Clinical features of thyroid cancer in paediatric age. Experience of a tertiary centre in the 2000-2020 period

doi:10.21203/rs.3.rs-2628307/v1

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Clinical features of thyroid cancer in paediatric age. Experience of a tertiary centre in the 2000-2020 period

https://doi.org/10.21203/rs.3.rs-2628307/v1

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published 18 Apr, 2023

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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 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 standardize management and reduce disease persistence in childhood.

thyroid cancer

pediatric age

prognostic factors

clinical features

Thyroid nodules in paediatric age are less frequent than in adults (0.2–0.5% vs 19–35%), but the rate of malignancy is higher, reaching up to 20–25% during childhood (1–2). Diagnostic evaluation include clinical, biochemical and ultrasound assessment. Fine-needle agobiopsy (FNAB) for cytological category determination is required when nodule size is greater than 1 cm or suspicious features of malignancy are present. Lymph node involvement, intra-nodal calcifications or vascularization, hypoechogenic pattern, “larger than taller” shape, margins undefined, right lobe localization, and upper normal range/high Thyroid Stimulation Hormone (TSH) levels have been considered predictive of malignancy (3–10). Previous radiation exposure or cancer treatment, underlying thyroid disease, family history 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, repeat FNAB, lobectomy or total thyroidectomy. The most worldwidely used cytological classification is the Bethesda System for Reporting Thyroid Cytopathology; in Italy, the Italian Society of Anatomical Pathology and Diagnostic Cytology (SIAPeC) has created a five-category classification with some difference regarding mostly on the undeterminated category. The diagnosis of thyroid cancer is defined in the case of a cytological category of certain malignancy (class VI for Bethesda, TIR5 for SIAPEC) or a definitive histological finding for thyroid cancer after surgery.

Differentiated thyroid cancer (DTC) represents the most common solid tumour in paediatric age, with a reported incidence of 0.2-1 per million child-years, which is higher in adolescence and in females. Papillary thyroid cancer (PTC) is the most frequent histological finding and accounts for 90% of DTC; follicular thyroid cancer (FTC) is less common in paediatric age (5%), as well as the mixed histologic 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 radioiodine (RAI) treatment and molecular profile differ from adults, therefore children and adolescents require specific management (11–23).

Although children more frequently display multifocality, local extension, lymph node involvement, distant metastases, persistent disease and risk of recurrence, the overall survival rate is higher than in adults and the prognosis is excellent (24–26). Younger age and advanced T and N stages are risk factors for multifocality, which is predictive of bilateral disease (27–28). The lungs are the most frequent site of distant metastases, occurring in 6–33% of children with DTC (29). 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 (30–32).

Persistent disease occurs more frequently with higher T stage and when lymph node or distant metastases are present or when high stimulated thyroglobulin is observed after surgery (33–34). A high lymph node ratio (LNR, ratio of the number of positive to the total number of lymph nodes removed) after initial therapy is considered an independent determinant predictive of persistent disease (35).

The risk of recurrence has been estimated to be 20–40% at 10 years and surveillance protocols are mandatory (36). 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 (37–38).

Total thyroidectomy with local lymph node dissection is in most cases the first-line treatment (39–41). 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 (42–43). Central ipsilateral neck dissection should be considered in all cases of paediatric PTC. Central neck dissection is absolutely indicated when central lymph node metastases are suspected radiologically or have been demonstrated by biopsy. Lateral neck dissection is indicated for biopsy-proven lateral lymph node metastases. American Thyroid Association (ATA) guidelines established risk stratification (low, intermediate, and high) according to the American Joint Committee on Cancer (AJCC) Tumor, Nodes, and Metastases (TNM) classification system (41). 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 (39–41). 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 cancer followed in a tertiary Department of Paediatric Endocrinology for a period of 20 years.

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 retrospectively reviewed. Demographic, clinical and biochemical (thyroid hormone profile, thyroglobulin levels and anti-thyroglobulin antibodies) data were analysed for each patient. The cytological category was assigned according to the Italian Society of Anatomical Pathology and Diagnostic Cytology (SIAPeC). The American Joint Committee on Cancer (AJCC) Tumor, 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 thyroglobulin and residual tissue caption at ¹³¹I – scintiscan investigation.

Disease recurrence was considered in case of significant increase of thyroglobulin level during follow-up after surgery 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 University Hospital of Turin (number of approval 13942/A1). Informed parental consent was obtained in all cases.

During the study period, 41 subjects (16 females and 25 males) followed for 6.8 ± 0.32 years were enrolled (Table 1). The mean age at diagnosis was 13.9 ± 0.49 years. Among the risk factors analysed the most frequent was autoimmune thyroiditis (16/41, 39%), followed by previous irradiation (6/41, 14.6%) and chemotherapy (2/41, 4.9%).

Table 1

Demographic and clinical data of pediatric patients affected by differentiated thyroid cancer in the period 2000–2020.
Demographic data
Gender	Male	16 (39%)
Gender	Female	25 (61%)
Age at diagnosis (years)		13.9 ± 0.49
Risk factors	Autoimmune thyroiditis	16 (39%)
	Radiotherapy	6 (14.6%)
	Chemotherapy	2 (4.9%)
Thyroid cancer data
Cytological	TIR3 b	16 (39%)
	TIR 4	4 (9.8%)
	TIR 5	21 (51.2%)
Hystological	Papillary	35 (85.4%)
	Follicolar	5 (12.2%)
	Mixed	1 (2.4%)
Dimension (mm)	< 10	5 (12.2%)
	10–40	20 (48.8%)
	> 40	16 (39%)
Focality	Unifocal	19 (46.3%)
Focality	Multifocal	22 (53.7%)
Lymph node	N 0	18 (43.9%)
Lymph node	N 1	23 (56.1%)
Distant metastasis	M 0	39 (95.1%)
Distant metastasis	M 1	2 (4.9%)
Risk level (only PTC)	Low	11 (30.5%)
	Intermediate	15 (41.7%)
	High	10 (27.8%)
Radiometabolic treatment	Yes	38 (92.7%)
Radiometabolic treatment	No	3 (7.3%)

Cytological categories after FNAB were TIR3b in 16/41 (39%), TIR4 in 4/41 (9.8%), TIR5 in 21/41 (51.2%) patients. Total thyroidectomy was performed in 39 patients. Near-total thyroidectomy was performed in 2 subjects due to impossibility of achieving a total resection due to adherences of the tumour lesion to the oesophagus and right recurrent laryngeal nerve. Histological findings showed PTC in 36 subjects (87.8%) and FTC in 5 subjects (12.2%).

Tumor size was < 10 mm in 5/41 (12.2%), 10–40 mm in 20/41 (48.8%) and > 40 mm in 16/41 (39%), while multifocality was observed in 22/41 (53.7%).

Lymph node involvement was present in 23/41 (56.1%), while distant metastasis in 2/41 (4.9%). Both patients displayed lung metastases.

After surgery, radioiodine treatment was performed in 38 subjects (92.7%).

Of the 36 subjects affected by PTC, according to ATA 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 category.

Table 2

Demographic and clinical data according to the American Thyroid Association risk class.
		Low risk (n = 11)	Intermediate risk (n = 15)	High risk (n = 10)	p
Gender	Male	5	7	2	0.35
Gender	Female	6	8	8	0.35
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
Lymph node involvement	No	0	2	0	0.89
Distant metastasis	Yes	0	0	2	0.21
Distant metastasis	No	11	15	8	0.21
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
TGAb	No	8	8	5	0.5
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
Dimension > 40 mm	No	10	7	1	< 0.005
Multifocality	Yes	1	9	9	< 0.005
Multifocality	No	10	6	1	< 0.005
Radioiodine (RAI) treatment	Yes	8	15	10	0.21
Radioiodine (RAI) treatment	No	3	0	0	0.21
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
Disease persistence	No	11	15	8	0.06
Disease relapse	Yes	1	0	4	0.04
Disease relapse	No	10	15	6	0.04

No differences were observed between risk categories with respect to gender, lymph node involvement and distant metastases, positive titration of anti-thyroglobulin antibodies, RAI treatment and ¹³¹I dose.

Age at diagnosis was 15.1 ± 0.92 years in the low-risk category, 14.7 ± 0.59 in the intermediate-risk category and 11.7 ± 0.89 years in the high-risk category (p = 0.01).

The most frequent cytological category observed in patients assigned to the low-risk class was TIR3b (7/11, 63.6%), while the TIR5 category was mainly observed in both the intermediate and the high-risk class, in 9/15 (60%) and 8/10 patients (80%), respectively [p = 0.04].

Post-surgical TSH was 127 ± 26.3 mUI/l in the low-risk category, 126.2 ± 16.8 in the intermediate-risk category and 217.4 ± 35.2 in the high-risk category (p = 0.02).

Post-surgical stimulated thyroglobulin levels were significantly increased in the high-risk class (407.8 ± 307.1 ng/ml), compared to the intermediate and low-risk category (11.7 ± 6.5 ng/ml and 7.56 ± 4.9 ng/ml, respectively) (p = 0.04).

Tumour size was larger in the high-risk category (42.6 ± 2.6 mm), than in the low and intermediate-risk categories (19.4 ± 3.5 mm and 28.5 ± 3.9 mm, respectively) (p = 0.008). Dimensions greater than 40 mm were observed more frequently in the intermediate and high-category, in 8/15 (53.3%) and 9/10 (90%) patients, respectively [p < 0.005].

Patients assigned to intermediate and high-risk categories showed tumour multifocality more frequently, found in 9/15 (60%) and 9/10 (90%) patients, respectively (p < 0.005).

Persistence of disease was observed in 2 (20%) patients assigned to the high-risk class. Radical thyroidectomy was not possible in both patients.

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).

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 (24–26).

The most frequently reported risk factors are underlying thyroid disease, previous head and neck irradiation, chemotherapy, predisposing genetic mutations and family history (3–10). 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 (43). 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.

Genetic mutations are known risk factors for developing DTC. MEN2 syndrome represents the only condition requiring prophylactic thyroidectomy at < 5 years, according to the mutation risk class. Other predisposing syndromes include DICER1, PTEN, McCune-Albright syndrome, Peutz-Jeghers syndrome. Periodic thyroid ultrasound evaluation is also indicated in these subjects (39–41). 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 and non-extrathyroidal involvement) [39–43]. 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 permanent hypoparathyroidism. Near-total thyroidectomy was performed in 2 patients due to tumour adherences to important anatomic structures such as the oesophagus and recurrent laryngeal nerve. Both patients showed persistent but stationary 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 thyroidectomy 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 recommend 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 (39–41, 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 localization, unilobar multifocality, extrathyroidal extension, incomplete surgical resection of the tumour and high post-ablation stimulated thyroglobulin levels (27–41).

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 (41). The indeterminate cytological category (TIR3b) was mainly observed in the low-risk category. To our knowledge this data has not been reported before in the literature.

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 prognostic 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 (44).

In conclusion, we confirm the more aggressive behaviour of DTC in pediatric 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 standardize management across tertiary centers and reduce disease persistence in childhood.

Acknowledgements: N/A

Funding: The authors declare that they have receive no funds, nor grants, or other support for the preparation of this manuscript.

Competing Interests: The authors have no material financial or non-financial interests to disclose.

Author Contributions: All authors contributed to the study design and conception. Material preparation, data collection and analysis were performed by Antonio Marino, Jessica Munarin and Gerdi Tuli. The clinical management of the enrolled subjects was managed by Andrea Corrias, Patrizia Matarazzo, Gerdi Tuli, Jessica Munarin, Francesco Quaglino and Luisa De Sanctis. The first draft of the manuscript was written by Gerdi Tuli and Jessica Munarin and all authors have commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

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)

Consent to partecipate: Written parental consent was obtained

Consent to publish: Consent to publish has been received from all partecipants

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Clinical features of thyroid cancer in paediatric age. Experience of a tertiary centre in the 2000-2020 period

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