Keywords
Clinical outcome - long-term follow-up - pediatric differentiated thyroid carcinoma
- radioactive iodine therapy - recurrence - survival analysis
Introduction
Differentiated thyroid cancer (DTC) is rare in children, constituting 0.5%–3.0% of
all pediatric malignancies, but it still remains the most common endocrine malignancy
in children. Papillary thyroid cancer (PTC) accounts for 90% or more of all childhood
cases.[1],[2],[3],[4]
Age is recognized as one of the most important prognostic factors for DTC. In patients
younger than 18 years, DTC has been found to behave differently than in adults DTC
is particularly rare in the first decade and more aggressive in ≤10 years children.[5],[6] Children generally present with advanced disease at diagnosis. Extrathyroidal extension,
tumor size, multicentricity, lymph node metastasis, and distant metastases at diagnosis,
are more frequent and important risk factors in DTC.[2],[7],[8],[9],[10],[11],[12] Although DTC has high rates of local and distant recurrences, the outcome and prognosis
are much better for pediatric patients with low mortality rate compared to the adults.[3],[6],[10],[11],[12] The goal of primary treatment of DTC is to eradicate disease and extend recurrence-free
survival. Treatment of DTC consists of total or near total thyroidectomy with selective
lymph node dissection (when involved) followed by remnant ablation with iodine-131
(I-131) in patients.[3],[6],[7],[11] The aim of this study was to analyze treatment response to radioactive iodine (RAI)
therapy, clinical outcomes, recurrences, survival analysis, and long-term follow-up
data in pediatric DTC.
Materials and Methods
We retrospectively reviewed the medical records of 43 pediatric patients (≤17 years
of age) with differentiated thyroid carcinoma diagnosis after thyroidectomy who were
treated with RAI and followed up in our clinic, between 1995 and 2015. Inclusion criteria
were patients with well-differentiated thyroid carcinoma diagnosis who were diagnosed
under 18-year-old, with minimum follow-up of 6 months. Exclusion criteria were patients
older than 17 years, the presence of medullary thyroid carcinoma or anaplastic carcinoma.
None of the patients had a history of the head-and-neck irradiation.
We analyzed the differences in the clinical variety between children ≤10 years and
>10 years. The medical data were evaluated according to their age, gender, type of
surgery, histopathology, RAI therapy, recurrences, long-term follow-up, survival analysis,
and mortality rate.
All the patients had undergone total/subtotal thyroidectomy with or without cervical
lymph node dissection.
Postoperative data on tumor characteristics included tumor size and type, tumor extension,
multicentricity, extra thyroidal extension, lymph node metastasis, lymphatic invasion,
soft tissue and vascular invasion.
Before the RAI treatment, neck ultrasonography (USG) and thyroid scintigraphy were
applied to all patients. Based on guidelines of the American Thyroid Association (ATA)
and of the European Thyroid Cancer Taskforce pretreatment serum concentration of free
T4 (fT4), free T3 (fT3) thyroid-stimulating hormone (TSH), thyroglobulin (Tg), and
anti-Tg antibodies (anti TgAb) were measured in order to reveal the presence or absence
of residual thyroid tissue.
RAI therapy remnant ablation was performed within 4–6 weeks after the thyroid surgery,
ranged from 30 to 200 mCi (mCi) (1.11–7.4 GigaBecquerel [GBq]) based on guidelines
of the ATA and of the European Thyroid Cancer Taskforce.[11],[13] Repeated RAI treatments were given to patients with evidence of local recurrence
or distant metastases.
There are two main practices for RAI dosing, empiric fixed doses and individualized
doses using either body surface area or weight. The empiric fixed doses are 30–100
mCi (1.11–3.7 GBq) for ablation, 150 mCi (5.55 GBq) for nodal involvement, and 150–200
mCi (5.55–7.4 GBq) for distant metastases. For children under or at the age of 10
years, doses were corrected using either body surface area or weight. The adult dose
was then scaled down according to the pediatric patient's body weight by using the
formula: Pediatric dose = Adult dose × body weight (kg)/70 (kg).[11],[13] Older children (>10 years) were given empiric fixed doses.
All patients received thyroid-stimulating hormone suppression treatment with levothyroxine
after the RAI therapy according to the ATA guidelines. Postablative I-131 whole body
scan (WBS) was performed 5–7 days after radioiodine administration.
The follow-up protocol consisted of detailed clinical examination, testing of thyroid
function (fT4, fT3, and TSH), determination of serum Tg and anti-TgAb, and neck USG
application. Diagnostic WBS with I-131 (2–5 mCi) was performed 12 months after ablation
therapy.
Intervals between examinations ranged from 3 to 6 months, depending on the estimated
risk of disease recurrence. All patients in whom recurrence was suspected were confirmed
using cytology and/or histology.
Response to treatment was evaluated with the following criteria:
-
Complete remission was achieved when the posttherapy whole-body I-131 scintigraphy
and repeated diagnostic scans were negative for any remnants of the thyroid tissue
or metastasis, and serum Tg levels were <2 ng/mL
-
Partial remission was considered when there were partial uptakes in the same areas
on follow-up whole-body I-131 scintigraphy along with constantly high serum Tg levels
-
The recurrent-persistent disease was considered when there were new foci of radioiodine
uptake on the whole-body I-131 scintigraphy, and/or the serum Tg levels were rising.
Statistical analysis
In the current study, statistical analysis was performed using IBM SPSS version 22.0
software (IBM Corp., Armonk, NY, USA). Compliance with the normal distribution of
parameters was evaluated using Shapiro–Wilks test. Data were analyzed using descriptive
statistical methods (mean, standard deviation, and frequency). Mann–Whitney U-test,
and Chi-square test was used for the comparison of quantitative data between the two
groups and Fisher's exact test, Chi-square test and Fisher Freeman Halton were used
for the comparison of qualitative data. Logistics analysis was performed for multivariate
analysis. The Kaplan–Meier method was used for survival analysis. The Log-Rank test
was used to determine group differences in survival curves. The values of P < 0.05 were considered statistically significant with 95% of confidence interval
(CI).
Ethics
The local ethics committee of Okmeydani Training and Research Hospital, located in
Istanbul, Turkey approved the study (08.042014/188) and informed consent was obtained
from all patients participating in this study.
Results
In the current study, 43 patients (34 females, 9 males) treated with RAI for differentiated
thyroid carcinoma in our institute. The age at diagnosis of DTC ranged from 3 to 17
years (mean age 14.7 ± 3.1 years) with female predominance (79%). The median follow-up
period was 54 months (range 7–238 months). At diagnosis, 4 patients (9.3%) were 10
years of age or under and 39 patients (90.7%) over 10 years of age. There was no statistically
significant difference at rates of recurrences in terms of age (P > 0.05). Family history of thyroid cancer was positive in 4 patients (9.3%), and
none of the patients had a history of the head-and-neck irradiation. The clinical
characteristics of all patients are summarized in [Table 1].
Table 1 Clinical and pathologic characteristics results and follow-up in pediatric differentiated
thyroid cancer patients
In 41 of 43 patients (95.3%) total thyroidectomy was performed, one patient had bilateral
subtotal thyroidectomy and 1 patient had right lobe total left lobe subtotal thyroidectomy.
In 17 of patients (39.5%), neck lymph node dissections were performed.
The primary tumor size at initial surgery was minimum of 0.1 cm, and maximum of 5
cm (median size 2.13 ± 1.32 cm). In 35 patients (81.4%) primary tumor size was ≥1
cm, and in 8 patients (18.6%) it was <1 cm. There was no significant difference in
tumor size among the recurrence and nonrecurrence groups (P > 0.05).
The histologic classification was PTC in 41 patients (95.3%) and the remaining 2 patients
(4.7%) had follicular thyroid cancer (FTC). The histologic subtypes of PTC were classic
type in 23 (53.5%), follicular variant in 15 (34.9%), diffuse sclerosis in 2 (4.7%),
and classic and follicular variant in 3 patients (7%). There were no statistically
significant difference rates at of recurrences in terms of histopathological subtypes
(P > 0.05). Hurthle cell carcinoma or insular carcinoma was not found in our series.
Extrathyroidal extension was found in 24 patients (55.8%), multicentricity in 23 patients
(53.5%), lymph node involvement in 15 patients (34.9%), lymphatic invasion in 24 patients
(55.8%), and soft tissue and vascular invasion in 21 patients (48.8%). Recurrence
rate was significantly influenced by tumor multicentricity (26.1%) (P < 0.05) and lymph node metastasis (33.3%) (P < 0.05). The risk of recurrence in patients with lymph node metastasis was 13.5 times
more than patients without lymph node metastasis (odds ratio: 13.500; 95% CI: 1.400–130.191).
Regarding the TNM staging, 83.7% (36 patients) were TNM stage I and (7 patients) 16.3%
stage II.
RAI treatment was administered for ablation of thyroid remnant in all of the patients
after the surgery. RAI dose at ablation ranged from 30 to 200 mCi (1.11–7.4 GBq) and
total RAI administered ranged from 30 to 850 mCi (1.11–31.4 GBq).
Thirty-one out of 43 patients (72.1%) were administered with a single dose of I-131,
12 patients (27.9%) underwent two or more dose of RAI treatment (between 2 and 4)
for recurrence or distant metastasis. RAI treatment was repeated once in 7 patients,
twice in 1 patient, three times in 1 patient, and four times in 3 patients. Total
cumulative activities were 189.25 ± 177.02 mCi (6.99–6.5 GBq).
After the initial RAI ablation, WBS revealed thyroid remnants in all patients, cervical
lymphadenopathy in 6 patients, lung metastasis in 4, bone metastasis (femur and sternum)
in 2, and mediastinal lymphadenopathy in 1 patient.
Twenty-nine out of 37 patients had complete remission after the initial dose, 6 patients
showed complete remissions in the second dose, one in third and one in forth dose.
After the last RAI treatment; recurrences were diagnosed in 9 patients (20.9%), including
1 recurrence in thyroid remnants, 1 neck lymph node metastasis, 2 neck lymph node
metastasis and lung metastasis, 1 neck and mediastinal lymph node metastasis, 1 lung
metastasis, 1 lung metastasis and recurrence in thyroid remnants, 1 multiple metastasis
(lung, bone, and lymph node), 1 bone metastasis (sternum), and local invasion [Table 2].
Table 2 Sites of carcinoma recurrences and follow-up
After the long-term follow-up, among all studied patients, complete remission, partial
remission, and recurrent-persistent disease were observed in 37 patients (86%), 3
patients (2M; 1F) (7%), and 3 patients (2M; 1F) (7%), respectively. Follow-up results
are summarized in [Table 3]. Recurrence rate was significantly higher in males than females (P < 0.05). The risk of recurrence in males is 12.8 times more than females. (Odds ratio:
12,800; 95% CI: 1837–89206).
Table 3 Long-term follow-up in children with differentiated thyroid cancer
No long-term adverse effect (myelosuppression) or any other secondary malignant disease
was documented in any of our patients.
The mortality rate in our series was 2.56%. Among our series, 1 death occurred. The
patient was diagnosed with follicular Ca with a 5 cm tumor diameter with locoregional
metastases extending beyond thyroid capsule invading soft-tissue DTC at the age of
14 years. Her TNM classification was T4aN1bM1 stage 2. She underwent total thyroidectomy
and cervical lymph node dissection. She received radioiodine treatment five times
with a mean cumulative dose of 700 mCi (25.9 GBq). The disease had an aggressive progression
with high Tg levels. She died at the age of 21 due to disseminated pulmonary metastasis
and bone metastasis.
There were 4 patients under or at 10 years of age. The youngest patient diagnosed
was 3 years old. He underwent 5 surgical operations due to recurrence and received
radioiodine treatment five times with mean cumulative dose of 400 mCi (14.8 GBq).
The cervical and lung metastasis persisted during the follow-ups. In other 3 patients,
under or at 10 years of age, complete remission is achieved by treated with a single
dose (75%).
Five female patients (11.6% of all treated female patients) subsequently had healthy
children, and no recurrence is seen during their follow-up.
In this study, 6 out of 43 patients (14%) were observed recurrences. The mean disease-free
survival time based on recurrence was 184.91 ± 18.6 months [Figure 1].
Figure 1 The mean disease-free survival time based on recurrence
In 2 out of 34 females (5.9%), 4 out of 9 males (44.4%) recurrences were observed
in our study. The mean disease-free survival times in female and male groups were
212.86 ± 18.17 months, 102.28 ± 18.16 months, respectively. There were significantly
higher in females than males in terms of the recurrence-free survival rate [P < 0.05, [Figure 2].
Figure 2 Disease free survival according to sex
In this study, a total of 4 children under the age of 10 is one of them (25%) recurrences
were observed. In this study, a total of 39 boys over 10-year-old, 5 of them (12.8%)
recurrences were observed. In 1 out of 4 patients under or at the age of 10 (25%),
5 out of 39 patients over the age of 10 (12.8%) recurrences were observed in our study.
The mean disease-free survival times in under or at the age of 10 and over the age
of 10 groups were 169.0 ± 48.79 months, 132.48 ± 8.16 months, respectively. When evaluated
by the Log-Rank test, there was no significant difference between the two groups in
terms of the recurrence-free survival rate [P > 0.05, [Figure 3].
Discussion
Figure 3 Disease free survival according to age
Childhood thyroid cancers are more often papillary and well differentiated. PTC is
the most common histological type of thyroid carcinoma in pediatric patients, whereas
FTC is uncommonly found.[5],[11],[14] In our series, PTCs and FTCs were found in 41 patients (95.3%) and in 2 patients
(4.7%), respectively.
Age is the most important prognostic factor for DTC. The younger the patient is at
initial diagnosis, the worse prognosis will be seen. Also, this rule is applicable
for recurrence in children.[15],[16]
In this study, the age at diagnosis of DTC ranged from 3 to 17 years (mean 14.7 ±
3.1 years) with female predominance (3.7:1) (79%). Contrary to the literature, there
was no statistically significant difference at the rates of recurrences in terms of
age (P > 0.05).
Papillary microcarcinoma, defined as a tumor <1 cm, is a rare diagnosis in childhood
and in most studies accounts for <3% of sporadic PTC.[17],[18] Zimmerman et al. described the incidence of microcarcinoma as 9%, whereas Park et
al. revealed an incidence of 20% in their series,[12],[19] which is concordant with the finding of an incidence of 18.6% (8 patients) in our
study. Three patients (37.5%) had lymph node and lung metastasis. One patient had
recurrence/persistence disease, whereas the other 2 achieved complete remission.
The smaller size of the thyroid gland tumor in children are usually multicentric and
lead to earlier invasion of the thyroid capsule, regional lymph node involvement,
extrathyroidal extension (ETE), and pulmonary metastasis.[11],[12],[17]
Previous studies have hypothesized that the tumor volumes tend to be relatively larger
in children when compared to adults, probably attributed to smaller thyroid volume
in children, thus higher chances of ETE and capsular invasion.[14],[17] The common use of high-resolution USG contributed to the increased number of discovered
small and microcarcinomas, which would not otherwise be discovered by palpation.
In our clinic in accordance with the ATA guideline recommendation 32(A), all of our
patients underwent routine near-total or total thyroidectomy with postoperative RAI
therapy.[11] This recommendation is based on data showing an increased incidence of bilateral
and multifocal disease (30% and 65%, respectively), as well as an increased risk of
recurrence.[1],[6],[9],[10],[11],[20]
The aim of postsurgical RAI ablation is an effort to eliminate residual thyroid tissue
in order to treat residual disease, such as metastatic or unresectable lesions, thus
decrease the risks of thyroid cancer recurrence.[11] The second aim is to accurately apply whole-body 131-I scanning, used to detect
distant sites of disease in otherwise asymptomatic patients.[21] In this study, patients over 10-year-old received empiric fixed doses in postsurgical
RAI ablation, whereas patients under or at 10-year-old received individualized doses
calculated by the above-mentioned formula.
Radioiodine therapy, although generally safe, has some potential side effects, classified
as early and late side effects.[6] In the current study, short-term side effects of the radioiodine therapy were seen
in our patients, but these side effects were well tolerated and temporary. Long-term
adverse effect (myelosuppression) or any other secondary malignant disease was not
documented in any of our patients.
The incidence of cervical lymph node involvement and distant metastasis has been reported
as two-four times higher in children than in adults with DTC.[4],[22] The range of prevalence reported in other pediatric series is in between 39% and
90%.[3],[20],[23],[24],[25] In our study, the incidence of lymph node involvement was found to be 39.5%, which
is in the lower range of prevalence reported.
Mihailovic et al. revealed in their series, even with a 69% lymph node involvement
in initial diagnosis, there was no correlation between lymph node metastasis at presentation
and risk of recurrence.[3] In our study, the recurrence rate was significantly influenced by lymph node metastasis
(33.3%) (P < 0.05).
Distant metastasis is seen in DTCs at presentation in children, the most common metastasis
site being the lungs, with the incidence of 6%–33%.[8],[12],[14],[19] Postoperative radioiodine evaluation immediately after primary thyroid disease surgery
plays an important diagnostic role in pulmonary metastasis.[26] Pulmonary micrometastasis are generally diffuse and highly concentrate radioiodine,
that is not apparent with chest radiographs or computerized tomography scanning but
is apparent with RAI scans[24] and they respond well to radioiodine treatment.[27] In our study, after surgery, postablation RAI revealed 4 cases of lung metastasis
(9.3%).
The distant metastasis outside the lungs is seen very rarely (20%).[7],[24] In our study, distant metastasis was found in 2 bones and 1 mediastinal LAP excluding
the lung metastasis.
Prior studies have shown that the recurrence rate ranges from 7.6% to 28%.[3],[8],[12],[19],[20],[25] Larger tumor size (>3 cm), palpable cervical nodes, male sex, and multicentricity
were suggested to be associated with an increased risk of recurrence.[3],[20] Other studies reported that tumor size was not a significant risk factor for recurrence
in children.[15],[28],[29] In our study, we found no correlation between tumor size and recurrence (P > 0.05). Golpanian et al., in agreement with prior studies, reported that lymph node
involvement is associated with recurrence, whereas Mihailovic et al. with a 69% of
lymph node involvement at presentation in their series, found no correlation between
lymph node metastasis at presentation and recurrence.[1],[3] In the current study, recurrence rate was significantly influenced by lymph node
metastasis (33.3%) (P < 0.05).
Some authors have found that recurrent disease is frequent in multicentric PTC.[3],[30] In the present study, tumor multicentricity significantly influenced the recurrence
rate (26.1%) (P < 0.05), which was consistent with the literature.
Given the risk of recurrence many years after diagnosis, long-term follow-up is important
for these patients.[31] Overall, thyroid cancer in children and adolescents has an excellent prognosis.[3] Demidchik et al. observed 5- and 10-year survival rate was 99.5% and 98.8%, respectively.[15] Parisi et al. reported overall survival of 98% at 10 years and overall survival
of 95% at 20 years.[10] Hogan et al. stated 90% survival at 30 years, and Hay et al. detected 98% survival
at 30–50 years after surgery.[6],[32]
In this study; the mean disease-free survival time based on recurrence was (97.6%)
at 15 years (7 month–20 years). The mean disease-free survival times in under or at
the age of 10 and over the age of 10 groups were 14 and 11 years, respectively. When
evaluated by the Log-Rank test, there were no significant differences between the
two groups in terms of the recurrence-free survival rate (P > 0.05). There were significantly more females than males with recurrence-free survival
rate (P < 0.05).
The disease-specific mortality for children with DTC is very low. Thus, it is unlikely
that modification of current treatment protocols will further reduce the disease-specific
mortality.[11],[12] The mortality rates for children with DTC range from 0% to 5.3% and usually <3.0%
in the majority of the reports.[9] In our series, 1 death occurred, due to disseminated pulmonary metastasis and bone
metastasis. The mortality rate is 2.56%.
Limitations of the current study are related to its retrospective design. The patients
treated with RAI in our clinic were analyzed after thyroidectomy. Therefore, the occurrence
of surgical complications could not be evaluated. Another limitation, that may be
controversial, is empiric fixed RAI doses given to patients over 10 years. Only for
children under or at the age of 10, doses were corrected using either body surface
area or weight by using the formula.
Conclusion
In the current study, there was no statistically significant difference between age,
tumor diameter, and histopathology with recurrence, whereas there was a statistically
significant difference between gender, multicentricity and lymph node metastasis with
recurrence in pediatric DTC.
Total thyroidectomy followed by RAI appears to be the most effective treatment for
patients with pediatric DTC in terms of reducing the rate of relapse and improving
surveillance for recurrent disease. The use of RAI seems to be safe, with no adverse
effects on subsequent fertility and pregnancy or secondary malignancy.
