Primary Small Bowel Neuroendocrine Tumors Research Articles

Toll-like receptors 1-9 in small bowel neuroendocrine tumors-Clinical significance and prognosis.

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immunity. TLRs are known to mediate both antitumor effects and tumorigenesis. TLRs are abundant in many cancers, but their expression in small bowel neuroendocrine tumors (SB-NETs) is unknown. We aimed to characterize the expression of TLRs 1-9 in SB-NETs and lymph node metastases and evaluate their prognostic relevance. The present study included 125 patients with SB-NETs, of whom 95 had lymph node metastases, from two Finnish hospitals. Tissue samples were stained immunohistochemically for TLR expression, assessed based on cytoplasmic and nucleic staining intensity and percentage of positively stained cells. Statistical methods for survival analysis included Kaplan-Meier method and Cox regression adjusted for confounding factors. Disease-specific survival (DSS) was the primary outcome. TLRs 1-2 and 4-9 were expressed in SB-NETs and lymph node metastases. TLR3 showed no positive staining. In primary SB-NETs, TLRs 1-9 were not associated with survival. For lymph node metastases, high cytoplasmic TLR7 intensity associated with worse DSS compared to low cytoplasmic intensity (26.4% vs. 84.9%, p = 0.028). Adjusted mortality hazard (HR) was 3.90 (95% CI 1.07-14.3). The expression of TLRs 1-6 and 8-9 in lymph node metastases were not associated with survival. SB-NETs and their lymph node metastases express cytoplasmic TLR 1-2 and 4-9 and nucleic TLR5. High TLR7 expression in SB-NET lymph node metastases was associated with worse prognosis. The current research has future perspective, as it can help create base for clinical drug trials to target specific TLRs with agonists or antagonists to treat neuroendocrine tumors.

Defining the number of lymph nodes needed to accurately stage small bowel neuroendocrine tumors: An 8-institution study from the US neuroendocrine tumor study group.

265 Background: Small bowel neuroendocrine tumors (SB-NETs) frequently involve regional lymph nodes (LNs). The prognostic value of LN positivity on recurrence of disease is not well defined. The number of LNs needed to accurately stage patients is unknown. Methods: All patients with primary SB-NETs who underwent curative-intent resection at 8 institutions in the US Neuroendocrine Tumor Study Group between 2000 and 2016 were identified. Patients with distant metastatic disease were excluded. The association of LN positivity with recurrence of disease and the extent of lymphadenectomy required were analyzed. Results: Of 2182 patients with resected NETs, 203 had SB-NETs. Median age was 60 yrs, 56% were male, and median follow-up was 39 months. 83.5% of patients (n = 157) had LN positive disease. There was no difference in 3-year recurrence free survival (3-yr RFS) among patients with 1 or 2 positive LNs compared to patients with negative LNs (p = 0.63). Patients who had 3 or more positive LNs had a worse 3-yr RFS compared to those with 0, 1, or 2 positive LNs (n = 92 vs n = 73; 3-yr RFS 82% vs 92%; p < 0.001). Retrieval of 8 or more LNs was associated with a higher positive LN count compared to less than 8 LNs (4.6 vs. 1.6; p = 0.002). However, an increasing LN ratio was not associated with 3-yr RFS. When examining patients who had less than 8 lymph nodes retrieved, there was no difference in 3-yr RFS in those patients with 3 or more positive LNs compared to those with 0, 1, or 2 positive LNs (3-yr RFS: 100% vs 91%; p = 0.37). Retrieval of more than 8 lymph nodes, however, accurately discriminated patients with 3 or more positive LNs compared to those with 0, 1, or 2 positive LNs (3-yr RFS: 79.7% vs 93.5%; p = 0.005). Conclusions: For patients undergoing curative-intent resection of small bowel NETs, accurate lymph node staging requires a minimum of 8 lymph nodes for examination. 3 or more positive LNs is associated with decreased 3-yr RFS compared to 0, 1, or 2 positive lymph nodes. A thorough regional lymphadenectomy is critical for accurate staging and management of patients with small bowel neuroendocrine tumors.

Changes in gene expression in small bowel neuroendocrine tumors associated with progression to metastases

Small bowel neuroendocrine tumors (SBNETs) present frequently with metastases, yet little is known about the molecular basis of this progression. This study sought to identify the serial differential expression of genes between normal small bowel, primary small bowel neuroendocrine tumors, and liver metastases. RNA isolated from matched normal small bowel tissue, primary small bowel neuroendocrine tumors, and liver metastases in 12 patients was analyzed with whole transcriptome expression microarrays and RNA-Seq. Changes in gene expression between primary small bowel neuroendocrine tumors and normal small bowels, and liver metastases versus primary small bowel neuroendocrine tumors were calculated. Common genes that were differentially expressed serially (increasing or decreasing from normal small bowel to primary small bowel neuroendocrine tumors to liver metastases) were identified, and 10 were validated using qPCR. Use of 2 transcriptome platforms allowed for a robust discrimination of genes important in small bowel neuroendocrine tumors progression. Serial differential expression was validated in 7/10 genes, all of which had been described previously in abdominal cancers, and with several interacting with members of the AKT, MYC, or MAPK3 pathways. Liver metastases had consistent underexpression of PMP22, while high expression of SERPINA10 and SYT13 was characteristic of both pSBTs and liver metastases. Identification of the serial differential expression of genes from normal tissues to primary tumors to metastases lends insight into important pathways for SBNETs progression. Differential expression of various genes, including PMP22, SYT13 and SERPINA10, are associated with the progression of SBNETs and warrant further investigation.

Multifocality in Small Bowel Neuroendocrine Tumors

BackgroundNeuroendocrine tumors (NETs) account for 30% of small bowel (SB) neoplasms. The objectives of this study were to evaluate the incidence of multifocality in primary small bowel neuroendocrine tumors (SBNETs) and to examine the associated outcomes. MethodsPatients with multifocal SBNET were compared to those with a solitary lesion. Only patients who underwent diagnostic workup and surgical intervention at our institution were included in this study. The primary aim of our study was surgical outcomes and mortality and recurrence. The second aim of our study was to evaluate the utility of double-balloon enteroscopy (DBE) and capsule endoscopy. ResultsOf 178 patients with SBNETs during the study period, 85 met inclusion criteria. The mean age was 61.0±12.6 years and 44.7% were male. The ileum was the primary tumor site for 66 patients (77.7%). Of DBE patients, 28 (62.2%) had additional lesions identified, of which 23 (82.1%) had NET confirmed on pathology. Average tumor size was 1.8 cm and most were well differentiated (89.9%), with Ki-67 of ≥ 2% (65.8%); 74.4% had nodal metastases and 51% of patients had stage IV disease. Forty-six patients (54.1%) had multifocal disease, of whom 37 (80.5%) had an ileal primary. No differences in survival or recurrence were seen for multifocal versus solitary disease. ConclusionsSBNETs have a high incidence of multifocality. DBE can be used in the preoperative assessment to detect multifocal NET. Multifocality has no impact on survival or recurrence outcomes.

The role of pre-operative imaging and double balloon enteroscopy in the surgical management of small bowel neuroendocrine tumors: Is it necessary?

Pre-operative localization of small bowel neuroendocrine tumors (SBNET) is important for operative planning. The aim was to determine the effectiveness of pre-operative imaging and double-balloon enteroscopy (DBE) in identifying extent of disease. Database review identified 85 patients with primary SBNET between 2006 and 2013. Analysis included patients who underwent imaging, endoscopy, and surgery at our institution. Average age was 60.7 years. Sixty-six (77.1%) patients had a primary NET in the ileum. Seventy-two patients (67.3%) underwent CT, 47 (46.7%) had MRI, 44 (46.7%) had somatostatin receptor imaging (SRI), and 41 (39.3%) underwent DBE. The sensitivity of each in identifying the NET was 59.7% for CT, 54% for MRI, 56% for SRI, and 88.1% for DBE. Eighteen (21.2%) patients had primary tumors not identified on imaging. Of these 18, 13 underwent DBE, and 12 of 13 (92.3%) DBEs identified the primary lesion. DBE was significantly better at identifying the primary NET than CT, MRI or SRI (P = 0.004, 0.007, and 0.012). Most SBNETs are identified with a combination of imaging modalities. In those with unidentified primary tumors after imaging, DBE should be considered as it may provide valuable information as to the location of the primary tumor.

The Incidence of Over-the-counter Medication Use in Patients with Midgut Neuroendocrine Tumors

Recent increases in the use of over-the-counter (OTC) medicines and the underreporting of the use of these medications to physicians have sparked interest in the number and types of "supportive" therapies used by patients with neuroendocrine tumors (NETS). Patients with NETS are of special interest as a result of the potential interactions/interferences between tumor-associated peptide and amine production and OTC supplements. A prospective analysis of patients with primary small bowel NETS between 1998 and 2012 was conducted to define and catalog each patient's prescription and OTC medication use at each clinic visit. The most recently recorded patient medications were used for this analysis. Three hundred sixty-two patients with small bowel primary NETS were studied. One hundred eighty-seven patients (51.6%) were taking nutritional supplements. Of these taking supplements, the per cent of patients taking one, two, three, or more than three supplements was 28.3, 24.1, 22.5, and 25.1 per cent, respectively. Females (n = 109) were more likely to take supplements in comparison to males (n = 78; P = 0.037). Fifty one patients (14.1%) took proton pump inhibitors and 31 patients (8.6%) took loperamide. OTC supplements were used by 50 per cent of patients with primary small bowel NETS in this study. Over one-third of our patients reported using three or more OTC medicines daily. These medicines have the potential to interact with the metabolism of prescribed medicines, modify ability to clot during surgery, exacerbate NET symptoms, and alter NET markers. Given the prevalence of OTC medications and their potential actions, it is important to carefully catalog their use.

Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors

BackgroundSomatostatin receptor scintigraphy (SRS; octreoscan) is used in neuroendocrine tumors to locate the primary tumor site and delineate the extent of disease. SRS has decreased sensitivity for small bowel neuroendocrine tumors (SBNETs). The reasons for SRS nonlocalization are not clear. We sought to determine factors that correlate with successful primary tumor localization by SRS in patients with resected SBNETs, and also identify factors that confound interpretation of SRS reports. MethodsRecords of patients with resected SBNETs were reviewed for SRS results, tumor size, multifocality, N, and M status. Somatostatin receptor 2 (SSTR2) expression was analyzed in resected tumors by quantitative polymerase chain reaction. SRS reports were reviewed and categorized as localizing the primary tumor or not. A nuclear medicine physician independently reviewed available images. ResultsOf 37 patients with preoperative SRS, the primary tumor was localized in 37%. Of all the factors tested, only small tumor size correlated significantly with SRS nonlocalization. Overexpression of SSTR2 was not significantly different between tumors that were or were not localized by SRS, regardless of tumor size. There were three instances where the SRS report did not agree with the nuclear medicine physician's interpretation as to whether SRS localized the primary tumor. In each case, uptake in mesenteric nodes was a confounding factor. ConclusionsSBNETs <2 cm are most likely to be missed by SRS. SSTR2 expression did not correlate with SRS nonlocalization of the primary tumor. Uptake in mesenteric nodes may help indicate an SBNET primary but can also interfere with its visualization within the small bowel.