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Gross cystic disease fluid protein (GCDFP-15) is currently used as an immunohistochemical marker of breast cancer, whereas thyroid transcription factor (TTF-1) is commonly used as a marker of primary lung neoplasms. Traditionally, a GCDFP-15+/TTF-1− immunohistochemical profile in lung tumors has been considered as highly suggestive of metastatic carcinoma of the breast. Here, we investigated the expression of GCDFP-15 and TTF-1 on a tissue microarray consisting of 381 primary lung carcinomas. GCDFP-15 was expressed in normal bronchial submucosal glands and bronchial epithelium, which were negative for TTF-1. Seventeen tumors (4.5%) were positive for GCDFP-15, including 11 of 186 (5.9%) adenocarcinomas, 1 of 97 (1%) squamous cell carcinomas, 1 of 23 (4.3%) carcinoid tumors, 2 of 47 (4.3%) large cell carcinomas, and 2 of 17 (11.8%) adenosquamous carcinomas. Of the 11 GCDFP-15 positive adenocarcinomas, 10 (91%) were TTF-1 negative. On whole sections, about half (55%) of GCDFP-15 positive cases were negative and one-third (33%) revealed focal TTF1 staining in areas distinct from the tumor regions that expressed GCDFP-15. All GCDFP-15 positive tumors were negative for mammaglobin, estrogen receptor, and progesterone receptor. Our study confirms that a small subset of primary lung adenocarcinomas exhibits a GCDFP-15 positive phenotype. Expression of TTF-1 in this group is not uniform and frequently negative in small specimens. Thus a GCDFP-15 positive/TTF-1 negative phenotype may not be indicative of metastatic breast carcinoma in every case. It is critical that pathologists be aware of this phenotypic subset of lung adenocarcinomas, especially when faced with small tissue or cytologic samples.