Aberrant TTF-1 expression in metastatic colorectal adenocarcinoma mimicking primary lung cancer: a case report and review of diagnostic pitfalls

Abstract A 43-year-old man with sigmoid colon adenocarcinoma (low-grade, moderately) developed multiple pulmonary metastases, presenting an unusual immunohistochemical profile. Histologically, resected lung nodules showed metastatic adenocarcinoma consistent with colorectal origin, yet the tumor cells paradoxically expressed thyroid transcription factor-1 (TTF-1) – a marker typically specific to primary lung adenocarcinoma. Immunophenotyping demonstrated TTF-1 nuclear positivity in the metastatic tumor alongside a classic colorectal profile: cytokeratin 7 (CK7) negativity, cytokeratin 20 (CK20) positivity, strong caudal-type homeobox transcription factor 2 (CDX2) and special AT-rich sequence-binding protein 2 (SATB2) nuclear expression, and absence of Napsin A. The patient underwent surgical resection of the primary sigmoid colon tumor and received 16 cycles of capecitabine plus bevacizumab chemotherapy. Molecular testing revealed a KRAS c.35G > T (p.G12V) mutation in the tumor. This case highlights a potential diagnostic pitfall in metastatic colorectal cancer: aberrant TTF-1 expression can mimic a primary lung tumor. We discuss how the comprehensive immunohistochemical panel and genetic findings confirmed the colorectal origin of the lung lesions, emphasizing that combined marker profiles (TTF-1 +/CK7 –/CK20 +/CDX2 +/SATB2 +/Napsin A –) are more consistent with metastatic colorectal adenocarcinoma rather than an enteric-type adenocarcinoma of the lung, primary. The report reviews relevant literature and underscores the importance of correlating clinical history with pathology to avoid misdiagnosis.