Xanthogranulomatous disease is a non-Langerhans (type II [older classification], C group [new classification]), histiocytosis that is characterized by a proliferation of histiocytes. These histiocytes originate from bone marrow stem cells where they mature into monocytes.⁸ They then differentiate into one of two pathways, the mononuclear-phagocytic system or the dendritic cell system.⁹ The mononuclear-phagocytic system consists of phagocytic monocytes as well as free and fixed tissue macrophages.⁸ The dendritic cell system includes follicular cells of the lymph nodes and Langerhans cells in the skin. Both of these cell types function as antigen-presenting cells.⁸ Although the pathogenesis of xanthogranulomatous diseases is not clearly understood, it is believed that they arise from a reactive proliferation of free tissue macrophages. The inciting factors remain elusive, but some evidence suggests a possible relation to virus infection. In a case of an infant with JXG, involvement of the salivary gland was associated with cytomegalovirus infection.¹⁰ In another case of oral JXG, cytomegalovirus antigens in the histiocytes were identified by immunohistochemistry.¹¹ In addition, several patients with JXG have been shown to have chromosomal instability within the lesions and peripheral blood cells.¹² It is unclear if these chromosomal abnormalities represent a fundamental genetic defect or just aberrations resulting from a cellular response to external factors such as viral infections.

The differences or variations in the pathogenesis of specific subtypes of xanthogranulomatous disease are poorly understood. The pathogenesis of JXG is unknown, but it is presumed to develop after unknown infectious or physical stimuli that then provoke a granulomatous histiocytic reaction. The reactive lesion is derived from monocytes or macrophages in response to unknown etiologic physical or infectious agents.¹³,¹⁴,¹⁵ Although the pathophysiologic relationship is not understood, JXG has been associated with juvenile chronic myelogenous leukemia, juvenile myelomonocytic leukemia, and neurofibromatosis.¹⁶ Other diseases associated with JXG include urticaria pigmentosa, insulin-dependent diabetes mellitus, aquagenic pruritus, and even cytomegalovirus infection.¹⁷

In NXG, an association with paraproteinemia is well known, and this immunoglobulin monoclonal gammopathy is present in at least 80% of cases. The paraprotein may serve as the primary inciting factor or act as a cofactor that facilitates a giant cell granulomatous reaction.¹⁸ To date, however, the precise pathogenesis of NXG and the other adult orbital xanthogranulomas is unknown.

The pathogenesis of ECD is speculated to be associated with a T-helper 1 (Th1) immune response. Patients with ECD have high levels of IFN-α, interleukin-6, IL-7, IL-12, and monocyte chemoattractant protein-1, supporting the idea of an inflammatory condition.¹⁹,²⁰,²¹ An oncogenic etiology has also been suggested because of the detection of a mutation in the BRAF proto-oncogene that has been identified in 40% to 80% of patients with ECD.²²,²³ The mutation causes the amino acid substitution of glutamic acid for valine at position 600 of the BRAF protein (V600E). The BRAFV600E mutation is usually detectable in biopsies and in circulating monocytes from patients with ECD, demonstrating that ECD is a clonal disease.²² It has been shown that patients with ECD treated with the selective BRAFV600E inhibitor, vemurafenib, showed dramatic clinical and radiographic improvement.²⁴

NXG originates from the mononuclear-phagocytic system, which consists of phagocytic monocytes and free and fixed tissue macrophages. The specific pathogenesis is not known, but it has been postulated to occur secondary to a reactive proliferation of free tissue macrophages. Possible causes for this proliferation include induction by a virus, paraproteinemia, immunoglobulin or lipid-Ig complex deposition, Borrelia species infection, or chromosomal instability.²

The cause of RDD is unknown, but autoimmune diseases and viruses such as human herpesvirus 6 or Epstein-Barr virus have been proposed as possible sources.⁷,²⁵,²⁶ The pathogenesis involves recruitment of monocytes from the peripheral blood to lymph nodes or extranodal sites, and these are then transformed into RDD histiocytes.²⁵ Emperipolesis, a process whereby histiocytes phagocytize intact lymphocytes or plasma cells, is characteristic of RDD and distinguishes it from other cutaneous xanthogranulomatous diseases.⁶,⁷ These histiocytes can release cytokines, such as tumor necrosis factor-α, which result in fever and other systemic symptoms.²⁵

JXG is a childhood form of xanthogranulomatous disorders²⁷ and is the most common variant of non-Langerhans xanthogranuloma disease. It is most commonly found in early childhood with 5% to 17% of cases occurring shortly after birth and 75% within the first 9 months of life.¹⁵ In children, there is a slight predilection to affect males in a ratio of 1.1:1 to 1.4:1,²⁸ but in adults, there is no sex prevalence. About 10% of cases may appear in adulthood.²⁹ In up to 90% of patients, JXG manifests with nodular cutaneous lesions that clinically appear as a well-defined papule or nodule mainly affecting the head and neck.³⁰ Eyelid lesions most often are solitary, firm, and asymptomatic and range in size from 5 mm to 2 cm (Figure 124.1).²⁷,³¹ Initially lesions appear pink to red, but in later stages, they tend to acquire a brownish-yellow color and may develop telangiectasias.¹⁵ The most common site of extracutaneous involvement is a solitary mass in the subcutis or deep soft tissues, but various organs may be involved.¹⁵,³²
Eye involvement is usually unilateral and commonly presents with an asymptomatic iris tumor, red eye, uveitis, or heterochromia iridis.¹⁵ The iris is most often involved and can be associated with spontaneous intraocular hemorrhages, glaucoma, and blindness.³³

Systemic manifestations may develop in 4% of children with JXG and 5% to 10% overall. This may involve muscles, liver, lung, pericardium, and spleen.¹⁵,³³ The central nervous system is involved in 1% to 2 % of systemic cases,¹⁷,³⁴ mostly manifesting with multiple intracerebral lesions and/or leptomeningeal involvement with seizures,³⁵ diabetes insipidus,³⁶ or ocular disturbance.³⁷ As mentioned above, JXG rarely may be associated with childhood leukemia²⁷,³⁸ and neurofibromatosis type 1.³⁹

AOX is the least common form and is sometimes referred to as late-onset JXG. It affects patients from teens to the ninth decade, with a median age at onset of 35 years.³² There is no significant gender preference, and it occurs mostly without significant systemic involvement.¹ AOX lesions involve the eyelids and periorbital skin in 50% of cases and are located in the orbit in 50%.¹ Cutaneous lesions occur predominantly in the head and neck region and are similar to those of JXG, although the nodules are often larger. They generally present as bilateral isolated or diffuse yellowish lesions on swollen eyelids (Figures 124.2 and 124.3). They involute spontaneously in about 54% of cases.⁴⁰ In rare reports, both AOX and AAPOX have been associated with IgG4-related disease.⁴¹,⁴²,⁴³

AAPOX was described by Jakobiec et al. in 1993.⁴⁴ It is associated with late-onset asthma that often precedes the periocular lesions by several years.⁴¹ Bilateral preseptal cutaneous or anterior orbital xanthomatous lesions affect adults aged between 20 and 70 years. Males are affected more frequently than females at a ratio of 2:1. Simultaneous involvement of conjunctiva has also been reported.⁴⁵ In addition to asthma, paraproteinemia and lymphadenopathy are found in 35% to 40% of patients, suggesting an underlying disorder of B cell proliferation.¹

AAPOX presents with progressive bilateral yellow or orange, indurated xanthomatous periocular masses. The anterior orbit and lacrimal gland are often infiltrated, but intraconal involvement is very rare.¹,⁴¹ Visual function can be impaired by eyelid occlusion from mechanical ptosis or diplopia from infiltration into extraocular muscles.⁴⁴ Although this variant is usually limited to the periocular region, mandibular gland infiltration has been described,⁴⁴ as has diffuse cervical, hilar, and inguinal adenopathy.⁴¹ No internal organ involvement has been reported.

NXG usually involves the periorbital region, trunk, and proximal extremities. It affects men and women equally in their sixth decade of life.⁴⁶ Lesions initially may resemble xanthelasmas, but gradually increase in number and size to become indurated yellowish plaques, 0.5-5 cm in diameter, that tend to ulcerate (Figure 124.4). Ocular manifestations include skin nodules and plaques, conjunctivitis, scleritis, keratitis, anterior uveitis, and orbital infiltration with extraocular limitation. Eyelid function can become compromised with mechanical ptosis and lagophthalmos, and corneal exposure has resulted in perforation with loss of the eye.⁴⁷ NXG can be associated with hypocomplementemia and cryoglobulinemia, and with monoclonal paraproteinemia in 80% of cases. It has also been associated with multiple myeloma, non-Hodgkin lymphoma, and other hematologic dyscrasias in 25% to 30% of cases,⁴⁸ so that NXG is a more life-threatening subtype of xanthogranuloma.¹,⁴⁴

ECD is a rare infiltrative xanthogranulomatous disease.⁴⁹ The disease usually becomes apparent in adulthood between 40 and 60 years of age with a median age at diagnosis of 53 years,⁵⁰ but a few cases have been described in the pediatric population.⁵¹ The male to female ratio is 3:1.⁵² The diagnosis is made on a combination of clinical presentation and imaging features and is confirmed on histopathology. The clinical picture of ECD may vary from indolent focal disease to multiorgan involvement with a fatal outcome. Radiological characteristics are pathognomonic and skeletal involvement occurs in more than 95% of patients. Bone
pain may be the presenting symptom in 50% of cases,⁵³,⁵⁴ and the distal ends of the femurs and proximal and distal tibia are the most frequently involved sites.⁵⁰ More than 50% of cases have other extraskeletal and internal organ involvement such as diabetes insipidus, progressive lung disease, and renal failure.⁵⁵ In about half of the patients the central nervous system is involved.⁵⁰ Cardiovascular manifestations are the major cause of death in patients with ECD, and about 60% of patients die due to a cardiac complication.⁵⁶ Orbital and periorbital lesions result in proptosis, papilledema, and nodular skin lesions. Xanthelasmas are the most frequent skin lesions in ECD, present in about 30% of patients, and are indistinguishable from those found in JXG.⁵⁷ Orbital infiltration is often bilateral and manifests as exophthalmos in about 25% of patients with ECD. Occasionally it is associated with retro-orbital pain, diplopia, or visual impairment from optic nerve compression.⁵⁷