Halfdanarson, Thorvardur R

Abstract Pancreatic neuroendocrine tumors (PanNETs) have an age-adjusted incidence of 1.5 per 100,000 people, with a notable rise in the incidence of small (≤2 cm) non-functional PanNETs (NF-PanNETs) in recent decades. While surgery is traditionally the preferred treatment for localized NF-PanNETs, active surveillance is now an accepted management strategy for tumors smaller than 2 cm due to their relatively benign behavior. However, this approach has not yet been fully integrated into routine clinical practice. There is considerable histopathological heterogeneity observed in NF-PanNETs, which results in significant variability in clinical presentation, behavior and treatment outcomes. Hence, tumor size alone does not provide sufficient certainty regarding a benign clinical course for decision-making. Although studies advocate for incorporating WHO grade into clinical prognostic assessments, this marker also has limitations. Several established tissue-based markers, such as ATRX and DAXX alterations, alternative lengthening of telomeres, and copy number variations, can be used for PanNET subtyping and correlate with metastatic risk. Combining these markers with traditional histopathological parameters may yield a more comprehensive and accurate prognostic assessment. This review discusses the advantages and limitations of current prognostication methods for small NF-PanNETs and highlights recently established prognostic markers, along with the requirements for their implementation into routine clinical practice. It also proposes practical solutions to address the challenges associated with the immediate integration of these biomarkers into routine care.

Abstract Background Sarcomatoid carcinomas (SC) are rare tumors with both epithelial and mesenchymal characteristics, linked to aggressive behavior and poor prognosis. Sarcomatoid carcinoma of unknown primary (SCUP) is an exceedingly rare subset with limited literature and no standardized management guidelines. This study aims to characterize the clinical presentations, treatment patterns, and genomic landscape of SCUP. Patients and Methods Data were retrospectively collected from the Mayo Clinic Rochester Cancer of Unknown Primary Registry. Patients included had biopsy-proven SC with no identifiable primary tumor despite comprehensive diagnostic evaluations. Baseline characteristics, immunohistochemistry (IHC) results, next-generation sequencing (NGS) data, and treatment outcomes were analyzed. Statistical analyses included descriptive statistics, Kaplan–Meier survival estimates, and Cox proportional hazards regression. Results Fifty-two SCUP patients were identified, with a median age of 60 years. Most patients presented with widely metastatic disease, particularly lytic bone lesions. Elevated alkaline phosphatase (ALP) was noted in nearly half of the patients. IHC showed high positivity for AE1/AE3 and OSCAR antibodies. Tumor NGS revealed 247 alterations, with TP53 being the most common mutation. Patients receiving definitive therapy had a median overall survival (OS) of 72 months, significantly longer than those receiving systemic therapy (14 months). Immunotherapy was a significant prognostic factor, reducing the risk of death by 90%. Conclusions This study provides essential insights into the clinical and genomic characteristics of SCUP, advocating for the integration of definitive therapy and immunotherapy in treatment protocols. Further prospective studies are needed to validate these findings and improve patient outcomes.

Abstract Insulin-producing pancreatic tumors are a common subtype of neuroendocrine tumor. Standard of care includes surgical resection of the pancreatic tumor and medical management with somatostatin analogs. For patients with metastatic disease, tumor control and hypoglycemic symptom relief can be achieved through surgical resection of the tumor, hepatic artery embolization, radiofrequency ablation, or radioembolization using radioactive isotopes as well as with systemic therapy such as somatostatin analogs and everolimus. We present the case of a 74-year-old male with metastatic insulin-producing pancreatic carcinoma. After a long history of successfully controlling his hypoglycemic episodes post-liver wedge resection, bland embolizations subsequently failed to maintain control of the frequency and severity of his hypoglycemic symptoms. Stereotactic body radiotherapy (SBRT) with protons was used to achieve symptomatic control and led to partial radiographic response with complete resolution of his hypoglycemic episodes. This case demonstrates the potential utility of proton SBRT in metastatic insulinomas.

The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NEN are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in grading system changed the definition of grade 3 to include high grade well differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although, these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis and clinical behavior which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited which impact their management. In this review, we will summarize the current advances in the multidisciplinary approach for management of high grade GEP-NENs including G3-NETs and NECs.