Rare interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung disorders with low prevalence and diverse etiologies that pose diagnostic and therapeutic challenges. We aimed to establish a nationwide, multicenter registry of rare ILDs in South Korea to characterize their clinical features and outcomes. We conducted a multicenter, observational cohort study involving 304 patients with rare ILDs including Birt-Hogg-Dubé syndrome (BHD), lymphangioleiomyomatosis (LAM), pulmonary alveolar proteinosis (PAP), pulmonary Langerhans cell histiocytosis (PLCH), pleuroparenchymal fibroelastosis (PPFE), and hypersensitivity pneumonitis (HP) enrolled across 20 centers in Korea between September 2023 and December 2024. Data on clinical characteristics, outcomes, and treatment were collected. LAM (28.3%) and PAP (26.6%) were the most prevalent, followed by BHD (18.1%), PLCH (13.2%), HP (7.6%), and PPFE (6.3%). Dyspnea was common in HP and PPFE, whereas BHD and LAM were often asymptomatic. Pneumothorax was frequent in BHD (44.6%) and LAM (11.6%) at diagnosis. PPFE showed the most impaired lung function and the highest mortality (26.3%), during a median follow-up of 69.5 months, followed by PAP (6.2%) and BHD (1.8%). During follow-up, cancer was reported in 25.0% of patients with BHD. Treatment strategies varied by disease: corticosteroids were commonly used in HP (86.9%), PPFE (42.1%), and PLCH (32.5%); sirolimus in LAM (53.5%); pirfenidone in PPFE (42.1%); and whole-lung lavage in PAP (23.5%). This is the first nationwide rare ILD registry in Korea, demonstrating heterogeneity in clinical features and outcomes and emphasizing the need for disease-specific diagnostic and therapeutic strategies.

Primary pulmonary Langerhans cell histiocytosis: comprehensive clinicopathologic and molecular genetic analysis of 13 cases.

1666 Spatial Transcriptomic Analysis of Pulmonary Langerhans Cell Histiocytosis and Erdheim-Chester Disease in the Lung

The natural history of pulmonary Langerhans cell histiocytosis (PLCH) is unpredictable. Therefore, the identification of prognostic biomarkers for PLCH represents a major goal for better management of patients. The aim of this study was to evaluate the levels of various blood mediators in PLCH patients at diagnosis and explore their relationships with forced expiratory volume in one second (FEV1) outcomes. We used multiplex immunoassays to measure at diagnosis the serum concentrations of thirty mediators in patients with stable vs. declining FEV1. Multivariable-adjusted logistic regression models, accounting for matched variables (age, sex, and daily tobacco consumption), were used to compare concentrations between patients stratified on the basis of their FEV1 values. Nine patients with declining FEV1 profiles over time who had an available blood sample at the time of PLCH diagnosis were paired with 16 patients whose FEV1 profiles remained stable over a median follow-up of 3.6years [IQR 2.2-5.1]. The levels of two biomarkers, TNF-α and MMP-7, were significantly greater in patients with a decreased FEV1 than in those with a stable FEV1 in the univariable analysis after adjustment for matching variables. The median serum levels of TNF-α were 137 [75-358] pg/mL in the declining FEV1 group and 60 [45-92] pg/mL in the stable FEV1 group (p = 0.032). Similarly, the median MMP-7 levels were 16344 [13318-18000] pg/mL and 11555 [9796-12495] pg/mL, respectively (p = 0.047). There was a negative correlation between FEV1 values and MMP-7 levels (rho = -0.65, p = 0.001) but not with TNF-α levels (rho = -0.33, p = 0.14). TNF-α and MMP-7 levels are potential prognostic blood biomarkers in PLCH.

Choriocarcinoma is a highly aggressive malignant germ cell tumour containing syncytiotrophoblasts that secrete beta-human chorionic gonadotropin, and it has a poor prognosis, with a dismal 5-year survival rate of <5%. It generally affects young individuals. Cystic lesions in the lung are uncommon in malignancies that can predispose patients to spontaneous pneumothorax. Multiple cystic lesions are less commonly seen in metastatic disease. Diffuse cystic lung diseases (DCLD) are a group of diseases characterised by cysts in the bilateral lung fields that are not necessarily evenly distributed. The differential diagnosis is limited and typically includes lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis. Sometimes, metastatic malignancy can present as DCLD. Metastatic leiomyoma, endometrial stromal sarcoma and cellular fibrous histiocytic tumours have been reported as causes of lung cysts. We report a case of choriocarcinoma with cystic lung metastasis in a woman in her 30s.

The efficacy of cladribine in treating pulmonary Langerhans cell histiocytosis (PLCH) has been suggested in select case reports. Treatment-related malignancies remain a concern. In this phase II trial, the efficacy and safety of cladribine was evaluated in symptomatic PLCH patients with airflow obstruction and/or a decrease in lung function within the previous year. Cladribine was administered for 4 monthly cycles combined with infectious prophylaxis. Patients were followed up every 3 months during the first year to assess efficacy and then until 48 months. The primary end-point was the cumulative incidence of response to treatment at 6 months, defined as ≥10% improvement in forced vital capacity (FVC) and/or forced expiratory volume in 1 s (FEV1), with an increase of ≥200 mL in the absolute value of FEV1. The study was registered with ClinicalTrials.gov (NCT01473797). 10 patients (six men; median (interquartile range (IQR)) age 37 (33-47.5) years; six current smokers) were included. The cumulative incidence of response to treatment at 6 months was 70% (95% CI 28.4-90.4%). The response to cladribine was associated with a median (IQR) decrease of 14.9 (10.5-23.5) points in the St George's Respiratory Questionnaire Total score. At 12 months, five patients were still responders. The median (IQR) duration of infection prophylaxis was 11.8 (11.7-29) months. One patient died before the 12-month visit. The remaining patients were alive at 48 months. No malignancies were detected. Cladribine improved lung function in half of the patients at 1 year of follow-up and was well tolerated overall.

Interstitial Lung Diseases Presenting as Small Nodules: Imaging Phenotypes.

Radiologic Approach to Cystic Lung Diseases: From Cyst Definition to Diagnosis.

Pulmonary Langerhans Cell Histiocytosis.

Pulmonary Langerhans cell histiocytosis (PLCH) and lymphangioleiomyomatosis (LAM) are both rare diseases with low incidence. They not only present characteristic diffuse cystic lesions on chest CT, but also share highly similar clinical manifestations, and most often occuring in young people, which makes differential diagnosis challenging. Here, we reported a case of a reproductive-aged female patient who was initially diagnosed with LAM based on the presence of multiple cystic lesions in both lungs shown by imaging. However, insufficient attention was given to her smoking history and to the specific characteristics and distribution of the cystic lesions. Asher disease progressed, the patient experienced worsening lung function, eventually developing respiratory failure and right heart failure, and bilateral lung transplantation. Taking into account her risk factors, the characteristics of her imaging evolution and pulmonary vascular lesion manifestations, PLCH was considered clinically, and this was confirmed by postoperative pathology.

Abstract Description PLCH occurs almost exclusively in cigarette smokers with a median duration of survival of 12.5 years. PLCH is characterized by bronchiolocentric histiocyte accumulation, inflammatory lesions, nodule formation, and cystic remodeling. A causative link between acquired BRAF kinase mutations in the myeloid/monocyte lineage and the development of neoplasms has been reported, and a common mutation in BRAF (V600E) was found in lung lesions of &amp;gt; 50% of PLCH patients. Although this causal link represents an important breakthrough, the mechanisms by which mutant histiocytes control the initiation and progression of PLCH are unknown. To address this critical gap, we previously developed a novel preclinical model that recapitulates hallmark features of PLCH. We showed that cigarette smoke (CS) exposure of mice expressing an inducible CD11c cre driven BRAFV600E mutation exhibit peribronchiolar inflammation, neoplasm formation, and airspace enlargement accompanied by cyst-like formations. These structural changes are accompanied by alterations in dendritic cell (DC) homeostasis, including increased expression of and responsiveness to CCL20, and the production of CCL7. Based on these findings, we hypothesize that PLCH pathogenesis is driven by a combination of RAS pathway mutations along with CS exposure to amplify CCL20 driven histiocyte accumulation and recruitment of inflammatory cells via CCL7. We are developing BMDCs expressing mutant BRAF to further investigate their role in PLCH. Funding Sources Funded by support from the NIH (HL162662, HL119538, U54HL127672, F31CA284547) and the Veterans Administration (I01BX002347). Other support and resources provided by the Center for Environmental Genetics (NIH/National Institute of Environmental Health Sciences, P30 ES006096), and the Center for Clinical and Translational Science and Training (NIH, 5UL1TR001425). Topic Categories Immune Mechanisms of Human Disease (HUM)

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder characterized by the proliferation of cells of the mononuclear phagocytic system. In addition, they predominantly affect children, with peak incidence between the ages of 1 and 4. However, it is not unusual for them to be diagnosed in adults. In particular, pulmonary involvement occurs in approximately 10% of LCH cases. The diagnosis is confirmed by histology. Treatment is adapted according to the spread of LCH. A 32-year-old female patient presented with a productive cough and exertional dyspnea on June 18, 2023. With a history of Nodular Sclerosis Hodgkin Lymphoma (NSHL) diagnosed on April 28, 2023, without treatment. Family history: mother alive with non-Hodgkin lymphoma treated with chemotherapy. A computed axial tomography (CT) scan was performed, reporting a right lung mass and adenopathy in the bilateral cervical supraclavicular region, bilateral axillary region predominantly on the right, bilateral mediastinal and inguinal regions. Denies a history of smoking and alcoholism. Biopsy and immunohistochemistry result: S100, CD1a, CD68 positive; cytokeratin and EMA negative) confirmed pulmonary LCH. Start treatment with MACOP-B, cytarabine and methotrexate. The patient showed disease progression and died from multiple organ failure. LCH occurs almost exclusively in smokers or former smokers, being considerably less frequent in non-smokers. In addition, it has been associated with Hodgkin’s lymphoma and following treatment with chemotherapy and radiotherapy. The definitive diagnosis is established by biopsy of the lesion associated with immunohistochemical techniques (CD1a+ and CD207+). PLCH remains an extremely rare condition in this population, which means that it is rarely considered in the diagnostic workup

ABSTRACTBilateral spontaneous pneumothorax is a rare condition that occurs mainly in patients with underlying lung disease. We report the case of a 26‐year‐old Chinese male with a history of smoking who presented with sudden onset of chest tightness and dyspnoea. Chest radiography revealed bilateral pneumothoraxes, prompting the insertion of bilateral chest tubes. Further imaging with high‐resolution computed tomography of the chest revealed multiple bilateral, thin‐walled cysts with relative sparing of the lung bases and tiny peripheral nodules. The patient underwent bilateral video‐assisted thoracoscopic surgery with bullectomy, pleurodesis, and surgical lung biopsy. Histopathological examination revealed cysts lined by Langerhans cells with eosinophilic infiltration, establishing the diagnosis of pulmonary Langerhans cell histiocytosis (PLCH). This case highlights the importance of considering cystic lung diseases, particularly PLCH, in young smokers presenting with spontaneous bilateral pneumothorax. Radiologic and histopathologic correlation is essential for definitive diagnosis. Smoking cessation remains the cornerstone of management.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease of unknown etiology, typically affecting individuals aged 20 to 40. Characteristic high-resolution computed tomography findings may obviate the need for biopsy. This study aims to raise awareness by describing clinical and imaging features of PLCH. This single-center retrospective cohort (2016–2024) included 26 confirmed PLCH patients. Demographics, smoking history, comorbidities, symptoms, lab results, 6-minute walk distance, pulmonary function tests, diffusion capacity for carbon monoxide (DLCO), and high-resolution computed tomography findings were reviewed. Median age was 46 years; 84.6% had a smoking history. Cough (46.2%) and dyspnea (53.8%) were common. Radiologically, cysts and nodules predominated. Initial DLCO was lower in dyspneic patients (P = .035). Over median 2.5 years of follow-up, pulmonary function tests and DLCO values remained stable. Early recognition of PLCH radiological features and smoking cessation are crucial. Despite limitations, these findings reinforce known patterns and highlight the need for larger, prospective studies.

The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Pulmonary hypertension (PH) is a significant complication of various lung diseases, including rare conditions such as lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH). This review explores the pathophysiology, diagnostic challenges, and therapeutic strategies for managing PH in these conditions, emphasizing recent findings and gaps in knowledge. In LAM, PH primarily results from parenchymal destruction and hypoxic vasoconstriction rather than direct vascular involvement, leading to its reclassification from Group 5 to Group 3 PH. Sirolimus, an mTOR inhibitor, has demonstrated benefits in stabilizing lung function and may indirectly reduce pulmonary pressures, though direct effects remain unproven. In PLCH, PH is often disproportionate to lung function impairment, suggesting a distinct pulmonary vasculopathy. Histopathologic studies reveal extensive vascular remodeling, including features of pulmonary veno-occlusive disease. Case reports suggest potential benefits of PH-specific therapies such as endothelin receptor antagonists and phosphodiesterase-5 inhibitors, but their use requires caution due to the risk of worsening gas exchange. PH in LAM and PLCH is uncommon but clinically relevant, particularly in advanced disease. While emerging therapies show promise, further research is needed to optimize management and improve patient outcomes.

Abstract Introduction: Pulmonary Langerhans Cell Histiocytosis (PLCH) is a rare cystic interstitial lung disease mainly associated with smoking in the adult population. Bronchoscopy with Bronchoalveolar Lavage (BAL) and Trans-Bronchial Lung biopsy (TBLB) revealing CD1a-positive Langerhans cells are pathognomonic findings for diagnosis. We are presenting a difficult-to-diagnose case of PLCH in a former smoker picked up on Trans-Bronchial Cryobiopsy (TBCB). Description: A 40-year-old female, former smoker with a 20-pack-year smoking history, presented with vague symptoms of dyspnea on exertion, chronic cough, chest pain, and weight loss for 4 months. The patient had multiple visits to the emergency department with a similar presentation with negative workup for common cardiac and pulmonary pathologies. She reported significant seasonal allergies and exposure to refineries, however she denied exposure to birds. The physical examination was significant for decreased breath sounds bilaterally, but no clubbing and cyanosis. Her CT scan findings were consistent with bilateral cystic lung disease. The patient met with a pulmonologist outpatient with negative workup for cystic fibrosis and alpha-1 antitrypsin deficiency. Pulmonary function testing (PFTs) revealed mild isolated reduction in DLCO to 67% of the predictive value. Due to persistent clinical presentation and imaging findings, the patient subsequently underwent a bronchoscopy with BAL and Trans-Bronchial Cryobiopsy. The specimen was sent to a reference lab for pathology. The results were significant for CD1a immunohistochemical-positive stain highlighting Langerhans cells, supporting a diagnosis of Pulmonary Langerhans Cell Histiocytosis (PLCH). The patient was symptomatically treated with systemic steroids, with significant improvement in subsequent follow-up visits. Discussion: PLCH is a rare histiocytic disorder marked by Langerhans cell proliferation, associated with smoking, primarily affecting the lungs but can affect multiple organs including skin, liver, and CNS. Diagnosing PLCH involves HRCT, BAL and trans-bronchial lung biopsy (TBLB). The crucial part of this case was the challenges faced in diagnosing the underlying etiology in the setting of persistent symptoms, and cystic changes on imaging with negative initial work-up. Our case highlights the importance of the efficacy of TBCB in diagnosing an atypical case of PLCH in a former smoker. Usually, smoking cessation is the mainstay of management of PLCH which generally results in drastic improvement both clinically and radiologically. However, our case is unique in this scenario as the patient did not improve despite quitting smoking. Physicians should keep a higher clinical suspicion for PLCH, even in atypical presentation, as proved in our case.

Abstract Introduction Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease, characterized by CD1a+ Langerhans-like cells infiltrating and damaging the walls of distal bronchioles and often presenting with pulmonary symptoms and/or incidental radiological findings. It usually affects middle-aged smokers. The association between PLCH and Human Immunodeficiency Virus (HIV) remains unclear, often posing a diagnostic challenge. Case description A 74-year-old male with a history of chronic smoking, prostate cancer and non-Hodgkin's Lymphoma in remission, and well-controlled HIV presented with unintentional weight loss. He was an active smoker. Initial computed tomography (CT) of the chest exhibited multiple new small pulmonary nodules in the upper lobe, with a repeat CT two months later showing an increase in the number of cavitary nodules. Subsequent imaging identified new centrilobular emphysema alongside the persistent cavitary nodules. In the setting of pre-existing HIV and new onset cavitary pulmonary nodules, an extensive infectious and autoimmune workup, including TB and fungal testing, returned negative. HIV RNA was undetectable and CD4 counts were within normal limits. Prostate specific antigen level was within normal range. Bronchoscopy was inconclusive, leading to a video-assisted thoracoscopic surgery (VATS)-guided lung wedge biopsy. Histology revealed granulomatous tissue with eosinophils and histiocyte-like cells, consistent with PLCH. Genetic testing showed a MAP2K1 gain-of-function mutation with a wild-type BRAF gene. A full body PET/CT showed no metabolically active disease, indicating isolated pulmonary involvement. Patient's extensive smoking history was thought to be the most likely contributing factor to his diagnosis of PLCH and hence, smoking cessation was advised. Patient successfully quit smoking and has since regained 10kg weight, with no requirement of steroid treatment owing to his excellent response to smoking cessation. Discussion PLCH can present a diagnostic challenge when appearing as new-onset pulmonary nodules without typical respiratory symptoms, especially in the context of HIV and chronic tobacco exposure. The patient's significant improvement highlights the critical role of smoking cessation in management and health outcomes of PLCH. Additionally, it emphasizes the need for a thorough evaluation of pulmonary nodules in immunocompromised patients.

Abstract Langerhans cell histiocytosis (LCH) is a rare disorder of an unknown etiology that typically manifests throughout the body, but can be unifocal in up to 20% of cases. Pulmonary LCH (PLCH) represents nearly 50% of focal cases. We present a 53-year-old male with a history of hypertension, dyslipidemia, type 2 diabetes mellitus, and active tobacco use disorder (40 pack-years) that presented with abnormal lung cancer screening findings of innumerable pulmonary nodules. Some of these nodules were cavitated and with irregular borders. For many years, he had experienced a chronic cough with yellow sputum production. Acid-fast bacillus and sputum cultures were negative. Pulmonary function tests demonstrated mild obstructive ventilatory defects with no significant change after bronchodilator administration. Lung volumes and diffusing capacity were normal. An 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scan demonstrated faintly FDG-avid subcentimeter paramediastinal lymphadenopathy with no evidence of a primary neoplasm site. The patient was recommended for video-assisted thoracoscopic surgery to determine tissue diagnosis. Histopathologic examination (Images A-D) demonstrated CD1a positive Langerhans cells, rare eosinophils, and numerous macrophages in the lung tissue, suggestive of PLCH. PLCH is often identified in young smokers between the ages of 20 to 40 with symptoms such as a dry cough, shortness of breath, or chest pain. Our patient was older and presented with a chronic productive cough. Common imaging findings include lung nodules that are FDG-avid, and this avidity is often used for both diagnostics and treatment responsiveness. Smoking cessation was discussed with the patient and follow-up CT recommended before initiating a therapeutic regimen. PLCH is a condition that occurs almost exclusively in smokers, and this case demonstrates the complexity of identifying, diagnosing, and treating LCH patients.

Abstract Introduction:Pulmonary Langerhans Cell Histiocytosis (PLCH) is a rare diffuse parenchymal lung disease that predominantly occurs in young adult smokers. PLCH usually presents as bilateral reticulonodular and cystic lung changes seen on a chest computed tomography (CT) scan. We present a case of PCLH manifesting as two isolated cystic lesions. Case:A 42-year-old-female presented to pulmonary clinic for evaluation of lung nodules. Two weeks prior to presentation, she underwent a biopsy of left breast and was diagnosed with invasive breast adenocarcinoma. Since the biopsy, she had experienced intermittent chest discomfort. She also reported a chronic cough with daily sputum production, though there was no change in the nature of her cough or sputum. She did not have hemoptysis, shortness of breath or fever. She was smoking 2-pack per day with a total of 45-pack year history. A chest CT was obtained which revealed two cavitary nodules in the right lower lobe, measuring 5 – 6 mm each. A PET(positron emission tomography) scan showed no FDG(fluorodeoxyglucose) avidity except at the known breast cancer site. She underwent a video assisted thoracoscopic surgery with wedge resection of one of the nodules. Pathology revealed Langerhans-like dendritic cells that stained positive for langherin, CD1a and S100 on immunostaining, consistent with Langerhans cells histiocytosis. After counseling, the patient successfully quit smoking with the support of nicotine replacement therapy. Discussion:PLCH primarily affects young adults with a peak frequency between 20 and 40 years of age. The etiology remains unknown. Cigarette smoking is the only consistent epidemiologic association. Over 90% of affected individuals have a history of smoking. High resolution chest CT is crucial for the diagnosis. The findings vary with the stage of the disease, but are usually bilateral and diffuse. Early-stage abnormalities consist of bronchiolocentric micronodules, along with thick-walled cysts in the upper and middle lung zones with sparing of costophrenic angles and bases. Nodules are initially more numerous than cysts. As the disease progresses, thick-walled cysts can evolve into thin-walled, irregularly shaped cysts. The combination of these findings frequently allows a clinician to establish a diagnosis obviating need for a lung biopsy. Atypical radiographic findings have been reported and cause a diagnostic challenge. Our case is unique, as the abnormalities are confined to a single lobe, with cystic lesions present without nodules. This serves to encourage physicians to consider PLCH in their differential diagnosis when faced with an atypical presentation.