IntroductionCarcinoid tumors are rare neuroendocrine tumors; about 5% of patients develop the carcinoid syndrome. We present the case of a patient with carcinoid syndrome undergoing cardiac surgery.Case reportA 74-year-old patient with carcinoid heart disease and hepatic metastases underwent double valve replacement and CABG. The patient was on octreotide therapy and antihypertensive medication. An octreotide infusion was commenced perioperatively. Pharmaceutical agents that could potentially precipitate histamine release or exacerbate catecholamine secretion and carcinoid crises were avoided. Postoperatively, recovery was complicated by atrial fibrillation, chest infection, pleural effusions, acute kidney injury and delirium.DiscussionHepatic metastases cause systemic hormones' secretion, which cause a carcinoid crisis. Perioperative administration of octreotide is used, while vigilance is required to differentiate between hemodynamic effects related to the operation or disease specific factors.ConclusionNo carcinoid crisis was evident perioperatively. High vigilance with appropriate monitoring, aggressive management combined with meticulous choice of pharmaceutical agents led to this outcome.

Surgery is the primary treatment for pancreatic neuroendocrine carcinoma (PNEC), however, the optimal surgical approach remains undetermined. We aimed to compare long-term survival outcomes between patients who received local resection (LR) and radical resection (RR) for PNEC without distant metastasis. Patients diagnosed with PNEC between 2000 and 2020 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Selection bias was minimized by using propensity score matching (PSM). The Kaplan-Meier method and multivariate Cox proportional hazards models were utilized to evaluate overall survival (OS) and cancer-specific survival (CSS). A total of 1331 patients were enrolled in the study, with 678 receiving LR and 653 undergoing RR. The RR group exhibited a poorer grade, larger tumor size, and TN stage compared to the LR group (P <  0.05). After PSM, 450 matched pairs of patients were compared, with no significant differences in demographic and clinical characteristics observed. No significant differences were observed in long-term OS (P =  0.746) or CSS (P =  0.634) between the two groups. Subgroup analyses also demonstrated comparable OS and CSS between the LR and RR groups (P >  0.05). Multivariate Cox analysis revealed age, AJCC stage, N stage, and chemotherapy as independent prognostic risk factors for OS, while AJCC stage and N stage were identified as independent prognostic risk factors for CSS. Our study demonstrated that in patients with PNEC without distant metastasis, LR and RR exhibit similar prognoses, suggesting that LR may be adequate as a treatment option for these patients.

A 67-year-old woman underwent a screening colonoscopy, which revealed a 7-mm rectal subepithelial lesion. Endoscopic submucosal dissection (ESD) confirmed a grade 1 rectal neuroendocrine neoplasm (NEN), and no further treatment was administered. One year after ESD, she was diagnosed with lung cancer, which recurred 4 years later and required chemotherapy. Nine years after ESD, multiple liver metastases from the rectal NEN were found, which were well controlled with radiofrequency ablation. The patient died 13 years after ESD due to the progression of lung cancer. This case highlights the need for long-term follow-up in patients with small rectal NENs treated with endoscopic resection.

Patients with neuroendocrine tumor liver metastases (NETLMs) may develop carcinoid syndrome, carcinoid heart disease, or other symptoms from overproduction of hormones. Hepatic resection and cytoreduction is the most direct treatment of NETLMs in eligible patients, and cytoreduction improves symptoms, may reduce the sequelae of carcinoid syndrome, and extends survival. Parenchymal-sparing procedures, such as ablation and enucleation, should be considered during cytoreduction to maximize treatment of multifocal tumors while preserving healthy liver tissue. For patients with large hepatic tumor burdens, high-grade disease, or comorbidities precluding surgery, liver-directed and systemic therapies can be used to palliate symptoms and improve progression-free survival.

Neuroendocrine neoplasms of the pancreas (pNENs) are rare. In February 2021, a 54-year-old woman was diagnosed with pNEN and multiple metastases within the liver. The patient, diagnosed with grade G2 neuroendocrine neoplasm (T4N0M1), underwent an ultrasonography-guided liver biopsy and radiofrequency ablation. After receiving Sandostatin LAR in April 2021, side effects led to its discontinuation after seven cycles. Following two sessions of radiofrequency ablation, the patient's condition was stable. However, disease progression was noted in September 2023, resulting in hemodialysis and closed peritoneal drainage. Surufatinib was administered, stabilizing the tumor by November 2023. The patient underwent transarterial chemoembolization due to a large tumor burden, with subsequent MRCP showing stability from diagnosis in February 2021 to June 2024. The present case report highlights the role of tailored treatment strategies considering patient comorbidities and tumor biology, and the significance of secondary puncture biopsy, which, despite not being pursued by the patient in the present study due to the associated risks, may provide survival benefits for patients with advanced or metastatic pNEN.

The Iowa Neuroendocrine Tumor (NET) Clinic was founded and developed by two remarkable physicians, Thomas and Sue O'Dorisio. Tom was an Endocrinologist and close friend and colleague of Aaron Vinik. Both men were pioneers in studies of gastrointestinal hormones and the management of patients with NETs. Sue was a Pediatric Oncologist and research scientist with great expertise in new drug development and clinical trials. She and Tom were leaders in bringing somatostatin analogs and somatostatin-conjugated radioligands to the clinic for the therapy and diagnosis of NETs. All three physicians received lifetime achievement awards for their contributions to the field of NETs. This is the story of how the Iowa NET Clinic developed over the years to become a model for the multidisciplinary mantagement of patients with NETs, culminating in its designation as a European Neuroendocrine Tumor Society NET Center of Excellence, and the receipt of a Specialized Project of Research Excellence (SPORE) grant for the study of NETs from the National Institutes of Health.

Neuroendocrine tumor (NET) brain metastases (BM) are rare malignancies which frequently bear a poor prognosis and have the potential to secrete hormones. The optimal treatment approach for these metastases remains unclear, with significant heterogeneity occurring both across and within primary tumor types, and outcome data are limited. Pancreatic neuroendocrine tumor (pNET) BM may be particularly aggressive. While stereotactic radiosurgery (SRS) for other NET BM has previously been described, no report has specifically investigated SRS for management of pNET BM.

A comprehensive literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search terms included ("neuroendocrine tumor" OR "neuroendocrine neoplasm" OR "neuroendocrine carcinoma" OR "NET") AND ("brain metastasis" OR "brain metastases" OR "intracranial metastases") AND ("stereotactic radiosurgery" OR "stereotactic body" OR "CyberKnife" OR "GammaKnife").

Our search strategy yielded 230 articles. After screening, a total of 16 articles with 256 patients were identified. Number of patients per study cohort ranged from 1 to 101 (mean = 16). Ten articles were single case reports. The most commonly investigated primary site was lung (5 studies), followed by skin (2 case reports), and uterine cervix (2 case reports). Median survival post-SRS ranged from 5 to 42 months. Median tumor volume ranged from 0.08 cm3 to 33.62 cm3. Local control rate was provided in 3 of 6 of the reviewed retrospective analyses. A pulmonary cohort of 101 patients reported a recurrence rate of 13.8 % at 12 months. A pulmonary case series similarly reported local progression in only 1 of 8 patients. The mixed primary cohort (33 patients) had a long-term local failure rate of 16.7 %. In addition, we describe a first reported individual case of pNET BM treated with SRS. Nearly 6-years after initial pNET diagnosis, multiple intracranial enhancing lesions were found, which were subsequently treated with SRS. Follow-up imaging demonstrated a statistically significant decrease in lesion diameter (p < 0.001), with none of the 18 BM progressing.

Given the recently increase in age-adjusted incidence of NET BM, determining an optimal treatment approach for these malignancies is of growing importance. Prognosis generally remains poor, with BM being a significant predictor of overall survival. Our review indicated large variability in outcomes both between and within primary tumor types, suggesting a need for further investigation of predictive molecular biomarkers. In addition, to the authors' knowledge, this represents the first reported case of pNET BM successfully treated with SRS.

Central nervous system (CNS) metastases of atypical carcinoid tumors are exceptionally rare. Isolated studies suggest a survival benefit in patients who receive whole-brain radiotherapy (WBRT); however, it has been known to have detrimental effects on long-term memory and executive function. Here, we present a case of a patient initially diagnosed with stage IIB bronchopulmonary carcinoid who later developed hepatic and intracranial metastases despite receiving adjuvant systemic therapy over a two-year period. She underwent hippocampal-sparing WBRT (HS-WBRT), receiving 30 Gy in 10 fractions via daily image-guided photon therapy using two coplanar arcs. Subsequent clinical evaluations and magnetic resonance imaging (MRI) of the brain at 11 months post-treatment demonstrated a decrease in the size and number of brain metastases, with the patient reporting stable memory and cognition. This case demonstrates the efficacious delivery of palliative HS-WBRT in a patient with a rare presentation of brain-metastatic atypical carcinoid, conferring effective local control and preservation of cognition. Multi-therapy regimens that incorporate HS-WBRT may be considered for improved disease control and quality of life. Further investigation of systemic agents, and possible molecular targets that could confer greater efficacy against treatment-progressive atypical carcinoids, is also warranted.

PAX6 immunohistochemistry (IHC) was proposed as a tool to identify a pancreatic origin of neuroendocrine neoplasms (NENs). To evaluate the diagnostic utility of PAX6 IHC, a tissue microarray containing 19,214 samples from 150 tumor types was analyzed. Data on progesterone receptor (PR) and glutamate decarboxylase 2 (GAD2) expression were available from previous studies. PAX6 staining occurred in 2.6% of 17,224 analyzable tumors and 60 tumor categories showed PAX6 positivity in at least one case. The highest rates of PAX6 positivity occurred in pancreatic (42.9-70.8%) and other NENs (up to 50.0%), testicular tumors (up to 58.3%), basal cell carcinomas of the skin (51.9%), squamous cell carcinomas of different organs (1.5-11.8%), and in gynecological tumors (up to 30%). For detection of pancreatic origin of NENs, sensitivity was highest for PAX6 (68.7%) followed by GAD2 (62.6%) and PR (52.5%) while specificity was highest for GAD2 (95.2%), followed by PR (91.3%), and PAX6 (91.1%). Of the analyzed combinations, the highest sensitivity (53.8%) and specificity (100%) was found for PAX6/GAD2, although combinations of PAX6/PR (49.5%/99.3%), PR/GAD2 (40.7%/98.9%), and PAX6/PR/GAD2 (40.6%/100%) did also result in high specificity. Only 14% of the 118 NENs with negativity for all three antibodies were of pancreatic origin. It is concluded that PAX6 IHC is useful to identify a pancreatic origin in case of NEN metastases of unknown origin. The combination with GAD2 and PR further increase the diagnostic performance of PAX6 and results in a >98% specificity in case of positivity for at least 2 of these markers.

Gastrointestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, with the gastric (stomach) subtype (G-NETs) representing a significant clinical focus. Type 1 G-NETs are particularly noteworthy due to their relationship with autoimmune atrophic gastritis (AAG) and pernicious anemia (PA), conditions that impact vitamin B12 absorption. This report presents the case of a patient with a type 1 G-NET identified at the initial diagnosis of PA, demonstrating the connection between these conditions. In the literature review, we discuss the general mechanisms underlying PA, including its etiology, pathogenesis, clinical presentations, and diagnostic approaches. Emphasis is placed on the importance of recognizing and diagnosing this condition early, given the treatable nature of the associated gastric neuroendocrine dysregulation. Additionally, the report examines the broad spectrum of G-NETs, with a special emphasis on the characteristics of type 1 tumors. By considering recent developments in the field, we provide an overview of the current understanding of G-NET epidemiology, classification, clinical features, diagnosis, and management strategies.

Primary hepatic neuroendocrine tumors (PHNET) are neuroendocrine tumors (NETs) originate from liver, they are rare kind of NETs, and only account for about 0.3 % of all NETs. The main symptom of PHNET is abdominal pain, diarrhea and flushing only account for about 7.2 % and 4.3 %, respectively. We report a PHNET patient with diarrhea and flushing face and review cases in the literature.

A 50-year-old male patient came to our hospital for repeated diarrhea and flushing face for more than 2 years. The patient was hepatitis B virus carrier. Contrast-enhanced computed tomographic scan of the abdomen showed multiple tumors in both right and left hepatic lobes. An ultrasound-guided percutaneous needle biopsy was performed. Pathological examination of the biopsy showed the neoplasm were consisted of cells having an eosinophilic cytoplasm and round to oval hyperchromatic nuclei, indicating adenocarcinoma. To further identify the nature of the masses, immunohistochemical examination was performed, the result was positive for β-catenin, Ber-EP4, CgA, CK19, Syn, Ki-67 (3 %). Finally, the patient accepted transcatheter arterial chemoembolization treatment, and his symptoms did not occur ever after.

PHNET is neuroendocrine tumor which originates from liver, it is a rare disease. The main clinical manifestation of PHNET is abdominal pain, in comparison, abdominal mass, weight loss, nausea, vomiting, diarrhea and flushing are relatively rare,In our case, the patient had repeated diarrhea, and his face turned blushing each time when diarrhea occurred. Fine needle aspiration biopsy guided by ultrasound was made, after immunohistochemical examinations, the patient was diagnosed PHNET. Treatments of PHNET include surgical resection, chemotherapy, TACE, percutaneous ethanol injection treatment (PEIT) and transplantation. The patient accepted TACE treatment, his diarrhea and blushing face were controlled.

We reported a PHNET patient who had symptoms of repeated diarrhea and flushing face, and accepted transcatheter arterial chemoembolization treatment. Transcatheter arterial chemoembolization is an effective treatment for PHNET patient with diarrhea.

Although gastric neuroendocrine tumors (NETs) are uncommon compared with gastric carcinomas, the incidence of NETs has been recently increasing. Gastric NETs are classified into three subgroups, and among these, gastrin-independent sporadic type 3 gastric NETs have a poor prognosis because of frequent lymph node or distant metastasis. We experienced a case of an early-stage type 3 gastric NET associated with lymphovascular and submucosal invasion. In a 54 year-old woman, esophagogastroduodenoscopy performed during a health screening identified an elevated lesion of the upper body of the stomach. The results of immunohistochemical analyses of endoscopic biopsy specimens obtained from the lesion were positive for chromogranin A and synaptophysin, indicating an NET. Because the patient's serum gastrin level was normal and she had no predisposing conditions for NET development, the tumor was diagnosed as a type 3 gastric NET. The patient underwent local resection of the tumor and regional lymph node dissection. The resected specimen indicated a diagnosis of type 3 gastric NET with invasion into the submucosa and lymphatic duct. This is an extremely rare case of an early-stage type 3 gastric NET. Our discussion provides insight into the pathogenesis and development of these tumors and the appropriate therapeutic strategy.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.

Neuroendocrine neoplasms (NENs) are a rare group of tumors originating from neuroendocrine cells in various organs. They include neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which differ in biological behavior and prognosis. NETs are usually well-differentiated and slow-growing, while NECs are poorly differentiated and more aggressive. Management of NETs often involves somatostatin analogs like octreotide and lanreotide to control tumor growth and alleviate symptoms, especially in well-differentiated NETs. Lanreotide is used to control tumor growth, and both lanreotide and octreotide alleviate symptoms. Treatment approaches may vary depending on the specific type and grade of the neuroendocrine neoplasm.

This review provides an update on the safety of lanreotide autogel in treating patients with NETs, through a comprehensive review of clinical trials, post-marketing surveillance, real-world evidence, and its safety profile. Specific adverse events, side effects, and potential risks associated with lanreotide autogel are discussed, along with risk mitigation strategies and recommendations for patient monitoring.

The findings highlight the overall safety of lanreotide autogel in managing NETs, focusing on its efficacy in controlling hormone secretion, tumor progression, and symptom management. New safety concerns and precautions are also addressed to help healthcare providers make informed decisions when prescribing lanreotide autogel.

Neuroendocrine tumors (NETs) are uncommon tumors that develop from specialized endocrine cells. Thyroid medullary carcinoma, phaeochromocytomas, pituitary tumors, carcinoid, and gastroenteropancreatic NET are just a few examples of the diverse group known as NET. In recent times, they have garnered significant interest due to their ease of palliation and ability to reveal the long-term impact of the specific hormone raised. Neuroendocrine indicators, particularly chromogranin A, are very helpful in the diagnostic process. Accurate biomarkers that can be employed for NET diagnosis, prognosis and follow-up, therapy stratification, and treatment response evaluation are greatly needed. Due to the great diversity of neuroendocrine neoplasms, particular biomarkers must be developed in order to diagnose, treat, and identify them. The several NET biomarkers covered in this review will aid in the fight against this uncommon illness.

The incidence of neuroendocrine neoplasms (NENs) has gradually increased over the past few decades with the majority of patients presenting with metastases on initial presentation. The liver is the most common site of initial metastatic disease, and the presence of liver metastasis is an independent prognostic factor associated with a negative outcome. Because NENs are heterogenous neoplasms with variable differentiation, grading, and risk of grade transformation over time, accurate diagnosis and management of neuroendocrine liver lesions are both important and challenging. This is particularly so with the multiple liver-directed treatment options available. In this review article, we discuss the diagnosis, treatment, and response evaluation of NEN liver metastases.

Rectal neuroendocrine tumors (NETs) have malignant potential, and lymph node (LN) or distant metastases can occur; however, treatment of NETs 1-2 cm in size is controversial.

This study aimed to identify predictive factors for LN metastasis and prognostic factors for recurrence of rectal NETs, especially tumors 1‒2 cm in size.

Between October 2004 and November 2020, 453 patients underwent endoscopic or surgical treatment for rectal NETs in Seoul National University Hospital. The data on these patients were prospectively collected in our database and reviewed retrospectively. In cases of local excision, we evaluated LN metastasis with radiologic imaging, including computed tomography or magnetic resonance imaging before treatment and during the follow-up periods.

LN metastasis was observed in 40 patients (8.8%). A higher rate of LN metastasis was observed in larger-sized tumors, advanced T stage, lymphovascular invasion (LVI), perineural invasion (PNI), and high tumor grade. In multivariable analysis, the significant risk factors for LN metastasis were tumor size (1 ≤ size < 2 cm: hazard ratio [HR] 64.07; size ≥2 cm: HR 102.37, p < 0.001) and tumor grade (G2: HR 3.63, p = 0.034; G3: HR 5.09, p = 0.044). In multivariable analysis for tumors 1-2 cm in size, the risk factor for LN metastasis was tumor grade (G2: HR 6.34, p = 0.013).

Tumor grade and size are important predictive factors for LN metastasis. In NETs 2 cm in size, tumor grade is also important for LN metastasis, and radical resection should be considered.

Glutamate decarboxylase 2 (GAD2) is the most important inhibitory neurotransmitter and plays a role in insulin-producing β cells of pancreatic islets. The limitation of GAD2 expression to a few normal cell types makes GAD2 a potential immunohistochemical diagnostic marker. To evaluate the diagnostic utility of GAD2 immunohistochemistry, a tissue microarray containing 19,202 samples from 152 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, GAD2 staining was restricted to brain and pancreatic islet cells. GAD2 staining was seen in 20 (13.2%) of 152 tumor categories, including 5 (3.3%) tumor categories containing at least 1 strongly positive case. GAD2 immunostaining was most commonly seen in neuroendocrine carcinomas (58.3%) and neuroendocrine tumors (63.2%) of the pancreas, followed by granular cell tumors (37.0%) and neuroendocrine tumors of the lung (11.1%). GAD2 was only occasionally (<10% of cases) seen in 16 other tumor entities including paraganglioma, medullary thyroid carcinoma, and small cell neuroendocrine carcinoma of the urinary bladder. Data on GAD2 and progesterone receptor (PR) expression (from a previous study) were available for 95 pancreatic and 380 extrapancreatic neuroendocrine neoplasms. For determining a pancreatic origin of a neuroendocrine neoplasm, the sensitivity of GAD2 was 64.2% and specificity 96.3%, while the sensitivity of PR was 56.8% and specificity 92.6%. The combination of PR and GAD2 increased both sensitivity and specificity. GAD2 immunohistochemistry is a highly useful diagnostic tool for the identification of pancreatic origin in case of neuroendocrine neoplasms with unknown site of origin.

Following the increase in colorectal neuroendocrine tumors (NETs), there is a consequent increase in the importance of their appropriate treatment and post-treatment management. It is widely accepted that colorectal NETs sized ≥20 mm and those with muscularis propria invasion are indicated for radical surgery, and those sized <10 mm without the invasion are indicated for local resection. No consensus has been reached regarding the treatment strategy for those sized 10-19 mm without the invasion. Endoscopic resection has become a primary option for the local resection of colorectal NETs. For rectal NETs sized <10 mm, modified endoscopic mucosal resection, such as endoscopic submucosal resection with ligation device and endoscopic mucosal resection with a cap-fitted panendoscope, seems favorable because of its ability to achieve a high R0 resection rate, safety, and convenience. Endoscopic submucosal dissection can also be helpful for these lesions; however, this procedure may be more effective for large lesions or those in the colon. Management following local resection of colorectal NETs is based on the pathological evaluation of factors associated with metastasis, including tumor size, invasion depth, tumor cell proliferative activity (NET grading), presence of lymphovascular invasion, and resection margins. There remain unclear issues in managing cases with NET grading ≥2, positive lymphovascular invasion, and positive resection margins following local resection. In particular, there is confusion regarding managing positive lymphovascular invasion because positivity has become remarkably high with the increased use of the immunohistochemical/special staining. Further evidence based on long-term clinical outcomes is required to address these issues.

People with neuroendocrine neoplasms (NENs) face a multitude of challenges, including delayed diagnosis, low awareness of the cancer among healthcare professionals and limited access to multidisciplinary care and expert centres. We have developed the first patient care pathway for people living with NENs in England to guide disease management and help overcome these barriers. The pathway was developed in two phases. First, a pragmatic review of the literature was conducted, which was used to develop a draft patient care pathway. Second, the draft pathway was then updated following semi-structured interviews with carefully selected expert stakeholders. After each phase, the pathway was discussed among a multidisciplinary, expert advisory group (which comprised the authors and the Deputy Chief Operating Officer, West Suffolk NHS Foundation Trust), who reached a consensus on the ideal care pathway. This article presents the outputs of this research. The pathway identified key barriers to care and highlighted how these may be addressed, with many of the findings relevant to the rest of the UK and international audiences. NENs are increasing in incidence and prevalence in England, compounding pre-existing inequities in diagnosis and disease management. Effective integration of this pathway within NHS England will help achieve optimal, equitable care provision for all people with NENs, and should be feasible within the existing expert multidisciplinary teams across the country.

Neuroendocrine neoplasms (NENs) are rare tumours that develop from neuroendocrine cells in various parts of the body. The management of this disease poses a significant challenge because of the heterogeneous clinical presentation and varying degrees of aggressiveness. A multidisciplinary approach is often required in complex clinical situations. Radiotherapy (RT) plays a key role in managing NETs in both curative and palliative settings.

In this review, we summarize and discuss recent developments in the field of advanced RT in early-stage, locally advanced, and metastatic NENs. We highlight limitations in current approaches and discuss future potential treatment strategies for patients with NENs.

The ocular involvement of neuroendocrine neoplasms (NENs) is uncommon and mainly represented by metastases from gastrointestinal and lung neuroendocrine tumors. Primary orbital NENs are even less common and their diagnostic and therapeutic management is a challenge.

A systematic review of the literature was conducted from 1966 to September 2023 on PubMed to identify articles on orbital NENs and to summarize their clinical-pathological features, diagnosis and therapeutic management. Furthermore, we presented a case of a locally advanced retro-orbital primary neuroendocrine tumor that was referred to the certified Center of Excellence of Sant'Andrea Hospital, La Sapienza University of Rome, Italy.

The final analysis included 63 records on orbital NENs and 11 records focused on primary orbital NENs. The localization was mostly unilateral and in the right orbit; proptosis or exophthalmos represented the initial symptoms. The diagnostic work-up and therapeutic management was discussed and a diagnostic algorithm for the suspicion of primary orbital NENs was proposed.

A multidisciplinary approach is required for the management of primary orbital NENs, emphasizing the importance of early referral to dedicated centers for prompt differential diagnosis, tailored treatment, and an improved quality of life and survival.

Patients with well-differentiated, low-grade metastatic neuroendocrine neoplasms (NENs) usually have a long median survival and require complex, expensive care over many years at multidisciplinary centers. The cost burden for patients and institutions serves as a barrier to care. Understanding the drivers of these costs and whether intense monitoring adds value will help to optimize value-based care.

We adapted the cost of care per patient per day (CCPD) validated methodology to measure cost while accounting for varying follow-up duration. We queried the Stanford NEN Database, which aggregates data from the electronic health record and other electronic sources, to study patients with metastatic NENs receiving regular care at Stanford. Current Procedural Terminology codes for services incurred during the monitoring period for each patient were mapped to the corresponding cost conversion factor and date in the Medicare fee schedule.

Two hundred two patients between 2010 and 2017 were studied with a mean CCPD of $119.11 in US dollars (USD); NEN-specific systemic therapy made up 55% of this cost. Somatostatin analogs were the costliest systemic therapy. Systemic therapy was the driver of cost differences among patients with various primary tumor types, stage of disease, tumor differentiation and grade, and functional hormone status. Patients in the most expensive CCPD group did not have a significant survival benefit (P = .66).

The CCPD methodology was effective in studying cancer care value in NENs. Systemic therapy, specifically somatostatin analogs, was the primary driver of cost, and intense monitoring and higher-cost care did not improve survival outcomes.

Incidental appendectomies (IAs) are often performed in laparotomies to prevent future complications caused by the buildup of scar tissue. Although neoplastic findings are rare, all appendectomy specimens should be sent for histopathological analysis. We present the case of a 38-year-old man found to have an appendiceal neuroendocrine tumor (NET) after receiving an IA secondary to a traumatic rectal perforation requiring exploratory laparotomy. Well-differentiated NETs isolated to the appendix have an excellent prognosis. Appendectomies are considered curative for NETs smaller than 2 cm that have not metastasized beyond the appendix. Appendiceal NETs are capable of secreting vasoactive substances and, therefore, causing carcinoid syndrome. However, the progression to carcinoid syndrome generally coincides with metastasis to the liver, indicating a poor prognosis. While histopathological analysis of appendectomy specimens rarely yields atypical findings, this analysis is crucial to ensure that the proper treatment is selected based on tumor progression in an appendectomy specimen staining positive for somatotropin and chromogranin.

Since 2013, North American Neuroendocrine Tumor Society (NANETS) consensus-guidelines have endorsed consideration of surgical intervention for pancreatic- neuroendocrine tumors (PNET) with liver metastases.

Patients with non-functional PNET with liver only metastases from 2010 to 2019 were identified from the National Cancer Database.

34.7% underwent surgical intervention (13% PNET resection, 2.1% surgical management of liver metastases (SMLM), 19.5% PNET resection ​+ ​SMLM). In multivariable analysis, government insurance, year of diagnosis>2013, increasing primary tumor size were associated with lower rate of surgical intervention. Receiving treatment at an academic center (OR 3.59, 95%CI 1.81-7.11; P ​< ​0.001) or integrated cancer network (OR 3.21, 95%CI 1.57-6.54; P ​= ​0.001) was associated with a higher rate of surgical intervention. The overall rate of surgical intervention decreased from 45.7% in 2010 to 23.0% in 2019.

Despite guideline recommendations and the suggested survival benefits, only one-third of patients underwent surgical intervention, potentially influenced by the rising utilization of systemic therapy in the past decade.

Large cell neuroendocrine carcinoma (LCNEC) is an extremely rare malignant tumor of the colon, presenting with more severe clinical outcomes in comparison to colonic adenocarcinoma. There are very few reported cases in the literature. We hereby add our voice to the incidence of this disease by presenting the first report of a patient with ileocolic intussusception secondary to a large cell neuroendocrine cancer of the cecum. The patient was a 48-year-old woman who presented with acute onset of generalized abdominal pain and leukocytosis. CT scan revealed an ileocecal intussusception and multiple liver metastases suggestive of a malignant bowel lesion. She underwent emergency surgery, and an extended right hemicolectomy with ileo-transverse anastomosis was performed. Histology of the resected lesion revealed large cell neuroendocrine carcinoma of the cecum with invasion through the muscularis propria into peri colorectal tissues. The tumor retained mismatch repair (MMR) proteins with low potential for microsatellite instability (MSI). With a clinical diagnosis of stage IV LCNEC, the patient began platinum doublet chemotherapy with carboplatin and etoposide; however, her disease progressed, and the patient expired within a few months after her diagnosis. Clinical diagnosis of adult intussusception should prompt clinicians to rule out malignant etiology. This patient had a large cell neuroendocrine carcinoma of the colon, a rare and extremely aggressive malignancy. Patients with LCNEC will benefit from a multidisciplinary approach to treatment.

Radical surgery is a common treatment for patients with gastric cancer; however, it can lead to postoperative complications and intestinal barrier dysfunction. Ultrasound-guided quadratus lumborum block is often used for postoperative analgesia, but its effects on stress response and intestinal barrier function are not well understood.

To investigate the effects of an ultrasound-guided quadratus lumborum block on stress response and intestinal barrier function in patients undergoing radical surgery for gastric cancer.

A total of 100 patients undergoing radical surgery for gastric cancer were randomly categorized into observation and control groups. Plasma adrenaline and cortisol levels, intestinal mucosal barrier indexes, and complication rates were compared between the two groups before, during, and 1 day after surgery.

The observation group had significantly lower plasma adrenaline and cortisol levels during surgery and at 1 day postoperatively than that of the control group (P < 0.05). Additionally, intestinal barrier indexes (endotoxin and D-dimer) at 1 day postoperatively were significantly lower in the observation group than in the control group (P < 0.05).

Ultrasound-guided quadratus lumborum block could reduce stress response, protect intestinal barrier function, and decrease the incidence of complications in patients undergoing radical surgery for gastric cancer. This technique has the potential for clinical applications.

Cervical high-grade neuroendocrine carcinoma (CHGNEC) is a rare but highly aggressive cancer. The purpose of this study is to develop a prognostic nomogram that can accurately predict the outcomes for CHGNEC patients.

We analyzed clinical data from the Surveillance, Epidemiology, and End Results (SEER) database of CHGNEC patients, including small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC). We investigated patient characteristics and prognosis, and developed a prognostic nomogram model for cancer-specific survival in CHGNEC patients. External validation was conducted using real clinical cases from our hospital.

Our study included 306 patients from SEER database, with a mean age of 49.9 ± 15.5 years. Most of the patients had SCNEC (86.9%). Among them, 170 died from the disease, while 136 either survived or died from other causes. Our final predictive model identified age at diagnosis, stage 1 status, stage 4 status, T1, N0, and surgery of the primary site as independent prognostic factors for CHGNEC. We validated our model using a group of 16 CHGNEC patients who underwent surgery at our center. The external validation showed that the prognostic nomogram had excellent discriminative ability, with an area under the receiver operating characteristic curve (AUC) of 0.76 (95% CI 0.49-1.00) for the prediction of 3-year cancer-specific survival (CSS) and an AUC of 0.85 (95% CI 0.62-1.00) for the prediction of 5-years CSS. The random survival forest model achieved an AUC of 0.80 (95% CI 0.56-1.00) for 3-years CSS and 0.91 (95% CI 0.72-1.00) for 5-years CSS, indicating its adequacy in predicting outcomes for CHGNEC patients.

Our study provides an excellent nomogram for predicting the prognosis of CHGNEC patients. The prognostic nomogram can be a useful tool for clinicians in identifying high-risk patients and making personalized treatment decisions.

Histological evaluation and grading assessment are key points in the diagnostic work-up of gastroentero-pancreatic neuroendocrine neoplasms (GEP-NENs).

To analyze the impact of histopathological revision on the clinical management of patients with GEP-NEN.

Patients referred to our Center of Excellence between 2015 and 2021 were included in this study. Immunohistochemical slides at the time of initial diagnosis were reviewed to assess tumor morphology, diagnostic immunohistochemistry, and Ki67.

101 patients were evaluated, with 65 (64.4%) gastrointestinal, 25 (24.7%) pancreatic, and 11 (10.9%) occult neoplastic lesions suspected to be of GEP origin. The main changes resulting from the revision were: first Ki-67 assessment in 15.8% of patients, Ki-67 change in 59.2% of patients and grading modification in 23.5% of patients. An additional immunohistochemical evaluation was performed in 78 (77.2%) patients, leading to a confirmation of GEP origin in 10 of 11 (90.9%) of unknown primary site neoplastic lesions and an exclusion of NEN diagnosis in 2 (2%) patients. After histopathological revision, a significant modification in clinical management was proposed in 42 (41.6%) patients.

Histopathological revision in a referral NEN center is strongly advised in newly diagnosed GEP-NENs to properly plan prognostic stratification and therapeutic choice.

Gastric neuroendocrine tumors (gNETs) are rare cancers for which surgery may improve survival. We aim to determine if facility type affects treatment and survival outcomes.

The NCDB was queried for patients with gNET from 2004-2016 and stratified into Academic/Research Program (ARP), Community Cancer Program (CCP), Comprehensive Community Cancer Program (CCCP), or Integrated Network Cancer Program (INCP). Overall survival along with clinical and demographic features was compared.

Median survival was improved in patients treated at an academic program: 137.3 months versus 88.0, 96.3, and 100.2 for CCP, CCCP, INCP, respectively (P < .0001). Patients treated at academic centers were more likely to have surgery (64.2% vs 59.1%, 57.5%, 51.4%, P < .0001). After propensity matching for age, race, grade, stage, insurance status, and comorbidity score, survival benefit from treatment at an academic center remained (P = .03), particularly for patients undergoing surgery (P < .0001) and chemotherapy (P = .04).

Patients with gNET treated at an academic hospital had improved median survival after propensity matching and may benefit from treatment at academic rather than community medical centers.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are one of the most common types of NETs, accounting for 65-75% of all NETs. However, epidemiological characteristics of patients with GEP-NETs in China are still lacking. The present retrospective study aimed to investigate the local epidemiology of GEP-NETs and assess the prognostic factors in China. The data of 267 patients with GEP-NETs who were admitted to the First Affiliated Hospital of Bengbu Medical College (Bengbu, China) and the Affiliated Hospital of West Anhui Health Vocational College (Lu'an, China) were retrospectively reviewed. The clinical and pathological characteristics of the patients, as well as follow-up information, were collected, and the 5-year survival rate was calculated. Kaplan-Meier curves and log-rank analysis were used to analyze the prognostic factors. The stomach (100/267; 37.5%) was the most common site of GEP-NETs and the liver (25/39; 64.1%) was the most common metastatic site. A total of 166 (62.2%) and 219 (82.0%) patients had positive results for chromogranin A (CgA) and synaptophysin (Syn), respectively. The percentage of patients with tumor grade G1, G2 and G3 was 33.3, 21.0 and 45.7%, respectively. The 5-year overall survival rate was 79.7%, and the age, tumor site, distant metastasis and tumor grading upon diagnosis were all prognostic factors. In conclusion, the present case series investigated the epidemiology and prognostic factors of GEP-NETs in China. CgA and Syn could be used as diagnostic markers for NETs and the stomach was the most common primary tumor site. Lymph node metastasis, tumor site, distant metastasis and tumor grading were important prognostic factors.

This study aimed to evaluate the optimal extent of lymphadenectomy in patients with nonfunctioning pancreatic neuroendocrine neoplasms. We retrospectively analyzed the clinicopathological data of patients with nonfunctioning pancreatic neuroendocrine neoplasms who underwent surgical resection. We investigated the frequency of metastases at each lymph node station according to tumor location and analyzed the factors contributing to poor overall survival (OS) and disease-free survival (DFS). Overall, data of 84 patients were analyzed. Among patients with pancreatic head tumors, metastases at stations 8, 13, and 17 were found in one (3.1%), four (12.5%), and three (9.3%) patients, respectively. However, none of the other stations showed metastases. For pancreatic body and tail tumors, metastases only at station 11 were found in two (5.1%) patients. Additionally, multivariate DFS and OS analyses showed that lymph node metastasis was the only independent prognostic factor. In conclusion, lymph node metastasis near the primary tumor was the only independent factor of poor prognosis in patients with nonfunctioning pancreatic neuroendocrine neoplasms after undergoing curative surgery. Peri-pancreatic lymphadenectomy might be recommended for nonfunctioning pancreatic neuroendocrine neoplasms.

Gastric neuroendocrine tumors are a heterogeneous group of neoplasms that produce bioactive substances. Their treatment varies according to staging and classification, using endoscopic techniques, open surgery, chemotherapy, radiotherapy, and drugs analogous to somatostatin.

To identify and review cases of gastric neuroendocrine neoplasia submitted to surgical treatment.

Review of surgically treated patients from 1983 to 2018.

Fifteen patients were included, predominantly female (73.33%), with a mean age of 55.93 years. The most common symptom was epigastric pain (93.3%), and the mean time of symptom onset was 10.07 months. The preoperative upper digestive endoscopy (UDE) indicated a predominance of cases with 0 to 1 lesion (60%), sizing ≥1.5 cm (40%), located in the gastric antrum (53.33%), with ulceration (60%), and Borrmann III (33.33%) classification. The assessment of the surgical specimen indicated a predominance of invasive neuroendocrine tumors (60%), with angiolymphatic invasion in most cases (80%). Immunohistochemistry for chromogranin A was positive in 60% of cases and for synaptophysin in 66.7%, with a predominant Ki-67 index between 0 and 2%. Metastasis was observed in 20% of patients. The surgical procedure most performed was subtotal gastrectomy with Roux-en-Y reconstruction (53.3%). Tumor recurrence occurred in 20% of cases and a new treatment was required in 26.67%.

Gastric neuroendocrine tumors have a low incidence in the general population, and surgical treatment is indicated for advanced lesions. The study of its management gains importance in view of the specificities of each case and the need for adequate conduct to prevent recurrences and complications.

Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.

Merkel cell carcinoma (MCC) but metastases to the pancreas are very rare. There are only a few cases of isolated metastases of MCC to the pancreas. Because of this rarity, it can be wrongly diagnosed as a neuroendocrine tumor of the pancreas(pNET), especially the poorly differentiated neuroendocrine carcinoma (PNEC) subtype, in which the treatment is vastly different than that of MCC with isolated metastases of the pancreas.

An electronic search of the PubMed and google scholar databases was performed to obtain the literature on MCC with pancreatic metastases, using the following search terms: Merkel cell carcinoma, pancreas, and metastases. Results are limited to the following available article types: case reports and case series. We identified 45 cases of MCC with pancreatic metastases from the PubMed and Google Scholar database search and examined their potential relevance. Only 22 cases with isolated pancreatic metastases were taken for review including one case that we encountered.

The results from our review of cases of isolated pancreatic metastases of MCC were compared to the characteristics of the poorly differentiated pancreatic neuroendocrine tumor (PNEC). We found the following: (a) MCC with isolated pancreatic metastases occurred at an older age than PNEC and with male gender predominance (b) Most of the metastases occurred within 2 years of initial diagnosis of MCC (c) Resection of pancreatic mass was the first line treatment in case of resectable PNECs whereas resection of metastases was infrequently performed in MCC with pancreatic metastases.

Gastric neuroendocrine carcinomas (NEC) are highly aggressive cancer with dismal prognosis. Platinum-based chemotherapy is used as the first-line treatment for this entity. However, there are no established therapeutic guidelines for platinum-resistant gastric NEC. We herein report a patient with metastatic gastric NEC who achieved durable and complete response to nivolumab with radiotherapy for oligoprogressive metastasis. A 70-year-old male patient had recurrences of resected gastric NEC, involving the liver and lymph nodes. His disease became refractory to cisplatin and etoposide combination therapy, after which he was treated with nivolumab. All the tumors showed marked shrinkage. However, 1 year after starting nivolumab, one metastatic lesion of the liver began to enlarge, and radiotherapy was performed to the lesion. Thereafter, a complete response was obtained, which has been maintained without any treatment for the past 2 years.

Aim: The RAISE project aimed to find a surrogate end point to predict treatment response early in patients with enteropancreatic neuroendocrine tumors (NET). Response heterogeneity, defined as the coexistence of responding and non-responding lesions, has been proposed as a predictive marker for progression-free survival (PFS) in patients with NETs. Patients & methods: Computerized tomography scans were analyzed from patients with multiple lesions in CLARINET (NCT00353496; n = 148/204). Cox regression analyses evaluated association between response heterogeneity, estimated using the standard deviation of the longest diameter ratio of target lesions, and NET progression. Results: Greater response heterogeneity at a given visit was associated with earlier progression thereafter: week 12 hazard ratio (HR; 95% confidence interval): 1.48 (1.20-1.82); p < 0.001; n = 148; week 36: 1.72 (1.32-2.24); p < 0.001; n = 108. HRs controlled for sum of longest diameter ratio: week 12: 1.28 (1.04-1.59); p = 0.020 and week 36: 1.81 (1.20-2.72); p = 0.005. Conclusion: Response heterogeneity independently predicts PFS in patients with enteropancreatic NETs. Further validation is required.

Surgery for metastatic gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) has not been well-studied. This retrospective cohort study describes patients in the United States with stage IV GEP-NEC and their survival outcomes segregated by surgery.

Patients diagnosed with stage IV GEP-NEC from 2004 to 2017 in the National Cancer Database were categorized into three groups: no surgery, primary site or metastatic site ("single-site") surgery, and primary site and metastatic site ("multisite") surgery. Factors associated with surgical treatment were identified, and risk-adjusted overall survival of each group was compared.

Of 4171 patients included, 958 (23.0%) underwent single-site surgery and 374 (9.0%) underwent multisite surgery. The strongest predictor of surgery was primary tumor type. Compared with no surgery, the risk-adjusted mortality reduction associated with single-site surgery ranged from 63% for small bowel (HR = 0.37, 0.23-0.58, p < 0.001) NEC to 30% for colon and appendix NEC (HR = 0.70, 0.61-0.80, p < 0.001), while the mortality reduction associated with multisite surgery ranged from 77% for pancreas NEC (HR = 0.23, 0.17-0.33, p < 0.001) to 48% for colon and appendix NEC (HR = 0.52, 0.44-0.63, p < 0.001).

We observed an association between extent of surgical intervention and overall survival for patients with stage IV GEP-NEC. Surgical resection should be further investigated as a treatment option for highly-selected patients with this aggressive disease.

Aim: The RAISE project assessed whether deep learning could improve early progression-free survival (PFS) prediction in patients with neuroendocrine tumors. Patients & methods: Deep learning models extracted features from CT scans from patients in CLARINET (NCT00353496) (n = 138/204). A Cox model assessed PFS prediction when combining deep learning with the sum of longest diameter ratio (SLDr) and logarithmically transformed CgA concentration (logCgA), versus SLDr and logCgA alone. Results: Deep learning models extracted features other than lesion shape to predict PFS at week 72. No increase in performance was achieved with deep learning versus SLDr and logCgA models alone. Conclusion: Deep learning models extracted relevant features to predict PFS, but did not improve early prediction based on SLDr and logCgA.