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.

• 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]

  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]

  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]

  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]

• Anemia

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

  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]

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

  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. [symptoma.com]

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

• Weight Loss

  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]

  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]

  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 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]

• Malaise

  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]

  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]

• Pediatric Disease

  CM is considered a benign skin disease representing the majority of pediatric cases. [tmsforacure.org]

  […] considered as having non-advanced disease. [oncotarget.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]

  Some of those patients may have extensive gastrointestinal tract infiltration resulting in low albumin, malabsorption, weight loss, and extensive diarrhea. [onclive.com]

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

  This abnormal growth of mast cells causes a range of symptoms, including itchy bumps on the skin, gastrointestinal (GI) issues such as diarrhea, and bone pain. [my.clevelandclinic.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

  […] 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]

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

  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]

  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]

• 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]

  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]

  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]

• Abdominal Pain

  pain, diarrhea, bone pain, and hepatosplenomegaly (1) clinical presentation of mastocytosis is heterogeneous, varying from sole skin presentation found in UP and mastocytoma, to different forms of systemic disease including indolent systemic mastocytosis [gpnotebook.co.uk]

  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]

  pain and sometimes diarrhea, nausea and vomiting. [orpha.net]

  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]

• 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]

• 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]

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

  […] 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.co.uk]

  Another antimediator-type drug is epinephrine which helps during most severe anaphylactoid reactions with hypotension and shock. [ecnm.net]

• 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]

  […] without impairment of liver function, and/or palpable splenomegaly without hypersplenism, and/or palpable visceral lymphadenopathy Palpable hepatomegaly with impairment of liver function, ascites, or portal hypertension Palpable splenomegaly with hypersplenism [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]

  Patients with significantly increasing sBT (sBT slope ≥0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly [journals.plos.org]

  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]

• Hepatosplenomegaly

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

  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 [medical-dictionary.thefreedictionary.com]

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

  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]

  […] 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 pain, and hepatosplenomegaly [gpnotebook.co.uk]

• Fracture

  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]

  […] mast cells is caused in many people by a KIT mutation.3 KIT D816V is the most common mutation in SM, occurring in about 90% of patients.4 In advanced SM, mast cells collect in such high quantities that they lead to organ damage and dysfunction, bone fractures [novartis.com]

  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]

  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

  All patients had mast cell mediator related symptoms (flushing, wheezing, diarrhoea with abdominal pain, pruritus, bone pain) and raised total serum tryptase levels persistently >20 ng/ml. [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]

  Nausea, stomach pain, diarrhea and vomiting. Bone pain. Flushing (when skin all over the body turns red). A drop in blood pressure. Fainting. Get useful, helpful and relevant health + wellness information enews More health news + info [my.clevelandclinic.org]

  diarrhea, bone pain, and hepatosplenomegaly (1) clinical presentation of mastocytosis is heterogeneous, varying from sole skin presentation found in UP and mastocytoma, to different forms of systemic disease including indolent systemic mastocytosis, [gpnotebook.co.uk]

  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]

• Arthralgia

  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]

  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]

  […] 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]

  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). [msdmanuals.com]

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

• Recurrent Fractures

  fractures Increased fracture rate Increased fractures Multiple fractures Multiple spontaneous fractures Varying degree of multiple fractures [ more ] 0002757 Splenomegaly Increased spleen size 0001744 Sudden cardiac death Premature sudden cardiac death [rarediseases.info.nih.gov]

• Flushing

  […] 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]

  All types can cause systemic symptoms (most commonly, flushing but sometimes anaphylactoid reactions). [msdmanuals.com]

  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]

  […] 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]

  Her mother reported allergies to several topical antibiotics and alcohol, with the reaction to all being cutaneous flushing and urticaria. [apicareonline.com]

• Urticaria

  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]

  Urticaria pigmentosa: an anesthetic challenge. J Clin Anesth 1990 ; 2 : 108 – 115. Villeneuve V, Kaufman I, Weeks S, et al. Anesthetic management of a labouring patient with urticaria pigmentosa. Can J Anaesth 2006; 53: 380-384. [apicareonline.com]

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

  Bullous urticaria pigmentosa. Cutis. 1996;58:358–60. 9. Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. Ann Allergy. 1994;73:197–202. 10. Azaña JM, Torrelo A, Mediero IG, Zambrano A. Urticaria pigmentosa: a review of 67 pediatric cases. [aafp.org]

• Pruritus

  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]

  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]

  Local or generalized pruritus is common after exposure to physical stimuli, as is dermatographism, localized erythema and generalized flushing. [aafp.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

  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]

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

  Epinephrine infusion corrected hemodynamic status, and the skin rash quickly disappeared. [casesjournal.biomedcentral.com]

  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]

• Headache

  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]

  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]

  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]

• Irritability

  Irritable Bowel Syndrome. Medscape, Last Update October 10, 2016. Available at: http://emedicine.medscape.com/article/180389-overview. Accessed December 20, 2016. Rowe W, Lichtenstein GR. Irritable Bowel Disease. [rarediseases.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]

  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]

• 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]

  This case highlights key abdominal structures that one should aim to identify when interpreting radiographs to avoid confusing anatomical variants with pathology. [radiopaedia.org]

  The majority of cases of right-sided stomach are associated with eventration of the diaphragm and are reported as being confused with spontaneous hydropneumothorax or pyopneumothroax at the base of the right lung. [pubs.rsna.org]

  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]

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]

  absolute monocytosis, decreased platelet count, anemia, and elevated alkaline phosphatase and transaminase levels. [jamanetwork.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.

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