British Journal of Radiology (2007) 80, e38-e43
© 2007 British Institute of Radiology
doi: 10.1259/bjr/52032397
Differentiated thyroid cancer presenting with thyrotoxicosis due to functioning metastases
M Haq, MRCP
1
S Hyer, FRCP
2
G Flux, PhD
3
G Cook, FRCR
4 and
C Harmer, FRCR
1
1 Thyroid Unit, 2 Medical Physics and 3 Nuclear Medicine, Royal Marsden Hospital, Sutton, Surrey, SM2 5PT and 4 Department of Endocrinology, St Helier's Hospital, Surrey, SW5 1AA, UK
Correspondence: Dr M Haq, Senior Clinical Research Fellow, Royal Marsden Hospital, Downs Road, Sutton, London, SM2 5PT, UK. E-mail: masudhaq{at}hotmail.com
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Abstract
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Thyrotoxicosis due to functioning metastases in differentiated thyroid cancer (DTC) is exceedingly rare. We report a case of follicular carcinoma in a 54-year-old manager, who presented with thyrotoxicosis, shortness of breath and lung metastases. Transbronchial biopsy of a pulmonary nodule demonstrated normal thyroid. This was interpreted as representing very well-differentiated thyroid cancer. CT, 131I whole-body imaging and dosimetry is described following total thyroidectomy and repeated radioiodine administration (cumulative activity 34.6 GBq). The patient became asymptomatic with almost complete eradication of the pulmonary metastases. Potential complications of thyroid storm, bone marrow failure and pulmonary fibrosis following radioiodine are discussed, together with methods to minimise these risks.
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Introduction
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The association of differentiated thyroid cancer (DTC) with thyrotoxicosis is uncommon. It may be discovered as an incidental histological finding after thyroidectomy for Graves' disease, toxic multinodular goitre or autonomous functioning nodule [1, 2]. However, functioning metastases from thyroid cancer causing thyrotoxicosis is a rare entity with only 68 cases reported in the literature [1, 3–13]. Radioiodine post-thyroidectomy is the treatment of choice, but since accentuation of hyperthyroidism may occur following administration of 131I, pre-treatment with an anti-thyroid drug is necessary to avoid the potentially lethal complication of thyroid storm.
Dosimetry can assist in treatment planning. Benua introduced the concept of 131I administration constrained by a maximum blood dose (BD) of 2 Gy, with a recommended whole-body retention at 48 h no greater than 4.44 GBq (120 mCi) in the absence of pulmonary metastases, or 2.96 GBq (80 mCi) if pulmonary metastases are present [14]. The use of whole-body dose (WBD) to predict BD with a maximum safe limit remaining at 2 Gy has been used as a substitute as it is relatively simple to perform with a high degree of accuracy.
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Case report
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A 54-year-old manager presented to his general practitioner in December 2001 with increasing shortness of breath, palpitations and profuse sweating. He was clinically thyrotoxic with no obvious thyroid mass or dysthyroid eye disease. At the age of 21 years, an adenoma of the left thyroid lobe had been excised. Thyroid function tests revealed a suppressed thyroid-stimulating hormone (TSH) of <0.05 mU l–1 (normal range: 0.49–4.67 mU l–1), elevated free thyroxine (FT4) of 45.7 pmol l–1 (9.1–23.8 pmol l–1) and serum thyroglobulin (Tg) of 1500 ug l–1. TSH receptor antibody levels were not known. Full blood count and serum biochemistry were normal. Carbimazole 40 mg daily and propanolol 40 mg twice daily were commenced.
To investigate the breathlessness a chest radiograph was performed, which unexpectedly displayed widespread cannon-ball metastases from an unknown primary tumour. Transbronchial biopsy identified normal follicular thyroid tissue (Figure 1
). CT without contrast demonstrated a 4.5x3 cm lobulated heterogeneous swelling of the left thyroid lobe with tracheal deviation, suspicious lymph nodes on the contralateral side of the neck and widespread pulmonary metastases, the largest being 2.6 cm in diameter (Figure 2a).
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Figure 1. Transbronchial biopsy displaying fragments of follicular thyroid tissue: a thin layer of follicular epithelial cells surrounds central colloid (magnification x 62.5).
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Figure 2. (a) Computerised tomography of chest at diagnosis (December 2001) demonstrating widespread cannonball metastases in both lungs up to 2.6 cm in diameter. (b) Following repeated 131I therapy (May 2005), only a few small rounded opacities are visible.
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Total thyroidectomy (January 2002) with right-sided selective lymph node dissection of the deep cervical chain was performed. Histology revealed what was thought to be a left-sided encapsulated follicular adenoma with degenerative change and microcalcification, arising in a multinodular goitre. No obvious capsular or vascular invasion was seen, features that are usually consistent with follicular carcinoma. Lymph nodes were free of tumour and there was no evidence of Graves' disease. An incidental 2 mm papillary microcarcinoma was identified in the left lobe. Review from the original adenoma identified another incidental 2 mm focus of papillary cancer, with surrounding thyroid multinodularity. Review of the transbronchial biopsy revealed follicular thyroid tissue, but no features of papillary carcinoma. These findings were interpreted as metastatic, very well-differentiated, follicular thyroid carcinoma, Stage pT3aN0M1 plus papillary thyroid carcinoma, Stage pT1bN0M0 (TNM classification, 5th edition, 1997).
Post-thyroidectomy, the patient remained thyrotoxic with FT4 41.1 pmol l–1 and TSH 0.05 mU l–1 suggesting functioning metastases (Table 1). Anti-thyroid medication was therefore continued with plans for radioiodine ablation, but several concerns remained. Would adequate iodine uptake occur while the TSH was suppressed? As an alternative, should recombinant TSH (rhTSH) be administered to stimulate TSH levels thereby increasing iodine uptake? Would radioiodine precipitate thyroid storm and what precautions were necessary?
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Table 1. Changes in thyroid function and serum thyroglobulin following surgery and radioiodine administration: a gradual improvement from thyrotoxicosis requiring antithyroids, to euthyroidism and eventual hypothyroidism requiring thyroxine replacement, was observed. Serum thyroglobulin levels became undetectable in the absence of antithyroglobulin antibodies following repeated radioiodine therapy
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In March 2002, radioiodine ablation with 3 GBq 131I was immediately preceded by an increase in carbimazole to 30 mg twice daily and continuation of propanolol 40 mg twice daily to avoid thyroid crisis. Administration of rhTSH was avoided. Despite the potential risks, no side effects were experienced. Whole-body and blood dosimetry was performed during admission [15–17] with WBD 1.48 Gy and BD 0.04 Gy (Table 2). A high retention of radioiodine of 80% was observed at 48 h, with post-ablation 131I whole-body scan (WBS) revealing minimal uptake in the neck, intense uptake throughout both lung fields and faint uptake in the right pelvis (Figure 3a). Subsequent 99mTc MDP bone scintigraphy did not reveal bone metastases.
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Table 2. Dosimetry results following successive radioiodine treatment. Whole-body dose and blood dose were both within a 2 Gy limit. The maximal 48 h biological retention for 131I was 3 GBq, the upper limit recommended to avoid pulmonary fibrosis in patients with diffuse lung metastases. Maximum doses received by lung metastases determined by voxel-based MIRD dosimetry are also illustrated
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Figure 3. (a) Post-ablation 131I whole-body scan (March 2002) demonstrates widespread intense irregular uptake in both lungs with further small focal abnormalities in the lower neck, mediastinum and pelvis. (b) Whole-body scan following repeated 131I therapy (April 2004) no longer demonstrates any significant lung uptake, but pelvic uptake has become more obvious. Physiological uptake in the stomach, right colon and bladder can be seen.
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1 month post-ablation (February 2002), thyroid function improved with FT3 (free triiodothyronine) levels falling from 7.9 pmol l–1 to 5.4 pmol l–1 (normal range: 2.51–5.3 pmol l–1) in association with a persistently suppressed TSH of 0.03 mU l–1. Propanolol was therefore discontinued and carbimazole reduced to 20 mg daily. In July 2002, 4.0 GBq 131I was administered based on a predicted 2 Gy WBD. Carbimazole was continued throughout the admission. Quantitative serial SPECT (single photon emission computerised tomography) scans were acquired to determine the absorbed dose [18, 19] to the largest of the lung metastases in addition to whole-body and blood dosimetry measurements. Maximum dose received by lung metastases was 241 Gy (Figure 4). In August 2002, both FT4 and FT3 levels had returned to normal, which permitted medication to be discontinued, although TSH levels remained suppressed.
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Figure 4. Absorbed dose map(transaxial view) through both lungs demonstrating absorbed dose distribution following 4.0 GBq 131I (July 2002). Superimposed isodose contours represent areas receiving similar absorbed dose. The colour scale depicts variation in dose with a maximum of 241 Gy.
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Due to persistent lung uptake, further treatment was planned. In November 2002, 5.4 GBq 131I was preceded by 0.9 mg rhTSH im administered on two successive days. This was felt to be safe, as free thyroid hormone levels had reverted to normal. This stimulated the suppressed TSH and promoted iodine uptake. No side effects were experienced. TSH levels rose above 100 mU l–1 with good localisation of iodine into pulmonary metastases. Over the next two months, TSH levels gradually climbed into the euthyroid (TSH 2.5 mU l–1, December 2002) then hypothyroid range (TSH 17.4 mU l–1, FT4 6.9 pmol l–1, Tg 342 ug l–1 January 2003), which necessitated commencement of liothyronine 20 mcg bd.
A fourth administration of 131I occurred in April 2003 with 5.7 GBq after a combination of liothyronine withdrawal for two weeks and rhTSH. This measure was employed to ensure maximal iodine uptake. Lung metastases continued to concentrate iodine with Tg falling to 139 ug l–1 (in the absence of anti-Tg antibodies). Liothyronine was replaced with 200 mcg thyroxine to maintain TSH suppression to <0.1 mU l–1. Following thyroxine withdrawal and rhTSH, two further therapies were given in October 2003 and April 2004. The latter 131I WBS no longer demonstrated significant lung uptake (Figure 3b
). A small focus of uptake which was now more intense was identified in the right-side of the pelvis and suggested osseous metastasis, but stimulated Tg was undetectable. Follow-up unenhanced CT confirmed almost complete eradication of the lung metastases (Figure 2b); pelvic bone windows reported a right-sided sacral cyst at the site of iodine uptake. Subsequent 18FDG (fluorodeoxyglucose) PET-CT following rhTSH confirmed faint tracer uptake in the right sacrum suggestive of osseous metastasis but no lung uptake. A further 5.4 GBq 131I (May 2005) has been administered with WBS demonstrating faint pelvic uptake only. Metastasectomy and external beam radiotherapy are now being considered.
The patient remains asymptomatic apart from mild xerostomia secondary to radiation-induced damage to the salivary glands. He denies pelvic pain or sciatica. Serial lung function has remained stable with dyspnoea having completely resolved, permitting him to cycle several miles regularly. A modest transient lymphopenia occurred following each 131I administration, but no long-term haematological toxicity has been observed despite a cumulative activity of 34.6 GBq. At the last follow-up (January 2006), serum Tg remained undetectable.
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Discussion
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DTC is seldom associated with thyrotoxicosis, but may occur in four different settings. The most frequent observation is an incidental papillary microcarcinoma, discovered on histopathology in patients who have undergone thyroidectomy for Graves' disease, toxic multinodular goitre, or an autonomous functioning thyroid nodule [1, 2]; overall reported incidence is 3–10% [20]. Thyrotoxicosis may also be caused by functioning extra-thyroidal tissue in ovarian teratoma (struma ovarii) and trophoblastic tumours, which may be either a benign hydatiform mole or malignant choriocarcinoma [21, 22]. Excess release of thyroid hormone can rarely be precipitated by infiltration of the thyroid by metastases, usually originating from a primary carcinoma of the breast or pancreas, or involvement of the gland from malignant lymphoma [23].
Thyrotoxicosis occurring in DTC due to autonomously functioning metastases remains exceedingly rare, with 68 reported cases [1, 3–13, 24]. The majority had concomitant follicular carcinoma and functioning metastases in bone or lung at presentation, but a few developed hyperthyroidism up to 15 years after the cancer diagnosis [1, 9]. Metastases from follicular carcinoma may be so well-differentiated as to be indistinguishable from normal thyroid. This is the source of the picturesque, but deservedly obsolete designation "benign metastasing goitre". The association of papillary thyroid carcinoma and functioning metastases has only been reported in five cases; three cases with mixed papillary and follicular carcinoma [9] and two with pure papillary thyroid carcinoma [3, 4].
Clinical presentation is similar to any patient with thyrotoxicosis; but metastatic disease is present and dysthyroid eye disease will be absent. Age at diagnosis, gender distribution and cause-specific survival (CSS) remains comparable with DTC presenting with functioning or non-functioning metastases (CSS at 10 years: 59% in patients presenting with functioning metastases vs 55% with non-functioning metastases) [1, 9, 10]. Over half of patients develop isolated T3 toxicosis with normal FT4 levels. Therefore, all suspected cases require measurement of both FT4 and FT3.
All of the following criteria must be fulfilled in order to make a diagnosis of functioning metastases [10]:
- failure of thyrotoxicosis to resolve after thyroidectomy
- exclusion of hyperfunctioning diffuse or nodular thyroid tissue
- low iodine uptake into the thyroid
- iodine uptake by metastases
Our patient met all the above. Failure of TSH to rise after thyroid hormone withdrawal in preparation for 131I treatment following thyroidectomy should prompt investigation of the pituitary–thyroid axis [25]. In patients with normal pituitary function, low TSH levels may herald the presence of functioning metastases.
The mechanism by which some metastases are functional whereas others are not remains unclear. In a number of cases the presence of thyroid stimulating immunoglobulins (TSIs), previously known as long-acting thyroid stimulators (LATS), may serve to stimulate TSH receptors promoting tumour growth, synthesis of thyroid hormone and development of hyperthyroidism. Alternatively, other cases may result from large tumour burden functioning autonomously.
The management of DTC with functioning metastases is similar to patients with non-functioning metastases, but several issues require special attention. High dose anti-thyroid drugs (carbimazole 60 mg daily or propylthiouracil 600 mg daily) are required to treat hyperthyroidism as metastatic disease is often widespread and standard doses often prove inadequate. Beta-blockade with propanolol 40 mg every 8 h alleviates sweating and palpitations. Patients refractory to these measures often have detectable TSIs. Under such circumstances, high-dose glucocorticoids prove beneficial as they reduce the synthesis of TSIs and further stimulation of thyroid hormone production.
Total or near-total thyroidectomy is essential to permit iodine uptake by metastases during 131I therapy. Lugol's iodide prior to thyroidectomy should be omitted. Normally, administration of iodide leads to transient inhibition of organic iodination and thyroid hormone synthesis in the euthyroid individual (Wolff–Chaikoff effect). However, in the presence of hyperfunctioning metastases after initial exposure to iodide, more efficient organification resumes following an adaptive mechanism that manifests in a delayed deterioration of thyroid symptoms.
Dosimetry permits administration of 131I within safe limits. Benua et al [14] recommended a BD no greater than 2 Gy from any single treatment to avoid haematological morbidity. The same study demonstrated that radiation-induced pulmonary fibrosis was more likely to develop in patients with diffuse lung metastases if 48 h retention exceeded 2.96 GBq. These guidelines hold true for the hypothyroid cancer patient. Autonomous metastases accumulate greater quantities of 131I, leading to higher whole-body retention and blood exposure. Our subject had widespread pulmonary metastases necessitating repeated treatment. Despite high 131I retention, management remained within safe boundaries and led to no significant adverse morbidity. 3-D dosimetry permitted dose calculation to the largest of the lung metastases. Maximum dose received was 241 Gy, a level exceeding the desired dose of 100–150 Gy generally accepted to treat metastases successfully. Following repeated therapies of 3–5.7 GBq, our patient gradually became euthyroid then hypothyroid, allowing anti-thyroids to be discontinued and replaced with life-long thyroxine.
Current guidelines recommend patients receiving 131I therapy to have TSH levels above an arbitrary level of >30 mU l–1 to increase uptake. Hyperfunctioning metastases can sequester large quantities of 131I even in the presence of suppressed TSH levels, an observation seen in our case. It was only after free thyroid hormone levels had normalised that rhTSH was employed to stimulate suppressed TSH levels and ensure optimal uptake.
Although 131I can successfully eradicate hyperfunctioning metastases, release of thyroid hormone can follow tumour cell lysis which can precipitate a thyroid storm. Attempts to render the patient euthyroid prior to 131I with steroids, high dose anti-thyroids and propanolol minimise this complication.
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Conclusion
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Functioning metastases from DTC rarely present as thyrotoxicosis. Transbronchial biopsy of metastases originating from follicular cancer may be so well-differentiated that they lack features of malignancy. Management comprises anti-thyroid medication, propanolol and occasionally steroids followed by total thyroidectomy, radioiodine ablation, and repeated 131I therapy. Dosimetry should be undertaken to maximise treatment response whilst minimising potential damage to the bone marrow. Extreme caution is necessary when administering 131I to avoid thyroid storm but, with successful treatment anti-thyroid drugs can gradually be withdrawn and replaced with life-long TSH suppression.
Received for publication August 1, 2005.
Revision received May 17, 2006.
Accepted for publication May 22, 2006.
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Abstract
Introduction
