History: A 55-year-old man with a ten year history of swollen eyes presented with asthmatic symptoms. He was found to have enlarged upper and lower eyelids with ocular secretions that prevented him from seeing properly. The clinical differential included inflammatory pseudotumor of the orbits, proptosis from Grave’s disease and multiple myeloma. The workup showed an elevation of free kappa light chains. A periocular biopsy was performed.
The examined tissue consisted of a diffuse infiltration of lymphocytes admixed with lipid-laden histiocytes (xanthoma cells). They had small rounded nuclei and abundant clear or vacuolated cytoplasm (Fig. 1). There were also scattered multi-nucleated giant cells of the Touton type (Fig. 2). Within the lymphoid component were prominent follicles with parafollicular fibrosis (Fig. 3). Immunohistochemically, the foamy histiocytes were strongly positive for CD68 and negative for S100. The lymphoid infiltration had a reactive profile with the germinal cells being CD20 positive and negative for Bcl-2. The parafollicular T cells were CD3 positive (Fig. 4).
Diagnosis: “Adult-Onset Asthma and Periocular Xanthogranuloma”
Jin Guo MD, Jun Wang MD and Donald R. Chase MD
Department of Pathology, Loma Linda University and Medical Center, Loma Linda, California
California Tumor Tissue Registry, Loma Linda, California
Discussion: Adult-onset asthma with periocular xanthogranuoloma (AAPOX) was first described by Jakobiec et al in 1993 when they reported 6 patients with periocular xanthogranulomatous disease associated with adult onset asthma, but lacking necrobiosis. The entity has now been placed into a heterogeneous group of syndromes called adult xanthogranulomatous disease (AXGD) that are rare and poorly understood. AXGD has variable clinical features which have resulted in subclassification into:
• Adult onset xanthogranuloma
• Necrobiotic xanthogranuloma
• Erdheim-Chester disease, and
Histopathologically, each of these four entities is characterized by infiltration of “hallmark cells” specifically foamy histiocytes and Touton-type giant cells, both of which are negative for S100 and CD1. The infiltration along with accompanying lymphocytes can replace the normal lacrimal gland architecture, causing mass effects and loss of tear production.
Adult onset xanthogranuloma is an isolated xanthogranulomatous lesion without significant systemic involvement.
Necrobiotic xanthogranuloma is characterized by subcutaneous skin lesions that tend to ulcerate and become fibrotic. Associated systemic findings frequently include paraproteinaemia and multiple myeloma.
Erdheim-Chester Disease is an idiopathic condition of lymphohistiocytic infiltration of the heart, lungs, retroperitoneum, bones, and other tissues. The elements are xanthogranulomatous with Touton giant cells and are accompanied by regional fibrosis.. The condition is often fatal, with death due to cardiomyopathy, severe lung disease, or chronic renal failure.
AAPOX often presents with bilateral yellow-orange, elevated, indurated and non-ulcerated xanthomatous eyelids and/or orbital masses. It typically extends into the anterior orbital fat, and sometimes involves the extraocular muscles and/or the lacrimal gland(s). Most patients experience adult-onset asthma within a few months to a few years of onset. Even when asthmatic symptoms are severe enough to require systemic corticosteroids and/or inhalation therapy, a chest X-ray may be negative.
AAPOX is rare with only 21 previous reported cases. Like other AXGDs, it usually has sheets of mononucleated foamy histiocytes, with lymphocytes, plasma cells and Touton giant cells. The cells characteristically infiltrate the orbicularis muscles and the anteriorbital tissues. Their Touton cells have a ring of nuclei about a central eosinophilic zone which is surrounded by a zone of pallor extending to the periphery of the cell. Lymphoid follicles are commonly scattered throughout. Unlike Erdheim-Chester Disease, fibrosis is usually minimal to moderate and unlike necrobiotic xanthogranuloma there is no necrobiosis of collagen. Because the eyelids remain intact and the process does not reach the deep orbital and perioptic connective tissues, visual acuity may not be affected and ocular motility is generally well preserved unless the extraocular muscles are involved. Only rarely are the corneas exposed to the infiltrate, but in rare cases where lacrimal gland involvement causes punctuate corneal epitheliopathy the patient may suffer from a dry eye condition. CT scanning may reveal preseptal and anterior orbital involvement with occasional posterior tracking along or within the orbital muscles and fat, usually sparing the perioptic nerve connective tissues. Facial bones are usually not involved.
Systemic evaluations are usually normal except for rare reports of elevated alpha high-density cholesterol and/or M-protein (IgG) on serum immunoelectrophoresis. The latter suggests that the inflammatory infiltrates have stimulated B cell populations.
The main differential diagnoses of AAPOX include other AXGDs including the aforementioned adult onset xanthogranuloma, necrobiotic xanthogranuloma, and Erdheim-Chester Disease. These conditions all share similar lymphogranulomatous infiltrates but have subtle differences in the amount of lymphoid follicles, number of Touton giant cells, degree of fibrosis and presence of necrosis. Curiously, these features may vary within the same specimen and change with time and treatment. Based upon morphology alone, therefore, the AXGDs are difficult to sub-classify on histomorphologic grounds alone and usually require correlation with patterns of systemic involvement.
Necrobiosis with palisading epithelioid histiocytes is most often seen in necrobiotic xanthogranuloma whereas large lymphoid aggregates with germinal centers are often found in cases of AAPOX. Whereas orbit/adnexal xanthogranulomas tend to be anterior in adult-onset xanthogranuloma, AAPOX, and in necrobiotic xanthogranuloma, in Erdheim-Chester disease the disease is often diffuse (and posterior) leading to visual loss. Bone involvement is common and death may occur despite aggressive therapies.
While the majority of cases can be classified as one of the four syndromes, there are cases that fall in between. These patients have varying combinations of periocular xanthogranuloma and other blood dyscrasias including thrombocytopenia, paraproteinaemia and/or monoclonal gammopathy of undetermined significance (MGUS).
In addition to AXGDs, AAPOX should also be differentiated from other non-Langerhans disorders of histiocytes, including juvenile xanthogranuloma (JXG). This tumor is usually manifested as a self-limited, corticosteroid-sensitive skin tumor that rarely has systemic manifestations. Infants and small children are mainly affected with head and neck lesions. Many extracutaneous sites, however, have been reported, particularly the eye where JXG may cause spontaneous hyphema and result in secondary glaucoma and eventual blindness. Approximately one half of patients with ocular involvement also have skin lesions.
Other entities involving ocular adnexal or orbital tissue that may require distinction from adult xanthogranulomatous disease include:
• Langerhans histiocytosis
• Rosai-Dorfman syndrome
• Inflammatory MFH
• Inflammatory myofibroblastic tumor (inflammatory pseudotumor)
• Graves disease
• Multiple myeloma, and
Despite surgical debulking, AAPOX often recurs within 6-12 months. Although systemic prednisone treatment may cause temporal shrinkage, it alone is usually not successful in causing a lasting resolution. Combined prednisone and systemic chemotherapy for paraproteinaemia may result in more complete resolution of the xanthogranulomatous eyelid deposits. Radiotherapy has also been successfully employed, but the results are more anecdotal than statistical. The eyelid lesions in necrobiotic xanthogranuloma can be successfully be treated with radiotherapy or systemic prednisalone and chlorambucil unless extensive destruction has occurred. Patients without detectable systemic disease at the time ocular adnexal lesions appear should be spared surgical debulking because of possible scarring. In this setting high doses of systemic corticosteroids and low doses of periobital radiotherapy may be given with hope of protection of the globe. If this approach fails, systemic corticosteroids and light chemotherapy may be tried. In patients with MGUS, follow-up should include serial serum protein immunoelectrophoresis and bone biopsy as needed.
A recent study evaluated the efficacy of methotrexate in the treatment of the periorbital changes in adult-onset xanthogranuloma with or without asthma. With follow-up of over 3 years, 10-20 mg/weeks of methotrexate with folate supplementation and a course of corticosteroids showed promising results in significantly reducing inflammation and ptosis.
In summary, AAPOX as well as other entities in the adult xanthogranulomatous disease are rare and pose challenges in daily clinical practice. Recognizing their clinical and histopathological features will facilitate early diagnosis and appropriate therapeutic management.
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