Thyroid Cancers in Children,Adolescents,and Young Adults With and Without a History of Childhood Exposure to Therapeutic Radiation for Other Cancers

Abstract

Background:

The thyroid is highly sensitive to the carcinogenic effect of radiation in children. We compared, in patients with and without earlier childhood radiation, the features of papillary thyroid cancer (PTC) diagnosed in later childhood through young adulthood.

Methods:

Patients were from the Rhône-Alpes Thyroid Cancer Registry. Twenty-four patients (RAD group) had been treated by radiation therapy for nonthyroid neoplasms at the age of 8.0±6.0 years (mean±SD) and by surgery for PTC at the age of 17±6.4 years. They were compared with 413 patients with PTC but no radiation exposure (sPTC group, age 23±4.8 years). The two groups were subdivided into three subgroups, ages 8–14 (children), 15–20 (adolescents), and 21–29 years (adults) at time of PTC diagnosis, and compared to matched subgroups from 80 patients in the sPTC group (M-sPTC). Age in years at PTC diagnosis (RAD vs. M-sPTC) was 12±2 compared with 12±2 for children, 17±1 compared with 19±1 for adolescents, and 25±3.2 compared with 25±2.5 for adults. The matched subgroups had comparable pTNM, treatments, and follow-up. We compared the histopathological characteristics of the initial specimens and the outcome events.

Results:

The RAD group and the sPTC group were similar in terms of age when PTC was diagnosed. RAD tumors had significantly more lymph node metastases (p=0.007) and a higher proportion of invasive pTN3 stage tumors (p=0.01). The adult RAD subgroup (n=8) was more likely to have lymph node metastases (p=0.004) and a higher proportion of invasive pT3N+ stage tumors (p=0.01) than the adult sPTC subgroup (n=316). During the 6.5 years of follow-up, there was no difference in the risk of cervical recurrence between the RAD group and the M-sPTC groups. Risk of cervical recurrence was also similar for tumors that were high risk (pT3N+).

Conclusion:

Young adults with PTC associated with radiation therapy for nonthyroid neoplasms in childhood have a more aggressive initial presentation than young adults with sporadic PTC. The risk of recurrent disease in patients who received radiation in early childhood through adolescence and who developed PTC in late childhood through early adulthood is similar to those who did not receive radiation.

Introduction

T he thyroid gland is highly sensitive to the carcinogenic effect of ionizing radiation, especially in children (1 –4). Epidemiological studies demonstrate that a high proportion of clinically apparent thyroid neoplasms that develop in patients previously exposed to external radiation are malignant (5). In addition, the risk of malignancy is proportional to the radiation dose to the thyroid (3,6,7). This risk remains elevated for decades after exposure. Most of these thyroid neoplasms are papillary carcinomas (5). In young people, thyroid carcinoma (TC) has typically an aggressive initial presentation. However, TC has a good general prognosis despite recurrences in 10–20% of patients (8,9). Aggressive behavior of TC in patients submitted to previous radiation exposure is associated with an elevated recurrence rate, but no influence on the mortality rate has been described in a study comparing cases to an unmatched control population (10). A case-control study matched for age, sex, and extension showed that external radiation–associated cancers are more aggressive than other thyroid cancers in terms of clinical presentation, but not in terms of mortality and recurrences (11). The risk factors of recurrence and thyroid cancer–related death were found to be similar between radiation-exposed TC and sporadic cancers (5,12,13).

The aims of the present study were to revisit the clinical presentation of thyroid cancers in patients with previous external radiation exposure, and to compare the evolution of such patients to that of nonexposed patients. We used a population-based collection of recently diagnosed thyroid cancers. Both cases and controls benefited from the same therapeutic protocols, according to international recommendations.

Patients and Methods

Study populations

The present study was approved by the institutional ethics committee. Patient information and characteristics were recorded by the endocrinologist in charge of follow-up.

Cases were TC patients diagnosed after a childhood exposure to external ionizing radiation for a first tumor. Twenty-four patients (11 men and 13 women; RAD group) were identified through the Thyroid Cancer Registry of the Rhône-Alpes region (TCR-RA) and the Childhood Cancer Registry of the Rhône-Alpes region (ARCERRA), from 2002 to 2006. The first and second malignancies were histologically confirmed for all patients. First malignancies included Hodgkin's disease (n=7), acute lymphoblastic leukemia (ALL; n=6), brain tumor (n=10), and cancer of the floor of the mouth (n=1). The mean age at diagnosis of the first cancer was 8 years old (range: 1.4–20 years) and 12 patients were <5 years old. The mean dose of radiation administered was 20 Gy for Hodgkin disease, 12 Gy for ALL, and 40 Gy for brain tumors. We did not estimate the dose to the thyroid. All patients received chemotherapy with protocols appropriate for their disease. Patient age at TC diagnosis was between 8 and 29 years (median 17 years). The median latent period between radiation therapy and TC was 9 years (range: 4–18). Of the 24 patients, 11 were children (8–14 years; 46%), 5 were adolescents (15–20 years; 21%), and 8 were young adults (21–29 years; 33%) (Table 1).

Table 1.

Ages at Thyroid Cancer Diagnosis in the RAD, sPTC, and M-sPTC Groups and the Three Age Subgroups of Patients (Children, Adolescents, and Young Adults)

	RAD	sPTC	M-sPTC
8–14 years of age
Number of patients (n)	11	35	22
Age at time of external radiation treatment (years, mean±SD)	4±2.9 (2–12)	N/A	N/A
Age at thyroid cancer diagnosis (years, mean±SD)	12±2	12±2	12±2
15–20 years of age
Number of patients (n)	5	62	21
Age at time of external radiation treatment (years, mean±SD)	4.5±4.2 (1.4–12)	N/A	N/A
Age at thyroid cancer diagnosis (years, mean±SD)	17±1	19±1	18±2
21–29 years of age
Number of patients (n)	8	316	37
Age at time of external radiation treatment (years, mean±SD)	14.8±3.7 (13–20)	N/A	N/A
Age at thyroid cancer diagnosis (years, mean±SD)	25±3.2	25±2.5	25.3±3
All patients
Number of patients (n)	24	413	80
Age at time of external radiation treatment (years, mean±SD)	8.0±6.0 (1.4–20)	N/A	N/A
Age at thyroid cancer diagnosis (years, mean±SD)	17±6.4	23±4.8	20±6.3

Group definitions: RAD, patients with thyroid cancers associated with previous radiation therapy in childhood for malignancy; sPTC, patients with thyroid cancer without previous radiation therapy; M-sPTC, patients with thyroid cancer without previous radiation therapy matched with RAD.

sPTC, sporadic papillary thyroid carcinoma; N/A, not applicable.

First, the RAD group was compared to all consecutive sporadic tumors (sPTC) removed from patients without childhood exposure to ionizing radiation (sPTC), in terms of histopathological characteristics. sPTC patients were between 8 and 29 years old, and a total of 413 were identified in the TCR-RA. They included 84 males and 329 females, 35 children (8.5%), 62 adolescents (15%), and 316 young adults (76.5%) Patient characteristics are detailed in Table 1.

Second, a case–control study was performed to evaluate clinical behavior. Control patients (M-sPTC) were selected from the TCR-RA, with the following inclusion criteria: (i) aged between 8 and 29 years old; (ii) no childhood exposure to ionizing radiation; (iii) thyroid cancers removed between 2002 and 2006; (iv) a follow-up length postsurgery of more than three years. For each case, 3.3 controls were selected and matched for age at diagnosis of the thyroid cancer, pTNM staging, and length of follow-up. A total of 80 controls (17 men and 63 women) were selected: 22 children (8–14 years), 21 adolescents (15–20 years), and 37 young adults (21–29 years) (Table 1).

Histopathology

All histological slides were reviewed by the same pathologist (N.B.). Histological subtypes of PTC were classified according to the World Health Organization (WHO) classifications (14), including the classic type of papillary thyroid carcinoma (CPTC), follicular variant (FVPTC), diffuse sclerosing variant (DSVPTC), and solid variant (SPTC). Tumors were classified by pTNM staging according to the 2009 edition (15): pT1N0, pT1N+, pT2N0, and pT2N+ were considered as a low-risk group, and pT3N+/M as a high-risk group.

Follow-up

Treatment modalities were in accordance with national recommendations (16). Surgery consisted of total or near total thyroidectomy in most patients. Neck dissection was performed in patients with preoperative (ultrasonography) or perioperative cervical nodal involvement (according to national consensus) (16). The mean length of follow-up was 6.5±3.4 years for cases and 6±2.2 years for controls. Most patients were followed in the same university hospital. According to national consensus, most patients received postoperative radioiodine thyroid remnant ablation (RAI) by administration of ¹³¹I (30–100 mCi), with whole body RAI scanning on the fifth day. If ¹³¹I extrathyroidal uptake was demonstrated, patients received iterative RAI therapy (100 mCi per treatment) or surgery, depending on clinical data. Thyrotropin (TSH) suppressive treatment was administered to all patients. Six to nine months after RAI initial treatment, all patients underwent neck ultrasonography (US) and determination of thyroglobulin (Tg) under under recombinant human TSH (rhTSH) stimulation. Annual determinations included clinical examination, ultrasound neck examination, fine needle aspiration cytology if appropriate, determination of thyroglobulin (Tg) levels and Tg autoantibodies while on LT4 treatment and stimulated by TSH (either off LT4 or after rhTSH stimulation), and radiological ancillary studies if necessary. Additional RAI therapies with scintigraphy were performed in function of clinical data. The functional sensitivity of the Tg assay was 0.4 ng/mL (Cis Bio International). Pathological findings included distant metastasis(es), discovered by abnormal RAI uptake and conventional imaging (CT scan), either at the first evaluation or thereafter as a secondary event. Cervical recurrence of invaded lymph nodes was detected by US, recorded after secondary surgical resection, and confirmed by pathological examination. Evaluation at the last visit allowed different disease classifications to be made. Disease-free status was defined as the absence of detectable residual disease, as well as undetectable basal Tg and rhTSH-stimulated Tg, <1.5 ng/mL (17). Conversely, persistent disease was defined as the presence of metastasis(es) disclosed by scintigraphy or other imaging modalities and/or an inappropriately elevated, unsuppressed Tg level under LT4, and/or Tg >0.5 ng/mL under rhTSH stimulation. Only a stable or increasing Tg value was considered as a marker of persistent disease. Recurrence was defined by the same criteria after a period of remission. Clinical data were obtained yearly for the RAD and sPTC patients, whether children, adolescents, or adults.

Statistical analyses

Cases (RAD) were compared to consecutive tumors from the registry (sPTC) and to matched controls (M-sPTC) using Fisher's exact test. Odds ratios were calculated to evaluate the effect of previous external radiation therapy on outcome events (GraphPad Prism 4). Significance was assumed if p<0.05.

Results

Characteristics of 24 radiation-associated thyroid cancers

Twenty-four cases of RAD cancers were identified. The median patient age at radiation therapy was 8 years old (range: 1.4–20 years) and 17 years old at the diagnosis of thyroid cancer (range: 8–29 years). We found no relationship between the age at the first cancer and the age at thyroid cancer diagnosis. All cancers were papillary with an equal proportion of the classic and the follicular variant (41.6%) and 16.6% of the diffuse sclerosing variant. Multifocality was found in 29% of tumors. Most tumors (62.5%) belonged to a low-risk group. Lymph node metastasis(es) (LNM) was found at diagnosis in 15 patients (62.5%): 6 out of 11 (54.4%) children, 1 out of 5 (20%) adolescents, and 7 out of 8 (87%) of adults. Nine tumors belonged to a high-risk group (pT3), with extrathyroidal invasion (ET). They were all associated with LNM and mainly found in the adult group, representing 50% of tumors. Microcarcinomas were found in 9 cases (37.5%): in 2 out of 11 children, 4 out of 5 adolescents, and 3 out of 8 adults. They were associated with LNM in 5 out of 9 cases and with ET in 2 out of 9 cases.

Comparison with sPTC

To determine whether there is a particular presentation of RAD tumors, we compared the histopathological characteristics of the initial thyroidectomy specimens to that of 413 sPTC tumors. The 413 sPTC were recorded in the TCR-RA and belonged to the same age groups as RAD patients. The RAD group and the sPTC group were similar in terms of proportions of CPTC and FVPTC. We compared the prevalence of the markers of aggressiveness—LNM and ET—between the two groups and within each age subgroup. RAD tumors had significantly more LNM (p=0.007) and a higher proportion of invasive tumors of pTN3 stage than the sPTC tumors (p=0.01). The prevalence of LNM was comparable in children and adolescent subgroups. Conversely, in the young adult subgroup, the level of LNM was significantly different between RAD and sPTC: 87.5% (7/8) compared to 22.7% (72/316) respectively (p=0.004; Fig. 1A). In the young adult subgroup, there was a higher prevalence of invasive tumors of the pT3N+ stage in RAD compared to sPTC tumors (p=0.01; Fig. 1B, C). The respective distributions of low and high-risk pTN stages were mirrored (Fig. 1C), with a higher proportion of pT3N+ in RAD and a higher proportion of pT1 and pT2 in sPTC. The proportion of microcarcinomas was higher in the RAD than the sPTC cohort (37.5% vs. 29.5%, ns). This was mainly true for the tumors of adolescents (80% vs. 17.7% in RAD and sPTC respectively).

FIG. 1.

(A) Distribution of lymph node metastases by age group in radiation-associated thyroid cancers (RAD) and sporadic tumors (sPTC). (B) Distribution of pTN stagings in RAD and sPTC. (C) Distribution of pTN stages by age group in RAD and sPTC. *p=0.01; **p=0.004.

Case–control study

Cases were defined as the radiation-associated papillary thyroid cancers (RAD). The control group consisted of 80 patients with PTC (M-sPTC) but without previous radiation exposure, and included 22 children, 21 adolescents, and 37 young adults. The tumors of this control group were matched for staging. However, some differences were noticeable between cases and matched controls (Table 2). The mean tumor size (largest diameter) was higher in controls. There was no difference in the proportions of multifocality, ET, and LNM between the two groups. The proportion of microcarcinomas was higher in cases versus controls (37.5% vs. 17.7%, p=0.05). This was mainly found in adolescents (80% vs. 33.3%, p=0.03).

Table 2.

Clinical and Histopathological Characteristics of RAD and M-sPTC Groups

	RAD (cases) n=24	M-sPTC (controls) n=80	p
Sex (M/F)	11/13	17/63
Age at diagnosis (years)	17±6.4	20±6.3
Tumor size (cm)	1.63±1.35	2.01±1.4	0.05
LNM (N+)	62.5%	51.2%	ns
ET+	33.3%	30%	ns
Multifocality	29%	27%	ns
pTN staging
pT1N0	7 (29%)	33 (39.7%)
pT1N+	6 (25%)	15 (18.7%)
pT2N0	2 (8%)	6 (7.2%)
pT2N+	0	0
pT3N+	9 (37.5)%	30 (36.1%)
Microcarcinomas (≤1 cm)	9 (37.5%)	14 (17.7%)	0.05
Micro N+	5 (20.8%)	9 (11%)

Data are presented as number and/or percent or as mean±SD.

LNM, lymph node metastasis(es); ET, extrathyroid extension; ns, not statistically significant.

Initial treatments were comparable for cases and controls. Total thyroidectomy had been performed in all cases and 87% of controls. Neck dissection was performed in most cases. There was a marked difference in the adolescent groups with more dissection in cases than in controls. RAI ablation treatments were comparable between the two populations. All patients had postoperative suppressive thyroid hormone therapy.

Metastatic status and cervical recurrences

Cases (RAD)

Lung metastases were found at the first RAI in one 24-year-old patient who was operated on for a pT3 CPTC with LNM. We did not find any additional metastatic sites during the follow up period. During follow-up, three patients (aged 10, 11, and 16 years old) presented with cervical LNM recurrence leading to secondary cervical surgery, with invaded lymph nodes despite previous neck dissection. All tumors were pT3N+. These events occurred in 2 out of 10 classical PTC and 1 out of 4 diffuse sclerosing tumor. At the last visit, the patient with lung metastases was the only patient with persisting disease.

Controls (M-sPTC)

Lung metastases were found at the first RAI in three young adult patients. We did not find any additional metastatic site during follow-up. Thirteen patients were operated for cervical LNM recurrence, 10 of whom previously underwent neck dissection with LNM removal at the first surgery. One of these patients had lung metastases. These recurrences were found in 6 out of 33 CPTC, 2 out of 24 FVPTC, 2 out of 3 SDPTC, 2 out of 5 solid, and 1 out of 1 tall cell tumor. These events occurred in 5 out of 22 children, 2 out of 21 adolescents, and 6 out of 37 young adults. At the last visit, eight patients had persistent disease that included lung metastases (n=2), recurrent LNM after secondary removal (n=3), and persistently elevated Tg without tumor localization (n=3).

There was no difference in the risk of cervical metastatic lymph node recurrence between cases and controls for all patients, OR=0.73 [CI 0.2–2.8], and for the three age groups. We found the same results for the group of patients with a high-risk tumor (pT3N+), OR=1 [CI 0.16–6.14] (Table 3), and those with a low-risk tumor (pT1+pT2), OR=0.66 [CI 0.05–8.16] data not shown.

Table 3.

Risk of Outcome Events During Follow-Up

	RAD (cases)	M-sPTC (controls)	Odds ratio [CI]
8–14 years of age
Number of patients	11	22
Metastasis(es) at first evaluation	0	0
Recurrence LNM	2	5	0.75 [0.12–4.7] ns
15–20 years of age
Number of patients	5	21
Metastasis(es) at first evaluation	0	0
Recurrence LNM	1	2	2.3 [0.17–33] ns
21–29 years of age
Number of patients	8	37
Metastasis(es) at first evaluation	1	3
Recurrence LNM	0	6	0.4 [0.02–8.9] ns
All patients
Number of patients	24	80
Metastasis(es) at first evaluation	1	3
Recurrence LNM	3	13	0.73 [0.19–2.83] ns
pT3N+
Number of patients	9	27
Metastasis(es) at first evaluation	1	3
Recurrence LNM	2	6	1 [0.16–6.14] ns

CI, 95% confidence interval.

Discussion

The aims of the present study were: (i) to determine the characteristics of RAD thyroid cancers by comparing their initial presentation to that of a population-based collection of consecutive sporadic cancers, and (ii) to determine the influence of radiation exposure on the evolution of TC through a case-control study. This study was conducted in a well-defined geographic area, the French Rhône-Alpes region, covered a recent time period (2002–2006), and had homogeneity in diagnostic and treatment procedures. Thyroid cancers occurring after external radiation exposure in childhood have been considered to be more aggressive than sporadic cancers, with greater extrathyroidal extension and multifocality (10,11). In the present study, we compared external RAD tumors and sPTC in patients of the same age groups. We found no differences between irradiated tumors and sPTC in children and adolescents. In these patients, the prevalence of LNM is comparable between the two groups, and it is in agreement with commonly reported data—50% and 30% LNM in children and adolescents, respectively. In contrast, the high prevalence of LNM (87%) and extrathyroidal invasion (65%) in young adults belonging to the irradiated group is unusual and clearly different from that observed in the sporadic group and also from the commonly reported values. This suggests that the adult patients did not benefit from prolonged systematic examination of the thyroid after radiation therapy. However, the number of patients in this irradiated group is low. Therefore, although significant, this result must be considered with caution. Another study did not find such aggressive features (18). The high prevalence of microcarcinomas among adolescent patients with previous irradiation suggests that these young patients are more carefully followed, probably by systematic repeated clinical and ultrasonographic examinations. This is also true for children, since there are more aggressive tumors in the sporadic group suggesting that the careful examination of irradiated children results in earlier cancer diagnosis.

The second aim of our study was to compare the clinical behavior of PTC in patients with previous external radiation exposure to that of patients without such a history. This study was performed using a strict matching for both age and pTNM, since PTC with an unfavorable tumor stage and PTC in children are more prone to recurrence. The small number of cases and the limited number of available control patients limits the power of the present study, due to the rare occurence of the disease in these age groups. The incidence rates for the age groups concerned in the present study in the Rhône-Alpes region have been previously reported (19). Treatment procedures were comparable between the two groups, except neck dissection, which was more frequent in the 15–20-year-old RAD group due to a more systematic surgical approach in this particular population. The key finding from our study is that there are no differences in the outcomes between patients with and without previous radiation exposure in the various age groups. Moreover, there is no greater risk of cervical LNM in the subgroup of patients with a high-risk tumor. The results of the present study, despite a limited number of cases, are in agreement with several studies based on various study protocols, including comparison with historical cohorts and case–control studies (11,13,20). A case-control study performed by Samaan et al. (11) and matched for the extent of disease showed that recurrence and mortality were similar. This was despite the fact that patients with previous irradiation presented more frequently with TC not limited to the thyroid and with bilateral involvement. Rubino et al. carried out a nested case–control study in a cohort of 91 cases and 273 controls matched for sex, age, and period of initial treatment of TC, and showed that the risks of recurrence and thyroid cancer–related death were similar (13). Several analyses of risk factors for recurrence show no difference between the external RAD thyroid cancers and the sPTC cancers (5,12,18,20). There were similar findings when a comparison was made between PTC that developed after internal exposure to radioiodine doses after Chernobyl and sPTCs (21). We limited the study to thyroid cancers diagnosed in individuals <30 years of age, despite the fact that cancers postradiotherapy may occur later on in a patient's life. Another limitation of the present study is the relatively short duration of the follow up. However, this mean six-year postoperative period is the window during which most events occur in young people. In 2002, Grigsby et al. reported a recurrence rate of 34% occurring at a mean first time of 5.3 years, in a series of 56 children and adolescents (22). In 2010, Hay et al. reported that, from a series of 215 children and adolescents, 78% initially had nodal metastases and recurrence occurred at a rate of 32% by 40 years of age, with recurrence rates of 20% at 5 years and 22% at 10 years post-treatment. The risk of recurrence was 1 in 5 at 5 years and 1 in 4 at 10 years (9). Thus, although the length of follow-up is not optimal, it is suitable for the age groups in this study.

Conclusion

Although the number of patients in the irradiated group was low, the prevalence of LNM and ET appears similar in irradiated PTC and sPTC, in children and adolescents. However, these markers of aggressiveness are significantly higher in irradiated young adults. There does not appear to be an increased risk of developing recurrent disease in any of the patient populations, including children, adolescents, and adults, with childhood exposure to external radiation.

Footnotes

Acknowledgments

The authors wish to thank the pathologists of the Rhône-Alpes region and the pediatricians and endocrinologists in charge of the patients. This work was supported by Electricité de France (Commission d'Epidémiologie du Conseil de Radioprotection) and the Région Rhône-Alpes.

Author Disclosure Statement

The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

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