Non-Langerhans Cell Histiocytoses
Andrea P. Moy
Louis P. Dehner
Rosalynn M. Nazarian
JUVENILE AND ADULT XANTHOGRANULOMA
Juvenile and adult xanthogranuloma are benign proliferations of non-Langerhans histiocytes. The juvenile xanthogranuloma (JXG) family of disorders is a large, diverse group of diseases, which lie on a clinical and morphologic spectrum.1,2,3 While these disorders often manifest in the skin, other organ systems may be involved.
In 1905, Adamson reported the first case of JXG in an infant under the name “congenital xanthoma multiplex.”4 Subsequently, multiple authors reported similar cases, although they had given different specific names to the lesion. For instance, McDonagh suggested the name “nevoxanthoendothelioma,” as he believed the entity was derived from endothelial cells.5 Finally, in 1954, Helwig and Hackney named the lesion JXG based on a study of histopathologic findings.6
JXG is the most common non-Langerhans cell histiocytosis. The exact incidence is unknown as most cases are diagnosed based upon clinical findings and without histologic evaluation. One study reported that JXG represents only 0.5% of pediatric tumors.7 The majority of cases are diagnosed in infants and young children, most often in the first year of life.7,8,9 Males may be slightly more affected than females, especially when lesions are multiple, and most patients are Caucasian.7,8 Less commonly, JXG occurs in adolescents and young adults.10 Older adults and elderly patients can also be affected, without a gender predilection; in such instances, the diagnosis of adult xanthogranuloma (AXG) can be made.11,12,13
In the skin, JXG presents as a well-demarcated, firm, round-to-oval dermal mass. Typically it is located in the head and neck region but can also occur on the trunk or upper limbs (Fig. 69-1).8 Less common locations include the genitalia, soles, and fingers.7 The shape of the lesions can vary greatly, as it may be keratotic, pedunculated, linear, flat, or plaque-like. The papules or nodules are usually 5 to 10 millimeters in diameter but can measure up to a few centimeters. Initially, the lesions are raised and pink to red in color, but over time they become yellow-brown (Fig. 69-1) and may flatten. Telangiectatic blood vessels or ulceration may be seen overlying the lesion. On dermoscopy, they usually have an orange-yellow background with an erythematous border.14 The lesions are often asymptomatic but may be pruritic or painful in some cases. In one study, approximately two-thirds of cases occurred as a solitary cutaneous lesion.8 The presence of multiple skin lesions occurs infrequently, in less than 10% of cases.7,8 Skin lesions often spontaneously regress within months to years and may result in residual hyperpigmentation, atrophy, or anetoderma.
FIGURE 69-1. Juvenile xanthogranuloma. Dome-shaped, smooth, yellowish papule on the arm of a 3-year-old girl. (Photo courtesy of Dr. Carrie C. Coughlin, Washington University, St. Louis.)
While JXG is typically limited to the skin, it may arise in extracutaneous sites with or without skin involvement. The most common extracutaneous site is the subcutaneous or deep soft tissue, which occurs in about 15% of cases.8 Distant systemic sites are involved in about 5% of cases and may include the oropharynx, nasopharynx, gastrointestinal tract, liver, lung, testis, spleen, lymph nodes, central nervous system, kidney, and bones.8,15 Most systemic cases occur in young children and can also spontaneously regress.9,15 Ocular JXG occurs in less than 1% of children with multiple JXGs, typically in young children, and presents without cutaneous involvement in about 60% of cases. Ocular lesions most commonly involve the iris, manifest with hyphema, and can cause secondary unilateral glaucoma.16
The physical exam findings in adults are similar to that seen in children. Pink-brown papules or nodules are present, most commonly on the trunk or head and neck. Solitary lesions are seen more commonly in adults as compared to children and rare adult cases have extracutaneous manifestations, even in the setting of multiple cutaneous lesions. Most cases of AXG have a benign natural history and regress spontaneously, but some lesions may be persistent.13,17 It is rare for an adult patient to have multiple AXGs and such cases may occur in the context of hematologic malignancy, such as essential thrombocytosis, chronic lymphocytic leukemia, large B-cell lymphoma, and monoclonal gammopathy.18
JXG and AXG were originally thought to arise from dermal/interstitial dendritic histiocytes.19 All histiocytes, including dermal dendritic histiocytes, arise from CD34+ hematopoietic stem cells. However, dermal dendritic histiocytes mature along a different line of differentiation than Langerhans cells. While Langerhans cells are CD14− histiocytes, dermal dendrocytes are CD14+. A subsequent immunohistochemical study suggested that JXGs arise from the plasmacytoid monocyte, a specific type of dendritic cell precursor of the monocyte/macrophage lineage.20
The exact etiology of JXG is unknown. It has been proposed to be a reactive histiocytic process, possibly related to an unknown stimulus. Some have hypothesized that an infectious agent, such as cytomegalovirus or varicella, or a traumatic factor may act as a trigger, but this remains unsubstantiated.21,22,23,24 Other authors have reported increased uptake and biosynthesis of lipids by the lesional macrophages in the setting of normal serum lipids.25 Others suspect that xanthogranuloma is linked to underlying hematologic malignancies via induction of cytokines and suggest that AXG is a cutaneous marker of underlying hematologic disease.18 Interestingly, clonality has been demonstrated in rare JXG cases.26,27
JXG has been associated with neurofibromatosis type 1 (NF1) and juvenile myelomonocytic leukemia (JMML).28 As approximately 5% to 10% of NF1 patients and up to 30% of NF1 patients less than 2 years of age have been reported to have JXG, the presence of cafe au lait macules and JXG can suggest a diagnosis of NF1. The association between JXG, NF1, and JMML, while well described, is poorly understood. JXG usually precedes the diagnosis of JMML; however, it is unclear if JXG is a reliable marker of subsequent development of JMML in NF1 patients.29 It has been suggested that mutation in the GTPase neurofibromin, which is present in NF1, can lead to Ras dysfunction and downregulation of Fas antigen with subsequent dysregulation of apoptosis in hematopoietic cells and development of leukemia and JXG.30
Histopathologic examination of JXG shows a dense infiltrate of histiocytes within the dermis (Fig. 69-2A). In small lesions, the infiltrate may be limited to the superficial dermis but, in larger lesions, may extend deeper, even into the subcutis. The margins of the lesion are usually well-demarcated but may be infiltrative. There is often flattening of the epidermis with loss of the rete ridges (Fig. 69-2B); however, the epidermis and adnexa are spared. The infiltrate is composed of small mononuclear cells, as well as multinucleated giant cells, which may be slightly pleomorphic. Lymphocytes, eosinophils, plasma cells, neutrophils, and mast cells are scattered throughout the infiltrate (Fig. 69-2C). The morphology of the histiocytes can vary depending on the age of the lesion.7,31 Early lesions show predominantly monomorphic histiocytes with abundant eosinophilic and minimally vacuolated cytoplasm. More mature lesions contain histiocytes that have a “lipidized” cytoplasm with a foamy xanthomatous appearance. Touton giant cells, which are characterized by a ring or wreath of nuclei surrounded by a rim of foamy cytoplasm, are a characteristic finding in this phase (Fig. 69-2D). Scalloped histiocytes with an angulated or jagged border and spindled histiocytes may also be seen. Mitotic figures may be seen but atypical mitotic figures are absent. Early lesions may have few lipid-laden cells and fibroblasts may be present in older lesions.
Immunophenotype and Electron Microscopy
The histiocytes present in JXG stain positively for CD68, CD163, CD4, CD14, Factor XIIIa, HLA-DR, fascin, vimentin, and lysozyme and are negative for CD1a and langerin. The histiocytes are usually negative for S100 but may be positive in some cases. Ultrastructural examination of mature lesions shows lipid vacuoles, lysosomes, cholesterol clefts, comma-shaped bodies, and myeloid bodies within the histiocytes. No Birbeck granules are present.32
A common differential diagnosis is Langerhans cell histiocytosis (LCH) and the distinction between JXG and LCH can be quite difficult. Similar to JXG, LCH encompasses a spectrum of diseases with overlapping clinical and histologic findings. Cutaneous involvement often presents in infants with a refractile dermatitis in a seborrheic distribution; petechiae, papules, nodules, or ulceration may be present. Histopathologic examination reveals a proliferation of histiocytes with lobulated, reniform, or “coffee-bean” nuclei within the papillary dermis. The histiocytes in LCH may infiltrate the epidermis but rarely involve the reticular dermis. However, despite these distinctions, immunohistochemical stains are often needed in order to distinguish these entities. In contrast to the histiocytes within JXG, Langerhans cells are positive for S100, CD1a, and langerin. While rarely JXG can contain S100+ cells, CD1a and langerin are negative in JXG. The presence of Birbeck granules by ultrastructural examination helps distinguish LCH from JXG.
In some instances, there may be histologic overlap between JXG and dermatofibroma. Dermatofibromas are benign, asymptomatic tan-pink papules typically present on the extremities of older children or adults. Histologically, the lipidized variant of dermatofibroma contains numerous large, foamy cells and Touton-like giant cells, reminiscent of JXG (Fig. 69-3A and B). However, areas of spindle cells in a whorled or storiform pattern may be present and collagen trapping can be seen at the periphery of the lesion (Fig. 69-3C). Furthermore, dermatofibromas tend to have overlying epidermal changes, such as acanthosis, hyperpigmentation of epidermal basal cells, or folliculosebaceous induction, and often contain hemosiderin. Both lesions can be positive for Factor XIIIa, but dermatofibromas are usually negative or only weakly positive for CD68.10
Reticulohistiocytoma also presents clinically as a solitary, firm, dermal lesion (often less than 1 cm in diameter) on the trunk or extremity. The histopathologic findings of reticulohistiocytoma, including the presence of densely eosinophilic “ground glass” or “oncocytic” cytoplasm, usually allow easy distinction from JXG; however, there may be immunohistochemical overlap between these lesions as the reticulohistiocytomas are also positive for CD68 and CD163, negative for CD1a, and often negative for S100.