Is the Thyroglobulin Measurement Under Thyroxine of Prognostic Value Before rhTSH-Aided Radioiodine Ablation in Differentiated Thyroid Carcinoma?
Introduction Total (or near-total) thyroidectomy followed by TSH-stimulated administration
of large activities of 131-iodine (131I) is the treatment of choice for DTC [1-3]. The serum
thyroglobulin (Tg) measurement during hypothyroidism, just before radioiodine thyroid
ablation, has proved to be effective for predicting persistent/recurrent disease [4-8].
Recently recombinant human TSH (rhTSH) showed to be safely employed instead of thyroxine
(T4) withdrawal (offT4) to prepare patients for radioiodine ablation [9-10]. However, the Tg
level are measured 48 hours after radioiodine administration when rhTSH is used as
stimulation . Consequently, due to the radioiodine-induced thyroid cells damage and Tg
release, the Tg measurement would not have reliable predictive value in patients treated by
rhTSH stimulation . The present study was undertaken to evaluate if preablativeTg
measurement under T4 treatment is of prognostic value and serves as surrogate marker of
offT4-stimulated preablative Tg.
Patients and methods
Patients selection We retrospectively enrolled 28 consecutive patients affected by
histologically proven DTC (23 papillary, 5 follicular) submitted to total thyroidectomy and
central compartment lymph-node dissection. Thyroxine (T4) treatment was started immediately
after surgery to suppress TSH levels. Six to nine weeks later Tg levels were measured both
basally (onT4-Tg) and after rhTSH (rhTSH-Tg) stimulation as previously described .
Subsequently, T4 was stopped for 4 weeks and serum Tg measured (offT4-Tg) just before 3700
MBq of 131I-iodide administration. A post-treatment whole body scan (PT-WBS) with
radioiodine uptake (RAIU) calculation was performed according to a previously described
protocol . All non physiologic iodine uptake areas out of the thyroid bed were considered
as positive findings [14, 15]. Patients with positive PT-WBS underwent specific treatment
and personalized follow-up. Patients with negative PT-WBS immediately restarted T4
suppressive treatment. Final restaging was performed in all patients 12 months after the
last treatment by neck ultrasound, onT4-Tg assay and both offT4-diagnostic WBS (DgWBS) and
Tg assay (4 weeks T4 withdrawal; required TSH>30 mUI/L). Clinical and pathological
characteristics of selected patients were summarized in the Table 1.
Serum Tg assay and screening for interferences Serum Tg was assayed in duplicate by a
specific high-sensitive IRMA assay (DYNOtest® Tg-plus, BRAHMS Diagnostica GmbH, Berlin,
Germany) according to the producer’ instructions. This method provided a sensitivity of 0.05
ng/mL and a functional sensitivity of 0.2 ng/mL [16, 17]. As previously published,
preablative offT4 serum Tg values above 4.5 ng/mL and 3.2 ng/mL were considered as positive
with respect to PT-WBS and 12 months restaging results, respectively . Otherwise,
offT4-Tg values higher than 0.2 ng/ml measured 12 months after thyroid ablation were
considered positive for persisting/relapsing disease. [18, 19]. The presence of
anti-thyroglobulin antibodies (AbTg) was screened by a specific radioimmunoassay (DYNOtest®
anti-TGn, BRAHMS Diagnostica GmbH, Berlin, Germany) and by recovery test with a specific
Tg-recovery buffer provided by the producer. Sera showing AbTg levels more than 60 U/mL
and/or recover less than 80% or more than 120% were excluded from the study. Quality control
was ensured by assaying two levels of control sera in each series, by re-assessing all sera
showing a coefficient of variation exceeding 10% and by a bimonthly partecipation in the
European inter-laboratory control OncocheckTM.
Statistics Quantitative data are expressed as mean ± SD. Differences between groups were
assessed by two-tailed unpaired t-test. The relationship between variables was assessed by
linear regression analysis. In order to allow statistical analysis the value of undetectable
serum Tg expressed as < 0.2 ng/nL was arbitrarily changed in 0.10 ng/mL. Statistical
significance was defined by a p-value < 0.05.
Ethics All diagnostic and therapeutic procedures were performed according to the regulations
of the local ethics committee. Informed consensus was obtained from each patient.
Results The overall results are summarized in the Table I. Relationship Between Post-surgery
onT4-Tg, rhTSH-Tg and offT4-Tg A significant positive relationship was found between onT4-Tg
and both rhTSH-Tg (p<.0001) and offT4-Tg (p<0.0001) (Figure 1, A-B-C) as well as between
rhTSH and offT4-stimulated Tg (p<.0001).
Relationship Between Post-surgery Serum Tg and Thyroid Remnant Radioiodine Uptake (RAIU)
Among 22 patients showing no DTC metastasis on PT-WBS the serum distribution of onT4-Tg,
rhTSH-Tg and offT4-Tg was 0.342±0.402; 0.664±0.803 and 1.195±1.485 ng/mL respectively. Both
rhTSH and offT4-stimulated Tg levels were related to RAIU (p <.05 and <.005, respectively)
while no significant relationship was found between RAIU and onT4-Tg levels (Figure 1,
Relationship Between Post-surgery Serum Tg and PT-WBS results The patients with positive
PT-WBS showed higher onT4-Tg (0.617±0.445 vs 0.341±0.402 ng/mL), rhTSH-Tg (2.150±1.249 vs
0.664±0.803 ng/mL) and offT4-Tg (4.417±2.136 vs 1.195±1.485 ng/mL) levels as compared with
patients with negative scan. Among 14 patients with undetectable onT4-Tg (i.e. ≤0.2 ng/mL)
none had positive PT-WBS neither recurrences at 12-months restaging. Additionally, none of
these patients showed stimulated Tg values more than 0.4 ng/mL and 1.0 ng/mL after rhTSH
stimulation and T4 withdrawal, respectively. Viceversa, among 14 patients with onT4-Tg
levels more than 0.2 ng/mL, 6 had positive PT-WBS (onT4-Tg: 0.3 to 1.4 ng/mL) and 3 showed
DTC recurrences at 12 months restaging (onT4-Tg: 0.9 to 1.7 ng/mL). Consequently, the
onT4-Tg levels predicts PT-WBS results with a 100% negative and 43% positive predictive
values, respectively. Additionally onT4-Tg levels of 0.9 ng/mL or more predicts 12-months
recurrences with 100% negative and 60% positive predictive value. In comparison, 1.0 ng/mL
or higher offT4-Tg values predicted PT-WBS results and 12-months restaging with 94% and 100%
negative and 45% and 27% positive predictive value, respectively.
Discussion Many reports indicate the usefulness of Tg concentration measurement before
radioiodine treatment to early detection of DTC relapse or metastasis [4-8, 20, 21]. Three
factors determine Tg concentration in most clinical situations: thyroid cell mass, thyroid
cell damage and activation of TSH receptors . When Tg is measured before radioiodine
ablation the effects of surgical damage are generally vanished and endogenous TSH levels are
increased in all patients: consequently the thyroid remnant mass is the major determinant of
the serum Tg concentrations . However, the rhTSH-stimulated Tg cannot be used instead of
preablative offT4-Tg when rhTSH is employed to prepare radioiodine ablation . Therefore
we evaluated the role of post-surgery onT4-Tg as surrogate prognostic marker. We choiced to
suppress TSH levels in order to normalize the effect of TSH stimulation on thyroid remnants.
Clearly, the TSH suppression reduced Tg levels: however, the high-sensitive Tg assays
provide a good distinction between the lower limit of the euthyroid reference range and the
functional sensitivity limit detecting small amounts of thyroid tissue even in the
TSH-suppressed state (22, 23). We showed a significant positive relationship between
post-surgery Tg measured during T4 treatment and after TSH stimulation. No relationship was
found between RAIU (i.e. expression of remnant mass) and onT4-Tg, probably due the
clustering of all Tg levels lower than 0.2 ng/mL (see statistics paragraph). However,
undetectable onT4-Tg after surgery identifies patients free of metastasis at PT-WBS and
without late recurreces during early 12-months follow-up. None of these patients showed a
significant increase in both rhTSH and offT4-stimulated Tg before radioiodine ablation. This
seems to indicate that the relationship between Tg expression and thyroid tissue mass is
manteined even in TSH suppression state: Therefore undetectable serum onT4-Tg really
identifies patients without significant thyroid tissue amount as well as stimulated Tg. All
patients performed extracapsular total thyroidectomy in a dedicated thyroid surgery unit and
the thyroid remnant, expressed as RAIU, was lower in our series than in others. This means
that our data cannot directly translated to patients treated by more limited surgery.
Globally, basing on our data we conclude that preablative onT4-Tg may be of value as
prognostic marker when rhTSH-aided radioiodine ablation is done. Additionally, the role of
preblative onT4-Tg measurement as a yard-stick for radioiodine ablation should be further
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Observational Model: Defined Population, Observational Model: Natural History, Time Perspective: Longitudinal, Time Perspective: Retrospective/Prospective
Luca Giovanella, MD
Oncology Institute of Southern Switzerland