Developing a predictive model for metastatic potential in pancreatic neuroendocrine tumor.

CONTEXT: Pancreatic neuroendocrine tumors (PNETs) exhibit a wide range of behavior from localized disease to aggressive metastasis. A comprehensive transcriptomic profile capable of differentiating between these phenotypes remains elusive. OBJECTIVE: Use machine learning to develop predictive models of PNET metastatic potential dependent upon transcriptomic signature. METHODS: RNA-sequencing data were analyzed from 95 surgically-resected primary PNETs in an international cohort. Two cohorts were generated with equally balanced metastatic PNET composition. Machine learning was used to create predictive models distinguishing between localized and metastatic tumors. Models were validated on an independent cohort of 29 formalin-fixed, paraffin-embedded samples using NanoString nCounter®, a clinically-available mRNA quantification platform. RESULTS: Gene expression analysis identified concordant differentially expressed genes between the two cohorts. Gene set enrichment analysis identified additional genes that contributed to enriched biologic pathways in metastatic PNETs. Expression values for these genes were combined with an additional 7 genes known to contribute to PNET oncogenesis and prognosis, including ARX and PDX1. Eight specific genes (AURKA, CDCA8, CPB2, MYT1L, NDC80, PAPPA2, SFMBT1, ZPLD1) were identified as sufficient to classify the metastatic status with high sensitivity (87.5% - 93.8%) and specificity (78.1% - 96.9%). These models remained predictive of the metastatic phenotype using NanoString nCounter® on the independent validation cohort, achieving a median AUROC of 0.886. CONCLUSIONS: We identified and validated an eight-gene panel predictive of the metastatic phenotype in PNETs, which can be detected using the clinically-available NanoString nCounter® system. This panel should be studied prospectively to determine its utility in guiding operative versus non-operative management.

Long-term impact of prophylactic central neck dissection in non-invasive classic papillary thyroid carcinoma.

BACKGROUND: The utilization of prophylactic central neck dissection (pCND) in cases of non-invasive clinical node-negative (cN0) papillary thyroid carcinoma (PTC) remains a topic of debate, with a dearth of long-term evidence. MATERIALS AND METHODS: We retrospectively reviewed 1181 cN0 PTC patients from 1997 to 2011. Of these, 641 underwent pCND (pCND + group) and 540 did not (pCND-group). Propensity score matching (PSM) was used to identify similar patients. Event-free survival and long-term complications including permanent hyperparathyroidism and permanent recurrent laryngeal nerve (RLN) paralysis were analyzed after PSM. RESULTS: The pCND + group had more aggressive characteristics. In the matched cohort after PSM, the 5-year, 10-year, and 15-year EFS rates were 98.9 %, 98.2 %, and 97.1 % for the pCND + group, and 97.7 %, 97.1 %, and 97.1 % for the pCND-group, respectively. There was no statistically significant difference in EFS rates between the two groups (Log Rank P = 0.38). There was no statistically significant difference in the incidence of permanent hyperparathyroidism (3.3 % vs. 1.5 %, P = 0.08) and permanent RLN paralysis (1.7 % vs. 0.9 %, P = 0.13) between the pCND+ and pCND- groups. CONCLUSION: Our study, with a median follow-up duration of 107 months, indicates that pCND does not lead to a significant reduction in nodal recurrence among non-invasive cN0 PTC patients.

Coexisting Papillary and Anaplastic Thyroid Cancer: Elucidating the Spectrum of Aggressive Behavior.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare and lethal form of thyroid cancer. Overall prognosis is unclear when it arises focally in a background of papillary thyroid cancer (PTC). Clinicopathologic features and outcomes of tumors with coexisting PTC and ATC histologies (co-PTC/ATC) were categorized. METHODS: The National Cancer Database was queried for histologic codes denoting PTC, ATC, and co-PTC/ATC, defined as Grade 4 PTC, diagnosed from 2004 to 2017. Clinicopathologic features, OS, and treatment outcomes were analyzed by histologic type. RESULTS: A total of 386,862 PTC, 763 co-PTC/ATC, and 3,880 ATC patients were identified. Patients with co-PTC/ATC had clinicopathologic features in-between those of PTC and ATC, including rates of tumor size >4 cm, extrathyroidal extension, and distant metastases. On multivariable Cox proportional hazards modeling, age >55 years, Charlson-Deyo score ≥2, positive lymph nodes, lymphovascular invasion, distant metastases, and positive surgical margins were associated with worse OS, whereas radioactive iodine (RAI) and external beam radiation therapy (EBRT) were associated with improved OS, irrespective of margin status. OS was worse for co-PTC/ATC than for PTC but better than for ATC and differed based on the presence or absence of "aggressive" tumor features, including lymph node positivity, lymphovascular invasion, distant metastases, and positive surgical margins. CONCLUSIONS: Survival of patients with co-PTC/ATC is dependent on the presence of aggressive clinicopathologic features and lies within a spectrum between that of PTC and ATC. Adjuvant RAI and EBRT treatment may be beneficial, even after R0 resection.

Prepubertal Children with Papillary Thyroid Carcinoma Present with More Invasive Disease Than Adolescents and Young Adults.

Introduction: Pediatric papillary thyroid carcinomas (PTCs) are more invasive than adult PTCs. No large, contemporary cohort study has been conducted to determine whether younger children are at higher risk for advanced disease at presentation compared to adolescents. We aimed to describe pediatric PTC and contextualize its characteristics with a young adult comparison cohort. Methods: The National Cancer Database was interrogated for pediatric and young adult PTCs diagnosed between 2004 and 2017. Clinical variables were compared between prepubertal (≤10 years old), adolescent (11-18 years old), and young adult (19-39 years old) groups. Multivariable logistic regression modeling for independent predictors of metastases was conducted. A subanalysis of microcarcinomas (size ≤10 mm) was performed. Results: A total of 4860 pediatric (prepubertal n = 274, adolescents n = 4586) and 101,159 young adult patients were included. Prepubertal patients presented with more extensive burden of disease, including significantly larger primary tumors, higher prevalence of nodal and distant metastases, and increased frequency of features such as lymphovascular invasion, and extrathyroidal extension (ETE). Prepubertal age was an independent predictor of positive regional nodes (adjusted odds ratio [AOR] = 1.36 [95% confidence interval {CI} 1.01-1.84], p = 0.04) and distant metastatic disease (AOR = 3.12 [CI 1.96-4.96], p < 0.001). However, there was no difference in survival between groups (p = 0.32). Prepubertal age independently predicted lymph node metastases for microcarcinomas (AOR = 2.19 [CI 1.10-4.36], p = 0.03). Prepubertal (n = 41) versus adolescent (n = 937) patient age was associated with gross ETE (p = 0.004), even with primary tumors ≤1 cm in size. Conclusions: Patients aged <11 years old present with more advanced disease than adolescents, with a higher likelihood of nodal and distant metastatic disease at time of diagnosis, although survival is high. Prepubertal children undergo more extensive treatment, likely reflective of more invasive disease at the outset, even in the setting of a subcentimeter primary tumor.

Association of medicaid expansion of the Affordable Care Act with the stage at diagnosis and treatment of papillary thyroid cancer: A difference-in-differences analysis.

BACKGROUND: The Affordable Care Act's (ACA) Medicaid expansion has increased insurance coverage and improved various cancer outcomes. Its impact in papillary thyroid cancer (PTC) remains unclear. METHODS: Non-elderly patients (40-64 years-old) with PTC living in low-income areas either in a 2014 expansion, or a non-expansion state were identified from the National Cancer Database between 2010 and 2016. Insurance coverage, stage at diagnosis, and RAI administration were analyzed using a difference-in-differences analysis. RESULTS: 10,644 patients were included. Compared with non-expansion states, the percentage of uninsured patients (adjusted-DD -2.6% [95%-CI -4.3to-0.8%],p = 0.004) and patients with private insurance decreased, and those with Medicaid coverage increased (adjusted-DD 9.7% [95%-CI 6.9-12.5%],p < 0.001) in expansion states after ACA implementation. The percentage of patients with pT1 did not differ between expansion and non-expansion states; neither did the use of RAI. CONCLUSIONS: Medicaid expansion has resulted in a smaller uninsured population in PTC patients, but without earlier disease presentation nor change in RAI treatment.

Epigenetics of gastroenteropancreatic neuroendocrine tumors: A clinicopathologic perspective.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEP-NET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA (lncRNA) differential expression profiles that are distinctive of GEP-NETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.