By Rodney T. Miller, M.D., Director of Immunohistochemistry


Transcription factors are nuclear proteins that have an important role in regulating gene expression, thereby determining and maintaining cellular phenotype. Thyroid transcription factor-1 (TTF-1) is a 38kDa protein (in the NKx2 family of DNA-binding proteins) that is expressed during embryonic development in the thyroid, diencephalon, and respiratory epithelium. Numerous studies have shown that antibodies to TTF-1 can be very useful reagents in diagnostic pathology. It is important to realize that only nuclear immunoreactivity to TTF-1 represents “true” reactivity, and for the purposes of diagnosis, any cytoplasmic reactivity should be ignored (similar to certain other nuclear antigens such as ER and PR).



TTF-1 as a marker of thyroid carcinoma 


A high percentage (> 95%) of follicular, papillary, and insular thyroid carcinomas show expression of TTF-1. In addition, a similar percentage of medullary carcinomas of thyroid express this marker. Reactivity of Hurthle cell tumors with TTF-1 is somewhat less common (reported range from 20- 75%). Anaplastic thyroid carcinoma is usually negative for TTF-1. Most authors report that parathyroid tissue is negative, and this agrees with our personal experience at ProPath.


TTF-1 as a marker of pulmonary adenocarcinoma 


One of the most useful roles of TTF-1 is in the recognition of pulmonary carcinoma. Roughly 75% of primary pulmonary adenocarcinomas show expression of TTF-1, a feature that can greatly aid in the identification of lung carcinomas when they present as metastatic disease. Squamous carcinomas are almost always negative for TTF-1, although adenosquamous carcinomas of pulmonary origin may show reactivity in the glandular component. TTF-1 is not expressed in mesothelioma, so it also has utility in the differential diagnosis of mesothelioma vs. primary pulmonary adenocarcinoma. Pulmonary sclerosing hemangioma has also been found to express TTF-1.






TTF-1 neuroendocrine tumors 


In addition to its expression in medullary carcinoma of thyroid, TTF-1 may be expressed in other neuroendocrine tumors. Some authors have identified expression of TTF-1 in >80% of primary pulmonary small cell carcinoma, although our experience at ProPath is closer to 50-60%. Non-pulmonary small cell carcinoma may also be reactive, although the frequency of positivity is substantially less than with pulmonary small cell carcinoma. In addition, some authors have found that when pulmonary small cell carcinomas express TTF-1, nearly 100% of cells stain, whereas non-pulmonary small cell carcinomas expressing TTF-1 usually show <50% of tumor cells staining. So-called “atypical carcinoids” of lung are frequently positive (80%). The reported rates of reactivity of typical lung carcinoids with TTF-1 range from 20%-95%, and there is some evidence to suggest that expression of TTF-1 may assist in the distinction of pulmonary (frequently positive) vs. non-pulmonary (usually negative). Due to its expression in neuroendocrine neoplasms, it is imperative that a neuroendocrine tumor be excluded, either by morphology or appropriate immunostains (in our opinion NSE is not an appropriate immunostain for this purpose) before using expression of TTF-1 as supportive evidence for primary pulmonary adenocarcinoma. One neuroendocrine tumor that has been found to be consistently negative for TTF-1 is Merkel cell carcinoma of the skin, so TTF-1 can assist in the distinction of Merkel cell tumor from metastatic pulmonary small cell carcinoma.


TTF-1 in miscellaneous tumors 


TTF-1 has been reported in a small percentage of gastric carcinomas (1.5%) and endometrial adenocarcinoma (17%). At ProPath we have personally observed TTF-1 in a few endometrial carcinomas, and in very rare cases of breast and colorectal carcinoma, as well as a small percentage of pancreatic adenocarcinomas, and a case of desmoplastic small cell tumor.


Coarse granular cytoplasmic reactivity with TTF- 1: a clue to hepatoma?


We have observed coarse granular cytoplasmic reactivity with some regularity in hepatoma, and we have had cases where this pattern of reactivity was the first hint that a particular tumor was indeed a hepatoma. (This reactivity does not represent endogenous biotin artifact, since it is even present when non-biotin based detection methods are used.) To my knowledge, this finding has not been reported in the literature, so it is best filed in the “personal observations awaiting further studies and hopefully confirmation by the literature” category, but we have found this pattern useful on a number of occasions. Nonspecific fine granular cytoplasmic reactivity may be observed in a number of other non-pulmonary carcinomas, including colorectal carcinoma, gastric carcinoma, prostate carcinoma, and cholangiocarcinoma.




TTF-1 is a very useful reagent in diagnostic pathology, and can assist in the identification of pulmonary adenocarcinoma, thyroid carcinomas, neuroendocrine tumors, and perhaps even hepatoma.




1. Beharano PA et al: Surfactant Proteins and Thyroid Transcription Factor-1 in Pulmonary and Breast Carcinomas. Modern Pathology 9 (4): 445-452, 1996.

2. Folpe AL et al: Thyroid Transcription Factor- 1:Immunohistochemical Evaluation in Pulmonary Neuroendocrine Tumors. Modern Pathology 12 (1): 5-8, 1999.

3. Kaufmann O et al: Thyroid Transcription Factor-1 Is the Superior Immunohistochemical Marker for Pulmonary Adenocarcinomas and Large Cell Carcinomas Compared to Surfactant Protein A and B. Histopathology 36: 8-16, 2000.

4. Byrd-Gloster AL et al: Differential Expression of Thyroid Transcription Factor 1 in Small Cell Lung Carcinoma and Merkel Cell Tumor. Human Pathology 31:58-62, 2000.

5. Kaufmann O et al: Expression of Thyroid Transcription Factor-1 in Pulmonary and Extra Pulmonary Small Cell Carcinomas and Other Neuroendocrine Carcinomas of Various Primary Sites. Histopathology 36: 415-420, 2000.

6. Ordonez NG: Thyroid Transcription Factor-1 Is a Marker of Lung and Thyroid Carcinomas. Advances in Anatomic Pathology 7 (2): 123-127, 2000.

7. Katoh T et al: Expression of Thyroid Transcription Factor-1 (TTF-1) In Human C cells and Medullary Thyroid Carcinomas. Human Pathology 31:386-393, 2000.

8. Agoff SN et al: Thyroid Transcription Factor-1 Is Expressed in Extra Pulmonary Small Cell Carcinomas but Not in Other Extra Pulmonary Neuroendocrine Tumors. Modern Pathology 13 (3):238-242, 2000.

9. Cheuk W et al: Immunostain for Thyroid Transcription Factor 1 and Cytokeratin 20 Aids the Distinction of Small Cell Carcinoma from Merkel Cell Carcinoma, but Not Pulmonary from Extra Pulmonary Small Cell Carcinomas. Archives of Pathology and Laboratory Medicine 125:228-231, 2001.

10. Ordonez NG: Value of Thyroid Transcription Factor-1 Immunostaining in Distinguishing Small Cell Lung Carcinomas from Other Small Cell Carcinomas. American Journal of Surgical Pathology 24 (9): 1217-1223, 2000.


Date of last revision: April 2001.