Clinicopathological Characterization of TSH-Producing Adenomas: Special Reference to TSH-immunoreactive but Clinically Non-functioning Adenomas

Abstract

Thyrotropin (thyroid-stimulating hormone (TSH))-producing pituitary adenomas have been known to be quite variable in clinical features covering from typical functioning TSH-producing adenomas (FTSHomas) associated with hyperthyroidism to clinically silent TSH cell adenomas (STAs) that are apparently unassociated with hyperthyroidism. It is important to distinguish STAs from other types of clinically non-functioning adenomas for adequate postoperative managements. However, because of rareness of TSH-producing adenomas, their histopathological features linking to the clinical manifestations have not been well characterized. Herein, we investigated clinical and histopathological findings to characterize 29 TSH-producing adenomas including 20 FTSHomas and nine STAs. Clinical symptoms of the patients with STAs included headache, visual defect, vertigo, and nausea. All STAs and 19 FTSHomas were macroadenoma. The average tumor size of STAs was significantly larger than that of FTSHomas (P < 0.05). The invasiveness was detected in 33% STAs and in 20% FTSHomas. Both STAs and FTSHomas showed a variety of morphological features and immunohistochemical profiles. Chromophobic polygonal or short-spindled tumor cells usually proliferated in a diffuse pattern, while they exhibited globoid or whorl-like appearance with intertwined cytoplasmic processes in both subgroups. Stromal fibrosis and calcification were often noted. Their nuclei were somehow pleomorphic. Ultrastructural features of all four STAs examined were similar to those of normal thyrotrophs. Thus, STAs and FTSHomas were indistinguishable by histology alone. Immunohistochemically, the number of TSH-positive cells in individual FTSHomas was highly various. Six tumors showed only a few TSH-positive cells (1-5%), and three were negative for TSH by conventional method without antigen retrieval. After proteinase K treatment, these tumors turned out TSH positive. As defined, STAs were TSH positive in more than 20% of tumor cells and three of them in more than 50%. Growth hormone- and/or prolactin-positive cells were detected in 55% STAs and 63% FTSHomas. Both pituitary-specific transcription factor 1 and GATA-binding protein 2 were expressed in all STAs and 20 FTSHomas. Membranous somatostatin receptor (SSTR)-2A immunoreactivity was found in 89% STAs and 94% FTSHomas, whereas SSTR5 was positive in 78% of both STAs and FTSHomas. MIB-1 labeling index was related to tumor invasiveness and tumor size (P < 0.05, P = 0.09, respectively). Thus, although both STAs and FTSHomas showed unique histopathological features distinct from other type adenomas, these two subgroups were indistinguishable by histopathology. Immunohistochemistry for TSH by use of antigen retrieval, transcription factors, and SSTRs may be useful to confirm STAs and to determine the postoperative therapy among various kinds of clinically non-functioning adenomas.

Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

“…However, and in common with protein-coding genes, miRNAs can be silenced through aberrant hypermethylation of CpG islands and/or by histone modifications. [18] Irrespective of pituitary adenoma subtype a significant proportion overexpress HMGA1 and HMGA2 [33,10,34,35], indeed, in the cohort we now describe, similar conclusions are apparent (data not shown). Convincing evidence for the role of these genes, and their protein products, in tumour evolution are provided through studies in transgenic mice, where, enforced expression of either hmga1 or hmga2 leads to the development of pituitary adenomas.…”

A Patient With a Thyrotropin-Secreting Microadenoma and Resistance to Thyroid Hormone (P453T)

“…TSH-secreting adenomas with positive immunoreactivity for multiple pituitary hormones not necessarily correlated with hypersecretion of the hormone has been reported (7,8). Although we recognize that the staining for multiple hormones raises questions about the nature of the lesion, we believe the adenoma is distinct on imaging and in the surgery video.…”

DIAGNOSIS OF ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma

“…Chromophobic polygonal or shortspindled tumor cells are often seen in a diffuse pattern. Also globoid or whorl-like appearance with intertwined cytoplasmic processes, stromal fibrosis, and calcification are often noted (42). This has been attributed to an expression of the basic fibroblast growth factor (bFGF) (43) and corresponds well with clinical findings of fibrotic characteristics (41), seen in approximately 40% of TSHomas (17).…”