Thyroid Transcription Factor-1 (TTF-1) Michael T. Deavers, M.D. The University of Texas M.D. Anderson Cancer Center Houston, Texas

Case History The patient is a 59-year old woman, non-smoker, who presented 11 months prior with postmenopausal spotting. She underwent a TAH-BSO and lymph node dissection for Endometrioid Endometrial Adenocarcinoma, Grade 2. Histologic examination showed that the tumor invaded 9 mm into an 18 mm thick myometrium (slide provided) and the cervical stroma. There was lymphvascular involvement, but the pelvic and para-aortic lymph nodes were negative. The patient received adjuvant brachytherapy. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Ten months after the TAH-BSO, her serum CA125 was 41 U/ML. A CT of the chest demonstrated multiple bilateral pulmonary nodules, and a CT of the abdomen and pelvis revealed carcinomatosis. A diagnosis of adenocarcinoma was made on material obtained from a CT guided FNA of the lung. The tumor cells were found to be positive for cytokeratin 7 and TTF-1. Initially, because of the TTF-1 expression by tumor cells, a pulmonary primary was favored. However, the relatively short interval since the patient's TAH-BSO, the bilateral and multiple nature of the pulmonary nodules, and the intra-abdominal disease were more consistent with recurrent endometrial carcinoma, so sections of the uterine tumor were subsequently submitted for immunohistochemistry. The endometrial carcinoma was found to be diffusely positive for TTF-1 and was also positive for estrogen and progesterone receptors. Chromogranin and synaptophysin stains were negative. The diagnosis of the aspirate was revised to metastatic endometrial carcinoma. Thyroid transcription factor-1 (TTF-1) is a nuclear protein of the NKx2 family of homeodomain transcription factors. TTF-1 was originally found in follicular epithelial cells of the thyroid, and later in type II pneumocytes and Clara cells of the lung. In the thyroid it regulates the expression of thyroid peroxidase, thyroglobulin, and the TSH receptor. In the lung, it regulates the expression of surfactant protein A, surfactant protein B, surfactant protein C, and Clara cell secretory protein. Other normal tissues expressing TTF-1 include parafollicular cells, parathyroid gland, anterior pituitary, and fetal basal forebrain. TTF-1 expression has been found to be relatively specific and sensitive for tumors originating in the thyroid and lung. Follicular adenomas, follicular carcinomas, papillary carcinomas (including follicular variants), medullary carcinomas, and some anaplastic thyroid carcinomas are positive for TTF-1. The majority of pulmonary adenocarcinomas (decreased expression in mucinous vs. non-mucinous), small cell carcinomas, and carcinoid tumors are also positive. Additionally, TTF-1 is expressed by some large cell carcinomas of the lung (both neuroendocrine and non-neuroendocrine), and a small percentage of pulmonary squamous cell carcinomas. The specificity of TTF-1 for thyroid and lung neoplasms, however, is not 100%. Small cell carcinomas from various sites, including the cervix, bladder, GI tract, and prostate are positive in 15-33% of cases. Other tumors with reports of occasional TTF-1 expression include ependymoma (2 of 27, Zamecnik et al), breast carcinoma (A. Sahin, personal communication), gastric carcinoma (1 of 66, Bejarano et al), and colonic adenocarcinoma (4 of 41, Comperat et al). Of interest, the study of the colonic adenocarcinomas found that the SPT24 anti-TTF-1 clone was more sensitive, but less specific, than the 8G7G3/1 clone. Cytoplasmic reactivity for TTF-1 has been reported to be useful in the diagnosis of hepatocellular carcinoma. In the gynecologic tract, endocervical, endometrial, and ovarian carcinomas occasionally express nuclear TTF-1. Two studies have reported positivity of ovarian adenocarcinomas. One, a study of effusion and fine needle aspiration specimens, found focal weak reactivity in 1 of 16 cases of metastatic ovarian carcinoma; the histotype was not specified (JL Hecht et al). A larger study using tissue microarrays examined 166 ovarian tumors of various histologic types; two of the tumors were positive. One, a stage III high grade mixed serous and endometrioid adenocarcinoma, had strong staining in all four microarray cores; the other was a stage III high grade serous carcinoma with strong staining in one of three cores. Neither of the patients had evidence of a pulmonary lesion (Graham et al). Struma ovarii, of course, also expresses TTF-1. In the cervix and endometrium, immunoreactivity has been reported in one of three cervical small cell carcinomas (Ordonez) and one of eight endometrial adenocarcinomas (Bejarano et al). At M.D. Anderson, we recently studied TTF-1 expression in 28 endocervical adenocarcinomas (9 well, 12 moderately, 6 poorly differentiated, and 1 adenosquamous) and 31 endometrial endometrioid adenocarcinomas (11 grade I, 8 grade II, and 12 grade III); none of the tumors had a neuroendocrine component. One (4%) of the endocervical adenocarcinomas was positive, with a diffuse distribution. TTF-1 immunoreactivity was more frequent in the endometrial tumors, being present in five cases (16%), and ranged from focal to diffuse in distribution. There was no correlation between the degree of differentiation and TTF-1 expression, and no distinguishing histologic features of the positive tumors were noted. TTF-1 is a sensitive and relatively specific marker of pulmonary and thyroidal tumors. However, a positive result does not automatically equate to origin from these sites, as occasional carcinomas from other sites such as the cervix, endometrium, and ovary are also positive. TTF-1, as with any other marker, should be interpreted in the context of the clinical setting, radiologic findings, histologic features, and other markers. References Bejarano PA, Baugham RP, Biddinger PW, et al. Surfactant proteins and thyroid transcription factor-1 in pulmonary and breast carcinomas. Mod Pathol 1996; 9:445-452. Comperat E, Zhang F, Perrotin C, et al. Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin. Mod Pathol 2005; 18:1371-1376. Graham AD, Williams ARW, Salter DM. TTF-1 expression in primary ovarian epithelial neoplasia. Histopathology 2006; 48:746-765. Hecht JL, Pinkus JL, Weinstein LJ, Pinkus GS. The value of thyroid transaction factor-1 in cytologic preparations as a marker for metastatic adenocarcinoma of lung origin. Am J Clin Pathol 2001; 116:483-488. Ordonez NG. Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol 2000; 24:1217-1223. Wieczorek TJ, Pinkus JL, Glickman JN, Pinkus GS. Comparison of thyroid transcription factor-1 and hepatocyte antigen immunohistochemical analysis in the differential diagnosis of hepatocellular carginoma metastatic adenocarcinoma, renal cell carcinoma, and adrenal cortical carcinoma. Am J Clin Pathol 2002; 118:911-921. Zamecnik J, Chanova M, Kodet R. Expression of thyroid transcription factor-1 in primary brain tumors. J Clin Pathol 2004; 57:1111-1113.