Pulmonary Langerhans cell histiocytosis

INTRODUCTION — Pulmonary Langerhans cell histiocytosis (PLCH), previously called eosinophilic granuloma of the lung, pulmonary Langerhans cell granulomatosis, and pulmonary histiocytosis X, is an uncommon cystic interstitial lung disease that primarily affects young adults [1-5]. It is caused by a disorder of myeloid dendritic cells. No occupational or geographic predisposition has been reported, but nearly all affected individuals have a history of current or prior cigarette smoking. Thus, tobacco smoke is thought to be a contributing factor.

The pathogenesis, clinical presentation, diagnosis, and treatment of PLCH will be reviewed here. A general review of Langerhans cell histiocytosis, including the more common, extrapulmonary manifestations of this disorder, is presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Treatment of non-pulmonary Langerhans cell histiocytosis".)

EPIDEMIOLOGY — The exact incidence and prevalence of PLCH are unknown, but it is uncommon [4-8]. PLCH is estimated to account for 3 to 5 percent of adult diffuse parenchymal lung disease [7,8]. Frequency depends on the prevalence of cigarette smoking in the population, as more than 90 percent of patients with PLCH are cigarette smokers [3-5]. White individuals are affected more commonly than Black individuals.

The rarity of the diagnosis is highlighted by a study from Japan, in which the prevalence estimates were 0.27 per 100,000 in males and 0.07 per 100,000 among females [6]. Similarly, a review from a specialty lung disease center in Italy found 40 cases over 10 years [5].

The age of onset peaks between 20 and 40 years of age [3]. In general, there is an equal distribution between males and females, though females tend to present at an older age [7].

BACKGROUND — The term "histiocyte" refers to large white blood cells resident in tissues and includes Langerhans cells, monocytes/macrophages, and dermal/interstitial dendritic cells. The pathologic cell type in PLCH is a dendritic cell of the monocyte-macrophage line that resembles cutaneous Langerhans cells [9]. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Histiocytic disorders'.)

Based on accumulating evidence of somatic oncogenic mutations in pulmonary CD1a dendritic cells, PLCH is thought to be an inflammatory myeloid neoplasm [10,11]. In LCH, both the CD1a dendritic cells and their progenitor cells, CD34+ mononuclear cells, carry somatic mutations in the mitogen-activated protein kinase (MAPK) pathway, particularly the BRAF genes discussed below [7,12]. (See 'Somatic mutations in MAPK pathway' below and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Pathophysiology'.)

Langerhans cells are normally found in low numbers in the dermis, the reticuloendothelial system, the lung, and the pleura. They can be present in increased numbers in the lung in association with cigarette smoking in otherwise healthy individuals and can also be seen in other pulmonary disorders, such as idiopathic pulmonary fibrosis [13,14]. (See "Pathogenesis of idiopathic pulmonary fibrosis".)

Pathology — In PLCH, the Langerhans-like cells, which express CD1a, S100 protein, and langerin (CD207), are characteristically found in clusters and in significantly greater numbers than in other lung diseases, although quantitative guidelines for the diagnosis of PLCH have not been established.

Early inflammatory lesions of PLCH surround the smaller bronchioles and usually contain an admixture of eosinophils, lymphocytes, and neutrophils (picture 1) and are associated with destruction of the bronchiolar wall and adjacent lung parenchyma [9,15]. Since eosinophils are not a prominent part of the pathology and the lesions can be devoid of eosinophils, the outdated term “eosinophilic granuloma” is a misnomer. The inflammatory lesions of PLCH can also involve pulmonary arterioles and venules (picture 2) [16].

There is often a predominance of disease in the mid to upper zones of the lung, in contrast with the typical lower zone predominance of idiopathic pulmonary fibrosis. Lesions frequently extend widely into the parenchyma of the lung surrounding the bronchovascular structures, producing the so-called stellate lesions that are characteristic of this disorder (picture 3A-C).

Interstitial fibrosis and cysts develop with advancing disease; the mechanism for cyst formation is unknown, but may be the end result of progressive destruction of bronchiolar and alveolar walls [7].

Three other pathologic features that may be seen in PLCH reflect, at least in part, exposure to tobacco smoke [7,16,17]:

●Pseudo-desquamative interstitial pneumonia (DIP), characterized by the accumulation of alveolar macrophages in the pulmonary parenchyma in between the typical lesions containing Langerhans-like cells. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Desquamative interstitial pneumonia'.)

●Respiratory ("smokers") bronchiolitis, characterized by pigmented macrophages filling the lumen of bronchioles and the surrounding alveolar spaces. (See "Respiratory bronchiolitis-associated interstitial lung disease", section on 'Definition'.)

●Intraluminal fibrosis, characterized by mural incorporation, alveolar obliteration, and intraluminal buds. This finding supports the hypothesis that intraluminal fibrosis is a mechanism for alveolar collapse with progression to interstitial fibrosis and lung remodeling [18].

On electron microscopy, which is rarely performed, Langerhans-like cells are identified by classic pentalaminar cytoplasmic inclusions or Birbeck granules (previously called X-bodies (picture 4)), of which langerin (CD207) is a component.

Somatic mutations in MAPK pathway — Somatic mutations that activate the mitogen-activated protein kinase (MAPK) pathway are present in virtually all cases of LCH and PLCH [11,19]. In both LCH and PLCH, the most common variants are BRAF V600E (50 percent) and MAPK2K1 (25 percent) genes encoding protein kinases, but numerous others have been described [11]. These variants lead to constitutive activation of MAPK signaling and downstream activation of transcription factors that promote cell proliferation and survival [10,11,20]. The individual variants do not appear to have a differential effect on the clinical presentation or prognosis of PLCH [19]. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Pathophysiology'.)

Sequencing studies suggest that PLCH involves clonal processes associated with these variants in MAPK pathway genes [11,20]. Somatic BRAF V600E mutations have been found in a number of benign and malignant tumors and are thought to contribute to the development of cancer. Both BRAF and NRAS mutations have been found in PLCH lesions and in circulating Langerhans-like CD1a⁺ cells [21,22]. The characteristics of BRAF mutations associated with lung cancer are described separately. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'BRAF mutations'.)

Role of cigarette smoking — The near universal association of PLCH with tobacco smoking strongly implies a causative role [17,23,24]. In contrast, there does not appear to be an association of smoking with extrapulmonary LCH. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

Various mechanisms by which smoking might contribute to the pathogenesis of PLCH have been hypothesized, including:

●Cigarette smoke promotes accumulation of nonneoplastic CD1a dendritic cells around airways and may also promote maintenance of CD1a cells with oncogenic mutations [11].

●Cigarette smoking may have an anti-apoptotic effect that contributes to accumulation of CD1a cells in PLCH.

●It is unclear whether inflammation from cigarette smoking contributes to the acquisition of oncogenic mutations by Langerhans-like cells in the lungs [11].

Abnormalities in immune function — Abnormalities in immune function are reported in association with PLCH [7], including:

●A nonspecific increase in IgG in bronchoalveolar lavage fluid

●Increased granulocyte-monocyte colony stimulating factor (GM-CSF), transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha in areas of PLCH, based on immunohistochemistry

●Abnormalities in T-cell function

The role of these changes in the pathophysiology of PLCH is not known; they may represent nonspecific generalized activation of immune effector cells [7].

CLINICAL PRESENTATION — Most cases of PLCH occur in young adults between 20 and 40 years of age, but PLCH is described among younger and older individuals (figure 1) [25-29]. The duration of illness is usually less than one year prior to diagnosis [1,2,30,31].

Symptoms and signs — Patients with PLCH present to medical attention in one of several ways [7,32,33]:

●With abnormalities incidentally detected on chest radiographs

●Following a spontaneous pneumothorax

●With respiratory or constitutional symptoms

●In follow-up to treatment of childhood LCH

When patients present with symptoms, the most common symptoms include [2,4,15,27,32,34-37]:

●Nonproductive cough (56 to 70 percent)

●Dyspnea (40 to 87 percent)

●Chest pain, which is frequently pleuritic (10 to 21 percent)

●Fatigue (approximately 30 percent)

●Weight loss (20 to 30 percent)

●Fever (15 percent)

The physical examination is usually unremarkable, except in cases of pneumothorax or advanced disease. Crackles and digital clubbing are uncommonly found on examination [7,38]. (See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

Extrapulmonary manifestations — Extrapulmonary LCH is noted in approximately 20 percent of reported cases of PLCH at the time of diagnosis [25,29]. Approximately 5 percent of patients with only pulmonary involvement at diagnosis develop extrapulmonary manifestations during follow-up [29]. When present, the following manifestations are most common:

●Bone lesions – Cystic bone lesions are present in 4 to 17 percent of patients and may be an incidental finding or produce localized pain or a pathologic bone fracture [3,25,29]. Skeletal involvement may precede the more typical pulmonary manifestations, and may be the sole manifestation of LCH. The radiographic pattern on bone films is not diagnostic. In most instances, the lesions are solitary and involve the jaw, vertebra, or flat bones. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●Diabetes insipidus – Hypothalamic involvement with LCH causing diabetes insipidus is seen in approximately 5 to 15 percent of patients, and is believed to portend a worse prognosis [3,25,29].

●Skin lesions – Skin lesions are reported in <5 percent of adults with PLCH [25,29]. Presentations vary, but brown to purplish papules and eczematoid or seborrhea-like lesions are more common. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Skin and oral mucosa'.)

EVALUATION — The signs and symptoms of PLCH are nonspecific and often mimic other, more common pulmonary diagnoses. However, PLCH should be suspected in patients with upper lung zone cystic or nodular radiographic abnormalities, or a history of recurrent pneumothorax, diabetes insipidus, or bone pain. A current or past history of tobacco smoking or exposure is an important (but not essential) historical feature. (See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

The evaluation is designed to identify characteristic features of PLCH (table 1), assess the severity of respiratory impairment, and exclude other processes in the differential diagnosis (eg, lymphangioleiomyomatosis, lymphoid interstitial pneumonia, Birt-Hogg-Dubé) (see 'Differential diagnosis' below). Approaches to the diagnosis of extrapulmonary LCH, interstitial lung disease, and cystic lung disease (table 2) are provided separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Diagnostic approach to the adult with cystic lung disease".)

Laboratory testing — The main role for laboratory testing is to exclude other causes of interstitial or cystic lung disease, as there are no routine laboratory tests that are diagnostic of PLCH. Routine laboratory studies are usually unrevealing, and the peripheral eosinophil count is normal. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests' and "Diagnostic approach to the adult with cystic lung disease", section on 'Laboratory testing'.)

Testing for alpha-1 antitrypsin deficiency is appropriate in patients with airflow limitation on pulmonary function tests and when the differentiation between cystic lung disease and bullous emphysema is unclear.

Patients with symptoms of polyuria and thirst should be evaluated for diabetes insipidus. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Endocrinopathies'.)

The role of peripheral blood polymerase chain reaction (PCR) testing for the BRAF V600E and other mitogen-activated protein kinase (MAPK; eg, MAPK2K1) mutations has not been determined. (See 'Somatic mutations in MAPK pathway' above.)

Imaging — Most evaluations for PLCH are prompted after a chest radiograph is noted to be abnormal. High-resolution computed tomography (HRCT) of the chest, if classic, can be diagnostic, and therefore should be obtained in all patients suspected of having the disease [39]. The radiographic appearance of PLCH can be very characteristic, if not diagnostic. A combination of the following features is felt to be highly specific for PLCH [40-43]:

●Ill-defined or stellate nodules (2 to 10 mm in size)

●Reticular and nodular opacities

●Upper zone cysts or honeycombing

●Preservation of lung volume

●Costophrenic angle sparing

The reticular and nodular opacities are typically seen in the middle to upper lung zones (image 1). The total lung volume is normal, although both hyperinflation and reduced volume can occur (image 2) [28,35]. Hilar or mediastinal adenopathy is rare and should prompt consideration of malignancy as a secondary diagnosis. Pleural thickening or effusion is rarely seen in the absence of a previous pneumothorax. Bone lesions can occur in any bone, including the ribs. (See "Evaluation of diffuse lung disease by conventional chest radiography".)

●Computed tomography – HRCT of the chest is an essential component of the evaluation of suspected PLCH. The combination of multiple cysts and nodules, with a mid to upper zone predominance, and interstitial thickening in a young smoker is so characteristic that it can be diagnostic of PLCH (image 3A-C) [41,44]. The nodules can be poorly or well defined; cysts are thin-walled, of varying size, and sometimes bizarrely shaped. Honeycombing can be seen in advanced disease. The degree of cyst formation is often under appreciated by routine chest radiography. (See "High resolution computed tomography of the lungs", section on 'Langerhans cell histiocytosis'.)

Studies of serial chest CT scans suggest a sequence of progression from nodules to cavitating nodules to cystic lesions [45,46]. This progression may explain a number of "spontaneous remissions" reported before the routine use of HRCT. The value of serial lung CT scanning in the routine follow-up of patients has been questioned [47].

●FDG-PET scan - Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans may show increased uptake in the lungs in patients with PLCH, particularly when obtained early in the course of disease [48], but are generally not helpful in the evaluation of PLCH unless extrapulmonary disease is suspected [49]. In a series of 11 patients with PLCH, five had abnormal FDG uptake in the lungs [48]. Patients with FDG-PET positivity were more likely to have a nodular radiographic pattern, suggesting earlier disease; those with negative FDG-PET scans were more likely to have a cystic pattern and fewer nodules, suggesting later disease. However, FDG-PET does not differentiate between nodules due to PLCH and lung malignancy [32].

FDG-PET scanning is frequently used to assess disease extent and activity in patients with extrapulmonary LCH [49], but is unlikely to identify unsuspected extrapulmonary disease in patients with PLCH and no extrapulmonary symptoms [48,50].

Pulmonary function testing — Pulmonary function tests with spirometry, lung volumes, diffusing capacity for carbon monoxide (DLCO), and six-minute walk test (6MWT) are obtained to assess the pattern and severity of respiratory impairment. In general, total lung capacity and expiratory flow rates are well-preserved in PLCH [15,35,51-53]. Predominantly nodular disease is usually associated with normal or restrictive pulmonary function tests, whereas cystic disease is more likely to be associated with abnormal physiologic testing [46].

The following abnormalities can be seen:

●Airflow limitation and hyperinflation occur in a minority of patients, typically in patients with more advanced, cystic disease [27,46,47]. Airflow limitation is sometimes reversible, with significant improvement after bronchodilator administration [13,28,35,52].

●A subgroup of patients shows predominantly restrictive disease [27], with reduced total lung volume and increased elastic recoil.

●The DLCO is disproportionately reduced, relative to changes in lung volume, in most patients [35].

●Pulse oxygen saturation (SpO₂) at rest and with ambulation is generally preferred to measurement of arterial blood gases (ABGs). ABGs obtained at rest usually show a normal alveolar-arterial oxygen difference and a normal carbon dioxide tension (PaCO₂) and pH and are an insensitive indicator of disease.

Patients with PLCH frequently demonstrate a degree of exercise intolerance out of proportion to pulmonary function abnormalities [35,54]. While not necessary in the majority of patients, cardiopulmonary exercise testing (CPET) can be helpful in clarifying that exercise intolerance is indeed due to a respiratory, rather than cardiac, limitation.

Exercise capacity assessed by CPET is decreased, whether measured by work achieved or oxygen utilization (VO₂) at maximal exercise. The oxygen pulse at maximal exercise and at anaerobic threshold is reduced in most patients. The maximal ventilatory response is excessive (but not limiting) for the maximal level of work.

Gas exchange abnormalities, reflected by a rising alveolar-arterial oxygen difference with increasing exercise, are seen in the majority of patients. In most patients, dead space to tidal volume ratio (VD/VT) is either abnormally elevated at rest or fails to decrease with exercise. This abnormality suggests either pathologic or functional involvement of the pulmonary vasculature by the disease process.

Flexible bronchoscopy — Flexible bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) can be helpful to evaluate for other causes of nodular or cystic disease, such as hypersensitivity pneumonitis, infection, lymphangioleiomyomatosis, and lymphoid interstitial pneumonia. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Diagnostic approach to the adult with cystic lung disease", section on 'Bronchoscopy'.)

In most cases, the combination of TBLB and BAL, supplemented with the identification cells that express CD-1a and CD207 in tissue and BAL fluid, is highly likely to result in the correct diagnosis [7,55]. However, in advanced disease with extensive fibrosis, the number of CD1a dendritic Langerhans-like cells in tissue specimens and BAL fluid decreases dramatically, making diagnosis difficult regardless of the laboratory methods used.

●Bronchoalveolar lavage – BAL is performed in an area of radiographic abnormality that is amenable to wedging of the bronchoscope. Samples of BAL fluid are sent for cell counts, microbiologic analysis, and cytology with immunostaining for CD1a and CD207 (algorithm 1). (See "Basic principles and technique of bronchoalveolar lavage" and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Cytology'.)

The finding of more than 5 percent CD-1a and CD207 positive cells on BAL strongly supports the diagnosis of PLCH (image 4) [3,30,56-59], but is poorly sensitive. Quantitative criteria for PLCH have not been conclusively established. A finding of less than 5 percent CD-1a positive cells does not exclude the diagnosis of PLCH. Lower proportions of Langerhans-like cells can be seen in current smokers, patients with other interstitial lung disorders, and patients with minimally invasive adenocarcinoma (formerly termed bronchioloalveolar carcinoma). Therefore, the mere presence of Langerhans-like cells on BAL is of little diagnostic value.

●Transbronchial lung biopsy – TBLB can be sufficient to make the diagnosis in patients with nodular disease [9,60]. However, a substantial number of false negative or nondiagnostic biopsies result from sampling error and insufficient tissue with an expected yield 15 to 50 percent [9,58-60]. Multiple specimens (preferably at least six) should be obtained and examined with immunohistochemical testing for CD1a and CD207 positive cells by an expert pathologist familiar with the disease [9].

Lung biopsy — For most patients with symptomatic disease, but nondiagnostic findings on HRCT, BAL, and TBLB, a surgical lung biopsy, usually by video-assisted thoracoscopy, is needed to determine the diagnosis. A trial of smoking cessation prior to proceeding with surgery is a reasonable alternative in a stable patient. (See 'Initial and supportive management' below.)

In a series of 38 patients with PLCH, the diagnosis was confirmed by TBLB in 50 percent, surgical lung biopsy in 45 percent, and BAL (≥5 percent CD1a-positive Langerhans-like cells) in 5 percent [58]. A biopsy of an extrapulmonary site (skin, mandible, tongue) was positive in 11 percent. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Transthoracic Doppler echocardiography — Pulmonary hypertension is a known complication of PLCH [36,61]. When pulmonary hypertension is suspected in patients with PLCH based on dyspnea or gas transfer abnormalities out of proportion to reductions in lung volumes or extent of HRCT abnormalities, we obtain echocardiography with assessment of pulmonary and right heart pressures [32,36]. Doppler echocardiogram evidence of pulmonary hypertension (ie, elevated pulmonary artery systolic pressure) needs confirmation by right heart catheterization. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

DIAGNOSIS

Diagnosis based on HRCT — A confident clinical diagnosis can often be made on the basis of characteristic clinical presentation and high-resolution computed tomography (HRCT) showing bizarrely shaped cysts with upper lobe predominance and sparing of the costophrenic angle, ill-defined upper lobe nodules (2 to 10 mm) and preservation of lung volume (table 1) [59]. In this setting, improvement in symptoms and HRCT with smoking cessation helps to solidify the diagnosis.

The finding of more than 5 percent Langerhans-like dendritic cells (CD-1a and CD207 positive) on bronchoalveolar lavage (BAL) strongly supports the diagnosis. (See 'Flexible bronchoscopy' above.)

Diagnosis based on lung biopsy — A firm diagnosis of PLCH requires a lung biopsy showing characteristic peribronchial inflammatory lesions containing an admixture of Langerhans-like cells, eosinophils, lymphocytes, and neutrophils (picture 1) with associated destruction of the bronchiolar walls and adjacent lung parenchyma. Langerhans-like dendritic cells are identified by immunostaining for CD1a, CD207, and S100. (See 'Pathology' above.)

On histopathology, inflammatory lesions of PLCH surround the smaller bronchioles (picture 1) and are associated with destruction of the bronchiolar wall and adjacent lung parenchyma. The Langerhans-like dendritic cell is distinguished by pale staining cytoplasm, a large nucleus and nucleoli, and a strong presence of CD1 antigen (CD1a) on the cell surface, a feature not observed in other cells of histiocytic origin [31]. Langerin (CD207) is a transmembrane protein associated with Birbeck granules; it tends to co-associate with CD1a in LCH [62,63]. Staining for the intracellular S100 protein is less specific and can be observed in macrophages and neuroendocrine cells [3].

Whenever possible, testing for the BRAF V600E and other MAPK variants is obtained, in case future targeted therapy is considered. BRAF expression can be assessed in biopsy samples via immunostaining [10] or by a sensitive quantitative polymerase chain reaction (PCR) test. (See 'Somatic mutations in MAPK pathway' above and "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Pretreatment evaluation' and 'Targeted therapy of MAPK pathway mutations' below.)

On electron microscopy, which is rarely performed, Langerhans-like cells are identified by classic pentalaminar cytoplasmic inclusions or Birbeck granules (X-bodies (picture 4)).

Diagnosis based on extrapulmonary LCH — If the patient has compatible lung disease, a biopsy of extrapulmonary lesions (skin or bone) showing LCH would support the diagnosis of PLCH.

If not previously performed, a baseline fluorodeoxyglucose-positron emission tomography (FDG-PET) scan may be helpful if symptoms suggest extrapulmonary disease, but is not needed in the absence of such symptoms. (See 'Imaging' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PLCH presenting with cystic changes on high-resolution computed tomography (HRCT) includes pulmonary lymphangioleiomyomatosis, tuberous sclerosis, lymphoid interstitial pneumonia, Birt-Hogg-Dubé syndrome, and sarcoidosis (algorithm 1 and table 2). (See "Diagnostic approach to the adult with cystic lung disease".)

For patients with reticular, nodular, or ground glass opacities on HRCT without cystic changes, the differential diagnosis is broad and often includes hypersensitivity pneumonitis and other idiopathic interstitial pneumonias, such as nonspecific interstitial pneumonia. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

TREATMENT — PLCH is usually limited to the lungs, but patients should be assessed for extrapulmonary involvement to determine whether treatment of additional sites is indicated. The evaluation of extrapulmonary LCH is described separately. (See 'Evaluation' above and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

All patients should be advised about smoking cessation and avoidance of smoke exposure. The optimal treatment regimen for patients with persistent and symptomatic disease has not been determined. Therapy is largely guided by expert opinion and extrapolation from experience in pediatric LCH [64].

Systemic glucocorticoid therapy may be beneficial, predominantly in patients with nodular disease. For patients who do not respond to smoking cessation or glucocorticoid therapy, the preferred choice is referral to a specialized center (Histiocytosis Association of America) and participation in a clinical trial. If this is not possible, we suggest treatment with cladribine or cytarabine with appropriate prophylaxis against opportunistic infection.

Initial and supportive management — The primary focus of any therapeutic regimen in patients with PLCH is cessation of tobacco smoking and avoidance of smoke exposure [7,32,65,66]. Many patients will have resolution or stabilization of disease with smoking cessation alone. Follow-up pulmonary function testing every three months in the first year after diagnosis may be useful in identifying patients who are likely to develop progressive disease [1,25].

In a series of 40 patients, smoking cessation was the only required therapy in 25 (62 percent) [5]. We counsel patients that continued smoking increases the likelihood of progressive disease and potential for needing chemotherapy for PLCH in the future. (See "Overview of smoking cessation management in adults".)

Patients with chronic obstructive pulmonary disease (COPD) related to cigarette smoking or with reversibility of airflow limitation on spirometry may have symptomatic improvement with inhaled bronchodilator and, possibly, inhaled glucocorticoid therapy. (See "Stable COPD: Initial pharmacologic management".)

Patients with dyspnea on exertion may benefit from pulmonary rehabilitation. (See "Pulmonary rehabilitation".)

Seasonal influenza and pneumococcal vaccination should be offered as appropriate [64]. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".)

Minimal symptoms and pulmonary function impairment — For patients with minimal or no symptoms or pulmonary function impairment, we usually observe without specific therapy other than smoking cessation. Among 58 patients monitored for two years after initial diagnosis, 22 (38 percent) experienced worsening of at least one component of pulmonary function [37]; forced expiratory volume in one second (FEV₁) and diffusing capacity for carbon monoxide (DLCO) decreased in 22 percent and forced vital capacity (FVC) worsened in 9 percent. Of note, only 20 percent quit smoking for the entire study period; complete smoking cessation would be expected to yield better stability or improvement in lung function. (See 'Initial and supportive management' above.)

Progressive and symptomatic PLCH — The optimal therapy for progressive PLCH has not been determined [67]. Patients who are still smoking require more aggressive efforts at smoking cessation. Systemic glucocorticoids have a limited role. For patients who are not candidates for or do not respond to glucocorticoids, the preferred choice is referral to a specialized center and participation in a clinical trial [68]. If this is not possible, we suggest a trial of cladribine or cytarabine with appropriate prophylaxis against opportunistic infection.

●Glucocorticoids – For patients with symptomatic and progressive nodular PLCH despite smoking cessation, we suggest a trial of systemic glucocorticoids (eg, prednisone 0.25 to 0.5 mg/kg per day or 30 mg/day initially with gradual tapering over six months). As evidence for improvement with glucocorticoids is limited, a reasonable alternative is not to prescribe glucocorticoids. In our experience, only patients with prominent nodular opacities respond to glucocorticoid therapy.

Published experience with glucocorticoids is mixed [25,28,30,31,69]. In a series of 36 patients who received prednisone 40 mg daily for a mean of 9.6 months, none of the patients experienced worsening of disease, including a subset of 14 patients who had a deteriorating trend prior to prednisone [28]. However, information about smoking cessation was not provided. In a separate study of 45 patients, glucocorticoid therapy was associated with increased mortality, but this may reflect selection bias [69].

●Cladribine – Case reports have described improvement in PLCH following treatment with cladribine (2-chlorodeoxyadenosine), a chemotherapeutic agent cytotoxic for lymphocytes and monocytes, typically used in regimens for leukemia and lymphoma [70-74]. Cladribine is used (off-label) in pediatric LCH [75], but has not been formally studied in PLCH. A clinical trial in PLCH is in progress (NCT01473797; clinicaltrials.gov). (See "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Relapsed or refractory disease'.)

Cladribine has been associated with symptomatic, radiographic, and pulmonary function improvement in adults with cystic PLCH [72,76]. Improvement in individual patients with nodular or nodulocystic disease that was refractory to prednisone has also been reported with four to five cycles of cladribine at doses of 3 to 5 mg/m² [70,71]. Cladribine can cause pancytopenia and is highly immunosuppressive, so therapy to prevent opportunistic infections with Pneumocystis jirovecii and herpes viruses (eg, trimethoprim-sulfamethoxazole, valacyclovir) is advised [32].

●Cytarabine – Cytarabine, a nucleoside (pyrimidine) analogue that inhibits DNA synthesis, is used in treatment regimens for myeloid leukemias. Cytarabine is used in adults with multiple bone or other noncutaneous lesions (100 mg/m² intravenously, daily for five days, repeated monthly for 12 months). It is also used alone or in combination regimens in pediatric LCH with high rates of clinical response. (See "Treatment of non-pulmonary Langerhans cell histiocytosis".)

●Vinblastine – Vinblastine, which is a successful therapy in pediatric LCH, was examined in 35 patients with LCH of whom 17 had lung involvement [77]. While extrapulmonary manifestations improved, pulmonary function did not. We do not use this agent in patients with PLCH in the absence of extrapulmonary LCH. (See "Treatment of non-pulmonary Langerhans cell histiocytosis".)

●Radiation therapy can be used to treat symptomatic bone lesions, but it is not useful in treatment of PLCH.

Pulmonary hypertension — For patients with pulmonary hypertension (PH) complicating PLCH (ie, mean pulmonary artery pressure is >20 mmHg at rest, measured by right heart catheterization), we suggest referral to a specialized center with experience treating PH and advanced lung disease. Supportive measures for PH include oxygen and diuretics, when indicated, and routine supportive measures as described above. (See 'Initial and supportive management' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)

The role of PH-targeted therapy in PH complicating PLCH is not well-established, but benefit has been described in a small number of patients [36,78,79]. In a series of 12 patients with pulmonary hypertension complicating PLCH, therapy with an endothelin receptor antagonist, phosphodiesterase 5 inhibitor, prostanoid (iloprost), or a combination led to modest improvements in mean pulmonary arterial pressure (from 56 ± 14 to 45 ± 12 mmHg) and pulmonary vascular resistance (from 701 ± 239 to 469 ± 210 dynes-sec-cm^-5) between baseline and follow up evaluations [36]. No significant worsening of oxygenation was observed with treatment. However, caution is advised as pulmonary arterial hypertension-directed therapy can exacerbate ventilation-perfusion abnormalities and worsen gas exchange in patients with parenchymal lung disease. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Our approach'.)

Refractory disease — For patients with progressive disease despite the above interventions, we prefer the option of treatment in the context of a clinical trial. Targeted therapy directed at mitogen-activated protein kinase (MAPK) pathway mutations is appealing, but needs rigorous assessment due to the high potential for adverse effects. Patients with advanced lung disease may be candidates for lung transplantation.

Clinical trials — Clinical trials of therapy for LCH are ongoing, and enrollment may be appropriate for selected patients. In the United States, the Histiocyte Society initiated a series of protocols for treatment of adults with LCH in 2001. Treatment protocols and other information can be obtained through the Histiocytosis Association of America (1-800-548-2758 or www.histio.org) and at https://www.clinicaltrials.gov/. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

Targeted therapy of MAPK pathway mutations — Identification of somatic mutations in the MAPK pathway, such as BRAF V600E and MAPK2K1, in patients with PLCH has led to the proposal of using targeted therapy with agents such as vemurafenib, dabrafenib, or trametinib [10,21,80]. In case reports, these agents have led to clinical response in patients with refractory or relapsed LCH, but recurrent disease was reported after cessation of therapy. (See "Treatment of non-pulmonary Langerhans cell histiocytosis", section on 'Relapsed or refractory disease'.)

The role of specific inhibitor drugs in PLCH remains to be defined [32,81].

Vemurafenib is approved in the United States for treatment of symptomatic patients with Erdheim–Chester disease (a related non-Langerhans cell histiocytic myeloid neoplasm) and the BRAF V600E variant. (See "Erdheim-Chester disease", section on 'BRAF inhibition'.)

Lung transplantation — Lung transplantation is an option for patients with advanced, progressive lung disease unless contraindications are present [5,82]. In a series of 40 patients who underwent single or bilateral lung transplantation for advanced PLCH, survival was 77 percent at one year and 54 percent at 10 years [82]. Recurrence of PLCH in the transplanted lung is reported in approximately 10 percent, but it is unclear if this affects overall post-transplant survival [5,82-84]. Preoperative extrapulmonary LCH is a risk factor for recurrence [82].

General information about lung transplantation and guidelines for patient selection are reviewed separately. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Disease-based choice of procedure".)

COMPLICATIONS — Complications of PLCH include pneumothorax, hemoptysis, and pulmonary vascular disease. Extrapulmonary manifestations of PLCH are described above. (See 'Extrapulmonary manifestations' above.)

●Pneumothorax – Recurrent spontaneous pneumothorax occurs in 10 to 25 percent of patients [29,85]. Pleural thickening or effusion is rarely seen in the absence of a previous pneumothorax. (See 'Symptoms and signs' above.)

The management of spontaneous pneumothorax in PLCH follows that for spontaneous secondary pneumothorax and, in general, includes pleurodesis. For patients who require surgical intervention, a lung biopsy at the time of the procedure can secure the diagnosis. (See "Treatment of secondary spontaneous pneumothorax in adults".)

●Pulmonary vascular disease – Pulmonary arteriopathy and veno-occlusive disease can occur independently from parenchymal and airway disease, and can impair diffusing capacity and exercise capacity to a degree disproportionate to radiographic findings [36,61,86-88]. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

Pulmonary hypertension can be present even in the absence of overt symptoms of right heart failure. An echocardiographic study of patients with histologically proven PLCH noted a resting peak pulmonary artery pressure ≥35 mmHg in 15 of 17 patients (88 percent) [61]. The development of pulmonary hypertension was strongly associated with increased mortality, suggesting that severe pulmonary hypertension is not limited to patients with end-stage cystic lung disease.

●Hemoptysis – Hemoptysis is occasionally reported (13 percent), but should prompt consideration of superimposed infection (eg, Aspergillus) or tumor [35,89]. (See "Evaluation of nonlife-threatening hemoptysis in adults".)

●Benign and malignant tumors – A number of malignant and nonmalignant tumors have been found in association with PLCH [90-94]. These include bronchogenic carcinoma (5 percent of patients) [25,29,91,95], Hodgkin and non-Hodgkin lymphoma [94,96], pulmonary carcinoid tumor, and mediastinal ganglioneuroma. The malignancy may precede, follow, or occur concomitantly with the diagnosis of PLCH. The carcinogenic effect of cigarette smoke may contribute to development of some of these tumors, but the lung cancer incidence is likely higher than expected for age and smoking history [29].

PROGNOSIS — The overall survival for PLCH is good, with a large prospective cohort indicating a 10-year survival of >90 percent [29]. However, the natural history of PLCH is variable, with some patients experiencing spontaneous remission of symptoms and others (approximately 5 percent) progressing to end-stage fibrotic lung disease (figure 2) [29,37].

Both smoking status and the radiographic picture can affect disease progression. Most subjects demonstrate gradual progression with continued cigarette smoking, while the disease may regress with the cessation of smoking [65]. Patients with radiographic sparing of the costophrenic angle are more likely to remain stable or improve compared to those with costophrenic angle involvement [42]. Pulmonary hypertension is common with advanced disease, and is independently associated with decreased survival [61]. The prognosis of PLCH does not appear to be influenced by the specific MAPK variant [19]. (See 'Somatic mutations in MAPK pathway' above.)

Despite the overall good prognosis of PLCH, a minority of patients will develop end stage lung disease or malignancy. In a large prospective cohort of 206 patients with pulmonary LCH, the 5- and 10-year survival were 94 and 93 percent, respectively, after a median 5.1 years of follow-up [29]. This survival was shorter than age-matched controls from the general population (figure 3), but longer than that seen in prior retrospective studies [25,36,69,97], possibly due to increasing early detection by high-resolution computed tomography (HRCT) and selective referral of later stage patients in previous studies. Half (6 of 12) of the deaths that occurred during the follow-up period were associated with respiratory failure and pulmonary hypertension; nearly half (5 of 12) were associated with malignancy.

SUMMARY AND RECOMMENDATIONS

●Definition, pathogenesis, and histopathology

•Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon cystic-interstitial lung disease that primarily affects young adult smokers. The pathologic cell of PLCH is a Langerhans-like dendritic cell that is a differentiated cell of the monocyte-macrophage line with CD1a, S100 protein, and langerin (CD207) expressed on the cell surface. These cells virtually always carry mutations in the mitogen-activated protein kinase (MAPK) pathway, most commonly BRAF V600E. (See 'Epidemiology' above and 'Background' above.)

•In PLCH, lung lesions frequently extend widely into the parenchyma surrounding the bronchovascular structures, producing the so-called stellate lesions that are characteristic of this disorder (picture 3A-C). (See 'Background' above.)

●Clinical presentation

•Patients can present with a spontaneous pneumothorax, an abnormal chest radiograph obtained for another reason, or a nonproductive cough, dyspnea, or constitutional symptoms, especially fever or weight loss. Recurrent spontaneous pneumothorax occurs in 15 to 25 percent of patients. The physical examination is usually normal. (See 'Clinical presentation' above.)

•High-resolution computed tomography (HRCT) findings can range from reticular opacities to nodules (2 to 10 mm) to cysts, or more typically a combination of multiple cysts and nodules, with a mid to upper zone predominance (table 1). The combination of nodules and cysts in the upper lung zones in a young smoker is so characteristic that it can be diagnostic of PLCH (image 3A-C). (See 'Imaging' above.)

●Diagnosis

•Flexible bronchoscopy with bronchoalveolar lavage (BAL) and usually transbronchial lung biopsy (TBLB) is performed in most patients to look for CD1a-positive Langerhans-like cells and evaluate for other causes of nodular or cystic disease (algorithm 1). The finding of more than 5 percent Langerhans-like cells (CD-1a and CD207 positive) on BAL or typical clusters of Langerhans-like cells on TBLB strongly suggests the diagnosis of PLCH (image 4), but is poorly sensitive. (See 'Flexible bronchoscopy' above.)

•When the HRCT and BAL are not sufficiently diagnostic, a surgical lung biopsy is often needed to confirm the diagnosis and exclude other causes of nodular or cystic lung disease. Alternatively, for patients with minimal or no symptoms or respiratory impairment, a trial of smoking cessation with follow-up assessment and imaging in three months may be reasonable. (See 'Lung biopsy' above.)

●Treatment

•The primary focus in all patients with PLCH is cessation of smoking and avoidance of smoke exposure. Approximately 60 percent of patients will improve with this intervention alone. (See 'Initial and supportive management' above.)

•For patients with progressive, nodular PLCH who remain symptomatic despite smoking cessation, we suggest a trial of systemic glucocorticoid therapy (Grade 2C). The usual initial dose is the equivalent of prednisone 0.25 to 0.5 mg/kg per day or 30 mg/day, with gradual tapering over six months. (See 'Progressive and symptomatic PLCH' above.)

•For patients who are not candidates for or do not respond to glucocorticoids, the preferred choice is referral to a specialized center (Histiocytosis Association of America) and participation in a clinical trial. If this is not possible, we suggest a trial of cladribine or cytarabine with appropriate monitoring of peripheral blood for cytopenia and prophylaxis against opportunistic infection (Grade 2C). (See 'Progressive and symptomatic PLCH' above.)

•Lung transplantation is an option for patients with advanced PLCH in the absence of other contraindications. Recurrence of PLCH in the allograft is reported, particularly in patients with multisystemic LCH, but may not affect survival. (See 'Lung transplantation' above.)

•Information about clinical trials for patients with PLCH can be obtained at www.histio.org or https://www.clinicaltrials.gov/. (See 'Treatment' above.)