Pulmonary injury after radioactive iodine therapy in pediatric papillary thyroid cancer: a case report.

INTRODUCTION: Radiation-induced lung injury is a rare complication of radioactive iodine therapy (RAIT) in pediatric thyroid cancer treatment. In this case report, we describe a pediatric patient with an ERC1::RET-positive classic papillary thyroid carcinoma who developed progressive respiratory symptoms and chest imaging abnormalities following RAIT for lymph node and pulmonary disease. CASE PRESENTATION: A pediatric patient with ERC1::RET-positive classic papillary thyroid carcinoma was hospitalized for pulmonary decompensation three months following one empiric dose of RAIT. Testing revealed no evidence of infection or progression of pulmonary metastases, and there was no improvement with empiric antibiotic therapy for pneumonia. Despite empiric anti-inflammatory therapies, the patient remains symptomatic from a respiratory standpoint with requirement for supplemental oxygen and evidence of fibrotic changes on chest imaging. CONCLUSIONS: This patient's pulmonary condition is consistent with radiation-induced pulmonary injury including development of pulmonary fibrosis. With the availability of RET fusion targeted inhibitors, this case highlights a rare pulmonary side effect of radioactive iodine for clinicians to recognize. Upfront targeted therapy protocols may help avoid radioactive iodine-associated adverse reactions.

Thyroid Ultrasound Screening in Childhood Cancer Survivors following Radiotherapy.

INTRODUCTION: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for differentiated thyroid cancer (DTC) in CCS post-RT remains controversial. We assessed the outcome of thyroid ultrasound (US) surveillance in CCS exposed to RT. METHODS: 306 CCS were surveilled with thyroid US between 2002-2021. Surveillance was dependent on age at the time of primary diagnosis, interval from receipt of RT, and individual provider. Thyroid US, clinicopathologic features, and outcomes were described. Cutpoints of CCS RT age associated with varying risk of nodule presentation were explored. The selected cutpoints were used to define age categories, which were then used to compare thyroid nodule-related outcomes. Risk factors for thyroid nodule(s) were evaluated using multivariate logistic regression (odds ratio [OR] [95% confidence interval]). RESULTS: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (45%) and/or RT to craniospinal (44%), chest (11%), and neck regions (6%). About 49% (n = 150) of patients had thyroid nodule(s). Forty-four patients underwent surgery, and 28 had DTC: 19 with American Thyroid Association (ATA) low-risk classification, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Age cutpoint analyses identified cutpoints 3 and 10; hence, ≤3, >3 to ≤10, and >10 years were used. Of the 9 patients with intermediate- or high-risk disease, 8 were ≤10 years and 1 was >10 years at the time of RT. Female sex (OR = 1.62 [1.13-2.12] p = 0.054) and greater interval between RT and first US (OR = 1.10 [1.04-1.16] p = 0.001) were independent risk factors for nodule presentation. CONCLUSIONS: Thyroid US surveillance may be beneficial for CCS exposed to RT at younger ages (≤10 years) for earlier detection of DTC, prior to developing advanced metastatic disease.

Incorporation and Utilization of an Additional Needs Screener by Surgical Trainees for Comprehensive Care of Underserved and Underinsured Surgical Patients.

OBJECTIVE: Comprehensive, socially-minded healthcare has historically been delivered in the primary care setting. For underserved patient populations, however, a surgical care episode may serve as the health care access point. To maximize patient wellbeing during the perioperative period, our surgical center developed the Additional Needs Screener (ANS). Operationalized into practice by GME and UME trainees, this tool screens surgical patients across 3 domains (social, emotional, and immigration needs) and connects patients to partner organizations if appropriate. This study describes the pilot utilization of the ANS among underserved and underinsured surgical patients. DESIGN: Clinical quality improvement and retrospective cohort study of patients completing the ANS from implementation in September 2021 to September 2022. SETTING: The Hospital of the University of Pennsylvania, PA-a tertiary care center. PARTICIPANTS: One hundred and 10 underinsured and/or underserved patients completed at least 1 ANS domain. RESULTS: Patients were majority female (55F, 53M, 2 other) and Hispanic/Latinx (72%) with a median age of 38 (IQR = 34-48). Most patients spoke a primary language other than English (77%), and nearly all were either uninsured (82%) or received emergency medical assistance or Medicaid (14%) at referral. Patients demonstrated significant needs; 39% endorsed difficulty affording housing, 32% endorsed difficulty paying for food, 29% endorsed experiencing current life-interfering distress, and 75% had undocumented immigration status. Ultimately, 57% of screened patients accepted referrals to our needs response teams. CONCLUSIONS: Underserved and underinsured patients presenting for surgical care face significant challenges relating to social, emotional, and immigration needs. Through adoption of the ANS, trainees gained competency identifying and addressing these barriers in the perioperative period. Future works will focus on categorizing referral outcomes, developing interventions to increase patient trust, and improving screener dissemination.

Outcomes of ATA Low-Risk Pediatric Thyroid Cancer Patients Not Treated With Radioactive Iodine Therapy.

CONTEXT: The American Thyroid Association (ATA) Pediatric Guidelines recommend patients not receive radioactive iodine therapy (RAIT) for differentiated thyroid cancer (DTC) confined to the thyroid. Since publication, there is ongoing concern whether withholding RAIT will result in a lower rate of remission. OBJECTIVE: This study explores whether ATA low-risk patients treated with and without RAIT achieved similar remission rates. METHODS: Medical records of patients <19 years old diagnosed with DTC and treated with total thyroidectomy between 2010 and 2020 were reviewed. Multivariate logistic regression was performed to evaluate factors influencing RAIT administration and remission rate. RESULTS: Ninety-five patients with ATA low-risk DTC were analyzed: 53% (50/95) and 47% (45/95) were treated with and without RAIT, respectively. RAIT was used to treat 82% of patients before 2015 compared with 33% of patients after 2015 (P < .01). No significant difference in 1-year remission rate was found between patients treated with and without RAIT, 70% (35/50) vs 69% (31/45), respectively. With longer surveillance, remission rates increased to 82% and 76% for patients treated with and without RAIT, respectively. Median follow-up was 5.8 years (IQR 4.3-7.9, range 0.9-10.9) and 3.6 years (IQR 2.7-6.6; range 0.9-9.3) for both cohorts. No risk factors for persistent or indeterminate disease status were found, including RAIT administration, N1a disease, and surgery after 2015. CONCLUSION: Withholding RAIT for pediatric patients with ATA low-risk DTC avoids exposure to radiation and does not have a negative impact on remission rates. Dynamic risk stratification at 1-year after initial treatment is a suitable time point to assess the impact of withholding RAIT for these patients.

Health-Related Quality of Life at Diagnosis for Pediatric Thyroid Cancer Patients.

CONTEXT: Pediatric thyroid cancer (TC) incidence rates are increasing, yet TC has one of the highest survival rates. Despite increased prevalence, little is known about youth adjustment to TC, particularly compared to other pediatric cancers. OBJECTIVE: The current study sought to describe health-related quality of life (HRQoL) in pediatric TC patients early after diagnosis compared to other pediatric cancer patients and healthy youth and examine predictors of HRQoL. METHODS: Pediatric TC patients (ages 8.5-23.4 years) and their caregivers from a pediatric thyroid center completed psychosocial questionnaires as part of a clinic-based screening program around time of surgery. TC HRQoL was compared to other pediatric cancer and healthy youth reported norms. Clinical and demographic data extracted from the medical record were examined for predictors of HRQoL. The main outcome measures included the Pediatric Quality of Life Inventory (PedsQL) and Distress Thermometer. RESULTS: Findings evidenced significantly higher HRQoL for TC patients than other pediatric cancers for all but emotional and school functioning. Compared to healthy youth, TC patients reported significantly lower functioning, except comparable social functioning. No significant differences in HRQoL were identified based on disease severity, thyroid disease history, or treatment. Patient distress was associated with HRQoL. CONCLUSION: The findings suggest general resilience in TC patients compared to youth with other cancers, yet worse HRQoL than peers. Early universal screening is warranted due to a short TC treatment regimen. If administrative barriers preclude comprehensive screening, the single-item Distress Thermometer may identify patients for further comprehensive screening.

Impact of Definitive Surgery for Graves' Disease on Adolescent Disease-Specific Quality of Life and Psychosocial Functioning.

Introduction: Pediatric Graves' disease (GD) is associated with hyperthyroid symptoms that impact psychosocial and physical functioning. Total thyroidectomy (TT) is a definitive treatment option that replaces antithyroid medication. While studies have examined health-related quality of life (QOL) in adults, there are no data describing impacts of TT in pediatrics. In this prospective longitudinal study, we explored the impact of TT on disease-specific QOL and satisfaction with TT and scar appearance in adolescent patients with GD undergoing TT. Methods: Patients 12-19 years old pursuing TT for GD and their parents were recruited to complete surveys before and at least 6 months after TT. Surveys assessed motivations for pursuing TT, QOL, perceived stigmatization, self-esteem, scar appearance, and surgery satisfaction. Paired scores were compared using Wilcoxon signed-rank tests, and subscore associations were assessed using Spearman association tests. Results: Thirty-seven patient-parent dyads completed baseline surveys, including 20 patient-parent dyads completing pre- and post-TT surveys. At baseline, patients reported physical and cognitive symptomology, including tiredness, anxiety, and emotional susceptibility through ThyPRO. Psychosocial functioning at school was low through PedsQL. Disease-specific QOL significantly improved after TT, with notable improvements associated with resolution of goiter (median change = -26.14, p = 0.003), hyperthyroid symptoms (median change = -43.75, p = 0.002), tiredness (median change = -26.79, p = 0.017), cognitive impairment (median change = -14.58, p = 0.035), anxiety (median change = -33.33, p = 0.010), and emotional susceptibility (median change = -28.99, p = 0.035). Physical (median change = 18.75, p = 0.005) and school-related functioning (median change = 30.00, p = 0.002) also significantly improved post-TT. Reported GD-associated eye symptomology (thyroid eye disease) was the second lowest scoring ThyPRO subscore at baseline and improved after surgery (median change = 14.06, p = 0.03). Families reported median recovery by two months, high satisfaction with the outcomes of TT, and minimal concerns over scar appearance. No permanent surgical complications (i.e., recurrent laryngeal nerve damage or hypoparathyroidism) were sustained. Conclusions: In the setting of a high-volume surgeon with low complication rates, TT for GD in pediatric populations may have substantial beneficial effects on disease-specific QOL and psychosocial functioning, with minimal adverse complaints about scar appearance.

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

Introduction: 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. Methods: 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. Results: 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 (p < 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 (p = 0.02). Conclusions: 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.

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

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.

Hormonal Crosstalk Between Thyroid and Breast Cancer.

Differentiated thyroid cancer and breast cancer account for a significant portion of endocrine-related malignancies and predominately affect women. As hormonally responsive tissues, the breast and thyroid share endocrine signaling. Breast cells are responsive to thyroid hormone signaling and are affected by altered thyroid hormone levels. Thyroid cells are responsive to sex hormones, particularly estrogen, and undergo protumorigenic processes upon estrogen stimulation. Thyroid and sex hormones also display significant transcriptional crosstalk that influences oncogenesis and treatment sensitivity. Obesity-related adipocyte alterations-adipocyte estrogen production, inflammation, feeding hormone dysregulation, and metabolic syndromes-promote hormonal alterations in breast and thyroid tissues. Environmental toxicants disrupt endocrine systems, including breast and thyroid homeostasis, and influence pathologic processes in both organs through hormone mimetic action. In this brief review, we discuss the hormonal connections between the breast and thyroid and perspectives on hormonal therapies for breast and thyroid cancer. Future research efforts should acknowledge and further explore the hormonal crosstalk of these tissues in an effort to further understand the prevalence of thyroid and breast cancer in women and to identify potential therapeutic options.

NTRK-fusions in pediatric thyroid tumors: Current state and future perspectives.

Pediatric and adult papillary thyroid cancer (PTC) share many similar oncogenic drivers, but differ in the pathological features and outcomes of the disease. The most frequent genetic alterations in adult PTCs are mutually exclusive point mutations in BRAF or the RAS family. In pediatric PTC, fusion oncogenes involving chromosomal translocations in tyrosine kinase (TK) receptors, most commonly RET and NTRK, are the most common genetic alterations observed. This review of the literature describes the current state of translational research in pediatric NTRK-driven thyroid cancer and highlights opportunities to improve our understanding and current models of pediatric PTC.

The clinical aspect of NTRK-fusions in pediatric papillary thyroid cancer.

Although adult and pediatric papillary thyroid cancer (PTC) share similar oncogenic drivers, they differ in the pathological features and outcomes of the disease. In adults with PTC, the most frequent genetic alterations are mutually exclusive point mutations in BRAFV600E or the RAS family with BRAFV600E commonly associated with invasive disease and decreased response to radioiodine therapy. In pediatric PTC, fusion oncogenes involving chromosomal translocations in tyrosine kinase (TK) receptors, most commonly RET and NTRK, are often found in patients with lateral neck and distant metastases. This brief report reviews clinical data from a single-institute's cohort of NTRK-driven pediatric PTC cases with an updated review of the literature and comparison to adult NTRK-driven PTC.

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

Introduction: Thyroid lobectomy reduces risks of surgical complications and need for levothyroxine (LT4). We aimed at identifying the clinical course and risk factors for postlobectomy hypothyroidism to optimize surgical counseling and management in pediatric patients undergoing lobectomy. Methods: Clinical and biochemical presentations pre- and postlobectomy were retrospectively reviewed for 110 patients who underwent thyroid lobectomy between 2008 and 2020 at the Children's Hospital of Philadelphia. Results: Approximately 28.2% of patients (31/110) developed postlobectomy hypothyroidism defined by an elevated thyrotropin (TSH) level, including 24.5% (27/110) with subclinical hypothyroidism (TSH >4.5 and <10.0 mIU/L) and 3.6% (4/110) with overt hypothyroidism (TSH >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 postlobectomy. When excluding patients with autonomous nodule(s), median preoperative TSH was 1.09 (interquartile range [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 postlobectomy hypothyroidism (odds ratio = 1.8 [confidence interval 1.08-3.13], p = 0.024). Of the patients who underwent thyroid lobectomy and developed postoperative hypothyroidism (n = 31), 38.7% (12/31) had a preoperative diagnosis of an autonomously functioning thyroid nodule. Conclusions: Thyroid function should be evaluated postlobectomy 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 >10.0 mIU/L. Suppressed preoperative TSH associated with autonomous nodules is an independent risk factor for postlobectomy hypothyroidism.