Neuroendocrine Tumors Research Articles

Ependymoma Alongside Hereditary Paraganglioma-Phaeochromocytoma Syndrome Due to a SDHB Mutation: A Case Report

Mutations in the SDHB gene cause a characteristic syndrome that includes paragangliomas (PGL) and phaeochromocytomas (PCC). Herein we present a rare case of an ependymoma in a patient with a germline SDHB mutation. A 41-year-old man with a positive family history of PGL/PCC syndrome was found to have the familial SDHB mutation. Screening imaging for paragangliomas revealed an incidental presumed ependymoma originating from the fourth ventricle. He was followed with serial imaging to assess for progression of the lesion. Due to slow, substantial growth of the tumour, and increasing symptoms which included diplopia, unsteadiness, and wide-based gait, he underwent a resection 5 years after the lesion’s identification. Following resection of the tumour, the pathology confirmed the tumour as a posterior fossa type B (PFB) ependymoma of the fourth ventricle. Unfortunately, on Day 26 post-operatively, the patient had a pulmonary embolism and died. His family consented to an autopsy, which revealed the presence of a clinically-silent pituitary neuroendocrine tumour (PitNET). Though ependymomas are not commonly seen in PGL/PCC syndrome, they can occur. This case represents the first molecularly-characterised ependymal tumour described in this tumour predisposition syndrome. Clinicians ought to be aware of the risk of ependymoma in patients with PGL/PCC syndrome and consider this tumour when conducting their screening and follow-up of asymptomatic SDHx mutation carriers.

The impact of peptide receptor radionucleotide therapy with Lutetium-177 DOTATATE on cardiac metastases in neuroendocrine tumors

Abstract Background Cardiac metastasis from neuroendocrine tumors (NET) is rare and has been thought to potentially result in life threatening sequalae. Peptide receptor radionucleotide therapy (PRRT), such as Lutetium-177 (Lu-177) DOTATATE, has been validated as effective treatment for patients with NET who have progressed on somatostatin analogue (SSA) therapy and more recently suggested for use in SAA-naïve higher risk grade 2 and grade 3 NETs. However, Lu-177 DOTATATE therapy has been found to have potentially serious adverse effects both locally and systemically. Overall, the clinical significance of cardiac metastasis of NET, as well as the safety and efficacy of Lu-177 DOTATATE in this cohort, has not been thoroughly evaluated. Purpose This study assessed the outcomes and clinical consequences of cardiac metastatic involvement in patients with NET. Furthermore, this study investigated the safety of Lu-177 DOTATATE therapy in patients with cardiac metastases from NET. Methods All patients who underwent 68Ga-DOTATATE positron emission tomography for evaluation of NET across three tertiary centers between 2016 and 2022 were retrospectively evaluated. Patients with evidence of cardiac metastasis were further evaluated. Baseline characteristics, treatment modality, and clinical outcomes including mortality, arrhythmia or conduction disease, carcinoid heart disease, and heart failure admissions were recorded. Patients with cardiac metastases were grouped and compared based on therapeutic modality (conservative therapy with surveillance or SSA, Lu-177 DOTATATE therapy, or surgical resection of metastases). Results From 3253 patients with NET, 51 patients were identified to have cardiac metastases (mean age 66.7 ± 12.2 years, 54% male). Three patients underwent surgical resection of cardiac metastases, and in two of whom this was concomitant while undergoing valve surgery for carcinoid heart disease. Patients with cardiac metastasis had significantly higher mortality than patients without cardiac metastasis (HR 2.12, 95%CI 1.00 – 4.52, p = 0.049, Figure 1A). Median follow-up from diagnosis of cardiac metastasis was 3.64 years [IQR 1.59 – 5.64]. There was no significant difference in clinical outcomes between patients that received Lu-177 DOTATATE therapy (n = 27) and conservative therapy (n = 21). Specifically, there was no significant difference in mortality risk at five years post the diagnosis of cardiac metastasis between these groups (p = 0.47, Figure 1B). Conclusion Patients with cardiac metastasis from NETs have worse clinical outcomes than NET patients without cardiac metastatic involvement. Lu-177 DOTATATE therapy appears to be safe in patients with cardiac metastasis from NET.Figure 1AFigure 1B

Neuroendocrine Tumors and Survival Rates in Multiple Endocrine Neoplasia Type 1 Patients: Impact of Gender Difference

Introduction: Multiple endocrine neoplasia type 1 (MEN-1) is the most common inherited syndrome associated with NET development and gender-specific differences are emerging in neuroendocrine tumors (NETs). This study aimed to analyze gender difference in a single cohort of MEN-1 patients focusing on duodeno-pancreatic (DP)-NET and survival rates. Methods: MEN-1 patients referred to the Endocrinology Unit of the “Federico II” University of Naples, ENETS CoE, were retrospectively evaluated. Results: Among 100 MEN-1 patients enrolled, 59 (59%) were female and 41 (41%) male, and mean age at diagnosis was 39.4 years (range 5–86). No statistically significant association was identified between MEN-1 clinical manifestations and gender (primary hyperparathyroidism [PHPT] p: 1.0, DP-NET p: 0.83, pituitary adenoma [PA] p: 0.84, lung NET p: 0.64, and thymic NET p: 0.10), and similarly, age at diagnosis of MEN-1 and its individual manifestations was similar between genders. Survival analysis revealed no statistically significant difference between genders in DP-NET patients regarding progression disease p: 1.0 and death p: 1.0. Mean progression-free survival (PFS) of patients with DP-NET was 98.6 months (range 3–288), and mean overall survival (OS) was 130.1 months (range 3–444 months), without differences between genders (PFS p: 0.67 and OS p: 0.60). The Kaplan-Meier survival curves for PFS and OS showed no differences between genders (PFS p: 0.92; OS p: 0.87). Conclusion: In this MEN-1 cohort, no gender differences in the occurrence of PHPT, PA, DP-NET, lung NET, and thymic NET, nor in survival outcomes including PFS and OS within the DP-NET subcohort, emerged. Therefore, this study supports similar screening and follow-up for both male and female MEN-1 patients.

Cystic ductal adenocarcinoma of pancreas complicated with neuroendocrine tumor: A case report and review of literature

BACKGROUND Difficulties in making an accurate preoperative diagnosis of cystic pancreatic lesions pose a challenge for radiologists. It would be helpful to report rare cases and review the literature. CASE SUMMARY In the present report, a case of a patient with a pancreatic cystic lesion initially misdiagnosed as a pseudocyst by radiologist was documented, which was later pathologically confirmed as pancreatic ductal adenocarcinoma with neuroendocrine tumor. However, subsequent literature review yielded no previous reports of pancreatic ductal adenocarcinoma with neuroendocrine tumors and cystic lesions. Therefore, literature on the imaging diagnosis of pancreatic cystic lesions was instead reviewed and discussed. CONCLUSION Careful evaluation of the characteristics revealed by multimodal imaging techniques, medical history, laboratory examination data and follow-up observations, is critical to the diagnosis and treatment of pancreatic cystic disease. We provide valuable insights into the diagnosis of pancreatic cystic disease through a rare case report and literature review.

Liver transplantation for primary and secondary liver tumours. patient-level meta-analyses compared to unos conventional indications.

Liver transplant (LT) for Transplant Oncology (TO) indications is being slowly adopted worldwide and has been recommended to be incorporated cautiously due to concerns on mid-long term survival and its impact on waiting list. We conducted four systematic reviews of all series on TO indications (intrahepatic (iCC) and perihilar cholangiocarcinoma (phCC)), liver metastases from neuroendocrine tumors (NET) and colorectal cancer (CRLM)) and compared them using patient-level meta-analyses to data obtained from UNOS database considering conventional daily-practice indications. Secondary analyses were done for specific selection criteria (Mayo-like protocols for phCC, SECA-2 for CRLM and Milan criteria for NET). A total of 112.014 LT were analyzed from 2005 to 2020 from the UNOS databases and compared with 345, 721, 494 and 103 patients obtained from meta-analyses on iCC and phCC, and liver metastases from NET and CRLM, respectively. Five-years overall survival was 53,3%, 56,4%, 68,6% and 53,8%, respectively. In Mantel-Cox one-to-one comparisons, survival of TO indications was superior to combined LT, second and third LT and and not statistically significant different to LT in recipients>70 years and high BMI. Liver transplantation for TO indications has adequate 5-years survival rates, mostly when performed under the selection criteria available in literature (Mayo-like protocols for phCC, SECA-2 for CRLM and Milan for NET). Despite concerns on its impact on waiting list, some other LT indications are being performed with lower survival. These oncological patients should be given the opportunity to have a definitive curative therapy within validated criteria.

Pituitary neuroendocrine tumors treated with stereotactic radiosurgery.

Pituitary neuroendocrine tumors (pitNETs) are benign tumors that may recur after surgical resection or persist following medical management. The objective of this study was to evaluate outcomes and toxicities of patients with pitNETs treated with stereotactic radiosurgery (SRS) at a single institution. We completed a retrospective, single-institution study of patients with pitNETs treated with frame-based, single-fraction, cobalt-60 SRS between September 2005 and June 2023. The primary endpoint was local tumor control. Secondary endpoints included endocrine control (for functional tumors), overall survival, and toxicities. A total of 88 lesions in 83 patients were treated with SRS. Most lesions (70%) were non-functional tumors. Of the 26 functioning tumors, 6 patients achieved endocrine remission with SRS alone (23%), and the remainder achieved remission with combined medical management. With a median patient follow-up of 4.7 years, no local tumor recurrences were observed with an estimated local control probability of 100%. Two- and five-year overall survival estimates were 97% (95% confidence interval [CI] 89-99) and 95% (95% CI 84-98), respectively. Causes of death were unrelated to PitNET or SRS. Twelve patients (14%) developed hypopituitarism after SRS. Despite the 34 lesions that were ≤ 3mm from optic structures, no patients developed any optic neuropathy or visual decline post SRS. SRS is a highly effective modality for recurrent or residual pitNETs. This study observed a local control of 100% with no cases of optic toxicities after a median follow-up of 4.7 years. These observed findings suggest that dose de-escalation may be possible for future treatment of pitNETs.

Current Status of Immunotherapy in Management of Small Bowel Neuroendocrine Tumors.

This study aims to present the current landscape of immunotherapy in the management of small bowel neuroendocrine tumors and identify ongoing and future targets for improved response. Somatostatin analogs and mTOR inhibitors remain cornerstones of non-surgical treatment, and applications of PRRT in SBNET are promising. Several efforts to replicate the success of immunotherapies in other solid tumors have been attempted in SBNET, with limited responses observed with current immune targets, such as PD-1/PD-L1 and CTLA-4. Epigenetic analyses have suggested a potential role for methylation and histone acetylation in SBNET tumorigenesis that warrant greater exploration. While the incidence of SBNET continues to increase, the number of effective therapies is few. Further elucidation of targetable components of the SBNET immune microenvironment with greater modulatory effects is necessary to improve outcomes in this growing patient population.

ASO Author Reflections: Seeing the Unseen-Predicting Nodal Disease in Pancreatic Neuroendocrine Tumors.

ASO Author Reflections: Seeing the Unseen-Predicting Nodal Disease in Pancreatic Neuroendocrine Tumors.

Combination Antitumor Activation of Anlotinib with Radiofrequency Ablation in Human Medullary Thyroid Carcinoma.

Currently, Medullary Thyroid Carcinoma (MTC) is considered a kind of rare neuroendocrine tumor, and molecular-targeted drugs have previously been used for MTC treatment. However, the prognosis of MTC patients is still not significant. In the present work, we aimed to explore the antitumor activity of the molecularly targeted drug anlotinib in combination with radiofrequency ablation on MTC. The targets of anlotinib were clearly expressed in MTC tissue specimens, and the expression level of these factors was much higher in MTC clinical specimens than in nontumor tissues. At the same time, anlotinib or Radiofrequency Ablation (RFA) showed clear antitumor activity against the MTC cell line TT (TT cells) and the tumor tissue it formed. Anlotinib, in combination with RFA, significantly increased the antitumor activity of RFA. These results indicated that the combination of anlotinib with radiofrequency ablation could be a promising therapeutic strategy for MTC treatment.

Immune checkpoint inhibitor therapy for primary neuroendocrine carcinoma of the gallbladder: A case report and literature review.

Gallbladder neuroendocrine carcinoma (GNEC) is indeed a relatively rare malignant tumor of the gallbladder with neuroendocrine differentiation and the ability to produce and secrete a number of neurotransmitters and hormones, characteristics that make its clinical presentation and biological behavior likely to be different from those of other types of gallbladder cancer. Current treatment mostly relies on surgery and adjuvant chemotherapy and radiotherapy. We report a 53-year-old middle-aged male patient who underwent radical surgery for gallbladder malignancy after a diagnosis of neuroendocrine carcinoma of the gallbladder. Diagnosis of neuroendocrine carcinoma of the gallbladder based on the return of pathologic findings. After local progression of postoperative chemotherapy with the first-line regimen of etoposide + cisplatin, an immune checkpoint inhibitor (traplizumab) + FOLIFIRI (fluorouracil + calcium folinate + irinotecan) regimen was used. The patient achieved 20 months of clinical survival and ultimately died of myelosuppression. The use of immune checkpoint inhibitors may become an effective tool in the treatment of neuroendocrine carcinoma of the gallbladder.

Rare Combination of Multiple Endocrine Neoplasia 1 with Medullary Thyroid Carcinoma and Clinical Value of 68Ga-DOTATATE PET/CT in Diagnosing Different Lesions and Exploring Theranostic Strategy

AbstractMultiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the presence of hyperplastic or neoplastic tumors in the parathyroid, pituitary, and gastroenteropancreatic endocrine tissues. The presence of lesions in at least two out of the three glands (pituitary, parathyroid, and pancreas) is indicative of MEN1 syndrome. Medullary thyroid carcinoma (MTC) is a type of tumor that originates from the parafollicular C cells of the thyroid gland. It is frequently found as part of MEN2 syndrome. MEN1 with MTC is a relatively uncommon occurrence. We report a rare case of MTC that later on developed parathyroid carcinoma, pituitary microadenoma, pancreatic neuroendocrine tumor (NET), and duodenal NET. The case was identified as part of MEN1 syndrome using exome sequencing and somatostatin receptor–based functional imaging 68Ga-DOTATATE positron emission tomography/computed tomography was employed for exploring theranostic strategy in the management of the patient.

Endoscopic full-thickness resection of type 1 gastric neuroendocrine tumor: step-by-step description of technique.

Endoscopic full-thickness resection of type 1 gastric neuroendocrine tumor: step-by-step description of technique.

Case Report: Unveiling an anomalous diaphragmatic paraganglioma mimicking a hepatic tumor

Abstract Paragangliomas are rare neuroendocrine tumors, often associated with catecholamine secretion. These tumors can arise in various locations, with the majority found in the abdomen and pelvis, while a smaller percentage occurs in the thorax and head and neck regions. Diaphragmatic paragangliomas are exceedingly rare, with only two documented cases in the literature. This report details a case of a primary diaphragmatic paraganglioma in a 59-year-old patient presenting with unexplained weight loss, tremors, and diaphoresis. Imaging studies revealed a mass in the right lobe of the liver, later identified as a diaphragmatic paraganglioma during surgery. The case underscores the importance of preoperative catecholamine assessment and careful surgical planning due to the risks associated with tumor manipulation. Complete surgical resection, although challenging, remains the definitive treatment, especially in hypervascular tumors located near major vascular structures.

Preoperative embolisation of head and neck paragangliomas - a single-centre experience.

Paragangliomas are neuroendocrine tumours commonly located in the abdomen, thorax, head and neck. The definitive treatment for these tumours is surgical resection, which in some cases can be very challenging due to the involvement of critical neurovascular structures and their high vascularity. Therefore, pre-operative embolisation may be performed to reduce the risk of complications. This study aimed to present our experience with endovascular embolisation of head and neck paragangliomas (HNP). In this single-centre study, we reviewed data from consecutive patients with HNP who underwent pre-operative embolisation from 2017 to 2023. The efficacy of embolisation, the method of embolisation, as well as the rate of complications, were noted. A total of 27 patients (15 females) with an average age of 47 years underwent selective embolisation of HNP. Satisfactory embolisation, defined as occlusion of > 75% of the blood supply, was achieved in 22/27 cases (81.5%). The most commonly used embolic agents included coils and microspheres. With the exception of minor vessel dissections in two patients and embolic agent migration in two patients causing reversible occlusion of the intracranial vessels, there were no other complications associated with embolisation. No neurological deficits occurred in relation to the endovascular procedure. The results of our study indicate that endovascular embolisation of HNP prior to surgical resection is a safe and efficacious procedure, with a relatively low complication rate and associated morbidity.

Circulating Chromogranin A as Surveillance Biomarker in Patients with Carcinoids - The CASPAR Study.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively indolent but can be more aggressive. The current recommendations for the use of serum CgA for GEP-NET patients are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in GEP-NET patients. A prospective, multi-center blinded observational study was designed to validate an automated chromogranin A (CgA) immunofluorescence assay for monitoring disease progression in GEP-NET patients. Tumor progression was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by CT/MRI. An increase ≥ 50% above the prior CgA concentration to a value > 100 ng/mL in the following CgA concentration was considered positive. 153 GEP-NET patients were enrolled. Using the pre-specified cut-off of CgA change for tumor progression, specificity was 93·4% (95%-CI: 90·4%-95·5%, p < 0·001), sensitivity 34·4% (25·6%-44·3%), positive predictive value 57·9% (45·0-69·8), negative predictive value (NPV) 84·3% (80·5-87·6), and area under the curve 0·73 (0·67-0·79). Changes in serial measurements of serum CgA had a favorable specificity and NPV, making this test a useful adjunct to routine radiographic monitoring.

Diagnosis of invasive encapsulated follicular variant papillary thyroid carcinoma by protein-based machine learning.

Although the criteria for follicular-pattern thyroid tumors are well-established, diagnosing these lesions remains challenging in some cases. In the recent World Health Organization Classification of Endocrine and Neuroendocrine Tumors (5th edition), the invasive encapsulated follicular variant of papillary thyroid carcinoma was reclassified as its own entity. It is crucial to differentiate this variant of papillary thyroid carcinoma from low-risk follicular pattern tumors due to their shared morphological characteristics. Proteomics holds significant promise for detecting and quantifying protein biomarkers. We investigated the potential value of a protein biomarker panel defined by machine learning for identifying the invasive encapsulated follicular variant of papillary thyroid carcinoma, initially using formalin- fixed paraffin-embedded samples. We developed a supervised machine-learning model and tested its performance using proteomics data from 46 thyroid tissue samples. We applied a random forest classifier utilizing five protein biomarkers (ZEB1, NUP98, C2C2L, NPAP1, and KCNJ3). This classifier achieved areas under the curve (AUCs) of 1.00 and accuracy rates of 1.00 in training samples for distinguishing the invasive encapsulated follicular variant of papillary thyroid carcinoma from non-malignant samples. Additionally, we analyzed the performance of single-protein/gene receiver operating characteristic in differentiating the invasive encapsulated follicular variant of papillary thyroid carcinoma from others within The Cancer Genome Atlas projects, which yielded an AUC > 0.5. We demonstrated that integration of high-throughput proteomics with machine learning can effectively differentiate the invasive encapsulated follicular variant of papillary thyroid carcinoma from other follicular pattern thyroid tumors.

Comparative Targeted Genome Profiling between Solid and Liquid Biopsies in Gastroenteropancreatic Neuroendocrine Neoplasms: A Proof-of-Concept Pilot Study

Plain Language SummaryGastroenteropancreatic tumors are rare neoplasms of the digestive tract that are difficult to diagnose and treat. Their characterization is key for patient management; however, these tumors frequently occur in body sites that are difficult to reach; therefore, we need alternative means to get a tumor sample that could help with diagnosis and management. Since tumor cells shed their DNA into blood circulation, we could sequence this DNA to find mutations mirroring those of the tumor. This procedure is called “liquid biopsy” (LB) and provides a genetic signature that could help follow up the patients and find the most effective cure. In our study, we withdrew a blood sample the day before the patients were operated on. Then, we isolated the DNA from those samples as well as from the tumors that were removed from the same patients. By means of advanced molecular biology techniques and data elaboration, we found that indeed the DNA in the blood shares mutations with that found in the primary tumor of the same individual, as previously demonstrated for other types of neoplastic disease. Therefore, we suggest that the LB could be feasible also in patients with gastroenteropancreatic tumors and could help better characterize the disease for both diagnostic and therapeutic purposes.

Highly Differentiated Neuroendocrine Tumor of the Appendix

Highly Differentiated Neuroendocrine Tumor of the Appendix

Treatment sequencing in gastroenteropancreatic neuroendocrine tumors

SummaryThe oncological treatment of neuroendocrine tumors (NET) has improved significantly in the last few years. Several informative clinical studies on NET have been conducted recently and updated NET guidelines have been published by the European Neuroendocrine Tumor Society (ENETS) in 2023 and 2024. With the growing number of positive phase III trials in NET, the main difficulty today is selecting the most appropriate treatment for a patient at the right time. The purpose of this short review is to delineate the main concepts and important changes in the therapy sequences for gastroenteropancreatic NET (gepNET) outlined in current European guidelines. In clinical practice, more individualized treatment decisions are often required that go beyond these general recommendations.

Synergizing traditional CT imaging with radiomics: a novel model for preoperative diagnosis of gastric neuroendocrine and mixed adenoneuroendocrine carcinoma.

To develop diagnostic models for differentiating gastric neuroendocrine carcinoma (g-NEC) and gastric mixed adeno-neuroendocrine carcinoma (g-MANEC) from gastric adenocarcinoma (g-ADC) based on traditional contrast enhanced CT imaging features and radiomics features. We retrospectively analyzed 90 g-(MA)NEC (g-MANEC and g-NEC) patients matched 1:1 by T-stage with 90 g-ADC patients. Traditional CT features were analyzed using univariable and multivariable logistic regression. Tumor segmentation and radiomics features extraction were performed with Slicer and PyRadiomics. Feature selection was conducted through univariable analysis, correlation analysis, LASSO, and multivariable stepwise logistic. The combined model incorporated clinical and radiomics predictors. Diagnostic performance was assessed with ROC curves and DeLong's test. The models' diagnostic efficacy was further validated in subgroup of g-NEC vs. g-ADC and g-MANEC vs. g-ADC cases. Tumor necrosis and lymph node metastasis were independent predictors for differentiating g-(MA)NEC from g-ADC (P < 0.05). The clinical model's AUC was 0.700 (training) and 0.667(validation). Five radiomics features were retained, with the radiomics model showing AUC of 0.809 (training) and 0.802 (validation). The combined model's AUCs were 0.853 (training) and 0.812 (validation), significantly outperforming the clinical model (P < 0.05). Subgroup analysis revealed that the combined model exhibited acceptable performance in differentiating g-NEC from g-ADC and g-MANEC from g-ADC, with AUCof0.887 and 0.823 in the training cohort and 0.852 and 0.762 in the validation cohort. A combined model based on traditional CT imaging and radiomic features provides a non-invasive and effective preoperative diagnostic method for differentiating g-(MA)NEC from g-ADC.