Erdheim-Chester disease is a rare nonfamilial histiocytic disorder of unknown etiology with characteristic long bone findings. The 3-year survival rate for patients with Erdheim-Chester disease is 50%. Approximately 50% of patients have disease involvement in other tissues, including skin, retro-orbital and periorbital tissues, pituitary-hypothalamic axis, heart, kidney, retroperitoneum, breast, skeletal muscle, and sinonasal mucosa; about 20% of patients have lung involvement. Prognosis generally depends on the extent of the extraosseous disease. For patients with lung involvement, gender distribution is equal, but men typically present at an older age than do women. Approximately 80% of patients present with dyspnea, and most patients have diffuse interstitial infiltrates and pleural and/or interlobar septal thickening on chest radiology. Characteristic lung histopathology includes the accumulation of histiocytes with variable amounts of fibrosis and a variable lymphoplasmacytic infiltrate in a lymphangitic distribution. Immunostains are diagnostically useful, showing immunopositivity for CD68 and factor XIIIa and immunonegativity for CD1a. Birbeck granules are uniformly absent ultrastructurally.

Erdheim-Chester disease is a rare nonfamilial histiocytic disorder first identified by William Chester in 1930 that primarily affects middle-aged and older adults and predominantly involves the long bones of the extremities.^1–3 Bone pain is the most common presenting symptom, and characteristic radiographic changes in the long bones—bilateral cortical sclerosis predominantly involving the metaphyses and diaphyses—is considered virtually pathopneomonic.² The etiology of Erdheim-Chester disease is unknown.⁴ It is undetermined whether Erdheim-Chester disease is a monoclonal proliferative disorder or whether it is a polyclonal reactive disease.^4,5 While Erdheim-Chester disease has been known to occur in patients who also have Langerhans cell histiocytosis, the 2 diseases are generally considered to be separate entities.⁴ Neither has Erdheim-Chester disease been found to be a lipid storage disease.⁵ Approximately 50% of patients have disease involvement in other tissues, including skin, retro-orbital and periorbital tissues, pituitary-hypothalamic axis, heart, kidney, retroperitoneum, breast, skeletal muscle, sinonasal mucosa, and lung.⁴ Prognosis generally depends on the extent of the extraosseous disease, with 59% of patients reportedly dying of their disease and 36% dying of the disease at 6 months.^2,6

One hundred seventy-six cases of Erdheim-Chester disease have been reported in the literature. One hundred sixty-four cases had been reported as of August 2002,⁴ and our review of the English-language literature shows 12 additional case reports published between August 2002 and June 2003.^7–18 Forty-one (23%) of the 176 cases showed pulmonary involvement. Detailed descriptions of the pulmonary histopathology were present for 23 of the 41 cases with pulmonary involvement (Table ). This case report represents the 24th reported case of Erdheim-Chester disease with pulmonary involvement that presents a detailed description of the pulmonary histopathology.

A 60-year-old man with no history of smoking and a past medical history of hypertension presented with painless loss of vision in one eye, dyspnea, iron deficiency anemia, decreased renal function, and sclerotic and lytic lesions on long bone x-ray. Prominent slightly elevated yellow plaque lesions were present on all 4 eyelids (Figure 1 ). Well-circumscribed lesions surrounding the optic nerves of each orbit were identified by magnetic resonance imaging. Left orbital biopsy showed a firm homogeneous yellow mass composed histologically of adipose tissue infiltrated by foamy histiocytes, with areas of fibrosis and a mixed inflammatory infiltrate surrounding the histiocytes (Figure 2 ). The histiocytes were immunopositive for CD68 and immunonegative for S100. A diagnosis of orbital xanthogranuloma was made, with the diagnosis of Erdheim-Chester disease suggested based on the presence of bilateral orbital masses.

Long bone radiology showed characteristic bilateral distal femoral and proximal tibial osseous involvement by Erdheim-Chester disease. Chest radiography showed bilateral hilar adenopathy and a mediastinal mass, focal pleural thickening, and diffuse bilateral interstitial opacities, predominantly in the upper lobes. Lung biopsies consisting of a left upper-lobe wedge biopsy (measuring 1.4 × 1.2 × 1.0 cm) and a left upper-lobe wedge resection (measuring 9.0 × 1.5 × 1.0 cm) were performed to evaluate the patient's progressive dyspnea. Histologically, the lung parenchyma contained areas of fibrosis and a mixed inflammatory infiltrate, with interspersed histiocytes arranged in a lymphangitic distribution, involving bronchi, bronchioles, interlobar septa, and subpleural parenchyma (Figures 3 and 4 ). Lung parenchyma adjacent to these areas was relatively normal. The histiocytes were immunopositive for CD68 and factor XIIIa, focally immunopositive for S100, and immunonegative for CD1a (Figure 5 ). A mediastinal mass biopsy showed fibroadipose tissue with fibrosis. The patient's pulmonary condition worsened and he died 5 months after presentation. Autopsy showed widespread visceral involvement of Erdheim-Chester disease, including pericardium, lungs, kidneys, bladder, retroperitoneum, and orbits.

Of the 24 reported Erdheim-Chester disease cases with lung involvement and detailed descriptions of the lung histopathology, gender distribution is equal, the cases describing 12 (50%) women and 12 (50%) men. Mean age is 56.9 years (range, 25–76 years), with only 1 patient who was younger than 40 years old. Men are generally older than women at diagnosis, with the mean age for women being 50.5 years (range, 25–69 years), and the mean age for men being 63.3 years (range, 49–76 years). As has been noted previously,² dyspnea is a frequent presenting feature, and 18 (82%) patients presented with dyspnea of variable duration. Findings of radiographic changes of diffuse interstitial infiltrates in 17 (89%) patients and pleural and/ or interlobar septal thickening in 12 (63%) patients are consistent with prior reported radiology findings in these patients.^2,3

Patient follow-up, available for 18 of the 24 patients with lung involvement, shows an overall 3-year survival rate of 66%. Eleven (61%) patients ultimately died of their disease (3 weeks to 16 years later), with 6 (33%) patients dead of their disease within 3 years. Five (28%) patients were alive with stable disease (8 months to 5.3 years). One patient was alive with severe respiratory compromise (at 4 years). These findings are similar to a prior report noting that 57% of patients died of the disease from 3 weeks to 8 years after diagnosis of lung involvement.²

Two recent articles have described the lung histopathology in patients with Erdheim-Chester disease.^2,3 Histopathologically, lung involvement is characterized by (1) accumulation of foamy or clear histiocytes; (2) variable amounts of associated fibrosis; and (3) a variable lymphoplasmacytic inflammatory infiltrate (4) arranged in a lymphangitic pattern.

The lymphangitic distribution—subpleural, interlobar septal, and bronchovascular—of histiocytes and associated fibrosis is identified in 18 (75%) patients. Three patients (patients 13, 15, and 16) were described as having granulomas; however, granulomas are not characteristically present in patients with lung involvement with Erdheim-Chester disease.

Immunostains were performed in 20 of the 24 reported Erdheim-Chester disease cases with lung involvement and detailed descriptions of the lung histopathology. CD68 was immunopositive in 13 patients (100% positivity); factor XIIIa was immunopositive in 6 patients (100% positivity); and CD1a was immunonegative in 14 patients (100% negativity). S100 immunostaining was performed in 20 cases and was variable. Six (30%) cases stained immunopositively, 3 (15%) cases stained variably immunopositively or had only a small number of immunopositive cells, and 11 (55%) cases stained immunonegatively. This variable S100 immunostaining pattern may be attributable to reactive histiocytes, which generally are S100 immunopositive, infiltrating the fibrohistiocytic areas in reaction to the Erdheim-Chester disease. Further examination of these S100-immunopositive histiocytes may be helpful in determining whether they are reactive histiocytes, histiocytes of Erdheim-Chester disease, or histiocytes of another origin. Ultrastructural studies were performed in 6 cases; none contained Birbeck granules, typically associated with Langerhans cell histiocytosis.

In summary, Erdheim-Chester disease is a rare nonfamilial histiocytic disorder of unknown etiology with characteristic long bone findings. Overall, the 3-year survival rate in Erdheim-Chester patients is 50%. About 1 in 5 patients have lung involvement. Our study found that for these patients, the 3-year survival rate was 66%. For patients with lung involvement, gender distribution is equal, but men typically present at an older age than women. Four of five patients present with dyspnea, and most patients have diffuse interstitial infiltrates and pleural and/ or interlobar septal thickening on chest radiology. Characteristic lung histopathology includes the accumulation of histiocytes with variable amounts of fibrosis and a variable lymphoplasmacytic infiltrate in a lymphangitic distribution. Immunostains are diagnostically useful, showing immunopositivity for CD68 and factor XIIIa and immunonegativity for CD1a. Birbeck granules are uniformly absent ultrastructurally.

Published Cases of Erdheim-Chester Disease With Detailed Descriptions of Pulmonary Histopathology*

Click on thumbnail for full-sized image.