Diagnosis of renal tumors in Birt-Hogg-Dube syndrome: Clinical presentation and risk factors in a single-center retrospective cohort.

BACKGROUND: Birt-Hogg-Dube (BHD) syndrome is a rare genetic condition associated with the development of renal tumors. This study aims to determine typical age ranges for detecting renal abnormalities, risk factors for tumor development, and long-term outcomes based on current surveillance strategies. METHODS: A single-center multi-site retrospective cohort study was performed on all patients with BHD diagnosed from 2000 to 2023. Baseline demographics, pulmonary function, laboratory, radiologic, and histopathologic findings were collected. Logistic regression was used to assess predictor variables for the development of renal tumors with survival analysis evaluated from the date of BHD diagnosis to date of death or last known follow-up. RESULTS: The study included 149 patients with BHD, 39 (26%) with diagnosed renal tumors, of which 28 had histopathologic confirmation. Mean age at renal tumor detection was 53.61 years. Older age and male sex were predictive of renal tumor development ((odds ratio 1.05; 95% CI, 1.01-1.08, P = 0.002) and (odds ratio 2.59; 95% CI, 1.17-5.73, P = 0.02), respectively). Time to all-cause mortality appeared shorter in those with renal tumors (Log-rank P = 0.02), though no deaths were from cancer or cancer-related complications. CONCLUSIONS: Current screening protocols for renal tumors in BHD suggest the most common presenting age range for presentation is late 40s to early 50s, with older age and male sex as risk factors for tumor development.

Computer-aided diagnosis of cystic lung diseases using CT scans and deep learning.

BACKGROUND: Auxiliary diagnosis of different types of cystic lung diseases (CLDs) is important in the clinic and is instrumental in facilitating early and specific treatments. Current clinical methods heavily depend on accumulated experience, restricting their applicability in regions with less developed medical resources. Thus, how to realize the computer-aided diagnosis of CLDs is of great clinical value. PURPOSE: This work proposed a deep learning-based method for automatically segmenting the lung parenchyma in computed tomography (CT) slice images and accurately diagnosing the CLDs using CT scans. METHODS: A two-stage deep learning method was proposed for the automatic classification of normal cases and five different CLDs using CT scans. Lung parenchyma segmentation is the foundation of CT image analysis and auxiliary diagnosis. To meet the requirements of different sizes of the lung parenchyma, an adaptive region-growing and improved U-Net model was employed for mask acquisition and automatic segmentation. The former was achieved by a self-designed adaptive seed point selection method based on similarity measurement, and the latter introduced multiscale input and multichannel output into the original U-Net model and effectively achieved the lightweight design by adjusting the structure and parameters. After that, the middle 30 consecutive CT slice images of each sample were segmented to obtain lung parenchyma, which was employed for training and testing the proposed multichannel parallel input recursive MLP-Mixer network (MPIRMNet) model, achieving the computer-aided diagnosis of CLDs. RESULTS: A total of 4718 and 16 290 CT slice images collected from 543 patients were employed to validate the proposed segmentation and classification methods, respectively. Experimental results showed that the improved U-Net model can accurately segment the lung parenchyma in CT slice images, with the Dice, precision, volumetric overlap error, and relative volume difference of 0.96 ± 0.01, 0.93 ± 0.04, 0.05 ± 0.02, and 0.05 ± 0.03, respectively. Meanwhile, the proposed MPIRMNet model achieved appreciable classification effect for normal cases and different CLDs, with the accuracy, sensitivity, specificity, and F1 score of 0.8823 ± 0.0324, 0.8897 ± 0.0325, 0.9746 ± 0.0078, and 0.8831 ± 0.0334, respectively. Compared with classical machine learning and convolutional neural networks-based methods for this task, the proposed classification method had a preferable performance, with a significant improvement of accuracy of 10.74%. CONCLUSIONS: The work introduced a two-stage deep learning method, which can achieve the segmentation of lung parenchyma and the classification of CLDs. Compared to previous diagnostic tasks targeting single CLD, this work can achieve various CLDs' diagnosis in the early stage, thereby achieving targeted treatment and increasing the potential and value of clinical applications.

Clinical and Functional Outcomes Associated with Quality of Life in Patients with Lymphangioleiomyomatosis: A Cross-Sectional Study.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare (twenty-one per million female inhabitants) neoplastic cystic lung disease that impairs health-related quality of life (HRQoL). However, the factors associated with impaired quality of life in patients with LAM are poorly understood. OBJECTIVE: To assess the clinical, psychosocial, and functional characteristics associated with impaired quality of life in patients with LAM. METHODS: This was a cross-sectional study performed on two nonconsecutive days. HRQoL (SF-36 and CRQ), lung function tests, anxiety and depression symptoms (HADS), maximal (CPET and ISWT), and submaximal exercise capacity (6MWT) were assessed. Linear associations among outcomes were assessed using Pearson's correlation and multivariate tests. RESULTS: Forty-five women with LAM (46 ± 10.years; FEV1,74%pred) were evaluated. The lowest SF-36 scores were observed for general health and vitality and the highest for the physical and social domains. The lowest CRQ scores were observed for dyspnea and fatigue, and the highest were for the emotional function and self-control domains. Sixteen (35%) women had anxiety, and 8 (17%) had depression symptoms. Most of the SF-36 and CRQ domains were associated with anxiety and depression symptoms (from r = 0.4 to r = 0.7; p < 0.05) and exercise capacity (from r = 0.3 to r = 0.5; p < 0.05). Lung function parameters were weakly or not associated with quality of life domains. After multiple linear regression, HRQoL was independently associated with depression symptoms and physical capacity but not with lung function. CONCLUSION: Our results show that aerobic capacity and depression symptoms are the main factors, rather than lung function, related to quality of life in patients with LAM.

Diffuse Cystic Lung Disease: A Clinical Guide to Recognition and Management.

TOPIC IMPORTANCE: Diffuse cystic lung diseases (DCLDs) represent a group of pathophysiologically heterogeneous entities that share a common radiologic phenotype of multiple thin-walled pulmonary cysts. DCLDs differ from the typical fibroinflammatory interstitial lung diseases in their epidemiology, clinical presentation, molecular pathogenesis, and therapeutic approaches, making them worthy of a distinct classification. The importance of timely and accurate identification of DCLDs is heightened by the impact on patient management including recent discoveries of targeted therapeutic approaches for some disorders. REVIEW FINDINGS: This article offers a practical framework for evaluating patients with DCLD, indicating the most appropriate and current diagnostic and management approaches. We focus on the DCLDs that are most likely to be encountered by practicing pulmonologists: lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and lymphoid interstitial pneumonia. Chest CT scan is the most informative noninvasive diagnostic modality to identify DCLDs. Thereafter, instituting a structured approach to high-yield associated factors (eg, medical, social, and family history; renal and dermatologic findings) increases the likelihood of identifying DCLDs and achieving a diagnosis. SUMMARY: Although the individual diseases that comprise the DCLD family are rare, taken together, DCLDs can be encountered more frequently in clinical practice than commonly perceived. An increased eagerness among general pulmonary physicians to recognize these entities, coupled with a practical and systematic clinical approach to examinations and investigations, is required to improve case findings, allow earlier intervention, and reduce morbidity and mortality.

Clinical Trial Validation of Automated Segmentation and Scoring of Pulmonary Cysts in Thoracic CT Scans.

In cystic lung diseases such as lymphangioleiomyomatosis (LAM), a CT-based cyst score that measures the percentage of the lung volume occupied by cysts is a common index of the cyst burden in the lungs. Although the current semi-automatic measurement of the cyst score is well established, it is susceptible to human operator variabilities. We recently developed a fully automatic method incorporating adaptive features in place of manual adjustments. In this clinical study, the automatic method is validated against the standard method in several aspects. These include the agreement between the cyst scores of the two methods, the agreement of each method with independent tests of pulmonary function, and the temporal consistency of the measurements in the consecutive visits of the same patients. We found that the automatic method agreed with the standard method as well as the agreement between two trained operators running the same standard method; both methods obtained the same level of correlation with laboratory pulmonary function tests; the automated method had better temporal consistency than the standard method (p < 0.0001). The study indicates that the automatic method could replace the standard method and provide better consistency in assessing the extent of cystic changes in the lungs of patients.

[Case report of a cystic lung disease: From a rarity to the discovery of an unknown genetic variant]. / À propos d'un cas clinique de maladie kystique pulmonaire : d'une rareté à la découverte d'un variant génétique inconnu.

INTRODUCTION: Cystic lung diseases are rare, with numerous differential diagnoses. Iconographic discovery consequently necessitates medical examinations in view of proposing an etiological orientation. CASE REPORT: A 57-year-old woman consulted in pulmonology following fortuitous detection of a cystic lung disease on an abdominal CT scan. Complementary medical examinations did not allow orientation towards a particular diagnosis. During a follow-up consultation, the patient informed her pulmonologist of the recent detection of a monoallelic variant of a FAT4 gene in one of her daughters, who was suffering from edema of the lower limbs secondary to a disease of the lymphatic system. As our patient had a similar history, she likewise received a genetic analysis. A monoallelic variant not described in the genetic databases was observed, and considered as a probable pathogenic variant (class 4/5 on the pathogenicity scale of genetic variants). CONCLUSION: After analyzing the available literature data, we raise questions about a possible link between this variant of the FAT4 gene, chronic lymphedema and our patient's cystic lung disease.

Retinoic Acid-Mediated Control of Energy Metabolism Is Essential for Lung Branching Morphogenesis.

Lung branching morphogenesis relies on intricate epithelial-mesenchymal interactions and signaling networks. Still, the interplay between signaling and energy metabolism in shaping embryonic lung development remains unexplored. Retinoic acid (RA) signaling influences lung proximal-distal patterning and branching morphogenesis, but its role as a metabolic modulator is unknown. Hence, this study investigates how RA signaling affects the metabolic profile of lung branching. We performed ex vivo lung explant culture of embryonic chicken lungs treated with DMSO, 1 µM RA, or 10 µM BMS493. Extracellular metabolite consumption/production was evaluated by using 1H-NMR spectroscopy. Mitochondrial respiration and biogenesis were also analyzed. Proliferation was assessed using an EdU-based assay. The expression of crucial metabolic/signaling components was examined through Western blot, qPCR, and in situ hybridization. RA signaling stimulation redirects glucose towards pyruvate and succinate production rather than to alanine or lactate. Inhibition of RA signaling reduces lung branching, resulting in a cystic-like phenotype while promoting mitochondrial function. Here, RA signaling emerges as a regulator of tissue proliferation and lactate dehydrogenase expression. Furthermore, RA governs fatty acid metabolism through an AMPK-dependent mechanism. These findings underscore RA's pivotal role in shaping lung metabolism during branching morphogenesis, contributing to our understanding of lung development and cystic-related lung disorders.

A case of Sjögren's syndrome in which diffuse cystic lung lesions led to an accurate diagnosis.

Key Clinical Message: Even in the absence of other symptoms or other pulmonary manifestations suggesting Sjögren's syndrome (SS), it is necessary to include SS in the differential diagnosis of diffuse cystic lung disease (CLD). Abstract: A case of SS that presented initially with diffuse CLD is reported. This case is considered rare because diffuse pulmonary cysts were observed in the early stage with few symptoms, only cysts were observed without other lung lesions on imaging, cyst formation was histologically considered to be alveolar loss, and airway lesions not observed on imaging were suspected based on lung function testing. The details of this case provide extremely important information to consider for the diagnosis and management of CLD and SS.

Bevacizumab-induced pulmonary cystic disease.

The use of Bevacizumab has significantly advanced the treatment of various malignancies. Bevacizumab's inhibition of angiogenesis is a known mechanism that impedes tumour growth and facilitates chemotherapy delivery; however, its association with the development of cystic lung disease is not fully understood. We report a unique case of a 73-year-old woman with a past medical history of metastatic endometrial adenocarcinoma status post-chemotherapy with bevacizumab that presented with worsening respiratory symptoms. A follow-up chest CT scan post chemotherapy showed the transformation of the metastatic lesions into cystic formations. After further extensive evaluation, she was diagnosed with pulmonary cystic disease secondary to bevacizumab. This case illustrates a rare presentation of secondary pulmonary cystic disease following Bevacizumab therapy in a patient with metastatic endometrial adenocarcinoma. It highlights the importance of recognizing uncommon side effects of targeted immunotherapy and underscores the need for ongoing research to understand the underlying mechanisms and manage such complications effectively.

Desquamative interstitial pneumonia: A case report.

Diffuse cystic lung diseases (DCLDs) are a group of heterogeneous lung diseases that are characterized by inflated spaces or cysts within the lung parenchyma. They also exhibit similar imaging characteristics and clinical manifestations compared with those of cystic lesions, such as pulmonary cavities, emphysema, bronchiectasis and honeycomb lung. The most common DCLDs encountered in the clinic include lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, Langerhans cell histiocytosis and lymphocytic interstitial pneumonia. In particular, accurate diagnosis of DCLDs in terms of the different lesions found is important, because their clinical courses, prognoses and treatment strategies vary widely. However, because DCLDs usually have overlapping clinical presentations, diagnosis typically requires a combination of clinical considerations that take into account characteristics of the cyst, its distribution, organ of origin and background parenchymal findings. The present report documents the case of a 73-year-old man diagnosed with desquamative interstitial pneumonia (DIP). The patient was admitted to the hospital due to chest tightness, shortness of breath and intermittent fever. The patient had been a smoker for >60 years and had stopped smoking for 6 months before being admitted. A transbronchial lung biopsy, bronchoscopy and alveolar lavage cytopathogen culture were performed to confirm the diagnosis of desquamative interstitial pneumonia (DIP). The patient was treated with hormonal therapy and advised to abstain from smoking. The diagnosis of DIP in comparison with other DCLDs was summarized for the purpose of providing a clinical basis for the accurate clinical diagnosis of DIP and the development of evidence-based practice guidelines.

[Genetic diffuse cystic lung disease in adults]. / Maladies kystiques pulmonaires de l'adulte d'origine génétique.

Multiple cystic lung diseases comprise a wide range of various diseases, some of them of genetic origin. Lymphangioleiomyomatosis (LAM) is a disease occurring almost exclusively in women, sporadically or in association with tuberous sclerosis complex (TSC). Patients with LAM present with lymphatic complications, renal angiomyolipomas and cystic lung disease responsible for spontaneous pneumothoraces and progressive respiratory insufficiency. TSC and LAM have been ascribed to mutations in TSC1 or TSC2 genes. Patients with TSC are variably affected by cutaneous, cognitive and neuropsychiatric manifestations, epilepsy, cerebral and renal tumors, usually of benign nature. Birt-Hogg-Dubé syndrome is caused by mutations in FLCN encoding folliculin. This syndrome includes lung cysts of basal predominance, cutaneous fibrofolliculomas and various renal tumors. The main complications are spontaneous pneumothoraces and renal tumors requiring systematic screening. The mammalian target of rapamycin (mTOR) pathway is involved in the pathophysiology of TSC, sporadic LAM and Birt-Hogg-Dubé syndrome. MTOR inhibitors are used in LAM and in TSC while Birt-Hogg-Dubé syndrome does not progress towards chronic respiratory failure. Future challenges in these often under-recognized diseases include the need to reduce the delay to diagnosis, and to develop potentially curative treatments. In France, physicians can seek help from the network of reference centers for the diagnosis and management of rare pulmonary diseases.

Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Cystic lung tuberculosis in children: A series of five cases.

Frequent imaging manifestations of pulmonary tuberculosis are airspace or interstitial nodules with or without tree-in-bud nodules, consolidation, cavitation, ground glass opacity, miliary nodules, lymphadenopathy and pleural effusion. It is unusual to encounter cystic changes in patients with pulmonary tuberculosis, and these findings should be differentiated from other cystic lung diseases. This case series describes five cases of cystic lung disease in children with tuberculosis (TB) with illustrative chest radiography and CT findings. Contribution: The manuscript highlights the need to consider tuberculosis as a possible cause of acquired cystic lung disease in appropriate clinical settings, particularly in endemic regions.

Pulmonary Langerhans cell histiocytosis diagnosed using transbronchial lung cryobiopsy: A case report.

A 63-year-old Japanese woman with multiple cysts in both lungs on chest computed tomography (CT) was referred to our hospital after a thorough examination, including a transbronchial lung biopsy (TBLB), failed to provide a diagnosis. Based on the findings on chest CT and pathological examination of the bronchoalveolar lavage fluid and transbronchial lung cryobiopsy (TBLC) specimen, the patient was diagnosed with pulmonary Langerhans cell histiocytosis (PLCH). TBLC may replace TBLB as the main diagnostic technique for PLCH, although further studies are required to determine the usefulness of TBLC for the diagnosis of PLCH.

Cystic Lung Disease Presenting as Recurrent Non-traumatic Chylothorax: Case Report and a Mini-Review.

Malignancy and infections are the most common causes of recurrent chylothorax. Cystic lung disease, especially sporadic pulmonary lymphangioleiomyomatosis (LAM), is a rare condition that may manifest as recurrent chylothorax. We present a case of a 42-year female who presented with dyspnea on exertion secondary to recurrent chylothorax, requiring three thoracenteses within a few weeks. Chest imaging showed multiple bilateral thin-walled cysts. Thoracentesis revealed milky-colored pleural fluid, which was exudative and lymphocytic predominant. Infectious, autoimmune, and malignancy workup was negative. Vascular endothelial growth factor-D (VEGF-D) levels were sent for testing, which came back elevated (2001 pg/ml). A presumptive diagnosis of LAM was made based on recurrent chylothorax, bilateral thin-walled cysts, and elevated VEGF-D levels in a reproductive age group woman. Given quick reaccumulation of chylothorax, she was started on sirolimus. After initiating therapy, there was a significant improvement in the patient's symptoms, with no recurrence of chylothorax in the five years of follow-up. Awareness of different forms of cystic lung diseases is vital to establish an early diagnosis, which may prevent disease progression. Rarity and heterogeneity of presentation often make the diagnosis challenging, requiring a high degree of suspicion.

Pericardial Cyst in Birt-Hogg-Dubé Syndrome: An Unexpected Discovery.

Birt-Hogg-Dubé syndrome (BHD) is a genetic disorder typically characterized by pulmonary cysts, cutaneous fibrofolliculomas, and renal tumors. We report a case of an 87-year-old male patient with a known diagnosis of BHD and a large pericardial cyst who presented to the emergency room with chest pain. BHD is classically associated with pulmonary cysts and not pericardial cysts. In this report, we highlight the potential of pericardial cysts to independently cause retrosternal pain resembling angina, while also mentioning that BHD too can cause chest pain through the rupture of a pulmonary cyst leading to spontaneous pneumothorax. In our case, coronary angiography revealed non-obstructive coronary arteries, so the cause of chest pain was attributed to myocardial infarction with non-obstructive coronary arteries (MINOCA). Atypical causes of chest pain should be considered, especially in patients with diagnosed genetic syndromes.

Outstanding Characteristics of Birt-Hogg-Dube Syndrome in Korea.

Birt-Hogg-Dube (BHD) is a rare genetic disorder characterized by multiple lung cysts, typical skin manifestations, and renal tumors. We prospectively enrolled thirty-one subjects from four South Korean institutions with typical lung cysts, and next-generation sequencing was conducted. We prospectively enrolled thirty-one subjects from four Korean institutions with typical lung cysts. Next-generation sequencing was performed to investigate mutations in the following genes: FLCN, TSC1, TSC2, CFTR, EFEMP2, ELN, FBLN5, LTBP4, and SERPINA1. BHD was diagnosed in 11 of the 31 enrolled subjects (35.5%; FLCN mutations). Notably, we identified three novel mutations (c.1098G>A, c.139G>T, and c.1335del) that have not been previously reported. In addition to FLCN mutations, we also observed mutations in CFTR (16.1%), LTBP4 (9.7%), TSC2 (9.7%), TSC1 (3.2%), ELN (3.2%), and SERPINA1 (3.2%). According to a systematic review of 45 South Korean patients with BHD, the prevalence of pneumothorax (72.7%) was greater in South Korea than in the rest of the world (50.9%; p = 0.003). The prevalence of skin manifestations (13.6%) and renal tumors (9.1%) was lower in Korea than in the rest of the world, at 47.9% [p < 0.001] and 22.5% [p = 0.027], respectively). This study confirmed a significant prediction model for BHD based on age, number of lung cysts (>40), and maximal diameter of lung cysts (>2 cm) regardless of skin manifestations and renal tumors. Importantly, three novel mutations (c.1098G>A, c.139G>T, and c.1335del) were identified. In conclusion, South Korean patients with BHD display characteristics that are different from those observed in patients of other nationalities. Detailed characterization of lung cysts is needed to define BHD, especially in South Korea, even if patients do not present with skin or renal lesions.

Transbronchial cryobiopsy proven amyloid diffuse cystic lung disease complicating a transthyretin mutated (ATTRm) amyloidosis: a case report.

We present a case report of transbronchial cryobiopsy proven diffuse amyloid cystic lung disease complicating a homozygous Val122Ile (V122I) transthyretin mutated amyloidosis (ATTRm). To the best of our knowledge, this is the first case in the literature reporting such pulmonary lesions in ATTRm amyloidosis, and notably diagnosed through cryobiopsy. A 51-year-old man from Mali with a past medical history of bilateral carpal tunnel syndrome presented erectile dysfunction, asthenia and worsening dyspnoea over the past year. He presented signs of cardiac failure; histological and radiological investigations diagnosed cardiac amyloidosis. He was found homozygote for the V122I mutation in transthyretin. A diffuse cystic lung disease (DCLD) was noted on computed tomography (CT) scan. We performed a transbronchial pulmonary cryobiopsy that revealed histological transthyretin amyloid deposits. This case report illustrates the safety and usefulness of cryobiopsy in the setting of DCLD and extends ATTRm amyloidosis as a possible cause of DCLD.