Endocrine (2023) 81:322–329

https://doi.org/10.1007/s12020-023-03366-y

ORIGINAL ARTICLE

Clinical features of thyroid cancer in paediatric age. Experience of a

tertiary centre in the 2000–2020 period
Gerdi Tuli 1 Jessica Munarin 1 Patrizia Matarazzo 1 Antonio Marino1,2 Andrea Corrias
● ● ● ●
1 ●

Nicola Palestini 3 Francesco Quaglino 4 Luisa De Sanctis 1

● ●

Received: 25 February 2023 / Accepted: 2 April 2023 / Published online: 18 April 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023

Abstract
Purpose To describe the clinical features of a paediatric cohort affected by differentiated thyroid cancer (DTC) followed in a
tertiary Department of Paediatric Endocrinology.
Methods Clinical data of 41 patients affected by DTC in the 2000–2020 period were reviewed.
Results The main risk factor was autoimmune thyroiditis (39%). Cytological categories were TIR3b in 39%, TIR4 in 9.8%,
TIR5 in 51.2%. After total thyroidectomy, radioiodine treatment was performed in 38 subjects (92.7%). ATA low-risk
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category was assigned in 11 (30.5%), intermediate-risk category in 15 (41.7%), and high-risk category in 10 patients
(27.8%). Age at diagnosis was 15.1 ± 0.92 years in low-risk category, 14.7 ± 0.59 in intermediate-risk category, 11.7 ± 0.89
years in high-risk category (p = 0.01). TIR3b was manly observed in low-risk class (63.6%), while TIR5 was mainly
reported in intermediate and high-risk class (60 and 80% respectively) (p = 0.04). Post-surgery stimulated thyroglobulin was
increased in high-risk class (407.8 ± 307.1 ng/ml) [p = 0.04]. Tumour size was larger in high-risk category (42.6 ± 2.6 mm),
than in low and intermediate-risk categories (19.4 ± 3.5 mm and 28.5 ± 3.9 mm, respectively) (p = 0.008). Patients in
intermediate and high-risk categories displayed more tumour multifocality (60 and 90% respectively) (p < 0.005). Disease
relapse was mainly observed in high risk category (40%, p = 0.04).
Conclusion DTC in childhood is more aggressive than in adults, but the overall survival rate is excellent. The therapeutic
approach is still heterogeneous, especially in low-risk category. Further studies are needed to standardise management and
reduce disease persistence in childhood.
Keywords Thyroid cancer Paediatric age Prognostic factors Clinical features
● ● ●

Introduction ultrasound assessment. Fine-needle agobiopsy (FNAB) for

cytological category determination is required when suspi-
Thyroid nodules in paediatric age are less frequent than in cious ultrasound features of malignancy or clinical risk
adults (0.2–0.5 vs 19–35%), but the rate of malignancy is factors are present [3–13]. Previous radiation exposure or
higher, reaching up to 20–25% during childhood [1, 2]. cancer treatment, underlying thyroid disease, family history
Diagnostic evaluation include clinical, biochemical and for thyroid cancer and predisposing genetic mutations
represents known risk factors for thyroid cancer [1]. Based
on the cytological assessment, the decision on further
management is made, from clinical-ultrasound follow-up,
* Gerdi Tuli
gerdi.tuli@unito.it
repeat FNAB, lobectomy or total thyroidectomy. The
diagnosis of thyroid cancer is defined in the case of a
1
Department of Public Health and Pediatrics, University of Turin, cytological category of certain malignancy or a definitive
Turin, Italy histological finding for thyroid cancer after surgery.
2
Department of Pediatric Endocrinology, Regina Margherita Differentiated thyroid cancer (DTC) represents the most
Children’s Hospital, Turin, Italy common solid tumour in paediatric age, with a reported
3
Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy incidence of 0.2–1 per million child-years, which is higher
4
Department of General Surgery, Maria Vittoria Hospital, ASL City in adolescence and in females. Papillary thyroid cancer
of Turin, Turin, Italy (PTC) is the most frequent histological finding and accounts
Endocrine (2023) 81:322–329
for 90% of DTC; follicular thyroid cancer (FTC) is less
common in paediatric age (5%), as well as the mixed his-
tologic type (3%), while medullary thyroid cancer (MTC)
represents 2%.
The behaviour of DTCs in paediatric age is very different
from adults. Disease presentation, local and distant spread,
disease persistence and recurrence rate, response to radio-
iodine (RAI) treatment and molecular profile differ from
adults, therefore children and adolescents require specific
management [14–26].
Although children more frequently display multifocality,
local extension, lymph node involvement, distant metas-
tases, persistent disease and risk of recurrence, the overall
survival rate is higher than in adults and the prognosis is
excellent [27–29]. Younger age and advanced T and N
stages are risk factors for multifocality, which is predictive
of bilateral disease [30, 31]. The lungs are the most frequent
site of distant metastases, occurring in 6–33% of children
with DTC [32]. Follicular histologic type, basal pre-ablation
thyroglobulin >14 ng/ml, or stimulated thyroglobulin
>154 ng/ml are the main known factors associated with a
higher risk of distant metastases [33–35].
Persistent disease occurs more frequently with higher T
stage and when lymph node or distant metastases are pre-
sent or when high stimulated thyroglobulin is observed after
surgery [36–38].
The risk of recurrence has been estimated to be 20–40%
at 10 years and surveillance protocols are mandatory [39].
Younger age, partial thyroidectomy, involvement of more
than 5 lymph nodes or incomplete primary lymph node
excision, distant metastases and absence of RAI ablation are
the main risk factors for recurrence [38, 40].
Total thyroidectomy with local lymph node dissection is
in most cases the first-line treatment [11, 12, 41]. Some
authors suggest considering lobectomy in case of tumour
size <10 mm and absence of extra-thyroidal invasion,
although this approach is still under discussion [42–44].
American Thyroid Association (ATA) guidelines estab-
lished risk stratification (low, intermediate, and high)
according to the American Joint Committee on Cancer
(AJCC) Tumour, Nodes, and Metastases (TNM) classifi-
cation system [12]. Some authors have suggested dynamic
risk stratification (DRS) to increase the accuracy of risk
class assignment [42]. Radioiodine (RAI) therapy is
necessary in cases of tumour larger than 40 mm, lymph
node involvement and distant metastases [11, 12, 41]. The
use of RAI in patients in the low-risk category patients is
still under discussion. Post-treatment staging with 131I –
scintiscan is useful for determining residual disease and for
evaluating subsequent follow-up strategies.
The aim of this study is to describe the clinical features
of a paediatric cohort affected by differentiated thyroid
323
cancer followed in a tertiary Department of Paediatric
Endocrinology for a period of 20 years.
Materials and methods
The data of all paediatric (<18 years) patients affected by
differentiated thyroid cancer referred to the Department of
Paediatric Endocrinology at Regina Margherita Children’s
Hospital of Turin in the period 2000–2020 were retro-
spectively reviewed. Demographic, clinical and biochem-
ical (thyroid hormone profile, thyroglobulin and calcitonin
levels and anti-thyroglobulin antibodies) data were analysed
for each patient. Patients with suspicious ultrasound of
malignancy or with known risk factors for developing DTC
were referred for FNAB. All specimens were evaluated in
the same hospital Pathological Anatomy Department. The
cytological category was assigned according to the Italian
Society of Anatomical Pathology and Diagnostic Cytology
(SIAPeC). The American Joint Committee on Cancer
(AJCC) Tumour, Nodes, metastases (TNM) classification
system was used to assign the post-surgical class of risk,
according to ATA guidelines.
All patients underwent total thyroidectomy and lymph
node dissection. Surgery was performed in a high-volume
surgery centre for thyroid disease (>150 thyroidectomies/
year). RAI therapy was performed in all patients included in
the intermediate and high risk categories, while case-by-
case evaluation was performed in the low-risk category. In
all patients, pre-ablation TSH increase was achieved by
discontinuing levothyroxine for 30–40 days before RAI.
Persistent disease was considered in case of subtotal
thyroidectomy, elevated post-ablation stimulated thyr-
oglobulin and residual tissue caption at 131I – scintiscan
investigation.
Disease recurrence was considered in case of significant
increase of thyroglobulin level during follow-up after sur-
gery and/or RAI treatment.
Follow-up was performed by clinical, radiological
(ultrasound or 131I – scintiscan) and biochemical (thyroid
hormone profile, basal and stimulated thyroglobulin levels)
assessment after treatment.
Statistical analyses were performed through Graphpad
7 software (GraphPad Software, La Jolla, CA, USA), using
ANOVA test to compare means and chi-square test to
compare differences between groups. Significant difference
between means was considered with p < 0.05.
The study was conducted according to the guidelines of
the Declaration of Helsinki and received the approval of the
Ethics Committee of the City of Health and Science Uni-
versity Hospital of Turin (number of approval 13942/A1).
Informed parental consent was obtained in all cases.
324 Endocrine (2023) 81:322–329

Results Table 1 Demographic and clinical data of paediatric patients affected

by differentiated thyroid cancer in the period 2000–2020

During the study period, 41 subjects (16 males and 25 Demographic data
females) followed for 6.8 ± 0.32 years were enroled (Table 1).
Gender Male 16 (39%)
The mean age at diagnosis was 13.9 ± 0.49 years. Among the
Female 25 (61%)
risk factors analysed the most frequent was autoimmune
Age at diagnosis (years) 13.9 ± 0.49
thyroiditis (16/41, 39%), followed by previous irradiation (6/
Risk factors Autoimmune thyroiditis 16 (39%)
41, 14.6%) and chemotherapy (2/41, 4.9%). Positive history of
Radiotherapy 6 (14.6%)
neck irradiation was observed in patients affected by high-risk
Chemotherapy 2 (4.9%)
acute lymphocytic leukaemia (LLA, 3/6), ependymoma (2/6)
and medulloblastoma (1/6), whereas the 2 patients treated with Thyroid cancer data
chemotherapy only were affected by standard-risk LLA. Cytological TIR3 b 16 (39%)
Cytological categories after FNAB were TIR3b in 16/41 TIR 4 4 (9.8%)
(39%), TIR4 in 4/41 (9.8%), TIR5 in 21/41 (51.2%) TIR 5 21 (51.2%)
patients. Total thyroidectomy was performed in 39 patients. Hystological Papillary 35 (85.4%)
Near-total thyroidectomy was performed in 2 subjects due Follicolar 5 (12.2%)
to impossibility of achieving a total resection due to Mixed 1 (2.4%)
adherences of the tumour lesion to the oesophagus and right Dimension (mm) <10 5 (12.2%)
recurrent laryngeal nerve. Histological findings showed 10–40 20 (48.8%)
PTC in 36 subjects (87.8%) and FTC in 5 subjects (12.2%). >40 16 (39%)
Considering pre-operative biochemical profile, all patients Focality Unifocal 19 (46.3%)
showed low calcitonin level. Multifocal 22 (53.7%)
Tumour size was <10 mm in 5/41 (12.2%), 10–40 mm in Lymph node N0 18 (43.9%)
20/41 (48.8%) and >40 mm in 16/41 (39%), while multi- N1 23 (56.1%)
focality was observed in 22/41 (53.7%). Distant metastasis M0 39 (95.1%)
Lymph node involvement was present in 23/41 (56.1%), M1 2 (4.9%)
while distant metastases in 2/41 (4.9%). Both patients dis- Risk level (only PTC) Low 11 (30.5%)
played lung metastases. Intermediate 15 (41.7%)
After surgery, radioiodine treatment was performed in High 10 (27.8%)
38 subjects (92.7%, 5/5 FTC and 33/36 PTC).
Radiometabolic treatment Yes 38 (92.7%)
Of the 36 subjects affected by PTC, according to ATA
No 3 (7.3%)
criteria, 11 patients were assigned to the low-risk (30.5%),
15 to the intermediate-risk (41.7%) and 10 to the high-risk
category (27.8%) [Table 2]. The three patient who did not
receive RAI treatment were assigned to the low-risk cate- Considering patients with negative anti-thyroglobulin
gory and presented tumour dimension lower than 1 cm. antibodies, post-surgical stimulated thyroglobulin levels
No differences were observed between risk categories were significantly increased in the high-risk class
with respect to gender, lymph node involvement and distant (407.8 ± 307.1 ng/ml), compared to the intermediate and
metastases, positive titration of anti-thyroglobulin anti- low-risk category (11.7 ± 6.5 ng/ml and 7.56 ± 4.9 ng/ml,
bodies, RAI treatment and 131I dose. respectively) (p = 0.04). Positive anti-thyroglobulin
Age at diagnosis was 15.1 ± 0.92 years in the low-risk antibodies after thyroidectomy were observed in 3/11
category, 14.7 ± 0.59 in the intermediate-risk category and low-risk, 7/15 intermediate-risk and 5/10 high-risk
11.7 ± 0.89 years in the high-risk category (p = 0.01). assigned patients.
The most frequent cytological category observed in Tumour size was larger in the high-risk category
patients assigned to the low-risk class was TIR3b (7/11, (42.6 ± 2.6 mm), than in the low and intermediate-risk
63.6%), while the TIR5 category was mainly observed in categories (19.4 ± 3.5 mm and 28.5 ± 3.9 mm, respectively)
both the intermediate and the high-risk class, in 9/15 (60%) (p = 0.008). Dimensions greater than 40 mm were
and 8/10 patients (80%), respectively [p = 0.04]. observed more frequently in the intermediate and high-
Post-surgical TSH (obtained after L-thyroxine with- category, in 8/15 (53.3%) and 9/10 (90%) patients,
drawal preceeding RAI treatment) was 127 ± 26.3 mUI/l in respectively [p < 0.005].
the low-risk category, 126.2 ± 16.8 in the intermediate-risk Patients assigned to intermediate and high-risk categories
category and 217.4 ± 35.2 in the high-risk category showed tumour multifocality more frequently, found in 9/15
(p = 0.02). (60%) and 9/10 (90%) patients, respectively (p < 0.005).
Endocrine (2023) 81:322–329 325

Table 2 Demographic and

Low risk Intermediate risk High risk (n = 10) p
clinical data according to the
(n = 11) (n = 15)
American Thyroid Association
risk class Gender Male 5 7 2 0.35
Female 6 8 8
Age at diagnosis (years) 15.1 ± 0.92 14.7 ± 0.59 11.7 ± 0.89 0.01
Cytological TIR 3b 7 5 0 0.04
TIR 4 1 1 2
TIR 5 3 9 8
Lymph node involvement Yes 11 13 10 0.89
No 0 2 0
Distant metastasis Yes 0 0 2 0.21
No 11 15 8
Post surgical TSH (ng/ml) 127 ± 26.3 126.2 ± 16.8 217.4 ± 35.2 0.02
Post surgical TG (mUI/l) 7.56 ± 4.9 11.7 ± 6.5 407.8 ± 307.1 0.04
TGAb Yes 3 7 5 0.5
No 8 8 5
Dimension (mm) 19.4 ± 3.5 28.5 ± 3.9 42.6 ± 2.6 0.008
Dimension > 40 mm Yes 1 8 9 <0.005
No 10 7 1
Multifocality Yes 1 9 9 <0.005
No 10 6 1
Radioiodine (RAI) Yes 8 15 10 0.21
treatment No 3 0 0
RAI dose (mCi/kg) 1.4 ± 0.1 1.6 ± 0.2 1.7 ± 0.2 0.58
Disease persistence Yes 0 0 2 0.06
No 11 15 8
Disease relapse Yes 1 0 4 0.04
No 10 15 6

Persistence of disease was observed in 2 (20%) patients
assigned to the high-risk class. Radical thyroidectomy was
not possible in both patients.
Despite RAI treatment, disease relapse was identified in 1
patient in the low-risk category (1/10, 10%), and in 4 subjects
assigned to the high-risk category (4/10, 40%) (p = 0.04).
Discussion
The management of thyroid cancer in paediatric age is still a
matter of debate. Compared to adults, young patients have
more advanced disease at presentation, but the clinical course
is not complicated, and overall survival is excellent [27–29].
The most frequently reported risk factors are underlying
thyroid disease, previous head and neck irradiation, che-
motherapy, predisposing genetic mutations and family his-
tory [3–13]. Based on these data, the most frequent risk
factor observed in our cohort was autoimmune thyroiditis,
followed by previous treatment for childhood cancer.
Among thyroid disease, autoimmune thyroiditis is the
most frequent risk factor associated with thyroid nodule, but
it is not clear whether the rate of malignancy is also higher
[45]. Grave’s disease and congenital hypothyroidism are
also considered predisposing factors for the development of
thyroid cancer [1]. In such cases, a periodic ultrasound
evaluation is therefore suggested, even if to date there is no
unanimous opinion. To avoid redundant procedures and
patient and familial anxiety, evaluation may be indicated
every 2 years in AIT, every year in Grave’s disease and
every 3-4 years in congenital hypothyroidism with eutopic
gland or ectopic thyroidal tissue.
Previous radiation exposure, particularly of the head and
neck region, is a known risk factor for thyroid malignancy
[46–50]. An irradiation dose <30 Gy is related to an
increased risk of second cancer, while higher doses lead to
tissue necrosis. Many chemotherapy agents are also related
to thyroid malignancy in childhood cancer survivors. Again,
there is no solid evidence of ultrasound monitoring in these
subjects, but evaluation every 2 years beginning 5 years
after cancer off-therapy, may be considered reasonable.
The most approved surgical approach in DTC is total
thyroidectomy, although some authors suggest lobectomy
in case of low-risk thyroid neoplasia (dimension <10 mm
326
and non-extrathyroidal involvement) [11, 12, 42, 43]. Total
thyroidectomy is related to a lower risk of recurrence, more
effective radioiodine ablation, and more reliable thyroglobulin
measurement during the postoperative follow-up. Conversely,
lobectomy is related to a lower rate of surgical complications
such as hypoparathyroidism, recurrent laryngeal nerve injury,
and bleeding. In our cohort, almost all patients underwent
total thyroidectomy, with no reported cases of permanent
recurrent laryngeal nerve injury and only one case of per-
manent hypoparathyroidism. Near-total thyroidectomy was
performed in 2 patients due to tumour adherences to impor-
tant anatomic structures such as the oesophagus and recurrent
laryngeal nerve. Both patients showed persistent but sta-
tionary disease after three sessions of RAI, confirming the
need for a radical surgical approach, when possible. To
reduce total thyroidectomy surgery complications, persistent
disease rates, and tumour relapse, it is critical that total thyr-
oidectomy is performed by an experienced surgeon with high-
volume surgery for thyroid diseases [51].
After surgery, RAI treatment is required in case of
tumour size >40 mm, lymph node involvement and distant
metastases, although recent European guidelines recom-
mend RAI ablation in all patients with DTC. In the present
cohort, we decided to perform RAI treatment in all patients
but three subjects included in the low-risk ATA class.
Considering the young age of children or adolescents with
DTC and the limited evidence of RAI safety data, a case-by-
case approach may be reasonable in subjects assigned to the
low-risk category, rather than absolute recommendation for
all patients [11, 12, 41, 52, 53].
According to the ATA classification, patients with DTC
are assigned to different risk categories (low, intermediate and
high) according to the Tumour, Nodes, metastases (TNM)
classification system of the American Joint Committee on
Cancer (AJCC). Risk is defined as the likelihood of having
persistent cervical disease and/or distant metastasis after initial
total thyroidectomy and lymph node dissection. Additional
negative prognostic factors include younger age, male gender,
tumour size, mixed hystotype, bilateral localisation, unilobar
multifocality, extrathyroidal extension, incomplete surgical
resection of the tumour and high post-ablation stimulated
thyroglobulin levels [11, 12, 30–41].
The majority of patients in our cohort were assigned to
the intermediate-risk class followed by low and high-risk
categories. We observed no differences in gender, lymph
node involvement and distant metastases, positive titration
of anti-thyroglobulin antibodies, RAI treatment and 131I
dose among the three risk categories.
According to literature data, the patients assigned to the
high-risk class in our study were younger [12]. The inde-
terminate cytological category (TIR3b) was mainly
observed in the low-risk category. To our knowledge this
data has not been reported before in the literature.
Endocrine (2023) 81:322–329
Tumour size greater than 40 mm and lobar multifocality
were mainly observed in intermediate and high-risk classes,
confirming their negative prognostic role. We observed
more severe induced hypothyroidism before RAI ablation in
high-risk patients, probably due to longer withdrawal period
to increase tissue avidity for 131I. The postoperative level of
stimulated thyroglobulin was increased in the high-risk
class compared to the intermediate and low-risk category,
indicating a probable association with a negative prognostic
role. Subjects included in the high-risk class showed a
higher relapse rate than other risk categories, in accordance
with literature data. Only 1 subject with relapsed disease
was included in the low-risk ATA category. In this case,
post-surgical basal thyroglobulin was persistently elevated,
even though there were no other associated negative prog-
nostic factors. These data confirm the need to increase the
accuracy of the ATA criteria for risk class assignment by
adding the well-known prognostic factors to the initial class
assignment or by following a dynamic risk stratification
approach [42].
In conclusion, we confirm the more aggressive behaviour
of DTC in paediatric age compared to adults. Despite this,
the overall survival rate is excellent. The therapeutic
approach is still heterogeneous, especially in the low-risk
category. Further studies are needed to standardise man-
agement across tertiary centres and reduce disease persis-
tence in childhood.
Author contributions All authors contributed to the study design and
conception. Material preparation, data collection and analysis were
performed by A.M., J.M. and G.T. The clinical management of the
enroled subjects was managed by A.C., P.M., G.T., J.M., F.Q. and
L.D. Sanctis. The first draft of the manuscript was written by G.T. and
J.M. and all authors have commented on previous versions of the
manuscript. All authors have read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Consent to publish Consent to publish has been received from all
partecipants.
Consent to partecipate Written parental consent was obtained.
Ethics approval This study was conducted in line with the principles
of the Declaration of Helsinki. The approval was granted by the Ethics
Committee of the City of Health and Science University Hospital of
Turin (01/10/2021, 13942/A1).
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