INTRODUCTION

TOP ABSTRACT INTRODUCTION DISCUSSION REFERENCES

Adult pulmonary Langerhans cell histiocytosis (LCH), also called pulmonary histiocytosis X, is a disease of unknown etiology characterized by the presence of granulomas containing large numbers of Langerhans cells (LC) that invade and destroy distal bronchioles (1). In a minority of patients, the disease follows a downhill course, leading to the appearance of diffuse cystic and bullous changes in the lung parenchyma, and ultimately resulting in respiratory insufficiency (4). This deterioration is typically progressive, although the rate at which lung function deteriorates can be quite variable. In the remainder of adults, pulmonary LCH initially follows a benign course, and clinical and radiological abnormalities either stabilize (50%) or regress (25% of patients), often without treatment (1, 4, 5, 7). Studies evaluating the long-term course of a large series of patients are not available. Thus, it remains unclear to what extent different patterns of long-term evolution can occur in patients with initially stable disease.

We describe four patients with biopsy-confirmed pulmonary LCH whose initial course was characterized by regression of nodular parenchymal abnormalities, but who subsequently developed one or more episodes of active disease 7 mo to 7.5 yr after their initial presentation.

	CASE REPORTS

Patient 1

A 22-yr-old woman with a 7-yr 2 pack/d smoking history presented in October 1987 with fever, cough, and dyspnea on effort. Chest radiography demonstrated diffuse nodular and cystic lesions in the lungs (Figure 1A), findings which were not present on a chest radiograph taken 2 mo earlier as part of a routine checkup. The presence of nodular lesions and cysts was confirmed by high-resolution computed tomography (HRCT). Clinical examination was normal. Pulmonary function was normal except for carbon monoxide diffusing capacity of the lungs (DL_CO) of 74% predicted value. The diagnosis of pulmonary LCH was established by open lung biopsy in December 1987. Treatment with oral corticosteroids was initiated, and was associated with the resolution of clinical symptoms. Corticosteroids were progressively tapered and stopped in June 1988. Serial chest radiographs demonstrated the disappearance of nodular lesions and the presence of diffuse cystic lesions, which remained unchanged between 1990 and 1995 (Figure 1B). The patient continued to smoke. Two pregnancies (1990 and 1991) had no apparent effect on the evolution of the process. In February 1995, 7.5 yr after initial diagnosis, symptoms reappeared and chest radiographs again showed the presence of nodular lesions (Figure 1C). HRCT demonstrated nodules associated with linear shadows and evidence of bronchial distortion. Further evaluation revealed no evidence of lung infection, and the patient was followed without treatment. Nodular lesions regressed spontaneously, and at her last follow-up visit (February 1996) a chest radiograph showed only cystic changes. Throughout this period, the patient continued to smoke.

View larger version (112K): [in this window] [in a new window]   View larger version (99K): [in this window] [in a new window]   View larger version (106K): [in this window] [in a new window]   Figure 1.   Chest roentgenograms from Patient 1. In October 1987, both nodular and cystic lesions were diffusely present in the lung (A). In September 1990, nodular lesions are no longer seen (B), but are again present in February 1995 (C ).

Patient 2

An asymptomatic 29-yr-old woman, who had smoked 20 cigarettes/d for 10 yr, was evaluated in August 1989 for bilateral nodular lesions in the upper lung fields discovered on a routine chest radiograph. No diagnosis was established. The patient received empiric antituberculous therapy, and the radiographic abnormalities showed moderate regression. In September 1990, the patient developed weakness, weight loss, and dyspnea on effort. Clinical examination was normal except for right axillary adenopathy. A chest radiograph showed a marked increase in the nodular pulmonary shadows, and HRCT confirmed that these lesions were purely nodular (Figure 2A). Pulmonary function testing was normal. Surgical biopsies of lung and axillary lymph node demonstrated typical histological findings of LCH. The patient stopped smoking in October 1990. Progressive clearing of the nodular lesions was seen on chest roentgenograms, which was confirmed by HRCT (Figure 2B). When seen in May 1991, the patient had remained asymptomatic and had continued to abstain from smoking. Nevertheless, chest radiography showed a marked increase in nodular lesions, including in regions that had initially showed no involvement on HRCT (Figure 2C). No other intercurrent pathology was identified, and the patient was treated with 0.5 mg/kg prednisone daily followed by tapering doses over a 6-mo period. Subsequent evolution was marked by regression of the nodular lesions and the appearance of cystic cavities, which, at last evaluation in May 1997, had remained stable for 24 mo. The only abnormality found on pulmonary function testing was a DL_CO of 67% predicted value.

View larger version (85K): [in this window] [in a new window]   View larger version (89K): [in this window] [in a new window]   View larger version (98K): [in this window] [in a new window]   Figure 2.   Lung HRCT from Patient 2. At the time of diagnosis (September 1990), only nodular lesions were present, which were found predominantly in the upper zones of the lungs (A). Progressive clearing of radiographic abnormalities occurred, and was confirmed by HRCT in November 1990 (B). Seven months later (May 1991), nodular lesions had reappeared, including in areas that had not previously shown involvement (C ).

Patient 3

An asymptomatic 38-yr-old woman, who had smoked 10 cigarettes/d for 18 yr, was discovered to have bilateral nodular and cystic lesions in the upper lung fields on a routine chest radiograph taken in November 1992. These findings were confirmed by HRCT. Pulmonary function tests demonstrated normal lung volumes, but DL_CO of 60% predicted values. The diagnosis of LCH was established by open lung biopsy. The patient was followed without treatment, and continued to smoke. Serial chest radiographs showed progressive resolution of the nodules. In August 1994, dry cough, exertional dyspnea, and fever developed. A marked increase in the number and size of nodular densities was observed on chest radiographs and confirmed by HRCT. Pulmonary function testing now demonstrated evidence of airway obstruction (FEV₁/FVC 70%) and a reduced DL_CO (52% predicted value). An extensive evaluation for infectious agents was negative. Oral corticosteroids (0.5 mg/kg/d) were begun in September 1994 and discontinued 10 mo later after gradual tapering. During this time, symptoms improved and nodular lesions seen by chest radiography resolved. When last seen in May 1997, diffuse cystic changes in the lung parenchyma were the only abnormalities seen on chest radiographs.

Patient 4

A 37-yr-old woman, who had smoked 20 cigarettes/d for 20 yr, presented in March 1995 with fever, weakness, night sweats, arthralgias, and a dry cough. Physical examination was normal. Chest radiography demonstrated nodular densities throughout both lung fields. HRCT confirmed the nodules and revealed the presence of rare cystic lesions. Pulmonary function was normal except for a DL_CO of 59% predicted value. Evaluation for infectious agents was negative. A 2-mo course of empiric antituberculous therapy was started in June 1995 and was without effect on signs or symptoms. Open lung biopsy was then performed and revealed the presence of florid and active LCH. Following surgery, the patient stopped smoking. Over the ensuing 4 mo, clinical symptoms abated without therapy and serial chest films demonstrated partial resolution of the nodular densities. In January 1996 the patient again started smoking (10 cigarettes/d). Three months later, symptoms similar to the initial episode developed. HRCT revealed the presence of new nodular lesions in regions that had been normal on the previous study. In addition, cystic spaces were now present in some of the areas previously found to contain nodular lesions. Pulmonary function test showed reduced lung volumes (total lung capacity 78% predicted) and reduced DL_CO (50% predicted value). The patient again quit smoking, and oral prednisone (0.75 mg/ kg/d) was started in May 1996. Three months later, the patient was asymptomatic while receiving 0.5 mg/d prednisone; she had again started smoking. A chest radiograph showed purely cystic lesions. In December 1997, the patient remained well while receiving 0.15 mg/kg/d prednisone. Chest radiographs were unchanged and lung HRCT showed the presence of diffuse cytic lesions without nodules.

	DISCUSSION

TOP ABSTRACT INTRODUCTION DISCUSSION REFERENCES

In this report, we describe patients with pulmonary LCH whose disease initially underwent regression, but who subsequently developed one or more episodes of active disease, in each case characterized by the appearance of new nodular pulmonary lesions and accompanied, in three cases, by a recrudescence of systemic and pulmonary symptoms. To our knowledge, this is the first report of the occurrence of such discrete episodes of active disease in the course of adult pulmonary LCH.

At the time of initial diagnosis, the patients described here had active pulmonary disease of recent onset. Thus, initial radiographic abnormalities were predominantly or exclusively nodular in all patients, florid granulomatous lesions containing large numbers of LC were present in tissue biopsies, and one patient had a normal chest radiograph only 2 mo prior to diagnosis. Resolution of disease occurs frequently in this context, and was initially observed in all the patients reported here. No single factor could be identified that was associated with subsequent relapse of disease in these patients.

Relapse of multifocal or diffuse forms of LCH in children is not uncommon, and often occurs when therapy is discontinued or reduced (8). Discontinuation of corticosteroids was clearly not a factor, because only one of the patients had previously received corticosteroids, and therapy had been stopped 7 yr prior to relapse.

Pregnancy has been reported to aggravate preexisting pulmonary LCH in a few patients, and recrudescence of extrapulmonary LCH at the time of pregnancy has also been reported (12, 13). Only one of our patients became pregnant during follow-up, but relapse of pulmonary LCH occurred several years after her last delivery.

Heavy cigarette smoking is known to be a strong risk factor for pulmonary LCH, and all the patients described here smoked at the time of initial diagnosis (1, 7). The extent that smoking cessation influences the evolution of pulmonary LCH remains to be established. As previously reported (14), initial improvement in symptoms and radiographic abnormalities was associated with smoking cessation in two of our patients, but two other patients showed spontaneous resolution even though they continued to smoke. Similarly, subsequent relapse of pulmonary LCH was temporally associated with a return to regular tobacco use in one patient, but also occurred in two patients who had continued to smoke without interruption and in one patient who had continued to abstain from smoking. Thus, no definite association between relapse and cigarette smoking could be established in this series.

HRCT is a more sensitive means to detect pulmonary abnormalities in patients with LCH than is chest radiography (15). In this regard, chest radiographs from Patient 1 were interpreted as showing complete absence of nodules between episodes of active disease, but no confirmation by HRCT was available. Thus, in this patient, the possible persistence of a small number of nodular lesions between episodes of active disease, as was seen for the other patients, cannot be excluded. Similarly, in the absence of multiple lung biopsies, it remains unknown to what extent pathological evidence of "active" disease would have been observed at a time when nodular lesions were greatly diminished and clinical symptoms had resolved.

It should be emphasized that the appearance of new symptoms or the rapid deterioration in pulmonary function in a patient previously diagnosed as having pulmonary LCH can have a variety of causes. Thus, patients with quiescent disease who have residual pulmonary abnormalities can suddenly deteriorate as a result of an intercurrent bronchopulmonary infection, the development of a pneumothorax, or secondary to decompensation of underlying cor pulmonale. For example, the late deterioration occurring in the patient described by Powers and colleagues appears to have been due to such causes, because no evidence of active disease was seen in lung tissue obtained at that time (16).

The occurrence of new episodes of LCH associated with the appearance of nodular pulmonary lesions may not be uncommon for patients with this disease; this pattern of evolution has been observed in four of the 65 patients with pulmonary LCH who have been followed by our service for more than 5 yr. Furthermore, because these episodes of active disease need not be symptomatic, the frequency of this pattern may have been underestimated. Further efforts are needed to determine the extent to which reappearence of nodular lesions modifies the long-term prognosis of patients with pulmonary LCH, and to determine whether this evolution can be prevented by cessation of smoking, corticosteroids, or other therapeutic agents.