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Mastocytosis: Urticaria pigmentosa, myelofibrosclerosis and occlusive panarteritis
MASTOCYTOSiS:
URTICARIA PIGMENTOSA, MYELOFIBROSCLEROSIS AND OCCLUSIVE PANARTERITIS
S. SCHORR, M.D., M. L O E W E N T H A L , M.D., CH. BERLIN, M.D., M. RABINOWITZ, B.A., and P. EFRATI, M.D.
Departments of Radiology, Pathology, Dermatology and Bacteriology of the Municipal Hospitals, Tel-Aviv- Yafo, and the Laboratory for Blood Morphology, Kaplan Hospital, Rehovot, Israel URTICARIApigmentosa is a condition of exceptional and bone marrow in various stages of maturation. interest and of most varying heterogenous mani- Focal osteosclerosis in the vertebrae probably festations. represented a lesion related to the basic disorder. Touraine et al (1933) first suggested that mast There has also been a renewed interest in the cells may infiltrate organs other than the skin, nature of the mast-cell and its function. predominantly those of the reticulo-endothelial Tissue mast-cells (T.M.C.) are thought by some system. With the description by Ellis (1949) of the authors to be connective tissue cells of the histiocase of a one-year-old child, showing mast-cell cytic type. Their cytoplasm contains granules lesions of the liver, spleen, lymph nodes, bone which stain metachromatically with toluidine blue marrow and other organs, the dermatosis began to and certain other basic dyes. It is thought that be considered as a systemic disease. the T.M.C. has nothing in common with the blood The changing concept of this dermatosis from a basophil except the basophilic metachromatic pure cutaneous lesion to a systemic disease gained staining of the granules in the cytoplasm (Michels more impetus with the finding of generalised 1938). changes mainly osteosclerotic in character by In the last decade a number of newer concepts Sagher, Cohen and Schorr (1952). The main concerning the properties and function of the mastradiologic aspects were described by Schorr, cells have been postulated. The tissue mast-cells Sagher and Liban (1956). are believed to be associated with increased conThe finding of systemic bone lesions by other centrations of three important constituents:-authors strengthened the concept that the bony heparin (Jorpes et al 1937); histamine (Riley and system is one of the systems which tissue mast- West 1953); and hyaluronic acid (Asboe-Hansen cells may involve. Sagher and Schorr (1956) gave 1950). a short report of a central registry on skeletal Fulton et al (1957) summarising the many surveys in urticaria pigmentosa. In a compre- physiologic properties which have been attributed hensive review Poppel et al (1959) listed seventy- to the tissue mast-cell suggest that mast-cells are one patients with the condition examined roent- like unicellular endocrines which produee heparin, genologically, thirty-two of whom had bone lesions. hyaluronic acid, histamine and serotonin (5With the recent recognition of the widespread hydroxytryptamine). It has not been conclusively nature of this disease there is an increasing ten- proven whether these substances are produced or dency to call the condition mastocytosis. The only stored in the mast-cells. clinical significance of the condition has been The present case is of special interest, because extended by the recognition of extracutaneous in addition to a four-year clinical and radiological lesions, which have been reviewed by Berlin (1955). skeletal follow-up, the presence of panarteritis was He described a seventy-one-year-old man with found in subcutaneous nodules of the thigh. hepatosptenomegaly, cachexia and a stubborn anemia in a case of urticaria pigmentosa. The CASE REPORT bone marrow disclosed a high degree of proliferaT. Sh., male, aged forty-six, born in Hungary. In the tion of tissue mast-cells in the bone marrow. family history it is of interest to note that three brothers had The autopsy of the same case was reported by peptic ulcer of the stomach, one brother has hypertensive Loewenthal et al (1957). Tissue mast-cells were vascular disease and another brother diabetes mellitus. found in many internal organs, especially the spleen, According to the patient the present skin eruption had appeared twelve years ago, on recruitment to the army. liver and bone marrow. Efrati et al (1957) described a case of a fifty-two- The army physician noted some skin changes on the left chest and on the upper abdominal region, which Were year-old woman with probable leukaemia showing diagnosed as urticaria pigmentosa. Seven years ago the numerous tissue mast-cells in the peripheral blood patient suffered from heartburn and epigastric pain. No 84
MASTOCYTOSIS
85
FIG. 1 FIG. 2 FIG. 1--Photograph of the buttocks, showing the extensive rnaculo-papular eruption of urticaria pigmentosa. Fro. 2--Skin biopsy (magnification 1:116, toluidine blue stain), cross-section of skin showing perivascular infiltration.
FIG. 3 FIG. 4 Fro. 3--Pelvis (June 1958): sclerosis of the pelvic bones. Fro. 4--Femur shaft (June 1958): reticulated appearance of sclerotic trabeculae.
hyperacidity was found in his stomach contents. No ulcer was found on x-ray examination. At that time in addition to the previous skin changes, the same lesions spread to the dorsal part of both hands. Five years ago the cutaneous lesions spread over the whole body. On 10th June 1958 the patient was admitted for the first time to the dermatological department. The patient felt tired on minimal exertion, and complained of dizziness and sexual impotence. Physical examination: Skin--scattered all over the body there were innumerable discrete, round or oval papular and mostly macular lesions of 3 to 4 mm. in diameter. The colour was brownish-red and did not fade under diascopic pressure. Nu spontaneous itching was present. On stroking the skin, wheeling occurred. The application of an ice bottle caused urticaria (Fig. 1). The skin biopsy revealed slight hyperkeratosis with moderate atrophy of the epidermis. The dermal capillaries, in a dense fibrotic tissue, showed promi-
nent perivascular aggregates of lymphoid cells and a number of mast-cells which with special staining (cresyl violet, toluidine blue) gave positive metachromatic properties (Fig. 2). X-ray examination of the stomach did not reveal any abnormalities. The body skeleton x-ray examination revealed (Figs. 3 and 4) diffuse trabecular sclerosis of the cervical, dorsal, lumbar vertebrae and extremities. The pelvic bones revealed moderate to severe generalised sclerosis reticulated in appearance. No x-ray changes were seen on the bones of the skull, ribs, hands and feet. Three sternal and one iliac crest punctures were performed without any results because of the hardness of the bone. Laboratory d a t a : - - H b . 12 gr./100 ml. R.B.C. of 3,700,000. W.B.C. of 5,400. Differential count--polymorphs 60 per cent, eosinophils 2 per cent, monocytes 3 per cent, lymphocytes 35 per cent. Platelets 200,000. Glucose, 68 rag. per cent; urea 42 rag. per cent; uric acid 3'5 rag. per cent; cholesterol
86
CLINICAL
RADIOLOGY
FIG. 5 FIG. 6 Fro. 5--Pelvis (April 1961): severe osteosclerosis. FIG. 6 - - F e m u r shaft (June 1961): note the advanced stage of the reticulated sclerotic trabeculae.
270 mg. per cent; prothrombin activity 87 per cent; coagulation time five minutes; bleeding time three minutes; Weltmann 6; thymol turbidity 3 to 4 U. ; cephalin test negative; fibrinogen 231 mg. per cent; serum proteins total 8.4 gin. per cent; albumen 4.75 gm. per cent; globulin 3.67 gin. per cent; bilirubin 0.3 mg. per cent. Urine--sugar negative; albumen 0,3 gm. per cent. On 9th October 1961 the patient was readmitted to the hospital for further investigation because he noted several subcutaneous nodules on the medial part of the left midthigh. The patient felt sleepy and complained of sexual impotence, a condition which depressed him markedly. On physical examination the patient had the same cutaneous lesions as previously on his first admission, possibly even the lesions were more spread. The liver was palpable 5 cm. below the costal margin of hard consistency. No splenomegaly, no glands on the inguinal or axillar region were palpated. Blood analysis showed little or no change. The following further laboratory examinations were carried out :--total protein 8 gm. per cent; albumen 4.7 gm. per cent; globulin 3-4 gm. per cent; calcium 10 mg. per cent; phosph. 3-5 rag. per cent; serum alkaline phosphatase activity 3.0 B.U.; acid phosphatase activity 0.3 B.U. ; B.S.R. (Westergreen) 6/25; electrophoresis within normal limits; albumen 48.4 gm. per cent; c~1--8.1 per cent; ~2--13'9 per cent; B1--8"1 per cent; fl2--5-2 per cent; 7--16'3 per cent. Urine--albumen 0.3 gm. per cent; several leucocytes and hyaline cylinders. Specific gravity 1010. E.C.G. normal. Eye fundus normal. Roentgenographic observations (Oct. 1961 ) (Figs. 5 and 6) :Examination of the pelvis, lumbar and dorsal spine revealed severe sclerosis. The trabeculae were thickened and accentuated, sclerotic. The femoral shaft, head and neck revealed marked osteosclerosis. The skull, hands and feet were radiographically normal. Slight sclerosis of the ribs. Since a specimen of bone marrow could not be obtained by sternal puncture, a bone wedge biopsy was taken from the left iliac ~r~s~, Slides were made of the marrow and were
stained with May-Grfinwald-Giemsa (Fig. 7). The erythropoietic and myeloid elements were normal. There was proliferation of mature lymphocytes and many peculiar cells. The latter were found singly or in small groups. The nucleus was elongated, cigar-shaped or bent, sometimes round, with a coarse reticular structure. The cytoplasm was irregularly delimited, bright and contained many fine basophilic granules. Some cells were binucleated, in others no granules were found. With toluidine blue (Fig. 8) in aqueous and alcoholic solutions, the granules were stained purple metachromatically. In summary.--A greatly increased number of tissue mastcells (T.M.C.) was found. Histological examination of the biopsy material revealed thickening of bony trabeculae with fibrosis of the bone marrow, as well as mild osteoblastic activity (Fig. 9). The bone marrow spaces revealed the presence of a small number of mast-cells, but due to the decalcification of the osseous tissue (in nitric acid), these mast-cells could not be demonstrated satisfactorily. The diagnosis was fibromyelosclerosis. A pea-sized nodular fragment of tissue, removed from the internal surface of left thigh examined histologically (Fig. 10) revealed a nodule in fat tissue containing a group of blood vessels, with partial to complete obliteration of lumen, accompanied by thickened intimal and mural infiltration by lymphocytes, leucocytes and plasma cells and a small nmnber of T.M.C. The same cells surrounded the vessels in a fibrotic circular layer. The histological diagnosis was obliterative panarteritis. The patient refused further biopsy examinations. On 18th March 1962 the patient was admitted again to the medical department (Professor S. G. Zondek) because of repeated attacks of several hours' duration of temperature up to 38.5 ° C., chills and flushing of the face and upper trunk, general weakness, headache and redness of most of the trunk. The liver was palpated about three fingers below the costal margin, of hard consistency. The tip of the spleen could be palpated. No lymph glands were found.
MASTOCYTOSI$
FIG. 7
87
ropiallic myelocyte m 0etween them.
FiG. 9 FIG. 10 FIG. 9--Iliac crest section (magnification 1:80, H. and E. stain), thickened bony trabeculae. Osteoblastic activity accompanied by fibrosis of bone marrow. FIG. 10--Subcutaneous nodule (magnification 1:50, elastica V. Gieson stain), obliterative panarteritis.
The skin eruption (two days after the 'attack') was the same as at the last hospital admission. No pruritus was felt. No involvement of the mucous membranes. On diaseopic pressure no changes had occurred. Urticaria appeared following rubbing. Laboratory data:--No significant change in the blood count; urea 20 mg. per cent; uric acid 5.2 rag. per cent; cholesterol 150 rag. per cent; protein 6-4 gin. per cent; albumen 4.2 gin. per cent; fibrinogen 380 rag. per cent; calcium 11 mg. per cent; diastase 7 U.; phosph. 3.4 rag. per cent; serum alkaline phosphatase activity 1 B.U.; bleeding time four minutes; coagulation time 5 minutes; prothrombin 78 per cent; B.S.R. 15/35; transaminase 8 U. ; macroglobulin negative; urine serotonin negative. The patient showed no abnormal bleeding tendency. The histologic examination of liver tissue taken by needle biopsy did not reveal the presence of tissue mast-cells; only slight degenerative changes were found.
DISCUSSION Myelofibrosclerosis is a s y n d r o m e o f progressive fibrosis o f b o n e m a r r o w associated with b o n e f o r m a t i o n within the marrow. N u m e r o u s conditions p r o d u c e a variable degree o f fibrosis and sclerosis o f the b o n e m a r r o w . Since the r e p o r t o f Sagher, C o h e n and Schorr (1952) and Schorr, Sagher and L i b a n (1956), urticaria p i g m e n t o s a has been regarded as one of the causes of this syndrome. The b o n e changes are confined a l m o s t entirely to the cancellous bone, where there is an increase in thickness and in n u m b e r o f the spongy trabeculae which causes obliteration o f the n o r m a l b o n y architecture and gives the overall effect o f
88
CLINICAL RADIOLOGY
osteosclerosis. The roentgenographic bony changes is essentially a connective tissue cell. Recent work in urticaria pigmentosa are not characteristic in supports this view (Riley 1954, 1959). themselves. They may closely simulate those seen Bowdler and Tullett (1960) on reporting a case in generalised osteosclerosis due to various blood of urticaria pigmentosa and polycythemia vera, disorders. Bertellotti (1943) considers the con- suggested that both represent hyperplastic condition to be a generalised blood disease. The ditions of mesenchymal cells. It was considered osteomyelosclerosis that occurs might be a reactive possible that the occurrence of the two conditions response to the presence of mast-cells in the marrow. in one patient could be due to a stimulus of the Osteosclerosis as a response to metastatic invasion kind postulated for myeloproliferative disorders of bone marrow by malignant cells is well known, acting simultaneously on the tissue mast-cells and and has been demonstrated by Schorr, Aviad and the bone marrow. Laufer (1959). Most probably mast-cell infiltration In vitro experiments (Morione 1952, Reilly et al and granulomata exert a similar influence on 1955) found that heparin is produced by mast-cells, medullary new bone formation. The histologic and promotes the formation of collagen fibres. changes of bone resorption and bone deposition It is possible that a similar mechanism may be tend to corroborate the radiologically observed operative in urticaria pigmentosa. The possibility findings of decreased bone density on one hand, of a relationship existing between the mast-ceU and increased thickening of trabeculae on the infiltrations of bone, myelofibrosclerosis and other. panarteritis merits serious consideration. Loewenthal et al (1957) described subendothelial According to Stark et al (1954), the marked bone changes have a granulomatous appearance with proliferation of mast-cells in the form of 'a button' The lesion thus numerous mast-cells, and they suggest the term protruding into the lumen. 'mast-cell granuloma of bone'. The casual rela- resembled arteritis and periarteritis or phlebitis and tionship of tissue mast-cell hyperplasia in bone periphlebitis. Collections of mast-cells under the marrow and bone lesions was proved by the autopsy endothelium of the aorta and around small vessels studies by Sagher, Liban, Ungar and Schorr (1956) in the aortic wall were noted. They expressed the of a fifty-five-year-old female with urticaria view that the disease is a reticuloendotheliosis, pigmentosa presenting bone lesions who died of giving the impression that the mast-cells arise from terminal monocytic leukaemia. Widespread myelo- the endothelium itself. fibrosis and osteosclerosis were found in the ribs, skull and vertebrae, associated with aggregates of SUMMARY tissue mast-cells in the marrow spaces. The skeletal 1. A case of an adult male suffering from prolesions showed a marked increase in the degree of gressive urticaria pigmentosa, osteomyelosclerosis osteosclerosis. The roentgenographic changes in and occlusive panarteritis in subcutaneous nodules the bones were consistent with the pathologic is described. Increased proliferation of tissue mastfindings encountered. cells were found in the bone marrow, in and around The present patient presents an hitherto unthe obliterated arteries. described condition of occlusive panarteritis, 2. The problem of whether the finding of dermal urticaria pigmentosa and osteosclerotic obstructive panarteritis in a patient with urticaria bone changes with increased proliferation of tissue pigmentosa and generalised osteomyelosclerosis mast-cells in the bone marrow. This occurrence of should be regarded as part of mastocytosis, is occlusive panarteritis in subcutaneous nodules in considered. an adult man raises several problems. Are we 3. Systemic mast-cell disorder with bone changes dealing with a coincidental lesion? Or, are we deserves consideration in the differential diagnosis dealing with a systemic collagen disease altogether ? of myelofibrosclerotic syndromes. It is suggested here tentatively that the panarteritis is a part and a clue to a basic syndrome. The bone REFERENCES lesions and vessel involvement may be an indication ASBOE-HANSEN,G. (1950). Ann. rheum. Dis. 9, 149. of a more advanced generalised systemic mast-cell BERLIN, CH. (1955). Arch. Derm. 71, 703. disorder. BERTELLOTTt,L. (1943). G. ital. Derm. Sir 184, 638. Reilly et al (1955) have stated that urticuria BOWDLER,A. J. & TULLETT,G. L. (1960). Brit. meal. J. l, 396. pigmentosa is 'a disorder best defined as a systemic EFRATI,F., KLAYMAN,A. & SmTZ, H. (1957). Blood, 12, 869. EHRLICH, P. (1879). Arch. Anat. Physiol. 3, 166. hyperplasia of one of the cells of the reticulo- ELLIS, J. M. (1949). Arch. Path. 48, 426. endothelial system'. FULTON, C. P., MAYNARD,F. L., RILEY, J. F. & WEST, G. B. EhrliCh (1879) first pointed out that the mast-cell (1957). Physiol. Rev. 37, 221.
MASTOCYTOSIS JORe~, E., HOLMGREN,H. & WILANDER, 0 . (1937). Z. mikr.-anat. Forsch. 42, 279. LOEWENTHAL, M., SCHEN, R. J., BERLIN, CH. • WECHSLER, L. (1957). Arch. Derm. 75, 512. MICHELS, N. A. (1938). The Mast Cell. In Handbook o f Hematology. Ed. DOWNEY, H. New York: Haber. MORIONE, T. G. (1952). J. exp. Med. 96, 107. poPPEL, M. H., GRUBER, W. F., SILBER, R., HOLDER, A. K. & CHRISTMAN, R. O. (1959). Amer. J. Roentgenol. 82, 239. REILLY, E. B., SHINTANI, J. • GOODMAN, J. R. (1955). Arch. Derm. 71, 561. RILEY, J. F. & WEST, G. B. (1953). J. Physiol. (Lond.), 120, 528. RILEY, J. F. (1954). Lancet, 1, 841.
BOOK Cancer: A General Guide to Research and its Treatment. Edited by Professor N. N. PETROV, translated by A. P. FLETCHER. Pp. 387, 102 illustrations. 1962. London: Pergamon Press. Price, £4.
THE publisher's blurb states that 'the first half of the book deals with experimental oncology and the second half deals with the treatment of human cancer by surgical methods, radiotherapy and chemotherapy. The occurrence of tumours in mammals, invertebrates and plants is discussed and the production of tumours in animals by means of carcinogenic agents is described'. The book begins with 'Definition of the Concept of a True Turnout' by N. N. Petrov, the editor, a laboured account of the elementary pathology of tumours, followed by further chapters on the distribution of tumours in the vegetable and animal kingdom and their methods of spread. We are then raced through the biochemistry of tumours, the importance of heredity, 'the influence of the nervous system, the endocrine system and diet on the genesis and growth of turnouts', experimental oncogenesis and the aetiology and pathenogenesis of turnouts. Some of these chapters are by other hands but Professor Petrov has the lion's share. By now we have reached the main course. 'The general diagnosis of malignant tumours' which we are glad to dismiss in 20 pages. Prognosis receives similar rapid attention and the poor surgeons 'Operative treatment of Cancer' require 18 pages. Concerning Chapter 13, the 'Principles of Electrosurgical Treatment of Malignant Turnouts' by S. A. Kholden it is kinder to say nothing. Among the disadvantages of the method, we are told, is 'the danger of fire when ether narcosis is given with an open mask'. Comment on this would not be helpful but it unfortunately sets the tone for much of the book. In succeeding chapters we romp through the Principles of Radiation Treatment of Malignant Tumours and the use of Cytotoxic Agents. As tailpiece we are given an account of the principles and organisation of the anti-cancer campaign. What is one to say about such a book ? It is of no use to the specialist because the treatment of each subject is altogether too cursory and the general reader will look elsewhere for lucid accounts of the various subjects discussed. The style is turgid and the illustrations mostly poor. It is most important to know what is going on in the cancer field in the Soviet Union but we must assume that this expensive book is not the best reflection of it. The translation is edited by W. J. P. Neish but the work of translation is apparently by A. P. Fletbher. Whatever the
89
RILEY,J. F. (1959). The Mast Cell. Edinburgh: Livingstone. SA6HER, F., COHEN, C. & SCrIORR, S. (1952). J. invest. Derm. 18, 425. SAGHER, F. & SCHORR, S. (1956). J. invest. Derm. 26, 431. SA~HER, F., LmAN, E., UN6AR, H. & SCHORR, S. (1956). J. invest. Derm. 27, 355. SCHORR, S., SAGIJER, F. & LmAN, E. (1956). Acta radiol. (Stockh.), 46, 575. SCHORR, S., AVIAD, J. & LAUFER, A. (1959). Radiology, 73, 410. STARK, E., VON BUSKIRK, F. W. & DALY, J. F. (1956). Arch. Path. 62, 143. TOURAINZ, A., SOLENTS, G. & RENAULT, F. (1933). Bull. Soc..fi'an¢. Derm. Syph. 40, 1691.
REVIEWS
distribution of labour, the style creaks throughout. This could, of course, be the fault of the original Russian. P.S. Diseases of the Chest. By H. CORWIN HINSHAW and L. HENRY GARLAND. 2nd Ed. Pp. 798, 308 illustrations. 1963. Philadelphia: W. B. Saunders Co. Price, £7.
THIS is the second edition of an interesting book produced by the close co-operation of a very experienced chest physician and a leading radiologist. There is a very sound forty-page section devoted to basic radiotogical technique and interpretation. The high dosage rate of chest fluoroscopy is emphasised by reporting that two minutes fluoroscopy entails the same skin and gonad radiation as 600 P.A. chest films, it is unfortunate, therefore, that the authors later include chest fluoroscopy as part of the routine radiological examination. Although the high dosage rate of single cut tomography is emphasised, multi-section box tomography is not mentioned. A useful thirty-page account of pulmonary function tests and their clinical application completes the first section. The rest of this 800-page book is devoted to a clinical, pathological and radiological account of the entire range of diseases affecting the chest, but excluding cardiac disease. The writing is always easy to understand and holds the attention. The emphasis throughout is on the clinical approach: each disease is liberally illustrated, usually by several chest radiographs. The succinct clinical legend accompanying each radiographic reproduction is very useful, and every case is interestingly (but briefly) presented. The 120-page section on pulmonary tuberculosis is particularly comprehensive. As expected in a text-book emanating from San Francisco, coccidioidomycosis is especially well illustrated and described. The chapter on puh-nonary heart disease, congestion and oedema does not quite reach the high standard set by the authors. There are more than 700 chest radiographic negativephase reproductions, which, although rather small when the entire thorax is included, are of excellent quality and almost always clearly demonstrate the lesion. This is a modern clinical text-book of chest disease, the enlightened authors of which fully appreciate the value of the radiologist as a 'clinical consultant who has particular experience in this specialised form of physical examination'. This volume is no substitute for a monograph on 'Radiology of the Chest', but it can be strongly recommended as an addition to the library of the Radiology Department for it provides a comprehensive, well-illustrated pre;entation of the modern practice, diagnosis and management of intrathoracic (non-cardiac) disease. R.G.G.
URTICARIA PIGMENTOSA, MYELOFIBROSCLEROSIS AND OCCLUSIVE PANARTERITIS
S. SCHORR, M.D., M. L O E W E N T H A L , M.D., CH. BERLIN, M.D., M. RABINOWITZ, B.A., and P. EFRATI, M.D.
Departments of Radiology, Pathology, Dermatology and Bacteriology of the Municipal Hospitals, Tel-Aviv- Yafo, and the Laboratory for Blood Morphology, Kaplan Hospital, Rehovot, Israel URTICARIApigmentosa is a condition of exceptional and bone marrow in various stages of maturation. interest and of most varying heterogenous mani- Focal osteosclerosis in the vertebrae probably festations. represented a lesion related to the basic disorder. Touraine et al (1933) first suggested that mast There has also been a renewed interest in the cells may infiltrate organs other than the skin, nature of the mast-cell and its function. predominantly those of the reticulo-endothelial Tissue mast-cells (T.M.C.) are thought by some system. With the description by Ellis (1949) of the authors to be connective tissue cells of the histiocase of a one-year-old child, showing mast-cell cytic type. Their cytoplasm contains granules lesions of the liver, spleen, lymph nodes, bone which stain metachromatically with toluidine blue marrow and other organs, the dermatosis began to and certain other basic dyes. It is thought that be considered as a systemic disease. the T.M.C. has nothing in common with the blood The changing concept of this dermatosis from a basophil except the basophilic metachromatic pure cutaneous lesion to a systemic disease gained staining of the granules in the cytoplasm (Michels more impetus with the finding of generalised 1938). changes mainly osteosclerotic in character by In the last decade a number of newer concepts Sagher, Cohen and Schorr (1952). The main concerning the properties and function of the mastradiologic aspects were described by Schorr, cells have been postulated. The tissue mast-cells Sagher and Liban (1956). are believed to be associated with increased conThe finding of systemic bone lesions by other centrations of three important constituents:-authors strengthened the concept that the bony heparin (Jorpes et al 1937); histamine (Riley and system is one of the systems which tissue mast- West 1953); and hyaluronic acid (Asboe-Hansen cells may involve. Sagher and Schorr (1956) gave 1950). a short report of a central registry on skeletal Fulton et al (1957) summarising the many surveys in urticaria pigmentosa. In a compre- physiologic properties which have been attributed hensive review Poppel et al (1959) listed seventy- to the tissue mast-cell suggest that mast-cells are one patients with the condition examined roent- like unicellular endocrines which produee heparin, genologically, thirty-two of whom had bone lesions. hyaluronic acid, histamine and serotonin (5With the recent recognition of the widespread hydroxytryptamine). It has not been conclusively nature of this disease there is an increasing ten- proven whether these substances are produced or dency to call the condition mastocytosis. The only stored in the mast-cells. clinical significance of the condition has been The present case is of special interest, because extended by the recognition of extracutaneous in addition to a four-year clinical and radiological lesions, which have been reviewed by Berlin (1955). skeletal follow-up, the presence of panarteritis was He described a seventy-one-year-old man with found in subcutaneous nodules of the thigh. hepatosptenomegaly, cachexia and a stubborn anemia in a case of urticaria pigmentosa. The CASE REPORT bone marrow disclosed a high degree of proliferaT. Sh., male, aged forty-six, born in Hungary. In the tion of tissue mast-cells in the bone marrow. family history it is of interest to note that three brothers had The autopsy of the same case was reported by peptic ulcer of the stomach, one brother has hypertensive Loewenthal et al (1957). Tissue mast-cells were vascular disease and another brother diabetes mellitus. found in many internal organs, especially the spleen, According to the patient the present skin eruption had appeared twelve years ago, on recruitment to the army. liver and bone marrow. Efrati et al (1957) described a case of a fifty-two- The army physician noted some skin changes on the left chest and on the upper abdominal region, which Were year-old woman with probable leukaemia showing diagnosed as urticaria pigmentosa. Seven years ago the numerous tissue mast-cells in the peripheral blood patient suffered from heartburn and epigastric pain. No 84
MASTOCYTOSIS
85
FIG. 1 FIG. 2 FIG. 1--Photograph of the buttocks, showing the extensive rnaculo-papular eruption of urticaria pigmentosa. Fro. 2--Skin biopsy (magnification 1:116, toluidine blue stain), cross-section of skin showing perivascular infiltration.
FIG. 3 FIG. 4 Fro. 3--Pelvis (June 1958): sclerosis of the pelvic bones. Fro. 4--Femur shaft (June 1958): reticulated appearance of sclerotic trabeculae.
hyperacidity was found in his stomach contents. No ulcer was found on x-ray examination. At that time in addition to the previous skin changes, the same lesions spread to the dorsal part of both hands. Five years ago the cutaneous lesions spread over the whole body. On 10th June 1958 the patient was admitted for the first time to the dermatological department. The patient felt tired on minimal exertion, and complained of dizziness and sexual impotence. Physical examination: Skin--scattered all over the body there were innumerable discrete, round or oval papular and mostly macular lesions of 3 to 4 mm. in diameter. The colour was brownish-red and did not fade under diascopic pressure. Nu spontaneous itching was present. On stroking the skin, wheeling occurred. The application of an ice bottle caused urticaria (Fig. 1). The skin biopsy revealed slight hyperkeratosis with moderate atrophy of the epidermis. The dermal capillaries, in a dense fibrotic tissue, showed promi-
nent perivascular aggregates of lymphoid cells and a number of mast-cells which with special staining (cresyl violet, toluidine blue) gave positive metachromatic properties (Fig. 2). X-ray examination of the stomach did not reveal any abnormalities. The body skeleton x-ray examination revealed (Figs. 3 and 4) diffuse trabecular sclerosis of the cervical, dorsal, lumbar vertebrae and extremities. The pelvic bones revealed moderate to severe generalised sclerosis reticulated in appearance. No x-ray changes were seen on the bones of the skull, ribs, hands and feet. Three sternal and one iliac crest punctures were performed without any results because of the hardness of the bone. Laboratory d a t a : - - H b . 12 gr./100 ml. R.B.C. of 3,700,000. W.B.C. of 5,400. Differential count--polymorphs 60 per cent, eosinophils 2 per cent, monocytes 3 per cent, lymphocytes 35 per cent. Platelets 200,000. Glucose, 68 rag. per cent; urea 42 rag. per cent; uric acid 3'5 rag. per cent; cholesterol
86
CLINICAL
RADIOLOGY
FIG. 5 FIG. 6 Fro. 5--Pelvis (April 1961): severe osteosclerosis. FIG. 6 - - F e m u r shaft (June 1961): note the advanced stage of the reticulated sclerotic trabeculae.
270 mg. per cent; prothrombin activity 87 per cent; coagulation time five minutes; bleeding time three minutes; Weltmann 6; thymol turbidity 3 to 4 U. ; cephalin test negative; fibrinogen 231 mg. per cent; serum proteins total 8.4 gin. per cent; albumen 4.75 gm. per cent; globulin 3.67 gin. per cent; bilirubin 0.3 mg. per cent. Urine--sugar negative; albumen 0,3 gm. per cent. On 9th October 1961 the patient was readmitted to the hospital for further investigation because he noted several subcutaneous nodules on the medial part of the left midthigh. The patient felt sleepy and complained of sexual impotence, a condition which depressed him markedly. On physical examination the patient had the same cutaneous lesions as previously on his first admission, possibly even the lesions were more spread. The liver was palpable 5 cm. below the costal margin of hard consistency. No splenomegaly, no glands on the inguinal or axillar region were palpated. Blood analysis showed little or no change. The following further laboratory examinations were carried out :--total protein 8 gm. per cent; albumen 4.7 gm. per cent; globulin 3-4 gm. per cent; calcium 10 mg. per cent; phosph. 3-5 rag. per cent; serum alkaline phosphatase activity 3.0 B.U.; acid phosphatase activity 0.3 B.U. ; B.S.R. (Westergreen) 6/25; electrophoresis within normal limits; albumen 48.4 gm. per cent; c~1--8.1 per cent; ~2--13'9 per cent; B1--8"1 per cent; fl2--5-2 per cent; 7--16'3 per cent. Urine--albumen 0.3 gm. per cent; several leucocytes and hyaline cylinders. Specific gravity 1010. E.C.G. normal. Eye fundus normal. Roentgenographic observations (Oct. 1961 ) (Figs. 5 and 6) :Examination of the pelvis, lumbar and dorsal spine revealed severe sclerosis. The trabeculae were thickened and accentuated, sclerotic. The femoral shaft, head and neck revealed marked osteosclerosis. The skull, hands and feet were radiographically normal. Slight sclerosis of the ribs. Since a specimen of bone marrow could not be obtained by sternal puncture, a bone wedge biopsy was taken from the left iliac ~r~s~, Slides were made of the marrow and were
stained with May-Grfinwald-Giemsa (Fig. 7). The erythropoietic and myeloid elements were normal. There was proliferation of mature lymphocytes and many peculiar cells. The latter were found singly or in small groups. The nucleus was elongated, cigar-shaped or bent, sometimes round, with a coarse reticular structure. The cytoplasm was irregularly delimited, bright and contained many fine basophilic granules. Some cells were binucleated, in others no granules were found. With toluidine blue (Fig. 8) in aqueous and alcoholic solutions, the granules were stained purple metachromatically. In summary.--A greatly increased number of tissue mastcells (T.M.C.) was found. Histological examination of the biopsy material revealed thickening of bony trabeculae with fibrosis of the bone marrow, as well as mild osteoblastic activity (Fig. 9). The bone marrow spaces revealed the presence of a small number of mast-cells, but due to the decalcification of the osseous tissue (in nitric acid), these mast-cells could not be demonstrated satisfactorily. The diagnosis was fibromyelosclerosis. A pea-sized nodular fragment of tissue, removed from the internal surface of left thigh examined histologically (Fig. 10) revealed a nodule in fat tissue containing a group of blood vessels, with partial to complete obliteration of lumen, accompanied by thickened intimal and mural infiltration by lymphocytes, leucocytes and plasma cells and a small nmnber of T.M.C. The same cells surrounded the vessels in a fibrotic circular layer. The histological diagnosis was obliterative panarteritis. The patient refused further biopsy examinations. On 18th March 1962 the patient was admitted again to the medical department (Professor S. G. Zondek) because of repeated attacks of several hours' duration of temperature up to 38.5 ° C., chills and flushing of the face and upper trunk, general weakness, headache and redness of most of the trunk. The liver was palpated about three fingers below the costal margin, of hard consistency. The tip of the spleen could be palpated. No lymph glands were found.
MASTOCYTOSI$
FIG. 7
87
ropiallic myelocyte m 0etween them.
FiG. 9 FIG. 10 FIG. 9--Iliac crest section (magnification 1:80, H. and E. stain), thickened bony trabeculae. Osteoblastic activity accompanied by fibrosis of bone marrow. FIG. 10--Subcutaneous nodule (magnification 1:50, elastica V. Gieson stain), obliterative panarteritis.
The skin eruption (two days after the 'attack') was the same as at the last hospital admission. No pruritus was felt. No involvement of the mucous membranes. On diaseopic pressure no changes had occurred. Urticaria appeared following rubbing. Laboratory data:--No significant change in the blood count; urea 20 mg. per cent; uric acid 5.2 rag. per cent; cholesterol 150 rag. per cent; protein 6-4 gin. per cent; albumen 4.2 gin. per cent; fibrinogen 380 rag. per cent; calcium 11 mg. per cent; diastase 7 U.; phosph. 3.4 rag. per cent; serum alkaline phosphatase activity 1 B.U.; bleeding time four minutes; coagulation time 5 minutes; prothrombin 78 per cent; B.S.R. 15/35; transaminase 8 U. ; macroglobulin negative; urine serotonin negative. The patient showed no abnormal bleeding tendency. The histologic examination of liver tissue taken by needle biopsy did not reveal the presence of tissue mast-cells; only slight degenerative changes were found.
DISCUSSION Myelofibrosclerosis is a s y n d r o m e o f progressive fibrosis o f b o n e m a r r o w associated with b o n e f o r m a t i o n within the marrow. N u m e r o u s conditions p r o d u c e a variable degree o f fibrosis and sclerosis o f the b o n e m a r r o w . Since the r e p o r t o f Sagher, C o h e n and Schorr (1952) and Schorr, Sagher and L i b a n (1956), urticaria p i g m e n t o s a has been regarded as one of the causes of this syndrome. The b o n e changes are confined a l m o s t entirely to the cancellous bone, where there is an increase in thickness and in n u m b e r o f the spongy trabeculae which causes obliteration o f the n o r m a l b o n y architecture and gives the overall effect o f
88
CLINICAL RADIOLOGY
osteosclerosis. The roentgenographic bony changes is essentially a connective tissue cell. Recent work in urticaria pigmentosa are not characteristic in supports this view (Riley 1954, 1959). themselves. They may closely simulate those seen Bowdler and Tullett (1960) on reporting a case in generalised osteosclerosis due to various blood of urticaria pigmentosa and polycythemia vera, disorders. Bertellotti (1943) considers the con- suggested that both represent hyperplastic condition to be a generalised blood disease. The ditions of mesenchymal cells. It was considered osteomyelosclerosis that occurs might be a reactive possible that the occurrence of the two conditions response to the presence of mast-cells in the marrow. in one patient could be due to a stimulus of the Osteosclerosis as a response to metastatic invasion kind postulated for myeloproliferative disorders of bone marrow by malignant cells is well known, acting simultaneously on the tissue mast-cells and and has been demonstrated by Schorr, Aviad and the bone marrow. Laufer (1959). Most probably mast-cell infiltration In vitro experiments (Morione 1952, Reilly et al and granulomata exert a similar influence on 1955) found that heparin is produced by mast-cells, medullary new bone formation. The histologic and promotes the formation of collagen fibres. changes of bone resorption and bone deposition It is possible that a similar mechanism may be tend to corroborate the radiologically observed operative in urticaria pigmentosa. The possibility findings of decreased bone density on one hand, of a relationship existing between the mast-ceU and increased thickening of trabeculae on the infiltrations of bone, myelofibrosclerosis and other. panarteritis merits serious consideration. Loewenthal et al (1957) described subendothelial According to Stark et al (1954), the marked bone changes have a granulomatous appearance with proliferation of mast-cells in the form of 'a button' The lesion thus numerous mast-cells, and they suggest the term protruding into the lumen. 'mast-cell granuloma of bone'. The casual rela- resembled arteritis and periarteritis or phlebitis and tionship of tissue mast-cell hyperplasia in bone periphlebitis. Collections of mast-cells under the marrow and bone lesions was proved by the autopsy endothelium of the aorta and around small vessels studies by Sagher, Liban, Ungar and Schorr (1956) in the aortic wall were noted. They expressed the of a fifty-five-year-old female with urticaria view that the disease is a reticuloendotheliosis, pigmentosa presenting bone lesions who died of giving the impression that the mast-cells arise from terminal monocytic leukaemia. Widespread myelo- the endothelium itself. fibrosis and osteosclerosis were found in the ribs, skull and vertebrae, associated with aggregates of SUMMARY tissue mast-cells in the marrow spaces. The skeletal 1. A case of an adult male suffering from prolesions showed a marked increase in the degree of gressive urticaria pigmentosa, osteomyelosclerosis osteosclerosis. The roentgenographic changes in and occlusive panarteritis in subcutaneous nodules the bones were consistent with the pathologic is described. Increased proliferation of tissue mastfindings encountered. cells were found in the bone marrow, in and around The present patient presents an hitherto unthe obliterated arteries. described condition of occlusive panarteritis, 2. The problem of whether the finding of dermal urticaria pigmentosa and osteosclerotic obstructive panarteritis in a patient with urticaria bone changes with increased proliferation of tissue pigmentosa and generalised osteomyelosclerosis mast-cells in the bone marrow. This occurrence of should be regarded as part of mastocytosis, is occlusive panarteritis in subcutaneous nodules in considered. an adult man raises several problems. Are we 3. Systemic mast-cell disorder with bone changes dealing with a coincidental lesion? Or, are we deserves consideration in the differential diagnosis dealing with a systemic collagen disease altogether ? of myelofibrosclerotic syndromes. It is suggested here tentatively that the panarteritis is a part and a clue to a basic syndrome. The bone REFERENCES lesions and vessel involvement may be an indication ASBOE-HANSEN,G. (1950). Ann. rheum. Dis. 9, 149. of a more advanced generalised systemic mast-cell BERLIN, CH. (1955). Arch. Derm. 71, 703. disorder. BERTELLOTTt,L. (1943). G. ital. Derm. Sir 184, 638. Reilly et al (1955) have stated that urticuria BOWDLER,A. J. & TULLETT,G. L. (1960). Brit. meal. J. l, 396. pigmentosa is 'a disorder best defined as a systemic EFRATI,F., KLAYMAN,A. & SmTZ, H. (1957). Blood, 12, 869. EHRLICH, P. (1879). Arch. Anat. Physiol. 3, 166. hyperplasia of one of the cells of the reticulo- ELLIS, J. M. (1949). Arch. Path. 48, 426. endothelial system'. FULTON, C. P., MAYNARD,F. L., RILEY, J. F. & WEST, G. B. EhrliCh (1879) first pointed out that the mast-cell (1957). Physiol. Rev. 37, 221.
MASTOCYTOSIS JORe~, E., HOLMGREN,H. & WILANDER, 0 . (1937). Z. mikr.-anat. Forsch. 42, 279. LOEWENTHAL, M., SCHEN, R. J., BERLIN, CH. • WECHSLER, L. (1957). Arch. Derm. 75, 512. MICHELS, N. A. (1938). The Mast Cell. In Handbook o f Hematology. Ed. DOWNEY, H. New York: Haber. MORIONE, T. G. (1952). J. exp. Med. 96, 107. poPPEL, M. H., GRUBER, W. F., SILBER, R., HOLDER, A. K. & CHRISTMAN, R. O. (1959). Amer. J. Roentgenol. 82, 239. REILLY, E. B., SHINTANI, J. • GOODMAN, J. R. (1955). Arch. Derm. 71, 561. RILEY, J. F. & WEST, G. B. (1953). J. Physiol. (Lond.), 120, 528. RILEY, J. F. (1954). Lancet, 1, 841.
BOOK Cancer: A General Guide to Research and its Treatment. Edited by Professor N. N. PETROV, translated by A. P. FLETCHER. Pp. 387, 102 illustrations. 1962. London: Pergamon Press. Price, £4.
THE publisher's blurb states that 'the first half of the book deals with experimental oncology and the second half deals with the treatment of human cancer by surgical methods, radiotherapy and chemotherapy. The occurrence of tumours in mammals, invertebrates and plants is discussed and the production of tumours in animals by means of carcinogenic agents is described'. The book begins with 'Definition of the Concept of a True Turnout' by N. N. Petrov, the editor, a laboured account of the elementary pathology of tumours, followed by further chapters on the distribution of tumours in the vegetable and animal kingdom and their methods of spread. We are then raced through the biochemistry of tumours, the importance of heredity, 'the influence of the nervous system, the endocrine system and diet on the genesis and growth of turnouts', experimental oncogenesis and the aetiology and pathenogenesis of turnouts. Some of these chapters are by other hands but Professor Petrov has the lion's share. By now we have reached the main course. 'The general diagnosis of malignant tumours' which we are glad to dismiss in 20 pages. Prognosis receives similar rapid attention and the poor surgeons 'Operative treatment of Cancer' require 18 pages. Concerning Chapter 13, the 'Principles of Electrosurgical Treatment of Malignant Turnouts' by S. A. Kholden it is kinder to say nothing. Among the disadvantages of the method, we are told, is 'the danger of fire when ether narcosis is given with an open mask'. Comment on this would not be helpful but it unfortunately sets the tone for much of the book. In succeeding chapters we romp through the Principles of Radiation Treatment of Malignant Tumours and the use of Cytotoxic Agents. As tailpiece we are given an account of the principles and organisation of the anti-cancer campaign. What is one to say about such a book ? It is of no use to the specialist because the treatment of each subject is altogether too cursory and the general reader will look elsewhere for lucid accounts of the various subjects discussed. The style is turgid and the illustrations mostly poor. It is most important to know what is going on in the cancer field in the Soviet Union but we must assume that this expensive book is not the best reflection of it. The translation is edited by W. J. P. Neish but the work of translation is apparently by A. P. Fletbher. Whatever the
89
RILEY,J. F. (1959). The Mast Cell. Edinburgh: Livingstone. SA6HER, F., COHEN, C. & SCrIORR, S. (1952). J. invest. Derm. 18, 425. SAGHER, F. & SCHORR, S. (1956). J. invest. Derm. 26, 431. SA~HER, F., LmAN, E., UN6AR, H. & SCHORR, S. (1956). J. invest. Derm. 27, 355. SCHORR, S., SAGIJER, F. & LmAN, E. (1956). Acta radiol. (Stockh.), 46, 575. SCHORR, S., AVIAD, J. & LAUFER, A. (1959). Radiology, 73, 410. STARK, E., VON BUSKIRK, F. W. & DALY, J. F. (1956). Arch. Path. 62, 143. TOURAINZ, A., SOLENTS, G. & RENAULT, F. (1933). Bull. Soc..fi'an¢. Derm. Syph. 40, 1691.
REVIEWS
distribution of labour, the style creaks throughout. This could, of course, be the fault of the original Russian. P.S. Diseases of the Chest. By H. CORWIN HINSHAW and L. HENRY GARLAND. 2nd Ed. Pp. 798, 308 illustrations. 1963. Philadelphia: W. B. Saunders Co. Price, £7.
THIS is the second edition of an interesting book produced by the close co-operation of a very experienced chest physician and a leading radiologist. There is a very sound forty-page section devoted to basic radiotogical technique and interpretation. The high dosage rate of chest fluoroscopy is emphasised by reporting that two minutes fluoroscopy entails the same skin and gonad radiation as 600 P.A. chest films, it is unfortunate, therefore, that the authors later include chest fluoroscopy as part of the routine radiological examination. Although the high dosage rate of single cut tomography is emphasised, multi-section box tomography is not mentioned. A useful thirty-page account of pulmonary function tests and their clinical application completes the first section. The rest of this 800-page book is devoted to a clinical, pathological and radiological account of the entire range of diseases affecting the chest, but excluding cardiac disease. The writing is always easy to understand and holds the attention. The emphasis throughout is on the clinical approach: each disease is liberally illustrated, usually by several chest radiographs. The succinct clinical legend accompanying each radiographic reproduction is very useful, and every case is interestingly (but briefly) presented. The 120-page section on pulmonary tuberculosis is particularly comprehensive. As expected in a text-book emanating from San Francisco, coccidioidomycosis is especially well illustrated and described. The chapter on puh-nonary heart disease, congestion and oedema does not quite reach the high standard set by the authors. There are more than 700 chest radiographic negativephase reproductions, which, although rather small when the entire thorax is included, are of excellent quality and almost always clearly demonstrate the lesion. This is a modern clinical text-book of chest disease, the enlightened authors of which fully appreciate the value of the radiologist as a 'clinical consultant who has particular experience in this specialised form of physical examination'. This volume is no substitute for a monograph on 'Radiology of the Chest', but it can be strongly recommended as an addition to the library of the Radiology Department for it provides a comprehensive, well-illustrated pre;entation of the modern practice, diagnosis and management of intrathoracic (non-cardiac) disease. R.G.G.