Failure of iodine uptake in microscopic pulmonary metastases after recombinant human thyroid-stimulating hormone stimulation

Abstract

Elevated thyroid stimulating hormone (TSH) is required when preparing for radioactive iodine therapy in patients with differentiated thyroid cancer. Recombinant human TSH (rhTSH: Thyrogen; Genzyme Corporation, Cambridge, MA) avoids hypothyroidism and has been commonly used in place of thyroid hormone withdrawal (THW) in this process. We describe a 31-year-old woman with sclerosing variant of papillary thyroid cancer with multiple lymph node metastases and elevated postoperative thyroglobulin suggesting the presence of distant metastases, who was found to have miliary pulmonary metastases on the posttherapy I-131 scan after THW, but not visible on the post therapy scan after rhTSH preparation.

Keywords

Hypothyroidism - radioiodine - recombinant human thyroid-stimulating hormone - thyrogen - thyroid cancer

Introduction

Prior to the availability of recombinant human thyroid-stimulating hormone (rhTSH), patients who needed radioactive iodine (RAI) therapy routinely underwent thyroid hormone withdrawal (THW) to become sufficiently hypothyroid before RAI therapy. rhTSH avoids the hypothyroid symptoms of THW, was approved in the United States by the Food and Drug Administration (FDA) for remnant ablation in 2007, and has been commonly used in preparation for RAI therapy. Currently, rhTSH is not approved by the FDA for the use in patients with metastatic or persistent disease but has been offered off-label to patients who may not tolerate THW and who are unable to mount TSH elevation such as patients with hypopituitarism. Although two retrospective studies showed comparable efficacy between rhTSH and THW in patients with distant metastases,[1],[2] iodine kinetics have been demonstrated to be different between rhTSH and THW.[3],[4],[5] We describe a patient with pulmonary military metastases that failed to take up iodine after131 I therapy prepared by rhTSH. The metastases were revealed on the posttherapy scan after131 I prepared by THW.

Case Report

A 31-year-old woman with a history of mesenchymal chondrosarcoma was found to have an FDG avid thyroid nodule on surveillance positron emission tomography-computed tomography (PET/CT). There was no evidence of distant metastases other than a few nonspecific lung nodules up to 4 mm on all cross-sectional imaging she underwent for the surveillance of chondrosarcoma. Additional evaluation with neck ultrasound and fine needle aspiration revealed papillary thyroid carcinoma. She underwent total thyroidectomy and left central and lateral modified neck dissection. Pathology revealed a 3 cm diffuse sclerosing variant of papillary thyroid cancer in the left lobe with lymphovascular invasion and minimal extrathyroidal extension. Seventeen of the resected 31 lymph nodes were positive for metastases, many with extranodal extension (TNM-T3N1bMx). Five weeks postoperatively in June 2014, thyroglobulin (Tg) was 18.1 μg/L on levothyroxine suppression. Because of a history of depression, the patient was prepared for RAI therapy by rhTSH.123 I scan [Figure 1a] and b] demonstrated focal uptake in the thyroid bed with no evidence of cervical or distant metastases and an uptake of 0.6%. The patient then received 150 mCi of131 I, a dose selected due to high-risk pathologic features and higher than expected postoperative Tg on levothyroxine suppression. Tg was stimulated to 133.8 μg/L on the day of RAI therapy 24 h after rhTSH stimulation, a level that is suggestive of distant metastases, with a TSH level of 103.84 mIU/L [Table 1].

Figure 1 Diagnostic ¹²³I whole body scan (a) and axial fused single-photon emission computed tomography/computed tomography (b) demonstrated focal uptake in the thyroid bed (arrow) with no evidence of cervical or distant metastases. Posttherapy ¹³¹I planar imaging (c) and axial fused single-photon emission computed tomography/computed tomography (d) demonstrated multiple foci of uptake in the neck compatible with nodal metastases (arrow)

Table 1 Thyroglobulin levels after recombinant human thyroid-stimulating hormone stimulation versus thyroid hormone withdrawal

However, posttherapy131 I imaging [Figure 1c] and [Figure 1d] demonstrated multiple areas of neck uptake consistent with cervical nodal metastases but no distant metastases. A follow-up neck ultrasound showed a few nonspecific nonenlarged cervical lymph nodes. Four months after RAI therapy, Tg was 18.6 μg/L on levothyroxine suppression, similar to the pretherapy level of 18.1 [Table 1]. Repeat CT and PET/CT for the surveillance of mesenchymal chondrosarcoma were unremarkable, demonstrating no evidence of metastases. Evaluation for heterophile antibodies against Tg was negative. Approximately 1 year after the initial RAI therapy, due to persistent although relatively stable Tg elevation, she underwent repeat RAI therapy prepared by THW in August 2015.

Pretherapy123 I scan [Figure 2] demonstrated subtle uptake in the neck with faint uptake in the lower thorax but no definitive distant metastatic disease. However Tg was stimulated to 495 μg/L with a concurrent TSH of 92 mIU/L, again suggesting the presence of distant metastases [Table 1]. The patient was treated with 100 mCi of131 I empirically for both therapeutic and diagnostic purposes. Posttherapy131 I scan [Figure 3] demonstrated diffuse bilateral pulmonary uptake in addition to multifocal uptake in the neck. A noncontrast chest CT performed soon after RAI therapy was again negative with no correlate to the diffuse pulmonary131 I uptake, suggestive of microscopic metastatic disease.

Figure 2 Approximately 1 year after initial radioactive iodine therapy, diagnostic ¹²³I anterior (a) and posterior (b) images demonstrated two subtle foci of uptake at the left base of neck with faint uptake in the lower thorax but no definitive distant metastatic disease

Figure 3 Posttherapy ¹³¹I whole body scan (a) and fused axial single-photon emission computed tomography-computed tomography through the thorax (b) demonstrated diffuse bilateral pulmonary uptake in addition to multifocal uptake in the neck. A noncontrast chest computed tomography performed at the time for further evaluation (c) demonstrated no correlate to the diffuse pulmonary ¹³¹I uptake

The patient's Tg levels have remained elevated but relatively stable, fluctuating mostly between 15 and 28 μg/L on TSH suppression (<0.1 mIU/L). The patient's last chest CT in November 2018 continued to show no evidence of macroscopic pulmonary metastases.

Discussion

Our case demonstrates a failure of iodine uptake in extensive microscopic pulmonary metastatic foci after rhTSH stimulation despite a higher dose of131 I compared to THW.

Although rhTSH aided RAI, therapy for remnant ablation has been found to be better tolerated and to result in noninferior clinical outcomes compared to THW in randomized controlled studies.[5],[6] Prospective studies using rhTSH for131 I therapy for metastatic disease are lacking. The two retrospective studies[1],[2] using rhTSH in patients with distant metastases showed similar outcomes, but both studies employed dosimetry to determine RAI dosing [Figure 2].

Several studies have demonstrated altered iodine kinetics following rhTSH compared to the hypothyroid phase after TWH.[3],[4],[5] With rhTSH,131 I effective half-life in the remnant was shown to be longer[4] and radiation dose to blood was lower.[5] However, studies by Pötzi et al.,[3] using dosimetry analyses and123 I, found rhTSH to be associated with lower iodine uptake and shorter median effective half-life in metastatic lesions. Impaired renal clearance during the hypothyroid phase after THW may be responsible for longer iodine retention with THW.[4] It has also been postulated that rhTSH's glycosylation pattern, which is distinct from endogenous pituitary TSH, might have led to different responses in iodine uptake because of variability in the TSH receptors on the tumor cells.[7]

Although progression of disease is a possible explanation for the discrepant uptake between rhTSH and TWH, the relatively stable Tg levels between the 1st and the 2nd RAI therapy suggest otherwise. The more elevated Tg after THW (495 μg/L) versus rhTSH (133.8 μg/L) does not imply disease progression. First, Tg measurement after rhTSH in our patient took place only 24 h after the final rhTSH injection because of physical isolation required after131 I therapy. The expected Tg level at 24 h after the final rhTSH dose is lower than the maximally stimulated Tg expected at 72 h[8]; second, stimulated Tg after rhTSH is known to be lower than stimulated Tg after THW.[9] The difference is thought to be due to more continuous and prolonged endogenous TSH stimulation in THW, leading to increased Tg synthesis and lower renal clearance rate in patients with hypothyroidism [Figure 3].[9]

Although military metastases were revealed on the post therapy scan after THW to explain the patient's chronically elevated Tg, our patient has continued to have persistent stable disease based on persistent but stably elevated Tg. It is unclear if a higher131 I dose might have resulted in a different clinical outcome.

Taïeb et al.[10] described a case similar to ours in which pulmonary micrometastases did not take up iodine after rhTSH stimulation but took up iodine consistently when131 I therapy was prepared by THW. Driedger and Kotowycz (reference) also documented two cases with metastases that failed to concentrate iodine after rhTSH stimulation but were able to concentrate iodine after THW in osseous and pulmonary metastases in both cases, as well as cervical lymph node metastases in one of the two cases.[7] Our case differs from prior reports in that the distant metastases were not apparent on cross-sectional imaging.

Although rhTSH avoids hypothyroid symptoms and is equally effective as THW for remnant ablation, prospective randomized control studies are lacking in patients with residual disease and distant metastases. rhTSH should be used cautiously in these situations. Our case adds to previous case reports, both in 2004,[7],[10] and serves as a reminder that THW-aided RAI therapy is preferred in patients with distant metastases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflict of Interest

There are no conflicts of interest.

Acknowledgments

We are grateful to the support of Randall Hawkins, MD, for his contribution in successfully bringing out this manuscript.

Financial support and sponsorship

Nil.

• References

• 1 Klubo-Gwiezdzinska J, Burman KD, Van Nostrand D, Mete M, Jonklaas J, Wartofsky L, et al. Radioiodine treatment of metastatic thyroid cancer: Relative efficacy and side effect profile of preparation by thyroid hormone withdrawal versus recombinant human thyrotropin. Thyroid 2012;22:310-7.
• 2 Tala H, Robbins R, Fagin JA, Larson SM, Tuttle RM. Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH. J Clin Endocrinol Metab 2011;96:2105-11.
• 3 Pötzi C, Moameni A, Karanikas G, Preitfellner J, Becherer A, Pirich C, et al. Comparison of iodine uptake in tumour and nontumour tissue under thyroid hormone deprivation and with recombinant human thyrotropin in thyroid cancer patients. Clin Endocrinol (Oxf) 2006;65:519-23.
• 4 Hänscheid H, Lassmann M, Luster M, Thomas SR, Pacini F, Ceccarelli C, et al. Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: Procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal. J Nucl Med 2006;47:648-54.
• 5 Pacini F, Ladenson PW, Schlumberger M, Driedger A, Luster M, Kloos RT, et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: Results of an international, randomized, controlled study. J Clin Endocrinol Metab 2006;91:926-32.
• 6 Schlumberger M, Catargi B, Borget I, Deandreis D, Zerdoud S, Bridji B, et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 2012;366:1663-73.
• 7 Driedger AA, Kotowycz N. Two cases of thyroid carcinoma that were not stimulated by recombinant human thyrotropin. J Clin Endocrinol Metab 2004;89:585-90.
• 8 Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, et al. Acomparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877-85.
• 9 Pacini F, Molinaro E, Lippi F, Castagna MG, Agate L, Ceccarelli C, et al. Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:5686-90.
• 10 Taïeb D, Jacob T, Zotian E, Mundler O. Lack of efficacy of recombinant human thyrotropin versus thyroid hormone withdrawal for radioiodine therapy imaging in a patient with differentiated thyroid carcinoma lung metastases. Thyroid 2004;14:465-7.

Publication History

Received: 05 April 2019

Accepted: 19 May 2019

Article published online:
19 April 2022