Bilateral Sequential Orbital Involvement by Eosinophilic Granuloma

Langerhans cell histiocytosis is an uncommon, multisystem disease with a clinical spectrum that includes benign unifocal disease (eosinophilic granuloma), chronic multifocal disease (Hand-Schüller-Christian disease), and acute or subacute fatal disseminated disease (Letterer-Siwe disease).¹ It accounts for 1% to 7% of biopsied orbital tumors.² Eosinophilic granuloma is the most common variant of Langerhans cell histiocytosis, with approximately 20% of cases affecting the orbital area.² When it occurs in the orbit, it is usually unilateral and localized. We are unaware of a previously reported case of eosinophilic granuloma with bilateral orbital involvement, and a computerized literature search using Medline disclosed no other examples. We herein report a case of eosinophilic granuloma that exhibited sequential bilateral orbital involvement.

In November 1988, a 5-year-old otherwise healthy boy was referred to us for evaluation of left eyelid swelling and proptosis that had developed over 1 month (Figure 1A). He had been diagnosed elsewhere as having allergic eyelid edema, and he had been treated with topical corticosteroids with no response. There was a history of head trauma 3 months earlier that caused bilateral eyelid ecchymoses, and spontaneous healing occurred.

Ocular examination disclosed visual acuity of 20/20 OU. There was 5 mm of left axial proptosis without palpable mass. Computed tomography (CT) showed an orbital mass with a heterogeneous internal structure in the lateral wall of the left orbit and temporal fossa, with erosion of the frontal and zygomatic bones (Figure 1B). Incisional biopsy findings revealed a dark brown mass consistent with degenerated blood. Histopathologic examination showed clotted blood that contained eosinophils, histiocytes, and small multinucleated giant cells (Figure 1C). These findings suggested the diagnosis of either giant cell reparative granuloma or Langerhans cell histiocytosis. The bone defect closed spontaneously without treatment in 8 months.

In June 1990, 18 months after initial examination, the boy developed painful, nonerythematous swelling of his right upper eyelid. The CT findings disclosed a similar lesion in the superolateral aspect of the right orbit with destruction of frontal bone and extension into the brain and temporal fossa. The mass contained densities consistent with fragments of bone. The previously affected left orbit appeared normal (Figure 2). Incisional biopsy of the right orbital mass was performed, and dark black tissue consistent with degenerated blood was observed intraoperatively. Histopathologic examination showed hemorrhagic tissue with small multinucleated giant cells, large histiocytes with folded nuclei, eosinophils, and fibrosis. The histiocytic cells showed intense positive immunoreactivity for S-100 protein, supporting the diagnosis of eosinophilic granuloma in the right orbit. After 6 months' follow-up, the second lesion healed spontaneously without further therapy. At 93 months' follow-up, the patient remains healthy without systemic problems.

Eosinophilic granuloma is a rare disease that is classified as a variant of Langerhans cell histiocytosis. It is generally diagnosed in children or young adults and shows a predilection for males.¹ In the orbit, it typically manifests as a painful, tender, erythematous swelling near the superolateral part of the orbit anteriorly. In more posteriorly located tumors, eyelid swelling or proptosis can be the first sign. Computed tomography is the most helpful diagnostic test and shows an irregular, serrated osteolytic lesion with sclerotic margins. Histopathologic evaluation displays a proliferation of large histiocytic cells with folded nuclei consistent with Langerhans cells with interspersed eosinophils and small multinucleated giant cells. The histiocytic cells show a positive immunoreactivity for S-100 protein, CD1 (OKT6) antigen, and α-1 antichymotrypsin. Electron microscopy demonstrates intracytoplasmic Birbeck granules corroborating the diagnosis of Langerhans cell histiocytosis.¹ In the orbit, the differential diagnosis in children includes dermoid cyst, lacrimal gland tumor, primary bone tumors such as osteosarcoma, aneurysmal bone cyst, ossifying fibroma, fibrous dysplasia, and metastatic tumors, such as neuroblastoma and Ewing sarcoma.

In the orbit, in contrast to eosinophilic granuloma, dermoid cyst is a round to ovoid lesion with a well-defined, enhancing thin wall and nonenhancing contents on CT evaluation. Epithelial tumors of the lacrimal gland (except adenoid cystic carcinoma) rarely affect young children and generally cause bone fossa formation rather than a large bone defect that reflects an epicenter of the lesion in the bone. Primary bone tumors do not exhibit the characteristic lytic lesion with sclerotic margin of eosinophilic granuloma on CT scan. Metastatic orbital tumors show the irregularly shaped bony defects, usually occurring late in the course of neuroblastoma or Ewing sarcoma, and systemic evaluation almost invariably reveals the primary tumor.

In a recent study, Lieberman et al³ suggested using the term Langerhans cell (eosinophilic) granuloma instead of Langerhans cell histiocytosis and classified it further into unifocal and multifocal eosinophilic granuloma. In a survey of 238 cases of eosinophilic granuloma from the general pathology laboratory in a cancer center, multifocal eosinophilic granuloma was found in 85 cases (36%) at the time of diagnosis.³ Of these cases, 63% involved only bones (n = 53), 24% involved both bone and soft tissue (n = 20), and 14% involved only soft tissue (n = 12). The involved bone included skull (52%), femur (29%), and rib (22%). Soft tissue involvement included skin (14%), lymph node (13%), and lung (11%). Another review of 348 cases treated in multiple pediatric hematology/oncology departments revealed that isolated bone lesions were mostly unifocal or bifocal in 39% of cases and multifocal in 19% of cases.⁴ Different from unifocal eosinophilic granuloma, multifocal eosinophilic granuloma usually has bimodal distribution and one peak between the ages of 0 to 10 years and the other between the ages of 20 to 30 years. Bilateral sequential orbital involvement, as seen in our case, is highly unusual, if not unique.

The treatment of eosinophilic granuloma may include surgical curettage, low dose irradiation, administration of cytotoxic agents, systemic corticosteroids, or intralesional corticosteroids.⁵ In some cases, initial biopsy followed solely by observation is curative, leading to spontaneous resolution of the inflammatory mass as occurred in our case.⁶ The systemic prognosis of patients with unifocal eosinophilic granuloma and multifocal eosinophilic granuloma limited to bone is excellent.³ In a review of 348 cases treated in pediatric hematology/oncology departments, the survival rate was 96% to 100% at 7 years in patients with eosinophilic granuloma limited to bone.⁴ However, in some cases, local recurrence of the lesion is observed between 6 and 18 months.³ In our case, there has been no recurrence or progression to disseminated disease after 8 years. The multivariate prognostic analysis in 348 cases showed that organ involvement, age younger than 1 year, and failure responding to therapy wereassociated with a bad prognosis.⁴ In our case, none of these factors were present.

This study was supported in part by the Paul Kayser International Award of Merit in Retina Research, Houston, Tex (Dr J. Shields), Macula Foundation, New York, NY (Dr C. Shields), the Noel T. and Sara L. Simmonds Endowment for Ophthalmic Pathology, Wills Eye Hospital (Dr Eagle), and the Eye Tumor Research Foundation, Philadelphia, Pa (Dr C. Shields).

Corresponding author: Carol L. Shields, MD, Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.