Management Of Neuroendocrine Tumors Research Articles

Clinical Intricacies and Advances in Neuroendocrine Tumors: An Organ-Based Multidisciplinary Approach

Abstract Neuroendocrine neoplasms (NENs) are rare neoplasms originating from neuroendocrine cells, with increasing incidence due to enhanced detection methods. These tumors display considerable heterogeneity, necessitating diverse management strategies based on factors like organ of origin and tumor size. This article provides a comprehensive overview of therapeutic approaches for NENs, emphasizing the role of imaging in treatment decisions. It categorizes tumors based on their locations: gastric, duodenal, pancreatic, small bowel, colonic, rectal, appendiceal, gallbladder, prostate, lung, gynecological, and others. The piece also elucidates the challenges in managing metastatic disease and controversies surrounding MEN1–neuroendocrine tumor management. The article underscores the significance of individualized treatment plans, underscoring the need for a multidisciplinary approach to ensure optimal patient outcomes.

Recent advances and future challenges in the diagnosis of neuroendocrine neoplasms.

Neuroendocrine neoplasms (NEN) are a heterogeneous group of malignancies with increasing incidence, whose diagnosis is usually delayed, negatively impacting on patients' prognosis. The latest advances in pathological classifications, biomarker identification and imaging techniques may provide early detection, leading to personalized treatment strategies. In this narrative review the recent developments in diagnosis of NEN are discussed including progresses in pathological classifications, biomarker and imaging. Furthermore, the challenges that lie ahead are investigated. By discussing the limitations of current approaches and addressing potential roadblocks, we hope to guide future research directions in this field. This article is proposed as a valuable resource for clinicians and researchers involved in the management of NEN. Update of pathological classifications and the availability of standardized templates in pathology and radiology represent a substantially improvement in diagnosis and communication among clinicians. Additional immunohistochemistry markers may now enrich pathological classifications, as well as miRNA profiling. New and multi-analytical circulating biomarkers, as liquid biopsy and NETest, are being proposed for diagnosis but their validation and availability should be improved. Radiological imaging strives for precise, non-invasive and less harmful technique to improve safety and quality of life in NEN patient. Nuclear medicine may benefit of somatostatin receptors' antagonists and membrane receptor analogues. Diagnosis in NEN still represents a challenge due to their complex biology and variable presentation. Further advancements are necessary to obtain early and minimally invasive diagnosis to improve patients' outcomes.

ASO Author Reflections: Simplifying the Fundamentals of Gastric Neuroendocrine Tumor Management.

ASO Author Reflections: Simplifying the Fundamentals of Gastric Neuroendocrine Tumor Management.

Comparative assessment of 111in-octreotide scintigraphy, 68GA-DOTATOC PET/CT and 18F-FDG PET/CT in the staging and management of neuroendocrine tumors (NETs)

Comparative assessment of 111in-octreotide scintigraphy, 68GA-DOTATOC PET/CT and 18F-FDG PET/CT in the staging and management of neuroendocrine tumors (NETs)

Perioperative management of patients with neuroendocrine tumours.

Octreotide is the cornerstone of perioperative management of neuroendocrine tumours, but there is no universal agreement on the optimal regimen. This article discusses the evidence for its use during different parts of the perioperative pathway.

Progress in immunotherapy for neuroendocrine neoplasm of the digestive system.

Neuroendocrine neoplasms (NENs) are rare heterogeneous tumors that can develop in almost any organ, with the digestive organs, including the gastrointestinal tract and pancreas being the most commonly affected sites. Despite the fact that advances in initial therapies have progressed, there is presently no recognized effective treatment for advanced NEN. Immune checkpoint inhibitors (ICIs) have shown superior efficacy in treating several types of solid tumors. Despite their successful role in the treatment of partial NENs, such as small cell lung cancer, and Merkel cell carcinoma, the role of ICIs in most of the NENs remains limited. Nevertheless, due to their specific anti-tumor mechanisms and acceptable safety profile, ICIs are a promising avenue for further study in NENs therapy. Recent clinical trials have illustrated that combination therapy with ICI is more efficient than monotherapy, and multiple clinical trials are constantly ongoing to evaluate the efficacy and safety of these combination therapies. Therefore, the purpose of this review is to provide a comprehensive summary of the clinical progress of immunotherapy in NENs affecting the digestive system, with a specific emphasis on the application of programmed cell death protein 1/programmed death receptor ligand 1 inhibitor. Furthermore, this review has an exploration of the potential beneficiary population and the inherent value of utilizing immunotherapy in the management of NENs.

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for colorectal neuroendocrine tumours.

This ENETS guidance paper, developed by a multidisciplinary working group, provides an update on the previous colorectal guidance paper in a different format. Guided by key clinical questions practical advice on the diagnosis and management of neuroendocrine tumours (NET) of the caecum, colon, and rectum is provided. Although covered in one guidance paper colorectal NET comprises a heterogeneous group of neoplasms. The most common rectal NET are often small G1 tumours that can be treated by adequate endoscopic resection techniques. Evidence from prospective clinical trials on the treatment of metastatic colorectal NET is limited and discussion of patients in experienced multidisciplinary tumour boards strongly recommended. Neuroendocrine carcinomas (NEC) and mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are discussed in a separate guidance paper.

A Systematic Review on Combined [18F]FDG and 68Ga-SSA PET/CT in Pulmonary Carcinoid.

Pulmonary carcinoids (PCs) are part of a spectrum of well-differentiated neuroendocrine neoplasms (NENs) and are classified as typical carcinoid (TC) and atypical carcinoid (AC). TC differ from AC not only for its histopathological features but also for its "functional imaging pattern" and prognosis. ACs are more undifferentiated and characterized by higher aggressiveness. Positron emission tomography/computed tomography (PET/CT) with somatostatin analogs (SSA) labeled with Gallium-68 (68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE) has widely replaced conventional imaging with gamma camera using 111In- or 99mTc-labelled compounds and represents now the gold standard for diagnosis and management of NENs. In this setting, as already described for gastro-entero-pancreatic NENs, 18F-Fluorodeoxiglucose ([18F]FDG) in addition to 68Ga-SSA can play an important role in clinical practice, particularly for ACs that show a more aggressive behavior compared to TCs. The aim of this systematic review is to analyze all original studies collected from the PubMed and Scopus databases regarding PCs in which both 68Ga-SSA PET/CT and [18F]FDG PET/CT were performed in order to evaluate the clinical impact of each imaging modality. The following keywords were used for the research: "18F, 68Ga and (bronchial carcinoid or carcinoid lung)". A total of 57 papers were found, of which 17 were duplicates, 8 were reviews, 10 were case reports, and 1 was an editorial. Of the remaining 21 papers, 12 were ineligible because they did not focus on PC or did not compare 68Ga-SSA and [18F]FDG. We finally retrieved and analyzed nine papers (245 patients with TCs and 110 patients with ACs), and the results highlight the importance of the combined use of 68Ga-SSA and [18F]FDG PET/CT for the correct management of these neoplasms.

Clinical utility of somatostatin receptor positron emission tomography imaging biomarkers for characterization of meningioma among incidental central nervous system lesions.

Somatostatin receptor (SSTR) PET imaging is utilized with increasing frequency in the clinical management of neuroendocrine tumors. Incidental PET-avid CNS lesions are commonly noted and presumed to be meningiomas. However, SSTR PET lacks specificity for meningioma identification. This study aimed to clarify the role of SSTR-based imaging in the classification of incidental CNS lesions based on current clinical practice. Patients who underwent both Ga-68-DOTATATE PET and brain MRI and had an incidental CNS lesion identified with a radiographic prediction of meningioma via one (discordant prediction) or both (concordant prediction) imaging modalities were retrospectively analyzed. Imaging indication, semiquantitative measures, and clinical history were recorded. Among 48 patients with a CNS lesion identified on both imaging modalities, most scans were performed for a history of neuroendocrine tumor (64.6%). Cases with concordant lesion-type prediction of meningioma between imaging modalities ( N = 24) displayed a significantly higher SUV max (median 7.9 vs. 4.0; P = 0.008) and Krenning score (median 3.0 vs. 2.0; P = 0.005) on Ga-68-DOTATATE PET compared with cases with a discordant prediction of meningioma ( N = 24). In cases with lower SUV max values, Ga-68-DOTATATE was more likely to discordantly predict meningioma without agreement by the corresponding MRI. Prior cranial radiation or use of somatostatin mimetics did not affect quantitative radiographic measures, and MRI-based tumor size was similar across groups. Lesions with increased avidity may be more confidently predicted as meningioma in Ga-68-DOTATATE PET scans, whereas there is more discrepancy in prediction among low SUV cases.

225Ac-Labeled Somatostatin Analogs in the Management of Neuroendocrine Tumors: From Radiochemistry to Clinic.

The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225Ac, its physical and radiochemical properties, as well as the place of 225Ac-DOTATOC and 225Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.

Diagnosis and management of neuroendocrine tumours

Neuroendocrine tumours (NETs) represent a heterogenous group of tumours, with diversity in their primary tumour sites, functional status (ie hormone secreting or non-functional) and degrees of aggressiveness (ranging from well-differentiated, grade 1 neuroendocrine tumours to poorly differentiated grade 3, neuroendocrine carcinomas). The most common sites are the lung, small bowel, pancreas and appendix. Clinical presentation is variable, ranging from incidental lesions detected on cross-sectional imaging, small bowel obstruction, carcinoid syndrome or other syndromic presentations (eg hypoglycaemia resulting from insulinoma) through to florid carcinoid heart disease. Diagnosis relies on biochemical markers, computed tomography (CT), magnetic resonance imaging (MRI) and somatostatin-receptor based functional imaging. Treatment comprises surgery where curative resection is possible through to approaches where disease stabilisation is the key, involving somatostatin analogues, peptide receptor radionuclide therapy (PRRT), everolimus, sunitinib, liver-directed therapies and sometimes chemotherapy. Although local and systemic complications can occur, they are associated with reasonable 5- and 10-year survival rates, respectively.

PET/MRI imaging in neuroendocrine neoplasm.

Molecular imaging plays a vital role in the management of neuroendocrine neoplasms (NENs). Somatostatin receptor (SSTR) PET is critical for evaluating NENs, ascertaining peptide receptor radionuclide therapy (PRRT) eligibility, and treatment response. SSTR-PET/MRI can provide a one-stop-shop multiparametric evaluation of NENs. The acquisition of complementary imaging information in PET/MRI has distinct advantages over PET/CT and MR imaging acquisitions. The purpose of this manuscript is to provide a comprehensive overview of PET/MRI and a current review of recent PET/MRI advances in the diagnosis, staging, treatment, and surveillance of NENs.

Evaluation of quality of clinical management of neuroendocrine tumors

AbstractBackgroundNeuroendocrine tumors (NETs) are a group of biologically and clinically heterogeneous neoplasms predominantly found in the gastrointestinal and bronchopulmonary tractus. Despite a rising incidence, implementation of evidence‐based standardized care for this heterogenous group remains challenging. The European Neuroendocrine Tumor Society regularly reviews guidelines regarding diagnostic and treatment strategies for NETs. The aim of this study is to shed light on the care of patients with a NET in Belgian Limburg, to provide data as a basis for future studies and to check whether data and results are according to consensus guidelines and outcomes described in literature.MethodsOur study concerned a detailed observational data collection of two large Belgian hospitals (Jessa Hospital Hasselt and Hospital Oost‐Limburg Genk) with special interest in patient profile, quality of pathology reports, use of diagnostic imaging, and overall survival. Data on 188 patients were assembled between January 2010 and December 2014 with follow‐up until June 2016 (median follow‐up: 33.6 months).ResultsFifty percent of patients were male. NETs were located mainly in the digestive tract (63.8%) and lung (20.2%). Appendiceal NETs were diagnosed at a significantly younger age than other tumors (41.3 vs. 64.0 years). Overall, a mean pathology report quality score of 3.0/5 was observed with the highest scores for small bowel NETs. Diagnostic and nuclear imaging was performed in 74.5% and 29.8% of cases, respectively. Seventy‐four percent of the population survived until the end of the observation period with highest survival rates for appendiceal and small bowel NETs.ConclusionOverall, epidemiological results were comparable with findings in the literature. Gastrointestinal NETs met most of the requirements of qualitative pathology reporting and diagnostic imaging as listed in the European Neuroendocrine Tumor Society consensus guidelines. However, consensus with regard to bronchopulmonary NETs is still scarce and remains an objective for future research. Moreover, discussing treatment strategies in specialized multidisciplinary tumor boards would facilitate regional care.

ODP032 Case Series: Prazosin in the Preoperative Management of Pheochromocytoma and Paraganglioma

Abstract Background Prazosin is a competitive alpha-1 adrenoreceptor antagonist. It is an ideal agent for preoperative blockade in neuroendocrine tumors compared to more commonly used agents such as phenoxybenzamine, a non-selective alpha blocker or doxazosin a longer acting alpha-1 blocker. Its affinity for alpha-1 receptors lessens the risk for systemic side effects while its short half-life and a relatively short duration of action of about 10-24 hours decreases the risk for intra and post-operative hypotension. Case 1 38 year old male was found to have resistant hypertension during routine follow up visit. Work up for secondary causes of hypertension revealed plasma metanephrines 5.1nmol/L, normetanephrine 6.7nmol/L, epinephrine 5990pg/mL, norepinephrine 15318 pg/mL, with 24 hour urine epinephrine 1329ug/24hr and norepinephrine 3115ug/24hr. Imaging findings shows 4.8cm right adrenal mass consistent with Pheochromocytoma. He was started on Prazosin titrated up to a dose of 5mg TID and labetalol 200mg TID to a goal systolic BP <130 mmHg. A right laparoscopic adrenalectomy was done and intraoperatively, he remained hemodynamically stable with no vasopressor or antihypertensive requirement. His blood pressure normalized immediately post op and did not require further antihypertensives for the rest of his hospitalization. Case 2 62 year old female was found to have an incidental 4.7cm left adrenal mass after a routine surveillance for pulmonary nodule. Biochemical data showed plasma metanephrines 14nmol/L, normetanephrine 3nmol/L, epinephrine 2719pg/mL, norepinephrine 701pg/mL, and chromogranin A 3507ng/m with a 24 hour urine epinephrine 938uh/24hr, consistent with Pheochromocytoma. The patient was started on Prazosin, titrated up to a maximum tolerated dose of 2mg TID before symptomatic hypotension occurred. Labetalol 100mg BID was later added. She underwent a left laparoscopic adrenalectomy but required Clevidipine drip and IV pushes of norepinephrine PRN intraoperatively for low blood pressure. However, she was taken off antihypertensives immediately post-op, and did not have any hypotensive episodes events thereafter. Case 3 50 year old female presented for left sided chest pain where a CT angiogram was done and incidentally found a para-aortic mass measuring 2.7×1.6×2.3cm in the organ of Zuckerlandl. Biochemical findings showed plasma normetanephrine 5.6nmol/L, norepinephrine 4564pg/mL, and chromogranin A 440ng/mL, consistent with a Paraganglioma. She was started on Prazosin titrated up to 6mg TID, labetalol 100mg TID and amlodipine 10mg daily to reach goal systolic blood pressure and heart rate. She underwent an open resection where there were no hypotensive events intraoperatively but did require Clevidipine drip for hypertension. Immediately post-op her BP normalized, the drip was discontinued, and she did not have any post-op hypotensive events. Conclusion This case series highlights the advantages of short acting alpha-1 blockade in the preoperative management of neuroendocrine tumors. All three patients did not have any post-operative hypotension and had an uncomplicated post-op course. Presentation: No date and time listed

ODP303 Cushing's Syndrome Due to Ectopic Adrenocorticotropic Hormone-Secreting Metastatic Neuroendocrine Tumor

Abstract Introduction Cushing's syndrome (CS) due to ectopic ACTH secretion (EAS), is an infrequent form of ACTH-dependent CS. EAS results from unregulated ACTH secretion by neuroendocrine tumors (NETs) of various locations resulting in severe hypercortisolism. The progression of CS is usually precipitous. To improve outcomes, it is imperative to recognize early so that treatments of cortisol-induced comorbidities and targeted treatments can be initiated. Case Presentation A 74-year-old female presented to an outside hospital with fatigue, bilateral lower extremity edema and intractable hypokalemia. She was later transferred to our facility, where workup of CS was initiated. She underwent a 1mgdexamethasone suppression test (DST)which resulted in an unsuppressed 8amcortisol of 34.7 ug/dL (<2 ug/dL). This was followed by a 4mgDST, again resulting in an unsuppressed 8amcortisol of25.4 ug/dL. A 24-hour urine cortisol level was collected and resulted at 2,108.9 ug/d (<45 ug/d). ACTH level was elevated at 136 pg/ml (7.2-63.3 pg/ml). CT abdomen/pelvis identified liver lesions concerning for metastatic disease. PET DOTATATE revealed multiple liver lesions and a few pulmonary nodules. Biopsy of liver lesions demonstrated strongly positive staining of synaptophysin and chromogranin confirming NET, with a weak TTF-1 positivity suggestive of pulmonary origin. Lanreotide injections were initiated for tumor control and ketoconazole for treatment of persistent hypercortisolism. Despite titration of ketoconazole, symptoms and labs showed minimal improvement. Osilodrostat was then added as a third line and examethasone was initiated in a block and replace approach. The regimen of lanreotide, osilodrostat and ketoconazole improved her24-hoururine cortisol to 15 from 2,109 ug/24hr. Subsequently patient underwent trans-arterial chemoembolization (TACE) of the liver lesions with resolution of hypercortisolism. She is currently only on Lanreotide for tumor control. Discussion NET with ectopic ACTH production is rare. While primary tumor location was not definitively identified, multiple lung lesions and histopathology suggested primary lung tumor with hepatic metastases. 20-40% of all NETS originate in the chest. Patient management necessitates a multidisciplinary approach not only for the diagnosis and treatment of CS but also for the specific management of neuroendocrine tumors (NET). This case highlights a rare presentation of EAS, and aggressive treatment modalities needed to treat symptoms of excess cortisol production and tumor progression. Presentation: No date and time listed

The management of neuroendocrine tumours

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The impact of COVID-19 on the management of neuroendocrine tumors (NETS): An international NET CONNECT survey of NET patients and healthcare professionals treating net patients.

The COVID-19 outbreak has added complexity in the management of patients with neuroendocrine tumors (NETs). Little information is currently available regarding the real impact of the pandemic in current practice. The present study aimed to capture patients' and healthcare professionals' experiences on how the NET management has changed during the pandemic and how it should be modified in a foreseeable post-pandemic environment. Physicians and nurses working in ENETS Centers of Excellence or other hospitals with high volume of NET patients (n=48), as well as NET patients residing worldwide (n=353), were asked to respond to two online anonymous surveys addressing different aspects of NET care. Deferred diagnoses, delayed surveillance procedures and postponed elective surgeries were among the main negative consequences of the COVID-19 outbreak according to 40%, 54% and 46% of healthcare professionals (HPs) respectively. Somatostatin analogs were increasingly used as bridging strategy for delaying surgery based on the views of 31% of HPs and were self-injected or delivered by home care services more frequently than before the initiation of the pandemic (53% of patients during the pandemic vs. 44% before the pandemic). Multidisciplinary tumor boards kept their usual schedule according to 58% of HPs, but were held virtually in the 77% of cases. The contact with healthcare professionals was maintained by remote methods more often than in the past (69% of patients), but only 34% of patients (59% among subjects < 41 years) would prefer telemedicine to face-to-face consultations in the future. New health policy measures should guarantee the highest standard of treatment to NET patients, regardless of the trajectory followed by the COVID-19 pandemic in the next months. Pros and cons of telemedicine should be carefully weighted before systematic implementation.

147 Synchronous Parathyroidectomy and Extended Thymectomy in Multiple Endocrine Neoplasia Type 1- a Case Report

Abstract In recent decades there has been a significant advancement in the management of neuroendocrine tumours (NETs) associated with multiple endocrine neoplasia type 1 (MEN-1). Hormone excess accounted for 75% of all MEN-1 deaths, however since the introduction of hormone blocking medication, deaths in patients with MEN-1 are now predominantly due to the malignant effects of the tumours. Half of all MEN-1 related deaths are due to tumours that are difficult to diagnose, including thymic NETs. Complete surgical resection is the mainstay of treatment for MEN-1 associated thymic NETs. The case patient was a 49-year-old male who was being investigated for a 3-month history of symptoms consistent with hypercalcaemia. Initially a chest X-ray demonstrated a large anterior mediastinal mass. Further imaging revealed parathyroid lesions and a calcified lesion in the uncinate process of the pancreas. This combination of symptoms and radiological evidence raised the possibility of MEN-1 as the diagnosis. The lesions were biopsy-proven atypical carcinoid NETs and the patient later underwent simultaneous neck dissection for bilateral subtotal parathyroidectomy and a midline sternotomy for total thymectomy of the large mediastinal mass. Further testing revealed the pancreatic mass was another primary tumour and the patient is scheduled for excision of this. In addition, the patient is also being treated with Lanreotide alongside chemotherapy. Mutation of the MEN-1 gene was later confirmed on genetic testing. Due to the increase in mortality from neuroendocrine malignancy, it is becoming ever more important to understand how to manage multiple NETs from a surgical perspective.

Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [Aktualizacja zaleceń ogólnych dotyczących postępowania diagnostyczno-terapeutycznego w nowotworach neuroendokrynnych układu pokarmowego (rekomendowane przez Polską Sieć Guzów Neuroendokrynnych)]

Continuous progress in the diagnostics and treatment of neuroendocrine neoplasms (NENs), the emerging results of new clinical trials, and the new guidelines issued by medical societies have prompted experts from the Polish Network of Neuroendocrine Tumours to update the 2017 recommendations regarding the management of neuroendocrine neoplasms. This article presents the general recommendations for the management of NENs, resulting from the findings of the experts participating in the Fourth Round Table Conference, entitled “Polish Guidelines for the Diagnostics and Treatment of Neuroendocrine Neoplasms of the gastrointestinal tract, Żelechów, June 2021”. Drawing from the extensive experience of centres treating these cancers, we hope that we have managed to formulate the optimal method of treating patients with NENs, applying the latest reports and achievements in the field of medicine, which can be effectively implemented in our country. The respective parts of this work present the approach to the management of: NENs of the stomach and duodenum (including gastrinoma), pancreas, small intestine, and appendix, as well as large intestine.

Management of neuroendocrine tumors of the rectum

Rectal neuroendocrine tumors (NETs) have increased in prevalence due to increased detection via endoscopic screening for colorectal neoplasia, advances and availability of imaging tools along with the indolent nature of the tumor. Imaging techniques to identify rectal NETs include computed tomography, magnetic resonance imaging, and endoscopic rectal ultrasound. Rectal NETs are typically categorized by tumor size to determine if they should undergo endoscopic resection, local excision or transanal excision, or a radical resection, as per National Comprehensive Cancer Network guidelines. However, while examining the literature, multiple studies have examined outcomes for patients who did not adhere to these guidelines and had similar recurrence rates and survival as those patients who did. Therefore, we propose less aggressive treatment for rectal NETs in the absence of adverse features.