Histiocytosis-X1 consists of three diseases of unknown etiology and includes Letterer-Siwe disease, Hand-Schuller-Christian disease, and eosinophilic granuloma of bone. Classification generally is based on the clinicopathologic course.
Frequently fatal, Letterer-Siwe disease is an acute process occurring in infancy or early childhood and is characterized clinically by fever, hepatosplenomegaly, skin rash, lymphadenopathy, and anemia. Organs involved in hematopoiesis such as liver, spleen, bone, and lymph nodes are infiltrated by inflammatory cells and histiocytes which are nonlipid-storing macrophages.
Ocular involvement predominantly affects the choroid although the retina, vitreous, anterior uvea, anterior chamber, and optic nerve sheaths maybe infiltrated by histiocytes.
This report describes the fundus appearance and fluorescein angiographic characteristics of a choroidal mass in a five-year-old girl with Letterer-Siwe disease,
At age three months, a female infant was admitted to the University of Iowa Hospitals with a five-day history of fever to 38.9 C and a skin rash. Physical examination revealed a temperature of 38.2 C. Generalized lymphadenopathy and marked hepatosplenomegaly were present. Scattered papulovesicular skin lesions approximately 2-3 mm in diameter were present over most of the body. The ocular fundi were recorded as normal, although the pupils were not dilated with mydriatics.
Laboratory data included hemoglobin of 8.9 mg percent, white cell count of 2,800 per cm m and platelet count of 8,800 per cmm. Decreased platelets, plentiful megakaryocytes, and increased phagocytic histiocytes were observed on bone marrow examination. Roentgenogram examination revealed lytic lesions in the skull, right humerus and left femur.
A skin biopsy was interpreted as histiocytosis with characteristic infiltrate of histiocytes in the upper dermis (Fig. 1).
Treatment consisted of systemic prednisone followed by two courses of vincristine sulfate which resulted in rapid resolution of the clinical findings. The patient remained in remission until the age of five when she was found on routine school screening to have reduced vision in her left eye and was referred again to the University of Iowa Hospitals.
Her visual acuity measured 6/7.5 in the right eye and 6/1 20 in the left eye. Her eyes were Orthophorie on Hirschberg examination. An afferent pupillary defect was present on the left. A cycloplegic refraction yielded +0.50 sph = +.75 cyl ? 1 80° on the right and +.75 sph = +1.00 cyl ? 180° on the left.
Examination of the right eye was normal. In the left eye the anterior segment examination was normal. In the left macular region there was a flat choroidal mass with an overlying neurosensory detachment extending to the temporal margin of the disc <Figs. 2 and 3). Cystic spaces were present in the foveal retina. The pigment epithelium was disrupted irregularly over the choroidal lesion.
The optic nerve head appeared slightly pale. The nasal margin of the optic disc was normal.
Echography of the left posterior pole revealed a 1 .75 mm elevated, partially solid disciform-like lesion consistent with a vascularized choroidal mass. The left optic nerve was noted to be minimally thickened as compared to the right.
During the early arteriovenous phase of the fluorescein angiogram, the temporal peripapillary region and choroidal mass were hyperfluorescent, suggesting prominent vascularity of the mass and atrophy of the overlying retinal pigment epithelium (Figs. 4 and 5). Leakage of fluorescein into the subretinal space, intense tissue staining of the choroidal mass, cystoid macular edema and staining of the optic nerve head were present during the late phase (Figs. 6 and 7).
Letterer-Siwe disease has been shown in pathology specimens to involve every part of the eye except the lens. Proptosis due to orbital involvement has been described.14'
Fig. 1. Punch biopsy of skin lesion. Upper dermis contains vacuolated histiocytes with eosinophilic cytoplasm and oval or indented nuclei, (hemotoxylin and eosin, original magnification x200)
Fig. 2. Fundus photograph of left eye. A neurosensory detachment extends between the temporal vascular arcades to the optic disc. The temporal retinal vessels are blurred because the surface of the detached retina is anterior to the plane of focus. The retinal pigment epithelium is atrophic along the temporal disc margin. The choroidal vascular pattern is obscured temporally by the detachment.
Fig. 3. Fundus photography of left eye. Confluent cystic spaces are present in the 1 ? ve al region (arrow) with underlying pigment epithelial disruption.
Fig. 4. Fundus fluorescein angiogram. During the early arteriovenous phase (13 sec) there is hyperfluorescence of the choroidal lesion and along the temporal margin of the optic disc. Fluorescence from the optic nerve head tissue appears normal. The parafoveal capillary net is abnormal with irregular margins and discontinuous blunted vessefs.
Fig. 5. Fundus fluorescein angiogram. During the arteriovenous phase (25 sec) the super otempor al portion of the choroidal infiltrate demonstrates hyperfluorescence.
Fig. 6. Fundus fluorescein angiogram. During the late venous phase (3 1/2 min) there is progressive staining of the optic nerve head and early cystoid staining at the fovea (arrow).
Ocular involvement tends to be generalized. Heath3 reported exophthalmos, papilledema, and fundus exudates during the terminal illness of a three and one-half year-old boy. At autopsy the globe showed histiocytic infiltration of the sclera, retina, vitreous, and walls of the ciliary vessels. There was lymphocytic accumulation in the choroid and edema of the optic nerve.
Most reports include choroidal involvement. A thrêe-month-old girl reported by Rupp and Holloman5 had a spontaneous hyphema, iris nodules, and a hypopyon. At pathology, histiocytes were found in the corneal stroma, trabecular meshwork, iris, ciliary body, and choroid. The retina and optic nerve head were edematous.
Lahav and Albert*" described a seven-day-old boy with histiocytic infiltration of the iris, ciliary body, choroid and meninges of the optic nerve. The retina was detached over areas of choroidal infiltrates with an eosinophilic subretinal exudate.
A 16-month-old boy with papilledema and uveitis was reported by Peterson and Kuwabara.7 Histiocytes were contained in the subretinal space, vitreous, anterior chamber, iris, ciliary body, and trabecular meshwork. The choroid and inner retina, which showed no degenerative change, were infiltrated by lymphocytes. An edematous optic nerve contained lymphocytes. The retinal pigment epithelium was separated in several areas from Bruch 's membrane by masses of lymphocytes.
Mittleman, Apple, and Goldberg8 described a corneal button from a 17-year-old girl with a history of Letterer-Siwe disease and bilateral perforating corneal ulcers, There was no evidence of Letterer-Siwe disease in the recipient cornea. The donor eye from a threeyear-old boy with Letterer-Siwe disease showed histiocytic infiltration of the choroid. Bruch's membrane and the retinal pigment epithelium were normal, but the overlying retina was degenerated. The optic nerve head was edematous.
Zimmerman9 described three autopsy eyes with histiocytic choroidal infiltrates. One globe had anterior uveal involvement, but not as prominent as the posterior uveal infiltrate.
Although not clinically evident in our patient, late disc staining on fluorescein angiography indicates optic nerve edema secondary to lymphocytic infiltration of the nerve or histiocytic infiltration of the optic nerve sheaths.
Fig. 7. Fundus fluorescein angiogram. During the late phase (1 1 min) there is subretinal accumulation of fluorescein, intense tissue staining of the choroidal mass and cystoid macular edema (arrow}.
A five-year-old child with Letterer-Siwe disease in remission was found to have decreased vision in one eye produced by a choroidal mass and secondary retinal detachment with cystic degeneration. Echography confirmed a vascularized disciform -like mass with possible involvement of the optic nerve, Fluorescein angiography showed a well vascularized, intensely staining lesion, with optic disc edema, destruction of the retinal pigment epithelium and cystoid macular edema.
1. Lichenstein L: Histiocytosis X: integration of eosinophilic granuloma of bone, "Letterer-Siwe disease," and "Schuller-Christian disease," as related manifestations of a single nosologic entity. Arch Pathol 56:84, 1 953.
2. Mortada A: Nonlipoid and lipoid retiçuloendotheliosis of orbital bones. Am J Ophthalmol 61:558, 1966.
3. Heath P: The ocular features of a case of acute reticuloendotheliosis (Letterer-Siwe type), Trans Am Ophthalmol Soc 57:290, 1959,
4. Pearlstone AB, Flom L: Letterer-Siwe's disease. J Pediatr Ophthalmol 7(2): 103, 1970.
5. Rupp RH, Holloman KR: Histiocytosis-X affecting the uveal tract. Arch Ophthalmol 84:468, 1970.
6. Lahav M, Albert DM: Unusual ocular involvement in acute disseminated Histiocytosis-X. Arch Ophthalmol 91:455, 1974.
7. Peterson RA, Kuwabara T: Ocular manifestations of familial lymphohistiocytosis. Arch Ophthalmol 79:413, 1968.
8. Mittleman D, Apple DJ, Goldberg MF: Ocular involvement in Letterer-Siwe disease. Am J Ophthalmol 75:261, 1973.
9. Zimmerman LF; Ocular lesions of juvenile xanthogranuloma: nevoxanthoendothelioma. Trans Am Acad Ophthalmol Otolaryngol 69:412, 1965.