B42-02 Diagnostic Algorithm Optimization for Lymphangioleiomyomatosis (LAM) Among Patients With Cystic Lung Disease (CLD): Integrating Clinical Features, Biomarkers, and Genotypes

Rationale Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease (CLD) that often poses diagnostic challenges among patients presenting with diffuse pulmonary cysts. This study aimed to establish a diagnostic model integrating clinical, radiologic, genetic, and biomarker data to improve diagnostic accuracy of LAM within the spectrum of CLD. Methods Between May 2024 and August 2025, 114 patients with computed tomography-confirmed diffuse CLD were prospectively enrolled. Clinical data, the first and most recent spirometry, and radiologic findings including pneumothorax, chylothorax, and renal angiomyolipoma (AML), were recorded. Blood and saliva samples underwent next-generation sequencing (NGS) for TSC1, TSC2, and FLCN mutations, and serum VEGF-D, KL-6, SP-A, and SP-D levels were measured. For each patient, we documented the diagnostic basis (NGS, VEGF-D > = 800 pg/ml, renal AML, or chylothorax) and compared baseline demographics, clinical features, pulmonary function tests (PFTs) (FEV1, FVC, DLCO) and biomarkers (VEGF-D, SP-D, SP-A, and KL-6) across TSC-LAM, Sporadic LAM (S-LAM), post-transplant S-LAM, Birt-Hogg-Dubé syndrome (BHDS) and an unclassified group. Results Among 114 candidate enrolled, 27 (23.7%) patients were diagnosed of TSC-LAM and 3 (2.6%) were diagnosed with BHDS by NGS. 58 patients (50.9%) were diagnosed of sporadic LAM by criteria of 1) VEGF-D > 800 pg/ml (n = 30, 26.3%), 2) renal AML (n = 8, 7.0%), 3) chylothorax (n = 1, 0.9%), 4) by surgical pathology of transplant (n = 10, 8.8% ), and by pathology of biopsy (n = 9, 7.9%). The remaining 26 patients were categorized into the group of unclassified CLD. Patients with LAM status post lung transplant were particularly separated from S-LAM for baseline characteristics comparison. Significant differences were observed among the groups in age, menopausal status, family history of pneumothorax, and multiple pulmonary function parameters including %FEV1, FVC, %FVC, %FEV1/FVC, %DLCO, TLC, and most recent %FEV1 (all p < 0.05). Post-transplant LAM patients were the oldest (mean 54.1 ± 6.6 years), whereas TSC-LAM patients were the youngest (41.9 ± 10.5 years). TSC-LAM patients had the highest mean %FEV1 (87.1 ± 16.0) and %FVC (91.4 ± 17.6), whereas post-transplant LAM showed the lowest pulmonary function indices. Serum VEGF-D levels were significantly higher in TSC-LAM (median 2060.9 pg/mL, IQR 898.7-3176.7) and sporadic LAM (1093.5 pg/mL, IQR 803.8-2099.6) compared with other groups (p < 0.001). Conclusion NGS makes confirmation of TSC-LAM relatively straightforward. By comparison, sporadic LAM is challenging, and in this study the most frequent basis for diagnosis was a serum VEGF-D level >800 pg/mL. This abstract is funded by: None