Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH), and its more common form, termed RTHβ, is caused by mutations in the thyroid hormone receptor beta (THRB) gene (Pappa and Refetoff, 2021). Surveys of 80,884 and 74,992 newborns using thyroid stimulating hormone (TSH) and thyroxine (T₄) measurements identified 2 and 4 infants with THRB gene mutations, indicating a prevalence of 1 in 40,000 and 1 in 18,750 live births, respectively (Lafranchi et al., 2003; Vela et al., 2019).

RTHβ is typically characterized by elevated thyroid hormone levels and concentrations of TSH either within the normal range or mildly elevated. The clinical phenotypes of RTHβ can be highly variable and include thyroid goiter, tachycardia, and abnormal neuronal development (Ortiga-Carvalho et al., 2014).

Several studies have demonstrated that thyroid hormone receptors (TRs) are involved in human cancer (González-Sancho et al., 2003). The reduced expression of TRs, caused by hypermethylation or deletion of TR genes, found in human cancers suggests that TRs could function as tumor suppressors (Kim and Cheng, 2013). A close association between somatic mutations of TRs and human cancers further supports the notion that the loss of normal TR functioning could lead to uncontrolled growth and loss of cell differentiation (Kim and Cheng, 2013).

In the present case report, two female Chinese patients with RTHβ and papillary thyroid carcinoma (PTC) are described. Furthermore, we conduct a literature review of patients with PTC coexisting with RTHβ, and we especially discuss the follow-up of TSH suppression therapy after surgery in this rare manifestation of PTC.

Since Taniyama et al. reported the first case of RTHβ coexisting with PTC in 2001, 17 cases of this rare disease have been reported, listed in Table 3. As a special type of PTC, the population characteristics of patients with this disease are similar to those of patients with classical PTC. For example, it occurs in all ages from 9 to 63, and 88% of them are adults, which is consistent with the much lower incidence of PTC in children than in adults. The ratio of males to females among patients with RTHβ coexisting with PTC is 1:3.25, which is similar to the ratio of males to females (approximately 1:4.39) with PTC (LeClair et al., 2021).

Usually, PTC in children and adolescents strongly tends to be multifocal and aggressive and easily invades outside the thyroid capsule, directly involving the recurrent laryngeal nerve, trachea, blood vessels and esophagus. Pediatric papillary thyroid carcinoma has a higher probability of lymph node metastasis and distant metastasis at the time of diagnosis, reaching up to 40%–80% (Piciu et al., 2012; Almosallam et al., 2020). In our literature review of 17 cases, two were children. Consistent with the findings of pediatric PTC, both had bilateral and multifocal thyroid cancer, and one had central lymph node metastases at the time of diagnosis (Ramos-Prol et al., 2013; Xing et al., 2017).

Among the 17 patients with RTHβ and PTC, two patients were diagnosed with RTHβ due to a refractory increase in TSH after total thyroidectomy, but the sizes, number, and lymph node metastasis of the thyroid tumors were not described. After excluding these two cases, 11 of the remaining 15 patients had papillary thyroid microcarcinoma (PTMC), 4 patients had lymph node metastases at diagnosis, and 1 patient had lymph node metastases 4 years after surgery; thus, the proportion of lymph node metastases was 33.3%. Postoperative risk of recurrence assessment showed that 13 cases were at low risk, 1 case was at intermediate risk, and the risk of the last case was not available. However, no distant metastases were reported.

Of the 15 cases, histopathologic variants of thyroid carcinoma associated with more unfavorable outcomes (e.g., tall cell, columnar cell, and hobnail variants of PTC) were not reported, and more favorable outcomes, such as a follicular variant of PTC, were found in 2 cases. BRAF testing was performed in only 5 of the 15 patients, and the BRAF ^V600E mutation was found in 4 of those 5 patients (80%). Other molecular markers (including THRB, N-RAS, H-RAS, and TERT) were detected in only 1 patient, but no mutations were found.

A challenging issue in patients with RTHβ and PTC is the determination of the optimal surgical treatment strategies for the tumors. Table 3 shows that 7 of the 15 patients (47%) had bilateral and multifocal PTC. The review of the literature revealed that 16 of the 17 patients underwent total thyroidectomy; among them, only 1 patient developed central lymph node metastasis. The ATA guidelines state that total thyroidectomy and central lymph node dissection can help prevent tumor persistence and recurrence in patients with differentiated thyroid cancer (DTC) (Haugen et al., 2015). Table 3 shows that 10 patients who had no lymph node metastases at the time of diagnosis did not undergo prophylactic central lymph node dissection. Among them, 9 adult patients had no recurrence or metastasis, whereas one 19-year-old adolescent girl developed central lymph node metastasis after total thyroidectomy. Therefore, prophylactic central lymph node dissection would be recommended in adolescents with this rare disease. However, for adults, it is not yet clear if it is necessary to perform prophylactic central lymph node dissection.

Another issue for patients with RTHβ and PTC is determining whether to implement RAI therapy after total thyroidectomy. The ATA guidelines indicate that ¹³¹I adjuvant therapy can effectively improve overall survival (OS) and disease-free survival (DFS) in DTC patients with a high risk of recurrence. For intermediate-risk patients, the overall benefit of ¹³¹I adjuvant therapy is still controversial, and low-risk patients do not exhibit significantly improved OS or DFS (Haugen et al., 2015). Among the 17 patients, one child with intermediate risk received RAI, and one adult with intermediate risk did not. No recurrence or lymph node metastasis was found in the 2 patients during the follow-up period. However, due to the small number of intermediate-risk cases, whether intermediate-risk patients need RAI therapy is unclear. All 13 patients at low risk did not have tumor recurrence or lymph node metastasis during follow-up, regardless of whether they received radioiodine therapy.

Another challenging issue in patients with RTHβ and PTC is TSH suppression therapy. Usually, the dose of LT₄ in TSH suppression therapy for classical PTC is between 1.5 and 2.5 μg/kg/day, but it is difficult to suppress TSH below the upper limit of the normal reference range in patients with RTHβ and PTC, even with very large doses of LT₄ (Table 3). Four patients were treated with triiodothyronine or thyroid tablets (a mixture of T₄ and T₃) to assist TSH suppression, but their cardiac side effects were difficult to overcome. It was demonstrated that 3,5,3’ triiodothyroacetic acid (TRIAC) has a higher affinity for TRβ1 than T₃, which may suppress TSH without causing as severe a peripheral tissue effect. LT₄ combined with TRIAC was used in 1 of the 17 cases (Ramos-Prol et al., 2013), and TSH was well inhibited without cardiac side effects (Beck-Peccoz et al., 1983; Salmela et al., 1988). Although bromocriptine also had a suppressive effect on serum TSH, the inhibition did not appear to be significant in our patient. The safe range at which serum TSH levels should be controlled to not only prevent the recurrence of PTC but also avoid the probable occurrence of TSH tumors caused by long-term high TSH levels requires further study.

Confusingly, although a very large dose of LT₄ was administered, the serum T₃ and T₄ concentrations in the patients with RTHβ and PTC were disproportionately elevated or within the normal reference range (Table 3). LT₄ is the same as the thyroxine naturally secreted by the thyroid gland. Usually, the intake of large doses of LT₄ can cause an increase in serum thyroxine levels. This prompted us to think about potential alterations in thyroxine metabolism in patients with RTHβ and PTC after total thyroidectomy, such as a shortened half-life of thyroxine or abnormal transformation from thyroxine to the other thyroid metabolites, but these hypotheses require further study.

The concomitant presence of RTHβ and PTC raises the question of whether patients with RTHβ are at an increased risk for thyroid cancer. The precise contribution of RTHβ to thyroid tumorigenesis is not fully understood, but there is evidence to suggest that it may play a contributory role. First, it has been postulated that TSH is a growth factor, and the continuous stimulation of TSH can promote the development of nodules and thyroid cancer. Second, the TRβ mutation itself can also be somewhat pro-oncogenic (Kim et al., 2010). The levels of TRβ mRNA were significantly higher in normal and hyperplastic thyroid tissues than in neoplastic thyroid tissues (Wallin et al., 1992). Sequencing of TRβ1 and TRα1 cDNAs cloned from 16 papillary thyroid cancers revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls (Puzianowska-Kuznicka et al., 2002). In addition, mice that harbored a knock-in mutant TRβ gene (TRβ PV mutant) spontaneously developed thyroid cancer and distant metastasis similar to human follicular thyroid cancer (Furuya et al., 2006). Further study indicated that the more aggressive thyroid tumor progression in Thrb ^PV/PV mice was due not only to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. This identifies a novel mechanism by which a mutated TRβ evolves with an oncogenic advantage to promote thyroid carcinogenesis (Lu and Cheng, 2011). Third, the BRAF ^V600E mutation, identified in between 29 and 83% of PTC cases (Trovisco et al., 2007; Xing et al., 2017) and considered an early or initiating event in PTC, is highly expressed in patients with RTH coexisting with PTC who have received BRAF testing (Table 3). Whether the BRAF ^V600E mutation and RTHβ are jointly involved in the occurrence of PTC deserves further study.

In conclusion, our literature review of the 17 cases of RTHβ coexisting with PTC revealed that patients with this rare disease seem to have a good prognosis. However, due to the limited number of patients and the short-term follow-up for many of them, the recurrence rate of this rare disease may be higher than that reported here. Unsuppressed or increased serum TSH levels in the background of RTHβ are associated with an increased risk of PTC recurrence and metastasis. Therefore, total thyroidectomy is recommended for adult patients, and total thyroidectomy and prophylactic central lymph node dissection are recommended for children and adolescents. Close follow-up of the current cases is needed, and benign or malignant thyroid nodules should be evaluated during the follow-up of patients with RTHβ.