Pulmonary Langerhans cell histiocytosis ; characteristics of 11 cases

1 Atatürk Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi. Göğüs Cerrahisi Bölümü, Ankara, 2 Afyon Kocatepe Üniversitesi Tıp Fakültesi, Göğüs Hastalıkları Anabilim Dalı, Afyonkarahisar, 3 Afyonkarahisar Devlet Hastanesi, Göğüs Hastalıkları Kliniği, Afyonkarahisar, 4 Atatürk Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi, Patoloji Bölümü, Ankara, 5 Gazi Üniversitesi Tıp Fakültesi, Göğüs Cerrahisi Anabilim Dalı, Ankara.


INTRODUCTION
The histiocytic disorders are uncommon diseases characterized by abnormal infiltration of certain organs by cells derived from monocyte/macrophage or dentritic cell lineage (1)(2)(3).The classification of the clinical patterns of Langerhans cell histiocytosis (LCH) is based on the number of organs involved (1).Single organ (bone, lung, pituitary gland or skin) involvement of LCH (eosinophilic granuloma and primary pulmonary histiocytosis) usually follows benign course and can regress spontaneously (1,3,4).Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon granulomatous disorder characterized by uncontrolled proliferation and infiltration of Langerhans cells (LCs) in the lung (1,5).It has been associated with cigarette smoking and is more common in young adults.The pathogenesis of PLCH is unclear (1,2,5).In the literature, there is limited number of studies investigating the characteristics and prognosis of PLCH.In the present study, we evaluated the characteristics, diagnosis, treatments modalities and prognosis of 11 cases of PLCH.

MATERIALS and METHODS
We retrospectively reviewed our case series of eleven patients who were pathologically diagnosed for PLCH between January 2001 and January 2011.Characteristics, symptoms and smoking habits of the patients, radiological [chest X-ray (CXR) and thorax computed tomography (CT) and high resolution computed tomography (HRCT)] findings, diagnostical procedures (bronchoscopy, transbronchial biopsy, bronchoalveolar lavage (BAL) findings and types of surgical procedu-res), treatment options and prognosis/relapses were noted.The CXR, thorax CT, HRCT and fiberoptic bronchoscopy were performed.All cases were diagnosed with pathological examinations.
Wedge biopsies that were taken via VATS were diagnostic in two patients (18.2%) and wedge biopsies taken via thoracotomy were diagnostic in 8 (72.7%) patients.Transbronchial parenchymal biopsy was successful in diagnosis of 1 (9.1%) patient (Figure 2).
Only smoking cessation was suggested to 9 (81.8%)patients.However, additional therapy of methylprednisolone was initiated for uncontrolled symptoms in one of these patients.Two (18.2%) of patients who were nonsmoker were treated only with methylprednisolone for six months.
Mean follow-up of ten patients was 5.40 ± 1.78 years.
Only one patient (case #4) did not come to his followup visits after 6 months of his diagnosis.Generally, symptoms were improved with smoking cessation or methylprednisolone therapy.One patient (case #11) was readmitted to our clinic with relapse of second pneumothorax.

DISCUSSION
In this study, we described the clinical-radiological findings, BAL characteristics, diagnostic procedures, treatment options and prognosis of eleven patients with PLCH.Nine of 11 patients was smoker.Although ten patients were diagnosed via surgical procedures, only one patient was diagnosed via transbronchial lung biopsy.Only three patients were needed to treat with methylprednisolone.Pulmonary involvement with LCH can be observed in patients of any age (6).PLCH in adults is a rare idiopathic parenchymal disease of the lung and commonly detected in adults with the smoking history (1).It is known that more than 90% of patients with PLCH are current smoker or ex-smoker (6)(7)(8).The pathogenic mechanisms that link tobacco smoke exposure to these disorders have not been clarified (7).Moreover, development of PLCH in nonsmokers especially in childhood period suggests that second-hand smoking play a role in the pathogenesis (2,6).PLCH mainly affects young adults with a peak frequency in the third to fourth decades (1,2,4).Although marked male predominance was initially reported, gender differences were disappeared in recent studies which may be due to increased cigarette smoking habit in female (1,4,6,7,9).In this study median age was 35 years (min-max: 19-51 years) and male to female ratio (M/F) was 5/6 (smoker male to female ratio was 4/5).The ratio of patients who smoke cigarette (81.8%) was lower than that was reported in the literature.This result may lead to consider the effect of passive smoking on pathogenesis of PLCH.
Although, in pediatric ages, pulmonary involvement is reported as the part of multisystemic LCH, single system disease (PLCH) in adult population was reported more than 80% of the patients (10,11).Symptoms show variability according to organ involvements.Clinical symptoms of patients with PLCH is miscellaneous (1,6).Approximately one fourth of the patients are asymptomatic (1,8).Persistent dry cough, exertional dyspnea, and chest pain are main symptoms (1,6,7,11).Pneumothorax is a complication resulting from the rupture of subpleural cystic lesions in 10-20% of the cases (1,6).Clubbing of the fingers is extremely rare finding in PLCH.Diabetes insipidus (5% of cases), bone lesions (> 20%) and skin lesions are the most common extrapulmonary findings (1,12,13).In our study, the most common symptoms were dyspnea (81.8%) and dry cough (72.7%) as reported in the literature.Pneumothorax was occurred in 18.2% of the cases and recurrent pneumothorax was diagnosed in only one patient.Diabetes insipidus was sole extrapulmonary presentation in this study.Although, it is a rare finding, clubbing was present in two patients.
The CXR is almost always abnormal.Reticulonodular infiltrates are predominant findings in early disease stage whereas cystic lesions are more dominant in advanced stage.Radiological changes in advanced stage can be difficult to differentiate from cigarette smoke-induced emphysema.Nodular or reticulonodular involvement is typically diffuse.Relative sparing of the lower lung fields and costo-phrenic angle is characteristic in adults (2,14).However, chest radiography in pediatric PLCH is almost always associated with involvement of the lower lung zones and the costo-phrenic angles (1,2,14,15).In our study, major CXR findings were bilateral cystic lesions (45.4%), bilateral nodular infiltrations (18.2%) and mixed pattern (36.4%).While, middle zone (81.8%) was predominant involved zone in the study population, lower zone and costo-phrenic sulci involvement was present in one patient.
Pulmonary function tests are normal up to 20% of patients (2,11).Restrictive pattern is more commonly seen in earlier stages of disease, while obstructive pattern is became predominant in advanced stages (2,13,20).At least 70% of patients have low carbon monoxide diffusion capacity (DLCO) which is the most common abnormality in PLCH (2,11,21).In this study, restrictive pattern (33.3%) was found to be more prevalent.As in the literature, 22.2% of all patients had normal pulmonary function test.DLCO was decreased in 63.6% of patients which was slightly lower than the literature.
Histopathological diagnosis with lung biopsies is needed for definitive diagnosis of PLCH.Transbronchial parenchymal biopsies obtained via fiberoptic bronchoscopy state the exact diagnosis in an approximately 15-40% of patients (2,22).Besides, BAL is also suggested diagnostic method performing to all patients underwent bronchoscopy.Detection of more than 5% CD1a (+), a cell surface marker for LCs, in BAL fluid with appropriate clinical symptoms and radiological findings (HRCT) are suggestive for PLCH (1,2,21).This test is problematic, however, because increased level of CD1a-positive cells can be identified in the BAL fluid of smokers without evidence of interstitial lung disease (2).Additional surface markers, such as an antibody against langerin (CD207), may improve the diagnostic utility of BAL in the diagnosis of PLCH (21,23).In this study, histopathological examination of transbronchial biopsy of lingular segment in one patient revealed the diagnosis of PLCH.CD1a was evaluated in 4 out of 7 patients whom BAL was performed.None of the results was greater than 5%.
In the case of uncertainty of making diagnosis, surgical lung biopsies by VATS or open thoracotomy may be required to make a definite diagnosis of PLCH by demonstrating the presence of the specific histopathological appearance (2,21).The diagnostic histological finding is LCs and the number of cells vary according to the disease stages (6,12).In our study, to diagnose the disease, wedge resections by thoracotomy and VATS were performed to 8 and 2 patients, respectively.
There is not an exact treatment guideline for PLCH management.A few recommendations are reported concerning to treatment of adult patients with PLCH (7,21).An important step of the treatment of patients with PLCH is smoking cessation.Smoking cessation alone may lead to improvement and marked resolution of the disease, so, it should be strongly encouraged (7,21).Although, corticosteroid treatment is also a kind of recommended therapeutic management, evidence of benefit is unclear (7,11,12,21).Especially, corticosteroid usage (0.5-1 mg/kg/day for 6-12 months) was suggested to progressive or the symptomatic patients with nodular lesions on HRCT (1,6,21).
Other chemotherapeutic agents including vinblastin, methotrexate, cyclophosphamide, etoposide may be preferred especially in the case of multiorgan involvement or unresponsiveness to steroid treatment (2,6,21,24).Lung transplantation is suggested when severe respiratory failure was occurred.Genetic, monoclonal antibody and cytokine treatments are the future potential treatment options in PLCH (2,21,25).In our study, all patients except two were current smokers.Passive smoking was noted in all patients.Only smoking cessation was suggested to current smokers.Clinical and radiological improvement was achieved in 8 patients.Steroid therapy was administered to three patients.
In conclusion, PLCH is an extremely rare benign disease.The present study is the first national case series evaluating the symptoms, radiological findings, diagnostic and treatment approaches for PLCH in our country.To our knowledge, there is not an exact consensus with respect to the guidelines on the treatment of PLCH.We believe that this article will add to the litera-ture in the context of treatment options and treatment outcomes of PLCH.In the future, with the understanding of the pathogenesis of the disease, new therapeutic agents will be discovered for this rare condition.