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January - March 2007: 
Volume 20, Issue 1

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Pulmonary Langerhans cell histiocytosis: Clinical and laboratory findings in 11 Greek patients and review of the literature
Abstract
SUMMARY. Pulmonary Langerhans granulomatosis is a rare disease. This study aimed at presenting the clinical and laboratory data of 11 Greek patients, with a review of the literature concerning the pathogenesis, clinical course, diagnosis and prognosis of this disease. The age of our patients ranged from 18 to79 years with almost all of them being active smokers. The main symptoms at the time of diagnosis were cough and dyspnoea on exertion, while in 3 patients extrapulmonary manifestations of the disease were detected. Radiological findings were indicative of the disease in 7 patients and pulmonary function tests were abnormal in most patients. Diagnosis was made by open lung biopsy in one case, thoracoscopic biopsy in 3 cases, detection of the characteristic immunological markers in bronchoalveolar lavage in 6 cases and characteristic radiological findings in one case. All the patients were advised to stop smoking and no other therapeutic interventions were carried out. Follow-up data were available in 7 patients. Pneumon 2007; 20(1):73-82.
Full text

Introduction

 

Langerhans cell histiocytosis (LCH) constitutes a significant part of a group of diseases, characterized by monoclonal proliferation and the involvement of tissues by Langerhans cells.1 The prevalence of the disease is low, between 1/200,000 and 1/2,000,000 people per year, being similarly manifested in both the sexes. The organs predominantly involved are lungs, bones, skin, hypophysis, liver, lymph nodes and the thyroid gland. The lungs are being involved either in isolation or in combination with other organs. Single-system disease is characterized by the involvement of a single organ (bone, lungs or skin) and it usually follows a benign course and may regress spontaneously. The term “Pulmonary Langerhans cell histiocytosis” (LCH) refers to isolated or predominant pulmonary involvement.1 The different forms of severe multisystemic disease include Letterer-Siwe disease and Hand-Schuller-Christian disease (typical triad of exophthalmus, diabetes insipidus and bone involvement), both of which are manifested in children rather than in adults and carry a poor prognosis.

 

During the last 15 years, the improvement of immunohistochemical techniques, with the use of monoclonal antibodies, as well as the extensive use of high resolution computed tomography (HRCT), have contributed significantly to the diagnosis of this disease, substituting open lung biopsy (OLB) and video assisted thoracoscopic surgery (VATS) in many cases. Nevertheless, many questions remain about the pathogenesis, clinical course and prognosis of this rare disease.

 

 In this of study, the clinical and laboratory data 11 Greek patients diagnosed in four Community Hospitals in Athens are presented.

 

Methods

 

Demographic data (age at diagnosis, smoking habits), clinical data (symptoms, clinical findings), imaging and laboratory data (pulmonary function tests, specific immunomarkers in Bronchoalveolar lavage (BAL) and biopsy specimens), were retrospectively studied in 11 Greek patients with pulmonary histiocytosis, all but one of them were diagnosed in the last five years (2001-2005); the one out of the 11 was diagnosed in 1993 and is under the follow up.

 

In this study, only patients with a confirmed diagnosis of pulmonary histiocytosis were included. The diagnosis was made by lung biopsy (open lung biopsy or VATS) or by BAL (specific immunomarkers detected Langerhans cells). In one patient the diagnosis was suggested by the specific findings in High Resolution Computed Tomography (HRCT) and confirmed by the impressive improvement of CT findings on smoking cessation. Follow-up data were available for seven patients.

 

Results

 

Demographic and clinical finding for patients under study are shown in Tables 1 and 2. Five males and six females were included with the average age being 30 years (range 19-79 years). All patients but one (whose smoking status was unknown) were active smokers. Cough and dyspnea were the main symptoms at the time of diagnosis (63.6% and 54.5% respectively), followed by fever (27.3%), malaise (18.2%) and weight loss (9%). In two patients (18.2%), pneumothorax was the first clinical manifestation of the disease. One patient was done completely asymptomatic at presentation and routine radiological examination revealed the pathology. Extrapulmonary manifestations were present in three patients; one presented diabetes insipidus, while in one, other osteolytic findings were observed (typical of eosinophilic granuloma) and in one patient, cervical and axillary lymphadenopathy was observed, with no malignant pathology. Specific immunohistochemical studies aimed at identifying Langerhans cells in the lymph node tissue had not been performed in this patient. The diagnosis of LCH was based on pulmonary tissue biopsy obtained by thoracoscopy. Consequently, the lymph node enlargement was attributed to this disease.

 

Radiological findings are listed in Table 3. In chest x-ray, reticulonodular lesions in the upper and middle pulmonary fields were observed in five patients and the lung volume was preserved. A reticular pattern with cyst formation was observed in one patient, and honeycombing was detected in two patients, in whom the volume reduction was also observed. In two patients, the chest x-ray findings were minimal and one patient had a completely normal chest x-ray. On HRCT the coexistence of cavitated small nodules with cysts was detected as the main finding in six patients and small nodules in three patients. In two patients, the cardinal finding on HRCT was only small cysts. In all the patients, the findings were manifested in the upper and middle pulmonary fields. Honeycombing with lung distortion and traction bronchiectasis were present in two patients. In seven patients the HRCT findings were characterized as highly specific for eosinophilic granuloma.

 

Lung function tests (table 4) were typical of an obstructive pattern in five patients and restrictive in two, whereas in three patients, spirometry was normal at diagnosis. Carbon monoxide diffusion capacity (DLCO) was measured in ten patients and found reduced in eight of them. In three of eight patients spirometry was normal; this was highly indicative of the sensitivity of DLCO in detecting lung function abnormality in such patients. In one patient, no lung function test was available at the time of diagnosis.

 

Blood gases at rest (21% O2) were available in nine patients and in five also after exercise. Hypoxaemia at rest (PO2 <70 mmHg) was detected in two patients, and a fall in PO2 ≥ 4 mmHg after exercise was observed in three patients, in two of whom DLCO was reduced; the third had normal DLCO. In two patients, exercise blood gases showed an increase in PaO2 and a decrease in PaCO2, whereas DLCO in these patients was reduced. It is noteworthy that the 79 year-old patient, in whom extensive honeycombing lesions were detected at HRCT, had almost normal lung volumes but marked hypoxaemia and severe reduction in DLCO (FEV1 = 83% pred, FVC = 75% pred, FEV1/FVC = 83%, TLC = 55% pred, DLCO = 13% pred, and PO2 = 36 mmHg on air).

 

 Diagnosis was confirmed OLB in one patient and VATS in three patients; in six patients the diagnosis was made by a combination of characteristic immunohistochemical markers in BAL and typical HRCT findings. In one patient, diagnosis was made solely on the very specific findings on HRCT (nodules and cysts in the upper lobes); BAL markers were negative in this patient, but since the patient was asymptomatic there was no reason for OLB or VATS. Τransbronchial biopsy (TBB) was not performed in this patient because of its relatively low diagnostic yield (10-40% in various series), the technical difficulties in performing TBB in the upper lobes, as well as the increased risk of pneumothorax in patients with pulmonary cysts. She stopped smoking and six months later HRCT showed significant improvement, thereby establishing the diagnosis.

 

BAL was performed in eight patients but unfortunately, not in the patients who were submitted to VATS. In the patient who was diagnosed by OLB, BAL was performed but the specific immunobiological markers were not evaluated, because they were not available at that time. Immunochemistry showed a positive CD1a antigen in six patients and S-100 protein positive in five of the six. In one patient, the above markers were negative and in another patient, there were no data available on them. BAL cytometry revealed increased total number of cells (>20 x 106 cells) predominantly alveolar macrophages (>48% of total cell count), as well as mild increasement of the number of eosinophils (6-12%) in all the patients.

 

Discussion

 

Pulmonary histiocytosis is a rare disease. In a large series of patients with diffused interstitial lung disease of unknown aetiology who underwent open lung biopsy, 5 % had histology findings consistent with pulmonary histiocytosis, thus certifying the rarity of the disease.3

 

The demographic findings and smoking habits for 11 patients in this study are summarized in Table 1. This study verified the equal incidence of disease in male and female participants. In the literature, disease incidence according to sex for histiocytosis is controversial. Some studies report a higher incidence in males,4 whereas more recent data demonstrate equal incidence for both sexes or even a slightly higher frequency of disease in the female patients,5,6 which may be related to a higher incidence of smoking observed in women in recent years. In this study the appearance of disease was in patients aged between 18 and 79 years, the average age being 35 ± 18.7 years. Pulmonary histiocytosis usually appears in young adults with a maximum incidence of appearance in patients aged between 20 and 40 years,2,5 however, the presentation of disease in older patients, although less frequent, cannot be excluded. Diagnostic methods for pulmonary histiocytosis including HRCT of the chest and the characteristic immunohistochemical findings in BAL make it possible to detect the disease in older patients, in whom the disease may have gone unnoticed prior to the availability of this diagnostic technology. In this study, the disease was diagnosed in a patient of 79 years and similar cases are sporadically reported in the literature.7,8

 

 Nearly all the patients in this study were smokers. Ten of 11 patients were active smokers (ranging from 3 to 100 pack years), and one patient’s smoking was unknown. There is ample verification of the causative relationship between smoking history and pulmonary histiocytosis in the literature.9,24-26 The majority of patients with pulmonary histiocytosis (over 90%) have a smoking history, being either active or past smokers. Additional verification comes from recent research, in which diffused granulomatous inflammation with histological characteristics similar to those of histiocytosis was experimentally provoked in mice exposed to cigarette smoke. When exposure of the mice to cigarette smoke was stopped, infiltration of lung parenchyma by Langerhans cells returned to levels similar to those in the control group.9

 

Although pulmonary histiocytosis in adults is directly related to cigarette smoke, this does not apply for extrapulmonary variations of Langerhans disease (approximately 60% of patients with extrapulmonary disease are smokers). Numerous references allude to the fact that pulmonary histiocytosis is represented by a polyclonal disturbance brought about by antigens present in cigarette smoke, in contrast to extrapulmonary histiocytosis, where a characteristic monoclonal hyperplasia of Langerhans cells is observed, similar to that in the neoplastic processes.10

 

The clinical findings of the patients in this study are summarized in Table 2. Cough and exertional dyspnea were the most common symptoms, present in 63.3% and 54.5% of the patients respectively. Fever (27.3%), fatigue (18.2%) and weight loss (9%) followed as the next most common symptoms. Other studies report that respiratory symptoms, particularly dry cough and dyspnea, which can exist for a period greater than six months, are present in 2/3 of patients with histiocytosis. Systemic symptomatology including fever, weight loss, night sweats and anorexia is reported in 1/3 of the patients with pulmonary histiocytosis.1,5 Two of the patients (18.2%) in this series presented with spontaneous pneumothorax as a primary clinical finding. Internationally, spontaneous pneumothorax is reported in 10%-20% of patients with eosinophilic granuloma and is due to subpleural cystic lesion rupture.5-8 One female patient was completely asymptomatic and the diagnosis was made during a random health check. The literature reports up to 25% of patients with eosinophilic granuloma to be asymptomatic during the diagnostic workup for other diseases.1,6

 

Extrapulmonary disease was present in 3, one of whom demonstrated an osteolytic lesion of the cranium, another one presented with supraclavicular and axillary lymph enlargement histologically negative for neoplastic disease at the time of diagnosis and one, an 18 year-old female presented with diabetes insipidus due to infiltration of the pituitary gland. Signs and symptoms as a result of extrapulmonary organ involvement occur in 5 - 15% of patients with eosinophilic granulomatous disease.1,2,6,7 Clinical symptomatology includes bone pain from osteolytic bone lesions (particularly of the cranium and ribs), polyuria and polydipsia due to diabetes insipidus, skin lesions, lymphadenopathy and hepatosplenomegaly.

 

 Physical examination of the chest usually does not reveal any remarkable symptoms, except for cases where spontaneous pneumothorax, osteolytic lesions of the ribs or signs of cor pulmonale in advanced disease occur. Other organ systems do not reveal pathological clinical signs on examination either, unless there is extrapulmonary organ involvement. In this study, only two patients demonstrated pathological clinical findings on examination. In one patient, auscultation revealed sparse bilateral crackles (pulmonary function testing in this patient showed a restrictive lung function with diminished diffusion capacity), while the second patient had diminished breath sounds bilaterally, accompanied by an obstructive dysfunction pattern and decreased diffusion capacity on pulmonary function assessment.

 

 Radiological findings on plain chest X-ray are directly related to the disease stage. These are usually bilateral and symmetrical, with upper and middle lung field distribution, sparing the pleurodiaphragmatic spaces.2,6,11,12 Upper lobe micronodular (< 5mm), or more commonly reticulonodular lesions are associated with recent disease. In more advanced disease, the nodules are absent and have been replaced by cystic lesions giving a “pseudoemphysematous” appearance. 6,11,12 Sometimes lytic lesions of the ribcage. Lung volume may remain normal or appear enlarged on plain chest films, which enables differential diagnosis of pulmonary hystiocytosis from other diffused interstitial lung disease, where lung volume is usually decreased (lymphangioleiomyomatosis is an exception). Unusual findings on plain chest X-ray include alveolar infiltrates, hilar lympadenopathy and pleural effusion, although hilar enlargement may occur in patients with pulmonary hypertension. Rarely (<10%),the chest X-ray is normal.13 Only one patient in this study had a normal chest X-ray (9%). Radiological findings in the remaining 10 patients included a predominant reticulonodular pattern of the upper lobes in five, (Figure 1), micronodular lesions in two (slightly discernable on chest x-ray), primarily cystic lesions in one and honeycomb lesions on plain chest films in two patients (including the 79 year-old).

Figure 1. Chest X-ray of a 46 year-old patient, smoker, with pulmonary langerhans-cell histiocytosis, showing a reticular pattern with a predominantly upper and middle lobe distribution.

 

HRCT is a very useful, sensitive diagnostic tool for pulmonary histiocytosis.11,14,17 Findings are related to the stage of disease. In a primary stage disease, small nodules (1-5 mm in diameter) are characteristically distributed around the small airways. With time, these nodules evolve into cystic lesions of varying size, shape, and wall thickness, and eventually the typical disease pattern with coexisting peribronchial nodules and cystic lesions of the upper and middle lung fields develops.11,14,15,17 As the disease progresses, the nodules disappear (they have now cavitated and have been replaced by initially thick-walled cystic lesions that in turn become thin-walled). During the final stages of the disease, fibrotic lesions, honeycombing and traction bronchiectasis are typical of disease. In the study patients the predominant HRCT lesion was the coexistence of nodules with or without cavitation with thick- or thin-walled cystic lesions (Figures 2 and 3), while in two patients, there were numerous lesions with extensive parenchymal destruction.

 

Figure 2. HRCT Scan of the chest of a 19 year-old patient, smoker, with pulmonary Langerhans-cell histiocytosis, showing a typical combination of cavitated nodules and cysts in the upper lobes.
Figure 3. HRCT Scan of the chest of a 18 year-old patient, smoker, with pulmonary Langerhans-cell histiocytosis, showing a combination of cavitated nodules, thin-walled cysts and traction bronchiectasis in the upper lobes.

When HRCT disease findings are typical of pulmonary hystiocytosis (coexistence of cavitated nodules with peribronchial distribution and cystic lesions of the upper and middle lung fields) with diagnosis being possible without the need for open lung biopsy.1,2,17 The typical form of the disease, however, is not the most commonly encountered form. Rare findings on chest CT include ground-glass alveolar opacities (differential diagnosis with hypersensitivity pneumonitis, obstructive bronchiolitis organizing pneumonia and chronic eosinophilic pneumonia) and mediastinal or paratracheal lymphadenopathy (up to 1/3 of cases on HRCT), leading to a differential diagnostic dilemma with sarcoidosis.11,14

 

Pulmonary function testing data reflect the duration of the disease as well as the nature of the parenchymal lesions. Patients with pulmonary hystiocytosis may present with either obstructive, restrictive or mixed dysfunction.1,4,5 Usually, vital capacity (VC) is reduced, residual volume (RV) is either normal or increased, and total lung capacity is maintained at normal levels, causing an increase in the RV/TLC ratio.2,4,6,16 This particular functional model has been associated with the presence of extensive cystic and emphysematous lesions on plain chest x-ray.4,6 The most characteristic and stable disease finding on pulmonary function testing is reduced diffusion capacity, observed in 70- 100% of patients.4-6,16 This reduced diffusion capacity has been associated with the degree of endurance limitation during exercise.16 An obstructive dysfunction in pulmonary function testing may also be due to the coexistence of obstructive pulmonary disease. Because the majority of patients are smokers, the obstructive pattern may reflect obstructive bronchiolitis due to peribronchiolar inflammation and fibrosis.1 At more advanced stages of the disease, the restrictive pattern predominates due to extensive fibrosis. It is of note that in some patients, despite extensive radiographic lesions, pulmonary function is minimally affected.2,4,16 Between 10% and 15% have normal lung function, despite the presence of radiological findings.2 In this study, as shown in Table 4, obstructive disease and decreased diffusion capacity were observed in the majority of patients. In three patients, dynamic and static lung volumes were normal at the time of diagnosis, but the diffusion capacity was decreased.

 

Arterial blood gases are usually normal or demonstrate a mild hypoxaemia which worsens during exercise.6,16 PCO2 usually remains within normal limits. Only two patients demonstrated hypoxaemia at rest, whereas three with normal blood gas analysis at rest had a greater than 4mmHg decline in PO2 following exercise. One patient had a mild hypocapnoia at rest (PCO2 = 31.2 mmHg), while in all the other patients, the PCO2 ranged between 34 and 42 mmHg. Although in this study no data were available concerning the presence and estimating the severity of pulmonary hypertension, it should be noted that pulmonary hypertension is a common complication in patients with end-stage pulmonary histiocytosis X, and its severity is independent of lung mechanics and hypoxaemia deterioration.42,43 Histopathological data show diffused pulmonary vasculopathy involving both pulmonary arteries and veins. These vascular changes consist of medial hypertrophy and intimal fibrosis leading to various degrees of luminal obstruction. Lesions in the pulmonary veins were similar with those observed in pulmonary veno-occlusive disease, whereas an involvement of the pulmonary arteries resembled idiopathic pulmonary hypertension. The pathogenesis of vascular remodeling is still under investigation but several mediators, such as cytokines and growth factors produced by the histiocytosis X granuloma, might play a role.42 Pulmonary hypertension, which is usually more severe than that described in other obstructive or interstitial lung diseases with the same degree of ventilatory limitation, presumably explains the severe reduction in DLCO and exercise limitation in patients with pulmonary histiocytosis X, which is out of proportion to the alterations in lung mechanics.42 The 79 year-old patient probably suffered from this disease.

 

Diagnosis of the disease is based on the detection of Langerhans cells in BAL lavage or in biopsy samples (obtained by TBB, thoracoscopic or open lung biopsy).1,2,17 Langerhans cells are recognized either by the presence of Birkbeck particles, which are cytoplasmic organelles resembling “tennis rackets” and can be seen only with the aid of an electron microscope,2 or through specific immunohistochemical detection of the intracellular protein S-10018-22 and the surface antigen CD1a.20-22 The intracellular protein and surface antigen have come to be recognized as the most specific markers in the diagnosis of the disease. When the percentage of CD1a positive cells in the BAL is >5% of the total number of cells, the diagnosis of pulmonary hystiocytosis is very much possible.20 Percentages between 2-5% are found in heavy smokers and in interstitial disease. Alternatively, percentages of >5% are thought to be highly probable diagnostically and are not affected by patient smoking habits. As reported in the literature, among patients with histologically verified pulmonary histiocytosis, detection of CD1a positive cells in BAL was highly diagnostic in all the patients.20,21,37 In this study was diagnostic in six of the eight who that underwent the procedure (in one patient, BAL was carried out without seeking the specific markers). The percentage of CD1a positive cells varied between 10% and 28% of the total number of cells in bronchoalveolar lavage (Figure 4). Specific S-100 protein was detected in five of six patients (Figure 5). BAL cytometry shows that the total number of neutrophils, eosinophils and lymphocytes is usually increased, as is the relative percentage of neutrophils and eosinophils (this applied to the patients in this study), without this being a specific disease finding.36

 

Figure 4. CD1a positive cells (Langerhans cells) (Immunoperoxidase x 40).
Figure 5. Langerhans Cells S-100 positive (Immunoperoxidase x 10).

TBB offers the lowest diagnostic value (10-40%) owing to the fact that the sample size is so small.5,23 This procedure was carried out in two of the study patients and was not diagnostic and these patients did have a diagnostic BAL. The gold standard for the diagnosis of the disease is lung parenchymal biopsy (either open or thoracoscopic) by which it is possible to obtain a large enough sample to make an accurate histopathological diagnosis of the disease.5,23 It is also reported that small Langerhans type granuloma may not be recognized in bioptic material even in advanced disease with extensive cystic lesions, being indicative of ongoing disease activity, despite the stage of the disease.17 Four patients, as shown in Table 5, were diagnosed through lung biopsy obtained either thoracoscopically (three patients) or via OLB (one patient).

 

Follow-up data, at least for the first year following diagnosis of disease, were available for seven of the eleven patients. One patient died due to severe respiratory failure following respiratory tract infection, one female patient who has been followed up regularly since 1993, when she was diagnosed with pulmonary hystiocytosis, demonstrated stable radiological findings as well as pulmonary function test data, despite the fact that she had only recently given up smoking, another female patient showed remarkable radiological improvement in six months after giving up smoking (pulmonary function testing in this patient was normal to begin with), whereas for the remaining 4 patients, it has come to be known through telephonic communication that they had stopped smoking, had no respiratory symptoms and demonstrated radiological improvement of disease according to their doctors. Lung function testing was not available for these patients. Other than smoking cessation, no other therapeutic intervention was performed on patients in this study at diagnosis and in the immediate follow-up period, at least for the above-mentioned seven patients.

 

 Τhe type of therapeutic intervention, and its results are difficult to assess due to the rarity of the disease, the variability in the natural course of the disease history (not infrequently the disease either remains stable for years or cures itself ), but also due to the lack of specific prognostic indicators thato determine the course of the disease in each patient at the time of diagnosis.

 

The cornerstone in the treatment of the disease is smoking cessation, which is essentially the only medical intervention in patients with pulmonary histiocytosis. 24,25 Smoking cessation promotes stabilization of the disease in most patients, and some studies report an improvement of the radiological findings and the functional parameters in patients who stopped smoking. 24-26 In addition, smoking cessation is necessary for the prevention of chronic obstructive pulmonary disease, lung cancer and respiratory infections that often complicate the course of disease in patients with eosinophilic granuloma. There have been no prospective studies that actually validate the effect of smoking cessation on patient survival.1

 

The therapeutic role of corticosteroids has not been clearly defined. Studies with a small number of patients report improvement in clinical symptomatology as well as in radiological findings in patients with pulmonary histiocytosis treated with corticosteroids, but without the extent to which smoking cessation or actual disease progress played a role in the therapeutic result.6,8 Generally, corticosteroids are recommended for patients with progressive disease or systemic symptoms, and definitely following smoking cessation.1

 

 Chemotherapeutic agents such as vinblastin, etoposide, cyclophosphamide and methotrexate have been used in the treatment of the diffused form of the disease in children, but experience of the use of these agents in adults is very limited.4,27 There is no evidence that these agents are beneficial in adults with isolated PLCH.41

 

 Lung transplantation is recommended for patients with severe respiratory insufficiency due to disease that has not responded to smoking cessation and the administration of corticosteroids and/or immunosuppressive agents.28,29 However, disease relapse in the transplanted lung has been noted in a significant percentage of patients.30,31

 

Disease prognosis varies. Approximately half of the patients remain asymptomatic or present with very minor clinical symptoms, accompanied by either partial or complete disappearance of radiological signs.1,2,4 About 10-20% of patients demonstrate progressively worsening disease with subsequent respiratory failure and cor pulmonale, and the remainder demonstrate stabilization of clinical signs and symptoms and laboratory findings, even though the disease relapse several years following remission is a distinct possibility.2,32,33 Factors associated with poor disease prognosis are the appearance of disease at a very young age, the persistence of systemic symptomatology, recurrent pneumothora clarification, the presence of extrapulmonary disease (except for bone lesions that do not seem to be related to disease prognosis), extensive occurrence of cystic lesions and honeycombing, significant decrease in DLCO and FEV1/FVC ratios, and an increase in the RV/TLC4,7,8 ratio.

 

 The disease appears to be related to an increased incidence of malignant disease, especially lymphoma and bronchogenic carcinoma.34,35 It appears that between 5 and 14% of patients with pulmonary Langerhans cell histiocytosis will later be diagnosed with lung cancer.38-40 Cumulative tobacco exposure and previous chemotherapy and radiation therapy confer an additional risk of developing cancer. These factors suggest that more aggressive cancer screening may be warranted in patients with LCH.

 

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