Stains & molecular markers
TTF1
Copyright: 2003-2020, PathologyOutlines.com, Inc.
PubMed Search: TTF1[TI] free full text[SB] pathology
TTF1
Editorial Board Member: Andrey Bychkov, M.D., Ph.D.
Editor-in-Chief: Debra Zynger, M.D.
Topic Completed: 16 September 2020
Minor changes: 25 September 2020
Copyright: 2003-2020, PathologyOutlines.com, Inc.
PubMed Search: TTF1[TI] free full text[SB] pathology
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Negative staining | Board review style question #1 | Board review answer #1 | Board review style question #2 | Board review answer #2Cite this page: Ulici V, Wang LJ. TTF1. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsttf1.html. Accessed September 26th, 2020.
Definition / general
- Thyroid transcription factor 1, also known as NKX2-1 or thyroid specific enhancer binding protein
- Homeodomain containing transcription factor, member of the NKX2 gene family (EMBO J 1990;9:3631)
- Preferentially expressed in thyroid, lung and brain structures of diencephalic origin (Mod Pathol 2000;13:238, Development 1991;113:1093)
- Different sensitivities for diverse neoplasms depending on the antibody clone used (Appl Immunohistochem Mol Morphol 2010;18:142, Am J Clin Pathol 2018;150:533)
- Highly specific clone 8G7G3/1 is well suited to thyroid and lung
- Highly sensitive clones SPT24 and SP141 are recommended for lung tumors, however their low specificity may produce aberrant staining in unusual locations
Essential features
- Nuclear marker with preferential expression in thyroid, lung and brain structures of diencephalic origin
- 2 commonly used commercially available clones and a novel clone with different sensitivities and specificities for pulmonary and extrapulmonary neoplasms
- Expressed in a high percentage of lung adenocarcinoma and small cell carcinoma, also in a variable percentage of extrapulmonary small cell carcinoma
- Consistently expressed in a wide range of differentiated thyroid tumors
- Expressed in a number of CNS tumors such as chordoid glioma and subependymal giant cell astrocytoma
Terminology
- NK2 homeobox 1 (official symbol: NKX2-1; gene ID: 7080), TITF1, T/EBP
- Do not confuse with transcription termination factor 1 (official symbol: TTF1, an essential protein responsible for terminating ribosomal gene transcription that is encoded by the TTF1 gene in humans; gene ID: 7270) (EMBO J 1990;9:3631, Mol Cell Biol 1991;11:4927)
Pathophysiology
- 38 kDa homeodomain containing transcription factor containing 371 amino acids and encoded by a gene located on chromosome 14q13 (Trends Endocrinol Metab 1996;7:247)
- Essential for morphogenesis and differentiation of the lungs and regulation of surfactant proteins A, B and C as well as Clara cell secretory protein (Trends Endocrinol Metab 1996;7:247)
- Essential for thyroid morphogenesis and gene regulation: thyroglobulin (TG), thyroid peroxidase (TPO) and thyrotropin receptor (TSHR) (Trends Endocrinol Metab 1996;7:247)
- Expressed in brain structures of diencephalic origin, including the developing neurohypophysis
- Plays important roles in both oncogenic and inhibitory activities in cancer development and progression (Development 1991;113:1093, Mol Cell Neurosci 2001;17:107, Mod Pathol 2000;13:238, Cancer Cell 2013;23:718, Cancer Sci 2017;108:1888)
Clinical features
- NKX2-1 / TTF1 mutations cause the brain lung thyroid syndrome characterized by congenital hypothyroidism, respiratory distress syndrome and benign hereditary chorea (J Pediatr Endocrinol Metab 2014;27:373, T Hum Mol Genet 2009;18:2266)
Interpretation
- Exclusively nuclear stain
Uses by pathologists
- Pulmonary
- Distinguish primary and metastatic lung carcinoma from nonlung primary tumors, especially for adenocarcinomas or large cell carcinomas (Appl Immunohistochem Mol Morphol 2010;18:142, Pathol Oncol Res 2004;10:85, Histopathology 2000;36:8, Cancer 2002;96:43)
- Differentiate between primary lung adenocarcinoma (overexpressed in up to 95%) and squamous cell carcinoma (virtually all negative with clone 8G7G3/1) (J Cancer 2018;9:4279, Am J Clin Pathol 2018;150:533, Appl Immunohistochem Mol Morphol 2010;18:142)
- Distinguish between cutaneous metastasis of small cell carcinoma and Merkel cell carcinoma (together with dot-like staining of CK20 in Merkel cell carcinoma) (Mod Pathol 2000;13:238, World J Gastrointest Oncol 2011;3:144)
- Distinguish pleural involvement by pulmonary adenocarcinoma from mesothelioma (Appl Immunohistochem Mol Morphol 2002;10:97, Arch Pathol Lab Med 2008;132:397)
- Could be used to distinguish between pulmonary carcinoid tumors and extrapulmonary carcinoid tumors (Am J Surg Pathol 2017;41:915, Am J Surg Pathol 2009;33:626)
- Extrapulmonary
- Marker of thyroid tumors, both primary and metastatic, usually in combination with thyroglobulin (except anaplastic thyroid carcinoma = complete loss)
- Distinguish subependymal giant cell astrocytoma from its histologic mimics, in particular gemistocytic astrocytoma and ganglioglioma (Mod Pathol 2017;30:318)
Prognostic factors
- Unclear prognostic role in non small cell lung cancer: most studies suggest association with a good prognosis, while some suggest no association (J Cancer 2018;9:4279, J Cancer Res Ther 2018;14:S1201, BMC Cancer 2019;19:574)
- Higher recurrence rate in papillary thyroid carcinoma with decreased nuclear expression of TTF1 (Hum Pathol 2019;91:36)
Microscopic (histologic) images
Contributed by Li Juan Wang, M.D., Ph.D.
Nonneoplastic lung
Nonneoplastic thyroid follicles
Lung small cell carcinoma
Lung adenocarcinoma
Papillary thyroid carcinoma
Medullary thyroid carcinoma
Rectal small cell carcinoma
Bladder invasive urothelial carcinoma
Contributed by Andrey Bychkov, M.D., Ph.D. and Carolyn Glass, M.D.
Lung adenocarcinoma
Lung small cell carcinoma
Positive staining - normal
- In developing lung starting at 11 weeks of gestation and in adult lung in type II pneumocytes and Clara cells (Mod Pathol 2000;13:238, J Pediatr Surg 2002;37:1258, Diagn Pathol 2015;10:21)
- Follicular cells and parafollicular cells in thyroid gland (Mod Pathol 2000;13:238)
- Expressed in embryonic diencephalon, including the developing neurohypophysis and postnatally in selective glial and neuronic hypothalamic subsets (Mod Pathol 2000;13:238, Development 1991;113:1093, Mol Cell Neurosci 2001;17:107)
Positive staining - disease
- 2 commonly used commercially available clones (monoclonal antibodies 8G7G3/1 and SPT24) and a new clone (SP141) with variable sensitivities for the detection of neoplasms of different origins (Appl Immunohistochem Mol Morphol 2010;18:142, Am J Clin Pathol 2018;150:533)
- Lung neoplasms:
- Lung adenocarcinoma:
- SPT24 and SP141 detect a higher percentage versus 8G7G3/1 (72 - 93% versus 65 - 89%)
- SPT24 and SP141 are more sensitive but less specific than 8G7G3/1 (Appl Immunohistochem Mol Morphol 2010;18:142, Am J Clin Pathol 2018;150:533)
- Small cell lung cancer:
- ~85 - 90% (Diagn Pathol 2015;10:21)
- Carcinoid tumor:
- SPT24 and SP141 versus 8G7G3/1 detect a higher percentage overall (61% versus 17%) and more positive tumor cells (71% versus 43%) (Appl Immunohistochem Mol Morphol 2010;18:142, Am J Clin Pathol 2018;150:533)
- Lung adenocarcinoma:
- Thyroid neoplasms:
- Well differentiated thyroid carcinoma (including papillary thyroid carcinoma, follicular thyroid carcinoma) and follicular adenoma:
- Poorly differentiated thyroid carcinoma and medullary thyroid carcinoma:
- CNS neoplasms:
- Glioblastoma multiforme:
- SPT24 in 50% versus 0% with 8G7G3/1 (Virchows Arch 2007;451:109)
- Chordoid gliomas:
- Expressed in most cases (both SPT24 and 8G7G3/1) (Am J Surg Pathol 2015;39:948)
- Other CNS tumors:
- Pituicytoma, spindle cell oncocytoma, granular cell tumor: 100% (3/3, 8/8 and 4/4)
- Ependymoma of the third ventricle (2/2)
- Subependymal giant cell astrocytoma (24/24, both SPT24 and 8G7G3/1) (Am J Surg Pathol 2015;39:948, J Neuropathol Exp Neurol 2009;68:482, J Clin Pathol 2004; 57:1111, Mod Pathol 2017;30:318)
- Glioblastoma multiforme:
- Other extrapulmonary neoplasms:
- Extrapulmonary small cell carcinoma: 7 - 84% (World J Gastrointest Oncol 2011;3:144)
Negative staining
- Merkel cell carcinoma (Hum Pathol 2000;31:58, J Clin Pathol 2001;54:727)
- Squamous cell carcinoma (SCC) (Appl Immunohistochem Mol Morphol 2010;18:142, Am J Clin Pathol 2018;150:533)
- SPT24 and SP141 detected more lung SCC versus 8G7G3/1 (6 - 17% versus 0 - 1%) (Appl Immunohistochem Mol Morphol 2010;18:142, Am J Clin Pathol 2018;150:533)
- Relative specificity of SPT24 clone for squamous neoplasms originating in the lungs (17%) versus squamous cell carcinomas of the head and neck (0%) (Appl Immunohistochem Mol Morphol 2010;18:142)
- Mesothelioma (Appl Immunohistochem Mol Morphol 2002;10:97)
- Extrapulmonary carcinoid tumor (< 1% positive) (World J Gastrointest Oncol 2011;3:144)
- Anaplastic thyroid carcinoma (0 - < 25%, can show immunoreactivity in the coexisting differentiated component) (Arch Pathol Lab Med 2015;139:67)
- Breast carcinoma (Appl Immunohistochem Mol Morphol 2010;18:142)
- Pancreatic carcinoma (Appl Immunohistochem Mol Morphol 2010;18:142)
- There is a growing number of reports of aberrant TTF1 staining detected in tumors previously considered TTF1 negative, mainly due to use of highly sensitive but low specific clones SPT24 and SP141:
- Gastric carcinoma (1%) (Appl Immunohistochem Mol Morphol 2016;24:603)
- Colorectal adenocarcinoma (Appl Immunohistochem Mol Morphol 2020;28:471)
- Invasive urothelial carcinoma
- Prostatic adenocarcinoma (Appl Immunohistochem Mol Morphol 2020;28:471)
- Endometrial cancer (Appl Immunohistochem Mol Morphol 2020 Jan;28:e6, Histopathology 2019 Mar;74(4):651)
- Salivary gland carcinoma
Board review style question #1
Which set of results favors a primary lung adenocarcinoma as a source of tumor in a brain biopsy?
- TTF1 positive, CK7 positive, CK20 negative, napsin A positive
- TTF1 positive, CK7 positive, CK20 positive, GATA3 positive
- TTF1 positive, CK7 positive, PAX8 positive
- TTF1 positive, EMA positive, GFAP positive
Board review answer #1
Board review style question #2
A 72 year old man presents with a neck mass, which shows sheets of small to medium sized cells with high N:C ratio, round / oval nuclei, finely dispersed chromatin (salt and pepper), indistinct nucleoli and scant cytoplasm. The tumor cells are positive for keratin, synaptophysin, chromogranin, CK20 (dot-like) and Ki67 proliferation index is 80%. The tumor cells are negative for CK7, TTF1, CDX2, calcitonin, melan A and S100. Which of the following is the most likely diagnosis of this tumor?
- Metastatic high grade neuroendocrine carcinoma from gastrointestinal tract
- Metastatic Merkel cell carcinoma
- Metastatic small cell carcinoma of lung
- Metastatic small cell melanoma
Board review answer #2
