Differentiated Thyroid Cancer in Two Patients with Resistance to Thyroid Hormone

Abstract

Background:

Resistance to thyroid hormone (RTH) is a genetic disease characterized by a reduced responsiveness of the pituitary and peripheral target tissues to TH. We describe two patients with RTH in whom differentiated thyroid cancer was diagnosed.

Patient Findings:

In both patients, RTH was unequivocally diagnosed and both underwent thyroidectomy for multinodular goiter. In Patient 1, histology showed a papillary thyroid carcinoma pT2. Because serum thyrotropin (TSH) levels were elevated even while the patient was taking 150 μg daily of levothyroxine (LT₄), the patient was treated with ¹³¹I 100 mCi for ablation of the thyroid remnant without discontinuing his LT₄ therapy. We obtained a clinically adequate response by administering LT₄ 175 μg/day (2.18 μg/kg), but the serum TSH was persistently elevated on this dose. The patient was considered “free of disease” after 8 years of follow-up. In Patient 2, histology revealed a papillary microcarcinoma (0.6 cm). Diagnostic whole-body scan was performed while the patient was taking 100 μg/day LT₄, a time that his serum TSH was 38 μU/mL. Only a small remnant was revealed, so ¹³¹I remnant ablation was not performed. While taking LT₄ at a dose of 175 μg/day (3 μg/kg), the serum TSH was persistently high, serum TH levels were in the normal-high range, and he appeared to be clinically euthyroid. There has been no evidence of persistent or recurrent thyroid carcinoma in ultrasonography and thyroglobulin measurements that have been performed on a yearly basis for 3 years.

Conclusion:

Patients with thyroid carcinoma and RTH are a unique model of thyroid cancer in which follow-up likely occurs in the setting of constantly elevated serum TSH concentrations. The concern in these patients is that their persistent elevation of serum TSH may have an adverse effect on their thyroid cancer, and management choices in terms of the dose of LT₄ that provides the optimum lowering of serum TSH without toxicity are difficult, particularly in the situation wherein, as was the case with one of our patients, there is cardiac disease.

Introduction

T he syndrome of resistance to thyroid hormone (RTH), first described by Refetoff in 1967 (1), is characterized by a reduced responsiveness of target tissues to thyroid hormone (TH). As a consequence, higher doses of exogenous TH are required to produce the metabolic responses in peripheral tissues and the expected suppressive effect on the pituitary secretion of thyrotropin (TSH) (2). Therefore, patients with RTH have persistent elevation of circulating free thyroxine (FT₄) and free triiodothyronine (FT₃) associated with nonsuppressed TSH levels. RTH is caused in about 90% of cases by point mutations in the gene that encodes the β-isoform of the TH receptor, THRB.

Thyroid hormone receptors (TRs) belong to the superfamily of ligand-dependent transcription factors. TRs are encoded by THRA and THRB genes located on chromosomes 17 and chromosomes 3, respectively (3). As different mutations in the THRB gene can lead to RTH, the clinical presentation of patients is variable and dependent on the type of mutations, their location, levels of tissue expression of each TR isoform, and possibly the presence of compensatory mechanisms, other associated genetic variables or defects, and the effect of prior therapy (2). Overall, the clinical presentation of patients affected by RTH is characterized by goiter and variable combinations of hypothyroid and hyperthyroid signs and symptoms, reflecting the different degree of target tissue RTH actions. Although the majority of patients are asymptomatic (4), some may present with variable degree of severity, short stature, decreased weight, tachycardia, hearing loss, attention deficit hyperactivity disorders, decreased IQ, and dyslexia (5).

RTH has been described in association with Hashimoto's thyroiditis (6,7) and toxic multinodular goiter (MG); in the latter case, a papillary thyroid microcarcinoma was found after subtotal thyroidectomy (8). Here, we describe two patients with RTH in whom differentiated thyroid cancer (DTC) was diagnosed after total thyroidectomies were performed for MG. The presence of these two conditions in the same patient raises important questions regarding management. As only about three patients with RTH and thyroid cancer have been described in the literature (8 –10), we considered it worthwhile sharing our experience with these patients.

Methods

Molecular analysis of THRB gene

Informed consent to perform genetic testing was obtained.

Genomic DNA was isolated from peripheral blood samples using High Pure PCR Template Preparation Kits (Roche Diagnostic), quantified by spectrophotometer at 260 nm, and stored at −20°C until use.

Eight genomic DNA fragments (spanning from exon 3 to 10 of the THRB gene) were amplified using a set of specific primers, as previously described (11,12). PCR-amplified fragments were directly sequenced using BigDye Terminator Cycle Sequencing kit v3.1 (Applied Biosystems) and ABI 3100 Avant Genetic Analyzer (Applied Biosystems) according to manufacturer's instructions. The results were analyzed using the SeqScape v2.5 software package (Applied Biosystems). The THRB sequence reference was NC_000003 (13).

Patients

A 48-year-old Caucasian man was referred to Catholic University of Rome in March 1998 to investigate an episode of paroxysmal atrial fibrillation and presence of MG. The patient had family history of hyperthyroidism with inappropriate TSH secretion (patient's younger sister and his sister's daughter). At the time of presentation, the patient was not taking any drugs. His blood pressure was 120/75 mmHg, pulse rate was 92 bpm and regular, body temperature 36.9°C, weight 78 kg, and height 174 cm (body mass index: 25.8). Physical examination revealed an enlarged thyroid gland with palpable nodule in the left lobe and tremor of the extremities, but no proptosis. Renal and hepatic function tests, electrolytes, hemocoagulative parameters, and electrocardiography were normal. Creatine phosphokinase value was 70 U/L (normal value [NV]: 30–170), total cholesterol was 160 mg/dL (NV: 130–200), HDL cholesterol was 60 mg/dL (NV: >45), and SHBG was 90 nM (NV: 15–65).

Serum thyroid function tests showed elevated FT₃ and FT₄ with inappropriate secretion of TSH (FT₃: 5.3 pg/mL; FT₄: 25.8 pg/mL; TSH: 3.1 μU/mL). Anti-thyroglobulin (anti-Tg) and anti-thyroperoxidase (anti-TPO) antibodies (Ab) were negative. A TSH response after 500 μg i.v. thyroid releasing hormone (TRH) was present (peak 21.7 μU/mL at 60 minutes). A magnetic resonance imaging (MRI) did not detect the presence of a pituitary tumor. RTH was suspected based on TSH responsiveness to TRH, normal pituitary MRI, and family history. T₃ suppression test was not performed because of the patient's cardiac condition (atrial fibrillation). There were no mutations in the regions of the THRB that were analyzed. A thyroid ultrasound (US) confirmed MG (thyroid volume: 22.4 mL), with a 2.4-cm solid, hypoechogenic, dominant nodule on the left lobe, with incomplete halo sign and intense intranodular blood flow at Doppler examination. Given the nodule's morphological aspects, a fine-needle aspiration biopsy (FNAB) was performed. Cytological examination of FNAB showed “follicular proliferation.”

The patient underwent total thyroidectomy in May 1999 and histological examination revealed the presence of papillary carcinoma pT2 (TNM, 5th edition). Hence, the patient was started on levothyroxine (LT₄) therapy 150 μg/day, but normalization of serum TSH levels with doses of LT₄ as high as 175 μg/day could not be achieved. While taking 150 μg/day, thyroid function test values were TSH 78 μU/mL, FT₃ 2.1 pg/mL, and FT₄ 20 pg/mL. As TSH values were elevated even while the patient was taking LT₄, ¹³¹I radio remnant ablation (RRA) was performed in November 1999 without interruption of LT₄ therapy. At the time of RRA, while taking LT₄ therapy (150 μg/day), the TSH value was 82.1 μU/mL, Tg was 5.4 ng/mL, and a test for anti-Tg Abs was negative.

Posttreatment whole-body scan (WBS) after ¹³¹I-100 mCi showed only two normal thyroid remnants in the neck. LT₄ therapy was eventually adjusted to 175 μg/day (∼2.18 μg/kg), to obtain clinical euthyroidism without achieving TSH suppression. Since then the patient has undergone careful yearly follow-up with clinical, biochemical, and radiological evaluation, which to date excludes persistence or recurrence of disease. In particular, in October 2000, a diagnostic ¹³¹I WBS was repeated on LT₄, without evidence of pathological findings, and US of the cervical region performed every 2 years have excluded the presence of remnant tissue or lymph node abnormalities. Annual anti-Tg Ab tests have been negative. Yearly laboratory evaluations of TSH, FT₃, FT₄, and Tg are summarized in Table 1.

Table 1.

Free Triiodothyronine, Free Thyroxine, Thyrotropin, and Thyroglobulin Measurement Performed During Follow-Up of Patient 1 as Related to Levothyroxine Doses

Date	FT₃ (pg/mL) (NV: 2.3–4.2)	FT₄ (pg/mL) (NV: 8.5–15.5)	TSH (μU/mL) (NV: 0.35–2.8)	Tg (ng/mL, IRMA)	LT₄ therapy (μg/day)
June 2000	4.74	19	106	1	175 (2.18 μg/kg)
June 2001	1.6	20	54.6	0.1	162.5 (2.04 μg/kg)
March 2002	2.3	15	98.3	<0.1	162.5 (2.05 μg/kg)
May 2003	2.03	15.5	68.7	<0.1	162.5 (2.11 μg/kg)
April 2004	4.26	18	47.9	<0.1	162.5 (2.13 μg/kg)
September 2005	4.01	10.4	84	<0.1	162.5 (2.12 μg/kg)
September 2006	3.63	13.1	115	<0.1	162.5 (2.15 μg/kg)
October 2007	3.14	17.3	69	<0.1	175 (2.19 μg/kg)
December 2008	4.01	18.2	72.1	<0.1	175 (2.13 μg/kg)

FT₃, free triiodothyronine; FT₄, free thyroxine; IRMA: immunoradiometric assay; LT₄, levothyroxine; NV, normal value; Tg, thyroglobulin; TSH, thyrotropin.

Patient 2, a 63-year-old Caucasian man, came to our attention in July 2002 because of asthenia and MG. His medical history was unremarkable and he had no psychological abnormalities or neurological disturbance. His family history revealed atrial fibrillation (younger brother) and hyperthyroidism with inappropriate TSH secretion (daughter). At admission, his blood pressure was 130/80 mmHg, pulse rate was 80 bpm and regular, body temperature 36.8°C, weight 67 kg, and height 171 cm (body mass index: 22.9). Physical examination showed no signs or symptoms of hyperthyroidism including tremor. There was no proptosis. However, the thyroid gland was enlarged with bilateral nodules. Routine renal and hepatic function tests, hematological tests, and electrocardiography were normal. The serum creatine phosphokinase was 95 U/L (NV: 30–170). Serum free THs were elevated (FT₃: 4.9 pg/mL, FT₄: 21.0 pg/mL) in the presence of inappropriately elevated TSH level (3.4 μU/mL). Serum tests for anti-Tg Ab and anti-TPO Ab were negative. TRH stimulation test showed the presence of TSH response (peak 17.6 μU/mL at 60 minutes). An MRI of the pituitary was negative for tumor. RTH was suspected. Hence, the patient underwent testing for THRB, which showed a missense mutation in exon 10 at codon 453 (P453T; c.1357C>A). This mutation had been previously reported as being associated with RTH (13).

A thyroid US showed an enlarged gland (thyroid volume: 26 mL) with several hypoechoic solid nodules, the largest in the right lobe measuring about 4 cm with elevated intranodular flow at Doppler examination. An FNAB of the nodule showed “colloid nodule.” In February 2004, the patient underwent total thyroidectomy for symptoms of compression, dysphagia, and cough. Histology revealed a 6-mm papillary microcarcinoma pT1 (TNM, 6th edition). The patient was started on LT₄ therapy (100 μg/day) during which serum TSH remained elevated (TSH: 68 μU/mL, FT₃: 2 pg/mL; FT₄: 10.9 pg/mL). In March 2005, he underwent a diagnostic ¹³¹I WBS. LT₄ was not stopped for this procedure as his serum TSH was elevated (30.7 μU/mL), Tg was 5.04 ng/mL, and anti-Tg Ab was negative. The WBS revealed a small area of focal uptake. As the patient was considered at “very low risk” for an adverse clinical course of his thyroid cancer, ablative doses of radioactive iodine were not administered. LT₄ therapy was adjusted on the basis of the patient's clinical evaluation and free TH concentrations. Clinical euthyroidism was eventually achieved with an LT₄ dosage that was relatively high based on the patient's weight (∼3 μg/kg).

Since his thyroidectomy, the patient has had periodic follow-up with biochemical and US evaluations, during which a progressive reduction of serum Tg levels has occurred. He is now considered “free of disease.” In the most recent US exam, performed in December 2008, Tg values were undetectable and serum TSH was 34.5 μU/mL (Table 2).

Table 2.

Free Triiodothyronine, Free Thyroxine, Thyrotropin, and Thyroglobulin Measurement Performed During Patient 2 Follow-Up as Related to Levothyroxine Doses

Date	FT₃ (pg/mL) (NV: 2.3–4.2)	FT₄ (pg/mL) (NV: 8.5–15.5)	TSH (μU/mL) (NV: 0.35–2.8)	Tg (ng/mL, IRMA)	LT₄ therapy (μg/day)
April 2004	2.0	10.9	78	5.2	100 (1.72 μg/kg)
June 2004	2.8	15.4	59.3	6.2	125 (2.15 μg/kg)
September 2004	3.0	20.1	36.0	5.1	150 (2.58 μg/kg)
March 2005	3.1	16.2	30.7	2.8	162.5 (2.80 μg/kg)
June 2006	2.4	16.2	21.5	3.01	162.5 (2.83 μg/kg)
December 2007	2.8	16.9	28.3	<0.1	175 (3.01 μg/kg)
December 2008	3.1	15.8	34.5	<0.1	175 (2.9 μg/kg)

It is important to underline that in both patients, despite normal-high serum TH concentrations, TSH remained elevated as shown in Tables 1 and 2. In an attempt to reduce TSH values, we tried a further increase of LT₄ to 200 μg/day in Patient 1 and to 187.5 μg/day in Patient 2. In both cases, after a short course with these dosages the sudden occurrence of clear symptoms of hyperthyroidism (arrhythmia in the former and tachycardia, insomnia, and anxiety in the latter) suggested the need for a quick reduction of LT₄ to the best tolerated dose. We were not able to check TSH values during these short high-dose treatments.

Discussion

RTH is a rare condition that has been described in about 2000 patients since the first publication by Refetoff in 1967 (14). Several reports have documented the concomitant presence of RTH and other endocrine diseases. Clinical features of a family showing RTH associated with chronic thyroiditis have been described by Fukata et al. in 2005 (7) and similarly by Sato and Sakai in 2006 (6). RTH has been reported in patients with primary hyperparathyroidism (15). Surprisingly, only about three cases of papillary thyroid carcinoma and RTH have been described in the literature (8 –10).

RTH is caused in about 90% of cases by point mutations in the THRB gene that encodes TRβ, but in some families with RTH no mutations of THRB or THRA genes have been detected (16). This condition, noted in about 10% of cases of RTH, is named “non-TR-RTH” and is thought to be associated with mutations of other cofactors. Patient 1 had negative molecular analysis for THRB. This patient probably falls into the 10% of non-TR-RTH, because molecular studies performed on 100% of codificant gene sequences, comprising eight genomic DNA fragments spanning from exon 3 to exon 10 of the THRB gene, were negative.

Our two cases, describing the concomitant presence of RTH and DTC, raise the question of whether patients with RTH are at an increased risk for thyroid cancer and whether those who develop thyroid cancer are likely to have a more aggressive course because of the difficulty in obtaining suppressed serum TSH concentrations or even serum TSH concentrations that are within the normal range.

TSH represents the most important thyroid growth factor, even if its role in thyroid carcinogenesis has been not well established. In experimental models, TRβ knockin mutant mice showed a significant increase in morbidity for spontaneous thyroid carcinoma compared with wild-type (17), and in TRβ knockin mutant mice with thyroid cancer, gene profiles analysis indicated activation of TSH-mediated signaling pathways (18). Based on the above preclinical evidence and the features of RTH, characterized by prolonged TSH stimulation and the difficulty in suppressing TSH levels, it might be expected that patients with RTH would have an increased risk of developing thyroid cancer, and when they do get thyroid cancer, they would have a more adverse course than the patients without RTH. Whether or not this is the case is not clear and the available information is limited to a few case reports.

Notably, the same pathophysiological features that may pose challenges to the patient's clinical management can make postsurgical management simpler. Tg measurements and WBS can be obtained at any time, without the need for interruption of LT₄ and without the use of recombinant TSH. Further, elevated TSH levels are generally desired in patients with prior DTC, as TSH stimulation improves sensitivity of Tg values without decreasing its specificity. These procedures are generally performed when TSH levels are higher than 25 μU/mL to stimulate adequate ¹³¹I uptake and Tg release from thyroid cells (19), and such condition is generally obtained by interruption of LT₄ therapy. In our patients, at the time of RRA, an adequate degree of TSH elevation (82.1 μU/mL for Patient 1 and 30.7 μU/mL for Patient 2) was obtained without LT₄ withdrawal, and in both cases these TSH levels, despite substitutive therapy, were more similar to the postoperative than preoperative values. Given that these patients are resistant to TH, it is clear that after surgery the LT₄ dose required to maintain a euthyroid-like state requires that there be an increase in the LT₄ dose to about 3 μg/kg per day.

Although in theory it may be possible to obtain an adequate degree of TSH suppression by increasing the dose of LT₄, in practice it is not feasible because such status can be achieved only at the cost of iatrogenic hyperthyroidism (such as arrhythmias and osteoporosis). On theoretical grounds, a case could be made for using T₃ as well as T₄ in patients with RTH and thyroid cancer, but it would be difficult to perform studies to determine whether this is rational considering the relatively small number of patients with concomitant RTH and thyroid cancer.

In our opinion, the therapeutic management of these patients should be done by following the clinical status of these patients and mimicking as much as possible the preoperative hormonal pattern for serum T₄ and T₃ even if optimal TSH suppression cannot be achieved. In our patients, the effort to further increase the LT₄ dose to suppress TSH levels caused symptoms of hyperthyroidism, mainly on the cardiovascular system. The balance obtained in our patients represents a “compromise” between the clinical wellbeing and biochemical features, supported by the consideration of an overall low neoplastic risk profile.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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