Edit concept Question Editor Create issue ticket

Systemic Mastocytosis

Mast Cell Disease

Systemic mastocytosis refers to a condition of excessive mast cell proliferation that affects different organ systems throughout the body, e.g., skin, lymph nodes, liver and spleen.


Presentation

Manifestation of SM strongly depends on the affected organ system. In this context, symptoms pointing at disturbances of the hematopoietic and immune system are most frequently seen, but symptoms regarding skin and gastrointestinal tract are also very common and still observed in more than half of all SM patients [7].

SM patients are more prone to anaphylactoid reactions because otherwise innocuous compounds may trigger mediator release. Presumably, the risk associated with bee or wasp stings is particularly high [8]. Food and drugs less frequently trigger such reactions, but risk awareness is of utmost importance since anaphylactoid reactions have been described after application of penicillin, non-steroidal anti-inflammatory drugs, narcotics and intravenous contrast agents [9] [10].

Urticaria pigmentosa, the most common symptom of cutaneous mastocytosis, is experienced by approximately 40% of SM patients. Pruritus and flushing can often be detected. With regards to the gastrointestinal tract, unspecific symptoms such as abdominal pain, nausea, vomitus and diarrhea are generally associated with SM. Due to increased histamine release, stomach acid production augments and some patients may report heartburn as an indicator of gastroesophageal reflux.

Musculoskeletal symptoms as well as those indicating anemia and coagulopathy may also be related to SM.

Of note, patients suffering from mastocytosis and other hematologic disorders may present additional symptoms that are not directly associated with SM. Myeloproliferative disorders such as the polycythemia vera, hypereosinophilic syndrome, different non-Hodgkin lymphoma and essential thrombocythemia have been related with SM.

Weight Loss
  • loss Progression and Transformation None Epidemiology and Mortality Age: primary second decade of life Sex: no male or female predominance Survival: patients with cutaneous involvement only follow indolent course and may have a normal life expectancy[seer.cancer.gov]
  • loss due to gastointestinal mast cell infiltrates 3.[bloodref.com]
  • loss, respiratory functions, diarrhea, lesions, and allergic reactions (some of these general terms may describe more than 1 assessment).[clinicaltrials.gov]
  • In mast cell leukemia and other advanced forms of the disease, neoplastic mast cells infiltrate organs leading to low blood counts, malabsorption, weight loss, bone fractures, splenomegaly and other organ enlargements, and liver dysfunction abnormalities[globenewswire.com]
  • loss) distinguishes indolent from aggressive systemic mastocytosis.[haematologica.org]
Malaise
  • She said that she did not have any constitutional symptoms like significant weight loss, fever, fatigue, malaise, night sweating or decreased appetite.[scielo.br]
Splenomegaly
  • Although the patient responded to the treatment, the relapse with splenomegaly and bicytopenia was observed after 10 months.[ncbi.nlm.nih.gov]
  • We present the case of a 41-year-old woman with thrombocytosis and mild splenomegaly. Clinical suspicion was of chronic myeloproliferative neoplasia (CMN).[ncbi.nlm.nih.gov]
  • This clinical overview clearly showed that the clinical characteristics differ between ISM (UP, anaphylaxis and osteoporosis) and SM-AHNMD/ASM (cytopenia, eosinophilia and splenomegaly).[ncbi.nlm.nih.gov]
  • […] without hypersplenism, and/or palpable visceral lymphadenopathy Palpable hepatomegaly with impairment of liver function, ascites, or portal hypertension Palpable splenomegaly with hypersplenism Malabsorption with weight loss due to gastointestinal mast[bloodref.com]
  • Mast cell infiltration may also affect the skin (urticaria pigmentosa, which is sometimes itchy), the spleen (splenomegaly, which is generally asymptomatic), and the skeleton (bone pain, arthralgia, and osteolysis, osteosclerosis or osteoporosis on medical[orpha.net]
Generalized Lymphadenopathy
  • On examination, splenomegaly occurs in 50% to 60% of patients, hepatomegaly in 50% to 70%, generalized lymphadenopathy in 40% and skin lesions are apparent in 60%.[healio.com]
Diarrhea
  • CASE REPORT: A 41-year-old woman presented with a three-year history of fatigue, occasional diarrhea, mild fever, skin rash and splenomegaly. Laboratory results showed severe anemia and thrombocytopenia.[ncbi.nlm.nih.gov]
  • The most common grade 3/4 nonhematologic drug-related AEs were diarrhea (6.6 %) and headache (4.9 %). Eleven patients (9 with ASM, 2 with MCL) died, 10 due to progressive disease; 7 deaths occurred 28 days after treatment discontinuation.[ncbi.nlm.nih.gov]
  • The most frequent adverse events were low-grade nausea, vomiting, and diarrhea.[ncbi.nlm.nih.gov]
  • Typical clinical features include urticaria pigmentosa, hepatosplenomegaly, bone pain, headache, flushing, pruritus, nausea, diarrhea, abdominal pain, and peptic ulcer.[n.neurology.org]
  • Symptoms related to the release of mast cell mediators are minor but may be multiple, including pruritus, flushing, syncope, headache and gastric events (vomiting and diarrhea).[orpha.net]
Nausea
  • The widespread physiologic distribution of mast cells causes a variety of symptoms with aberrant expression including fatigue, headache, depression, dyspnea, dyspepsia, nausea, and abdominal pain.[ncbi.nlm.nih.gov]
  • The most frequent adverse events were low-grade nausea, vomiting, and diarrhea.[ncbi.nlm.nih.gov]
  • In patients with SM, mast cells produce high levels of these mediators, causing symptoms that range from mild to life-threatening, including pain, nausea, hives, bleeding, fever and anaphylaxis.[blueprintmedicines.com]
  • […] pigmentosa Systemic mastocytosis A potentially aggressive condition characterized by mast cell proliferation in the skin, liver, lymph nodes, BM, GI tract Clinical Histamine hyperproduction with flushing, vertigo, palpitations, pruritus, colic, dyspnea, nausea[medical-dictionary.thefreedictionary.com]
  • Typical clinical features include urticaria pigmentosa, hepatosplenomegaly, bone pain, headache, flushing, pruritus, nausea, diarrhea, abdominal pain, and peptic ulcer.[n.neurology.org]
Vomiting
  • The most frequent adverse events were low-grade nausea, vomiting, and diarrhea.[ncbi.nlm.nih.gov]
  • Symptoms related to the release of mast cell mediators are minor but may be multiple, including pruritus, flushing, syncope, headache and gastric events (vomiting and diarrhea).[orpha.net]
  • Other common symptoms include the following: • Anaphylaxis • Shortness of breath • Low blood pressure • Hives and swelling • Itching • Nausea and vomiting • Diarrhea • Fainting • Headache • Uterine cramps/bleeding • Flushing • Musculoskeletal pain Diagnosis[aaaai.org]
  • […] type of white blood cell) occurs in one or more organs, including the GI tract, spleen, lymph nodes and bone marrow. 1 Mast cells release substances, such as histamine, which can lead to symptoms including itching, fever, abdominal pain, nausea and vomiting[novartis.com]
Abdominal Pain
  • The widespread physiologic distribution of mast cells causes a variety of symptoms with aberrant expression including fatigue, headache, depression, dyspnea, dyspepsia, nausea, and abdominal pain.[ncbi.nlm.nih.gov]
  • Abstract Ultrasonography (US) is often the first imaging study performed in patient with abdominal pain or vague symptoms related to the gastrointestinal tract.[ncbi.nlm.nih.gov]
  • Typical clinical features include urticaria pigmentosa, hepatosplenomegaly, bone pain, headache, flushing, pruritus, nausea, diarrhea, abdominal pain, and peptic ulcer.[n.neurology.org]
  • pain Anemia Arthralgias Bone pain Dermatographism Diaphoresis Eosinophilia Fatigue Fever Flushing Fractures Headache Hepatosplenomegaly Hypotension Leukocytosis Myalgias Neutropenia Pruritis Respiratory problems Syncope Tachycardia Thrombocytopenia Urticaria[seer.cancer.gov]
  • With regards to the gastrointestinal tract, unspecific symptoms such as abdominal pain, nausea, vomitus and diarrhea are generally associated with SM.[symptoma.com]
Dyspepsia
  • The widespread physiologic distribution of mast cells causes a variety of symptoms with aberrant expression including fatigue, headache, depression, dyspnea, dyspepsia, nausea, and abdominal pain.[ncbi.nlm.nih.gov]
  • Symptoms result mainly from mediator release and include pruritus, flushing, and dyspepsia due to gastric hypersecretion. Diagnosis is by skin or bone marrow biopsy or both. Treatment is with antihistamines and control of any underlying disorder.[msdmanuals.com]
  • Flushing, tachycardia, dyspepsia and diarrhea may occur. Narcotics and several anesthetic agents are also powerful mast cell activators.[cancertherapyadvisor.com]
  • Hyperacidity, dyspepsia and peptic ulcers. Hepatomegaly and splenomegaly. Cardiovascular: Syncope, hypotension or anaphylactic shock. Haematological and bones: Anaemia or other cytopenias (if bone marrow involvement). Hypersplenism. Lymphadenopathy.[patient.info]
Hepatosplenomegaly
  • RESULTS: We included 88 patients with ISM, of whom 9 developed new hepatosplenomegaly during follow-up.[ncbi.nlm.nih.gov]
  • We describe the clinicopathological findings of a 59-year-old Latin American man who presented to the emergency room with fatigue, leukocytosis, thrombocytopenia and mild hepatosplenomegaly.[ncbi.nlm.nih.gov]
  • We report the case of a 48-year old male patient who presented with hepatosplenomegaly for 12 years, yellow-brown colored maculopapular pigmentation on the skin and pancytopenia.[sciforschenonline.org]
  • Clinical findings Hepatosplenomegaly, abdominal lymphadenopathy. mastocytosis A heterogeneous group of uncommon, poorly understood lesions characterized by mast cells in one or more tissues or organs, especially skin; mastocytosis may be classified according[medical-dictionary.thefreedictionary.com]
  • Typical clinical features include urticaria pigmentosa, hepatosplenomegaly, bone pain, headache, flushing, pruritus, nausea, diarrhea, abdominal pain, and peptic ulcer.[n.neurology.org]
Hepatomegaly
  • […] dL, platelets 100 x10 9 /L Signs of dysplasia or myeloproliferation in non-mast cell lineage cells but insufficient for the WHO criteria for other clonal hematologic malignancies Skeletal involvement with large osteolytic lesion(s) and/or fractures Hepatomegaly[bloodref.com]
  • Mast cell infiltration may also affect the digestive system with esophageal, gastric, intestinal (malabsorption syndrome) and hepatic (ascites, portal hypertension, hepatomegaly which can evolve into portal fibrosis, and more rarely, cirrhosis) involvement[orpha.net]
  • Hepatomegaly-for 12 years (20 cm), splenomegaly (23,5 cm) and lymphadenopathy (Para-aortic, aorta caval, Para-celiac and portal) were evaluated on MRI and CT scanning and US of the abdomen. His mother had hepatomegaly that was not examined.[sciforschenonline.org]
  • On examination, splenomegaly occurs in 50% to 60% of patients, hepatomegaly in 50% to 70%, generalized lymphadenopathy in 40% and skin lesions are apparent in 60%.[healio.com]
  • Physical findings may include splenomegaly, lymphadenopathy and hepatomegaly. Patients with the systemic mastocytosis usually show mild symptoms.[path.upmc.edu]
Hypotension
  • BACKGROUND: Systemic mastocytosis is a rare medical disorder in which an increased number of mast cells can precipitate immediate hypersensitivity reactions, leading to hypotension, shock, and death.[ncbi.nlm.nih.gov]
  • Treatment with a combination of H1 and H2 receptor blockers reduced flushing and eliminated hypotension. Maintenance medication included aspirin, cetirizine, ranitidine, montelukast, oral cromolyn sodium and an epinephrine autoinjector (as needed).[ncbi.nlm.nih.gov]
  • Sudden transient loss of consciousness and hypotensive or anaphylactic shock may also occur. 2 Patients with undiagnosed SM can also present with neurologic symptoms. 3 We describe a 64-year-old woman with unexplained recurrent episodes of loss of consciousness[n.neurology.org]
  • […] effective October 01, 2015) D47.02 Systemic mastocytosis (effective October 01, 2015) Signs and Symptoms Abdominal pain Anemia Arthralgias Bone pain Dermatographism Diaphoresis Eosinophilia Fatigue Fever Flushing Fractures Headache Hepatosplenomegaly Hypotension[seer.cancer.gov]
  • Unintended release of mast cell mediators has the potential to cause significant hypotension, multi-system organ dysfunction, and death.[apicareonline.com]
Bone Pain
  • Radiotherapy of refractory bone pain due to systemic mast cell disease. Am J Clin Oncol 1994 ; 17 : 328 –30.[ard.bmj.com]
  • Fig. 7: This 29 year old Indian woman presented with bone pain and lethargy. Radiographically all her bones have increased density with a blurred trabecular pattern.[healio.com]
  • Typical clinical features include urticaria pigmentosa, hepatosplenomegaly, bone pain, headache, flushing, pruritus, nausea, diarrhea, abdominal pain, and peptic ulcer.[n.neurology.org]
  • pain Dermatographism Diaphoresis Eosinophilia Fatigue Fever Flushing Fractures Headache Hepatosplenomegaly Hypotension Leukocytosis Myalgias Neutropenia Pruritis Respiratory problems Syncope Tachycardia Thrombocytopenia Urticaria Weight loss Progression[seer.cancer.gov]
  • These systemic changes contribute to bone pain and malabsorption and produce small, reddish brown macules or papules, termed urticaria pigmentosa within the skin which are present in 90 per cent or more patients with indolent systemic mastocytosis.[netdoctor.co.uk]
Arthralgia
  • 10 Codes C96.2 Malignant mast cell tumor Corresponding ICD-10-CM Codes (U.S. only) C96.21 Aggressive systemic mastocytosis (effective October 01, 2015) D47.02 Systemic mastocytosis (effective October 01, 2015) Signs and Symptoms Abdominal pain Anemia Arthralgias[seer.cancer.gov]
  • Mast cell infiltration may also affect the skin (urticaria pigmentosa, which is sometimes itchy), the spleen (splenomegaly, which is generally asymptomatic), and the skeleton (bone pain, arthralgia, and osteolysis, osteosclerosis or osteoporosis on medical[orpha.net]
  • It is equally common in men and women.0 The signs and symptoms depend to some extent on which organs are involved, but fatigue, night sweats and weakness are common (50% to 60%), diarrhea occurs in 40% and weight loss in 20%, arthralgias and generalized[healio.com]
  • […] dermatographism); 3) mediator-related events (abdominal pain, nausea, vomiting, diarrhea, gastrointestinal distress, syncope, flushing, hypotension/hypertension, headache, tachycardia, respiratory symptoms); and bone-related complaints (bone pain, fractures, arthralgia[path.upmc.edu]
Flushing
  • At 6-month follow-up, the patient remained free of PEA arrests, flushing, or any clinical signs of mastocytosis or mast cell degranulation. PEA cardiac arrests may therefore be a presenting sign of untreated systemic mastocytosis.[ncbi.nlm.nih.gov]
  • Pruritus and flushing can often be detected. With regards to the gastrointestinal tract, unspecific symptoms such as abdominal pain, nausea, vomitus and diarrhea are generally associated with SM.[symptoma.com]
  • […] marrow, liver, spleen, and lymph nodes (1) the clinical presentation of mastocytosis is diverse, and many patients do not fit the classical description - namely, a variably long history of urticaria pigmentosa (UP), followed by the insidious onset of flushing[gpnotebook.co.uk]
  • For instance, I have facial flushing, itching, rapid heartbeat, abdominal cramps (twice), lightheadedness, loss of consciousness, nausea, vomiting.[alvinalexander.com]
  • […] which may be cutaneous or extracutaneous and urticaria pigmentosa Systemic mastocytosis A potentially aggressive condition characterized by mast cell proliferation in the skin, liver, lymph nodes, BM, GI tract Clinical Histamine hyperproduction with flushing[medical-dictionary.thefreedictionary.com]
Urticaria
  • CONCLUSION: Rate of resolution of mastocytosis is only shown in urticaria pigmentosa and mastocytoma. Better management guidelines are required to improve the health of these patients.[ncbi.nlm.nih.gov]
  • Mastocytosis is rare, and is actually a heterogeneous group of diseases that may only involve the skin (urticaria pigmentosa) or that may have a systemic presentation with multiorgan involvement.[ncbi.nlm.nih.gov]
  • Urticaria pigmentosa Mastocytosis Localized mastocytosis • Focal: Single skin lesion: mast cell 'nevus' • Generalized: Urticaria pigmentosa Systemic mastocytosis • Indolent • Progressive • Malignant Mast cell leukemia Mast cell sarcoma Pathogenesis Some[medical-dictionary.thefreedictionary.com]
  • Skin and bone marrow biopsies confirmed a diagnosis of SM, initially presenting with urticaria pigmentosa.[ncbi.nlm.nih.gov]
Pruritus
  • After 9 years of controlled disease, the patient presented with increasingly severe breakthrough pruritus and new skin lesions on the head and neck.[ncbi.nlm.nih.gov]
  • Cladarabine chemotherapy and adjuvant antihistaminic agent alleviated the pruritus.[acgcasereports.gi.org]
  • […] extracutaneous and urticaria pigmentosa Systemic mastocytosis A potentially aggressive condition characterized by mast cell proliferation in the skin, liver, lymph nodes, BM, GI tract Clinical Histamine hyperproduction with flushing, vertigo, palpitations, pruritus[medical-dictionary.thefreedictionary.com]
  • Typical clinical features include urticaria pigmentosa, hepatosplenomegaly, bone pain, headache, flushing, pruritus, nausea, diarrhea, abdominal pain, and peptic ulcer.[n.neurology.org]
  • Symptoms related to the release of mast cell mediators are minor but may be multiple, including pruritus, flushing, syncope, headache and gastric events (vomiting and diarrhea).[orpha.net]
Darier's Sign
  • SM may be heralded by the skin rash of urticaria pigmentosa (UP) with reddish-brown freckling on the trunk and extremities; these lesions urticate upon rubbing (Darier's sign) and dermatographism (wheal and flare development with scratching) is frequently[cancertherapyadvisor.com]
  • The presence of the Darier sign indicates the presence of mastocytosis. The Darier sign is when rubbing an affected area on the skin can cause the skin to become more red, itchy, and swollen.[medfriendly.com]
  • This is known as Darier's sign. It's usually possible to confirm a diagnosis by carrying out a biopsy , where a small skin sample is taken and checked for mast cells. Five tests are commonly used to look for systemic mastocytosis.[nhs.uk]
Dermatographia
  • […] cutaneous mastocytosis: almost exclusive to children mastocytoma of skin: usually occurs as a solitary lesion in infants. systemic mastocytosis signs and symptoms: constitutional; fatigue, fever, weight loss skin manifestations; urticaria, pruritus, dermatographia[e-immunohistochemistry.info]
Headache
  • The widespread physiologic distribution of mast cells causes a variety of symptoms with aberrant expression including fatigue, headache, depression, dyspnea, dyspepsia, nausea, and abdominal pain.[ncbi.nlm.nih.gov]
  • Treatment may include antihistamines, drugs to reduce stomach acid, migraine headache drugs for headache, and cromolyn for bowel symptoms. CONTINUE SCROLLING OR CLICK HERE FOR RELATED ARTICLE Reviewed on 12/21/2018[medicinenet.com]
  • The most common grade 3/4 nonhematologic drug-related AEs were diarrhea (6.6 %) and headache (4.9 %). Eleven patients (9 with ASM, 2 with MCL) died, 10 due to progressive disease; 7 deaths occurred 28 days after treatment discontinuation.[ncbi.nlm.nih.gov]
  • The signs and symptoms vary based on which parts of the body are affected but may include: 0002027 Abnormal eosinophil morphology 0001879 Headache Headaches 0002315 Malabsorption Intestinal malabsorption 0002024 Mastocytosis 0100495 Nausea and vomiting[rarediseases.info.nih.gov]
Irritability
  • These spots are called urticaria pigmentosa and can transform into hives and itch if stroked or irritated, or if the skin is exposed to sudden changes in temperature such as a hot shower.[aaaai.org]
  • Irritable Bowel Syndrome. Medscape, Last Update October 10, 2016. Available at: . Accessed December 20, 2016. Rowe W, Lichtenstein GR. Irritable Bowel Disease. Medscape, Last Update June 17, 2016.. Available at: . Accessed December 20, 2016.[rarediseases.org]
  • […] cause jaundice (yellowing of the skin and eyes) and make you feel lethargic swelling of the spleen, which can cause abdominal (tummy) and shoulder pain joint pain swelling of the lymph nodes weakness fatigue changes in mental state, such as confusion, irritability[geneticgenie.org]
Confusion
  • Presentation as a solitary vertebral body lesion is extremely uncommon and may be confused with more ominous conditions such as metastasis.[ncbi.nlm.nih.gov]
  • In short, SM can present with unexplained life-threatening crises which can be confused for an infectious disease being acute in nature.[ncbi.nlm.nih.gov]
  • Systemic mastocytosis can be confused either clinically or histologically with a variety of disorders.[path.upmc.edu]
  • Musculoskeletal involvement is common, and patients may have bone pain or pathological fractures, with imaging suggesting osteolysis and sclerosis, easily confused with osteoporosis.[acgcasereports.gi.org]
Dysarthria
  • CASE DESCRIPTION: A 67-year-old male presented with a 3-weeks history of unsteady gait, dysarthria and a dysfunctional right arm.[ncbi.nlm.nih.gov]

Workup

Medical history and clinical picture should prompt laboratory analyses of blood samples. Complete blood counts and blood chemistry should be realized. The most common findings are anemia, leukocytosis and thrombocytopenia. Almost half of all SM patients present with anemia. Eosinophil, basophil and monocytic cell counts are often elevated. However, as has been indicated above, leukopenia and thrombocytosis have also been detected in cases of SM and should therefore not be considered exclusion criteria. Serum levels of mast cell mediator tryptase are often increased in SM patients. Total serum tryptase levels > 20 ng/ml and a ratio of total-to-beta tryptase > 20 are suggestive of SM [11].

Elevated urinary levels of the histamine metabolite N-methyl imidazole may further support the diagnosis.

Upon tentative diagnosis of SM, bone marrow fine-needle aspiration and biopsy need to be performed and analyzed.

Molecular biological tests may reveal further evidence for SM. The vast majority of SM patients tests positive for KIT gene mutation D816V. The degenerated mast cell clone is CD-117 positive and most likely CD-25 and/or CD-2 positive. Positivity for CD-25 has been proposed as a distinctive feature in relation to reactive mast cell hyperplasia [12]. Of note, cytogenetic abnormalities, particularly pathological karyotypes such as monosomy and trisomy, are seen in about 20% of SM patients.  The share of positive patients is higher among subgroups suffering from aggressive mastocytosis or mastocytosis associated with other hematologic disorders.

Imaging techniques may be helpful to assess the extend of organ damage. While liver, spleen and gastrointestinal tract will best be visualized by X-ray, ultrasonography or endoscopy, bone and joint involvement may be evaluated with computed tomography images. Biopsies may be required for further analysis.

Decreased Platelet Count
  • Preoperative laboratory investigations were normal, except for moderate anemia (hemoglobin 99 g/L), increased alkaline phosphatase (196 U/L, normal 36-108 U/L), and decreased platelet count (38 g/L).[journals.lww.com]

Treatment

Treatment is symptomatic and is based on preventing mast cell degranulation and inhibiting the effects of mast cell mediators.

In this context, H1- and H2-antihistaminika help to reduce allergic reactions and protect the gastrointestinal tract. Effectivity is not guaranteed for all H1- and H2-antihistaminika [13]. Cromoglicic acid should be administered to prevent mast cell degranulation (200 mg po qid in adults; 100 mg po qid in children aged 2 to 12 years, maximum 40 mg per kg body weight and day). Although acetylsalicylic acid controls flushing, it may aggravate other symptoms triggered by mast cell mediators and is therefore not recommended.

Immunomodulatory therapy is indicated in patients suffering from more aggressive forms of SM. Corticosteroids may be administered (e.g., prednisone, up to 60 mg po qd for up to 3 weeks). IFN-α may be administered in a dose of up to 3 million units per day to treat bone lesions [14].

Cytostatics may be required to treat mast cell leukemia. There is little data regarding the effectivity of determined compounds. Tyrosine kinase receptor inhibitors may slow down mast cell proliferation, but imatinib is ineffective in patients with KIT gene D816V mutation. Midostaurin is currently under study. Daunomycin, etoposide and 6-mercaptopurine may be applied.

Some patients may benefit from splenectomy. In order to prepare SM patients for surgery, special guidelines should be followed [10].

Prognosis

Prognosis is strongly dependent on the subtype of SM. A good prognosis is associated with indolent SM. For this kind of disease, a median survival time of about 18 years has been calculated. Considering the average age of patients at the moment of diagnosis, this is not significantly different from the general population. The median survival time for patients suffering from aggressive SM is considerably lower and has been estimated to range between 3 and 4 years. If SM is diagnosed in patients that simultaneously suffer from other hematological disorders, the median survival time reduces to 2 years. Mast cell leukemia is associated with a poor prognosis and a median survival time of only two months. While there is not always a clearly defined transition from one subtype to another, it is unlikely for an indolent SM to transform into mast cell leukemia [6].

Additional parameters have been defined to allow for a more specific prognosis. In this context, old age, hepatosplenomegaly, ascites, weight loss in the course of the disease, anemia (hemoglobin < 10.0 mg/dl), excess bone marrow blasts (> 5%), thrombocytopenia (platelet count < 150,000/μl), hypoalbuminemia (albumin < 3.5 g/dl), elevated levels of alkaline phosphatase and lactate dehydrogenase are considered unfavorable prognostic parameters.

Etiology

Most cases of SM may be ascribed to mutations of the KIT gene that encodes for the proto-oncogene c-kit [3] [4]. Nearly 70% of all SM patients present the KIT D816V mutation. The KIT gene is mainly expressed on hematopoietic stem cells. c-kit is a member of the tyrosine kinase family and forms a cell surface receptor that binds cytokines. It stimulates growth and proliferation promoting intracellular pathways upon activation. In this context, any mutation enhancing cytokine binding or tyrosine kinase activity, any mutation interfering with ligand dissociation or receptor deactivation may trigger uncontrolled growth and proliferation. In fact, KIT mutations related to SM are gain-of-function mutations and yield excessive numbers of mast cells that subsequently infiltrate different organs.

Epidemiology

Reliable data regarding SM incidence can only be provided for specific regions. In this line, a study realized in Great Britain determined SM incidence to be about 7 per 1,000,000 inhabitants.

While SM may be detected in children, the majority of cases occurs in adults.

Sex distribution
Age distribution

Pathophysiology

In patients suffering from SM, increased numbers of mast cells can be found in several organs. The skin may or may not be involved in the disease process.

Mast cells derive from hematopoietic cells in the bone marrow. If for any as of yet unknown reason mutations affect the KIT gene expressed by those cells, mast cells start to proliferate in an uncontrolled manner. Clones of the degenerated mast cell may subsequently spread through the cardiovascular system and will easily reach liver, spleen, lymph nodes, the gastrointestinal tract, particularly stomach, small intestine and pancreas, as well as other organ systems [5].

The vast majority of adult SM patients presents focal mast cell lesions in their bone marrow. Bone marrow and blood cell counts, however, have to be interpreted with caution. Excess mast cell proliferation in the bone marrow does usually not affect erythropoiesis. Numbers of eosinophil granulocytes, which also originate from myeloid precursor cells, may even be increased. Despite the augmented mast cell proliferation, the overall number of cells as visible in bone marrow samples is not necessarily enhanced. This apparent contradiction may possibly be explained with general shifts in blood cell counts. Lymphocyte counts, for instance, are usually diminished. Of note, these parameters may only serve for rough orientation since there are significant shares of patients who present with anemia, leukopenia or leukocytosis, thrombocytopenia or thrombocytosis. Finally, hypocellular bone marrow indicates advanced stages of the disease and is associated with a poor prognosis.

Furthermore, mast cell infiltrates may be detected in the above mentioned organs and may interfere with their respective function. With regards to the spleen, some patients show diffusion infiltration of the red pulp, while others depict focal infiltration of the white pulp. Mast cell infiltration in lymph nodes is most often seen in the paracortical area, but sometimes follicles and medullary sinus are also affected.

The immune system of SM patients is weakened for two reasons. On the one hand, mast cells infiltrate immune organs and impede their correct function. On the other hand, mast cells themselves release cytokines such as interleukin 4 that promotes T helper cell differentiation towards type 2. Immunoglobulin E synthesis and histamine release are also stimulated. Indeed, SM patients have a higher risk for peptic ulcers due to elevated histamine levels and excess stomach acid.

Prevention

No preventive measures can be recommended.

Summary

Mastocytosis refers to a condition of elevated numbers of mast cells. While the majority of mastocytosis cases is limited to the skin, systemic mastocytosis (SM) affects several other organ systems. SM is characterized by mast cell infiltration in skin, lymph nodes, liver, spleen, gastrointestinal tract, bones and joints [1] [2].

SM is usually triggered by acquired gene mutations and typically diagnosed in adults. Inheritable forms of the disease exist, may affect several members of one family, but are less common.

A patient does not necessarily show increased numbers of mast cells in all the above mentioned organs. Therefore, symptoms may differ widely between individual patients. They are mainly determined by the organ systems that are compromised. In general, four types of SM are distinguished:

  • An indolent mastocytosis will be diagnosed if mast cell proliferation does not interfere with organ function. Its prognosis is good.
  • In contrast, aggressive mastocytosis is associated with more severe symptoms and a less favorable prognosis because it does impair the functionality of the organs affected.
  • In some cases, mastocytosis and other hematologic disorders, e.g., myeloproliferative disorders and lymphoma, will be diagnosed in the same patient.
  • An unfavorable prognosis is associated with mast cell leukemia. This condition is defined as a bone marrow mast cell content that exceeds 20%. While there are typically no skin lesions, patients may die from multi organ failure.

Patient Information

Mast cells pertain to the immune system. They fulfill important function in immune defense, wound healing and other processes. If mast cells proliferate in an uncontrolled manner and infiltrate several organs throughout the body, this condition is called systemic mastocytosis (SM).

Causes

Most cases of SM result from acquired mutations of the KIT gene. This gene is expressed by hematopoietic stem cells in the bone marrow and encodes for a cell surface receptor that controls cell growth and proliferation. The mutation that accounts for the majority of SM cases renders this receptor constantly active. The consequence is excess mast cell proliferation and spread throughout the body.

Symptoms

Mast cells may infiltrate skin, lymph nodes, liver, spleen, gastrointestinal tract, bones and joints. Thus, symptoms vary widely and may include flushing and pruritus, abdominal pain, nausea, heartburn, vomiting, diarrhea, bone and joint paint, among others.

Diagnosis

Symptoms are rather unspecific and only allow for a tentative diagnosis of SM. Laboratory analyses of blood samples may reveal anemia, high counts of white blood cells and lack of platelets and thus support the above mentioned diagnosis. However, analyses of bone marrow aspirates and biopsies are essential to confirm diagnosis of SM and to specify which subtype the patient suffers from.

Imaging techniques may be applied to assess the damage to internal organs.

Treatment

Only symptomatic treatment can be provided. Therapy aims at avoiding mast cell degranulation and inhibiting mast cell mediator effects. This may be realized with mast cell stabilizers and antihistamines. However, mast cell proliferation can hardly be reduced. In severe cases, cytostatics will probably be administered, but their effectivity is not guaranteed.

References

Article

  1. Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004; 55:419-432.
  2. Bain BJ. Systemic mastocytosis and other mast cell neoplasms. Br J Haematol. 1999; 106(1):9-17.
  3. Ma Y, Zeng S, Metcalfe DD, et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood. 2002; 99(5):1741-1744.
  4. Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet. 2003; 362(9383):535-536.
  5. Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000; 14(3):579-623.
  6. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113(23):5727-5736.
  7. Ho CL, Kito H, Squillace DL, Lasho TL, Tefferi A. Clinical correlates of serum pro-major basic protein in a spectrum of eosinophilic disorders and myelofibrosis. Acta Haematol. 2008; 120(3):158-164.
  8. Bonadonna P, Zanotti R, Pagani M, et al. How much specific is the association between hymenoptera venom allergy and mastocytosis? Allergy. 2009; 64(9):1379-1382.
  9. Butterfield JH. Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other Lipid Mediat. 2009; 88(3-4):122-124.
  10. Chaar CI, Bell RL, Duffy TP, Duffy AJ. Guidelines for safe surgery in patients with systemic mastocytosis. Am Surg. 2009; 75(1):74-80.
  11. Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am. 2000; 14(3):641-657.
  12. Horny HP. Mastocytosis: an unusual clonal disorder of bone marrow-derived hematopoietic progenitor cells. Am J Clin Pathol. 2009; 132(3):438-447.
  13. Póvoa P, Ducla-Soares J, Fernandes A, Palma-Carlos AG. A case of systemic mastocytosis; therapeutic efficacy of ketotifen. J Intern Med. 1991; 229(5):475-477.
  14. Lehmann T, Beyeler C, Lammle B, et al. Severe osteoporosis due to systemic mast cell disease: successful treatment with interferon alpha-2B. Br J Rheumatol. 1996; 35(9):898-900.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 21:01