O R I G I N A L A R T I C L E

Radioactive iodine ablation does not prevent recurrences in

patients with papillary thyroid microcarcinoma
Hye Jeong Kim, Na Kyung Kim, Ji Hun Choi, Se Won Kim, Sang-Man Jin, Sunghwan Suh, Ji Cheol Bae, Yong-Ki
Min, Jae Hoon Chung and Sun Wook Kim
Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, Korea
Summary
Objective Although papillary thyroid microcarcinoma (PTMC)
has a favourable long-term prognosis, disease recurrence after
initial treatment remains a problem and controversy exists
regarding the role of radioactive iodine (RAI) ablation in PTMC.
We performed this study to evaluate the effect of RAI ablation
on disease recurrence in patients with PTMC.
Patients and Methods Between 1994 and 2004, 2579 patients
underwent thyroid surgery for thyroid cancer at Samsung Medi-
cal Center. Among these patients, 704 patients with PTMC pre-
sumed disease-free after initial treatment were followed up for
disease recurrence (median, 64 months; range, 1185 months).
Patients with PTMC with microscopic extrathyroidal extension,
cervical lymph node metastases or multifocality were considered
to be in the intermediate-risk group for recurrence.
Results Disease recurrence was found in six patients at a med-
ian of 29 months (range, 1070 months) after initial treatment;
all six patients with recurrent tumours had received RAI treat-
ment after total thyroidectomy. Disease-related mortality was
not observed, even after recurrence. Based on a Cox regression
model considering the standardized inverse probability of treat-
ment weight (IPTW) within each propensity score stratum of
patients with a similar likelihood of having received RAI abla-
tion, the likelihood ratio for recurrence did not differ between
the RAI ablation group and no RAI group (P = 017). When we
performed a subgroup analysis considering only patients with
PTMC at intermediate-risk for recurrence, RAI ablation again
did not have a signicant effect on recurrence (P = 079).
Conclusions Radioactive iodine ablation after total thyroidec-
tomy in low- and intermediate-risk patients with PTMC did not
prevent recurrent tumours. Future randomized, controlled, mul-
ticenter prospective trials involving a larger sample of patients
followed-up for a longer duration are warranted to conrm our
ndings.
(Received 9 July 2012; returned for revision 4 August 2012; nally
revised 3 September 2012; accepted 3 September 2012)
Introduction
The incidence of papillary thyroid microcarcinoma (PTMC),
dened as a papillary thyroid carcinoma (PTC) with a maximal
diameter of 1 cm or less by the World Health Organization
(WHO),
1
has increased rapidly in recent years.
2
This increase in
incidence is due largely to increased detection of small nonpal-
pable nodules by thyroid ultrasound and other imaging modali-
ties such as computed tomography, magnetic resonance imaging
and
18
F-uorodeoxyglucose positron emission tomography scan-
ning.
3,4
Because the clinical signicance of these incidentally
detected PTMCs is not well established, the rapid rise in the
incidence of these carcinomas has issued controversies in man-
agement strategies.
Although the vast majority of patients with PTMC have an
excellent prognosis, disease recurrence after initial treatment
does occur. Moreover, some studies have demonstrated that
the prevalence of aggressive tumour features and disease recur-
rence of PTMC are similar to those found in PTCs larger than
1 cm.
5,6
According to recent American
7
and European
8
man-
agement guidelines for patients with thyroid cancer, selective
use of radioactive iodine (RAI) ablation is recommended in
tumours of any size with microscopic extrathyroidal extension
and/or cervical lymph node metastasis. For patients who have
multifocal cancer with all foci <1 cm and no higher risk fea-
tures, RAI ablation appears not to prevent recurrence.
9,10
Although microscopic extrathyroidal extension,
11,12
cervical
lymph node metastasis
9,10,13
and multifocality
3,9,10
are associ-
ated with an increased recurrence rate, it remains unclear
whether RAI ablation in PTMC patients with these risk factors
reduces recurrence.
We designed this study to determine whether RAI ablation
after total thyroidectomy inuences the risk of recurrence in
patients with PTMC, especially patients at low to intermediate-
risk for recurrence.
Correspondence: Sun Wook Kim, Division of Endocrinology and Metab-
olism, Samsung Medical Center, #50 Irwon-dong, Gangnam-gu, 135-710
Seoul, Korea. Tel.: (82)10 9933 1653; Fax: (82)2 3410 3849;
E-mail: swkimmd@skku.edu
614 2012 Blackwell Publishing Ltd
Clinical Endocrinology (2013) 78, 614620 doi: 10.1111/cen.12034
Patients and methods
Study population
Between October 1994 and December 2004, 2579 patients
underwent thyroid surgery for thyroid cancer at Samsung Medi-
cal Center. Institutional review board approval for this study
was obtained. Patient charts were reviewed to collect the follow-
ing data: demographic information such as gender, age at diag-
nosis; extent of surgery; various histological parameters
including primary tumour size, extrathyroidal extension and cer-
vical lymph node involvement [absence of lymph node metasta-
sis (N0), presence of central lymph node metastasis (N1a),
presence of lateral lymph node metastasis (N1b)]; distant metas-
tasis; RAI therapy and accumulated RAI doses; and clinical out-
come at the last follow-up. For multifocal tumours, the diameter
of the largest tumour focus was taken as the primary tumour
size. Tumour-node-metastasis (TNM) staging was based on the
UICC/AJCC 7th edition.
14
Of 2417 patients who had PTCs, 963
(40%) had PTMCs. Among 963 PTMCs, 711 patients underwent
total thyroidectomy. Seven patients were excluded from the
analysis because one patient had distant metastasis at the time
of PTMC diagnosis and six patients had macroscopic extrathy-
roidal invasion, which is a high risk factor for disease recur-
rence. Thus, data from a total of 704 patients who were
considered disease-free after initial therapy were analysed
(Fig. 1). Disease-free was dened as patients who had undergone
grossly complete resection of their tumours and who had no
imaging evidence of tumours regardless of serum thyroglobulin
(Tg) levels. Patients were classied as low risk or intermediate-
risk according to the risk of recurrence. Low-risk patients were
dened as follows: complete tumour resection, no extrathyroidal
extension, no cervical lymph node metastasis and no distant
metastasis. Patients who had PTMC with microscopic extrathy-
roidal extension, cervical lymph node metastases or multifocality
were considered to be at intermediate-risk of recurrence.
Management strategy
Total thyroidectomy with or without RAI ablation and TSH
suppression therapy by levothyroxine were the initial therapies
considered. Completion thyroidectomy that was performed
within 3 months of the initial surgery was also classied as total
thyroidectomy. Our candidate criteria for RAI ablation in
patients with PTMC was the presence of any of the following:
extrathyroidal extension, cervical lymph node involvement or
multifocality. However, nal decision on RAI ablation was made
by attending physicians and patient preference. TSH suppression
therapy was maintained to achieve a serum TSH level below
05 mU/l. All patients were followed by clinical examination,
Fig. 1 Flow chart of the study population.
2012 Blackwell Publishing Ltd
Clinical Endocrinology (2013), 78, 614620
Radioactive iodine ablation in papillary thyroid microcarcinoma 615
assessment of serum Tg levels and Tg antibodies, and ultrasound
of the neck every 6 months for 2 years, and annually thereafter.
In the presence of a signicantly elevated level of Tg and/or Tg
antibodies, recurrent tumours were searched for using various
imaging modalities, and histological proof was obtained when
necessary.
Study end-points
Tumour recurrence was dened as when a patient who
initially met the criteria for remission was later found to have
new evidence of a recurrence, and these recurrences were all
pathologically proved. The criteria for remission were no clini-
cal or imaging evidence of tumours and serum Tg levels
lower than 2 ng/ml during TSH suppression and stimulation
in the absence of interfering antibodies. Biochemical persistent
disease was dened as when a patient did not meet the crite-
ria for remission throughout the documented observation
xperiod without clinical or imaging evidence of tumours. Bio-
chemical evidence of persistent disease with Tg level higher
than 2 ng/ml only without evidence of pathologically proven
disease after initial treatment was not considered to indicate
recurrence.
Statistical analysis
Age at diagnosis and primary tumour size were expressed as
means (SD) or medians (25th, 75th percentile), and differ-
ences between groups were compared using the independent-
sample Students t-test or KruskalWallis test as appropriate.
Group comparisons of categorical variables were made using
the chi-square test or, for small cell values, Fishers exact test.
Results of categorical data were summarized using frequencies
and percentage values. The specic therapy examined in our
analysis was postoperative RAI for remnant ablation vs no RAI
in patients who underwent total thyroidectomy. The outcomes
of all patients with follow-up data were considered in the anal-
ysis of disease recurrence. Recurrence-free survival curves were
estimated using KaplanMeier estimation and were compared
using the log-rank test. Due to the potential impact of bias in
the selection of patients for RAI therapy in this observational
study, the standardized inverse probability of treatment weight
(IPTW) was calculated using the probability of receiving RAI
(propensity score).
15,16
The propensity score was estimated
using a logistic regression model that included gender, age,
tumour size, extrathyroidal invasion, cervical lymph node
metastasis and multifocality of the tumour at presentation. The
goodness of t of the propensity score was calculated to deter-
mine whether the model discriminated well between patients
who received RAI ablation and those who did not, thus balanc-
ing covariates that might have inuenced outcomes. We analy-
sed the data with a Cox regression model considering IPTW.
Likelihood ratio statistics were calculated. The Efron method
was used due to tied recurrence times. Statistical analyses were
executed using SAS version 9.1.3 (SAS Institute, Cary, NC,
USA). A P-value <005 was considered statistically signicant.
Results
Baseline clinicopathologic features of patients with
PTMC
We evaluated 704 patients with PTMC who were not considered
at high risk of recurrence, that is, no evidence of macroscopic
extrathyroidal extension or distant metastasis at the time of
study entry. The median follow-up duration in all patients with
PTMC was 64 months (range, 1185 months), and 65 months
(1153 months) in intermediate-risk group, specically. The
clinicopathologic characteristics of these patients are summarized
in Table 1. Among the 704 patients, 631 (90%) were women
and 73 were men. The mean (SD) age was 47 (11) years (range,
1775 years), and 56% of the patients were older than 45 years
at the time of diagnosis. The median (25th, 75th percentile)
tumour size was 06 (05, 08) cm (range, 0110 cm). Thirty-
two percentage of patients had multifocal tumours, and 46% of
patients had tumours with microscopic extrathyroidal extension.
Cervical LN metastasis was noted in 168 patients (24%), and
N1a and N1b were 120 (17%) and 48 (7%), respectively. Sixty-
three percentage of patients were classied as having stage I dis-
ease, 23% as having stage III disease and 14% as having stage IV
disease. Two hundred twenty-four patients (32%) were identi-
Table 1. Baseline clinicopathological characteristics of patients with
papillary thyroid microcarcinoma at initial diagnosis
Characteristic n = 704
Female gender 631 (90%)
Age (years) 47 11
Age 45 394 (56%)
Primary tumour size (cm) 06 (05, 08)
Multifocality 228 (32%)
Extrathyroidal invasion 326 (46%)
Cervical LN metastasis
N1a 120 (17%)
N1b 48 (7%)
TNM staging
Stage I 443 (63%)
Stage III 160 (23%)
Stage IV 101 (14%)
Risk of recurrence
Low risk 224 (32%)
Intermediate-risk 480 (68%)
RAI therapy
No RAI 126 (18%)
<100 mCi 333 (47%)
100 mCi 245 (35%)
Disease status at last follow-up
Remission 617 (88%)
Recurrence 6 (1%)
Biochemical persistence 81 (11%)
Death of thyroid cancer 0 (0)
RAI, radioactive iodine.
Data are presented as weighted numbers (percentage), means (SD), or
medians (25th, 75th percentile) as appropriate.
2012 Blackwell Publishing Ltd
Clinical Endocrinology (2013), 78, 614620
616 H. J. Kim et al.
ed as having a low risk of recurrence, and 480 (68%) were
identied as having an intermediate-risk of recurrence. Of 704
patients, 126 did not undergo RAI ablation. Three hundred
thirty-three patients (333/704, 47%) received <100 mCi of RAI
after total thyroidectomy, while 245 (245/704, 35%) received
more than 100 mCi RAI after total thyroidectomy. At last fol-
low-up, six patients (1%) had disease recurrence, and 81 (11%)
had biochemical persistent disease.
Comparison of patient characteristics according to RAI
To assess the likelihood of receiving RAI ablation based on clini-
copathologic features, we compared the clinicopathologic char-
acteristics of the patients according to whether they received
RAI ablation or not (Table 2).
Among all patients with PTMC (n = 704), 578 patients (82%)
received RAI ablation after total thyroidectomy, and 126 (18%)
did not receive RAI after total thyroidectomy. A larger median
PTMC size (P = 0008), multifocality (P < 00001), extrathyroidal
extension (P < 00001), cervical lymph node involvement
(P < 00001) and advanced TNM stage (P < 00001) were associ-
ated with an increased likelihood of receiving RAI in all patients
with PTMC.
When we focused on intermediate-risk patients (n = 480),
RAI ablation was performed in 450 patients with PTMC (94%).
The patients who received RAI generally had a more advanced
TNM stage than those who did not receive RAI (P = 004).
However, demographic and pathologic data other than the TNM
stage did not differ between patients who received RAI and
those who did not.
Effect of RAI ablation on recurrence
During follow-up, disease recurrence after initial treatment
occurred in six patients at a median of 29 months (range,
1070 months). Their characteristics are shown in Table 3. All
recurrences were localized to the thyroid bed or regional neck
nodes, and none of these patients developed distant metastases
during follow-up. Unexpectedly, all patients with recurrent
tumours had previously received RAI ablation. However, dis-
ease-related mortality was not observed.
The recurrence-free survival curve for intermediate-risk
patients who received RAI and those who did not was not sig-
nicantly different (P = 052, Fig. 2). Based on a Cox regression
model considering IPTW within each propensity score stratum
of patients with a similar likelihood of having received RAI abla-
tion, the likelihood ratio for recurrence did not differ signi-
cantly between the no RAI and RAI ablation groups in any of
the patients with PTMC (P = 017, Table 4). Moreover, there
was no signicant difference in the likelihood ratio for recur-
rence between intermediate-risk patients who received RAI and
intermediate-risk patients who did not receive RAI (P = 079,
Table 4).
Discussion
In our cohort of 704 patients with PTMC, only six (08%)
developed disease recurrence and no disease-related mortality
was observed. The risk of recurrence did not differ signicantly
between those patients who received RAI after total thyroidec-
tomy and those who did not. In subgroup analysis of patients
with intermediate-risk PTMCs, there was also no difference in
Table 2. Clinicopathologic features of intermediate-risk patients with papillary thyroid microcarcinoma according to radioactive iodine therapy
Characteristic
All (n = 704)
P
1
-value
Intermediate-risk (n = 480)
P
2
-value
No RAI
(n = 126)
RAI
(n = 578)
No RAI
(n = 30)
RAI
(n = 450)
Female gender 110 (87%) 521 (90%) NS 27 (90%) 406 (90%) NS
Age (years) 47 12 47 11 NS 43 13 47 11 NS
Age 45 74 (59%) 320 (55%) NS 12 (40%) 252 (56%) NS
Primary tumour size (cm) 06 (04, 07) 06 (05, 08) 0008 06 (05, 07) 07 (05, 08) NS
Multifocality 15 (12%) 213 (37%) <00001 15 (50%) 213 (47%) NS
Extrathyroidal extension 19 (15%) 307 (53%) <00001 19 (63%) 307 (68%) NS
Cervical LN metastasis
N1a 3 (2%) 117 (20%) <00001 3 (10%) 117 (26%) NS
N1b 3 (2%) 45 (8%) 3 (10%) 45 (10%)
TNM stage
Stage I 112 (89%) 331 (57%) <00001 22 (73%) 213 (47%) 004
Stage III 7 (6%) 153 (26%) 6 (20%) 153 (34%)
Stage IV 7 (6%) 94 (16%) 2 (7%) 84 (19%)
RAI, radioactive iodine; LN, lymph node; NS, not signicant.
Intermediate-risk patients with papillary thyroid microcarcinoma were dened as patients who had any of the following: microscopic extrathyroidal
extension; cervical lymph node metastases; multifocality. Data are presented as numbers (percentage), means (SD) or medians (25th, 75th percentiles)
as appropriate. Age at diagnosis was compared by the independent-sample Students t-test. Primary tumour size was analysed using the MannWhitney
U-test. Group comparisons of categorical variables were performed using the chi-square test or, for small cell values, Fishers exact test.
2012 Blackwell Publishing Ltd
Clinical Endocrinology (2013), 78, 614620
Radioactive iodine ablation in papillary thyroid microcarcinoma 617
the likelihood ratio for recurrence according to RAI ablation
therapy. Our study specically focused on intermediate-risk
PTMCs, which we dened as a tumour(s) with any of the fol-
lowing characteristics: microscopic extrathyroidal extension, cer-
vical lymph node metastases or multifocality, for which
conicting or inadequate data have previously been reported in
the literature. This question remains important because of the
rapid increase in the incidence of PTMCs.
Microscopic extrathyroidal extension,
11,12
cervical lymph node
metastasis
9,10,13
and/or multifocality
3,9,10
are known to be associ-
ated with an increased incidence of recurrence. Some studies
reported that the incidence of microscopic extrathyroidal exten-
sion, cervical lymph node metastasis and/or multifocality in
PTMC was similar to that in PTCs larger than 1 cm, and these
authors proposed that PTMCs should be treated like PTCs larger
than 1 cm.
5
The reported prevalence of microscopic extrathyroi-
dal extension varies, but has been reported in up to 32% of
patients with PTMC.
13,17
Cervical lymph node metastasis was
noted in about 2243% of patients,
5,9,10,13
and multifocality was
discovered in 2356% of patients with PTMC.
5,9,10,13
Similarly,
we found that 24% of patients with PTMC had cervical lymph
node metastasis and 32% had multifocality. The frequency of
microscopic extrathyroidal extension in our study was 46%,
which is higher than the value reported in previous studies.
13,17
However, ATA and ETA guidelines do not recommend for or
against RAI ablation after surgery in patients with PTMC with
microscopic extrathyroidal extension and/or cervical lymph node
metastasis.
7,8
Furthermore, RAI ablation is not recommended
for patients with multifocal PTMC in the absence of other
higher risk features in the ATA guidelines.
7
The dilemma that
clinicians face when deciding among therapeutic options for
PTMC is compounded by the lack of prospective randomized
trials. Some retrospective studies that support the use of RAI as
adjuvant therapy have showed a signicant reduction in the
rates of disease recurrence in patients with PTMC.
13,18
However,
recent data have brought the efcacy of RAI in patients with
PTMC into doubt. Ross et al.
10
described their experiences in a
group of 611 patients with PTMC. They found that multifocality
and nodal metastasis were common and were associated with
recurrence. However, RAI ablation did not reduce the incidence
of recurrence in patients with multifocal tumours or patients
with cervical lymph node involvement. Hay et al.
9
reported that
higher recurrence rates in PTMC patients with multifocal
tumours as well as node-positive patients. However, neither
more extensive surgery nor RAI ablation reduced the recurrence
rates compared with unilateral lobectomy. Pelizzo et al.
19
evalu-
ated a group of 403 patients with PTMC and found no signi-
Table 3. Summary of clinicopathologic data of the six patients with recurrence
No. Sex
Age
(year)
Size
(cm)
No. of
tumours ETE
N
staging
TNM
staging
RAI
therapy
Site of
recurrence
1 F 35 07 1 No N1a I Yes Thyroid bed
2 F 38 07 1 Yes N1a I Yes Thyroid bed + Nodes
a
3 F 42 06 2 Yes N0 I Yes Nodes
a
4 F 43 08 4 Yes N1a I Yes Nodes
a
5 M 56 09 3 Yes N1b IV Yes Thyroid bed
6 F 38 07 2 Yes N1a I Yes Nodes
a
ETE, extrathyroidal extension; N staging, cervical lymph node metastasis; RAI, radioactive iodine; N0, absence of lymph node metastasis; N1a, presence
of central lymph node metastasis; N1b, presence of lateral lymph node metastasis.
a
Cervial lymph node recurrence was found in the lateral compartment.
Fig. 2 KaplanMeier estimate of recurrence-free survival in intermediate-
risk patients with papillary thyroid microcarcinoma stratied according to
radioactive iodine (P = 052).
Table 4. The impact of radioactive iodine (RAI) ablation on disease
recurrences according to RAI
RAI effect P-value
All (n = 704) 017
Intermediate-risk (n = 480) 079
Due to the potential impact of bias in selecting patients for RAI therapy
in this observational study, the standardized inverse probability of treat-
ment weight was calculated using the probability of receiving RAI (pro-
pensity score). The propensity score was estimated by a logistic
regression model that included gender, age, tumour size, extrathyroidal
invasion, cervical lymph node metastasis and multifocality of tumour at
presentation. We analysed the data by Cox regression analysis using
inverse probability of treatment weight. Likelihood ratio statistics were
used for the test. The Efron method was used due to tied recurrence
times.
2012 Blackwell Publishing Ltd
Clinical Endocrinology (2013), 78, 614620
618 H. J. Kim et al.
cant difference in recurrence between patients treated by total
thyroidectomy alone and those treated by both total thyroidec-
tomy and RAI ablation. Lin and Bhattacharyya
20
also demon-
strated that there was no thyroid cancer-specic survival benet
from the use of RAI therapy in PTMC patients without evidence
of locoregional or distant disease when compared with the out-
comes of a similar group of patients who did not receive RAI.
In the intermediate-risk patients with PTMC evaluated in this
study (patients with tumours with microscopic extrathyroidal
extension, cervical lymph node metastasis and/or multifocality),
RAI ablation did not lower the risk of recurrence. Moreover, all
recurrences (n = 6) were local in nature and occurred in
patients who had undergone RAI ablation after total
thyroidectomy. We performed Cox regression analysis using the
IPTW propensity score due to the possibility of patient selection
bias for the use of RAI ablation. According to this rather com-
plex statistical analysis, RAI ablation did not provide a signi-
cant advantage with regard to preventing disease recurrence in
patients with PTMC; our data support the nding of several
previous studies
9,10,19,20
that RAI ablation does not result in
superior outcomes for small tumours. In addition, all recur-
rences were localized to the thyroid bed or regional neck nodes,
and none of the patients developed distant spread during fol-
low-up. Therefore, we believe that postoperative follow-up by
neck ultrasound, measurement of serum Tg levels and TSH sup-
pressive hormonal therapy without RAI ablation is an adequate
strategy for the management of patients with PTMC who are at
low to intermediate-risk for recurrence.
Postsurgical administration of RAI is increasingly being used
to destroy any remaining thyroid remnants after total thyroidec-
tomy to facilitate follow-up
21
or to destroy any remaining
microscopic cancer cells.
7
Although the risk of subsequent can-
cer from a single dose of RAI administration is low, it is not
zero.
22,23
Preparation for RAI treatment requires either with-
drawal of thyroid hormone or injection of recombinant human
thyrotropin, as well as a 2-week low-iodine diet, which decreases
quality of life. Furthermore, when the patient is treated, precau-
tions have to be taken to reduce the radiation exposure of family
members and the public. Finally, after treatment, there could be
transient or permanent impairment of the salivary and lacrimal
glands.
24,25
Considering the expected excellent outcome in
patients with PTMC, we consider it reasonable to limit RAI to
patients with high risk features such as macroscopic extensions
or distant metastases.
Our study has some limitations. First, this study is retrospec-
tive analysis and consequently suffers from the inherent limita-
tion of bias in selection of patients for RAI ablation, which
could serve as confounding factors in evaluating treatments
effects of RAI ablation. Thus, we adopted the standardized
IPTW in analysing the effect of RAI ablation on disease recur-
rence. The IPTW method based on the propensity score is the
approaches utilized to adjust for confounding variables between
binary treatment groups and is a powerful method for use with
observational data.
15,16
To test the statistical power of this study,
we calculated the difference in 10-year recurrence-free survival
rate according to RAI and estimated 95% condence interval for
the difference. The calculated difference in 10-year recurrence-
free survival rate according to RAI was 18%, and the 95% con-
dence interval for the difference was (03%, 39%). So, we
could conclude that our data were adequately powered. Second,
only six patients developed a recurrent tumour, and analysis of
disease-specic survival was not possible because there was no
disease-related death in this study subjects. Despite these caveats,
we believe that our ndings can inform the management of
patients with PTMC after surgery and serve as a legitimate basis
for future prospective studies.
In summary, our data suggest that patients with PTMC have
an excellent prognosis even if there is microscopic extrathyroidal
extension, cervical lymph node metastasis and/or multifocality.
Postoperative RAI ablation in low- to intermediate-risk patients
with PTMC does not prevent disease recurrence. Future pro-
spective, randomized, controlled, multicenter trials with a larger
sample of patients and a longer follow-up duration are required
to conrm our ndings.
Disclosure
The authors have no competing interests to disclose.
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