Aberrant Thyroid Transcription Factor-1 Expression in Extrapulmonary Malignancies: A Multiorgan Case Series Highlighting Diagnostic Pitfalls

Abstract Thyroid transcription factor-1 (TTF-1) is a widely used immunohistochemical marker for identifying tumors of pulmonary and thyroid origin. Although TTF-1 is a highly sensitive immunohistochemical marker for pulmonary adenocarcinomas and neuroendocrine neoplasms, aberrant expression in extrapulmonary malignancies may lead to diagnostic uncertainty. We present a case series of five extrapulmonary malignancies demonstrating aberrant TTF-1 expression, including metastatic colorectal adenocarcinoma to the lung, high-grade serous carcinoma of the ovary, intestinal-type gastric adenocarcinoma, small cell neuroendocrine carcinoma of the cervix, and Merkel cell carcinoma. In each case, TTF-1 positivity initially raised the possibility of a pulmonary primary tumor. However, integration of clinical history, radiologic findings, morphologic features, and organ-specific immunohistochemical markers, including SATB2, CDX2, PAX8, WT1, p16, CK20, and Napsin A, established the correct diagnosis. Stronger staining was consistently observed with the SPT24 clone compared with the 8G7G1/1 clone. This series highlights the limitations of TTF-1 specificity and emphasises the importance of comprehensive clinicopathological correlation and the use of lineage-specific markers to avoid misclassification of tumor origin.