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Background: Cystic and nodular lung diseases encompass a broad spectrum of diseases with different etiologies and clinicoradiological presentations. Their differentiation is crucial for patient management but can be complex due to diseases with features of both categories and overlapping radiological patterns., Objective: This study aims to describe the imaging features of cystic and nodular lung diseases in high-resolution computed tomography (CT) in detail-primarily based on their etiology-in order to allow a more accurate differential diagnosis of these diseases., Materials and Methods: A narrative review based on current literature on the topic was conducted from a clinicoradiological perspective., Results: This paper systematically categorizes the differential diagnosis of cystic and nodular lung disease and provides insights into their radiological patterns and etiologies. It highlights the role of CT in the diagnosis of these diseases and emphasizes the importance of multidisciplinary panels combining expertise from radiology, pulmonology, rheumatology, and pathology., Conclusion: Reliable differential diagnosis of cystic and nodular lung diseases, particularly based on their radiological features alone, remains difficult due to their overlapping and dynamic nature. Multidisciplinary boards should be the clinical standard for accurate work-up of these diseases, as they combine the medical history, symptoms, radiological findings, and, if necessary, histopathological examinations, thus providing a more robust framework for diagnosis and management., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Rare cystic lung diseases are increasingly recognised due the wider application of CT scanning making cystic lung disease management a growing part of respiratory care. Cystic lung diseases tend to have extrapulmonary features that can both be diagnostic but also require surveillance and treatment in their own right. As some of these diseases now have specific treatments, making a precise diagnosis is crucial. While Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, lymphoid interstitial pneumonia and lymphangioleiomyomatosis are becoming relatively well-known diseases to respiratory physicians, a targeted and thorough workup improves diagnostic accuracy and may suggest other ultrarare diseases such as light chain deposition disease, cystic pulmonary amyloidosis, low-grade metastatic neoplasms or infections. In many cases, diagnostic information is overlooked leaving uncertainty over the disease course and treatments., Aims: This position statement from the Rare Disease Collaborative Network for cystic lung diseases will review how clinical, radiological and physiological features can be used to differentiate between these diseases., Narrative: We highlight that in many cases a multidisciplinary diagnosis can be made without the need for lung biopsy and discuss where tissue sampling is necessary when non-invasive methods leave diagnostic doubt. We suggest an initial workup focusing on points in the history which identify key disease features, underlying systemic and familial diseases and a clinical examination to search for connective tissue disease and features of genetic causes of lung cysts. All patients should have a CT of the thorax and abdomen to characterise the pattern and burden of lung cysts and extrapulmonary features and also spirometry, gas transfer and a 6 min walk test. Discussion with a rare cystic lung disease centre is suggested before a surgical biopsy is undertaken., Conclusions: We suggest that this focused workup should be performed in all people with multiple lung cysts and would streamline referral pathways, help guide early treatment, management decisions, improve patient experience and reduce overall care costs. It could also potentially catalyse a national research database to describe these less well-understood and unidentified diseases, categorise disease phenotypes and outcomes, potentially leading to better prognostic data and generating a stronger platform to understand specific disease biology., Competing Interests: Competing interests: AGN reports fees from Galapagos, Medical Quantitative Image Analysis, Roche, Boehringer Ingelheim in relation to interstitial lung disease and lecture fees from Boehringer Ingelheim, UpToDate. PMG reports grants and consulting fees from Boehringer Ingelheim; speaker fees from Boehringer Ingelheim, Roche Pharmaceuticals, AstraZeneca and Cipla; meeting support from Boehringer Ingelheim and Roche Pharmaceuticals; and stock options in Brainomix. SRJ reports grants from the Medical Research Council, NIHR, LAM Action and the LAM Foundation, and educational fees from Boehringer Ingelheim. SRD reports educational fees from Boehringer Ingelheim and advisory fees from GlaxoSmithKline and AstraZeneca., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We report a rare case of Sjogren's syndrome complicated with Birt-Hogg-Dubé syndrome (BHDS) not previously mentioned in the literature. Further, there is insufficient evidence linking the two diseases. Here, we review existing diagnostic algorithms for diagnosing diffuse cystic lung disease and provide new insights. The patient initially complained of thirst and dry eyes for ten years, and gradually developed shortness of breath. After admission, physical examination showed five missing teeth, decreased respiratory sounds in both lower lungs, and Velcro rales. Computed tomography showed multiple thin-walled cystic lesions in both lungs. Initial xerophthalmia and labial gland biopsy seemed to reveal a pulmonary cystic change associated with Sjogren's syndrome. Before discharge, a rash suspected to indicate a fibrofollicular tumor in the neck was observed, and then FLCN variant has been found. The challenges how to clarify the diagnosis of DCLD causes are discussed., (© 2023. The Author(s).)

Introduction: Although very uncommon, severe injury and death can occur during scuba diving. One of the main causes of scuba diving fatalities is pulmonary barotrauma due to significant changes in ambient pressure. Pathology of the lung parenchyma, such as cystic lesions, might increase the risk of pulmonary barotrauma., Areas Covered: Birt-Hogg-Dubé syndrome (BHD), caused by pathogenic variants in the FLCN gene, is characterized by skin fibrofolliculomas, an increased risk of renal cell carcinoma, multiple lung cysts and spontaneous pneumothorax. Given the pulmonary involvement, in some countries patients with BHD are generally recommended to avoid scuba diving, although evidence-based guidelines are lacking. We aim to provide recommendations on scuba diving for patients with BHD, based on a survey of literature on pulmonary cysts and pulmonary barotrauma in scuba diving., Expert Opinion: In our opinion, although the absolute risks are likely to be low, caution is warranted. Given the relative paucity of literature and the potential fatal outcome, patients with BHD with a strong desire for scuba diving should be informed of the potential risks in a personal assessment. If available a diving physician should be consulted, and a low radiation dose chest computed tomography (CT)-scan to assess pulmonary lesions could be considered.

Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤2 mm) from cavities and characterize their distribution as focal or multifocal versus diffuse. Focal cavitary lesions are often caused by inflammatory, infectious, or neoplastic processes in contrast to diffuse cystic lung diseases. An algorithmic approach to diffuse cystic lung disease can help narrow the differential diagnosis, and additional testing such as skin biopsy, serum biomarkers, and genetic testing can be confirmatory. An accurate diagnosis is essential for the management and disease surveillance of extrapulmonary complications., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Idiopathic multicentric Castleman disease (MCD) has been reported to form lung cysts at a relatively high rate. However, the radiological and pathological features of cystic formation in MCD are unclear., Methods: To clarify these questions, we retrospectively investigated the radiological and pathological findings of cysts in MCD patients. Eight consecutive patients who underwent surgical lung biopsies in our center from 2000 to 2019 were included., Results: The median age was 44.5 years, with three males and five females. On the initial computed tomography, cyst formation was found in seven patients (87.5%). All of the cysts were multiple, round, and thin walled, accompanying ground-glass attenuation (GGA) around cysts. In six patients (75%), cysts increased during their clinical courses, and the new cysts had emerged from GGA, although GGA was improved by treatment. In all four cases, whose pulmonary cysts could be pathologically evaluated, a marked plasma cell infiltration around the cyst wall, and loss of elastic fibers of the alveolar wall were observed., Conclusions: Pulmonary cysts emerged in the area of GGA pathologically consistent with plasma cell infiltration. Cysts in MCD may be formed by the loss of elastic fibers due to marked plasma cell infiltration and may be considered irreversible changes.

Diffuse cystic lung disease (DCLD) is a complex disease that can be caused by various reasons. Although the chest CT scan plays a vital role in suggesting the etiology of DCLD, it is apt to lead to misdiagnosis simply based on the CT image of the lung. Here, we report a rare case of DCLD caused by tuberculosis and misdiagnosed as pulmonary Langerhans cell histiocytosis (PLCH). A 60-year-old female DCLD patient with a long-term smoking history was admitted to the hospital because of a dry cough and dyspnea, and the chest CT scan showed diffuse irregular cysts in both lungs. We considered the patient to be PLCH. To alleviate dyspnea, we chose to give her intravenous glucocorticoids. However, she developed a high fever during the use of glucocorticoids. We performed flexible bronchoscopy and bronchoalveolar lavage. Mycobacterium tuberculosis (specific sequence reads: 30) was detected in BALF. She was finally diagnosed with pulmonary tuberculosis. Tuberculosis infection is one of the rare causes of DCLD. We have discovered thirteen similar cases by searching Pubmed and Web of Science. For DCLD patients, glucocorticoids should not be used blindly unless the existence of a tuberculosis infection is ruled out. TBLB for pathology and bronchoalveolar lavage fluid (BALF) for microbiological detection are helpful for diagnosis., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work., (Copyright © 2023 The first hospital of jilin university. Published by Elsevier Ltd.. All rights reserved.)

Head and neck skin angiosarcoma is a rare and aggressive tumor (1 % of head and neck tumors). Prognosis remains poor, with a 5-year survival rate ranging from 10 to 54%, depending on the initial stage. Metastatic disease markedly worsens the prognosis. Metastatic lung involvement is classic and can take on several forms. The cystic form is responsible for numerous complications, particularly pneumothorax. In this case, an 83-year-old patient was diagnosed with bilateral pneumothorax complicating cystic interstitial lung disease, which was revealed by hemoptoic sputum. Skin examination revealed two large necrotic lesions of the calvaria. Anatomo-pathological examination confirmed cutaneous angiosarcoma on both skin biopsy and lung resection. At a metastatic stage, only systemic treatment with paclitaxel can be proposed. The clinical course was unfavorable, leading to death before any specific treatment. This observation highlights the importance of a complete clinical skin examination in the assessment of pulmonary cystic lesions., (Copyright © 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Diffuse cystic lung disease refers to multiple rounded lucencies or low-attenuating areas with well-defined interfaces with normal lung. Parenchymal lucencies, such as cavitary disease, may mimic cystic lung disease. Cystic lung disease generally has a nonspecific presentation. Pulmonary cysts may present in isolation or with ancillary imaging features, such as ground-glass opacities or nodules. Clinical features, such as connective tissue disease, can narrow the differential diagnosis. In cases with indeterminate imaging and clinical features, open lung biopsy should be considered. Ultrarare cystic lung diseases, such as light chain deposition disease, can mimic more common diseases., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Penetrance estimates of Birt-Hogg-Dubé syndrome (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a health care system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes., Methods: Exomes from 135,990 patient-participants in Geisinger's MyCode cohort were assessed for P/LP truncating FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between P/LP FLCN variants and BHD-related phenotypes was assessed using Firth's logistic regression., Results: P/LP truncating FLCN variants were identified in 35 individuals (1 in 3234 unrelated individuals), 68.6% of whom had BHD-related phenotype(s), including cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). A total of 4 (11.4%) individuals had prior clinical BHD diagnoses., Conclusion: In this health care population, the frequency of P/LP truncating FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes, a minority were previously clinically diagnosed, likely because cutaneous manifestations, pneumothoraces, and kidney cancer were observed at lower frequencies than in clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD., Competing Interests: Conflict of Interest D.H.L is an employee of Unified Patient Network, Inc and scientific consultant for Natera, Inc; MyOme, Inc; and Seven Bridges Genomics. All other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diagnosis of rare diseases remains a challenge in China. We describe our experience with Birt-Hogg-Dubé syndrome (BHDS) encountered at a Rare Lung Disease Clinic recently established in China., Methods: After the first patient with BHDS was recognized in 2017, a Rare Lung Disease Clinic with a multidisciplinary team of specialists was established. We retrospectively analyzed the data of consecutive patients with BHDS encountered from inception to December 2021., Results: There were 1, 1, 15, 12 and 21 cases with BHDS diagnosed from year 2017 to 2021, respectively. All 50 patients (34 women) were of Han race with a mean age of 47.4 years. The common manifestations were pulmonary cysts (98%), pneumothorax (54%) and skin lesions (68%). Renal cancer was detected in two patients and renal angiomyolipoma in four other patients. The main presentations leading to diagnosis were pneumothorax (42%), family screening (36%), and lung cysts identified on radiologic imaging (20%). The average delay in diagnosis was 8.3 years, and 4.7 years in patients with only pulmonary cysts. The most frequent pathogenic variant was c.1285del/dup on exon 11 (23%) among 44 patients confirmed by genetic testing. Renal cancer has not been found on follow-up surveillance thus far., Conclusions: Increasing number of patients with BHDS are being recognized in China, facilitated by establishment of a Rare Lung Disease Clinic. Pulmonary cysts and pneumothorax were commonly encountered features, but skin lesions appeared to be more prevalent in Chinese subjects than previously reported in other Asian countries., (© 2022. The Author(s).)

Postoperative pneumatocele is a rare complication of lung surgery. Here we describe 2 cases of pneumatoceles arising from the unaltered bottom part of the lower lobe a month or more after upper lobectomy. Based on histopathologic findings, we speculated that (1) negative pressure created by the volumetric gap between the thoracic cavity and the remnant lung and (2) increased positive pressure by the check valve mechanism from kinking or flexion of the airway after an upward movement of the remnant lung play crucial roles in the pathogenesis of postoperative pneumatoceles., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene ( Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5 , resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β-β-catenin-Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.

A 30-year-old gentleman with a medical history of HIV, on HAART therapy and pulmonary amyloidosis proven by lung biopsy presented with progressive, worsening shortness of breath and chronic productive cough over the last year. Pulmonary function tests showed a severely obstructive process and CT scan of the thorax manifested diffusely thin-walled, air-filled cysts. After reviewing the patient's prior histories, PFTs and CTof the thorax, the most likely cause of his symptoms was amyloid-related cystic lung disease. After being placed on a LABA/ICS, and LAMA inhaler, the man's condition remained stable. Active oncologic and pulmonary surveillance were continued every three to six months as the patient's respiratory status, PFTs and imaging remained stable. Thoughts of chemotherapy and lung transplant have been suggested, but not initiated at this time. Amyloid-related cystic lung disease is a rare presentation of amyloidosis in the thorax. It has been associated with collagen vascular diseases and mucosa-associated lymphoid tissue lymphoma. After an extensive literature search, it does not appear that this condition has been referenced in an HIV-positive patient; thus making this report unique. More case reports will need to be published and reviewed to see whether an association with HIV and amyloid-associated cystic lung disease exists.

Pediatric cystic lung lesions have long been a source of confusion for clinicians, radiologists, and pathologists. They encompass a wide spectrum of entities with variable prognostic implications, including congenital lung malformations, pulmonary neoplasms, and hereditary conditions. As our understanding of the developmental and genetic origins of these conditions has evolved, revised nomenclature and classifications have emerged in an attempt to bring clarity to the origin of these lesions and guide clinical management. This review discusses cystic lung lesions and the current understanding of their etiopathogenesis., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Pulmonary cysts and spontaneous pneumothorax are presented in most patients with Birt-Hogg-Dubé (BHD) syndrome, which is caused by loss of function mutations in the folliculin ( FLCN ) gene. The pathogenic mechanisms underlying the cystic lung disease in BHD are poorly understood., Methods: Mesenchymal Flcn was specifically deleted in mice or in cultured lung mesenchymal progenitor cells using a Cre/loxP approach. Dynamic changes in lung structure, cellular and molecular phenotypes and signalling were measured by histology, immunofluorescence staining and immunoblotting., Results: Deletion of Flcn in mesoderm-derived mesenchymal cells results in significant reduction of postnatal alveolar growth and subsequent alveolar destruction, leading to cystic lesions. Cell proliferation and alveolar myofibroblast differentiation are inhibited in the Flcn knockout lungs, and expression of the extracellular matrix proteins Col3a1 and elastin are downregulated. Signalling pathways including mTORC1, AMP-activated protein kinase, ERK1/2 and Wnt-β-catenin are differentially affected at different developmental stages. All the above changes have statistical significance (p<0.05)., Conclusions: Mesenchymal Flcn is an essential regulator during alveolar development and maintenance, through multiple cellular and molecular mechanisms. The mesenchymal Flcn knockout mouse model provides the first in vivo disease model that may recapitulate the stages of cyst development in human BHD. These findings elucidate the developmental origins and mechanisms of lung disease in BHD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in Folliculin gene (FLCN). BHD is characterized by lower lobe-predominant pulmonary cysts with risk of pneumothorax, benign skin tumors (fibrofolliculomas), and renal cell carcinoma, often of an unusual chromophobe/oncocytic hybrid histology. The FLCN protein functions in multiple signaling and metabolic pathways including positive regulation of mechanistic target of rapamycin complex 1 (mTORC1) activity via FLCN's GTPase (GAP) activity for Rag C, positive regulation of Wnt signaling (in mesenchymal cells), and negative regulation of TFE3 nuclear localization. Therefore, FLCN-deficient cells are predicted to have reduced mTORC1 and Wnt activity and enhanced TFE3 activity. Folliculin also has functions in autophagy, mitochondrial biogenesis, cell-cell adhesion, 5' AMP activated protein kinase activity, and other pathways. The specific contributions of these pathways to the lung manifestations of BHD are largely unknown. This review is focused on the pulmonary manifestations of BHD, highlighting selected recent advances in elucidating the cellular functions of FLCN and current hypotheses related to the pathogenesis of cystic lung disease in BHD, including the "stretch hypothesis." We also discuss important knowledge gaps in the field, including the genetic, cellular and physical mechanisms of cyst pathogenesis, and the timing of cyst initiation, which may occur during lung development., Competing Interests: Dr. Kennedy reports grants from National Institutes of Health-Loan Repayment Division, grants from National Institutes of Health-National Heart Lung and Blood Institute-T32, during the conduct of the study., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: Light chain deposition disease is a rare anatomo-clinical disorder, which rarely leads to cystic lung destruction., Case Report: We report the case of a 62years old female patient with a history of a monoclonal gammopathy of unknown significance who developed progressive dyspnea. Thoracic CT-scan demonstrated a diffuse pulmonary cystic disorder with predominance in the right lower lobe. Thoracoscopic surgical resection of that lobe led to a diagnosis of non-amyloid kappa light chain deposits. Surgery also resulted in a lung volume reduction effect with clinical and functional benefits related to improved ventilation of adjacent segments., Conclusion: This report of pulmonary cystic disorder related to a light chain deposition disease highlights the potential clinical and functional benefits observed after lung volume reduction surgery., (Copyright © 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Pulmonary involvement, mainly originating from vasculitis, is one of the features of Behçet's syndrome (BS). We describe, for the first time in literature, computerised tomography images of a male BS patient with multiple pulmonary cystic lesions possibly originated from vasculitis or bronchiolar stenosis.

Langerhans cell histiocytosis is a multisystem disease affecting young children. Lung involvement has a myriad of manifestations and the outcomes for these patients have been poorly defined. We present a 2-year-old child who presented with multisystem disease with multiple lung cysts. Treatment consisted of multiagent chemotherapy for 18 months and was associated with a slow but favorable response.

Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts and renal cell carcinomas. Affected individuals inherit germline mutations in the folliculin gene (FLCN). Approximately 150 pathogenic FLCN variants have been identified worldwide. Many Japanese probands of BHD syndrome were first identified by pulmonologists and/or radiologists during treatment of pneumothoraces. Lung specimens obtained through video-assisted thoracoscopic surgery (VATS) have characteristic features unique to BHD syndrome; however, pathologists often miss key findings and diagnose patients with "bullae/blebs". The pleural and subpleural cysts of BHD syndrome-associated lung diseases are often modified by tissue remodeling and can be difficult to distinguish from emphysematous bullae/blebs. Intraparenchymal unruptured cysts tend to retain distinctive features that are different from other cystic lung diseases. Here, we review the clinicopathological findings of BHD syndrome in a Japanese population based on data from 200 probands diagnosed by genetic testing and a total of 520 symptomatic family members identified through BHD-NET Japan (http://www.bhd-net.jp/). Detailed morphology of pulmonary cysts obtained from VATS and autopsied lung specimens are described, and pathological clues for differentiating miscellaneous cystic lung disorders are discussed., (© 2019 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Cysts are commonly seen on CT scans of the lungs, and diagnosis can be challenging. Clinical and radiographic features combined with a multidisciplinary approach may help differentiate among various disease entities, allowing correct diagnosis. It is important to distinguish cysts from cavities because they each have distinct etiologies and associated clinical disorders. Conditions such as emphysema, and cystic bronchiectasis may also mimic cystic disease. A simplified classification of cysts is proposed. Cysts can occur in greater profusion in the subpleural areas, when they typically represent paraseptal emphysema, bullae, or honeycombing. Cysts that are present in the lung parenchyma but away from subpleural areas may be present without any other abnormalities on high-resolution CT scans. These are further categorized into solitary or multifocal/diffuse cysts. Solitary cysts may be incidentally discovered and may be an age related phenomenon or may be a remnant of prior trauma or infection. Multifocal/diffuse cysts can occur with lymphoid interstitial pneumonia, Birt-Hogg-Dubé syndrome, tracheobronchial papillomatosis, or primary and metastatic cancers. Multifocal/diffuse cysts may be associated with nodules (lymphoid interstitial pneumonia, light-chain deposition disease, amyloidosis, and Langerhans cell histiocytosis) or with ground-glass opacities (Pneumocystis jirovecii pneumonia and desquamative interstitial pneumonia). Using the results of the high-resolution CT scans as a starting point, and incorporating the patient's clinical history, physical examination, and laboratory findings, is likely to narrow the differential diagnosis of cystic lesions considerably., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Loss-of-function mutations in the folliculin gene (FLCN) on chromosome 17p cause Birt-Hogg-Dube syndrome (BHD), which is associated with cystic lung disease. The risk of lung collapse (pneumothorax) in BHD patients is 50-fold higher than in the general population. The cystic lung disease in BHD is distinctive because the cysts tend to be basilar, subpleural and lentiform, differentiating BHD from most other cystic lung diseases. Recently, major advances in elucidating the primary functions of the folliculin protein have been made, including roles in mTOR and AMPK signaling via the interaction of FLCN with FNIP1/2, and cell-cell adhesion via the physical interaction of FLCN with plakophilin 4 (PKP4), an armadillo-repeat containing protein that interacts with E-cadherin and is a component of the adherens junctions. In addition, in just the last three years, the pulmonary impact of FLCN deficiency has been examined for the first time. In mouse models, evidence has emerged that AMPK signaling and cell-cell adhesion are involved in alveolar enlargement. In addition, the pathologic features of human BHD cysts have been recently comprehensively characterized. The "stretch hypothesis" proposes that cysts in BHD arise because of fundamental defects in cell-cell adhesion, leading to repeated respiration-induced physical stretch-induced stress and, over time, expansion of alveolar spaces particularly in regions of the lung with larger changes in alveolar volume and at weaker "anchor points" to the pleura. This hypothesis ties together many of the new data from cellular and mouse models of BHD and from the human pathologic studies. Critical questions remain. These include whether the consequences of stretch-induced cyst formation arise through a destructive/inflammatory program or a proliferative program (or both), whether cyst initiation involves a "second hit" genetic event inactivating the remaining wild-type copy of FLCN (as is known to occur in BHD-associated renal cell carcinomas), and whether cyst initiation involves exclusively the epithelial compartment versus an interaction between the epithelium and mesenchyme. Ultimately, understanding the mechanisms of cystic lung disease in BHD may help to elucidate the pathogenesis of primary spontaneous pneumothorax, with more than 20,000 cases reported annually in the United States alone., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We describe the demographic, clinic and radiologic features of nontuberculous cavitary pulmonary diseases in 42 patients with a mean age of 91.1±6.8 months. Infectious etiology was the most common cause (64%), including necrotizing pneumonia (n=15), ruptured hydatid cyst (n=5), lung abscess (n=5) and fungal infection (n=2). Other causes were bronchiectasis, congenital anomalies, foreign body aspiration, sarcoidosis and tumor.

Aims: To characterize the pathological features of pulmonary cysts, and to elucidate the possible mechanism of cyst formation in the lungs of patients with Birt-Hogg-Dubé syndrome (BHDS), a tumour suppressor gene syndrome, using histological and morphometric analyses., Methods and Results: We evaluated 229 lung cysts from 50 patients with BHDS and 117 from 34 patients with primary spontaneous pneumothorax (PSP) for their number, size, location and absence or presence of inflammation. The BHDS cysts abutted on interlobular septa (88.2%) and had intracystic septa (13.6%) or protruding venules (39.5%) without cell proliferation or inflammation. The frequencies of these histological characteristics differed significantly from those seen in the lungs of patients with PSP (P < 0.05). Although the intrapulmonary BHDS cysts were smaller than the subpleural BHDS cysts (P < 0.001), there was no difference in size between them when there was no inflammation. The number of cysts diminished logarithmically and the proportion of cysts with inflammation increased as their individual sizes became greater (P < 0.05)., Conclusions: These results imply that the BHDS cysts are likely to develop in the periacinar region, an anatomically weak site in a primary lobule, where alveoli attach to connective tissue septa. We hypothesize that the BHDS cysts possibly expand in size as the alveolar walls disappear at the alveolar-septal junction, and grow even larger when several cysts fuse., (© 2014 The Authors. Histopathology Published by John Wiley & Sons Ltd.)

Objective: To evaluate the high resolution CT (HRCT) features of cyst-like lung adenocarcinoma, explore the correlation between HRCT image features and histopathological characteristics, and observe the pathological basis of air-containing space., Methods: HRCT and histopathologic findings of cyst-like lung adenocarcinoma in 86 patients were investigated retrospectively. The image features of both tumor and air-containing space were analyzed. All surgically resected specimens were reviewed. The pathological analysis included histologic subtype, differentiation degree, and the pathological basis of air-containing space formation. The correlation between HRCT image features and histopathologic grades was analyzed., Results: On HRCT, intratumoral necrosis was detected in 17 cases (19.8%), air-containing space with septa in 40 cases (46.5%), wall nodule in the air-containing space in 16 cases (18.6%), mixed thick and thin walls of air-containing space in 49 cases (57.0%). Air-containing space and its wall were observed in 63 cases on histological specimens, among which destruction of the alveolar wall by tumor cells might be the pathological basis of air-containing space in 42 (66.7%) cases. Differences of tumor attenuation (P = 0.030), intratumoral necrosis (P = 0.003) and proportion of thin-wall in air-containing space (P = 0.014) among different histopathologic grades were significant. The proportion of thin-wall in air-containing space was negatively correlated with histological grade (r = 0.267, P = 0.015). Differences of tumor contour (P = 0.002), tumor attenuation (P = 0.006), intratumoral necrosis (P < 0.001), septa in air-containing space (P = 0.016) and proportion of thin-wall in the air-containing space (P = 0.005) among different differentiation degrees were significant. The proportion of thin-wall in air-containing space was positively correlated with differentiation degree (r = 0.266, P = 0.013)., Conclusions: On HRCT, cyst-like lung adenocarcinoma may manifest as an air-containing space with septa and mixed thin and thick walls, whereas wall nodule of air-containing space and intratumoral necrosis are not common. There is a certain correlation of HRCT manifestation with pathological subtype grading and tumor differentiation. Analysis of HRCT image features is helpful in prediction of the histopathologic grading and histological differentiation degree of the tumors. Destruction of the alveolar structure by tumor cells may be the main pathological basis of air-containing space formation in cyst-liked lung adenocarcinoma.

Cystic lung diseases present a considerable diagnostic challenge because they are less frequently encountered in clinical practice and high-resolution computed tomography findings are often similar in many of these diseases. Here, we review the high-resolution computed tomography findings of cystic lung diseases and their mimics and provide a systematic approach to their diagnosis. Specific diseases that are discussed include pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, and light chain deposition disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominantly inherited genodermatosis that predisposes to cystic lung disease, leading to spontaneous pneumothoraces. This retrospective analysis of five BHD cases (two men, three women) compared lung histology and computed tomography (CT) imaging to a matched cohort of non-BHD patients with spontaneous pneumothoraces (SPN)., Methods and Results: Lung was sampled during pleurodesis to resect bullae. Recurrent pneumothoraces was seen in two patients. Fourteen sets of histological slides (seven in each group) and 10 CT scans (five in each group) were reviewed. CT scans in BHD showed multiple cysts with a basal predominance and intraparenchymal/peribronchial distribution. On histological examination, BHD lungs showed punch-out cysts with no inflammation, and lacked subpleural fibroelastotic scars and smoking changes. In contrast, all SPN cases showed respiratory bronchiolitis and subpleural fibroelastotic scars., Conclusions: This study emphasizes the importance of smoking history and topography of the lesions in assessing cystic lung disease. Pathologists need to remain alert to the possibility of BHD in the setting of recurrent pneumothoraces in a non-smoker, in particular in a woman, at any age, and should take part in a multidisciplinary approach to the diagnosis of cystic lung disease to obtain clinical and CT scan details., (© 2013 John Wiley & Sons Ltd.)

We herein report a case involving a 58-year-old female patient with multiple cystic lesions in the right lobe of the lung. The lesions were revealed on chest computed tomography in 2002 and followed up. Transbronchial lung biopsy showed no malignancy in June 2013. The lesions gradually increased in size and thickness and were associated with fluid-filled cysts. We performed a right lower lobectomy in November 2013. Pathological examination revealed inflammatory pseudotumor. Such a case of inflammatory pseudotumor presenting as a pulmonary cyst has not been previously described. Intractable infection and inflammation are regarded as common causes of inflammatory pseudotumor. This condition should be considered in patients with a medical history consistent with infectious disease and a pulmonary cyst found on chest computed tomography.

Background: Cystic lung disease can be seen in patients with Sjögren's syndrome (SS) and is generally thought to be due to lymphocytic interstitial pneumonia., Methods: Using computer-assisted search we identified patients with primary SS seen at Mayo Clinic, Rochester, MN during a 14-year period from 1997 to 2010 who were diagnosed with pulmonary amyloidosis confirmed on lung biopsy. Clinical records, imaging studies, and pathologic specimens were reviewed to delineate presenting features, diagnostic evaluation, and clinical course., Results: Eight patients (7 women, 1 man) with primary SS were diagnosed with pulmonary amyloidosis by lung biopsy (7 surgical, 1 bronchoscopic). Their median age was 55 years (range, 32-75 years) and all were nonsmokers. Presenting symptoms included dyspnea and cough but 4 patients presented with radiologic abnormalities in the absence of respiratory symptoms. CT findings included cystic lesions and nodular opacities in all eight patients. PET scan performed in six patients did not reveal (18)F-2-deoxyglucose (FDG) uptake except in one nodule with borderline uptake. Lung biopsy demonstrated the presence of amyloid in all patients and was associated with mucosa-associated lymphoid tissue (MALT) lymphoma in three patients. Pulmonary function results were normal in five patients and revealed mild impairment in a mixed pattern in one patient., Conclusions: We conclude cystic and nodular lung lesions seen in patients with primary SS can represent amyloidosis which can be associated with MALT lymphoma in some of these patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant inherited disorder characterised by fibrofolliculomas, renal tumours, pulmonary cysts and pneumothorax. The pulmonary cysts and repeated episodes of pneumothorax are the clinical hallmarks for discovering families affected by the syndrome. This disorder is caused by mutations in the gene coding for folliculin (FLCN). FLCN forms a complex with FLCN-interacting protein 1 (FNIP1) and FNIP2 (also known as FNIPL), and the complex cross-talks with signalling molecules such as 5'-AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). Heterozygous Flcn knockout mice and rats with Flcn gene mutations develop renal cysts, adenomas and/or carcinomas. These findings suggest that FLCN functions as a tumour suppressor that inhibits renal carcinogenesis. However, the mechanisms of the formation of pulmonary cysts and pneumothorax associated with heterozygous mutations in FLCN are poorly understood. Resected lung specimens from patients with BHD are often misdiagnosed by pathologists as non-specific blebs or bullae or emphysema, and patients with BHD who have pulmonary cysts and repeated pneumothorax frequently do not receive appropriate medical investigations. This review discusses the clinical and pathological features of lungs of patients with BHD, focusing on the diagnostic pathology and possible mechanisms of cyst formation.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors and pulmonary cysts with repeated pneumothorax. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is known to be involved in the signaling of mammalian target of rapamycin (mTOR). We investigated the lung of a BHD patient who presented with a unique mutation. A 33-year-old woman visited our hospital due to repeated pneumothorax. Histopathologic study of the resected lung demonstrated multiple epithelial cysts. An increase of blood vessels was observed in the vicinity of subpleural cysts. Genomic DNA analysis revealed heterozygous mutation at the 3' end of intron 5 of the FLCN gene. Total mRNA and protein were extracted from the resected lung tissue. RT-PCR and sequence analysis demonstrated the production of exon 6-skipped FLCN mRNA. In Western blotting, the band intensities of phospho-mTOR, phospho-S6, phospho-Akt, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were increased in the BHD lung compared with normal lungs. Histopathologic analysis demonstrated strong immunostainings of mTOR signaling molecules in cyst-lining cells. Collective data indicates that dysregulation of mTOR signaling facilitates S6-mediated protein synthesis and HIF-1α-mediated angiogenesis, which may contribute to the development of pulmonary cysts in this disorder., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Lung pneumatoceles are characterized by a thin-walled air-filled cavity present in lung parenchyma. Mostly they are the result of acute bronchopneumonia after spontaneous drainage of altered lung parenchyma with subsequent development and progression of cavities due to ventile mechanism. This disease is more prevalent in infants and young children, it is rather rare in adults. In the present case report, videothoracoscopy resection of lung pneumatocele of the right lower lobe was performed a 43-years old man. The operation was indicated for the presence of chronic persisting and progressing pneumatocele as a preventive measure of pneumatocele complications.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling.

Background: to describe clinical, radiologic and pathologic features of lung lesions in Birt-Hogg-Dubè syndrome (BHDS) (MIM 135150)., Method: review of 12 patients of BHDS from 3 unrelated Italian families evaluated at GB Morgagni Hospital, Forlì, from 2005 to 2010., Results: mean age (±SD) at diagnosis was 44.6 (±16) years, 8 (66%) were male. All three index cases presented with a history of recurrent pneumothorax and/or cystic lung lesions evaluated by CT scan request by referring pulmonary physicians, none were diagnosed to have BHDS at the time of initial pulmonary evaluation. One of the three cases was a middle-aged female patient with a clinical phenotype indistinguishable from lymphangioleiomyomatosis (LAM), characterized by cystic lung lesions and kidney angiomyolipoma. In one case of BHDS presenting with recurrent pneumothorax and a solitary lung nodule, surgical lung resection revealed a pulmonary histiocytoma. In one case a novel mutation of BHD gene was detected (c.771 del, exon 7)., Conclusions: BHDS is associated with cystic lung disease largely under-recognized by pulmonary physicians and can mimic LAM and may be associated with lung tumor, pulmonary histiocytoma. In one case we found a novel mutation in exon 7, c.771 del (ref.seq. NM&#95;144997.5) never reported before., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Contrast computer tomography (CT) scanning is the investigation of choice for the further assessment of suspected cystic congenital lung lesions (CCLL). Its use to identify the presence of anomalous feeding vessels supplying the lesion is well documented, but data regarding its accuracy is limited. This study compares CT results to operative and pathological findings to determine the accuracy of CT in identifying these anomalous vessels., Methods: 51 consecutive cases of cystic congenital lung lesions managed in one hospital by a single consultant were reviewed. All cases had contrast CT scans performed preoperatively, as standard practice in this institution. We compared the results of these CT scans to the macroscopic appearance at surgery and histological findings postoperatively. We also compared the results of 2 CT protocols used in our institution between 1999-2007 and 2007-2009, respectively., Results: Anomalous vessels were reported on CT in 9 cases. All but 1 had concordant operative and pathological findings. In the remaining 42 cases, no anomalous vessels were seen on CT. Of these, 9 cases were found to have an anomalous blood supply at surgery, 6 of which were hybrid lesions and 3 isolated sequestrations. The specificity of CT in identifying feeding vessels in the study was 97% (95% CI: 0.83-0.99) and the sensitivity was 47% (95% CI: 0.23-0.71). The positive predictive value was 89% (95% CI: 0.50-0.99) and negative predictive value 79% (95% CI: 0.62-0.89). The most recent protocol yielded an improved sensitivity of 75% (95% CI: 0.22-0.98) and a specificity of 100% (95% CI: 0.46-1.0) with a 100% (95% CI: 0.31-1.0) positive and 83% (95% CI: 0.36-0.99) negative predictive value., Conclusion: CT is a specific investigation for identifying anomalous vessels in CCLL but lacks sensitivity, leading to a relatively low negative predictive value. This emphasises the need in every case to look for anomalous vessels at surgery to avoid morbidity and potential mortality. An improved protocol for CT scans leads to improved specificity and sensitivity and predictive values.

A 64-year-old male with throat discomfort visited our hospital, and a chest computed tomography (CT) scan revealed a cystic lesion with a central solid component in the right lung (in the lower lobe, 4.1 x 3.9 cm in diameter). Transbronchial lung biopsy was performed and the lesion was diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma of the lung. No other lymphoma lesion was detected and it was diagnosed as the stage I-E, and a right lower lobectomy was performed. The cystic lesion derived from alveolus and bronchus destroyed by lymphoma infiltration and it might be caused by air retention due to check-valve mechanism.

A 39-year-old woman presented with right-sided pneumothorax. Partial lung resection was done via thoracoscopy. Five years later, left-sided pneumothorax occurred, and she underwent thoracoscopy again. However, air leakage continued, and pleurodesis was performed. Although she had no skin eruptions or renal tumors, Birt-Hogg-Dubé (BHD) syndrome was suggested by radiographic findings. BHD gene analysis was performed, which revealed the BHD gene mutation. Reevaluation of pathological findings showed elastic fibers in the alveolar walls with fine granular changes and accumulation of macrophages. BHD syndrome should be considered in patients presenting with multiple pulmonary cysts with or without skin eruption, or kidney tumor.