CLiNlCOPATHOLOGlC

CONFERENCE

Systemic Mastocytosis

Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologic conferences held in Barnes and Wohl Hospitals, are published in each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine and Pathology of Washington University School of Medicine. A 58 year old Caucasian woman was admitted to Barnes Hospital on February 27, 1976, for evaluation because of multiple skeletal fractures. The patient was well until 1967 when she sustained a fracture of the left femoral neck after minimal trauma. Attempts to pin the hip were unsuccessful, but in 1975 total hip replacement was performed with a good functional result. During this time she took analgesics in substantial quantities for chronic pain in that hip. Among these was indomethacin which was continued until 1974 when symptomatic peptic ulcer disease developed. Subsequently, antacids (including aluminum hydroxide) were taken occasionally to relieve epigastric pain. Between 1967 and 1976 there were several episodes of acute back pain, and compression fractures of the vertebrae were documented roentgenographically. Approximately one month before admission the right seventh rib was fractured with no recognized trauma. These fractures occurred despite the administration of calcium supplements and estrogens. The patient had noticed a progressive skin rash for approximately two to three years. She deniedrhaving gastrointestinal symptoms and weight loss. Physical findings included marked kyphosis, bilateral cataracts, a palpable 1 by 1.5 cm left axillary lymph node and a profusion of brownish red, small, maculopapular skin lesions, particularly over the trunk. There was no bone tenderness. The vital signs were normal. Routine serum chemistry values were normal including a serum calcium of 9.8 mg/lOO ml, a serum phosphate of 4.1 mg/lOO ml, a serum alkaline phosphatase of 61 mlU/ml and a serum cholesterol of 173 mg/lOO ml. The urine calcium was 90 mg/24 hours, the urine phosphate 270 mg/24 hours and the serum parathyroid hormone concentration was 3 ~1 eq/ml (normal < 10 I.LIeq/ml). The white blood cell count was 5,400/mm3 with 5 per cent eosinophils, the erythrocyte sedimentation rate 8 mm/hour and the prothrombin time normal. Serum immunoglobulin electrophoresis revealed an immunoglobulin G (IgG) paraprotein; the total serum IgG level was 1,800 mg/lOO ml. lmmunoglobulin electrophoresis of the urine disclosed no abnor-

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malities. The urine pH was 6.0; 10 white blood cells per high power field were noted in the urine sediment, and Escherichia coli were cultured from the urine. Roentgenograms of the chest showed a large calcified lesion, believed to be a granuloma, in the right mid-lung field. Multiple bone films demonstrated widespread osteopenia, particularly marked in the axial skeleton; there were several compressed vertebrae. Pseudofractures were not seen. Bone density, by photon absorption osteodensitometry, was normal at the radial mid-shaft. A duodenal deformity, consistent with chronic peptic ulcer disease, was noted on an x-ray series of the upper gastrointestinal tract. Biopsies of skin and bone were performed. CLINICAL DISCUSSION Dr. Charles Parker: In summary, this 58 year old woman had symptoms of bone disease for nine years, and of peptic ulcer disease and skin rash for two years. We will begin the discussion with the roentgenograms. Dr. R. Gilbert Jost: The roentgenogram of the chest demonstrated cardiomegaly and an ill defined infiltrate in the right mid-lung field. Laminograms, however, showed definite calcification within the infiltrate, indicating that it most likely represented the residual effects of some old inflammatory disease. A lateral view of the chest indicated severe demineralization of the skeleton with multiple compression deformities in the thoracic spine: the compression deformities were even more pronounced in the lumbar area. Severe generalized demineralization of this kind has a variety of causes. Osteoporosis, of course, needs to be considered with its many underlying etiologies such as osteogenesis imperfecta tarda, exogenous steroid therapy, endogenous Cushing’s syndrome or poor diet. Osteomalacia could also present this roentgenographic picture. In fact, it is often difficult to distinguish between osteomalacia and osteoporosis simply on the basis of the roentgenograms. Looser’s zones, or pseudofractures, when they are present, offer a means of differentiating between osteomalacia and osteoporosis; Looser’s zones are characteristic of osteomalacia, but none was present in this patient. Hyperparathyroidism is another condition which can present with severe demineralization, although this patient’s films showed none of the accessory findings to support that diagnosis. In the hand films there was periarticular demineralization, but there was certainly no evidence of subperiosteal resorption. A good place to look for the characteristic lace-like appearance of subperiosteal resorption is on the radial surface of the middle phalanx of either the third or fourth finger. However, the cortices in the patient’s hands were sturdy and thick. There was certainly no evidence of cortical

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resorption of the kind that we associate with hyperparathyroidism. Incidentally, the mineralization of the radius was nearly normal. In this patient, demineralization was much less severe in the appendicular skeleton than it was in the axial skeleton. This would account for the rather high bone densitometry reading which was obtained. A final consideration in an older patient with demineralization would be multiple myeloma. Multiple myefoma certainly can present with diffuse demineralization, although more characteristically it presents with discrete punched out lesions. There was no roentgenographic evidence of the characteristic lesions of multiple myeloma in this patient. In summary, we have a patient with generalized demineralization of the skeleton with no specific roentgenographic findings to support any one diagnosis. This is not an unusual situation. On the basis of films alone, it is frequently very difficult to explain the underlying cause of generalized demineralization. Bone biopsy is often necessary. Dr. Parker: Thank you. When I read through the protocol the first time, I found myself wondering why an immunologist had been selected to discuss a case in which the most prominent manifestations were in the skin and bone. The only thing I could think of was that the Residents had decided that I needed to learn more about those areas, which is no doubt true. But, after a second reading, it occurred to me that this whole story might be put together as mastocytosis involving both the skin and bone. At the risk of spending a considerable amount of time describing a disease that the patient may conceivably not have, I have decided to orient my discussion almost exclusively from that point of view. The term mastocytosis is used to describe a disease in which focal collections of mast cells involve one or a combination of organs. As a rule, these mast cells have a normal morphologic appearance with no suggestion of malignant change. Only approximately 1,000 cases of mastocytosis have been reported, but the true incidence is undoubtedly higher with an estimated frequency of one in every 1,000 to 2,500 new patient visits in dermatologic practice [ 11. Since mast cells are secretory cells, the clinical manifestations of mastocytosis fall into two general categories: (1) Infiltrative manifestations. In organs infiltrated by mast cells, discrete lesions can often be seen, particularly in the skin. In addition, marked degrees of infiltration can occur in a wide variety of other tissues, including bone, liver, spleen, lymph nodes, gastrointestinal tract, heart and lung, leading to localized collections of mast cells, organomegaly or functional impairment. (2) Pharmacologic manifestations. The mast cells that accumulate in this condition appear to be perfectly normal from a biosynthetic point of view and, therefore, contain his-

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tamine and other mediators of immediate hypersensitivity. Under a variety of circumstances, these substances are released and produce acute pharmacologic changes either locally or systemically. The organ involvement in mastocytosis varies, and five distinct clinical syndromes [2] are possible. (1) Involvement of the skin (urticaria pigmentosa) without obvious systemic involvement. This is the most common form of mastocytosis accounting for about 90 per cent of all the cases in affected persons [ 11. (2) Skin lesions in association with bone changes. This appears to be the second most common mode of presentation of mastocytosis and may well be the form of the disease in our patient, assuming mastocytosis is indeed her problem. (3) Systemic mastocytosis and skin involvement. In perhaps as many as 10 per cent of the patients with involvement of the skin, there are clinical manifestations referable to involvement of systemic organs. Of the ones I have just mentioned, the most common are bone, liver, spleen and lymph nodes. (4) Mastocytosis in association with leukemia. In up to 4 or 5 per cent of the patients with mastocytosis some form of leukemia ultimately develops. Although this can be a mast cell leukemia it usually is not, and all forms of leukemia are represented. (5) Systemic mastocytosis without ur-ticaria pigmentosa. This is a rare presentation, although it may be a challenging one from the diagnostic point of view. Let us now consider the individual organ manifestations of mastocytosis in greater detail. Since Dr. Bauer will also discuss the skin manifestations, I will limit my remarks to a consideration of whether or not the changes shown by our patient fit with the diagnosis of cutaneous mastocytosis. To begin with, her age is not a problem. To be sure, skin involvement in this condition most commonly begins in infancy or early childhood, but in some 25 per cent of all cases of recognized mastocytosis, the onset is in adults. In addition, the occurrence of initial symptoms in above the age of 70 years has been described. Secondly, the lesions described in our patient conform, at least superficially, to what is usually found in mastocytosis in that they were macular, round or oval, and especially marked on the trunk. Moreover, although the color of urticaria pigmentosa lesions varies widely, among the colors listed is red-brown which was the color of the lesions in our patient. There is one other very common clinical feature of urticaria pigmentosa that I would prefer to have had before making this diagnosis-urtication, that is, the occurrence of a local urticarial exacerbation when involved areas of skin are stroked. The bone lesions also appear to fit with a diagnosis of mastocytosis in that bone lesions, when they occur in this condition, are very likely to appear in cases of adult onset, especially in those beginning in people over

the age of 50. As will be discussed in more detail by Dr. Haddad, both osteosclerosis and osteoporosis are seen, either together or separately [ 11. The lesions may be static or slowly or rapidly progressive; therefore, the course of our patient’s illness, dating back over a period of nine years, is perfectly consistent with this diagnosis. The only reservation I have in ascribing the bone involvement to mastocytosis is the presence of paraprotein in her serum which, of course, raises the possibility of multiple myeloma. It is well recognized that diffuse myelomatous involvement of bone can cause the roentgenologic changes of osteopenia without the typical punched out lesions of myeloma being demonstrable. But, I find it hard to believe that this patient had multiple myeloma with diffuse bone involvement back in 1967 and that she still does not have any punched out bone lesions or, for that matter, is still alive. How then can the presence of paraprotein be explained? Although the association of bone disease and paraproteinemia in this patient may be coincidental (e.g., she may have a benign monoclonal gammapathy and also happen to have bone involvement), there are now a handful of cases in the literature in which both severe idiopathic or postmenopausal osteoporosis and a paraprotein were present [3]. Several of these patients have been followed for six years or longer with no change being noted in the level of paraprotein in their serum and with no clinical evidence of myeloma, either initially or later. In addition, at least one case in which the patient had both amyloidosis and mastocytosis has been reported, and it is now recognized that many persons with amyloidosis have paraproteins [4]. In any event, I am unable to make a diagnosis of myeloma and, although the bone lesions in this patient might be explained by osteoporosis per se without mast cell infiltration, I strongly suspect that mastocytosis is, indeed, present and that it does involve her bones. Systemic symptoms of mastocytosis include weight loss, fever and flushing. The flushing varies in intensity, sometimes to the point that the malignant carcinoid syndrome is simulated. Originally, episodic flushing was thought to be rare in mastocytosis but Dr. Joseph Demis, who was Professor of Dermatology here in the early 1960’s, pointed out that as many as 35 per cent of the patients with mastocytosis have this symptom [5]. The flush is typically bright red and involves primarily the face and upper thorax. It may be provoked by a variety of stimuli including emotional stress, exposure to cold and drugs, such as aspirin, which also produce exacerbations of chronic idiopathic urticaria. Several subjects have been described in whom symptoms of an upper respiratory tract infection developed followed by marked exacerbations of symptoms of flushing which continued until the infection was brought under control. It seems likely that these subjects had

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large numbers of mast cells in their respiratory tract and that, in response to a local immunologic or nonspecific irritant reaction, these cells were releasing their intracellular content of mediators. Other symptoms of systemic release include pounding headaches, bronchospasm, hypotension, diarrhea, rhinorrhea, urticaria, palpitation and dyspnea; many of these are probably due largely to histamine. Mastocytosis is similar to epinephrine-secreting pheochromocytoma in that hypotension and other systemic symptoms may be precipitated by trauma or surgery, although this is unusual. Occasionally fever is a prominent clinical finding with episodes lasting from a few hours to several days or, rarely, for many weeks, leading to diagnostic difficulties as a fever of unknown origin. Facial or peripheral edema or ascites occasionally occurs, presumably as a manifestation of mediator effects on vascular permeability. Differentiation of the episodes of flushing seen in mastocytosis from those seen in the carcinoid syndrome should not present serious difficulties. In mastocytosis, the flush is bright red and usually lasts for 10 to 30 minutes. The skin is warm and permanent telangiectatic changes in the skin are unusual, even in those with repeated flushing [ 11. In the carcinoid syndrome, the flush tends to be cyanotic near its periphery, it usually lasts 10 minutes or less, the skin may be cool and, not infrequently, permanent skin changes eventually occur. Moreover, urticaria pigmentosa is not a feature of the carcinoid syndrome. As further verification, measurements of histamine and Shydroxyindoleacetic acid in the urine will ordinarily clearly differentiate between these two conditions. Physical findings associated with systemic mastocytosis include hepatomegaly (70 per cent), splenomegaly (50 per cent) and lymphoadenopathy (30 per cent) [6]. Often, the enlarged organs contain markedly increased numbers of mast cells. However, this is not always true even when the tissue appears to have been properly fixed. In the liver, it has been suggested that mast cell products, particularly histamine, may be capable of stimulating hepatic cell proliferation and fibrosis. As far as our patient is concerned, she did not have splenic or hepatic enlargement, but she did have axillary lymphadenopathy which may be a manifestation of systemic mastocytosis. Gastrointestinal manifestations also are common in systemic mastocytosis. Bleeding occurs in up to 10 per cent of the patients either on the basis of peptic ulcer disease or, less commonly, some other factor. The incidence of peptic ulcer in this condition is listed as 5 to 10 per cent which is no higher than in the general population. Nonetheless, the occurrence of ulcer symptoms has been observed for the first time in association with other symptoms of systemic mastocytosis and, certainly, histamine is a potent stimulator of

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acid secretion.

In addition

to peptic

ulcer disease

and

gastrointestinal bleeding, giant rugae have been described in the stomach. Diarrhea, with or without associated steatorrhea, may occur and can be quite severe. One case has been reported in which the diarrhea was quite well controlled by disodium cromoglycate [7]. a drug currently being used to control mediator release in bronchial asthma. The patient under discussion does have a peptic ulcer which was first described in 1974 and, although she has also received drugs which promote ulcer formation, it seems quite possible that mastocytosis is an important contributing factor. A variety of hematologic manifestations are seen in association with systemic mastocytosis including anemia, leukocytosis, leukopenia, eosinophilia, basophilia, peripheral blood mastocytosis and, more rarely, one of a variety of different types of leukemias [ 11. The anemia seen in association with this condition is not completely understood, but possible contributing factors include bone marrow infiltration by mast cells, splenomegaly and the enhancing effects of heparin on erythrophagocytosis. Mast cells contain sizeable quantities of heparin but, aside from occasional episodes of gastrointestinal bleeding or local ecchymosis in the skin, in which heparin may or may not be a contributing factor, bleeding manifestations are not a problem. The one hematologic manifestation that our patient may have is eosinophilia. Eosinophilia is seen in about 15 per cent’of the subjects with systemic mastocytosis and is presumably due to release of eosinophil chemotactic factors from mast cells. Our patient also has a serum cholesterol value which is near the lower limits of normal for her age and sex. Hypocholesterolemia is seen in about 10 to 20 per cent of the patients with mastocytosis and is probably secondary to the effects of heparin on cholesterol metabolism.. Results of urine or serum measurements of histamine or other mast cell products are not available to us and presumably were not obtained prior to biopsy. In summary, taking the skin, bone and peptic ulcer manifestations together, including their apparent onset after the age of 50 years within seven years of one another, and perhaps the eosinophilia and suggestion of hypocholesterolemia, I believe this patient does, indeed, have systemic mastocytosis. We will now hear from Dr. Bauer and Dr. Haddad, both of whom have seen the patient, for a more detailed discussion of her skin and bone manifestations. Dr. Eugene Bauer: The skin lesions in this patient consist of numerous erythematous to tan macules and papules localized primarily on the trunk. Lesions are less prominent on the extremities and on the face. The lesions on the skin are clinically quite typical of urticaria pigmentosa and are urticated upon gentle stroking. The dermatologic differential diagnoses here should include several erythematous or pigmented lesions.

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Benign pigmented nevi are somewhat more sharply circumscribed and usually palpable, although they need not be. To find them so profusely, as in this patient, would be unusual. Perhaps a more realistic consideration in the differential diagnosis is multiple lentigines, but these lesions would not urticate when stroked. Furthermore, in addition to the lentigines, several other features of the lentiginosis profusa syndrome may be present, such as ocular hypertelorism, prognathism, deafness, electrocardiographic abnormalities and pulmonary stenosis [8,9]. A third possibility would be neurofibromatosis. The typical cafe au lait spots, which are somewhat more well defined than we see in our patient with urticaria pigmentosa, axillary freckling and a family history of the disease would help to confirm the diagnosis. Older lesions of eruptive xanthomas might superficially resemble lesions of urticaria pigmentosa. However, early in the course of the eruption there should be little confusion, since they began as pink papules, often with a slight yellow color. They later tend to form rosettes and become slightly tan. In addition, the dermal character of these lesions is easily appreciated. In briefly discussing the types of urticaria pigmentosa, we should consider at least two important parameters: the number of lesions and the age of onset. The solitary mastocytoma is usually present at birth or in infancy and resolves spontaneously within the first few years. The prognosis is very good in the absence of systemic involvement, including both bone and other organ involvement [lo]. Not only solitary mastocytomas, but also multiple pigmented papules and nodules occurring early in childhood are associated with a good prognosis. The lesions often resolve spontaneously, and the chances of extracutaneous involvement are slim. It is important to note, however, that cases of systemic mast cell disease have been reported even in young children. [6]. There may be such a vigorous response to stroking the skin that a blistered lesion will actually develop. An important aside with respect to obtaining a skin biopsy specimen in these patients is that the mast cell degranulation involved in urtication may make it difficult for the pathologist to visualize the mast cells with a metachromatic stain [ 111. Thus, if one wishes to induce urtication (Darier’s sign), the biopsy specimen should be taken from a different lesion. With the onset of lesions later in childhood, adolescence or adult life, the prognosis becomes more guarded [ 12,131. In these patients, the skin lesions often persist throughout life and, just as we have seen in this patient, the possibility of extracutaneous involvement is greater. Finally, there is the telangiectatic variety of urticaria pigmentosa called telangiectasia macularis eruptiva perstans. This disease occurs primarily in middle-aged patients and clinically there are few, if any, palpable lesions. The most prominent feature is mottled pigmentation and

telangiectasia of the skin of the trunk. Rarely is there extracutaneous involvement, and the prognosis is very good. Dr. Parker: Dr. Bauer, when you saw this patient, what was your clinical impression? Dr. Bauer: Our clinical impression was urticaria pigmentosa. Her lesions did urticate. Dr. Parker: Dr. Haddad.will discuss the patient’s bone problem. Dr. John Haddad: This patient’s skeletal difficulties seem to be more appropriate for a woman 10 to 20 years older, and yet they mimic idiopathic osteoporosis best of all. Normal serum and urine values undermine the likelihood of intestinal malabsorption, renal tubular osteomalacia, myelomatosis, thyroid and parathyroid disorders. There is no important history of excessive aluminum hydroxide, heparin or cot-ticosteroid therapy. In brief, then, she appears to have experienced an earlier onset of severe osteopenia than would be reasonably explained by idiopathic osteoporosis, and a more protracted course than would be likely for osteolysis secondary to common neoplasias. Despite her impressive history of vertebral, femoral and rib fractures, the radius bone density was not subnormal. This resembles a recently reported case of urticaria pigmentosa with vertebral osteoporosis and a roentgenographically normal appendicular skeleton [ 141. As many as 40 per cent of patients with urticaria pigmentosa have roentgenographically detectable bone lesions [ 151 which often include a focal or generalized sclerotic process in addition to a cystic or stippled demineralization or apparent trabecular loss and thinning [ 161. It is of interest that sclerotic lesions can dominate [ 171, and argues for a complex, imperfectly understood effect of mast cells on the skeleton. The link between one of the mast cell products, heparin, and bone has derived from “cofactor” promotion of bone resorption in vitro [ 181, and its association with clinical osteoporosis in subjects receiving 15,000 to 30,000 units/day [ 191. Further, an increase in bone mast cells has been observed in animals receiving low calcium diets [20], as well as in the bone marrow of human subjects with osteoporosis [21]. However, the bone lesions in mast cell disorders often show sclerotic foci which are not observed in heparin-induced osteopenia. Therefore, it is likely that other products of the mast cell do contribute directly or indirectly to the disordered skeletal formation and resorption seen in these conditions. PATHOLOGIC DISCUSSION Dr. Raul Garza: The skin biopsy specimen did show ut-ticaria pigmentosa. A low power view of the specimen showed clusters of cells around blood vessels in the superficial dermis (Figure 1) beneath a normal epidermis. Under high power view, these cells were oval to

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Figure 1. Punch biopsy specimen of the skin showing an increase in cellularity in the upper dermis mainly around blood vessels. Hematoxylin and eosin stain; original magnification X 150, reduced by 28 per cent. Inset, 5 mast cells are seen with a dark cytoplasm (granules). Toluidine blue stain; original magnification X 350, reduced by 28 per cent.

Figure 2. Bone biopsy specimen showing thinning ot the bone spicules and normal looking bone marrow (A) and undecalcified bone section with a rim of osteod (arrow) in the periphery of a bone trabeculum (B). Hematoxylin and eosin stain (A) and Phloxine-Taitrazine stain (B); original magnification X 150, reduced by 28 per cent.

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Figure 3. Bone biopsy specimen under high power showing a granuloma-like formation with mononuclear cells. Inset, mast cells in perivascular arrangement. Hematoxylin and eosin stain; original magnification X 350, reduced by 28 per cent.

spindle-shaped with a round hyperchromatic nucleus and a slightly basophilic granular cytoplasm. Special stains demonstrated the granules of mast cells; these granules are metachromatic, and with toluidine blue they stain red (Figure 1, inset). The von Leder (nonspecific esterase) stain colors the granules bright orange to red. There were not too many mast cells in the punch biopsy specimen of the skin, but there were enough to make an adequate diagnosis. The bone biopsy was an open surgical biopsy from the iliac crest. Under low power view, there was thinning of the bone spicules with areas of total or partial loss of the bone trabeculation (Figure 2A). The bone marrow cellularity was about normal in relation to erythroid, myeloid and megakaryocytic series. Scattered throughout the marrow, however, were small granuloma-like foci composed of a slight increase in fibrous tissue and inflammatory cells (Figure 3). With metachromatic staining, these foci showed scattered cells with red granules in their cytoplasm. I must say that this bone biopsy specimen was slightly overdecalcified; this procedure causes granules in mast cells to lose their staining properties but, even with that consideration, there were a good number of mast cells scattered in a perivascular arrangement and they were easily seen in the granuloma-like areas in which they tended to cluster. The Giemsa stain is also useful in showing the mast cells, staining them purple-blue in color.

Fortunately, the surgeon at the time of biopsy sent a piece of bone to Dr. Teitelbaum for uncalcified sections. These sections showed a marked increase in mast cells in the bone marrow with striking perivascular arrangement (Figure 3, inset). The bone itself showed an increase in osteoblastic and osteoclastic activity with prominent deposition of osteoid at the periphery of the trabeculae (Figure 28) and an over-all decrease in bone mass. In summary, this patient has urticaria pigmentosa with bone lesions consistent with systemic mastocytosis. Dr. Parker: Thank you. Several of the sources I used in preparing my presentation commented on the danger of missing the diagnosis in decalcified bone samples, due to mast cell degranulation, so I think your suggestion that the decalcification process is responsible for the failure to find large numbers of mast cells in all the bone specimens is correct. Fortified by a tissue diagnosis of mastocytosis, I would like now to continue my discussion. To begin with, what is known about the etiology of mastocytosis? Since mast cells are critically involved in immediate hypersensitivity reactions, one might wonder about the relationship of mastocytosis to chronic allergic stimulation. In point of fact, there is no evidence whatever that allergies or parasitic infections, in which increased levels of immunoglobulin E (IgE) are incurred over sustained periods of time, in any way predispose to

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mastocytosis. Nonetheless, it does appear that if mastocytosis is already present and a systemic allergic reaction then occurs the reaction is more likely to be severe: this is not terribly surprising considering the large reservoir of mast cell mediators available in subjects who have this condition. There is one very interesting case report of a patient with carcinoma of the colon associated with mastocytosis in whom the tumor was resected and in whom the mastocytic involvement of the skin disappeared entirely only to reappear when the tumor recurred [22]. Thus, it would appear that mastocytosis may rarely occur as a reaction to a systemic disease. Even though only one such case has been described, further efforts to identify systemic factors which might be chemotactic for mast cells or basophils or which otherwise might promote mast cell infiltration into tissues appear to be well worth pursuing. On the other hand, mastocytosis has been observed to occur with increased frequency in certain families and often begins in infancy, suggesting that it may often be congenital in origin. Let us now consider how mast cells function under ordinary circumstances. Mast cells contain or rapidly generate a number of substances with potent physiologic activities including histamine, heparin, various mucopolysaccharides, eosinophil chemotactic factor A, slow reacting substance of anaphylaxis (SW-A), serotonin, one or more kinin generating enzymes and prostaglandins. All these substances appear to be present either in a preformed or a precursor state in granules and are released into the extracellular medium at the time of the releasing stimulus. Histamine is the best known mast cell mediator. It is present in large quantities in mast cells and no doubt contributes importantly to the changes in vascular permeability and smooth muscle tone seen in acute allergic responses. Serotonin, another vasoactive substance, is present in variable amounts in animal mast cells, and probably in human mast cells as well, although this has not been conclusively established. On one or two occasions, increased amounts of 5-hydroxyindoleacetic acid have been demonstrated in the urine of patients with mastocytosis, but as a rule no alterations are found. Enzymes released from stimulated mast cells, and presumably derived from the granules, are capable of activating kinins, which also are vasoactive. SRS-A is another substance of considerable interest in immediate hypersensitivity reactions which Dr. Barbara Jakschik in our Division has recently shown to be definitely present in rat mast cells. It is an acidic lipid of unknown structure with potent bronchoconstrictor activity and less marked effects on vascular reactivity. SRS-A is generated de novo in mast cells at the time of the releasing stimulus and may be the most important phar-

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macologic Moreover,

mediator mast cells

in human presumably

bronchial asthma. have the synthetic

capacity to produce prostaglandins, which also act on smooth muscle and blood vessels. Thus, at least four vasoactive or smooth muscle reactive agents, in addition to histamine, are released when mast cells are stimulated. Heparin, which is also preformed, is well known for its anticoagulant activity, but why it is present in mast cells and what role, if any, it plays in the early or late stages of immediate hypersensitivity responses are not presently clear. Several substances present in mast cells stimulate the directional migration of eosinophils and may be involved in the eosinophilia of bronchial asthma and acute allergic reactions. These include histamine itself as well as two acidic tetrapeptides recently characterized and synthesized in Austen’s laboratory [23]. In addition, studies in progress by Dr. Seth Eisen in our group indicate that there is at least one other potent eosinophil chemotactic factor in rat basophilic leukemia cells, presumably in normal basophils and mast cells as well, which has not yet been structurally characterized. Mast cells are prominently represented in the lung and skin in close association with blood vessels whereas a functionally and morphologically analogous cell, the basophil, is present in peripheral blood. The possibility has been raised that acute hypersensitivity reactions in the lung and skin involve mast cells whereas systemic anaphylactic responses involve circulating basophils, but this is difficult to establish conclusively. Both cell types contain high affinity glycoprotein receptors for IgE on their surfaces. The bond formed between IgE and the receptor is reversible, but it is sufficiently stable that skin sites passively sensitized with IgE antibody sometimes remain reactive for at least several weeks. The cell is unaffected by bound IgE unless antigen is present. Antigen appears to act by cross-linking IgE molecules on the cell surface; when this occurs, there is a very rapid release of granule contents into the extracellular fluid. Exactly how this is achieved is not altogether clear, but studies by Dr. Sullivan in our laboratory as well as those of others suggest that an initial plasma membrane event is followed both by increased uptake of calcium into the cell and alterations in intracellular cyclic adenosine monophosphate [ 241. A number of nonimmunologic stimuli, including drugs, polycations, ionophores and extremes of temperature or pH, also result in histamine release. During release, some granules are physically extracted from the cell. Others remain within the cell but, nonetheless, release their mediator content through channels, formed at the time of the allergic stimulus, which communicate directly with the cell exterior. The over-all result of the

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release reaction is to increase local vascular permeability and fluid accumulation, produce contraction of smooth muscle and stimulate an influx of eosinophils and other leukocytes into the area. Although the utility of this reaction is not altogether clear, IgE-mediated reactions may be of help in resisting parasitic and other infections. In addition to their well recognized role in immediate hypersensitivity, mast cells are important in cellular immune reactions as evidenced by the frequent presence of marked basophilic infiltration in delayed cutaneous reactions to foreign protein antigens. As far as the syndrome of systemic mastocytosis is concerned, it seems logical to assume that histamine is important in the urticaria, flushing, hypotension, peptic ulceration, facial edema, rhinorrhea and bronchospasm. It is more questionably involved in the eosinophilia, fever and intestinal hypermotility. Since SRS-A, kinins, prostaglandins and serotonin overlap in their pharmacologic effects with histamine, quite possibly they contribute to some of the symptoms. The reason symptoms of flushing tend to be episodic may relate to partial depletion of mast cell mediators after an acute release reaction. In addition, as in pheochromocytoma, sustained low grade mediator release may result in reduced end-organ responsiveness. At a more speculative level, a marked atrophy of lymph node follicles has been noted in mastocytosis on occasion [ 11. Moreover, at least one person with this condition has been described as having an impairment of cellmediated immunity. This is of interest in regard to the observation that lymphocytes appear to have receptors

for histamine and that, under appropriate circumstances, histamine inhibits both lymphocyte transformation and lymphocyte-mediated cytotoxicity. It is, therefore, possible that, in at least a few people with mastocytosis, exposure to continuing high levels of histamine might be associated with partial impairment of lymphocyte reactivity. Histamine may also be involved in the liver fibrosis sometimes seen in this condition although this also is speculative. As far as what heparin may be doing, Dr. Haddad mentioned the work that suggests that heparin may be directly involved in the pathogenesis of the osteoporosis. I find that evidence very provocative, although certainly more work is needed. Since prostaglandins are known to have potent effects on bone resorption, they may also be involved. Clinically significant coagulation defects appear to be rare in these patients but, as noted, occasionally there are bleeding manifestations in the skin or gastrointestinal tract in which heparin may be a contributory factor. Heparin stimulates lipoprotein lipase and has been used on occasion as a cholesterol lowering agent helping to explain the moderate degree of hypocholesterolemia seen not infrequently in people with mastocytosis. Finally, it may be worth noting that only about 10 to 15 per cent of the patients with systemic mastocytosis have eosinophilia, which is somewhat surprising if histamine and the acidic tetrapeptides are as potent as chemotactic factors for eosinophils in vivo as they appear to be in vitro. This may be a clue that sensitized lymphocytes are at least as important as mast cells in chronic eosinophilic states.

REFERENCES

5. 6. 7.

8. 9.

Sagher F, Even-Paz 2: Mastocytosis and the Mast Cell, Chicago, Year Book Medical Publishers, Inc., 1967. Szweda JA, Abraham JP, Fine G, et al.: Systemic mast cell disease. Am J Med 32: 227, 1962. Maldonado JE, Riggs BL, Bayrd ED: Pseudomyeloma. Arch Intern Med 135: 267, 1975. Rukavina JG, Dickison G, Curtis AC: The simultaneous occurrence of urticaria pigmentosa and primary systemic amyloidosis. Report of a case with autopsy findings.J Invest Dermatol 28: 243, 1975. Demis DJ: The mastocytosis syndrome. Clinical and biological studies. Ann Intern Med 59: 194, 1963. Mutter RD, Tannenbaum M, Ultmann JE: Systemic mast cell disease. Ann Intern Med 59: 887, 1963. Dolovich J, Punthakee ND, MacMillan AB, et al.: Systemic mastocytosis: control of lifelong diarrhea by ingested disodium cromoglycate. Can Med Assoc J 111: 684, 1974. Capute AJ, Rimoin DL, Konigsmark BW, et al.: Congenital deafness and multiple lentigenes. Arch Dermatol 100: 207, 1969. Smith RF, Pulicicchio LU, Holmes AV: Generalized lentigo.

10. 11.

12. 13. 14. 15.

16.

17.

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Electrocardiographic abnormalities, conduction disorders and arrhythmias in three cases. Am J Cardiol 25: 501, 1970. Klaus SN, Winkelmann RK: Course of urticaria pigmentosa in children. Arch Dermatol 86: 68, 1962. Parker F, Odland GF: The mastocytosis syndrome. Dermatology in General Medicine (Fitzpatrick TB, Arndt KA, Clark WH Jr, Eisen AZ, Van Scott EJ. Vaughn JH, eds), New York, McGraw-Hill Book Co., 1971. Caplan RM: Urticaria pigmentosa and systemic mastocytosis. JAMA 194: 1077, 1965. Caplan RM: The natural course of urticaria pigmentosa. Arch Dermatol 87: 146, 1963. Ives DR: Urticaria pigmentosa with spinal osteoporosis. Proc Roy Sot Med 66: 175, 1973. Poppel MH, Gruber WF, Sibber R, et al.: Roentgen manifestations of urticaria pigmentosa (mastocytosis). Am J Roentgen01 Radium Ther Nucl Med 82: 239, 1959. Sagher F, Schorr S: Bone lesions in urticaria pigmentosa. Report of central registry on skeletal x-ray survey. J Invest Dermatol 26: 431, 1956. Bendel WL Jr, Race 61: Urticaria pigmentosa with bone in-

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18. 19. 20.

21.

660

volvement. J Bone Joint Surg 45: 1043, 1963. Goldhaber P: Heparin enhancement of factors stimulating bone resorption in tissue culture. Science 147: 407, 1964. Griffith GC, Nichols G Jr, Asher JD. et al.: Heparin osteoporosis. JAMA 193: 85, 1965. Urist MR. McLean FC: Accumulation of mast cells in endosteum of bones of calcium-deficient rats. Arch Pathol 63: 239, 1957. Frame B, Nixon RK: Bone marrow mast cells in osteoporosis of aging. N Engl J Med 279: 626, 1968.

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22.

23.

24.

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Cohen HJ, Raisbeck Ml, Baer RL: Acquired (adult) urticaria pigmentosa. Disappearance after removal of intestinal carcinoma. Dermatologica 121: 386, 1960. Goetzl EJ, Austen FK: Purification and synthesis of eosinophilotactic tetrapeptides of human lung tissue. Identification as eosinophil chemotactic factor of anaphylaxis. Proc Natl Acad Sci 72: 4123, 1975. Sullivan TJ, Parker CW: Pharmacological modulation of the inflammatory mediator release by rat mast cells. Am J Pathol (in press).