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ABSENCE OF TTF-1 EXPRESSION IN INVASIVE DUCTAL CARCINOMAS-NOS OF BREAST M. Bisceglia, M. Vairo, L. Zaffarano, G. Perron

ABSENCE OF TTF-1 EXPRESSION IN INVASIVE DUCTAL CARCINOMAS-NOS OF BREAST M. Bisceglia, M. Vairo, L. Zaffarano, G. Perrone, M. Cassano, A. Danza. Department of Pathology, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo. . Background . .

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ABSENCE OF TTF-1 EXPRESSION IN INVASIVE DUCTAL CARCINOMAS-NOS OF BREAST M. Bisceglia, M. Vairo, L. Zaffarano, G. Perron

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  1. ABSENCE OF TTF-1 EXPRESSION IN INVASIVE DUCTAL CARCINOMAS-NOS OF BREAST M. Bisceglia, M. Vairo, L. Zaffarano, G. Perrone, M. Cassano, A. Danza. Department of Pathology, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo.

  2. Background. • TTF-1 is a nuclear transcription factor expressed in the early stages of thyroid, lung, and ventral diencephalic development and it has been widely applied as a tissue marker for epithelial-derived neoplasms of the lung and thyroid, whether benign or malignant, primary or metastatic, and orthotopic or ectopic (such as thyroid tumors found in thyroglossal duct cysts and struma ovarii). • TTF-1 immunohistochemistry is therefore considered a useful adjuvant in supporting or excluding lung or thyroid derivation in both histopathological and cytopathological specimens (e.g., FNA and serous fluid cytology).

  3. Counterpoint to the specificity claims of TTF-1 as a tissue marker of lung and thyroid lesions, are publications cautioning against the organ specificity of TTF-1 expression in tumors. • A considerable proportion of extrapulmonary and extrathyroid tumors of disparate origins and different lineages have been proved reactive for TTF-1 (for a review on this topic: see Bisceglia M, et al 1). • Most of these extrapulmonary and extrathyroid TTF-1 positive tumors are of neuroendocrine nature, mainly small cell carcinomas, except Merkel cell tumor of skin and small cell carcinoma of the ovary (non-pulmonary, hypercalcemic type).

  4. However, among these TTF-1 positive tumors are even adenocarcinomas of several visceral organs (stomach, colon, ovary, uterine cervix and corpus, nasopharynx, and even peritoneum), totalling 48 cases so far reported, either primary or metastatic(same source as above 1). • Positivity (defined as nuclear staining) was obtained using either of the two main commercial clones raised against TTF-1 protein, i.e., SPT24 and 8G7G3/1, with stronger affinity being credited to the former and higher specificity to the latter.

  5. Design. • Invasive ductal carcinoma of breast (IDC) (both primary and metastatic) has already been investigated, with no positive case on record with either of these antibodies (2-5). This includes a total of more than one hundred cases studied by Kaufman and Dietel (2), Ordonez (3), Medina-Flores et al (4), and Strickland-Marmol et al (5) (59,25,20, and 10 cases, respectively, both primary and metastatic). • Therefore, TTF-1 should be considered a keystone in excluding breast origin for metastatic TTF-1 positive tumors in any site. However, we draw attention to the citing (6) of 4 TTF-1 positive IDCs of breast (out of 5 cases) from, in our opinion, a questionable report (7).

  6. Therefore, even considering the progressively expanding spectrum of extra-thyroid and extra-pulmonary TTF-1 positive tumors, we wanted to assess the TTF-1 expression (if any) by IDC of breast by studying 30 IDCs-NOS (18 primary, 2 local recurrences, 10 distant metastates). • The monoclonal antibody to TTF-1 used was from clone 8G7G3/1 (1:30 dilution; DakoCytomation, Carpinteria, CA, USA).

  7. Results. No case of IDC of breast was positive.

  8. IDCs of breast included in this study were of various grade of differentiation.

  9. TTF-1 No case in our study was immunopositive

  10. References. • Bisceglia M, Ragazzi M, Galliani C, Lastilla G, Rosai J. TTF-1 expression in nephroblastoma. Am J Surg Pathol 2008, in press. • Kaufmann O, Dietel M. Thyroid transcription factor-1 is the superior immunohistochemical marker for pulmonary adenocarcinomas and large cell carcinomas compared to surfactant proteins A and B. Histopathology. 2000;36:8-16. • Ordóñez NG. Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol. 2000;24:1217-23. Comment in:Am J Surg Pathol. 2001;25:545-546. • Medina-Flores R, Lawson D, Cotsonis G, et al.Diagnostic utility of thyroid transcription factor (TTF-1) in primary and common metastatic tumors of lung. Mod Pathol. 2000;13:214A.

  11. Strickland-Marmol LB, Khoor A, Livingston SK, et al.Utility of tissue-specific transcription factors thyroid transcription factor 1 and Cdx2 in determining the primary site of metastatic adenocarcinomas to the brain. Arch Pathol Lab Med. 2007;131:1686-1690. • Kubba LA, McCluggage WG, Liu J, Malpica A, Euscher D, Silva EG, Deavers MT.Thyroid transcription factor-1 expression in ovarian epithelial neoplasms. Mod Pathol. 2008;21:485-490. • Yamamoto J, Ohshima K, Nabeshima K, et al. Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. Oncol Rep. 2004;11:825-831.

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