Eosinophilic Granuloma

Mark Levine, MD · Meena D. Chaudhary, MD · Amarpreet Singh, MD

Introduction

Langerhans first described dendritic cell histopathology in 1868. Eosinophilic granuloma is part of a spectrum of histiocytic disorders. These disorders were originally named histiocytosis X in 1953 by Lichtenstein, but were reclassified as Langerhans cell histiocytosis (LCH) in 1987.¹ This classification included Letterer-Siwe (acute disseminated disease), Hand-Schuller-Christian syndrome (multifocal LCH with the triad of lytic bone lesions, diabetes insipidus, and proptosis), and unifocal eosinophilic granuloma. This tutorial focuses on unifocal eosinophilic granuloma. The preferred terms today are unifocal or multifocal granuloma of bone and diffuse soft-tissue histiocytosis.²

Unifocal eosinophilic granuloma is at the benign end of the spectrum and is attended with no mortality, which is in contrast to multifocal and diffuse histiocytosis, which affect bone, skin, lymphoid tissue, lungs, gastrointestinal tract, and the brain, and cause significant mortality.

Most cases occur in patients between birth and 20 years of age with the oldest reported patient being 51 years old. The majority of children develop clinical symptoms prior to age 5. Eosinophilic granuloma is exceedingly rare, representing one case of 645 biopsies performed at Wills Eye Hospital and one case of another series of 250 patients.³ NCI Surveillance, Epidemiology, and End Result data predict an incidence of 1.5 children per million between the ages of 0 and 4. One cluster of three cases in Arizona, representing 40 children per million, suggests an environmental trigger.⁴ United States statistics indicate incidence of 2 to 5 children per million.⁴

Pathogenesis

In children, Langerhans cells arise from the pluripotent stem cells and are located in the bone marrow at the age when these lesions arise within the active bone marrow.² Histiocyte stem cells are influenced by cytokines differentiating along several paths. Appropriate regulation leads toward normal Langerhans cells, while dysregulation leads to an abnormal collection of cells. In adulthood, normal Langerhans cells migrate to skin, mucous membranes, and visceral sites, functioning as antigen processing cells. Once they have encountered antigen, they travel to lymph nodes and present to T cells. Any immune or cytokine dysregulation of this process leads to accumulation of the monoclonal Langerhans cells, forming the eosinophilic granuloma. Proposed inciting etiologies include transient ones, e.g., HSV-6 (herpes simplex virus) or environmental toxins and, perhaps, more sustained triggers in the diffuse histiocytoses, e.g., genetic or neoplastic. Other authors have postulated a deficiency of suppressor T-cell function, increase in GM-CSF (granulocyte-macrophage colony stimulating factor), and abnormal cell adhesion molecules.¹ Uncommon associations with HLA BW-61 (54%) and CW-7 (2% over control) have been reported.⁴

The signature diagnostic features of Langerhans cells, in distinction to the non-Langerhans histiocytoses are the presence of CD1a (OKT-6), S-100, and Birbeck granules.¹ Although the cells are monoclonal, they are benign and produce IL-1 and PGE2, which are responsible for stimulating osteolysis.² The morbidity of Langerhans cell histiocytosis results from mass effect of the proliferating Langerhans cells within multiple organ systems.

Clinical Presentation

Eosinophilic granuloma generally occurs in the first two decades of life with peak incidence at ages 1 to 3 years. Patients may have upper lid ptosis, swelling, erythema and edema, along with proptosis and pain (Slide 1, Slide 2). Orbital involvement can mimic preseptal cellulitis and nasolacrimal duct obstruction. It appears to be more common in males, although female patients have been described. Bony lesions are reported in 80% to 100% of patients and most often involve the frontal bone or orbital roof, sphenoid and, rarely, the ethmoid bone.² The bony lesion may extend into adjacent soft tissue and central nervous system (CNS) structures. Hypothalamic, pituitary, frontal and temporal lobe involvement has been reported in up to 16% of cases.⁴

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Differential diagnosis of lid edema, erythema, and proptosis includes orbital cellulitis, neuroblastoma, Ewing sarcoma, Wilms tumor, rhabdomyosarcoma, neurofibroma, inflamed dermoid, bone cyst, giant cell granuloma (Brown tumor), osteomyelitis, and fibrous dysplasia.

Diagnostic Features

Computed tomography (CT) scans show osteolytic bone lesions with sclerosis, classically in the superotemporal orbit. However, this is not specific, as metastatic orbital tumors also have a predilection for the superotemporal orbit. A presumptive diagnosis can be made with typical appearance on hemoglobin and eosin (H&E) of Langerhans-type histiocytes and eosinophils with scattered lymphocytes (Slide 3), along with S-100, which stains in 60% of patients.⁴

A definitive diagnosis requires demonstration of CD 1a (Slide 4) or, in 47% of patients, Birbeck granules may be found on electron microscopy (Slide 5). Diagnosis is also made with two or more of the less specific markers, including S-100, adenosine triphosphatase, alpha-mannosidase or peanut lectin.

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Evaluation And Treatment

• Unifocal disease, even if there is massive adjacent extension, portends a good prognosis, unlike multifocal disease. Thus, it is essential to thoroughly search for other foci of disease in conjunction with a pediatric oncologist. Standard workup includes CBC with differential, hemoglobin, hematocrit, platelet count, PT/PTT/INR, chest radiograph and bone survey. In preschool-aged children, urine osmolarity should be obtained to check for diabetes insipidus. Magnetic resonance imaging (MRI) can reveal CNS disease. Management is also determined by the focality of disease. Incisional, open (Slide 6) or diagnostic excisional biopsy with frozen section or needle biopsy are used to obtain tissue. Eosinophilic granuloma may be watched, as case reports of spontaneous resolution have been reported.⁵ Glover and Grove⁵ reported a 13-year-old boy whose lesion resolved after incisional biopsy without further treatment. Furthermore, his bony lesion reossified normally. However, this is unusual.

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The following are the four basic modes of therapy:

1. Simple curettage
2. Curettage with intralesional steroids
3. Radiation
4. Chemotherapy

Curettage of orbital lesions alone or with injection of 125-mg methylprednisolone has been successful for painful bony lesions (Slide 7, Slide 8, Slide 9). Yasko and colleagues⁶ reported 100% resolution of symptoms and a resolution of lesion in 89% of patients with a single dose of intralesional corticosteroid. They studied eosinophilic granuloma in the axial and appendicular skeleton and found that 100 mg to 150 mg of intralesional methylprednisolone alone with no other intervention resulted in both rapid relief of pain and resolution of lesions. In vitro studies support inhibition of IL-1, PGE2 and PGD2 production by corticosteroids as the mechanism of action.¹ If surgical margins extend into the frontal lobe, however, steroid injection into the lesion is avoided.²

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Recurrence of orbital lesions is not common; however, serial CT scans are recommended. Eighteen percent of patients will have recurrence, most often at the original site, at a median of 4 months (3 weeks to 25 months).² Sessa and colleagues recommend that patients be followed for 5 years after treatment. Song and colleagues¹ at Bascom Palmer reported a case of a 9-year-old boy who had recurrence of his orbital mass 6 weeks after excision, and no systemic involvement. He was disease-free 6 months after a regimen of prednisone, vinblastine, 6-mercaptopurine, and methotrexate.

Irradiation may also be performed; however, secondary tumors in young children, cataractogenesis, and radiation retinopathy may occur.¹ Extensive multifocal disease or lesions threatening vital visual or CNS structures may be treated with systemic corticosteroids alone or with vinca alkaloids, etoposide, 6-mercaptopurine, or methotrexate. Experimental therapies targeted at recalcitrant multifocal or systemic disease include the purine analog 2-chlorodeoxyadenosine; anti-CD1, a monoclonal antibody; and cytokine inhibitors, such as cyclosporine.⁷

Conclusion

Transient immune dysfunction may provoke the cytokine-mediated proliferation of pathologic Langerhans cells within the hematopoietic marrow of bones. The recommendation is for incisional biopsy, diagnosis, subtotal curettage, intralesional corticosteroid injection, postoperative systemic evaluation, and long-term observation. In recurrent cases, chemotherapy and radiation are adjunctive.

References

1. Song A, Johnson TE, Dubovy SR, Toledano S. Treatment of recurrent eosinophilic granuloma with systemic therapy. Ophthal Plast Reconstr Surg. 2003; 19:140-144.
   
   
2. Woo KI, Harris GJ. Eosinophilic granuloma of the orbit: understanding the paradox of aggressive destruction responsive to minimal intervention. Ophthal Plast Reconstr Surg. 2003; 19:429-439.
   
   
3. Song A. Treatment of recurrent eosinophilic granuloma with systemic therapy. Paper presented at: ASOPRS Scientific Symposium; November 9-10, 2001; New Orleans, La.
   
   
4. Kramer TR, Noecker RJ, Miller JM, Clark LC. Langerhans cell histiocytosis with orbital involvement. Am J Ophthalmol. 1997; 124:814-824.
   
   
5. Glover AT, Grove AS. Eosinophilic granuloma of the orbit with spontaneous healing. Ophthalmology. 1987; 94:1008-1012.
   
   
6. Yasko AW, Fanning CV, Ayala AG, Carrasco CH, Murray JA. Percutaneous techniques for the diagnosis and treatment of localized Langerhans-cell histiocytosis. J. Bone Joint Surg Am. 1998; 80: 219-228.
   
   
7. Sessa S, Sommelet D, Lascombes P, Prevot J. Treatment of Langerhans-cell histiocytosis in children. J Bone Joint Surg Am. 1994; 76:1513-1525.
   
   
8. Broadbent V, Gadner H. Current therapy for Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998; 12:327-338.
   
   
   

Additional recommended reading:

1. Char DH, Ablin A, Beckstead J. Histiocytic disorders of the orbit. Ann Ophthalmol. 1984; 16:872-873.
   
   
2. Kindy-Degnan NA, Laflamme P, Duprat G, Allaire GS. Intralesional steroid in the treatment of an orbital eosinophilic granuloma. Arch Ophthalmol. 1991; 109:617-618.
   
   
3. LaBorwit SE, Karesh JW, Hirschbein MJ, Dankner SR. Multifocal Langerhans' cell histiocytosis involving the orbit. J Pediatr Ophthalmol Strabismus. 1998; 35:234-236.
   
   
4. Smith JH, Fulton L, O'Brien JM. Spontaneous regression of orbital Langerhans cell granulomatosis in a three-year-old girl. Am J Ophthalmol. 1999; 128:119-121.