Clinicopathologic Characteristics of Pediatric Follicular Variant of Papillary Thyroid Carcinoma Subtypes: A Retrospective Cohort Study.

2022

1353-1361

11/2022

1557-9077

Follicular patterned thyroid nodules with nuclear features of papillary thyroid carcinoma (PTC) encompass a range of diagnostic categories with varying risks of metastatic behavior. Subtypes include the invasive encapsulated follicular variant of PTC (Ienc-fvPTC) and infiltrative fvPTC (inf-fvPTC), with tumors lacking invasive features classified as noninvasive follicular thyroid neoplasms with papillary-like features (NIFTPs). This study aimed to report the clinical and histological features of pediatric cases meeting criteria for these histological subtypes, with specific focus on Ienc-fvPTC and inf-fvPTC. In this retrospective cohort study, pediatric patients with thyroid neoplasms showing follicular patterned growth and nuclear features of PTC noted on surgical pathology between January 2010 and January 2021 were retrospectively reviewed and classified according to the recent 2022 World Health Organization (WHO) criteria. Clinical and histopathologic parameters were described for NIFTP, Ienc-fvPTC, and inf-fvPTC subtypes, with specific comparison of Ienc-fvPTC and inf-fvPTC cases. The case cohort included 42 pediatric patients, with 6 (14%), 25 (60%), and 11 (26%) patients meeting criteria for NIFTP, Ienc-fvPTC, and inf-fvPTC, respectively. All cases were rereviewed, and 5 patients originally diagnosed with Ienc-fvPTC before 2017 were reappraised as having NIFTPs. The NIFTP cases were encapsulated tumors without invasive features, lymph node or distant metastasis, or disease recurrence. Ienc-fvPTC tumors demonstrated clearly demarcated tumor capsules and capsular/vascular invasion, while inf-fvPTC tumors displayed infiltrative growth lacking a capsule. inf-fvPTC cases had increased prevalence of malignant preoperative cytology, lymph node metastasis, and distant metastasis ( < 0.01). These cases were treated with total thyroidectomy, lymph node dissection, and subsequent radioactive iodine therapy. Preliminary genetic findings suggest a predominance of fusions in inf-fvPTC cases versus point mutations in Ienc-fvPTC ( = 0.02). Pediatric NIFTP and fvPTC subtypes appear to demonstrate alignment between clinical and histological risk stratification, with indolent behavior in Ienc-fvPTC and invasive features in inf-fvPTC tumors.

10.1089/thy.2022.0239

Thyroid

36103376

Indeterminate Thyroid Fine-Needle Aspirations in Pediatrics: Exploring the Clinicopathologic Features and Utility of Molecular Profiling.

2022

07/2022

1663-2826

INTRODUCTION: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis.

METHODS: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children's Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics.

RESULTS: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) pediatric guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low-risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low-risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high-risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration.

CONCLUSIONS: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.

10.1159/000526116

Horm Res Paediatr

35871517

Clinicopathologic Characteristics of Pediatric Follicular Variant of Papillary Thyroid Carcinoma Subtypes: A Retrospective Cohort Study.

2022

09/2022

1557-9077

Follicular patterned thyroid nodules with nuclear features of papillary thyroid carcinoma encompass a range of diagnostic categories with varying risks of metastatic behavior. Subtypes include invasive encapsulated fvPTC (Ienc-fvPTC) and infiltrative fvPTC (inf-fvPTC) with tumors lacking invasive features classified as non-invasive follicular thyroid neoplasm with papillary-like features (NIFTP). This study aimed to report the clinical and histologic features of pediatric cases meeting criteria for these histological subtypes with specific focus on Ienc-fvPTC and inf-fvPTC. In this retrospective cohort study, pediatric patients with thyroid neoplasms showing follicular patterned growth and nuclear features of papillary thyroid carcinoma noted on surgical pathology between January 2010 and January 2021 were retrospectively reviewed and classified according to the recent 2022 World Health Organization (WHO) criteria. Clinical and histopathologic parameters were described for NIFTP, Ienc-fvPTC, and inf-fvPTC subtypes, with specific comparison of Ienc-fvPTC and inf-fvPTC cases. The case cohort included 42 pediatric patients, with 6 (14%), 25 (60%), and 11 (26%) patients meeting criteria for NIFTP, Ienc-fvPTC, and inf-fvPTC, respectively. All cases were re-reviewed, and 5 patients originally diagnosed with Ienc-fvPTC prior to 2017 were reappraised as NIFTP. The NIFTP cases were encapsulated tumors without invasive features, lymph node or distant metastasis, or disease recurrence. Ienc-fvPTC tumors demonstrated clearly demarcated tumor capsules and capsular/vascular invasion, while inf-fvPTC tumors displayed infiltrative growth lacking a capsule. Inf-fvPTC cases had increased prevalence of malignant pre-operative cytology, lymph node metastasis, and distant metastasis ( < 0.01). These cases were treated with total thyroidectomy, lymph node dissection, and subsequent radioactive iodine therapy. Preliminary genetic findings suggest a predominance of fusions in inf-fvPTC cases versus point mutations in Ienc-fvPTC ( < 0.01). Pediatric NIFTP and fvPTC subtypes appear to demonstrate alignment between clinical and histological risk stratification, with indolent behavior in Ienc-fvPTC and invasive features in inf-fvPTC tumors.

10.1089/thy.2022.0239

Thyroid

36103376

Surgical outcomes in survivors of childhood cancer undergoing thyroidectomy: A single-institution experience.

2022

e29674

2022 Mar 26

1545-5017

<p><strong>BACKGROUND: </strong>Childhood cancer survivors (CCS) are at increased risk for thyroid disease, and many require definitive management with thyroid surgery. Despite this, there is limited evidence on surgical outcomes among CCS. We sought to evaluate postoperative outcomes at our institution among CCS undergoing thyroid surgery compared to patients without a history of primary childhood malignancy.</p>

<p><strong>PROCEDURE: </strong>Medical records were reviewed for 638 patients treated at the Children's Hospital of Philadelphia Pediatric Thyroid Center between 2009 and 2020. Rates of surgical complications, including recurrent laryngeal nerve (RLN) paralysis and hypoparathyroidism, among CCS were compared to patients with sporadic/familial thyroid cancer, Graves' disease, and other benign thyroid conditions. Operative time and intraoperative parathyroid hormone levels were also evaluated.</p>

<p><strong>RESULTS: </strong>There were no significant differences in long-term surgical complication rates, such as permanent RLN paralysis and hypoparathyroidism, between CCS and patients without a history of primary childhood malignancy (all p&nbsp;&gt;&nbsp;.05). For all surgical outcomes, there were no significant differences in complication rates when CCS were compared to those undergoing surgery for sporadic/familial thyroid cancer or Graves' disease (all p&nbsp;&gt;&nbsp;.05). CCS with benign final pathology had significantly higher rates of transient hypoparathyroidism compared to patients with benign thyroid conditions (p&nbsp;&lt;&nbsp;.001).</p>

<p><strong>CONCLUSIONS: </strong>Our study suggests that CCS are not at higher risk of long-term complications from thyroid surgery when treated by high-volume surgeons within a multidisciplinary team.</p>

10.1002/pbc.29674

Pediatr Blood Cancer

35338690

Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers.

2022

JCO2101861

2022 Jan 11

1527-7755

<p><strong>PURPOSE: </strong>In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, -like and -like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC.</p>

<p><strong>METHODS: </strong>Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into -mutant (), -mutant ( p.V600E), and / fusion (, , and fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed.</p>

<p><strong>RESULTS: </strong>Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with / fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within or -mut subgroups.</p>

<p><strong>CONCLUSION: </strong>Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with / fusions having worse outcomes than those with -mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.</p>

10.1200/JCO.21.01861

J Clin Oncol

35015563

Clinical Course of Early Postoperative Hypothyroidism Following Thyroid Lobectomy in Pediatrics.

2021

2021 Oct 29

1557-9077

<p><strong>INTRODUCTION: </strong>Thyroid lobectomy reduces risks of surgical complications and need for levothyroxine (LT4). We aimed to identify the clinical course and risk factors for post-lobectomy hypothyroidism to optimize surgical counseling and management in pediatric patients undergoing lobectomy.</p>

<p><strong>METHODS: </strong>Clinical and biochemical presentations pre- and post-lobectomy were retrospectively reviewed for 110 patients who underwent thyroid lobectomy between 2008 and 2020 at the Children's Hospital of Philadelphia.</p>

<p><strong>RESULTS: </strong>Approximately 28.2% of patients (31/110) developed post-lobectomy hypothyroidism defined by an elevated thyroid stimulating hormone (TSH) level, including 24.5% (27/110) with subclinical hypothyroidism (TSH &gt; 4.5 and &lt; 10.0 mIU/L) and 3.6% (4/110) with overt hypothyroidism (TSH &gt; 10.0 mIU/L). LT4 was initiated in 12.7% (14/110) of cases. Most patients (81.6%; 84/103) recovered euthyroidism within 12 months post-lobectomy. When excluding patients with autonomous nodule(s), median preoperative TSH was 1.09 (IQR = 0.70-1.77) mIU/L and 1.80 (IQR = 1.02-2.68) mIU/L in euthyroid and hypothyroid patients, respectively, with multivariate logistic regression confirming the association between an increased preoperative TSH and post-lobectomy hypothyroidism (OR = 1.8; 95% CI = 1.08-3.13; p = 0.024). Of the patients who underwent thyroid lobectomy and developed post-operative hypothyroidism (n = 31), 38.7% (12/31) had a pre-operative diagnosis of an autonomous thyroid nodule.</p>

<p><strong>CONCLUSIONS: </strong>Thyroid function should be evaluated post-lobectomy to assess the need for LT4. LT4 should be considered if the TSH remains elevated, especially if an upward trend is observed or TSH is &gt; 10.0 mIU/L. Suppressed preoperative TSH associated with autonomous nodule(s) is an independent risk factor for post-lobectomy hypothyroidism.</p>

10.1089/thy.2021.0396

Thyroid

34714171

Thyroid Lobectomy for T1 Papillary Thyroid Carcinoma in Pediatric Patients.

2021

2021 Sep 23

2168-619X

<p><strong>Importance: </strong>The current recommendation for pediatric patients with papillary thyroid cancer (PTC) is a total thyroidectomy. This recommendation applies to all stages of PTC, including papillary thyroid microcarcinoma (≤1 cm, T1a) tumors.</p>

<p><strong>Objective: </strong>To evaluate the characteristics of American Joint Committee on Cancer T1 PTC tumors in a large pediatric population and to identify a subgroup of patients who may benefit from a thyroid lobectomy instead of a total thyroidectomy.</p>

<p><strong>Design, Setting, and Participants: </strong>This retrospective cohort study was conducted from January 1, 2009, to May 31, 2020. The study took place at a tertiary care medical center and included 102 patients who were surgically treated for T1 PTC: 52 with stage T1a (≤1 cm) tumors and 50 with stage T1b (&gt;1 cm but ≤2 cm) tumors.</p>

<p><strong>Main Outcomes and Measures: </strong>Primary outcomes included the presence of bilateral disease and lymph node metastasis.</p>

<p><strong>Results: </strong>A total of 102 patients (mean age, 15.3 years [range, 9.7-18.9 years]; 84 girls [82.4%]) were included in the analysis. Among 52 patients with T1a tumors, 10 (19.2%) had bilateral disease, and 15 (28.8%) had central neck lymph node (N1a) metastasis. Among 50 patients with T1b tumors, 10 (20%) had bilateral and 13 (26%) had N1a disease. Of those with T1a, unilateral multifocality was associated with bilateral disease (odds ratio [OR], 2.1; 95% CI, 1.3-3.4) and N1a disease (OR, 5.1; 95% CI, 1.5-17.6). Both N1a disease (OR, 20.0; 95% CI, 3.5-115.0) and ≥4 positive lymph nodes (OR, 8.6; 95% CI, 1.2-60.9) were associated with bilateral disease. In patients with no pathologic evidence of lymph node metastasis (N0), there was a 95% rate of unilateral PTC. In patients with T1b tumors, unilateral multifocality was also associated with bilateral disease (OR, 1.8; 95% CI, 1.3-2.7). Patients with T1b tumors had an increased risk of lateral (N1b) neck lymph node metastasis when compared with those with T1a tumors (OR, 3.7; 95% CI, 1.0-14.5).</p>

<p><strong>Conclusions and Relevance: </strong>The findings of this cohort study suggest that, in patients with unifocal T1a PTC without clinically evident nodal disease on preoperative ultrasonography, a thyroid lobectomy and central neck dissection may be considered. If there is no evidence of unilateral multifocality or if there are fewer than 4 positive lymph nodes on postoperative pathology, then close observation may be considered. These findings have substantial clinical implications and may result in practice changes regarding the extent of thyroid surgery on low-stage pediatric PTC.</p>

10.1001/jamaoto.2021.2359

JAMA Otolaryngol Head Neck Surg

34554217

Utility of Fine-Needle Aspirations to Diagnose Pediatric Thyroid Nodules.

2021

2021 Sep 01

1663-2826

10.1159/000519307

Horm Res Paediatr

34469888

miRNA expression can classify pediatric thyroid lesions and increases the diagnostic yield of mutation testing.

2020

e28276

2020 Mar 20

1545-5017

<p><strong>BACKGROUND: </strong>Genetic alterations in multiple cell signaling pathways are involved in the molecular pathogenesis of thyroid cancer. Oncogene mutation testing and gene-expression profiling are routinely used for the preoperative risk management of adult thyroid nodules. In this study, we evaluated the potential value of miRNA biomarkers for the classification of pediatric thyroid lesions.</p>

<p><strong>PROCEDURE: </strong>Double-blind case-control study with 113 resected pediatric lesions: 66 malignant and 47 benign. Quantitative and qualitative molecular data generated with a 10-miRNA expression panel (ThyraMIR) and a next-generation sequencing oncogene panel (ThyGeNEXT) were compared with clinicopathological parameters.</p>

<p><strong>RESULTS: </strong>miRNAs were differentially expressed in benign versus malignant tumors with distinct expression patterns in different histopathology categories. The 10-miRNA classifier identified 39 (59%) malignant lesions with 100% specificity. A positive classifier score was associated with lymph node metastasis, extrathyroidal extension and intrathyroidal spread. Genetic alterations associated with increased risk for malignancy were detected in 35 (53%) malignant cases, 20 positive for point mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, or TERT and 15 positive for gene rearrangements involving ALK, NTRK3, PPARG, or RET. The 10-miRNA classifier correctly identified 11 mutation-negative malignant cases. The performance of the combined molecular test was 70% sensitivity and 96% specificity with an area under the curve of 0.924.</p>

<p><strong>CONCLUSIONS: </strong>These data suggest that the regulatory miRNA pathways underlying thyroid tumorigenesis are similar in adults and children. miRNA expression can identify malignant lesions with high specificity, augment the diagnostic yield of mutation testing, and improve the molecular classification of pediatric thyroid nodules.</p>

10.1002/pbc.28276

Pediatr Blood Cancer

32196952