Adult Onset Orbital Xanthogranuloma, a Variant of Adult Orbital Xanthogranulomatous Disease: An Infrequent Entity

Abstract

Adult orbital xanthogranulomatous diseases (AOXGD) present clinically with symmetrical swellings around the eyes and are collectively considered within the broader group of non-Langerhans cell histiocytosis. A 45-year-old female presented with asymptomatic progressive, skin-colored, thick raised lesions around the eyes of 1 year duration. On dermatological examination, large indurated, lobulated, skin-colored thick plaques were seen bilaterally over infraorbital areas, along with a few hard, discrete nodules over the left infraorbital area. Histopathology showed pan-dermal infiltration with foamy histiocytes, non-lipidized histiocytes, a few multinucleate giant cells, lymphocytes, and a few plasma cells, with immunohistochemistry showing CD68 and S100 positivity. Laboratory and imaging studies did not show any abnormality. Based on the above findings and the absence of internal organ involvement, the patient was diagnosed with adult-onset orbital xanthogranuloma (AOX). The patient was treated with three monthly sessions of intralesional corticosteroid injections, along with methotrexate 12.5 mg per week for 8 weeks, resulting in a moderate reduction in the size of the plaques. The patient is under regular follow-up. The present case highlights the rare case of AOX and the importance of prompt recognition and evaluation in view of its potential hematological and systemic associations.

Introduction

Xanthogranulomatous disorders of the orbit are a group of rare disorders of unknown etiopathogenesis that are a form of non-Langerhans cell (LC) histiocytosis.[1] They affect the skin and subcutaneous tissue of the orbit and ocular adnexae.[2] The disorders of this group show considerable heterogeneity and overlap, with some patients manifesting with only indolent disease localized to the skin, whereas others manifest with severe symptoms and systemic invasive disease.[3] Among these disorders, necrobiotic xanthogranuloma is the most frequently reported, whereas adult-onset orbital xanthogranuloma (AOX) is the least common subtype.[4] We report an extremely rare case of AOX, which highlights the importance of prompt recognition and evaluation of adult orbital xanthogranuloma due to its potential hematological and systemic associations.

Case Report

A 45-year-old female presented with the complaints of asymptomatic, progressive, skin-colored, thick raised lesions around both eyes of 1 year duration. The patient was apparently normal 1 year ago, when she developed discrete, small, skin-colored and painless hard swellings initially over the right infraorbital area. Later, these nodules progressed to involve adjoining areas and coalesced to form large, hard swellings. Similar initial lesions with gradual progression to attain the current size were noticed on the left peri-orbital region. The swellings caused disfigurement but were not associated with any symptoms. No history of fever, weight loss, or other constitutional symptoms was reported. There was no history of asthma, ocular, or systemic symptoms.

No history of similar illness, systemic illness, or recent infections was reported. Personal history and family history were not contributory. A general physical examination was normal except for mild pallor. Systemic examination did not show any abnormality in cardiovascular, respiratory, gastrointestinal, and central nervous system. On dermatological examination, a large, indurated, lobulated, shiny skin-colored thick plaque of size 8 × 2.5 cm was seen over the right infra-orbital area, extending from the lateral canthus to the edge of the nose, forming a groove below the lower eyelid. A similar smaller, softer, shiny plaque of size 6 × 2 cm was seen over the left infraorbital area, extending from the lateral canthus to the middle of the eye. Two closely arranged shiny skin-colored nodules of sizes 4 mm and 6 mm were seen over the left infra-orbital region near the medial canthus [Figure 1].

Figure 1.

Large indurated lobulated plaque over the right infra-orbital region forming a groove below the lower eyelid

Based on the above clinical picture, a differential diagnosis of tuberous xanthoma, necrobiotic xanthogranuloma, nodular sarcoidosis, lymphomas involving the orbit, and IgG4 related skin disease were considered. The patient was subjected to thorough laboratory investigations. A complete blood picture showed the presence of anemia (hemoglobin-9.4 g/dl), platelet count of 1.05 L/cu.mm, and a raised erythrocyte sedimentation rate of 20 mm/1^st hour. Serum biochemistry, including blood sugar, renal function tests, liver function tests, lipid profile, and routine urine examination, were within normal limits. Complete work-up for monoclonal gammopathy, including screening for elevated immunoglobulins and monoclonal proteins done by serum and urine protein electrophoresis, and serum and urine immunofixation, did not show any abnormality. The serum-free light chain assay and detection of free light chains in the urine (Bence Jones proteins) were negative. Imaging studies, including computed tomography and magnetic resonance imaging of the orbit, showed only soft tissue swellings in the periorbital skin with no evidence of involvement of the orbit or infiltration of pre-septal soft tissue.

A 4 mm punch biopsy was taken from the edge of the lesion for histopathological examination, which showed thin epidermis with basket weave orthokeratosis and markedly reduced thickness of the stratum spinosum with complete effacement of rete ridges. Upper dermis showed oedema with pan-dermal infiltration with foamy histiocytes, non-lipidized histiocytes, a few multinucleate giant cells, lymphocytes, and occasional plasma cells [Figure 2a and b]. Immunohistochemistry (IHC) staining revealed CD68 and S 100 positivity and CD1a negativity [Figure 3]. Based on the following clinical features, serology, histopathology, and IHC findings, diagnosis of xanthoma was ruled out and AOX was favored – absence of hyperlipidemia, absence of extracellular-lipid deposition, presence of inflammatory cells including lymphocytes, and a few Touton giant cells. Treatment with intralesional corticosteroid injections was planned in view of the asymptomatic and non-invasive nature of the skin lesions. The patient was treated with 3 monthly sessions of triamcinolone acetonide at a concentration of 5 mg/ml, along with methotrexate 12.5 mg per week given orally for 12 weeks, resulting in a moderate reduction in the size of the plaques [Figure 4]. The patient is under regular follow-up. No clinical and biochemical signs of asthma and hematological abnormalities were noted during the follow-up period of 6 months.

Figure 2.

(a) Foreign body type of giant cells (black arrows) with foamy macrophages in the background (H and E, 40X) (b) Diffuse infiltration with foamy macrophages (black arrow) and lymphocytes (pink arrow) (H and E, 40X)

Figure 3.

CD68 immunohistochemistry with strong cytoplasmic reactivity (4X)

Figure 4.

Moderate reduction in the size of the plaques on both sides observed after 12 weeks of treatment

Discussion

The non-Langerhans cell histiocytoses (non-LCH) are a group of disorders defined by the accumulation of histiocytes that do not meet the phenotypic criteria for the diagnosis of LCs. Non-Langerhans histiocytic disorders encompass four distinct entities, namely adult-onset xanthogranuloma, adult-onset asthma with periocular xanthogranuloma (AAPOX), Erdheim– Chester disease (ECD), and necrobiotic xanthogranuloma (NXG).[5] AOX is characterized by bilateral periorbital yellowish plaques without any systemic association. AAPOX has a similar presentation but is associated with asthma, lymphadenopathy, and paraproteinemia. ECD presents with progressive and diffuse fibrosclerosis of the orbits with multisystem fibrotic involvement. NXG clinically presents as subcutaneous nodules with a tendency for ulceration and fibrosis and is associated with paraproteinemia, multiple myeloma, and hematological abnormalities.[6]

AOX presents with isolated orbital involvement without accompanying immune dysfunction, asthma, or internal organ involvement. In AOX, hematological abnormalities such as thrombocytopenia, eosinophilia, anemia, and lymphopenia have been anecdotally reported.[7] To rule out hematological involvement, local extension, and systemic abnormality, thorough investigations including bone marrow aspiration, serum protein electrophoresis, immuno-phenotyping by flow cytometry, skull imaging, and baseline systemic evaluation should be carried out. In the present case, anemia and thrombocytopenia were noticed, but no systemic abnormality was detected.

All adult orbital xanthogranulomatous diseases (AOXGD) subtypes share common histopathologic features characterized by sheets of mononucleated foamy histiocytes (xanthoma cells) infiltrating the orbicularis muscles and the orbital tissue, variable numbers of dispersed and/or aggregates of lymphocytes, plasma cells, and Touton giant cells.[8] NXG is characterized histologically by the presence of necrobiosis surrounded by palisading epithelioid histiocytes, more numerous Touton giant cells and cholesterol clefts. AOX is characterized by xanthomatous histiocytes, lymphocytes, lymphoid aggregates, eosinophils, Touton giant cells, and small necrobiotic foci. Immunohistochemically, the foamy histiocytes are strongly positive for CD68, CD163, and factor XIIIa but are usually negative for CD21, CD35, S100, and CD1a. In the present case, necrobiosis was absent, and IHC showed CD68 and S100 positivity. Histopathology and IHC findings were in favor of AOX.

Xanthogranulomatous diseases, including Erdheim-Chester disease, AOX, juvenile xanthogranuloma, and necrobiotic xanthogranuloma, may involve the orbit and ocular adnexa, and the various ocular symptoms seen include iritis, keratitis, scleritis, diplopia, exophthalmos, and blindness.[9] Dermatologists should be aware of these ocular complications, which may require radiological analysis as part of a complete assessment. In AOX, the extraocular muscles, adnexal tissue, and lacrimal gland may be affected. In the present case, the clinical examination done by an ophthalmologist was normal and imaging studies of the orbit did not show invasion of the orbit. The common treatment modalities used for invasive and more severe forms of AOXGD include surgical debulking, radiotherapy, intralesional corticosteroid injections, systemic corticosteroids, chemotherapeutic agents like methotrexate, azathioprine, and a combination of systemic corticosteroids with azathioprine.[10] In the present case, treatment with intralesional corticosteroid injection was given along with oral methotrexate in view of the absence of systemic involvement and local invasion.

To conclude, AOXGD is a heterogeneous entity that should prompt a thorough evaluation along with clinicopathological correlation for diagnosis and detecting potential systemic associations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.