Here we report a case of a patient with a highly proliferating pancreatic NET G3 who died rapidly after three lines of therapy. Despite comprehensive diagnostic workup over the course of the disease, including functional imaging and molecular tumor analysis, treatment options were limited and sustained response to therapy was lacking. Considering that the median overall survival for NET G3 patients and NEC patients is 33–98.7 months and 8.5–17 months, respectively [3, 5, 6], the limited survival time of roughly 14 months in our patient despite confirmed NET morphology raises the question whether there is an in-between subgroup of patients with an intermediate prognosis who would profit from different treatment modalities.

Overlapping features aside, genetic and epigenetic analyses demonstrate a fundamental difference between NET G3 and NEC and suggest that some pancreatic NEC cases are closely related to conventional ductal adenocarcinoma, as they share TP53 and KRAS alterations as well as positivity for the exocrine lineage markers MUC1 and CEA [7, 8]. Interestingly, there are many studies showing grade heterogeneity and grade progression in well-differentiated NET, e.g., NET G3 in the setting of prior NET G1/2 diagnosis [9]. However, most instances of poorly differentiated NEC are unlikely to be a neoplastic progression of NET, and they appear to arise from squamous or glandular cells [10]. Given these presumed differences in pathogenesis, a true grey zone or biological continuum between these two subentities seems implausible.

The current European Society for Medical Oncology (ESMO) guidelines for gastroenteropancreatic NEN recommend platinum/etoposide as the first-line chemotherapy in NEC, while upfront CAPTEM treatment has become the treatment standard in NET G3 [4]. Depending on the clinical presentation, treatment alternatives for NET G3 include 5‑fluorouracil/streptozotocin, everolimus, sunitinib, and peptide receptor radionuclide therapy (PRRT) [4, 11], but the optimal treatment strategy is currently unclear due to lack of data. As our patient had a tumor with a very high proliferation rate for a NET G3 specimen, he received first-line cisplatin/etoposide, however, without substantial benefit (progression-free survival [PFS] of 1.9 months, Fig. 1). Generally, platinum/etoposide therapy is less active in NET G3 compared to NEC (response rate of 20% versus 35%, median PFS of 2.4–5 months versus 5 months) [3, 5]. The outcome reported for CAPTEM, on the other hand, favors its application in NET G3 (response rate of 34.8% in NET G3 versus 14.3% in NEC and median PFS of 9.3 months versus 3.5 months) [12]. In line with these results, our patient had a progression-free survival of 7.8 months with CAPTEM.

Over the past decade, the distinct features of NET G3 and NEC have become increasingly characterized clinically and pathologically. The treatment paradigm of NET G3 has evolved considerably since the conception of this new disease subgroup, but further and more effective therapies are needed, especially for certain very aggressive NET G3.