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Infantile Xanthogranuloma of the Orbit*
I N F A N T I L E XANTHOGRANULOMA O F T H E ORBIT* A REPORT OF THREE CASES T. E.
SANI >ERS, M.D.
St. Louis, Missouri For over 50 years, nevoxanthogranuloma, a benign skin disease of children, has been well recognized in dermatology.1"7 The le sions consist of multiple, discreet, yellowish papules which have a characteristic clinical appearance as well as a diagnostic histologie pattern. The skin lesions usually regress spontaneously and very rarely are associated with systemic involvement. The term nevoxanthoendothelioma was first suggested in 1912 by McDonagh2 who originally de scribed the lesion. He felt this term was de scriptive for he thought the lesion was a congenital endothelioma with secondary fatty changes. Over the years, with the in creasing knowledge of the histiocytic dis eases, this term has become obsolete. In 1954, Helwig and Hackney6 first introduced the term juvenile xanthogranuloma as being descriptive of the lesion. This term has be come generally accepted. In the past 10 years, the intraocular le sion has become well recognized. The first case involving the iris was reported in the pédiatrie literature by Blank, Eglick, and Beerman in 1949.8 However, it was not until 1956 that Maumenee9 first recorded this condition in the ophthalmic literature. The following year Newell10 reported two cases, one of which represents the first re ported case that was correctly diagnosed clinically. The first series, consisting of 20 cases, including three of my own, was re ported by me in I960.11 The syndrome of intraocular juvenile xanthogranuloma consists of an infiltrative histiocytic lesion of the iris, spontaneous hyphema and secondary glaucoma in an infant who may have typical skin lesions. It is now accepted that the iris lesion was not recog* From the Department of Ophthalmology, Wash ington University School of Medicine.
nized and was misdiagnosed both clinically and pathologically on a number of occasions in the past.11-12 The story of the develop ment of our knowledge of this condition, both clinically and pathologically, has re cently been completely described by Zimmerman12 who reported a series of 32 cases of the iris, including 18 reported by me. The disease has only recently been rec ognized in Europe. 12 The iris lesion at pres ent represents the most important clinical aspect of this disease, as the skin nodule is benign but the iris lesion may lead to loss of the eye. Until recently, juvenile xanthogranuloma of the ocular adnexa has been practically unknown, the only recorded case apparently being that of an epibulbar lesion reported in 1958 by Cogan, Kuwabara, and Parke. 13 In the paper by Zimmerman12 already men tioned, the first series of ocular adnexal le sions of juvenile xanthogranuloma was re ported. This report includes 13 cases of eye lid disease, seven cases of epibulbar lesions and five cases of intraorbital involvement. The five cases of intraorbital disease re ported by Zimmerman12 were collected from files of the Armed Forces Institute of Pa thology. However, two of them, Zimmer man's Cases 1 and 2, were contributed by the Washington University Laboratory of Ophthalmic Pathology. My second case is of particular interest as, apparently, it is unique in two respects. Because of these unique features, it was reported as a clinical patho logic case at the Academy last fall.14 After hearing this report Dr. Charles Mahoney, of Terre Haute, Indiana, recalled a case which he later referred to me. This case, my Case 3, proved to be one of juvenile xanthogran uloma. (This case is mentioned by Zimmerman12 in a footnote.) Inasmuch as I
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Five years later the physician father reported that the child had remained completely well with no recurrence and excellent cosmetic result (fig. 1). At no time were any skin lesions noted nor was there any evidence of any systemic involve ment. Histologically the mass was composed chiefly of histiocytes containing very little lipid (fig. 2 ) . Eosinophils were very numerous but no teuton giant cells were observed. The original diagnosis by several competent pathologists was eosinophilic granuloma. This case was presented to the Midwest Ophthalmic Pathology Club at the 1960 meeting by Dr. Ley as an eosinophilic granuloma. However, on later review the histologie diagnosis was thought to be consistent with juvenile xanthogranuloma both by local pathologists and by several observers at the Armed Forces Institute of Pathology. The benign clinical course is consis tent with juvenile xanthogranuloma. CASE 2
Fig. 1 (Sanders). Case 1. Appearance five years after operation.
have personally examined three of the six known cases of intraorbital juvenile xanthogranuloma, both clinically and histologically, I thought these cases worthy of a separate report.
L. R., a four and one-half month-old, white, male infant, was admitted to St. Louis Children's Hospital on March 28, 1962, on the service of Dr. James E. Miller, having been referred by Dr. J. B. Cross of Little Rock, Arkansas, because of right exophthalmos, present since birth. Abnormal physical findings were confined to the eye and skin. The right eye was exophthalmic with downward and lateral displacement of the globe (fig. 3 ) . There was excessive lacrimation and injection of the bulbar conjunctiva on the right. There was definite limitation of upward movement of the right globe. In the left axilla were two skin lesions mea suring two and three cm in diameter. Each was raised and had a yellow central portion and a
REPORT OF CASES CASE 1
P . R., a white male infant five months of age, was first seen by Dr. A. P. Ley on November 20, 1959. For over two months the parents had noted a swelling in the right upper lid which gradually increased in size, with some downward displace ment of the globe. The father, a physician, thought he had noted a mass in the lid. Examination showed a fullness of the upper lid with slight downward displacement of the globe. A bilobed mass could be palpated at the upper orbital rim. Radiographic studies showed some erosion of the superior orbital rim but the roof was intact. Both the X-ray and clinical di agnosis was dermoid cyst. T h e patient was admitted to St. Louis Chil dren's Hospital and, on December 8, 1959, an or bital exploration was done by Dr. Ley. A diffuse xanthochromic soft tissue mass was found filling the upper quarter of the orbit as far back as the orbital fissure. It was adherent to periosteum but the bone was uninvolved. The orbit was subse quently given 400 r of X-ray. The postoperative course was uneventful.
Fig. 2 (Sanders). Case 1. Histologie appearance of the lesion, showing lipid histiocytes.
XANTHOGRANULOMA OF THE ORBIT pink periphery. The entire lesion was covered with a corrugated and atrophie surface. About these lesions were a number of small (one mm or less) pink papules and smaller macules. The lat ter blanched on pressure. Similar lesions were noted on the lateral surface of the left upper thigh and the ring finger of the left hand (fig. 4). The blood count, urinalysis and serology studies were normal. The alkaline phosphatase, cholesterol, bilirubin, NPC, total and fractional serum proteins, SGOT, and SGPT were also nor mal. Examination of the cerebrospinal fluid re vealed nothing unusual. Radiographie examination of the skull and or bits demonstrated bone destruction involving the roof and posterior lateral wall of the right orbit (fig. S). Most of the greater wing of the sphe noid on the right was absent. The right optic for amen and superior orbital fissure were indistinct. Laminograms of the orbits demonstrated these orbital lesions more clearly. A skeletal survey and intravenous pyelograms were normal. Pneumoencephalography demonstrated no intracranial mass or orbital encephalocele. Although radiographie findings showed definite bony destruction of the orbital wall, the appear ance of this lesion was so unusual that no exact diagnosis could be made from the films. Although the skin biopsy was diagnostic of juvenile xanthogranuloma (fig. 6), it could not be assumed that the orbital lesion was similar. Because of the position of the lesion in the bony wall of the orbit, the patient was referred to neurosurgery. On April 13, 1962, a right frontal craniotomy was performed, at which time a yellow-white tumor was found involving the soft tissues of the apex of the orbit (fig. 7) and the bony roof of the orbit (fig. 8), with some of the tissue involv ing the overlying dura. Superior orbital de compression was carried out. An infiltrative histiocytic lesion similar to that present in the skin
Fig. 3 (Sanders). Case 2. Patient prior to surgery.
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Fig. 4 (Sanders). Case 2. Skin lesions near the tip of the third finger.
was found in both the soft tissue of the apex of the orbit and in the bone of the orbital wall. The child made an uneventful recovery from this sur gery. On September 17, 1963, the patient was re-ex amined by Dr. A. J. Gay, who found residual right exophthalmos and about 25 diopters of right hypotropia which increased on upward gaze, with limitation of the right eye. Ophthalmoscopic examination showed no definite lesions of the fundus and the optic nerve appeared to be nor mal. Apparently the skin lesions were getting smaller but were still obvious under the left arm. Dr. Gay felt that there had been no progression of the lesion since discharge, at which time he had seen the patient with Dr. Miller. This patient was next examined by me on July 23, 1964. The right eye was still proptosed about seven mm, with downward displacement. The globe was rotated downward but otherwise was normal. The skin lesion on the tip of the finger was still present but the lesions in the axilla were atrophie. Radiologie studies were done by Dr. Wen dell Scott. He reported that there was a moderate amount of bone repair over the roof of the orbit. The right foramen was still enlarged. There was a well-defined osteolytic lesion in the posterior and inferior portion of the frontal bone, around the right orbit, about 2.S cm in diameter, which had not been identified on the films taken two years earlier and was probably an active lesion. A series of radiation treatments were given to this area by Dr. William J. Rhinehart of Little Rock, Arkansas, using a 3 by 4-cm right lateral frontal field, with a total dose of about 1800 r. The patient was examined on May 7, 1965, and again on October 1, 1965 (fig. 9). The parents believed the condition to be unchanged, with the chief abnormality being the drooping lid. The visual acuity was very unsatisfactory being approximately: O.D., counting fingers; O.S. 20/50 with pictures.
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T. E. SANDERS
Fig.* S (Sanders). Case 2. (Left) Posteroanterior roentgenogram, showing large, indistinct right optic foramen and associated bone destruction. (Right) Normal left optic foramen. The right eye was displaced downward about four mm with three to four mm of proptosis. A ptosis covered most of the pupil but pupillary reactions were normal. There was right esotropia of about IS to 20 prism diopters with poor fixa tion. There was some limitation of upward gaze. The slitlamp and ophthalmoscopic examinations were not unusual. The skin lesion on the tip of the finger had disappeared but there were several large atrophie areas in the left axilla. The films showed the osteolytic lesion, noted in July, 1964, to be un changed, but no new lesions were noted. The skin nodule, the soft tissue lesion in the orbit and the bony involvement were all thought to show a characteristic histologie lesion of ju venile xanthogranuloma, not only by local pathologists, but also by Drs. L. E. Zimmerman and E. R. Helwig of the Armed Forces Institute of Pa thology.
time. Films of the orbit showed no bony defect. After one month's observation, Dr. Mahoney found no change and an exploration of the orbit was done on October 1, 1964. In the superior nasal quadrant of the orbit a thin, elongated, yel lowish tumor was found around the medial and superior rectus muscles, possibly extending back as far as the posterior ethymoids. Most of this mass was removed. Postoperatively the patient did very well, with disappearance of the mass and also apparently of the exophthalmos. The mother stated she believed there was some difficulty in moving the eye upward.
CASE 3
B. A. D., a white female infant aged four months, was first seen by Dr. Charles L. Mahoney of Terre Haute, Indiana, because of a small lump noted in the inner fourth of the left upper lid at about the age of two months. On examina tion, a small mass was noted immediately above the internal canthal ligament, which was thought possibly to be due to enlargement of the upper dome of the tear sac. However, a small amount of exophthalmos was apparently present at this * Figures 5, 6, 7 and 8 are reproduced with per mission of the American Journal of Radiology from the previous report of this case.
Fig. 6* (Sanders). Case 2. Skin biopsy, showing diagnostic lesion with one Touton giant cell in center of field.
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Fig. 7* (Sanders). Case 2. Lesion from the apex of orbit, showing similar histologie findings.
Fig. 8* (Sanders). Case 2. Bony invasion by the characteristic tissue.
The patient was first seen by me on November 27, 1964. A curved, well-healed incisional scar was seen in the upper nasal aspect along the orbi tal brim. No mass could be noted, nor was any exophthalmos present. However, the globe seemed to be displaced downward about two mm. There also was some apparent limitation of upward gaze. The globe itself was normal. No skin le sions were present on the body surface. The pa tient was again seen by me on April 12, 1965 (fig. 10), with apparently very little change in the condition, except that there was probably less displacement of the eye. At this time a slight left hypotropia was apparent. As will be noted, some striate muscle was seen in some of the sections so possibly there was involvement of the superior rectus. Section consisted of a diffuse infiltrating le sion made up almost entirely of histiocy'tes (fig. 11). Throughout the lesion, there were many teu ton giant cells. There was some infiltration of or bital fat and, in one area, some involvement of striate muscle was noted. A diagnosis of "xanthoma" had originally been made by the local surgi cal pathologist. However, it was felt that the le sion was consistent with juvenile xanthogranuloma. This diagnosis was substantiated by Drs. L. E. Zimmerman and E. R. Helwig of the Armed Forces Institute of Pathology. DISCUSSION
Fig. 9 (Sanders). Case 2. Appearance three years after operation.
It has long been recognized that juvenile xanthogranuloma of the skin is a disease of infants and very young children. This is also apparently true of the intraocular le sion. In my series of 20 iris lesions, 17 of the patients were under one year of age. In Zimmerman's recent report 85% of his pa-
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T. E. SANDERS
Fig. 10 (Sanders). Case 3. Appearance six months after operation.
tients with iris involvement were under one year of age and 64% were under the age of seven months. In every one of the three pa tients here reported, the lesion was first noted when the child was less than three months of age. This is also true in the three additional cases reported by Zimmerman.12 Apparently the orbital lesion occurs at as young an age as any of the manifestations of juvenile xanthogranuloma. This suggests that the descriptive term infantile in this condition is preferable to juvenile. Unilateral exophthalmos in a very young infant is an unusual condition, the most common causes being dermoid cyst and hemangioma. In the very rare case of teratoma
of the orbit, the exophthalmos may be mas sive. In Case 2, the skin lesions were pres ent and were shown to be juvenile xantho granuloma by biopsy. This suggested a pre sumptive diagnosis of juvenile xanthogran uloma in the orbit, which was verified by biopsy. In the other two cases in which an anterior palpable mass was present, a biopsy was necessary to establish the diagnosis. As suggested by the experience with the iris le sions, it is possible that some of these orbi tal lesions in infants have been misdiagnosed and unrecognized. Therefore, in any unilateral exophthalmos in an infant, partic ularly if a palpable mass is present, the pos sibility of juvenile xanthogranuloma as being the underlying lesion should be con sidered. About one half of the known cases of in traorbital juvenile xanthogranuloma involve extraocular muscle. Two of the cases re ported by Zimmerman were described as being "wrapped around a rectus muscle"— the inferior rectus in one and the medial rectus in another. My Case 3 showed in volvement of both the internal and the supe rior rectus muscles, with some residual par esis of the superior rectus. Paresis of the
Fig. 11 (Sanders). Case 3. His tologie appearance of the lesion, showing Touton giant cells. r" >>'
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XANTHOGRANULOMA OF THE ORBIT
muscles in this condition could be either due to primary involvement of the muscle with disease or damage to the muscle during re moval of the lesion. It is possible that mus cle involvement may be one of the most im portant complications of the condition. Case 2 is unique in two respects: the presence of the skin lesion and the involve ment of bone. In my series of iris cases,11 skin lesions were present in eight of the 20 cases, and absent in only three in which they were searched for; the possibility of their being ignored in the early unrecognized cases is evident. As the skin manifestations were present in only one of six cases with orbital involvement, it is possible that the patients with orbital lesions are less likely to manifest skin lesions. This makes the diag nosis of the orbital lesion more difficult. This case is also apparently the only known instance of bone involvement. No other known case of bony involvement ap pears in any of the several hundred cases in the dermatologie literature.7'12 From the in formation obtained by roentgenographic study, orbital exploration and histologie ex amination, it is impossible to determine the exact site of origin of the lesion in this case. It is possible that it could have arisen pri marily in the orbital tissue, in the bony wall of the orbit or, less likely, in the méninges, with secondary involvement of the other structures. The roentgenographic findings in this case were most unusual but not diag nostic. These findings were considered to be worthy of a report in the radiologie litera ture which appeared some months ago.15 Juvenile xanthogranuloma is a disease the exact nature of which is unknown. In the early ophthalmologic reports, it was in cluded in the histiocytosis X group.9·10 In reviewing my 20 cases of iris involvement, I stated : "It is probably a unique disease, this idea being supported particularly by Helwig and Nomland."11 Zimmerman12 in his recent review of the disease, also holds with this concept. The intraorbital cases, both from their histologie appearance and from their
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clinical course, contribute additional support to this view. Some specific reasons stated previously for this belief still seem to be true: 1. Although similar, there is probably some distinct and diagnostic histologie differences be tween the skin lesion of nevoxanthoendothelioma and the reticuloendothelioses. 2. Iris lesions such as seen in nevoxanthoen dothelioma have not been reported in the reticuloendotheloses. 3. The lack of transition forms between the histiocytosis X group and nevoxanthoendothelioma. No case of nevoxanthoendothelioma has been re ported which has merged into the other group. 4. The apparent lack of visceral lesions other than of the iris is characteristic of nevoxan thoendothelioma, while the lesions of the reticu loendothelioses tend to be multiple. As noted, it is possible that visceral lesions of nevoxanthoen dothelioma are not determined in the absence of autopsy. 5. The benign course of nevoxanthoendothelioma with spontaneous regression is quite different than the severe course, often fatal, of the reticuloen dothelioses." TREATMENT
Therapy of the skin lesions is obviously unnecessary because of the tendency to re gress spontaneously, leaving a small atro phie scar. Several of the first patients with iris involvement had enucleation because of the mistaken diagnosis of iris tumor. Even the first patients who were correctly diag nosed clinically went on to loss of the globe from severe secondary glaucoma. Later radiation therapy was shown to be effective in the control of the iris lesions.16-18 Recent ly, topical steroid therapy has been reported19 to be effective, but this is con trary to my experience.11 Although the iris lesion is usually diffuse, in localized lesions excision has been reported to be effective.19'20 In all three of the present orbital cases, there apparently has been complete recovery from the orbital lesion following soft tissue removal at orbital exploration. However, in Case 1, a total of 400 r was given postoperatively; however, the patient in Case 3 has had no radiation. In Case 2, most of the original soft
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tissue and involved bone were apparently removed at the original operation. Over two years later, a new osteolytic lesion was noted. Radiation of the orbit was done, giv ing a total dose of about 1800 r. After one year, the lesion was unchanged but no addi tional lesions were noted. From my limited experience in the man agement of this disease, obviously no defini tive treatment can be suggested. However, since surgical exploration is necessary for diagnosis, most of the soft tissue lesion should be removed, avoiding injury to the surrounding structures, particularly extraocular muscle. Postoperative radiation, using a small amount, is probably desirable. In my Case 2, immediate postoperative radiation might have prevented the additional bony in volvement. SUMMARY
Three cases of infantile xanthogranuloma of the orbit are reported. One case seems unique in that skin lesions were present as well as bone involvement ; the other two were characterized by lesions of the orbital soft tis sue. Involvement of the extraocular muscles, with residual paresis, is an important aspect of the condition. In each case, the original manifestations of the disease were first noted under the age of three months. In any unilateral exophthalmos in an infant, the possibility of this condition should be con sidered. The two patients without bone in volvement recovered completely after surgi cal removal of the lesion. The soft tissue le sion in the patient with bone involvement was also cured by surgical removal but the bone involvement persisted despite radiation therapy. 100 North Euclid Avenue
(63108).
REFERENCES 1. McDonagh, J. R. E. : Spontaneous disappear ance of endotheliomata (naevo-xanthoma), Brit. J. Derm. 21:2S4, 1909. 2. ■ : A contribution to our knowledge of
the naevo-xantho-endotheliomata. Brit. J. Derm. 24 :8S, 1912. 3. Adamson, H. G. : A note on multiple erup tive xanthoma in infants : naevo-xanthoendothelioma (McDonagh). Brit. J. Derm. 48:366, 1936. 4. Senear, F . E., and Caro, M. R. : Nevoxantho-endothelioma or juvenile xanthoma. Arch. Derm. 34:195, 1936. 5. Nomland, R. : Nevoxantho-endothelioma : a benign xanthomatous disease of infants and chil dren. J. Invest. Derm. 22 :207, 1954. 6. Helwig, E. B., and Hackney, V. C. : Juven ile xanthogranuloma (nevoxantho-endothelioma) Am. J. Path. 30:625, 1954. 7. Fleischmajer, R., and Hyman, A. B. : Juve nile giant cell granuloma (Nevoxanthoendothe lioma). In Fleischmajer, R. : The Dyslipidoses. Springfield, 111., Thomas, 1960, chap. 18, pp. 329-372. 8. Blank, H., Eglick, P. G., and Beerman, H. : Nevoxanthoendothelioma with ocular involvement. Pediatrics, 4:349, 1949. 9. Maumenee, A. E. : Ocular lesions of nevo xanthoendothelioma (infantile xanthoma disseminat u m ) . T r . Am. Acad. Ophth. Otolaryng. 60:401, 1956. 10. Newell, F . W . : Nevoxanthoendothelioma with ocular involvement : A report of two cases. Arch. Ophth. 58:321,1957. 11 Sanders, T. E. : Intraocular juvenile xantho granuloma (nevoxanthogranuloma) : A survey of 20 cases. Tr. Am. Ophth. Soc. 58:59, I960; Am. J. Ophth., 53 :455, 1962. 12. Zimmerman, L. E. : The ocular manifesta tions of juvenile xanthogranuloma (nevoxan thoendothelioma). Tr. Am. Acad. Ophth. Otolar yng. 69:412, 1965. 13 Cogan, D. G., Kuwabara, T., and Parke, D. : Epibulbar nevoxanthoendothelioma. Arch. Ophth. 59:717, 1958. 14. Sanders, T. E., and Miller, J. E . : Infantile xanthogranuloma of the orbit: Report of a case. Tr. Am. Acad. Ophth. Otolaryng. 69:458, 1965. 15. Stapel, T. W , McAllister, W. H., Sanders, T. E., and Miller, J. E. : Juvenile xanthogranuloma of the orbit; report of a case with bony destruc tion. Am. J. Radiol. 91:629, 1964. 16. Hedges, C. C., Jr. : Nevoxanthoendothelioma of the eye treated with superficial X-ray therapy. Am. J. Ophth. 47 :683, 1959. 17. Maumenee, A. E., and Longfellow, D. W. : Treatment of intraocular nevoxantho-endothelioma (juvenile xanthogranuloma). Am. J. Ophth. 4 9 : 1 , 1960. 18. Cleasby, G. W . : Nevoxanthoendothelioma (Juvenile xanthogranuloma) of the iris: Diagnosis by biopsy and treatment with X-ray. Arch. Ophth. 66 :26, 1961. 19. Gass, J. D. M. : Management of juvenile xan thogranuloma of the iris. Arch Ophth. 71:344, 1964. 20. Howard, G. M. : Spontaneous hyphema in childhood. Arch. Ophth. 68 :621, 1962.
SANI >ERS, M.D.
St. Louis, Missouri For over 50 years, nevoxanthogranuloma, a benign skin disease of children, has been well recognized in dermatology.1"7 The le sions consist of multiple, discreet, yellowish papules which have a characteristic clinical appearance as well as a diagnostic histologie pattern. The skin lesions usually regress spontaneously and very rarely are associated with systemic involvement. The term nevoxanthoendothelioma was first suggested in 1912 by McDonagh2 who originally de scribed the lesion. He felt this term was de scriptive for he thought the lesion was a congenital endothelioma with secondary fatty changes. Over the years, with the in creasing knowledge of the histiocytic dis eases, this term has become obsolete. In 1954, Helwig and Hackney6 first introduced the term juvenile xanthogranuloma as being descriptive of the lesion. This term has be come generally accepted. In the past 10 years, the intraocular le sion has become well recognized. The first case involving the iris was reported in the pédiatrie literature by Blank, Eglick, and Beerman in 1949.8 However, it was not until 1956 that Maumenee9 first recorded this condition in the ophthalmic literature. The following year Newell10 reported two cases, one of which represents the first re ported case that was correctly diagnosed clinically. The first series, consisting of 20 cases, including three of my own, was re ported by me in I960.11 The syndrome of intraocular juvenile xanthogranuloma consists of an infiltrative histiocytic lesion of the iris, spontaneous hyphema and secondary glaucoma in an infant who may have typical skin lesions. It is now accepted that the iris lesion was not recog* From the Department of Ophthalmology, Wash ington University School of Medicine.
nized and was misdiagnosed both clinically and pathologically on a number of occasions in the past.11-12 The story of the develop ment of our knowledge of this condition, both clinically and pathologically, has re cently been completely described by Zimmerman12 who reported a series of 32 cases of the iris, including 18 reported by me. The disease has only recently been rec ognized in Europe. 12 The iris lesion at pres ent represents the most important clinical aspect of this disease, as the skin nodule is benign but the iris lesion may lead to loss of the eye. Until recently, juvenile xanthogranuloma of the ocular adnexa has been practically unknown, the only recorded case apparently being that of an epibulbar lesion reported in 1958 by Cogan, Kuwabara, and Parke. 13 In the paper by Zimmerman12 already men tioned, the first series of ocular adnexal le sions of juvenile xanthogranuloma was re ported. This report includes 13 cases of eye lid disease, seven cases of epibulbar lesions and five cases of intraorbital involvement. The five cases of intraorbital disease re ported by Zimmerman12 were collected from files of the Armed Forces Institute of Pa thology. However, two of them, Zimmer man's Cases 1 and 2, were contributed by the Washington University Laboratory of Ophthalmic Pathology. My second case is of particular interest as, apparently, it is unique in two respects. Because of these unique features, it was reported as a clinical patho logic case at the Academy last fall.14 After hearing this report Dr. Charles Mahoney, of Terre Haute, Indiana, recalled a case which he later referred to me. This case, my Case 3, proved to be one of juvenile xanthogran uloma. (This case is mentioned by Zimmerman12 in a footnote.) Inasmuch as I
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Five years later the physician father reported that the child had remained completely well with no recurrence and excellent cosmetic result (fig. 1). At no time were any skin lesions noted nor was there any evidence of any systemic involve ment. Histologically the mass was composed chiefly of histiocytes containing very little lipid (fig. 2 ) . Eosinophils were very numerous but no teuton giant cells were observed. The original diagnosis by several competent pathologists was eosinophilic granuloma. This case was presented to the Midwest Ophthalmic Pathology Club at the 1960 meeting by Dr. Ley as an eosinophilic granuloma. However, on later review the histologie diagnosis was thought to be consistent with juvenile xanthogranuloma both by local pathologists and by several observers at the Armed Forces Institute of Pathology. The benign clinical course is consis tent with juvenile xanthogranuloma. CASE 2
Fig. 1 (Sanders). Case 1. Appearance five years after operation.
have personally examined three of the six known cases of intraorbital juvenile xanthogranuloma, both clinically and histologically, I thought these cases worthy of a separate report.
L. R., a four and one-half month-old, white, male infant, was admitted to St. Louis Children's Hospital on March 28, 1962, on the service of Dr. James E. Miller, having been referred by Dr. J. B. Cross of Little Rock, Arkansas, because of right exophthalmos, present since birth. Abnormal physical findings were confined to the eye and skin. The right eye was exophthalmic with downward and lateral displacement of the globe (fig. 3 ) . There was excessive lacrimation and injection of the bulbar conjunctiva on the right. There was definite limitation of upward movement of the right globe. In the left axilla were two skin lesions mea suring two and three cm in diameter. Each was raised and had a yellow central portion and a
REPORT OF CASES CASE 1
P . R., a white male infant five months of age, was first seen by Dr. A. P. Ley on November 20, 1959. For over two months the parents had noted a swelling in the right upper lid which gradually increased in size, with some downward displace ment of the globe. The father, a physician, thought he had noted a mass in the lid. Examination showed a fullness of the upper lid with slight downward displacement of the globe. A bilobed mass could be palpated at the upper orbital rim. Radiographic studies showed some erosion of the superior orbital rim but the roof was intact. Both the X-ray and clinical di agnosis was dermoid cyst. T h e patient was admitted to St. Louis Chil dren's Hospital and, on December 8, 1959, an or bital exploration was done by Dr. Ley. A diffuse xanthochromic soft tissue mass was found filling the upper quarter of the orbit as far back as the orbital fissure. It was adherent to periosteum but the bone was uninvolved. The orbit was subse quently given 400 r of X-ray. The postoperative course was uneventful.
Fig. 2 (Sanders). Case 1. Histologie appearance of the lesion, showing lipid histiocytes.
XANTHOGRANULOMA OF THE ORBIT pink periphery. The entire lesion was covered with a corrugated and atrophie surface. About these lesions were a number of small (one mm or less) pink papules and smaller macules. The lat ter blanched on pressure. Similar lesions were noted on the lateral surface of the left upper thigh and the ring finger of the left hand (fig. 4). The blood count, urinalysis and serology studies were normal. The alkaline phosphatase, cholesterol, bilirubin, NPC, total and fractional serum proteins, SGOT, and SGPT were also nor mal. Examination of the cerebrospinal fluid re vealed nothing unusual. Radiographie examination of the skull and or bits demonstrated bone destruction involving the roof and posterior lateral wall of the right orbit (fig. S). Most of the greater wing of the sphe noid on the right was absent. The right optic for amen and superior orbital fissure were indistinct. Laminograms of the orbits demonstrated these orbital lesions more clearly. A skeletal survey and intravenous pyelograms were normal. Pneumoencephalography demonstrated no intracranial mass or orbital encephalocele. Although radiographie findings showed definite bony destruction of the orbital wall, the appear ance of this lesion was so unusual that no exact diagnosis could be made from the films. Although the skin biopsy was diagnostic of juvenile xanthogranuloma (fig. 6), it could not be assumed that the orbital lesion was similar. Because of the position of the lesion in the bony wall of the orbit, the patient was referred to neurosurgery. On April 13, 1962, a right frontal craniotomy was performed, at which time a yellow-white tumor was found involving the soft tissues of the apex of the orbit (fig. 7) and the bony roof of the orbit (fig. 8), with some of the tissue involv ing the overlying dura. Superior orbital de compression was carried out. An infiltrative histiocytic lesion similar to that present in the skin
Fig. 3 (Sanders). Case 2. Patient prior to surgery.
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Fig. 4 (Sanders). Case 2. Skin lesions near the tip of the third finger.
was found in both the soft tissue of the apex of the orbit and in the bone of the orbital wall. The child made an uneventful recovery from this sur gery. On September 17, 1963, the patient was re-ex amined by Dr. A. J. Gay, who found residual right exophthalmos and about 25 diopters of right hypotropia which increased on upward gaze, with limitation of the right eye. Ophthalmoscopic examination showed no definite lesions of the fundus and the optic nerve appeared to be nor mal. Apparently the skin lesions were getting smaller but were still obvious under the left arm. Dr. Gay felt that there had been no progression of the lesion since discharge, at which time he had seen the patient with Dr. Miller. This patient was next examined by me on July 23, 1964. The right eye was still proptosed about seven mm, with downward displacement. The globe was rotated downward but otherwise was normal. The skin lesion on the tip of the finger was still present but the lesions in the axilla were atrophie. Radiologie studies were done by Dr. Wen dell Scott. He reported that there was a moderate amount of bone repair over the roof of the orbit. The right foramen was still enlarged. There was a well-defined osteolytic lesion in the posterior and inferior portion of the frontal bone, around the right orbit, about 2.S cm in diameter, which had not been identified on the films taken two years earlier and was probably an active lesion. A series of radiation treatments were given to this area by Dr. William J. Rhinehart of Little Rock, Arkansas, using a 3 by 4-cm right lateral frontal field, with a total dose of about 1800 r. The patient was examined on May 7, 1965, and again on October 1, 1965 (fig. 9). The parents believed the condition to be unchanged, with the chief abnormality being the drooping lid. The visual acuity was very unsatisfactory being approximately: O.D., counting fingers; O.S. 20/50 with pictures.
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Fig.* S (Sanders). Case 2. (Left) Posteroanterior roentgenogram, showing large, indistinct right optic foramen and associated bone destruction. (Right) Normal left optic foramen. The right eye was displaced downward about four mm with three to four mm of proptosis. A ptosis covered most of the pupil but pupillary reactions were normal. There was right esotropia of about IS to 20 prism diopters with poor fixa tion. There was some limitation of upward gaze. The slitlamp and ophthalmoscopic examinations were not unusual. The skin lesion on the tip of the finger had disappeared but there were several large atrophie areas in the left axilla. The films showed the osteolytic lesion, noted in July, 1964, to be un changed, but no new lesions were noted. The skin nodule, the soft tissue lesion in the orbit and the bony involvement were all thought to show a characteristic histologie lesion of ju venile xanthogranuloma, not only by local pathologists, but also by Drs. L. E. Zimmerman and E. R. Helwig of the Armed Forces Institute of Pa thology.
time. Films of the orbit showed no bony defect. After one month's observation, Dr. Mahoney found no change and an exploration of the orbit was done on October 1, 1964. In the superior nasal quadrant of the orbit a thin, elongated, yel lowish tumor was found around the medial and superior rectus muscles, possibly extending back as far as the posterior ethymoids. Most of this mass was removed. Postoperatively the patient did very well, with disappearance of the mass and also apparently of the exophthalmos. The mother stated she believed there was some difficulty in moving the eye upward.
CASE 3
B. A. D., a white female infant aged four months, was first seen by Dr. Charles L. Mahoney of Terre Haute, Indiana, because of a small lump noted in the inner fourth of the left upper lid at about the age of two months. On examina tion, a small mass was noted immediately above the internal canthal ligament, which was thought possibly to be due to enlargement of the upper dome of the tear sac. However, a small amount of exophthalmos was apparently present at this * Figures 5, 6, 7 and 8 are reproduced with per mission of the American Journal of Radiology from the previous report of this case.
Fig. 6* (Sanders). Case 2. Skin biopsy, showing diagnostic lesion with one Touton giant cell in center of field.
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Fig. 7* (Sanders). Case 2. Lesion from the apex of orbit, showing similar histologie findings.
Fig. 8* (Sanders). Case 2. Bony invasion by the characteristic tissue.
The patient was first seen by me on November 27, 1964. A curved, well-healed incisional scar was seen in the upper nasal aspect along the orbi tal brim. No mass could be noted, nor was any exophthalmos present. However, the globe seemed to be displaced downward about two mm. There also was some apparent limitation of upward gaze. The globe itself was normal. No skin le sions were present on the body surface. The pa tient was again seen by me on April 12, 1965 (fig. 10), with apparently very little change in the condition, except that there was probably less displacement of the eye. At this time a slight left hypotropia was apparent. As will be noted, some striate muscle was seen in some of the sections so possibly there was involvement of the superior rectus. Section consisted of a diffuse infiltrating le sion made up almost entirely of histiocy'tes (fig. 11). Throughout the lesion, there were many teu ton giant cells. There was some infiltration of or bital fat and, in one area, some involvement of striate muscle was noted. A diagnosis of "xanthoma" had originally been made by the local surgi cal pathologist. However, it was felt that the le sion was consistent with juvenile xanthogranuloma. This diagnosis was substantiated by Drs. L. E. Zimmerman and E. R. Helwig of the Armed Forces Institute of Pathology. DISCUSSION
Fig. 9 (Sanders). Case 2. Appearance three years after operation.
It has long been recognized that juvenile xanthogranuloma of the skin is a disease of infants and very young children. This is also apparently true of the intraocular le sion. In my series of 20 iris lesions, 17 of the patients were under one year of age. In Zimmerman's recent report 85% of his pa-
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T. E. SANDERS
Fig. 10 (Sanders). Case 3. Appearance six months after operation.
tients with iris involvement were under one year of age and 64% were under the age of seven months. In every one of the three pa tients here reported, the lesion was first noted when the child was less than three months of age. This is also true in the three additional cases reported by Zimmerman.12 Apparently the orbital lesion occurs at as young an age as any of the manifestations of juvenile xanthogranuloma. This suggests that the descriptive term infantile in this condition is preferable to juvenile. Unilateral exophthalmos in a very young infant is an unusual condition, the most common causes being dermoid cyst and hemangioma. In the very rare case of teratoma
of the orbit, the exophthalmos may be mas sive. In Case 2, the skin lesions were pres ent and were shown to be juvenile xantho granuloma by biopsy. This suggested a pre sumptive diagnosis of juvenile xanthogran uloma in the orbit, which was verified by biopsy. In the other two cases in which an anterior palpable mass was present, a biopsy was necessary to establish the diagnosis. As suggested by the experience with the iris le sions, it is possible that some of these orbi tal lesions in infants have been misdiagnosed and unrecognized. Therefore, in any unilateral exophthalmos in an infant, partic ularly if a palpable mass is present, the pos sibility of juvenile xanthogranuloma as being the underlying lesion should be con sidered. About one half of the known cases of in traorbital juvenile xanthogranuloma involve extraocular muscle. Two of the cases re ported by Zimmerman were described as being "wrapped around a rectus muscle"— the inferior rectus in one and the medial rectus in another. My Case 3 showed in volvement of both the internal and the supe rior rectus muscles, with some residual par esis of the superior rectus. Paresis of the
Fig. 11 (Sanders). Case 3. His tologie appearance of the lesion, showing Touton giant cells. r" >>'
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XANTHOGRANULOMA OF THE ORBIT
muscles in this condition could be either due to primary involvement of the muscle with disease or damage to the muscle during re moval of the lesion. It is possible that mus cle involvement may be one of the most im portant complications of the condition. Case 2 is unique in two respects: the presence of the skin lesion and the involve ment of bone. In my series of iris cases,11 skin lesions were present in eight of the 20 cases, and absent in only three in which they were searched for; the possibility of their being ignored in the early unrecognized cases is evident. As the skin manifestations were present in only one of six cases with orbital involvement, it is possible that the patients with orbital lesions are less likely to manifest skin lesions. This makes the diag nosis of the orbital lesion more difficult. This case is also apparently the only known instance of bone involvement. No other known case of bony involvement ap pears in any of the several hundred cases in the dermatologie literature.7'12 From the in formation obtained by roentgenographic study, orbital exploration and histologie ex amination, it is impossible to determine the exact site of origin of the lesion in this case. It is possible that it could have arisen pri marily in the orbital tissue, in the bony wall of the orbit or, less likely, in the méninges, with secondary involvement of the other structures. The roentgenographic findings in this case were most unusual but not diag nostic. These findings were considered to be worthy of a report in the radiologie litera ture which appeared some months ago.15 Juvenile xanthogranuloma is a disease the exact nature of which is unknown. In the early ophthalmologic reports, it was in cluded in the histiocytosis X group.9·10 In reviewing my 20 cases of iris involvement, I stated : "It is probably a unique disease, this idea being supported particularly by Helwig and Nomland."11 Zimmerman12 in his recent review of the disease, also holds with this concept. The intraorbital cases, both from their histologie appearance and from their
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clinical course, contribute additional support to this view. Some specific reasons stated previously for this belief still seem to be true: 1. Although similar, there is probably some distinct and diagnostic histologie differences be tween the skin lesion of nevoxanthoendothelioma and the reticuloendothelioses. 2. Iris lesions such as seen in nevoxanthoen dothelioma have not been reported in the reticuloendotheloses. 3. The lack of transition forms between the histiocytosis X group and nevoxanthoendothelioma. No case of nevoxanthoendothelioma has been re ported which has merged into the other group. 4. The apparent lack of visceral lesions other than of the iris is characteristic of nevoxan thoendothelioma, while the lesions of the reticu loendothelioses tend to be multiple. As noted, it is possible that visceral lesions of nevoxanthoen dothelioma are not determined in the absence of autopsy. 5. The benign course of nevoxanthoendothelioma with spontaneous regression is quite different than the severe course, often fatal, of the reticuloen dothelioses." TREATMENT
Therapy of the skin lesions is obviously unnecessary because of the tendency to re gress spontaneously, leaving a small atro phie scar. Several of the first patients with iris involvement had enucleation because of the mistaken diagnosis of iris tumor. Even the first patients who were correctly diag nosed clinically went on to loss of the globe from severe secondary glaucoma. Later radiation therapy was shown to be effective in the control of the iris lesions.16-18 Recent ly, topical steroid therapy has been reported19 to be effective, but this is con trary to my experience.11 Although the iris lesion is usually diffuse, in localized lesions excision has been reported to be effective.19'20 In all three of the present orbital cases, there apparently has been complete recovery from the orbital lesion following soft tissue removal at orbital exploration. However, in Case 1, a total of 400 r was given postoperatively; however, the patient in Case 3 has had no radiation. In Case 2, most of the original soft
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tissue and involved bone were apparently removed at the original operation. Over two years later, a new osteolytic lesion was noted. Radiation of the orbit was done, giv ing a total dose of about 1800 r. After one year, the lesion was unchanged but no addi tional lesions were noted. From my limited experience in the man agement of this disease, obviously no defini tive treatment can be suggested. However, since surgical exploration is necessary for diagnosis, most of the soft tissue lesion should be removed, avoiding injury to the surrounding structures, particularly extraocular muscle. Postoperative radiation, using a small amount, is probably desirable. In my Case 2, immediate postoperative radiation might have prevented the additional bony in volvement. SUMMARY
Three cases of infantile xanthogranuloma of the orbit are reported. One case seems unique in that skin lesions were present as well as bone involvement ; the other two were characterized by lesions of the orbital soft tis sue. Involvement of the extraocular muscles, with residual paresis, is an important aspect of the condition. In each case, the original manifestations of the disease were first noted under the age of three months. In any unilateral exophthalmos in an infant, the possibility of this condition should be con sidered. The two patients without bone in volvement recovered completely after surgi cal removal of the lesion. The soft tissue le sion in the patient with bone involvement was also cured by surgical removal but the bone involvement persisted despite radiation therapy. 100 North Euclid Avenue
(63108).
REFERENCES 1. McDonagh, J. R. E. : Spontaneous disappear ance of endotheliomata (naevo-xanthoma), Brit. J. Derm. 21:2S4, 1909. 2. ■ : A contribution to our knowledge of
the naevo-xantho-endotheliomata. Brit. J. Derm. 24 :8S, 1912. 3. Adamson, H. G. : A note on multiple erup tive xanthoma in infants : naevo-xanthoendothelioma (McDonagh). Brit. J. Derm. 48:366, 1936. 4. Senear, F . E., and Caro, M. R. : Nevoxantho-endothelioma or juvenile xanthoma. Arch. Derm. 34:195, 1936. 5. Nomland, R. : Nevoxantho-endothelioma : a benign xanthomatous disease of infants and chil dren. J. Invest. Derm. 22 :207, 1954. 6. Helwig, E. B., and Hackney, V. C. : Juven ile xanthogranuloma (nevoxantho-endothelioma) Am. J. Path. 30:625, 1954. 7. Fleischmajer, R., and Hyman, A. B. : Juve nile giant cell granuloma (Nevoxanthoendothe lioma). In Fleischmajer, R. : The Dyslipidoses. Springfield, 111., Thomas, 1960, chap. 18, pp. 329-372. 8. Blank, H., Eglick, P. G., and Beerman, H. : Nevoxanthoendothelioma with ocular involvement. Pediatrics, 4:349, 1949. 9. Maumenee, A. E. : Ocular lesions of nevo xanthoendothelioma (infantile xanthoma disseminat u m ) . T r . Am. Acad. Ophth. Otolaryng. 60:401, 1956. 10. Newell, F . W . : Nevoxanthoendothelioma with ocular involvement : A report of two cases. Arch. Ophth. 58:321,1957. 11 Sanders, T. E. : Intraocular juvenile xantho granuloma (nevoxanthogranuloma) : A survey of 20 cases. Tr. Am. Ophth. Soc. 58:59, I960; Am. J. Ophth., 53 :455, 1962. 12. Zimmerman, L. E. : The ocular manifesta tions of juvenile xanthogranuloma (nevoxan thoendothelioma). Tr. Am. Acad. Ophth. Otolar yng. 69:412, 1965. 13 Cogan, D. G., Kuwabara, T., and Parke, D. : Epibulbar nevoxanthoendothelioma. Arch. Ophth. 59:717, 1958. 14. Sanders, T. E., and Miller, J. E . : Infantile xanthogranuloma of the orbit: Report of a case. Tr. Am. Acad. Ophth. Otolaryng. 69:458, 1965. 15. Stapel, T. W , McAllister, W. H., Sanders, T. E., and Miller, J. E. : Juvenile xanthogranuloma of the orbit; report of a case with bony destruc tion. Am. J. Radiol. 91:629, 1964. 16. Hedges, C. C., Jr. : Nevoxanthoendothelioma of the eye treated with superficial X-ray therapy. Am. J. Ophth. 47 :683, 1959. 17. Maumenee, A. E., and Longfellow, D. W. : Treatment of intraocular nevoxantho-endothelioma (juvenile xanthogranuloma). Am. J. Ophth. 4 9 : 1 , 1960. 18. Cleasby, G. W . : Nevoxanthoendothelioma (Juvenile xanthogranuloma) of the iris: Diagnosis by biopsy and treatment with X-ray. Arch. Ophth. 66 :26, 1961. 19. Gass, J. D. M. : Management of juvenile xan thogranuloma of the iris. Arch Ophth. 71:344, 1964. 20. Howard, G. M. : Spontaneous hyphema in childhood. Arch. Ophth. 68 :621, 1962.