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JCP Online First, published on April 27, 2015 as 10.1136/jclinpath-2015-202998 PostScript
CORRESPONDENCE
TTF-1 positive breast cancer: a cautionary tale Expression of thyroid transcription factor-1 (TTF-1) by primary breast carcinoma and ductal carcinoma in situ (DCIS) is extremely rare and can potentially lead to diagnostic confusion. Here, we present an instructive case, including the first report of mutation analysis on such a tumour, and discuss the ways in which diagnostic pitfalls can be avoided in this situation.
CASE REPORT A 69-year-old female non-smoker with a past medical history of hypertension presented to the emergency department with cough and a right breast lump. Examination of the right breast revealed a 60 mm mass at the 12 o’clock position, with no skin tethering or fixation to deep structures. Mammography and ultrasound showed a well-defined lobulated mass measuring 30.5 mm in the upper half of the right breast, consistent with malignancy. In addition, chest radiography showed a right paramediastinal swelling of uncertain significance. Core biopsy of the right breast mass showed a grade 3 invasive ductal carcinoma with high-grade
DCIS. Immunohistochemistry showed the tumour cells to be negative for oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) (figure 1). In view of the unexplained lung lesion on radiology, TTF-1 staining (SPT24 clone) was also carried out in order to exclude a metastatic adenocarcinoma of the lung and was strongly and diffusely positive in both the invasive and in situ components of the tumour (figure 2). In this situation, the differential diagnosis lay between metastatic lung carcinoma in the breast and a primary TTF-1-expressing breast carcinoma. Here, the latter option was strongly favoured by the presence of an in situ component positive for TTF-1. CT imaging of the chest failed to identify a definitive lung primary, and subsequent immunohistochemistry using a different antibody clone of TTF-1 (8G7G3/1) was negative (figure 2), providing further support for the diagnosis. The patient was treated with neoadjuvant chemotherapy followed by a right mastectomy, which showed low-grade DCIS but no residual tumour. She is currently undergoing adjuvant endocrine treatment and radiotherapy.
DISCUSSION Metastatic adenocarcinoma of the lung can mimic primary breast carcinoma in its
location and microscopic appearance. As these two conditions have radically different treatments, an accurate diagnosis is essential, and this is usually assisted by immunohistochemistry. TTF-1, also known as Nkx2, is a tissue-specific transcription factor that has a role in the regulation of protein expression in the thyroid, lung and diencephalon and is a specific and sensitive marker in the diagnosis of pulmonary adenocarcinoma.1 It is frequently used in routine surgical pathology practice to distinguish between adenocarcinomas of the lung (positive) and breast (negative), but this was unsuccessful here due to the expression of TTF-1 by this primary breast carcinoma. There are very few reports of TTF-1 positive breast cancer in the literature, although small population-based studies have estimated that up to 2.8% of primary breast cancers may express TTF-1 at least weakly or focally.2 3 TTF-1 positivity has been reported in several histological subtypes, including invasive ductal,2–5 invasive lobular,2 3 medullary4 and small cell carcinoma.6 A population-based study featuring seven positive cases suggested that TTF-1 expression is significantly associated with grade 3 tumours and ‘triple negative’ (ER, PR and HER2 negative) disease,3 a phenotype consistent with our case. Although consistent with these previous reports, our case is extremely unusual in
Figure 1 (A) On morphology (H&E stain), the tumour is a grade 3 invasive ductal carcinoma with high-grade ductal carcinoma in situ (DCIS) (DCIS component not shown). Immunohistochemistry shows the tumour to be negative for (B) oestrogen receptor, (C) HER2 and (D) progesterone receptor. Inset panels are positive controls. J Clin Pathol Month 2015 Vol 0 No 0
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
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PostScript
Figure 2 Thyroid transcription factor-1 immunohistochemistry. The SPT24 clone shows positive staining in (A) invasive tumour and (B) ductal carcinoma in situ (DCIS) component. The 8G7G3/1 clone shows negative staining in (C) invasive tumour and (D) DCIS component.
demonstrating a strongly TTF-1 positive DCIS component. In the largest series of TTF-1 positive breast cancers until now, only 8/13 core biopsy specimens had a DCIS component, and only 2/8 of these were strongly TTF-1 positive with the SPT24 clone, giving an overall prevalence of 0.4% in the study.2 The mutational profile of TTF-1 positive breast tumours has not been reported before, and we decided to perform mutation analysis by next-generation sequencing on this tumour to highlight any targeted therapies that might prove valuable to the patient. Using a multigene panel (Life Technologies Colon & Lung Panel V2), we detected missense mutations in the PIK3CA and TP53 genes, both of which have been previously described in triple negative primary breast carcinomas.7 No variants in the BRAF, EGFR, KRAS or NRAS genes were detected. How can the surgical pathologist avoid diagnostic difficulty in cases such as these? First, the choice of antibody clone is important. Several authors have suggested that of the two commercially available TTF-1 clones, SPT24 is more sensitive and less specific than 8G7G3/1,4 8 and this is supported by our results. We suggest that pathologists should be aware of their laboratory protocols and consider the routine use of
2
8G7G3/1 to avoid similar confusion. The presence of TTF-1 in biopsies of triple negative breast cores without a DCIS component can be challenging. TTF-1 positive breast cancer should always be borne in mind by the pathologist, specimens should be searched thoroughly for an in situ disease component and clinicopathological correlation will be essential in difficult cases. 1
1
2
To cite Ellery P, Archard N, Saetta A, et al. J Clin Pathol Published Online First: [please include Day Month Year] doi:10.1136/jclinpath-2015-202998 Received 4 March 2015 Accepted 2 April 2015 J Clin Pathol 2015;0:1–2. doi:10.1136/jclinpath-2015-202998
REFERENCES 1
Peter Ellery, Nicholas Archard, Ally Saetta, Michael Gandy,3 Mary Falzon1
1 Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK 2 Bart’s and The London School of Medicine and Dentistry, London, UK 3 UCL Advanced Diagnostics, University College London, London, UK
Correspondence to Dr Peter M Ellery, Department of Cellular Pathology, 3rd Floor, Rockefeller Building, 21, University Street, London WC1E 6DE, UK; p.ellery@ucl. ac.uk Acknowledgements Many thanks to Philip Thompson (Histopathology Department, Leeds Teaching Hospitals NHS Trust) for performing the immunohistochemistry for TTF-1 clone 8G7G3/1. Contributors We confirm that all authors fulfil the criteria for authorship. Competing interests None declared.
2
3
4
5
6
7
Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
8
Ordonez NG. Value of thyroid transcription factor-1 immunostaining in tumor diagnosis: a review and update. Appl Immunohistochem Mol Morphol 2012;20:429–44. Robens J, Goldstein L, Gown AM, et al. Thyroid transcription factor-1 expression in breast carcinomas. Am J Surg Pathol 2010;34:1881–5. Klingen TA, Chen Y, Suhrke P, et al. Expression of thyroid transcription factor-1 is associated with a basal-like phenotype in breast carcinomas. Diagnostic Pathology 2013;8:80. Sakurai A, Sakai Y, Yatabe Y. Thyroid transcription factor-1 expression in rare cases of mammary ductal carcinoma. Histopathology 2011;59:143–61. Ni Y, Tsang JYS, Shao M, et al. TTF-1 expression in breast carcinoma: an unusual but real phenomenon. Histopathology 2014;64:504–11. Ersahin C, Bandyopadhyay S, Bhargava R. Thyroid transcription factor-1 and “basal Marker”’-expressing small cell carcinoma of the breast. Int J Surg Pathol 2009;17:368–72. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012;486:395–9. Bisceglia M, Galliani C, Rosai J. TTF-1 expression in breast carcinoma—the chosen clone matters. Am J Surg Pathol 2011;35:1087.
J Clin Pathol Month 2015 Vol 0 No 0
Downloaded from http://jcp.bmj.com/ on July 21, 2015 - Published by group.bmj.com
TTF-1 positive breast cancer: a cautionary tale Peter Ellery, Nicholas Archard, Ally Saetta, Michael Gandy and Mary Falzon J Clin Pathol published online April 27, 2015
Updated information and services can be found at: http://jcp.bmj.com/content/early/2015/04/26/jclinpath-2015-202998
These include:
References Email alerting service
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JCP Online First, published on April 27, 2015 as 10.1136/jclinpath-2015-202998 PostScript
CORRESPONDENCE
TTF-1 positive breast cancer: a cautionary tale Expression of thyroid transcription factor-1 (TTF-1) by primary breast carcinoma and ductal carcinoma in situ (DCIS) is extremely rare and can potentially lead to diagnostic confusion. Here, we present an instructive case, including the first report of mutation analysis on such a tumour, and discuss the ways in which diagnostic pitfalls can be avoided in this situation.
CASE REPORT A 69-year-old female non-smoker with a past medical history of hypertension presented to the emergency department with cough and a right breast lump. Examination of the right breast revealed a 60 mm mass at the 12 o’clock position, with no skin tethering or fixation to deep structures. Mammography and ultrasound showed a well-defined lobulated mass measuring 30.5 mm in the upper half of the right breast, consistent with malignancy. In addition, chest radiography showed a right paramediastinal swelling of uncertain significance. Core biopsy of the right breast mass showed a grade 3 invasive ductal carcinoma with high-grade
DCIS. Immunohistochemistry showed the tumour cells to be negative for oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) (figure 1). In view of the unexplained lung lesion on radiology, TTF-1 staining (SPT24 clone) was also carried out in order to exclude a metastatic adenocarcinoma of the lung and was strongly and diffusely positive in both the invasive and in situ components of the tumour (figure 2). In this situation, the differential diagnosis lay between metastatic lung carcinoma in the breast and a primary TTF-1-expressing breast carcinoma. Here, the latter option was strongly favoured by the presence of an in situ component positive for TTF-1. CT imaging of the chest failed to identify a definitive lung primary, and subsequent immunohistochemistry using a different antibody clone of TTF-1 (8G7G3/1) was negative (figure 2), providing further support for the diagnosis. The patient was treated with neoadjuvant chemotherapy followed by a right mastectomy, which showed low-grade DCIS but no residual tumour. She is currently undergoing adjuvant endocrine treatment and radiotherapy.
DISCUSSION Metastatic adenocarcinoma of the lung can mimic primary breast carcinoma in its
location and microscopic appearance. As these two conditions have radically different treatments, an accurate diagnosis is essential, and this is usually assisted by immunohistochemistry. TTF-1, also known as Nkx2, is a tissue-specific transcription factor that has a role in the regulation of protein expression in the thyroid, lung and diencephalon and is a specific and sensitive marker in the diagnosis of pulmonary adenocarcinoma.1 It is frequently used in routine surgical pathology practice to distinguish between adenocarcinomas of the lung (positive) and breast (negative), but this was unsuccessful here due to the expression of TTF-1 by this primary breast carcinoma. There are very few reports of TTF-1 positive breast cancer in the literature, although small population-based studies have estimated that up to 2.8% of primary breast cancers may express TTF-1 at least weakly or focally.2 3 TTF-1 positivity has been reported in several histological subtypes, including invasive ductal,2–5 invasive lobular,2 3 medullary4 and small cell carcinoma.6 A population-based study featuring seven positive cases suggested that TTF-1 expression is significantly associated with grade 3 tumours and ‘triple negative’ (ER, PR and HER2 negative) disease,3 a phenotype consistent with our case. Although consistent with these previous reports, our case is extremely unusual in
Figure 1 (A) On morphology (H&E stain), the tumour is a grade 3 invasive ductal carcinoma with high-grade ductal carcinoma in situ (DCIS) (DCIS component not shown). Immunohistochemistry shows the tumour to be negative for (B) oestrogen receptor, (C) HER2 and (D) progesterone receptor. Inset panels are positive controls. J Clin Pathol Month 2015 Vol 0 No 0
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from http://jcp.bmj.com/ on July 21, 2015 - Published by group.bmj.com
PostScript
Figure 2 Thyroid transcription factor-1 immunohistochemistry. The SPT24 clone shows positive staining in (A) invasive tumour and (B) ductal carcinoma in situ (DCIS) component. The 8G7G3/1 clone shows negative staining in (C) invasive tumour and (D) DCIS component.
demonstrating a strongly TTF-1 positive DCIS component. In the largest series of TTF-1 positive breast cancers until now, only 8/13 core biopsy specimens had a DCIS component, and only 2/8 of these were strongly TTF-1 positive with the SPT24 clone, giving an overall prevalence of 0.4% in the study.2 The mutational profile of TTF-1 positive breast tumours has not been reported before, and we decided to perform mutation analysis by next-generation sequencing on this tumour to highlight any targeted therapies that might prove valuable to the patient. Using a multigene panel (Life Technologies Colon & Lung Panel V2), we detected missense mutations in the PIK3CA and TP53 genes, both of which have been previously described in triple negative primary breast carcinomas.7 No variants in the BRAF, EGFR, KRAS or NRAS genes were detected. How can the surgical pathologist avoid diagnostic difficulty in cases such as these? First, the choice of antibody clone is important. Several authors have suggested that of the two commercially available TTF-1 clones, SPT24 is more sensitive and less specific than 8G7G3/1,4 8 and this is supported by our results. We suggest that pathologists should be aware of their laboratory protocols and consider the routine use of
2
8G7G3/1 to avoid similar confusion. The presence of TTF-1 in biopsies of triple negative breast cores without a DCIS component can be challenging. TTF-1 positive breast cancer should always be borne in mind by the pathologist, specimens should be searched thoroughly for an in situ disease component and clinicopathological correlation will be essential in difficult cases. 1
1
2
To cite Ellery P, Archard N, Saetta A, et al. J Clin Pathol Published Online First: [please include Day Month Year] doi:10.1136/jclinpath-2015-202998 Received 4 March 2015 Accepted 2 April 2015 J Clin Pathol 2015;0:1–2. doi:10.1136/jclinpath-2015-202998
REFERENCES 1
Peter Ellery, Nicholas Archard, Ally Saetta, Michael Gandy,3 Mary Falzon1
1 Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK 2 Bart’s and The London School of Medicine and Dentistry, London, UK 3 UCL Advanced Diagnostics, University College London, London, UK
Correspondence to Dr Peter M Ellery, Department of Cellular Pathology, 3rd Floor, Rockefeller Building, 21, University Street, London WC1E 6DE, UK; p.ellery@ucl. ac.uk Acknowledgements Many thanks to Philip Thompson (Histopathology Department, Leeds Teaching Hospitals NHS Trust) for performing the immunohistochemistry for TTF-1 clone 8G7G3/1. Contributors We confirm that all authors fulfil the criteria for authorship. Competing interests None declared.
2
3
4
5
6
7
Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
8
Ordonez NG. Value of thyroid transcription factor-1 immunostaining in tumor diagnosis: a review and update. Appl Immunohistochem Mol Morphol 2012;20:429–44. Robens J, Goldstein L, Gown AM, et al. Thyroid transcription factor-1 expression in breast carcinomas. Am J Surg Pathol 2010;34:1881–5. Klingen TA, Chen Y, Suhrke P, et al. Expression of thyroid transcription factor-1 is associated with a basal-like phenotype in breast carcinomas. Diagnostic Pathology 2013;8:80. Sakurai A, Sakai Y, Yatabe Y. Thyroid transcription factor-1 expression in rare cases of mammary ductal carcinoma. Histopathology 2011;59:143–61. Ni Y, Tsang JYS, Shao M, et al. TTF-1 expression in breast carcinoma: an unusual but real phenomenon. Histopathology 2014;64:504–11. Ersahin C, Bandyopadhyay S, Bhargava R. Thyroid transcription factor-1 and “basal Marker”’-expressing small cell carcinoma of the breast. Int J Surg Pathol 2009;17:368–72. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012;486:395–9. Bisceglia M, Galliani C, Rosai J. TTF-1 expression in breast carcinoma—the chosen clone matters. Am J Surg Pathol 2011;35:1087.
J Clin Pathol Month 2015 Vol 0 No 0
Downloaded from http://jcp.bmj.com/ on July 21, 2015 - Published by group.bmj.com
TTF-1 positive breast cancer: a cautionary tale Peter Ellery, Nicholas Archard, Ally Saetta, Michael Gandy and Mary Falzon J Clin Pathol published online April 27, 2015
Updated information and services can be found at: http://jcp.bmj.com/content/early/2015/04/26/jclinpath-2015-202998
These include:
References Email alerting service
This article cites 8 articles, 1 of which you can access for free at: http://jcp.bmj.com/content/early/2015/04/26/jclinpath-2015-202998 #BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
