The Many Faces of Systemic Mastocytosis

Source: Annals of Allergy, Asthma & Immunology
Vol. 87, No. 1, July 2001, Page 6 – 15
Copyright © 2004 by the American College of Allergy, Asthma & Immunology. All rights reserved.

The Many Faces of Systemic Mastocytosis
Laura Ispas, MD, Ruth Ann Henriksen, PhD and W. James Metzger, MD

Objective: This short review article will augment the reader’s knowledge of mast cell physiology and will offer an overview of current information on the pathophysiology, heterogeneity, and treatment of human mastocystosis.

Data sources and study selection: Articles published since 1980, textbooks, information from computerized databases, references identified from bibliographies of relevant articles, and books published in the last 10 years.

Results and conclusions: Mastocytosis is a complex disease with a multitude of clinical presentations, often misdiagnosed, which can embrace characteristics of other diseases and generate a chameleon-like picture. Mast cells possess many important physiologic functions in the human body, but as a consequence of poorly understood events, they can also start a cascade of pathologic reactions. Although a great deal is known about mechanisms involved in physiologic and pathologic processes of mast cells, many areas are waiting to be explored in this millennium.

INTRODUCTION

Systemic mastocytosis is a complex, fascinating, and intriguing disease which, despite the effort of intense medical research in recent years, continues to hold many secrets. Nettleship and Tay, in 1869 1-4 first described cutaneous mastocytosis; Sangster named urticaria pigmentosa in 1878 4; and the first description of systemic disease was given by Ellis in 1949. 4-6 Mast cells were first described by Paul Ehrlich in 1877 who named themmastzellen which means overnourished cells. 4,6

This article describes mast cell morphology, physiology, and pathophysiology, as well as the classification, epidemiology, clinical presentation, diagnosis, treatment, and prognosis of systemic mastocytosis.

DEDICATION

This article is dedicated in memory of Dr. W. James Metzger, who suddenly passed away on November 17th, 2000. We have all benefited from his remarkable contributions to the field of allergy. He served as an exemplary mentor to me and many other fellows and will be tremendously missed.

Mast Cell Development, Physiology, and Pathophysiology

Mast cells are derived from progenitor cells that express the CD34 antigen (CD34+/c-kit/CD 13+), 7,8 the receptor for stem cell factor (SCF), c-kit (CD117), and the low affinity IgG receptor FcRII (CD32), but not the high affinity IgE-receptor, FcRI. 9 Mast cells also express the panleukocyte antigen CD45. 3 The early stages of differentiation are dependent on interleukin (IL)-3 and possibly IL-4, IL-5, and IL-10. 10 Also, recent studies suggest a potential role for IL-15 as a stimulant for proliferation and mastocytosis. 11

Mast cells are found in bone marrow, blood, mucosal, and connective tissues. They migrate into the loose connective tissue of all organs, surrounding blood vessels, nerves, and lymphatics. Other sites where they are found in abundance include the mucosa of the upper and lower respiratory tract, the gastrointestinal, and the reproductive tract. 12

Mast cells live in tissues for months after which, they undergo apoptosis (programmed cell death). Recent studies indicate that a sudden decrease in the SCF level is necessary for apoptosis. Further research is necessary to better understand mechanisms of apoptosis in mast cells and the mast cell hyperplasia that occurs in mastocytosis. 9

Functions of mast cells include regulation of gastric acid secretion, regulation of the microvasculature, and repair and remodeling of connective tissues. Their association with atopic disease is well known. Mast cells have also been observed in a multitude of neoplastic, fibrotic, and inflammatory processes such as lymphoproliferative disorders, interstitial lung disease, the synovium in rheumatoid arthritis, the testis in infertility, and in the heart and blood vessels in a number of cardiovascular disorders. 6,12

Based on morphology, functional, histologic, and biochemical properties, human mast cells can be divided into two types: connective tissue and mucosal. 13,14 An additional classification is based on neutral protease content: MC-T for mast cells with tryptase alone, and MC-TC for those with tryptase, chymase, carboxypeptidase, and cathepsin G. MC-T granules have a scroll-like pattern, and the MC-TC granules have a lattice-like configuration.

MC-Ts are mostly located in the lungs and MC-TCs are located mostly in the skin. 13 In vitro studies have shown that MC-TCs are more responsive to exogenous stimuli than MC-Ts. The significance of these differences is not fully understood. 15

Human Mast Cell Products

Mast cells contain a variety of preformed secretory granule mediators, which are released after cellular activation. These mediators include histamine, eosinophil chemotactic factor of anaphylaxis, neutrophil chemotactic factor, heparin, and enzymes such as tryptase, arylsulfatase A, -glucuronidase, peroxidase and superoxide dismutase ( Table 1).

6,16 Mature mast cells have the FcRI receptor on their surface and are activated as a consequence of allergen binding and Ig-E cross-linking of this receptors. There are also non-IgE-dependent mechanisms of mast cell activation: C3a, C5a in vivo, concanavalin A, calcium ionophores such as A23187 and X537 A in vitro. 14,17,18

Histamine was the first of the preformed mediators to be discovered and is the best known. Mast cells which may contain 4 to 10 pg per cell are the main source of histamine in the skin. 12 Histamine causes vasodilation and pruritus and is implicated in initiating the processes in which de novo eicosanoid mediators are produced. Other specific effects of histamine include bronchoconstriction, increased gastric acid secretion, and spasmodic contractions of various segments of the gastrointestinal tract. 12 Serum levels of histamine in patients with systemic mastocytosis exhibit a diurnal variation; the highest levels occur around 2:00 AM and the lowest levels at 2:00 PM. 1,19

De novo mediators produced after stimulation of mast cells include the arachidonate metabolites: prostaglandin D2 (PGD2), leukotrienes C4, D4, E4, as well as chemokines and cytokines. 6,16 PGD2 is the predominant arachidonate metabolite produced by human mast cells and is a major mediator of the humoral manifestations of systemic mastocyte activation. Its systemic effects include bronchoconstriction, inhibition of platelet aggregation, and the sensation of pruritus and pain. 16

Cytokines released from the mast cell include tumor necrosis factor- and IL-10, both of which have been implicated in inflammatory processes. Paradoxically, these cytokines also possess anti-inflammatory properties and protect tissues from necrosis. Other cytokines released include interferon-, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, and IL-16. 13,19,20

Because most mast cell-derived mediators can be produced by other inflammatory cells, the presence of a specific mediator cannot be correlated directly with activation. However, tryptase, PGD2, and histamine seem to be specific markers of mast cell activation. Tryptase has a variety of effects including stimulation of bronchial contractility and cleavage of a protein closely related to type IV collagenase in the epidermis. 13,14 In the lung, tryptase can stimulate human epithelial cell DNA synthesis and proliferation by the activation of protease-activated receptor (PAR)-2. 21 Recent studies suggest a role for tryptase activation of PAR-2 in the regulation of pigmentation. 22

MASTOCYTOSIS

Definition and Etiology

Mastocytosis is characterized by proliferation and excessive accumulation of mast cells in normal sites of distribution as the result of a hyperplastic response to an abnormal stimulus. 16 The skin is the most commonly involved site, but numerous other organs may also be involved. Local and systemic effects, summarized in Table 2,

depend on the location of the mast cells and the release of chemical mediators. 16 At least two pathogenic mechanisms exist in systemic mastocytosis. In one a somatic mutation and activation of c-kit leads to mast cell hyperplasia, and the other involves overexpression of soluble SCF. 15,19,23

SCF is the ligand for the transmembrane tyrosine kinase receptor c-kit, which is expressed on mast cells, hematopoetic progenitor cells, melanocytes, and germ cells. SCF is an important growth factor for the maturation and development of mast cells and can also play a role in cell chemotaxis and mediator release. Injection of the SCF/c-kit ligand CD 117, 3 also known as mast cell growth factor, into animals has induced skin changes similar to mastocytosis. 16 Apparently, an increased local concentration of SCF in the skin is present in systemic disease. SCF also stimulates melanocyte proliferation and melanin production, which may explain the skin changes in this group of patients. 16

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is important to the survival of the mast cells. Recently, mutations of c-kit (substitution of valine for aspartic acid 816, and glycine for valine 560) have been identified in the mast cell leukemia cell line HMC-1 and in some patients with mastocytosis. 3,23 Other point mutations of c-kit, appear to be related to different forms of disease. An example is the substitution of glycine-839 by lysine, which is associated with a typical pediatric mastocytosis that is mostly cutaneous. 3

Bone marrow mast cells in patients with adult onset disease express the cell surface markers CD2 and CD25. CD2 (LFA-2) is expressed only on neoplastic cells and is a potential indicator of mast cell neoplasm. 3 In some patients, bone marrow mast cells overexpress CD35, CD63, and CD69. In patients with mast cell leukemia, a malignant form of mastocytosis, the cells overexpress members of the bcl-2 family. 3

Epidemiology

Although the true prevalence of mastocytosis is unknown, in one study of patients seen in a dermatologic clinic, the frequency was reported as 1 in 2,500 patients. 17 No sex predilection is apparent. Onset may occur in early childhood and incidence peaks again in the third and fourth decade of life. 16,19 Familial cases are unusual, but one report suggested that cutaneous mastocytosis may be transmitted as an autosomal dominant trait. 6,24 Consequently, the disease is often misdiagnosed because of its rarity and complexity.

Presentation

Patients presenting with mastocytosis often complain of flushing, which may be accompanied by headache, dyspnea, wheezing, diarrhea, or syncope. They also can experience a variety of other signs and symptoms including tachycardia, hypotension, hypertension, rhinorrhea, or bone pain. 6,17 Some patients present with neuropsychiatric symptoms. Anaphylaxis is common, and occasionally can result in vascular collapse and death. 6,16,19

Symptoms are often triggered by a physical stimulus such as heat, cold, pressure, vibration, sunlight, or exercise. Drugs, such as morphine, codeine, aspirin, sulfa, penicillin, nonsteroidal anti-inflammatory drugs, amphotericin B, polymyxin B, dextran, and radiographic dyes have also been noted to trigger symptoms. Alcohol and certain foods such as chocolate or nuts have also been reported as triggers. 6 Clinicopathologic features of mastocytosis are summarized in Table 2.

Classification

Mastocytosis may be classified as benign (indolent), associated with a hematologic disorder, mast cell leukemia, or aggressive mastocytosis as detailed in Table 3. 16,19

The majority of cases (70% to 80%) are indolent in nature. 16,25 These patients usually present with cutaneous disease, which can be accompanied by syncope, coronary artery spasm, peptic ulcer disease, malabsorption, myelofibrosis, hepatosplenomegaly, or ascites. Mast cell leukemia has a poor prognosis, but, fortunately, is the least common form of the disease. Aggressive mastocytosis is also described as lymphadenopathic mastocytosis with eosinophilia. 10

Figure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7

Mastocytosis can also be classified by the affected organ system as cutaneous mastocytosis, extracutaneous mastocytosis, and other forms. Types of cutaneous mastocytosis include urticaria pigmentosa, mastocytoma (solitary lesion), diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans. 1,16,19,25

Urticaria pigmentosa (Fig 1) ,the most common form of cutaneous mastocytosis is present in >90% of patients with indolent mastocytosis but in only 50% of patients with aggressive disease. 19 In children, lesions can regress spontaneously in contrast to adult-onset mastocytosis in which lesions usually persist. Urticaria pigmentosa occurs almost exclusively in Caucasians. 6 Rare cases of familial urticaria pigmentosa have been reported. 6 Patients may urticate spontaneously or after trauma; they can have a few to several thousand lesions. The highest density is usually on the trunk. 8 Interestingly, the palms, soles, face, and the scalp are often free of lesions. 1

Typical lesions are red-brown macules and papules, which may be related to tryptase activation of PAR-2. 21 Patients may have pruritus, dermatographism, and flushing telangiectasia (Fig 2).8,16 Scratching over the lesions can lead to wheal and flare over and around the macules, which is known as Darier sign (Fig 3) . 8,16,25,26 In aggressive mastocytosis, urticaria pigmentosa tends to disappear. 10 Less common forms of urticaria pigmentosa include xanthomatous, pseudoxanthomatous, bullous, and nodular (Fig 4). 6 Lesions of urticaria pigmentosa are histologically very similar to the lesions in mastocytoma. 16

Mastocytoma is characterized by a solitary lesion 2 to 4 cm in diameter, located typically on the trunk or extremities (hands are usually spared). 8,16 Epidermal hyperpigmentation, Darier sign, vesicles, or bullae may also be present. These very rare lesions can be present at birth but usually appear within the first 3 months of life. In the majority of cases, the lesions will disappear (Figs 5 and 6) . 1,16 In adults, solitary mast cell tumors of the lung have been reported. 19

Diffuse and erythrodermic mastocytosis is a type of cutaneous mastocytosis that occurs almost exclusively in infants. 8 Lesions are typically round bullae, tense, and filled with clear fluid. The lesions can also be described as peau d’orange or peau chagrine which is edematous skin of a preblister formation. 16 In most of these cases, the lesions are not present at birth. Blisters occurring in neonatal period can be an early indicator of the disease. 16

Dermatographism with formation of hemorrhagic blisters is common. 1 Lesions usually resolve spontaneously between 15 months and 5 years, but a very important aspect is that the children are at risk for complications such as hypotension, shock, severe diarrhea, and malabsorption. 1,8

Telangiectasia macularis eruptiva perstans is a rare form of mastocytosis that occurs mostly in adults, specifically middle-aged, obese women. 1 The lesions are tan-brown-red telangiectatic macules. Patients usually do not present with pruritus and have no blisters (Fig 7). 1,16,19

In isolated cases, patients can have splenomegaly, an increased number of mast cells in the bone marrow, and radiographic changes, which suggest systemic involvement. 1

Extracutaneous mastocytosis can affect the hematopoetic, gastrointestinal, reticuloendothelial system, and also bones and lungs. The hematologic abnormalities most commonly seen in adults with mastocytosis are normocytic, normochromic anemia, and thrombocytopenia associated with leukocytosis or leukopenia. 6,16,17

The majority of the patients with systemic disease have gastrointestinal symptoms. Abdominal pain that is either dyspeptic or nondyspeptic with crampy, colicky symptoms is observed. 27 Flares of nondyspeptic pain are usually associated with ingestion of certain foods and stress. 27 Interestingly, approximately 15% to 20% of patients will complain of intolerance to alcohol, which is described as intense flushing commonly accompanied by abdominal discomfort.

Gastrointestinal symptoms are more common in adults than children (in adults 35% to 80%, in children 4%). 16 Other common complaints include nausea, vomiting, and diarrhea. 6,16,19,27 The pathogenesis of diarrhea can involve several mechanisms including gastric hypersecretion, malabsorption, and motility dysfunction. 19 Mediators which may be involved, include PGD2, histamine, gastrin, and vasoactive intestinal peptide. 6 Patients may present with peptic ulcer disease, esophagitis, evidence of portal hypertension, and ascites. Portal hypertension is probably secondary to obstruction of the intrahepatic veins as a result of desmoplastic fibrosis in the portal areas or hepatic sinusoids associated with the mast cell infiltrates. 6,16 In 17% of the cases, patients will present with ascites. 16 According to some studies, hepatomegaly is present in 40% to 70% of adults presenting with systemic mastocytosis. Abnormal liver function tests occur in 30%, and splenomegaly occurs in 50% of patients. 6,16

Other complications may include malabsorption and GI bleeding. 16,19,27 One case of mastocytosis-induced nyctalopia caused by malabsorption of vitamin A was reported. 28 An unusual case was reported, in which systemic mastocytosis was the cause of intrahepatic cholestasis. 29

Bone abnormalities are present in 70% to 75% of patients and most commonly include diffuse osteolysis, fractures, and osteosclerosis, which affect primarily the axial skeleton and the ends of the long bones. 6,16,30 The pathogenesis of osteoporosis and osteosclerosis in systemic mastocytosis is not clearly understood, but cell culture studies have implicated prostaglandin and heparin. 6 Only one-third of patients diagnosed with mastocytosis have increased mast cells in a bone marrow biopsy. These biopsies show histologic foci of spindle-shaped mast cells with lymphocytes and eosinophils around the periphery in 80% of the patients. 16,19,25 A decreased number of fat cells in the bone marrow can occur as a result of extensive mast cell infiltration or as a result of an increase in the hematopoietic elements. A reduced percentage of fat cells (<20%) is associated with a poor prognosis. 10,19 Lobulation of mast cell nuclei represents a cell atypia, and correlates also with a poor prognosis. 6

Other organs that may be involved in extracutaneous mastocytosis are the heart (endocardium, pericardium, and myocardium), bladder (which can possibly lead to interstitial cystitis), lungs, omentum, and meninges. 6 Respiratory manifestations occur in approximately 20% to 30% of the patients. Most of the patients will complain of wheezing and dyspnea. 6,13 Some patients have interstitial lung disease and progressive respiratory failure; others will develop chronic bronchitis or allergic rhinitis. 6

A wide spectrum of neuropsychiatric abnormalities including anxiety, depression, dementia with cerebral atrophy, Eaton-Lambert syndrome, seizure disorder, glioblastoma multiforme, and pituitary adenoma have been described in association with mastocytosis. 6,16,19 The pathogenesis of neurologic manifestations is controversial and poorly understood. This is another area in which research is needed.

Hematologic neoplastic disorders associated with mastocytosis include myeloproliferative disorders, mast cell leukemia, and malignant lymphomas. 6 In one reported case, a patient developed systemic mastocytosis 8 years after the diagnosis of multiple myeloma. 31

There also seems to be an increased risk for development of solid tumors such as breast carcinomas, pancreatic adenocarcinomas, carcinomas of the bladder, small-cell carcinomas of the lung, colon cancer, and hepatic cholangiocarcinomas. 6 In one case report, a patient developed systemic mastocytosis after a malignant ovarian germ cell tumor. 32 Some studies, however have failed to prove an association between solid tumors and mastocytosis. 6,25,27

Diagnosis of Mastocytosis

The most important tool for diagnosing systemic mastocytosis is a complete and detailed history. Patients may present with pruritus, flushing, urticaria, abdominal pain, nausea, vomiting, diarrhea, headaches, memory disturbances, depression, or difficulty in concentration. 8,25 Mast cell infiltration of tissues can be associated with bone pain and malabsorption. 7,25,33

A complete physical examination may show evidence of skin lesions, which are suggestive of mastocytosis. Many patients will have dermatographism. Half the patients will present with skin lesions. A skin biopsy may show an increased number of the mast cells (10 times normal or more). 10,19,25 It is important to note that a small increase in mast cell numbers on skin biopsy (three or four times normal) is not diagnostic, although patients have symptoms suggestive of mastocytosis.

Although, the need for obtaining a bone marrow biopsy in all patients remains controversial, those with clinical suspicion of organ involvement other than the skin, such as those with hepatosplenomegaly, lymphadenopathy, anemia, leukocytosis, or thrombocytopenia, require a bone marrow biopsy. 19 An especially helpful tool in diagnosing mastocytosis can be tryptase-staining of the bone marrow. Even a few mast cell infiltrates, can be detected using antitryptase antibody G3. 3,34,35

Radiologic exams are also important. Patients can present with x-ray findings of osteosclerosis, osteoporosis, and osteolytic bone lesions. Other investigations which can help to make the diagnosis include upper gastrointestinal radiograph, small bowel radiograph, computed tomography, and endoscopy. 25

Laboratory tests useful in diagnosis of mastocytosis include plasma and urine histamine, 24-hour urine collection for histamine, 1-methylhistamine and 1-methylimidazoleacetic acid, PGD2 metabolites, in addition to serum levels – and -tryptase. 19,36 -Tryptase is constitutively secreted as -protryptase and is commonly elevated in patients with aggressive disease. Recent data show that a serum -protryptase level (which is calculated by subtracting the measured -tryptase level from the total tryptase level) seems to be a valuable screening test indicative of mastocytosis when the total to -tryptase ratio is >20 ng/mL. 3,6,37-39

In most patients with cutaneous mastocytosis without systemic involvement, serum -tryptase and -tryptase levels are within normal limits. -Tryptase levels may be normal in mastocytosis patients, but when elevated, indicate systemic disease. 3 Serum tryptase levels may also be useful to monitor response to treatment, which diminishes the number of mast cells. Peak plasma levels of tryptase occur 1 to 2 hours after an attack, whereas peak plasma levels of histamine occur at 5 to 30 minutes. 3

Because of the relatively rapid clearance of histamine, serial urine specimens, collected every hour, for 4 hours after an acute attack should be obtained. Sometimes the histamine level may be increased in only one of these specimens and normal in others. Increased urinary excretion of histamine with levels above 40 g/24 hours (normal <30 g/24 hours) can be diagnostic. 6

Detection of elevated levels of PGD2 metabolites in urine, measured by mass spectroscopy, may be helpful for diagnosis. However, this test is not always available. Because several symptoms of mastocytosis (especially flushing) are shared with carcinoid syndrome, a 5-hydroxyindol acetic acid level in urine should be obtained. It is also important to check metanephrine levels in the urine to rule out pheochromocytoma. 19,25

A delay in blood drawing after the acute attack, delay in transportation to the laboratory, or delay in processing may interfere with the accuracy of these test results. Diagnosis of mastocytosis depends on the cumulative findings from patient history, laboratory markers for mast cell involvement, radiologic examination, and bone marrow biopsy. Other disorders that should be included in the differential diagnosis are shown in Table 4.

Treatment

Treatment of mastocytosis is mostly conservative and symptomatic. An important aspect of therapy, but sometimes very difficult to implement, is avoidance of factors such as physical exercise, friction, temperature changes, alcohol ingestion, or use of medications listed previously, that can trigger acute responses. 8 General anesthesia can be troublesome. 8,16

Severe anaphylaxis after Hymenoptera stings is possible 1; patients are advised to carry an Epi-Pen (epinephrine; Dey, Napa, CA) with them at all times. Anaphylactoid shock from Hymenoptera sting can be the presenting symptom of mastocytosis. 40 Venom immunotherapy in these patients is indicated. 41,42 Patients should also wear medical alert (MedicAlert, Turlock, CA) bracelets. In case of shock, aggressive intervention with epinephrine and volume repletion is critical and potentially life-saving. 6,42

Drugs useful in the treatment of mastocytosis are listed in Table 5.

Commonly used as first line treatment, H1 and H2 blockers can alleviate symptoms of pruritus and whealing. 1,6,19,42 Any antihistamine can be useful, but doxepin (Roerig/Pfeifer, New York, NY) may be a superior choice because of its central nervous system effects combined with its extremely potent antihistaminic activity. 16 The nonsedating antihistamines may be better tolerated by patients. Instead of H2 blockers, proton-pump inhibitors can be used to inhibit gastritis. 42 Anticholinergics may alleviate diarrhea. The oral administration of disodium cromoglycate (Gastrocrom Medeva, Rochester, NY), a mast cell stabilizer, can also improve GI symptoms. 6,13 Cromolyn sodium can also be used as an inhaler for respiratory symptoms. 19,42 Antileukotrienes can be useful in treatment of mastocytosis. 42 Ketotifen has been reported to be somewhat helpful, as has an antagonist of platelet activating factor (BN520630). 1,6

Chronic treatment with aspirin (in non-aspirin-sensitive patients) has also been advocated. Aspirin inhibits the formation of cyclooxygenase-derived products of arachidonic acid, including PGD2. Because aspirin can induce mast cell activation and severe hypotension, therapy needs to be started at low doses and advanced as tolerated to obtain a serum concentration of 20 to 30 mg/dL. 16,17,42 Recently, treatment with cyclosporin combined with low-dose methylprednisolone has been reported as successful. 43

For skin lesions treatment with topical corticosteroids can decrease the hyperpigmentation and the mast cell infiltrates for several months. 1 Steroids should be applied topically under a plastic wrap occlusion for 8 hours a day more than 8 to 12 weeks. 19 In mastocytosis patients with skin lesions, psoralens (8-methoxypsoralen) are often combined with ultraviolet A. Photochemotheray can have general and cosmetic benefits. The mechanism of action of PUVA is unclear, but circulating levels of histamine are decreased. 16,19,25

Recent studies investigating the use of interferon -2b as a treatment for aggressive forms of mastocytosis have yielded mixed results. 8,16,42,44 Tacrolimus (FK 506), a macrolide with anti-tumor and immunosuppressive properties that blocks cellular degranulation as well as the transcription of several mast cell cytokine genes, such as IL-3 and IL-5, may need clinical evaluation. 45 Chemotherapy is used in malignant forms of disease. 25,42

The treatment of systemic mastocytosis remains empirical, and does not adequately address the progression of the disease.

Prognosis

The prognosis in young children is nearly always good. In adults, the prognosis is best when systemic mastocytosis occurs with only skin involvement. Characteristics that have been associated with a poor prognosis include being male, constitutional symptoms, presence of hepatosplenomegaly, abnormal bone x-rays, absence of urticaria pigmentosa or other skin signs, 1 and a decreased number of fat cells in the bone marrow biopsy. 8,19 Mastocytosis patients with hematologic disorders have a significantly reduced 5-year survival rate. 8 Mean survival in mast cell leukemia is <6 months. 19

CONCLUSION

Mast cells play a major role in many physiologic processes, but for reasons that are unclear, they may become an aggressive force, which can damage the natural biologic balance. Probably one of the most difficult tasks for the clinician is early recognition of this disease, which has a multitude of clinical presentations. Although appropriate referral to a specialist is essential, the relatively weak arsenal presently available for treatment is a considerable hindrance. Further studies are necessary to clarify the mechanisms by which systemic mastocytosis overcomes the normal physiologic processes and to develop a more sophisticated approach to treatment.

ACKNOWLEDGMENTS

Pictures have been provided through the courtesy of Drs. William Burke and Clayton Wheeler.