The incidence of DTC in children and adolescents is low, and there are large differences among different ages and genders: the incidence of DTC in people aged less than 10 years, 10-14 years, and 15-18 years is 1 in 1 million, 1 in 2 million, and 1 in 75,000, respectively; and the incidence has been increasing year by year in recent years, with an annual incidence rate of about 1.1%. DTC in children and adolescents mainly includes papillary and follicular carcinomas of epithelial origin.
Compared with adult DTC, it is more aggressive and has a higher recurrence rate. 40%-90% of children with DTC have lymph node metastasis at the time of diagnosis, 20%-30% of children have lung metastasis, and multifocal metastasis is more common than adults. Surgical resection of DTC in children and adolescents followed by 131 I therapy is effective in reducing the risk of recurrence. Most children with DTC have well-differentiated tumor pathology and are sensitive to 131 I treatment, and the 30-year survival rate for those with metastases can still be as high as 90-99%.
1.Risk factors of DTC in children and adolescents
The susceptibility factors of DTC in children and adolescents are not clear. A history of low-dose external head and neck irradiation has been identified as a risk factor for DTC. The incidence of DTC in children exposed to low doses of less than 30 Gy increases linearly with increasing irradiation dose; after the age of 20 years, the risk of DTC triggered by low-dose irradiation decreases significantly. Recent studies have confirmed that children undergoing dental surface tomography for various dental diseases increased the incidence of thyroid cancer by nearly 2-fold.
Brignardello et al. reported a higher incidence of DTC in children with malignant tumors (e.g., lymphoma) treated with head and neck irradiation, with a latency period of about 5-20 years. The author believes that thyroid ultrasonography should be routinely performed 5 years after irradiation therapy and should be repeated annually thereafter if no thyroid nodules are found.
It has been found that DTC in children and adolescents has a certain tendency to run in families. If there is a clear family history of thyroid cancer, thyroid ultrasound should be performed every year or every 2 years after the age of 8 to detect the lesion as early as possible. In addition, some rare genetic syndromes are also associated with the development of thyroid cancer. The literature reports that Cowdens syndrome (an autosomal dominant disorder), caused by mutations in the PTEN gene, is closely associated with the development of mucosal malformations and DTC.
Gardner syndrome (familial colorectal polyposis) is an autosomal dominant disorder associated with multiple polyps in the intestine and multiple malignancies, including DTC, caused by mutations in the APC gene located on chromosome 5q21. It has also been shown that congenital hypothyroidism (hypothyroidism) due to mutations in the TPO gene may be associated with the development of nodular goiter and DTC.
2. Evaluation of thyroid nodules in children and adolescents
The prevalence of thyroid nodules in children and adolescents is 7.04% (diagnosed by ultrasound), of which 66.7% are multiple nodules, with a male-to-female ratio of 1:1.4. The evaluation of thyroid nodules in children and adolescents is basically the same as in adult patients, including history taking, physical examination, laboratory tests, imaging and fine needle aspiration biopsy (FNAB). aspiration biopsy (FNAB).
If a thyroid nodule is found on palpation, serum thyroid hormone and TSH levels should be measured, and ultrasound of the neck should be performed. If the child’s TSH is below normal, thyroid nuclear imaging should be performed to determine if the nodule is an autonomous functional thyroid nodule. The percentage of malignant thyroid nodules in children and adolescents can be as high as 30%, and “hot nodules” on nuclear imaging are at risk for malignancy and should be evaluated further.
Signs of malignancy on ultrasound imaging of thyroid nodules include microcalcifications, poorly defined nodules, and uneven internal echogenicity. In addition to accurately localizing the nodule, ultrasound examination of the neck can also reveal any abnormalities in the lymph nodes of each region at the same time. However, ultrasonography alone cannot accurately differentiate benign from malignant thyroid nodules in children and adolescents, and FNAB should be performed if necessary.
When the cytologic features of the specimen are atypical, the difficulty of FNAB diagnosis becomes greater, so repeat ultrasound and FNAB within 3-6 months after the first FNAB is necessary. The latest American Thyroid Association (ATA) guidelines recommend FNAB for thyroid nodules over 1.0 cm in diameter in adults, but are inconclusive for children and adolescents. FNAB can be performed under ultrasound guidance to improve the sensitivity of diagnosis.
3. Staging of thyroid cancer in children and adolescents
The ATA guidelines recommend using the AJCC grading criteria for clinical staging of tumors. However, according to this method, patients aged <45 years old, regardless of tumor size, degree of local invasion and lymph node metastasis, without distant metastasis are considered stage I, and those with distant metastasis are considered stage II. Therefore, the tumor staging of children with DTC is either stage I or stage II. This method is of high value in assessing the prognosis of adult DTC, but the recurrence rate of DTC in children and adolescents is high while the mortality rate is low, so the simple classification of tumor staging into stage I or II cannot reflect the risk of tumor recurrence and guide the choice of treatment plan.
For assessing the risk of recurrence in children and adolescents with DTC, the combined score of metastases, age, completeness of resection, extra-thyroidal invasion, and tumor size (metastases, age, completeness of resection, invasion, size,MACIS) is more meaningful, but only for patients with papillary carcinoma. The assessment is limited to patients with papillary carcinoma. Low risk factors for DTC in children and adolescents include: tumor diameter <1.0 cm, tumor confined to the thyroid gland, and no lymph node metastasis.
Although most children with DTC do not have local or distant metastases, visible residual tumor tissue, tumor invasion of local tissue structures, or histologic types that are prone to invasive metastases (high columnar cell type, etc.) as suggested by ATA guidelines for adults with DTC, data show that children who are not treated with total thyroidectomy and 131I may have a tumor recurrence rate as high as 20-30%, and therefore are generally not Therefore, children with DTC are generally not considered as low-risk patients.
4.Selecting the operation style
The preoperative evaluation of children with DTC should include detailed physical examination of the neck (especially the thyroid gland), thyroid hormone levels and airway status. If the child has vocal cord invasion or a history of previous neck surgery, the condition of the vocal cords should also be evaluated preoperatively. High-resolution ultrasound (7.5 MHz or higher) of the neck provides a more accurate picture of the size, number, location and morphology of nodules in the thyroid gland, as well as the central and lateral cervical lymph nodes. The lymph nodes in the neck are often divided into six zones (zones I-VI), and zone VI (i.e., central zone) lymph nodes are the most common site of metastasis. Definitive zoning of metastatic lymph nodes is essential for evaluating the extent of tumor invasion, clarifying clinical staging and deciding surgical plan.
DTC procedures in children and adolescents include total (near-total) thyroidectomy, subtotal thyroidectomy and lobectomy. Total (near-total) thyroidectomy reduces the probability of tumor recurrence and reoperation, facilitates accurate assessment of postoperative staging and monitoring of tumor recurrence and metastasis, and also facilitates postoperative 131I therapy. Subtotal thyroidectomy is more conducive to protecting parathyroid function, significantly reducing the incidence of lateral recurrent laryngeal nerve injury, and reducing the dose of postoperative thyroxine replacement therapy. Lobectomy may miss microscopic lesions in the contralateral lobe and may not facilitate postoperative 131I therapy.
Some studies have shown that the younger the child with DTC undergoing total thyroidectomy, the higher the incidence of postoperative adverse effects, with 22%, 15% and 11% of children with DTC aged <6 years, 7-12 years and 13-17 years, respectively. Several clinical studies on the procedure and prognosis of children and adolescents with DTC have demonstrated a higher rate of tumor recurrence after lobectomy compared to total thyroidectomy, and Hay et al. demonstrated a 30% recurrence rate after lobectomy compared to 12% after total thyroidectomy in children and adolescents with DTC.
Combined lymph node metastases are more common in DTC. The more extensive the local lymph node invasion, the higher the risk of distant metastasis. Routine lymph node dissection in the central region and selective ipsilateral or contralateral cervical lymph node dissection may increase the risk of bleeding, parathyroid gland and laryngeal nerve injury. Therefore, in my opinion, total (near-total) thyroidectomy and central lymph node dissection can be the recommended procedure for most children with DTC, and selective ipsilateral or contralateral cervical lymph node dissection should be performed only for children with preoperative imaging or FNAB confirmed lymph node metastasis.
5.131I therapy and levothyroxine suppression therapy
131I has been used to treat DTC for more than 60 years, and long-term clinical application has confirmed that.
(1) 131I treatment can reduce the risk of recurrence of DTC and improve patient prognosis.
(2) 131I removal of residual thyroid tissue can reduce the incidence of recurrence or metastasis of DTC.
(3) Excessive cumulative treatment doses, such as more than 29.6 GBq, may increase the risk of developing malignancies in the remaining sites.
(4) The efficacy of 131I treatment is related to factors such as tumor biological behavior and radiation dose received by tumor tissues.
DTC lymph node metastasis is closely related to tumor recurrence and distant dissemination, etc. 131 I treatment can effectively reduce the risk of tumor recurrence. Compared with adults, children are more sensitive to ionizing radiation, therefore, some scholars have conducted clinical studies on the effects of 131 I treatment in children, the dose of 131 I treatment, and the short-term and long-term effects after 131 I treatment.
Chow et al. performed high-dose 131I treatment in children with tumor diameter >1 cm, lymph node metastasis, extra-thyroidal invasion, residual tumor tissue after surgery, and distant metastasis, and the treatment dose was 2.96 GBq in children without distant metastasis and 5.55 GBq in children with distant metastasis. The recurrence rate in the untreated group was 42%, while the recurrence rate in the treated group was only 6.3%.
A 30-year clinical study by Handkiewicz-Junak et al. analyzed the incidence of in situ recurrence of thyroid bed and local lymph node metastases in 235 children with DTC, 174 of whom (74%) received 131I postoperatively: the dose was 74-111 MBq/kg by body mass for <12 years of age and 2.55 MBq/kg for 12-18 years of age without distant metastases. After 10 years of follow-up, the incidence of in situ recurrence of thyroid bed and lymph node metastasis in children not treated with 131I was found to be 20% and 15%, respectively, while the incidence of both in children treated with 131I was only 1% and 4%.
Recent studies have shown that high-dose 131I therapy may increase the risk of developing hematologic tumors and other solid second primary malignancies (SPM) with a latency period of approximately 3 years. Treatment with 131I in patients with low-risk DTC is associated with an increased risk of developing SPM.
Some adult patients with low-risk DTC can be treated electively with 131 I to remove residual thyroid tissue (referred to as nail clearing) after surgery, but this is not always appropriate for children for the following reasons.
(1) Children and adolescents are more likely to have tumor recurrence or metastasis than adults.
(2) Positive TgAb may interfere with the monitoring of Tg in follow-up.
(3) Long-term regular follow-up of children is relatively more difficult.
(4) Children’s compliance with drug therapy is relatively poor, so long-term TSH suppressive therapy cannot be relied on to prevent tumor recurrence.
The dose of 131I treatment is usually 3.7-7.4 GBq, which can be adjusted according to 50-100 MBq/kg for younger children. In low-risk children (i.e., tumor < 1.0 cm in diameter, confined to the thyroid gland, without lymph node metastasis), 1.11 GBq 131I should be given postoperatively to clear the nail, followed by Tg measurement and periodic ultrasound monitoring. If Tg is elevated again, subsequent 131I therapy should be considered.
TSH has a role in promoting the growth of thyroid tumors. Giving adequate levothyroxine replacement therapy to children with DTC not only promotes the growth and development of children and adolescents, but also suppresses TSH elevation and effectively reduces the recurrence of DTC. To achieve complete suppression of TSH, long-term levothyroxine administration in adults in excess of physiological requirements can affect bone mineral density and increase the risk of cardiovascular disease.
Compared to adults, children require higher doses of levothyroxine based on body mass, so overdoses of levothyroxine in children may affect growth and development and further impact on behavior and learning ability. The issue of subclinical hyperthyroidism (hyperthyroidism) due to levothyroxine in the treatment of children with DTC is still under investigation, and Baudin et al. recommended that TSH should be suppressed to less than 0.1 mU/L during the initial treatment of children with DTC, and adjusted to less than 0.5 mU/L after clinical remission.
6.Follow-up
(1) After successful nail clearing in Tg patients, if Tg is not detected in TSH stimulation state, the patient can be considered to have reached clinical cure and there is basically no residual lesion in the body. If Tg is 0.1- 2.0ug/L, about 30% of patients still have residual lesions and follow-up neck ultrasound is recommended; if Tg is 2.0-10.0ug/L, there is a high possibility of residual lesions in the body and neck ultrasound must be reviewed; if Tg is more than 10ug/L, neck ultrasound and CT or MRI of the neck and chest should be reviewed.
The Tg in TSH stimulated state and the Tg level in suppressed (or basal) state have good correlation, when the latter is less than 0.1 ug/L, the former is often less than 2.0ug/L. Therefore, the Tg in suppressed state can be followed up every six months to know whether the tumor has It is not necessary to discontinue levothyroxine or apply recombinant human TSH (rhTSH) before the examination.
The presence of TgAb can interfere with the detection of Tg. Clinical studies have confirmed that 20-80% of children with DTC are TgAb positive or have combined autoimmune thyroiditis, so it is difficult to evaluate tumor recurrence by monitoring Tg levels during the follow-up of children with DTC. Although TgAb may turn negative after surgery and 131I treatment, about 44% of children with DTC continue to be TgAb positive for 5 years after successful nail clearance.
(2) Ultrasound of the neck: Postoperative ultrasound of the neck should be repeated every 6 months for residual thyroid tissue and enlarged lymph nodes in patients with DTC. The scope of the examination should include the thyroid bed and the lymph nodes in each subdivision of the neck. Since children are more likely to have inflammatory lymph node enlargement, it has been suggested that the neck ultrasound should be repeated every 3 months to assess for potential lymph node metastases. Ultrasound-guided FNAB should be considered if fixed or enlarged lymph nodes are found on palpation, especially if they are accompanied by increased Tg levels.
(3) 131 I diagnostic dose whole-body imaging. Diagnostic 131 I whole-body imaging in children and adolescents should be performed after 74-185 MBq of oral 131 I. It is of great significance in the search for distant metastases such as pulmonary metastases, especially when TgAb is positive and interferes with Tg detection. Most scholars suggest that at least one diagnostic dose of whole-body imaging should be done after the last 131 I treatment, and Tg levels should be measured in the stimulated state to further clarify the success of nail clearance and to determine the presence of lesions without abnormal concentrations of 131 I in the body.
(4) PET imaging. A small number of children with DTC have tumor lesions that do not take 131I, and some of them have negative Tg test when the tumor recurs, which makes clinical management and follow-up difficult. 18F-FDG PET imaging can clarify the presence of residual lesions in the body and evaluate and monitor the disease. However, due to factors such as inflammatory lymph nodes and incisional granuloma, the 18F-FDG PET image may be falsely positive, so other tests such as histology and cytology should be used to further clarify whether the positive site of PET image is a DTC lesion.
7. Outlook
Although a large number of studies have been reported on the evaluation, clinical management, and follow-up of DTC in children and adolescents, there is still some work that needs to be done in depth.
(1) To further evaluate the risk of SPM after high-dose 131 I therapy in children with DTC in different age groups.
(2) To analyze the exposure doses received by the whole body and all vital organs of children with DTC after high-dose 131 I treatment.
(3) Adopting individualized 131 I treatment protocols to replace empirical dosing and minimize the whole-body irradiation dose while striving for successful treatment.
(4) Genetic abnormalities in children with DTC may be different from those in adult DTC patients, so genetic markers in children with DTC should be further defined to predict disease progression, etc.
(5) To develop a clinical staging plan that meets the clinical characteristics of children with DTC and is more appropriate for assessing their risk of recurrence and metastasis.
(6) To assess whether long-term treatment with levothyroxine for TSH suppression in children with DTC has any impact on their growth and development.