Undetectable serum thyroglobulin levels in patients with medullary thyroid carcinoma after total thyroidectomy without radioiodine ablation.

Abstract

Recently, we reported that the thyroglobulin (Tg) doubling time (DT) was the most potent prognostic factor in patients with papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. Interestingly 16.2% of the study patients had a decrease in Tg levels over time, giving negative values in Tg-DT. These patients had an excellent outcome. However, most of the patients did not receive ablation with radioactive iodine. Therefore, whether the Tg in these patients was derived from persistent disease or residual thyroid tissue could not be concluded. To resolve this question, we measured serum Tg levels in patients with medullary thyroid carcinoma (MTC) who underwent total thyroidectomy using similar surgical techniques for the treatment of PTC.
Twenty-seven consecutive patients with MTC who underwent total thyroidectomy were selected. Of them, five patients with antibodies to Tg were excluded from the study. In the remaining 22 patients, serum Tg levels were measured before and after surgery. None of the patients received radioactive iodine ablation. They were prescribed levothyroxine as a replacement for the lost thyroid function.
Serum Tg levels were detectable preoperatively, while postoperative serum Tg levels were lower than the detectable level, 0.5 ng/mL, in all 22 patients.
The results indicate that most of the patients with detectable Tg levels and negative Tg-DT values after total thyroidectomy for PTC in our previous study had persistent disease, and that their serum Tg was not from residual thyroid tissue, suggesting that up to 50% of patients with persistent PTC have a decrease in serum Tg levels in response to thyroid-stimulating hormone-suppressive therapy.

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THYROID CANCER AND NODULES
Undetectable Serum Thyroglobulin Levels in Patients
with Medullary Thyroid Carcinoma After Total
Thyroidectomy Without Radioiodine Ablation
AU1c
Chisato Tomoda and Akira Miyauchi
Background: Recently, we reported that the thyroglobulin (Tg) doubling time (DT) was the most potent prog-
nostic factor in patients with papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. Inter-
estingly 16.2% of the study patients had a decrease in Tg levels over time, giving negative values in Tg-DT. These
patients had an excellent outcome. However, most of the patients did not receive ablation with radioactive
iodine. Therefore, whether the Tg in these patients was derived from persistent disease or residual thyroid tissue
could not be concluded. To resolve this question, we measured serum Tg levels in patients with medullary
thyroid carcinoma (MTC) who underwent total thyroidectomy using similar surgical techniques for the treat-
ment of PTC.
Methods: Twenty-seven consecutive patients with MTC who underwent total thyroidectomy were selected. Of
them, five patients with antibodies to Tg were excluded from the study. In the remaining 22 patients, serum Tg
levels were measured before and after surgery. None of the patients received radioactive iodine ablation. They
were prescribed levothyroxine as a replacement for the lost thyroid function.
Results: Serum Tg levels were detectable preoperatively, while postoperative serum Tg levels were lower than
the detectable level, 0.5ng/mL, in all 22 patients.
Conclusions: The results indicate that most of the patients with detectable Tg levels and negative Tg-DT values
after total thyroidectomy for PTC in our previous study had persistent disease, and that their serum Tg was not
from residual thyroid tissue, suggesting that up to 50% of patients with persistent PTC have a decrease in serum
Tg levels in response to thyroid-stimulating hormone–suppressive therapy.
Introduction
T
distant metastases, age at surgery, and gender are gen-
erally accepted prognostic factors for well-differentiated
thyroid carcinoma, and the TNM stage and MACIS or AMES
score are used to evaluate the prognosis (1–4). Detectable
serum thyroglobulin (Tg) in patients with papillary thyroid
carcinoma (PTC) after total thyroidectomy also indicates a
high risk of recurrence (5). Recently, we reported that the Tg
doubling time (DT) was the only independent prognostic in-
dicator on multivariate analysis in 426 patients with PTC who
underwent total thyroidectomy and who do not have anti-
bodies to Tg (6). Tg-DT was computed in 137 patients who
had 4 or more detectable Tg levels when thyroid-stimulating
hormone (TSH) was suppressed to <0.1mIU/L after surgery.
Short Tg-DTs were strongly associated with a poor outcome.
Interestingly, 69 patients or 16.2% of all patients had a de-
umor size, extrathyroidal extension, node metastases,
crease in Tg levels over time, giving negative values in Tg-DT
(6). These patients had an excellent outcome. However, most
of the patients did not receive thyroid ablation with radioac-
tive iodine. Therefore, whether the Tg in these patients was
derived from persistent disease or residual thyroid tissue
could not be concluded. To resolve this question, we mea-
sured serum Tg levels in patients with medullary thyroid
carcinoma (MTC) who underwent total thyroidectomy using
similar surgical techniques for PTC. MTC produces calcitonin
but not Tg.
Patients and Methods
We selected 27 consecutive patients with MTC who un-
derwent total thyroidectomy with central compartment dis-
section with or without modified neck dissection between
January 2007 and March 2009. None of the patients had PTC
or follicular thyroid carcinoma, tumors that produce Tg. Our
Kuma Hospital, Kobe, Japan.
THYROID
Volume 22, Number 7, 2012
ª Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2011.0508
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THY-2011-0508-ver9-Tomoda_1P
Type: research-article
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total thyroidectomy technique for thyroid cancer is basically
extracapsular removal of the thyroid gland. Due to anatomi-
cal situations, however, subcapsular dissection may be per-
formedonlyinthevicinityofthesuperiorparathyroidglands,
which we usually try to preserve. Estimated residual thyroid
tissue with this procedure is <50mg. Serum levels of TSH
were measured before and 3 months after surgery as part of
routine clinical studies. Frozen-stored serum samples, re-
maining from these studies, were subjected to measurement
of Tg and Tg antibody. Five patients were positive for Tg
antibody. They were excluded from the study, since the
presence of Tg antibody may affect Tg measurement. There
were 13 women and 9 men, ages 21–68 years (median: 49
years).
Serum Tg was measured with the Elecsys Tg Electro-
chemiluminescenceImmunoassay(RocheDiagnosticsGmbH),
which has a lower limit of detection of 0.5ng/mL. The assay
methodforTSH was theARCHITECTTSHChemiluminescent
Microparticle Immunoassay (Abbott), which has a sensitivity
of0.003mIU/L.PresenceofTgantibody wasassessedwiththe
ElecsysAnti-TgElectrochemiluminescence
(RSR Ltd.), and >28IU/mL was regarded as positive for Tg
antibody.
No patient underwent thyroid remnant ablation. The pa-
tientswereprescribedlevothyroxineasareplacementtherapy
after surgery.
Immunoassay
Results
Before surgery, the median TSH level was 1.82mIU/L
(range: 0.7–2.98mIU/L)and medianTglevel was17.8ng/mL
(range: 2.0–74.3ng/mL). In all patients, Tg levels 3 months
after total thyroidectomy decreased to <0.5ng/mL. Serum
TSH concentrations at the time of Tg measurement were
within the normal range in 18 patients, mildly suppressed in 2
patients, and mildly elevated in 1 patient (range: 0.03–
22mIU/L, median: 0.271mIU/L).
Discussion
In 2011, we reported that 16.2% of patients with PTC who
underwent total thyroidectomy and who did not show Tg
antibody had detectable Tg levels that decreased over time
during TSH suppression therapy without radioactive iodine
ablation (6). These patients had an excellent prognosis. There
are two possibilities regarding the origin of Tg in these pa-
tients. The origin might be from residual thyroid tissue, or
from persistent PTC disease. In thecase ofdetectable Tg being
a product of residual thyroid tissue, TSH suppression therapy
will reduce Tg production from this tissue. Most articles
showed that patients after total or nearly total thyroidectomy
have detectable Tg levels before radioactive iodine ablation
(7,8). If the actual extent of intended ‘‘total thyroidectomy’’ is
less than total removal of the thyroid gland leaving a large
amount of thyroid tissue, postoperative serum Tg level
should be detectable. However, the present study showed
that the postoperative serum Tg levels were less than the
lowest detectable level, 0.5ng/mL, in all patients with MTC
who underwent total thyroidectomy using our surgical tech-
niques, similar for PTC, although none of them received ra-
dioactive iodine ablation. So, this fact strongly argues against
thispossibility.Therefore,mostofthepatientswithdetectable
Tg after total thyroidectomy in our previous study should
have had persistent disease, and their serum Tg was not from
residualthyroidtissue.TSHcanstimulateTgproductionfrom
PTC, especially when the cancer is well differentiated (5).
Thus, the patients with decreasing Tg values and negative Tg-
DT in our previous article are most likely to have had meta-
static PTC of a well-differentiated and indolent nature. This
assumption is in accordance with the fact that they had an
excellent prognosis.
In Western countries, total thyroidectomy or near-total
thyroidectomy followed by radioiodine ablation of thyroid
tissue(remnantablation)isconsideredthestandardtreatment
for differentiated thyroid carcinoma (5). Ablation might pos-
sibly reduce the recurrence rate by killing occult micro-
metastases. Mazzaferri et al. reported that cancer mortality
rates were lower in patients who received thyroid ablation
than in those treated with only surgery and those treated with
surgery and levothyroxine therapy alone (9). Our previous
study showed that 137 (32.2%) of 426 patients with PTC had
detectable Tg aftertotal thyroidectomy, indicating thata large
proportionofthepatientshadpersistentdiseaseaftersurgery,
although 74.9% had advanced disease (stage III, IVa, or IVc)
(6). However, 69 patients, 16.2% of the whole study patients
and 50.4% of the patients with persistent disease, had a de-
crease in Tg levels during TSH-suppressive therapy. Al-
though this fact does not directly indicate the shrinkage or
regression of persistent tumors, it suggests that up to 50% of
cases of persistent PTC respond to TSH-suppressive therapy.
Although short Tg-DT was strongly associated with a poor
outcome, patients with long Tg-DT or negative Tg-DT values
have an excellent outcome. Patients with short Tg-DT need
additional treatment, such as radioactive iodine and TSH-
suppressive therapy. They may be good candidates for clini-
cal trials of new drugs. Conversely, for patients with a long
Tg-DT or a Tg-DT that was negative, a watch-and-wait policy
avoiding unnecessary treatment might be appropriate be-
cause these patients would be expected to have a very indo-
lent clinical course.
Conclusions
Serum Tg was not detectable in any of the 22 patients with
MTC after total thyroidectomy. This indicates that most of the
patients with detectable Tg and negative Tg-DT values after
total thyroidectomy for PTC in our previous study had per-
sistent disease, suggesting that a large proportion of patients
with persistent PTC have a decrease in serum Tg levels in
response to TSH-suppressive therapy.
Disclosure Statement
None of the authors has a conflict of interest.
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Address correspondence to:
Akira Miyauchi, M.D., Ph.D.
Department of Kuma Hospital
8-2-35 Shimoyamate-dori, Chuo-ku
Kobe 650-0011
Japan
E-mail: miyauchi@kuma-h.or.jp
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AUTHOR QUERY FOR THY-2011-0508-VER9-TOMODA_1P
AU1: Please review all authors’ surnames for accurate indexing citations.
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