INTRODUCTION

TOP ABSTRACT INTRODUCTION DISCUSSION REFERENCES

Fifty-nine cases of Erdheim-Chester disease (ECD) have been reported in the literature. The age range of patients appears to be wide, but most are middle-aged or elderly (mean age, 53 yr) with a male/female ratio of 33/26 (1). Bone involvement is constant, and radiologic investigations provide strong indicators of the diagnosis (2). Associated extraskeletal lesions are described in more than 50% of patients at the time of diagnosis and in nearly all patients at the time of death, reflecting a progressive disseminated granulomatous infiltration of soft tissues. Among them, kidney, retroperitoneal space, skin, brain, and lung are affected in decreasing order of frequency (1, 3, 4). In all locations, interstitial connective tissue is the primary target of pathologic lesions. The case we report raises the issue of a primary macrophage disorder rather than a lipid dysmetabolism.

	CASE REPORT

A 41-yr-old white woman was admitted to the hospital for shortness of breath. She had experienced progressive dyspnea for 3 yr. She had had bilateral leg pain for a few months. Physical examination was normal, without clubbing or crackles. Laboratory findings, including erythrocyte sedimentation rate, hemoglobin, hematocrit, white cell count, and lipid profile (cholesterol, triglyceride, and LDL and HDL cholesterol) were unremarkable.

Pulmonary function tests indicated a minor mixed restrictive and obstructive defect, with reduced CO transfer. Arterial blood gas determinations demonstrated a moderate hypoxemia (Pa_O2, 64 mm Hg) with hypocapnia (Pa_CO2, 34 mm Hg). Chest radiography and computed tomographic scan of the thorax (Figure 1) demonstrated a pattern of diffuse interstitial pneumonia without micronodular lesions. Interstitial thickening involved both upper and lower pulmonary parenchyma, but it predominated in peripheral areas. The diagnosis of a Langerhans' cell granulomatosis was excluded with only 1% of bronchoalveolar lavage cells stained with CD1a and S100 protein monoclonal antibodies. A radiograph of the tibias revealed a symmetrical irregular and heterogeneous pattern in the metaphyses. A radiograph of the humeral diaphyses demonstrated large mixed lytic and sclerotic lesions, surrounded by a reparative bone process.

View larger version (186K): [in this window] [in a new window]   Figure 1.   Computed tomographic scan of the thorax demonstrating an interlobular thickening, subpleural cystic air spaces, and honeycombing.

An open lung biopsy was performed on the left lower lobe. Histologic examination revealed an interstitial infiltration of large macrophages thickening the peribronchiolar, perivascular, periseptal, and subpleural spaces. These cells had a small round nuclei and a large eosinophilic cytoplasm, rarely vacuolated or foamy (20 to 50 mm in diameter). They dissociated interstitial connective tissue in association with lymphocytes and a rich capillary network (Figure 2). Beside florid lesions, nodular fibrosis was frequent, with dense collagen deposition in the granuloma and retraction of tissue, resulting in stellar fibrous scars extending to peripheral alveolar walls (Figures 3 and 4). Areas of microscopic honeycombing were present. An immunohistochemical study showed that these interstitial macrophages were CD68 positive but S100 protein and CD1a negative. An ultrastructural study did not show Birbeck granules but it did show the presence of numerous secondary lysosomes and phagolysosomes, demonstrating the phagocytic nature of these cells. Lipid vacuoles were scarce and were not suggestive of a lipid storage disease.

View larger version (160K): [in this window] [in a new window]   View larger version (162K): [in this window] [in a new window]   Figure 2.   Peribronchiolar (left panel ) and perivascular (right panel ) spaces infiltrated by large cells (arrowheads) associated with lymphocytes and mild fibrosis (HES; original magnification: ×800).

View larger version (140K): [in this window] [in a new window]   Figure 3.   At higher magnification, pleural tissue is sparsely infiltrated by the same large cells with eosinophilic cytoplasm (arrowhead ) (HES; original magnification: ×2,400).

View larger version (163K): [in this window] [in a new window]   Figure 4.   In late lesions, stellar fibrous scars sometimes extend to alveolar walls (asterisk) (HES; original magnification: ×125).

Pulmonary infiltration and mixed lytic sclerotic metaphyseal and diaphyseal bone lesions were consistent with radiologic changes of Erdheim-Chester disease. Histologic, immunohistochemical, and electron microscopic features excluded the possibility of a Langerhans' cell granulomatosis.

In the absence of significant progressive disease over time, no therapy was introduced.

	DISCUSSION

TOP ABSTRACT INTRODUCTION DISCUSSION REFERENCES

To our knowledge, only 12 Case Reports of ECD with lung involvement have been published (3, 5). Besides pulmonary lesions, mediastinal fibrosis, and pleural thickening or effusion have been reported (1). Dyspnea and cough are the most frequent symptoms, with pulmonary involvement (54%). However, physical examination often remains normal. Crackles and pulmonary rhonchi were described in two cases (4, 16). Results of pulmonary function tests are rarely reported, but a moderate restrictive defect seems to be a common functional feature. Arterial blood gases are usually not impaired. Moderate to severe hypoxemia was reported twice (13, 16). In contrast to Langerhans' cell granulomatosis, acute pulmonary complications have rarely been described during the course of ECD. Pneumothorax has never been reported. However, a fatal outcome associated with respiratory failure in end-stage lung ECD is more frequent than during histiocytosis X (12, 16, 17).

Computed tomography (CT) scan and high-resolution CT (HRCT) findings in the lung have been well described (2, 11). Radiologic abnormalities precede clinical symptoms (16). A symmetrical smooth thickening of interlobular septa, subpleural micronodules, and areas of ground glass attenuation represent the most common features. Secondly the presence of cystic air spaces and honeycombing with a peripheral predominance are often seen, related to the development of pulmonary fibrosis. However, none of these radiologic profiles are specific for ECD. They can be observed in other interstitial disorders such as pulmonary venous dilatation, lymphangitic disorders, pulmonary edema, and idiopathic fibrosis (14, 18). In pulmonary histiocytosis X, HRCT patterns appear different, with progressive nodular-cystic air-space changes. Chest CT scan shows a diffuse distribution of the disease, without preferential peripheral localization of abnormalities (19).

Bone lesions are considered to be specific enough to suggest the diagnosis of ECD. Radiographic changes in the skeleton are characteristic, occurring symmetrically in tubular long bone with mixed lytic and sclerotic areas of the metaphyseal and diaphyseal portions (4). However, overlap of radiographic presentation with Langerhans' cell granulomatosis has been described in ECD with asymmetrical, axial skeleton, and flat bone (ribs, pelvis, and skull) involvement (3, 20). Conversely, long bone tubular lesions have been described in Langerhans' cell granulomatosis (21). Moreover, a recent case of mixed disease has been reported associating ECD and Langerhans' cell granulomatosis in the mandibula (22).

A relationship between the physiopathologic aspects of ECD and a lipid storage disorder has been suspected, but it has never been established (7, 20). To our knowledge, a lipid analysis had been performed on bone lesion in two instances, revealing a mixed cholesterol, cholesterol ester, and palmitic acid esters profile (20, 23). This lipid profile was not consistent with an enzyme defect reliable to a lipid storage disorder. In the current case, we could not perform such an analysis because lung lesions were microscopically lipidless. Histologic findings were very similar when compared between different infiltrated tissues, and lipid-rich macrophages have been essentially described in previous reports (3, 20, 22, 23). However, the literature is poor in histologic description of lung lesions (2, 6, 10, 16). It is possible that macrophages were more lipid-laden because they are more prone to adaptative forms of cell degenerescence at other locations than in the florid lung lesions as observed in the present case. Our patient showed numerous macrophagic granulomas that were not lipid-laden. Only electron microscopy could identify small amounts of lipids in some cells. This finding provides strong argument against the commonly accepted hypothesis that ECD is primarily a lipid storage disorder. Pathologic changes are consistent with an interstitial infiltration by histiocytes or macrophages forming granulomatous lesions with fibrosis. These histiocytic cells are not Langerhans' cells. Immunohistochemical study using monoclonal antibodies anti-S-100 protein and anti-CD1a remained negative, and electron microscopy did not show Birbeck granules but phagolysosomes. Our histologic and ultrastructural findings are consistent with an infiltration by a macrophage cell type. The peripheral subpleural, peribronchovascular and interlobular distribution of the lesions help to explain HRCT findings (2).

Therapeutic successful interventions have not been described, but chemotherapy, corticosteroids, and hemibody radiation have been proposed, with variable effects (8, 12, 13, 16, 21). Impacts of treatments on lung outcomes are not described in the literature. Steroids alone or combined with chemotherapy have been used in six cases of ECD associated with lung involvement (1). The first aim of treatment was to control extrarespiratory symptoms. Transient benefit on bone pains, exophthalmia, and reduction or stabilization of retroperitoneal mass have been reported. The simultaneous effects on pulmonary infiltration and respiratory symptoms have never been reported in the follow-up series.