Journal of Cutaneous Pathology 1979: 6: 42-52

Systemic Mastocytosis and the Mastocytosis Syndrome 'GARY D. MONHEIT, ^TARIQ MURAD AND 'MARCEL CONRAD Departments of 'Dermatology, 'Pathology and 'Medicine, University of Alabama Medical Center, Birmingham, Alabama, U.S.A. A patient with extensive systemie mastocytosis and the mastocytosis syndrome was studied by light and electron microscopy. Mast cell proliferation was found in the bone marrow, the Uver, spleen and lymph node. In addition, the patient had telangiectasia maeularis eruptiva perstans and elevated histamine levels. (Received for publication April 13, 1978)

Mastocytosis is an abnormal prohferation of mast eells occurring most commonly in the skin but also occurring systemieaUy. It was first deseribed by Nettleship in 1869 as a localized cutaneous infiltration or tumor (Fitzpatrick et al. 1971). In 1933 Touraine described urticaria pigmentosa involving organs other than the skin (EUis 1949). Recent reviews have demonstrated the spectrurn of systemic mastocytosis to include involvement of bone, viscera, and hematopoietic system (Sagher & Even-Paz 1967). The disease may occur as a single skin lesion, a mastocytoma, or a generahzed cutaneous eruption such as urticaria pigmentosa. Infiltrations in the reticuloendothelial system of lymph nodes, spleen, bone marrow and hver may occur in the systemic form (Mihas 1973). On rare occasions the systemic form may evolve into a mast cell leukemia characterized by large numbers of mast cells in the circulating blood and a rapidly fatal course (Efrati 1957). The clinical presentation of mast cell disease is determined by the extent and loeation of the mast cell infiltrate as well as by the pharmacologic action of the histamine and heparin released (Demis 1972). The case described here is that of a patient with multisystem mast cell tumor infiltration and its resultant pharmaco-dynamic effects. Histopathological, histoehemical and electron microscopic data confirmed the widespread extent of the disease.

tVtateriat and tVtethods

Case Report Clinieal Features. The patient was a 45-yearold Caucasian tnale who related a 15-year history of active mast cell disease. He was the produet of a normal childbirth with no noticeable cutaneous eruption in the neonatal period or infancy. The patient described sporadic eruptions of urticaria during childhood. In his mid-twenties he noted frequent urticarial eruptions and bullae that could be induced by mechanical stimulation. With advancing age, the cutaneous manifestations became more frequent and were accompanied by diffuse hyperpigmentation. At that stage (1965) a biopsy confirmed the diagnosis of generalized urticaria pigmentosa. He was treated with antihistamines, topical steroids and lubricants with some resolution of the lesions. In 1968 the patient noted intermittent attacks consistitig of flushing, palpitations, tlirobbing headache, tinnitus, dizziness, nausea with occasional vomiting, explosive diarrhea and tenesmus occurring as a sudden paroxysm. The attacks were precipitated by exertion, hot baths, spicy foods, or emotional strain. Gastrointestinal symptoms included epigrastic pain, nausea, vomiting and diarrhea. An upper GI series in 1 970 revealed multiple duodenal ulcers. Two years prior to admission the patient began experiencing severe bone pain through

0303-6987/79/010042-11 $02.50/0 © 1979 Munksgaard, Copenhagen

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Fig. 1. Clinical photograph of the skin showing diffuse macules of various sizes interlaced byfinetelangiectatic vessels. the axial skeleton and Hmb-girdle area. Generahzed osteosclerosis was noted on Xray of the lumbosacral spine and pelvis which led to a course of prednisone therapy. Other problems related to the patient's mast cell disease included otosclerosis, chronic laryngitis, iridocychtis, impotence, anemia and thrombocytopenia. In 1975 the patient was referred to University Hospital beeause of his progressive symptoms. At the time of admission, he appeared grossly eushingoid with moon faeies, striae, trunkal obesity and a dorsal fat pad. His skin was diffusely involved with tan to brown macules. These were confluent in sun exposed areas and there was a flush of the face and upper trunk (Fig. I). Fine telangieetatie vessels interlaced between the macules in a reticulate pattern as found in telangieetasia maeularis eruptiva perstans. Darier's sign was positive and hehenification was present in the flexural areas. The patient was subject to dermographism and urticaria but there were no blisters or tumors. The patient was hypertensive and experienced tachycardia at rest. Grade II hypertensive

retinopathy was present. The tympanic membranes were dull and retracted. In addition the patient had evidence of congestive heart failure with jugulovenous distension at 30 degree elevation, bibasilar rales, a gallop rhythm and dependent edema. Hepatosplenomegaly was present with tenderness over the abdomen. Shotty, non-tender lymph nodes were present in the submandibular and axillary areas. The neurologic examination was essentially normal. Laboratory Studies. There was anemia with a PCV of 35, red blood cell precursors in the peripheral blood, and a platelet count of 90,000. Twenty-four hour urinary excretion of free histamine was elevated at 450 mgm/ 24 h, and the serum liistamine was also elevated at 3.0 megm/100 ml. Radiologic studies revealed diffuse sclerotic changes in all long bones and laminated sclerosis in the axial skeleton consistent with osteosclerotic mast cell reticulosis. An upper Gl series revealed healed duodenal ulcer craters with a normal small bowel series. The patient was given large doses of

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bromphemiramine, peractin, and oral croma- aspiration was performed at the iliac crest lyn sodium without significant change in the using an Illinois biopsy needle and sections flush syndrome, pruritus or other related were prepared for histoehemical analysis. A symptoms. The bone pain was treated with liver biopsy was removed using a Menghini intravenous Mithramycin for 2 weeks with needle and the tissue was examined by light moderate relief of pain. The congestive heart and electron microscopy. failure was treated with Digoxin, Lasix, and The histologie sections of skin stained by potassium supplements. The patient was hematoxylin and eosin revealed infiltration tapered to a lower alternate day maintenance of the upper dermis by mononuclear cells steroid dosage. (Fig. 2). The infiltrate varied in intensity in Because of his continued anemia, throm- different parts of the dermis with a prebocytopenia and splenomegaly the patient dominant upper dermal and perivascular was readmitted to the hospital for splenee- distribution. On higher magnification the tomy 1 month after discharge. At surgery tumor cells were ovoid with abundant eosinothe spleen appeared markedly enlarged phihe cytoplasm and large elongated nuclei weighing 1,250 g. The patient did well post- giving them a fibroblastic appearance (Eig. operatively and responded with a brisk ele- 3). Scattered among the neoplastic cells vation of his platelet count. He was discharged were a few macrophages and occasional on alternate day steroids, antihistamines, eosinopliils. Special stains demonstrated the multivitamins with iron, Digoxin and specific mast cell granules in the majority of the cells, especially around the capillaries diuretics. (Fig. 4). Histopathologie and Electron Mieroseopic By electron microscopy the mast cells Findings. Skin biopsy specimens were taken were easily identified in the infiltrate: they from representative areas of the macules on were ovoid in shape with numerous long the trunk for histological and electron micro- villous projections from the cell membranes scopic study. A bone marrow biopsy and (Eig. 5). Within the cytoplasm were the

Fig. 2, Skin showing upper dermal accumulation of mononuclear cells. The infiltrate is more intense around dermal vessels. H&E Stain X 100.

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F/;?. i. Higher magnification of same section as in Fig. 2, demonstrating the presence of large number of ovoid cells with abundant cytoplasm. H&E Stain X 400.

Fig. 4. Toluidine blue stain demonstrating the metaehromatie granules in the eytoplasm of the mast cells, X 440.

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Fig, 5. Electron micrograph of a skin lesion demonstrating a characteristic mast cell with its long cytoplasmic microvilli and typical granules. X 7,000.

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y^/;?. (5. Electron micrograph of a skin lesion showing large number of niast cells (M) with perivascular distribution. X 4,500.

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MONHEIT ET AL.

Fig. 7. Light micrograph of iliac crest biopsy showing replacement of the marrow spaces by the ovoid appearing mast eells. H & E Stain X 300.

Fig. 8. Liver biopsy showing extramedullary hematopoiesis with megakaryoeyte. Reticulin stain. X 400.

MASTOCYTOSIS SYNDROME characteristic mast cell granules that had parallel concentric laminations. The scroll of finger-print configuration could be seen in some granules while others showed an amorphous dense material The intimate relationship of the mast eeU with blood vessels was well demonstrated (Fig. 6). Bone marrow revealed diffuse sclerosis with narrow replacement by ovoid fibroblastic-appearing cells with abundant cytoplasm (Fig. 7). Giemsa staining confirmed that the majority of the cells in the infiltrate had the characteristics of mast cells. The marrow aspirate revealed a shift to the left but with normal erythroid and granulocytic precursors. Mast cells were identified individually and in small clusters. Liver biopsy revealed extramedullary erythropoiesis with megakaryocytes, myeolid and erythroid precursors in the liver sinusoids (Fig. 8). Mast cells were also identified in these areas. Electron rhicroscopic sections confirmed the extramedullary precursors in relationship to hepatic sinusoids (Fig. 9). The spleen was grossly enlarged with aggregates of round cell infiltrates and fibrosis. An accompanying granulomatous reaction was seen with surrounding fibrosis. Touch preps of the splenic tissue stained with Giemsa and toluidine blue confirmed the

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numerous metaehromatie staining mast cells throughout the cellular reaction. The splenic hOar nodes were enlarged and contained an abnormally large number of mast cells. Discussion

Mastocytosis syndrome includes the complex of: 1) skin involvement; 2) systemic organ involvement, i.e. bone, lymph node, spleen, liver, gastrointestinal traet, etc.; and 3) intermittent histamine symptoms of pruritis, headache, flushing, tachycardia, syncope, hypotension and gastrointestinal complaints (Demis 1972). A modified classification of mast cell disease is presented in Table 1 (Fitzpatrick et al. 1971, Demis 1972). Although mastocytosis occurs most commonly as a localized cutaneous form, involvement of other organs occurs in approximately 10% of all patients (Sagher & Even-Paz 1967). Review of the world literature uncovered 71 cases of'proven'systemic mastocytosis with at least two organ systems involved. The most common combinatior\ was skin and bone, followed by lymph nodes, liver, spleen, and then other organs (Sagher & Even-Paz 1967, Demis 1972), The only organs spared in all cases were muscle and nerve tissue. One third of all systemic cases

Table 1 Classification of mast cell diseases in children and adults Age

Involvement

Childhood

Cutaneous generalized lesions Isolated nodule(s) Multisystemic Widespread skin changes (spleen, liver, nodes) Cutaneous Generalized lesions Isolated nodule(s) Telenagiectasia

Adult

Multisystemic -any of the above skin changes with flushing -Diffuse skin changes with spleen, liver, nodes, skeletal -Generalized

Type Urticaria Pigmentosa Mastocytoma(s) Diffuse mastocytosis Erytltroedermic mastocytosis Urticaria Pigmentosa Mastocytoma(s)-rare Telangiectasia maeularis eruptiva perstans Mastoeytosis syndrome Systemic mastocytosis Mast cell leukemia

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Fig. 9. Eleetron microgaph of liver biopsy showing infiltration of an hepatic sinusoid by precursor of hematopoietic cells. X 9,500.

MASTOCYTOSIS SYNDROME proved fatal; documation of systemic involvement in these cases was confirmed while each patient was still alive (Sagher & EvenPaz 1967). Extensive mast eell invovlement has been associated with hyperglobinemia, abnormal blood Hpids and clotting factors and xanthomatosis (Asboe-Hansen & Kaalund-Jorgensen 1956). Our patient presented in adolescence with generalized urticaria pigmentosa and developed in early adulthood the mastocytosis syndrome with histamine mediated symptoms. The flushing episodes did involve the face, neck, and upper chest as most commonly recorded in adult mastocytosis cases. The cutaneous eruptions later evolved a clinical and liistologie pattern of telangiectasis maeularis eruptiva perstans with a chronic symptomatic flush. The diagnosis was confirmed by an elevated urinary free histamine level of 450 mgm/24 cm, with the accepted normal range being from 5-60 mgm/24 h. Urinary levels of free histamine are commonly elevated in the mastocytosis syndrome (100-200 mgm/24 h), while patients with the telangiectasia maeularis eruptiva perstans form of mastocytosis have even higher values (200-700 mgm/24 h) (Dermis 1972). Histaminuria is an indication of widespread mast cell proliferation with production of excessive amounts of histamine, and currently not thought of as an alteration in histamine synthesis, degradation or excretion. The telangiectasia and erythematous flush this patient demonstrated are perpetuated by elironic release of mast cell mediators and their pharmacologic effect on dermal vasculature. The intimate relationship of mast cells to dermal vessels is well demonstrated by the electron microscopic studies of our case, and probably has a significant role in the evolution of this cutaneous pattern of mastocytosis. Peptie uleer disease in this patient was regarded as a response to the secretion of excessive histamine. Sagher reported a 7% incidence of peptic ulcer disease in liis series of patients with systemic mastocytosis. The positive correlation of telangiectasia maeularis eruptiva perstans with peptic ulcer

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disease and high levels of urinary histamine implicate a pharmacologic relationship (Demis 1972, Tempka 1973). The accompanying episodes of diarrhea, steatorrhea and probably malabsorption suggest primary gastrointestinal tract involvement (Tempka 1973). Bone involvement has been demonstrated in approximately 70% of patients with systemic mastocytosis (Harvard 1959, Sagher & Even-Paz 1967). The diffuse form is more common than the occasional localized bone lesion that may disappear spontaneously (Sagher & Even-Paz 1967). The widespread bone lesions are tnost often seen in the axial skeleton with osteosclerosis, thickening of the cortical and trabecular bone, osteoporosis and osteopetrosis. The mast cell deposits appear in the skull, long bones and pelvis as radiolucencies and opacities with characteristic laminations (Mutter 1963). Our patient demonstrated the diffuse form of osteoporotie and osteosclerotic bone lesions in vertebrae, pelvis, ribs, skull, and proximal limb bones. Biopsy of bone marrow revealed extensive myelofibrosis and osteoselerosis. Osteosclerosis is considered either a direct osteoblastic response to proliferating mast cell enzymes or a systemic pharmacologic effect of circulating histamine (Sagher 1965). The marrow aspirate in tliis patient was normal as to cell morphology and maturation but demonstrated mast cells and myeloid fibrous metaplasia. In addition to mast cells it is common to find myeloid hyperplasia with a shift to the left, reduced erythropoiesis and eosinophilia (Burgoon 1968). Demonstration of mast cells in marrow aspirate is the most frequent basis on which a diagnosis of systemic mastocytosis has been confirmed. Reduced erythropoiesis and myelofibrosis are assumed to be stimuli for the extramedullary erythropoiesis demonstrated on Uver biopsy in this patient (Sagher & EvenPaz 1967, Mihas 1973). Reticulin stain and electron microscopy localized the erythroid precursors and mast cells within the Uver sinusoids. Enlargement of the liver and/or spleen is

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an unfavourable prognostic sign in systemic mastocytosis, with a fatal outcome in 50% of cases (Sagher & Even-Paz 1967). Mast cell involvement was demonstrated histologically in both organs in this patient. Splenic hilar nodes of this patient were positive for mast cells confirming the widespread nature of this reticulosis. In summary, this report presents an unusual example of the mastocytosis syndrome with documentation of mast cell proUferation in bone marrow, Uver, spleen, lymph nodes, and the cutaneous pattern of telangieetasia maeularis eruptiva perstans. CUnieal markers for the mastocytosis syndrome in this patient included the histamine flushing syndrome with an elevated histamine level in the urine and serum, hepatosplenomegaly, osteosclerosis, and erythroblastic anemia and thrombocytopenia. A review of the reeent case reports documents the significance of this case of systemie mastocytosis as an example of the pharmacologic and anatomic aspects of this syndrome (Parkes-Weber 1940, Bigelow 1952, Sagher & Even-Paz 1967, Demis 1972). References

Burgoon, C. (1968) Mast CeU Disease. Archives of Dermatology 98, 590-602. Demis, D. L. (1963) The Mastoeytosis Syndrome: Clinical and biological studies. Atmals of Internal Medicitie 59, 194-204. Demis, D. L. (1972) 'Mastocytosis', Eds. Demis, Crounse, Dobson & MeGuire. Clinical Dermatology, Vol. I, 2-18. Efrati, P. (1957) Mast Cell Leukemia-Malignant Mastocytosis with Leukemia-like Manifestations. S/oorf 12, 869-888. Ellis, J. M. (1949) Urticaria ligmentosa. Arehives of Pathology 45,426-435. Fitzpatrick, T. B. (1911) Dermatology in General Medicitie, pp. 577-588. New York: McGrawHill Book Company. Harvard, C. W. (1959) Urticaria pigmentosa with visceral and skeletal lesions. Quarterly Journal of Medicine 28, 459-470. Mihas, M. (1973) Mast CeU Infiltrates of the Skin and the Mastocytosis Syndrome.//«ma« Pathology 4, 231-239. Mutter, R. (1963) Systemic mastocytosis. Annals of Internal Medicine 59, 887-904. Parkes-Weber, F. (1940) Telangiecstasia Maeularis Eruptiva Perstans. British .lournal of Dertnatology 24, 372-376. Sagher, F. (1965) The Mast Cell. pp. 247-301, London: Butterworth and Company, Ltd. Sagher, F. & Even-Paz, Z. (1961) Mastocytosis and the Mast Cell. pp. 56-125. Chicago: Year Book Publications. Tempka, T. (1973) Systemic proliferation of mast ceils with special localization in the digestive tract. Acta Medica Polona 14, 291-303.

Asboe-Hansen, G. & Kaalund-Jorgensen, O. (1956) Systemic Mast Cell Disease Involving Skin, Liver, Bone Marrow, and Blood Assoeiated with Disseminated Xanthomata. Aeta haematologica 16, 273-279. Bigelow, E. L. (1952) Changing concepts concern- Address: ing mastocytosis. Journal of Pediatrics 58, 499- Gary D. Monheit, M.D. Dept. of Dermatology 505. University of Alabama Medical Center Birt, A. R. (1959) Generalized flushing of the skin with urticaria pigmentosa. Archives of Derma- Birmingham, Alabama 35294 U.S.A. tology 80, 311-313.

Systemic mastocytosis and the mastocytosis syndrome.

Journal of Cutaneous Pathology 1979: 6: 42-52 Systemic Mastocytosis and the Mastocytosis Syndrome 'GARY D. MONHEIT, ^TARIQ MURAD AND 'MARCEL CONRAD D...
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