considered in selected patients with SM-AHNMD, ASM and MCL.

Inheritance

Most cases of systemic mastocytosis (SM) are sporadic (not inherited), occurring in people with no family history of the condition. The genetic mutations that often cause SM are somatic, which means they are acquired after conception and are only present in certain cells. Because they are not present in the germ cells (egg and sperm), they are not passed on to the next generation.

Rarely, SM has been reported in more than one family member. In this case, it may be inherited in an autosomal dominant manner.[3] Mutations that cause autosomal dominant conditions are located in the germ cells. To be affected with an autosomal dominant condition, a person needs to have a mutation in only one copy of the responsible gene in each cell. A person with this form of SM has a 50% chance with each pregnancy of passing the mutation to his or her child.

Treatment

Treatment for systemic mastocytosis (SM) is based on the signs and symptoms present in each person. For example, the following medications may used to treat various symptoms associated with SM:

  • Antihistamines to treat or prevent skin and gastrointestinal symptoms
  • Proton pump inhibitors to treat increased stomach acid
  • Epinephrine to treat anaphylaxis
  • Steroids to treat malabsorption (impaired ability to take in nutrients)
  • Mast-cell stabilizers such as ketotifen to treat some of the skin symptoms

Cromolyn sodium to treat gastrointestinal symptoms, bone pain, headaches, and some of the skin manifestations

If systemic mastocytosis is cancerous (mast cell leukemia) or associated with a blood disorder, steroids and/or chemotherapy may be necessary.

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What Is Aggressive Mastocytosis?

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