Thyroid transcription factor-1 positive primary breast cancer: a case report with review of the literature
This case describes an infiltrating breast tumour with thyroid transcription factor-1 (TTF-1) positive staining and ductal differentiation in a 72-year-old woman. The presence of ductal carcinoma in situ with positive TTF-1 is a strong indication that this is a primary tumour and not a metastasis from lung.
On PET scan and CT follow up there were no other tumours found in this patient. We are not aware of any previously reported TTF-1 positive primary breast carcinoma with ductal differentiation.
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ABSTRACT: At least four major categories of invasive breast cancer that are associated with different clinical outcomes have been identified by gene expression profiling: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) and basal-like. However, the prevalence of these phenotypes among cases of ductal carcinoma in situ (DCIS) has not been previously evaluated in detail. The purpose of this study was to compare the prevalence of these distinct molecular subtypes among cases of DCIS and invasive breast cancer. We constructed tissue microarrays (TMAs) from breast cancers that developed in 2897 women enrolled in the Nurses' Health Study (1976 to 1996). TMA slides were immunostained for oestrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR). Using these immunostain results, cases were grouped into molecularly defined subtypes. The prevalence of the distinct molecular phenotypes differed significantly between DCIS (n = 272) and invasive breast cancers (n = 2249). The luminal A phenotype was significantly more frequent among invasive cancers (73.4%) than among DCIS lesions (62.5%) (p = 0.0002). In contrast, luminal B and HER2 molecular phenotypes were both more frequent among DCIS (13.2% and 13.6%, respectively) as compared with invasive tumours (5.2% and 5.7%, respectively) (p < 0.0001). The basal-like phenotype was more frequent among the invasive cancers (10.9%) than DCIS (7.7%), although this difference was not statistically significant (p = 0.15). High-grade DCIS and invasive tumours were more likely to be HER2 type and basal-like than low- or intermediate-grade lesions. Among invasive tumours, basal-like and HER2 type tumours were more likely to be more than 2 cm in size, high-grade and have nodal involvement compared with luminal A tumours. The major molecular phenotypes previously identified among invasive breast cancers were also identified among cases of DCIS. However, the prevalence of the luminal A, luminal B and HER2 phenotypes differed significantly between DCIS and invasive breast cancers.Breast cancer research: BCR 08/2008; 10(4):R67. · 5.87 Impact Factor
- Advances in Anatomic Pathology - ADV ANAT PATHOL. 01/2000; 7(2):123-127.
- Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancerR67. doi: 10.1186/1746-1596-5-37 Cite this article as: Klingen et al., Thyroid transcription factor-1 positive primary breast cancer: a case report with review of the literature Diagnostic Pathology. Breast Cancer Res 10 37..
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Thyroid transcription factor-1 positive breast cancer: a case report with review
of the literature
Diagnostic Pathology 2010, 5:37doi:10.1186/1746-1596-5-37
Tor A Klingen (firstname.lastname@example.org)
Ying Chen (email@example.com)
Marian D Gundersen (firstname.lastname@example.org)
Hans Aas (email@example.com)
Bjorn Westre (firstname.lastname@example.org)
Torill Sauer (email@example.com)
28 May 2010
17 June 2010
17 June 2010
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Thyroid transcription factor-1 positive primary breast cancer: a case
report with review of the literature
Tor A Klingen¹, Ying Chen¹, Marian D Gundersen², Hans Aas³, Bjørn Westre⁴, Torill Sauer⁵
¹Department of Pathology, Vestfold County Hospital, Halfdan Wilhelmsens Alle` 17, N-3116
²Department of Radiology, Vestfold County Hospital, Halfdan Wilhelmsens Alle` 17, N-3116
³Department of Surgery, Vestfold County Hospital, Halfdan Wilhelmsens Alle` 17, N-3116
⁴Department of Pathology, Ålesund Hospital, Åsehaugen 5, N-6017 Ålesund, Norway
⁵Department of Pathology, Ullevål University Hospital, Kirkeveien 166, N- 0407 Oslo, Norway
Tor A Klingen, Department of Pathology, Vestfold County Hospital, Halfdan Wilhelmsens Alle`
17, N-3116 Tønsberg, Norway Telephone: +47-33342239 firstname.lastname@example.org
This case describes an infiltrating breast tumour with thyroid transcription factor-1 (TTF-1)
positive staining and ductal differentiation in a 72-year-old woman. The presence of ductal
carcinoma in situ with positive TTF-1 is a strong indication that this is a primary tumour and not
a metastasis from lung.
On PET scan and CT follow up there were no other tumours found in this patient. We are not
aware of any previously reported TTF-1 positive primary breast carcinoma with ductal
TTF-1 is a tissue-specific transcription factor expressed in epithelial cells of the lung and the
thyroid, including C-cells as well as certain areas of the brain. TTF-1 is expressed in
approximately 72% of pulmonary adenocarcinomas, and may be a valuable marker for
identifying the lung as the site of origin of a metastatic adenocarcinoma.
A 72-year-old gravida 1/ para 1 woman presented with a palpable mass in the left breast.
Her sister died of breast cancer some years earlier. There was a past history of operated
parathyroid adenoma some years ago but no previous history of any malignancy. The patient was
a non- smoker and had never used hormonal drugs.
Clinical examination demonstrated a palpable tumour in her left breast in the upper inner
quadrant, no fixation to skin or underlying fascia.
Mammography from upper inner quadrant of the left breast showed a dense, relatively well
defined, oval shaped mass lesion with a microlobulated margin measuring 51 x 33 x 35 mm
with coarse calcifications centrally in the mass and in addition finer micro calcifications antero
lateral to the main tumour , malignant in appearance. The total maximal diameter including the
calcifications was approximately 6 cm.
Ultrasound left breast showed an irregular solid malignant appearing tumour, corresponding to
the mammographic lesion, measuring approximately 38 mm maximal diameter. No enlarged
lymph nodes in the left axillae. PET scan and CT scan showed no other malignancy other than
known breast tumour.
As no other origin for the tumour was found, the patient was treated with left mastectomy and
sentinel lymph node mapping .The sentinel node was normal. The patient had an uncomplicated
recovery and was discharged the next day following the operation.
Methods and Materials
We performed immunohistochemical investigation using the indirect streptavidin-biotin method
on 3-5 µm slices. Regarding TTF-1 staining we used same methods at two different laboratories
for verification of the findings. Further staining for CK5/6, CK 7, CK20, CK 18, mammaglobin,
GCDFP-15, ER, PGR, chromgranin, synaptophysin, CD 56, HER 2/neu, Ki67, p 63 and MA was
performed (table 1).
Macroscopic investigation showed a mastectomy specimen measuring 21 x 18 x 3cm, weighing
1042 gram. In the upper inner quadrant there was a round, well-circumscribed tumour with
largest diameter 3,8cm laying 0,6cm from the chest wall. The tumour was white with pale yellow
necrotic areas (Figure 1).
Microscopic investigation showed a sharp demarcation of the tumour to the surrounding breast
tissue. There was some necrosis centrally, with more preserved structure peripherally in the
tumour. The tumour tissue grew as trabeculae and confluent nests with scanty glandular tissue.
The tumour cells were large with moderate amount of cytoplasm. The nuclei were variable in
appearance being round, oval or spindle shaped. The chromatin was coarsely granulated and
vesicular. There were numerous mitoses and apoptotic bodies (Figure 2).
The nuclei in the invasive tumour cells showed diffuse and strong positive immunoreactivity to
TTF-1 marker (Figure 3). The neuroendocrine marker CD56 was slightly positive (Figure 4),
whilst chromogranin and synaptophysin were negative. CK 5/6 was demonstrated in isolated cells
within the tumour (Figure 5). Ki67 was positive in over 50% of the tumour cells. The tumour
was positive for CK7 and CK18 but negative for ER, mammaglobin, GCDPF-15 and CK20.
HER2/neu showed heterogeneous C-erb-2 protein score 2+/ 3+, but silver in situ hybridization
(SISH) without gene amplification. There was a weak positive reaction to PGR in the biopsy
material, but not in the mastectomy tissue.
An in situ component was seen in the vicinity of the tumour. The myoepithelial layer of the
carcinoma in situ was verified immunohistochemically with p63 and MA. The in situ tumour
cells had the same morphological appearance as in the invasive tumour (Figure 6). The in situ
component showed a positive reaction to TTF-1(Figure 7) and CK5/6 (Figure 8).
We believe this case represents TTF-1 positive infiltrating ductal breast carcinoma, histological
grade 3. The tumour was heterogeneous with small areas of basal-like and neuroendocrine
In three large studies of primary breast carcinomas [1-3] there were 96, 51 and 35 (total 182)
carcinoma cases, respectively, that were all TTF-1 negative. Only a few cases of TTF-1 primary
small-cell carcinoma in breast have been reported [4,5]. Yamamoto described two small-cell
breast carcinomas with positive TTF-1 whilst Ersahin reported one case of small-cell breast
carcinoma which was positive for TTF-1 and basal-like markers. In the case we report, we found
no areas typical for small cell carcinoma growth, although some areas with trabecular growth
gave a partial neuroendocrine impression. Because of heterogeneous growth with focally oval
and spindled shaped nuclei, a metaplastic carcinoma was considered. It is difficult to rule out this
alternative, but a lack of squamous or heterologous metaplasia makes this less possible.
The initial investigations of the biopsy gave suspicion of metastasis from lung cancer because of
the positive TTF-1 reaction. Previous studies have shown that lung cancer, malignant melanoma
and lymphoma are the three most common candidates for secondary breast tumours [6-8]. An
almost round tumour could resemble a metastasis, but some high grade primary tumours can also
have this shape. In our case the tumour was deep seated in the breast (6mm from the chest wall).
This correlates poorly with secondary breast tumours which are often found near to the skin [6,8].
The presence of a positive TTF-1 reaction in the in situ component as well as in the invasive
component in this case gives strong support for primary breast carcinoma. We are not aware of
any previously reported TTF-1 positive ductal carcinoma in situ of non small-cell type. In order
to be quite sure that this represented breast ducts and not vessels with tumour tissue or
peritumoral retraction artefacts, we also investigated these areas with MA and p63. Both markers
were positive for myoepithelial cells.
Mammaglobin and GCDFP-15 were negative in the tumour, but this does not exclude primary
breast carcinoma as these markers have a varied sensitivity of 60-75 % in primary breast
HER2/neu expression can be seen in both carcinomas of breast and lung . Our findings with
C-erb-2 protein score 2+/3+ and SISH without gene amplification have no differential value in
this case. We found weak postive reaction for PGR in the core biopsies. Positive reactions for
both ER and PGR have been reported for lung cancer  and give therefore no support to either
breast cancer or metastasis diagnosis.
In agreement with Ersahin et al we found a positive expression of the basal-like marker CK5/6.
This was especially noticeable in the in situ component, but only scattered positive cells in the
invasive component. This can possibly represent a dedifferentiation in the tumour tissue.
Previous studies have considered ductal carcinoma in situ with basal- like phenotype as a
possible precursor to invasive basal-like cancer [13,14].
Our case showed high grade ductal carcinoma in situ and invasive tumour, and such tumours are
more commonly basal like than low to intermediate grade lesions .
We have presented an unusual case of TTF-1 positive primary infiltrating ductal carcinoma with
focal basal-like and neuroendocrine differentiation. The in situ component with positive TTF-1
is the most important indication that this represents a primary tumour. Despite the fact that TTF-1
is known as a specific marker for lung and thyroid tumours, this case shows that primary non
small-cell breast carcinomas can also be positive.
The authors declare that they have no competing interests.
Written informed consent was obtained from the patient for publication of this case report and
accompanying images. A copy of the written consent is available for review by the Editor –in-
Chief of this journal.
TK wrote the manuscript and participated in histological diagnosis. YC participated in
histological diagnosis and writing. MG supplied the relevant radiological details and participated
in writing. HA operated the patient and supplied the relevant clinical details. BW participated in
immunohistochemical analysis. TS participated in histological diagnosis and reviewed the
manuscript. All authors have read and approved the final manuscript.
We thank Marianne Odnakk Ludahl and Henning Jørgensen (Department of Pathology, Vestfold
County Hospital) for excellent technical assistance.
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Table 1: Immunohistochemistry
Antibody Clone Dillution Company
TTF-I SPT24 1:100 Novocastra
CK5/6 D5/16B4 1:800 Chemicon
CK7 OV-TL-12/30 1:100 DAKO
CK20 Ks20.8 Ready to use Roche
CK18 DC10 1:40 DAKO
Mammaglobin 304-1A5 1:150 DAKO
GCDFP-15 23A3 1:200 Novocastra
ER SP1 Ready to use Roche
PGR 1E2 Ready to use Roche
Chromogranin LK2H10 Ready to use Roche
Synaptophysin 27G12 1:80 Novocastra
CD56 1B6 1:50 Novocastra
Her2 / neu 4B5 Ready to use Roche
Ki67 30.9 Ready to use Roche
P63 4A4 Ready to use Roche
MA HUC1-1 Ready to use Roche
Figure 1: Gross specimen showing well-circumscribed deep seated tumour with yellow necrotic
Figure 2: Tumour with glandular elements, vesicular nuclei and mitoses.
Figure 3: Invasive glandular tumour area is immunoreactive for TTF-1.
Figure 4: CD56 immunoreactivity in a focal invasive tumour area.
Figure 5: CK5/6 immunoreactivity demonstrated in isolated cells within the invasive tumour.
Figure 6: Ductal carcinoma in situ in vicinity of the tumour
Figure 7: Ductal carcinoma in situ with TTF-1 immunoreactivity.
Figure 8: Ductal carcinoma in situ with CK 5/6 immunoreactivity