First name
Lea
Middle name
F
Last name
Surrey

Title

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

Year of Publication

2022

Number of Pages

1353-1361

Date Published

11/2022

ISSN Number

1557-9077

Abstract

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.

DOI

10.1089/thy.2022.0239

Alternate Title

Thyroid

PMID

36103376

Title

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

Year of Publication

2022

Date Published

07/2022

ISSN Number

1663-2826

Abstract

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.

DOI

10.1159/000526116

Alternate Title

Horm Res Paediatr

PMID

35871517

Title

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

Year of Publication

2022

Date Published

09/2022

ISSN Number

1557-9077

Abstract

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.

DOI

10.1089/thy.2022.0239

Alternate Title

Thyroid

PMID

36103376

Title

Thyroid Lobectomy for T1 Papillary Thyroid Carcinoma in Pediatric Patients.

Year of Publication

2021

Date Published

2021 Sep 23

ISSN Number

2168-619X

Abstract

<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>

DOI

10.1001/jamaoto.2021.2359

Alternate Title

JAMA Otolaryngol Head Neck Surg

PMID

34554217

Title

Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies.

Year of Publication

2021

Date Published

2021 Apr

ISSN Number

2373-2873

Abstract

<p>Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia but is approximately 500 times more likely to develop in children with Down syndrome (DS) through transformation of transient abnormal myelopoiesis (TAM). This study investigates the clinical significance of genomic heterogeneity of AMKL in children with and without DS and in children with TAM. Genomic evaluation of nine patients with DS-related TAM or AMKL, and six patients with non-DS AMKL, included conventional cytogenetics and a comprehensive next-generation sequencing panel for single-nucleotide variants/indels and copy-number variants in 118 genes and fusions involving 110 genes. Recurrent gene fusions were found in all patients with non-DS, including two individuals with complex genomes and either a or a - fusion, and the remaining harbored a fusion, which arose from both typical and atypical cytogenetic mechanisms. These fusions guided treatment protocols and resulted in a change in diagnosis in two patients. The nine patients with DS had constitutional trisomy 21 and somatic mutations, and those with DS-AMKL had two to four additional clinically significant somatic mutations. Comprehensive genomic characterization provides critical information for diagnosis, risk stratification, and treatment decisions for patients with AMKL. Continued genetic and clinical characterization of these rare cancers will aid in improving patient management.</p>

DOI

10.1101/mcs.a005975

Alternate Title

Cold Spring Harb Mol Case Stud

PMID

33832921

Title

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

Year of Publication

2020

Number of Pages

e28276

Date Published

2020 Mar 20

ISSN Number

1545-5017

Abstract

<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>

DOI

10.1002/pbc.28276

Alternate Title

Pediatr Blood Cancer

PMID

32196952

Title

Extrathyroidal Extension is an Important Predictor of Regional Lymph Node Metastasis in Pediatric Differentiated Thyroid Cancer.

Year of Publication

2019

Date Published

2019 Oct 01

ISSN Number

1557-9077

Abstract

<p>The American Joint Committee Cancer (AJCC) TNM system predicts survival in patients with differentiated thyroid cancer (DTC). In the eighth edition of the AJCC TNM, microscopic extrathyroidal extension (microETE) was removed and tumor size &gt;4 cm was maintained in the definition of T3 disease to reduce unnecessarily aggressive therapy for adults at low risk of death from DTC. In pediatric patients where DTC survival rates are high, the AJCC TNM is used to identify patients at increased risk of persistent, postsurgical disease, to identify patients who benefit from radioactive iodine therapy. The aim of this study was to assess the correlation of microETE with cervical lymph node (LN) metastasis in pediatric patients and to determine if tumor size or microETE is more informative in predicting regional LN disease. Patients with DTC &lt;19 years of age at the time of thyroidectomy with AJCC T3 tumors (seventh edition) and the presence of LNs on the surgical specimen were included in this retrospective chart review. Pathological findings were confirmed by pathologist review. Forty-five patients with AJCC T3 designation were included, 34 with microETE and 11 without microETE. Of those with microETE, 32 (94.1%) demonstrated regional LN metastasis compared with 5/11 patients (45.5%) without microETE ( = 0.001). In addition, microETE was associated with lateral neck LN metastasis ( = 0.004), bilateral disease ( = 0.001), and tumor multifocality ( = 0.003). Patients with microETE had smaller tumors (median = 2.5 cm, interquartile range [IQR]: 1.6-4.5) compared with patients without microETE (median = 5 cm, IQR: 4.2-5.4;  = 0.02). No increased association was found between microETE and vascular invasion, distant metastasis, or persistent/recurrent disease. In pediatric patients with DTC, microETE is a strong predictor of LN metastasis when compared with tumor size. For patients who do not undergo prophylactic central neck LN dissection, the presence of microETE predicts an increased risk of postsurgical disease and should be included in future revisions of the American Thyroid Association pediatric risk stratification categories.</p>

DOI

10.1089/thy.2019.0229

Alternate Title

Thyroid

PMID

31573414

Title

Development and Clinical Validation of a Large Fusion Gene Panel for Pediatric Cancers.

Year of Publication

2019

Date Published

2019 Jun 27

ISSN Number

1943-7811

Abstract

<p>Gene fusions are one of the most common genomic alterations in pediatric cancer. Many fusions encode oncogenic drivers and play important roles in cancer diagnosis, risk stratification, and treatment selection. We report the development and clinical validation of a large custom-designed RNA sequencing panel, CHOP Fusion panel, using anchored multiplex PCR technology. The panel interrogates 106 cancer genes known to be involved in nearly 600 different fusions reported in hematological malignancies and solid tumors. The panel works well with different types of samples including formalin-fixed, paraffin-embedded samples. The panel demonstrated excellent analytic accuracy with 100% sensitivity and specificity on 60 pediatric tumor validation samples. In addition to identifying all known fusions in the validation samples, three unrecognized yet clinically significant fusions were also detected. Two-hundred and sevety-six clinical cases were analyzed after the validation and 51 different fusions were identified in 104 cases. Of these, 16 fusions were not previously reported at the time of discovery. These fusions provided genomic information useful for clinical management. Our experience demonstrates that CHOP Fusion panel can detect the vast majority of known and certain novel clinically relevant fusion genes in pediatric cancers accurately, efficiently, and cost effectively, and provides an excellent tool for new fusion gene discovery.</p>

DOI

10.1016/j.jmoldx.2019.05.006

Alternate Title

J Mol Diagn

PMID

31255796

Title

Clinical utility of custom-designed NGS panel testing in pediatric tumors.

Year of Publication

2019

Number of Pages

32

Date Published

2019 May 28

ISSN Number

1756-994X

Abstract

<p><strong>BACKGROUND: </strong>Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers.</p>

<p><strong>METHODS: </strong>Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed.</p>

<p><strong>RESULTS: </strong>NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration.</p>

<p><strong>CONCLUSIONS: </strong>Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.</p>

DOI

10.1186/s13073-019-0644-8

Alternate Title

Genome Med

PMID

31133068

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