Ectopic TSH-secreting pituitary tumor: a case report and review of prior cases
© Song et al.; licensee BioMed Central Ltd. 2014
Received: 22 April 2014
Accepted: 14 July 2014
Published: 28 July 2014
Ectopic TSH-secreting pituitary adenoma (TSH-oma) is a very unusual disorder. To date, there are only four cases reported. It is difficult to distinguish ectopic cases from both regular TSH-omas and resistance to thyroid hormone (RTH).
A newly identified case of ectopic TSH-oma arising from the nasal pharynx was described, and reports of four prior cases were reviewed. The patient was a 41-year-old male who developed what appeared to be typical hyperthyroidism and atrial fibrillation in 2009. Thyroid function tests showed elevated basal levels of free T3 (FT3, 24.08 pmol/L), free T4 (FT4, 75.73 pmol/L), and serum TSH (7.26 μIU/ml). Both TSH-oma and resistance to thyroid hormone syndrome were considered. TRH stimulating test was negative, whereas octreotide inhibition test showed a reduction in TSH by 30.8%. Furthermore, a large space-occupying lesion located at the nasopharynx was found by computed tomography and magnetic resonance imaging (MRI). A normal pituitary was visualized. Ectopic TSH-oma was preliminarily established. Using an endoscopic endonasal approach, the tumor was resected. Histological features and immunophenotypes were consistent with those of TSH-secreting tumor. The levels of both free thyroxine and TSH returned to normal ranges the day after surgery and remained within normal range for 48 months.
Although exceedingly rare, ectopic TSH-oma should be considered for patients with inappropriate secretion of TSH with hyperthyroidism and pituitary tumor undetectable by computed tomography and MRI. To our knowledge, this is the first case followed up more than 4 years. The characteristics and successful interventions summarized in this report provide a guideline for clinicians.
KeywordsEctopic TSH-secreting pituitary adenoma Resistance to thyroid hormone (RTH) TRH stimulating test Octreotide inhibition test Hyperthyroidism
TSH-secreting pituitary adenomas (TSH-omas) are an unusual disorder, accounting for ~2% of all pituitary tumors . 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.
Plasma thyroid hormone and TSH levels
PTU 300 mg/d
PTU 300 mg/d
PTU 300 mg/d
24 h post surgery
48 m post surgery
Comparison of five ectopic TSH-omas
Age of onset (y)
Age of diagnosis
Location of tumor
no recurrence at 2 months
recurrence at 10 months
no recurrence at 4 months
no recurrence at 3 months
no recurrence at 48 months
consisted of monomorphous cells with secretory granules of small thyrotroph-like cells
consisted of polymorphous cells with secretory granules
Octreotide inhibition test
TRH stimulating test
This patient was diagnosed as ectopic TSH-oma in November 2009. Similar to the other cases, the patient went to see the doctor for hyperthyroidism with diffuse goiter and atrial fibrillation; ophthalmopathy, pretibial myxedema, and periodic paralysis were not presented. Additionally, the previous four cases had a common specific symptom of airway obstruction resulting from space occupying effects. Nevertheless, it was not evident in this patient, leading to overlook of existence of tumor by both the patient and physicians.
With regard to the phylogenetics of ectopic pituitary adenoma, it is broadly accepted that the tumor is derived from the embryonic residues of pituitary cells along the path of migration of Rathke's pouch. The anterior pituitary primordium appears at the fourth week of embryogenesis. The pituitary then divides into sellar and pharyngeal parts in the eighth week. The craniopharyngeal canal allows for migration of the pituitary tissue into the sphenoid sinus/bone or nasopharynx. Nasopharyngeal and sphenoid sinus or sphenoid bone ectopic pituitary tissue can be fully functional, since pharyngeal pituitary tissue begins to produce hormones around the 17-18th week of gestation (about 8 weeks later than sellar pituitary function begins) . Landolt and co-workers found that 90 - 100% of adults had ectopic pituitary tissue in the sphenoid sinus/bone . The pharyngeal hypophysis released all six normal pituitary hormones (ACTH, TSH, PRL, LH, FSH, and GH) . It is postulated that the embryonic residues of pituitary cells produce tumor lesion, and synthesize pituitary hormones.
Of note, the first case received radioactive iodine treatment without prior measurement of the TSH level. Although hyperthyroidism was abrogated, the consequence was hypothyroidism with an increased level of TSH. This obscured the nature of the disease and complicated the diagnostic process. This was the only case that received radiation therapy for the thyroid prior to final diagnosis. Therefore, it was difficult to determine whether the tumor was a primary ectopic TSH-secreting tumor or resulted from radioiodine thyroid ablation-induced hypothyroidism. Remission of the latter could be achieved by administration of thyroid hormones. Indeed, invasive transformation of the tumor and high occurrence of invasive macroadenomas were described in patients with previous thyroid ablation by surgery or radioiodine. It resembled the occurrence of Nelson’s syndrome after adrenalectomy for Cushing’s disease.
Ectopic TSH-oma and pituitary TSH-secreting tumor in the sellar area cannot be differentiated by their biological characteristics. Both present high levels of serum FT3 and FT4, in addition to either normal or high level of TSH. The difference between these two tumor types is that the ectopic TSH-oma has a normal pituitary gland and sellar turcica. Nowadays, with high-resolution CT and MRI, large pituitary adenomas are easy to find; moreover, it is not difficult to detect micro-adenomas either [9, 10].
TSH-omas are generally benign tumors. However, transformation of TSH-oma into carcinoma with multiple metastases and loss of pituitary α-GSU has been reported . TSH-secreting carcinoma could also develop from previously non-functioning pituitary adenoma . All five cases of ectopic TSH-omas had characteristics of benign tumors. Although tumors of some cases invaded into adjacent tissues, none showed distant metastasis .
Morphological characteristics of tumor cells were inconsistent including unitary shape, irregular morphology, and multiple types of cells. Cells contained abundant granular cytoplasm and round or oval nuclei. Relatively large amounts of blood sinuses existed in the tumor. The adenoma consisted of monomorphous cells as visualized by electron microscopy. Numerous secretory granules were scattered across the cytoplasm or along the cell membrane . They were similar in size and shape of electron dense with a diameter of 60-120 . In comparison, the tumor cells of this case were pleomorphic, and the size of their electron dense granules was larger with a diameter of 100-200 nm, and were scattered or clustered in the cytoplasm.
Immunohistochemical examination is essential for studying the nature of the tumor cells and hormone secretion. Almost all neuroendocrine tumors have enhanced expression of chromogranin A, synaptophysin, and neuron-specific enolase [6, 19]. Therefore, these proteins have been used as biomarkers of neuroendocrine tumor. Except for the case reported by Collie, strong expression of various neuroendocrine biomarkers, including chromogranin A, synaptophysin, and neuron-specific enolase was confirmed. As for cell proliferation, the amount of Ki-67-positive cells was less than 2%, suggesting that cell proliferation of the ectopic TSH-oma was low, in agreement with what was known of TSH-oma in situ. The types of hormones secreted by ectopic TSH-oma were not identical (Table 2). Except for the second case, GH expression in the tumor tissues was detected. In addition, augmentation of the expression of TSH and GH was also described in vitro . However, the serum level of GH in the fourth patient was normal, inconsistent with biochemical changes and clinical manifestation in vivo [20, 21]. The mechanism remains unclear. It may be due to lesser secretion of secondary hormone or limited release into blood.
The therapeutic approach in all five cases was adenomectomy. The primary objectives of the surgical treatment were to remove the ectopic TSH-oma, to eliminate the excessive secretion of TSH, and to restore euthyroidism. The prerequisite was to reduce the level of thyroid hormone to ease thyrotoxicosis prior to adenomectomy. The most common strategy is to take either anti-thyroid drugs (methimazole 20-30 mg/d or propylthiouracil 200-300 mg/d) or somatostatin analogs (octreotide, 100 μg, s.c., bid or tid. Sandostatin®, Novartis Pharma Schweiz AG, Switzerland) as well as propranolol (80-120 mg/d orally). Obviously, somatostatin analogs should be preferred theoretically, and this has been borne out in practice. For example, the TSH level of the fourth case returned to normal one day post octreotide treatment (100 μg, ih, q8h). Meanwhile, the levels of FT3 and FT4 declined to normal in 7 days. In contrast, it was difficult to control TSH and thyroid function with anti-thyroid drugs. In this case, PTU (300 mg/d) could not reduce free thyroxine to normal levels (Table 1). TSH and free thyroxine levels were normal within a few days , even within 24 hr after surgery in our case study. Apparently, it is feasible to treat TSH-omas by in situ radiotherapy. However, this intervention was not applied to all five cases of ectopic TSH-omas [2–5].
Given that somatostatin (somatotropin release-inhibiting hormone, SRIH) receptor was expressed in TSH-omas [23, 24], somatostatin analogues have been used to treat TSH-oma in situ. Somatostatin analogues are potent in reducing TSH secretion. Long-acting somatostatin analogues, including octreotide LAR, lanreotide SR, and lanreotide autogel were preferred [9, 10, 25, 26]. These medicines decreased TSH and α-GSU secretion, and restored euthyroidism. Circulating thyroid hormone levels were normalized in more than 95% of patients, and pituitary tumor mass shrinkage occurred in approximately 40% of patients . Furthermore, the efficiency of the somatostatin analogue was observed in an ectopic TSH-oma patient .
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.
This work was supported by NIH grant HL87017 and partially by AHA award 14GRNT20130034. The authors thank Ms. Yvette Chin (a freelance writer and science editor, Memorial Sloan-Kettering Cancer Center, New York) for her superb English edition.
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