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Background:
To evaluate the performance of TBSRTC through multi-institutional experience in the paediatric population and questioning the management recommendation of ATA Guidelines Task Force on Paediatric Thyroid Cancer; Methods: A retrospective search was conducted in 4 institutions to identify consecutive thyroid FNAC cases in paediatric popul...
Contexts in source publication
Context 1
... ND category 23% of the cases were subjected to surgery. Of the patients undergoing surgery, 76 of them (49.7%) had a benign or low-malignancy potential (LMP) lesion, whereas 50.3% of them had a classical malignancy (Table 3). Regarding the biological behaviour of the different diagnostic entities by histology of the 10 cases referred to ND category, 7 (70%) were benign and 3 (30%) malignant. ...Context 2
... the 22 cases diagnosed as SFM, 16 were malignant (73%), 3 (14%) were of LMP and 3 (14%) were benign. Finally, M presented 37 (86%) malignant cases, whereas 5 cases (12%) were come out as benign and 1 (2%) as low malignancy potential (Table 3). ...Context 3
... both ways, ND and B categories were found to have a higher ROM than the suggested ranges of TBSRTC. (Table 3). In Table 4, brief literature review of the distribution of TBSRTC categories based on ROMs was summarized to be able to compare the current study results, as well as the TBSRTC. ...Similar publications
Background
Pediatric thyroid nodules have a lower prevalence but a higher rate of malignancy (ROM) than those in adults. Ultrasound features suspected of malignancy lead to fine needle aspiration biopsy (FNAB) and subsequent cytological determination, upon which management is decided. Based on the characteristics of ultrasound, to standardize clini...
Citations
... Our study aims to address the clinical challenges posed by Bethesda 3 and 4 thyroid nodules, with a goal to enrich the literature with insights specifically targeting these ambiguous categories in the pediatric population Within our investigation, 53% of the nodules classified as Bethesda 3 were determined to have benign pathologies postoperatively. This finding is corroborated by Canberk et al.'s (20), substantial cohort study, which identified 67% of AUS instances as benign. These concurrent findings raise questions about the American Thyroid Association's (ATA) stance in favor of prompt surgical involvement for AUS/FLUS nodules (2). ...
Purpose:
The study aimed to assess the postoperative outcomes of pediatric thyroid nodules with Atypia of Undetermined Significance (AUS/FLUS) or Suspicious for a Follicular Neoplasm (SFN) and their EU-TIRADS scoring.
Methods:
The study retrospectively reviewed 44 patients at a single center with thyroid nodules classified as Atypia of Undetermined Significance or Suspicious for a Follicular Neoplasm from August 2019 to December 2022. Data on demographics, thyroid function, nodule size, and ultrasonographic features were collected. Postoperative pathologies were categorized into benign, low-risk, and malignant neoplasms according to WHO 2022 criteria, with EU-TIRADS used for radiologic scoring.
Results:
Among 21 pediatric patients, 72% had Bethesda 3 and 28% had Bethesda 4 thyroid nodules. Pathological outcomes post-surgery classified 43% as benign, 19% as low-risk, and 38% as malignant. Notably, EU-TIRADS 3 and 5 scores were present in 44% and 56% of benign cases, respectively. Malignant cases showed a prevalence of higher EU-TIRADS scores, with 64% rated as EU-TIRADS 5. Bethesda category 4 nodules had a 66% malignancy rate, significantly higher than the 27% in category 3.
Conclusion:
The investigation revealed that EU-TIRADS scoring showed a substantial proportion of benign cases were classified as EU-TIRADS 5, suggesting that EU-TIRADS may lead to unnecessary biopsies in benign cases. Malignant cases were more likely to have a higher EU-TIRADS score, indicating a positive correlation with malignancy risk, particularly in Bethesda 4 cases. However, the EU-TIRADS system's predictive value for malignancy in Bethesda 3 cases was less definitive.
... However, more recent research demonstrated a decrease in malignancy rates for AUS/FLUS and FN/SFN nodules. Therefore, children with such nodules may benefit from molecular testing and repeat FNA to avoid unnecessary surgery [84,85]. ...
Thyroid cancer is the most common endocrine malignancy, with increasing incidence over the past few decades. Fine needle aspiration (FNA) biopsy is the gold standard for preoperative diagnosis of thyroid malignancies. Nevertheless, this method renders indeterminate results in up to 30% of the cases. Therefore, these patients are often referred to unnecessary surgery to establish the diagnosis. To improve the accuracy of preoperative diagnosis, several other ways, such as ultrasonography, elastography, immunohistochemical analysis, genetic testing, and core needle biopsy, have been developed and can be used either in association with or as an alternative to FNA. This review aims to evaluate all these diagnostic tools to determine the most appropriate way of managing thyroid nodules and subsequently improve the selection of cases referred to surgery.
... Overall, four different consortia have developed risk stratification reporting systems to assess the likelihood of malignancy when a thyroid nodule is detected in adulthood: the American College of Radiology (ACR-TIRADS), the European Thyroid Association (EU-TIRADS), the Korean Society of Thyroid Radiology (K-TIRADS) and the American Thyroid Association (ATA). The strengths and weaknesses of each scoring system have already been widely outlined (134). The diagnostic accuracy of K-TIRADS has been recently assessed among 107 patients and it has resulted in the lowering of the threshold size for suggesting biopsy from ≥1.0 cm to ≥0.6 cm for K-TIRADS 4 and ≥0.5 cm for K-TIRADS 5 (135). ...
Thyroid disorders (TD) represent a remarkable share of all the late morbidities experienced following pediatric haematopoietic stem cell transplantation (HSCT), with long-term reported occurrence often exceeding 70%. In addition, the data collected on wide cohorts of survivors assessed longitudinally outlined a progressive increase in the cumulative incidence of TD as far as 30 years following transplantation. Accordingly, a life-long monitoring of thyroid health is warranted among patients exposed to HSCT in childhood, in order to early detect TD and undertake a prompt dedicated treatment. Although several national and international consortia have provided recommendations for the early detection of thyroid disorders among childhood cancer survivors exposed to radiotherapy and alkylating agents, no guidelines specifically and thoroughly focused on HSCT-related TD have been published to date. As stem cell transplantation has become the standard-of-care in a growing body of non-oncological conditions, this urge has become pivotal. To highlight the challenging issues specifically involving this cohort of patients and to provide clinicians with the proposal of a practical follow-up protocol, we reviewed published literature in the light of the shared experience of a multidisciplinary team of pediatric oncologists, transplantologists, pathologists and endocrinologists involved in the long-term care of HSCT survivors. As a final result, we hereby present the proposals of a practical and customized risk-based approach to tailor thyroid health follow-up based on HSCT-related detrimental factors.
... malignant [59] According to the multicentral study by Canberk et al. [75], the distribution of cytopathology findings among 405 FNA specimens were: 44 (11%) for nondiagnostic, 204 (50%) for benign category, 40 (10%) for AUS/FLUS, 36 (9%) for follicular neoplasm/suspicious for a follicular neoplasm, 24 (6%) for suspicious for malignancy and 57 (14%) for malignancy categories. The actual risk of malignancy in nodules surgically excised among adults is 20% for nondiagnostic, 2.5% for benign category, 14% for AUS/FLUS, 25% for follicular neoplasm/suspicious for a follicular neoplasm, 70% for suspicious for malignancy and 99% for malignancy categories [76]. ...
Thyroid diseases in children and adolescents include acquired or congenital conditions, including genetic disorders either isolated or part of a syndrome. Briefly, we will review the physiology and pathophysiology of the thyroid gland and its disorders. The aim of this chapter is to describe genetic abnormalities of the thyroid gland.
... PTC and FTC exhibit major clinical differences. PTC is frequently multifocal and bilateral and metastasizes to regional neck lymph nodes in the vast majority of children (10,12,13,15,23,24,31,(43)(44)(45)(46)(47). Hematogenous metastases to the lungs occur in up to 25% of cases (9,11,14,24,31,43,(48)(49)(50)(51)(52) and generally occur only with significant regional lymph node metastases (10,53). ...
... However, nodules diagnosed in children carry a greater risk of malignancy compared to those in adults (22%-26% versus 5%-10% in most series) (27,55,56). Second, when histology and tumor size are controlled for, children with PTC are more likely to have regional lymph node involvement, extrathyroidal extension, and pulmonary metastasis (9)(10)(11)(12)(13)(14)(15)23,24,31,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). Third, despite extensive disease at clinical presentation, children are much less likely to die from disease (2% or less long-term cause-specific mortality) than are adults (5,(8)(9)(10)(11)(12)(13)(14)(15), and many children with pulmonary metastases (30%-45%) develop persistent albeit stable disease following 131 I therapy (24,57). ...
... The limited data suggest that, in children, TT with prophylactic CND is associated with increased DFS, as high as 95% at 5 and 10 years (46,163). However, the data are mixed and possibly related to the use of adjunctive RAI remnant ablation. ...
Background:
Population-based studies have demonstrated an association of single nucleotide polymorphisms close to the thyroid transcription factor forkhead box E1 (FOXE1) gene with thyroid cancer. The dysregulation of forkhead proteins is increasingly recognized to play a role in the development and progression of cancer. The objective of the study was to seek to identify novel mutations in FOXE1 in papillary thyroid cancer (PTC) and to assess the effect of these mutations on protein expression and transcriptional function on FOXE1 responsive promoters.
Methods:
The study was conducted at two tertiary referral hospitals. The coding region of FOXE1 was sequenced in tissue-derived DNA or RNA from 120 patients with PTC and 110 patients with multinodular goiter (MNG). In vitro studies were performed to examine the protein expression and transcriptional function of FOXE1 mutants. A molecular model of the forkhead domain (FHD) of FOXE1 was generated using the SWISS-MODEL online server with the three-dimensional structure of FOXD3 as a template.
Results:
Three somatic missense mutations were detected in PTC resulting in the amino acid substitutions P54Q, K95Q, and L112F. One additional mutation was detected in a MNG (G140R). In vitro studies demonstrated marked impairment in transcriptional activation by all four FOXE1 mutants, which was not explained by differences in protein expression. Molecular modeling localized three of the mutations to highly conserved regions of the FHD.
Conclusions:
We have identified novel somatic mutations of FOXE1 in PTC. Mutational inactivation of FOXE1 is an uncommon event in thyroid tumors but may contribute to thyroid carcinogenesis and dedifferentiation in concert with other oncogenic drivers.
Since 2009, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has provided a standardized framework for reporting thyroid fine needle aspiration (FNA) specimens and introduced the indeterminate category of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) with a low risk of malignancy. In TBSRTC, the AUS/FLUS diagnostic category is reserved for suboptimal specimens (hypocellular/with smearing and/or staining artifacts) that contain cells (follicular, lymphoid, or other) with architectural and/or nuclear atypia that raise concern for neoplasm/malignancy but are insufficient to be classified as follicular neoplasm/suspicious for follicular neoplasm, suspicious for malignancy, or malignant. Conversely, the atypia is more marked than can be attributed confidently to benign changes. This heterogeneous category has significantly evolved over time with updated criteria, refined risk stratification, the introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), the incorporation of molecular testing, and a shift toward more conservative management. Despite these refinements, AUS/FLUS remains problematic, at both the diagnostic and management level. In this chapter, we review the AUS/FLUS category in the context of the upcoming third edition of TBSRTC.
The guidelines for the workup of thyroid nodules have been established in adult populations and secondarily applied to paediatric populations. In particular, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is commonly applied to both adult and paediatric thyroid nodules. However, as paediatric nodules have distinct molecular drivers and behavioural trajectories, there is renewed interest in diagnostic and management strategies that are paediatric specific. Here, we review key differences between paediatric and adult thyroid cancer and recent literature evaluating the use of TBSRTC in paediatric populations.
Simple Summary
Children are not little adults, when it comes to many things, especially in medicine. Sometimes, a new radiology or pathology test is developed for use in adults, and only later are pediatric applications considered—perhaps the disease being tested for is more common in adults. In this study, we aim to understand differences between adults and children when it comes to how we test for thyroid cancer. Thyroid nodules are much more common in adults, but they are much more likely to be malignant in children. Ultrasound is typically the first test when a patient has a thyroid nodule, and radiologists have developed risk stratification systems to try and determine who can be safely followed clinically and with repeat ultrasound, versus those who need to proceed to a second test, fine-needle aspiration biopsy, in which cells are removed from the thyroid and examined under a microscope, sometimes with molecular testing.
Abstract
While thyroid nodules are less common in children than in adults, they are more frequently malignant. However, pediatric data are scarce regarding the performance characteristics of imaging and cytopathology classification systems validated to predict the risk of malignancy (ROM) in adults and select those patients who require fine-needle aspiration (FNA) and possibly surgical resection. We retrospectively reviewed the electronic medical records of all patients 18 years of age or younger who underwent thyroid FNA at our institution from 1 July 2015 to 31 May 2022. Based on surgical follow-up from 74 of the 208 FNA cases, we determined the ROM for the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) ultrasound risk stratification system and The Bethesda System for Reporting Thyroid Cytopathology and added our results to those of pediatric cohorts from other institutions already published in the literature. We found the following ROMs for 1458 cases using ACR TI-RADS (TR): TR1. Benign: 2.2%, TR2. Not Suspicious: 9.3%, TR3. Mildly Suspicious: 16.6%, TR4. Moderately Suspicious: 27.0%, and TR5. Highly Suspicious 76.5%; and for 5911 cases using the Bethesda system: Bethesda I. Unsatisfactory: 16.8%, Bethesda II. Benign: 7.2%, Bethesda III: Atypia of Undetermined Significance: 29.6%, Bethesda IV. Follicular Neoplasm: 42.3%, Bethesda V. Suspicious for Malignancy: 90.8%, and Bethesda VI. Malignant: 98.8%. We conclude that ACR TI-RADS levels imply higher ROMs for the pediatric population than the corresponding suggested ROMs for adults, and, in order to avoid missing malignancies, we should consider modifying or altogether abandoning size cutoffs for recommending FNA in children and adolescents whose thyroid glands are smaller than those of adults. The Bethesda categories also imply higher ROMs for pediatric patients compared to adults.
Atypia of Undetermined Significance (AUS) was introduced in 2008 as one of three “indeterminate” (not clearly benign or malignant) diagnostic categories for reporting thyroid fine needle aspiration (FNA). The previous alternative term, Follicular Lesion of Undetermined Significance (FLUS), has been eliminated in this update to avoid confusion with reporting terminology and management. Each of the indeterminate categories has an elevated risk of malignancy (ROM) compared to a benign aspirate. The AUS category is reserved for cases with atypia that is insufficient for either of the other two indeterminate categories of “Follicular Neoplasm” and “Suspicious for Malignancy.” Among the three indeterminate categories, AUS has the lowest ROM (average 22%; range 13–30%) meriting its distinction from the other two. Furthermore, malignancy risk differs according to the nature of the atypia prompting the AUS interpretation. Specifically, AUS with nuclear atypia raising concern for papillary carcinoma has a higher ROM than AUS associated with other patterns, particularly those characterized by architectural atypia alone or a predominance of oncocytic cells. The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) terminology in 2016 decreased the overall ROM for AUS. The clinical approach to a nodule with an initial AUS interpretation is a repeat FNA or molecular testing, although patient preference and clinical risk factors may also impact management with diagnostic lobectomy or active surveillance being alternative options.Based on published experience with AUS in clinical practice, this update describes:1. appropriate use of the AUS diagnostic terminology.2. subclassification of AUS with an emphasis on the importance of distinguishing nuclear atypia from other common AUS patterns to improve communication regarding the ROM, between cytopathologists and the clinical team managing the patient; and3. updates to the management of AUS, including the role of molecular testing and discussion of concerns specific to pediatric patients.KeywordsThyroidFine needle aspiration (FNA)Atypia of undetermined significance (AUS)Nuclear atypiaSubclassificationMolecular testing
The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) established a uniform, tiered reporting system for thyroid fine needle aspiration (FNA) specimens. TBSRTC recommends that every thyroid FNA report begin with one of six diagnostic categories: I. Nondiagnostic; II. Benign; III. Atypia of Undetermined Significance (AUS); IV. Follicular Neoplasm; V. Suspicious for Malignancy; and VI. Malignant. Each category has an implied cancer risk that averages from 4% for the “Benign” category to virtually 100% for the “Malignant” category, and, in this third edition, the malignancy risks have been revised based on additional (post 2nd edition) data. As a function of these risk associations, each category is linked to evidence-based clinical management guidelines. This chapter also includes a separate diagnostic framework for reporting pediatric thyroid FNA specimens. The recent classification of thyroid neoplasms based on molecular profiles and clinical outcomes has implications for the risk of malignancy, and this is accounted for both adult and pediatric cases in this and subsequent chapters of this book. For some of the general diagnostic categories, subcategorization can be informative and is often appropriate. Additional descriptive comments (beyond such subcategorization) are optional and left to the discretion of the cytopathologist. Notes and recommendations can be useful, especially due to the introduction of risk based classification of thyroid neoplasms, changing management strategies, and widespread use of molecular testing.KeywordsThyroidNodulesTerminologyBethesdaFine needle aspirationRisk of malignancy
