Multiomic sequencing of paired primary and metastatic small bowel carcinoids.

Background: Small bowel carcinoids are insidious tumors that are often metastatic when diagnosed. Limited mutation landscape studies of carcinoids indicate that these tumors have a relatively low mutational burden. The development of targeted therapies will depend upon the identification of mutations that drive the pathogenesis and metastasis of carcinoid tumors. Methods: Whole exome and RNA sequencing of 5 matched sets of normal tissue, primary small intestine carcinoid tumors, and liver metastases were investigated. Germline and somatic variants included: single nucleotide variants (SNVs), insertions/deletions (indels), structural variants, and copy number alterations (CNAs). The functional impact of mutations was predicted using Ensembl Variant Effect Predictor. Results: Large-scale CNAs were observed including the loss of chromosome 18 in all 5 metastases and 3/5 primary tumors. Certain somatic SNVs were metastasis-specific; including mutations in ATRX, CDKN1B, MXRA5 (leading to the activation of a cryptic splice site and loss of mRNA), SMARCA2, and the loss of UBE4B. Additional mutations in ATRX, and splice site loss of PYGL, leading to intron retention observed in primary and metastatic tumors. Conclusions: We observed novel mutations in primary/metastatic carcinoid tumor pairs, and some have been observed in other types of neuroendocrine tumors. We confirmed a previously observed loss of chromosome 18 and CDKN1B. Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.

Frequency and Prognostic Significance of Intertumoural Heterogeneity in Multifocal Jejunoileal Neuroendocrine Tumours.

BACKGROUND: A recent study found that multifocal jejunoileal neuroendocrine tumors (SI-NETs) are genetically unrelated synchronous neoplasms. So far, it is unclear if this finding of synchronous independent neoplasms is mirrored by heterogeneity of key morphological parameters of SI-NETs and how it affects patient survival. METHODS: We separately assessed WHO grade (based on the Ki-67 index), expression of basal diagnostic markers (synaptophysin/chromogranin A/CDX2/serotonin), SSTR2a, and the contexture of the immunogenic microenvironment in 146 separate tumors from 28 patients with multifocal SI-NETs and correlated the results with clinicopathological factors and survival. RESULTS: Synaptophysin and chromogranin A were strongly expressed in all tumors. WHO grade was concordant within all multifocal lesions in more than 80% of cases and the highest grade was usually found in the most advanced primary. Intertumoral expression of serotonin, SSTR2, and CDX2 was discrepant in 32%, 43%, and 50% of all patients, respectively. Neither heterogeneity of any of the aforementioned markers nor multifocality itself had any impact on patient survival (p = n.s.). DISCUSSION: Multifocal SI-NET show considerable variability in some of the central diagnostic parameters. However, neither intertumoral heterogeneity of those parameters nor multifocality itself had any impact on patient survival, showing that extensive testing of all multifocal lesions is not necessarily required.

Artificial Intelligence and Machine Learning in the Diagnosis and Management of Gastroenteropancreatic Neuroendocrine Neoplasms-A Scoping Review.

Neuroendocrine neoplasms (NENs) and tumors (NETs) are rare neoplasms that may affect any part of the gastrointestinal system. In this scoping review, we attempt to map existing evidence on the role of artificial intelligence, machine learning and deep learning in the diagnosis and management of NENs of the gastrointestinal system. After implementation of inclusion and exclusion criteria, we retrieved 44 studies with 53 outcome analyses. We then classified the papers according to the type of studied NET (26 Pan-NETs, 59.1%; 3 metastatic liver NETs (6.8%), 2 small intestinal NETs, 4.5%; colorectal, rectal, non-specified gastroenteropancreatic and non-specified gastrointestinal NETs had from 1 study each, 2.3%). The most frequently used AI algorithms were Supporting Vector Classification/Machine (14 analyses, 29.8%), Convolutional Neural Network and Random Forest (10 analyses each, 21.3%), Random Forest (9 analyses, 19.1%), Logistic Regression (8 analyses, 17.0%), and Decision Tree (6 analyses, 12.8%). There was high heterogeneity on the description of the prediction model, structure of datasets, and performance metrics, whereas the majority of studies did not report any external validation set. Future studies should aim at incorporating a uniform structure in accordance with existing guidelines for purposes of reproducibility and research quality, which are prerequisites for integration into clinical practice.

Multiple Small Intestinal Neuroendocrine Tumors With Findings of Intestinal Obstruction.

Carcinoid tumors are one of the most common types of small intestinal neuroendocrine tumors (SI-NETs). However, SI-NETs that manifest as subacute intestinal obstruction are extremely rare. The annual occurrence rate of jejuno-ileal NETs is 0.28-0.8 per 100,000 people. In this report, we describe a case of subacute intestinal obstruction due to a mid-ileal stricture. The patient underwent laparotomy after evaluation and investigation. Mid-ileal growth was noted, and small bowel resection was performed with primary end-to-end anastomosis. Postoperative histopathology revealed the growth to be a well-differentiated NET.

PTPRM, a candidate tumor suppressor gene in small intestinal neuroendocrine tumors.

Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTPµ (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2'-deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.