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.

• Anemia

  Diffuse osteopenia is almost identical to that in osteoporosis, osteomalacia, hyperparathyroidism, sickle cell anemia, Gaucher's disease, and plasma cell myeloma. [eurorad.org]

  If you have PNH, you can also develop aplastic anemia, which is anemia with a lower platelet and white blood count. Some patients who have aplastic anemia develop PNH. [ohsu.edu]

  CASE REPORT We report a 72-year-old caucasian male referred to our hospital due to severe anemia. [wjgnet.com]

  Patient evolved with progressive tension ascites and worsening anemia (6.3 gm/dl) requiring PRBC transfusions. [gotoper.com]

  Myelodysplastic syndrome (MDS) and autoimmune hemolytic anemia contributing to the patient’s anemia could not completely be excluded. [hindawi.com]

• Weight Loss

  loss, hepatomegally and ascitis, splenomagally and hypersplenism B findings: BM MCs count 30% and / or tryptase 200 ng/mL BM hypercellularity Dysmyelopoiesis without cytopenia Organomegally without functional impairment Diagnosis Examine bone marrow [pathologyoutlines.com]

  The authors report a clinical case of a 72-year-old woman with no history of allergies, with bicytopenia, weight loss, and diffuse axial osteolytic lesions. [scielo.br]

  On review of systems the patient was noted to have weight loss. He denied any cough or shortness of breath. On exam the patient was cachectic with numerous skin excoriations from scratching. [journal.chestnet.org]

  In addition, there was a significantly (p 0.05) higher incidence of hepatosplenomegaly, ascites, lymphadenopathy and weight loss. [clinical-lymphoma-myeloma-leukemia.com]

  loss over 24 weeks. [rush.edu]

• 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]

  He had urticaria pigmentosa and progressive mast-cell infiltration of the bone marrow, liver, and spleen, accompanied by ascites; in addition, he had fever, malaise, night sweats, and weight loss. [nejm.org]

  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. [rarediseases.org]

• Pediatric Disease

  The incidence of systemic pediatric disease was previously unknown, but systemic forms have now been proven to exist in some children.8-10 The majority of adult patients are diagnosed with systemic disease. [tmsforacure.org]

  disease onset (n 7) and/or familial aggregation (n 4). [oncotarget.com]

• Splenomegaly

  Although the patient responded to the treatment, the relapse with splenomegaly and bicytopenia was observed after 10 months. [ncbi.nlm.nih.gov]

  The patients with splenomegaly also had a normal FDG metabolism, with the exception of one patient who showed slightly increased radiotracer uptake in the enlarged spleen. [ajronline.org]

  […] 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]

• Generalized Lymphadenopathy

  One patient had generalized lymphadenopathy; and in four patients, splenomegaly was diagnosed. All images were performed on a dedicated fullring PET scanner (Advance; General Electric Medical Systems, Milwaukee, WI) following the same protocol. [ajronline.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]

  Autopsy specimens showed massive infiltration of the spleen and BM by malignant cells, generalized lymphadenopathy, in which the lymph nodes sinuses were filled by the atypical population, and malignant infiltration of portal tracts of the liver. [karger.com]

• Diarrhea

  Her diarrhea resolved without further incidence to date. Discussion Gastrointestinal manifestations of SM such as nausea, vomiting, and diarrhea are not uncommon. [cureus.com]

  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]

  When the disease is in the intestinal tract, it can lead to nausea, vomiting, diarrhea, and abdominal pain. To diagnose this disorder, our doctors may take a biopsy (sample) of the bone marrow or gastrointestinal tract. [mskcc.org]

• Nausea

  Symptoms may include pruritus, flushing, hypotension, headaches, abdominal pain, nausea, vomiting, and diarrhea. [cureus.com]

  The most common adverse effects of midostaurin were nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 20% of patients.2 Rydapt is available in 25-mg capsules. [secure.medicalletter.org]

  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]

  When the disease is in the intestinal tract, it can lead to nausea, vomiting, diarrhea, and abdominal pain. To diagnose this disorder, our doctors may take a biopsy (sample) of the bone marrow or gastrointestinal tract. [mskcc.org]

• Vomiting

  Symptoms may include pruritus, flushing, hypotension, headaches, abdominal pain, nausea, vomiting, and diarrhea. [cureus.com]

  The most common adverse effects of midostaurin were nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 20% of patients.2 Rydapt is available in 25-mg capsules. [secure.medicalletter.org]

  When the disease is in the intestinal tract, it can lead to nausea, vomiting, diarrhea, and abdominal pain. To diagnose this disorder, our doctors may take a biopsy (sample) of the bone marrow or gastrointestinal tract. [mskcc.org]

  The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. [ncbi.nlm.nih.gov]

  The clinical features relate to the release of histamin and prostaglandins out of the mast cells, causing local urticaria, flushes, diarrhea and vomiting. Hematologic abnormalities include anemia, leukopenia, thrombocytopenia and eosinophilia. [eurorad.org]

• 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]

  Symptoms may include pruritus, flushing, hypotension, headaches, abdominal pain, nausea, vomiting, and diarrhea. [cureus.com]

  When the disease is in the intestinal tract, it can lead to nausea, vomiting, diarrhea, and abdominal pain. To diagnose this disorder, our doctors may take a biopsy (sample) of the bone marrow or gastrointestinal tract. [mskcc.org]

  He recently presented to the emergency room for abdominal pain of seven months duration. There he was diagnosed with gallstones and an inguinal hernia and discharged with primary care followup. [journal.chestnet.org]

  Advanced SM In advanced systemic mastocytosis, mast cells are inappropriately released, causing various symptoms in multiple organs, such as skin rash, abdominal pain, nausea and vomiting. [blueprintclinicaltrials.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. [merckmanuals.com]

  Flushing, tachycardia, dyspepsia and diarrhea may occur. Narcotics and several anesthetic agents are also powerful mast cell activators. [cancertherapyadvisor.com]

• 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]

  […] disease result from skin involvement, mast cell mediator release and massive mast cell infiltration, as found in aggressive variants of the disease symptoms of mast cell degranulation may vary from pruritus and flushing to anaphylaxis with profound hypotension [gpnotebook.com]

  Unintended release of mast cell mediators has the potential to cause significant hypotension, multi-system organ dysfunction, and death. [apicareonline.com]

  […] 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]

• Hepatosplenomegaly

  RESULTS: We included 88 patients with ISM, of whom 9 developed new hepatosplenomegaly during follow-up. [ncbi.nlm.nih.gov]

  Ultrasonography demonstrated marked hepatosplenomegaly. Liver biopsy was suggestive for hemochromatosis. Skin biopsy of the brown cutaneous lesions was diagnostic for urticaria pigmentosa. [eurorad.org]

  A: Homogeneous hepatosplenomegaly; B: Normal spleen on computed tomography scan performed two years earlier. Figure 3 Immunohistochemistry study identified positive staining for CD117 and CD25. [wjgnet.com]

  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]

• Hepatomegaly

  He had mild right upper quadrant tenderness, hepatomegaly, and a reducible inguinal hernia. Labs were notable for an alkaline phosphatase of 652 IU/L and a leukocytosis of 11.8 cells per mL with 29% eosinophils. [journal.chestnet.org]

  /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]

  Liver involvement in ASM is common and may include abnormal liver tests, hepatomegaly, portal hypertension, fibrosis, cirrhosis and liver failure. Hepatomegaly is found in 41%-72% of patients. [wjgnet.com]

  C-findings include bone marrow (BM) dysfunction, palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension, skeletal involvement with large osteolytic lesions and/or pathological fractures, palpable splenomegaly with [orpha.net]

  Hepatomegaly without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/or lymphadenopathy. [oncohemakey.com]

• Fracture

  The risk of osteoporotic fractures is high especially in men. Furthermore, back pain secondary to osteoporotic fracture may be the only presenting symptom in systemic mastocytosis. [endocrine-abstracts.org]

  Between 28-34% of patients with SM are related to bone condition at the time of diagnosis and 16% have symptomatic fractures. The presentation of SM as clinical vertebral fractures in young men is rare. [ncbi.nlm.nih.gov]

  Van der Veer et al studied 157 patients with indolent SM and found a high prevalence of osteoporotic fractures (38%). Male preponderance was noted, with 62% of the men having osteoporotic manifestations (BMD of -2.5 or osteoporotic fracture). [panafrican-med-journal.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]

  Indolent or Smoldering SM People with indolent and smoldering systemic mastocytosis can experience severe symptoms which often present as severe allergies, but can include rashes, GI problems, fatigue, “brain fog,” risk of anaphylaxis, bone pain, osteoporosis [blueprintclinicaltrials.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]

  […] 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, cramping abdominal pain, diarrhea, bone [gpnotebook.com]

  Bone pain secondary to bone marrow involvement is the hallmark of SM. SM should be strongly considered in any patient presenting with debilitating bone pain and unexplained osteoporosis. [panafrican-med-journal.com]

• Arthralgia

  […] activation of osteoclasts (Age Ageing 1996;25:1) Clinical features Course is variable from benign self limited to aggressive Spectrum of symptoms depending on type Variable symptoms of diarrhea, weight loss, weakness, fractures or osteoporosis in 25%, arthralgia [pathologyoutlines.com]

  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]

  Despite antibiotic treatment, the patient still had fevers, worsening arthralgias, and an increasing leukocytosis; he was transferred to our institution. [mayoclinicproceedings.org]

  […] 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]

• Urticaria

  Multiple organ systems are involved, including skin (urticaria pigmentosa), liver, spleen, lymph nodes and skeleton. [eurorad.org]

  Hypocellularity was most pronounced in those with urticaria pigmentosa. Hematogone increases were highest, on average, in patients with diffuse cutaneous mastocytosis or mastocytomas. [grantome.com]

  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]

  It manifests most commonly as urticaria, flushing, and angioedema. Our patient had urticaria and flushing for many years, we suspect that these were wrongly attributed as allergic reactions to medications. [panafrican-med-journal.com]

  Treatment of urticaria pigmentosa with corticosteroids. Arch Dermatol. 1985; 121:1516-23. PubMed Scholar Lavker RM, Schechter NM, Guzzo C, Lazarus GS. [haematologica.org]

• 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]

  It manifests most commonly as urticaria, flushing, and angioedema. Our patient had urticaria and flushing for many years, we suspect that these were wrongly attributed as allergic reactions to medications. [panafrican-med-journal.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.com]

  H1 antihistamine is usually prescribed for flushing and pruritus in ASM patients. This patient, however, did not exhibit such symptoms. [gotoper.com]

  Symptoms Symptoms of systemic mastocytosis include facial flushing, itching, or belly cramps. Other symptoms include feeling lightheaded or losing consciousness. [mayoclinic.org]

• Pruritus

  Clinical History consulted with fatigue, pruritus and icterus. Physical examination revealed brown, round cutaneous lesions on the trunk and limbs. Laboratory tests disclosed a definitely increased level of serum ferritine (1330mg/l). [eurorad.org]

  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]

  Case Report A 46-year-old woman presented with a rash that had been present for more than 20 years but had progressed over the past 6 years and was associated with pruritus, burning, and blistering precipitated by temperature changes or anxiety. [mdedge.com]

  The only other complaint the patient had was persistent pruritus for over one year. On review of systems the patient was noted to have weight loss. He denied any cough or shortness of breath. [journal.chestnet.org]

• Darier's Sign

  This is known as Darier’s sign. Darier’s sign is an important dermatological finding and may be elicited by stroking a mastocytosis skin lesion approximately 5 times with moderate pressure with a tongue spatula. [askhematologist.com]

  This is called Darier’s sign. Most, but not all mastocytosis skin lesions will become raised with rubbing, so a negative Darier’s sign (no response) does not rule out mastocytosis. [ukmasto.org]

  Diagnosis Recognition of mastocytosis can be difficult, especially in patients who do not have the characteristic skin lesions and Darier's sign. [aafp.org]

• Skin Rash

  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]

  Advanced SM In advanced systemic mastocytosis, mast cells are inappropriately released, causing various symptoms in multiple organs, such as skin rash, abdominal pain, nausea and vomiting. [blueprintclinicaltrials.com]

  Its presentation may be as benign as the characteristic skin rash of urticaria pigmentosa or as life threatening as anaphylaxis and shock. [cancertherapyadvisor.com]

  Mast cell density in the skin did not correlate with the macroscopic intensity of the skin rash (P 0.912). Analysis of DNA from the paraffin sections revealed KIT D816V in 52% (14/27) of the patients. [nature.com]

• 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 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]

  Experienced dermatologists may feel confident diagnosing a child by inspecting the skin lesions, and perhaps rubbing a lesion to see if it because raised and irritated from the friction. This is called Darier’s sign. [ukmasto.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]

  Other symptoms include epigastric pain due to peptic ulcer disease, nausea, vomiting, chronic diarrhea, arthralgias, bone pain, and neuropsychiatric changes (eg, irritability, depression, mood lability). [merckmanuals.com]

• 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]

  Marked eosinophil infiltrates were present in four patients, in one patient leading to confusion with eosinophilic colitis. Architectural distortion was noted in three cases. The D816V KIT mutation was present in all four cases tested. [nature.com]

  Systemic mastocytosis can be confused either clinically or histologically with a variety of disorders. [path.upmc.edu]

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

  platelet count, anemia, and elevated alkaline phosphatase and transaminase levels. [jamanetwork.com]

  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 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 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.

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.

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.

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.

No preventive measures can be recommended.

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.

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.

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.