Dr Sorbye on Separating NET G3 From NEC Before Choosing Therapy

Halfdan Sorbye, MD, PhD, professor of oncology at Haukeland University Hospital in Bergen, Norway, discusses why an accurate diagnosis is among the most consequential steps in managing high-grade neuroendocrine neoplasms, and how a misstep at the start of care can affect a patient's outcome for the rest of the disease course.

In this interview with Targeted Onc from the 2026 North American Neuroendocrine Tumor Society (NANETS) Symposium, Sorbye acknowledges that separating neuroendocrine tumor grade 3 (NET G3) from neuroendocrine carcinoma (NEC) can be difficult, even for experts. He describes several tools that can help clarify the distinction. Immunohistochemical staining for Rb and p53 may assist in separating the 2 entities, as loss of Rb expression and an abnormal p53 staining pattern can support a diagnosis of NEC. For tumors of pancreatic origin, he also recommends molecular testing, including assessment of KRAS and BRAF alterations, which may provide additional information to help clarify tumor classification.

Even with this workup, some cases remain uncertain. In those situations, Sorbye recommends referring the case for a second opinion rather than proceeding without a clear diagnosis.

Sorbye explains why this step carries so much weight, drawing on findings from the NORDIC NEC 2 study conducted by his group. Among patients with NET G3 and a Ki-67 index below 55%, first-line platinum/etoposide therapy was associated with a median progression-free survival (PFS) of 3.5 months and median overall survival (OS) of 14.3 months. By comparison, patients receiving temozolomide/capecitabine had a median PFS of 10.4 months and OS of 22.5 months, while those receiving temozolomide/everolimus had a median PFS of 12.5 months and OS of 31.4 months.

According to Sorbye, the survival disadvantage associated with suboptimal first-line treatment was not recovered later in the course of treatment. Subsequent lines of therapy did not compensate for the inferior outcomes associated with initial platinum-based treatment in these patients.

"If you start out wrong, it doesn't matter what happens later. The patient will survive shorter," Sorbye said. "So that's why it is so important to get the right diagnosis."

His comments underscore a central theme in the management of high-grade neuroendocrine neoplasms: the choice of first-line therapy depends on how the tumor is classified, and that classification depends on careful pathologic and molecular evaluation. Rb and p53 staining, molecular testing, and expert review when results remain unclear all serve the same goal of ensuring that the initial treatment matches the true nature of the disease.

Because the consequences of an incorrect first-line choice can persist through later therapy, Sorbye emphasizes that getting the diagnosis right at the outset is essential to giving each patient the best opportunity for longer survival.