Case Report: Neuroendocrine-low POU2F3-positive small cell lung cancer presenting as a diagnostically unstable thoracic malignancy.

POU2F3-positive small cell lung cancer (SCLC) is a tuft-cell-like, neuroendocrine-low subtype that may be difficult to classify in small specimens. We report a 61-year-old man with a left-upper-lobe high-grade thoracic malignancy radiographically staged as cT2aN2bM0. The cN2b component was imaging-based, and inflammatory nodal uptake could not be fully excluded because of previous pulmonary tuberculosis. Bronchoscopic biopsy from the opening of the left-upper-lobe lingular bronchus and CT-guided core biopsy of the primary mass sampled anatomically distinct sites within the same tumor process. Both samples showed morphology favoring small cell carcinoma, but conventional neuroendocrine markers were absent, focal, or weak and the immunophenotype varied by specimen and review. Morphology and specimen-specific immunophenotyping, integrated with specialist consultation, supported small cell carcinoma; POU2F3 nuclear positivity supported subtype assignment and explained the neuroendocrine-low phenotype rather than establishing the diagnosis alone. Nab-paclitaxel, cisplatin, and pembrolizumab were used as an empiric bridge strategy while histologic classification remained unresolved. After four induction cycles and marked radiographic response, a highly selected multidisciplinary decision led to surgery for pathologic assessment. Resection showed pCR/ypT0N0M0, followed by four postoperative cycles of TP plus pembrolizumab. On May 26, 2026, surveillance imaging showed no recurrence or metastasis; no ctDNA was detected on subsequent plasma testing, which was interpreted as MRD-negative. This single case is illustrative and does not define a treatment standard, a POU2F3-specific response phenotype, or evidence of cure.