From the Guidelines
Neuroendocrine tumors (NETs) are considered high risk when they exhibit several key features, including larger tumor size, high proliferation rates, poor differentiation, and presence of metastases, particularly to the liver or distant sites, as indicated by recent guidelines 1. The primary indicators of high-risk NETs include:
- Larger tumor size (typically greater than 2 cm)
- High proliferation rates (measured by Ki-67 index >20% or high mitotic count)
- Poor differentiation
- Presence of metastases, particularly to the liver or distant sites Tumors with vascular or perineural invasion, as well as those with invasion into surrounding tissues or organs, also carry higher risk. The location of the primary tumor matters significantly; for instance, pancreatic NETs generally have worse prognosis than those in the gastrointestinal tract, as noted in the NCCN guidelines 1. Certain genetic mutations or molecular markers, such as alterations in p53 or Rb pathway genes, can indicate more aggressive behavior. Functional tumors producing excessive hormones (like gastrinomas or insulinomas) may present additional clinical challenges, as discussed in the ESMO clinical practice guidelines 1. Rapid growth rate between imaging studies and presence of symptoms related to hormone hypersecretion or mass effect further classify NETs as high risk. These features are important to recognize because they guide treatment decisions, including the aggressiveness of intervention, frequency of surveillance, and consideration of adjuvant therapies beyond surgical resection, as outlined in the guidelines for the management of gastroenteropancreatic neuroendocrine tumors 1. The diagnosis and management of NETs should be based on current evidence, including the use of somatostatin analogs, hepatic-directed therapies, and molecularly targeted agents, as discussed in the NCCN guidelines 1 and the ESMO clinical practice guidelines 1. Overall, the management of NETs requires a multidisciplinary approach, taking into account the key features of the tumor, as well as the patient's overall health and quality of life, as emphasized in the guidelines for the diagnosis, treatment, and follow-up of gastroenteropancreatic neuroendocrine neoplasms 1.
From the FDA Drug Label
treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.
The features that make a NET high risk are not explicitly stated in the provided drug label. However, it can be inferred that unresectable locally advanced or metastatic disease may be associated with high-risk NET, as these are the conditions for which sunitinib is indicated for the treatment of pNET 2.
- Unresectable disease may indicate a higher risk due to the inability to remove the tumor surgically.
- Locally advanced disease may also be associated with a higher risk due to the potential for further progression.
- Metastatic disease is typically considered high risk due to the spread of the tumor to other parts of the body.
From the Research
Features of High-Risk NET
The following features are associated with high-risk neuroendocrine tumors (NETs):
- High-grade tumors, defined as having a Ki-67 index ≥20% and/or >20 mitoses per 2 mm2 3, 4
- Presence of TP53 and RB1 co-alteration, similar to neuroendocrine carcinoma (NEC) 4
- Tumors with a high proliferation rate, as measured by Ki-67 index 3, 5
- Tumors with extrahepatic metastases, which may have a poorer prognosis 5
- Tumors with a mutation in the MEN1, DAXX, and/or ATRX genes, which may have a distinct clinical behavior 5
Clinical Behavior of High-Risk NET
High-risk NETs can exhibit aggressive clinical behavior, including:
- Rapid progression and short overall survival 4
- Poor response to treatment, including chemotherapy and peptide receptor radionuclide therapy (PRRT) 3, 5
- High risk of metastasis and tumor spread 6
- Poor prognosis, with a mean overall survival of 41 months from the first metastatic disease and 12 months from acquisition of RB1/TP53 co-alteration 4
Treatment of High-Risk NET
The treatment of high-risk NETs is challenging and may involve: