URTICARIA PIGMENTOSA WITH BONE INVOLVEMENT

MAST CELL AGGREGATES IN BONES AND MYELOSCLEROSIS FOUNDAT AUTOPSY IN A CASE DYING OF MONOCYTIC LEUKEMJA*

F. SAGHER, M.D., U. LIBAN, MI)., H. UNGAR, M.D. ANI) S. SCHORR, Ml).

Following the first recorded observation of bone lesions in a ease of urticariapigmentosa in 1952 (1) a number of reports have appeared in which bone in-volvement has been described (2—7). The bone lesions noted thus far on X-rayexamination have been of two different types: (1) generalized wide-spread osteo-porotic and osteosclerotic areas and (2) similar areas confined mainly to theskull, femur or humerus.

The question concerning the nature of these bone lesions remained open.Sternal or rib bone marrow puncture in which large numbers of mast cells weresometimes found suggested that skin and bone lesions are of the same nature(7, 8). The following is a report of a case of urticaria pigmentosa in which bonelesions were followed for two years prior to the patient's death from monocyticleukemia and in which post-mortem examination was subsequently performed.

REPORT OF CASE

The patient, a woman aged 55, was referred to the Dermatological OutpatientDepartment in 1953. Her chief complaints were a skin eruption, general malaiseand loss of weight amounting to about 10 kg during the preceding five years.The skin eruption had first appeared more than five years earlier, involving thetrunk, the upper and lower extremities and especially the forehead and scalp.Itching was very slight and occurred mainly at night. The history revealed thatshe had had a daily temperature of up to 38°C during the preceding year. Thefamily history was negative for skin and neoplastic disease.

Examination revealed an eruption involving the whole face, the scalp, thetrunk and the extremities, diminishing in intensity peripherally. The lesionswere discrete, fairly numerous, mostly macular and papular; on the foreheadand inner parts of the thighs the lesions were denser than elsewhere. The colorof the lesions was brownish-red; they were round or oval in shape, and theirdiameter varied between 2 and 10 mm. On stroking the skin, a distinct whealingoccurred in the lesions which became about two or three times their previoussize. The normal skin showed redness but no urtication following irritation.

The patient's general condition was poor but examination revealed no otherspecific abnormalities; the lymph nodes were not enlarged; the liver and thespleen were not palpable.

Two biopsy specimens from different parts of the affected skin revealed mast* From the Department of Dermatology and Venereology (A. Dostrovsky, Director),

the Department of Pathology (H. Ungar, Director) and the Department of Radiology(A. Druckman, Director), Hadassah University Hospital and Hehresv University-HadassahMedical School, Jerusalem, Israel.

Received for puhlication June 22, 1956355

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356 THE JOURNAL OF INVESTIGATiVE DERMATOLOGY

FIG. 1, A) Skin specimen one month before death. Typical picture of urticaria pig-mentosa with metnchromatic tissue mast cells scattered in the upper and mid-dermis.Toluidine blue. X125. B) Skin specimen taken at autopsy from an urticaria pigmentosalesion near the umbilicus. Dense monocytic infiltrations in the whole dermis, with manycapillaries filled with monocytic cells. Hematoxylin and eosin. X85.

FIG. 2. Peripheral blood smear, July, 1955. Monocytic cells arc seen, containing large,round, oval, indented or lobulated nuclei with coarse chromatin. Many fine azurophilicgranules are scattered in the slightly basophilic cytoplasm. May-Gruenwald-Giemsa. X1,500.

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UIITICARIA PIGMENTOSA WITH BONE INVOLVEMENT 357

cell accumulations in the upper and mid-dermis characteristic of urticaria pig-mentosa.

X-ray examination, July, 1953Ribs: Scierosed trabeculae along the entire course of the bones with tiny

demineralized areas scattered between these trabeculae.Pelvis, dorsal and lumbar spine: Thickened trabeculac with tiny interspaces

throughout the vertebral bodies, pelvis and head and neck of each femur.Skull: Numerous tiny islets of increased density dispersed throughout the

whole skull, involving also the diploe; margins of inner and outer tables distinct.Extremities: Traheculae of spongiosa of the shafts of the long bones thickened

and indistinct; outline of cortex normal; bony pattern of distal parts of radiusand ulna, the carpal bones, metacarpals and phalanges of each side completelynormal.

Laboratory examinations

Urine: Routine chemical and microscopic examination revealed no abnormalfindings.

Stool: Microscopic examination revealed no abnormal findings.Blood: Erythrocytes 3,900,000 per du. mm; Hb. 80 per cent; leukocytes 6,000

per cu. mm with 27 per cent segmented neutrophiles, 2 per cent eosinophiles,54 per cent lymphocytes and 17 per cent monocytes. Wassermann Reaction andKahn test negative. Blood phosphorus 3.1 mg%; alkaline phosphatase 5.8Bodansky units; serum calcium 10.7 mg%.

During the subsequent two years the patient was seen several times; theonly changes observed were in the radiological appearances of the bones andthese are described below. In June, 1955, however, her general condition beganto worsen. Two skin biopsies again showed the typical features of urticariapigmentosa (Fig. 1, A) and blood examination revealed the following picture:erythrocytes 3,700,000 per cu. mm; leukocytes 43,400 per cu. mm with 8 percent polymorphonuclear leukocytes, 14 per cent bandforms, 1 per cent eosino-philes, 11 per cent lymphocytes, 50 per cent monocytes and 16 per cent atypicalcells of a monocytic type (Fig. 2).

This picture suggested monocytic leukemia and the patient was hospitalizedin July, 1955. On admission she was cacheetic, her weight being 45 kg. Allsuperficial lymph nodes were enlarged. The liver was palpable and firm, extend-ing about 6-8 cm below the costal margin; the spleen, too, was palpable. Bloodpressure 110/65.

X-ray examinations, March and July, 1955Ribs: Marked thickening of trabeculae of all ribs. The osteoporotic changes

previously seen are not present.Pelvis, lumbar, dorsal and cervical spine: Very marked sclerosis of whole bony

structure.

358 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Skull: The multiple islets of increased density, noted two years earlier, nownot seen; outer and inner tables and diploic spaces form one continuous undif-ferentiated sclerotic density.

Humerus, radius and ulna: The sclerotic process has advanced markedlysince previous examination. Inner aspect of cortex merges with scierosed medul-lary cavity; no clear distinction between cortex and spongiosa. Distal parts ofradius, ulna, carpal and metacarpal bones show marked thickening and coarsetrabeculation.

Laboratory examinations

Blood urea, blood uric acid, serum chloride, blood glucose, serum cholesterol,total blood proteins, serum albumin, serum globulin and various liver functiontests were all within normal limits. Blood sedimentation rate: 45/106 (Wester-gren). Sternal puncture was unsuccessful.

During hospitalization the skin eruption progressed and besides the typicallesions of urticaria pigmentosa there appeared bluish-white infiltrations of about1 cm in diameter mainly on the chest and back and a net-like erythema overthe upper part of the chest. The patient's general condition deteriorated rapidly;she developed a high temperature and in spite of the immediate start of corti-sone therapy, combined with nitrogen mustard, she died on July 25, 1955. Fivefurther blood examinations had confirmed the diagnosis of monocytic leukemia.Shortly before death the leukocyte count had risen to 248,000 cells per cu. mmwith 78 per cent monocytes and liver function tests had given the followingresults: Takata-Ara +, thymol turbidity 5.9 units, thymol flocculation +,cephalin flocculation +, Weitman 8.

AutopsyAutopsy revealed a terminal bronchopneumonia of the right lung with sero-

fibrinous pleurisy. Generalized lymphadenopathy was present, involving alsothe intrathoracic and intra-abdominal glands; the glands were harder thannormal and the cut surfaces revealed homogeneous greyish tissue. The palatineand lingual tonsils were likewise enlarged.

The liver was hard and weighed 2885 gm.; the lobular pattern was well pre-served, the portal spaces being markedly enlarged by greyish-white tissue. Thespleen, weighing 560 gm., was likewise of firm consistency; the cut surface washomogeneous greyish-red with small hemorrhages in some places.

The kidneys were slightly enlarged and the cut surfaces showed greyish-whitefoci of various sizes; many hemorrhages were scattered in and around the grey-ish foci.

The skeletal system showed marked changes (Figs. 3, 4).The cranial vault measured 6—8 mm in thickness and the cut surface was of a

uniformly grey-white color. After maceration in antiformin the diploe wasfound to he almost completely sclerosed and fused with both tables; however,the inner table was still sharply defined in some places. The internal surfaceof the bone had a worm-eaten appearance due to innumerable nutrient vesselsthe entrance points of which were surrounded by hyperplastic bone.

UItTICARIA PIGMENTOSA WITH BONE INVOLVEMENT 59

Ribs: Following maceration, a slight roughening of the outer surface was seenand the corticalis appeared in many places irregularly thickened, in other placesvery thin. The marrow cavity was considerably narrowed by scierosed cancel-bus bone.

Lumbar vertebrae: The marrow was firm in consistency and grey in color, tinyfoci of dark-red marrow being only occasionally found. Maccrated specimenìsshowed densely packed, thickened trabeculae; the corticalis was extremely thinand appeared incorporated into the hyperplastic spongiosa.

Cross-section through the shaft of the right femur revealed a corticalis ofnormal thickness and in the marrow cavity greyish-pink fibrous tissue of leatheryconsistency.

Histological examinationTissues for sectioning were fixed in 10 per cent formalin, in 80 per rent alcohol and in

Zenker's fluid. Paraffin sections were stained with hematoxylin and eosin, Van Gieson'sstain, Laidlaw's reticulum stain, Heidenhain's azan stain, 1 per cent aqueous solution oftoluidine blue, 0.01 per cent aqueous or alcoholic solution of Azure A and with polychromemethylene blue. The bones were decalcified in 5 per cent nitric acid; their staining withmetachromatic stains was difficult and succeeded only after treatment of the slides with an0.5 per cent solution of potassium permanganate followed by oxalic acid rinse. After decalci-fication of the bones by EDTA (ethylen-diamine-tetraacetic acid) at pH 6.5 according toHunter and Nikiforuk (9) the sections could easily be stained by the metachromatic stains.

8km (Fig. 1, B) Urticaria pigmentosa lesions near the umbilicus, the leftbreast and the right thigh revealed, throughout the dermis, a dense cellular

FIG. 3. Bones after macoration with antiformin. 1<3.5. A) Lumbar vertebra, composedof thick, densely packed, irregular trabeculae. B) Cranial vault; the diploe is almost com-pletely scierosed and fused with the outer table. The inner table in this particular area issharply defined. C) A rib showing the corticalis of the upper surface fused with the scieroseddiploe, and that of the lower surface irregularly thickened.

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infiltration having an arrangement more tumor-like than inflammatory. Thecells were mostly monocytes similar to those found in the peripheral blood ofthe patient during life; among them typical mast cells were found, being mostlyperivascular in location; in different sections the number of mast cells variedfrom 10 to 40 per cent of all cells present. In addition, a few eosinophiles werescattered among the infiltrations. Congested capillaries, present in large numbersparticularly in the upper part of the dermis, were filled with dense accumulationsof monocytic cells.

Skin taken from the bluish-white infiltrations and from the net-like erythemaover the right breast again showed dense monocytic infiltrations in the dermisand in the subcutaneous fatty tissue, with only occasional admixture of a fewmast cells.

Liver: Enlarged portal spaces were filled with cellular infiltrations composedpredominantly of monocytes with a lesser number of lymphocytes, eosinophilesand neutrophiles and a few mast cells. Accumulations of monocytic cells werepresent also in the sinusoids and in some areas around the central veins.

Spleen: Only a few very small lymph follicles were preserved. The pulp wasoccupied by monocytes which infiltrated also the capsule, the fibrous trabeculaeand the walls of the larger blood vessels. In addition, scattered plasma cells,mast cells, eosinophiles, megakaryocytes and macrophages containing granules

Fin. 4. X-ray photographs of maccrated post-mortem specimens of the cranial vault,two lumbar vertebrae and a rib showing the marked osteoscierosis.

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UBTICARIA PIGMENTOSA WiTH BONE INVOLVEMENT 361

FIG. 5. Axillary lymph node. Complete destruction of the normal pattern by monocyticinfiltrations which penetrate through the fibrous capsule into the pericapsular fatty tissue.Hematoxylin and eosin. X85 (A); X560 (B).

of hernosiderin were found throughout. No increase in the quantity of reticulumfibers was noticed.

Lymph nodes (Fig. 5): In most nodes the normal pattern was completelydestroyed and replaced by monotonous infiltrations of monocytes. Amongstthese were found mast cells varying in amount from 1 to 10 per low power fieldand also single megakaryocytes and eosinophilic leukocytes.

Similar monocytic infiltrations of varying intensity were observed in thetonsils, the lymphatic tissue at the base of the tongue, the kidneys, the pancreas,some parts of the epicardium and the adjacent myocardium, the submucosa ofthe larger bronchi and the pen-bronchial and perivascular tissues of both lungs.Dense infiltrations of monocytes were seen in the various layers of the stomachand intestines, the adrenals and in the episcleral tissues and choroid of the eyes.

The blood vessels of many organs, particularly the veins of the brain and ofthe thyroid, contained large accumulations of monocytes in their lumina.

Bones. Cranial vault: The compacta was very thick and composed of severallayers of lamellar bone. The diploe (Fig. 6) was formed by a dense network ofthick trabeculae consisting almost entirely of layers of slightly basophilic lame!-lar bone with here and there thin layers of fibrillary bone.

Many marrow spaces were filled with accumulations of mast cells, lying partlywithin a delicate network of loose connective tissue (Fig. 7) and partly withindense connective tissue. Other marrow spaces were completely fibrosed and ina few monocytic infiltrations only were observed.

The quantity and staining of the granules in the mast cells were variable. Insome cells they were clearly metachromatic and completely filled the cytoplasm,

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Fm. 6. Diploe of cranial vault, formed by a dense network of thick trabeculae. Theseconsist of several layers of slightly basophilic lamellar bone. Here and there rests of fibril-lary, basophilic bone are still present. The marrow spaces are partly filled with mast cells,partly fibrosed. Hematoxylin and eosin. X48.

Fin. 7. A small marrow space in the skull filled with mast c2lls lying in a loose networkof connective tissue fibers. Toluidine blue. X400.

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URTICARIA PIGMENTOSA WITH BONE INVOLVEMENT 363

Fic. 8. Lumbar vertebra. The diploe shows irregular thickened trabeculae which consistin many places of a core of old bone with an apposition of immature, strongly basophilicfibrillary bone. In some places knobs of immature bone include in their centers rests of oldspongiosa. The marrow spaces are partly fibrosed and partly filled by cells. Hematoxylinand eosin. X8 (A); X35 (B).

Fin. 9. Lumbar vertebra. A) Marrow spaces showing mast cell accumulations and, onthe right, fibrosis with mast cell infiltrations. Hematoxylin and eosin. X33. B) Typicalmast cells from one of these marrow spaces. Hematoxylin and eosin. X580.

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while in others the granules were orthochromatic or metachromatic and fewerin number; in some places granules were dispersed extracellularly.

Lumbar vertebrae (Figs. 8, 9): Some of the thickened trabeculae were built ofmature bone, others of immature bone; mostly they consisted of a slender coreof mature bone on one or both sides of which new, strongly basophilic immature,coarse fibrillary bone was apposited in layers of varying width. In some placesthe immature bone formed round knobs or buds, sometimes with rests of oldspongiosa within them. The immature bone contained large osteocytes, irregularin shape and distribution, lying in a matrix of basophilic fibers. In some placesthe immature bone trabeculae were lined by a thin margin of osteoid.

The marrow spaces were similar to those of the skull; many were filled withaccumulations of mast cells, others were fibrosed and some of them containedabundant monocytic cells, intermingled with a varying number of mast cells.Mast cells were also observed lining large, empty vascular spaces (Fig. 10, A).Except for a few megakaryocytes found scattered in the areas of monocyticinfiltrations, no active hemopoietic tissue was found. The ribs and iliac crestpresented the same histologic picture as the lumbar vertebrae.

Bone marrow from the shaft of the right femur showed large areas of densefibrous tissue containing, at the periphery, a few small trabeculae of the maturespongiosa. A number of blood capillaries present in the fibrous tissue were linedby a layer of mast cells (Fig. 10, B). Here and there mast cells were also presentwithin the lumen or in a pen-capillary location. A few small monocytic infiltra-tions were found and also small foci of hemopoietic tissue showing monocytic,myeloid and red cells in different stages of development.

FIG. 10. A) Marrow space in a lumbar vertebra. Tissue mast cells are seen lining large,empty vascular spaces. Toluidine blue. X360. B) Fibrosed bone marrow of the right femur.Some of the capillaries are lined by a layer of mast cells. Toluidine blue. X460.

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TJRTICAIIIA PIGMENTOSA WITH BONE INVOLVEMENT 365

Pathologic-anatomic diagnosisUrticaria pigmentosa with mast cell infiltrations in skin and bones. Osteo-

sclerosis and myelofibrosis. Monocytic leukemia with involvement of skin, bonemarrow, many groups of lymph nodes, tonsils, liver, spleen, kidneys, pancreas,epicardium, myocardium, lungs, stomach, intestines, adrenals and eyes. Broncho-pneumonia, and serofibrinous pleurisy of the right lung.

DISCU55ION

The essential features of the case here described, apart from the skin lesions,are the systemic accumulations of mast cells, the myeloflbrosis and osteosclero-sis and the terminal monocytic leukemia.

The extensive mast cell infiltrations of bones in the present case lend somesupport to the view that the skin and bone lesions of urticaria pigmentosa areof the same nature (1—7). Mast cell accumulations in bone marrow in conditionsother than urticaria pigmentosa have, indeed, been described. Thus smalleraccumulations of mast cells have been observed in the bone marrow of patientswith generalized or partial bone marrow depression (11—13). It has even beenmaintained by some that tissue mast cells are present in normal bone marrow(11, 14) but this has been disputed by others (12, 13). Mast cells in bone marrowhave never been reported in such abundance as in this case nor in such numbersas in bone marrow smears from previously reported cases of urticaria pig-mentosa (7, 8, 10).

The possibility that urticaria pigmentosa is sometimes systemic in nature isalso supported by the finding in some cases of mast cell infiltrations in lymphnodes (15) and in various internal organs (3, 7, 8, 10). Of interest in this con-nection, too, is the description by Degos et al. (16 a—d) and Hissard et al. (17a—c) of systemic mastocytosis with cutaneous lesions different from those pres-ent in urticaria pigmentosa.

In the present case mast cells were occasionally seeii replacing capillary endo-thelial cells. This incidental observation, while not contradicting the generallyaccepted view that mast cells originate from undifferentiated mesenchymal cellsin the adventitia of blood vessels (18, 19) or from fibroblasts (17, b) may signifythat mast cells perhaps also arise from endothelial cells.

The possibility of a relationship existing between the mast cell infiltrationsin the bones and the myelotibrosis merits consideration. Riley (20 a, b) hasreviewed earlier work on the role possibly played by mast cells in the formationof fibrous tissue; more specific mention may be made of in vitro experiments (7,21) which seem to show that heparin, which is known to be produced by mastcells (20 a), promotes the formation of collagen fibers. While this speculationseems attractive, it cannot be said to be substantiated in view of the dearth ofinformation on the bone marrow in urticaria pigmentosa and in view also of thegreat variety of blood diseases associated with myelofibrosis without increasein the number of mast cells.

The determination of the sequence of events resulting in myeloflbrosis andosteosclerosis in our case presents difficulties. It is known that osteosclerosis

366 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

and myelofibrosis may occur in a number of blood diseases such as leukemia,polycythemia vera and anemias of various types (22—25); this has been explainedby some authors as an event in the progress of these blood diseases towardshealing or scarring (25—30). Our patient appeared stigmatized for the develop-ment of the terminal leukemia two years before death when a monocytosis of17 per cent was found in the peripheral blood. One might presume that duringthis period the patient suffered from chronic aleukemic monocytic leukemiawhich caused the myeloflbrosis. However, this is not confirmed by the clinicalfindings, namely absence of lymphadenopathy and absence of a palpable liveror spleen until relatively late in the course of the disease. Furthermore, themonocytic infiltrations in the internal organs, where fibrosis was absent, wereon the whole more massive than iii the bone marrow. In the bone marrow itself,monocytic infiltrations were not present in areas of fibrosis.

It is, therefore, possible that in our case it was not the leukemia which pro-duced the myelofibrosis but that progressive myelofibrosis had stimulated extra-medullary hemopoiesis, eventually leading to monocytic leukemia; it is recog-nized that primary myeloflbrosis may be followed by proliferative disorders ofthe blood elements (22—25). Alternatively, it is possible that both the myelo-fibrosis and the leukemia were results of proliferative activity of descendants ofmultipotent mesenchymal cells (25, 32, 33, 34). In either event, the myelo-fibrosis and osteosclerosis, in turn, may have been the direct result of tissuemast cell accumulations in the bone marrow as an expression of systemic urti-caria pigmentosa. Whether the urticaria pigmentosa was also causally relatedto the leukemia is unknown. Leukemia as a rare complication of urticaria pig-mentosa has been reported by Balbi (35), Hermans (36) and Efrati (37), andinstances of pseudoleukemia have been observed by Touraine et al. (38) butthese scattered reports do not permit of any conclusions to be drawn.

It is possible that the underlying lesions also in other reported cases of urti-caria pigmentosa with roentgenologically detected bone changes consist of mye-lofibrosis, osteosclerosis and mast cell accumulations. Since bone changes of thiskind are known to be connected with various blood diseases the hematologicalinvestigation of such cases of urticaria pigmentosa would seem to be indicated.

SUMMARY

A case of urticaria pigmentosa with disseminated bone involvement is re-ported. The case was followed for two years prior to the patient's death frommonocytic leukemia.

Post-mortem examination revealed mast cell accumulations in the bonemarrow of the affected bones, suggesting that the bone lesions were of the samenature as the skin lesions. In the bones the mast cell accumulations alternatedwith widespread myeloflbrosis. Osteosclerosis was also present and was charac-terized by extensive formation of immature bone.

Infiltrations of monocytes were present in the skin, the internal organs andthe bone marrow.

The possibility that the mast cell accumulations were causally related to the

URTICA1IIA PIGMENTOSA WITH BONE INVOLVEMENT 367

myelofibrosis is discussed, as also that the leukemia was not merely coincidentalbut causally related to the progressive myelo6brosis.

Tissue mast cells replacing the endothelial lining of blood capillaries wereobserved.

ACKNOWLEDGMENT

The authors wish to express their appreciation and thanks to Dr. S. Gill,Dr. G. Gitlin, Dr. N. Herz, Dr. G. Izak, Dr. A. Behar, Mrs. R. Ungar andMrs. H. Weinmann for their help and cooperation.

REFERENCES

1. SAGHER, F., COHEN, Cii. AND SCHORR, S.: Concomitant bone changes in urticaria pig-mentosa. J. Invest. l)ermat., 18: 425—432, 1952.

2. ASBOE-HANSEN, G.: Urticaria pigmentosa with bone lesions. Acta Dermat. venereol.,33: 471—475, 1953.

3. BLUEFARB, S. M. AND SALK, M. R.: Urticaria pigmnentosa with bone lesions, gastro-intestinal symptoms and splenomegaly. Arch. I)ermat. & Syph. 70: 376—378, 1954.

4. CALNAN, C. 1).: Urticaria pigmentosa with hone lesions. Two cases. Presented at theRoyal Society of Medicine, Section of l)errnat. Brit. J. l)ermat., 65: 375-376, 1953.

5. CLYMAN, S. G. AND REIN, C. R.: Urticaria pigmentosa associated with bone lesions.

A survey and report of eight cases. J. Invest. l)enniat., 19: 179—185, 1952.

6, a. GRUI'PER, Cii. AND DE BRUX, J.: Urticaire pigmentaire, quelques acquisitions récentesBull. Soc. franc. de dermat. et syph., 59: 363—367, 1952.

6, b. SOBEL, N.: Urticaria pigmentosa. Presented at the Bronx Dermat. Society, March19, 1953. Arch. l)ermat. & Syph., 69: 108—110, 1954.

6, c. PARMANTIER, J.: Les lesions osseuses de l'urticaire I)igiflefltaire. These, Paris, 1954,cited by i)egos in Actas dermosif., 46: 759—785, 1953.

7. REILLEY, E. B., SHINTANI, J. AND GOODMAN, J.: Systemic mast-cell disease with urti-

caria pigmentosa. Arch. 1)ermat. & Syph., 71: 561—569, 1955.

8. BERLIN, CR.: Urticaria pigmentosa as a systemic disease. Arch. 1)ermat. & Syph.,71: 703—712, 1955.

9. HUNTER, H. A. AND NIKIFORUK, G. V.: Staining reactions following demnineralization

of hard tissues by chelating and other decalcifying agents. J. Dent. Research, 33:136—138, 1954.

10. Ews, J. M.: Urticaria pigmentosa. A report of a case with autopsy. Arch. Path. 48:

426—435, 1949.11. Wiiu.&iis, F. T.: Tissue mast cells in human bone marrow. Ahi. J. Cliii. l'ath., 22:

1039—1043, 1952.12. FADEM, R. S.: Tissue mast cells in human bone marrow. Blood, J. of Hemat., 6: 614—630,

1951.

13. RoME,K.: Das menschliche Knochenmark. II. Edition pp.70—71. Leipzig, Georg Thieme,1949.

14. J0HNST0NE, J. M.: Appearance and significance of tissue mast cells in human bonemarrow. Am. J. Cliii. Path., 7: 275—280, 1954.

15. BERTELLOTTI, L.: L'urtiearia pigmentosa come rcticolo-endoteliosi sistemica ad orien-tamento monomorfo (A propo.sito di Un caso.) Gior. ital. di dermat. e sif., 84: Fasc.VI., 1943.

16, a. 1)EGos, R., LORTAT-JACUB, ET., MALLARME, J. AND SAIJVAN, R.: RCticulose a masto-cytes. Bull. Soc. franc. de dermat. et syph., 58: 435—440, 1951.

16, b. 1)EGOs, H., LORTAT-JACOB, ET., HEWITT, J. AND OssmPowSKI, B.: RCticulose a mas-tocytes. Forme cutanCe diffuse. ibid. 59: 247—249, 1952.

16, c. l)EGos, IL: l)ELORT, J. AND HEWITT, J.: Réticulose C mastocytes. Forme cutanCe

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diffuse sans urticaire pigmentaire. ibid. 61: 97—98, 1954. (1)iscussion: Grupper, M.Ch.) [Séance 11.3. 1954.]

16, d. DEous, It.: Urtiearia pigmentaria y utros tipos de mastoeitosis. [Ensayo de Clasi-fleacion de las mastoeitosis cutaneas.] Aetas dermu-sif., 46: 759—785, 1955.

17, a. HI55ARD, it., M0NC0UHIER, L. AND JACQUET, J.: Une nouvelle affection hémato-dermique, la mastoeytose. Compt. rend. Acad. d. se. 231: 253—255, 1950.

17, b. HI55ARD, H., MoNcoumEa, L. AND JACQUET, J.: A propos d'un eas de mastocytosepure. Origine et evolution des mastocytes. ibid. 231: 1178—1179, 1950.

17, e. HI55ARD, R., M0NC0UEIEE, L. AND JAcQUET, J.: Etude d'une nouvelle hCmatodermie;Ia Inastoeytose. La Presse Médicale, 59: 1765—1767, 1951.

18. RILEY, J. F.: The relationship of the tissue mast cells to the blood vessels in the rat.J. Path. & Baet., 65: 461—469, 1953.

19. FAWCETT, 1). W.: An experimental study of mast cell degranulation and regeneration.Anat. Ree., 121: 29—52, 1955.

20, a. RILEY, J. F.: Pharmacology and functions of the mast cells. Pharm. Rev. 7: 267—277,1955.

20, b. RILEY, J. F.: The riddle of the mast cells. Laneet, 1: 841—844, 1954.21. MOREIONE, T. C.: The formation of collagen fibers by the action of heparin on soluble

collagen: An electron-microscopic study. J. Exper. Med., 96: 107—114, 1952.22. STuaoIs, C. C.: Hematology, pp. 322-323. Springfield, Illinois, U. S. A. Ch. C. Thomas,

1948.23. JORDAN, H. E. AND SCOTT, J. K.: A ease of osteoselerosis with extensive extramedullary

hemopoiesis and a leukemie blood reaction. Arch. Path., 32: 895—909, 1941.24. BEATTIE, J. B. AND WITHEY, J. L.: Polycythemia, leueo-erythroblastosis and myeloscle-

rosis. Brit. M. J., 2: 414—417, 1953.25. RoBsoN, H. N.: Myeloselerosis: A study of a condition also known as myeloflbrosis,

aleuehaemie myelosis, agnogenie myeloid metaplasia, and other titles. AustralianAnn. of Med., 2: 170—178, 1953.

26. C1-IUECH, J. AND WACHSYEIN, M.: ()steosclerosis, myeloflbrosis and leukemia. Am. J.M. Se., 207: 141—152, 1944.

27. HEWER, T. W.: Megakaryocytic myelosis with osteoselerosis. J. Path. & Bact., 45:383—390, 1937.

28. PI5cI0TTA, A. V.: Clinical and pathological effects of space-occupying lesions of the

bone marrow. Am. J. Clin. Path., 20: 915—933, 1950.

29. SILvERMANN, F. N.: The skeletal lesions in leukemia: Clinical and roentgenographieobservations in 103 infants and children, with review of literature. AIR. J. Roentgenol.,59: 819—844, 1948.

30. SU55MANN, M. L.: Skeletal changes associated with diseases of the blood. Bull. New

York Aead. Med., 26: 763—778, 1950.

31. WINDHOLZ, F. AND FosTER, S. E.: Bone sclerosis in leukemia and, in non-leukemic

myelosis. Am. J. Roentgenol., 61: 61—76, 1949.

32. DAME5REK, W.: Some speculations on the myeloproliferative syndrome. Blood, J. ofHemat., 6: 372—375, 1951.

33. VAUGHAN, J. M. AND HAaEI50N, C. V.: Leuco-erythroblastic anemia and myelosele-

rosis. J. Path. & Bact., 48: 339—352, 1939.

34. PEACE, R. J.: Myelonecrosis, extramedullary myelopoiesis and leuko-erythrohlastosis.(A meseDehymal reaction to injury.) Am. J. Path., 29: 1029—1057, 1953.

35. BALE:, E.: Ricerehe intorno alla patogenesi dell'urtiearia pigmentosa. Gior. ital. di

dermat. e sif., 90: 82—100, 1949.

36. HEEMAN5, E. H., Sa.: Personal communication.37. EFEATI, P.: Personal communication.38. TOUHAINE, A., SOLENTE AND RENAULT, P.: Urticaire pigmentaire avec reaction splC-

nique et myélémique. Bull. Soc. franc. de dermat. et syph., 40: 1691—1694, 1933.