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Patients undergoing transthoracic needle core lung biopsy (TTNB) are at risk for biopsy-related pneumothorax. Instilling pleural sealant at the pleural puncture site reduces this risk. The impact of histologic changes associated with pleural sealant on assessing the histologic type and pathologic stage in lung cancer resection specimens has not been previously evaluated. All lung cancer resection specimens from 2015 to 2018 in which polyethylene glycol hydrogel pleural sealant was instilled during TTNB were reviewed. Thirty-three cases were identified. TTNB preceded lobectomy by an average of 35 days. Amphophilic, weakly polarizable, crinkled pleural sealant material was associated with tumor in 11 cases (33%), including 8 adenocarcinomas, 2 squamous cell carcinomas, and 1 pleomorphic carcinoma that averaged 1.7 cm in greatest dimension. Surrounding the sealant material was a 0.25 to 1.0 cm in greatest dimension pseudocystic space with a thin granulomatous rim of macrophages and multinucleated giant cells that occupied on average 17% of the tumoral area. Pleural sealant could have impaired assessment of pathologic stage in 1 case by obscuring the visceral pleural elastic layer, but definitive visceral pleural invasion was present nearby. Although hydrogel pleural sealant instilled during TTNB has the potential to obscure important histologic features, in practice, it appears to have little or no adverse impact on the assessment of histologic type and pathologic stage in subsequent lung cancer resection specimens. Recognition of the histologic appearance of hydrogel pleural sealant and its associated tissue response is important for avoiding diagnostic misinterpretation.