Pediatric differentiated thyroid carcinoma
Klein Hesselink, Mariëlle
DOI:
10.33612/diss.145073752
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Klein Hesselink, M. (2020). Pediatric differentiated thyroid carcinoma: Diagnosis, outcome and late effects
of treatment. University of Groningen. https://doi.org/10.33612/diss.145073752
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
SEVEN
Summary, general discussion, and
future perspectives
7
Summary
Differentiated thyroid carcinoma (DTC), which develops from thyroid follicular cells, includes both papillary and follicular thyroid carcinomas (PTC and FTC). Although the incidence of pediatric DTC is increasing, it is an uncommon disease, affecting approximately 10 children (≤18 years) annually in the Netherlands, compared with more than 700 adults (1–5). Due to this low incidence, randomized prospective studies have not been performed in children (6). In most pediatric patients with DTC specific risk factors cannot be identified, although in a subset of patients radiation exposure has been recognized as predisposing to this disease (6). Pediatric DTC is sometimes associated with genetic syndromes, and has also been observed in children from families with familial non-medullary thyroid cancer (7).
Compared to adults, children often present at a more advanced tumor stage and show higher recurrence rates (8,9). Nevertheless, the prognosis of childhood-onset DTC is excellent, with 15-year survival rates higher than 95%, thus even more favorable than in adults (2,10).
The initial treatment for patients with pediatric DTC consists of (near) total thyroidectomy with or without additional lymph node dissection. In the majority of patients surgical treatment is followed by ablation therapy with radioactive iodine (131-I). During follow-up, TSH suppressive therapy has for years been applied to diminish the risk of recurrent disease (11,12). However, recent years have seen increasing discussion as to whether the benefits of 131-I administration and TSH suppressive therapy outweigh the risk of possible adverse effects. Therefore, at present, 131-I administration often depends on risk stratification, and the use of TSH suppressive therapy is tempered in pediatric patients who show no evidence of disease (13,14). However, recommendations are based mainly on findings in adult patients, as data on pediatric DTC patients regarding (long-term) effects of 131-I treatment, long-term TSH suppressive therapy, and quality of life are limited.
Studies on the genetic background of sporadic pediatric DTC have shown alterations that induce dysregulation of the mitogen-activated protein kinase (MAPK) signaling pathway (15,16). In pediatric patients with sporadic PTC, mainly gene fusions are encountered (16). Dysregulation of microRNAs (miRNAs), which are small (18-24 nucleotides), endogenous non-coding RNAs that post-transcriptionally regulate gene expression, is related to cancer development in different tumor types including thyroid cancer (17). Thus, miRNA analysis may be a useful method to confirm the diagnosis of thyroid carcinoma and to differentiate between DTC subtypes. However, the expression of miRNAs in pediatric DTC has yet to be assessed.
In this thesis we aimed to evaluate the outcome, surgical complications, and late effects of 131-I treatment and TSH suppressive therapy, as well as quality of life, in survivors of pediatric DTC treated in the Netherlands. In this patient group, we also aimed to evaluate the presence of somatic genetic alterations, and their relationship with clinical presentation and long-term outcome, as well as miRNA expression. Detailed insight into outcome and treatment-related damage is needed to improve evidence-based treatment
and follow-up strategies. Knowledge about the predictive value of the genetic alterations in thyroid tumors could support the choice of more patient-tailored treatment.
In chapter 1 we provided a general introduction and outlined the aims of this thesis. In chapter 2 we evaluated the presentation, surgical complications, and long-term outcome in patients with pediatric DTC. We also assessed the presence and type of second malignant neoplasms (SMNs) in these patients. A study in the United States reported complication rates of thyroid surgery to be higher in children than in adults (18). Outcomes were optimized when surgeries were performed by high-volume surgeons. Data on the development of SMNs after 131-I administration in children are scarce (19,20). In adults, although several studies reported an increase in SMNs after 131-I for thyroid cancer (21–23), others could not confirm these data (10,24). In a nationwide study we identified 170 patients with pediatric DTC treated in the Netherlands between 1970 and 2013. Overall survival was 99.4% after a median follow-up of 13.5 years (range 0.3-44.7 years); one patient with familial adenomatous polyposis and a PTC with lung metastases died at the age of 20 years due to complications of his colon carcinoma. Extensive follow-up data were available for 105 patients (83.3% females). The median age at diagnosis was 15.6 years (range 5.8-18.9 years). PTC was diagnosed in 81.0% of the patients and 19.0% had FTC. Upon initial diagnosis, 43.8% of the patients had metastases to the cervical lymph nodes and 13.3% had distant metastases, mainly to the lungs. All patients underwent total thyroidectomy and 97.1% were treated with 131-I, with a median cumulative activity of 5.66 GBq (range 0.74-35.15 GBq). The patients were treated in 39 different hospitals. Life-long postoperative complications (i.e. permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) occurred in almost one-third of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. These recurrences were not associated with TSH suppression. SMNs after pediatric DTC were found in three patients, two of whom developed breast cancer.
In chapter 3 we assessed the long-term effects of 131-I on salivary gland function (SGF) in survivors of pediatric DTC, and the prevalence of salivary gland dysfunction (SGD) in relation to patient and 131-I treatment characteristics in this group. We also evaluated xerostomia complaints in relation to salivary flow rates. In adults, it has been shown that 131-I treatment may reduce SGF (25). The uptake of 131-I through the sodium-iodine transporter (NIS) in the salivary gland striated ducts is most likely responsible for the adverse effects of 131-I on the salivary glands (26). As data regarding SGF after 131-I administration in pediatric patients with DTC are limited, we therefore assessed the SGF by sialometry, sialochemistry, and a xerostomia (subjective feeling of a dry mouth) inventory in long-term survivors of pediatric DTC. We included 65 survivors in the analyses. SGD, defined as an unstimulated whole saliva flow of <0.2 mL/min or a stimulated whole saliva flow <0.7 mL/min, was present in 47.6% of this group. A higher cumulative 131-I activity was associated with decreased stimulated salivary secretion. Furthermore, one in three survivors reported moderate to severe complaints of xerostomia, again related to higher cumulative administrations of 131-I.
7
TSH suppressive therapy leads to subclinical hyperthyroidism. Possible adverse effects of long-term subclinical hyperthyroidism on cardiac function are increasingly being recognized (27,28). In chapter 4 we studied the prevalence of cardiac dysfunction in long-term adult survivors of pediatric DTC in relation to treatment variables including TSH level during follow-up, the association between cardiac dysfunction and plasma biomarkers, and the prevalence of atrial fibrillation (AF) in this patient group. Cardiac assessments were performed in 66 survivors and included echocardiography, measurement of plasma biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive Troponin-T, galectin-3), and 24-hour Holter electrocardiography. Reference data for echocardiography were derived from the recommendations of the American Society of Echocardiography (29–31). Echocardiographic measurements were also compared with retrospective data of 66 unaffected sex- and age-matched Dutch controls. The median follow-up was 17 years. Regarding the left ventricular (LV) systolic function, LV ejection fraction <50% was found in one survivor, and median global longitudinal systolic strain was nearly normal. Diastolic dysfunction, according to a strict definition, was present in 14 asymptomatic survivors (21.2%) when compared with reference values from literature (29). Overall, diastolic function of survivors was lower than that of controls (e’mean 14.5 versus 15.8 cm/s, P = 0.006). A higher attained age and larger waist circumference were associated with decreased diastolic function, whereas TSH levels and cumulative administered radioiodine dose were not. In the survivors, biomarkers were not associated with diastolic dysfunction, and AF was not observed.
In chapter 5 we evaluated generic health-related quality of life (HRQoL), fatigue, anxiety, and depression in long-term survivors of pediatric DTC compared with age- and gender-matched controls, and assessed thyroid cancer-specific HRQoL in survivors. Sixty-seven survivors and 56 controls were evaluated using the Short Form 36 (SF-36), Multidimensional Fatigue Inventory 20 (MFI-20), and Hospital Anxiety and Depression Scale (HADS). Survivors also completed the thyroid cancer-specific HRQoL questionnaire (THYCA-QoL). Median follow-up was 17.8 years. We found overall normal HRQoL, fatigue, anxiety, and depression in the survivors compared to the matched controls. However, survivors reported more physical problems, role limitations due to physical problems, and mental fatigue. Thyroid cancer-specific complaints (mainly neuromuscular, throat/ mouth, psychosocial, and sensory problems) were reported by some survivors, but the majority reported few or no complaints. More extensive treatment characteristics and unemployment were most frequently associated with lower QoL.
In chapter 6 we analyzed thyroid tissues of 85 pediatric DTC patients to evaluate the presence of somatic BRAF mutations and RET/PTC rearrangements, and their relationship with clinical presentation and long-term outcome in pediatric patients with PTC. We also assessed the expression of miRNA-146b, -221 and -222 in pediatric patients with DTC. RET/PTC rearrangements and classical BRAFV600E mutations were present in,
respectively, 21.7% and 5.8% of the patients with histologically confirmed PTC. These gene alterations were associated neither with the initial tumor staging (TNM classification)
nor the clinical outcome. A significant association was found between increased expression of miRNA-146b, -221 and -222 and the diagnosis of PTC. Analysis of miRNA expression may therefore be helpful for establishing the diagnosis of PTC in pediatric patients.
General discussion and future perspectives
Despite the frequent presence of cervical lymph node and distant metastases, pediatric patients with DTC have an excellent long-term survival rate, generally because of well differentiated tumors and the availability of effective therapy (2). However, in a large single center study performed in the United States, the excellent survival in children was followed by a later death from a non-thyroid malignancy, found to be a cause of death in 68% of patients who died 30 to 50 years after initial diagnosis. Most of these cases had undergone antecedent irradiation (131-I or external beam therapy) (8). Our nationwide study (chapter 2) and a recent multicenter review from the United Kingdom (32) have confirmed the excellent survival in this patient group, but the median durations of follow-up were too short (13.5 and 14.1 years, respectively) to evaluate excess mortality later in life.
To safeguard the excellent long-term survival of pediatric DTC, it is vital to prevent early and late adverse events of treatment. However, long-term follow-up data of pediatric DTC patients, especially on treatment-related complications, are scarce. Over recent years, the occurrence of adverse events after cancer treatment have gained more attention. In this chapter, we will first discuss the surgical complications of treatment and late effects of 131-I administration and TSH suppressive therapy. We will then address recent developments in thyroid pathology. After that we will explore the knowledge gaps regarding pediatric DTC, and future directions for research possibilities. Finally, we will discuss ways to improve the organization of care for pediatric patients.
Surgical complications
Total thyroidectomy, recommended for the majority of pediatric patients with DTC, is associated with a higher complication risk than partial thyroidectomy, particularly when total thyroidectomy is combined with lymph node dissection (13,14,18,33). In our cohort, all patients underwent total thyroidectomy. Using strict definitions, we found transient and permanent hypoparathyroidism in 15.2% and 23.8% of the patients, respectively. This is relatively high when compared with other cohorts of children treated for DTC (7.4%-32.7% for transient and 0%-32% for permanent hypoparathyroidism, respectively) (20,34–37). In our cohort, the occurrence of recurrent laryngeal nerve injury was 12.4%, which is within the ranges of other pediatric cohorts (0%-40%) (35,38). As definitions of surgical complications in the literature are heterogeneous, the reported complication rates vary widely and are therefore problematic to compare. Moreover, patients in our cohort were surgically treated in 39 different hospitals. This scattered treatment may have contributed to our complication rates. Because of the low number of surgical treatments per hospital in our cohort we were unable to analyze differences in the occurrence of surgical complications between high- and low-volume centers. However, complications of
7
thyroid surgery in pediatric patients have shown to be reduced when surgery is performed by high-volume surgeons (18,39). We therefore regard centralization of care for pediatric patients to be crucial. This will be discussed below (see Organization of care).
Late effects of 131-I therapy
Ablation therapy with radioiodine has long been part of standard DTC treatment, and is effective because thyroid cells specifically take up (radio)iodine. Thereby, it is one of the oldest targeted therapies in oncology. However, in recent years the possible adverse effects of radioiodine administration have been increasingly acknowledged. In children, as compared to adults, the effects of 131-I may be amplified, as 131-I activity is distributed over a smaller body and accumulates in cells that have increased potential to proliferate. In this section we will focus on effects of 131-I administration on the salivary glands, bone marrow, fertility, and development of second malignant neoplasms.
Salivary gland dysfunction
Saliva is vital for maintaining oral health (40). The striated ducts of the salivary gland express NIS, and are therefore able to concentrate iodine selectively (26). This mechanism is most likely responsible for the SGD and the xerostomia complaints described in this thesis, which we found in respectively almost half and one-third of the long-term survivors of pediatric DTC. Both SGD and xerostomia were related to a higher cumulative administration of 131-I. These effects may be interpreted as permanent damage to the salivary glands, as they were observed in survivors after a median follow-up of 11 years. Regarding the salivary composition, in survivors of pediatric DTC the levels of total protein and amylase were reduced, as compared to reference values from non-affected individuals. This indicates that SGF remains impaired many years after treatment. We postulate that the
β
-radiation, emitted due to the accumulation of 131-I in the salivary glands, directly affects the salivary gland stem cells, resulting in a reduced regenerative potential (41).In the literature, only one other study, by Albano et al., evaluated SGD after 131-I administration in pediatric patients with DTC (42). Albano’s study reports SGD in 1.9% of the survivors, versus 47.6% in our study. This difference could be explained by the methods used, as Albano et al. used qualitative data from retrospectively assessed medical records and did not specify their definition of SGD (42).
At the time that pediatric patients in our study were treated, fixed 131-I activities were standard and generally similar to those used in adult patients. Thus the survivors of pediatric DTC in our study received relatively higher activities of 131-I per kilogram of body weight compared to adults. They were, moreover, treated during a period of growth and development. The long-term SGD found in our study, related to cumulative 131-I administration, emphasizes the need for more patient tailored 131-I dosage for children.
Recommendations to prevent salivary gland damage after 131-I treatment include generous intake of fluids, use of gustatory sialogogues (e.g. lemon juice, candy), and gland massage (28,43). However, whether sialogogues should be used immediately after
131-I administration remains controversial (28). Patients who used sialogogues soon after 131-I therapy were found to have a decreased radioiodine absorption in the parotid glands (44,45). Conversely, others proposed that early initiation of sialogogues increases salivary gland blood flow, and thereby 131-I exposure (46,47). Up till now, the treatment of sialadenitis after 131-I administration in most cases still involves the intake of high volumes of fluid and administration of sialogogues. Anti-inflammatory drugs are also proposed, as well as sialendoscopy (43,48). Furthermore, withdrawal of thyroid hormone, which is part of the preparation for 131-I treatment, causes a transient decrease of renal function, and thereby a slower renal clearance of 131-I. The use, instead, of recombinant human thyroid-stimulating hormone (rhTSH), prevents the impairment of renal function, which may theoretically reduce salivary gland toxicity (28). However, for adult patients, rhTSH is applied particularly in ablative therapy, and not used in consecutive 131-I treatment. Furthermore, because it is not a standard treatment for children, it is not an alternative in the prevention of salivary damage.
Our findings emphasize the need for surveillance of possible salivary gland dysfunction during follow-up in pediatric patients with DTC. In case of xerostomia-related complaints, referral to a dentist or an oral medicine specialist should be considered at an early stage, to prevent caries and maintain quality of life. In general, the importance of good oral hygiene should be discussed before start of therapy. We therefore propose to include recommendations for oral care, including regular dental hygienist visits, as part of the standard treatment and follow-up of pediatric patients with DTC. Importantly, the 131-I activity to be administered should be weighed very carefully to prevent salivary gland damage.
Bone marrow suppression
Another effect reported after 131-I therapy is transient bone marrow suppression (49). This is manifested by a transient reduction in leukocyte and/or, more frequently, platelet count three to five weeks after 131-I administration. In a population of adult patients with DTC, the cumulative 131-I dose was independently associated with thrombocytopenia (50). Post-treatment platelets and leukocytes, which were transiently decreased compared to pre-treatment values, normalized to baseline levels 5 years after treatment. This suggests that in most adult patients the clinical effects of bone marrow toxicity are limited. As part of our nationwide study, we evaluated blood counts in long-term survivors of pediatric DTC. Leukocytes and platelet levels were within the reference ranges (data not shown). These findings are in line with the findings in adults (50). However, patients with multiple bone metastases treated with high cumulative 131-I dosages may develop severe bone marrow toxicity, which might lead to myelodysplasia or aplastic anemia (51). Leukemia has been described in adult patients with multiple bone metastases who received more than 18.5 GBq (500 mCi) 131-I (52). One case report described chronic myeloid leukemia in a child, following treatment of thyroid cancer (20).
7
Fertility
Whether 131-I administration has adverse effects on fertility remains a subject of debate. Up to one year after treatment a higher incidence of miscarriages and transient amenorrhea or irregular menses have been shown in adult patients with DTC (53-55). Also, a transient decrease has been reported in the levels of Anti-Müllerian Hormone (AMH, a marker for ovarian reserve) (56,57). Long-term effects of 131-I on ovarian function seem to be limited to a slightly earlier onset of menopause in adult DTC survivors (55,58). In our cohort of long-term female survivors of pediatric DTC, we found no abnormalities in fertility based on evaluation of fertility outcomes, parameters of reproductive health, indications of impaired fertility, and AMH (59). Previous studies in survivors of pediatric DTC were limited by lack of definitions and a small number of patients (42,60). Fertility is represented by reproductive characteristics (number of pregnancies, pregnancy outcomes, health of offspring), gonadal function and serum AMH level. The latter is commonly used as a marker for ovarian reserve in studies with cancer survivors, as the AMH level is not influenced by the menstrual cycle (61,62). However, consensus on the clinical value of AMH is lacking (63).
Although overt hyperthyroidism can lead to disturbances in the menstrual cycle (64), the effects of the subclinical hyperthyroidism resulting from TSH suppressive therapy are less well established (65,66). Therefore, subclinical hyperthyroidism may only have limited effects on fertility in female survivors of pediatric DTC.
In males, the germinal epithelium, and particularly the spermatogonia within it, are very sensitive to the effects of radiation (67,68). Transient elevation of serum follicle-stimulating hormone (FSH) and reduction in sperm motility have been reported following 131-I therapy (69,70). One study reported that 33% of males treated during adulthood had oligospermia after high cumulative 131-I activities (71). These data have resulted in recommendations to preserve semen of post-pubertal males who are expected to receive 14.8 GBq (400 mCi) 131-I (13). A more recent study in adult DTC patients showed a significant increase in FSH and a decrease in inhibin B levels 3 months after administration of a single 131-I activity of 3.7 Gbq (100 mCi) compared with pre-treatment values. Also, sperm concentrations and the percentage of morphologically normal spermatozoa were transiently decreased 3 months after 131-administration. The authors propose sperm preservation for DTC patients requiring 131-I activities higher than 3.7 Gbq, a recommendation more cautious than the current guidelines on pediatric DTC (13,72). As the incidence of pediatric DTC in boys is very low, international collaboration is needed to study the effects of 131-I administration on fertility in male survivors of pediatric DTC.
Second malignant neoplasms
In the cohort described in this thesis, three female patients developed a second malignant neoplasm (SMN) during follow-up of pediatric DTC (supplemental data of chapter 2). Two had received 131-I before development of the SMN, which in both cases was breast cancer. The respective cumulative 131-I activities administered to these patients were 8.33 GBq
(225 mCi) and 35.15 GBq (950 mCi). During follow-up, the patient who received 35.15 GBq developed two recurrences, for which she was treated with 131-I. Although, especially in the latter patient, the cumulative administered 131-I activities were relatively high, patient numbers are too low to draw conclusions regarding causality. In the literature, several studies reported an increase of SMNs in adult patients treated with 131-I for thyroid cancer (21,22). An increased risk for second malignancies was found after administration of higher cumulative dosages (21). However, others did not confirm these data (10,24). Verkooijen et al. described an overall increased standardized incidence rate for SMNs in DTC patients, either preceding or following thyroid cancer diagnosis, but not specifically for SMNs following 131-I administration (73). This finding suggests that these patients may have had a genetic predisposition for the development of malignancies. The cases described in this thesis add to the sparse data on SMNs in survivors of pediatric DTC (19,20,42).
Late effects of TSH suppressive therapy
During follow-up, TSH suppressive therapy has for years been advocated to diminish the risk of recurrent disease (11). However, as TSH suppression induces an iatrogenic (subclinical) hyperthyroid state, it may cause adverse effects. In particular it may affect the skeletal and cardiovascular systems (74,75). In 524 adult patients with DTC, a 3.3-fold increased risk of cardiovascular mortality was found. Each 10-fold decrease in geometric mean TSH level was associated (independently) with a 3.1-fold greater risk of cardiovascular mortality (27).
Bone mineral density and growth
Normal euthyroid status is essential for skeletal development, growth and maintenance of adult bone mass and strength (76,77). Thyroid hormone receptor
α
(TRα
) is the main thyroid hormone receptor expressed in bone. It mediates the action of triiodothyronine (T3) on bone and cartilage (78). During childhood, thyroid hormones stimulate bone growth and mineralization. Although rare in children, thyrotoxicosis accelerates skeletal development and bone mineral deposition, which may result in premature fusion of the growth plates, thereby leading to reduced height (77). Conversely in adults T3 stimulates bone loss (78). TSH has also been proposed to be involved in bone turnover by binding directly to TSH receptors on osteoblasts and osteoclasts. However, to date, the underlying mechanisms by which TSH may affect the skeleton are not completely understood (78).In adult pre-menopausal women and in men, two systematic literature reviews showed little or no effect of TSH suppressive therapy with levothyroxine on BMD (79,80). In post-menopausal women on TSH suppressive therapy, data are conflicting, but this group may in general be at risk of bone loss and osteoporosis (77).
Few studies have been performed on the late effects of TSH suppressive therapy during childhood on bone mineral density (BMD) and target height. Although two cross-sectional studies in survivors of pediatric DTC showed no effects on BMD (81,82), cross-sectional designs do not allow exploration of changes in BMD over time. Moreover, other factors like gender and age may influence BMD (83). It is worth noting that, as described in this
7
thesis (chapter 2), a significant number of pediatric patients with DTC experience surgical complications including hypoparathyroidism, which may lead to an increased BMD, but also may result in atypical bone structure and bone turnover (84). Recognizing that evaluation of possible intra-individual BMD changes in pediatric DTC survivors would be of great value, we have therefore collected these data as part of this study. The first BMD measurements were performed between 2012 and 2014, and the second measurements are currently under evaluation.
Cardiovascular morbidity
In our cohort, we found diastolic dysfunction in 21.2% of survivors of pediatric DTC when compared with reference values from literature (29). Survivors with diastolic dysfunction had a median age of 37.9 years. As diastolic function declines with age, our findings may indicate early cardiac aging in asymptomatic survivors. This finding is of interest, as diastolic dysfunction may be the first manifestation of more overt heart failure (85). Longitudinal measurements are needed to explore the course of the diastolic function, and the potential clinical consequences of diastolic dysfunction, found at an early age in a subset of the survivors of pediatric DTC. In our cohort of survivors of pediatric DTC, a higher attained age and larger waist circumference were associated with decreased diastolic function; these are established risk factors for diastolic dysfunction (85). However, in our cohort, TSH levels and cumulative administered radioiodine dose were not associated with a decrease in diastolic function. Yet an association between TSH suppression and diastolic dysfunction has previously been reported in adult survivors of DTC (86). These different findings may be explained by the younger age of the survivors in our cohort. Furthermore, in the two studies the definitions and statistical approach to measuring TSH during follow-up are not fully comparable.
According to traditional risk classifications like the Systematic Coronary Risk Evaluation (SCORE), younger persons, i.e. the majority of survivors of pediatric DTC in our cohort, would be classified as having a low (absolute) risk of developing coronary heart disease and stroke death (87). Among adult thyroid cancer survivors, however, it has been reported that 9.7%, 6.9% and 19.1% developed cardiovascular disease after respectively <10 years, 10-20 years, and >20 years of follow-up (patient self-reported data) (88). Early treatment of cardiovascular damage might be more beneficial than preventive interventions in the few years preceding a cardiovascular event (89,90). Therefore, while awaiting the results of follow-up studies, the assessment and treatment of cardiovascular risk factors may be considered in survivors of pediatric DTC.
The use of TSH suppressive therapy is currently tempered in both adult and pediatric patients who have long term disease free survival (13,14,91,92). In the majority of adult patients with DTC, more profound TSH suppression has been shown to provide little or no benefit (93). Moreover, improvement of techniques for detection and treatment of residual or recurrent disease might diminish the need for aggressive TSH suppression. However, as long as data regarding the effect of tempered TSH suppression on long-term
oncological outcomes are limited in adults - and altogether lacking in pediatric patients - close monitoring of the latter patients remains necessary.
Quality of life
Although diagnosis and treatment of pediatric DTC constitute a major life event, we found overall normal HRQoL, fatigue, anxiety, and depression scores in long-term survivors of pediatric DTC, compared to matched controls. Survivors of pediatric DTC more frequently showed physical problems, role limitations due to physical problems, and mental fatigue, but survivors’ overall scores on these domains were still within the normal range. Furthermore, although some survivors reported thyroid cancer-specific complaints, the majority had few or no complaints. These results correspond with the normal QoL described in survivors of adolescent DTC (94,95), and with the finding of similar achievement of psychosocial developmental milestones (social, autonomy, and psychosexual domains) in long-term survivors of pediatric DTC compared with controls (96). As for impaired physical functioning of survivors compared to controls, this has also been described in survivors of other childhood cancers, as well as in survivors of adult DTC (97-99). Although mental fatigue in survivors of (adult) DTC has been proposed to be related to suboptimal TSH levels (100), we did not find a relation between TSH and fatigue. Furthermore, other groups also reported impaired HRQoL to be independent of TSH level (94,101).
Although we reported an overall normal QoL in survivors of pediatric DTC, the QoL scores varied more among survivors compared to controls; the survivors relatively more often reported lower QoL. In our study, lower QoL was associated with unemployment and more extensive treatment characteristics. These data underscore the need for an individual approach of these patients and the importance of identifying vulnerable patients at an early stage so as to provide adequate psychological care. For this purpose, assessment of QoL should be implemented during follow-up, as is also advised by the Dutch Childhood Oncology Group (DCOG) (102). For the study described in this thesis, we selected both widely used questionnaires (Short Form 36, Multidimensional Fatigue Inventory 20 and Hospital Anxiety and Depression Scale) and a thyroid cancer specific questionnaire (THYCA-QoL). These questionnaires were chosen with the aim of comparing our data with the available literature, as well as for gathering information on disease specific problems. The DCOG advises using the General Health Questionnaire 28 (GHQ-28, in our study used for screening) and the Short Fatigue Questionnaire (in Dutch: Verkorte Vermoeidheidsvragenlijst) for all adult childhood cancer survivors (102). For survivors of pediatric DTC, we suggest adding a disease specific questionnaire to identify thyroid cancer-specific problems, like voice problems. Physicians are often known to underestimate the incidence of thyroid cancer-specific complaints in DTC survivors (103). Thus, the implementation of QoL questionnaires in care paths may help to detect complaints and improve quality of care for pediatric DTC survivors.
7
Pathology
We reassessed the histology of all formalin-fixed paraffin-embedded (FFPE) tissues of the pediatric DTC patients included in chapter 6, i.e. all patients who gave informed consent for reassessment of their tissue and of whose FFPE material was available for this study. It is remarkable that the reassessed histopathological diagnosis was less frequently an FTC compared to the initial diagnosis (2.4% vs. 17.6%). Also, during reassessment, in two patients (2.4%) we found only an adenoma, and in 6 patients (7.1%) the diagnosis was ambiguous. These differences may be explained by the fact that only a selection of FFPE blocks were available for reassessment. Although representative material was requested and, where possible, the same blocks in which the tumor was described in the original pathology report were used for reassessment, the lesions on the FFPE blocks available to us may not necessarily have been the same as those reported by the pathologists who made the initial diagnosis. Another explanation may be that, as pediatric DTC occurs infrequently, pathologists having extensive experience with this disease are more familiar with the interpretation and classification of DTC histology. Finally, during reassessment poorly differentiated thyroid carcinoma (PDTC) was diagnosed in 6 patients (7.1%), three of whom were initially diagnosed with a (micro) PTC and three with an FTC. PDTC was for the first time included in the 2004 edition of the WHO classification of thyroid tumors (104). This may explain the absence of initial diagnoses of PDTC in our cohort, although two patients found to have a PDTC during reassessment were diagnosed after 2004. As studies in pediatric patients with thyroid cancer are limited and PDTC is still a relatively new diagnosis, data on the incidence of PDTC during childhood are scarce.
Between children and adults the biological behavior of DTC differs considerably. This may be explained by differences in genetic alterations. We observed somatic RET/
PTC rearrangements and BRAFV600E mutations in only 23.5% of the patients in our cohort,
suggesting that many other alterations are involved. This has recently been confirmed and updated by Cordioli et al., who studied the prevalence of RET/PTC1, RET/PTC2, RET/
PTC3, BRAFV600E, ETV6-NTRK3, AGK-BRAF, and NRASQ61 in primary thyroid tumors of 35
pediatric PTC patients (16). Mutations were detected in 20 out of 35 PTC cases (57%): RET/ PTC rearrangements in 13 (37%), BRAFV600E mutations in 3 (9%), ETV6-NTRK3 in 3 (9%), and
AGK-BRAF in 4 (11%). In another series these researchers showed that AGK-BRAF fusions were associated with distant metastases and younger age, and the BRAFV600E mutation
was associated with a larger tumor size and older age (105). In 43% of the 35 patients described by Cordioli et al. no genetic event was identified, which suggests that other (epi)genetic factors may be associated with the pathogenesis and biological behavior of these tumors (16). These factors still need to be unraveled.
We have shown increased expression of miRNA-146b, -221 and -222 to be significantly associated with PTC diagnosis; this may be helpful for establishing the diagnosis of PTC in pediatric DTC cases. Moreover, Liang et al. confirmed in their meta-analysis that miRNA-221/222 may significantly improve accuracy in the diagnosis of thyroid cancer (106).
The assessment of miRNA may also be of value for understanding the clinical behavior of thyroid tumors as has been illustrated by Li et al., who showed a high expression of miRNA-146b-5p in thyroid cancer tissue of patients with histological features of Hashimoto thyroiditis. The level of expression of miRNA-146b-5p was associated with TNM stage (107).
A diagnosis of thyroid cancer during childhood raises the question of hereditability. In pediatric DTC patients an increased risk of second primary tumors is present (7). Although these second malignancies are easily ascribed to 131-I radiation, a genetic background can also play a role in the development of the tumors.
Familial DTC, or familial non-medullary thyroid cancer (FNMTC), can be a part of a tumor predisposition syndrome (about 5% of cases). Nowadays several well distinguished syndromes are known: PTEN Hamartoma tumor syndrome/Cowden syndrome (PTEN gene, 10q23.31), familial adenomatous polyposis (APC gene, 5q22.2), Werner syndrome (WRN gene, 8p12), Carney complex (PRKAR1A gene, 17q24.2), Pendred syndrome (SLC26A4 gene, 7q21-34) and DICER1 syndrome (DICER1 gene, 14q32.13). However, in the majority of FNMTC, thyroid cancer is the only manifestation within families and the genetic susceptibility is less well-defined (7). When defining FNMTC as the occurrence of the disease in two or more relatives of the index patient, about 3-9% of the DTC cases may have a familial origin (7). From a different perspective, based on data from the US, 31-38% of family members who have two first-degree relatives with thyroid cancer, are likely to carry the familial trait, with the rest being sporadic cases. However, when defining FNMTC as the occurrence of thyroid cancer in three or more family members, 96% of the members of the family are likely to carry the familial trait for FNMTC (7,108). Other arguments can also be provided to support a genetic background of DTC, such as a high proportion of multifocality and the presence of occult tumors (109). Data collection of KIKA project 265 ‘The Genetic Background of Non-Medullary Paediatric Thyroid Carcinoma’ has recently been completed in the Netherlands. The data are currently analyzed and will provide information on the frequency of germline mutations in children with pediatric DTC, and on the yield of standard genetic screening in this patient group.
As described in chapter 6, the genetic analyses in our cohort were performed between 2013 and 2015, using the established methods of that time. As techniques have evolved over the last few years and the data of this project will be used for additional analyses in the above mentioned KIKA project 265, the genetic analyses will be repeated using state-of-the-art methods.
Organization of care
In 2015, the American Thyroid Association (ATA) published the first guidelines for children with DTC (13), followed by Polish guidelines (110). Although these guidelines emphasize collaboration and uniformity of diagnostic work-up and treatment for pediatric DTC, recent data have illustrated that treatment appears to be different and scattered in European countries and that the centralization of care is limited (111), which may have direct
7
consequences on the outcome. Although data are scarce, Youngwirth et al. showed that pediatric DTC patients in the US who were treated in low volume facilities were more often treated in a way inconsistent with the national guidelines, and more likely to be readmitted to the hospital in the first month after surgery, in comparison to patients treated in high-volume facilities (112).
This has also been the standard of care in the Netherlands as, until recently, pediatric DTC patients were treated by pediatric endocrinologists, adult endocrinologists or pediatric oncologists in a large number of centers. This resulted in a lack in uniformity of treatment and lack of registration of treatment and outcome. The current project has been the beginning of a national cooperation, and nowadays, the treatment of pediatric thyroid cancer is centralized in the Dutch University Medical Centers and coordinated by the Princess Máxima Medical Center (Dr. H.M. van Santen, pediatric endocrinologist). The Dutch Childhood Thyroid Carcinoma Working Group formulated recommendations for the organization of care for children with cancer predisposition syndromes, thyroid nodules and (suspected) thyroid cancer. More recently, this group has finalized the evidence-based Dutch pediatric guideline for the treatment of thyroid cancer (92). A national multidisciplinary workgroup has a web-based meeting every three months to discuss the diagnosis and treatment of pediatric thyroid cancer patients. Also, in 2019, an international cooperation on pediatric thyroid cancer was started within the European Reference Network (ENDO ERN). These initiatives are expected to improve care and outcomes for pediatric DTC patients. Prospective data registration on specific parameters and biobanking of tissue will ultimately further improve knowledge and care for these patients. The treatment of pediatric DTC has moved into a less aggressive, more patient-tailored approach; there is a big difference in the therapy for a patient diagnosed at the age of 17 or 19 years. In the coming time, the patients aged between 18 and 30 years may be considered as a specific entity, and become the focus of prospective studies.
Conclusions
In this thesis, we have confirmed the favorable prognosis of patients with pediatric DTC in terms of survival. However, we have also described frequent occurrences of post-operative complications and late effects of treatment. The challenge remains to maintain the low mortality and reduce treatment-related morbidity. For this, a personalized approach is crucial. In our opinion, intelligent organization of care, with harmonization of diagnostic approach, treatment and follow-up, and centralization of care where needed, is vital to achieve this. The recent presentation of the new national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands marks an important step in this direction (92).
References
1. Netherlands Comprehensive Cancer Organisation (IKNL), Netherlands Cancer Registry, 2019.
2. Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J
Surg Res 2009;156:167-172.
3. Siegel DA, King J, Tai E, Buchanan N, Ajani UA, Li J. Cancer incidence rates and trends among children and adolescents in the United States, 2001-2009.
Pediatrics 2014;134:e945-955.
4. Vergamini LB, Frazier AL, Abrantes FL, Ribeiro KB, Rodriguez-Galindo C. Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults: a population-based study. J
Pediatr 2014;164:1481-1485.
5. Pole JD, Zuk AM, Wasserman JD. Diagnostic and treatment patterns among children, adolescents, and young adults with thyroid cancer in Ontario: 1992–2010.
Thyroid 2017;27:1025-1033.
6. Rivkees SA, Mazzaferri EL, Verburg FA, et al. The treatment of differentiated thyroid cancer in children: emphasis on surgical approach and radioactive iodine therapy.
Endocr Rev 2011;32:798-826.
7. Peiling Yang S, Ngeow J. Familial non-medullary thyroid cancer: unraveling the genetic maze. Endocr Relat
Cancer 2016;23:R577-R595.
8. Hay ID, Gonzalez-Losada T, Reinalda MS, Honetschlager JA, Richards ML, Thompson GB. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008.
World J Surg 2010;34:1192-1202.
9. Jarzab B, Handkiewicz-Junak D, Wloch J. Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocr Relat
Cancer 2005;12:773-803.
10. Links TP, van Tol KM, Jager PL, et al. Life expectancy in differentiated thyroid cancer: a novel approach to survival analysis.
Endocr Relat Cancer 2005;12:273-280.
11. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, Jaffiol C. Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin
Endocrinol Metab 1996;81:4318-4323.
12. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J
Endocrinol 2006;154:787-803.
13. Francis GL, Waguespack SG, Bauer AJ, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid 2015;25:716-759. 14. Perros P, Boelaert K, Colley S, et al. Guidelines
for the management of thyroid cancer. Clin
Endocrinol (Oxf) 2014;81(Suppl 1):1-122.
15. Vu-Phan D, Koenig RJ. Genetics and epigenetics of sporadic thyroid cancer. Mol
Cell Endocrinol 2014;386:55-66.
16. Cordioli MI, Moraes L, Bastos AU, et al. Fusion oncogenes are the main genetic events found in sporadic papillary thyroid carcinomas from children. Thyroid 2017;27:182-188.
17. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev
Genet 2009;10:704-714.
18. Sosa JA, Tuggle CT, Wang TS, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin
Endocrinol Metab 2008;93:3058-3065.
19. Dottorini ME, Vignati A, Mazzucchelli L, Lomuscio G, Colombo L. Differentiated thyroid carcinoma in children and adolescents: a 37-year experience in 85 patients. J Nucl Med 1997;38:669-675. 20. van Santen HM, Aronson DC, Vulsma T, et
al. Frequent adverse events after treatment for childhood-onset differentiated thyroid carcinoma: a single institute experience.
Eur J Cancer 2004;40:1743-1751.
21. Rubino C, de Vathaire F, Dottorini ME, et al. Second primary malignancies in thyroid cancer patients. Br J Cancer 2003:89:1638-1644. 22. Brown AP, Chen J, Hitchcock YJ, Szabo A,
7
primary malignancies up to three decades afterthe treatment of differentiated thyroid cancer. J
Clin Endocrinol Metab 2008:93:504-515.
23. Silva-Vieira M, Carrilho Vaz S, Esteves S, et al. Second primary cancer in patients with differentiated thyroid cancer: does radioiodine play a role?
Thyroid 2017;27:1068-1076.
24. Berthe E, Henry-Amar M, Michels JJ, et al. Risk of second primary cancer following differentiated thyroid cancer. Eur J Nucl
Med Mol Imaging 2004;31:685-691.
25. Klein Hesselink EN, Brouwers AH, de Jong JR, et al. Effects of radioiodine treatment on salivary gland function in patients with differentiated thyroid carcinoma: a prospective study. J Nucl
Med 2016;57:1685-1691.
26. La Perle KM, Kim DC, Hall NC, et al. Modulation of sodium/iodide symporter expression in the salivary gland.
Thyroid 2013;23:1029-1036.
27. Klein Hesselink EN, Klein Hesselink MS, de Bock GH, et al. Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: an observational study.
J Clin Oncol 2013;31:4046-4053.
28. Klein Hesselink EN, Links TP. Radioiodine treatment and thyroid hormone suppression therapy for differentiated thyroid carcinoma: adverse effects support the trend toward less aggressive treatment for low-risk patients. Eur Thyroid J 2015;4:82-92.
29. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc
Echocardiogr 2009;22:107-133.
30. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J
Am Soc Echocardiogr 2015;28:1-39.
31. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from
the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J
Cardiovasc Imaging 2016;17:1321-1360.
32. Lee KA, Sharabiani MT, Tumino D, et al. Differentiated thyroid cancer in children: a UK multicentre review and review of the literature. Clin Oncol (R Coll
Radiol) 2019;31:385-390.
33. Scholz S, Smith JR, Chaignaud B, Shamberger RC, Huang SA. Thyroid surgery at Children’s Hospital Boston: a 35-year single-institution experience. J
Pediatr Surg 2011;46:437-442.
34. Haveman JW, van Tol KM, Rouwé CW, Piers DA, Plukker JT. Surgical experience in children with differentiated thyroid carcinoma. Ann Surg Oncol 2003;10:15-20. 35. Thompson GB, Hay ID. Current strategies
for surgical management and adjuvant treatment of childhood papillary thyroid carcinoma. World J Surg 2004;28:1187-1198. 36. O’Gorman CS, Hamilton J, Rachmiel M,
Gupta A, Ngan BY, Daneman D. Thyroid cancer in childhood: a retrospective review of childhood course. Thyroid 2010;20:375-380. 37. Kundel A, Thompson GB, Richards ML, et
al. Pediatric endocrine surgery: a 20-year experience at the Mayo Clinic. J Clin
Endocrinol Metab 2014;99:399-406.
38. Enomoto Y, Enomoto K, Uchino S, Shibuya H, Watanabe S, Noguchi S. Clinical features, treatment, and long-term outcome of papillary thyroid cancer in children and adolescents without radiation exposure.
World J Surg 2012;36:1241-1246.
39. Drews JD, Cooper JN, Onwuka EA, Minneci PC, Aldrink JH. The relationships of surgeon volume and specialty with outcomes following pediatric thyroidectomy. J Pediatr
Surg 2019;54:1226-1232.
40. Walter MA, Turtschi CP, Schindler C, Minnig P, Müller-Brand J, Müller B. The dental safety profile of high-dose radioiodine therapy for thyroid cancer: long-term results of a longitudinal cohort study. J
Nucl Med 2007;48:1620-1625.
41. van Luijk P, Pringle S, Deasy JO, et al. Sparing the region of the salivary gland containing
stem cells preserves saliva production after radiotherapy for head and neck cancer. Sci
Transl Med 2015;7:305ra147.
42. Albano D, Bertagna F, Panarotto MB, Giubbini R. Early and late adverse effects of radioiodine for pediatric differentiated thyroid cancer.
Pediatr Blood Cancer 2017;64:e26595.
43. van Nostrand D. Sialoadenitis secondary to
131I therapy for well-differentiated thyroid
cancer. Oral Dis 2011;17:154-161. 44. Van Nostrand D, Atkins F, Bandaru VV, et al.
Salivary gland protection with sialagogues: a cases study. Thyroid 2009;19:1005-1008. 45. Kulkarni K, Van Nostrand D, Atkins F, Mete
M, Wexler J, Wartofsky L. Does lemon juice increase radioiodine reaccumulation within the parotid glands more than if lemon juice is not administered? Nucl Med
Common 2014;35:210-216.
46. Nakada K, Ishibashi T, Takei T, et al. Does lemon candy decrease salivary gland damage after radioiodine therapy for thyroid cancer? J Nucl Med 2005;46:261-266. 47. Jentzen W, Balschuweit D, Schmitz J, et al.
The influence of saliva flow stimulation on the absorbed radiation dose to the salivary glands during radioiodine therapy of thyroid cancer using 124I PET(/CT) imaging. Eur J Nucl Med Mol Imaging 2010;37:2298-2306.
48. de Luca R, Vicidomini A, Trodella M, Tartaro G, Colella G. Sialoendoscopy: a viable treatment for I131 induced sialoadenitis. Br J Oral Maxillofac Surg 2014;52:641-646.
49. Jarzab B, Handkiewicz-Junak D, Wloch J. Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocr Relat
Cancer 2005;12:773-803.
50. Prinsen HT, Klein Hesselink EN, Brouwers AH, et al. Bone marrow function after (131) I therapy in patients with differentiated thyroid carcinoma. J Clin Endocrinol
Metab 2015;100:3911-3917.
51. Hyer SL, Newbold K, Harmer CL. Early and late toxicity of radioiodine therapy: detection and management. Endocr
Pract 2010;16:1064-1070.
52. Maxon HR, Smith HS. Radioiodine-131 in the diagnosis and treatment of
metastatic well differentiated thyroid cancer. Endocrinol Metab Clin North
Am 1990;19:685-718.
53. Garsi JP, Schlumberger M, Rubino C, et al. Therapeutic administration of
131I for differentiated thyroid cancer:
radiation dose to ovaries and outcome of pregnancies. J Nucl Med 2008;49:845-852. 54. Schlumberger M, De Vathaire F, Ceccarelli
C, et al. Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. J Nucl Med 1996;37:606-612. 55. Sioka C, Fotopoulos A. Effects of I-131
therapy on gonads and pregnancy outcome in patients with thyroid cancer. Fertil
Steril 2011;95:1552-1559.
56. Evranos B, Faki S, Polat SB, Bestepe N, Ersoy R, Cakir B. Effects of radioactive iodine therapy on ovarian reserve: a prospective pilot study. Thyroid 2018;28:1702-1707. 57. Yaish I, Azem F, Gutfeld O, et al. A single
radioactive iodine treatment has a deleterious effect on ovarian reserve in women with thyroid cancer: results of a prospective pilot study. Thyroid 2018;28:522-527.
58. Sawka AM, Lakra DC, Lea J, et al. A systematic review examining the effects of therapeutic radioactive iodine on ovarian function and future pregnancy in female thyroid cancer survivors. Clin Endocrinol
(Oxf) 2008;69:479-490.
59. Nies M, Cantineau AE, Arts EG, et al. Long-term effects of radioiodine treatment on female fertility in survivors of childhood differentiated thyroid carcinoma. Thyroid 2020 [Epub ahead of print].
60. Sarkar SD, Beierwaltes WH, Gill SP, Cowley BJ. Subsequent fertility and birth histories of children and adolescents treated with 131I for thyroid cancer. J Nucl Med 1976;17:460-464.
61. La Marca A, Stabile G, Artenisio AC, Volpe A. Serum anti-Mullerian hormone throughout the human menstrual cycle.
Hum Reprod 2006;21:3103-3107.
62. Lambert-Messerlian G, Plante B, Eklund EE, Raker C, Moore RG. Levels of antimüllerian
7
hormone in serum during the normal menstrualcycle. Fertil Steril 2016;105:208-213.e1. 63. Gnoth C, Godehardt E, Frank-Herrmann
P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility.
Hum Reprod 2005;20:1144-1147.
64. Krassas GE. Thyroid disease and female reproduction. Fertil Steril 2000;74:1063-1070. 65. Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes.
Obstet Gynecol 2006;107:337-341.
66. Cho MK. Thyroid dysfunction and subfertility.
Clin Exp Reprod Med 2015;42:131-135.
67. Mazzaferri EL. Gonadal damage from 131I
therapy for thyroid cancer. Clin Endocrinol
(Oxf) 2002;57:313-314.
68. Hyer S, Vini L, O’Connell M, Pratt B, Harmer C. Testicular dose and fertility in men following I(131) therapy for thyroid cancer.
Clin Endocrinol (Oxf) 2002;56:755-758.
69. Pacini F, Gasperi M, Fugazzola L, et al. Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine. J Nucl Med 1994;35:1418-1422. 70. Wichers M, Benz E, Palmedo H,
Biersack HJ, Grünwald F, Klingmüller D. Testicular function after radioiodine therapy for thyroid carcinoma. Eur J Nucl
Med 2000;27:503-507.
71. Rosário PW, Barroso AL, Rezende LL, et al. Testicular function after radioiodine therapy in patients with thyroid cancer.
Thyroid 2006;16:667-670.
72. Bourcigaux N, Rubino C, Berthaud I, et al. Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma.
Hum Reprod 2018;33:1408-1416.
73. Verkooijen RB, Smit JW, Romijn JA, Stokkel MP. The incidence of second primary tumors in thyroid cancer patients is increased, but not related to treatment of thyroid cancer.
Eur J Endocrinol 2006;155:801-806.
74. Botella-Carretero JI, Gómez-Bueno M, Barrios V, et al. Chronic thyrotropin-suppressive therapy with levothyroxine and short-term overt hypothyroidism after
thyroxine withdrawal are associated with undesirable cardiovascular effects in patients with differentiated thyroid carcinoma.
Endocr Relat Cancer 2004;11:345-356.
75. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid 2010;20:135-146.
76. Gogakos AI, Duncan Bassett JH, Williams GR. Thyroid and bone. Arch Biochem
Biophys 2010;503:129-136.
77. Williams GR, Bassett JH. Thyroid diseases and bone health. J Endocrinol
Invest 2018;41:99-109.
78. Bassett JH, Williams GR. Role of thyroid hormones in skeletal development and bone maintenance. Endocr Rev 2016;37:135-187. 79. Murphy E, Williams GR.
The thyroid and the skeleton. Clin Endocrinol
(Oxf) 2004;61:285-298.
80. Heemstra KA, Hamdy NA, Romijn JA, Smit JW. The effects of thyrotropin-suppressive therapy on bone metabolism in patients with well-differentiated thyroid carcinoma.
Thyroid 2006;16:583-591.
81. Leonova TA, Drozd VM, Saenko VA, et al. Bone mineral density in treated at a young age for differentiated thyroid cancer after Chernobyl female patients on TSH-suppressive therapy receiving or not Calcium-D3 supplementation.
Endocr J 2015;62:173-182.
82. Mendonça Monteiro de Barros G, Madeira M, Vieira Neto L, et al. Bone mineral density and bone microarchitecture after long-term suppressive levothyroxine treatment of differentiated thyroid carcinoma in young adult patients. J Bone Miner Metab 2016;34:417-421. 83. Kalkwarf HJ, Zemel BS, Gilsanz V, et al.
The bone mineral density in childhood study: bone mineral content and density according to age, sex, and race. J Clin
Endocrinol Metab 2007;92:2087-2099.
84. Rubin MR, Dempster DW, Zhou H, et al. Dynamic and structural properties of the skeleton in hypoparathyroidism. J Bone
Miner Res 2008;23:2018-2024.
85. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis
and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129-2200. 86. Smit JW, Eustatia-Rutten CF, Corssmit
EP, et al. Reversible diastolic dysfunction after long-term exogenous subclinical hyperthyroidism: a randomized, placebo-controlled study. J Clin Endocrinol
Metab 2005;90:6041-6047.
87. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur
J Prev Cardiol 2016;23:NP1-NP96.
88. Schultz PN, Stava C, Vassilopoulou-Sellin R. Health profiles and quality of life of 518 survivors of thyroid cancer. Head
Neck 2003;25:349-356.
89. Nayak A, Hayen A, Zhu L, et al. Legacy effects of statins on cardiovascular and all-cause mortality: a meta-analysis. BMJ
Open 2018;8:e020584.
90. Daniels SR. Prevention of atherosclerotic cardiovascular disease: what is the best approach and how early should we start? J
Am Coll Cardiol 2014;63:2786-2788.
91. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-133. 92. Lebbink CA, Dekker BL, Bocca G, et al. New
national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands [submitted].
93. Grani G, Ramundo V, Verrienti A, Sponziello M, Durante C. Thyroid hormone therapy in differentiated thyroid cancer.
Endocrine 2019;66:43-50.
94. Oren A, Benoit MA, Murphy A, Schulte F, Hamilton J. Quality of life and anxiety in adolescents with differentiated thyroid cancer.
J Clin Endocrinol Metab 2012;97:E1933-E1937.
95. Metallo M, Groza L, Brunaud L, Klein M, Weryha G, Feigerlova E. Long-term quality of life and pregnancy outcomes of differentiated thyroid cancer survivors treated by total thyroidectomy and I(131) during adolescence and young adulthood.
Int J Endocrinol 2016;2016:7586482.
96. Nies M, Dekker BL, Sulkers E, et al. Psychosocial development in survivors of childhood differentiated thyroid carcinoma: a cross-sectional study. Eur J
Endocrinol 2018;178:215-223.
97. Rueegg CS, Gianinazzi ME, Rischewski J, et al. Health-related quality of life in survivors of childhood cancer: the role of chronic health problems. J Cancer Surviv 2013;7:511-522. 98. Sundberg KK, Doukkali E, Lampic C,
Eriksson LE, Arvidson J, Wettergren L. Long-term survivors of childhood cancer report quality of life and health status in parity with a comparison group. Pediatr
Blood Cancer 2010;55:337-343.
99. Gamper EM, Wintner LM, Rodrigues M, et al. Persistent quality of life impairments in differentiated thyroid cancer patients: results from a monitoring programme. Eur J
Nucl Med Mol Imaging 2015;42:1179-1188.
100. Berger AM, Abernethy AP, Atkinson A, et al. NCCN clinical practice guidelines cancer-related fatigue. J Natl Compr Canc
Netw 2010;8:904-931.
101. Hoftijzer HC, Heemstra KA, Corssmit EP, van der Klaauw AA, Romijn JA, Smit JW. Quality of life in cured patients with differentiated thyroid carcinoma. J Clin
Endocrinol Metab 2008;93:200-203.
102. Stichting Kinderoncologie Nederland (SKION). Richtlijn follow-up na kinderkanker
meer dan 5 jaar na diagnose. Den Haag/
Amsterdam; 2010.
103. Aschebrook-Kilfoy B, James B, Nagar S, et al. Risk factors for decreased quality of life in thyroid cancer survivors: initial findings from the North American Thyroid Cancer Survivorship Study.
Thyroid 2015;25:1313-1321.
104. DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds.
World Health Organization Classification of Tumours. Pathology and genetics of tumours of endocrine organs. 3rd ed. Lyon,
France: IARC Press; 2004.
105. Sisdelli L, Cordioli MI, Vaisman F, et al. AGK-BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma. Pediatr Blood
7
106. Liang L, Zheng X, Hu M, et al.MiRNA-221/222 in thyroid cancer: a meta-analysis.
Clin Chim Acta 2018;484:284-292.
107. Li N, Liu X, Han L, et al. Expression of miRNA-146b-5p in patients with thyroid cancer in combination with Hashimoto’s disease and its clinical significance. Oncol
Lett 2019;17:4871-4876.
108. Charkes ND. On the prevalence of familial nonmedullary thyroid cancer in multiply affected kindreds. Thyroid 2006;16:181-186. 109. Links TP, van Tol KM, Meerman GJ, de Vries EG.
Differentiated thyroid carcinoma: a polygenic disease. Thyroid 2001;11:1135-1140.
110. Niedziela M, Handkiewicz-Junak D, Malecka-Tendera E, et al. Diagnostics and treatment of differentiated thyroid carcinoma in children - Guidelines of Polish National Societies. Endokrynol
Pol 2016;67:628-642.
111. Dekker BL, Newbold KL, Führer D, et al. Survey on paediatric differentiated thyroid cancer care in Europe. Horm Res
Paediatr 2018;89-58-62.
112. Youngwirth LM, Adam MA, Thomas SM, Roman SA, Sosa JA, Scheri RP. Pediatric thyroid cancer patients referred to high-volume facilities have improved short-term outcomes. Surgery 2018;163:361-366.
