Grade Progression and Intrapatient Tumor Heterogeneity as Potential Contributors to Resistance in Gastroenteropancreatic Neuroendocrine Tumors

Simple Summary Neuroendocrine neoplasms (NENs) have a varied biology. While well-differentiated neuroendocrine tumors (NETs) typically demonstrate indolent behavior, a subset of these tumors exhibits rapid growth, and eventual resistance to various treatments over time is the rule. We discuss intratumoral heterogeneity as a potential contributor to tumor progression and treatment resistance in these tumors. Clinicians should be aware of the potential for intratumoral heterogeneity, including variable somatostatin receptor (SSTR) expression, molecular alterations, Ki67 indices, and grade progression over time. Histopathologic heterogeneity can exist at baseline within primary tumors, metastases, or between a primary tumor and synchronous metastases. In addition, some NETs demonstrate increases in Ki67 index and/or grade over the disease course. Apparent reductions in tumor grade over time should be interpreted with caution, considering the potential impact of prior treatment and the biopsy size and site. Future strategies may include incorporation of liquid biopsies, serial tumor biopsies, and imaging techniques to identify the most highly proliferative regions for biopsies (recognizing that a Ki-67 index obtained from a routine FNA or core needle biopsy may not adequately represent the whole tumor). Long term, a better understanding of the mechanisms underlying tumor heterogeneity and resistance to therapy will help guide a personalized approach to patients with GEP-NETs. Gastroenteropancreatic neuroendocrine neoplasms (NENs) are a heterogenous group of tumors that are incurable when metastatic, regardless of grade. The aim of this article is to understand tumor heterogeneity and grade progression as possible contributors to drug resistance in gastroentropancreatic neuroendocrine tumors (GEP-NETs). Heterogeneity has been observed in the genetic, pathological, and imaging features of these tumors at baseline. Diagnostic challenges related to tumor sampling and the potential for changes in grade over time further confound our ability to optimize therapy for patients. A better understanding of NEN biology and tumor heterogeneity at baseline and over time could lead to the development of new therapeutic avenues.