Primary neuroendocrine carcinoma (NEC) of the anal canal is a rare, highly malignant tumor with a poor prognosis. Despite the standard first-line treatment with etoposide or irinotecan combined with cisplatin, effective second-line therapies are lacking. In 2019, Japan approved cancer genome profiling (CGP) tests for solid tumors to enhance genomic understanding. We present the case of a 79-year-old woman with NEC of the anal canal, treated with etoposide, carboplatin, and amrubicin. As Post-standard therapy, CGP suggested pemigatinib, a tyrosine kinase inhibitor; however, the patient died before receiving it. This case highlights the potential of personalized medicine to improve outcomes in such cases.

Endoscopic ultrasonography (EUS)-guided ethanol injection (EI) has recently been introduced as one of the management strategies for pancreatic neuroendocrine neoplasms (PNENs); however, its role as a surgical alternative is unclear. We evaluated the efficacy and safety of EUS-EI in treating small PNENs through a prospective multicenter study.Patients with grade 1 tumors of ≤15 mm confirmed by pathology were included. The primary end point assessed efficacy and safety, measuring complete ablation using computed tomography at 1 and 6 months, prevention of adverse events (AEs) within 1 month, severe pancreatic fistula at 1 month, and incidence/worsening of diabetes mellitus (DM) at 6 months. The composite end point of EUS-EI was compared with that of historical results of a study based on surgical treatment.25 patients with PNENs, with a median tumor size of 10.1 mm, were treated using EUS-EI. The composite primary end point was achieved by 76.0% of patients (19/25; 95%CI 54.9%-90.6%), a proportion significantly higher than that of surgical treatment (P = 0.008). Regarding efficacy, 88.0% (22/25) of patients achieved complete ablation at 1 and 6 months (95%CI 68.8%-97.5%). Regarding safety, 96.0% (24/25) of patients had no severe AEs within 1 month (95%CI 79.7%-99.9%). No patients had severe pancreatic fistulas at 1 month, and 84.0% (21/25) had no incidence or exacerbation, or both, of DM at 6 months (95%CI 63.9%-95.5%).EUS-EI is safe and could be a potent treatment option for patients with small PNENs.

Endoscopic ultrasonography (EUS)-guided radiofrequency ablation has recently been introduced as one of the management strategies for small pancreatic neuroendocrine neoplasms (PNENs). However, prospective data on its safety and efficacy remain limited.

This prospective pilot study was conducted at Okayama University Hospital from May 2023 to December 2024. Patients with grade 1 PNENs ≤15 mm, confirmed by EUS-guided fine-needle aspiration, were included. The primary endpoint was safety (adverse events [AEs] evaluated according to the 2010 guidelines of the American Society for Gastrointestinal Endoscopy. Severe AEs were defined as moderate or higher in American Society for Gastrointestinal Endoscopy grading and grade ≥3. Secondary endpoints included efficacy (complete response on contrast-enhanced computed tomography at 1 and 6 months), treatment details, device failure, diabetes mellitus exacerbation, and overall survival at 6 months.

Five patients with non-functional PNENs (median age: 64 years; median tumor size: 10 mm) were treated. AEs occurred in two patients (40%, 2/5), although none was severe. Both patients developed asymptomatic pseudocysts, one experienced mild pancreatitis, and both resolved with conservative treatment. The complete response rates on contrast-enhanced computed tomography at one and 6 months were 100%. The median procedure time was 16 min without any device failure, and the median hospitalization was 5 days. None of the patients developed new-onset or worsening diabetes mellitus. The 6-month overall survival rate was 100%.

EUS-guided radiofrequency ablation demonstrated a high complete response rate with no severe AEs in this pilot study, suggesting a minimally invasive option for small, low-grade PNENs (jRCTs062230014).

Gastrointestinal neuroendocrine tumors (GI-NETs) are slow-growing tumors with the potential for malignancy that originate from neuroendocrine cells. Therefore, early diagnosis and treatment of GI-NETs are necessary to prevent metastasis. The widespread use of colonoscopy, which allows early detection of rectal neuroendocrine tumors (rNETs) that are small enough to be treated endoscopically, has resulted in an increasing rate of endoscopic resection of rNETs. However, whether the long-term prognosis of endoscopically resected rNETs is favorable has not yet been determined. This study aimed to assess whether endoscopically resected rNETs affect the long-term prognosis of patients.

We retrospectively reviewed the medical records of 163 consecutive patients with rNETs who underwent endoscopic resection at 11 hospitals in Japan between 1999 and 2012. The primary analysis focused on 47 patients with 51 rNETs who underwent ≥ 10 years of follow-up. The secondary analysis focused on patients who underwent less than 10 years of follow-up.

The median follow-up period of patients included in the primary analysis was 12.3 years (range, 10-19.1 years). The median lesion size was 5 mm (range, 2-12). Three lesions were treated using conventional endoscopic mucosal resection (EMR). Twenty-nine lesions were treated using modified EMR. Nineteen lesions were treated using endoscopic submucosal dissection. The R1 resection rate and lymphovascular invasion rate were 15.7% and 25.5%, respectively. The curative resection (CR) rate and non-CR rate were 66.7% and 33.3%, respectively. Two patients with lesions treated with non-CR underwent radical surgery. None of the 47 patients experienced lesion recurrence during the 10-year follow-up period. Two patients whose lesions were treated with CR died of other diseases.

Death attributable to rNETs did not occur among patients who underwent at least 10 years of follow-up after endoscopic resection.

Advancements in diagnostic technology have led to the improved detection of pancreatic neuroendocrine tumors (PNETs) and thus to an increase in the number of reported cases. Endoscopic ultrasound (EUS) technology, including in combination with contrast-enhanced harmonic imaging, aids in distinguishing PNETs from other tumors, while EUS-guided fine-needle aspiration or biopsy has improved the histological diagnosis and grading of tumors. The recent introduction of EUS-guided ablation using ethanol injection or radiofrequency ablation has offered an alternative to surgery in the management of PNETs. Comparisons with surgery have shown similar outcomes but fewer adverse effects. Although standardized protocols and prospective studies with long-term follow-up are still needed, EUS-based methods are promising approaches that can contribute to a better quality of life for PNET patients.

There are as yet no data on the long-term clinical outcomes or the frequency of lymph node metastasis after surgical resection in patients with rectal neuroendocrine tumors (NETs). Our study investigated the long-term clinical outcomes and the frequency of lymph node metastasis in patients with rectal NETs treated by surgical resection.

Fifty-one patients with rectal NETs who underwent rectal resection with total mesorectal excision between January 2000 and July 2020 at our hospital were enrolled. Twenty-eight patients had undergone preoperative endoscopic mucosal resection or endoscopic submucosal dissection before surgical resection. The indication for surgery was determined based on the Japan Neuroendocrine Tumor Society guidelines. Patients diagnosed with neuroendocrine carcinoma were excluded. Main outcome measures are frequency of pathological diagnosis of lymph node metastasis, site of lymph node metastasis, and the long-term prognosis after surgical resection.

Lymph node metastasis was observed in 20 patients (39.2%) with lateral lymph node metastasis occurring in 4 patients (7.8%). There was no significant association between lymph node metastasis and 5-year relapse-free survival (90% for metastasis-negative patients vs 58.1% for metastasis-positive patients, p = 0.094).

The rate of lymph node metastasis in patients with rectal NETs treated by surgical resection with total mesorectal excision was found to be high. However, a good prognosis was achieved by surgical resection even in patients with lymph node metastasis.

Fulminant type 1 diabetes mellitus (F1DM) is a subtype of type 1 diabetes that typically arises from viral infections or exposure to anticancer drugs. In the absence of these triggers, F1DM rarely develops concurrently with pancreatic tumors. This report presents a unique case of F1DM occurring alongside a pancreatic neuroendocrine tumor (PanNET) and pancreatic metastasis of renal cancer. A 72-year-old man with a history of right nephrectomy for renal cancer 20 years prior presented with a sudden onset of severe thirst. Laboratory investigations revealed hyperglycemia, ketoacidosis, and depleted insulin levels, leading to a diagnosis of F1DM. Abdominal computed tomography imaging identified multiple, rapidly enhancing tumors within the pancreatic body and tail, suggestive of metastatic renal cancer. The patient underwent a distal pancreatectomy and splenectomy. Pathological examination confirmed the presence of metastatic renal cell carcinoma and neuroendocrine tumors within the pancreas. A significant reduction in the number of pancreatic islets was observed, and the remaining islets exhibited a complete absence of insulin production. The postoperative course was uneventful, with a notable decrease in the required insulin dosage by approximately 50%. We experienced a rare case of PanNET and pancreatic metastasis of renal cancer complicated with F1DM, in the absence of chemotherapy or viral infection. The possibility of a coexisting pancreatic tumor should be considered in cases of fulminant type 1 diabetes.

Pancreatic neuroendocrine tumors (PNETs) are uncommon and heterogeneous neoplasms, often exhibiting indolent biological behavior. Their incidence is rising, largely due to the widespread use of high-resolution imaging techniques, particularly influencing the diagnosis of sporadic non-functioning tumors, which account for up to 80% of cases. While surgical resection remains the only curative option, the impact of factors such as tumor grade, size, and type on prognosis and recurrence is still unclear.

To investigate prognostic risk factors and outcomes in patients with sporadic PNETs treated surgically.

A retrospective analysis was conducted on patients with sporadic PNETs who underwent pancreatic resection. Data were collected from medical records.

A total of 113 patients were included: 32 with non-functioning tumors (NF-PNETs), 70 with insulinomas, and 11 with other functioning tumors (OF-PNETs). Patients with insulinoma were significantly younger, had a higher BMI, lower prevalence of comorbidities and ASA scores, and underwent significantly more pancreatic enucleations compared to patients with OF-PNET and NF-PNET. The insulinoma group had more grade I tumors, smaller tumor diameter, lower TNM staging, and lower disease recurrence rates. In univariate analysis, age, tumor type, tumor size, and TNM staging were identified as potential risk factors for tumor recurrence. In multivariate analysis, only the NF-PNET type was identified as an independent prognostic factor for disease recurrence.

NF-PNETs are an independent prognostic risk factor for disease recurrence. This finding supports the need for closer follow-up of patients with small tumors who are selected for conservative management.

The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy.

Rare cancers collectively account for a significant proportion of the overall cancer burden in Japan. We aimed to describe and examine the incidence of each rare cancer and the temporal changes using the internationally agreed rare cancer classification. Cancer cases registered in regional population-based cancer registries from 2011 to 2015 and the National Cancer Registry (NCR) from 2016 to 2018 were classified into 18 families, 68 Tier-1 cancer groupings, and 216 single cancer entities based on the RARECAREnet list. Crude incidence rates and age-standardized incidence rates (ASR) were calculated for Tier-1 and Tier-2 cancers. The annual percent change and the 95% and 99% confidence limits for annual ASR for each of the 68 Tier-1 cancers were estimated using the log-linear regression of the weighted least squares method. The differences in ASRs between 2011 and 2018 were evaluated as an absolute change. A total of 5,640,879 cases were classified into Tier-1 and Tier-2 cancers. The ASRs of 18 out of 52 Tier-1 cancers in the rare cancer families increased, whereas the ASR for epithelial tumors of gallbladder decreased. The ASRs of 6 out of the 16 Tier-1 cancers in the common cancer families increased, whereas those of epithelial tumors of stomach and liver decreased. There was no significant change in the incidence of the other 40 Tier-1 cancers. The incidence of several cancers increased due to the dissemination of diagnostic concepts, improved diagnostic techniques, changes in coding practice, and the initiation of the NCR.

While endoscopic resection of rectal neuroendocrine tumors (NETs) has significantly increased, long-term data on risk factors for recurrence are still lacking. Our aim is to analyze the long-term outcomes of patients with rectal NETs after endoscopic resection through risk stratification.

In this multicenter retrospective study, we included patients who underwent endoscopic resection of rectal NETs from 2009 to 2018 and were followed for ≥12 months at five university hospitals. We classified the patients into three risk groups according to the clinicopathological status of the rectal neuroendocrine tumors: low, indeterminate, and high. The high-risk group was defined if the tumors have any of the followings: size ≥ 10 mm, lymphovascular invasion, muscularis propria or deeper invasion, positive resection margins, or mitotic count ≥2/10.

A total of 346 patients were included, with 144 (41.6%), 121 (35.0%), and 81 (23.4%) classified into the low-, indeterminate-, and high-risk groups, respectively. Among the high-risk group, seven patients (8.6%) received salvage treatment 28 (27-67) days after the initial endoscopic resection, with no reported extracolonic recurrence. Throughout the follow-up period, 1.1% (4/346) of patients experienced extracolonic recurrences at 56.5 (54-73) months after the initial endoscopic resection. Three of these patients (75%) were in the high-risk group and did not undergo salvage treatment. The risk of extracolonic recurrence was significantly higher in the high-risk group compared to the other groups (p = 0.039).

Physicians should be concerned about the possibility of metastasis during long-term follow-up of high-risk patients and consider salvage treatment.

Background: Neuroendocrine carcinomas (NECs) of the tubular gastrointestinal tract (GI-NECs) are rare and associated with worse clinical outcomes. This population-based study aims to highlight key demographics, clinicopathological factors, and survival outcomes in the US population. Methods: Data from 10,387 patients with GI-NECs were extracted from the Surveillance, Epidemiology, and End Result (SEER) database from 2000 to 2020. Results: Most patients were >40 years old at the time of presentation with a median age of 63 years old, with almost equal ethnic distribution per US population data. The most common primary tumor site was the small intestine (33.6%). The metastatic spread was localized in 34.8%, regional in 27.8%, and distant in 37.3% of cases, and the liver was the most common site of metastasis (19.9%) in known cases of metastases. Most NEC patients underwent surgery, presenting the highest 5-year overall survival of 73.2% with a 95% confidence interval (CI) (95% CI 72.0-74.4%), while chemotherapy alone had the lowest 5-year survival of 8.0% (95% CI 6.4-10.0%). Compared to men, women had a superior 5-year survival rate of 59.0% (95% CI 57.6-60.5%). On multivariate analysis, age > 65 (HR 2.49, 95% CI 2.36-2.54%, p ≤ 0.001), distant metastasis (HR 2.57, 95% CI 2.52-2.62%, p ≤ 0.001), tumor size > 4 mm (HR 1.98, 95%, CI 1.70-2.31%, p ≤ 0.001), esophageal (HR 1.49, 95% CI 0.86-2.58%, p ≤ 0.001), transverse colon (HR 1.95, 95% CI 1.15-3.33%, p ≤ 0.01), descending colon (HR 2.12, 95% CI 1.12, 3.97%, p = 0.02) anorectal sites, and liver or lung metastases were associated with worse survival. Surgical intervention and tumors located in the small intestine or appendix showed a better prognosis. Conclusion: GI-NECs are a group of rare malignancies associated with a poor prognosis. Therefore, epidemiological studies analyzing national databases may be the best alternative to have a more comprehensive understanding of this condition, assess the impact of current practices, and generate prognosis tools.

Endoscopic resection is widely accepted as a local treatment for rectal neuroendocrine tumors sized ≤ 10 mm. However, there is no consensus on the best method for the endoscopic resection of rectal neuroendocrine tumors. As a simplified endoscopic procedure, endoscopic submucosal resection with a ligation device (ESMR-L) indicates a histologically complete resection rate comparable to that of endoscopic submucosal dissection (ESD). We hypothesized that ESMR-L than ESD would be preferred for rectal neuroendocrine tumors. Hence, this trial aimed to verify whether ESMR-L is non-inferior to ESD in terms of histologically complete resection rate.

This is a prospective, open-label, multicenter, non-inferiority, randomized controlled trial of two parallel groups, conducted at the Shizuoka Cancer Center and 31 other institutions in Japan. Patients with a lesion endoscopically diagnosed as a rectal neuroendocrine tumor ≤ 10 mm are eligible for inclusion. A total of 266 patients will be recruited and randomized to undergo either ESD or ESMR-L. The primary endpoint is the rate of en bloc resection with histologically tumor-free margins (R0 resection). Secondary endpoints include en bloc resection rate, procedure time, adverse events, hospitalization days, total devices and agents cost, adverse event rate between groups with and without resection site closure, outcomes between expert and non-expert endoscopists, and factors associated with R0 resection failure. The sample size is determined based on the assumption that the R0 resection rate will be 95.2% in the ESD group and 95.3% in the ESMR-L group, with a non-inferiority margin of 8%. With a one-sided significance level of 0.05 and a power of 80%, 226 participants are required. Assuming a dropout rate of 15%, 266 patients will be included in this study.

This is the first multicenter randomized controlled trial comparing ESD and ESMR-L for the R0 resection of rectal neuroendocrine tumors ≤ 10 mm. This will provide valuable information for standardizing endoscopic resection methods for rectal neuroendocrine tumors.

Japan Registry of Clinical Trials, jRCTs042210124. Registered on Jan 6, 2022.

As laparoscopic surgery becomes more prevalent worldwide, Meckel's diverticula are increasingly being discovered incidentally during surgery. There is no consensus on whether to follow up or resect such diverticula, which are usually asymptomatic. In cases of transabdominal preperitoneal inguinal hernia repair, resection of such a diverticulum might add the risk of mesh infection. Thus, it is unclear whether simultaneous intestinal resection is advisable.

A 64-year-old man diagnosed with a left indirect inguinal hernia underwent laparoscopic inguinal hernia repair, during which a 2-cm Meckel's diverticulum located contralateral to the mesentery of the ileum approximately 30 cm from Bauhin's valve was detected incidentally. Because of the potential risk of future complications such as hemorrhage, diverticulitis, or tumor development, wedge resection of the ileum was performed extracorporeally through an extended umbilical port site after completion of the hernia repair. Pathological examination revealed a neuroendocrine tumor (G1) in Meckel's diverticulum, which was successfully resected without any mesh infection or postoperative complications.

Our patient's clinical course raises two important issues. First, a Meckel's diverticulum detected incidentally during laparoscopic surgery should be resected promptly because malignant tumors within such diverticula have frequently been reported. Second, simultaneous resection with hernia repair using mesh seems to be as safe as other clean-contaminated surgery.

Management of incidental Meckel's diverticula should be selected by appropriate assessment for the risk of malignancy and complications.

Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogenous behavior, whereby some small tumors are aggressive with a propensity for metastasis. Detection of somatic mutations associated with aggressive biology may help with patient stratification and surgical decision-making in patients with well-differentiated PanNETs. Using next-generation sequencing (NGS), we investigated the feasibility of detecting somatic mutations in endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA) specimens and determining the mutational concordance between the EUS-FNA specimens and the primary tumors.

Thirty-eight patients with well-differentiated, nonfunctioning PanNETs were obtained from two tertiary referral centers. Patient demographic characteristics and tumor, clinicopathologic features were collected. Tissue from both the EUS-FNA specimen and the primary tumor was extracted from archival tissue blocks. NGS using a panel of ten genes was performed on both samples.

In our series, the median age was 61.1 years. Tumors were predominantly left-sided (60.5%) and unifocal (94.7%). The median tumor size was 2.2 cm. NGS detected somatic mutations in 29% of primary tumors and 36.8% of EUS-FNA specimens. In primary tumors, DAXX/ATRX mutations were predominantly detected (63.6%). In EUS-FNA specimens, MEN1 mutations were predominantly detected (64.3%). Among non-wild-type specimens, mutational concordance was achieved in 31.6% of cases. In 11 patients with a detectable mutation in the primary tumor, a mutation was detected in the EUS-FNA specimen in 45.5% of cases, with a mutational concordance of 54.5%.

NGS can detect somatic mutations in EUS-FNA specimens of well-differentiated PanNETs. Efforts to improve detection sensitivity and mutational concordance are required to overcome current technical limitations.

Paraneoplastic neurological syndromes, a diverse group of neurological syndromes, are associated with small cell lung, testicular, ovarian, and breast cancers; however, their association with neuroendocrine carcinoma of the small intestine remains unreported. In this report, we present the case of a 78-year-old man diagnosed with neuroendocrine carcinoma of the small intestine and experienced symptoms such as subacute progressive numbness of the extremities and impaired gait. These symptoms were diagnosed as tumor-associated neurological syndrome. The patient had also undergone pyloric gastrectomy for early-stage gastric cancer several years prior to the appearance of the neurological symptoms. Therefore, we could not determine whether the tumor-related neurologic syndrome was owing to gastric cancer or neuroendocrine carcinoma of the small intestine; however, one of these conditions was the cause of the neuropathy. The gait disturbance and numbness relatively improved after surgery for the neuroendocrine carcinoma of the small intestine, suggesting that the neuroendocrine carcinoma of the small intestine likely caused the paraneoplastic neurological syndrome. Collectively, we present a unique report highlighting the putative relationship between small bowel neuroendocrine carcinoma and tumor-associated neurologic syndromes.

Neuroendocrine tumors (NETs) typically present in the setting of metastasis from other solid organs and are considered late manifestations of the disease. Therefore, primary tumors are extremely rare. NETs of the colonic mesentery occur more than 70% of the time in the appendix, small intestine, and rectum. Here, we describe the case of a patient who presented with multiple episodes of diarrhea and abdominal pain, which was waxing and waning in occurrence, with CT findings of a rare primary NET.

Esophageal neuroendocrine carcinoma (ENEC) is a rare cancer that is highly malignant and related to a poor prognosis. In this retrospective study we aimed to elucidate the clinical characteristics, diagnosis and management of patients with ENEC and to evaluate the potential prognostic factors.

Altogether 82 patients diagnosed with ENEC between January 2009 and December 2020 at the Fudan University Shanghai Cancer Center were retrospectively enrolled. Patients' survival was analyzed using the Kaplan-Meier and log-rank methods. Univariate and multivariate analyses and a Cox regression model were used to identify the prognostic factors.

The median overall survival (mOS) was 13 months in all patients. Multivariate analysis revealed that advanced tumor stage (hazard ratio [HR] 2.67, 95% confidence interval [CI] 1.07-6.66, P = 0.0353), liver (HR 3.36, 95% CI 1.53-7.41, P = 0.0026) and lung metastasis (HR 3.37, 95% CI 1.20-9.51, P = 0.0214) were associated with a poor prognosis. While positive chromogranin A (CgA) expression was related to a favorable outcome (HR 0.21, 95% CI 0.09-0.49, P < 0.001). Also, patients had adjustment of chemotherapy (dose reduction or less than three cycles) were prone to a worse prognosis compared with those did not (HR 4.36, 95% CI 2.10-9.08, P < 0.001).

In patients with ENEC, advanced cancer stage, adjustment of chemotherapy, liver and lung metastasis were associated with a poor survival, while CgA expression was related to a favorable prognosis.

Neuroendocrine neoplasms (NENs) comprise malignancies involving neuroendocrine cells that often lead to fatal pathological conditions. Despite escalating global incidences, NENs still have poor prognoses. Interestingly, research indicates an intricate association of tumor viruses with NENs. However, there is a dearth of comprehension of the complete scenario of NEN pathophysiology and its precise connections with the tumor viruses. Interestingly, several cutting-edge experiments became helpful for further screening of NET for the presence of polyomavirus, Human papillomavirus (HPV), Kaposi sarcoma-associated herpesvirus (KSHV), Epstein Barr virus (EBV), etc. Current research on the neuroendocrine tumor (NET) pathogenesis provides new information concerning their molecular mechanisms and therapeutic interventions. Of note, scientists observed that metastatic neuroendocrine tumors still have a poor prognosis with a palliative situation. Different oncolytic vector has already demonstrated excellent efficacies in clinical studies. Therefore, oncolytic virotherapy or virus-based immunotherapy could be an emerging and novel therapeutic intervention. In-depth understanding of all such various aspects will aid in managing, developing early detection assays, and establishing targeted therapeutic interventions for NENs concerning tumor viruses. Hence, this review takes a novel approach to discuss the dual role of tumor viruses in association with NENs' pathophysiology as well as its potential therapeutic interventions.

Neuroendocrine tumors of the small intestine (si-NET) describe a heterogenous group of neoplasms. Based on the Ki67 proliferation index si-NET are divided into G1 (Ki67 < 2%), G2 (Ki67 3-20%) and rarely G3 (Ki67 > 20%) tumors. However, few studies evaluate the impact of tumor grading on prognosis in si-NET. Moreover, si-NET can form distinct lymphatic spread patterns to the mesenteric root, aortocaval lymph nodes, and distant organs. This study aims to identify prognostic factors within the lymphatic spread patterns and grading.

Demographic, pathological, and surgical data of 208 (90 male, 118 female) individuals with si-NETs treated at Charité University Medicine Berlin between 2010 and 2020 were analyzed retrospectively.

A total of 113 (54.5%) specimens were defined as G1 and 93 (44.7%) as G2 tumors. Interestingly, splitting the G2 group in two subgroups: G2 low (Ki67 3-9%) and G2 high (Ki67 10-20%), displayed significant differences in overall survival (OS) (p = 0.008) and progression free survival (PFS) (p = 0.004) between these subgroups. Remission after surgery was less often achieved in patients with higher Ki67 index (> 10%). Lymph node metastases (N +) were present in 174 (83.6%) patients. Patients with isolated locoregional disease showed better PFS and OS in comparison to patients with additional aortocaval and distant lymph node metastases.

Lymphatic spread pattern influences patient outcome. In G2 tumors, low and high grading shows heterogenous outcome in OS and PFS. Differentiation within this group might impact follow-up, adjuvant treatment, and surgical strategy.

Small-bowel tumors represent a rare entity comprising 0.6% of all new cancer cases in the US, and only 3% of all gastrointestinal neoplasms. They are a heterogenous group of neoplasms comprising of about forty different histological subtypes with the most common being adenocarcinoma, neuroendocrine tumors, stromal tumors and lymphomas. Their incidence has been reportedly increasing over recent years, partly owing to the advances and developments in the diagnostic modalities. Small-bowel capsule endoscopy, device assisted enteroscopy and dedicated small-bowel cross-sectional imaging are complimentary tools, supplementing each other in the diagnostic process. Therapeutic management of small-bowel tumors largely depends on the histological type and staging at diagnosis. The aim of the present review article is to discuss relevant advances in the diagnosis and management of small-bowel tumors.

O6-methylguanine-DNA methyltransferase (MGMT) has been linked with alkylating agent resistance and tumor growth suppression. However, its role remains undetermined in pancreatic neuroendocrine tumors (Pan-NET). The MGMT expression was examined by immunohistochemistry in 142 patients to evaluate MGMT immunoreactivity and clinicopathological factors. We analyzed the relationship between MGMT expression and treatment efficacy in 19 patients who received STZ-based regimens. In 142 Pan-NET, 97 cases (68.3%) were judged as MGMT-positive and 45 cases (31.6%) as negative. MGMT negativity was significantly more common in NET-G2 (62.5%) than in NET-G1 (11.2%, p < 0.001). MGMT-negative cases were associated significantly with larger tumor size (p < 0.01), higher Ki-67 index (p < 0.01), higher mitotic index (p < 0.05), and more frequent liver metastasis (p < 0.05). Of the 19 cases treated with STZ, 6 cases were determined as SD and 4 cases as PD in MGMT-positive patients (N = 10), while 5 cases were determined as PR and 4 cases as SD in MGMT-negative patients (N = 9). Progression-free survival in MGMT-negative cases was significantly better than in MGMT-positive cases (p < 0.05). MGMT expression was lower in NET-G2 than in NET-G1, and STZ-based regimens improved the therapeutic outcomes of MGMT-negative Pan-NET. These findings indicate that NET-G2 may represent a better therapeutic target for STZ treatment.

Neuroendocrine tumours of the gastrointestinal tract are rare. The incidence has increased in recent years due to improvements in diagnostic methods for detecting these lesions. These tumours have a poor prognosis, especially when detected at an advanced stage. The basis of the treatment is resection, and non-surgical treatments are also standard in the treatment process. The situation is similar in even rarer neuroendocrine tumours of the reproductive tract, which are associated with an equally poor prognosis. In this article, we focus on learning about the risk factors (including genetic mutations) that increase the risk of the disease and comparing the effectiveness of non-surgical treatments-chemotherapy, radiotherapy, peptide receptor radionuclide therapy, somatostatin analogues, and immunotherapy. The efficacy of these treatments varies, and immunotherapy appears to be a promising form of treatment; however, this requires further research.

Bouveret Syndrome (BS) is a rare type of gallstone ileus, where a gallstone passes via a cholecystoduodenal fistula and causes gastric outlet obstruction. It comprises 0.3-0.5% of cholelithiasis complications. It primarily affects females with an average incidence age of 74 years. Gastric Neuroendocrine Tumors (G-NETs) make up merely 2% of all forms of gastric neoplasia and are known to be an extremely rare occurrence. Their annual incidence is estimated to be one to two per 1 million individuals, and they comprise 8.7% of all known neuroendocrine neoplasia of the gastrointestinal system.

We present the case of a 44-year-old Middle Eastern female who presented to the clinic due to multiple episodes of food containing biliary nonprojectile emesis accompanied by epigastric pain. Preoperative radiological workup revealed a Bezoar blocking the gastric outlet and a G-NET in the mucosal layer of the stomach.

Surgical intervention consisted of excising the impacted calculus to relieve the existing gastric outlet obstruction simultaneous to performing an uncut Roux-en-Y to treat the G-NET condition. The patient underwent complete recovery.

BS is an extremely rare form of gallstone ileus and gastric outlet obstruction. Its clinical presentation is nonspecific and results in misdiagnosis. Additionally, it is rare to occur in our patient's age group. NETs are also profoundly rare forms of neoplasia. To the best of our knowledge, no previous cases of simultaneous BS and G-NET have been documented. Therefore, clinical awareness should be raised to timely implement the necessary therapeutic interventions.

Both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) exhibit neuroendocrine differentiation and are classified as neuroendocrine neoplasms (NENs). NECs and nonneuroendocrine neoplasms (non-NENs), such as adenocarcinoma, have similar mutational profiles. The purpose of this study was to identify differences in metastatic patterns and to identify the key factor causing these differences by simultaneously comparing the metastatic patterns of NETs, NECs and non-NENs from various primary organs.

We retrieved data for 4,223 patients with NENs and 41,637 patients with non-NENs arising at various primary sites from an institutional database and then compared NET, NEC, and non-NEN metastatic patterns.

NETs and NECs showed generally similar metastatic patterns. Most NEN patients had a higher liver organotrophic metastasis rate, lower lung organotrophic metastasis rate, and lower pleural/peritoneal organotrophic metastasis rate than non-NEN patients. Some differences were characteristics of specific organs. Some of these site-specific differences were not caused by NENs but by non-NENs, including a higher bone organotrophic metastasis rate for medullary thyroid carcinoma and a lower bone organotrophic metastasis rate for pulmonary NEN. Other differences were probably caused by NENs, including a higher bone organotrophic metastasis rate for colorectal NETs. Uterine cervical NEC showed unique patterns of metastasis compared to NEN from other sites.

Significant differences between the metastatic patterns of NENs and non-NENs were detected. The multigene program that causes neuroendocrine differentiation might be associated with organotropic metastasis.

The incidence of neuroendocrine neoplasms (NENs) has increased over the last decades. The prevalence of NENs has to a lesser extent been previously reported. We wanted to study the trends in incidence and prevalence of NEN in Norway from 1993 to 2021 through the Cancer Registry of Norway. This registry, which covers the whole population, has been found to be 99% complete. The neoplasms were classified as neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). From 1993 to 2021 altogether 10.288 NETs and 13,982 (1.756 outside the lungs) NECs were diagnosed. The incidence of NETs increased from 3.72 to 9.97 per 100,000 per year, corresponding to a 268% increase, p < .001. The largest increase in incidence for NETs was found for pancreas (338%), lung (330%) and small intestine (303%). For NECs there was no change in the incidence, from 9.74 to 9.95 per 100,000 per year, p = .4, but there was an increase in the incidence of NECs originating from the skin (Merkel cell carcinoma) (287%), p < .001, and the GI tract (200%), p = .03. There were no changes in stage distribution at diagnosis for NETs and NECs. The prevalence for NENs increased 666% during the study period, NETs increased from 10.77 to 99.37 per 100.000 (927%), p < .001. For NECs the increase was from 7.4 to 21.56 per 100.000 (291%), p < .001. GI-NECs increased the most from 0.005 to 0.94 (1880%), p = .002. In conclusion, there was a substantial increase in incidence and prevalence of neuroendocrine neoplasms in Norway from 1993 to 2021. This is the first study to report complete prevalence of NENs for a whole nation.

Somatostatin is known to inhibit the secretion of various hormones by acting on endocrine cells through the somatostatin receptor 2 (SSTR2). Immunohistochemical evaluation of SSTR2 has become increasingly important in clinical practice to determine treatment strategies for patients with a neuroendocrine tumor (NET). Gastrointestinal (GI) tracts contain various neuroendocrine cells that constitute a diffuse endocrine system and some NETs are derived from those cells. In addition, NETs have been well known to express a variable spectrum of proteins shared by their normal cell counterparts of the specific anatomical sites. Thus, we may derive the kinetics of SSTR2 expression of NETs, including de novo expression, from the SSTR2 expression of the corresponding normal neuroendocrine cells. Therefore, a detailed study on the distribution of SSTR2 in normal human neuroendocrine cells may contribute to understanding the expression of SSTR2 in GI-NETs. However, the detailed cellular localization of SSTR2 in non-neoplastic neuroendocrine cells remains unknown. Therefore, we immunolocalized SSTR2 in neuroendocrine cells of normal human GI tracts, including the stomach, duodenum, ileum, and rectum, obtained from 41 surgically resected tissue specimens. Double immunohistochemistry of SSTR2 and hormones or hormone-associated proteins was performed. In all GI neuroendocrine cells, cell types other than D- and EC-cells demonstrated a high percentage of SSTR2-positive cases or a high double-positive ratio. In particular, EC-cells showed lower SSTR2-positive ratios in all sites. Midgut NETs, which often produce serotonin, are excellent targets for somatostatin analogs and are positive for SSTR2. Thus, we speculated that EC-cell NETs might lead to the de novo expression of SSTR2. In addition, a previous report showed high SSTR2 expression in ECL-cell NETs and gastrinomas, which could be because they are derived from neuroendocrine cells with high SSTR2 expression. This study may contribute to understanding the expression of SSTR2 in GI-NETs.

Neuroendocrine tumors (NETs) are a type of rare tumor that can occur at multiple organs. Rectal NETs are the most common NETs in gastrointestinal tract. Due to the rarity of rectal NETs in rectal cancer, the molecular features and the correlation with patient therapeutic response and prognosis have not been investigated in detail. In this review, we focused on the molecular features, potential therapeutic targets and prognosis of rectal NETs. By summarizing the relevant studies, we established the mutational landscape of rectal NETs and identified a series of large fragment variations. Driver genes including TP53, APC, KRAS, BRAF, RB1, CDKN2A and PTEN were found as the top mutated genes. Large fragment alterations mainly involved known driver genes, including APC, TP53, CCNE1, MYC, TERT, RB1 and ATM. Germline mutations of APC, MUTYH, MSH6, MLH1 and MSH2 associated with Lynch syndrome or FAP were also found in rectal NETs. The BRAF-V600E mutation was reported as an actionable target in rectal NETs, and the combined BRAF/MEK inhibitors were found to be effective targeting BRAF-V600E in advanced or metastatic NETs. The known prognostic risk factors of rectal adenocarcinoma, including a series of demographic and clinicopathological factors were also prognostic factors for rectal NETs. Furthermore, three types of markers, including genetic alterations, protein expression levels and methylation, were also suggested as prognostic factors for rectal NETs. In summary, we established the landscape of mutations and large-fragment alterations of rectal NETs, and identified potential therapeutic targets and a series of prognostic factors. Future studies may focus on the optimization of therapeutic strategies based on potential actionable biomarkers.

The number of cases of pancreatic cancers in 2019 in Poland was 3852 (approx. 2% of all cancers). The course of the disease is very fast, and the average survival time from the diagnosis is 6 months. Only <2% of patients live for 5 years from the diagnosis, 8% live for 2 years, and almost half live for only about 3 months. A family predisposition to pancreatic cancer occurs in about 10% of cases. Several oncogenes in which somatic changes lead to the development of tumours, including genes BRCA1/2 and PALB2, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1, are involved in pancreatic cancer. Between 4% and 10% of individuals with pancreatic cancer will have a mutation in one of these genes. Six percent of patients with pancreatic cancer have NTRK pathogenic fusion. The pathogenesis of pancreatic cancer can in many cases be characterised by homologous recombination deficiency (HRD)-cell inability to effectively repair DNA. It is estimated that from 24% to as many as 44% of pancreatic cancers show HRD. The most common cause of HRD are inactivating mutations in the genes regulating this DNA repair system, mainly BRCA1 and BRCA2, but also PALB2, RAD51C and several dozen others.

Neuroendocrine tumors (NETs), which are a rare type of tumor, are defined as epithelial cells with predominantly neuroendocrine differentiation and consist of a spectrum of tumors emerging from stem cells throughout the body and can occur anywhere in the body. While they are rare, the incidence over the past few decades has increased. Here we present a case of a 64-year-old female who was incidentally found to have a duodenal neuroendocrine tumor. The patient initially presented to the emergency department secondary to syncope and collapse. During her trauma evaluation, an incidental lobulated soft tissue mass inferior to the distal stomach was seen on complete computed tomography (CT) scans. The surgery team was consulted for resection of the mass and an octreotide scan was performed prior to resection to further evaluate the mass and to check for any signs of metastatic disease. The octreotide scan demonstrated intense radiotracer accumulation within the duodenal mass consistent with a neuroendocrine tumor and no areas of abnormal radiotracer accumulation suspicious for metastatic disease. Pathology of the resected mass was positive for a well-differentiated neuroendocrine tumor with an organoid pattern and homogenous oval-round neoplastic cells with a salt-pepper nuclear and pseudo glandular arrangement that was well-circumscribed and partially encapsulated with negative margins. Immunohistochemistry was positive for AE ⅓, CD56, Synaptophysin, and chromogranin and negative for CD117, DOG-1, CD34, and CD45. The prevalence of NETs has increased over the years due to the improvement in diagnostic tools, such as upper gastrointestinal endoscopy. In addition to the fact that the duodenum is a rare location for such tumors, neuroendocrine tumors are also typically found in those under 50 years old. However, our patient was found to have both a duodenal mass and was over the age of 50 at the time of presentation and diagnosis. To date, a consensus on a conclusive treatment of duodenal NETs (D-NETs) has not been reached. This case brings to light the importance of further research in diagnosing and treating neuroendocrine tumors and also raises awareness for clinicians to have this in their differential.

Pancreatic neuroendocrine neoplasms (PNETs) are rare but can be associated with significant morbidity and mortality. PNETs can be difficult to diagnose and have a propensity for metastasis before their diagnosis is established. To this end, many PNETs do not become apparent until late in their clinical course. Endoscopic ultrasound (EUS) has become the modality of choice for detecting these lesions due to its high tumor detection rate. Additionally, therapeutic techniques have arisen from EUS which allow for the treatment of PNETs. Overall, EUS has become a powerful diagnostic and therapeutic modality for addressing pancreatic lesions such as PNETs. In this perspective article, we provide an overview of the therapeutic potentials of EUS in the management of PNETs.

The purpose of this study was to examine trends in the incidence and incidence-based (IB) mortality of functional pancreatic neuroendocrine tumors(F-PNETs), and to identify factors associated with survival times.

Data were obtained from the Surveillance, Epidemiology, and End Results database from 2000 to 2017. Trends in the age-adjusted incidence of F-PNETs and IB mortality were examined using the Joinpoint Regression Program. Statistical analyses were run using chi-square tests, Kaplan-Meier curves, and the Cox proportional hazards model. Multiple imputation was used to deal with missing data.

A total of 142 patients with F-PNETs met the study inclusion criteria. It was found that the incidence of F-PNETs decreased over the study period, with an annual percent change (APC) of -2. 5% (95% CI [-4. 3, -0. 5], P<0. 05). This decrease was found to be significant for women, and also when limited to cases with distant disease or rare F-PNETs, with APCs of -4. 2% (95% CI [-7. 4, -0. 9], P<0. 05), -6. 7% (95% CI [-10. 4, -2. 8], P<0. 05), and -9. 1% (95% CI [-13. 5, -4. 4], P<0. 05), respectively. The Cox regression analysis revealed that the tumor size, tumor stage, tumor type, and surgical resection were associated with F-PNETs mortality.

This was the first population-based epidemiological study of F-PNETs and we found a continual decrease in the incidence of F-PNETs from 2000 to 2017. The prognosis and survival times were closely related to the calendar year at diagnosis, tumor stage, and tumor size.

A 61-year-old woman was referred to our hospital for intraductal papillary mucinous neoplasm with no symptoms. Magnetic resonance imaging (MRI) depicted a 15 mm nodular lesion at the descending portion of duodenum. Upper gastrointestinal endoscopy showed a submucosal tumor-like mass at the minor duodenal papilla. A boring biopsy of the tumor revealed a neuroendocrine neoplasm (NEN). Various blood hormone tests were all within normal limits, and the tumor was considered to be nonfunctional. Contrast-enhanced computed tomography showed no obvious distant metastasis, and subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) was performed. Histopathological examination revealed a dense cluster of spindle-shaped cells forming a sheet-like foci and areas showing glandular lumen formation, and immunohistochemistry showed synaptophysin ( + ), chromogranin ( + ). Mitotic rate was about 11 mitoses per 2 square millimeters, Ki-67 index was about 0.2%. She was pathologically diagnosed with NEN G2 at the minor duodenal papilla with regional lymph node metastasis according to the WHO2010 classification. The patient has been currently under outpatient observation with a good postoperative course. Review of the literature identified 43 cases of NENs of the minor duodenal papilla. NENs of the minor duodenal papilla have a high rate of lymph node metastasis, even if the tumor size is small.

Calcitonin-producing pancreatic neuroendocrine neoplasms (PanNENs) are extremely rare. There have been no reports of a patient in whom liver metastases were the presenting finding, and a calcitonin-producing PanNEN was subsequently detected after a lengthy period.

A 53-year-old man had diarrhea for several years. Computed tomography (CT) revealed multiple liver tumors. We performed a left trisectionectomy with a bile duct resection. The histologic examination showed neuroendocrine tumors G1. Immunohistochemistry was positive for calcitonin and the serum calcitonin level was elevated. Neuroendocrine neoplasms of hepatic origin are extremely rare, so a systemic exploration was performed, but no tumor was detected. CT showed a 4-mm calcification in the pancreatic body, but no contrast-enhanced mass was noted. Although the liver tumors were resected, the diarrhea and high serum calcitonin level persisted. Serial examinations were performed for 6 years, but no tumor was identified; however, 6.5 years after the hepatectomy the serum calcitonin level increased. CT showed a 10-mm contrast-enhanced mass in the calcified area of the pancreatic body. A distal pancreatectomy was performed. The histologic examination showed a neuroendocrine tumor G1, which mimicked the liver tumors. Immunohistochemistry was positive for calcitonin. After the distal pancreatectomy, the serum calcitonin level decreased and diarrhea resolved. The calcitonin-producing neuroendocrine neoplasm was considered the pancreatic primary and the hepatic tumors were metastases.

Calcitonin-producing PanNENs may be initially recognized as liver tumors and may become evident after a lengthy period, thus long-term observation is recommended. Aggressive surgeries may contribute to long-term survival.