Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort

Abstract

Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Treatment efficacy in a metastatic small intestinal neuroendocrine tumour grade 2 cohort

“…Limited data point to PRRT efficacy even in G3 NEN with high SSTR expression (Lithgow et al 2021), which is consistent with the early plateau we observed in the relationship between Ki-67 and PFS. On the other hand, pivotal SSA studies included only patients with Ki-67 <10%, and small series indicate minimal effect in patients with G3 tumours (McGarrah et al 2020;Lithgow et al 2021;Merola et al 2021).…”

Well-Differentiated Grade 3 Neuroendocrine Tumors

“…They originate more commonly from the pancreas (33–65%), 3 – 8 are usually metastatic at diagnosis (62–80%) 4 , 6 , 9 – 11 with liver metastases being the most common site of metastases (74–95%), 7 , 9 , 12 and are more likely to be clinically nonfunctional (75–95%) 5 , 6 , 9 , 10 despite being octreotide-avid on functional imaging (87–92%). 4 – 7 , 9 , 13 Grade 3 NETs are also frequently fluorodeoxyglucose-avid (75%) and a positive fluorodeoxyglucose-positron emission tomography does not appear to distinguish G3 NETs from NECs. 4 , 6 , 7 Ki-67 is usually lower in G3 NETs (20–50%) than NECs (60–100%) 4 – 7 , 9 , 10 , 12 and overall survival has been reported between 19 and 99 months 4 , 6 , 7 , 9 , 10 compared with 11 to 17 months for NECs.…”

“… 4 – 7 , 9 , 13 Grade 3 NETs are also frequently fluorodeoxyglucose-avid (75%) and a positive fluorodeoxyglucose-positron emission tomography does not appear to distinguish G3 NETs from NECs. 4 , 6 , 7 Ki-67 is usually lower in G3 NETs (20–50%) than NECs (60–100%) 4 – 7 , 9 , 10 , 12 and overall survival has been reported between 19 and 99 months 4 , 6 , 7 , 9 , 10 compared with 11 to 17 months for NECs. 4 – 6 , 9 , 10 , 14 , 15 …”

“… 4 , 6 , 7 Ki-67 is usually lower in G3 NETs (20–50%) than NECs (60–100%) 4 – 7 , 9 , 10 , 12 and overall survival has been reported between 19 and 99 months 4 , 6 , 7 , 9 , 10 compared with 11 to 17 months for NECs. 4 – 6 , 9 , 10 , 14 , 15 …”

“…4,6,7 Ki-67 is usually lower in G3 NETs (20-50%) than NECs (60-100%) [4][5][6][7]9,10,12 and overall survival has been reported between 19 and 99 months 4,6,7,9,10 compared with 11 to 17 months for NECs. [4][5][6]9,10,14,15 There are no established treatment guidelines for G3 NETs. They were excluded from landmark clinical trials establishing the role of various systemic therapies in the management of advanced well-differentiated NETs.…”