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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
131
I 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, Ho
ˆpital Necker–Enfants Malades, 149 rue de Se
`vres, 75743 Paris Cedex 15, France
Abstract. 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
131
I. 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
131
I, therapeutic
131
I doses of 3.7 GBq may cause stunning. We describe
stunning of papillary thyroid cancer lung and bone metastases after a therapeutic dose of
131
I (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
131
I 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
131
Iin
close succession without each dose hampering the effectiveness of the subsequent one.
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
131
I. Initial
treatment usually combines total thyroidectomy and
destruction of thyroid remnants with an ablative ther-
apeutic dose of
131
I [1–3]. Post-thyroidectomy diagnostic
scintigraphy with a small dose of
131
I (37–111 MBq) can
detect cervical thyroid remnants before administration of
an ablative dose of 3.7 GBq of
131
I. Because it is now
known that the higher the diagnostic dose of
131
I, 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
131
I might be responsible for the subsequently
diminished capture of ‘‘therapeutic’’
131
I [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
131
I, resulting in the loss of efficacy of therapeutic
131
I. Stunning was recently described after fractionated
ablative doses of
131
I [20].
In the case of rapidly progressing thyroid cancer with
distant metastases taking up iodide, it would be desirable
to administer several successive therapeutic
131
I 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
131
I.
Case report
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 exer-
esis of the lymph nodes yielded an 8 mm diameter, non-
encapsulated, papillary thyroid adenocarcinoma with
numerous vascular emboli on the left, and lateral tracheal
(n58) and jugular–carotid lymph node metastases (n55)
also on the left.
A therapeutic dose (3.7 GBq) of
131
I was given 4 weeks
after thyroidectomy. Laboratory findings are reported in
Table 1. Scintigraphy, performed 7 days after
131
I admin-
istration, detected four cervical foci of
131
I uptake, and
diffuse
131
I trapping in both lungs, estimated at 1/1000
(Figure 1a). CT scan showed micronodules at the limit of
visibility in the lung bases. Thyroid hormone replacement
with levothyroxine (L-T4) was initiated.
6 months later, a second therapeutic dose of
131
I
(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
131
I (3.7 GBq) was administered. Scintigraphy 4 days later
showed that the upper jugular–carotid focus had dis-
appeared, but the lower cervical and lung trapping
(estimated to be 8/10 000) of
131
I persisted (Figure 1b).
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.
Received 7 July 2004 and in revised form 29 October 2004, accepted
9 December 2004.
The British Journal of Radiology, 78 (2005), 428–432 E2005 The British Institute of Radiology
DOI: 10.1259/bjr/92548685
428 The British Journal of Radiology, May 2005
Upon re-examination of the
131
I scintigram (posterior
view), the T4 region was difficult to interpret because of
bilateral
131
I trapping by the lungs. Prior to scheduled
surgery on T1 and after administration of recombinant
thyroid-stimulating hormone (rTSH), 0.7 GBq of
131
I were
given 37 days after the third therapeutic dose and
scintigraphy was performed 48 h later. To our surprise,
no
131
I was taken up at T1, T4 or in the lungs (Figure 1c),
but the physiological sites (salivary glands and mediasti-
num) of scintigraphic contrast were clearly visible. The
absence of iodine overload was verified (Table 1). T1 was
surgically removed. Radiation therapy delivered 40 Gy to
the spine C6–T5.
6 months later, the fourth therapeutic dose of
131
I
(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 1d).
1 year later, the fifth therapeutic dose of
131
I (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
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
131
I. Iodine overload, with
diminished iodide clearance by the thyroid, is the first
hypothesis to explain the association of known metastases
that trapped
131
I 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
131
I given 37 days before the
absorption of 0.7 GBq of
131
I 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
131
I 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
131
I 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 accumu-
lation 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
131
I 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
131
I 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
131
I, which emits beta and gamma rays, but also
after high doses of pure gamma-emitting
123
I [17].
Table 1. Biological data at the times of therapeutic and diagnostic
131
I doses
131
I dose TSH (mIU l
21
)Tg
a
(mgl
21
) Total serum
iodine (nmol l
21
)
Urinary iodine
(nmol l
21
)
Urinary I/C
b
No. GBq
1 3.7 44.8 92.7 226 1113 65
2 3.7 251.9 116.0 197 1058 64
3 3.7 307.6 88.7 13 554 21
rTSH 0.7 32.7
c
17.9 609 935 77
4 3.7 324.6 48.2 118 177 41
5 3.7 345.0 22.5 68 1756 73
Normal values 0.5–3 ,35.0
d
338–724 ,800 in France 30–300
a
No anti-thyroglobulin (Tg) antibodies were detected.
b
Urinary iodine/urinary creatinine ratio.
c
40 h after the second injection of recombinant thyroid stimulating hormone (rTSH).
d
Normal Tg after thyroidectomy and ablative dose of
131
I: ,1mgl
21
.
Stunning of thyroid cancer metastases after 3.7 GBq of
131
I
429The British Journal of Radiology, May 2005
(a)
(
c
)
(b)
(
d
)
Figure 1.
131
I scintigrams of the head and thorax, anterior views. (a) 7 days after the first therapeutic dose, several cervical foci of
131
I 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
131
I 37 days after recombinant thyroid stimulating hormone (rTSH) and the third therapeutic
dose: disappearance of
131
I 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.
A F Leger, M Pellan, F Dagousset et al
430 The British Journal of Radiology, May 2005
Stunning intensity seems to parallel the
131
I dose. In the
literature, the threshold of
131
I 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
21
, 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
131
I doses
could be responsible for more intense, more rapid and/or
more prolonged stunning than that provoked by diag-
nostic 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
131
I 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 scintigra-
phy. 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
131
I 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 diag-
nostic stunning. Better understanding of the mechanism
inducing it, the time to its appearance and its duration is
needed, perhaps using
123
I studies, to adapt treatment
protocols.
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