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British Journal of Radiology (2005) 78, 428-432
© 2005 British Institute of Radiology
doi: 10.1259/bjr/92548685
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A case of stunning of lung and bone metastases of papillary thyroid cancer after a therapeutic dose (3.7 GBq) of 131I and review of the literature: implications for sequential treatments

A F Leger, MD M Pellan, MD F Dagousset, MD A Chevalier, PhD I Keller, MD and J Clerc, MD, PhD

Department of Nuclear Medicine, Hôpital Necker–Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France


   Abstract
Top
 Abstract
Introduction
 Case report
 Discussion
 References
 
Thyroid stunning is usually defined as the inhibition or suppression of iodide trapping by remnant thyroid tissue or by functioning metastases following a diagnostic dose of 131I. The risk of stunning increases progressively with larger doses. Because the threshold above which this effect occurs in thyroid remnants seems to be between 37 MBq and 111 MBq of 131I, therapeutic 131I doses of 3.7 GBq may cause stunning. We describe stunning of papillary thyroid cancer lung and bone metastases after a therapeutic dose of 131I (3.7 GBq). A T1 bone metastasis and bilateral lung metastases were diagnosed by post-therapeutic dose whole-body scan. Nuclear MRI detected another lesion at T4, whose 131I fixation was not obvious. An additional 0.7 GBq were given after recombinant TSH, 37 days after the therapeutic dose; 24 h later, uptake by the lung and T1 metastases had disappeared, but trapping was again seen 6 months later on the post-therapeutic scan. This re-appearance is evidence in favour of the transitory and reversible character of stunning, and confirms its correspondence to the decreased ability of viable thyroid cells to trap iodine and not to their destruction. A better understanding of stunning would make it possible, in the event of rapidly progressing disease and in conjunction with recombinant thyroid stimulating hormone (TSH), to give several therapeutic doses of 131I in close succession without each dose hampering the effectiveness of the subsequent one.


   Introduction
Top
 Abstract
 Introduction
Case report
 Discussion
 References
 
The treatment of differentiated thyroid cancer and the diagnosis of its metastases are based on the capacity of thyroid cells to actively trap radioactive iodine 131I. Initial treatment usually combines total thyroidectomy and destruction of thyroid remnants with an ablative therapeutic dose of 131I [1–3]. Post-thyroidectomy diagnostic scintigraphy with a small dose of 131I (37–111 MBq) can detect cervical thyroid remnants before administration of an ablative dose of 3.7 GBq of 131I. Because it is now known that the higher the diagnostic dose of 131I, the better the sensitivity of scintigraphy to render visible more foci trapping radioactivity [4], the diagnostic dose has been increased up to 185 MBq.

In 1986, it was hypothesised that these high diagnostic doses of 131I might be responsible for the subsequently diminished capture of "therapeutic" 131I [5]. Since then, numerous studies [6–19] have confirmed the existence of stunning, usually defined as the inhibition or suppression of iodide trapping by thyroid cells, following diagnostic doses of 131I, resulting in the loss of efficacy of therapeutic 131I. Stunning was recently described after fractionated ablative doses of 131I [20].

In the case of rapidly progressing thyroid cancer with distant metastases taking up iodide, it would be desirable to administer several successive therapeutic 131I doses at close intervals. But in so doing, the possibility of one therapeutic dose blocking, by stunning, the efficacy of the subsequent one must be avoided.

We describe stunning induced by a therapeutic dose of 3.7 GBq of 131I.


   Case report
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 Abstract
 Introduction
 Case report
Discussion
 References
 
A 16-year-old Caucasian boy (height 183 cm; weight 55 kg) had left cervical adenopathy for 3 years. Biopsy of the lesion showed it to be a metastasis of papillary thyroid adenocarcinoma. Total thyroidectomy with bilateral exeresis of the lymph nodes yielded an 8 mm diameter, non-encapsulated, papillary thyroid adenocarcinoma with numerous vascular emboli on the left, and lateral tracheal (n=8) and jugular–carotid lymph node metastases (n=5) also on the left.

A therapeutic dose (3.7 GBq) of 131I was given 4 weeks after thyroidectomy. Laboratory findings are reported in Table 1Go. Scintigraphy, performed 7 days after 131I administration, detected four cervical foci of 131I uptake, and diffuse 131I trapping in both lungs, estimated at 1/1000 (Figure 1aGo). CT scan showed micronodules at the limit of visibility in the lung bases. Thyroid hormone replacement with levothyroxine (L-T4) was initiated.


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  		Table 1. Biological data at the times of therapeutic and diagnostic 131I doses

 


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  		Figure 1. 131I scintigrams of the head and thorax, anterior views. (a) 7 days after the first therapeutic dose, several cervical foci of 131I uptake and diffuse trapping in the lungs. (b) 4 days after the third therapeutic dose, persistence of one cervical focus and lung uptake. (c) Scintigram with 0.7 GBq of 131I 37 days after recombinant thyroid stimulating hormone (rTSH) and the third therapeutic dose: disappearance of 131I uptake at T1 and in the lungs, but the salivary glands and mediastinum are clearly radiolabelled. (d) 5 days after the fourth therapeutic dose: re-appearance of the radiotracer in both lungs and persistence of weak uptake in T1 despite surgery.

 
6 months later, a second therapeutic dose of 131I (3.7 GBq) was administered. Scintigraphy performed 4 days later revealed the persistence of two of the cervical foci – left lower paramedian and upper external jugular–carotid – and bilateral lung uptake estimated at 6/10 000.

After a further 6 months, the third therapeutic dose of 131I (3.7 GBq) was administered. Scintigraphy 4 days later showed that the upper jugular–carotid focus had disappeared, but the lower cervical and lung trapping (estimated to be 8/10 000) of 131I persisted (Figure 1bGo). Bone scintigraphy showed that the persistent cervical uptake corresponded to the first thoracic vertebral body, T1. Nuclear MRI visualized a 10 mm lytic metastasis in the left half of T1 and a sub-centimetre lytic image in vertebral body T4 of unknown nature.

Upon re-examination of the 131I scintigram (posterior view), the T4 region was difficult to interpret because of bilateral 131I trapping by the lungs. Prior to scheduled surgery on T1 and after administration of recombinant thyroid-stimulating hormone (rTSH), 0.7 GBq of 131I were given 37 days after the third therapeutic dose and scintigraphy was performed 48 h later. To our surprise, no 131I was taken up at T1, T4 or in the lungs (Figure 1cGo), but the physiological sites (salivary glands and mediastinum) of scintigraphic contrast were clearly visible. The absence of iodine overload was verified (Table 1Go). T1 was surgically removed. Radiation therapy delivered 40 Gy to the spine C6–T5.

6 months later, the fourth therapeutic dose of 131I (3.7 GBq) was administered. Scintigraphy performed 5 days later revealed the re-appearance of radioactive uptake in both lungs (estimated to be 2/10 000) and weak trapping at T1 but not T4 (Figure 1dGo).

1 year later, the fifth therapeutic dose of 131I (3.7 GBq) was administered. Scintigraphy performed 3 days later showed trace uptake at T1 and faint pulmonary uptake comparable with that of the mediastinum.


   Discussion
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 Abstract
 Introduction
 Case report
 Discussion
References
 
The need for emergency surgery on the T1 metastasis and MRI discovery of a T4 lesion led us to repeat the scintigraphy with 0.7 GBq of 131I. Iodine overload, with diminished iodide clearance by the thyroid, is the first hypothesis to explain the association of known metastases that trapped 131I and negative scintigraphy. The increased intrathyroid concentration of iodide beyond a certain threshold decreases the sodium/iodide symporter (NIS) activity [21, 22] and increases its turnover, leading to fewer NIS complexes. An iodine overload in our patient was excluded because of normal blood and urine iodine levels. The persistence of the effect of a recent iodine overload cannot be excluded: however, an in-depth inquiry found no potential source of iodine intake for this 16-year-old teenager.

A second hypothesis raises the possibility of thyroid stunning by the 3.7 GBq of 131I given 37 days before the absorption of 0.7 GBq of 131I for scintigraphy.

The existence of this phenomenon remains controversial [23–27], with the results of most studies confirming that it exists in vivo [6–17] and in vitro [18, 19], but those of other studies failing to do so [28–31].

Stunning corresponds either to a partial destruction of iodine-trapping tissues by the diagnostic dose, with an irreversible phenomenon of radiation-induced cell death, or to transitory, reversible episodes, with less cellular uptake of iodide, attesting to the viability of remaining cells.

In the first case, a possible mechanism to explain stunning is the cell death resulting from early necrosis (within 24–48 h) or differed apoptosis. Guiraud-Vitaux et al [18] administered increasing 131I doses to rat thyroid cells and observed morphological and ultrastructural modifications typical of necrosis with no signs of apoptosis. The number of affected cells paralleled the 131I dose. Other authors found signs of apoptosis in response to ionizing radiation [32].

Postgard et al [19] used pig thyroid epithelial cells to measure transcellular transport of iodide and its accumulation in the follicular lumen. 5 days after irradiation with 3 Gy, iodide transport was diminished by almost 50% and almost 90% after 30 Gy; but no signs of cell death were observed.

Several groups studied stunning using qualitative [28, 29, 33] or quantitative methods [5, 7, 13, 17, 24]. The qualitative approaches required subjective comparison of diagnostic and post-therapeutic scintigrams, taking into account the number of foci trapping the radioelement and the intensity of the uptake. Given that the scintigraphic appearance depends on the activity of the iodine administered, the imaging technique, and the interval between iodine administration and scintigraphy, these qualitative methods are often open to criticism.

The quantitative approaches measure the reduction of iodide uptake. All the studies that used such a method confirmed the existence of stunning. Other researchers compared the effect of a diagnostic dose of 131I on the effectiveness of an ablative dose, as assessed by the disappearance at the next evaluation, at least 6 months later, of iodine trapping by thyroid remnants. Successful outcomes were more frequent after a diagnostic 131I dose of 37 MBq than after 111 MBq [10]. It was concluded that stunning might hinder ablative therapy. The transitory disappearance of foci known to take up radioactive iodine, although not strictly a quantitative method, appears to be a convincing argument in favour of stunning [9, 14].

Stunning has mainly been described after diagnostic doses of 131I, which emits beta and gamma rays, but also after high doses of pure gamma-emitting 123I [17].

Stunning intensity seems to parallel the 131I dose. In the literature, the threshold of 131I diagnostic activities responsible for stunning was estimated to range between 74 MBq [11, 13] and 111 MBq [8, 17]. The radiation absorbed dose, estimated in Gy, and the dose rate, estimated in Gy h–1, are undoubtedly more appropriate parameters than the administered dose. Jeevanram et al [5] observed stunning in remnants that had received an absorbed dose of at least 10 Gy. Muratet et al [10] found a threshold of 17.5 Gy, whereas Kao [33] reported a threshold of 35 Gy, as did Sabri et al [34], for benign thyroid diseases. However, the radiation absorbed dose is difficult to determine because the mass of the targeted tissue is most often unknown. Since thyroid stunning is dose-dependent, it seems logical that therapeutic 131I doses could be responsible for more intense, more rapid and/or more prolonged stunning than that provoked by diagnostic doses.

The interval between iodine exposure and stunning has not yet been clearly established. There is an indication from some data that the degree of diagnostic stunning may increase with time up to 20–25 days, then diminish [17, 35].

It has even been suggested that the therapeutic iodine dose itself could induce immediate "intratherapeutic stunning" or "self-stunning": during the hours following the administration of a therapeutic 131I dose, the high radiation dose might have a major impact on the subsequent iodide clearance rate by the thyroid [12].

The salivary glands do not seem to be affected by stunning because they remained visible on the scintigraphy. The lack of adaptative iodide clearance in the salivary glands suggests that the mechanism of active iodide transport differs from that in thyroid cells [36].

In the past few years, the presence of thyroid remnants has been quasi-constant, even after total thyroidectomy. The trend has been to administer a therapeutic 131I dose of 3.7 GBq, without diagnostic scintigram [37], followed by whole-body scintigraphy to visualize the remnants and detect possible metastases. This approach could avoid diagnostic dose induction of stunning.

In contrast, therapeutic stunning raises a major practical problem. The intensity of iodide trapping by thyroid cells depends on the TSH level. The recent synthesis of rTSH now enables scintigraphy to be performed and treatments to be given after two rTSH injections without stopping L-T4 [38]. In the case of rapidly progressing disease, the availability of rTSH means that several therapeutic doses can be given in close succession without stopping L-T4. But to do so, one therapeutic dose must not interfere with the next.

Our data support the idea that stunning is a transitory inhibition of iodide uptake. Therapeutic stunning is probably more intense and more prolonged than diagnostic stunning. Better understanding of the mechanism inducing it, the time to its appearance and its duration is needed, perhaps using 123I studies, to adapt treatment protocols.

Received for publication July 7, 2004. Revision received October 29, 2004. Accepted for publication December 9, 2004.


   References
Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 

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