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Pediatric Mastocytosis

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The onset of mastocytosis occurs between birth and 2 years of age in approximately 55 percent of all cases; an additional 10 percent develop the disease before the age of 15 years. Mastocytosis in these age groups differs in many respects from mastocytosis that has its onset in adulthood. The typical presentation of pediatric-onset mastocytosis consists of cutaneous manifestations: either a solitary mastocytoma, urticaria pigmentosa, or less commonly, diffuse cutaneous mastocytosis. Particularly in infants, bullous eruptions may occur. Mastocytosis in infants and children may involve internal organs, including the bone marrow and the gastrointestinal tract, although such manifestations appear to be less common in children than in adults. Plasma histamine levels may be elevated in pediatric-onset mastocytosis. Treatment usually involves the use of H1 and H2 antihistamines to control itching and to control the hypersecretion of gastric acid that may occur. The prognosis for children with mast cell disease is variable; approximately half of the children with urticaria pigmentosa may experience resolution of lesions and symptoms by adolescence.

Mastocytosis may present during infancy, childhood or adulthood. The disease is characterised by an increased number of tissue mast cells and symptoms caused by the release of mast cell mediators. The organ system most frequently involved is the skin (cutaneous mastocytosis); however, mastocytosis may involve the lymphoreticular (liver, spleen, lymph nodes), gastrointestinal, bone marrow, and skeletal systems (systemic mastocytosis).

The symptoms are both isolated to the organ system involved and systemic, due to local or generalised release, respectively, of histamine and other mast cell mediators, i.e., leukotrienes,prostaladins, and platelet-activating factor. In addition to the age of onset, adult and pediatric forms of mastocytosis differ in their clinical course and pathophysiology. This article will review pediatric-onset mastocytosis, providing information for counselling parents of children with mastocytosis and a starting point for study and treatment of this unusual and protean disorder.

Clinical Manifestations

The onset of mastocytosis occurs in approximately 55 percent of patients between birth and 2 years of age; another 10 percent develop symptoms between the ages of 2 years and 15 years (pediatric onset). The remaining 35 percent of patients develop symptoms after 15 years of age (adult onset). In the pediatric population evaluated at the National Institute of Health, 16 of the 17 children had onset of their disease before 2 years of age, with 14 manifesting the disease by 6 months of age. Two patients, one with urticaria

pigmentosa and a second with diffuse cutaneous mastocytosis, presented at birth with skin lesions (congenital mastocytosis). In children there appears to be an equal sex distribution, and although individuals from varied ethnic groups have been affected, mastocytosis appears to be more common in Caucasians. The occurrence of mastocytosis appears to be sporadic, yet 47 cases of familial mastocytosis have been reported, with dominance in 14 families. In the pediatric-mastocytosis study population at NIH, we have not yet identified a family in which mastocytosis could be shown to be familial.

The typical presentation of pediactric-onset mastocytosis consists of cutaneous manifestations of either a solitary mastocytoma, urticaria pigmentosa, or less commonly, diffuse cutaneous mastocytosis. In addition, adults may present with telangiectasia macularis eruptive persitans, but that lesion is rarely if ever observed in pediatric patients. The nodular form of mastocytosis that has been reported most likely reflects a localised collection of mast cells, which may be associated with either urticaria pigmentosa or diffuse cutaneous mastocytosis, as we observed in one child with diffuse cutaneous mastocytosis followed at the NIH. Although some children manifest one form of skin lesion, overlap of classifications can occur.

Lesions of urticaria pigmentosa may continue to increase in number after diagnosis, but children who present with a mastocytoma rarely demonstrated additional lesions more than 2 months subsequent to the initial lesion.

Strokig or trauma of affected skin results in a wheal with flare (Darier’s sign) or (less commonly than with large lesions, i.e. mastocytomas) flushing and hypotension. Infrequently, an infant will exhibit hepatosplenomegaly or skeletal lesions in addition to other clinical findings due to mast cell hyperplasia in these organ systems. Rarely, an infant with cutaneous mastocytosis will initially present with an extensive bullous eruption that must be differentiated from other bullous diseases of infancy.

Pruritus is the primary presenting symptom in children with mastocytosis.

The pruritus may be intermittent or unremitting, with itching leading to extensive excoriation of the skin. Additional symptoms include flushing, gastrointestinal complaints (i.e., vomiting, colicky pain, diarrhea), headaches, and in children less than 2 years of age, bullae. In the NIH patient population of 17 children with pediatric-onset mastocytosis, 88 percent manifested pruritus, 65 percent flushing, 53 percent vesicles/bullae, 41 percent abdominal pain, 18 percent bone pain, and 12 percent headache.

Asthma was an infrequent symptom and was seen in only one of 17 pediactric mastocytosis patients.

Prolonged bleeding, usually in the skin or gastrointestinal tract, has been observed in pediatric mastocytosis, especially in infants with diffuse cutaneous mastocytosis. In some cases, abnormal coagulation studies with reversal of abnormal thrombin clotting time in vitro with protamine (a heparin antagonist) have been documented, although circulating heparin has yet to be established as the cause of the bleeding diathesis. In vivo reversal of the abnormal coagulation with protamine has been considered but has yet to be employed. Perhaps the bleeding tendency in skin may result when heparin contained in skin mast cells acts as a local anticoagulant, permitting prolonged bleeding from wound sites. Gastrointestinal hemorrhage appears to be associated with peptic ulcer formation due to high levels of circulating histamine.

Children with mastocytosis appear to be at no greater risk than other children for the development of allergies. In the NIH study, the patient group demonstrated no increase in atopy and their serum IgE levels were within normal limits. Those observations suggest that the etiology of pediatric-onset mastocytosis is not related to the development of allergic diseases.

Adult patients with mastocytosis have been reported to experience systemic anaphylaxis after insect stings. This does not appear necessarily to relate to an immunoglobulin E (IgE)-mediated allergy to insect venom, but may in some cases be secondary to direct activation of mast cells by the insect venom itself. The possibility of an adverse reaction to an insect sting suggests that epinephrine (Epi-Pen, ANA-Kit) might be prescribed for selected children.

Mastocytosis patients are often instructed to avoid mast cell degranulating agents to minimise the potential of systemic mast cell mediator release. Information supporting that recommendation is deficient. Only one study of five patients (two adults, one child, and two infants) has reported systemic symptoms to codeine (three of five patients) and polymyxin B (three of five challenges) given subcutaneously and intramuscularly, respectively.

During our study of pediatric mastocytosis, the synthetic narcotic meperidine was a constituent of a sedative used prior to diagnostic and investigational procedures. This synthetic narcotic has been reported to be safely used in patients with mastocytosis. One child with urticaria pigmentosa who received the medication developed extensive bullae without other symptoms of mast cell degranulation 2h after receiving the meperidine-containing sedative. As we could not rule out an adverse reaction to the synthetic narcotic, we no longer routinely use it but now use intravenously administered lorazepam, a short-acting benzodiazepam. This sedative has not resulted in any adverse reactions to date in our patient population. We believe that routine use of narcotics should be avoided if possible in this patient population. If they must be used, caution and close observation are essential.

The use of any potential mast cell secretagogue is of concern.

However, one review of general anesthesia in 12 children with cutaneous mastocytosis revealed no significant adverse reactions.

Diagnosis And Laboratory Evaluation

Typically the diagnosis of pediatric-onset mastocytosis is based on the recognition of the clinical appearance of the cutaneous lesions. Because other pediatric skin lesions, i.e., xanthomas, juvenile xanthogranulomas, and pigmented nevi, may have a similar appearance, diagnosis should be confirmed by documentation of significant mast cell hyperplasia on biopsy, employing toluidine or Giemsa staining techniques. Bullous lesions may precede the typical skin lesions of urticaria pigmentosa or diffuse cutaneous mastocytosis in infants with mastocytosis and may resemble other bullous skin diseases of infancy, such as bulllous erythema multiform or scalded skin syndrome. Thus biopsy of bullous lesions is essential for diagnois. Examination of bullous fluid from one patient revealed a predominance of neutrophils without mast cells. The skin biopsies from pediactric mastoctosis patients may exhibit extensive mast cell infiltration around blood vessels and within skin appendages, in some cases resulting in the disruption of normal skin architecture. Despite the gross differences in the cutaneous lesions in children with urticaria pigmentosa and diffuse cutaneous mastocytosis, skin mast cell numbers and dermatopathology were similar in four children with urticaria pigmentosa and one child with diffuse cutaneous mastocytosis.

Plasma histamine levels have been elevated in the majority of pediatric mastocytosis patients studied. In children with urticaria pigmentosa the histamine levels vary from normal to several times normal. In those with diffuse cutaneous mastocytosis, plasma histamine levels can reach remarkably high levels, even exceeding values reported in adults with systemic mastocytosis. High levels of plasma histamine in children with diffuse cutaneous mastocytosis may reflect the extreme hyperplasia of their dermal mast cells. One child in our study, who had markedly elevated plasma histamine levels (more than 100 times normal), developed esophageal ulcerations with hemorrhage, with no other systemic histamine effects observed. Thus, plasma histamine levels may be useful in following the clinical course of pediatric-onset mastocytosis and may identify those children who are at risk for the development of gastrointestinal ulcerations.

Further diagnostic evaluations, such as gastrointestinal radiography/endoscopy, skeletal surveys/bone scans, and bone marrow examinations, should be reserved for those children who exhibit evidence of organ-system involvement (e.g., anemia, leukopenia, thrombocytopenia, hematochezia, melena, severe bone pain).

In our study, bone marrow examinations in 17 children with mastocytosis revealed marrow pathology. Bone marrow aspirates identified five children with increased mast cell numbers and 10 children with eosinophilia.

Trephine core bone marrow biopsies in 17 children demonstrated focal areas of mast cell hyperplasia in 10 children. Those lesions consistd of focal perivascular and paratravecular aggregated of mast cells, eosinophils, and early myeloid cells; they differ markedly from the typical lesions observed in

the bone marrow of patients with adult-onset mastocytosis. Such adult lesions consist of nodular collections of fusiform mast cells associated with lymphocytes and eosinophils. Despite the presence of mast cell hyperplasia in the marrow of 10 to 15 children, such lesions were not pathognomonic for pediatric-onset mastocytosis, as these were observed in three of 16 control pediatric patients with other hematologic diseases. The significance of such lesions is unknown, but may reflect an abnormality of mast cell proliferation.

The usefulness of skeletal surveys in pediatric mastocytosis is limited.

A review of 95 patients who underwent skeletal surveys revealed no skeletal lesions attributable to mastocytosis in 81 patients. Although 14 patients demonstrated significant bone lesions thought to be due to systemic mast cell involvement, none developed a malignant course. A follow-up of three patients revealed resolution of their skeletal abnormalities. The significance of these skeletal lesions remains unclear and does not appear to predict systemic progression.

Treatment

The treatment of pediatric onset mastocytosis is currently limited to the palliation of symptoms, usually pruritus. The treatment of choice is a classical H1 antihistamine, such as hydroxyzine. In a recent study of hydroxyzine versus ketotifen, hydroxyzine provided substantial relief of pruritus, bullae, flushing, and abdominal pain without significant side effects from the hydroxyzine. In the child who exhibits gastrointestinal symptoms of hyperacidity or ulceration, the addition of an H2 antihistamine may be warranted. The use of oral sodium cromolyn in adult-onset mastocytosis, although having shown no effect on urine histamine and N-methylimidazole acetic excretion, had ameliorated gastrointestinal symptoms of diarrhea, abdominal pain, nausea, and vomiting. No improvement in symptoms of flushing, urticaria, headache, or bone pain was observed. That study and the known pathophysiology of gastrointestinal-system involvement in mastoctosis suggests that the use of oral sodium cromolyn in pediatric patients with gastrointestinal symptoms is reasonable, but documentation of efficacy requires a formal study utilizing a double-blind placebo-controlled design with crossover. A previous study of three children with pediatric-onset mastocytosis suggested improvement in both gastrointestinal symptoms (100%) and non-gastrointestinal symptoms(pruritus, 66%; wealing, 33%), but the protocol of that study did not control for maturational improvement.

Rarely, infants with pediatric-onset mastocytosis may develop a shock-like illness accompanied by bullous eruptions and gastrointestinal hemorrhage. These infants require intensive care support with treatment with both H1 and H2 antihistamines as well as corticosteroids to correct the systemic effects of the massive mast cell mediator release. In patients with adult-onset disease, epinephrine has been useful in reversing severe hypotension unresponsive to antihistamines and fluid administration. This treatment appears to be reasonable for children with severe hypotension unresponsive to standard therapy.

The use of topical corticosteroids to aid the resolution of skin lesions has shown some efficacy, although widespread and long-term use of potent topical corticosteroids may cause hypothalamic-adrenal suppression in young infants. This treatment should only be undertaken in severely affected children and in conjunction with a physician experienced in high potency topical steroid use in children.

Treatment of the bullae that may occur in children less than 2 years of age is similar to that of a scald injury: local care and prevention of infection. Bullae heal without scarring but may leave an area of hyperpigmentation. Intravenous steroids have been reported to be useful in the treatment of severe and progressive bullae of infantile urticaria pigmentosa. In the child with isolated mastocytomas with resultant severe systemic symptoms from mast cell mediators, surgical excision of the mastocytoma may be the treatment of choice, although the majority of mastocytomas spontaneously resolve after several years.

Prognosis

The prognosis for children with mast cell disease is variable. Children with mastocytomas have not been reported to develop systemic involvement, and their lesions typically exhibit involution during childhood. Retrospective studies report that approximately half of the children with urticaria pigmentosa will experience resolution of lesions and symptoms by adolescence, with the remainder exhibiting marked reduction in symptomatic cutaneous lesions and dermatographism. One report of 47 adults and 122 children with urticaria pigmentosa disclosed that 27 of the adults experienced onset of their mastocytosis in childhood. Children whose mastocytosis persists into adult life typically exhibit a course similar to adult-onset mastocytosis, in which 15-30% of patients develop systemic involvement.

Rarely a child will develop aggressive mastocytosis, most often with bone marrow involvement, although any organ system may be involved. This systemic involvement may be infiltrative (not unlike reticuloendotheliosis, such as histiocytosis) or may exhibit circulationg mast cells, resembling a leukemia.

Importantly, the observation of circulating mast cells does not always imply an aggressive malignant condition; it has been reported in children with urticaria pigmentosa who have been otherwise healthy. In a reported case of “mast cell leukemia”, circulating mast cells were found at one hospitalization, but in a subsequent hospitalization (during which the child died) there was no evidence of circulating mast cells despite extensive organ-system involvement. Several reports of the occurrence of acute lymphocytic leukemia raise the possibility of hematologic malignancy in children with rapid or late-onset urticaria pigmentosa, although the association has yet to be firmly established.

The prognosis for infants with diffuse cutaneous mastocytosis appears to depend on whether they exhibit bullae early in the neonatal period or if such bullae are delayed relative to the appearance of their skin lesions. Eight infants who manifested bullae as their initial symptoms of mastocytosis all exhibitied systemic involvement, and two died of their disease. Children who manifest diffuse cutaneous mastocytosis prior to bullous eruptions appear to have a better chance of a gradual improvement in their disease.

The development of systemic disease appears to be more common in adult mastocytosis than in pediatric mastocytosis. A report of 71 patients with systemic disease revealed a ratio of pediatric to adult patients of 1:2.8.

The association or development of malignancy appears to be less frequent in children. Of 20 mastocytosis patients with an associated malignancy, only four were children (pediatric to adult ratio of 1:4). Death in children with mastocytosis has been reported to be secondary to hemorrhage, leukemia, and cachexia.

Childhood Mastocytosis

Camila Krysicka Janniger, MD.

One of the most fascinating tumors occurring in children is mastocytosis.

In this disease infiltrations of mast cells may release their pharmacologically active products to induce local urticaria (Darier’s Sign) a generalized mastocytosis syndrome analogous to the carcinoid syndrome, or even massive degranulation of mast cells that can lead to vascular collapse. To reach a diagnosis dermatoligist employ uncommonly utilize stains such as Giemsa or Toluidine blue to identify mast cells by staining their intracytoplasmic granules metachromatically (reacting with a different color from that of the dye employed to stain them). Fortunately, for most children this disease is not life threatening, except in rare cases where massive mast cell degranulation occurs or when an associated leukemia or related disorder developes.

The Mast Cell

The mast cell itself is truly remarkable. The symptoms produced by mast cells may be explained by the release of their products. Mast cells contain heparin, histamine, cytokines such as interleukins (1l-1,1l-3,1l-4.1l-5,1l-6) as well as multiple postaglandins and tumor necrosis factor alpha. They also contain other substances such as tryptase, chymase, and two other natural proteases; all four of these enzymes are homologous with pancreatic proteases.

Epidemiology of Childhood Mastocytosis

Mastocytosis is a disease characterized by the infiltration of various organs by mast cells, with the skin being the most affected organ. It’s heterolgenous nature can provide a difficult challenge for dermatologists.

Mastocytosis is a very uncommon disease that is classified into two types (pediatric and adult). Fifty five per cent of cases develope between birth and two years of age. In another ten per cent, mastocytosis developes between two and fifteen.

Mastocytosis occurs equally in both sexes and affects all races, although it predominates in caucasians. Despite it’s sporadic occurrence, there are forty-seven families with more than one person affected with urticaria pigmentosa. It occurs in monozygotic twins, and some consider diffuse cutaneous mastocytosis to be inherited as an autosomal dominant trait.

Others believe that mastocytosis is not a hereditary disease. Cutaneous mastocytosis in pediatric groups can be divided into the following conditions; Urticaria pigmentosa; mastcytoma; diffuse mastocytosis; and very rarely common telangiectasia macularis eruptiva perstans. Visceral involvement (mastocytosis may develope but does not occur with solitary mastocytosis.)

Urticaria Pigmentosa

Urticaria Pigmentosa (UP) is the most commonly observed type of mastocytosis that occurs in children. It usually developes within the first six months of life (media age, two months) and comprises 80 per cent of the mast cell diseases noted in this pediatric age group. Lesions characteristically consists of well demarcated red-brown macules and papules that have a tendency to coalesce into plaques and are characterized by increased skin markings. The distribution of lesions is diffused, with the trunk most commonly affected. Lesions may occur anywhere on the cutaneous omucosal surface. After the age of ten, lesions tend to be smaller but more numerous. Lesions of urticaria pigmentosa may be associated with bullac formation, especially infants; bullous lesions sometimes precede the typical one of urticaria pigmentosa. A useful diagnostic sign is histamine release in which erythema with urtication developes after the lesion is mildly traumatized. This sign can be easily produced in the office by stroking the skin with a tongue blade or rubbing it with a key (Darier’s sign).

Dermatographism is also characteristic and easily elicited.

Solitary Mastocytoma

Mastocytoma, the other common form of mastocytosis presents in 10 to 15 percent of children with mast cell disease. It starts usually within the first three months of life. Lesions may be solitary or multiple and appear as reddish brown nodules or plaques that range in size up to seven centimeters in diameter. As in urticaria pigmentosa, dermatographism ad Darier’s sign can be elicited easily.

Diffuse Cutaneous Mastocytoma

Diffuse cutaneous mastocytoma is a rare form of the condition that is characterized by diffuse infiltration of the entire skin by mast cells. It presents usually before the age of three years. The skin may appear normal in color or may have a reddish yellow hue with thickening and palpable edema.

Severe dermatographism with formation of hemorrhagic bullae is very common in this form of the disease. Bullae followed by erosion and crusting may be the first presenting sign, often induced by minor trauma. In this form of mast cell disease, there is a high-risk of massive histamine release from mast cell granules that can result in hypotension and shock. Diarrhea may be a common gastrointestinal symptom. Patients with this form have the highest frequency of systemic mast cell disease.

Rare Childhood Forms of Mastocytosis

Telangiectasia macularis eruptiva perstans is noted very rarely among children. It is characterized by telangiectatic and erythematous macules, 2 to 6 mm in diameter, that exhibit a poorly demarcated border. Mast cell leukemia is fortunately quite rare, sometimes presenting with cutaneous lesions of urticaria pigmentosa.

Systemic Mastocytosis

In sytemic mastocytosis, which occurs most commonly in older children, symptoms are induced by activation of mast cells in organs other than the skin. Mast cell activation can be accomplished by immunological or nonimmunological stimuli. Evidence of systemic involvement includes diarrhea, nausea, vomiting, abdominal pain, tachycardia, flushing and headache.

Malabsorption can develop as a rare complication. Hepatomegaly, splenomegaly, and lymphadenopathy may also be evident. Bones are most commonly affected by systemic mast cell disease, with osteosclerosis or osteoporosis visualized on roentgenographic or scintographic studies. Bone pain may be a clinical problem. Respiratory symptoms are unusual. Systemic mast cell disease may be associated with lymphocytic or myelogenous leukemia or related disorders. Rarely, circulating mast cells may be seen that resemble the deadly but rare mast cell leukemia. These cells, however, do not have an aggressive course.

Diagnosis

Diagnosis of mast cell disease is based upon the clinical appearance of the lesions and confirmed by skin biopsy with special stains such as toluidine blue or Giemsa stain, which show metachromatic mast cell granules by staining them red-blue or purple. A new method of visualizing mast cell granules is accomplished by the fluorescent staining technique which employs avidine conjugated to fluorochrome dye. The yellowish coloration of mastocytomas and some nodules of urticaria pigmentosa may suggest juvenile xanthogranuloma clinically. Bullous forms in childhood must be distinguished from forms of epidermolysis bullosa, erythema multiforme, and other blistering disorders.

Systemic Work-up in Children

The approach in treating solitary mastocytomas is easy, as these are localized cutaneous lesions. But it is difficult in children to justify the use of invasive testing to evaluate the urticaria pigmentosa and diffuse cutaneous mastocytosis for systemic involvement. The plasma histamine level may be useful for pediatric onset cases, identifying those at risk of gastrointestinal ulcerations. It sometimes reflects systemic involvement, but may be even more elevated in patients with diffuse cutaneous mastocytosis.

Histamine levels are increased in most patients with mastocytosis. Urinary histamine metabolites, N-methylhistamine, and N-methylimidazoleacetic acid are more sensitive than histamine and correlate well with bone marrow involvement.

Often, the skin biopsy, a routine blood chemistry study, routine complete blood count with peripheral smear, and a serum or urine histamine (or histamine metabolite) level are the only tests to perform in a child with mastocytosis.

Tryptase and selected other mast cell products may be as useful to monitor as is histamine, but commercial assays are not available for diagnostic use.

Additional clinical testing, including gastrointestinal x-rays or endoscopy, bone marrow aspiration or biopsy and skeletal surveys or bone scans should be reserved for children with clinical evidence of specific organ involvement. Although the bone marrow is infiltrated at least focally with mast cells in up to 90 percent of childhood cases of systemic mast cell disease, bone marrow aspirations and biopsies may be of limited value unless the patient has severe bone pain, anemia, leukopenia, and thrombocytopenia.

The significance of skeletal lesions in these patients is unclear and does not predict a fulminant progression.

Prognosis

The prognosis of mastocytoma is good, with spontaneous involution typical.

Children with urticaria pigmentosa have a more variable course, with one-half of them having lesions disappear before puberty and the other half usually having significant improvement. Among children with lesions persisting into adulthood, 30 percent have systemic involvement. However, in some patients there is an aggressive course, with fatal visceral involvement. In addition, in patients with systemic mastocytosis there is an increased risk of lymphoma/leukemia, although its incidence is well below the 24 percent noted in the literature.

Treatment Approaches

Treatment with antihistamine H-1 blockers is a good therapy for mastocytosis that is associated with pruritus. When there are marked gastrointestinal symptoms, an H-2 blocker may be added. Abrupt release of histamine causing circulatory collapse should be treated with epinephrine filled syringes for self-injection. Cromolyn sodium decreases bone pain, headaches, and gastrointestinal complaints. Aspirin may cause mast cell degranulation, yet paradoxicallly it can be used clinically with caution to alleviate the prostaglandin-induced flushing after premedication with H-1 and H-2 blockers.

Potent steroids under occlusion can reduce local symptoms. PUVA therapy may also help fade the lesions of urticaria pigmentosa. Patients with systemic mastocytosis must be educated to avoid substances that induce mast cell degranulation.

 

Disorders of Mast Cells

Mastocytosis

The term mastocytosis encompasses a group of clinical disorders that result from an abnormal proliferation of tissue mast cells. Although a wide range of clinical symtoms may occur, pruritus and lesional skin urtication (hive or wheal formation) are the most common complaints. Several different cutaneous lesions have been noted in patients with mastocytosis, including a solitary nodule or plaque (mastocytoma), hyperpigmented papules or macules, and telangiectatic pigmented macules. Two subgroups of mastocytosis patients are recognized: those with only skin involvement (cutaneous mastocytosis) and those with mast cell infiltrates involving several different organs (systemic mastocytosis). Both benign and malignant forms of systemic mastocytosis are known. Treatment is directed at inhibiting both the local and systemic efects of released mast cell secretory products.

Clinical Features

Cutaneous Mastocytosis

Patients with abnormal accumulations of mast cells localized to the skin frequently seek medical attention because of their cutaneous lesions and associated symptoms. Pruritic urticarial wheals at the site of skin mast cell infiltrates are the most frequent complaint. More severe symptoms, such as flushing, dyspnea, diarrhea, and syncope have been reported in this patient subgroup and are generally associated with extensive cutaneous involvement.

Cutaneous and systemic symptoms may be exacerbated by exercise, heat, or local trauma to the lesions. A variety of compounds, including alcohol, narcotics, salicylates, and anticholinergic medications also have been implicated in provoking the clinical manifestations. The skin lesions most frequently encountered in patients with cutaneous mastocytosis include either a yellow to tan solitary nodule or plaque (mastocytoma) or a variable number of hyperpigmented macules and/or papules. A mastocytoma may be present at birth or can arise within several months thereafter and classically involves a distal extremity. The onset of the macular/papular variant (urticaria pigmentosa) occurs over a much greater range of age which can be anywhere from several weeks after birth to adult-hood. Generally these lesions spare the face, palms, and soles. Both the localized and diffuse forms of cutaneous mastocytosis may urticate spontaneously and occcasionally may evolve into transient nonscarring vesicles or bullae. Vesicle or blister formation occurs exclusively in infants and greatly decreases in frequency by 3 years of age.

The cutaneous lesions of mastocytosis in children generally resolve by early adult life, whereas those occurring in adults persist indefinitely. Mast cell infiltrates in the skin can be identified clinically by firmly rubbing a characteristic lesion. The formation of an urticarial wheal (Darier’s sign) at the lesion site is indicative of mast cell mediator release.

Systemic Mastocytosis

The term systemic mastocytosis refers to an abnormal infiltration of mast cells into several organs and usually also includes involvement of the skin.

Although systemic mastocytosis has been reported in all ages, adults appear to have a greater incidence than children. Two forms of the systemic variant are recognized: a benign form, which remains relatively static and is characterized by mast cell infiltrates in a limited number of extracutaneous sites, and a rare malignant form, which is typified by uncontrolled mast cell proliferation and widespread organ involvement. The same wide range of cutaneous mastocytosis patients also may be found in patients with extracutaneous disease. Many symptoms are attributable to the diverse physiologic effects of secreted mast cell mediators such as histamine and prostaglandin D2. Additional symptoms of fever, malaise, weight loss, bone pain, epigastric distress, and problems with mentation (cognitive disorganization) may signal systemic involvement.

Types of cutaneous lesions that have been described in patients with systemic mastocytosis include: widespread hyperpigmented macules and papules; discrete telangiectatic, pigmented macules; diffuse infiltrative plaques and nodules; and dermographism associated with episodic flushing. Hyperpigmented macular/papular lesions occurring with systemic disease are indistinguishable from the lesions seen in this variant of the isolated cutaneous disease; however, when these skin changes are observed in an adult patient, the likelihood of systemic involvement is significantly increased. The telangiectatic form of mastocytosis (telangiectasia macularis eruptiva perstans) is readily identified by discrete, reddish brown macules with overlying telangiectasias. Frequently, these lesions are distributed symmetrically over the trunk and proximal extremities but spare the face, palms, and soles. The rare infiltrative form of mastocytosis is characterized by highly pruritic, yellow to tan lichenified plaques, which have a striking “grained leather” appearance. Because of their yellow color, these skin lesions have been likened to zanthomatous infiltrates.

Recently, an additional group of systemic mastocytosis patients has been identified. Most lack persistent cutaneous lesions, but some experience an intermittent erythematous papular eruption. Frequently these patients have a number of recurrent symptoms, which include: flushing of the face, neck, and upper chest; episodes of dizziness or syncope oftern associated with mild to severe hypotension; chest pain, palpitations, and dyspnea; and nausea, vomiting, abdominal cramping, and diarrhea.

Common sites of extracutaneous involvement in patients with systemic mastocytosis include bone, liver, spleen, lymph nodes and the gastrointestinal tract. Thus, findings of localized bone tenderness, hepatomegaly, splenomegaly, or lymphadenopathy on physical examination may serve as important clinical signs of systemic involvement. Symptoms and signs indicative of peptic ulcer disease also may be present in some systemic mastocytosis patients.

Although most patients with systemic disease have a relatively benign course, a few have a malignant and ultimately fatal process. The malignant form may occur in patients who often are without obvious cutaneous lesions and therefore have not been previously diagnosed with mastocytosis, or it may arise in mastocytosis patients known to have systemic involvement. Although more common in adults, malignant mastocytosis has rarely been reported in children. Approximately one-third of the patients with this malignant process develop a myeloid or monocytic leukemia prior to their death, while others develop a mast cell leukemia. To date, no prognostic parameters have been identified that permit early detection of persons predisposed to development of this rare malignant disorder.

Laboratory And Histopathology

The diagnosis of cutaneous mastocytosis is best established by biopsy of a characteristic skin lesion. Because mast cells are not easily recognized in routine hemetoxylin and eosin-stained tissue sections, special stains, such as toluidine blue, Giemsa, or conjugated avidin, are necessary for identifying these cells. The conjugated avidin stain has been combined with a morphometric point counting technique to accurately quantify mast cell infiltrates in different mastocytosis skin lesions. Nodular, papular, and macular lesions of mastocytosis have been reported to have mean mast cell densities of 63.2% (+/-8.2% standard error of the mean), 16.1% (+/-4.8%), and 3.5%(+/-1.8%), respectively, while the skin mast cell content in normal volunteers was shown to be 0.4% (+/-0.1%).

The diagnosis of extracutaneous involvement in systemic mastocytosis patients is dependent, in large part, on indirect laboratory tests.

Radiologic studies are often helpful in evaluating patients suspected of having systemic disease, since approximately two-thirds have bone involvement.

Two types of bone changes are recognized radiologically: a limited type, in which focal areas of osteosclerosis or osteoporosis appear in the skull and long bones, and a diffuse type, characterized by a widespread reticulated or “ground glass” appearance. Radionuclide bone scans also may serve as a useful screening tool, especially in patients with diffuse skeletal disease.

Although liver involvement has been documented in at least half of patients with systemic mastocytosis, routine liver function tests are usually normal.

Abnormalities of the gastrointestinal tract also have been reported, including gastric and duodenal ulcerations, exaggerated mucosal folds, and nonspecific motility disturbances.

The detection of circulating mast cell mediators and/or their metabolites offers strong indirect evidence for a proliferative mast cell disorder.

Urinary histamine levels above normal values may be detected in mastocytosis patients following symptomatic episodes. The major urinary histamine metabolite, 1,4-methylimidazole acetic acid, appears to be persistently elevated in patients with systemic mastocytosis and therefore may serve as an additional, indirect indicator of extracutaneous involvement. Elevated plasma levels or mast cell-derived tryptase also have been reported in patients with systemic mastocytosis, although similar findings have been noted in patients without mastocytosis experiencing anaphylaxis. Increased urinary excretion of the metabolite of mast cell-derived prostaglandin D2 also has been demonstrated in some systemic mastocytosis patients, however, measurements of this substance are available only for investigative purposes.

Although mast cells are known to store significant amounts of heparin, abnormal clotting studies are rarely observed in patients with systemic mastocytosis.

In general, more invasive diagnostic procedures in mastocytosis patients suspected of having extracutaneous disease are rarely warranted.

Occasionally,biopsy of the bone marrow, liver, and/or gastrointestinal tract may be reequired to establish the presence of a systemic process.

Etiology

The etiology of mastocytosis remains unknown. Children who develop this disease usually have a self-limited disorder, whih often resolves before adulthood. Although in adults mastocytosis freuently persists throughout life, rarely do they succumb to a malignant mast cell process. Skin mast cells from cutaneous and systemic mastocytosis patients have been assessed by morphometric analysis under electron microscopy and compared with normal controls. Mast cells from cutaneous mastocytosis patients have been shown to resemble normal skin mast cells in terms of their overall surface area, nuclear size, granule diameter, and granule number. Mast cells from systemic mastocytosis patients, on the other hand, have been noted to have a marked increase in cytoplasmic area, nuclear size, and granule diameter when compared with mast cells from cutaneous mastocytosis patients and normal volunteers.

These observations suggest that there may be important differences in the underlying mechanisms responsibe for the development of cutaneous and systemic mastocytosis.

Management

Because most solitary mast cell lesions resolve spontaneously, generally no treatment is required. For those few patients who have associated severe local or systemic symptoms, excision of the lesion is curative. Since no effective therapy exists for controlling mast cell proliferation, treatment for the remaining subgroups of mastocytosis patients is directed at inhibiting the local and systemic effects of released mast cell mediators.

At the time of diagnosis, patients with mastocytosis should be cautioned about the potential exacerbation of their symptoms from the use of alcohol, anticholinergic preparations, aspirin, narcotics, and polymyxin B sulfate.

Histamine antagonists are of fundamental importance in the treatment of most mastocytosis patients. In general, H1 histamine antagonists alone are often sufficient to control both local and systemic symptoms. In some instances, addition of an H2 antagonist may prove beneficial, especially in patients with gastric acid hypersecretion. While combination H1 and H2 antihistamine therapy has proved effective in controlling the symptoms of many patients, others have been refractory to this treatment regimen. The addition of aspirin( as an inhibitor of prostaglandin D2 synthesis) in combination with H1 and H2 antagonists has proved effective in eliminating life-threatening hypotensive episodes in several mastocytosis patients. Because aspirin and nonsteroidal anti-inflammatory agents are potential mast cell stimulators, it is most prudent to initially treat patients with H1 and H2 antihistamines.

If symptoms persist, small doses of aspirin (40 mg/day in adults) can be used, and in the absence of worsening clinical symptoms, the dosage may be gradually increased until plasma salicylate levels rise to a 20 to 30 mg/dl range (approximately 3.9 to 5.2 g/day of aspirin in the adult). Oral administration of disodium cromoglycate (400 to 800 mg/day) has been reported to alleviate the gastrointestinal, cutaneous, and central nervous system symptoms associated with mastocytosis and may be useful in patients refractory to other treatment approaches. Oral disodium cromoglycate also has proved effective in controlling pruritis and blister formation in infants with mastocytosis.

Psoralens and ultraviolet radiation (PUVA) may be efficacious in reducing pruritis in some mastocytosis patients but improvement requires 4 to 10 weeks of treatment. Unfortunately, most patients experience recurrence of their cutaneous symptoms following cessation of therapy. The response of mastocytosis patients to systemic corticosteroid therapy is anecdotal, but relief of both cutaneous and gastointestinal manifestations has been noted.

My experience has been that systemic corticosteroids have little effect on either local or systemic symptoms. Repeated application of potent topical corticosteroids under occlusion, however, appears to markedly reduce the number of cutaneous mast cells in patients with mastocytosis. Recurrent, life-threatening episodes of hypotension following mast cell mediator release have been reversed by early administration of subcutaneous epinephrine.

Therefore, patients who experience such episodes should be instructed to have a premeasured epinephrine preparation with them at all times for emergency use. A number of antineoplastic agents, including methotrexate,chlorambucil, vinblasine, and 6-mercaptopurine, have been used to treat malignant systemic mastocytosis. Unfortunately, no significant clinical responses have been observed.