Thyrotropin (TSH)-secreting adenoma (TSH-oma) is a type of functional pituitary adenoma, which produces excessive amounts of TSH causing elevated levels of serum thyroid hormone. Also, it has a very rare occurrence and accounts for only 0.5 to 3% of all types of pituitary adenomas (1). The main manifestations of this disease are central hyperthyroidism and pituitary lesions. Most patients present with typical symptoms of hyperthyroidism, and inappropriate secretion of TSH which means elevated thyroid hormones with unsuppressed TSH levels. Further, pituitary macroadenomas usually result in visual field defects and vision loss. As Pit-1 lineage tumors, approximately 16% and 10% of the TSH-oma can co-secrete growth hormones (GH) and prolactin (PRL), respectively (2). Therefore, patients may also exhibit symptoms of gigantism, acromegaly, lactation, oligomenorrhea, etc. The first-line therapy for TSH-oma is transsphenoidal surgery (3). Further, somatostatin analogs can be used effectively to normalize the thyroid hormones, preoperatively (4). Adolescent-onset cases of TSH-oma are rare and have unknown potential differences between underage and adult TSH-oma patients. We presented the clinical features, treatments, and follow-ups of six adolescent-onset TSH-oma patients in our center along with reviewing 14 cases from the literature. Thus, we aimed to summarize the characteristics of adolescent-onset TSH-oma and gather some opinions about its management.

TSH-oma is extremely rare, especially in adolescent cases. Herein, we described six cases in our center and 14 cases retrieved from literature to summarize the characteristics of clinical manifestations and therapeutic outcomes in adolescent-onset TSH-oma patients. Of the 20 cases, 16 (80.0%) showed macroadenomas and four (20.0%) showed microadenomas, which was consistent with the overall 70–90% macroadenomas ratio summarized before (1). However, adolescent-onset patients may have more large pituitary tumors than adult patients (36.8% vs 9.3%) along with significantly higher baseline TSH, FT3, FT4, T3, and T4 levels ( Table 3 ). Both of these observations contribute to the therapeutic challenges seen in adolescent-onset patients. In the case of complications, five pure TSH-oma cases in our center showed normal height growth and puberty development and also the lipid level and bone turnover indexes. Arrhythmia and valvular diseases were seen in more than 30% of the TSH-oma cases at our center. Recently, a meta-analysis revealed that atrial fibrillation or heart failure happened in 11.1% of 535 adult TSH-oma cases (22). Another research found that TSH-oma can significantly induce left atrial enlargement and subclinical atrial fibrillation since excess thyroid hormones can increase the arrhythmogenic activity of the pulmonary veins, and increase the hemodynamic load (23). Thus, the potential cardiovascular complications caused by the TSH-oma may be more common than reported and should be taken seriously.

SSAs can normalize thyroid functions without increasing the TSH levels, and reduce the operative difficulties. Thus, it is generally applied when the tumor is large or invasive. Compared to the 90% (24) or 73–100% (1) remission rates reported in all age patients, the effectiveness of SSAs can be considered worse in adolescent patients considering that only four out of seven (57.1%) patients achieved biochemical remission. For intractable cases, combination medical therapy such as SSAs combined with dopamine analogs and (or) antithyroid drugs may work well. There is a need to be cautious while using antithyroid drugs alone preoperatively because it may increase TSH levels through feedback regulation (19).

SSAs bind with high affinity to SSTR2 and lower affinity to SSTR3 and SSTR5, making in vivo effects by activating these specific SSTR subtypes (25). It is suggested that SSAs may inhibit TSH secretion in all TSH-omas that express SSTR2 while the coexistence of SSTR5 can enhance the effectiveness of SSAs (26, 27). Thus, the difference in the expression levels of SSTR5 and SSTR2 in TSH-omas may explain or even predict the different outcomes of treatment with SSAs. However, since SSTR staining has not yet been deployed in our center, the data on its expression remain unavailable in our cases.

TSS is the first-line therapy for TSH-omas. In the 20 cases, seven out of 18 (38.9%) were in remission, three out of 18 (16.7%) didn’t relieve, while eight out of 18 (44.4%) relapsed. Two cases died from postoperative infection, probably due to failed primary therapies and limited surgical techniques used. The recurrences in adolescent-onset patients are more frequent than the overall 0–21.4% recurrence rates observed (28–31). Similarly, the cavernous sinus invasion and larger tumor size are related to the tendency of recurrence (28). Only three out of 14 (21.4%) macroadenoma patients attained remission after one TSS, while the remission rate in microadenoma patients was 100%. For relapsed cases, repeat surgeries, radiotherapies, and (or) SSAs were applied. Overall, relatively high occurrence rates highlight the importance of having multidisciplinary therapy and close follow-up in adolescent patients.

The results of IHC showed that a special case diagnosed as TSH-GH-PRL mixed adenoma was found to be negative for TSH staining. However, the normalization of his thyroid functions after TSS suggested correct clinical diagnosis, so the negative pathological result may be due to inappropriate tissue sampling. Also, the positive staining of GH and (or) PRL in pure TSH-oma patients was actually understandable because positive IHC staining did not necessarily mean the hypersecretion of hormones, such as silent pituitary adenoma (4). Ki-67 index of case 1 was approximately 3% with the tumor invading into the cavernous sinus and surrounding the left internal carotid. According to recent studies, Ki-67 is a cell proliferation-associated antigen. A higher Ki-67 index usually means more aggressive tumor behavior and more recurrence risk with 2.5–3% cut-off points for pituitary adenomas (32–35). The treatment for TSH-oma in the case of higher Ki-67 index was also more challenging, for example, in one case where the Ki-67 index was 11%, three TSSs had to be performed along with providing SSAs and RTs. However, whether the Ki-67 index is generally higher in adolescent patients or not is still unknown. Meanwhile, it is necessary to understand the genetic background of TSH-oma tumorigenesis in early-onset patients. Current research has found a very uncommon germ-line MEN1 and AIP mutation in familial cases (4) and some somatic mutations and copy number changes in sporadic cases (36). But no oncogenes or proto-oncogene mutations have been identified (4). However, these findings are very limited in clarifying the molecular mechanisms of TSH-oma and need further studies. Additionally, our study has some limitations. As a retrospective study, some data are missing causing a loss of information about the follow-up. The postoperative heart functions, thyroid ultrasonographic manifestations, and glucolipid metabolisms have not been followed up adequately. Also, some studies were published long ago; hence, the diagnosis and treatments may be non-standard. Moreover, the indiscoverable pituitary microadenomas may cause misdiagnosis of TSH-oma along with a statistical bias.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Peking Union Medical College Hospital. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

YMY wrote the manuscript and prepared figures and tables. YMY and JL collected the data. KD, LL, HJZ, XLL, XJB, LD, and YY diagnosed and provided treatments for the cases involved in this study. HJZ, LD, and YY designed the study and provided suggestions for the manuscript writing. All authors contributed to the article and approved the submitted version.

This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (CAMS-2016- I2M-1-002).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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