A woman in her 50s with Lynch syndrome and a history of malignant neoplasms had a superior vena cava thrombus and a necrotic mass in the mediastinum on imaging. The initial biopsy yielded only necrotic remains, and the procedure was complicated by a mediastinal hematoma. A patient treated empirically with antibiotics for fear of infection was examined by broad-spectrum 16S polymerase chain reaction (BRPCR) on formalin-fixed, paraffin-embedded (FFPE) tissue. The test was negative for fungi and mycobacteria, but revealed the DNA of normal oral flora. She later developed superior vena cava syndrome, which led to the suspicion of a mediastinal abscess. Repeat biopsy confirmed carcinoma with necrosis. The case highlights the need for careful interpretation of BRPCR on FFPE tissue in the clinical context.