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Two Cases of Thyroid Carcinoma That Were Not Stimulated by Recombinant Human Thyrotropin

Department of Nuclear Medicine (A.A.D.), London Health Science Centre, London, Ontario, Canada N6A 4G5; and Division of Nuclear Medicine (A.A.D.) and Faculty of Medicine (N.K.), University of Western Ontario, London, Ontario, Canada N6A 5B8

Address all correspondence and requests for reprints to: Dr. A. A. Driedger, Department of Nuclear Medicine, London Health Science Centre, 375 South Street, London, Ontario, Canada N6A 4G5. E-mail: al.driedger{at}lhsc.on.ca.

	Abstract

Top Abstract Introduction Case 1: Patient CD Case 2: Patient MB Discussion References

 
Recombinant human TSH (rhTSH) is being widely used to monitor patients who were previously treated for differentiated thyroid cancers for evidence of recurrence. Its value lies in the avoidance of recurrent episodes of hypothyroidism in the follow-up protocols. rhTSH is also being evaluated as a potential therapeutic adjunct that would spare patients the experience of becoming hypothyroid when undergoing thyroid remnant ablation or treatment for metastases. In some centers, rhTSH is also used to support compassionate care of patients with advanced disease who cannot safely become hypothyroid. The ¹³¹I uptake response to rhTSH, presently an off-label application, is expected to be similar to that of endogenously raised TSH levels. The two cases presented here are cautionary tales in which ¹³¹I uptake by metastases was present under hypothyroid conditions, but absent in one patient and present in only a portion of the lesions in the other, with rhTSH stimulation.

	Introduction

Top Abstract Introduction Case 1: Patient CD Case 2: Patient MB Discussion References

 
PATIENTS WHO ARE diagnosed with unresectable metastatic differentiated thyroid cancers may benefit from treatment with ¹³¹I (1, 2, 3, 4, 5). The most frequently used method to prepare patients for ¹³¹I treatment is to increase TSH levels by withdrawing thyroid hormone replacement therapy. This maneuver stimulates maximal ¹³¹I uptake by the metastatic deposits. Treatment with radioactive iodine may fully destroy occult microscopic carcinoma (1) or serve to decrease the rate of progression of metastatic lesions. However, the patient’s experience of hypothyroidism is unpleasant and frequently has an adverse effect on quality of life.

Thyroid hormone withdrawal has been found to be associated with multiple psychosocial changes, including increased familial distress, changes in relationships and sexuality, as well as an increased difficulty in performing day-to-day household tasks (6). Patients who are withdrawn from their thyroid hormone replacement have also been found to have a decreased motivation to work, and up to 50% experience clinical depression (6). In rare instances, thyroid hormone withdrawal has been linked to accelerated tumor growth as a result of elevated TSH concentrations (7, 8). In particular, compressive symptoms resulting from tumor growth have been reported in the presence of bone metastases after hormone withdrawal (7). It is important to note that thyroid hormone withdrawal may be contraindicated in patients who are medically compromised, frail, and elderly, or in those suffering from depression. Thyroid hormone withdrawal may also be futile if the patient, after thyroid hormone withdrawal, proves unable to raise the TSH level to a therapeutically effective level, as would be the case in hypopituitarism (3).

Recombinant human TSH (rhTSH; Thyrogen; Genzyme Corporation, Cambridge, MA) may provide clinicians with a new approach to prepare patients for ¹³¹I therapy. This would enable patients to remain on thyroid hormone replacement and therefore avoid the morbidity of hypothyroidism that accompanies thyroid hormone withdrawal (9, 10). The use of rhTSH has been associated with a small number of side effects, the most common being headaches (9) and nausea (9, 11). It has been found that the recombinant and endogenous forms of TSH have a similar effectiveness for detecting thyroid cancer and residual carcinoma (9, 12) as well as in preparing patients for ¹³¹I thyroid remnant ablation (13, 14). Furthermore, it has been shown that rhTSH-stimulated ¹³¹I treatment can be effective in patients with well-differentiated thyroid carcinomas (14, 15, 16) and metastases (16). Most recently, it was reported that rhTSH is at least equivalent to thyroid hormone withdrawal when used as an adjunct to radioiodine treatment of advanced differentiated thyroid carcinoma (17).

At the London Health Science Centre, rhTSH has been used to support the compassionate care of patients who either could not raise their TSH to therapeutic levels, had a contraindication to the induction of hypothyroidism, or did not consent to becoming hypothyroid. In general, we have found that rhTSH-stimulated therapy is effective. The purpose of this communication is to document two cases where significant discrepancies were seen between therapeutic ¹³¹I uptake after rhTSH stimulation and under hypothyroid conditions. In the first case, ¹³¹I uptake into metastases was significant under hypothyroid conditions and completely negative under rhTSH stimulation. In the second case, ¹³¹I uptake under rhTSH stimulation was initially similar to that of previous uptake under hypothyroid conditions. However, serial treatment with recombinant TSH led to the regrowth of tumor that was insensitive to rhTSH stimulation, while continuing to take up iodine under hypothyroid conditions.

	Case 1: Patient CD

Top Abstract Introduction Case 1: Patient CD Case 2: Patient MB Discussion References

 
CD was a 71-yr-old woman who, in April 1996, began to experience pain in her left clavicle. She sought medical care 8 months later for a mass in her clavicle. A closed biopsy was performed and demonstrated a malignancy of unknown primary site. Several subsequent pathological examinations confirmed a follicular carcinoma of the thyroid with atypical Hurthle cell changes. She was placed on a TSH-suppressive dosage of thyroid hormone and was not subjected to surgery because she had an obvious metastatic malignancy.

When CD presented at the London Health Science Centre on January 6, 1997, she had lost about 10 lbs. in weight. She had a large palpable mass around the left clavicle, which extended into the supraclavicular fossa. On radiographic examination, multiple metastatic lesions were seen in both lungs, and they ranged in size to a maximum diameter of 3.5 cm. At this time, her thyroglobulin (Tg) was elevated at 2249 µg/liter.

It was felt that CD was not a candidate for thyroidectomy because of her frail status, and as a result, she was referred to the Department of Nuclear Medicine for consideration of ¹³¹I treatment. At this time, her thyroid hormone replacement was discontinued, and she was placed on a low-iodine diet.

The low-iodine diet is designed to reduce iodine intake to approximately 50–60 µg/day. This is significant, because in this geographic area, the daily urinary excretion of iodine may be as high as 600–800 µg/day (18). All patients are provided with a handbook that outlines the objective of the diet and provides information about food choices and sources of inadvertent iodine contamination such as multivitamins and mineral supplements. Urinary iodine excretion measurements were not performed. The patients were asked about their adherence to the diet at their clinic appointments, and we believe that they adhered carefully to their diets.

Three weeks later, the 24-h ¹³¹I uptake was 20%. The scan revealed a normal and intact left lobe, but there was very little functioning tissue on the right side. On clinical examination, there was no palpable abnormality in the thyroid gland, and biochemical tests revealed a TSH of 10.34 mIU/liter and an elevated Tg of 2258 µg/liter. At this time, it was recommended that CD receive external beam irradiation to control discomfort related to the clavicular lesion. She received six treatments to the clavicle, and this was followed by ¹³¹I therapy for thyroid gland ablation. Treatment with thyroid hormone was resumed 2 wk later.

In the following month, she suffered a pathological fracture of the proximal end of her right humerus, a previously asymptomatic site. She required internal fixation and external beam radiotherapy. A bone scan in this interval verified lesions in the left clavicle and right humerus.

Three months later, thyroid hormone was withdrawn, and her Tg rose to 5220 µg/liter. She was treated with 200 mCi (7.4 GBq) ¹³¹I, and a 10-day posttherapy scan showed intense ¹³¹I uptake into the clavicular lesion, three lung lesions, and, to a lesser extent, the right humeral lesion.

¹³¹I therapy appeared to stabilize her disease, and as a result, additional treatments were given under hypothyroid conditions to monitor and control her clinical situation. The total series of treatments is summarized in Table 1. After the first treatment, all subsequent posttherapy scans were performed on day 5.

View larger version (76K): [in this window] [in a new window]   FIG. 1. A, A representative fifth-day posttherapy 131I scan after any of the first seven treatments given under hypothyroid conditions to patient CD before use of rhTSH. B, A fifth-day posttherapy scan after therapy given with rhTSH stimulation. C, The fifth-day posttherapy scan after treatment while hypothyroid. Scan performed subsequent to attempts with rhTSH.

In September 2000, CD developed pain at the tip of her left scapula. She received external beam irradiation to this new metastatic site.

During the year 2000, although it was evident that the ¹³¹I therapies were helping to control her disease, the morbidity associated with the recurrent thyroid hormone withdrawal was becoming increasingly more difficult for her. Given her age and demanding domestic commitments, she was prepared for her next ¹³¹I treatment using rhTSH stimulation. The first rhTSH injection was given on January 8, 2001. It may be important to note that, the night before commencing these injections, the refrigerator in which the product was stored warmed to room temperature. After consultation with a manufacturer’s representative, it was felt that the short duration of warming should not have affected the potency of rhTSH, and it was used as directed. On this occasion, the posttherapy scan demonstrated no uptake of ¹³¹I into any of the metastatic sites (Fig. 1B). It is interesting to note that her Tg before rhTSH was 2905 µg/liter (January 8), and unlike her previous therapies given under hypothyroid conditions, the Tg was not further increased by the rhTSH injections. On January 12, 2000, her Tg was only 2834 µg/liter.

In May 2001, CD suffered a pathological fracture of the right humerus, directly below the end of the previously placed internal fixation rod. The fracture was treated by casting and external beam irradiation, but unfortunately, it did not unite and she was left with a flail arm.

It was hypothesized that the warming of rhTSH might have affected its potency, and as a result, the patient agreed to undergo another course of therapy with rhTSH stimulation. This was done on August 15, and once again, the posttherapy scan revealed virtually no uptake into any of the known lesions. On this occasion, the Tg was 2310 µg/liter before rhTSH stimulation and only 1260 µg/liter after its administration; the latter was a time at which TSH stimulation ought to have been maximal.

This result forced the conclusion that rhTSH was not capable of stimulating her tumors to take up iodine. She has since been treated under hypothyroid conditions on two separate occasions, and both of the posttherapy scans showed uptake of ¹³¹I into all of the known lesions (Fig. 1C). Every time she became hypothyroid, her Tg rose significantly (Table 1). Together, the absence of ¹³¹I uptake coupled with the lack of a Tg response indicated that her tumor was not stimulated by rhTSH.

	Case 2: Patient MB

Top Abstract Introduction Case 1: Patient CD Case 2: Patient MB Discussion References

 
MB was a 32-yr-old male who had a well-differentiated follicular carcinoma with vascular and capsular invasion. After a thyroidectomy in January 1996, he was treated with ¹³¹I to ablate any thyroid remnants and was placed on thyroid hormone replacement. In May 1999, the disease recurred in his right neck, and this required surgical resection. A left neck recurrence followed 5 months later.

MB was first seen at our clinic on November 26, 1999, and was treated with 200 mCi (7.4 GBq) ¹³¹I. At the time of the treatment, his TSH and Tg were elevated at greater than 150 mIU/liter and at 211.3 µg/liter, respectively. The posttherapy scan documented bilateral neck disease, central disease at the thoracic inlet, as well as a number of bilaterally located foci in the lower lung fields.

In April 2000, he had an additional right neck recurrence and was retreated with ¹³¹I. The resulting scan revealed disease progression in the interval between treatments. He had neck, lung, and potential lumbar bone metastases (Fig. 2A).

View larger version (70K): [in this window] [in a new window]   FIG. 2. A, A fifth-day posttherapy scan performed under hypothyroid conditions on May 25, 2000, on patient MB. B, The fifth-day posttherapy scan (December 20, 2000) after the first therapy given under rhTSH stimulation. The scan is similar to the one performed under hypothyroid conditions. C, The fifth-day posttherapy scan for the sixth consecutive treatment under rhTSH stimulation. The arrow indicates the location of the palpable recurrent neck disease, which did not concentrate 131I. The apparent increase in background in this panel is an artifact resulting from the manner of image processing and not from decreased iodine excretion. D, The fifth-day posttherapy scan performed under hypothyroid conditions subsequent to the rhTSH-stimulated therapeutic series. There is 131I uptake into the site of the palpable lesion in the neck as well as into multiple lung and bone lesions.

In the next 2 yr, MB underwent six ¹³¹I treatments under rhTSH stimulation. The total series of treatments is summarized in Table 2. During this interval, he also had surgery to debulk the recurrent neck disease.

In November 2002, he presented with palpable right neck recurrence, and a posttherapy scan on November 25 revealed intense iodine uptake into a number of metastases in his lungs; however, the recurrent nodule in his right neck did not take up any iodine (Fig. 2C).

By April 2003, the neck recurrence increased to 2 cm in size, and there was also a new mass in his left scapula. Because there was a documented recurrence that was ¹³¹I negative under rhTSH stimulation, he was retreated under hypothyroid conditions. On this occasion, his posttherapy scan demonstrated high uptake into various lesions, including the palpable neck lesion. Multiple lesions involving bone, which were not previously seen with rhTSH-stimulated therapy, were also documented. There were large lesions in the left humerus, in the proximal and distal left femur, and in the distal third of the right femur, as well as several smaller lesions in the ribs (Fig. 2D). At the time of treatment, blood studies demonstrated a substantially elevated Tg of 1131.9 µg/liter.

	Discussion

Top Abstract Introduction Case 1: Patient CD Case 2: Patient MB Discussion References

 
In summary, these two cases demonstrate that rhTSH is not able to stimulate differentiated thyroid cancer cells to take up iodine or produce Tg in all circumstances, even when endogenous TSH elevation is able to do so. In the case of patient CD, all of the metastatic lesions failed to take up iodine and were not stimulated to produce Tg with rhTSH stimulation. On the other hand, in the case of patient MB, the metastases became heterogeneous with respect to their iodine uptake after serial exposures to rhTSH, and his Tg was then only moderately stimulated by the recombinant form. These observations suggest that caution is warranted when considering rhTSH stimulation as an alternative to hypothyroidism in ¹³¹I therapy.

The possible mechanism(s) by which cancer cells may discriminate between the native and recombinant forms of TSH need to be understood. The mechanism by which TSH stimulates iodine uptake into normal follicular cells, through binding to the TSH receptor and stimulating the sodium iodide symporter, is known in some detail (19, 20, 21). Thus far, it has been appropriate to assume that this mechanism would be comparable in differentiated thyroid cancer cells, and that it would not discriminate between endogenous and recombinant TSH. Our observations demonstrate that this is not always the case, and as a result, it would be invaluable to examine whether variations exist in the mechanism by which iodine uptake is stimulated in cancer cells.

There are several possible explanations for the observed discrepancy between the effectiveness of the two forms of TSH: there may be a variation in the potency of the rhTSH lots; after rhTSH administration, variations may exist in the time required to stimulate Tg production and iodine uptake by the cancer cells; critical differences may exist between the configurations of the receptor-specific portion of the natural and recombinant forms of TSH. This implies that genetic variations in the TSH receptor could lead to differences in tissue response to endogenous vs. recombinant TSH.

In the case of patient CD, the two exposures to rhTSH failed to stimulate iodine uptake by the tumor cells. Therefore, it is unlikely that the reproducible lack of effect was due to either degradation of the drug at the hospital or to a fault at the manufacturing level.

Our experience with patient MB suggests that the differences in timing of maximal iodine uptake after rhTSH exposure are not particularly significant. In this patient, during the first treatment with rhTSH, satisfactory uptake into known metastases was seen at the usual 48-h interval after the first rhTSH injection; this response was no longer seen by the sixth treatment. A transition occurred from iodine avidity by all known metastases under initial rhTSH stimulation to a number of iodine-negative metastatic deposits. This suggests that the serial exposure to rhTSH may have exerted a progressive selection pressure on the TSH receptor, favoring an rhTSH-insensitive variant. This observation insinuates that the TSH receptor may be polyclonal, at least in malignant cells.

It is well known that there may be differences between diagnostic ¹³¹I scans obtained in the hypothyroid compared with rhTSH-stimulated states (9, 11). Although the majority of lesions were similarly seen on both scan sets in those studies, there were also instances in which one or the other imaging protocol revealed unique lesions. In those studies, the hypothyroid scans always followed the rhTSH imaging by several weeks, and the failure to visualize a lesion on the second set of images could arguably be attributed to an interval stunning effect from the first dose of ¹³¹I. On the other hand, failure to identify some lesions on the initial rhTSH-stimulated images in those studies is not so readily explicable. These observations may indicate an intrinsic difference between the two forms of TSH in some patients. It is reasonable to speculate that this tumor behavior might translate into the response we observed during treatment in our patients. In this connection, it is also intriguing to note that a single case has been reported in which a carcinoma that was negative under hypothyroid conditions became iodine avid when stimulated by both hormone withdrawal and rhTSH administration (20), another indication of receptor mutability.

It is important to note that the natural and recombinant forms of TSH are not identical. Although the amino acid sequence is identical for the two forms of TSH, it is known that there are some differences in the addition of sialic acid residues between the natural and synthetic forms (22). It is also known that the behavior of TSH can be varied by changes in the degree of glycosylation (23). In the case of patient CD, the malignant cells may have been unable to recognize the recombinant form on account of resulting conformational changes in rhTSH, whereas in MB, the tumor was likely polyclonal, and repeated therapy with rhTSH stimulation exerted a selection pressure in favor of TSH receptors that were unable to recognize the recombinant hormone.

In the case of CD, it may be noted that, between the two rhTSH-stimulated treatments, her Tg dropped from 2905–2310 µg/liter (Table 1). This may indicate that the treatment was partially effective despite a negative posttherapy scan, but it may also be attributed to a change in the differentiation of the tumor in that time period.

To date, there is no evidence that T₄ at physiologic doses blocks the action of TSH on the sodium iodide symporter in the clinical setting. However, one could speculate that the daily iodine consumption associated with thyroid replacement may affect ¹³¹I uptake. This could be the result of directly blocking uptake or through an indirect mechanism by diluting the ¹³¹I in a larger pool of cold iodine. We suspect that this is not an important explanatory factor, because patient MB initially had similar scans under both hypothyroid conditions and with rhTSH stimulation, the latter being a time where he was on thyroid replacement. For perspective, we note that a daily intake of 150 µg L-thyroxine is equivalent to an iodine intake of 100 µg.

A series of patients has recently been reported whose metastatic thyroid cancer responded similarly to radioiodine treatment with induced hypothyroidism and under rhTSH stimulation (17). The authors of that study treated 50 patients with metastatic disease under hypothyroid conditions and then retreated them with rhTSH stimulation 6 months later. They report that 74% of the 50 paired scans were concordant, 16% favored rhTSH, and 10% favored thyroid hormone withdrawal. They conclude that rhTSH-stimulated therapy safely and effectively aids radioiodine treatment of advanced differentiated thyroid carcinoma. In general, our experience with rhTSH-supported therapy in compassionate care settings has also been positive, but as these two cases demonstrate, rhTSH needs to be used with caution. It is evident that there are cases in which ¹³¹I treatment must continue to be given under hypothyroid conditions.

At the present state of knowledge, the application of rhTSH as a therapeutic adjunct should preferably be limited to settings in which failures to stimulate ¹³¹I uptake can be carefully evaluated. Our experience with these two patients also serves to identify the need for a better understanding of the molecular basis for the behavioral differences between native and recombinant forms of TSH.

	Footnotes

 
Abbreviations: rhTSH, Recombinant human TSH; Tg, thyroglobulin.

Received September 22, 2003.

Accepted November 6, 2003.

	References

Top Abstract Introduction Case 1: Patient CD Case 2: Patient MB Discussion References

 

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