Thyroid transcription factor-1, TTF-1, Nkx2.1, thyroid-specific enhancer-binding protein

A 38 kD homeodomain-containing nuclear transcription protein of the Nkx2 gene family59. The TTF-1 polypeptide of 371 amino acids have been highly conserved, sharing 98% identity with the rat TTF-1 polypeptide59. The homeobox gene HOXB3 (expressed in early mammalian embryogenesis in the anterior neuroectoderm, branchial arches and their derivatives, including the area of the thyroid primordia and thyroid gland) activates expression of TTF-156. TTF-1 in turn acts as a master regulator gene, binding to the promoters for surfactant apoproteins A57, B60 and C62, Clara cell-specific protein (mCC10)61 and T1a65. TTF-1 is also required for expression of thyroid-specific genes58. During embryogenesis, it is first expressed at the emergence of the laryngeotracheal diverticulum and is localised to the bronchial epithelium. Once the bronchial tree has developed, expression shifts to the peripheral airway epithelium, a pattern retained throughout life18.

The commercially available monoclonal antibody 8G7G3/163 can be used on formalin-fixed, paraffin-embedded tissues: this antibody has been used in most studies of TTF-1. A second monoclonal antibody, SPT24, appears to have greater sensitivity, at the expense of loss of specificity: see comparison of monoclonal antibodies. The monoclonal antibodies probably have greater sensitivity than the polyclonal antibody used in some early studies.

Staining for TTF-1 is nuclear. Cases should be regarded as positive even if the nuclear staining is only focally present in the tumour (i.e. 1% to 10% of the tumour cells)23. In up to 10% of TTF-1-positive lung adenocarcinomas, staining is present in less than 10% of the tumour cells24,25. Even this focal staining is not encountered in adenocarcinomas of non-pulmonary and non-thyroid origin.

A rapid technique has been developed for use with intra-operative frozen sections37,86.

Cytoplasmic immunoreactivity for TTF-1 has been reported as useful in the diagnosis of hepatocellular carcinoma.

Immunohistochemical expression

TTF-1 is expressed in various normal tissues: follicular cells of the thyroid, type II epithelial cells of the alveoli4 and a subset of bronchiolar cells4, the anterior pituitary, parathyroid gland, parafollicular C-cells and in certain regions of the brain.

Non-neoplastic lung disease:

In infantile hyaline membrane disease with alveolar hemorrhage, oedema, or airway collapse, little or no TTF-1 is present except in open terminal airways. In bronchopulmonary dysplasia, TTF-1 is absent in areas of alveolar collapse or infection, being present in regenerating open airways64.

There is a case report of epithelial cyst of the cardiac papillary muscle positive for TTF-185.

Positivity has been reported in ciliated metaplasia in the stomach and in non-ciliated cells in atrophic gastritis93. This positivity has been attributed to gastric broncho-pulmonary transdetermination.

Tumours reference 5 reviews multiple papers up to 19994:

Lung

adenocarcinoma

78% (1625/2083; 95% confidence interval 76.2% to 79.8%)

158/2082, 19/334, 70/976, 23/2612, 42/4715, 12/1516, 14/1719, 37/4320, 24/3522, 11/1123, 67/9824 , 30/4025, 37/5026, 46/6418, 110/12831, 37/5035, 51/7538, 27/3039, 220/23145, 42/5046, 13/1647, 15/1748, 35/4649, 8/1350, 5/663, 16/2166, 12/1867, 3/1668, 27/3469, 10/1171, 8/972 , 21/3973, 31/4275, 31/4277, 46/5580 , 29/4082, 41/5084, 12/2287, 42/4678, 4/1590, 11/1191, 22/3092, 4/10102, 13/14103, 5/8104, 20/28105 , 18/21106

bronchoalveolar carcinoma

25/292, 25/2820, 34/5035, 8/1636, 11/1439, 42/6742, 23/2345

small cell carcinoma

84.4%(448/527; 95% confidence interval 82% to 87%)

113/1205, 30/377, 27/288, 43/529, 1/415,11/1218, 6/723, 30/3724, 47/5532, 24/3039, 3/540, 20/2141, 19/3645, 20/2252, 10/1266, 2/568, 6/771, 23/2877, 27/3088, 3/378, 10/1090, 13/1391, 38/41104, 35/36108, 28/33109

squamous cell carcinoma

5.5%(31/569; 95% confidence interval 3.6% to 7.3%)

0/1012, 20/2015, 6/1196, 0/1212, 1/715, 0/323, 0/2024 , 0/1030, 0/2931, 9/4338, 1/3039, 4/9945, 0/1049, 3/866 0/868, 3/871, 0%77, 4/778, 3/1390, 0/1291, 0/39102, 0/5103, 1/9104, 13/60105

basaloid squamous cell carcinoma

0/2812

basaloid carcinoma

0/2812

adenosquamous carcinoma

1/339, 2/26

large cell carcinoma

25% (50/197; 95% confidence interval 19% to 31%)

16/612, 6/625, 0/26, 15/1923, 8/2024 , 3/1030, 0/131, 0/238, 4/2539, 26%2, 1/668, 0/190, 5/991

large cell neuroendocrine carcinoma

50.6% (83/164; 95% confidence interval 43% to 58%).

2/47, 6/85, 18/4412, 2/424 , 2/231, 31/6432, 6/1039, 6/840, 6/841, 6/1676, 2/3103, 4/10107

pleomorphic carcinoma

~55%, 0/2345

lymphoepithelioma-like carcinoma

0/2545

Carcinoma not otherwise specified

21/2855, 1/371, 13/3088

Pulmonary blastoma

4/454

Pulmonary tumourlet (neuroendocrine cell hyperplasia)

0/3832, 8/1176, 0/1532, 0/2332

typical carcinoid

4/97, 16/1710, 11/1613, 6/1224 , 1/131, 0/2732†, 6/2339, 18/5141, 0/845, 10/3676, 0/890, 6/12113

atypical carcinoid

2/37, 3/310, 2/324 , 0/2332†, 9/941, 0/345, 5/1776, 2/3113

metastatic pulmonary carcinoid

8/1810

sclerosing haemangioma

36/373, 16/1614, 39/4445

pulmonary papillary adenoma

1/127, 2/2111

alveolar adenoma

5/5110

inflammatory myofibroblastic tumour

0/999

Extra-pulmonary adenocarcinoma (excluding thyroid)

3%

Extra-pulmonary small cell carcinoma (excluding skin)

36% (42/114), various sites

Extra-pulmonary squamous cell carcinoma

0/323, 0/1171

Extra-pulmonary large cell neuroendocrine carcinoma

1/4 (various sites)7, 0/376, 1/195

Extra-pulmonary carcinoid

1% (1/207, 0/5010, 0/4911, 1/4613), 0/67, 0/270, 1/274, 0/2876

Extra-pulmonary endocrine tumours

parathyroid adenoma

0/1010

pituitary adenoma

0/2010

pancreatic endocrine tumour

0/1010, 0/1511, 0/12613

paraganglioma

0/2111, 0/196

adrenocortical carcinoma

0/23

phaeochromocytoma

0/510

Malignant mesothelioma

0% (0/952, 0/244, 0/1415, 0/4122, 0/60)26, 0/50, 0/1269, 0/678, 0/1592

Thyroid

adenoma

13/155, 5/510, 10/1228, 6/6112

follicular carcinoma

14/145, 5/510, 4/428, 3/3, 10/10112

papillary carcinoma

27/285, 5/510, 8/828, 7/7, 3/363, 10/10112

Hurtle cell carcinoma

1/55, 2/628

Insular carcinoma

5/55

medullary carcinoma

15/165,7, 10/1010, 8/811, 1/228

poorly differentiated carcinoma

0/23, 6/728

anaplastic carcinoma

2/3517, 0/85, 2/510, 1/428, 0/4112

spindle epithelial tumor with thymus-like differentiation (SETTLE)

0/183

Thyroid-like nasopharyngeal papillary adenocarcinoma

2/279, 1/189, 3/398

Struma ovarii

2/270

Thymic neoplasms

0/201, 0/310, 0/5729, 0/3030

Renal tumours

nephroblastoma

8/4894

metanephric adenoma

0/594

cystic nephroma

0/194

Testicular choriocarcinoma

0/521

Sarcomas

leiomyosarcoma

0/10

synovial sarcoma

1/5
   

Primary brain tumours

2/7353, 0/3253, 0/5081, dependent on clone used101

Melanoma

0/115, 0/67, 0/499, 1/70100, 5/73100

Merkel cell carcinoma of skin

0/61, 0/215, 0/167, 0/239

Among primary pulmonary adenocarcinomas, there is a higher rate of positivity in tumours thought to be derived from the terminal respiratory unit (TRU, in the WHO classification these are most non-mucinous bronchioloalveolar, mixed bronchioloalveolar and acinar subtypes and some papillary subtypes); 42/48 with TRU morphology were positive, as against 4/16 with non-TRU morphology18. In one paper, immunoreactivity in adenocarcinomas is more common in females (27/31 positive) than males (19/33 positive) and in nonsmokers (26/31 positive) than in smokers (20/33 positive), in p53-negative tumours and in retinoblastoma-positive tumours18. However, another reports that no associations were noted with gender6. A comparison of primary tumours and their metastases showed no tendency to loss of staining during dissemination18.

Two studies showed postivity for TTF-1 in conventional pulmonary adenocarcinomas to be a significant independent predictor of survival35,38. A second study Another found a tendency (p=0.096) to an association between TTF-1 positivity and better survival34, along with a negative correlation with Ki-67 proliferative activity (p=0.003): another found no association of TTF-1 positivity with survival31.

When large cell neuroendocrine carcinoma of the lung is a component of a combined tumour, it adopts the TTF-1 reactivity of the other component, positive where it is small cell carcinoma and with some adenocarcinomas, negative where it is squamous cell carcinoma12,32. In one of these studies, three combined small cell / squamous cell carcinomas showed negativity of both components32.

†The inconsistent results in carcinoids, typical and atypical, may be due to the use of polyclonal antibodies in early studies, misinterpretation of granular cytoplasmic staining that overlaps the nucleus, and the misclassification of large cell neuroendocine carcinomas at atypical carcinoids prior to the 1999 WHO classification32.

Diagnostic utility

 

positive predictive value

negative predictive value

To differentiated pulmonary from extrapulmonary adenocarcinoma (best used in combination with cytokeratins 7 and 20)

99%

70%

To show tumour is an extra-pulmonary small cell carcinoma, not a Merkel cell carcinoma

100%

76%

 To show carcinoid is of pulmonary origin

97%

30%

Im the development of an algorithm to locate the primary site of adenocarcinomas, TTF-1 appears high in the decision tree78.

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