IDH mutation and MGMT promoter methylation are reliable prognostic and predictive biomarkers in grade II-IV diffuse gliomas. Recurrent mutations in the promoter region of the telomerase reverse transcriptase (TERTp) gene have also been found in diffuse gliomas. However, the prognostic and predictive effects of TERTp mutation on IDH or MGMT status are largely unknown. IDH1/2 and TERTp mutations, as well as MGMT methylation statuses, were examined via peptide nucleic acid-mediated PCR clamping and MGMT methylation-specific PCR in 67 paraffinized tumor samples, respectively. TERTp mutation was associated with older patients (≥60 years) and frontally located gliomas. Old age, frontal location, and grade IV were found to be predictive factors of TERTp mutation. TERTp mutation resulted in poor prognosis in overall diffuse gliomas. TERTp mutation was not correlated with overall survival (OS) or progression-free survival (PFS) in the diffuse gliomas. However, TERTp mutations, in combination with MGMT methylation or IDH mutation, showed that there were statistical significant survival differences between MGMT-unmethylated/TERTp-mutated and MGMT-unmethylated/TERTp-wildtype subgroups in grade II gliomas. There was a statistical significant survival difference of OS between IDH-wildtype/TERTp-mutated and IDH-mutated/TERTp-mutated subgroups in grade III gliomas. No significant associations between survival and MGMT/TERTp or IDH/TERTp status were found in grade IV gliomas. In conclusion, the combination of TERTp with IDH or MGMT status may be a prognostic indicator depending on grades.

Rectal neuroendocrine tumors (NETs) are the most common gastrointestinal (GI) NETs with an uncertain malignant potential despite their small size. There are limited data about driver mutations in rectal NETs, which may explain the tumors' unexpected behavior or common histologic morphology with other GI-NETs. Here, we investigated the clinically and pathologically relevant mutations of rectal and nonrectal NETs and compared the frequency and clinical significance of detected mutations between them. We sequenced 84 primary GI-NETs (69 rectal, 7 gastric, 5 appendiceal, and 3 sigmoid colon NETs) and 3 metastatic GI-NETs using targeted next-generation sequencing. Twenty-one rectal NETs (30.4%) showed at least 1 mutation in 24 cancer-related genes; the most common mutations were TP53 (10.1%) and FBXW7 (7.2%), of which 73% were pathogenic/likely pathogenic mutations. TP53 (p.R337C and p.R213*), PTEN (p.W111*, p.Q214*), CDKN2A (p.W110*), FBXW7 (p.R465H), and AKT1 (p.R23Q) were repetitive mutations found exclusively in rectal NETs, whereas SMAD4 (p.R361C) and STK11 (p.D176N) were repetitive mutations found only in gastric NETs. PTEN (p.G129K), EGFR (p.E709K), and KIT (p.V555I) were shared mutations between rectal and appendiceal NETs, whereas SMAD4 (p.R361C), ALK (p.G1202R), VHL (p.Q132*), and IDH1 (p.R132H) were concurrently detected between rectal and gastric NETs. GI-NETs with higher histologic grades, lymphovascular invasion, or recurrence tended to have higher numbers of mutation variants than other tumors; however, there was no significant difference. In conclusion, rectal NETs commonly carried pathogenic/likely pathogenic mutations. Because most mutations were identified in nonhotspot positions, next-generation sequencing is useful in identifying potential drug targets in rectal NETs.

Because rectal neuroendocrine tumors (NETs) are usually small-sized despite of malignant potential, endoscopic resection techniques are recommended. It is unclear whether the lymphovascular invasion (LVI) in the endoscopic resected specimens of small rectal NETs should be indicated for completion surgery. We performed a systematic review and meta-analysis for the incidence of LVI in small rectal NETs (≤20 mm) treated by endoscopic resection and its prognostic impacts. We searched the relevant literature published before January 2019. A total of 21 publications including 1816 patients were enrolled. Overall prevalence of LVI in small rectal NETs was 21.8%. Immunohistochemical method significantly increased the detection rate of LVI up to 35.8% compared than H&E staining only (13.2%). Tumor size more than 5 mm was a risk factor for LVI in small rectal NET, whereas tumor grade did not influence the risk. The LVI in the endoscopic resected specimens was a risk factor for subsequent lymph node metastasis. Separately analyzed in detail, the vascular invasion had a stronger impact on lymph node metastasis than the lymphatic invasion. The prognosis of endoscopically treated rectal NET with LVI was excellent with only 0.3% of recurrence rate during the 5-year follow-up period. LVI is highly prevalent and a risk factor for lymph node metastasis in the small rectal NETs. Endoscopically treated small rectal NETs had excellent short-term prognoses despite of LVI. Immediate completion radical surgery is not absolutely necessary for the LVI-positive small rectal NETs. However, long-term follow-up is recommended for any delayed recurrence.