Recurrence Factors and Characteristic Trends of Papillary Thyroid Cancer over Three Decades

Abstract

Background:
The prevalence of thyroid cancer is rising worldwide. Although thyroid cancer has a favorable prognosis, up to 20% of patients experienced recurrent disease during the follow-up period. The present study aimed to examine the trend of incidence and factors associated with recurrence and outcomes of papillary thyroid cancer (PTC) in Thai patients over the last 30 years.

Methods:
We reviewed the clinical data of all patients with PTC who were treated between 1987 and 2019 at Theptarin Hospital. Clinical characteristics, epidemic trend, factors associated with the persistence/recurrence of the disease, overall disease-specific survival rate, and overall disease-free survival rate were analysed.

Results:
A total of 235 patients with PTC who were registered between 1987 and 2019 were reviewed. The mean age was 42.5 ± 14.3 years, with a mean follow-up of 9.5 years. Papillary thyroid microcarcinoma (PTMC) was consistently increased and accounted for 21.4% (50/235) of total cases. The American Thyroid Association (ATA) risk stratification was high in 24% of all PTMCs in the last decade, and 16.0% of these patients experienced local recurrence during the follow-up period. Coexistence with Hashimoto's thyroiditis (HT) was found in one-fifth of the patients with PTC and was correlated with a low recurrence rate (HR: 0.16, P=0.013). Only age ≥55 years associated with the persistence/recurrence of the disease. The overall disease-free survival and disease-specific survival rates were 77.4% and 98.3%, respectively.

Conclusions:
The prognosis of PTC is generally considered favorable. However, approximately one-fourth of patients with PTMC demonstrated more aggressive clinical behavior, particularly in the last decade of the study. Coexistence of HT contributed to a better prognosis.

Full text

Research Article
Recurrence Factors and Characteristic Trends of Papillary Thyroid
Cancer over Three Decades
Waralee Chatchomchuan , Yotsapon Thewjitcharoen , Krittadhee Karndumri,
Sriurai Porramatikul, Sirinate Krittiyawong, Ekgaluck Wanothayaroj,
Somboon Vongterapak, Siriwan Butadej, Veekij Veerasomboonsin,
Auchai Kanchanapitak, Rajata Rajatanavin, and Thep Himathongkam
Diabetes and yroid Center, eptarin Hospital, Bangkok, ailand
Correspondence should be addressed to Waralee Chatchomchuan; waralee.md@gmail.com
Received 3 April 2021; Accepted 29 April 2021; Published 11 May 2021
Academic Editor: Andrea Palermo
Copyright ©2021 Waralee Chatchomchuan et al. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Background. e prevalence of thyroid cancer is rising worldwide. Although thyroid cancer has a favorable prognosis, up to 20% of
patients experienced recurrent disease during the follow-up period. e present study aimed to examine the trend of incidence
and factors associated with recurrence and outcomes of papillary thyroid cancer (PTC) in ai patients over the last 30 years.
Methods. We reviewed the clinical data of all patients with PTC who were treated between 1987 and 2019 at eptarin Hospital.
Clinical characteristics, epidemic trend, factors associated with the persistence/recurrence of the disease, overall disease-specific
survival rate, and overall disease-free survival rate were analysed. Results. A total of 235 patients with PTC who were registered
between 1987 and 2019 were reviewed. e mean age was 42.5±14.3 years, with a mean follow-up of 9.5 years. Papillary thyroid
microcarcinoma (PTMC) was consistently increased and accounted for 21.4% (50/235) of total cases. e American yroid
Association (ATA) risk stratification was high in 24% of all PTMCs in the last decade, and 16.0% of these patients experienced
local recurrence during the follow-up period. Coexistence with Hashimoto’s thyroiditis (HT) was found in one-fifth of the patients
with PTC and was correlated with a low recurrence rate (HR: 0.16, P�0.013). Only age ≥55 years associated with the persistence/
recurrence of the disease. e overall disease-free survival and disease-specific survival rates were 77.4% and 98.3%, respectively.
Conclusions. e prognosis of PTC is generally considered favorable. However, approximately one-fourth of patients with PTMC
demonstrated more aggressive clinical behavior, particularly in the last decade of the study. Coexistence of HT contributed to a
better prognosis.
1. Introduction
yroid cancer is the most common form of endocrine
cancer, accounting for 3% of all new cancer cases in the
United States [1, 2]. Recently, an incidental finding of a small
thyroid cancer, known as microcarcinoma, has gained
considerable attention [3]. Papillary thyroid cancer (PTC)
has generally been documented as an indolent, nonag-
gressive cancer with a low mortality rate [4]. However,
several studies have reported a recurrence in approximately
20% of patients with this disease, in which nearly half of
them were identified more than five years after the initial
operation [1, 4]. Although recurrence of the disease is not
necessarily fatal, it inflicts lifelong and economic burdens to
the patients.
Recently, the changing characteristics of papillary thy-
roid microcarcinoma (PTMC) were observed. PTMC was
previously considered as having a good prognostic factor;
however, additional studies have revealed otherwise on
disease recurrence and metastasis [5]. It is unclear whether
this occurrence is because of an increase in thyroid cancer
incidence or changes in the disease itself. Recent guidelines
have recommended PTMC treatment by lobectomy, unless
it has aggressive characteristics [6]. However, a recent meta-
Hindawi
International Journal of Endocrinology
Volume 2021, Article ID 9989757, 7 pages
https://doi.org/10.1155/2021/9989757

analysis showed that less aggressive treatment in patients
with PTMC increased the risk of recurrence compared with
total thyroidectomy [7]. Identifying clinical characteristics
for high-risk patients is essential for effective treatment of
PTMC.
Racial disparity also affects cancer incidence and out-
comes. Several studies revealed that thyroid cancer incidence
was relatively high among Chinese, but lower in South Asian
and non-Hispanic White [8–10]. A small cohort showed
thyroid cancer tended to be more aggressive, with a higher
rate of recurrence and death, in Filipinos compared to other
races [11].
e present study aimed to explore the evolution of PTC
in ai patients regarding clinical characteristics, unfavor-
able risk factors, aggressiveness, and survival over a 30-year
period.
2. Materials and Methods
2.1. Subjects and Data Collection. We reviewed the clinical
data of all patients diagnosed with PTC who were registered
between 1987 and 2019 at eptarin Hospital, an endocrine
center in ailand. Exclusion criteria included age <15 years,
non-PTC types (poorly differentiated thyroid cancer,
medullary thyroid cancer, anaplastic thyroid cancer, and
other differentiated thyroid cancers), incomplete data, and
follow-up time less than six months (Figure 1).
All patients were categorized according to the American
yroid Association (ATA) risk of recurrence stratification
system and tumor-node-metastasis (TNM) staging criteria
proposed by the American Joint Committee on Cancer
(AJCC), 8
th
edition [12]. Data on preoperative thyroid ul-
trasonography, type of operation, and the association of
Hashimoto’s thyroiditis (HT) were included for analysis. HT
was confirmed by pathology. PTC with ≤1 cm diameter was
defined as PTMC [6]. Serum thyroid-stimulating hormone
(TSH) level, basal and stimulated thyroglobulin levels, neck
ultrasonography, dosage and date of radioactive iodine
ablation, and whole-body scan were monitored postopera-
tively. is study was approved by the Ethical Committee of
eptarin Hospital (EC number: 2/2019).
2.2. Treatment and Follow-Up. All patients were treated by
surgeons performing more than 30 thyroid surgeries per
year [13]. Disease monitoring and treatment were deter-
mined by the attending endocrinologists. Response to
treatment was classified into four categories: excellent, in-
determinate, biochemical incomplete, and structural in-
complete response, according to the recent guidelines [6].
Time to recurrence was calculated from the day of initial
surgery to the day of recurrence confirmed by cytological
and/or pathological data. Persistence was defined as in-
complete remission after the first surgery within one year.
2.3. Statistical Analysis. Statistical Package for the Social
Sciences (version 21.0; IBM, New York, USA) was used for
statistical analysis. Data were presented as means ±standard
deviations or medians ±interquartile ranges (IQRs). Chi-
square test was used to compare different categories. Dif-
ferences in the mean between groups were analysed using a
t-test or ANOVA test. Cox proportional hazards model was
used to perform univariate and multivariate analyses to
analyze the factors associated with recurrence. Potential risk
predictors were age, sex, body mass index (BMI), ATA risk,
coexistence of HT, tumor size, extrathyroidal extension, and
multifocality. e disease-free survival rate was estimated
using the Kaplan–Meier method and compared by using the
log-rank test. All Pvalues were two-sided. P<0.05 was
considered statistically significant.
3. Results
3.1. Clinical Characteristics and Trends of yroid Cancer.
Table 1 summarizes the 235 cases that were included in the
study. Approximately one-fifth of all cases of PTC were
PTMC (n�50, 21.4%). Coexisting thyroid disease, including
Graves’ disease and HT, was found in 23 (9.8%) and 46
(19.6%) of the total patients, respectively. Patients with
persistent/recurrent disease were older than those with re-
mission, with the mean age of 44.7 ±16.3 years vs. 41.8 ±13.6
years, respectively. e median follow-up was 9.5 years
(range: 0.5–31.3 years).
In total, 201 (85.5%) patients presented with a neck mass.
Physical examination revealed thyroid tumors in 30
asymptomatic patients (12.8%). Two patients (0.9%) had
abnormal neck ultrasonography. e remaining patients
(n�2, 0.9%) had other initial presentations, including ax-
illary lymph node enlargement and an incidental finding
from a thyroidectomy specimen.
Of 235 patients, 81.7% underwent surgery at our hospital,
while the rest were referred from other hospitals for further
management after the initial operation. Total or near-total
thyroidectomy was the most performed procedure (n�226,
96.2%). Most patients (n�231, 98.3%) received at least one
dose of postoperative radioactive iodine. Transient and per-
manent hypoparathyroidism were found in 35.3% (n�83) and
4.7% (n�11) of patients, respectively. Only 2.1% of patients
experienced permanent recurrent laryngeal nerve injury. Most
patients (n�205, 87.2%) received thyroid hormone sup-
pression therapy, with serum TSH levels <0.01 mU/L.
Table 2 shows the prevalence rate of thyroid cancer
divided by decade. e incidence of PTMC increased over
the study time, from 15.2% in 1987–1996 to 24.8% in
2007–2019, but without statistical significance, while the age,
sex, BMI, and TNM stage revealed no differences. A sig-
nificant increase of the high-risk ATA group among overall
PTC patients was observed (13.0% in 1987–1996 vs. 34.4% in
2007–2019).
Additionally, a subgroup analysis of PTMC showed that
24% of all PTMCs belonged to the high-risk ATA group. is
trend continued to rise over the study period. In the first
decade of the study, all patients with PTMC were classified as
low-risk ATA group, whereas in the second and third decades
of the study, 4.7% and 7.2% of patients with PTMC were
classified as high-risk ATA group, respectively (Figure 2).
Furthermore, 16.0% of all PTMC patients developed a local
recurrence.
2International Journal of Endocrinology

3.2. Follow-Up and Clinical Response Status after Initial
Treatment. Most patients had an excellent response
(n�151, 64.3%). e biochemical incomplete and structural
incomplete response rates were 17.0% (n�40) and 8.5%
(n�20), respectively. After completing initial treatment, 53
patients (22.6%) developed persistent/recurrent cancer
during the follow-up period. Overall disease-free survival
was 77.4%. A low mortality rate was observed in 11 patients
(4.7%) who died during the study period. Only four patients
(1.7%) died from a cancer-specific cause.
3.3. Factors Associated with Persistent and Recurrent Disease.
Table 3 summarizes the potential risk factors of various
clinicopathological characteristics on persistence and re-
currence of cancer. Univariate analysis showed that age ≥55
years, high ATA risk, and tumor size >4 cm were associated
with an increased risk of recurrence/persistence of cancer,
whereas gender, BMI >27 kg/m
2
, multifocality, and extra-
thyroidal extension had no effects. In multivariate analysis,
only age ≥55 years was a significant predictor of a poor
outcome. Further analysis revealed that higher recurrent rate
Table 1: Demographic data of 235 papillary thyroid cancer patients.
Total (n�235) No recurrence (n�182) Persistence/recurrence (n�53) Pvalue
Age at initial diagnosis (years) 42.5 ±14.3 41.8 ±13.6 44.7 ±16.3 0.180
<55 189 (80.4) 154 (84.6) 35 (66.0)
55–70 38 (16.2) 23 (12.6) 15 (28.3)
>70 8 (3.4) 5 (2.8) 3 (5.7)
Female (%) 192 (81.7) 153 (84.1) 39 (73.6) 0.082
BMI (kg/m
2
) 22.1 ±3.8 22.9 ±3.8 22.9 ±3.6 0.925
ATA risk (%) 0.013
Low 124 (52.8) 105 (57.7) 19 (35.8)
Intermediate 42 (17.8) 31 (17.0) 11 (20.8)
High 69 (29.4) 46 (25.3) 23 (43.4)
Size (cm) 2.3 ±1.4 2.2 ±1.3 2.7 ±1.7 0.031
≤1 50 (21.4) 42 (23.1) 8 (15.4)
>1–2 76 (32.0) 57 (31.3) 19 (34.6)
>2–4 90 (38.5) 72 (39.6) 18 (34.6)
>4 19 (8.1) 11 (6.0) 8 (15.4)
Extrathyroidal extension (%) 18 (7.7) 12 (6.6) 6 (11.5) 0.238
8
th
AJCC staging (%) <0.001
I 211 (89.7) 171 (94.0) 40 (75.4)
II 19 (8.1) 10 (5.5) 9 (17.0)
III 2 (0.9) 0 2 (3.8)
IV 3 (1.3) 1 (0.5) 2 (3.8)
Follow-up time (years) 9.5 ±7.7 9.4 ±7.6 9.7 ±7.8 0.769
Coexistence of Hashimoto’s thyroiditis (%) 46 (19.6) 44 (24.2) 2 (3.8) <0.001
AJCC: the American Joint Committee on Cancer.
All thyroid cancer patients
in Theptarin Hospital Registry
during 1987–2019
(N = 439)
Excluded
Age < 15 years (N = 2)
Non-PTC types (N = 48)
Surgery outside the hospital and no
Pathological reports (N = 66)
Incomplete data (N = 21)
Follow-up time < 6 months (N = 40)
PTC
(N = 235)
Total DTC patients analyzed
(N = 262)
No recurrence
(N = 182)
Persistence/recurrence
(N = 53)
FTC
(N = 20)
Others
(N = 7)
Figure 1: Flowchart depicting the protocol used in this study.
International Journal of Endocrinology 3

was found only in patients at age ≥55 years in the high-risk
ATA group when compared to patients <55 years old
(P�0.001). is effect was not found in patients with low
and intermediate ATA risk groups (P�0.270 and 0.051,
respectively). Coexistence of HT was revealed to be a pro-
tective factor in both univariate and multivariate analyses.
Table 2: Demographic data of papillary thyroid cancer in each decade of the study period.
1987–1996 (n�46) 1997–2006 (n�64) 2007–2019 (n�125) Pvalue
Age at initial diagnosis (years) 38.6 ±13.2 43.6 ±15.2 43.3 ±14.0 0.128
Female (%) 41 (89.1) 48 (75.0) 103 (82.4) 0.160
BMI (kg/m
2
) 22.3 ±3.2 23.1 ±3.9 23.0 ±3.9 0.502
ATA risk (%) 0.036
Low 29 (63.1) 37 (57.8) 58 (46.4)
Intermediate 11 (23.9) 7 (10.9) 24 (19.2)
High 6 (13.0) 20 (31.3) 43 (34.4)
8
th
AJCC staging (%) 0.597
I 43 (93.5) 57 (89.1) 111 (88.8)
II 3 (6.5) 5 (7.8) 11 (8.8)
III 0 0 2 (1.6)
IV 0 2 (3.1) 1 (0.8)
Coexistence of Hashimoto’s thyroiditis (%) 7 (15.2) 10 (15.6) 29 (23.2) 0.328
PTMC (%) 7 (15.2) 12 (19.0) 31 (24.8) 0.348
1987–1996 1997–2006 2007–2019
Low ATA risk (%) 15.2 14.0 14.4
Intermediate ATA risk (%) 0 0 3.2
High ATA risk (%) 0 4.7 7.2
0
5
10
15
20
25
30
Prevalence (%)
Figure 2: e prevalence of papillary thyroid microcarcinoma classified by ATA risk in each decade of the study period.
Table 3: Potential factors of persistent/recurrent papillary thyroid cancer.
Univariate analysis Multivariate analysis
Factor HR 95% CI Pvalue HR 95% CI Pvalue
Age ≥55 years 2.83 1.41–5.68 0.003 2.67 1.27–5.61 0.010
Male 1.89 0.91–3.92 0.086
High ATA risk 2.27 1.20–4.29 0.012 1.73 0.86–3.45 0.122
Tumor size >4 cm 3.24 1.45–7.22 0.004 2.16 0.91–5.12 0.081
Coexistence of Hashimoto’s thyroiditis 0.12 0.03–0.53 0.005 0.16 0.04–0.68 0.013
BMI >27 kg/m
2
0.84 0.34–2.04 0.696
Multifocality 1.52 0.78–2.98 0.219
Extrathyroidal extension 1.84 0.66–5.19 0.244
4International Journal of Endocrinology

Supplementary 1 shows the characteristics of PTC according
to the coexistence of HT. Disease-free survival curves of the
HT and ATA risk category are shown in Figure 3.
4. Discussion
Our main finding consistently showed that the prevalence
rate of thyroid cancer has risen, particularly in the past
decade due to an increase in the incidence of PTMC. A
recent study reported that PTMC contributed to 30% of all
cases of PTC [1], supported our finding (24.8%). An increase
in incidental findings from imaging and the need for a
diagnosis have contributed to this observation. Moreover,
genetic mutation and carcinogenesis from an increase in
radiation exposure, dietary changes, and the use of chemical
fertilizers or genetically modified food may also be re-
sponsible [14]. However, recurrence and mortality rates have
been growing despite early diagnosis and treatment. A re-
cent large cohort study showed that the mortality rate of
thyroid cancer has sharply increased during the past decade
[1]. Possible explanations may include an underestimation
of the aggressiveness of the cancer from under-risk strati-
fication or mutation of the tumor.
According to current guidelines, PTMC has a good
prognosis. However, a previous study conducted during the
early 2000s reported that 14% of PTMCs were aggressive
[15]. More recent study in 2019 indicated that up to 19% of
PTMCs had advanced features, including lymph node
metastasis, extrathyroidal extension, lymphovascular inva-
sion, and distant metastasis [5]. ese trends and clinical
findings were similar to those found in our study. e 8
th
edition AJCC guidelines do not suggest fine needle aspi-
ration for PTMCs unless they have clear evidence of ag-
gressive behavior and highly suspicious ultrasonography
findings. is recommendation was based on the data from
1940 to 2000, which stated that PTMC had an excellent
prognosis and a very low rate of recurrence (2–6%) [16].
However, regarding the upward trend of PTMC aggres-
siveness, an individual tailored approach to treatment is
essential.
Older age and recurrent rate have found a linear cor-
relation. Chereau et al. indicated worse prognosis with in-
creasing age, especially in patients >75 years old. e
recurrence rate increased almost twofold in patients >75
years old compared to patients <65 years old (6.2% vs. 11.7%,
respectively) [17]. In addition, a recent study by Kauffmann
et al. showed that older patients had a higher five-year
mortality rate (hazard ratio �2.3) compared to patients <45
years old. is effect was independent of gender, race,
number of comorbidities, type of operation, hospital vol-
ume, or insurance coverage [18]. However, previous study
showed that the ATA risk category applying with age
showed differences in survival [19]. Similar to our results,
only high-risk ATA category with age at cutoff 55 years
showed significantly higher recurrent rate, while this effect
was not found in low and intermediate ATA risk category.
erefore, very old patients should be considered high-risk
patients, and age should be applied with the ATA risk
category to improve the stratification system.
Our study showed that patients with PTC and coexisting
HT had favorable outcomes. HT has long been debated
whether it is a risk factor for thyroid cancer and contribution
of the prognosis [20]. It is believed that chronic inflam-
mation of the thyroid gland and high TSH levels, typically
found in patients with HT, might be associated with neo-
plastic changes [21, 22]. Several observational studies and
meta-analyses have shown that HT was associated with PTC
incidence [23–25] and better prognosis regarding less lymph
node involvement, less extrathyroidal extension, smaller
tumor size, and longer survival [25, 26]. In a large retro-
spective study with a nine-year follow-up, the cancer-spe-
cific mortality and recurrence rates were lower in patients
0
Months
Disease-free survival
HT
No HT
0.2
0.4
0.6
0.8
1.0
060 120 180 240 300 360
P value = 0.002
(a)
0
Months
Disease-free survival
1.0
0.8
0.6
0.4
0.2
060 120 180 240 300 360
P value < 0.001
Low ATA risk (all ages)
Intermediate ATA risk (all ages)
High ATA risk (age ≥ 55 years)
High ATA risk (age < 55 years)
(b)
Figure 3: Disease-free survival curves of patients with papillary thyroid cancer based on the following classifications: (a) coexistence of
Hashimoto’s thyroiditis (HT); (b) ATA risk category.
International Journal of Endocrinology 5

with coexisting PTC and HT compared to those without HT
(2.2% vs. 4.6% and 4.3% vs. 14%, respectively) [27]. Tumor
cells can trigger both innate and noninnate immunity, which
may lead to an antineoplastic immune response [28].
Recurrence/persistence of PTC has been reported to
range from 8.4% to 32% [29], which was similar to our
results. ese variations might result from different initial
approach methods, severity of the disease, treatment, race,
and follow-up duration. In this study, most of our patients
had a serum TSH level <0.01 over the treatment period
which might affect the treatment outcomes.
4.1. Limitation of the Study. Our study has some limitations
because of its retrospective nature and possible selection
bias. Additionally, the data might not be fully representative
of the total population because of the limited sample size.
However, this study provides the trends and clinical char-
acteristics of PTC over a 30-year period.
5. Conclusions
e incidence and aggressiveness of thyroid cancer have
increased, and increased incidence of PTMC has contributed
to this trend. e outcome of PTMC may not be favorable.
Treatment should be in accordance with risk stratification.
Coexistence with HT is considered a good prognostic, and
age ≥55 years is associated with poorer outcomes.
Data Availability
e data that support the findings of this study are restricted
to the Institutional Review Board of eptarin Hospital. Due
to the privacy of patients, the data are available from the
corresponding author upon reasonable request.
Disclosure
Parts of this manuscript had previously been presented as a
poster in Endocrine Society Conference 2021 (virtual
meeting). e funder had no role in the study design, data
collection, and analysis.
Conflicts of Interest
e authors declare that there are no conflicts of interest
regarding the publication of this paper.
Acknowledgments
is research would not have been possible without the
support of all the staff in the research unit. e authors also
thank the staff of eptarin Hospital for their assistance. is
work was supported by the eptarin Research Unit,
eptarin Hospital (Grant no. 2/2019).
Supplementary Materials
Supplementary 1: demographic data of 235 papillary thyroid
cancer patients according to the coexistence of HT. (Sup-
plementary Materials)
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