Juvenile xanthogranuloma classically presents as multiple yellow-red papules on the face, neck, axillae, and extensor surfaces of the extremities, which range in size from 0.5 cm to several centimeters in diameter [5, 9, 13, 14]. The average age of onset is 2 years, with no sex predilection. Cutaneous manifestations are usually self-limited and resolve spontaneously within 2 years. Extracutaneous involvement has been described, including the heart, lungs, liver, testes, and hematopoietic system [5, 9]. The eye, however, is the most common site to be affected after the skin. The most common ocular manifestation of JXG is iris infiltration leading to spontaneous hyphema and treatment-resistant secondary glaucoma [5, 13]. Also described is involvement of the eyelid, conjunctiva, cornea, episclera, uveal tract, optic nerve, and orbit [9]. Orbital involvement is extremely rare, with 80 % of orbital JXG lacking the typical skin findings [10, 13].

Systemic evaluation for potential malignancies should be considered because other organ systems may be affected [14]. Specifically in the setting of neurofibromatosis type 1 (NF-1), JXG has been associated with an increased rate of myelomonocytic leukemia [14]. Biopsy of any orbital mass is necessary to rule out malignancy, such as rhabdomyosarcoma, and secure a diagnosis.

Observation is usually recommended because most lesions resolve spontaneously [5, 9, 14, 15]. Topical, oral, and intralesional corticosteroids have been used with success in the setting of an associated systemic disease or if an amblyogenic mass is present [9, 13, 14]. Surgical excision has been successful in solitary masses with only a rare risk of recurrence [14]. External radiotherapy has also been used sparingly for refractory cases, but the risk of secondary head and neck malignancies limits its use [13, 14].

An isolated xanthogranulomatous lesion without significant systemic involvement is classified as adult orbital xanthogranuloma. This is the least common of these syndromes and is really a diagnosis of exclusion. The diffuse, yellow-orange, elevated, indurated eyelid plaque is virtually diagnostic of AOX and tends to affect the eyelids and anterior orbital tissues, producing mild proptosis [6, 10, 16]. It is a disease of middle-aged to elderly adults without sex predilection and often involves both sides. Biopsy is necessary to rule out necrosis. Systemic evaluation is necessary to rule out immunologic disease, asthma, Erdheim-Chester disease, and hyperlipidemia. It is often self-limited and does not require aggressive treatment [5]. Intralesional corticosteroid injection has been successfully used in controlling adult-onset xanthogranuloma [16, 17].

Figure 7.1 is an external photograph of a patient with biopsy-proven adult orbital xanthogranulomatosis.

Adult-onset asthma and periocular xanthogranuloma is a rare condition, first reported by Jakobiec in 1993 [18]. The range of reported cases is 22–74 years of age, with a 2:1 male to female preponderance [5]. Typically, bilateral, elevated, non-ulcerated, yellow-orange xanthomatous lesions affect the eyelids and may extend into the anterior orbital fat, as well as infiltrate the extraocular muscles and lacrimal gland [5, 18]. The yellow skin plaques may be preceded by diffuse periorbital swelling by as much as 5 years [10]. Biopsy shows the classic xanthogranulomatous infiltrate and Touton giant cells but lacks necrosis [18]. It often contains germinal centers and scattered eosinophils.

As the name implies, systemic association can include adult-onset asthma that may present within a few months to a few years of the eyelid lesions [5, 19]. Asthma is just one of the many types of immune dysfunction frequently seen in adult patients with orbital xanthogranulomatous diseases. Others include autoimmune thyrotoxicosis, paraproteinemia, lymphadenopathy, and other lymphoproliferative disorders (multiple myeloma, chronic lymphocytic leukemia, benign lymphoproliferation, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and Burkitt lymphoma) [5, 6]. In fact, Sivak et al. found evidence of immune dysfunction in all pooled cases of AAPOX and NXG [6]. Therefore, thorough evaluation and close follow-up by a hematologist/oncologist is recommended [5, 18].

Treatments for AAPOX have been broad, with varying results. Systemic corticosteroids may cause temporary improvement, but their long-term efficacy is questionable [5]. Cytotoxic and chemotherapy agents have been tried in limited series with significant improvement in some but were limited by side effects [5, 20]. Surgical debulking helps but may cause significant inflammatory reaction and scarring, as well as recurrence after 6–12 months [5, 18]. In another series by Elner et al., multiple (1–22) intralesional corticosteroid injections either stabilized or improved all six patients with AOX and NXG [16]. It might be possible to extrapolate this data to AAPOX patients, with little adverse risk. Despite no consensus to the best treatment, overall prognosis is still good [6].

Necrobiotic xanthogranuloma was initially described in 1980 by Kossard and in 1984 by Robertson and Winkelmann [21, 22, 23]. NXG manifests in 20–95-year-olds, but typically the sixth decade, with no sex predilection [5, 23]. Skin lesions are described as yellow, indurated nodules or plaques that are slowly progressive and relentlessly destructive [4, 19]. Ulceration is a predominant feature and is present in 42 % of cases [3, 4, 10, 23]. Skin lesions on the trunk and extremities are the initial presenting sign in 65 % of cases [4]. It affects the ocular adnexa, periorbital skin, trunk, and flexure surfaces of the extremities [4]. Cutaneous involvement is present in nearly all cases, with a clear predilection for periorbital tissues, but the classic periorbital lesions may be absent in 15 % of cases [4, 23]. Ocular manifestations are present in about 81 % of NXG and are usually limited to the eyelids and anterior orbit but may include cellulitis, proptosis, episcleritis, keratitis, uveitis, and dacryoadenitis [4, 6, 16, 19]. Periorbital skin changes may lead to exposure keratopathy, corneal ulceration, and, ultimately, perforation as in reports by Reddy and Oestreicher [4, 23]. Histologically, typical Touton and foreign body giant cells are present, but NXG is distinct from the other xanthogranulomatoses by the presence of necrosis and cholesterol clefts [4, 19]. NXG shows necrobiosis of collagen surrounded by palisading epithelioid histiocytes.

There is a clear association with paraproteinemias, which exists in 80–90 % of NXG cases [4, 19, 23]. IgG monoclonal gammopathy is the most common disorder, specifically kappa light chain in 65 % [3, 10]. Approximately 50 % of these paraproteinemias and blood disorders progress to hematologic malignancies, such as multiple myeloma, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia [3, 4, 10, 17, 19]. An elevated erythrocyte sedimentation rate, low serum complement, and occasional mild hyperlipidemia are accompanying hematologic abnormalities [10]. Eleven percent of NXG patients also had evidence of internal organ disease (heart, lung, kidney, liver, intestine, spleen, ovary, and pharynx) [3].