What is the most likely microscopic finding in a patient with a history of heavy tobacco use, presenting with progressive breathlessness, mild restrictive lung changes, decreased Diffusing Capacity of the Lung for Carbon Monoxide (DLCO), and diffuse ground-glass opacities on chest Computed Tomography (CT) scan?

Respiratory Bronchiolitis-Interstitial Lung Disease (RB-ILD)

The most likely microscopic finding in this heavy smoker with progressive breathlessness, mild restrictive changes, decreased DLCO, and diffuse ground-glass opacities without honeycombing is bronchiolitis with intra-alveolar accumulation of macrophages, consistent with Respiratory Bronchiolitis-Interstitial Lung Disease (RB-ILD).

Clinical-Pathologic Correlation

The clinical presentation strongly points toward a smoking-related interstitial lung disease:

• Heavy tobacco use is the critical risk factor that narrows the differential diagnosis to smoking-related ILDs, which encompass RB-ILD, desquamative interstitial pneumonia (DIP), and Langerhans cell histiocytosis 1
• RB-ILD occurs exclusively in current or former cigarette smokers and represents an extensive form of respiratory bronchiolitis that becomes clinically significant enough to manifest as interstitial lung disease 1
• The characteristic HRCT features of RB-ILD are ground-glass opacity and centrilobular nodules, which matches this patient's imaging pattern 1

Distinguishing Microscopic Features

RB-ILD (The Correct Answer)

• Pigmented macrophages accumulate within the lumens of respiratory bronchioles, alveolar ducts, and peribronchiolar alveolar spaces in a patchy, bronchiolocentric distribution 1
• Peribronchiolar fibrosis extends to contiguous alveolar septa, which are lined by hyperplastic type 2 cells and cuboidal bronchiolar-type epithelium 1
• The changes are patchy at low magnification with a bronchiolocentric distribution, accompanied by submucosal and peribronchiolar infiltrates of lymphocytes and histiocytes 1
• The prognosis is substantially better than IPF, and smoking cessation is critical for resolution 1

Why Not DIP?

• DIP shows uniform, diffuse intraalveolar macrophage accumulation that extends diffusely throughout the lung parenchyma, not just bronchiolocentric 1
• DIP typically presents with more extensive ground-glass opacity in the middle and lower lung zones on HRCT, whereas this patient has diffuse but not necessarily uniform distribution 1
• The macrophage accumulation in DIP may be accentuated around respiratory bronchioles but extends diffusely, unlike the patchy bronchiolocentric pattern of RB-ILD 1

Why Not Dense Eosinophilic Infiltration?

• Dense eosinophilic infiltration of alveolar septa would suggest eosinophilic pneumonia, which is not characteristically associated with heavy tobacco use and would typically show peripheral consolidation rather than diffuse ground-glass opacities 1

Why Not Heterogeneous Fibrosis with Fibroblastic Foci?

• Heterogeneous areas of dense mature fibrosis and fibroblastic foci are the hallmark of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis 1
• UIP characteristically shows honeycombing, peripheral reticular opacities, and basal predominance on HRCT—all of which are explicitly absent in this patient 1
• The absence of honeycombing essentially excludes UIP as the primary diagnosis 1

Why Not Proteinaceous Fluid?

• Proteinaceous fluid filling alveolar spaces would indicate pulmonary alveolar proteinosis or pulmonary edema, neither of which fits the clinical context of progressive breathlessness over 6 months in a heavy smoker with restrictive changes 1, 2

Key Diagnostic Features Supporting RB-ILD

• Mild restrictive pattern on pulmonary function testing is characteristic of RB-ILD, though a mixed obstructive-restrictive pattern is also common 1
• Moderate decrease in DLCO is a consistent finding in RB-ILD and helps distinguish it from simple respiratory bronchiolitis without clinical disease 1
• Progressive breathlessness over 6 months fits the subacute to chronic presentation typical of RB-ILD 1
• Ground-glass opacities without honeycombing on CT strongly favor RB-ILD over fibrotic lung diseases like UIP 1

Clinical Pitfalls to Avoid

• Do not confuse RB-ILD with DIP based solely on macrophage accumulation—the distribution pattern (bronchiolocentric vs. diffuse) is the critical distinguishing feature 1
• Do not assume all ground-glass opacities in smokers represent the same disease—the absence of honeycombing and peripheral reticular changes excludes UIP/IPF 1
• Do not overlook the importance of smoking history—RB-ILD is essentially diagnostic in the appropriate clinical and radiologic context when the patient is a current or former heavy smoker 1
• Ground-glass opacity can represent either active inflammation or early fibrosis, but in RB-ILD it primarily reflects the combination of alveolar septal thickening, epithelial hyperplasia, and pigmented intraluminal macrophages 1, 3