Nuclear Brachyury Expression Is Consistent in Chordoma, Common in Germ Cell Tumors and Small Cell Carcinomas, and Rare in Other Carcinomas and Sarcomas: An Immunohistochemical Study of 5229 Cases

Abstract

Brachyury is a transcription factor of the T-box family typically expressed in notochord and chordoma. Some studies report brachyury as highly specific for chordoma, whereas others have concluded that brachyury is expressed in many types of common carcinomas by reverse transcription polymerase chain reaction and immunohistochemistry and could be involved in the epithelial-mesenchymal transition and metastatic process. In this study, we immunohistochemically evaluated 5229 different tumors for nuclear brachyury expression using a new rabbit monoclonal antibody and automated immunostaining (Leica Bond Max). Only nuclear labeling was scored, and antibody dilution of 1:2000 was used. In normal tissues, only rare cells in seminiferous tubules were labeled; all other organs were negative. All chordomas (75/76), except a sarcomatous one, were positive, whereas chondrosarcomas were negative. Among epithelial tumors, positivity was often detected in embryonal carcinoma (74%) and seminoma (45%). Pulmonary small cell carcinoma was often positive (41%), whereas pulmonary and pancreatic adenocarcinomas only rarely showed nuclear brachyury positivity (3% to 4%). Common carcinomas such as ductal carcinomas of the breast or adenocarcinomas of the prostate only exceptionally showed nuclear positivity (<1%). No colorectal, hepatocellular, renal cell, squamous cell, thyroid or urothelial carcinoma, or mesothelioma showed nuclear brachyury positivity. Among mesenchymal and neuroectodermal tumors, only isolated cases of melanoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and follicular lymphoma showed nuclear expression. However, as shown previously with lung carcinoma, experiments with lower antibody dilutions (1:200 to 1:500) showed weak cytoplasmic and nuclear labeling in breast cancers. In addition to chordoma, we show here for the first time that nuclear brachyury expression is prevalent in embryonal carcinoma, seminoma, and small cell carcinoma of the lung but very rare in common carcinomas, sarcomas, and melanoma. With these reservations, we have demonstrated the presence of nuclear brachyury immunoreactivity to be a sensitive and fairly specific marker for chordoma.

Fig. 1

Nuclear brachyury expression in chordoma and its histologic mimics. A. Chordoma cells show strong nuclear and moderate cytoplasmic expression. B. Chondrosarcoma with myxoid stroma shows cytoplasmic but no nuclear brachyury-positivity. C. A chordoma-like extra-axial tumor shows both nuclear and cytoplasmic positivity. D. A mixed tumor of soft tissue shows nuclear positivity.

Fig. 2

Nuclear brachyury expression in germ cell tumors. A. Seminoma commonly showing nuclear positivity. B. Embryoid body in embryonal carcinoma and rare cells outside it are positive. C. Embryonal carcinoma with a strongly positive area showing brachyury expression. D. Yolk sac tumor with focal positivity.

Fig. 3

Lung cancers with nuclear brachyury expression. A. Small cell carcinoma was the most common carcinoma showing positivity. B–C. Two examples of acinar adenocarcinomas with focal brachyury expression. D. An embryonal type adenocarcinoma showing brachyury expression.

Fig. 4

Other carcinomas with nuclear brachyury expression. A. Only one breast cancer, a high-grade ductal carcinoma was focally positive. B. A poorly differentiated prostatic adenocarcinoma was positive. C. Endometrial adenocarcinoma and D. ovarian endometrioid carcinomas with brachyury expression.

Fig. 5

Brachyury expression in melanoma and sarcomas. A. A minority of melanoma cells showed nuclear positivity. B. Only occasional malignant peripheral nerve tumors showed nuclear positivity. C. A Ewing sarcoma with strong nuclear immunoreactivity. D. Isolated cells were positive in a synovial sarcoma.