Combined small-cell lung carcinoma with dual false-negative diagnosis on preoperative biopsy and intraoperative frozen section: a case report highlighting sampling bias pitfalls

Abstract Background Combined small‑cell lung carcinoma (C‑SCLC) is a rare heterogeneous lung malignancy prone to sampling‑related diagnostic errors. Limited tissue from percutaneous biopsy or intraoperative frozen sections may only capture inflammatory stroma instead of biphasic tumor components, leading to false-negative benign interpretations and delayed definitive diagnosis. Case presentation An 80-year-old male presented with an imaging-highly suspicious malignant left lower lobe pulmonary nodule. Both preoperative needle biopsy and intraoperative frozen section were misdiagnosed as chronic inflammatory fibrosis. Wedge resection with lymph node sampling was performed, and final formalin-fixed paraffin-embedded (FFPE) pathology confirmed C-SCLC (70% small-cell component, 30% squamous cell carcinoma) with station 7 lymph node metastasis (pT2aN1M0, stage IIB). Immunohistochemistry validated dual histologic subtypes. The dual false-negative result was fully attributed to severe intratumoral spatial heterogeneity and insufficient limited sampling. Postoperative adjuvant chemoimmunotherapy following standard C‑SCLC guidelines was administered, with dynamic but non‑diagnostic fluctuations of serum tumor markers observed. Conclusions Clinicians and pathologists must recognize that radiologically suspicious pulmonary lesions cannot be ruled out for C‑SCLC even if biopsy/frozen sections show inflammation. Discordant clinicoradiologic and rapid pathologic results mandate comprehensive multi-block FFPE sampling with immunohistochemistry for definitive diagnosis.