At the North American Neuroendocrine Tumor Society (NANETS) 2023 Multidisciplinary NET Medical Symposium, one of the areas of interest was grade evolution and its potential implications for clinical practice. Intraindividual tumor heterogeneity was also a topic of discussion.

Following these proceedings, featured expert Jennifer R. Eads, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives on these findings from Dr Eads are presented here.

I like to say that we are only as good as our pathologists in the management of NETs. Getting down to the details of the histology, grade, and other pathologic features is so important to disease management. At the same time, at the individual patient level, interpretation can be tricky since we recognize that you can biopsy 2 different sites and find different Ki-67 scores, resulting in 1 lesion being grade 1 and the other being grade 2, for example.

Fortunately, grades 1 and 2 disease are often treated similarly, but grade differences might factor into your plans for monitoring and surveillance. Initially, we may explain to patients that we want to image them more frequently to “get to know” their tumor. In terms of monitoring, for a patient with grade 1 disease with a Ki-67 of less than 1%, I might try to keep their imaging more spread out. I might obtain imaging a bit more frequently in patients with grade 2 tumors in the higher end of the Ki-67 range and in those with well-differentiated grade 3 disease, and this can help provide reassurance when the patient continues to maintain their somatostatin receptor (SSTR) avidity. For the most part, both grades 1 and 2 tumors are typically avid on SSTR positron emission tomography scans, while more aggressive or poorly differentiated lesions may not be SSTR avid.

Currently, the standard practice is typically to obtain one biopsy at the time of diagnosis, along with SSTR imaging. If all of the disease looks SSTR avid, we approach it essentially as though we are dealing with a homogeneous population of tumors, although this may vary. If we have a patient who has a mix of avid and nonavid disease, we will want to understand the difference(s) between the lesions.

Grade creep in NETs has been receiving greater attention more recently. I think that the phenomenon is real, and it does appear to impact both progression-free and overall survival. So, it is important to watch for it or to be aware of it in some way. In clinical practice, it might be that we start to see a little bit more repeat biopsying over the course of a patient’s journey, but not necessarily; rather, we might incorporate grade creep into our expectations. For instance, in a patient who has had disease for 5 years, we might just expect that it has been smoldering along, using that information in the context of how we are otherwise treating the patient. However, we would really want to implement a repeat biopsy at the time of progression or if there is one lesion in particular that seems to be behaving discrepantly.

At our institution, we often will obtain a second biopsy during liver-directed therapy as part of a research protocol. There is an opportunity to do that because we are already performing an interventional procedure for the liver metastases. At the NANETS 2023 Multidisciplinary NET Medical Symposium, Daniel DePietro, MD, shared some of the findings from these analyses during the NANETS/Society of Interventional Oncology joint symposium, highlighting the association between grade creep and survival outcomes. We now have some studies that suggest an approximate 1% increase in the Ki-67 per year.

Ultimately, it is important to remember that these patients may have their disease for an extended period of time. So, if someone has had the disease for 15 years, does this mean that their tumor grade can creep from grade 1 to high grade 2? I have clinically seen this occur with patients, where their disease may be stable for a period of time and then it progresses more rapidly at a certain point.