Tall cell percentage alone in PTC without aggressive features should not guide patients' clinical management

Abstract

Purpose
Recent diagnostic criteria updates of the tall cell variant of papillary thyroid carcinoma (TCPTC) by the World Health Organization (WHO) have determined the inclusion of tumours with 30-49% of tall cells. However, the impact of tall cell percentage on papillary thyroid carcinoma (PTC) patients’ prognosis is still debated. We aimed to evaluate whether tall cell percentage affects patients’ outcome in the absence of aggressive features.

Methods
Rates of aggressive features, recurrence-free survival (RFS) and distant RFS (DRFS) (5-year median follow-up) were compared among tumours with less than 30%, 30-49% and at least 50% of tall cells. We also evaluated the impact of the new tall cell cut-off on patient management.

Results
Overall, 3092 tumours (15.7% of all PTC) were collected: 792 PTC had less than 30%, 503 had 30-49%, and 1797 had 50% or more tall cell areas. With the new definition of WHO, the number of TCPTC increased by 28%. There were no differences in recurrence rates according to tall cell percentage. The coexistence of BRAF and TERT promoter mutations predicted a worse RFS. Considering the new definition of TCPTC, the level of risk according to the American Thyroid Association increased from low to intermediate in 4.2% of cases. However, the recurrence rate within this subgroup was comparable to low-risk.

Conclusions
TCPTC and PTC with tall cell areas can be considered as a unique group with similar recurrence risk. However, whenever aggressive features are absent, tumors have a low risk of recurrence independently of tall cell percentage.

Full text

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Tall cell percentage alone in PTC without aggressive features should not
guide patients' clinical management
Anello Marcello Poma, PhD1*, David Viola, MD2*, Elisabetta Macerola, PhD1, Agnese Proietti, PhD,
MD3, Eleonora Molinaro, MD2, Dario De Vietro, MD2, Rossella Elisei, PhD, MD2, Gabriele Materazzi,
PhD, MD1, Paolo Miccoli, PhD, MD1, Fulvio Basolo, PhD, MD1 and Clara Ugolini, PhD, MD1
1 Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa
2 Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa
3 Section of Pathology, University Hospital of Pisa
* equally contributed
Funding. This work did not receive any financial support.
Disclosure. The authors have no conflict of interest to declare.
Corresponding author
Prof. Fulvio Basolo
Via Savi 10, 56126 Pisa, Italy
+39 050 992892
fulvio.basolo@med.unipi.it
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Abstract
Purpose. Recent diagnostic criteria updates of the tall cell variant of papillary thyroid carcinoma (TCPTC) by the
World Health Organization (WHO) have determined the inclusion of tumours with 30-49% of tall cells.
However, the impact of tall cell percentage on papillary thyroid carcinoma (PTC) patients’ prognosis is still
debated. We aimed to evaluate whether tall cell percentage affects patients’ outcome in the absence of
aggressive features.
Methods. Rates of aggressive features, recurrence-free survival (RFS) and distant RFS (DRFS) (5-year median
follow-up) were compared among tumours with less than 30%, 30-49% and at least 50% of tall cells. We also
evaluated the impact of the new tall cell cut-off on patient management.
Results. Overall, 3092 tumours (15.7% of all PTC) were collected: 792 PTC had less than 30%, 503 had 30-49%,
and 1797 had 50% or more tall cell areas. With the new definition of WHO, the number of TCPTC increased by
28%. There were no differences in recurrence rates according to tall cell percentage. The coexistence of BRAF
and TERT promoter mutations predicted a worse RFS. Considering the new definition of TCPTC, the level of risk
according to the American Thyroid Association increased from low to intermediate in 4.2% of cases. However,
the recurrence rate within this subgroup was comparable to low-risk.
Conclusions. TCPTC and PTC with tall cell areas can be considered as a unique group with similar recurrence
risk. However, whenever aggressive features are absent, tumors have a low risk of recurrence independently
of tall cell percentage.
Keywords. Tall cells, papillary thyroid carcinoma, prognosis, recurrence-free survival.
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Introduction
Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy with a growing incidence
worldwide (1). Several histological variants associated with a different rate of aggressive features and clinical
behaviour are well recognised. The tall cell variant of PTC (TCPTC), characterized by cells that are two-to-three
times taller than wide, is the most common among the aggressive variants, with a prevalence of up to 12% of
all PTC (2,3). It has been reported that the incidence of TCPTC in the United States increased by 158% between
2001 and 2008, outpacing the overall incidence increment of PTC, which amounted to 68%(4). The diagnosis
of TCPTC is subject to considerable inter-observer variability (5), and the diagnostic criteria have been debated
for years. According to the third edition of the World Health Organization (WHO) classification of tumours of
endocrine organs of 2004, TCPTC was characterized by the presence of at least 50% of tall cells (namely three
times taller than wide) (6). More recently, some authors have observed that tumours with less than 50% (or
even 30%) of tall cell areas showed higher rates of aggressive features and worse clinical outcomes than
classical PTC (CVPTC) (7–9). These findings led to a significant update for the diagnosis of TCPTC which,
according to the WHO 2017 criteria, is defined by the presence of more than 30% of cells that are two-to-three
times as high as wide (WHO 2017) (10).
This change in TCPTC definition may have a non-negligible impact on the level of risk according to the
American Thyroid Association (ATA) (11) and, consequently, on the clinical management of patients.
To address the impact of this change, we gathered the largest mono-institutional series of TCPTC by
retrospectively selecting cases with any tall cell areas over a 17-year period. We compared the clinical and
pathological features among PTC with less than 30%, from 30 to 49%, and more than or equal to 50% of tall
cells. Moreover, we analysed recurrence-free survival (RFS) and evaluated the impact of the change of WHO
classification in treatment decision.
Materials and methods
Study population
All PTC patients with any tall cell component diagnosed at the Unit of Surgical Pathology of Pisa University
Hospital between 2001 and 2017 were included in this study. All patients underwent total thyroidectomy and,
whenever appropriate, lymph node dissection and radioiodine treatment according to the ATA guidelines
(11,12). For each case, glass slides were retrieved and re-evaluated independently by three pathologists (C.U.,
A.P., F.B.) specifically trained in thyroid pathology, according to the WHO criteria of 2004 and 2017. Tumours
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with aspects of other aggressive variants such as hobnail, columnar and solid/trabecular were excluded. All
cases were re-staged according to the latest edition of the American Joint Committee on Cancer (AJCC) staging
system (10). Follow-up data were available for a subgroup of patients. The study was approved by the Ethics
Committee, and informed consent was signed by each patient.
Genotyping
The mutational status of BRAF (exon 15) and TERT promoter was investigated for a subgroup of patients with
follow-up data. Manual macro-dissection was performed for each case. DNA was purified from two unstained
formalin-fixed paraffin-embedded 10 µM-thick sections using the QIAmp DNA mini kit (Qiagen, Hilden,
Germany). Direct sequencing was performed according to standard procedures on a 3130 Genetic Analyzer
(Thermo Fisher, Waltham, MA, United States).
Statistical analyses
The prevalence of TCPTC according to the 2004 and 2017 criteria and of PTC with any tall cell area was
analysed. Firstly, a segmented regression was fit by assigning as breakpoints the values in which a change of
slope was observed in the original data (13,14). Secondly, average annual percent change (AAPC) was
estimated by weighting the slopes from the segmented regression model (15). These analyses were performed
following the procedures of the segmented R package v.1.1-0 (13).
Categorical variables were analyzed by Pearson’s chi-square test or by Fisher’s exact text whenever
appropriate. Kruskal-Wallis H test with Dunn’s pairwise multiple comparison test with Benjamini-Hochberg
correction was used for continuous variables. Adjusted p-values below 0.05 were considered significant.
Survival curves were estimated by the Kaplan-Meier method and differences among curves were tested by the
Log-rank test. A Cox proportional hazard model was used in multivariate settings. A p-value of 0.05 was set as
significance level. All analyses were conducted in R environment (version 4.0.2, last accessed in December
2020, https://www.R-project.org).
Results
Prevalence of TCPTC and PTC with any tall cell areas across seventeen years
Overall, 19736 PTC were diagnosed between 2001 and 2017. A total of 3092 PTC (15.7%) with any tall cell
areas were included in the study, 1797 (9.1%) of which were diagnosed as TCPTC according to the 2004 WHO
criteria. Instead, TCPTC raised to 2300 (11.7% of total PTC) with an overall increment of 28.0% when applying
the 2017 criteria.
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The prevalence of TCPTC diagnosed with the 2004 criteria did not increase significantly over the 17-year
period. However, an AAPC of 0.48% (95% CI 0.24-0.72) and of 0.79% (95% CI 0.45-1.12) was observed for
TCPTC diagnosed with 2017 criteria and considering all PTC with any tall cell features respectively. Details are
reported in Figure 1. Raw numbers of PTC per year included in the study are reported in Table 1.
Differences in clinico-pathological features
Patients were divided into three groups: 792 PTC had less than 30% of tall cells; 503 had between 30 and 49%
of tall cells; and 1797 had 50% or more tall cell areas according to the WHO criteria of 2017.
Overall, the median age was 46 years (range 12-88) and the median size was 1.3 cm (range 0.1-11.5). The
female/male ratio was 3.8, and 43.1% of patients presented with thyroiditis. Only 149 PTC (4.8%) were
encapsulated, 81 (2.6%) of which non-invasive, with no differences among the three groups (p=0.27 and
p=0.25 respectively). The proportion of cases with aggressive features was considerable, including 52.8% with
ETE, 51.1% with multifocal tumours, 23.9% with lymph node metastases and 23.0% with vascular invasion.
BRAF gene status was already available in 739 out of 3092 tumours, of which 592 were mutated (80.1%) and
147 were wild-type (19.9%). BRAF mutation prevalence was not associated with the percentage of tall cell
areas (p=0.99). Details are shown in Table 2.
Patients’ outcome
The follow-up data of 1302 patients were available. Median follow-up was 5 years (interquartile range 3-7).
Overall, 120 patients (9.2%) experienced structural recurrence. Five patients (0.4%) died of the disease and
they all had tumours with more than 50% of tall cells.
Patients were divided into three groups according to the percentage of tall cell areas: 312 with less than 30%;
207 between 30 and 49%; and 783 with more than 50% of tall cells. No differences in RFS (p=0.3) were
observed among the patients of the three groups (Figure 2A). Clinico-pathological predictors of structural
recurrence were: age (cut-off 55 years, p=0.01), gender (p=1e-07), infiltration of thyroid parenchyma (p=0.04),
ETE (p=3e-07), multifocality (p=5e-05), bilaterality (p=7e-05), lymph node metastases at diagnosis (p=2e-12),
vascular invasion (p=4e-06), extra-nodal extension (ENE, p=2e-05), pT (p=2e-16) and distant metastasis at
diagnosis (p=2e-16). In addition, also TERT promoter mutation both alone (p=0.003) and coexisting with BRAF
mutation (p=0.002), MACIS high-risk (p=2e-16), AMES high-risk (p=2e-06), advanced AJCC stage (p=2e-16), and
ATA high-risk (p=2e-15) were predictive of poor RFS.
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A total of 28 patients (2.1%) had distant metastases including 5 (0.4%) at diagnosis. Patients with less than 30%
of tall cells had a lower rate of distant metastases, but differences in terms of distant recurrence-free survival
were not significant (p=0.3, Figure 2B).
In a further subgroup of patients with follow-up, genotyping yielded a result of 450 and 247 cases for BRAF and
TERT respectively. Overall, 364 cases (80.9%) harboured BRAF mutation; all but three (two p.T599I and one
p.T599_V600insEIAT) were p.V600E. Twenty-seven cases (10.9%) presented a mutation of TERT promoter
including nineteen C228T, seven C250T and one C242T/C243T. Twenty-five out of 27 TERT promoter mutations
coexisted with BRAF mutation. BRAF and TERT mutations were similarly distributed among the groups
according to different percentages of tall cell areas (Table 3).
Since ATA risk stratification is the most effective and widely used tool to predict recurrence, and does not
include multifocality, ENE, and coexistence of BRAF and TERT promoter mutations, we tested the ATA risk
category in a multivariate setting for each feature. They were all significantly predictive of poor RFS
independently of ATA risk, p=0.0007 (hazard ratio – HR, 95% CI: 2, 1.3-2.9), p=0.02 (HR, 95% CI: 2.5, 1.2-5.1)
and p=0.003 (HR, 95% CI: 2.9, 1.4-5.8) for multifocality, ENE, and coexisting BRAF and TERT promoter
mutations respectively.
Clinical impact of the new definition of WHO on patients’ management
According to the ATA risk stratification system, tumours that lack distant or lymph node metastases, vascular
invasion, ETE, and are N0 or have less than 5 nodal micro-metastases (<0.2 cm) are low-risk diseases, unless an
aggressive histology such as tall cell variant is present (11). Since the tall cell variant of PTC is sufficient to
change the PTC category from low- to intermediate-risk according to ATA risk stratification, a direct
consequence of the 30% cut-off, introduced in the fourth edition of the WHO classification, was the upgrade of
PTC with 30 to 49% of tall cells from low- to intermediate-risk. In our series with follow-up data, 55 tumours
(4.2%) would have been upgraded from low- to intermediate-risk on the basis of this change in the WHO
criteria. In this group of patients, 2 recurrences (3.6%) and no distant recurrences were observed in a median
follow-up of 6 years, without any differences with low-risk category (Table 4).
Discussion
The tall cell variant is recognised as an aggressive variant of PTC (4,16). However, several grey zones
concerning histological diagnosis and even prognosis have emerged in recent years. Indeed, TCPTC diagnosis
criteria have gone through consistent modifications according to the findings that even tumours with tall cell
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areas below 50% present higher rates of aggressive features and worse outcomes than CVPTC (7–9,17,18).
However, it has not yet been completely understood whether the worse prognosis of TCPTC is linked to the
presence of aggressive clinico-pathological features or to TCPTC histology itself (19–21). In this study, we
analysed the largest mono-institutional series of PTC with any tall cell features over a 17-year period, re-
evaluating tumours according to both the WHO 2004 and the 2017 criteria.
Overall, 3092 PTC with any tall cell features were collected. TCPTC diagnosis raised from 1797 cases with the
2004 criteria to 2300 with the 2017 criteria, with an overall increase of 28.0%.
However, it is worth noting that in the last years the increment of TCPTC diagnosed with the 2017 criteria has
been much higher, rising up to 49.7%. This increase is lower than that observed by other authors who reported
that TCPTC diagnoses had tripled with the new diagnostic criteria (22).
Over the 17-year period, the prevalence of TCPTC in our series has increased yearly, on average, by 0.48%; and
it is driven by an increment of tumours with moderate proportions (lower than 50%) of tall cell areas, as
confirmed by the stable prevalence of TCPTC diagnosed with 2004 criteria. A further confirmation is the even
more pronounced (0.79%) increment when considering all PTC with any tall cell areas. These findings might
reflect greater attention to reporting tumours with focal tall cell aspects.
As regards the pathological characteristics, the distribution of lymph node metastasis, vascular invasion, ETE,
and multifocality among PTC with less than 30%, between 30 and 49%, and at least 50% of tall cells was
different but remarkably high in all the three groups, especially in those with a moderate to low percentage of
tall cell areas. Follow-up data were available for a large subgroup of patients. The clinico-pathological
characteristics of this subgroup are similar with those of the entire cohort. One hundred and twenty patients
(9.2%) experienced structural recurrence in a median of 5 years, with almost one fourth affected by distant
metastases. Similarly to the prevalence of aggressive features, there were no differences in RFS and in DRFS
according to the percentage of tall cell areas. It is interesting to note that in a previous series of CVPTC, we
observed a 7.2% recurrence/disease persistence rate after 15 years follow-up (23), which is lower than the
overall 9.2% recurrence rate observed in the present study despite the shorter median follow-up period (i.e. 5
years). In addition, a recent metanalysis reported a big difference in terms of pooled recurrence rate between
TCPTC and CVPTC (22.2% vs 6.5%) (24).
Well-known pathological features such as ETE, vascular invasion, and lymph node metastasis were confirmed
to be important predictors of RFS. In addition, multifocality, ENE, and coexistence of BRAF and TERT promoter
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mutations proved to be independent predictors of recurrence, which are not included in the ATA risk
stratification system but should be considered at least in this subgroup of tumours.
There are some limitations that should be highlighted. Firstly, the follow-up data of our study were not
sufficiently mature to be tested for survival differences. However, AJCC stage and MACIS score could be used
as reliable surrogates of survival prediction. In this series, we did not observe strong dissimilarities in the
distribution of AJCC stages nor in MACIS score in the three groups with different tall cell percentages, despite
the higher proportion of MACIS high-risk and stage IV disease in the group of tumours with more than 50% of
tall cells. Further studies with long-term follow-up should address whether tall cell percentage affects patients’
survival even in the absence of aggressive clinico-pathological features.
Secondly, the retrospective nature of the study is unsuitable to directly evaluate the effect of different
treatments on outcome. However, we observed that following the WHO changes of the TCPTC criteria and the
current ATA guidelines, a significant proportion of patients with an actual low-risk of recurrence would receive
potential overtreatment.
In conclusion, our findings suggest that the presence of tall cell areas, even focal, define a rather
homogeneous group of tumours with similar molecular background, high rate of histological aggressive
features and recurrence risk. These tumours should thus be considered as a single entity. However, aggressive
disease is driven by the classical clinico-pathological features of aggressiveness, and the clinical impact of tall
cell percentage alone is negligible.
Data Availability
Some or all data generated or analyzed during this study are included in this published article.
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Figure legends
Figure 1. Number of tumours with any tall cell areas across seventeen years. A) Total number of tumours
considered across seventeen years; B) average annual percent change of TCPTC diagnosed with 2004 criteria;
C) average annual percent change of TCPTC diagnosed with 2017 criteria; D) average annual percent change of
PTC with any tall cell areas. Black, blue and red lines represent the actual prevalence at each timepoint, the
fitted segmented regression and the fitted linear regression respectively. Asterisk indicate non-significant
increment.
Figure 2. Kaplan-Meier curves. Recurrence-free survival (A) and distant recurrence-free survival (B) according
to tall cell percentage groups.
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Table 1. Prevalence of TCPTC diagnosed according to the WHO 2004 criteria, the WHO 2017 criteria
and PTC with any tall cell areas per year.
Y
e
a
r
TCPTC
(WHO
2004),
n
TCPTC
(WHO
2017),
n
PTC with
any tall
cell
areas,
n
Increment of
TCPTC with
WHO 2017
criteria,
%
all
PT
C,
n
Prevalence
TCPTC
(WHO
2004),
%
Prevalence
TCPTC
(WHO
2017),
%
Prevalence
PTC with any
tall cell areas,
%
2
0
0
1
31
31
31
0
37
4
8.3
8.3
8.3
2
0
0
2
45
47
54
4.4
51
2
8.8
10.2
10.5
2
0
0
3
54
65
71
20.4
37
3
14.5
16.1
19.0
2
0
0
4
76
80
102
5.3
64
0
11.9
15.3
15.9
2
0
0
5
92
102
130
10.9
73
8
12.5
16.3
17.6
2
0
0
6
121
161
183
33.1
96
7
12.5
14.8
18.9
2
0
0
7
67
76
82
13.4
10
13
6.6
7.2
8.1
2
0
0
8
68
88
101
29.4
12
00
5.7
6.8
8.4
2
0
0
9
140
172
203
22.9
13
82
10.1
12.4
14.7
2
0
1
0
158
185
243
17.1
14
81
10.7
14.6
16.4
2
0
1
158
193
238
22.2
13
20
12.0
15.4
18.0
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1
2
0
1
2
137
179
260
30.7
14
63
9.4
14.9
17.8
2
0
1
3
120
143
239
19.2
14
95
8.0
14.4
16.0
2
0
1
4
115
162
246
40.9
17
22
6.7
11.6
14.3
2
0
1
5
102
148
265
45.1
17
90
5.7
12.2
14.8
2
0
1
6
122
182
273
49.2
15
84
7.7
13.4
17.2
2
0
1
7
191
286
371
49.7
16
82
11.4
16.4
22.1
PTC, Papillary Thyroid Carcinoma; TCPTC, Tall Cell variant of Papillary Thyroid Carcinoma; WHO,
World Health Organization
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Table 2. Clinico-pathological features of the entire cohort.
Pathological
features
<30% TC
(n=792)
30% to 49% TC
(n=503)
≥50% TC
(n=1797)
total
(n=3092)
p-value
Gender
0.0067
male
182 (23.0%)
122 (24.3%)
339 (18.9%)
643 (20.8%)
female
610 (77.0%)
381 (75.7%)
1458 (81.1%)
2449 (79.2%)
Age (median,
years)
44 (IQR 35-53)
45 (IQR 36-54)
47 (IQR 38-57)
46 (IQR 37-56)
<0.0001
Size (median,
cm)
1.4 (IQR 1-1.9)
1.5 IQR (1-2)
1.2 (IQR 0.8-1.7)
1.3 (IQR 0.9-1.8)
<0.0001
Thyroid
parenchyma
infiltration
0.2691
yes
746 (94.2%)
483 (96%)
1714 (95.4%)
2943 (95.2%)
no
46 (5.8%)
20 (4.0%)
83 (4.6%)
149 (4.8%)
Extra-thyroidal
extension
none
435 (54.9%)
217 (43.1%)
806 (44.8%)
1458 (47.2%)
<0.0001
minimal
346 (43.7%)
281 (55.9%)
966 (53.8%)
1593 (51.5%)
gross
11 (1.4%)
5 (1.0%)
25 (1.4%)
41 (1.3%)
Multifocal
0.0002
yes
453 (57.2%)
256 (50.9%)
870 (48.4%)
1579 (51.1%)
no
339 (42.8%)
247 (49.1%)
927 (51.6%)
1513 (48.9%)
Bilateral
0.0063
yes
318 (40.2%)
202 (40.2%)
621 (34.6%)
1141 (36.9%)
no
474 (59.8%)
301 (59.8%)
1176 (65.4%)
1951 (63.1%)
Thyroiditis
0.1082
yes
332 (41.9%)
200 (39.8%)
802 (44.6%)
1334 (43.1%)
no
460 (58.1%)
303 (60.2%)
995 (55.4%)
1758 (56.9%)
Pathological
lymph nodes*
0.0003
N0
124 (36.9%)
72 (32.3%)
334 (47.0%)
530 (41.8%)
N1a
115 (34.2%)
91 (40.8%)
207 (29.2%)
413 (32.5%)
N1b
97 (28.9%)
60 (26.9%)
169 (23.8%)
326 (25.7%)
NX
456
280
1087
1823
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Vascular invasion
<0.0001
yes
199 (25.1%)
157 (31.2%)
356 (19.8%)
712 (23.0%)
no
593 (74.9%)
346 (68.8%)
1441 (80.2%)
2380 (77.0%)
BRAF status**
0.9854
mutated
153 (79.7%)
94 (80.3%)
345 (80.2%)
592 (80.1%)
wild-type
39 (20.3%)
23 (19.7%)
85 (19.8%)
147 (19.9%)
NA
600
386
1367
2353
TC, tall cells; NA, not available.
* NX cases were not considered for statistics.
** NA cases were not considered for statistics.
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Table 3. Clinico-pathological features of the subgroup of patients with follow-up data.
Pathological features
<30% TC
(n=312)
30% to 49% TC
(n=207)
≥50% TC
(n=783)
total
(n=1302)
p-value
Gender
0.1250
male
81 (26.0%)
52 (25.1%)
163 (20.8%)
296 (22.7%)
female
231 (74.0%)
155 (74.9%)
620 (79.2%)
1006 (77.3%)
Age (median,
years)
45 (35-54 IQR)
45 (36-54 IQR)
48 (IQR 38-58)
47 (IQR 37-56)
<0.0001
Size (median, cm)
1.5 (IQR 1-2)
1.5 (IQR 1.1-2)
1.3 (IQR 0.9-1.8)
1.3 (IQR 1-1.9)
<0.0001
Thyroid parenchyma
infiltration
0.3874
yes
293 (93.9%)
199 (96.1%)
749 (95.7%)
1241 (95.3%)
no
19 (6.1%)
8 (3.9%)
34 (4.3%)
61 (4.7%)
Extra-thyroidal
extension
0.0095
none
156 (50.0%)
83 (40.1%)
314 (40.1%)
553 (42.5%)
minimal
149 (47.8%)
121 (58.5%)
461 (58.9%)
731 (56.1%)
gross
7 (2.2%)
3 (1.4%)
8 (1.0%)
18 (1.4%)
Multifocal
0.2083
yes
173 (55.4%)
101 (48.8%)
392 (50.1%)
666 (51.2%)
no
139 (44.6%)
106 (51.2%)
391 (49.9%)
636 (48.8%)
Bilateral
0.6665
yes
107 (34.3%)
79 (38.2%)
280 (35.8%)
466 (35.8%)
no
205 (65.7%)
128 (61.8%)
503 (64.2%)
836 (64.2%)
Thyroiditis
0.4104
yes
124 (39.7%)
78 (37.7%)
332 (42.4%)
534 (41.0%)
no
188 (60.3%)
129 (62.3%)
451 (57.6%)
768 (59.0%)
Pathological lymph
nodes*
0.0080
N0
47 (30.3%)
32 (32.3%)
131 (42.0%)
210 (37.1%)
N1a
53 (34.2%)
45 (45.5%)
108 (34.6%)
206 (36.4%)
N1b
55 (35.5%)
22 (22.2%)
73 (23.4%)
150 (26.5%)
NX
157
108
471
736
Extra-nodal
extension**
0.2150
yes
12 (11.1%)
3 (4.5%)
12 (6.6%)
27 (7.6%)
no
96 (88.9%)
64 (95.5%)
169 (93.4%)
329 (92.4%)
Vascular invasion
0.0024
yes
89 (28.5%)
63 (30.4%)
164 (20.9%)
316 (24.3%)
no
223 (71.5%)
144 (69.6%)
619 (79.1%)
986 (75.7%)
Distant metastases at
diagnosis
0.3486
yes
0 (0%)
0 (0%)
5 (0.6%)
5 (0.4%)
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no
312 (100%)
207 (100%)
778 (99.4%)
1297 (99.6%)
BRAF status***
0.3684
mutated
85 (76.6%)
59 (84.3%)
220 (81.8%)
364 (80.9%)
wt
26 (23.4%)
11 (15.7%)
49 (18.2%)
86 (19.1%)
NA
201
137
514
852
TERT promoter
status***
0.9581
mutated
7 (11.3%)
3 (8.6%)
17 (11.3%)
27 (10.9%)
wt
55 (88.7%)
32 (91.4%)
133 (88.7%)
220 (88.9%)
NA
250
172
633
1055
AJCC stage
0.7077
stage I
288 (92.3%)
193 (93.2%)
720 (92%)
1201 (92.2%)
stage II
20 (6.5%)
12 (5.8%)
53 (6.8%)
85 (6.6%)
stage III
2 (0.6%)
1 (0.5%)
1 (0.1%)
4 (0.3%)
stage IV
2 (0.6%)
1 (0.5%)
9 (1.1%)
12 (0.9%)
MACIS
(cut-off 7)
0.0855
high-risk
10 (3.2%)
12 (5.8%)
52 (6.6%)
74 (5.8%)
low-risk
302 (96.8%)
195 (94.2%)
731 (93.4%)
1226 (94.2%)
AMES
0.0078
high-risk
157 (50.3 %)
124 (59.9%)
473 (60.4%)
754 (58.0%)
low-risk
155 (49.7%)
83 (40.1%)
310 (39.6%)
548 (42.0%)
ATA-risk
NP§
low
122 (39.1%)
0 (0%)
0 (0%)
122 (9.4%)
intermediate
182 (58.3%)
202 (97.6%)
761 (97.2%)
1144 (87.9%)
high
8 (2.6%)
5 (2.4%)
22 (2.8%)
35 (2.7%)
Recurrence
yes
29 (9.3%)
23 (11.1%)
68 (8.7%)
120 (9.2%)
0.3§§
no
283 (90.7%)
184 (88.9%)
715 (91.3%)
1182 (90.8%)
Distant recurrence
yes
3 (1.0%)
5 (2.4%)
20 (2.5%)
28 (2.1%)
0.3§§
no
309 (99.0%)
202 (97.6%)
763 (97.5%)
1274 (97.9%)
TC, tall cells; NA, not available; AJCC, American Joint Committee on Cancer; MACIS, distant Metastasis, Age,
Completeness of resection, local Invasion and tumour Size score; AMES, Age, distant Metastasis, Extent of
disease, Size score; ATA, American Thyroid Association.
* NX cases were not considered for statistics.
** Only positive lymph nodes were considered.
*** NA cases were not considered for statistics.
§ NP, not performed since ATA risk and tall cell groups are not independent.
§§ log-rank p-value.
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Table 4. Redistribution of ATA risk according to the 2017 change of criteria for tall cell histology.
ATA risk
TCPTC 2004
criteria
ATA risk
TCPTC 2017
criteria
Cases,
no.
Follow-up,
median
(IQR)
Recurrences,
no. (%)
Distant
metastases
(any time)
no. (%)
Distant
recurrences
without M1 at
diagnosis
Low
low
122
5 years
(3-7)
3 (2.5%)
0 (0%)
0 (0%)
Low
intermediate
55
6 years
(4-8)
2 (3.6%)
0 (0%)
0 (0%)
intermediate
intermediate
1090
5 years
(3-7)
100 (9.2%)
12 (0.1%)
12 (0.1%)
High
high
35
5 years
(3-7)
15 (42.9%)
16 (45.7%)
12 (34.3%)
ATA, American Thyroid Association; TCPTC, tall cell variant papillary thyroid carcinoma.
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Figure 1
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Figure 2
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