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.
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
77% (2025/2631; 95% confidence interval 75.42% to 78.6%) |
158/208(using
clone 8G7G3/1)2,
19/33(using
a polyclonal antibody)4,
70/97(using
clone 8G7G3/1)6,
23/2612, 42/47(8/8 primary and 34/39
metastatic, using cell blocks from FNA)15,
12/1516,
46/64(This
paper set the threshold for positivity at 50% of nuclei. 8
cases showed positivity below this threshold with only 10 cases
completely negative)18, 14/1719,
37/4320,
24/3522, 11/11(brain metastases)23, 67/98(using
clone 8G7G3/1)24
, 30/40(using
clone 8G7G3/1)25,
37/50(8
case >75% of cells stained, 15 cases 50-75% of cells, 10 cases
25-50% of cells, 4 cases 1-25% of cells)26,
46/6418,
110/128(96/128
pulmonary adenocarcinomas showed high levels of TTF-1 expression;
14 more showed only weak expression. This
study also broke down the results by tumour subtype)31,
37/5035,
51/75(using
tissue microarray)38,
27/30(strong
in 14/15 well differentiated, 7/8 moderately differentiated: the
negative case was a mucinous cystadenocarcinoma, and 6/7 poorly
differentiated.39,
220/231(169/176
solitary adenocarcinomas, 34/34 multifocal carcinomas, 1/1 signet
ring cell carcinoma, 16/20 mucinous carcinomas: using monoclonal
8G7G3/1)45,
42/50(in
addition, four cases showed cytoplasmic staining, using clone
8G7G3/1)46,
13/16(cell
blocks from cases with metastatic adenocarcinoma to serous cavities,
using clone 8G7G3/1)47,
15/17(cell
blocks from cases with metastatic adenocarcinoma to serous cavities,
using clone 8G7G3/1)48,
35/46(using
a polyclonal antibody)49,
8/13(using
monoclonal 8G7G3/1)50,
5/6(using
clone 8G7G3/1)63,
16/21(using
clone 1-2.A5.9 on cytological cell blocks)66,
12/18(using
clone 8G7G3/1 on lung adenocarcinoma metastatic to brain)67, 3/16(on
cell blocks, using clone 8G7G3/1)68, 27/34(using
cell blocks from tumour in serous effusions)69, 10/11(metastases
to cervical lymph nodes)71, 8/9(metastases
to CNS)72
, 21/39(using
clone 8G7G3/1 and cytospin preparations from body cavity fluids)73,
31/4275,
31/4277,
46/55(10
of the cases positive for TTF-1 were also positive for oestrogen
receptors)80
, 29/4082, 41/50(using a cell transfer
technique on serous effusion specimens)84,
12/22(metastatic
to brain)87,
42/4678,
4/15(using
a polyclonal antibody)90,
11/1191, 22/3092, 4/10102,
13/14103, 5/8(using a polyclonal
antibody on cytological specimens)104,
20/28(using
a polyclonal antibody)105
, 18/21(using
clone 8G7G3/1)106,
69/95(using
TMAs and clone 8G7G3/1:
38/47 well differentiated,
24/32 moderately differentiated,
7/16 poorly differentiated)114,
134/200(using
TMA and clone 8G7G3/1)115,
127/158116, 30/52(Using
clone 8G7G3/1 on cell blocks from serous effusions)
|
bronchoalveolar
carcinoma |
25/292, 25/28(20/20
non-mucinous or mixed, 5/8 mucinous)20, 34/50(30/32 non-mucinous
and 4/18 mucinous)35, 8/16(1 of 6 mucinous, 7/10
non-mucinous)36,
11/14(10/10
non-mucinous, 1/1 mixed and 0/3 pure mucinous)39, 42/67(36/48 non-mucinous, 0/12
mucinous, 6/7 mixed; in 5 cases, staining was restricted to
the non-mucinous component)42,
23/23(non-mucinous
bronchoalveolar carcinomas: using monoclonal 8G7G3/1)45, 26/29(using
TMA and clone 8G7G3/1)115 |
small
cell carcinoma
84.4%(448/527; 95% confidence interval 82% to 87%) |
113/120(this
is a review of other papers listed here),
30/37,
27/28(using
clone 8G7G3/1)8,
43/529, 1/415,11/1218, 6/7(brain
metastases)23,
30/37(using
clone 8G7G3/1)24,
47/5532,
24/3039, 3/540, 20/21(using
clone 8G7G3/1)41,
19/36(using
monoclonal 8G7G3/1)45,
20/22(using
monoclonal 8G7G3/1)52,
10/12(using
clone 1-2.A5.9 on cytological cell blocks)66,
2/5(on
cell blocks, using clone 8G7G3/1)68, 6/7(metastases
to cervical lymph nodes)71, 23/2877, 27/3088,
3/378,
10/10(using
a polyclonal antibody)90,
13/1391, 38/41(using a polyclonal
antibody on cytological specimens)104,
35/36(using
clone 8G7G3/1)108,
28/33(using
clone 8G7G3/1)109,
1/3(using
TMAs and clone 8G7G3/1)114,
1/1(using
TMA and clone 8G7G3/1)115
|
squamous
cell carcinoma
8.5%(79/930; 95% confidence interval 6.7% to 10.3%),
excluding one anomalous paper115,
6.1% (95% confidence interval 4.4% to 7.7%) |
0/101(using
clone 8G7G3/1)2,
20/201(this
is a review of other papers listed here)5
6/119(using
clone 8G7G3/1)612, 1/7(using
cell blocks from FNA)15, 0/3(brain
metastases)23,
0/20(using
clone 8G7G3/1)24
, 0/1030,
0/2931,
9/43(using
tissue microarray)38,
1/30(2%
of nuclei in one case)39,
4/99(using
monoclonal 8G7G3/1)45, 0/10(using
a polyclonal antibody)49,
3/8(using
clone 1-2.A5.9 on cytological cell blocks)66
0/8(on
cell blocks, using clone 8G7G3/1)68, 3/8(metastases
to cervical lymph nodes)71, 0%(of ? 34 cases)77,
4/778,
3/13(using
a polyclonal antibody)90,
0/1291, 0/39102, 0/5103,
1/9(using
a polyclonal antibody on cytological specimens)104,
13/60(using
a polyclonal antibody)105,
0/48(using
TMAs and clone 8G7G3/1)114,
30/122(using
TMA and clone 8G7G3/1)115,
0/39116
, 1/35119 |
basaloid
squamous cell carcinoma |
0/2812 |
basaloid
carcinoma |
0/2812 |
adenosquamous
carcinoma |
1/3(only
glandular component positive)39
2/2(using
clone 8G7G3/1; only glandular component positive)6, 2/10(using
TMA and clone 8G7G3/1)115 |
large
cell carcinoma
25% (50/197; 95% confidence interval 19% to 31%) |
16/61(using
clone 8G7G3/1)2,
6/625,
0/2(using
clone 8G7G3/1)6, 15/19(brain metastases)23, 8/20(using
clone 8G7G3/1)24
, 3/1030,
0/131,
0/2(using
tissue microarray)38,
4/2539, 26%(of 61 cases)2, 1/6(on
cell blocks, using clone 8G7G3/1)68, 0/1(using
a polyclonal antibody)90,
5/991, 4/9114,
16/37(using
TMA and clone 8G7G3/1)115
|
large
cell neuroendocrine carcinoma
50.6% (83/164; 95% confidence interval 43% to 58%). |
2/47, 6/85, 18/4412,
2/4(using
clone 8G7G3/1)24
, 2/231,
31/6432,
6/1039, 6/840,
6/8(using
clone 8G7G3/1)41,
6/1676,
2/3103, 4/10107, 3/5(using
TMA and clone 8G7G3/1)115 |
pleomorphic
carcinoma |
~55%, 0/23(using monoclonal 8G7G3/1)45 |
lymphoepithelioma-like
carcinoma |
0/25(using
monoclonal 8G7G3/1)45 |
Carcinoma
not otherwise specified |
21/28(brain
metastases from lung primaries)55,
1/3(undifferentiated
carcinoma metastases to cervical lymph nodes)71, 13/3088,
3/12(using
TMAs and clone 8G7G3/1: non small cell, not otherwise specified)114 |
Pulmonary blastoma |
4/454 |
Pulmonary
tumourlet (neuroendocrine cell hyperplasia) |
0/3832,
8/1176,
0/15(neuroendocrine
hyperplasia)32 , 0/23(tumourlets)32 |
typical
carcinoid |
4/97,
16/1710, 11/1613, 6/12(using
clone 8G7G3/1)24
, 1/131,
0/27(using
monoclonal antibody , clone 8G7G3/1, Microm, Francheville, France,
with heat-induced antigen retrieval)32, 6/2339,
18/51(using
clone 8G7G3/1)41,
0/8(using
monoclonal 8G7G3/1)45,
10/36(most
positive cases were peripheral and had a spindle cell morphology)76,
0/890, 6/12113,
1/2(using
TMAs and clone 8G7G3/1) 114
|
atypical
carcinoid |
7,
3/310, 2/3(using clone 8G7G3/1)24 , 0/23(using
monoclonal antibody, clone 8G7G3/1, Microm, Francheville, France,
with heat-induced antigen retrieval)32, 9/9(using
clone 8G7G3/1)41,
0/3(using
monoclonal 8G7G3/1)45,
5/17(most
posiitve cases were peripheral and had a spindle cell morphology)76,
2/3113, 1/1(using TMAs and clone
8G7G3/1) 114
|
metastatic pulmonary
carcinoid |
|
sclerosing
haemangioma |
36/37(using
monoclonal 8G7G3/1)3,
16/16(using
monoclonal 8G7G3/1)14,
39/44(using
monoclonal 8G7G3/1)45 |
pulmonary
papillary adenoma |
1/127, 2/2(using
monoclonal 8G7G3/1)111 |
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 |
0/3(brain
metastases from tongue, pharynx and oesophagus)23,
0/11(0/5
nasopharyngeal, 0/1 tongue, 0/3 oesophageal 0/2 uterine cervical
primaries metastatic to cervical lymph nodes)71 |
Extra-pulmonary
large cell neuroendocrine carcinoma |
1/4
,
0/3(2
thymic, 1 ovarian)76, 1/195 |
Extra-pulmonary
carcinoid |
1% (1/207,
,
0/49(using
Dako antibody; 22 small intestinal, 1 duodenal, 1 jejunal, 4 ileal,
1 appendiceal, 19 colonic, 1 gallbladder) ,
0/1 (intestinal
carcinoid metastatic to brain)67,
0/2(carcinoid
associated with struma ovarii)70,
1/2(carcinoid
of urinary bladder: one case showing positivity of 20% of tumour
nuclei)74,
0/28(11
thymic (3 typical, 8 atypical), 17 gastrointestinal or pancreatic
(13 typical, 4 atypical))76
, 0/2(carcinoid tumors of the extrahepatic biliary
ducts)117 |
Extra-pulmonary
endocrine tumours |
parathyroid adenoma |
0/1010 |
pituitary adenoma |
0/2010 |
pancreatic endocrine
tumour |
0/1010, 0/15(using
Dako antibody)11
|
paraganglioma |
0/21(using
Dako antibody)11,
0/1(within
the thyroid)96 |
adrenocortical
carcinoma |
0/1 (brain
metastasis)23 |
phaeochromocytoma |
0/510 |
Malignant
mesothelioma |
0%
( 0/95(using
clone 8G7G3/1)2,
0/24(using
a polyclonal antibody)4,
0/14[using
cell blocks from FNA]15, 0/4122,
0/60[all
epithelioid mesotheliomas])26,
0/50(using
clone 8G7G3/1)25,
0/12(using
cell blocks from tumour in serous effusions)69, 0/678, 0/1592,
0/38(using
TMAs and clone 8G7G3/1)114
|
Thyroid |
adenoma |
13/155, 5/510, 10/12(5/6
follicular and 5/6 oncocytic adenomas)28,
6/6112 |
follicular carcinoma |
14/145, 5/510, 4/428,
3/3(using
clone 8G7G3/1)25,
10/10112 |
papillary carcinoma |
27/285,
5/510,
8/828, 7/7(using clone 8G7G3/1)25, 3/363,
10/10112, 37/38(using TMAs and clone
8G7G3/1)114 |
Hurtle cell carcinoma |
1/55,
2/628 |
Insular carcinoma |
5/55 |
medullary carcinoma |
15/165,7, 10/1010,
8/8(using
Dako antibody)11,
1/228 |
poorly differentiated
carcinoma |
0/1 (brain
metastasis)23,
6/728 |
anaplastic carcinoma |
17, 0/85, ,
1/4(all
negative for thyroglobulin)28, 0/4112 |
spindle epithelial
tumor with thymus-like differentiation (SETTLE) |
0/183 |
Thyroid-like
nasopharyngeal papillary adenocarcinoma |
2/2(both
cases also positive for CK7 and CK19)79, 1/189, 3/3(all
cases negative for thyroglobulin)98 |
Struma
ovarii |
2/270 |
Thymic
neoplasms |
0/201, ,
0/57(35
thymomas and 22 thymic carcinomas)29, 0/30(14
thymomas and 6 thymic carcinomas)30, 1(type AB, with no evidence
of neuroendocrine differentiation)118 |
Renal
tumours |
nephroblastoma |
8/48(diffuse
in 3 cases, focal in 5 cases)94 |
metanephric
adenoma |
0/594 |
cystic nephroma |
0/194 |
Testicular
choriocarcinoma |
0/5(10
normal placentas were also negative)21 |
Sarcomas |
leiomyosarcoma |
0/10 |
synovial sarcoma |
1/5 |
| |
|
Primary
brain tumours |
2/73(both
positive cases were ependymomas {2/27} in the third ventricle)53, 0/32(Astrocytic
brain tumours)53,
0/50(all
glioblastoma multiforme)81, dependent
on clone used101 |
Melanoma |
0/1[using
cell blocks from FNA]15, 0/1 (melanoma
metastatic to brain)67,
0/499, 1/70(primary tumours)100, 5/73(metastases)100 |
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
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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