TTF1

Synonyms: Thyroid Transcription Factor 1, TTF-1

by Jan Klos

Background

Thyroid transcription factor-1 (TTF1) is a 38 kDa nuclear protein member of the NKX2 family of transcription factors regulating genes in the thyroid, lung and brain. TTF1 activates transcription of the genes encoding thyroglobulin, thyroperoxidase and thyrotropin receptor in thyreoid and transcription of the surfactant proteins A to D and the Clara cell secretory protein in lung.

Staining pattern

Nuclear.

Staining in normal tissues

Epithelial cells of thyroid and lung.

Staining in tumors

Positivity is seen in almost all cases of follicular adenomas, follicular and papillary carcinomas and their variants as well as in medullary carcinomas of thyroid. Most cases of anaplastic thyroid carcinomas have been reported as negative. Among lung neoplasms, TTF1 is expressed in ~80%, pulmonary adenocarcinomas, however frequency of positive tumors is depending on the clone applied. The mAb SPT24 is more sensitive and stains higher percentage (>80%) of lung adenocarcinomas than mAb 8G7G3. It is important to remember that mucin production in lung tumors correlates with lower frequency of positive staining (i.e. bronchiolo-alveolar carcinoma of mucinous type is positive only in <20%) and mucin-producing adenocarcinomas are positive ~ 50% of cases.
Some primary lung tumors showing enteric differentiation also show nuclear positivity for CDX2 (>70% being CDX2+/CK7+) and even CK20 positivity. Varying percentage of these tumors shows retained reactivity for TFF1, but differentiation from metastatic colorectal adenocarcinoma may be challenging and use of extended antibody panel may not always help. Pulmonary neuroendocrine tumors, e.g. typical and atypical carcinoid and large cell neuroendocrine carcinoma may show variable positivity (according to the literature 0-95%).
Small cell lung carcinoma express TTF1 almost consistently (>90%), but non pulmonary small cell carcinomas are also positive in ~40% despite the primary organ location. Constant nuclear positivity is reported in sclerosing pneumocytoma (sclerosing hemangioma of lung).
A potential pitfall especially with limited antibody panel is usually low percentage (<10%) of non-thyroid/non-pulmonary origin tumors including adenocarcinomas of colon and rectum, pancreas and uterus as well some mesenchymal tumors which may stain positive (more often with mAb SPT24 than mAb 8G7G3).  Squamous cell carcinoma of the lung may in rare cases show weak nuclear positivity.

  • Granular cytoplasmic staining in normal hepatocytes is seen when using mAb 8G7G3/1 due to crossreactivity but not seen with other antibodies.

Control tissue

Lung.

Application

  • Sensitive and relatively specific marker of cell origin where positive nuclear staining is supporting the primary origin in thyroid or lung.
  • Subtyping lung tumors (with limited panel of antibodies strong positive staining of nuclei supports non squamous tumor type)
  • CAVE! Remember that adenocarcinomas and neuroendocrine tumors originating outside lung and thyroid may be positive. Pay attention to the clinical data and support the origin of tumors with other markers in appropriately designed panel of antibodies.
  • Some cases of gliomas are also reported positive.

Selected references

  1. Chen M, Liu P, Yan F, et al. Distinctive features of immunostaining and mutational load in primary pulmonary enteric adenocarcinoma: implications for differential diagnosis and immunotherapy. J Transl Med. 2018 Mar 27;16(1):81. doi: 10.1186/s12967-018-1449-z.
  2. Compérat E, Zhang F, Perrotin C, et al. Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin. Appl Immunohistochem Mol Morphol. 2011 Oct;19(5):437-43. doi: 10.1097/PAI.0b013e31820e6baf.
  3. https://app.immunoquery.com/
  4. https://www.nordiqc.org/epitope.php?id=75
  5. Kristensen MH1, Nielsen S, Vyberg M. Thyroid transcription factor-1 in primary CNS tumors. Mod Pathol. 2005 Oct;18(10):1371-6
  6. Siami K, McCluggage WG, Ordonez NG, et al. Thyroid transcription factor-1 expression in endometrial and endocervical adenocarcinomas. Am J Surg Pathol. 2007 Nov;31(11):1759-63
  7. Cowan ML, Li QK, Illei PB. CDX-2 Expression in Primary Lung Adenocarcinoma. Appl Immunohistochem Mol Morphol. 2016 Jan;24(1):16-9. doi: 10.1097/PAI.0000000000000250.
  8. Zhang J, Xiang C, Han Y, et al. Differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal carcinoma with the assistance of next-generation sequencing and immunohistochemistry. J Cancer Res Clin Oncol. 2019 Jan;145(1):269-279. doi: 10.1007/s00432-018-2788-0. Epub 2018 Nov 10. PMID: 30415301
  9. Yatabe Y, Dacic S, Borczuk A. C., et al. Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer J Thorac Oncol. Author manuscript; available in PMC 2020 Mar 1. Published in final edited form as: J Thorac Oncol. 2019 Mar; 14(3): 377–407. Published online 2018 Dec 18. doi: 10.1016/j.jtho.2018.12.005 , PMCID: PMC6422775