Diagnostic Reassessment of a Pulmonary Mass Initially Suspected to Represent IgG4-Related Lung Disease: The Complementary Role of Tissue Metagenomic Sequencing.

Background/Objectives: Pulmonary mass-like lesions may mimic malignancy, infection, or inflammatory disease, complicating diagnosis when radiologic, histopathologic, and microbiologic findings overlap. This case illustrates the importance of diagnostic reassessment when the clinical course and treatment response are not fully consistent with the initial diagnosis. Methods: A 69-year-old man with diabetes mellitus and mild emphysema presented with chronic cough, purulent sputum, and a recurrent left upper lobe mass. Computed tomography-guided biopsy revealed dense lymphoplasmacytic infiltration with eosinophils, fibrosis, and increased IgG4-positive plasma cells, leading to a presumptive diagnosis of IgG4-related lung disease. Limited improvement with steroid therapy and recurrent hemoptysis prompted multidisciplinary reassessment, including tissue metagenomic next-generation sequencing (mNGS). Results: Imaging findings were compatible with subacute invasive aspergillosis, although conventional fungal staining, culture, antigen testing, serologic studies, and bronchial washing analyses were negative. Tissue mNGS detected 348 low-abundance Aspergillus-derived reads, accounting for 0.03% of non-host reads. Following initiation of voriconazole, the lesion decreased from 47 mm to 32 mm within six weeks and regressed further thereafter. Symptoms resolved, and hemoptysis did not recur. Conclusions: This case highlights the importance of diagnostic reassessment when findings and treatment response do not fully support the initial diagnosis. Tissue mNGS may provide complementary evidence for probable subacute invasive aspergillosis when interpreted alongside radiologic findings, exclusion of alternative diagnoses, and treatment response.