Abstract
The purpose of this study was to clarify the clinicopathological features and prognosis of histological subtypes of papillary thyroid carcinoma (PTC) in the pediatric population treated at a single institution. A total of 153 PTC patients ≤18 years of age who underwent initial surgery between 1979 and 2019 were investigated. There were 135 female and 18 male patients, with a mean age at the time of surgery of 16 (range, 8–18) years. The most common subtypes included classic PTC in 124 (81%), solid variant in 16 (10%), diffuse sclerosing variant in 7 (5%) and follicular variant in six (4%) according to the 5th edition of the WHO classification. At initial surgery, 49 patients (32%) had clinical lymph node metastases (cN1), 137 patients (90%) had pathological lymph node metastases (pN1), 73 patients (48%) had number of lymph node metastases (NLNMs) ≥10, 16 (10%) had gross extrathyroidal extension (ETE) and 18 (12%) had lung metastases. During a mean follow-up of 16 years, three (2%) patients died of their disease and 34 (25%) patients had recurrent disease. The 30-year cause-specific survival rate was 97.2%, and the 30-year disease-free survival (DFS) rate was 65.0%. On multivariate analysis, gross ETE, cN1 and NLNMs ≥10 identified as significant factors related to DFS (hazard ratio (HR) 4.13, confidence interval (CI) 1.48–9.96, P = 0.009; HR 2.34, CI 1.09–4.95, P = 0.0293; HR 2.81, CI 1.30–6.59, P = 0.008), but not histological subtype, were associated with disease recurrence. Histological subtypes were not associated with disease recurrence, but long-term follow-up of pediatric patients is necessary to investigate the biological characteristics.
Synopsis
This retrospective study investigated the clinicopathological features and clinical outcomes of histological subtypes of PTC in a large series of pediatric patients treated at a single institution. It found that the prognosis of pediatric patients with PTC was excellent, but recurrence was common. In pediatric PTC, histological subtype did not affect survival and recurrence.
Introduction
Incidence and prognosis
The incidence of pediatric differentiated thyroid carcinoma (DTC) has been rising in recent years, with papillary thyroid carcinoma (PTC) accounting for most of the DTC cases (Vergamini et al. 2014, Qian et al. 2019, Lee et al. 2021). Compared with adult DTC, the biological behavior of pediatric DTC is different. The spectrum of genetic mutations of pediatric DTC is reported to differ from that of adult DTC (Cordioli et al. 2015). Pediatric PTC shows a higher prevalence of lymph node metastasis and distant metastasis, and a higher incidence of recurrence than adult PTC (Brink et al. 2000, Borson-Chazot et al. 2004, Collini et al. 2006, Markovina et al. 2014, Balachandar et al. 2016, Hay et al. 2018, Lee et al. 2021). However, pediatric PTC has an excellent long-term prognosis, with 30-year survival rates of 90–99% (Qian et al. 2019, Sugino et al. 2020). Several risk factors for recurrence gender (male), age, multifocality, gross extrathyroidal extension (ETE), preoperative lymph node metastasis and number of metastatic lymph nodes (NMLNs) have also been reported (Thompson & Hay 2004, Sugino et al. 2015, Jeon et al. 2018, Sugino et al. 2020). We have proposed that lobectomy may be sufficient as the initial surgical procedure for low-risk pediatric patients (Sugino et al. 2015, Sugino et al. 2020).
Pathological diagnosis
According to the 5th edition of the WHO classification, there are many subtypes of PTC, with the diffuse sclerosing variant (DSV) and the solid variant of PTC common in the pediatric population (Juhlin et al. 2023). The cribriform-morular variant of PTC (CMV-PTC) was also common in the pediatric population, but the recent WHO classification defined CMV-PTC among the ‘thyroid tumors of uncertain histogenesis’ (Juhlin et al. 2023). Tall cell variant, columnar cell variant, DSV and the solid variant of PTC were classified as a ‘high-risk’ group than classical PTC, as in the adult criteria (Silver et al. 2011). It is uncertain whether the histological subtype of PTC affects the prognosis in the pediatric population. This study was conducted to clarify the clinicopathological features and clinical outcomes of histological subtypes of PTC in a large series of pediatric cases treated at a single institution in the past 40 years. To date, pediatric PTC has been treated using the same strategies as adult PTC. In 2015, the American Thyroid Association (ATA) published the first guidelines targeted for DTC children, those under 18 years of age, and classified pediatric patients into three categories (low-, intermediate- and high-risk groups), with risk stratification based on having persistent cervical disease and/or distant metastases after initial surgery (Francis et al. 2015). However, this guideline did not specify cutoff points for LN metastasis as minimal or extensive disease. The clinical utility of such risk stratification is limited. Therefore, the present study aimed to validate this risk stratification.
Materials and methods
Patients
A total of 21,355 PTC patients underwent initial surgery at Ito Hospital in Tokyo between 1979 and 2019. Of them, 153 (7%) PTC patients ≤18 years of age were evaluated. All PTCs were reviewed by experienced endocrine pathologists, TK and RK, co-authors of this study, blinded to patients’ outcomes, according to the 5th edition of the WHO classification (Juhlin et al. 2023). In the 4th WHO classification, CMV-PTC was classified as a subtype of PTC, but in the 5th WHO classification, it was included among ‘thyroid tumors of uncertain histogenesis’ (Juhlin et al. 2023). All patients were retrospectively staged according to the 8th TNM classification (Amin et al. 2017). All information used in the present study, including the patients’ characteristics, operative findings, postoperative treatment and follow-up, was collected from the patients’ medical records. Neck ultrasonography (US) and computed tomography (CT) have been routinely used preoperatively to evaluate neck disease and lung metastasis. Distant metastases were diagnosed by CT and whole body scintigraphy after total thyroidectomy. For all patients diagnosed with distant metastasis at initial surgery, radioactive iodine (RAI) therapy was performed within 6 months after initial surgery. All samples were obtained with informed patient consent and with approval from the Ito Hospital Institutional Review Board (approval no. 2018: 222). The protocol of this study was reviewed and approved by the institutional review board, and the study was performed in accordance with the Declaration of Helsinki.
Follow-up
Postoperative follow-up examinations were usually performed at 1, 3, 6 and 12 months, and every 6 months thereafter. The serum thyroglobulin (Tg) level was routinely measured at every hospital visit. Whenever a gradual increase in the postoperative Tg level was observed in patients who had not undergone completion thyroidectomy, CT was performed. However, patients with positive Tg antibody were followed by CT and US, because the presence of Tg antibody interferes with the Tg immunometric assay and makes the Tg levels unreliable. If these examinations resulted in detection of metastasis, completion thyroidectomy was performed, followed by RAI scintigraphy. Postoperative thyrotropin (TSH) suppression therapy was performed selectively in patients at high risk, such as those with distant metastasis, gross extrathyroidal extension (ETE) and massive lymph node metastases (N1), but the patients’ TSH levels were not analyzed in this study according to the ATA guideline. The clinical response rate of distant metastasis to RAI therapy was evaluated according to the 2015 ATA guideline for adult DTC management (Haugen et al. 2016) and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1 (Eisenhauer et al. 2009).
Statistical analysis
Cause-specific survival (CSS), disease-free survival (DFS), lymph node recurrence-free survival (LNRFS) and distant metastasis-free survival (DMFS) rates were calculated using the Kaplan–Meier method. DFS rates were calculated in patients who underwent curative surgery without distant metastases at diagnosis. The impact of various factors on survival was analyzed by the log-rank test. Multivariate analyses of prognostic factors were based on the Cox proportional hazards model. A chi-squared test or Fisher’s exact test was performed for categorical variables. The Wilcoxon signed rank-sum test was performed for nonparametric continuous data. All P-values were two-sided, and values of P < 0.05 were considered significant. All statistical analyses were performed with computer software (JMP ver. 12.0; SAS Institute Inc., USA).
Results
Patients’ characteristics
The patients’ characteristics are shown (Table 1). There were 135 female (88%) and 18 male patients (12%), with a mean age at the time of surgery of 16 (range, 8–18) years, and 5% (8 patients) were ≤10 years of age at diagnosis. There was no history of radiation exposure. At initial surgery, 49 patients (32%) had clinical lymph node metastases (cN1), 16 (11%) had gross ETE and 18 (12%) had distant metastases. Total thyroidectomy was performed in 55 (36%) patients and 98 (64%) patients underwent less than total thyroidectomy. Central lymph node dissection was performed in 42 patients (27%) and modified lateral lymph node dissection was performed in 109 patients (70%). A total of 137 (90%) patients had pathological lymph node metastases (pN1) and 73 patients (48%) had NLNMs ≥10. The median number of metastatic LNs was nine (0–58), and the cutoff for the number of metastatic LNs (NLNMs) by the ROC curve was ten (AUC 0.75) for predicting recurrence; the cutoff point showed sensitivity (0.31) and specificity (0.73).
Clinical characteristics of the 153 pediatric patients with PTC.
| Characteristic | n (%) | Range |
|---|---|---|
| Median age at diagnosis, y (range) | 16 (8–18) | |
| Sex | ||
| Female | 135 (88%) | |
| Male | 18 (12%) | |
| Histology | ||
| Classical | 124 (81%) | |
| Solid | 16 (10%) | |
| DSV | 7 (5%) | |
| Follicular | 6 (4%) | |
| Primary tumor size | ||
| <40 mm | 106 (69%) | 24 (4–80) mm |
| >40 mm | 47 (31%) | |
| Distant metastasis | ||
| M0 | 18 (12%) | |
| M1 | 135 (88%) | |
| Clinical lymph node metastasis | ||
| cN0 | 104 (68%) | |
| cN1 | 49 (32%) | |
| Pathological lymph node metastasis | ||
| pN0 or pNX | 16 (10%) | |
| pN1a | 39 (25%) | |
| pN1b | 98 (65%) | |
| Gross extrathyroidal extension | ||
| Yes | 16 (10%) | |
| No | 137 (90%) | |
| Thyroidectomy | ||
| Total (TTx) | 82 (54%) | |
| Less than TTx | 71 (46%) | |
| Lymph node dissection | ||
| None | 5 (3%) | |
| CND | 41 (27%) | |
| MND | 107 (70%) | |
| RAI therapy | ||
| Ablation | 21 (46%) | |
| 100 mCi | 25 (54%) |
DSV, diffuse sclerosing variant; Tx, thyroidectomy; CND, central node dissection; MND, modified neck dissection; RAI, radioactive iodine; PTC, papillary thyroid carcinoma.
Histopathological characteristics
The histopathological characteristics are shown (Table 2). The most common subtypes included classic PTC in 124 (81%), solid variant in 16 (10%), DSV in 7 (5%) and follicular variant in six (4%). The subtypes of PTC accounted for only 29 (9%) patients of a small number of patients. The median primary tumor size was 24 (range, 4–80) mm.
Comparison of patient characteristics.
| Classical n (%) | Variants n (%) | P value | ||
|---|---|---|---|---|
| Sex | Female | 111 (90%) | 24 (83%) | NS |
| Male | 13 (11%) | 5 (17%) | ||
| Age (years) | ≤10 years | 5 (4%) | 3 (10%) | NS |
| >10 years | 119 (96%) | 26 (90%) | ||
| T (primary tumor size) | ≤40 mm | 104 (84%) | 17 (59%) | NS |
| >40 mm-diffuse* | 20 (16%) | 12 (41%) | ||
| N (clinical lymph node metastasis) | cN0 | 88 (71%) | 36 (74%) | NS |
| cN1 | 36 (29%) | 13 (26%) | ||
| Massive extra-thyroidal invasion (ETE) | No | 112 (90%) | 25 (86%) | NS |
| Yes | 12 (10%) | 4 (14%) | ||
| Distant metastasis (M1) | No | 110 (89%) | 25 (86%) | NS |
| Yes | 14 (11%) | 4 (14%) | ||
| NMLNs | <10 | 66 (53%) | 14 (48%) | NS |
| ≥10 | 58 (47%) | 15 (52%) | ||
| Multifocal | No | 60 (48%) | 12 (41%) | NS |
| Yes | 64 (52%) | 17 (59%) | ||
| Extent of thyroidectomy | Total (TTx) | 78 (63%) | 14 (47%) | NS |
| Less than TTx | 46 (37%) | 15 (53%) | ||
| Lymph node dissection | None/PCND | 39 (31%) | 7 (24%) | NS |
| PMND | 85 (69%) | 22 (76%) | ||
| RAI therapy | No | 90 (73%) | 17 (59%) | NS |
| Yes | 34 (27%) | 12 (41%) | ||
Diffuse, diffuse sclerosing variant.
ETE, extrathyroidal extension; pN, pathological lymph node metastasis; PTC, papillary thyroid carcinoma.
RAI therapy and tyrosine kinase inhibitor (TKI) therapy
RAI therapy was performed in 46 of 82 (56%) patients who underwent total thyroidectomy containing completion to total thyroidectomy. All 18 patients with distant metastasis at initial surgery underwent RAI therapy. Of the ten patients who developed distant metastasis during follow-up, eight were treated with RAI therapy. Their disease in the lung was RAI-avid, and they underwent RAI therapy several times. The median total radiation dose was 100 (range, 30–700) mCi. The response rate for the 23 patients treated with RAI at 100 mCi or more was 57%. The remaining two with micronodular disease refused RAI therapy. No patients received TKI therapy.
Clinical outcomes
During a mean follow-up of 16 years, lung metastases were the cause of death of all three patients who died (Table 3). Recurrences were diagnosed in 37 patients. The recurrence was in lymph node metastases in 30 patients, remnant thyroid in four patients and both in one patient. Distant metastasis was detected at presentation in 18 patients and during follow-up in the other ten patients. Cumulative CSS, DFS, LNRFS and DMFS are shown (Fig. 1). The 10-, 20- and 30-year CSS rates were 99.2, 99.2 and 97.2%, respectively. The 10-, 20- and 30-year DFS rates were 81.8%, 69.5 and 65.0%, respectively. The 10-, 20- and 30-year LNRFS rates were 85.1, 73.4 and 67.9%, respectively, and the 10-, 20- and 30-year DMFS rates were 98.4, 94.3 and 88.2%, respectively. Furthermore, survival was compared between the classical PTC group and the variant PTC group (Fig. 2). The three fatal cases were all classical PTC cases. There were no significant differences between classical PTC and variants of PTC. The 30-year CSS rate was 96.6% in classical PTC and 100% in variant PTC. The 30-year DFS rates were 68.3% in classical PTC, 62.5% in solid variant, 57.1% in DSV and 57.1% in follicular variant. There were no significant differences between classical PTC and each variant of PTC.
Clinical characteristics and treatment of the three fatal cases with lung metastasis.
| No. | Age (y) | Sex | Histology | T | cN | pN | M | ETE | Dose of RAI therapy (mCi) | Follow-up (y) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 9 | M | Classical | T4a | cN1 | pN1b | Lung | Trachea, RLN | 100 | 22.9 |
| 2 | 12 | F | Classical | T3 | cN1 | pN1b | Lung | None | 100 | 36.4 |
| 3 | 17 | F | Classical | T4a | cN0 | pNx | Lung | Trachea, RLN | 500 | 7.4 |
RLN, recurrent laryngeal nerve.
CSS, DFS, LNRFS and DMFS rates in all subjects.
Citation: Endocrine Oncology 5, 1; 10.1530/EO-24-0078
Comparison of CSS, DFS, DMFS and LNRFS rates between the classical PTC group and the variant group.
Citation: Endocrine Oncology 5, 1; 10.1530/EO-24-0078
Risk factor analysis and risk stratification
Results of univariate and multivariate analyses to identify prognostic factors of recurrence are given in Table 4. On univariate analysis, gross ETE (P = 0.001), cN1 (P = 0.003) and NLNMs ≥10 (P = 0.0002) were found to be significant (Fig. 3A, B, C). On multivariate analysis, gross ETE, cN1 and NLNMs ≥10 were identified as significant factors related to DFS (hazard ratio (HR) 4.13, confidence interval (CI) 1.48–9.96, P = 0.009; HR 2.34, CI 1.09–4.95, P = 0.0293; HR 2.81, CI 1.30–6.59, P = 0.008). Based on this result, the patients were classified into two groups according to the presence of ETE, the status of cervical LN metastases and/or distant metastasis. The definitions were modified from the recent ATA guideline for DTC children shown in (Table 5). Patients with N0, NX or N1a disease or patients with minimal N1b with NLNMs <10 were assigned to the low-risk group. Patients with extensive N1b with NLNMs ≥10 or patients with gross ETE or patients with distant metastasis were assigned to the high-risk group. According to this original classification, 77 (50%) and 76 (50%) patients were assigned to the low- and high-risk groups, respectively. Of the 135 patients who underwent curative surgery without distant metastases at diagnosis, recurrence was observed in eight (10%) of the low-risk group and 26 (45%) of the high-risk group. The 10-year DFS rates were 92.9 and 67.9% in the low- and high-risk groups, respectively. The high-risk group had significantly higher disease recurrence than the low-risk group (P = 0.0002) (Fig. 3D).
Univariate and multivariate analyses to identify prognostic factors of recurrence related to clinicopathological characteristics.
| Factors related to DFS | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| HR | CI | p | HR | CI | p | |
| Gross extrathyroidal extension (ETE) | 3.97 | 1.48–9.01 | 0.001 | 4.13 | 1.48–9.96 | 0.009 |
| Clinical lymph node metastasis (cN1) | 2.73 | 1.34–5.43 | 0.003 | 2.34 | 1.09–4.95 | 0.0293 |
| NLNMs ≥10 | 3.82 | 1.84–8.69 | 0.0002 | 2.81 | 1.30–6.59 | 0.008 |
NLNMs, number of lymph node metastases; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval.
Comparison of DFS rates between patients with low-risk or high-risk group by modified ATA guideline.
Citation: Endocrine Oncology 5, 1; 10.1530/EO-24-0078
Definitions of the modified recent ATA guideline for DTC children.
| Category | Definition | Total | Incidence of death | Incidence of recurrence |
|---|---|---|---|---|
| n (%) | n (%) | n (%) | ||
| Low | N0 or NX or N1a or minimal N1b with NLMs<10 | 77 (50%) | 0 (0%) | 8/77 (10%) |
| High | Extensive N1b with NLNMs ≥10 or gross ETE or distant metastasis | 76 (50%) | 3 (4%) | 26/58 (45%) |
DTC, differentiated thyroid carcinoma.
Discussion
The ATA guidelines defined children as those under 18 years of age and proposed treatment strategies for DTC in children. In our previous study, we suggested that an age cutoff of <15 years rather than <19 years may be more suitable in pediatric DTC (Francis et al. 2015). Therefore, in the present study, PTC patients under 18 years of age were defined as children. The study in the United States from 1973 to 2013 reported that, of 1,806 patients with thyroid cancer who were younger than 20 years, 1,454 (80.5%) were female, the male-to-female ratio was 1:4 and most patients were aged 15–19 years (Qian et al. 2019). In the present study, the male-to-female ratio was 1:8, and there were more female patients. Distribution by age showed a trend toward an increase in the late teens. Lymph node metastasis and distant metastasis were frequent at the time of diagnosis.
In the present study, 29 (19%) patients had a subtype, solid variant in 16 (10%) and DSV in seven (5%). However, both variants had an excellent prognosis, similar to that of classical PTC in pediatric PTC patients, possibly due to the positive effect of younger patient age. The solid variant is more common in patients with a history of exposure to ionizing radiation (Nikiforov & Gnepp 1994). Vuong et al. reported a meta-analysis of the solid variant of PTC, and vascular invasion, extraglandular invasion and distant metastasis were more common, and recurrence and mortality rates were higher than that in the other types of PTC (Vuong et al. 2018). Ohashi et al. reported that DFS was shorter than that of classical PTC (Ohashi 2020). In the present study, all 16 patients with solid variant of PTC did not have a history of exposure to neck radiation. All patients were alive, and five patients had recurrence. The 30-year CSS and DFS rates were 100 and 62.5%, respectively. The prognosis for the solid variant was the same as for classical PTC.
In 1985, Vickery et al. described the DSV of PTC (Vickery et al. 1985). This variant is rare, accounting for 1–2% of PTC cases, and it is more common in young women in their teens and 20s (Vickery et al. 1985, Fujimoto et al. 1990, Koo et al. 2009). More extensive lymph node metastasis, extrathyroidal invasion and distant metastasis are seen than in classical PTC (Fukushima et al. 2009, Pillai et al. 2015, Vuong et al. 2017). Outcomes for DSV were good, but recurrence was more common than for classical PTC (Akaishi et al. 2015). Balachander et al. reported that event-free survival was not associated with histological subtype (Balachandar et al. 2016). In the present study, the three fatal cases all had classical PTC, and histological subtype did not affect survival and recurrence. The subtypes of PTC accounted for only 29 (9%) patients of a small number of patients, which may not have been reflected in a difference in prognosis.
Recent ATA guidelines for DTC children did not specify cutoff points of the number of LN metastases and the clinical utility of such risk stratification is limited (Francis et al. 2015). In the present study, risk factors related to DFS were gross ETE, clinical lymph node metastasis (cN1) and NLNMs ≥10 on multivariate analysis. Therefore, we have modified the ATA guideline to include the presence of ETE and the status of cervical LN metastases and/or distant metastasis, and divided the patients into two categories, reflecting the results of the multivariate analysis. The DFS rate of the high-risk group was significantly lower than that of the low-risk groups (P = 0.0002).
Even with higher prevalence of lymph node metastasis and distant metastasis, the long-term prognosis is excellent in pediatric patients with PTC. This is considered due to the better response to RAI therapy in pediatric PTC patients with lung metastasis than in adults (Pawelczak et al. 2010). However, secondary primary malignancy has been reported to be high in pediatric DTC patients treated with RAI therapy (Marti et al. 2015, Zhao et al. 2021, Pasqual et al. 2022). However, large amounts of data from other centers have not shown an increase in breast cancer or a secondary cancer risk with RAI therapy (Kim et al. 2022, Nappi et al. 2022).
Most genetic abnormalities in PTCs are concentrated in the MAPK pathway, with RET gene rearrangements, BRAF point mutations (BRAF-V600E) and NTRK gene rearrangements (Kondo et al. 2006). RET gene rearrangements are the most frequent in PTCs in children and young adults, and BRAF mutations are less frequent than in adults (Kebebew et al. 2007). RET/PTC3 was reported frequently in pediatric thyroid cancers after the Chernobyl accident, suggesting an association with childhood thyroid cancer after radiation exposure of different types of RET/PTC (Nikiforov et al. 1997). DSV has a higher frequency of RET/PTC rearrangement, but BRAF mutation is rare (Nakazawa et al. 2005). In 52/93 (55.9%) pediatric PTC patients, a fusion gene, 20 different types of RET, NTRK3, ALK, NTRK1, BRAF and MET fusions were detected, and RET fusions were associated with more frequent lymph node and distant metastases, and NTRK3 fusions were associated with the follicular variants of PTC (Pekova et al. 2020). In Japan, molecular-targeted agents have been indicated for advanced thyroid carcinoma that is either unresectable or resistant to RAI therapy since 2014. Subsequently, BRAF/MEK inhibitors, RET inhibitors and TRK inhibitors were approved for advanced thyroid carcinoma. In thyroid carcinomas, genetic testing is recommended to determine the indication for therapeutic agents tied to specific genetic abnormalities. In the present study, the three fatal cases due to pulmonary metastases could not undergo genetic testing and could not be treated by TKI therapy because TKI had not yet been approved at that time.
Several limitations must be considered in interpreting the results of this retrospective study. Our hospital is a single center without a pediatric department, which may introduce bias in the patient population. Further study is needed to evaluate more cases. The indications for RAI therapy in Japan are limited to patients with gross ETE, massive lymph node metastasis or distant metastasis.
Conclusions
The prognosis of pediatric patients with PTC was excellent, but recurrence was common. In pediatric PTC, histological subtype did not affect survival and recurrence. Long-term follow-up of pediatric patients is necessary to investigate the biological characteristics. In particular, it is important to understand the special characteristics of histological subtypes.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
JA designed the study, carried out data analysis and wrote the original draft. KS, TK and RK designed the study. WK, KM, AS, CT, RO, KH, CM, YS, KY, KI and KI reviewed and edited the article. All authors revised and approved the final version of the article.
References
Akaishi J , Sugino K , Kameyama K , et al. 2015 Clinicopathologic features and outcomes in patients with diffuse sclerosing variant of papillary thyroid carcinoma. World J Surg 39 1728–1735. (https://doi.org/10.1007/s00268-015-3021-9)
Amin MB , Greene FL , Edge SB , et al. 2017 The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 67 93–99. (https://doi.org/10.3322/caac.21388)
Balachandar S , La Quaglia M , Tuttle RM , et al. 2016 Pediatric differentiated thyroid carcinoma of follicular cell origin: prognostic significance of histologic subtypes. Thyroid 26 219–226. (https://doi.org/10.1089/thy.2015.0287)
Borson-Chazot F , Causeret S , Lifante JC , et al. 2004 Predictive factors for recurrence from a series of 74 children and adolescents with differentiated thyroid cancer. World J Surg 28 1088–1092. (https://doi.org/10.1007/s00268-004-7630-y)
Brink JS , van Heerden JA , McIver B , et al. 2000 Papillary thyroid cancer with pulmonary metastases in children: long-term prognosis. Surgery 128 881–887. (https://doi.org/10.1067/msy.2000.109728)
Collini P , Mattavelli F , Pellegrinelli A , et al. 2006 Papillary carcinoma of the thyroid gland of childhood and adolescence: morphologic subtypes, biologic behavior and prognosis: a clinicopathologic study of 42 sporadic cases treated at a single institution during a 30-year period. Am J Surg Pathol 30 1420–1426. (https://doi.org/10.1097/01.pas.0000213264.07597.9a)
Cordioli MI , Moraes L , Cury AN , et al. 2015 Are we really at the dawn of understanding sporadic pediatric thyroid carcinoma? Endocr Relat Cancer 22 R311–R324. (https://doi.org/10.1530/erc-15-0381)
Eisenhauer EA , Therasse P , Bogaerts J , et al. 2009 New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45 228–247. (https://doi.org/10.1016/j.ejca.2008.10.026)
Francis GL , Waguespack SG , Bauer AJ , et al. 2015 Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid 25 716–759. (https://doi.org/10.1089/thy.2014.0460)
Fujimoto Y , Obara T , Ito Y , et al. 1990 Diffuse sclerosing variant of papillary carcinoma of the thyroid. Clinical importance, surgical treatment, and follow-up study. Cancer 66 2306–2312. (https://doi.org/10.1002/1097-0142(19901201)66:11<2306::aid-cncr2820661109>3.0.co;2-p)
Fukushima M , Ito Y , Hirokawa M , et al. 2009 Clinicopathologic characteristics and prognosis of diffuse sclerosing variant of papillary thyroid carcinoma in Japan: an 18-year experience at a single institution. World J Surg 33 958–962. (https://doi.org/10.1007/s00268-009-9940-6)
Haugen BR , Alexander EK , Bible KC , et al. 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26 1–133. (https://doi.org/10.1089/thy.2015.0020)
Hay ID , Johnson TR , Kaggal S , et al. 2018 Papillary thyroid carcinoma (PTC) in children and adults: comparison of initial presentation and long-term postoperative outcome in 4432 patients consecutively treated at the mayo clinic during eight decades (1936–2015). World J Surg 42 329–342. (https://doi.org/10.1007/s00268-017-4279-x)
Jeon MJ , Kim YN , Sung TY , et al. 2018 Practical initial risk stratification based on lymph node metastases in pediatric and adolescent differentiated thyroid cancer. Thyroid 28 193–200. (https://doi.org/10.1089/thy.2017.0214)
Juhlin CC , Mete O & Baloch ZW 2023 The 2022 WHO classification of thyroid tumors: novel concepts in nomenclature and grading. Endocr Relat Cancer 30 e220293. (https://doi.org/10.1530/erc-22-0293)
Kebebew E , Weng J , Bauer J , et al. 2007 The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 246 466–471. (https://doi.org/10.1097/sla.0b013e318148563d)
Kim S , Bang JI , Boo D , et al. 2022 Second primary malignancy risk in thyroid cancer and matched patients with and without radioiodine therapy analysis from the observational health data sciences and informatics. Eur J Nucl Med Mol Imaging 49 3547–3556. (https://doi.org/10.1007/s00259-022-05779-9)
Kondo T , Ezzat S & Asa SL 2006 Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6 292–306. (https://doi.org/10.1038/nrc1836)
Koo JS , Hong S & Park CS 2009 Diffuse sclerosing variant is a major subtype of papillary thyroid carcinoma in the young. Thyroid 19 1225–1231. (https://doi.org/10.1089/thy.2009.0073)
Lee YA , Yun HR , Lee J , et al. 2021 Trends in pediatric thyroid cancer incidence, treatment, and clinical course in Korea during 2004–2016: a nationwide population-based study. Thyroid 31 902–911. (https://doi.org/10.1089/thy.2020.0155)
Markovina S , Grigsby PW , Schwarz JK , et al. 2014 Treatment approach, surveillance, and outcome of well-differentiated thyroid cancer in childhood and adolescence. Thyroid 24 1121–1126. (https://doi.org/10.1089/thy.2013.0297)
Marti JL , Jain KS & Morris LG 2015 Increased risk of second primary malignancy in pediatric and young adult patients treated with radioactive iodine for differentiated thyroid cancer. Thyroid 25 681–687. (https://doi.org/10.1089/thy.2015.0067)
Nakazawa T , Kondo T , Kobayashi Y , et al. 2005 RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan). Cancer 104 943–951. (https://doi.org/10.1002/cncr.21270)
Nappi C , Klain M , Cantoni V , et al. 2022 Risk of primary breast cancer in patients with differentiated thyroid cancer undergoing radioactive iodine therapy: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging 49 1630–1639. (https://doi.org/10.1007/s00259-021-05625-4)
Nikiforov Y & Gnepp DR 1994 Pediatric thyroid cancer after the Chernobyl disaster. Pathomorphologic study of 84 cases (1991–1992) from the Republic of Belarus. Cancer 74 748–766. (https://doi.org/10.1002/1097-0142(19940715)74:2<748::aid-cncr2820740231>3.0.co;2-h)
Nikiforov YE , Rowland JM , Bove KE , et al. 1997 Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 57 1690–1694.
Ohashi R 2020 Solid variant of papillary thyroid carcinoma: an under-recognized entity. Endocr J 67 241–248. (https://doi.org/10.1507/endocrj.ej19-0414)
Pasqual E , Schonfeld S , Morton LM , et al. 2022 Association between radioactive iodine treatment for pediatric and young adulthood differentiated thyroid cancer and risk of second primary malignancies. J Clin Oncol 40 1439–1449. (https://doi.org/10.1200/jco.21.01841)
Pawelczak M , David R , Franklin B , et al. 2010 Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following (1)(3)(1)I treatment: a systematic review. Thyroid 20 1095–1101. (https://doi.org/10.1089/thy.2009.0446)
Pekova B , Sykorova V , Dvorakova S , et al. 2020 RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid 30 1771–1780. (https://doi.org/10.1089/thy.2019.0802)
Pillai S , Gopalan V , Smith RA , et al. 2015 Diffuse sclerosing variant of papillary thyroid carcinoma – an update of its clinicopathological features and molecular biology. Crit Rev Oncol Hematol 94 64–73. (https://doi.org/10.1016/j.critrevonc.2014.12.001)
Qian ZJ , Jin MC , Meister KD , et al. 2019 Pediatric thyroid cancer incidence and mortality trends in the United States, 1973–2013. JAMA Otolaryngol Head Neck Surg 145 617–623. (https://doi.org/10.1001/jamaoto.2019.0898)
Silver CE , Owen RP , Rodrigo JP , et al. 2011 Aggressive variants of papillary thyroid carcinoma. Head Neck 33 1052–1059. (https://doi.org/10.1002/hed.21494)
Sugino K , Nagahama M , Kitagawa W , et al. 2015 Papillary thyroid carcinoma in children and adolescents: long-term follow-up and clinical characteristics. World J Surg 39 2259–2265. (https://doi.org/10.1007/s00268-015-3042-4)
Sugino K , Nagahama M , Kitagawa W , et al. 2020 Risk stratification of pediatric patients with differentiated thyroid cancer: is total thyroidectomy necessary for patients at any risk? Thyroid 30 548–556. (https://doi.org/10.1089/thy.2019.0231)
Thompson GB & Hay ID 2004 Current strategies for surgical management and adjuvant treatment of childhood papillary thyroid carcinoma. World J Surg 28 1187–1198. (https://doi.org/10.1007/s00268-004-7605-z)
Vergamini LB , Frazier AL , Abrantes FL , et al. 2014 Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults: a population-based study. J Pediatr 164 1481–1485. (https://doi.org/10.1016/j.jpeds.2014.01.059)
Vickery AL Jr , Carcangiu ML , Johannessen JV , et al. 1985 Papillary carcinoma. Semin Diagn Pathol 2 90–100.
Vuong HG , Kondo T , Pham TQ , et al. 2017 Prognostic significance of diffuse sclerosing variant papillary thyroid carcinoma: a systematic review and meta-analysis. Eur J Endocrinol 176 433–441. (https://doi.org/10.1530/eje-16-0863)
Vuong HG , Odate T , Duong UNP , et al. 2018 Prognostic importance of solid variant papillary thyroid carcinoma: a systematic review and meta-analysis. Head Neck 40 1588–1597. (https://doi.org/10.1002/hed.25123)
Zhao X , Chen M , Qi X , et al. 2021 Association of radioiodine for differentiated thyroid cancer and second breast cancer in female adolescent and young adult. Front Endocrinol 12 805194. (https://doi.org/10.3389/fendo.2021.805194)
