What’s Your Diagnosis?
|WE GET A LOOK. Hertel exophthalmometry showed measurements of 18 mm in the right eye and 20 mm in the left eye. Motility on the left showed a reduction in abduction and elevation (Fig. 1). An MRI exam of the brain with and without contrast revealed an enhancing mass, 3 x 3 x 2 cm, in the superior/temporal left orbit that extended into the anterior cranial fossa (Fig. 2).
|FURTHER WORKUP. The histopathological evaluation provided some clues. Photomicrograph shows Langerhans cells with characteristic indented nuclei (arrow) and histiocytic cells admixed with eosinophils, neutrophils and lymphoplasmacytic cells (Fig. 3A). Immunohistochemical staining was strongly positive for CD1a (Fig. 3B).
Langerhans cell histiocytosis (LCH), formerly known as “histiocytosis X,” historically includes three subgroups: eosinophilic granuloma, Hand-Schüller- Christian disease and Letterer-Siwe disease, representing a spectrum from unifocal to multifocal/multisystem involvement. The lesions of LCH may involve the bones, skin, hypothalamus-pituitary region, as well as other organs. While the characteristic granuloma-like lesions of LCH consists of Langerhans cells, macrophages, eosinophils, T lymphocytes and plasma cells, it is thought that clonal expansion of defective immature Langerhans cells is the key pathogenetic element.2
Epidermal Langerhans cells were first described by the German physician Paul Langerhans in 1868. Because the branched cells demonstrated an affinity for gold chloride (a stain for nervous tissue) the cells were thought to be of neural origin. The hematopoietic origin and antigen-presenting function of the dendritic cells would remain unknown for more than a century.3
In 2010, LCH remains an enigmatic disease, and the dispute over its neoplastic vs. reactive nature is unsettled. The current understanding of histiocyte development is based on in vitro studies and suggests that an immune/inflammatory reaction leads susceptible Langerhans cells to undergo a clonal expansion resulting in LCH.2
Incidence. LCH is predominantly a disease of childhood with a peak incidence between 1 and 4 years. Children less than one year tend to have more aggressive disease with a worse prognosis. 4 LCH has an estimated annual incidence of 2 to 5 in one million children and represents approximately 1 to 3 percent of pediatric orbital tumors.2,5 In a retrospective chart review of 24 consecutive patients with LCH treated at a tertiary referral center, the orbit was involved in nine (37.5 percent) patients. The most common site of involvement was the frontal (n = 6) followed by zygomatic (n = 3), sphenoid (n = 3) and maxillary (n = 2) bone.4
Histology/diagnosis. The histological diagnosis of LCH lesions is based on staining for S-100 protein and CD1a antigen or finding Birbeck granules (shaped like tennis rackets) on electron microscopy. Further histological examination explains the osteolytic potential of the lesions. Pathologic Langerhans cells have been shown to elaborate cytokines, including IL-1, which is an osteoclast-activating factor, and prostaglandin E2, which induces bone resorption. In addition, osteoclast- like multinucleated giant cells have been shown in the bony lesions of LCH.2,6
Prognosis. LCH represents a spectrum from the benign unifocal bone lesion to aggressive multisystem disease. In a large cohort study of 314 Mayo Clinic patients with histologically proven LCH, 111 of 114 (97 percent) of patients with isolated bone LCH lesions achieved disease-free survival after treatment. The proportion of patients achieving disease-free survival was significantly less in patients with multisystem disease vs. single system disease (74 vs. 91 percent; p < 0.003; 95 percent CI, 0.26 and 0.08).7 While isolated LCH of the orbit is thought to be a relatively benign condition responsive to limited local treatment, it should be noted that in a recent retrospective study by Vosoghi and colleagues, seven of nine patients with unifocal bone disease progressed to multifocal bone disease during follow-up, including two patients with unifocal orbital disease. Even though these results may be inflated due to a strong referral bias, the study highlights the possible progression of unifocal bone disease and the importance of a comprehensive workup and follow-up.4
Management and treatment. All patients with unifocal orbital disease require a biopsy to establish the diagnosis and rule out other malignant disease. Patients should be referred to a pediatric oncologist for a comprehensive systemic evaluation and ongoing follow-up in order to monitor for recurrence or progression. Single-system disease confined to a single site (e.g., small orbital lesions without intracranial extension) usually only requires local therapy (e.g., curettage, steroid injection or radiation therapy) or observation. On the other hand, multifocal disease usually requires systemic therapy with prednisone with or without chemotherapeutic agents (vinblastine and/or etoposide) depending on the extent of the disease.4
Our Patient’s Case
Our patient received prednisone and vinblastine due to concern regarding multisystem involvement (bone and lymph nodes as well as orbit and brain). He has done well and is disease-free at his six month follow-up visit.
* Patient name is fictitious.
1 Hurwitz, C. A. and W. C. Faquin. N Engl J Med 2002;346:513–520.
2 Savasan, S. Int J Dermatol 2006;45:182–188.
3 Namazi, M. R. Arch Dermatol 2008;144:1109.
4 Vosoghi, H. et al. Ophthal Plast Reconstr Surg 2009;25:430–433.
5 Castillo, B. V. and L. Kaufman. Pediatr Clin North Am 2003;50:149–172.
6 Harris, G. J. Am J Ophthalmol 2006;141:374–378.
7 Howarth, D. M. et al. Cancer 1999;85:2278–2290.
Dr. Hester is a resident at the California Pacific Medical Center (CPMC) in San Francisco. Dr. Silkiss is chief of oculofacial plastic, reconstructive and orbital surgery at CPMC.
Grand Rounds in Chicago
Attend Grand Rounds: Cases and Experts From Across the Nation, event code “Sym17.” Several academic programs will be sending residents to present some of the most intriguing cases that have been discussed at their grand rounds. A panel of experts will analyze each case. This free symposium takes place Monday, Oct. 18, from 8:30 to 9:30 a.m. in Room S102abc.