What every physician needs to know:
Systemic mastocytosis (SM) is a disorder with protean manifestations. Its presentation may be as benign as the characteristic skin rash of urticaria pigmentosa or as life threatening as anaphylaxis and shock. The variety of symptoms is attributable to the intermittent release of multiple cytokines and vasoactive factors reflecting mast cell activation; tissue accumulation of neoplastic mast cells in the spleen, liver, marrow, and lymph nodes may create organ dysfunction as well.
The great majority of SM patients experience an indolent form of the disorder that may be complicated by mild to severe allergic reactions. Recognition of the condition and its various sub-categories allows the introduction of treatments that help to eliminate these threats.
The World Health Organization (WHO) classification of SM consists of four groups:
Indolent SM with no evidence of organ dysfunction
Aggressive SM with organ dysfunction
SM with another clonal non-mast cell disease
Mast cell leukemia
The latter three categories have abbreviated survivals. Indolent SM presages a near normal life survival.
Are you sure your patient has systemic mastocytosis? What should you expect to find?
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 present. UP may exist solely as a cutaneous disorder but in adults, it is usually part of SM.
Bone marrow and spleen are the earliest sites of systemic involvement in SM. Bone marrow contains the characteristic spindle-shaped mast cell infiltrates, which may be accompanied by marrow fibrosis. Cytopenia can result from marrow replacement and hypersplenism. Splenomegaly is attributable to mast cell infiltration although portal hypertension secondary to hepatic fibrosis may also be contributory.
Bony lesions are common with a mixture of osteosclerosis and/or osteopenia. Mastocytomas may involve the vertebrae and result in vertebral collapse and long bone fractures.
Serum tryptase levels are elevated (greater than 20ng/ml) in most cases to a degree which parallels the tumor burden of mast cells; histamine, leukotrienes and prostacyclins may also be increased.
Episodic flushing and urticaria are frequent. Paroxysmal hyper and hypotension occur ,as well as tachycardia. Bronchoconstriction and coronary artery ischemia can occur. Gastrointestinal symptoms are common with abdominal pain, peptic ulceration, hypersecretion, diarrhea and celiac disease.
Neuropsychiatric involvement is not infrequent. Coagulation abnormalities (prolonged partial thromboplastin time [PTT]), secondary to mast cell release of heparin may be complicated by bleeding.
Beware of other conditions that can mimic systemic mastocytosis:
Other conditions that can mimic mastocytosis
Which individuals are most at risk for developing systemic mastocytosis:
Cutaneous involvement (UP) is most commonly a disease of childhood and the condition usually resolves with maturation to adolescence. Systemic disease occurs in adults across the age spectrum with only very rare reports of familial clustering; younger individuals more frequently manifest the indolent form of the disease.
Environmental contributions to the disorder have not been described.
Boxer dogs have a predilection for development of mastocytomas.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Studies to be ordered
Skin biopsy of any suspicious lesions for evidence of mast cell infiltration
Serum tryptase levels
– Measurement of serum tryptase levels which are consistently elevated in SM; histamine and prostaglandin D2(PGD2) levels may correlate with exacerbations of mast cell activation, but are less frequently positive than is tryptase elevation.
Bone marrow examination
– Bone marrow examination with specific staining for CD117 identifies mast cells; the presence of CD25, CD2 and CD30 on mast cells marks for the neoplastic mast cells of SM. KITD816V and alpha and beta-type platelet-derived growth factor receptor (PDGFRA/PDGFRB) (in the presence of hypereosinophilia) molecular mutations support the diagnosis when present.
Metastatic bone survey to establish the presence of osteosclerotic and/or osteopenic lesions
Endoscopy and biopsy
– Endoscopy and biopsy if gastrointestinal symptoms are present. Investigation for celiac disease is also appropriate.
The initial laboratory studies include serum tryptase and urinary histamine and PGD2 levels. An acute allergic reaction may transiently elevate these studies, making it important that the levels are measured in a quiescent period of the disease. Most patients with SM have tryptase levels greater than 100ng/ml which separates them from reactive mast cell activation. If these levels are elevated and/or the suspicion of the disorder is high, a bone marrow is indicated.
Mast cell accumulation on the marrow aspirate may be minimal secondary to marrow fibrosis; the cells are frequently most evident in the marrow stroma. Marrow biopsy preparation and decalcification often leach the granules of mast cells causing the lesions to be overlooked. Immunohistochemical staining (CD117 and tryptase) highlights the cells and avoids this problem.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of systemic mastocytosis?
Helpful imaging studies
Metastatic bone series and bone densitometry
Computed tomography (CT) scans to document any liver, spleen, or lymph node involvement
Positron emission tomography
– Positron emission tomography (PET) scans are not positive in SM; this permits the differentiation of lymphoma from mast cell masses as a cause of lymph node enlargement.
If you decide the patient has systemic mastocytosis, what therapies should you initiate immediately?
The majority of cases of SM fall into an indolent category and require no immediate treatment other than symptomatic control. Symptoms attributable to mast cell release phenomenon are treated with histamine blockers (H1 and H2); doxepin may be added to provide more powerful effect. If symptoms persist, oral cromolyn (Gastrocrom) is indicated. In patients with prostacyclin elevation who frequently have gastrointestinal manifestations of the disease, daily aspirin is often helpful; this therapy should not be administered until histamine blockade is in place. Leukotriene inhibitors may offer relief in rare patients.
Because anaphylaxis is the most serious complication, patients should carry an epi-pen for such emergencies. Surgical procedures may be associated with anaphylactic shock; steroids and histamine blockers need be administered prior to anesthesia induction. Aggressive fluid resuscitation may also be necessary to correct for vasodilatation.
More definitive therapies?
Patients with the aggressive form of SM require reduction of the tumor masses and infiltrates that create multi-organ dysfunction. Cytoreduction can be attempted with several different agents. In those patients with wild type c-kit (that is, absent c-kit mutation), the tyrosine-kinase inhibitor imatinib is very efficacious; it is not effective in individuals with the KITD816V mutation. Alpha-interferon and 2-chlorodeoxyadenosine (2-CDA) are options for c-kit positive SM; the former is less effective than the latter but 2-CDA is associated with the known risks of chemotherapy.
Second and third generation tyrosine kinase inhibitors are being introduced on an experimental basis for SM. In patients with an associated clonal hematological disorder, the hematological disorder defines the choice of therapy for the combined condition.
What other therapies are helpful for reducing complications?
The lesions of urticaria pigmentosa may be transiently reduced with photopheresis. Standard treatment for osteoporosis with biphosphonates is indicated.
What should you tell the patient and the family about prognosis?
Prognosis is dependent upon the category of SM that is present. Childhood UP usually resolves with the onset of puberty; its persistence or new onset in adulthood usually indicates systemic disease. Indolent mastocytosis is not associated with any shortening of life span. Aggressive SM, SM-AHNMD (Systemic mastocytosis with associated hematologic non-mast cell lineage disorder), and MCL (mast cell leukemia) have median survivals that are less than 24 months, although the new generations of tyrosine kinase inhibitors may improve these outcomes.
What if scenarios.
Myelofibrosis frequently accompanies SM and may comprise the major pathologic feature of the marrow; SM should be pursued in all patients with marrow fibrosis.
Mast cell hyperactivity may mimic SM, but tissue accumulation of mast cells is not present and secondary organ dysfunction does not occur; the serum tryptase levels are usually less than 20ng/ml in this reactive disorder.
Gain-of-function somatic mutations in the KIT tyrosine kinase domain in mast cells are considered necessary, but not sufficient alterations to explain all of the clinical manifestations of SM. Constitutive activation of KIT affects the proliferation and maturation of mast cells that are independent of growth factor control. Transgenic mice models expressing KITD816V mutations in mature mast cells manifest the picture of indolent disease, but additional somatic mutations are thought necessary for full MC transformation. The developmental stage of the MC is an important determinant of the gain of function effect; more aggressive forms of the disease occur with alterations of more immature mast cells. KIT mutations other than (D816V) and mutations of TET and RAS genes have also been described which likely alter the phenotype of the disease.
What other clinical manifestations may help me to diagnose systemic mastocytosis?
Alcohol frequently causes mast cell release signs and symptoms. Flushing, tachycardia, dyspepsia and diarrhea may occur.
Narcotics and several anesthetic agents are also powerful mast cell activators. Preparation for surgery needs incorporate steroids and histamine blockade with readiness to correct vascular collapse if it occurs.
Foods and odors may cause exacerbations of the disorder.
Anaphylaxis may occur with bee stings. Epi-pens should always be available. Desensitization to bee stings can be successfully undertaken.
Mast cell activation may lead to heparin release and transient prolongation of the activated partial thromboplastin time (aPTT). A mixing study can identify the presence of an inhibitor with a prolonged thrombin time that is reversed with the addition of protamine or toluidine blue proving the presence of heparin.
Mast cell disease may mimic an acute chest syndrome; clear coronary arteries in a patient with otherwise unexplained chest syndrome should be considered candidates for SM.
Telangiectatic lesions over the malar area (telangiectasia macularis perstans eruptive) may mimic the butterfly rash of lupus.
Skin lesions are absent in approximately one third of patient with SM; their absence may delay the diagnosis of the disorder.
Important physical findings include: the urticarial reddish-brown freckling, telangiectasias of the malar area, hepatosplenomegaly and lymphadenopathy.
What other additional laboratory studies may be ordered?
Prostaglandin G2 is elevated in some patients with SM and may cause severe diarrhea; its elevation calls for the administration of aspirin, but only after histamine blockade is achieved. Aspirin may induce histamine release when administered alone.
Hypereosinophilia occurs with mutations in platelet-derived growth factor receptors (PDGF-R) which code for a response to imatinib. Fluorescence in situ hybridization (FISH) or reverse transcriptase-plymerase chain reaction (RT-PCR) can be used for this identification.
Ascites may be the initial presentation of SM, the result of hepatic infiltration/fibrosis and secondary cirrhosis.
Malabsorption and protein-losing enteropathy may be manifested by hypoalbuminemia and weight loss.
What’s the evidence?
Valent, P, Speer, WR, Akin, C. “How I treat patients with aggressive systemic mastocytosis”. Blood. vol. 116. 2010. pp. 581-2. [A comprehensive compendium of state-of-the-art management strategies for systemic mastocytosis.]
Pardanani, A. “Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification and management”. American Journal of Hematology. vol. 86. 2011. pp. 363-71. [An excellent clinical summary of a large population of individuals with SM.]
Sokol, H, Georgin-Lavialle, S, Grandpeix-Guyodo, C. “Gastrointestinal involvement and manifestations in systemic mastocytosis”. Inflammatory Bowel Diseases. vol. 16. 2010. pp. 1247-53. [Gastroenterological manifestations of the disease may mimic a host of other disorders involving this system.]
Yamada, Y, Cancelas, J. “FIP1L1/ PDGFR alpha associated systemic mastocytosis”. Inter Arch Allergy & Immunology. vol. 152. 2010. pp. 101-5. [Molecular markers contribute to characterization of hypereosinophilic disorders in the spectrum of mast cell disease.]
Chaang, C, Bell, R, Duffy, T, Duffy, A. “Guidelines for safe surgery in patients with systemic mastocytosis”. American Surgeon. vol. 75. 2009. pp. 74-80. [Mast cell patients require management in surgery to avert sometimes disastrous consequences.]
Ustun, C, DeRemer, D, Akin, C. “Tyrosine kinase inhibitors in the treatment of systemic mastocytosis”. Leukemia Research. vol. 35. 2011. pp. 1143-52. [Role of TKI inhibitors in the successful treatment of some subtypes of SM.]
Gleixner, K, Mayerhofer, M, Cerny-Reiterer, S. “KIT-D816V – independent oncogenic signaling in neoplastic cells in systemic mastocytosis; Role of Lyn and Btk activation and disruption by dasatinib and bosutinib”. Blood. vol. 118. 2011. pp. 1885-98. [Exploration of the role of TKI inhibitors other than GleevEc in SM.]
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- Systemic mastocytosis
- What every physician needs to know:
- Are you sure your patient has systemic mastocytosis? What should you expect to find?
- Beware of other conditions that can mimic systemic mastocytosis:
- Which individuals are most at risk for developing systemic mastocytosis:
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of systemic mastocytosis?
- If you decide the patient has systemic mastocytosis, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- What other clinical manifestations may help me to diagnose systemic mastocytosis?
- What other additional laboratory studies may be ordered?