リンパ脈管筋腫症

INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare systemic disease characterized by progressive cystic destruction of the lung parenchyma, resulting in extreme parenchymal fragility. Surgical treatment of lung cancer in patients with LAM is technically challenging due to the high risk of intractable air leaks. We report a case of robot-assisted thoracoscopic surgery (RATS) for lung cancer in a patient with LAM, highlighting a strategic hybrid approach to managing the exceptionally fragile lung tissue. CASE PRESENTATION: A 56-year-old woman with tuberous sclerosis complex-associated LAM was diagnosed with Stage IA1 adenocarcinoma in the left upper lobe. We performed a RATS left upper lobectomy using the da Vinci Xi system (Intuitive Surgical, Sunnyvale, CA, USA). To protect the exceptionally fragile lung, a "no-touch" retraction technique was employed using rolled gauze and blunt-tipped robotic instruments. A fissureless technique was applied to minimize parenchymal injury. Crucially, for the division of the incomplete interlobar fissure and the bronchus, we utilized manual staplers equipped with bioabsorbable reinforcement material (buttressed staplers) deployed by a bedside assistant, which provided superior sealing for the fragile lung compared to the robotic staplers available at that time. Despite these precautions, a pinhole air leak occurred in the S8 segment, likely due to unintentional contact with a robotic joint, illustrating the extreme sensitivity of the LAM lung. This was identified via a meticulous sealing test and repaired with polyglycolic acid sheets and fibrin glue. The patient was discharged on POD 5 without persistent air leaks. At 1 year post-surgery, her respiratory function was well-preserved, exceeding predicted values. CONCLUSIONS: RATS offers superior visualization for lung cancer surgery in patients with LAM. However, given the extreme fragility of the lung, the selective use of manual buttressed staplers is a vital adjunct to prevent postoperative air leaks. Optimal outcomes depend on a constant awareness of lung fragility, a hybrid technical strategy, and a rigorous intraoperative sealing test to identify and repair even minor pleural injuries.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signalling might influence LAM biology and clinical features. METHODS: We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2 -/- embryonic fibroblasts and human TSC2 -/- AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. RESULTS: In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift towards slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated adrenocorticotropic hormone (ACTH) and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiological disease stage. AML cells showed elevated expression of POMC, which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. CONCLUSIONS: Our findings suggest that GR signalling may contribute to aspects of LAM cell behaviour and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.

Diffuse cystic lung diseases (DCLDs) are a heterogeneous group of disorders requiring careful evaluation due to distinct management and prognostic implications. A 32-year-old woman presented with dyspnea and chest pressure following a coughing episode and was found to have a right-sided pneumothorax. CT chest showed bilateral, small, round-elliptiform, basal-predominant cysts. Workup, including autoimmune serologies and abdominal imaging, was unrevealing. Serum vascular endothelial growth factor (VEGF)-D was elevated at 839pg/ml, supporting a clinical diagnosis of lymphangioleiomyomatosis (LAM). However, critical re-evaluation of cyst morphology was more suggestive of Birt-Hogg-Dubé syndrome (BHD). Genetic testing revealed a pathogenic folluculin gene mutation, thus confirming the diagnosis of BHD. Surgical lung biopsy, obtained afterwards at the time of elective pleurodesis, did not reveal features of LAM. This case represents a rare instance of falsely elevated VEGF-D in patient with non-LAM DCLD and highlights the importance of critical review of chest radiology in the diagnostic evaluation of patients with cystic lung disease.

Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease caused by mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. While mTOR inhibitor sirolimus, the only FDA approved drug for this disease, stabilizes lung function in most LAM patients, the drug does not eliminate LAM cells, underscoring a critical gap in our understanding of the tumor microenvironment and cellular heterogeneity that drive disease progression. This study provides the first comprehensive multiomics atlas of the human LAM niche, integrating single-cell/nucleus RNA-seq, single-nucleus ATAC-seq, and spatial transcriptomics to deconvolute its complex architecture. We elucidate LAM cellular heterogeneity by identifying three distinct subtypes: the canonical, uterine smooth muscle-like, mTORC1-hyperactive LAMCORE1; a novel, fibroblast-like LAMCORE2 subtype with potent extracellular matrix (ECM) remodeling activity; and LAMCORE3, a substate of LAMCORE1 that shares LAM and myogenic signatures but is characterized by a lower transcriptional activity and specific functional enrichment in protein translation.Our analysis reveals the transcriptomic heterogeneity of the LAM subtypes, orchestrated by distinct transcriptional drivers and networks. Furthermore, we uncover spatially resolved LAM-associated fibroblast (LAF) states, LAF-seed and LAF-niche, that orchestrate TGF-β signaling, ECM deposition and remodeling, and niche expansion. Spatial mapping uncovers a structured ecosystem where LAMCORE1 cells form a central core enmeshed with the lymphatic endothelium, which is surrounded by LAFs, LAMCORE2 cells, and reprogrammed immune and epithelial cells. Findings were validated through multimodal imaging technologies. Present work advances the field by providing the first high-resolution blueprint of the LAM niche microenvironment, revealing novel cell states and crosstalk that identify promising therapeutic targets.