Purpose To present the outcomes of ultrasound (US) follow-ups in children with autoimmune thyroid disease who did not have a thyroid nodule on admission but developed papillary thyroid carcinoma (PTC) and to characterize the parenchymal changes in the thyroid gland prior to the development of PTC. Methods A retrospective thyroid US scan review of 327 patients diagnosed with AIT was performed. Forty patients (40/327, 12.2%) presented nodular AIT variant with a normoechogenic background. Eleven patients (11/327, 3.4%, 11/40, 27.5%) presenting this variant were diagnosed with PTC (nine females—mean age 15.3 years; two males aged 11 and 13 years). In five of 11 patients, the suspicious nodule that was later confirmed to be PTC was detected on the initial US at presentation. For the remaining six females (6/11) who developed PTC during the follow-up, we retrospectively analysed their US thyroid scans and these patients were selected for analysis in this study. Results On admission, the US evaluation revealed an enlarged normoechogenic thyroid gland in three patients and a hypoechogenic thyroid gland with fibrosis as indicated by irregular, chaotic hyperechogenic layers in three patients. No thyroid nodules were identified. Ultrasound monitoring revealed increasing echogenicity of the thyroid parenchyma during the follow-up. PTC developed in a mean time of 4.6 years (1 9/12–7 4/12 years) since referral to the outpatient thyroid clinic and 2.9 years (6/12–6 9/12) since the last nodule-free US thyroid scan. Conclusions Sonographic follow-up assessments warrant further exploration as a strategy to determine PTC susceptibility in the paediatric population. Keywords Autoimmune thyroiditis · Papillary thyroid carcinoma · Ultrasonography of thyroid gland · Normoechogenic background of thyroid gland * D. Januś Department of Pediatric Surgery, Institute of Pediatrics, email@example.com Jagiellonian University Medical College, Krakow, Poland Department of Clinical Immunology and Transplantation, Department of Pediatric and Adolescent Endocrinology, Institute of Paediatrics, Jagiellonian University Medical Chair of Pediatrics, Institute of Pediatrics, Jagiellonian College, Krakow, Poland University Medical College, Wielicka St. 265, 30-663 Krakow, Poland Department of Radiology, University Children Hospital, Krakow, Poland Department of Pediatric and Adolescent Endocrinology, University Children Hospital, Krakow, Poland Department of Pediatric Surgery, University Children Hospital, Krakow, Poland Vol.:(0123456789) 1 3 Journal of Endocrinological Investigation incidence of thyroid nodules is 13–30% [18–20]. The co- Introduction existence of AIT and PTC ranges between 6.3 and 43% depending on the patient population and continues to rise Differentiated thyroid carcinoma (DTC) accounts for the [18, 19, 21–25]. In paediatric patients with PTC, Niedziela vast majority of paediatric thyroid cancers . Papillary et al. found that the prevalence of autoimmune thyroiditis thyroid carcinoma (PTC) accounts for more than 90% of increased tenfold between 1996 and 2000 and 2001–2015 all childhood DTC cases . Thyroid cancer is the most . Increases in both the PTC incidence and the occur- common paediatric endocrine malignancy in the United rence of PTC with AIT were noted in our centre [14, 18]. States . The most recent statistical data estimate a thy- Thirteen patients with PTC (30.8% with AIT) between roid cancer rate of 0.59 per 100,000 patients less than 2000 and 2010 and 20 patients with PTC (55% with AIT) 19 years of age, with the incidence increasing at a rate between 2010 and 2017 were treated in our centre in Kra- of approximately 1% per year . The annual incidence kow, Lesser Poland . of thyroid cancer is < 1 case per million/year in children According to the current paediatric guidelines, neck US under 10 years of age, 3.5 cases per million/year in chil- in children with autoimmune thyroid disease should be per- dren between the ages of 10 and 14 years, and 15.4 cases formed at least every 12 months . Since thyroid US is a per million/year in those aged 15–19 years [4–8]. Accord- sensitive and noninvasive procedure, it was incorporated into ing to the data of the Polish National Cancer Registry from our institutional follow-up protocol for children with thyroid 2003 to 2013, new cases of thyroid cancer in patients less disorders. Access to ultrasound in our outpatient endocrine than 19 years of age constitute every second solid neo- clinic enables long-term monitoring of patients in thyroid plasm in girls and every eighth solid neoplasm in boys . cancer risk groups, including patients with the normoecho- The prevalence of chronic autoimmune thyroiditis genic AIT variant. (AIT) is reportedly up to 2% in children and almost 10% The present study expands upon the previous works from in adolescents and continues to rise [9, 10]. The disease our centre with new observations from ultrasound monitor- has a female predominance, and although observed in ing of a selected group of AIT patients [14, 18]. The aim of children up to 3 years of age, it often occurs after the age this study was to present the outcomes of ultrasound (US) of six and peaks at 10–12 years of age . US surveys follow-ups in children with autoimmune thyroid disease who have reported that 5 of every 1000 children aged between did not have a thyroid nodule on admission but developed 11 and 18 years are diagnosed with Hashimoto thyroidi- PTC and to characterize the parenchymal changes in the tis every year . Not only an increase in the annual thyroid gland prior to the development of PTC that may be frequency of AIT between 1975 and 2005 (+ 350% after useful in identifying a PTC risk group among paediatric 1995) but also progressive decreases in both the age at patients with AIT. presentation and the female-to-male (F/M) ratio were reported in a large Italian study . Autoimmune thyroiditis is responsible for approxi- Methods mately 55–65% of all paediatric euthyroid goitres [13, 14]. It is considered a premalignant lesion with an increased A retrospective chart and thyroid US scan review of 327 prevalence in cancer [15–17]. patients (245 females) diagnosed with autoimmune thy- The sonographic appearance of lymphocytic thyroiditis roiditis (AIT) between January 2015 and December 2017 varies, likely reflecting the phase and severity of the disease was performed. The mean age of the patients was 13.1 years process . In our previous work, we presented five ultra- (range 3–19 years). The patients were subdivided according sonographic variants of autoimmune thyroiditis in children to AIT variants (as described before by our group ): (in decreasing frequency): (1) the most common form of (a) diffuse thyroiditis with a hypoechogenic background diffuse thyroiditis with a hypoechogenic background and (114/327, 34.9%), (b) diffuse thyroiditis with an irregular normoechogenic parenchyma, (2) diffuse thyroiditis with an background (98/327, 29.9%), (c) micronodulations (65/327, irregular background, (3) a nodular variant with a normoe- 19.9%), (d) a nodular AIT variant with a normoechogenic chogenic irregular background, (4) micronodulations, and background (40/327, 12.2%), and (e) a variant with a diffuse (5) a variant with a diffuse hypoechogenic background . hypoechogenic background (10/327, 3.1%). We also reported that patients with the nodular AIT variant The nodular AIT variant with a normoechogenic back- with a normoechogenic irregular background of the thyroid ground was identified in 12.2% (40/327) of the whole group. gland are at risk of developing PTC and should be followed In 29 patients (29/40, 72.5%) with the nodular AIT variant up with regular neck ultrasound (US) assessments . with a normoechogenic background, fine-needle aspiration In the general paediatric population, the incidence biopsy (FNAB) results were benign and corresponded to col- of thyroid nodules is 1–18% . In AIT patients, the loid cysts (3/29, 10.3%), ectopic thymic tissue (2/29, 6.9%), 1 3 Journal of Endocrinological Investigation and focal AIT (24/29, 82.8%). Eleven patients with the nodu- solid structure, vascularity as detected with Doppler flow, lar AIT variant with a normoechogenic background were and/or pathologic lymph nodes, were referred to paediatric diagnosed with papillary thyroid carcinoma (nine females, oncologic surgeons for FNAB. PTC was diagnosed when the mean age 15.3 years (range 11–19 years); two males aged FNAB results fulfilled the Bethesda criteria . In patients 11 and 13 years). Patients with PTC constituted 27.5% of with PTC, total thyroidectomy with lateral and central lymph the nodular AIT variant cases and 3.4% of the whole group. node histopathological verification was performed. In 5 of 11 patients, the suspicious nodule that was later Postoperative staging was performed based on the confirmed to be PTC was detected on the initial US at pres- tumour, nodes, and metastases (TNM) system proposed by entation. For the remaining six females (6/11) who devel- the American Joint Committee on Cancer . oped PTC during the follow-up at the endocrine outpatient The study was approved by the Institutional Review department, we retrospectively analysed their US thyroid Board. scans, performed between 2009 and 2017, showing paren- chymal changes in the thyroid gland prior to the develop- ment of PTC, and these patients were selected for analysis Results in this study. The analysis included the reason for referral to the endo- The clinical and hormonal data of the patients are presented crinologist, age at AIT and PTC diagnosis, thyroid status, in Table 1. levels of autoantibodies (TPOAb—thyroperoxidase antibody Ultrasound follow-ups with transversal and longitudinal and TgAb—thyroglobulin antibody), US features of the scans of the thyroid glands of all patients are presented in thyroid gland at presentation (with the date and age of the Figs. 1, 2, 3, 4, 5, and 6. patient) prior to PTC diagnosis, and US features at the initial All patients were referred for endocrine evaluation detection of the nodule (with the date and age of patient). because of an enlarged thyroid gland. Thyroid palpation AIT was confirmed in six patients based on clinical fea- revealed diffuse firm goitre in all cases. tures (presence of goitre, firm consistency of the thyroid On admission, the US evaluation revealed an enlarged gland), hormonal features (hypothyroidism or subclinical normoechogenic thyroid gland in three patients and a hypothyroidism), and increased TPOAb and/or TgAb lev- hypoechogenic thyroid gland with fibrosis as indicated by els. Compensated (or subclinical) hypothyroidism was diag- irregular, chaotic hyperechogenic layers in three patients. nosed if the TSH level was above the upper normal range (n: The median thyroid volume was 10.5 ml (range 5.6–21.7 ml, 0.4–4.0 µIU/ml) and fT4 was close to the low normal range the reference thyroid volume data for age and gender are (n: 10–25 pmol/l). Ultrasonography of the thyroid gland was presented in Table 1 and separately for individual patients). performed to determine the AIT variant. At the time of the initial US, no thyroid nodules were identi- US of the thyroid gland was performed at the Univer- fied in the study group. sity Children’s Hospital by board US-certified doctors (DJ, One patient was diagnosed with hypothyroidism (patient PS, and ŁW). Thyroid US was performed using a high- 5), and five patients were diagnosed with subclinical hypo- resolution Voluson 730 GE Medical System (8–12-MHz thyroidism. Because of the presence of a goitre and abnor- linear transducer), Philips Epiq5 (L12-5 linear transducer), mal thyroid function, all patients received therapy with levo- Philips iE22 (L11-3 linear transducer), and Logiq P6, GE thyroxine. TPOAb levels were increased in five patients (1, Healthcare (11L linear transducer). The US examination 3–6). In patient 2, the TPOAb level was within the normal was performed in the transversal and longitudinal planes. range, but the TgAb level was increased, thus confirming Scans indicating background parenchymal echogenicity autoimmunity (Table 1). were reviewed retrospectively. Normal thyroid parenchyma Ultrasound monitoring revealed increasing echogenic- (normoechogenic background) was defined as demonstrat- ity of the thyroid parenchyma in relation to the adjacent ing homogenous echogenicity and relative hyperechogenic- sternothyroid, sternohyoid, sternocleidomastoid, and omo- ity compared with the adjacent sternohyoid, sternothyroid, hyoid muscles in all patients during the follow-up. Finally, omohyoid, and sternocleidomastoid muscles as described in all patients, malignant nodules developed in the thyroid previously . Abnormal parenchymal features of the thy- gland with a normoechogenic background without typical roid gland, including irregular echotexture, micronodular- ultrasound AIT features such as diffuse hypoechogenicity ity, and diffuse or focal hypoechogenic lesions and nodules, or micronodulations as demonstrated in our previous study were also evaluated. . Papillary thyroid carcinoma developed in a mean Patients presenting a nodule with suspicious features, time of 4.6 years (1 9/12–7 4/12 years) since referral to such as hypoechogenicity, a hyperechogenic `border` the outpatient thyroid clinic and 2.9 years (6/12–6 9/12) between a nodule and the thyroid parenchyma, poorly since the last nodule-free US thyroid scan (Figs. 1, 2, 3, defined margins, an irregular shape, microcalcifications, a 4, 5, 6). The median maximum nodule size on US was 1 3 Journal of Endocrinological Investigation Table 1 Clinical and hormonal data of patients Patient 1 2 3 4 5 6 Age at AIT diagnosis (years) 11 11/12 9 3/12 9 8/12 9 6/12 12 6/12 11 8/12 Age (years) and 12 9 3/12 10 4/12 9 9/12 15 5/12 11 8/12 date (DD-MM-YYYY) of US at 23-03-2011 8-08-2015 28-12-2010 27-12-2011 10-07-2015 28-05-2009 presentation Thyroid volume (ml) 10 ml 11 ml 5.6 ml 8.2 ml 17.7 ml 21.7 (N < 9.5) (N < 5.4 ml) (N < 5.4 ml) (N < 5.4 ml) (N < 10.9) (N < 9.5) TSH at AIT diagnosis (µIU/ 5.01 6.6 4.8 8 18.2 9.2 ml N: 0.4–4.0) fT4 at AIT diagnosis 11.2 11.1 12.1 10.7 9.7 10.3 (pmol/l N: 10–25) TPOAb at AIT diagnosis (IU/ 1271.7 10.9 > 1300 226.6 > 1000 > 9000 ml N < 30) TgAb at AIT diagnosis – 195 154.3 – – > 1000 (U/ml N < 30) Age (years) and 16 8/12 11 14 10/12 13 6/12 16 9/12 18 5/12 date (DD-MM-YYYY) of US at 16-11-2015 15-05-2017 06-06-2015 09-09-2015 30-11-2016 11-02-2016 first detection of the nodule Age at PTC diagnosis (years) 16 11/12 11 14 10/12 13 6/12 17 5/12 19 Thyroid volume at PTC diagno- 16 ml 14.9 ml 6.4 ml 11.8 6.0 ml 9.3 ml sis (ml) (N < 18 ml) (N < 9.5 ml) (N < 16.1) (N < 13.1 ml) (N < 18 ml) (N < 18 ml) Nodule size on US scan (mm) 10.8 × 10.4 × 16.4 6.5 × 4.7 × 6.7 7 × 5 × 6 8 × 8 × 9 6.6 × 9.8 × 4.1 12.2 × 7.4 × 8.9 TSH at PTC dgn 0.7 7 2.9 1.5 3.5 0.7 (µIU/ml N: 0.4–4.0) fT4 at PTC diagnosis 16.8 9.2 16.7 19.3 15.3 19.8 (pmol/l N:10–25) TPOAb at PTC dgn – 167.7 925.9 126.2 1920 245.2 (IU/ml N < 30) TgAb at PTC dgn – 93.4 21.1 154.3 467.5 404.2 (U/ml N < 30) Time to PTC detection since 5 1 9/12 4 10/12 4 4 11/12 7 4/12 referral (years) Time to PTC detection since 4 8/12 10/12 6/12 3 9/12 1 4/12 6 9/12 last nodule-free US scan (years) AACE/ACE/AME risk group Class 3 Class 3 Class 3 Class 3 Class 3 Class 3 TNM pT1aN0M0 pT1aN0M0 pT1aN0M0 pT1aN1aM0 pT1aN0M0 pT1aN0M0 ATA risk group I I I II I I PTC variant Classic Follicular Classic, solid, follicular Classic, follicular Classic Classic ATA (The American Thyroid Association) pediatric risk group: I—low risk, II— intermediate risk, and III—high risk  AACE/ACE/AME (The American Association of Clinical Endocrinologists, American College of Endocrinology and Associazione Medici Endocrinologi) US Classification System: Class 1—Low-risk thyroid lesion; Class 2—Intermediate-risk thyroid lesion; Class 3—High-risk thy - roid lesion  TPOAb thyroperoxidase antibody, TgAb thyroglobulin antibody, AIT autoimmune thyroiditis, PTC papillary thyroid carcinoma, TNM tumour, nodes, and metastases system Thyroid volume references [41, 42] 9.4 mm (range: 6.7–16.4 mm) and the growth rate of the In five patients, the nodules were hypoechogenic. In four nodules was fast (Figs. 1, 2, 3, 4, 5, and 6). The volume of these patients, the nodules were surrounded by a hyper- of the nodule increased by 82% at 6 months in Patient 1, echogenic ‘margin’, and in one patient, the nodule had mixed 92% at 1 month in Patient 2, 84% at 1 month in Patient 3, echogenicity and an irregular lobulated border. No microcal- 132% at 8 months in Patient 5, and 316% at 7 months in cic fi ations were observed in the nodules. The vascularization Patient 6 during observation in the outpatient clinic before of the nodules was centralized and increased in relation to FNAB was performed. the surrounding thyroid parenchyma. 1 3 Journal of Endocrinological Investigation Fig. 1 Patient 1. Transversal (a) and longitudinal (b) scans of the ment. The growth of the nodule was fast from 8.1 × 9.5 × 13.1 mm to hypoechogenic thyroid gland revealed formation of the nodule 10.8 × 10.4 × 16.4 mm in 6 months (82% increase). During follow-up, 5 years since referral and 4 8/12 years since last ultrasound assess- the echogenicity of the thyroid gland increased Fig. 2 Patient 2. Transversal (a) and longitudinal (b) scans of ultrasound assessment. The growth of the nodule was fast from the hypoechogenic thyroid gland revealed the formation of the 5.4 × 4.7 × 4.2 mm to 6.5 × 4.7 × 6.7 mm in 1 month (92% increase). nodule 1 9/12 years since referral and 10/12 months since last During follow-up, the echogenicity of the thyroid gland increased Apart from one non-compliant patient who stopped variants were found in two patients: classic/solid/follicular levothyroxine treatment for 1 year (Patient 2), in all cases, and classic/follicular (Table 1). decreases in goitre volume were observed at the time of PTC After surgery, the outcomes of therapy were favour- diagnosis from a median volume of 10 ml (5.6–21.7 ml) on able. No complications after thyroidectomy were noted. All US at presentation to a median of 9.3 ml (6–16 ml). The patients are currently followed up at the Institute of Oncol- median TSH levels decreased from 8 µIU/ml (5.01–18.2) to ogy and are in remission. Tg and TgAb levels are negative 1.5 µIU/ml (0.7–7.0). in all cases. After FNAB confirmation according to the Bethesda cri - teria (category V-suspicious for malignancy) , total thy- roidectomy with central and lateral lymph node dissection was performed in all patients. Discussion TNM classification revealed pT1aN0M0 in 5/6 patients, and these patients did not receive I therapy. Only Patient To our knowledge, this is the first report of ultrasound pres- 4 was classified as pT1aN1aM0 with a nodule < 10 mm and entations of parenchymal changes in the thyroid gland in received radionuclide therapy. young patients with autoimmune thyroiditis evaluated sono- The classic PTC variant was found in three patients, the graphically prior to the development of histologically con- follicular PTC variant was found in one patient, and mixed firmed papillary thyroid carcinoma. 1 3 Journal of Endocrinological Investigation Fig. 3 Patient 3. Transversal scans of the normoechogenic thyroid the nodule was fast from 5.4 × 4.6 × 4.6 mm to 7 × 5 × 6 mm (84% gland revealed the formation of the nodule 4 10/12 years since refer- increase) in 1 month. The nodule was surrounded by a hyperecho- ral and 6 months after last ultrasound assessment. The growth of genic border Fig. 4 Patient 4. Transversal (a) and longitudinal (b) scans of the ment. The nodule was surrounded by a hyperechogenic border. Dur- normoechogenic thyroid gland revealed the formation of the nodule ing follow-up, the echogenicity of the thyroid gland increased 4 years since referral and 3 9/12 months since last ultrasound assess- In the overall group of 327 AIT patients, the distribution retrospectively analyse US thyroid scans presenting paren- of sonographic AIT variants was similar to our observation chymal changes in the thyroid gland prior to the develop- in the previous work . A total of 87.8% of the patients ment of PTC and these patients were chosen for presentation presented typical US variants of AIT (diffuse thyroiditis in this study. with a hypoechogenic background, diffuse thyroiditis with PTC was detected early via US in our study before the an irregular background, micronodulations, or a diffuse nodule was clinically apparent. Four of six confirmed cancer hypoechogenic background) and changes were not observed cases were associated with thyroid nodules < 1 cm, which in the parenchyma or the nodules in this group of patients are difficult to detect by manual palpation alone. The most during the follow-up . common sonographic presentation of a malignant lesion in The nodular AIT variant with a normoechogenic back- our group was a solid hypoechoic nodule with an irregu- ground was identified in 12.2% of the whole group. Eleven lar hyperechoic margin (histopathologically identified as patients (female predominance) presenting this variant were fibrosis and lymphocytic infiltration) and without microcal- diagnosed with papillary thyroid carcinoma. Patients with cifications. The detected nodules showed fast growth rates PTC constituted 27.5% of the nodular AIT variant cases and over time, with volumes that doubled or even tripled within 3.4% of the whole group; these results are similar to those 6–8 months of observation before FNAB was performed. In of other paediatric series [19, 20]. one patient with a nodule diameter less than 10 mm, metas- In six females who did not have a thyroid nodule on tases to several lymph nodes were detected and this patient admission but who developed PTC, we have been able to received radioactive iodine therapy (RAI). 1 3 Journal of Endocrinological Investigation Fig. 5 Patient 5. Transversal (a) and longitudinal (b) scans of the to 6.6 × 9.8 × 4.1 mm in 8 months (132% increase). The nodule was hypoechogenic thyroid gland revealed the formation of the nodule 4 surrounded by a hyperechogenic border. During follow-up, the echo- 11/12 years since referral and 1 4/12 year since last ultrasound assess- genicity of the thyroid gland increased ment. The growth of the nodule was fast from 6.5 × 5.5 × 3.2 mm Fig. 6 Patient 6. Transversal (a) and longitudinal (b) scans of the ment. The growth of the nodule was fast from 6.3 × 7.3 × 4.2 mm to normoechogenic thyroid gland revealed formation of the nod- 12.2 × 7.4 × 8.9 mm in 7 months (316% increase). The nodule was ule 6 9/12 years since referral and since last ultrasound assess- surrounded by a hyperechogenic border Our results suggest that the use of US can increase the Unlike adults, children with papillary thyroid cancer may detection rate of thyroid malignancies in patients with the present with more advanced disease and have higher rates normoechogenic AIT variant who seem to be at a higher of local recurrence and distant metastases, even though risk of cancer than the overall population of children with their prognosis is favourable, with overall 10-year survival autoimmune thyroiditis . This higher risk may justify rates of 80–95% . Children have a longer posttreatment the need for closer monitoring, especially considering the life expectancy and, therefore, more time for recurrence or rapid growth rate of malignant nodules in young patients. potential treatment effects to manifest [1 ]. Recent studies 1 3 Journal of Endocrinological Investigation have confirmed that radioactive iodine (RAI) ablation is development of PTC. In our study group, three girls had a associated with an increased risk for the development of normoechogenic thyroid gland at presentation, and whether additional malignancies as well as an increase in overall these findings reflected the early stage of AIT or a normal mortality for patients with DTC . Frequent US follow- thyroid gland was questionable considering that up to 20% up examinations enable the early detection of PTC, radical of the population has positive thyroid autoantibodies without surgery, and avoidance of RAI therapy. In our study, five any thyroid disease . AIT was confirmed in our patients of six patients did not receive radionuclide therapy, which by the presence of goitre, subclinical hypothyroidism, and will probably impact their future quality of life considering autoantibodies to thyroglobulin and thyroid peroxidase. the long-term side effects associated with RAI . We are Follow-up scans did not reveal typical sonographic AIT convinced that certain sonographic features of the thyroid features (micronodularity or decreased echogenicity with gland observed in our follow-up study may facilitate the visible hyperechogenic septations). However, during the early detection of malignancies. follow-up, we detected a solitary hypoechogenic nodule that An ongoing debate in the literature is whether the nodu- was later confirmed to be PTC. Therefore, we suggest that lar variant of AIT with a normoechogenic background indi- not only nodular AIT but also AIT with a normoechogenic cating the presence of residual thyroid tissue identified in background on sonography at presentation (with no nodules) patients with PTC is a different type of disease compared may be an entirely different clinical entity with an increased to diffuse AIT and whether autoimmune thyroiditis is sec- PTC risk, which warrants further research in the paediatric ondary to cancer in this group of patients [18, 31–34]. As population [18, 31, 33]. Our study also found that during the presented in our previous study, patients with typical vari- follow-up of hypoechogenic thyroid glands with irregular ants of diffuse AIT more often developed abnormalities of hyperechogenic layers, an increase in echogenicity due to thyroid function (overt hypothyroidisms or hyperthyroidism) parenchymal changes was evident, probably due to fibrosis compared to patients with the nodular AIT variant with a and follicular destruction in the thyroid gland during the normoechogenic background . The decreased echogenic- disease process prior to detection of a nodule [37, 38]. ity of the parenchyma in diffuse AIT has been shown to be In our AIT cohort, the incorporation of thyroid US fol- related to lymphocyte infiltration and correlated with hypo- low-ups enabled relatively early detection of thyroid malig- thyroidism [31, 34]. A lower incidence of hypothyroidism in nancies that were not clinically apparent over a mean of patients with nodular AIT and normal background thyroid 4.6 years since referral and AIT diagnosis. The data pre- parenchyma was also observed in other studies [33, 34]. Our sented here are consistent with those of the Italian study by findings are consistent with those of Oppenheimer et al., Rizzo et al., demonstrating that the lag time between AIT indicating that at least two distinct patterns of AIT exist on diagnosis and PTC detection was approximately 5 years, thyroid sonography: diffuse AIT and nodular AIT . As which is very similar to the average value reported in our hypothesized by Paparodis et al. and Imam et al., in patients paediatric study . In addition, a novel and practical find- with euthyroid/functional AIT and low titres of TPOAb, a ing of our study is that the shortest lag time from the last different immune disorder that does not completely destroy nodule-free scan to the detection of a suspicious nodule was the thyroid gland may be present, or cancer may actively 6 months. participate in regulating immunity or autoimmunity (cancer Another point of interest in our study is the observation immunoediting) [33, 35]. As suggested by Ehlers and Schott, that although all patients received levothyroxine treatment, the reason for the induced antitumour immune response except for one patient, and exhibited decreased goitre vol- (with increased but low TPOAb or TgAb levels in serum) umes and TSH levels, l-thyroxine replacement therapy failed may be the presence of undiagnosed papillary thyroid micro- to provide any protection from nodule development. This carcinomas . Consistent with this observation, Paparo- finding may support the hypothesis that thyroid oncogen- dis et al. reported an association between AIT duration and esis may precede autoimmunity; however, further research PTC development after finding that a shorter AIT dura- on larger series of patients is required to confirm these tion was associated with PTC development, while a longer observations. duration was not . Interestingly, Italian authors reported Several limitations exist in our study. Due to the low that the annual increase in the AIT incidence preceded the incidence of PTC in young patients, our sample was small; annual increase in the PTC incidence, and suggested that therefore, the study had insufficient power to establish sta - environmental influences may have favoured both thyroid tistical significance. Nevertheless, we propose that sono - autoimmune disease and PTC-oriented thyroid oncogenesis graphic follow-up assessments warrant further exploration as . The new information reported in our study is consist- a strategy to determine PTC susceptibility in the paediatric ent with the hypothesis that autoimmune thyroiditis may population. be secondary to thyroid oncogenesis as half of our patients In accordance with the ATA and Polish Guidelines, chil- exhibited normoechogenic thyroid parenchyma prior to the dren with AIT should undergo US evaluation annually. We 1 3 Journal of Endocrinological Investigation 6. Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, are convinced, however, that children with a normoecho- Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer genic background of the thyroid gland or a hypoechogenic EJ, Cronin KA (eds) SEER Cancer Statistics Review, 1975-2015, background with fibrosis appearing as irregular hyperecho- National Cancer Institute. Bethesda, MD. https://seer .cancer .gov/ genic layers should be considered to have a higher risk of csr/1975_2015/. Based on November 2017 SEER data submis- sion, posted to the SEER web site, April 2018 cancer and should be followed more closely with more fre- 7. Bernstein L, Gurney JG (1999) Carcinomas and other malignant quent ultrasound evaluations [2, 39]. epithelial neoplasms. ICCCXI. Pediatric Monograph. In: Ries LAG, Smith MA,Gurney JG et al.(eds): Cancer Incidence and Author contributions Study design: DJ. Study conduct: DJ. Data col- Survival Among Children And Adolescents. United States SEER lection: DJ, MW, DR, AW, LW, GD, AT, and PS. Data analysis: DJ. Program 1975–1995. National Cancer Institute, SEER Program Data interpretation: DJ, MW, AT, PS, and JS. Drafting manuscript: DJ. NIH Pub. No.99-4649, Bethesda, MD Revising manuscript content: DJ, MW, and JS. Approving final version 8. Waguespack S, Wells S, Ross J, et al. (2006) Thyroid cancer. of manuscript: DJ, MW, and JS. DJ takes responsibility for the integrity SEERAYA monograph. In: Bleyer WA, O’Leary M, Barr R, of the data analysis. et al.(eds): Cancer Epidemiology in Older Adolescents and Young Adults 15–29 years of age, including SEER Incidence and Funding This study has not received any funding. Survival: 1975–2000.[NIH Pub. No. 06-5767, Bethesda, MD]; National Cancer Institute, Bethesda, MD, 2006;143–154 9. Zdraveska N, Kocova M (2012) Hashimoto thyroiditis in child- Compliance with ethical standards hood—review of the epidemiology, genetic susceptibility and clinical aspects of the disease. Maced J Med Sci 15:336–345 Conflict of interests The authors have nothing to disclose and there are 10. Zois C, Stavrou I, Kalogera C, Svarna E, Dimoliatis I, Sefe- no conflicts of interests. riadis K, Tsatsoulis A (2003) High prevalence of autoimmune thyroiditis in school children after elimination of iodine defi- Ethical approval The authors confirm that this retrospective work was ciency in northwestern Greece. Thyroid 13:485–489. https ://doi. performed in compliance with Ethical Standards and according to Insti- org/10.1089/10507 25033 22021 151 tutional Review Board standards. 11. Radetti G, Gottardi E, Bona G, Corrias A, Salardi S, Loche S (2006) The natural history of euthyroid Hashimoto’s thyroiditis Informed consent Informed consent was obtained from all individual in children. J Pediatr 149:827–832. https://doi.or g/10.1016/j.jpeds participants included in the study. .2006.08.045 12. Rizzo M, Rossi RT, Bonaffini O, Scisca C, Altavilla G, Calbo L, Rosanò A, Sindoni A, Trimarchi F, Benvenga S (2010) Increased Open Access This article is distributed under the terms of the Crea- annual frequency of Hashimoto’s thyroiditis between years 1988 tive Commons Attribution 4.0 International License (http://creat iveco and 2007 at a cytological unit of Sicily. 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