1. PRIMARY NON-SMALL CELL NEURO- ENDOCRINE CARCINOMA OF THE BREAST: ANALYSIS OF A SERIES YIELDING RESULTS CONFLICTING WITH DATA IN THE LITERATURE M. Bisceglia, L. Dicandia, M. Vairo, L. Zaffarano, F. Scaramuzzi, D. Urbano. Department of Pathology, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo.

2. TTF-1 is a nuclear transcription factor expressed at the onset of thyroid, lung, and ventral diencephalic development (1). Accordingly, TTF-1 is frequently expressed in both benign and malignant epithelial-derived tumors of the lung and thyroid, including small cell carcinomas (SCC), well- differentiated neuroendocrine tumors (WDNET) from these two organs, and large cell neuroendocrine carcinoma (LCNEC) of the lung. Background.

3. Over the last years a considerable proportion of extrapulmonary and extrathyroid neuroendocrine tumors (NET), mostly SCC type, of disparate origins have been proved reactive for TTF-1. Hence, TTF-1 expression cannot be used to distinguish pulmonary from extrapulmonary SCC or LCNEC, the only exception being cutaneous Merkel cell tumor which is consistently negative for TTF-1. Even WDNET of digestive tract and pancreas (with the exception of 2 cases in large series from the digestive tract), NET of the adrenal and extra-adrenal paraganglia, and endocrine tumors of pituitary and parathyroid are also consistently TTF-1 negative (for a review see Bisceglia et al 2 ).

4. NETs of breast, partly due to their rarity, have not been extensively examined in this respect. To the best of our knowledge, 4 of only 6 primary SCCs of breast investigated for TTF-1 expression 3-7 have been positive 4,6,7, drawn from fewer than 40 cases mentioned in the literature (35 of these fully reported 4,6,7 ). On the other hand, we have found only one study assessing TTF-1 expression in non-small cell neuroendocrine carcinomas of breast, according to which 5 of 5 proved positive for TTF1 7. We selected from our archival materials 14 primary invasive NETs of the breast (5 so-called carcinoid tumors of Cubilla-Woodruff type, 2 neuroendocrine carcinomas-NOS, 2 IDCs with neuroendocrine features, 1 lobular carcinoma with neuroendocrine features, and 4 colloid carcinomas type B). Design.

5. All documented cases were positive for at least 2 neuroendocrine markers (chromogranin A and synaptophysin in all), but 2 which were positive for one of these markers together with positive argyrophilia.

6. Chromogranin A Synaptophysin

7. Chromogranin A Argyrophilic stain

8. These cases were immunostained according to the following protocol: heat-induced antigenic retrieval on deparaffinized 4 µm sections for 2 cycles, each of 15 minutes, in 10 mM citrate buffer (pH 6.0) using a 360 W microwave oven. The antibody to TTF-1 used was from clone 8G7G3/1 (1:30 dilution; DakoCytomation, Carpinteria, CA, USA). Immunohistochemical staining was performed using the labeled streptavidin-biotin peroxidase complex system (LSAB2) according to the manufacturer’s recommendations in a DAKO Autostainer.

9. Results All cases were unreactive to TTF-1.

10. TTF-1

11. Conclusion. Based on our own experience, TTF-1 may help in distinguishing NETs of the breast, other than SCC, from WDNETs of lung (classic and atypical carcinoids). The lack of TTF-1 expression in our cases is in contrast with previously reported data in the literature, therefore additional studies are strongly encouraged and would be commended.

12. References 1.Bingle CD. Thyroid transcription factor-1. Int J Biochem Cell Biol. 1997;29:1471-1473.Bingle CD. 2.Bisceglia M, Ragazzi M, Galliani C, Lastilla G, Rosai J. TTF-1 expression in nephroblastoma. Am J Surg Pathol 2008, in press.Bisceglia M, Ragazzi M, Galliani C, Lastilla G, Rosai J. 3.Mariscal A, Balliu E, Díaz R, Casas JD, Gallart AM. Primary oat cell carcinoma of the breast: imaging features. AJR Am J Roentgenol. 2004;183:1169-1171.Mariscal A, Balliu E, Díaz R, Casas JD, Gallart AM. 4.Kitakata H, Yasumoto K, Sudo Y, Minato H, Takahashi Y. A case of primary small cell carcinoma of the breast. Breast Cancer. 2007;14:414-419.Kitakata H, Yasumoto K, Sudo Y, Minato H, Takahashi Y.

13. 5.Zhang W, Hoda SA. Mammary small-cell carcinoma with dimorphic phenotype. Breast J. 2007;13:529-530.Zhang WHoda SA 6.Kaufmann O, Dietel M. Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites. Histopathology. 2000;36:415-20. Histopathology 2000;36:415-420.Kaufmann O, Dietel M. 7.Yamamoto J, Ohshima K, Nabeshima K, Ikeda S, Iwasaki H, Kikuchi M. Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. Oncol Rep. 2004;11:825-831.Yamamoto JOhshima KNabeshima KIkeda S Iwasaki HKikuchi M