Systemic mast cell disease

Systemic Mast Cell Disease * A Review and Report of Three Cases JOHN A . SZWEDA, M .D ., I JOSEPH P . ABRAHAM, M .D ., G . FINE, M .D ., ROBERT K . NIXON, M .D . and C . E . RuPE, M .D .

Detroit, Michigan Touraine et al . [6] reported the first case of urticaria pigmentosa in which the mast cell infiltrated organs other than the skin, and sixteen years later Ellis [7] reported the first autopsy case of urticaria pigmentosa with systemic involvement . Sagher et al . [8] recognized the association of urticaria pigmentosa with bone lesions in

YsTEMtc mast cell disease is characterized by infiltration of various organs, particularly the reticuloendothelial system, with mast cells . The signs and symptoms of this condition reflect the unique functions of these cells, which yield histamine, heparin (serotonin in some animals) and possibly hyaluronic acid . The past decade has seen the concept of mast cell disease enlarged from that of a mere cutaneous infiltration (the relatively common urticaria pigmentosa) to that of a systemic disease . To date, at least twenty-one cases of systemic mast cell disease have been described, chiefly in the dermatologic literature . The main reasons for lack of recognition of the disorder are the unfamiliarity of internists with the condition, coupled with the lack of structural stability of mast cells when subjected to ordinary fixatives and stains . The important role of the mast cell in normal and pathologic states, and the apparent rarity of the systemic disease it produces, prompted us to add three instructive cases to the

S

1952 . MORPHOLOGY AND FUNCTION OF THE MAST CELL The mast cell is characterized by cytoplasmic granules showing a strong affinity for basic dyes and is found in the loose fibrillary connective tissue surrounding blood vessels and underlying epithelial and serous membranes . The cell is polymorphous in cytoplasmic contour, the cytoplasm staining little if at all . The nucleus is round or oval, small in comparison to the cell volume, and shows a coarse chromatin network . Michels [9] was of the opinion that the tissue mast cell and the blood basophils had only basophilic granulation in common, but Riley [10] suggested that there was a functional similarity between the cells .

literature . The first case of what is now designated urticaria pigmentosa was described by Nettleship [1] in 1869 . Sangster [2] followedin 1878 with a report of an "anomalous mottled rash accompanied by pruritus, urticaria and pigmentation" which he named "urticaria pigmentosa ." Sangster thus preceded, by several years, Ehrlich's [3] original characterization of the mast cell as to distribution, morphology and staining . The histopathology of the skin lesions was first elaborated by Unna [4] who showed dense accumulations of mast cells in the dermis . By 1923, 306 cases were reviewed [5] and to the present time at least 600 cases of urticaria pigmentosa have been reported . In 1933

Jorpes et al . [11] proved satisfactorily that the mast cell is a source of heparin . Their findings have been amply confirmed and elaborated [12-77] . Ashoe-Hansen [18] proposed that the mast cell is a source of hyaluronic acid and demonstrated a correlation between the mast cell count and the hyaluronic acid content in normal and abnormal tissues . According to his formulation, the granules are the sulfated precursors (possibly heparin) of this mucopolysaccharide which, under varying hormonal influences, yield hyaluronic acid . West [19] points out, as evidence against this suggestion, that hyaluroni-

* From the Departments of Medicine and Pathology, Henry Ford Hospital, Detroit, Michigan . Manuscript received February 20, 1961 . f Present address : Department of Medicine, St, Joseph and Lutheran Hospitals, Beaver Dam, Wisconsin . VOL . 32, FEBRUARY 1962

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dase does not destroy the metachromasia of the mast cell granules and that there is sometimes a poor correlation between the mast cell count and the hyaluronic acid content of tissues . Schiller and Dorfman [17] reported convincing studies which indicated that no polysaccharide other than heparin was present in the mast cell . Whatever may be the final resolution of this problem, an intimate relationship of the mast cell to formation of connective tissue is indicated by the followingconsiderations : (1) Desulfation of heparin would yield hyaluronic acid . (2) Addition of heparin to a solution of collagen or procollagen yields collagen fibrils [20] . (3) Mast cells disappear with acute injury and reappear when connective tissue fibrils are being laid down . (4) Release of histamine and/or serotonin causing edema fluid to accumulate locally would promote removal of foreign products and leave a protein-rich fluid for the process of repair [19] . Since the studies of Riley and West [27], confirmed amply by others [22-31] no doubt remains that the mast cell is the chief source of histamine . Benditt et al . [32] extracted serotonin from mast cells of the peritoneal washings in the rat, but there is sufficient evidence to dissuade one from implicating the mast cell of man as a source of serotonin [24,28,29,33] . The mast cell, as a chief source of histamine in man and of serotonin in animals, must play a fundamental role in the allergic reaction . Asboe-Hansen [18,34,35] has suggested that mast cells may be transmitters in the action of hormones on connective tissue . In myxedema, many mast cells are present in the edema fluid, together with the mucopolysaccharide-protein complex . With thyroid therapy there is a change in the mast cells from large and well granulated cells to small and degranulated forms . Cortisone, with its profound effects on connective tissue, has been shown to have an effect on the mast cell . There is some evidence that mast cells may offer protection against atherosclerosis and that a lack of mast cells may predispose to it [36-38] . The action of heparin, through lipoprotein lipase, on chylomicrons may be an important factor in this reported relationship of the mast cell to atherosclerosis . Cramer and Simpson [39] showed an increase in mast cells in mice resistant to tumor development . A decrease in mast cell numbers was noted when the tumor in mice proceeded from a precancerous to a cancerous phase .

The role of the mast cell in a wide variety of connective tissue diseases has been alluded to [35], but not elucidated . Further speculation and study concerning this relationship would be pertinent . It is thus readily apparent that the mast cell plays an important role in normal and abnormal human physiology . In the disease characterized by multiplication of essentially normal mast cells, nature has given us an unusual opportunity to see gross evidence of the function of this cell . A close inspection of the cases to be reviewed from the literature will bear this point out . SPECTRUM OF MAST CELL DISEASE

Urticaria Pigmentosa. Urticaria pigmentosa characterized by a mast cell infiltration confined to the dermis is relatively rare . Havard and Scott [40] record an incidence of one in every 2,500 attendances at the dermatologic department of St . Bartholomew's Hospital . The lesions are usually nodular in children, macular in adults and hullous in infants . The condition is characterized by erythema, edema and residual pigmentation upon rubbing an area of involved skin . Urticaria Pigmentosa with Bone Changes Noted on Roentgenograms . The varied bone lesions noted

on roentgenograms in association with urticaria pigmentosa, as reported by Sagher, Cohen and Schorr [8], served further notice that mast cell disease could trespass skin boundaries . In reviewing the subject, they listed fifty-two patients examined roentgenologically, nineteen of whom had bone lesions [41] which varied from generalized changes resembling osteosclerosis and/or generalized osteoporosis (both occurring in different bones of the same patient) to localized osteoblastic or osteoclastic lesions . Most of these patients gave no other evidence of systemic involvement . In a recent comprehensive review Poppel et al . [42] listed seventy-one patients examined roentgenologically, thirtytwo of whom had bone lesions . In eight of eleven of those in whom bone marrow biopsy was carried out an increased number of mast cells was found . Several of this group had evidence of mast cell infiltration of other organs . Urticaria Pigmentosa with Systemic Involvement .

In 1933 Touraine et al . [6] first suggested that mast cells at times infiltrated organs other than the skin, predominantly those of the reticuloendothelial system . They described a fifty-five year old man with urticaria pigmentosa since AMERICAN JOURNAL OF MEDICINE



Systemic Mast Cell Disease-Szweda el al . infancy in whom splenomegaly developed . Bertellotti [4.3] followed with a report of a similar phenomenon in a forty-nine year old man with urticaria pigmentosa for six years in whom splenomegaly then developed . There was a marked increase in mast cells in bone marrow and lymph nodes . Ellis [7] gave impetus to recognition of the systemic potentiality of mast cell disease by describing the first autopsy case . The patient, a one year old female infant, had had urticaria pigmentosa since birth . The liver and spleen were enlarged . There was diarrhea, with voluminous foul-smelling stools . At autopsy there was enlargement of the liver, spleen and lymph nodes ; microscopically all were infiltrated with mast cells which seemed to have provoked fibrous tissue proliferation in the bone marrow, liver, spleen, lymph nodes, kidney and pancreas . Degos et al, [44] described a fifty-six year old man with pigmented nodules and extensive erythematous infiltration of the skin . Hepatosplerrornegaly and lymphadenopathy were noted . Systemic involvement can only be presumed since liver biopsy revealed infiltration of the portal areas with lymphocytes, but no mast cells were seen . Berlin [45] described in detail a seventy-one year old man who had a maculopapular and nodular eruption of several months' duration which produced wheals on scratching . He had had diarrheaa for twenty years . Two years after the appearance of the skin eruption there was massive hepatosplenomegaly . The hemoglobin was 50 per cent and white count 3,000 per cu . mm . with a normal differential . Gastric analyses showed diminished to normal hydrochloric acid . Results of liver function studies were normal . Roentgenograms of the chest, gastrointestinal tract and bones were within normal limits . The patient was treated with ACTH without benefit . The administration of antihistaminics relieved the itching . Radiation therapy and ultraviolet rays caused little change in the lesions . Somewhat later mucous membrane lesions developed . The prothrombin time ranged from 83 to 62 per cent ; bleeding time was four minutes, clotting time three minutes . Results of tests for heparin in venous blood were within normal limits ; however, blood from the papules showed levels of 49 .3 to 235 .2 seconds (normal range by their method was twenty-five to thirty-five seconds) . In 1957 the autopsy findings in this VOL, 32, FEBRUARY 1962

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case were reported . Mast cells were found in the liver, spleen, lymph nodes, skin, kidneys, small intestine, pancreas and aorta . Brodeur and Gardner [46] described a five year old boy with urticaria pigmentosa . The skin lesions were first noted at the age of two months, hepatosplenomegaly appeared at age five . Mast cells were found in the blood, bone marrow and lymph nodes . Studies of the liver revealed an increase in heparin and histamine content . Sagher et al . [8] reported the first case of urticaria pigmentosa with systemic mastocytosis associated with bone lesions . The patient was a fifty-three year old man with hepatomegaly and osteoporosis of the ribs and vertebrae . Reilly et al . [47] described a thirty-four year old man who had symptoms of severe gastroenteritis and urticaria pigmentosa . The liver and spleen were enlarged . Biopsy specimens of hone marrow and liver showed aggregates of mast cells . The coagulation time was normal before and after the administration of ACTH and cortisone . Roentgenograms of the bones showed osteoporosis and pagetoid thickening of the trabeculae of the pelvis, skull, ribs and humeri . A similar case was reported by Bluefarb and Salk [48] in a thirty year old man who had nausea, vomiting, diarrhea and abdominal cramps for five years . This patient's skin disease dated from age eleven . The spleen was enlarged . On proctoscopic examination there was diffuse mottling of the mucosa, with spasm of the sigmoid and excessive mucus production . Roentgenograms of the vertebrae, ribs and clavicles showed a finely mottled osteosclerosis . Treatment with toluidine blue, para-aminobcnzoic acid, cortisone and antihistaminics was of no avail . Mast cells were demonstrated in the skin biopsy specimen but bone marrow aspiration was negative . Stark et al . [49] described a fiftyfour year old woman in whom urticaria pigmentosa developed at age thirteen . Roentgenograms of the bones showed increased trabecular thickening, areas of rarefaction and osteoporosis . A biopsy specimen of the bone showed nests of mast cells . There was no enlargement of liver, spleen or lymph nodes. Rider et al . [50] reported on a two and a half year old girl with urticaria pigmentosa, whose prominent symptoms were diarrhea, vomiting, abdominal pain and blood in the stool . There was moderate enlargement of liver and spleen . Roentgenograms of the bone showed coarsening of trabeculae and thinning of the cortex . Gastrointestinal roentgenograms



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were within normal limits . The prothrombin time ranged from 30 to 80 per cent of normal . The bleeding and clotting times were normal . Clot retraction and prothrombin consumptions were within normal limits . 5-Hydroxyindolacetic acid excretion and plasma clearing factors were negative . Biopsy specimens of the skin, liver and bones showed many mast cells . Benadryl ' was used with doubtful benefit . Zak et al . [51] reported on a fifty-eight year old woman with symptoms of weakness, nervousness, vomiting, diarrhea and loss of weight . On examination urticaria pigmentosa, hepatosplenomegaly, palmar erythema, sparse hair and 2 plus edema of the legs were noted . There was a grade 2 apical systolic murmur . Roentgenograms of the bones showed demineralization with scattered moth-eaten and osteoblastic areas . Roentgenograms of the stomach showed hypertrophic rugae . There were laboratory evidences of chronic liver disease . Gastric analysis showed achlorhydria . Bone marrow aspiration revealed an increase in the mast cells . A liver biopsy specimen, however, did not reveal the presence of mast cells . Havard and Scott [40] described a sixty-seven year old woman who complained of abdominal pain, lassitude and swelling of the ankles . Twelve years earlier urticaria pigmentosa had appeared and accompanying this were symptoms of epigastric distress, flatulence and occasional diarrhea . Hepatosplenomegaly was present for three years . Roentgenograms of the bones showed a mixed picture of generalized osteosclerotic and osteoporotic changes . The platelets were decreased in number and the hemoglobin was 8 .7 gm . per cent . There was laboratory evidence of hepatic dysfunction . Urine assay for histamine was within normal limits . Biopsy specimens of the skin and bone revealed an infiltration of mast cells . There was little change in the patient's condition during the following eighteen months, with the exception of development of a blood and bone marrow eosinophilia and gradual further impairment of liver function . Asboe-Hansen [52] described a thirty-eight year old man who complained of fatigue, weight loss, anorexia, itching and a sprue-like diarrhea . In addition to urticaria pigmentosa there were scattered yellowish nodules of the skin . Over a period of three years hepatosplenomegaly, lymphadenopathy, ascites and edema of the lower extremities developed . Roentgenograms revealed an increased density

in the right lung field . The lumbar spine showed patches and bands of increased density. The white count varied from 5,000 to 35,000 per cu . mm ., with an increase in blood basophils ranging from 1 to 9 percent . Hemoglobin and platelet counts were normal . Protamine titration, thrombin generation, clotting time and bleeding time were normal . The prothrombin time was persistently elevated . Results of liver function tests were normal . Mast cell infiltration was found in the skin, bone marrow, liver, spleen and lymph nodes . Splenectomy was carried out in 1958 with some relief of his condition. Biopsy of the yellow lesions revealed lipid-laden histiocytes .

Urticaria Pigmentosa Associated with Leukemia . Efrati et al. [53] described a fifty-two year old woman with red papular skin lesions, a few of which showed wheals on trauma . The patient complained of anorexia, nausea, vomiting and symptoms suggesting a duodenal ulcer . There was massive hepatosplenomegaly . Roentgenograms of the bones showed punched out areas in the ribs . The hemoglobin was 8 .9 gm . per cent . The white blood count ranged from 38,000 to 62,000 per cu . mm. The differential showed 23 per cent mast cells (with immature cells noted) and in the 62,000 count it was noted that 50,000 of the cells were mast cells . The platelets ranged from 15,000 to 60,000 per cu . mm . A bone marrow biopsy specimen revealed 18 to 26 per cent mast cells . A biopsy specimen of the liver was normal . A skin biopsy specimen showed a few mast cells not characteristic of urticaria pigmentosa . Treatment with cortisone and folic acid was ineffective . Autopsy examination revealed multiple duodenal ulcers and infiltration of the liver, spleen, kidneys and duodenum with mast cells. The tonsils showed mast cells in the capsule . The lymph nodes were free of mast cells . A few mast cells were notedd in the bone, together with focal osteosclerosis . Waters and Lacson [54] described a five year old boy whose course was interpreted as being consistent with "mast cell leukemia ." The skin lesions, typical of urticaria pigmentosa, had been noted at age nine months, at which time lymphadenopathy was also found . At age five his course became fulminant, with ease of bruising and prolonged bleeding . The liver and spleen were moderately enlarged . The hemoglobin was 8 .1 gm . per cent, the white count 7,200 per cu . mm . with 46 per cent lymphocytes and 3 per cent monocytes (a review of this slide revealed AMERICAN JOURNAL OF MEDICINE



Systemic Mast Cell Disease-Szweda el al . mast cells at the periphery) . The platelet count was 256,000 per cu . mm . Results of coagulation studies were negative . Biopsy specimens of bone marrow, skin and lymph nodes showed nests of mast cells . During the next two months the patient's condition deteriorated, the liver and spleen became massively enlarged, and at autopsy mast cell infiltration in most of the organs was found, There was a suhcapsular hematoma in the liver . The heparin and histamine content of the liver was 100 times normal . Saghcr et al. [55] reported a unique case of a fifty-five year old woman who died of monocytic leukemia . She had urticaria pigmentosa for at least five years- Neither hepatosplenomegaly nor lymphadenopathy had been noted two years prior to death, but the bones showed demineralization and sclerosis . At this time the white count was 6,000 per cu . mm . with 17 per cent monocytes . Two years later the white count rose to 43,000 per cu . mm . with 50 per cent monocytes . Lymph nodes, liver and spleen were now enlarged . Before death the count was up to 248,000 per cu . mm . with 78 percent monocytes . At autopsy, monocytes and mast cells were found in almost all the organs, especially the spleen, liver and lymph nodes . Examination of the bones revealed a dense network of thick trabeculae consisting mostly of lamellar bone . There was an accumulation of mast cells in the loose connective tissue and a few monocytic aggregates were noted . Systemic Masterytosis withoul Urticaria Pigmentosa . Hissard et al . [56] described a fifty

year old man who had paroxysms of itching, precordial pain, tachycardia and swelling of the skin . The skin showed erythema, pachydermia, nodules and tumors with hemorrhage on slight trauma . No pigmentation was present . Hepatosplenomegaly was noted . Mast cells were found in the sternal marrow and the spleen . Fifteen per cent of the white cells of the peripheral blood were mast cells after epinephrine injection and 45 per cent after splenic puncture . Persistent monocytosis, up to 20 per cent, was found . Lennert et al . [57] described a young man with marked leukocytosis and up to 50 per cent mast cells observed in the peripheral blood for at least five years . At autopsy, there was intra- and extramedullary myelopoiesis with many mast cells and marked fibrosis of the liver, spleen, lymph nodes and bone marrow . Friedman et al . [58] reported on a thirty-four year old woman with epigastric pain, nausea, vomiting and VOL . 32, FEBRUARY 1962

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weakness . Examination revealed ecchymoses and hepatomegaly . There were discrete irregular erythematous patches on the skin which appeared and disappeared without residual pigmentation . Tissue mast cells were found in the blood and bone marrow . A roentgenogram revealed a duodenal ulcer . The patient died of complications of the ulcer . At autopsy there was hepatomegaly, the tissue mast cells were noted in the lymph nodes, liver, spleen and in the area of the ulcer . Bone marrow taken from the vertebra showed 90 per cent replacement with mast cells . Ende and Cherniss [59] described a thirty-five year old man whose symptoms included episodic flushing and vomiting . Examination revealed hepatosplenomegaly . The white blood count was 2,400 per cu . mm . ; bleeding time, clotting time and prothrombin time were normal . No 5hydroxyindolacetic acid was found in the urine . A biopsy specimen of the liver revealed local necrosis and portal fibrosis . A spleen biopsy specimen showed 6 per cent mast cells . The coagulation time was more than a half hour, but serum collected during bleeding failed to reveal any heparin abnormality by protamine titration . A splenectomy was performed and after surgery the white blood count, hemoglobin and platelet counts increased ; results of coagulation studies were normal. Nine months after splenectomy the patient was asymptomatic . Imprints of the spleen showed 8 per cent mast cells . The histamine content of the spleen was 100 pg . per gm . of tissue (normal being 1 .5 to 3 .3 pg . per gm .) . Analysis of the spleen for serotonin revealed extremely low levels . The preceding classification of mast cell disease is admittedly arbitrary and simply serves to categorize the major potentialities of this disorder . Thus, bone lesions when noted in urticaria pigmentosa may be merely the prelude to more overt systemic involvement with mast cells . The high incidence of bone lesions, when searched for in otherwise uncomplicated urticaria pigmentosa, suggests that systemic mast cell disease may be far more common than the number of cases reported in literature would suggest . CASE REPORTS CASE

r.

Henry Ford

Hospital

Record No . 649713 .

T. C., a forty year old machine operator, has been followed up for the past nine years at the Henry Ford Hospital . His three children and eight of his siblings are well . One brother died at age forty-nine with

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Fin . 1 . Case I. carcinoma of the colon ; his father died at age sixty-five of a stroke . His mother is living and well at age eighty-eight. A macular pigmentation of the skin has been present since age fourteen . The macules became livid on exposure to cold, andd on slight trauma to the skin there was immediate local edema . The patient was otherwise well until the age of thirty-one when superficial ulcers appeared at the ankles, associated with

varicose veins . He was admitted to the Henry Ford Hospital for the first time in 1950 . There was evidence of vasospasticity as a major factor in the disease of the lower extremities and a lumbar sympathectomy was performed . (Fig. 1 .) About this time he began to have episodes of severe nausea and vomiting, usually occurring during the morning hours, and associated with facial edema and severe flushing of the anterior portion of his face and chest. With each attack the erythema and edema lasted about a half hour and usually terminated a short time after vomiting. The patient noted that on exposure to severe cold, for any period of time, a febrile reaction occurred within an hour, with severe flushing of the skin, shaking chills, vomiting, diarrhea and rapid, vigorous heart action . Similar attacks were precipitated by infections of the upper respiratory tract, and on one occasion the symptom complex was joined by hematemesis and tarry stools . Hepatosplenomegaly was first noted in 1951 . There were macular pigmented lesions over the trunk, extremities and face, varying in size and color from pink to purple to brown . Ascultatory evidence of mitral stenosis and pulmonary hypertension was present . A chest roentgenogram revealed prominent linear shadows and nodularity . Electrocardiograms and cardiac fluoroscopy showed no abnormalities . During the past nine years the patient was observed frequently and hospitalized on several occasions when attacks of fever and flushing had persisted for several days, usually associated with obvious infection of the upper respiratory tract . Between hospitalization he was able to carry on normally, working at a strenuous occupation . On his most recent examination the height was 6 feet 1 inch, weight 141 pounds . The pigmented macules over the trunk, extremities, thighs and face varied from a few millimeters to a centimeter in diameter, appeared brownish, and a telangiectatic vascular pattern was visible within the larger ones They yielded wheals readily on local trauma . There were varicosities of the lower extremities and scarring was noted over the sites of the previous ulcers, with a fresh superficial ulcer between the right great and second toes . The nails were spooned and the nail beds dusky . The hands were cold to the touch . The mucous membranes were normal . The lungs were clear to percussion and auscultation . The blood pressure was 130/70 mm . Hg, pulse 90 and all peripheral pulses were readily palpable . The neck veins were slightly distended at 30 degrees elevation and pulsation was visible . The apical impulse was felt 10 cm . from the mid-sternal line and there was a palpable parasternal heave . A grade 2 systolic murmur was heard over the pulmonary area, with accentuation of the second pulmonary sound . At the apex there was a holodiastolic murmur with presystolic accentuation . Massive hepatosplenomegaly had persisted, the liver descending 15 cm . and the spleen 11 cm . below the

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Pro . 2 . Case L Metactu'omatic granulation of mast cells in skin . Azure-eosinate stain, magnification X 1,100

Fro . 3 . Case L Metachromatic granulation of mast cells in liver . Azure-eosinate stain, magnification X 1,100 .

costall margin in the respective mid-clavicular lines, Both organs were hard in consistency and non-tender on palpation . Small, discrete lymph nodes were noted in the axillary and inguinal regions . The hemoglobin varied from 10 .2 to 15 .5 gm. per cent. The white counts ranged from 5,000 to 11,000 per cu . mm . A recent differential count showed 0 .5 per cent basophils, 8 per cent monocytes, 12 per cent eosinophils and 79 .5 per cent polymorphonuclear leukocytes. The platelets appeared adequate in the smear and the red cells were normocytic . The clotting time was eight and again ten minutes . The prothrombin time was eighteen seconds, as compared to a control of fifteen seconds . The plasma clotting time was 158 seconds and the prothrombin consumption time was nineteen and a half seconds . Serum electrophoretic pattern showed a total protein of 6 .9 gm ., with albumin 41 per cent, alpha, globulin 6 per cent, alpha, globulin 16 per cent, beta globulin 19 per cent and gamma globulin 19 per cent . Urinalyses were within normal limits except during a severe attack when there was 1-plus albuminuria, 2-plus hyaline casts, 5 red cells and 3 white cells per high power field . The blood urea nitrogen was 30 mg . per cent, antistreptolysin-O titer 50 units, C-reactive protein 5 mg ., cold agglutinins negative, porphobilinogen negative . There was no bromsulphalein retention, serum cholesterol levels were 62 and 92 mg, per cent, thymol and cephalin flocculation reactions were negative and thymol turbidity was 4 units . Gastric analysis revealed normal volumes of fluid and content of hydrochloric acid . L .E . preparations were consistently negative . The stool was free of ova and parasites and no free fat was found . Bone marrow aspiration showed a myeloid : erythroid ratio of 6 .7 :1, with 7 .2 per cent tissue mast cells, but an otherwise normal differential The blood histamine was 53 .8 mg . per L ., urinary histamine 591 .5 µg . in twenty-four hours . Urinary 5-hydroxyindolacetic acid excretion was 2 .72 mg . in twenty-four hours . Hematoxylin and eosin-stained sections of multiple biopsy specimens of formalin-fixed skin and liver and a single specimen of bone marrow revealed the folvoL . 32, FEBRUARY 1962

lowing : There was no significant histologic variation among the skin biopsy specimens. The epidermis was of normal thickness, the basal laver containing abundant finely granular melanin . Increased cellularity in the upper third of the dermis was noted, principally about the small blood vessels and sweat ducts, but in areas the cells were more diffusely distributed and occasionally concentrated within the papillary portion of the dermis . (Fig . 2 .) Round and oval mononuclear cells (5 to 12 µ in diameter) predominated, with fewer areas comprised of elongated cells separate or mixed with other mononuclear forms . The smaller mononuclear cells were typical small lymphocytes but the larger ones and the spindle cells contained large nuclei with finely disbursed chromatin and finely granular, lightly basophilic cytoplasm . Focal aggregates of polymorphonuclear leukocytes were seen principally in the lumen and less frequently in the wall of small blood vessels in the subcutis in one skin specimen . Rarely, sparse neutrophils, plasma cells and eosinophils were associated with the other cell types . Dermal fibrous tissue was not increased . Cells similar to those of the skin were found in increased numbers in the liver, concentrated in the portal areas with only sparse single cells in the sinusoids . (Fig . 3 .) Rare plasma cells, neutrophils and moderate numbers of eosinophils were also noted . Parenchymal cells of the liver were not altered . Examination of the bone marrow showed a normal distribution of the hcmatopoietic cells . The cells seen in the skin and liver were difficult to detect and would have been overlooked had we not been cognizant of the diagnosis. While some cells in the skin and liver were suspected of being tissue mast cells with the hematoxylin and eosin stain, positive identification was established only with the aid of the azure-eosinate stain . This revealed characteristic diffusely metachromatic cytoplasmic granules in all biopsy sites, not only within the larger oval and round mononuclear forms but also in many of the elongated cells which were interpreted as fibroblasts with the hematoxin and eosin stain . (Fig. 4 .) Metachromatic granules often corresponded with

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Fro . 4. Case I . Portal and sinusoidal infiltrate in liver . Hematoxylin and eosin stain, magnification X 150 .

the lightly basophilic granulations seen in the hematoxin and eosin stain . Mast cells in the sinusoids of the liver, connective tissue, hemangioma of the skin and the bone marrow, not detected with the hematoxin and eosin stain, were obvious with the azure-eosinate stain . An x-ray series upper gastrointestinal tract showed coarsening of the folds in the duodenum . Study of the small bowel and colon was normal . A recent chest fluoroscopy revealed a transverse cardiac diameter of 145 nun . as compared to the predicted 118 mm . There was right ventricular and slight left atrial enlargement. Increased pulmonary vascularity, with fibrotic densities scattered throughout the lung fields, was noted . Skeletal survey revealed no bone lesions . Right heart catheterization revealed the following pressures in millimeters of mercury : Right auricular mean pressure 7, right ventricular pressure 45/7-9, pulmonary artery pressure 45/20, pulmonary wedge pressures IS and 20. Apart from the episodes described and the necessity to bind his legs to prevent malleolar ulceration, the patient continues to be active and to do well despite massive hepatosplenomegaly and mitral stenosis . CASE it . Henry Ford Hospital Record No . 580568. J. K ., a fifty year old white widow, was admitted to the Henry Ford Hospital on January 10, 1957, complaining of chills, fever and weakness . She had been hospitalized elsewhere in August 1956 for "nervousness" and had received electroshock therapy. At about this time she had experienced chills and fever with temperatures up to 101 °F . This subsided after a period of approximately three weeks . In December 1956 these symptoms recurred and were accompanied by dyspnea, orthopnea and frequent episodes of rapid and irregular heart beat . The patient had suffered a 38 pound weight loss in the preceding year . One month before admission to this hospital her family

physician had noted a pericardial friction rub. She had been investigated in another hospital in July 1956 for protracted vomiting and epigastric pain and at that time a diagnosis of duodenal ulcer had been established . There was an additional history of recurrent erythematous flushing with associated sweating involving the upper thorax and extremities during the year preceding admission . On physical examination the patient was well developed, poorly nourished, oriented and alert . The temperature was 99 .4°F . There was pallor of the skin and conjunctivas . A small posterior cervical node was palpated . The thyroid was not enlarged . The heart was slightly enlarged to the left and there was a grade I apical systolic murmur . The pulse was 76 per minute, weight 113 pounds, blood pressure 116/80 mm . Hg . The liver was palpable at the right costal margin and the spleen extended 6 cm . below the left costal margin in the mid-clavicular line . It was smooth and non-tender . There was bilateral palmar erythema ; the skin was otherwise clear . The hemoglobin was 8 .3 gm . per cent, red blood count 3 .20 million per cu . mm., white count 6,750 per cu . mm . with 4 per cent myelocytes, 3 per cent metamyelocytes, 9 per cent band forms, 53 per cent neutrophils, 2 per cent eosinophils, 21 per cent lymphocytes, 3 per cent leukocytoid lymphocytes and 5 per cent monocytes . There was slight polychromasia and slight poikilocytosis . The red blood cells were essentially normocytic but numerous macrocytes were noted . The platelets appeared adequate on stained smear and numbered 126,000 per cu . mm ., the reticulocyte count was 2 .9 per cent, prothrombin time 15 per cent (90 per cent) . The reaction to repeated L .E . tests was negative . The sternal marrow aspirate was found to be hypercellular and approximately one-fourth of the cells were mast cells with granular cytoplasm, immature nuclei and indistinct cytoplasmic borders . Differential bone marrow showed 1 .6 per cent progranulocytes, 5 per cent neutrophilic mvelocytes, early ; 4 per cent neutrophilic myclocytes, late ; 3 .8 per cent neutrophilic myelocytes, 5 .6 per cent band cells, 26 .2 per cent neutrophils, 16 per cent pronormoblasts, 6 per cent basophilic normoblasts, 14 .6 per cent polychromic normoblasts, 0 .8 per cent normochromic normoblasts, 0 .2 per cent phagocytic histiocytes, 25 .6 per cent mast cells. Megakaryocytes appeared somewhat decreased in number . Urinalysis was within normal limits. The serologic test for syphilis was non-reactive, Fasting blood sugar was 108 mg . per cent, non-protein nitrogen 30 mg . per cent, serum albumin 5 gm. per cent, globulin 2 .2 gm . per cent . The antistreptolysin-O titer was less than 12 units . Bromsulphalein retention was 3 per cent in forty-five minutes, serum total bilirubin 0 .5 mg . percent, direct 0 .25 mg. percent. Results of direct and indirect Coombs' tests were negative . The reaction to the ccphalin cholesterol test was 2 plus, thymol turbidity 3 units, thymol flocculation 2 plus. Blood AMERICAN JOURNAL OP MEDICINE

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Fm . 5 . Case n. Biopsy specimen of liver showing mast cells in sinusoids. Original magnification )( 1,100 . cultures were negative . Protein-bound iodine was 6 .2 µg . percent and alkaline phosphatase 2 .6 Bodansky units . The urine was negative for 5-hydroxyindolacetic acid . Chest fluoroscopy was within normal limits . Roentgenograms of the upper gastrointestinal tract disclosed an ulcer along the lesser curvature of the duodenal bulb . Bone survey, including thoracic cage, lumbar spine, pelvis and skull, was within normal limits . X-ray examination of the colon was non-contributory . A biopsy specimen of the liver revealed tissue mast cells in the sinusoids and portal areas . (Fig . 5 .) The patient had a continued fever, with temperatures ranging from 101° to 102 .4°r., throughout her hospitalization . She noted dull, constant aching epigastric distress and postprandial distention and eructation . There was no vomiting . The physical findings remained essentially unchanged . She had several episodes of recurrent flushing, with erythema of the upper thorax and extremities which lasted from thirty to sixty minutes ; these cleared and left no residual pigmentation . No peripheral lymph nodes were felt . On February 6 a course of nitrogen mustard was started and repeated on three successive days . The patient was discharged to be followed in the Out-PavoL . 32, FEBRUARY 1962

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Fm . 6 . Case n . Mast c Its in peripheral blond smear. dent Department . She was subjectively improved, although she continued to note chronic aching discomfort in the left shoulder and was still having episodic flushes with sweating and redness of the upper portion of the thorax . She was readmitted on March 28, of the same year, complaining of nausea, vomiting and pain in the upper right portion of the abdomen . Her general condition was essentially unchanged, as were the physical findings . The hemoglobin was 9 .4 gm . per cent; the reaction to the stool guaiac test was negative; fecal urobilinogen was 350 mg . per cent ; the white count was 6,100 per cu . mm . with I per cent myelocytes, 5 per cent metamyelocytes, 9 per cent band forms, 65 per cent neutrophils, 10 per cent lymphocytes, 6 percent monocytes and 4 percent mast cells . The red blood cells were hypochromic, with some polyehromasia and numerous macrocytes . (Fig. 6 .) There was mild basophilic stippling ; occasional spherocytes and target cells were noted . There were 4 polychromatic normoblasts per 100 white cells . The urine was negative for bile . The serum non-protein nitrogen was 34 mg. per cent . The result of the direct Coombs' test was negative . The reticulocyte count was 3 .4 per cent. On May 16 the white count had fallen to 3,700 per cu . mm . and the hemoglobin was 10 .8 gm . per cent- A low grade fever persisted during the fiveday hospitalization . There was symptomatic improve-



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ment with blood transfusion and continuation of an ulcer regimen . On April 27 the patient was readmitted because off easy fatigue and shortness of breath, and headaches accompanied by flushing and heat . At that time a grade 3 apical systolic murmur was noted, as well as massive enlargement of the liver, now extending to the pelvic brim. The spleen had enlarged further and was 12 cm . . below the left costal margin in the midclavicular line . There was continued evidence of an active duodenal ulcer, as well as recurrent episodes of chills, fever and erythema of the upper half of the body . The patient remained anemic and thrombocytopcnia developed (92,000 per cu . mm .) . A course of x-ray therapy was initiated on May 3 . There was a gradual decline in the white blood count to 2,850 per cu. mm., with no appreciable decrease in the size of the spleen . There were several episodes of chest pain during the following three weeks . On June 4, the patient was brought into the emergency room with complaints of severe abdominal and chest pains and associated dyspnea. She quickly became disoriented and cyanotic, and died . Autopsy revealed hepatosplenomegaly, generalized lymphadenopathy and a duodenal ulcer . Mast cells similar to those described in Case r were found in increased numbers in the bone marrow, liver, esophagus, stomach in the region of the ulcer, colon, lymph nodes, spleen and epicardial tissue in the region of the aortic and pulmonary valves . Staining of the mast cell granules varied in different organs as well as with the many stains utilized . Hematopoiesis was prominent in the liver and spleen . It was believed to account for a large part of the enlargement of these organs . Fibrosis did not accompany the increase in mast cells . One section of aortic valve, however, showed an increase in large mononuclear cells embedded in a loose fibrillar stroma with a chromatin pattern of the Anitschkow myocyte. Scattered mast cells were present in this area . The skin and central nervous system were not examined . CASE in . Henry Ford Hospital Record No . 998662 . W . S ., a fifty-one year old white male welder, was admitted to the Henry Ford Hospital on August 8, 1960, with the chief complaint of "lumps" in the neck and axillae. The patient had been feeling quite well until six months prior to admission when he experienced gradual onset of malaise, fatigue, slight exertional dyspnea, night sweats and intermittent fever . There was occasional diarrhea which he related to the intake of food and beer . A peanut-sized enlargement in the left posterior cervical chain had first been noted three months before admission . This node was removed by his family physician and was reported as "hyperplastic lymphoid tissue ." Other nodes then appeared in the neck bilaterally and, a week prior to his admission, large lymph nodes developed rather rapidly in both axillae . He noted, for the first time, low back

pain which awakened him at night and was aggravated by the recumbent position. The patient had been aware of a brown-red maculopapular skin rash over the trunk for the past ten years . The color intensity of this rash varied and he thought that it was possibly aggravated by exposure to sunlight . In addition, upon direct questioning, a history of episodes of flushing of the face was elicited, occurring intermittently and seemingly accentuated by alcohol intake . Coffee and strawberries had, in the past, been productive of hives . Physical examination revealed a well developed, ruddy faced, white man with slightly pallid conjunctivas and palm surfaces . Diffuse reddish brown maculopapular skin lesions were present over the trunk, extending somewhat into the cervical areas and upper part of the arms bilaterally . The lesions averaged 3 to 5 mm . in size and on surface irritation they were noted to form wheals . Symmetrical, discrete adenopathy of the cervical, axillary, epitrochlear and inguinal areas was present bilaterally, the nodes varying in size up to several centimeters . The blood pressure was 180/100 mm . Hg, pulse 88 per minute and regular, temperature 99.4°r . Examination of the chest revealed scattered rhonchi bilaterally . The heart was slightly enlarged to the left, with a hypertensive configuration . A grade 1 to 2 systolic murmur was heard at the initial area . Heart tones were regular, of normal intensity, and the second aortic sound equaled the second pulmonic sound . Abdominal examination revealed the liver to be palpable 3 cm . below the right costal margin, with over-all increase in size of the liver as determined by percussion of the upper border . The spleen was felt 2 cm . below the left costal border and percussion of the upper border confirmed enlargement. Proctoscopic examination was within normal limits with the exception of slightly pale mucosa . The hemoglobin was 10 .2 gm. per cent on admission and 8 .4 gm . on examination four weeks later . The white blood cell count was 9,800 per cu . mm . with 82 per cent neutrophils, 4 per cent eosinophils, 4 per cent lymphocytes, 2 per cent leukocytoid lymphocytes and 6 per cent nronocytes . Slight hypochromia and anisocytosis was noted. Platelets were adequate on the smear and numbered 210,000 per cu . mm. The hematocrit was 36 percent. The result of the Rumpel-Leede test was slightly positive ; LeeWhite clotting time was six and a half to eight and a half minutes, prothrombin time eighteen seconds with a control of fifteen seconds . The plasma clotting time was 116 seconds and prothrombin consumption time 17 .2 seconds. The thromboplastin generation test result was within normal limits . The urinalysis were within normal limits . The result of the serologic test for syphilis was non-reactive . Serum protein electrophoresis revealed a total protein of 6 .8 gm ., albumin 3 .6 gm ., alpha, globulin 0 .45 gm ., alpha, globulin 0 .58 gm ., beta globulin 0 .67 gm ., and gamma globulin 1 .49 gm . Fasting blood sugar was 100 mg . per cent,

AMERICAN JOURNAL OP MEDICINE



Systemic Mast Cell Disease-Szweda et al . blood urea nitrogen 12 mg . per cent, alkaline phosphatasc 3 .4 Bodansky units, transaminase 13 units, total cholesterol 156 rug . per cent, calcium 8 .8 mg . per cent (later 9 .6 and 9 mg . per cent) ; serum phosphorus was 3 .8 mg . per cent. 'I he reaction to the bromsulphalein test was negative as well as the qualitative test for urinary 5-hydroxyindolacetic acid . Cephalin-cholesterol flocculation was 3 plus, thymol turbidity 5 units . Two blood cultures were negative . The phenolsulfonphthalein test revealed 20 per cent excretion in fifteen minutes and a total of 84 per cent excretion in two hours . Agglutinations for salmonella and brucella were negative . Chest fluoroscopy showed slight generalized enlargement of the heart and bilateral hilar node enlargement . A general skeletal survey revealed only slight degenerative changes of the cervical and thoracic spine . The electrocardiogram was within normal limits . Examination of marrow smears revealed a marked increase in the mast cells present in the connective tissue trabeculae but apart from moderately increased cellularity, the marrow was otherwise non-contributory . Splenic aspiration biopsy disclosed only occasional mast cells in the smear preparation . A skin biopsy specimen was diagnostic of urticaria pigmentosa . Following hospitalization the patient's chief and most aggravating complaint related to lower abdominal pain radiating through to the lumbar back . The pain became gradually more severe and persistent; initially it was relieved slightly by sitting up and bending forward, and aggravated by the supine position . The patient was given a course of deep x-ray therapy to the abdomen on the presumption that the pain was probably due to retroperitoneal node involvement . For a short time after cessation of x-rav therapy the patient had relief of his pain but during and in the immediate postradiation period he experienced exacerbation of shaking chills and fever occurring daily with a temperature to 102 °x. Profuse rhinorrhea accompanied these symptoms but was considerably relieved by antihistaminic therapy . '[ he patient was discharged on September 9, 1960, and is being followed up in the Out-Patient Department . COMMENTS

The three patients herein cited exemplify the gamut of symptoms attributed to histamine release-local and generalized flushing, local urtication, palpitation and peptic ulceration . Nausea, vomiting, diarrhea, fever, night sweats and facial edema may also be related to liberation of histamine . Inciting causes of histamine liberation from the mast cells in these cases were cold, trauma, infection, alcohol, radiation of the spleen and retroperitoneal nodes . The hepatosplenomegaly due to mast cell infiltration appeared to incite some fibrosis but little functional damage resulted in the first case . VOL .

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The role of hyaluronic acid release from the mast cell in this reaction can only be conjectured . Local reaction to the stasis ulceration and the persistent ulcer between the toes may likewise have reflected the role of the mast cell in inflammation and tissue repair . Although no histologic study of the lung is available, the nodular interstitial fibrosis noted on the chest roentgenogram may also represent abnormal collagenous deposit or altered tissue reactivity due to increased mast cell release of histamine, heparin and hyaluronic acid . Stenosis of the mitral valve in the first case cannot be causally related to systemic mast cell disease, but in the absence of a history of rheumatic fever one might speculate a possible relationship . Several possibilities might be considered : First, the local sclerosing effect of mast cells in the valve leaflets ; second, release of histamine and heparin from mast cells in the lung ; and third, serotonin liberated in the pulmonary vessels by the action of histamine on the platelets with an effect on the mitral valve similar to that of the tricuspid and pulmonary valves in the carcinoid syndrome . Our first patient had increased excretion of 5-hydroxyindolacetic acid and the levels were further increased by rubbing the skin with a towel . Since serotonin has not been established as a part of the chemical anatomy of the human mast cell, we assume that histamine release with subsequent platelet disruption and serotonin release might be postulated . The eosinophilia noted in the first case may well be related to histamine released from the mast cells since it has been shown that histamine is chemotactic for eosinophils . Indeed, the increased numbers of eosinophils may be to some extent protective since it has been shown that injection of histamine into a skin site rich in eosinophils produces little or no edema when compared to injection of histamine into a skin site without eosinophils [63] . Even though serotonin has not been demonstrated in the human mast cell, the work of Waalkes et al . [64] showing serotonin release in rabbits during anaphylactic shock, with a concomitant fall in the platelet count as the histamine and serotonin blood levels rose, suggests that in man histamine released from the mast cells may chronically disrupt the platelets, releasing a considerable amount of serotonin which in turn may play a part in the pathogenesis of the disease .

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Several modes of treatment have been attempted, including cortisone [60,61], antihistaminics [3.3] and reserpine [G2] . None of these agents has been particularly effective . However, the work of Rowley and Benditt [22] demonstrating a local protective effect by antihistamines and antiserotonins suggests that further trial of this form of therapy is in order . The diagnosis of systemic mast cell disease depends entirely on the index of suspicion of the examiner, since no laboratory examination or non-directed biopsy material will reveal its presence . A search for systemic involvement in cases of urticaria pigmentosa is indicated . Beyond this, systemic mast cell disease deserves consideration in the differential diagnosis of flushing, diarrhea, nausea and vomiting, hepatosplenomegaly, unexplained bone lesions, fever of obscure origin and perhaps in disorders of the clotting mechanism . In Case in there were signs and symptoms suggestive of a lymphoma . At present, alcohol-fixed biopsy tissue serves best in confirming a diagnosis, although careful search of peripheral blood and bone marrow aspirates may be helpful . Small numbers of mast cells were consistently found in the peripheral blood in the second case ; the marrow was heavily infiltrated with mast cells . Urinary histamine excretion is an indirect help in diagnosis . The course of the disease is frequently benign, compatible with several decades of normal activity but, as indicated, may ultimately lead to death . SUMMARY

Twenty-one cases of systemic mast cell disease reported in literature are reviewed . Three additional patients, one with mast cell leukemia and two with systemic mast cell disease, are described . The relationship of the signs and symptoms of systemic mast cell disease to the known products formed by the mast cell is discussed . REFERENCES 1 . NETFTLESHIP, B . Rare forms of urticaria . Brit. M. J., 2 : 323, 1869 . 2. SANGSTER, A. An anomalous mottled rash, accompanied by pruritus, factitious urticaria and pigmentation, "urticaria pigmentosa ." Tr. Clin . Soc . Land., 11 : 161, 1878 . 3 . EHRLICH, P . Beitrage zur Kenntniss der Anilinfarbungen and ihrer Verwendung in der mikroskopischen Technik. Arch . mikr . Anal,, 13 : 263, 1877 . 4. UNNA, P. G. The Histopathology of the Diseases of the Skin, p. 955 . Translated from the German with

the assistance of the author by Norman Walker . New York, 1896. Macmillan & Co . 5. FINNERDO, C . W. Urticaria pigmentosa (nodular type) with a summary of the literature ; report of a case. Arch . Dermat . & Syph., 8 : 344, 1923 . 6 . TOURAINE, A ., SOLENTE, G . Rod RENAULT, P . Urticaire pigmentaire avec reaction splenique et myelemique. Bull . Sac . Frang . dermas . et syph ., 40 : 1691, 1933 . 7 . ELLIS, J . M . Urticaria pigmentosa : report of a case with autopsy. Arch . Path ., 48 : 426, 1949 . 8. SAGHER, F ., COHEN, G . and SCHORR, S . Concomitant bone changes in urticaria pigmentosa. J. Invest . Dermat., 18 : 425, 1952 . 9. MICHELS, N . A . The mast cells . In : Handbook of Hematology, vol . 1, p . 235. Edited by Downey, H . New York, 1938 . Paul B . Hoeber. 10, RILEY, J . F. Heparin, histamine and mast cells . Blood, 9 : 1123, 1954. 11 . JORPES, E ., HOLMGREN, H . and WILANDER, O . Heparin in vessel walls and in the eyes. Zischr . Mikroskop .Anat . Forsch ., 42 : 279, 1937. 12 . JORPES, J. E . Heparin in the Treatment of Thrombosis, 2nd ed . London, 1946 . Oxford University Press . 13. OLIVER, J., BLOOM, F. and MANCIERI, C . N . On origin of heparin : examination of heparin content and specific cytoplasmic particles of neoplastic mast cells . J. Exper. Med ., 86 : 107, 1947 . 14. KONRAD, J . and WINKLER, A . Zur Pathogenese der Urticaria Pigmentosa in Zusammenhang Hut der Mastzellenfunktion . Haatarzt, 4 : 119, 1953 . 15 . UREACH, F ., BELL, W . N. and JACOBSON, C . Studies on urticaria pigmentosa ; release of heparinoid material into circulation following direct stimulation of urticaria pigmentosa lesions . J. Invest . Dermat ., 25 : 211, 1955 . 16. HILL, M . Secretion of heparin by mast cells . Nature, London, 180 : 654, 1957 . 17. SCHILLER, S . and DORFMAN, A. Isolation of heparin from mast cells of the normal, rat . Biochim . et biaphyi. acta ., 31 : 278, 1959. 18 . AsaoE-HANSEN, G. Origin of synovial mucin ; Ehrlich's mast cell-secretorv element of connective tissue . Ann . Rheumat . Dis., 9 : 149, 1950 . 19 . WEST, G . B . Pharmacology of the tissue mast cell . Brit. J. Dermat ., 70 : 409, 1958, 20 . MORRIONE, T. G. Formation of collagen fibers by action of heparin on soluble collagen ; electron microscope study . J. Exper . Med., 96 : 107, 1952 . 21 . RILRY, J . F. and WEST, G . B . Presence of histamine in tissue mast cells . J. Physiol ., 120 : 528, 1953 . 22 . ROWLEY, D . A. and BENDITT, E. P . 5-Hydroxytryptamine and histamine as mediators of the vascular injury produced by agents which damage mast cells in rats. J. Exper . Med., 103 : 399, 1956 . 23 . BHATTACHARYA, B. K . and LEWIS, G . P . Release of 5-hydroxytryptamine by histamine liberators . Brit . J. Pharmacal., 11 : 202, 1956 . 24 . SJOERDSMA, A ., WAALR85, T. P. and WEsssaAcH, H . Serotonin and histamine in mast cells . Science, 125 : 1202, 1957 . 25 . ARCHER, G. T. Release of histamine from mast cells by tissue extracts . Nature, London, 182 : 726, 1958 . 26 . BLOOM, G ., DUNRR, H., PRRNOW, B ., WINRERC, J. and ZETTERSTROM, R Spontaneous histamine shocks AMERICAN JOURNAL OF MEDICINE



Systemic Mast Cell Disease--Szweda in urticaria pigmentosa . Acta Poediat ., 47 : 152, 1958 . 27. CASS, R ., MARSHALL, P. B . and RILEY, J . F . 5-Hydroxytryptamine and histamine in mast cells of the mouse and rat . J . Physiol„ 141 : 510, 1958 . 28, ENDS, N. and CHERNISS, E . I . Mast cells histamine and serotonin ; studies of the human spleen . Am . J. Clin . Pat{, ., 30 : 35, 1958 . 29 . GARDNER, L . I . and 'lice, A . A . Histamine and related compounds in urticaria pigmentosa : analyses of tissues having mast cell infiltration . Pediatriuq 21 : 805, 1958 . 30 . Sasrrx, D . E. Dynamics of release of histamine from mast cell. Science, 128 : 207, 1958 . 31 . SCHINDLER, R ., DAY, M . and FISCHER, G . A . Culture of neoplastic mast cells and their synthesis 5-hydroxytryptamine and histamine in vitro. Cancer Res., 19 : 47, 1959 . 32 BENDITT, E . P., WoNC, R . L., ABASE, M . and ROEPER, E . 5-Hydroxytryptamine in mast cells . Proc. Sac. Exper . Biol . & Med., 90 : 303, 1955 . 33 . DAVIS, M. J., LAWLER, J . C . and HIGnoN, R . S . Studies on an adult with urticaria pigmentosa ; report of a case. Arch . Dermal., 77 : 224, 1958 . 34. ASBOE-HANSEN, G. The mast cell : cortisone action on connective tissue . Proc . Soc. Exper. Biol. & Med., 80 : 677, 1952 . 35 . AsBOE-IIANSEN, C . Hormonal effects on connective tissues . In : Conference on Connective Tissue, vol . 5, p . 123 . New York, 1954 . Josiah Macy, Jr . Foundation . 36 . CAIRNS, A . and CoNS'rAN'TINIDES, P . Mast cells in human atherosclerosis . Science, 120 : 31, 1954 . 37 . PATERSON, J. C . and MILES, J . Myocardial mast cell counts in coronary sclerosis . Arch, Path ., 66 : 355, 1958 . 38, WATSON, W . C . Role of the tissue mast cell in experimental atherosclerosis . Brit . J. Exper- Path., 39 : 540, 1958 . 39 . CRAMER, W. and SIMPSON, W . L. Mast cells in experimental skin carcinogenesis . Cancer Res., 4 : 601,1944 . 40 . HAVARD, C . W. II. and SCOTT, R . B . Urticaria pigmentosa with visceral and skeletal lesions . Quart . J . Meet., 28 : 459, 1959, 41 . SAGHER, F . and SCHORR, S . Bone lesions in urticaria pigmentosa ; report of central registry on skeletal x-ray survey- J. Incest . Dermal ., 26 : 431, 1956. 42 . POPPEL, M . H ., GRUBER, W . F., SILBER, R ., HOLDER, A. K. and CHRISTMAN, R . O. Roentgen manifestations of urticaria pigmentosa (mastocytosis . Am . J. Roentgenol ., 82 : 239, 1959 . 43 . BERTRLLOTTI, L. Case report of urticaria pigmentosa with systemic involvement . Cior . teal . dermal . e sif., 184 : 698, 1943 . 44 . DECOs, R ., LORTAT-JACOB, E ., HEWITT, JI and Ossmowssu, B . Reticulose a mastocytes, forme cutanee d iffuse . Bull. Soc. Franc. dermal. e t syph., 59 : 247, 1952 . 45 . BERLIN, C . Urticaria pigmentosa as systemic disease . Arch. Dermal., 71 : 703, 1955 .

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46 . BRODEUR, P . and GARDNER, L . 1 . Urticaria pigmentosa as problem in diagnosis ; report of two cases, one with systemic involvement . Aeu England J . Med ., 254 : 1165, 1956 . 47. REILLY, E . B ., SmNTANI, J. and GOODMAN, J. R. Systemic mast cell disease with urticaria pigmentosa. Arch . Dermal ., 71 : 561, 1955 . 48 . BLUEFARB . S . M . and SALE, M . R. Urticaria pigmentosa with bone lesions, gastrointestinal symptoms and splenomegaly . Arch . Dermal. & Syph ., 70 : 376, 1954. 49. STARK, E ., VAN Busxxsx, F . W, and DALY, J . F. Radiologic and pathologic bone changes associated with urticaria pigmentosa ; report of case. Arch. Path., 62 : 143,195650 . RIDER, T. L ., STEIN, A. A. and ABBUHL, J . W. Generalized mast cell disease and urticaria pigmentosa ; report of case . Pediatrics, 19 : 1023, 1957 . 51 . ZAK, F . G ., COVEY, J . A . and SNODGRASS, J . J . Osseous lesions in urticaria pigmentosa. New England J . Med ., 256 : 56, 1957 . 52 . :'+SHOE-HANSEN, C . Urticaria pigmentosa with generalized tissue mastocytosis and blood basophilia . Arch . Dermal ., 81 : 198, 1960. 53 . EPRATI, P., KLAJMAN, A . and SPITZ, H . Mast cell leukemia-malignant mastocytosis with leukemialike manifestations . Blood, 12 : 869, 193' . 54 . WATERS, W . J . and LACSON, P . S. Mast cell leukemia presenting as urticaria pigmentosa . Pediatrics, 19 : 1033, 1957 . 55 . SAGHER, F ., LIBAN, E ., UNGAR, H . and SCHORR, S. Urticaria pigmentosa with bone involvement . J. Invest. Dermal ., 27 : 355, 1956. 56 . HISSARD, R ., MoNocourER, L . and JACQUET, J . Etude d'une nouvelle hematodermie : la mastocytose . Pre.cre med., 59 : 1,7 65, 1951 . 57 . LENNERT, K., KOSTER, E. and MARTIN, H. Uber die Mastzcllenleukamie . Act, haemat., 16 : 255, 1956 . 58 . FRIEDMAN, B . I ., WILL, J . J ., FREIMAN, D . G . and BRAUNSTEIN, H . Tissue mast cell leukemia . Blood, 13 : 70, 1958 . 59 . ENDE, N . and CILERNISS, E . I . Splenic mastocytosis. Blood, 13 : 631, 1958. 60 . BLOOM, G . Cytological changes in human tissue mast cells after cortisone treatment Acta morphol . Mcerl., 1 : 331, 1958 . 61 . URBACH, F., JACOBSON, C . and BELL, W . Urticaria pigmentosa treated with desoxycorticosterone . Arch . Dermal ., 70 : 675, 1954. 62. BAER, R . L ., BERSANI, R . and PELZIC, A . Effect of reserpine on urticaria pigmentosa . J. Invest. Dermal ., 32 : 5, 1959 . 63 . ARCHER, R . K. Eosinophil leucocytes and their reactions to histamine and 5-hydrosytryptamine. J. Path . & East ., 78 : 95, 1959 . 64 . WAALKES, T . P ., WEISSBACH, H ., BOZIECEVICH, J. and UDENPRIEND, S . Serotonin and histamine release during anaphylaxis in the rabbit . J. Clin . Invest., 36 :1115,1957 .