[Abstract] Adolescent differentiated thyroid cancer has a low incidence but has some distinctive features compared with adult differentiated thyroid cancer: it is often large in size at the time of detection, with more cervical lymph nodes or distant metastases at the time of diagnosis, high frequency of sodium iodine transporter expression in tumor cells, and a high recurrence rate after treatment; nevertheless, its overall survival rate is high. Post-surgical 131I removal of residual thyroid tissue and 131I treatment of distant metastases remain important tools in the treatment of juvenile differentiated thyroid cancer. The Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China 131I treatment for differentiated thyroid cancer, including papillary thyroid cancer and follicular carcinoma, has become an important treatment for differentiated thyroid cancer. 131I treatment includes removal of normal residual thyroid tissue and local microscopic lesions, as well as treatment of cervical lymph node metastases and distant metastases. treatment of distant metastatic lesions. The incidence of adolescent differentiated thyroid cancer is low, but successful treatment not only helps to improve the survival rate, but also contributes to the physical and psychological health development of adolescents. Therefore, treatment strategies for adolescent differentiated thyroid cancer should not be neglected. This article reviews the epidemiological characteristics, natural course, complications of 131I therapy, and dose setting of adolescent differentiated thyroid cancer. 1. Epidemiological characteristics The incidence of differentiated thyroid cancer in adolescents is low, with less than 15% of all age groups diagnosed with differentiated thyroid cancer under the age of 18 years. In the United States, the number of people diagnosed with thyroid cancer under the age of 20 years is approximately 350 per year [1]. Of these, differentiated thyroid cancer accounts for 90-95% of thyroid cancers in adolescents. Thyroid cancer in younger age groups is often overlooked, and the literature [2] reports that it can develop in infants 4-6 months of age, and even in newborns there are disseminated cases. From the age of 10 years, the incidence of thyroid cancer in both sexes starts to change, with a significant increase in females from the age of 13-14 years [3]. between 1975 and 1995, the incidence of thyroid cancer remained largely stable in the UK, US and Germany. However, in the last 60 years, there have been two peaks in the incidence of juvenile differentiated thyroid cancer. The first peak occurred due to the use of radioactive irradiation to treat benign diseases such as tinea capitis, acne, chronic tonsillitis, and thymic hypertrophy, and the incidence of thyroid cancer began to decline when external irradiation was realized to cause thyroid cancer and irradiation to the neck was reduced [4]. The second peak in the incidence of juvenile differentiated thyroid cancer occurred in Eastern European countries after the Chernobyl nuclear power plant leak in 1986 [5]. This unfortunate event reaffirmed the role of radioactive radiation as a cause of adolescent differentiated thyroid cancer and showed that adolescent thyroid tissue is very sensitive to ionizing radiation. The classification of adolescent differentiated thyroid cancer according to its etiology includes both sporadic and radiological types, but there is no difference in their clinical presentation. 2. Natural course of adolescent differentiated thyroid cancer Adolescent differentiated thyroid cancer presents the following distinctive features when compared with adult differentiated thyroid cancer: 2.1 Large tumor size In comparison with papillary thyroid cancer tumors in patients aged 20-50 years, papillary carcinomas under 20 years of age are larger in size at diagnosis [6].Zimmerman et al [7] found that newly diagnosed papillary thyroid cancer , with diameters greater than 4 cm in 36% of adolescents and 15% of adults, and those less than 1 cm in 9% of adolescents and 22% of adults. Due to the highly publicized Chernobyl nuclear power plant leak in the former Soviet Union, thyroid cancer in the affected areas was detected early and most of the tumors were 1-2 cm in size at the time of diagnosis. The possible reason for this is that the thyroid gland in adolescents is smaller than that of adults, and the tumor can easily invade the thyroid envelope as well as the surrounding tissues. It is generally believed that adolescent differentiated thyroid cancer is often multicentric and total thyroidectomy must be chosen for surgery. Adolescent differentiated thyroid cancer is more likely to develop lymph node metastasis or distant metastasis in the neck. Among 1039 patients with papillary thyroid cancer seen at the Mayo Clinic, 90% of adolescents had lymph node metastasis in the neck and 7% had distant metastasis, compared to 35% and 2% of adults. Distant metastases were mainly pulmonary metastases, and metastases to other sites were uncommon. According to the literature, bone metastases, brain metastases, and other soft tissue metastases are uncommon [8]. It is worth mentioning that lung metastases in adults appear nodular on X-ray, while adolescent lung metastases tend to appear cornified. Adolescent differentiated thyroid cancer lung metastases tend to have iodine uptake, in other words, they are functional. This also tells us that pulmonary metastases from adolescent differentiated thyroid cancer are more suitable for treatment with 131I. 2.3 High number and frequency of sodium/iodide symporter (NIS) expression In fact, adolescent differentiated thyroid cancer tissues express less NIS than normal tissues, but the number and frequency of NIS expression are higher compared to adult thyroid cancer [9]. In the absence of thyroid stimulating hormone (TSH) stimulation, 65% of papillary thyroid cancer patients aged under 20 years had no NIS expression and 56% of follicular thyroid cancer tissues could not find NIS expression. By means of reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, 90% of differentiated thyroid cancer tissues were found to lack NIS expression or to have lower NIS expression than normal tissues. This difference indicates that adolescent differentiated thyroid cancer is highly differentiated and has some 131I uptake. In fact, the degree of NIS expression is positively correlated with the degree of 131I uptake in metastatic lesions, and also with the response to 131I therapy. 2.4 High recurrence rate Mazzaferri et al [6] followed up the recurrence of differentiated thyroid for 16.6 years, with a recurrence rate of 40% in the cohort under 20 years of age at diagnosis and 20% in the cohort between 20 and 50 years of age at diagnosis. 2.5 High overall survival rate Adolescent differentiated thyroid cancer is mostly advanced at the time of diagnosis, with a significantly higher recurrence rate, but a fairly low mortality rate, which contrasts with the ease of metastasis and recurrence. 2.6 The high incidence of papillary thyroid carcinoma in adolescents compared to differentiated thyroid carcinoma in adults is not entirely shared by some scholars. In fact, it has been observed that the incidence of follicular thyroid cancer in adolescents is comparable to that of adults. Like adults, adolescent differentiated thyroid cancer is treated with surgery, followed by 131I therapy and thyroid hormone suppression therapy. For adolescent differentiated thyroid cancer, the tumor is large at the time of definite diagnosis, often metastatic, sensitive to 131I treatment, but prone to recurrence, and these factors often influence the treatment decision. Although 131I removal of residual thyroid tissue after total thyroidectomy is still a controversial therapy, it has positive implications anyway: it reduces the local recurrence rate of juvenile differentiated thyroid cancer; plasma thyroglobulin (Tg) is elevated after removal of residual thyroid tissue, especially when TSH is elevated, and becomes a very sensitive and specific marker to determine recurrence or metastasis. It can improve the iodine uptake of lymph node metastasis or lung metastasis and clarify metastatic lesions by 131I whole-body scan; the discontinuation of thyroid hormone does not affect the increase of endogenous TSH, making the detection of Tg and 131I whole-body scan more sensitive. This is beneficial to the psychological development of adolescents. Most adolescents with metastatic thyroid cancer present with multiple cornu in both lungs and are often inoperable. Adolescent metastatic differentiated thyroid cancer is more sensitive to 131I and the survival rate is greatly improved after treatment. The literature [10] reported that most of the pulmonary metastases obtained complete remission after 131I treatment. 4. Toxic side effects of 131I treatment 131I treatment for differentiated thyroid cancer will bring some recent and late toxic side effects. Since adolescents are in the growth phase, the toxic side effects of 131I treatment appear to be more notable. Adolescent patients with differentiated thyroid cancer are more likely to experience nausea and vomiting with 131I therapy than adults. The incidence of nausea is statistically 30% and vomiting is 5% in adults [11]. Neck pain and edema are also uncommon. Salivary gland function may be impaired in the form of xerostomia, which can be reduced or avoided by taking acidic juices or vitamin C. A transient myelosuppression, manifested by a decrease in white blood cells or platelets, may occur 1-2 months after 131I treatment. There is also the possibility of nasolacrimal duct obstruction, manifested by increased tearing. Late toxicities such as increased incidence of malignancies and effects on fertility are also important in adolescents. dottorini et al [12] reported two cases of other tumors after 131I treatment, one breast cancer and the other gastric cancer. A large sample of differentiated thyroid cancer in various age groups revealed an increased risk of salivary gland cancer, colon cancer, rectal cancer, soft tissue and skeletal malignancies. The risk of developing leukemia has prompted to limit the cumulative dose of 131I treatment for differentiated thyroid cancer to 1000 mCi. To date, there is no information linking adverse pregnancy outcomes such as miscarriage, infertility, and fetal developmental malformations to 131I exposure. Pulmonary metastases from multiply differentiated thyroid carcinoma have iodine uptake and may develop pulmonary fibrosis after multiple 131I treatments, which is an uncommon long-term complication. reiners [13] et al. have found pulmonary fibrosis in an adolescent group, but it was not clear whether it was caused by 131I or bleomycin. samuel [14] pointed out that clinical inability to differentiate between pulmonary metastasis-induced restrictive lung disease and ionizing radiation-induced pulmonary fibrosis. However, since the lesions of differentiated thyroid cancer lung metastases are functional, 131I treatment inevitably has adverse effects on the lungs. 5. Dose of 131I for adolescent differentiated thyroid cancer Achieving optimal treatment with minimal toxicity is the principle of designing 131I to remove residual thyroid tissue and treat metastatic thyroid lesions. There are two methods of designing the dose, the most common being the fixed dose method and the other being the dosimetric method. For the removal of residual thyroid tissue in adults, most centers use an empirical fixed dose of 100 mCi, while many institutions choose a minimum dose of 30 mCi, but others choose an intermediate dose such as 60 mCi. For the removal of residual thyroid tissue in adolescents, some calculate the dose by kilogram of body weight, such as 1 mCi/kg. others use a dose estimation method, where a 15-year-old need to receive five-sixths of the adult dose, 10-year-olds are given one-half of the adult dose, and 5-year-olds are given one-third of the adult dose. The fixed-dose method is controversial in adults. Recently Bal et al. published the results of a prospective randomized controlled study of 509 patients that a dose of 131I between 25-50 mCi to remove residual thyroid tissue is an appropriate dose [15]. The dose of 131I for the treatment of metastatic thyroid cancer lesions is higher than the dose for removal of residual thyroid, generally 150 mCi in adults. if the lesions do not disappear, treatment is repeated at 6-month intervals, and the cumulative dose reaches 500 mCi at 12-month intervals. The dose for treating metastatic lesions of adolescent differentiated thyroid cancer is more variable, with some advocating giving 30-200mCi at a time and a cumulative dose range of 100-840mCi [16]. Some give 150mCi per dose, others 1mCi/kg by kilogram of body weight, or 1.9-2.2mCi/kg. there is a lack of prospective studies to demonstrate the optimal dose of 131I for the treatment of pulmonary metastases. Adolescent differentiated thyroid cancer is mostly advanced at the time of diagnosis, with a higher risk of developing metastases, and aggressive treatment can significantly improve survival. Therefore, treatment strategies include total thyroidectomy, lymph node dissection, 131I to remove residual thyroid tissue, and aggressive 131I therapy for inoperable functional metastatic lesions.