Lung cancer remains as the primary cause of cancer-related mortality in both the United States and globally (1).Early detection of lung cancer significantly increases the chances of successful treatment and cure. Early stage lung cancer, presenting as a pulmonary nodule, can be difficult to distinguish from benign causes. An increase in pulmonary nodules has corresponded to increased use of computed tomography (CT) chest imaging in clinical care and lung cancer screening (2). This has paralleled increased utilization of percutaneous and bronchoscopic biopsies for lung cancer diagnosis (3, 4). Recent guidelines highlight the importance of differentiating specific malignant and benign pathologic diagnoses from non-diagnostic, non-specific findings (5). This is critical to maximize diagnostic accuracy and ultimately to ensure timely care for patients undergoing bronchoscopic procedures (6).

One of these benign pathologic diagnoses is organizing pneumonia (OP). OP can be classified as primary, also known as a cryptogenic organizing pneumonia, and secondary OP, the latter of which forms the larger group of OP seen in clinical practice (76.2%) (7). Further complicating the matter is the variety of conditions associated with secondary OP, which include infections, connective tissue diseases, cancer-based treatments, environmental exposures, organ transplantations, and also occult malignancy (8–11). There have been case reports where OP may be the only sign of malignancy and may not necessarily be adjacent to the primary tumor (12–14). In several instances, malignancy was missed for years despite multiple minimally invasive procedures, such as transbronchial lung biopsies (TBLB), CT-guided biopsies, and lymph node sampling. These findings highlight the need for better characterization of malignancy-associated OP and a deeper understanding of its clinical significance when identified on lung biopsy.

The aim of this study is to assess the prevalence of organizing pneumonia (OP) in association with lung cancer. We hypothesize that OP is not uncommonly identified concurrently with pulmonary malignancy. This retrospective analysis evaluates the frequency of combined pathologic findings in tissue samples, determines the prevalence of lung cancer in bronchoscopically obtained transbronchial biopsies classified as OP, and describes associated tumor and patient characteristics. Understanding the risk of concurrent lung cancer in patients diagnosed with OP is critical to avoid delayed cancer diagnoses and to prevent the misclassification of a potentially malignant process as benign.

This study presents one of the largest case series of Organizing pneumonia (OP) and concurrent lung cancer, helping to further characterize this phenomenon. Correlation between lung malignancy and OP has been described and may be the only sign of malignancy in some cases (15). OP is a relatively common concurrent finding in lung cancer, observed in up to 37% of resected specimens. However, the mechanisms underlying this association remain poorly understood (15). Proposed explanations include bronchial obstruction from malignancy leading to OP, chronic inflammation from OP increasing cancer risk, and OP triggered by prior chemotherapy or radiation (7, 12–14, 16). Our study examined a total of 61 cases of malignancy associated with OP over a 13-year period. The predominant malignancies associated with OP were non-small cell subtypes, particularly squamous cell carcinoma and adenocarcinoma. Most specimens were obtained via surgical resection rather than minimally invasive techniques. Only one minimally invasive biopsy showed malignancy and OP concurrently. Additionally, our study found that OP can be associated with Lung malignancies of all T-stages. While lower stages were more common (44% T1 and 29% T2), a significant proportion of higher-stage tumors was also observed (16% T3 and 11% T4).

Squamous cell carcinoma accounted for 46% of cases which is higher than the expected 25–30% in the general NSCLC population, whereas adenocarcinoma typically comprises about 40% and large cell carcinoma 10–15% (17, 18). This finding is consistent with previous reports by Romero et al., suggesting a potential association between OP and lung squamous cell carcinoma (15). One hypothesis is that the typical central location of squamous tumors may predispose to airway obstruction and a subsequent inflammatory response, which can trigger OP; however, this remains speculative and requires further investigation (19).

Multiple studies have noted that cancer diagnoses can be missed with less invasive techniques, as surgical specimens may reveal scattered tumor cells within a background of OP (12, 14, 15, 20). In our study, 88% of Cohort 1 patients underwent surgical lung biopsy or resection, and 38 of 50 had prior bronchoscopic or CT-guided biopsies. None of these initial biopsies demonstrated histologic evidence of organizing pneumonia (OP), although tissue or cytology was often described as inflammatory, non-diagnostic, or suspicious. Despite prior biopsies, malignancy was ultimately confirmed in 76% of cases, prompting surgical resection. This discrepancy likely reflects sampling limitations with fine needle aspiration or small transbronchial biopsies and the patchy nature of OP, which can be missed in limited samples (19). To further explore this issue, we examined a second cohort of 40 patients diagnosed with OP via transbronchial lung biopsy (TBLB) and subsequently followed for at least two years. While only one patient had carcinoma identified at the time of initial biopsy, four additional patients (10%) were later diagnosed with malignancy from the same anatomical region through repeat biopsy or surgical resection. These findings are consistent with prior reports, including one study where 11.2% of patients with OP diagnosed on CT-guided biopsy were ultimately found to have malignancy (20). This highlights an important clinical consideration: a diagnosis of OP does not exclude other etiologies, including malignancy, particularly when clinical suspicion remains high or thoracic lymphadenopathy is present (13, 16). As interventional pulmonology increasingly adopts minimally invasive approaches such as robotic navigational bronchoscopy, awareness of these limitations remains essential (21).

This single-center retrospective study examines the characteristics of malignancy associated with organizing pneumonia (OP), but several limitations should be noted. Selection and sampling bias may exist due to the predominance of surgical specimens (Cohort 1) and inclusion of cases after non-diagnostic biopsies, which could overrepresent complex or high-suspicion cases. Variability in pathology reporting over the 13-year period introduces potential information bias and limited our ability to assess the proximity of OP to the primary tumor. Additionally, whether advances in bronchoscopy techniques, such as larger cryobiopsies, would alter the detection of concurrent malignancy in Cohort 2 remains uncertain. As Indiana University Health is a major referral center, some patient data from outside institutions were not uniformly captured despite manual chart review. Finally, staging information was unavailable for some patients due to the type of biopsy performed. Future prospective studies with standardized pathologic criteria are needed to clarify these relationships.

Lung malignancy can be found concurrently with OP. The presence of OP on minimally invasive biopsy should prompt continued suspicion for cancer when clinical or radiographic features suggest malignancy.