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1 1 Changes of Clinicopathologic Characteristics and Survival Outcomes of Anaplastic and 1 Poorly Differentiated Thyroid Carcinoma 2 Doh Young Lee, MD 1 , Jae-Kyung Won, MD 2 , Se Hoon Lee, MD, PhD 3 , Do Joon Park, MD, 3 PhD 4 , Kyeong Cheon Jung, MD, PhD 2 , Myung-Whun Sung, MD, PhD 5 , Hong-Gyun Wu, 4 MD, PhD 6 , Kwang Hyun Kim, MD, PhD 5 , Young Joo Park, MD, PhD 4* , J. Hun Hah, MD, 5 PhD 5* 6 1 Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of 7 Medicine, Seoul, Korea; 8 2 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea; 9 3 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 10 Sungkyunkwan University School of Medicine, Seoul, Korea 11 4 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 12 Korea; 13 5 Department of Otorhinolaryngology-Head and Neck Surgery and Cancer Research Institute, 14 Seoul National University College of Medicine, Seoul, Korea; 15 6 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, 16 Korea. 17 18 19 20 Page 1 of 46 Thyroid Changes of Clinicopathologic Characteristics and Survival Outcomes of Anaplastic and Poorly Differentiated Thyroid Carcinoma (doi: 10.1089/thy.2015.0316) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Transcript of Changes of Clinicopathologic Characteristics and Survival Outcomes … › data › board_notice ›...
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Changes of Clinicopathologic Characteristics and Survival Outcomes of Anaplastic and 1
Poorly Differentiated Thyroid Carcinoma 2
Doh Young Lee, MD1, Jae-Kyung Won, MD
2, Se Hoon Lee, MD, PhD
3, Do Joon Park, MD, 3
PhD4, Kyeong Cheon Jung, MD, PhD
2, Myung-Whun Sung, MD, PhD
5, Hong-Gyun Wu, 4
MD, PhD6, Kwang Hyun Kim, MD, PhD
5, Young Joo Park, MD, PhD
4*, J. Hun Hah, MD, 5
PhD5* 6
1Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of 7
Medicine, Seoul, Korea; 8
2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea; 9
3Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 10
Sungkyunkwan University School of Medicine, Seoul, Korea 11
4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 12
Korea; 13
5Department of Otorhinolaryngology-Head and Neck Surgery and Cancer Research Institute, 14
Seoul National University College of Medicine, Seoul, Korea; 15
6Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, 16
Korea. 17
18
19
20
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Authors’ contact information 21
Doh Young Lee: Tel: +82-2-920-6280, E-mail: [email protected] 22
Jae-Kyung Won: Tel: +82-2-2072-2788, E-mail: [email protected] 23
Se Hoon Lee: Tel: +82-2-2072-0832, E-mail: [email protected] 24
Do Joon Park: Tel: +82-2-2072-2228, E-mail: [email protected] 25
Kyeong Cheon Jung: Tel: +82-2-2072-2828, E-mail: [email protected] 26
Myung-Whun Sung: Tel: +82-2-2072-2916, E-mail: [email protected] 27
Hong-Gyun Wu: Tel: +82-2-2072-3177, E-mail: [email protected] 28
Kwang Hyun Kim: Tel: +82-2-2072-2448, E-mail: [email protected] 29
Young Joo Park: Tel: +82-2-2072-4183, E-mail: [email protected] 30
J. Hun Hah: Tel: +82-2-2072-3649, E-mail: [email protected] 31
32
Running title: Anaplastic/poorly differentiated thyroid cancer 33
Key Words: anaplastic thyroid cancer, poorly differentiated cancer, anaplastic foci, survival, 34
lymphatic invasion, resectability 35
This article was presented in 84th
annual meeting of American Thyroid Association, 36
Coronado, CA, USA. 37
38
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ABSTRACT 39
40
Background: This study aimed to analyze the temporal changes of the clinicopathologic 41
characteristics, and the long-term outcomes, of various types of anaplastic and poorly 42
differentiated thyroid cancer. 43
Methods: A retrospective analysis was conducted on patients with anaplastic and poorly 44
differentiated thyroid cancer who were treated from the period 1985 to 2013. The outcome 45
measures included the clinical response to treatment and the survival rates of three separate 46
thyroid cancer groups: anaplastic thyroid cancer (ATC), poorly differentiated thyroid cancer 47
(PDTC), and differentiated thyroid cancer (DTC) with anaplastic foci. 48
Results: The 5 year disease specific survival rate was significantly higher, both in DTC with 49
anaplastic foci and in PTDC (81.3% and 65.8%, respectively), than in ATC (14.3%; p<0.001). 50
The proportion of cases of DTC with anaplastic foci has been increasing over time, while that 51
of ATC has decreased. Survival rate was found to be significantly higher in resectable tumors 52
(71.4% and 26.5%, respectively) (p<0.001). In ATC, external beam radiation therapy showed 53
longer survival rates than surgery-based treatment in unresectable tumors (19.2 vs 7.7 months, 54
p=0.006). Adjuvant treatment with external beam radiation or radioactive iodine increased 55
survival duration in PDTC and in DTC with anaplastic foci. Lymphatic invasion was the most 56
significant postoperative prognosticator in ATC (p=0.013). 57
Conclusions: The choice of treatment of ATC and PDTC could be modified according to 58
resectability and lymphatic invasion of the cancer. 59
60
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INTRODUCTION 61
62
The theory is now generally accepted that anaplastic thyroid cancer (ATC) and 63
poorly differentiated thyroid cancer (PDTC) usually develop from the transformation or 64
dedifferentiation of differentiated thyroid cancer (DTC); this has been supported by several 65
studies that have assessed the histological coexistence and biomolecular coincidence of ATC 66
and PDTC with DTC in the same tumor (1-6). With the development of improved diagnostic 67
tools, detection of early thyroid cancer has increased, revealing an increased relative 68
incidence of ATC or PDTC presenting with a co-existing DTC component (7). 69
Although ATC is one of the most virulent and aggressive of all malignancies, 70
showing extremely short survival outcomes regardless of treatment modality (8,9), tumors 71
with small anaplastic foci in the background of DTC have been reported to have better 72
prognoses (7). Moreover, PDTC has a better prognosis than does ATC, although treatment-73
refractory disease can occur, not infrequently with death as the outcome (10). Given these 74
reported better outcomes of tumors with anaplastic foci in the background of DTC and of 75
PDTC (7), and the various differing prognoses according to the histologic components, the 76
evaluation of the clinicopathologic characteristics of the changes and the outcomes of ATC or 77
PDTC has become important for appropriate management. However, until recently, only a 78
limited number of studies regarding the various types of ATC and PDTC have been reported. 79
Therefore, this study aimed to analyze the temporal changes of the clinicopathologic 80
characteristics of ATC or PDTC according to their histologic components, and to compare 81
their survival outcomes and related factors. 82
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MATERIALS AND METHODS 83
84
Subjects 85
A retrospective chart review was performed on 184 patients who were diagnosed 86
with ATC or PDTC at Seoul National University Hospital from January 1985 to December 87
2013. The medical records were reviewed, including year of diagnosis, sex, age at diagnosis, 88
blood chemistry, tumor pathology, stage, method of treatment, and follow-up and survival 89
duration from the date of diagnosis. Tumor size was defined either as the maximal diameter 90
of the surgical specimen or the size as measured by imaging modalities (usually CT scan). To 91
evaluate the time trend regarding diagnosis, treatment, and survival outcomes, the subjects 92
were divided according to the study period as follows: 1) from 1985 to 1994, 2) from 1995 to 93
2004, and 3) from 2005 to 2013. This study was conducted in accordance with the principles 94
of the Declaration of Helsinki, and approved by the Institutional Review Board of Seoul 95
National University Hospital (No. B-1405-096-580). 96
97
Definition of pathologic findings and categorization 98
Pure ATC was defined as a tumor with no demonstrable areas of coexisting 99
differentiated thyroid cancer. ATC arising from DTC was defined as a tumor in which more 100
than 10% of its volume was occupied by undifferentiated cells, while DTC with anaplastic 101
foci was defined as a tumor in which less than 10% of the tumor volume was occupied by 102
undifferentiated cells in the background of differentiated cancer. Because there is not yet a 103
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6
definitive established pathologic definition of these categories, the definitions adopted in this 104
study were based on the experience of clinicians and pathologists. The ATC component in 105
tumors mixed with differentiated thyroid cancer was defined based on the following features: 106
the nuclei without the characteristic features of differentiated thyroid cancer and showing a 107
greater ratio of nucleus/cytoplasm, nuclear pleomorphism other than the features of 108
differentiated thyroid cancer, and a more solid growth pattern with or without p53 expression. 109
Recurred ATC from DTC was defined as a recurrent tumor with undifferentiated cells in a 110
patient who was diagnosed as DTC at the first operation, but with a DTC component detected 111
in the recurrent tumor. PDTC was defined on the basis of the Turin proposal for the use of 112
uniform diagnostic criteria (11). For the purposes of accurate diagnosis, previous pathologic 113
specimens were re-evaluated by a pathologist (J. K. Won) in 22 (57.9%) of cases where the 114
slides were available and confirmed as PDTC if showing a solid/trabecular/insular growth 115
pattern with the absence of conventional nuclear features of papillary carcinoma, and the 116
presence of at least one of the following features: tumor necrosis, mitotic count ≥ 3/10 HPF, 117
or convoluted nuclei. Based on the primary diagnosis, we combined pure ATC, ATC arising 118
from DTC, and recurrent ATC from DTC together as single ‘anaplastic thyroid cancer’. 119
Therefore patients were thus categorized into three groups; ATC, DTC with anaplastic foci, 120
and PDTC. 121
122
Treatment and survival outcomes 123
Resectability of the tumour was determined by interpretation of the preoperative 124
computed tomography (CT) scan or magnetic resonance imaging (MRI) by two independent 125
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experienced head and neck surgeons who were blinded to the clinical data. A resectable tumor 126
was defined as a tumor which was expected to be completely removed with an adequate 127
safety margin. An unresectable tumor was defined as a tumor invading extensively into the 128
laryngotracheal, esophageal or prevertebral space, or the carotid arteries or jugular veins, 129
which could not be resected even with aggressive surgery (i.e. total laryngectomy, tracheal 130
resection and anastomosis, pharyngoesophagectomy with reconstruction, and vascular 131
reconstruction). There was no standardized treatment and follow-up strategy; surgical 132
removal, external beam radiation therapy (EBRT), radioactive iodine therapy, or 133
chemotherapy was given based on each patient’s individual status and the patient’s own 134
decision. Treatments were categorized according to the first-line treatment modality given as 135
follows: 1) operation (OP)-based (surgical treatment with or without adjuvant therapies, 136
n=137), 2) EBRT-based (EBRT with or without chemotherapy, n=19), 3) chemotherapy (n=7), 137
and 4) none (n=21). A total of 124 patients (67.4%) were treated with curative intent (122 138
patients by surgical resection and two by EBRT). Among 137 patients who received an OP-139
based treatment, total thyroidectomy (n=110, including two cases of total laryngectomy), or 140
near- or sub-total thyroidectomy (n=12) was performed to remove the tumors as completely 141
as possible, while palliative debulking surgery for decompression was performed in 15 142
patients (7.8%) to control tumor bleeding or airway obstruction. Adjuvant EBRT was 143
performed in 77 patients after the operation. Among the 19 patients who received EBRT-144
based treatment, two patients were treated with curative intent, and subsequently received 145
adjuvant chemotherapy. The remaining 17 patients were treated with palliative intent; of these, 146
one patient received adjuvant chemotherapy. Radioactive iodine therapy was performed in 28 147
patients. 148
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Data regarding disease-specific mortality were reviewed based on the medical 149
records or the Statistics Korea national database, and 1-year, 2-year, and 5 year disease 150
specific survival rates were calculated. 151
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Statistical analysis 153
Continuous outcomes were analyzed using independent t-tests between groups of two, 154
and one-way analysis of variance (ANOVA) among groups of three or more. Dichotomous 155
outcomes were analyzed using the chi-square test for trend and logistic regression analysis. 156
Survival curves were compared using a log-rank test. Cumulative recurrence and mortality 157
rates were calculated by life table, and log-rank test was performed to analyze the changes in 158
outcome. Cox regression analysis was performed to assess the difference in risk factors for 159
survival, and values were presented as hazard ratio (HR), 95% confidence interval (CI), and 160
P-value. In multivariate analysis, we divided the models according to the preoperative, 161
intraoperative, and postoperative findings, which were adjusted with the pre-existing risk 162
factor of ATC. All statistical analyses were performed using SPSS V20.0 (IBM SPSS, New 163
York, NY, USA). Statistical significance was defined as p<0.05. 164
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RESULTS 165
166
General characteristics and differences according to the time of diagnosis 167
A total of 184 patients were included in this study. The age at diagnosis was 59.4 ± 168
15.0 and the male-to-female ratio was 1:2.12. The median follow-up duration was 38.9 169
months (range, 1–207). Among 137 patients who received OP-based treatment, total 170
thyroidectomy (n=110, including 2 cases of total laryngectomy) or near- or sub-total 171
thyroidectomy (n=12) was performed to remove the tumors as completely as possible, while 172
palliative debulking surgery for decompression was performed in 15 patients (7.8%) to 173
control tumor bleeding or airway obstruction. Adjuvant EBRT was performed in 77 patients 174
after the operation. Tracheostomy for palliative airway management was undertaken in 27 175
patients, but tracheostomy alone was not considered as a treatment. Among the 19 patients 176
who received EBRT-based treatment, 2 patients were treated with curative intent, and they 177
received adjuvant chemotherapy. The remaining 17 patients were treated with palliative intent, 178
and among these 1 patient received adjuvant chemotherapy. 179
Age at diagnosis, and sex ratio did not differ among the three time periods (Table 1). 180
The absolute number of patients in all three diagnostic groups increased over time. However, 181
the relative proportion of patients with ATC decreased significantly (p<0.001), while that of 182
DTC with anaplastic foci increased, and that of PDTC remains unchanged over time. Patients 183
who underwent surgery and those with a resectable tumor also significantly increased during 184
the time periods (p<0.001, p=0.001, respectively). Preexisting known goiter or tumor was 185
more prevalent in the period covering1985 to 2004 than the period 2005 to 2013 (p=0.002). 186
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Tumor size, and nodal status were not significantly different among the three time periods, 187
although there was a trend of a decrease in tumor size and positive lymph nodes. OP-based 188
treatment and survival rate was significantly increased during the time periods (p<0.001, 189
p<0.001, respectively). 190
191
Comparison of clinical pathologic characteristics and survival among the different 192
pathologic groups 193
When comparing the 5 year disease-specific survival, ATC showed significantly 194
lower survival rates compared to those in DTC with anaplastic foci and PDTC (Fig. 1, Table 195
2, Supplementary Table 1). Although there was no significant difference in survival between 196
those in PDTC and DTC with anaplastic foci groups, there was a distinct slightly poorer 197
survival in the PDTC compared to DTC with anaplastic foci group in 5 year disease specific 198
survival (65.8% vs 81.3%, respectively). Among ATC, there was no significant difference in 199
survival of pure ATC, ATC arising from DTC, and recurred ATC from DTC (Fig 1); and 200
although the 1 or 2 year survival rate was slightly lower in pure ATC, the 5 year disease 201
specific survival was similar in each (17.9%, 20.6%, and 17.6%, respectively). 202
Age at diagnosis was older in ATC and sex ratio showed no significant different 203
among the three pathologic groups (p<0.001, 0.983, respectively). A previous history of 204
goiter was more prevalent in ATC (36.7%) than in PDTC (26.3%) and DTC with anaplastic 205
foci (4.2%) (p<0.001). Small resectable tumors with less advanced stages were more 206
prevalent in DTC with anaplastic foci, followed by PDTC (Table 2). When comparing the 207
clinicopathologic factors between survival and non-survival, T category, M category, 208
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resectability, tracheal invasion, treatment modality, and lymphatic invasion were significantly 209
different in ATC (p=0.027, 0.008, 0.002, 0.024, 0.039, and 0.007, respectively). Age, 210
resectability, tracheal invasion, and treatment modality was different in PDTC (p=0.002, 211
0.006, 0.026, and 0.010, respectively), while age, resectability, treatment modality, lymphatic 212
invasion, vascular invasion, and positive resection margin are different variables between 213
survivor and non-survivor in DTC with anaplastic foci (p<0.001, p=0.032, 0.032, 0.001, 214
0.002, and 0.011, respectively) (Table 3). 215
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Survival outcomes according to the treatment methods in ATC 217
Survival outcomes were significantly higher in those patients with resectable tumors 218
than in those with unresectable tumors (Supplementary Fig. 1). In resectable tumors, those 219
treated solely with surgery and those with surgery and adjuvant EBRT (n=31) showed no 220
significant difference in their clinicopathologic characteristics. Although survival was not 221
significantly different between the two groups, the median survival duration was longer in 222
those patients treated with additional EBRT (25.9 vs 43.6 months, p=0.345) (Fig. 2a, Table 4, 223
Supplementary Table 2). Among 38 patients with unresectable tumors, survival rates were 224
significantly different according to the treatment modality (Fig 2b), and patients who 225
underwent EBRT-based treatment showed the longest median survival of 19.2 months 226
(p=0.007) (Table 4, Supplementary Table 2). Multivariate analysis revealed that resectability 227
(unresectable tumor, OR=1.39, CI=1.21-1.74) and tracheal invasion (OR=4.45, CI=2.32-9.33) 228
were the most significant factors in the preoperative findings (p=0.004, 0.042, respectively), 229
while lymphatic invasion (OR=4.87, CI=1.40-16.97) was the most significant factor in the 230
Page 11 of 46
Thy
roid
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nges
of
Clin
icop
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c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
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and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
12
12
postoperative findings (p=0.013) (Table 5). 231
232
Survival outcomes according to treatment methods in PDTC 233
The 1 and 2 year survival rate was 87.9% and 84.3% respectively in the patients with 234
PDTC (median survival was 54.9 months) (Table 2). Adjuvant treatment after surgery showed 235
increased disease-specific survival (OP only (n=9), 77.8%; OP+ EBRT (n=11), 90.0%; 236
OP+RAI (n=14), 57.1%) although this did not reach statistical significance (p=0.236) (Fig. 2c, 237
Table 4, Supplementary Table 2). Survival difference between OP+ EBRT and OP+RAI also 238
showed no statistical difference (p=0.104). Age (OR=1.07, CI=1.02-1.13) and resectability 239
(unresectable tumor, OR=8.32, CI=2.21-31.35) were the significant prognostic factors for 240
survival in univariate analysis (p=0.012, 0.002, respectively). Multivariate analysis revealed 241
that resectability was the only significant prognosticator (unresectable tumor, OR=11.40, 242
CI=2.65-49.10, p=0.001) (Supplementary Table 3). 243
244
Survival outcomes according to treatment methods in DTC with anaplastic foci 245
The 1 and 2 year survival rate was 97.7% and 95.3% respectively for DTC with 246
anaplastic foci (with a median survival of 71.8 months) (Table 2). Adjuvant treatment after 247
surgery also showed increased disease-specific survival (OP only (n=6), 50.0%; OP+EBRT 248
(n=28), 89.3%; OP+RAI (n=12), 91.7%) but without statistical significance (p=0.771) (Fig. 249
2d, Table 4, Supplementary Table 2). In univariate analysis, the significant factors of 250
prognosis were age (OR=1.12, CI=1.01-1.24), sex (OR=6.63, CI=1.28-34.41), and tracheal 251
Page 12 of 46
Thy
roid
Cha
nges
of
Clin
icop
atho
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c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
13
13
invasion (OR=12.04, CI=1.25-115.85) (p=0.029, 0.024, and 0.031, respectively) 252
(Supplementary Table 4). 253
Page 13 of 46
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roid
Cha
nges
of
Clin
icop
atho
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c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
14
14
DISCUSSION 254
255
This study demonstrates that the incidence of DTC with anaplastic foci has increased, 256
while the relative incidence of ATC has gradually decreased over time. The relative incidence 257
of PDTC has remained about the same over the study period. Although ATC and PDTC are 258
known to be different disease entities, both have shown locoregional aggressiveness and have 259
resulted in poorer survival outcomes. In ATC, resectability of the cancer, including those tumors 260
with tracheal invasion, showed the best predictability for survival at pre- and intraoperative evaluation; 261
and lymphatic invasion was the best predictive factor after surgery. Interestingly, EBRT showed 262
some beneficial effects on survival of ATC in both resectable and unresectable tumors, 263
suggesting the possibility of an important role of EBRT in treating ATC. 264
The incidence of thyroid cancer has been increasing, partly due to improved 265
diagnostic techniques such as ultrasonography. In particular, in 2005 the incidence of 266
papillary thyroid cancer abruptly rose mainly due to the increasing detection of cases in 267
Korea by health checkup examination (12-14). When comparing the clinical characteristics of 268
ATC or PDTC in our study with those of the previous report on DTC (15), age at diagnosis 269
and the proportion of male patients were found to be higher in tumors with aggressive 270
pathology in our study. Time trends showed that the number of cases in all three diagnostic 271
groups as well as the number of surgical cases with resectable tumors have increased; while 272
cases with a previous history of goiter and stage T4b tumors have decreased. Among the three 273
groups, the increment was obvious in DTC with anaplastic foci, in accordance with 274
increasing cases of DTC. Overall, these data regarding trends over time may result partially 275
from the earlier detection of thyroid cancer, thus showing increasing detection of tumors at an 276
Page 14 of 46
Thy
roid
Cha
nges
of
Clin
icop
atho
logi
c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
15
15
early stage of anaplastic transformation in DTC (i.e. small and resectable tumors). Moreover, 277
the increment in absolute numbers in all groups may be a true increment, although this could 278
not be determined just based on data from a single institute. 279
However, the definition of the categories of DTC with anaplastic foci is still unclear. 280
Treatment of those cases of DTC with a small focus of an anaplastic component has been 281
reported to negatively influence the prognosis of DTC (16), nevertheless such cancers 282
showed a better long-term survival rate than ATC (7). However, the criteria for the definition 283
of anaplastic foci have not been clearly established and a previous report of DTC with 284
anaplastic foci did not show the percentage of anaplastic foci used in their criteria (7,16). In 285
our study, we defined the cut-off point of contained anaplastic component to distinguish DTC 286
with anaplastic foci from ATC arising from DTC as 10%, however, all cases of ATC arising 287
from DTC were composed of more than 50% of anaplastic component in this study. 288
Therefore, further study is needed to define the criteria by elucidating the relation between 289
the proportion of anaplastic component of tumors and their prognosis.. 290
ATC arising from DTC was defined as a tumor in which more than 10% of its volume was 291
occupied by undifferentiated cells, while DTC with anaplastic foci was defined as a tumor in 292
which less than 10% of the tumor volume was occupied by undifferentiated cells in the 293
background of differentiated cancer 294
Interestingly, in PDTC a slightly poorer survival was evident in the 5-year survival 295
rates and it continuously decreased faster than that of DTC with anaplastic foci (Fig 1). A few 296
previous studies have also reported similar 5 year survival rates of approximately 50–60 per 297
cent in PDTC (17,18). Therefore, it should be kept in mind that PDTC might progress after 298
Page 15 of 46
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roid
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nges
of
Clin
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c C
hara
cter
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s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
16
16
long-term follow-up, while the prognosis of DTC with anaplastic foci in complete remission 299
status could remain excellent. 300
Orita et al. reported that survival of ATC was higher in patients who were diagnosed 301
between 1999 and 2009, compared to those diagnosed between 1976 and 1999 (19). Han et al. 302
have also reported on the time trend of ATC, noting an increased number of small tumors and 303
improved survival outcomes (7). In this study, although a previous history of goiter in ATC 304
patients was less prevalent, there were still a significant number of cases of unresectable 305
tumors with cervical lymph node or distant metastases. Thus, this trend may indicate that the 306
early detection of thyroid cancer might only benefit patients with PDTC and DTC with 307
anaplastic foci. 308
In both PDTC and DTC with anaplastic foci, resectibility was also the most 309
significant prognosticator, and most resectable tumors could be treated with curative-intended 310
surgery as a first-line treatment. Most cases of DTC with anaplastic foci have been found 311
incidentally after surgical resection of a predominantly non-anaplastic tumor (20-22). In this 312
study, most (i.e. 72.9%) cases of differentiated thyroid cancer with anaplastic foci were also 313
detected during a routine thyroid health checkup, so most (95.8%) of the tumors were 314
resectable, thereby underwent surgery as a first-line treatment. Therefore, to know the 315
efficacy of adjuvant EBRT after surgery should be very important. Whether these tumors 316
necessitate adjuvant EBRT or whether they could be treated similarly to DTC remains 317
controversial and there is unfortunately no meaningful data to define the best approach. The 318
data presented here suggest that adjuvant EBRT as well as RAI might improve survival rates 319
in PDTC and DTC with anaplastic foci, although there was no statistical significance. 320
Page 16 of 46
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roid
Cha
nges
of
Clin
icop
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c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
17
17
Considering the small number of patients in this study, the results remain, however, 321
inconclusive. 322
In ATC, resectability is a well-known prognosticator of the decision to perform 323
surgery (1,3,20,23-27). Currently, radical surgery and additional multimodality therapy is 324
deemed to be the best treatment protocol for resectable tumors (28-33). In addition, an R0/R1 325
resection is reported to correlate with better survival outcomes (34,35). In our study, patients 326
with fatal outcomes due to ATC and PDTC showed a higher prevalence of unresectable 327
tumors, carotid incasement, prevertebral space invasion, tracheal invasion, and esophageal 328
invasion, although statistical significance was attained mainly for resectability and tracheal 329
invasion. Therefore, surgeons should be aware of their own surgical expertise and thoroughly 330
evaluate the possibility of resectability with preoperative imaging studies. An improvement in 331
the quality of images over the study period partly affected decision-making in regard to 332
resectability. However, a positive resection margin in “resectable tumors” was found to be 333
stable with 14.2%, 8.3%, and 19.7% of cases during the study period (Table 1). Therefore, the 334
interpretation of past and current imaging studies regarding resectability did not differ 335
substantially over time. 336
This study demonstrated that EBRT on unresectable tumors was beneficial in terms 337
of disease-specific survival rate and median survival duration, however, its efficacy could not 338
be determined because of limited number of subjects in this study. Others reported that higher 339
doses of EBRT do not always improve response rate or survival (36). Nevertheless, EBRT 340
sometimes renders an unresectable tumor potentially resectable, potentially resulting in an 341
increase in survival (9,21,37). Therefore, primary EBRT on unresectable tumors might 342
improve survival in ATC, but this aspect requires further investigation. 343
Page 17 of 46
Thy
roid
Cha
nges
of
Clin
icop
atho
logi
c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
18
18
Several studies have suggested that the prognostic factors for ATC include age, acute 344
symptoms, leukocytosis, size, T category, and M category (7,38-40). The novel finding 345
presented here is that lymphatic invasion is the most significant factor affecting long-term 346
survival of ATC. Although postoperative treatment is not expected to be modified on the basis 347
of lymphatic invasion, it could be used as a basis for stratification. Moreover, a more 348
thorough examination of locoregional and distant recurrence of the patients with lymphatic 349
invasion may be needed during follow-up. 350
In this study, survival duration appeared to be longer than in previous studies. 351
However one recent study of ATC patients (25) showed survival data comparable with this 352
study suggesting improvement of survival in the last two decades. Moreover, in cases which 353
were lost to follow-up without knowing the survival status, data regarding the date and cause 354
of death in our study were obtained from the National Statistical Office; thus, the survival 355
data is relatively accurate. There could have been some cases which were not diagnosed as 356
ATC because of undifferentiated histology and advanced extent. Thus, very aggressive 357
tumors could have been excluded from our study. Moreover, mean tumor size in our study 358
seemed smaller than in other studies, which might have resulted from earlier detection and 359
resulted in better survival outcomes. 360
This study has some limitations. For example, this is a retrospective analysis in 361
which an inappropriate diagnosis and categorization of patients diagnosed by fine needle 362
aspiration or incisional biopsy may have occurred. Indeed, among PDTC cases, the pathology 363
review revealed that the diagnosis for 22.7% (5 out of 22) of cases had been changed. A lack 364
of accuracy of results using FNA or incisional biopsy in early cohorts may have biased the 365
result. In addition, a possible limitation could consist in discrepancies concerning what 366
Page 18 of 46
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roid
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nges
of
Clin
icop
atho
logi
c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
19
19
constitutes a “resectable tumor” among physicians who retrospectively performed analyses 367
and who actually decided treatment plans and performed the surgery. Moreover, diagnostic 368
categorization was arbitrary, especially in regards to the use of 10% of undifferentiated cells 369
to separate DTC from ATC. In addition, the lack of a standard treatment protocol could bias 370
the findings. However, this study is one of the largest cohorts by far from a single institution, 371
thereby minimizing other confounding factors. To the best of our knowledge, this study is the 372
first to compare the clinicopathological characteristics and survival outcomes of various 373
aggressive pathologic entities of thyroid cancer and their temporal trends. By inspecting the 374
time trends and comparing the treatment outcomes according to the histopathologic 375
categorization, this study is potentially valuable. 376
In conclusion, the incidence of DTC with anaplastic foci has increased and the 377
incidence of ATA has decreased over time. DTC with anaplastic foci and PDTC show a better 378
survival than ATC. Resectability is the most significant prognostic factor in preoperative 379
findings, while lymphatic invasion is the most significant postoperative prognosticator in 380
ATC. In ATC, because surgery with additional EBRT showed longer survival than surgery 381
alone in resectable tumors, adjuvant EBRT should be applied. In contrast, EBRT-based 382
therapy may be of benefit for unresectable tumors and applied without surgical treatment. In 383
PDTC and DTC with anaplastic foci, adjuvant EBRT or RAI seems to confer survival gain. 384
Although further research is needed to elucidate the role of adjuvant therapy, the choice of 385
treatment of ATC and PDTC could be modified according to the stratification by 386
perioperative parameters including resectability and lymphatic invasion of the cancer. 387
388
Page 19 of 46
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roid
Cha
nges
of
Clin
icop
atho
logi
c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
20
20
ACKNOELEDGEMENT 389
This study was supported by the Research Grant Number CB-2011-03-01 of the Korean 390
Foundation for Cancer Research. 391
392
Author Disclosure Statement: The authors have nothing to disclose. 393
394
*Corresponding authors 395
J. Hun Hah, M.D., Ph.D. 396
Associate Professor 397
Department of Otorhinolaryngology-Head and Neck Surgery 398
Seoul National University Hospital 399
101 Daehak-Ro Jongno-Gu, Seoul, Korea 400
Tel: +82-2-2072-0215 401
Fax: +82-2-745-2387 402
E-mail: [email protected] 403
404
Young Joo Park, M.D., Ph.D. 405
Professor 406
Page 20 of 46
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roid
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nges
of
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icop
atho
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c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
21
21
Department of Internal Medicine, Seoul National University College of Medicine 407
Seoul National University Hospital 408
101 Daehak-Ro Jongno-Gu, Seoul, Korea 409
Tel: 82-2-2072-4183 410
Fax: 82-2-764-2199 411
E-mail: [email protected] 412
413
Page 21 of 46
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roid
Cha
nges
of
Clin
icop
atho
logi
c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
22
22
REFERENCES 414
415
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nges
of
Clin
icop
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c C
hara
cter
istic
s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
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evie
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and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
23
23
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utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
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arci
nom
a (d
oi: 1
0.10
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316)
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s ar
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n pe
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evie
wed
and
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d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
24
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tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
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n pe
er-r
evie
wed
and
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epte
d fo
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blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
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fer
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this
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of.
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nd P
oorl
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iffe
rent
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d T
hyro
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a (d
oi: 1
0.10
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316)
Thi
s ar
ticle
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n pe
er-r
evie
wed
and
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d fo
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atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
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fer
from
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pro
of.
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of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
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arci
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a (d
oi: 1
0.10
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316)
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s ar
ticle
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n pe
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evie
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n, b
ut h
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et to
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ergo
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ting
and
proo
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rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
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fer
from
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pro
of.
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FIGURE LEGENDS
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29
Figure 1. Comparison of disease-specific survival according to diagnosis
DTC, differentiated thyroid cancer; PDTC, poorly differentiated thyroid cancer; ATC,
anaplastic thyroid cancer
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Figure 2. Disease-specific survival according to the treatment modalities applied
(a) ATC, resectable tumor; (b) ATC, unresectable tumor; (c) PDTC; (d) DTC c anaplastic foci
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31
Table 1. Time trend of clinicopathologic characteristics
1985-1994 1995-2004 2005-2013 P-value
Number of cases 25 73 86
Age at diagnosis 58.8±14.6 59.8±13.8 59.3±16.2 0.951
Sex (M:F) 1:1.50 1:2.48 1:2.07 0.578
Diagnosis <0.001
ATC 21 (84.0%) 43 (58.9%) 34 (39.5%)
PDTC 1 (4.0%) 19 (26.0%) 18 (21.0%)
DTC with anaplastic foci 3 (12.0%) 11 (15.1%) 34 (39.5%)
Previous history of goiter
or tumor 9 (36.0%) 27 (37.0%) 12 (14.0%) 0.002
Final diagnosis by <0.001
Surgery 7 (28.0%) 56 (76.7%) 72 (83.7%)
Incisional biopsy 11 (44.0%) 5 (6.8%) 4 (4.7%)
Aspiration cytology 7 (28.0%) 12 (16.4%) 10 (11.6%)
Follow-up duration
(months)
17.3
(1~124)
51.4
(1~207)
34.5
(1~159) 0.005
Mean tumor size (cm) 4.05±2.66 3.64±2.21 2.86±1.96 0.191
Resectable tumor 7 (28.0%) 56 (76.7%) 68 (79.1%) 0.001
Positive resection margin* 1/7 (14.2%) 3/36 (8.3%) 13/66 (19.7%) 0.162
T4b* 15 (60.0%) 18 (24.7%) 19 (22.1%) <0.001
Nodal status (N+) 20 (80.0%) 37 (50.7%) 48 (55.8%) 0.150
Distant metastasis 7 (28.0%) 6 (8.2%) 10 (11.6%) 0.068
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Treatment <0.001
OP-based 7 (28.0%) 57 (78.1%) 73 (84.9%)
EBRT-based 13 (52.0%) 5 (6.8%) 1 (1.2%)
chemotherapy 3 (12.0%) 1 (1.4%) 3 (3.5%)
none 2 (8.0%) 10 (13.7%) 9 (10.5%)
Disease specific survival
1YSR 34.5% 56.6% 71.3% 0.021
2YSR 29.5% 52.2% 66.9% 0.031
5YSR 16.0% 28.8% 51.9% <0.001
*proportion of the patients among the OP-based treatment and pathologic review was possible
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33
Table 2. Difference in clinicopathologic characteristics of anaplastic thyroid carcinoma (ATC), poorly differentiated thyroid
carcinoma (PDTC), and differentiated thyroid carcinoma (DTC) with anaplastic foci
ATC
(n=98)
PDTC
(n=38)
DTC with
anaplastic foci
(n=48)
P-
value
Age at disgnosis 63.5±13.4 51.7±17.2 57.3±13.8 <0.001
Sex (M:F) 1:2.1 1:2.2 1:2.2 0.983
Follow-up duration
(months) 21.1 (1~205) 51.5 (1~207) 65.2 (1~159) <0.001
Previous history of
goitre or tumour 36 (36.7%) 10 (26.3%) 2 (4.2%) <0.001
Tumour size (cm)* 4.2±2.5 3.5±1.5 2.2±1.5 <0.001
Resectable tumour* 50 (56.8%) 32 (84.2%) 46 (95.8%) <0.001
T4b* 45 (45.9%) 5 (13.2%) 2 (4.2%) <0.001
Positive lymph node* 69 (70.4%) 14 (36.8%) 22 (45.8%) 0.001
Distant metastasis* 20 (20.4%) 3 (7.9%) 0 <0.001
Treatment <0.001
OP-based 57 (58.2%) 34 (89.5%) 46 (95.8%)
EBRT-based 17 (17.3%) 0 2 (4.2%)
chemotherapy 7 (7.1%) 0 0
none 17 (17.3%) 4 (10.5%) 0
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34
Disease specific survival
1YSR 34.3% 87.9% 97.7% <0.001
2YSR 28.6% 84.3% 95.3% <0.001
5YSR 14.3% 65.8% 81.3% <0.001
*Resectability, tumor size, T category, nodal status, and distant metastasis were evaluated among the patients whose imaging modalities were
available.
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35
Table 3. Difference in clinicopathologic variables between survivor and non-survivor in each pathologic group
ATC
(n=98)
PDTC
(n=38)
DTC with anaplastic foci
(n=48)
Survivor
(n=14)
Non-survivor
(n=84)
Survivor
(n=25)
Non-survivor
(n=13)
Survivor
(n=39)
Non-survivor
(n=9)
Age 58.1±15.8 65.4±12.5 45.9±17.1* 63.0±10.9 54.8±14.0* 68.1±4.6
Sex 1:2.5 1:2.0 1:2.1 1:2.3 1:3.3* 1:0.5
Tumor size (cm) 3.8±2.6 4.3±2.6 3.3±1.3 4.1±1.9 2.0±1.4 3.1±1.5
WBC (x103/μl) 6.59±2.95 9.33±6.59 8.50±4.24 8.24±7.28 6.74±1.33 7.65±3.09
T4b category 6 (42.9%)* 39 (46.4%) 2 (8.0%) 3 (23.1%) 0 2 (22.2%)
Positive node 8 (57.1%) 61 (72.6%) 9 (36.0%) 5 (38.5%) 18 (46.2%) 4 (44.4%)
Distant metastasis 0* 20 (23.8%) 1 (4.0%) 2 (15.4%) 0 0
CT finding
Resectability 13 (92.9%)* 37 (44.0%) 25 (100%)* 7 (53.8%) 39 (100%)* 7 (77.8%)
Carotid encasement 0 7 (8.3%) 0 0 0 0
Prevertebral space invasion 0 12 (14.3%) 0 0 0 1 (11.1%)
Tracheal invasion 0* 15 (17.9%) 0* 6 (46.2%) 0 1 (11.1%)
Esophageal invasion 1 (7.1%) 17 (20.2%) 0 0 0 1 (11.1%)
Treatment modality * * *
OP-based 13 (92.9%) 44 (52.4%) 25 (100%) 9 (69.2%) 39 7 (77.8%)
EBRT-based 1 (7.1%) 16 (19.0%) 0 0 0 2 (22.2%)
Chemotherapy 0 7 (8.3%) 0 0 0 0
None 0 17 (20.2%) 0 4 (30.8%) 0 0
Pathologic findings
Lymphatic invasion 0/11* 12/30 4/17 2/5 5/37* 1/7
Vascular invasion 1/11 8/29 2/18 2/5 1/37* 2/7
Positive resection margin 2/11 10/31 2/18 2/5 0/37* 1/7
p53 + 3/4 6/8 NA NA NA NA
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al O
utco
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of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
36
36
*statistically significant (p=0.027, 0.008, 0.002, 0.024, 0.039, and 0.007 in T4b category, distant metastasis, resectability, treatment modality,
and lymphatic invasion of ATC, respectively; p=0.002, 0.006, and 0.010 in age, resectability, and treatment modality of PDTC, respectively;
p<0.001, p=0.018, 0.032, 0.032, 0.001, 0.002, and 0.011 in age, sex, resectability, treatment modality, lymphatic invasion, vascular invasion,
and positive resection margin of DTC with anaplastic foci, respectively)
NA; not available
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hara
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s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
37
37
Table 4. Survival outcomes according to the treatment modality in each pathologic
diagnosis
*adjusted with age, sex, WBC count, and staging in ATC, and adjusted with age, sex, and
staging in PDTC and DTC with anaplastic foci
Mortality, N
(%)
Person-
year
Hazard Ratio*
(95% CI) P-Value
DTC c anaplastic foci
OP only 3/6 (50.0) 46.7 0.43 (0.02–8.24) 0.573
OP+EBRT 3/28 (10.7) 163.2 0.64 (0.05-7.58) 0.724
OP+RAI 1/12 (8.3) 65.2 (reference)
PDTC
OP only 2/9 (22.2) 56.3 0.49 (0.09–2.57) 0.397
OP+EBRT 1/11 (9.1) 48.7 0.13 (0.02-1.08) 0.059
OP+RAI 6/14 (42.9) 50.7 (reference)
Resectable ATC 37/50 (74.0) 141.5
OP only 10/12 (83.3) 23.9 0.14 (0.04-0.54) 0.005
OP+EBRT 20/31 (64.5) 112.7 0.12 (0.04-0.42) 0.001
OP+others 4/4 (100) 4.3 0.22 (0.05-1.10) 0.066
RT/chemo/none 3/3 (100) 0.7 (reference)
OP only vs. OP+EBRT
OP only 1.11 (0.45-2.71) 0.819
OP+EBRT (reference)
Unresectable ATC 38/38 (100) 30.9
OP-based treatment 9/9 (100) 5.8 0.24 (0.08-0.70) 0.009
EBRT-based treatment 15/15 (100) 24.0 0.12 (0.04-0.40) 0.001
Chemotherapy 4/4 (100) 0.4 0.53 (0.13-2.12) 0.367
None 10/10 (100) 0.8 (reference)
OP- vs. EBRT-based
treatment
OP-based treatment 1.94 (0.72-5.27) 0.192
EBRT-based treatment (reference)
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of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
38
38
Table 5. Univariate and multivariate analyses to identify prognostic factors for survival
in anaplastic thyroid carcinoma
Univariate analysis*
Multivariate analysis*
Model
1†
Model
2‡
Model
3§
OR (CI) P OR (CI) P OR (CI) P OR (CI) P
Age at diagnosis 1.02 (1.00-
1.04) 0.024
1.05 (0.01-
1.10) 0.029
1.11 (0.01-
1.38) 0.069
1.97 (0.85-
4.55) 0.115
Sex 0.78 (0.47-
1.28) 0.318
1.38 (0.54-
3.55) 0.506
0.86 (0.64-
1.16) 0.329
1.69 (0.57-
5.03) 0.348
WBC count 1.05 (1.01-
1.10) 0.018
1.05 (0.99-
1.10) 0.054
1.15 (1.01-
1.32) 0.040
1.12 (0.74-
3.33) 0.246
Tumor size 1.15 (0.95-
1.39) 0.150
1.08 (0.82-
1.42) 0.570
0.91 (0.69-
1.20) 0.500
1.12 (1.00-
1.26) 0.043
LN metastasis 1.30 (0.73-
2.33) 0.372
1.12 (0.55-
2.25) 0.758
1.28 (0.50-
3.32) 0.608
1.29 (0.56-
2.97) 0.547
Image findings
Resectability 2.57 (1.60-
4.15) <0.001
1.39 (1.21-
1.74) 0.004
Carotid
encasement
1.88 (0.81-
4.34) 0.142
1.12 (0.81-
2.24) 0.075
Prevertebral
space invasion
1.92 (1.06-
3.46) 0.031
1.99 (0.78-
4.30) 0.129
Tracheal
invasion
4.04 (1.86-
8.76) <0.001
4.45 (2.32-
9.33) 0.042
Esophageal
invasion
2.19 (1.25-
3.84) 0.006
1.65 (1.25-
2.72) 0.652
Pathologic
findings
Lymphatic
invasion
3.63 (1.58-
8.33) 0.002
4.87 (1.40-
16.97) 0.013
Vascular
invasion
2.20 (1.19-
4.09) 0.012
1.38 (0.58-
2.29) 0.464
Positive
resection margin
1.51 (0.74-
3.09) 0.263
1.10 (0.99-
1.22) 0.067
Positive p53 1.01 (0.98-
1.04) 0.583
1.43 (0.27-
7.56) 0.672
*Cox regression analysis with characteristics entry to the cohort.
†Model 1: Resectability was adjusted with age, tumor size, WBC count, and N staging.
‡Model 2: Preoperative imaging findings were adjusted with age, tumor size, WBC count,
and N staging.
§Model 3: Postoperative pathologic findings were adjusted with age, tumor size, WBC count,
and N staging.
Page 38 of 46
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utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
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and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
39
39
Page 39 of 46
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al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
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evie
wed
and
acc
epte
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r pu
blic
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n, b
ut h
as y
et to
und
ergo
cop
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ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
40
40
Supplementary figure 1. Disease specific survival of ATC according to resectability
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of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
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arci
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a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
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n pe
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and
acc
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blic
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ut h
as y
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cop
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ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
41
41
Supplementary Table 1. Survival outcomes according to the pathologic diagnosis
Mortality, N(%) Hazard Ratio (95% CI)
Overall Person-year Unadjusted P-Value Age/sex adjusted P Value
DTC c anaplastic foci 9/48 (18.8) 278.2 (reference) (reference)
PDTC 13/38 (34.2) 163.9 2.45 (1.01–5.92) 0.047 2.86 (1.18–6.93) 0.020
ATC 84/98 (85.7) 188.5 10.08 (4.83–21.03) <0.001 9.06 (4.32–19.03) <0.001
Page 41 of 46
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utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
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n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
42
42
Supplementary Table 2. Survival outcomes and treatment modalities according to
diagnostic group and resectability
N
Overall
survival
(%)
Duration
of FU
(mo)
1YSR
(%)
2YSR
(%)
Duration of
survival (mo)
Resectable tumor
ATC
Total 50 26.0 32.3 48.5 39.3 34.7 (1-205)
OP only 12 16.7 16.6 60.0 37.5 25.9 (1-124)
OP+EBRT * 31 35.5 43.3 52.4 45.4 43.6 (1-205)
OP+others† 4 0 13.7 25.0 25.0 14.0 (4-41)
EBRT/chemo/none‡ 3 0 0.5 0 0 1.3 (1-2)
PDTC
Total 35§ 60.5 54.6 87.9 84.3 54.9 (1-207)
OP only 9 77.8 74.9 90.9 90.9 75.0 (1-207)
OP+EBRT 11 90.9 53.1 94.5 91.6 53.2 (1-129)
OP+RAI 14 57.1 42.7 91.3 85.6 43.5 (4-109)
OP+chemotherapy 1 100 54.0 100 100 54.4
DTC with anaplastic foci
Total 46∫ 84.8 69.5 97.7 95.3 71.8 (1-176)
OP only 6 50.0 88.6 100 100 93.3 (16-176)
OP+EBRT 28 89.3 67.6 96.4 92.6 70.0 (2-135)
OP+RAI 12 91.7 64.3 100 100 65.2 (1-159)
OP+chemotherapy 0 - - - - -
Unresectable tumor
ATC
Total 38 0 8.4 15.8 13.2 10.0 (0-101)
OP-based treatment 9 0 6.3 11.1 0 7.7 (1-39)
EBRT-based treatment 15 0 16.8 26.7 17.8 19.2 (1-101)
chemotherapy 4 0 1.1 0 0 1.7 (1-4)
None 10 0 0.4 0 0 0.9 (0-2)
FU, follow-up; YSR, year survival rate
Two patients with differentiated thyroid carcinoma with anaplastic foci and 10 with
anaplastic thyroid carcinoma were excluded because the preoperative images were not
available.
*26 patients with EBRT, 3 patients with EBRT+chemotherapy, and 2 patients with
EBRT+radioactive iodine therapy, †2 patients with radioactive iodine therapy and 2 patients
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utco
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of
Ana
plas
tic a
nd P
oorl
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iffe
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iate
d T
hyro
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arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
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ticle
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evie
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and
acc
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r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
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The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
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43
with chemotherapy, ‡1 had EBRT-based treatment, and 2 received no treatment.
§Three
patients with EBRT-based treatment were excluded. ∫Two patients with EBRT-based treatment
were excluded.
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utco
mes
of
Ana
plas
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nd P
oorl
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iffe
rent
iate
d T
hyro
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arci
nom
a (d
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0.10
89/th
y.20
15.0
316)
Thi
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ticle
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evie
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and
acc
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r pu
blic
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as y
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cop
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ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
44
44
Supplementary Table 3. Univariate and multivariate analyses to identify prognostic
factors for survival in poorly differentiated thyroid carcinoma
Univariate analysis*
Multivariate analysis*
Model
1†
Model
2‡
Model
3§
OR (CI) P OR (CI) P OR (CI) P OR (CI) P
Age at
diagnosis
1.07 (1.02-
1.13) 0.012
1.57 (0.08-
2.74) 0.210
1.16 (0.18-
2.01) 0.432
1.18 (0.91-
1.54) 0.215
Sex 0.36 (0.41-
4.51) 0.615
0.49 (0.09-
2.47) 0.388
0.70 (0.19-
2.55) 0.593
0.64 (0.12-
3.59) 0.614
Tumor size 1.52 (0.76-
3.06) 0.239
1.20 (0.40-
3.60) 0.740
1.56 (0.74-
3.29) 0.239
0.11 (0.30-
4.16) 0.871
LN metastasis 0.37 (0.11-
1.24) 0.105
0.27 (0.06-
1.17) 0.080
0.74 (0.18-
2.98) 0.670
0.55 (0.10-
2.94) 0.483
Image
findings
Resectability 8.32 (2.21-
31.35) 0.002
11.40 (2.65-
49.10) 0.001
Tracheal
invasion
5.90 (0.94-
37.22) 0.059
0.90 (0.32-
2.53) 0.848
Pathologic
findings
Lymphatic
invasion
1.13 (0.90-
1.42) 0.277
1.20 (0.87-
1.67) 0.267
Vascular
invasion
1.03 (0.81-
1.31) 0.817
0.40 (0.11-
1.49) 0.174
Positive
resection
margin
0.78 (0.39-
1.55) 0.478
1.26 (0.47-
3.37) 0.649
*Cox regression analysis with characteristics entry to the cohort.
†Model 1: Resectability was adjusted with age, tumor size, and N staging.
‡Model 2: Preoperative imaging findings were adjusted with age, tumor size, and N staging.
§Model 3: Postoperative pathologic findings were adjusted with age, tumor size, and N
staging.
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rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
y D
iffe
rent
iate
d T
hyro
id C
arci
nom
a (d
oi: 1
0.10
89/th
y.20
15.0
316)
Thi
s ar
ticle
has
bee
n pe
er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
45
45
Supplementary Table 4. Univariate and multivariate analyses to identify prognostic
factors for survival in differentiated thyroid carcinoma with anaplastic foci
Univariate analysis*
Multivariate analysis*
Model
1†
Model
2‡
OR (CI) P OR (CI) P OR (CI) P
Age at diagnosis 1.12 (1.01-
1.24) 0.029
1.04 (0.88-
1.87) 0.140
1.46 (0.93-
2.30) 0.099
Sex 6.63 (1.28-
34.41) 0.024
2.03 (1.02-
4.61) 0.083
1.44 (0.51-
3.41) 0.127
Tumor size 1.65 (0.99-
2.72) 0.051
1.56 (0.67-
3.61) 0.301
0.95 (0.40-
2.23) 0.906
LN metastasis 2.36 (0.48-
11.58) 0.290
1.04 (1.00-
1.59) 0.241
1.21 (0.92-
1.60) 0.177
Image findings
Tracheal invasion 12.04 (1.25-
115-85) 0.031
0.15 (0.02-
1.44) 0.099
Pathologic
findings
Lymphatic
invasion
1.22 (0.97-
1.53) 0.095
1.46 (0.93-
2.30) 0.099
Vascular invasion 1.12 (0.91-
1.38) 0.281
1.40 (0.91-
2.15) 0.126
Positive resection
margin
0.73 (0.32-
1.67) 0.455
0.79 (0.29-
2.17) 0.644
*Cox regression analysis with characteristics entry to the cohort.
†Model 1: Preoperative imaging findings were adjusted with age, tumor size, and N staging.
‡Model 2: Postoperative pathologic findings were adjusted with age, tumor size, and N
staging.
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s an
d Su
rviv
al O
utco
mes
of
Ana
plas
tic a
nd P
oorl
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iffe
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iate
d T
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a (d
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0.10
89/th
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15.0
316)
Thi
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ticle
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and
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r pu
blic
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n, b
ut h
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rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
46
46
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of
Ana
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Thi
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er-r
evie
wed
and
acc
epte
d fo
r pu
blic
atio
n, b
ut h
as y
et to
und
ergo
cop
yedi
ting
and
proo
f co
rrec
tion.
The
fin
al p
ublis
hed
vers
ion
may
dif
fer
from
this
pro
of.
