Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders that are associated with many clinical presentations with involvement of 1 or more organ systems. In particular, bone is affected, but skin, soft tissue, central nervous system, heart, lungs, or abdominal viscera can also be involved. Although the causative cell of LCH is derived from the Langerhans dendritic cell line and that of ECD is from the monocyte-macrophage lineage, the clinical presentations can be similar, with bony involvement most frequent in both disease states. There are several key features, particularly immunohistochemical profile, that allow LCH and ECD to be distinguished. There are rare reports of patients who present with features of both diseases, but none to our knowledge, with both orbital and neuro-endocrinologic involvement.
A previously healthy 26-year-old woman presented to the neurosurgical service with a new scalp mass. Neuroimaging revealed that the lesion involved the skull, and bilateral soft tissue masses were found in both orbits (Fig. 1). Neuro-ophthalmic examination revealed normal visual acuity, color vision, pupils, motility, and fundi. The scalp mass and involved skull were excised, and histopathological examination (Fig. 2) was consistent with eosinophilic granuloma and a diagnosis of LCH. A skeletal survey did not reveal any other bony lesions.
Three months later, the patient developed diplopia in upgaze. On examination, supraduction of the left eye was limited to 75% of normal. The motility disturbance was attributed to the orbital lesions, and the patient received bilateral orbital radiation (total dose 18 Gy in 10 fractions). Following radiotherapy, she remained stable, and a follow-up MRI is shown in Figure 3.
One year later, the patient developed acute visual loss in the left eye. Her visual acuity measured 20/20 in the right eye and 20/50 in the left eye. Ductions of the right eye were limited to 75% in all directions and 50% in all directions of the left eye. There was left optic disc edema. Repeat neuroimaging showed increased size of the retrobulbar masses and coexistent sinusitis. The diagnosis of Wegener granulomatosis was considered, but antineutrophilic cytoplasmic antibody testing was negative. Symmetric diffuse uptake in both distal femurs and tibias was seen on bone scan. Because of presumed compressive optic neuropathy, the patient was started on 60 mg of prednisone daily. An orbital biopsy was canceled due to a pericardial effusion found on preoperative testing. She then developed periorbital xanthogranulomatous skin lesions (Fig. 4), which on biopsy revealed foamy macrophages, which were CD68+, S100− and CD1a− consistent with ECD. The patient eventually underwent orbital biopsy which revealed foamy histiocytes, which were CD68+, S100− and CD1a−, also consistent with ECD (Fig. 5). The patient was maintained on 60 mg of prednisone daily for the following month and her visual acuity remained stable.
One month later, the patient was admitted for syncope. She had profound hypotension, and a cystic lesion in the pericardium was found on echocardiogram. In addition, she had diabetes insipidus. Although brain MRI did not reveal any visible abnormalities of the hypothalamus or pituitary stalk or gland, a presumptive clinical diagnosis of neuroendocrine involvement was made. Visual acuity subsequently worsened to no light perception in the right eye, and count fingers in the left eye, and her optic nerves became atrophic. Once she was medically stable, chemotherapy with 2-chlorodeoxyadenosine (2CdA) was begun. Cardiac and endocrine abnormalities improved, as did ocular motility. Vision remained unchanged. On MRI, the orbital masses had become smaller.
The patient received 2CdA for 1 year, and then interferon-alpha (IFN-α) was initiated to treat her residual pericardial and neuroendocrinologic disease. She received IFN-α for approximately 2 years. Her disease is now stable, and she has been maintained on thyroid replacement and desmopressin for the past year. Follow-up MRI and bone scans have shown resolution of all previous bone disease.
A 32-year-old woman with a history of asthma and polycystic ovarian syndrome presented with a 4-year history of gradually increasing proptosis and blurred vision of the left eye. Visual acuity was worse than 20/400 in the left eye, and there was a left relative afferent pupillary defect. Apart from 3 mm of left proptosis, the remainder of her ophthalmologic examination was normal. The CT scan revealed an infiltrative lesion involving the medial, lateral, and superior rectus muscles in the left orbit (Fig. 6). Left orbital biopsy and decompression were performed. Nonspecific inflammatory tissue with very few cells was seen on pathologic examination. As she was thought to have thyroid eye disease, no further treatment was given.
Follow-up imaging 6 months later demonstrated enlargement of the intraorbital process and thickening of the left temporal bone. During the next 6 months, the patient developed a bitemporal hemianopia, and neuroimaging revealed an infiltrative process within the pituitary gland (Fig. 7). Laboratory evaluation revealed panhypopituitarism. Biopsy of the sellar mass was performed via a transfrontal craniotomy. Foamy cells, which were CD68+, S100−, and CD1a−, consistent with ECD were seen on histological examination. A bone scan was performed demonstrating lytic lesions of the distal femurs and skull, which were consistent with LCH. Bone marrow biopsy showed histiocytes with an immunohistochemical profile of CD68+, S100−, and CD1a+. This result also supported the diagnosis of LCH (1,2). The patient received IFN-α, her orbital and sellar lesions decreased in size, and she has remained stable for over 1 year without recurrence of either disease.
Both LCH and ECD are rare histiocytic disorders of unknown etiology that can involve multiple organ systems that share a common CD34+ progenitor cell. However, the causal cell of LCH is derived from the Langerhans dendritic cell line, while that of ECD is derived from the monocyte-macrophage group. The disorders are characterized by specific radiographic appearances with LCH causing asymmetric lytic lesions of the flat bones and skull and ECD causing symmetric sclerosis of the long bones. However, with multisystem involvement, the disorders occasionally can be difficult to differentiate clinically, and immunohistochemical analysis is required (Table 1). Both of our patients had bony involvement due to LCH, and orbital lesions and neuroendocrine involvement presumably due to ECD.
ECD, first described in 1930 (3), is characterized by diffuse bone soft tissue infiltration with foamy histiocytes that demonstrate a specific immunohistochemical profile (CD68+, S100−, CD1a−, and no Birbeck granules). The symmetric, distal, long bone osteosclerotic lesions are considered almost pathognomonic for the disease (4). In addition, retroperitoneal, skin, brain, lung, orbit, and cardiac involvement have been reported (4). In large clinical case series (5,6), the most common nonskeletal manifestations of ECD included hypothalamic infiltration that causes diabetes insipidus (29%-47%), retroperitoneal involvement (3%-29%), exophthalmos (17%-27%), and skin lesions (19%). When ECD affects the orbit, the disease often affects the intraconal space (7). Mortality rate has been reported between 48% and 57% and most often is associated with neuroendocrinologic, cardiac, and respiratory involvement (5,6). Several treatments have been employed in ECD, including steroids (which control acute symptoms approximately 50% of the time (5)), and various chemotherapeutic regimens (2CdA and IFN-α). Radiation may also be effective, although it generally does not reduce the size of orbital lesions (5).
LCH is characterized by a mixed cellular infiltrate predominated by a clonal proliferation of immature Langerhans cells (CD68+, S100+, CD1a+, and Birbeck granules) without atypia (8). LCH can be multiostotic (formerly called eosinophilic granuloma), multisystemic (formerly called Hand-Schuller-Christian disease), or multiostotic and multisystemic (formerly called Letterer-Siwe disease). Eosinophilic granuloma represents 60%-80% of LCH (8), and bony lesions typically affect the flat bone of the skull, ribs, or pelvis (8). However, patients also can present with exophthalmos due to a nonskeletal infiltrative lesions of the orbit, diabetes insipidus, or infiltrative central nervous system lesions that involve the cerebellum, pons, or cerebral hemispheres (8). The treatment for LCH depends in part on which site is involved. Surgical curettage and/or local radiation are usually sufficient for local disease (8). However, with systemic involvement, various chemotherapeutic agents may be necessary.
The causal cell of LCH is monoclonal but not malignant (9). It is not clear whether LCH is primarily a neoplastic process or a cytokine-driven reactive disease. The pathogenesis that leads to a clonal proliferation of benign cells in LCH is poorly understood. It may be related to an undiscovered inciting event in genetically predisposed individuals that then leads to disruption of immune regulation and culminates in an alteration in cytokine production that influence histiocyte stem cells. This eventually leads to uncontrolled accrual of antigen-presenting cells at an early, yet active, stage of the cell cycle (9). In contrast, whether there is monoclonality in ECD is debated (10), and therefore, the pathogenesis of ECD remains poorly elucidated.
Coexistence of ECD and LCH in the same patient is rare (Table 2). While there are 3 reported cases (11-13) where the presence of ECD and LCH is probable in the same patient, but not proven by biopsy, we are aware of 8 reported patients with biopsy-proven ECD and LCH (14-21). Among these 8 cases, 3 had both ECD and LCH solely in the skeletal system (14-16). Among the other 4 cases, there was bony involvement of LCH combined with varying systemic involvement of ECD (bone (17-19), lung (17,18), peritoneum (17), orbit (18), or skin (19)) skin LCH with ECD involvement of the central nervous system (pontine and hypothalamic infiltration) (20), or intracerebral LCH combined with cardiac ECD (21). In our literature review, we were unable to find another case with systemic involvement similar to ours.
Several theories have been proposed to explain the coexistence of ECD and LCH. Initially, it was thought that ECD might be a manifestation of “late-stage healing” of LCH (22). However, this theory is now thought unlikely since features of the 2 disease states, including the immunohistochemical features, have been further characterized. In addition, the progenitor cell to both cell lineages has been traced to a common CD34+ cell that can be cultured in vitro to differentiate into either pathway based on its chemokine milieu (22). In theory, an abnormality in the common progenitor cell could be responsible for coexistence of the 2 disease states. Alternatively, the same inciting factor may be implicated in both diseases. Finally, it is possible that ECD and LCH fall within a spectrum of diseases attributable to an abnormal CD34+ progenitor cell. Some patients may be in an “intermediate zone” of this spectrum and demonstrate features of both diseases, based on the cytokine milieu at different points in time or in different organs. Additionally, the presence of both disease states at different points in time could represent an evolution of the disease from a Langerhans cell predominance (LCH) to a non-Langerhans cell predominance (ECD) due to a change in the patient's immune response perhaps driven by therapeutic interventions.
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