Steven G. Waguespack

Background: Germline RET codon 634 pathogenic variants (PVs) are at high-risk for early-onset medullary thyroid carcinoma (MTC), but prior reports suggest that RET p.C634R PV may confer a more aggressive phenotype. Methods: We compared MEN2A phenotype and MTC outcomes with germline RET p.C634R vs other RET p.C634X PVs. We conducted a retrospective single-center cohort study of patients harboring a germline RET p.C634 PV, enrolled in the MTC Collaborative Registry (MTCCoRe) and seen at least once between May 2012 and May 2024. Results: One hundred and thirty-five patients included: p.C634R (n = 60) and other p.C634X variants (n = 75). The p.C634R PV was associated with higher penetrance of pheochromocytoma (PHEO) (67% vs 37%, P < .001) and primary hyperparathyroidism (PHPT) (30% vs 15%, P = .036). Prevalence of MTC (87% vs 80%, P = .362), cutaneous lichen amyloidosis (17% vs 9% P = .296), and median age at initial thyroidectomy (18 vs 20 years, P = .479) did not differ significantly between groups. Medullary thyroid carcinoma characteristics, including stage, multifocality, extrathyroidal extension, vascular invasion, lymph node metastases, and distant metastases, were comparable. There were no significant differences in disease-free survival, overall survival, or distant metastasis-free survival for MTC. Disease status at last follow-up also was similar between p.C634R and other p.C634X PVs: no evidence of disease in 43% vs 62% (P = .059), biochemical evidence of disease in 25% vs 17% (P = .226), and structural evidence of disease in 27% vs 20% (P = .298). Conclusion: In this large single-center cohort, germline RET p.C634R was associated with a higher penetrance of PHEO and PHPT but did not increase MTC aggressiveness or worsen clinical outcomes compared with other RET p.C634 PVs.

Although uncommon, thyroid nodules (TNs) in pediatric and young adult patients carry a higher malignancy risk and often present with a high burden of metastatic disease than in adults. The molecular features underlying this distinct clinical behavior remain unclear. We analyzed Afirma Genomic Sequencing Classifier (GSC) data from 283,621 TNs, comparing patients <21 and ≥21 years old. Cytology (Bethesda), GSC benign (B) vs suspicious (S) calls, and Afirma Xpression Atlas (XA) variant/fusion profiles were evaluated in GSC-S and Bethesda V/VI samples. Genome-wide expression was used to derive pathway signatures and thyroid cancer-related scores: BRAF-RAS score (BRS), ERK signaling score, follicular-to-mesenchymal transition (FMT) score, epithelial-to-mesenchymal transition (EMT) score, and thyroid differentiation score (TDS). Among 2,397 patients <21 years (median age: 18.9; 81.4% female) and 281,224 adults ≥21 years (median age: 59.8; 77.1% female), the <21-year samples showed more Bethesda V/VI cytology (14.5% vs 5.0%; P < 0.0001) and a lower GSC-B rate (43.5% vs 68.8%; P < 0.0001). In GSC-S samples, total variant detection was higher in the <21-year group (45.3% vs 37.4%), with enriched BRAF p.V600E, TSHR, and DICER1 variants, while HRAS variants were more common in adults (all P < 0.01). Gene fusions involving RET, NTRK3, and ALK were enriched in the <21-year group (14.5% vs 5.5%; P < 0.0001). TERT promoter mutations were absent in <21-year GSC-S and Bethesda V/VI samples (vs 4.2% and 9.3% in adults). The GSC-S <21-year cohort showed cell-cycle pathway enrichment. The RET/NTRK/ALK-positive <21-year group demonstrated enrichment of angiogenesis and EMT pathways, higher ERK/EMT/FMT scores, and lower BRS/TDS vs genotyped-matched adults. These molecular differences provide mechanistic insight into the more invasive phenotype in pediatric and young adult TNs.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms arising from the sympathetic and parasympathetic nervous systems. Their heterogeneous clinical behavior and metastatic potential present significant management challenges. Pseudohypoxia driven by oxygen metabolism dysregulation is the central oncogenic mechanism in cluster 1 PPGLs, which carry the highest metastatic risk. In these tumors, pathogenic variants in the succinate dehydrogenase complex (SDHx) or von Hippel–Lindau (VHL) gene create an intracellular environment that mimics chronic hypoxia, leading to hypoxia-inducible factor 2 alpha (HIF 2α) activation and driving the hypervascularity and aggressive clinical phenotype. Belzutifan, a first in class selective HIF 2α inhibitor, has emerged as a promising therapeutic strategy for pseudohypoxia driven PPGLs. In the LITESPARK 015 phase 2 trial, belzutifan achieved a disease control rate of 85% and an overall response rate of 26% in patients with locally advanced or metastatic disease. Beyond radiographic outcomes, belzutifan provides meaningful clinical benefits, including improved blood pressure control and enhanced quality of life. Unlike cytotoxic therapies, belzutifan's safety profile is characterized by predictable, mechanism-based adverse events, most commonly grade 1 to 3 anemia. Belzutifan is the first oral and the second Food and Drug Administration–approved therapy for metastatic PPGLs establishing a new therapeutic option for these complex rare tumors. While its development underscores the utility of precision oncology, definitive molecular correlations with clinical efficacy remain to be demonstrated.

Larotrectinib is the first-in-class, highly selective, central nervous system-active TRK inhibitor approved for tumour-agnostic use in TRK fusion cancer. It has previously demonstrated rapid and durable disease control and favourable safety in patients with advanced TRK fusion thyroid carcinoma (TC). After an additional 4 years of follow-up with inclusion of 2 additional patients, and utilising an independent review committee (IRC) to assess overall response rate (ORR), we report updated pooled analyses from 3 phase 1-2 larotrectinib clinical trials, focusing only on patients with TRK fusion differentiated TC (DTC). The primary endpoint was the IRC-determined ORR per RECIST v1.1. Duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety were also assessed. Twenty-four patients (papillary TC, n = 21; follicular TC, n = 2; poorly DTC, n = 1) were included (data cut-off: 20 July 2024). ORR was 79% (95% confidence interval [CI] 58-93); best responses were complete response in 3 (13%) patients, partial response in 16 (67%), stable disease in 3 (13%), progressive disease in 1 (4%) and not evaluable in 1 (4%). Median DoR and PFS were 35 (95% CI 22-not estimable [NE]) and 44 (35-NE) months, respectively; 6-year OS rate was 71% (95% CI 50-91). Six patients remained on treatment. Treatment-related adverse events (TRAEs) were mainly Grade 1/2; no patients permanently discontinued treatment due to TRAEs. Larotrectinib continues to demonstrate durable disease control, extended survival, and a favourable long-term safety profile in patients with advanced TRK fusion DTC requiring systemic therapy.

PURPOSE: Loss of thyroid differentiation underlies the aggressive behavior of a subset of papillary thyroid carcinomas (PTCs). The Thyroid Differentiation Score (TDS), introduced by The Cancer Genome Atlas (TCGA), quantifies tumor differentiation but has limited reproducibility and clinical applicability. We developed and validated a revised score (xTDS) that enables reproducible assessment of tumor differentiation with prognostic relevance across cohorts. METHODS: We analyzed RNA sequencing data from 570 patients with PTC across three independent cohorts: a discovery cohort from the MD Anderson Cancer Center (n = 111) and two external validation cohorts from Vanderbilt University (n = 69) and TCGA (n = 390). xTDS was evaluated for correlation with the original TDS, association with oncogenic drivers, and prognostic value for disease-specific survival (DSS) and progression-free survival (PFS). RESULTS: xTDS showed near-perfect correlation with the original TDS (Spearman ρ = 0.98) and recapitulated known biological patterns, with BRAF V600E–driven tumors exhibiting the lowest differentiation scores and RAS -driven tumors the highest across all cohorts ( P < .001). Low xTDS was associated with worse DSS in the MD Anderson ( P < .001) and Vanderbilt ( P = .005) cohorts and showed a similar numerical trend in TCGA, without statistical significance because of limited events. Low xTDS was consistently associated with worse PFS across all three cohorts ( P = .048, <0.001, and 0.007, respectively). CONCLUSION: xTDS is a reproducible measure of thyroid differentiation that preserves the biological and prognostic relevance of the original TDS while overcoming technical constraints affecting reproducibility.

PURPOSE: Survivorship care models that extend beyond recurrence surveillance to ones that also address treatment-related symptoms are needed. Using data obtained in routine clinical care, we aimed to examine patient-reported symptom burden among adult thyroid cancer survivors. METHODS: Between September 2019 and September 2022, adults were electronically administered the MDASI-Thy, a patient-reported outcome measure that measures symptom severity and interference, within 7 days before their visit at a dedicated thyroid cancer survivorship clinic. The MDASI-Thy generates (1) core symptom severity, (2) thyroid-specific symptom severity, and (3) symptom interference scores, where lower is better. High alert values (HAVs) were defined for four symptoms: Distress (Upset), Pain, Sad, and Shortness of Breath. Multivariable generalized linear models examined associations of patient, cancer, and treatment factors with scores and any HAV. RESULTS: Among 1,557 thyroid cancer survivors, 864 (55.5%) responded. Respondents were a median of 5 years from diagnosis (IQR, 4-8) and predominantly female (79.1%), and most had papillary thyroid carcinoma (92.5%). Mean (standard deviation) scores were 1.20 (1.34) for core severity, 0.99 (1.26) for thyroid-specific severity, and 1.07 (1.80) for interference. Fatigue (11.5%) and Disturbed Sleep (11.3%) were the most common severe symptoms. HAVs occurred in 72 survivors (8.3%), of whom 54 (75%) had a documented plan addressing the HAV. Higher symptom burden was associated with female sex, Black race, greater comorbidity, active smoking, and total thyroidectomy. CONCLUSION: Routine patient-reported symptom screening in thyroid cancer survivorship identified generally low symptom burden but meaningful variations, with a subset reporting severe symptoms, functional interference, and HAVs requiring action.

Introduction: Pituitary carcinoma (PC) is a rare, aggressive endocrine neoplasm characterized by metastasis and challenging clinical management. The transformation from pituitary adenoma (PA) to PC is poorly understood, and predictors of metastasis remain elusive. This study evaluates the clinical course, surgical outcomes, and molecular characteristics of PC. Methods: We retrospectively reviewed patients with PC treated at the M. D. Anderson Cancer Center between 1993 and 2023. Primary outcomes included metastasis-free survival and overall survival (OS). Clinical features, radiographic findings, surgical strategies and outcomes, immunohistochemical profiles, and MIB-1 were analyzed. Results: The cohort (n = 20) had a median age at PA and PC diagnosis of 33.9 and 43.3 years, respectively. The median metastasis-free interval was 7.4 years. GH- and ACTH-secreting tumors showed shorter times to PC diagnosis, while nonfunctioning PAs had longer metastasis-free survival. PAs with MIB-1 > 10% had shorter survival. Dura was the most common site of metastasis within the CNS, and bone was the most common outside the CNS. Leptomeningeal disease was seen in six patients. PAs became aggressive > five years after initial surgical resection (n = 13) or metastasized early within the first five years (n = 7). Median OS from PA diagnosis was 13.7 years, and 8.6 years from PC diagnosis. A total of 102 neurosurgical procedures were performed, with a median of five per patient; the median was similar in patients surviving longer than five years vs. those whose survival was shorter (5.0 vs. 4.5 procedures, p = 0.661). Most surgical interventions post-PC diagnosis were for optic decompression or metastasectomy. All long-term survivors (at least five years after PC diagnosis) received temozolomide-based therapy, with most also receiving radiotherapy. Conclusions: PC shows a variable clinical course, with some PAs progressing to PC after years, while others transform rapidly. All long-term survivors received temozolomide-based therapy, most in combination with radiotherapy and repeated surgical intervention, suggesting that aggressive multimodal management may be associated with prolonged survival. Future research will focus on identifying reliable predictors of metastasis at different time points in the complex clinical evolution of these tumors.

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) accounts for 8-18% of Cushing syndrome cases and is typically due to neuroendocrine tumors such as small cell lung carcinoma and bronchopulmonary neuroendocrine tumors. EAS arising from Ewing sarcoma (EwS) is rare, with only 9 pediatric and 5 adult cases reported to date. We present the case of a 40-year-old woman with refractory, metastatic EwS who developed progressive swelling, fatigue, hypokalemia, profound proximal muscle weakness, and intermittent confusion over 2 months. Physical examination revealed facial plethora, supraclavicular fat pads, hirsutism, ecchymoses, and bilateral lower extremity weakness. Laboratory evaluation was consistent with severe ACTH-dependent hypercortisolism, confirmed to be secondary to EAS after further evaluation, including the radiographic finding of rapid-onset bilateral adrenal hyperplasia. She started metyrapone, an 11-β hydroxylase inhibitor, which resulted in rapid biochemical improvement and allowed for discontinuation of insulin and potassium therapies. Due to the refractory, progressive EwS and the patient's poor performance status, she transitioned to palliative care at home, continuing metyrapone for hypercortisolism management until her death 4 months later. Herein, we summarize the existing literature of EAS in EwS, emphasize the importance of prompt recognition of the condition, and highlight the therapeutic challenges of managing paraneoplastic EAS.

BACKGROUND Patients with rare cancers experience clinical vulnerability owing to limited expert clinicians, equivocal treatment options, and a lack of accessible, reliable information. Medullary thyroid cancer (MTC) is a rare cancer characterized by an advanced, progressive, chronic disease state that often has clinical equipoise in treatment decisions. OBJECTIVE In a previous needs assessment study, an MTC stakeholder group of patients, caregivers, and clinicians identified needs for patient and caregiver education regarding each disease stage and for effective strategies for patient-clinician communication. Here, we report the patient-centered development of a novel online educational resource and patient decision aid, MTCEducate.org, as well as its online dissemination and usability and acceptability analysis. METHODS Working with the same stakeholder group as in the needs assessment and additional patient input, we used the identified needs to guide the development and refinement of MTCEducate.org, e.g., by using storyboarding with iterative feedback. The finalized site was strategically promoted through patient support organizations, social media platforms, national conferences, the American Thyroid Association, and a robust MTC Registry listserv. Site metrics were assessed via Google Analytics for one year following site publication, and site usability and acceptability were evaluated via a confidential survey embedded within the website. RESULTS MTCEducate.org underwent six rounds of stakeholder feedback before its online dissemination in April 2023. Over the first year after publication, the site had 2079 unique visitors and 376 return users. To access the site, 63.6% of visitors used a mobile device, and 36.5% used a desktop computer or tablet. The site had visitors from 69 countries; most visitors (69.3%) were from the United States. Visitors accessed the site most often via direct links found in emails, newsletters, or X posts (51.6%), followed by Facebook (44.8%). Seventy-six visitors fully completed the site usability and acceptability survey. Most respondents identified as women (73%), non-Hispanic (92%) and White (96%). Most respondents were ≥45 years (87%), had an associate’s degree or higher (92%), and were MTC patients or survivors (92%). Most respondents correctly answered MTC knowledge–based questions about tumor markers (96%), lymph node dissection (93%), and Food and Drug Administration–approved medications (73%). Most respondents found the site easy to use (88%) and well-integrated (84%) and indicated that they could learn to use it quickly (86%) and confidently (81%). CONCLUSIONS Using a patient-centered approach, we created MTCEducate.org, an online patient decision aid, whose multipronged deployment reached an international audience. MTCEducate.org’s format and content were well received and had high usability and acceptability. The site visitors’ lack of racial and ethnic diversity and their advanced educational status underscore the need to understand the preferred access and communication styles and educational resources desired by underrepresented populations.

Context: Differentiated thyroid carcinoma (DTC) is rare in children, comprising 2% to 4% of pediatric cancers. Because of low case volumes at individual institutions, comprehensive data on patient and tumor characteristics and treatment outcomes are limited. The Child and Adolescent Thyroid Consortium was established in 2019 to address this gap and to assess impact of changes in practice on outcomes. Objective: This inaugural Child and Adolescent Thyroid Consortium study analyzes the landscape of pediatric DTC and predictors of invasive disease. Design: International, multicenter retrospective analysis of children (<age 19 years) with DTC diagnosed from 2010 to 2019. Setting: Five high-volume pediatric centers. Results: The cohort included 715 children (78.3% female) diagnosed with DTC at median age 15.2 years (range: 3.2-18.9). There were 673 (94%) patients with papillary thyroid carcinoma (PTC) and 42 (6%) had follicular thyroid carcinoma. Among patients with PTC, stage 1(M0) disease was present in 562 individuals (83.5%; 222 N0, 161 N1a, and 179 N1b). Stage 2 (M1) disease was present in 111 (16.5%) children with PTC and 1/42 (2.4%) with follicular thyroid carcinoma. Males and children aged <10 years exhibited more advanced T, N, and M stages. Any extrathyroidal extension correlated with increased nodal and pulmonary metastases. Oncogenic fusions, compared with BRAFV600E, were associated with more advanced N and M stages. Deintensification of therapy since 2015 was not associated with changes in disease outcomes. Conclusion: Invasive DTC is associated with age <10 years, male sex, tumors driven by oncogenic fusions, and extrathyroidal extension. Despite less aggressive therapies in recent years, disease outcomes have not worsened. Recognition of these associations may guide care and prognostication.