2022年 · 第102卷第14期

Gastric neuroendocrine tumors (G-NENs) are a rare class of gastric tumors whose incidence has increased nearly 15-fold over the past 40 years. The WHO in 2010 classified G-NENs into well-differentiated gastric neuroendocrine tumors (G-NET) and poorly differentiated gastric neuroendocrine carcinomas (G-NEC), with significant differences in prognosis. There is significant heterogeneity in G-NENs, and there is still no effective model or marker to predict the prognosis of G-NENs patients. Through analysis of the SEER database (1973-2016), the study found that the age-adjusted incidence of G-NENs increased from 0.309/100,000 in 1975 to 6.149/100,000 in 2016. The study then used data from G-NENs patients in the SEER database to perform regression analysis on G-NET and G-NEC, respectively, and constructed nomograms to predict survival. Finally, the study collected clinical data from G-NENs patients from 8 hospitals in Jiangsu Province, China, verifying the validity of the nomogram. Multivariate analysis in the study revealed independent prognostic factors for both G-NEC and G-NET, including age, distant metastasis, and surgical intervention (P<0.05）。 Furthermore, T, N stage, and pathological grade were significantly associated with survival in patients with G-NEC, while tumor size was a predictor of G-NET prognosis (P<0.05）。 The C-index of the G-NEC and G-NET nomograms was 0.840 and 0.718, respectively, higher than the AJCC staging system in version 8 (0.773 and 0.599). The simultaneous study observed good discrimination of nomograms in the validation cohort (C-index: G-NEC vs. AJCC stage 0.743 vs. 0.714; G-NET vs. AJCC stage 0.945 vs. 0.927). The survival rates predicted by nomograms in the training and validation sets are very close to the actual survival rates.

pancreatic neuroendocrine tumor (PanNET) is heterogeneous and can be divided into hereditary and sporadic. Among them, hereditary PanNET is mostly a component of genetic syndromes. The most common genetic syndrome is multiple endocrine neoplasia 1 (MEN1). The characteristic clinical manifestations of MEN1 are parathyroid adenoma, PanNET and pituitary tumors, in addition to thymic tumors. The molecular basis of MEN1 onset is MEN1 mutation. In sporadic PanNET, MEN1 mutation is also the most common gene change. Whole exon sequencing shows that the proportion of MEN1 mutation in sporadic PanNET reaches 44%. Moreover, MEN1 mutations appeared early in the evolution of PanNET. Therefore, MEN1 is one of the most important genes in the development of PanNET. However, targeted therapies for MEN1 are not ideal.

High-grade gastrointestinal pancreatic neuroendocrine neoplasm (HG-GEP-NEN) is a rare but poorly prognostic type of tumor, and it is an understudied type of tumor. Including well-differentiated neuroendocrine tumors (NET G3) and poorly differentiated intraneurocarcinomas (NEC). NET G3 has a better prognosis than NEC, but is less sensitive to platinum-based chemotherapy than NEC. The treatment of HG GEP-NEC refers to the treatment of small cell lung cancer. At present, there is a general lack of molecular markers for the classification, treatment, and prognosis of HG GEP-NEN. Following pathological reevaluation, the study analyzed tumor DNA and matched blood samples from 181 patients with HG-GEP-NEN, including 152 NEC and 29 NET G3. Based on the sequencing of 360 cancer-related genes, mutations and copy number changes were assessed. The high-frequency mutant genes in NEC were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). Only 14% of RB1 was mutated, but 34% of the copy number changes affected RB1. Other high-frequency copy number deletions were ARID1A (35%), ESR1 (25%), and ATM (31%), of which the two genes that showed high-frequency copy number amplification/increase were MYC (51%) and KDM5A (45%). While the similarity of these molecular features to small cell lung cancer (SCLC) is limited, potentially targeted alterations were found in 66% of NEC samples. Mutations and copy number changes vary depending on the primary tumor site, with BRAF mutations mainly seen in the colon (49%) and FBXW7 mutations mainly seen in rectal cancer (25%). Eight out of 152 NEC (5.3%) were microsatellite instability (MSI). High frequency mutations in NET G3 were common in MEN1 (21%), ATRX (17%), DAXX (14%), SETD2 (14%), and TP53 (14%). In addition, the study also found that the molecular differences of HG-GEP-NEN are related to morphological differentiation and origin site. In summary, its molecular level similarities with small cell lung cancer are limited, but the high proportion of targeted changes suggest that there is great potential for individualized treatment.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for locally advanced or metastatic neuroendocrine tumors (NEN). Although studies have shown that complete or more than 90% tumor reduction therapy can prolong the survival of patients with advanced neuroendocrine tumors, the need for resection of the primary lesion remains controversial. The study compared the effect of pre-resection of primary tumor on patient survival after PRRT treatment. Progression-free survival (PFS) and overall survival (OS) were compared by retrospectively analyzing data from 889 patients with advanced neuroendocrine tumors (G1-G3, stage IV) who received at least one cycle of PRRT (including 486 patients with primary tumors resected before PRRT in Group 1 and 403 patients with unresected primary tumors in Group 2). The median OS in group 1 was 134.0 months [95%CI: 118 to 147 months], compared to 67.0 months (95%CI: 60-80 months,HR=2.79，P<0.001）。 In addition, the median PFS in group 1 after the first PRRT was 18.0 months (95%CI: 15 to 20 months), compared to 14.0 (95%) in group 2CI: 15-18 months,HR=1.21，P=0.012）。 Most of the primary lesions were located in the pancreas (n=335； 38%) and small intestine (n=284； 32%) of patients had primary tumor resection prior to PRRT treatment. In primary gastrointestinal pancreatic and bronchial and pulmonary neuroendocrine, surgical resection of the primary lesions can provide significant survival benefits after PRRT for patients with advanced metastases.