Paediatric thyroid lesions: lessons from recent guidelines

The main purpose of this commentary is to evaluate the incidence and impact of thyroid lesions in the cytological and histological evaluation of paediatric populations, through the different guidelines published over the past few years.^1,2

From data from the literature, it is evident that the incidence of thyroid lesions in children and adolescents is low, even though the risk of malignancy is higher than in adulthood.^3,4 The prevalence of thyroid nodules ranges from 0·05% to 1·8% compared with a prevalence in adulthood of 3·2% to 8%. For this reason, the detection of a thyroid lesion in a paediatric patient requires careful evaluation and potentially more aggressive diagnostic management. Every year in the USA, thyroid cancer represents 4% of all malignancies diagnosed in children and adolescents. The probability of malignancy within paediatric and adolescent thyroid nodules varies by study and has been reported within the wide range of 5% to 50%.^3-5 Nonetheless, there is agreement in the field that papillary thyroid carcinoma and its subtypes represent the most common endocrine malignancy in children, with a 1·6-fold higher cancer risk than adults.^3-7 Many factors have been attributed to this increased risk of malignancy including a history of head and neck irradiation, female sex, age of puberty, familial history of thyroid diseases, and iodine deficiency, among others. Given the young age of these patients, early diagnosis and a tailored management is likely to favour a better prognosis and a longer disease-free survival. It is well known that there are substantial differences between adult and paediatric thyroid carcinoma, including clinical, morphological, and molecular features. Differentiated paediatric thyroid carcinomas usually present at an advanced stage, with lymph node involvement, multifocality, and extrathyroidal infiltration. However, despite the increased aggression at presentation, paediatric patients usually have an excellent prognosis. Some studies have linked these aggressive features to the fact that paediatric cancers more commonly harbour RET-PTC and NTRK fusions, while BRAF^V600E and RAS point mutations are less frequent.^3-9

In 2015, based on emerging data showing an increased risk of malignancy in paediatric thyroid nodules, the American Thyroid Association (ATA) suggested specific paediatric guidelines for the management of thyroid nodules, underlying the importance of neck ultrasound evaluation combined with fine needle aspiration (FNA) in the paediatric population.² These guidelines have represented the gold standard management in the USA, but there has been less adherence to these guidelines worldwide. Specifically, in Europe, those recommendations have not been followed due to differences in medical care and the cultural approach to the management of thyroid lesions (lobectomy vs total thyroidectomy). For those reasons, specific European recommendations have been suggested.¹

The efforts from the European Thyroid Association (ETA) led to the 2022 ETA Guidelines¹ for the management of paediatric thyroid nodules and differentiated thyroid carcinoma, using the ATA guidelines² as a framework. Both guidelines emphasised and underlined that a child with suspicion of thyroid cancer should be referred to an experienced multidisciplinary thyroid team mostly specifically dedicated to paediatric thyroid cancer.

Until the recent publication of the 3rd edn of The Bethesda System for Reporting Thyroid Cytopathology⁸ in July 2023, there has not been a specific diagnostic classification system for paediatric thyroid lesions. For the first time, in a thyroid classification system, a specific risk of malignancy and management approach was reported for paediatric patients. The first chapter of the Bethesda classification system, organised as an overview of diagnostic terminology and reporting, added a specific table with the implied risk of malignancy for each diagnostic category in children based on published studies, confirming that it can be applied for reporting paediatric thyroid FNA specimens. The overview suggested that the same diagnostic categorisation reported in adults can be applied to children with higher risk for each diagnostic category⁸ (appendix).

The recent edition of the Bethesda classification system recognises challenges with paediatric thyroid nodule management and the current absence of unified international guidelines. There is a clear need for global evaluation of serum tests, imaging analysis, and cytological interpretation in children and adolescents. Additionally, improvements in thyroid ultrasound have allowed for the identification of smaller and clinically silent thyroid cancers. Studies are now critically needed for assessing whether conservative management is required and how to improve overall patient health outcomes.^2-7 The enhanced use of paediatric-specific cytological interpretation, in combination with paediatric-specific management, will aid in reducing the number of indeterminate diagnoses such as atypia of undetermined significance (AUS) and follicular neoplasm.

For AUS and follicular neoplasm, clinicians face the most critical management decisions when deciding between clinical follow-up (in the majority of cases) and surgical procedure. Although the ATA guidelines suggest surgery for indeterminate results, the ETA guidelines proposed a more conservative approach with a “repeat biopsy” in the case of AUS and follicular neoplasm, and surgery only for suspicious of malignancy.^1,2 However, the new subclassification of AUS, into AUS with “nuclear” atypia and AUS with “other” non-nuclear atypia, suggested by the Bethesda 3rd edn, is likely, as shown in other classification systems, to better perform in identifing nodules with higher risk of malignancy also in the paediatric population.⁸

Moving forward, the field will need to think critically about other diagnostic features that provide enhanced malignancy prediction for paediatric nodules. Although the Bethesda system does not currently encourage identification of specific histological subtypes in cytology, this discrimination is of particular relevance for paediatric patients with more frequent diagnoses of aggressive subtypes (figure), which could justify a more aggressive and extensive surgical management.⁸ It is not uncommon that paediatric thyroid carcinoma shows extrathyroidal extension and lymph nodal metastases, which are typically diagnosed in aggressive subtypes such as diffuse sclerosing, tall cell subtype, or hobnail subtype.^3-9

Figure: Examples of thyroid lesions.

Panel A shows the cytological details from an hematoxylin and eosin (H&E) stained fine needle aspiration smear with a cluster of malignant thyroid cells, showing a papillary organisation within the cluster and nuclear details of papillary carcinoma characterised by nuclear grooves and nuclear pseudoinclusions with marked nuclear atypia (H&E). Panels B and C show histological details of a diffuse sclerosing papillary carcinoma subtype. The pictures show the cellular details of papillary thyroid carcinoma, the sclerosing stromal component intermingled with the neoplastic cells and the presence of psammoma bodies (H&E). Panel D shows the cytological details on liquid based cytology of a case diagnosed as positive for malignancy with focal evidence of hobnail features (PAP stain). Panels E and F show details of hobnail cells in the context of the classic papillary thyroid carcinoma diagnosis (H&E).

Every effort should be adopted to make a more correct and precise diagnosis, including the support of ancillary techniques such as the performance of molecular or immunocytochemical platforms. In this regard, the guidelines and classification systems all agree that the performance of ancillary testing might be needed in challenging clinical cases where the support of an additional tool is likely to lead to a more tailored and personalised management.^3-7

Both the 2015 ATA guidelines² and the 2022 ETA guidelines¹ recognise the need for specific recommendations and personalised approaches in paediatric patients with thyroid lesions based on the evidence that paediatric thyroid cancer has a distinct disease process with different molecular drivers and genetic mechanisms from adult thyroid disease. Furthermore, emerging research, as well as the new ATA guidelines for paediatric thyroid nodules, will aid in providing more personalised and paediatric-specific care for our youngest and most vulnerable patients.