Ectopic TSH-secreting pituitary tumor: a case report and review of prior cases

TSH-secreting pituitary adenomas (TSH-omas) are an unusual disorder, accounting for ~2% of all pituitary tumors [1]. Ectopic TSH-oma is extremely rare. Since the first description of the disease by Cooper and colleagues in 1996, only four cases have been reported to date [2‐5]. Here a newly identified case is reported, and the clinical and laboratory features of previous published cases are reviewed.

A 41-year-old male suffering from palpitations, dyspnea, weight loss, and fatigue for one year was referred to Weihai Municipal Hospital in June 2009. He also had atrial fibrillation. Thyroid functional tests showed increased FT₃ (24.08, normal 2.8-7.1 pmol/L), FT₄ (75.73, normal 12-22 pmol/L), and TSH (7.26, normal 0.27-4.2 μIU/ml). He was diagnosed with hyperthyroidism and given propylthiouracil (300 mg daily) together with either propranolol or propafenone. The patient's electrocardiogram displayed sinus rhythm. The levels of FT₃ and FT₄ (FT₃ 11.54 pmol/L, FT₄ 27.09 pmol/L) but not TSH (14.08 μIU/ml) were reduced after six months of treatment. However, the concentration of free thyroid hormones were still not normal. In sharp contrast, the TSH level was further elevated after intensive treatment. Pituitary MRI examination was therefore performed to rule out TSH-oma. The MRI image indicated a normal pituitary gland (Figure 1A and B). Thus, resistance to thyroid hormone syndrome was diagnosed, and triiodothyroacetic acid was prescribed. The plasma levels of FT₃, FT₄, and TSH transiently decreased and then rebounded.Over the course of the disease, the patient lost 6 kg of body weight. He had no symptoms of headache, nausea, dizziness, subnormal vision, impaired visual field, and obvious nasal obstruction. His physical examination was normal (T 36.7°C, P 80/min, R 17/min, BP120/80 mmHg, Ht 173 cm, Wt 65 Kg). He had a symmetrical figure, normal hair distribution, sweaty skin, normal superficial lymph nodes, and normal degree of convexity of eyeballs. Palpation revealed swelling of the thyroid gland, no nodules, medium texture, and no haphalgesia. Vascular murmur was not heard on auscultation. The patient had uneven cardiac sounds and arrhythmia with a heart rate of 100/min. No abdominal abnormalities were found. The proximal muscles did not show signs of atrophy. Mild tremor was observed when he raised his hands. The patellar tendon reflex was normal, and the pathological reflex was not observed. Lab and imaging results showed normal liver and kidney. TG-Ab <30%, TM-Ab <15%, GH 0.7 (normal <5.0 ng/ml), FSH 16.8 (normal 1.5-12 mIU/ml), LH 13.72 (normal 1.7-8.6 mIU/ml), PRL 14.9 (normal 4.1-18.4 ng/ml), and T 13.20 (normal 2.8-8.0 ng/ml). The blood electrolytes were within normal ranges: Ca 2.27 mmol/L, P 1.23 mmol/L, and K 3.87 mmol/L. Tumor biomarkers were analyzed, including carbohydrate antigen-199 12.26 (normal <37 U/ml), carcinoembryonic antigen 1.90 (normal <10 ng/ml), and neuron specific enolase (NSE) 22.31 (normal <16.3 ng/ml). Given a normal pituitary gland as pictured by magnetic resonance imaging (MRI) with gadolinium contrast, abnormal TSH level, and a large space-occupying lesion within the nasal cavity and the nasopharynx, with a maximum cross-section area of 1.9 × 1.7 cm (Figure 1C & D), as detected by CT scan, an ectopic TSH-secreting pituitary tumor was suspected. Emission computed tomography (ECT) demonstrated strong technetium-uptake by the thyroid. However, as shown in Figure 2A, the stimulating test was negative for TSH level was not up-regulated by TRH (Shanghai Lizhudongfeng Biologic Technology Inc., China). The amount of TSH was increased <2 μIU/ml. In comparison, the octreotide inhibition test was positive; a decrease of up to 30.8% in TSH level was observed (Figure 2B). Taken together, a diagnosis of ectopic TSH-secreting tumor in the nasopharynx was tentatively established. The strategy to combine resection and quick pathological examination was proposed to release patient’s financial burden and surgical stress. Nevertheless, his surgery was postponed due to treatment of the atrial fibrillation.The patient underwent endoscopic endonasal surgery, through which the mass was removed in November 2009. Pathological examination confirmed invasive ectopic pituitary tumor extending to the bone parenchyma. Microscopic examination showed that the unenveloped tumor tissue lay beneath the nasal mucosa (pseudostratified ciliated columnar epithelium) (Figure 3A & B). The tumor cells invading the mucosa and fibrous tissue led to a tumor tissue type that was diffusive, solid lesion, and sinusoidal. The irregular tumor cells were mostly round or polygonal, while others were spindle shaped, filled with rich cytoplasm bearing fine particles. Some cells were found to have a round to ovoid nucleus with transparent cytoplasm (Figure 3A & B). Immunohistochemical assays detected expression of TSH (brown) and GH (brown) (Figure 3C & D). No other pituitary hormones, including ACTH, LH, FSH, and PRL, or thyroglobulin and thyroid transcription factor1 were detectable. In contrast, pan-cytokeratin, chromogranin, synaptophysin, and neuron specific enolase were detected. Electron microscopy examination found that the tumor was composed of pleomorphic cells (Figure 3E and F). Round, unenveloped electron-dense granules were dispersed throughout the cytoplasm. Some granules formed clusters. The diameter of granules was 0.1-0.2 μm.

Upon resection of the tumor, the levels of plasma TSH, FT₃, and FT₄ returned to normal ranges, as analyzed 24 hours post surgery (Table 1). The patient gained 3 kg of body weight in two months. In addition, the symptoms of sweating, palpitation, and fatigue disappeared. Atrial fibrillation was treated with metoprolol and warfarin. We re-examined plasma TSH, FT₃ and FT₄ levels 48 months post surgery and found them still normal (Table 1). Meanwhile, CT scan did not indicate recurrence of the tumor (Figure 1E & F).

In toto, ectopic TSH-oma is extremely rare. To date, only four cases have been reported. The phylogenetic mechanism of ectopic TSH-oma should be similar to other ectopic pituitary tumors, which are probably derived from the embryonic residues of pituitary cells along the path of migration of Rathke's pouch. All five cases were found to have a mass in the nasopharyngeal region. Their clinical manifestations were almost the same as those of ordinary hyperthyroidism (high metabolic syndrome). Nevertheless, they all had high levels of TSH as well as increased serum free thyroxine. Alpha-GSU and α-GSU/TSH ratio are valuable for distinguishing TSH-oma from other diseases. Moreover, TRH stimulating and octreotide inhibition tests could differentiate ectopic TSH-oma from RTH. The primary therapy for ectopic TSH-oma is the resection of adenoma. Nonsurgical intervention through long-acting somatostatin analogues can suppress TSH secretion. Whether in situ radiation therapy could be an effective intervention remains unknown.

Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.