Granulomas or Not? A Diagnostic Dilemma in Pulmonary Pathology

Abstract Introduction:Granulomatous lung disease can be particularly challenging in patients receiving anti-tumor necrosis factor (TNF) agents. These patients are at increased risk for granulomatous diseases, which may not only include infections but also drug-induced granulomatosis. Sarcoidosis is a rare but recognized side effect of anti-TNF therapy. In these cases, clinical and pathological presentations are indistinguishable from classic sarcoidosis, further complicating the diagnostic process.Case Description:A 32-year-old man with ankylosing spondylitis on certolizumab presented to his primary care physician with a dry cough associated with occasional night sweats, fevers, and decreased appetite for 8 weeks. Over the course of his illness, he experienced progressive fatigue, an unintentional weight loss of 10lbs, and occasional nausea. Prior to the onset of symptoms, he had been healthy, physically active, and worked as a teacher and high school baseball coach. He reported no exposure to birds, livestock, tobacco, or illicit drugs, and had no recent travel history. A chest x-ray was revealed bilateral cavitary lesions at the bases. CT of the chest demonstrated patchy nodular consolidation with reverse halo signs present in the lower lobes bilaterally and mildly enlarged mediastinal nodes. Transbronchial biopsies were reported as noncaseating granulomas with a few scattered inflammatory cells, prompting consideration of drug-induced sarcoidosis with atypical radiographic features. However, a secondary review by a pulmonary pathologist reinterpreted the noncaseating granulomas as polypoid plugs of organizing spindle cells with rounded contours, reflecting their intraluminal location in the distal airspaces. These histopathologic findings represented organizing pneumonia without specific features in this case. The patient clinically improved on systemic steroids and certolizumab was discontinued. Discussion: The “atoll” or “reversed halo” sign initially considered characteristic of organizing pneumonia has now been described in association with other causes including medications, connective tissue disease, hypersensitivity pneumonitis, infections, and granulomatosis with polyangiitis. In most patients, a histopathological diagnosis is warranted due to this broad list of differentials. Our case highlights the importance of seeking a secondary review of tissue biopsies, ideally from pathologists with subspecialty expertise, in challenging cases. A second opinion can help improve diagnostic accuracy, especially when the presentation is atypical or when the differential diagnosis includes multiple conditions with overlapping features. While less common, the reverse halo sign has also been observed in sarcoidosis. Thus, a secondary review of pathology facilitated an accurate diagnosis, highlighting the value of expert consultation in complex cases.