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Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well-differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although GEP-NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP-NETs is surgery, which offers the best chance for a cure. However, because GEP-NETs are often slow-growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide-receptor radionuclide therapy with α and β emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies., (© 2024 American Cancer Society.)

As novel biomarkers for gastroenteropancreatic neuroendocrine tumors (GEPNET) are in demand, we aimed to validate the clinical value of the NETest in Japanese patients. Between 2021 and 2023, blood and clinical data were collected from patients with GEPNET. Among 35 patients (median age: 59 [49-66] years), 27 cases originated from the pancreas and eight from the gastrointestinal tract. Of 69 samples sent to the laboratory, 56 (81.2%) underwent NETest. The diagnostic sensitivity was 97.1%. Among three patients who underwent R0 resection and four treated with peptide receptor radionuclide therapy, the changes in NETest scores closely correlated with disease progression. The NETest demonstrated high diagnostic efficacy and accurate therapeutic monitoring capabilities in a Japanese population.

Neuroendocrine neoplasms (NENs), also known as neuroendocrine tumors (NETs), are rare tumors derived from cells with characteristics of both nerve and endocrine cells. The clinical presentation, diagnosis, and treatment of NENs vary significantly depending on the type, location, whether the neoplasm is hormonally functional, how aggressive it is, and whether it has metastasized to other parts of the body. This article provides an overview of specific types of NETs, clinical presentations and related syndromes, diagnosis, and approach to management of common NENs., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Peritoneal metastases (PM) of neuroendocrine neoplasm (NEN) origin are identified with increasing frequency and exert a significant effect on quality of life and clinical status of the patients. The aim of this study was to identify the characteristics and the prognostic significance of PM in patients with NENs., Methods: A retrospective analysis of the data of patients from two tertiary referral centers was performed. We defined a control group of age- and gender-matched NEN patients with comparable stage IV disease but no PM., Results: We analysed 70 patients (41 females) with PM. Small intestine was the most common primary NEN site (87.1%). PM prevalence was 10.3%. Forty-four patients presented with synchronous PM, whereas 26 developed metachronous PM. The majority of patients had other concomitant metastases (50 hepatic, 6 lung and 12 bone metastases). Twelve patients developed intestinal obstruction. After PM diagnosis, 76% of patients received treatment with somatostatin analogues while six patients (8.6%) were treated with peptide receptor radionuclide therapy (PRRT). The median progression-free survival (PFS) in the PRRT-treated group was 15 months (95% CI 2-28). Median overall survival (OS) in the PM group was 142 months [95% CI 71-213] while it was not reached in the control group., Conclusion: Peritoneal metastases show low prevalence among NEN patients and are most likely to develop in patients with small intestinal NENs and advanced metastatic disease. The presence of PM does seem to be associated with a negative prognostic impact on OS of NEN patients and their identification and prompt treatment is of major importance., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

This review presents a comprehensive comparative analysis of international guidelines for managing advanced, non-functioning, well-differentiated pancreatic neuroendocrine tumors (panNETs). PanNETs, which represent a significant proportion of pancreatic neuroendocrine neoplasms, exhibit diverse clinical behaviors and prognoses based on differentiation, grading, and other molecular markers. The varying therapeutic strategies proposed by different guidelines reflect their distinct emphases and regional considerations, such as the ESMO guideline's focus on advanced disease management and the ENETS guidance paper's multidisciplinary approach. This review examines the most recent guidelines from ESMO, NCCN, ASCO, ENETS, and NANETS, analyzing the recommendations for first-line therapies and subsequent treatment pathways in different clinical scenarios. Significant variations are observed in the recommendations, particularly concerning the choice and sequence of systemic therapies, the role of tumor grading and the Ki-67 index in therapeutic decisions, and the integration of regional regulatory and clinical practices. The analysis highlights the need for a tailored approach to managing advanced NF panNETs, advocating for flexibility in applying guidelines to account for individual patient circumstances and the evolving evidence base. This work underscores the complexities of managing this patient population and the critical role of a multidisciplinary team in optimizing treatment outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Angela Lamarca declares travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, Delcath Advanz Pharma and Roche. Speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA/Novartis, QED, Servier, Astra Zeneca, EISAI, Roche, Advanz Pharma and MSD; advisory and consultancy honoraria from EISAI, Nutricia, Ipsen, QED, Roche, Servier, Boston Scientific, Albireo Pharma, AstraZeneca, Boehringer Ingelheim, GENFIT, TransThera Biosciences, Taiho and MSD; principal Investigator-associated Institutional Funding form QED, Merck, Boehringer Ingelheim, Servier, Astra Zeneca, GenFit, Panbela Therapeutics, Novocure GmbH, Camurus AB, Albireo Pharma, Taiho, TransThera, Jazz Therapeutics and Roche; she was also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. Nicola Fazio: IPSEN, Advisory Board, Personal; Merck, Advisory Board, Personal; MSD, Advisory Board, Personal; NOVARTIS, Other, Personal, Steering committee; NOVARTIS, Invited Speaker, Personal; NOVARTIS, Advisory Board, Personal; Astellas, Local PI, Institutional, Financial interest; Beigene, Local PI, Institutional, Financial interest; Boehringer, Local PI, Institutional, Financial interest; FIBROGEN, Local PI, Institutional, Financial interest; IPSEN, Local PI, Institutional, Financial interest; IPSEN, Research Grant, Institutional, Financial interest; ITM, Local PI, Institutional, Financial interest; Merck, Research Grant, Institutional, Financial interest; MSD, Local PI, Institutional, Financial interest; NOVARTIS, Research Grant, Institutional, Financial interest; NUCANA, Local PI, Institutional, Financial interest. Non-Financial Interests: AIOM, Other, Internal reviewer of NET guidelines; ENETS, Member of Board of Directors; ESMO, Other, Member of the NET Faculty; SPARC Europe, Other, Steering committee. Francesco Panzuto: Advisor honoraria form Mylan (Viatris), Advanz pharma. Novartis, Camurus, Ipsen, Local PI, Institutional. Non-financial interest: AIOM, author of NET guidelines; ENETS, chair of the advisory board; Itanet, chief of the society]., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pancreatic neuroendocrine tumors are the second most common tumors of the pancreas, and approximately half of patients are diagnosed with liver metastases. Currently, the improvement in the efficacy of relevant treatment methods is still limited. Therefore, there is an urgent need for in-depth research on the molecular biological mechanism of pancreatic neuroendocrine tumors. However, due to their relatively inert biology, preclinical models are extremely scarce. Here, the patient-derived organoid, and patient-derived xenograft were successfully constructed. These two models and the previously constructed cell line named SPNE1 all derived from the same patient with a grade 3 non-functional pancreatic neuroendocrine tumor, providing new tumor modeling platforms, and characterized using immunohistochemistry, whole-exome sequencing, and single-cell transcriptome sequencing. Combined with a tumor formation experiment in immunodeficient mice, we selected the model that most closely recapitulated the parental tumor. Overall, the patient-derived xenograft model most closely resembled human tumor tissue., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Introduction: The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied., Materials and Methods: Retrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS)., Results: Of the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017)., Conclusion: A higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs., (© 2024. The Author(s).)

Lung neuroendocrine neoplasms (L-NEN) are heterogeneous tumors. While bone metastases (BM) have been associated with worse prognosis in other NEN, their role in L-NEN deserves in-depth analysis. This study analyzes the clinical presentation, treatment and survival outcomes of L-NEN, focusing on patients with BM compared with patients without metastases or with metastases in other sites (OtherMtx). The clinicopathological and survival data of L-NEN admitted to the Federico II University were retrospectively evaluated. Fifty L-NEN were included. Among 27 metastatic patients (54%), 13 (26%) had BM, more commonly occurring in males than females and in primary bilateral L-NEN or L-NEN > 26 mm, with higher Ki67. Atypical carcinoid and hypovitaminosis D were associated with BM. The number of metastatic sites was higher in patients with BM than OtherMtx. Synchronous metastases were associated with shorter overall survival (OS). The median progression-free survival (PFS) and OS in patients with BM were similar to OtherMtx, but a two-times increased risk of shorter OS was detected. BM do not impact PFS or OS more than OtherMtx, but the increased risk of shorter OS in patients with BM should be considered. Periodic bone evaluation in L-NEN should be recommended.

Functioning pancreatic neuroendocrine neoplasms other than insulinomas and gastrinomas (rf-pNENs) are exceptionally rare tumours. Thus, their characteristics and long-term prognosis have not been well defined. This article aims to present data and experience from a single institution concerning this topic. Twelve of 216 (5.5%) patients with pNENs operated between 2002 and 2022 in the ENETS Centre of Excellence Marburg had rf-pNENs and their data were retrospectively analysed. We identified three vasoactive intestinal polypeptide producing pNENs, four glucagonomas and five calcitoninomas. The tumour could be visualised by preoperative imaging in all 12 patients, and six patients had distant metastases at the time of diagnosis. The tumour was located in the pancreatic tail in nine patients and the median tumour size was 82 (range 12-220) mm. Eleven patients underwent tumour resections (two robotic, nine conventional), nine of which were R0. After a median follow-up of 75 (range 1-247) months, six patients were alive, five of whom had no evidence of disease. All patients who remained disease-free had an initial R0 resection of the primary tumour and no initial liver involvement. This study sheds light on the distinct characteristics and outcomes of these exceedingly rare tumours, offering insights for improved understanding and management., (© 2024. The Author(s).)

Background: High-grade neuroendocrine cancers (NEC) of the head and neck (HN) are rare and aggressive, accounting for ≤1 % of all HN cancers, with a 5-year overall survival (OS) of ≤20 %. This case series examines clinical characteristics, treatments, and outcomes of patients diagnosed at a regional UK HN cancer centre over the last 23 years., Methods: A retrospective review of medical records was conducted for all patients diagnosed with NEC HN from 1st January 2000 until 1st March 2023 at Velindre Cancer Centre., Results: During the study period, 19 cases of NEC HN were identified, primarily affecting males (n = 15, 79 %). Median age of 67 years (range: 44-86). At diagnosis, 32 % of patients (n = 6) were smokers. The most common primary tumour sites were larynx (n = 5, 26.3 %) and sinonasal (n = 5, 26.3 %). Most patients presented with advanced loco-regional disease or distant metastasis, with stage IVA (n = 6, 32 %) and stage IVC (n = 6, 32 %) being the most common. The key pathology marker was synaptophysin, present in 100 % of the tested patients (n = 15). In the study, of the 12 patients with non-metastatic disease, 10 received a combination of treatments that included radiotherapy (RT). Some of these patients also received chemotherapy (CT) at the same time as their radiotherapy. Surgery alone was used in two patients with stage II disease. Seven subjects had complete responses, and one achieved a partial response. Among the seven metastatic patients, three received CT, and one underwent palliative RT, all achieving a partial response. In all cases, the CT used was carboplatin and etoposide. After a median follow-up of 11 months (range: 1-96), the median OS was 27 months for the overall population, 51 months for those treated radically, and three months for metastatic patients with palliative treatment. The 1-year OS for all patients was 54.3 %, the 2-year OS was 46.5 %, and the 5-year OS was 23.3 %. Among patients treated radically, these rates were 65.3 %, 52.2 %, and 26.1 %, respectively. For patients treated palliatively, the 1-year OS was 33.3 %., Conclusion: This case series contributes preliminary observations on the characteristics and management of non-metastatic NEC HN, suggesting potential benefits from multimodality treatment strategies. Given the small cohort size, these observations should be interpreted cautiously and seen as a foundation for further research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: We declare no competing interests.

Despite, or perhaps because of the rarity of neuroendocrine neoplasms, the diagnosis and treatment of these malignancies is of particular importance. Nuclear medicine can make an important contribution to this challenge. It offers the most sensitive and specific imaging of these tumor entities and can be helpful in treatment due to the radiotherapeutic drugs that have recently been approved. This theragnostic (fusion of therapeutic and diagnostic) concept is based on the frequent overexpression of somatostatin receptors on neuroendocrine tumor cells.Using diagnostic and therapeutic pharmaceuticals based on analogues from somatostatin, most applications from the nuclear medicine are successful, an additional therapeutic method is SIRT, also known as TARE, in which the hypervascularization of NEN-metastases is used as a therapeutic target., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Lung carcinoid tumours are neuroendocrine neoplasms originating from the bronchopulmonary tract's neuroendocrine cells, accounting for only 1%-3% of all lung cancers but 30% of all neuroendocrine tumours. The incidence of lung carcinoids, both typical and atypical, has been increasing over the years due to improved diagnostic methods and increased awareness among clinicians and pathologists. The most recent WHO classification includes a subgroup of lung carcinoids with atypical morphology and higher mitotic count and/or Ki67 labelling index. Despite appropriate surgery, the 5-year survival rate for atypical carcinoids barely exceeds 50%-70%. The role of adjuvant therapy in lung carcinoids is not well-defined, and clinical decisions are generally based on the presence of high-risk features. Long-term follow-up is essential to monitor for recurrence, although the optimal follow-up protocol remains unclear. To address the lack of consensus in clinical management decisions, the European Neuroendocrine Tumor Society (ENETS) initiated a survey among 20 expert centres. The survey identified varied opinions on approaches to imaging, surgery, use of adjuvant therapy, and follow-up protocols. Notably, the absence of dedicated multidisciplinary lung neuroendocrine tumour boards in some centres was evident. Experts agreed on the need for a prospective adjuvant trial in high-risk patients, emphasizing the feasibility of such a study. In conclusion, the study highlights the need for a more uniform adoption of existing guidelines in the management of lung carcinoid tumours and emphasizes the importance of international collaboration to advance research and patient care. Close collaboration between healthcare providers and patients is vital for effective long-term surveillance and management of these rare tumours., (© 2024 British Society for Neuroendocrinology.)

Pancreatic neuroendocrine tumors (PNETs) are considered rare pancreatic neoplasms, and it is a challenging disease entity due to its indolent behavior and is difficult to manage. Diagnostic challenge is usually found in the imaging-based approach, such as transabdominal ultrasound, abdominal CT scan, and abdominal MRI. Surgery is still the main key player in controlling the disease. The main problems in clinical practice are the early detection of small PNETs lesion and non-functional PNET (NF-PNET) cases. Most cases usually come with large tumor size or metastatic disease. Endoscopic ultrasound (EUS) has been well-known as the most sensitive tool for early detection of pancreatic malignancy. It has now also been developed for managing pancreatic cancer, such as tumor ablation therapy. We presented four variety of PNETs cases (one patient with non-functioning PNETs and three patients with functioning PNETs) who have been successfully treated with EUS-guided radiofrequency ablation (RFA) with good control of tumor growth during follow-up. One patient with a large-size insulinoma could have the tumor controlled gradually after several EUS-RFA sessions. No adverse events or major complications were observed during and after the EUS-RFA procedure. EUS has been shown as a promising tool not only for more accurate diagnosis but also for tumor growth control. However, it would need further comparison studies between EUS and surgical approaches to make a better treatment strategy., (© 2024. Japanese Society of Gastroenterology.)

The understanding of the nature of catecholamine-secreting tumors has changed significantly in recent years, affecting terminology and classification. Phaeochromocytoma/paraganglioma (PCC/PG) is a rare neuroendocrine tumor from chromaffin tissue that produces and secretes catecholamines. The incidence of PCC/PG is relatively low, with 2-8 cases per 1 million population per year; among patients with arterial hypertension, their prevalence is 0.2-0.6%. However, delayed diagnosis of PCC/PG is associated with a high risk of cardiovascular complications and a high mortality rate. The consensus presents the clinical manifestations of the disease with an emphasis on the course of arterial hypertension as the most common symptom in PCC/PG; modern ideas about the features of diagnosis, aspects of preoperative preparation, treatment, and follow-up of patients with PCC/PG are considered.

Background: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs)., Aim: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort., Methods: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed., Results: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods., Conclusion: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Clinical Issue: Neuroendocrine neoplasms of the lung are a heterogenous tumor group. The pathological classification comprises diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, classic neuroendocrine tumors, and neuroendocrine carcinoma. Classic neuroendocrine tumors include typical and atypical carcinoid tumors., Diagnostic Work-Up: Imaging plays an important role in diagnosis and can help in identifying the tumor biology. Overall, this tumor group is rare, comprising less than 2% of all thoracic tumors., Practical Recommendations: In the current review, the various tumors are presented and important aspects regarding pathological classification, imaging modalities, and treatment are described., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Abstract: Neuroendocrine neoplasms (NENs) are a diverse group of tumors that express neuroendocrine markers and primarily affect the lungs and digestive system. The incidence of NENs has increased over time due to advancements in imaging and diagnostic techniques. Effective management of NENs requires a multidisciplinary approach, considering factors such as tumor location, grade, stage, symptoms, and imaging findings. Treatment strategies vary depending on the specific subtype of NEN. In this review, we will focus on treatment strategies and therapies including the information relevant to clinicians in order to undertake optimal management and treatment decisions, the implications of different therapies on imaging, and how to ascertain their possible complications and treatment effects., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Small bowel cancer (SBC) is a rare and aggressive disease with a poor prognosis, necessitating the exploration of novel treatment approaches. This narrative review examines the current evidence on targeted therapy and immunotherapy for SBC, focusing on the two most common subtypes: adenocarcinoma and neuroendocrine tumor. A comprehensive search of PubMed, Scopus, and Google Scholar databases was conducted to identify relevant clinical trials and case reports published in English up to September 2023. The review includes 17 clinical trials and 10 case reports, indicating that targeted therapy and immunotherapy can have the potential to improve survival rates in patients with SBC. Notably, promising targeted medicines include bevacizumab, cetuximab, and trastuzumab, while pembrolizumab and nivolumab show potential as immunotherapies. However, it should be noted that the magnitude of the increase in survival rates with these interventions was small. Further research is needed to determine the optimal combination of targeted therapy and immunotherapy for individual patients with SBC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background & Aims: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs., Methods: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort., Results: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate., Conclusions: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The majority of patients with neuroendocrine tumors (NET) develop liver metastases during the course of the disease, significantly impacting prognosis and quality of life., Clinical Issue: Radiologically guided interventional therapies, such as thermal ablation, transarterial embolization (TAE)/chemoembolization (TACE), and selective internal radiotherapy (TARE), can play a crucial role in the treatment of metastatic NET., Data: Due to the rarity of the disease, the majority of evidence is based on retrospective studies. For thermal ablation, the complete response rates ranging from 31.6 to 95.3% depending on the study. No significant differences in outcomes were found between TAE, TACE, and TARE. In several studies, all intra-arterial procedures led to a reduction of tumor-related symptoms and achieved disease control., Conclusion: Thermal ablation can be used as a curative therapy in oligometastatic patients with nonresectable liver metastases from NETs. In cases of disseminated liver metastases, intra-arterial therapy using TAE, TACE, or TARE can be employed., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP-NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP-NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP-NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP-NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix., (© 2024 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Well-differentiated neuroendocrine tumors (NET) are rare malignancies that are clinically very heterogeneous. Accordingly, their treatment is also complex and dependent on various factors. With currently available systemic therapies, the prognosis is often favorable., Objectives: This article aims to provide an overview of current treatment strategies for NET, addressing the most important NET locations., Methods: The current European guidelines and further relevant literature on the treatment of NET were reviewed for this purpose., Results: The therapeutic spectrum for NET is extremely broad: For NET of the stomach/duodenum, appendix, and rectum, endoscopic or surgical resection is often sufficient, and metastatic tumors are rare. NET of the pancreas, small intestine and lung should also undergo potentially curative resection in the early stages. In the metastatic stage, locoregional treatments such as surgery and liver tumor embolization play a role. Major advances have been made in drug therapy, with somatostatin analogs (octreotide and lanreotide), an mTOR inhibitor (everolimus), and a tyrosine kinase inhibitor (sunitinib) being widely used. Peptide receptor radionuclide therapy (PRRT) is also an invaluable option. In some cases, classic chemotherapy is indicated., Conclusions: Many effective therapies are now available for NET. It is important to select the right therapy at the right time for each patient through interdisciplinary management., (© 2024. The Author(s).)

Introduction: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival., Methods: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group., Results: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P <0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous ( P =0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade ( P =0.977) and location ( P =0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion ( P =0.387)., Conclusion: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Gastrointestinal neuroendocrine tumours (NETs) are rare and clinically heterogeneous. From a diagnostic perspective, well-differentiated tumours must be distinguished from poorly differentiated neuroendocrine carcinomas. The disease may be associated with autonomous hormone secretion by the tumour, and the resulting syndromes are often associated with reduced survival. Somatostatin analogues form the backbone of antiproliferative and antisecretory treatment alongside local ablative procedures. In pancreatic NET, prospective studies confirm the value of specific chemotherapy, particularly in terms of higher remission rates. New tyrosine kinase inhibitors are an option for patients that have failed to respond to standard treatments. Inhibition of HIF2-alpha is an emerging effective treatment option for patients with von Hippel-Lindau-syndrome associated tumours, e.g. pancreatic NET. Radioligand therapy is an established second-line option for advanced NET of the small intestine, and recent study results support its use in pancreatic NET in earlier-line treatment. Due to the complexity of the disease, management of NET patients should be performed in close collaboration with a specialized multidisciplinary team., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Neuroendocrine neoplasms (NEN) are heterogenous with an increasing incidence in recent years., Objectives: Overview on incidence, symptoms, diagnostics, grading, imaging and prognostic determinants, including factors having an impact on therapeutic management., Methods: Review on current literature, including original articles, reviews, guidelines and expert opinions., Results: NEN are mainly located in the gastrointestinal tract and their incidence has increased in recent years, mainly due to improved diagnostics, e.g., cross-sectional imaging. Clinical characteristics include hormone excess syndromes (carcinoid syndrome). Laboratory markers such as chromogranin A are commonly used as part of routine diagnostics, followed by endoscopic and endosonographic procedures, which also allow biopsies to be obtained. Tumor spread can be determined by contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) or somatostatin receptor (SSRT)-PET/CT (positron emission tomography). Prognostic factors include Ki67 index, type, and grading. Resection with curative intent is the therapy of choice. In a metastasized setting, SSRT-directed treatment approaches are favored, while in dedifferentiated NEN, conventional chemotherapy is needed., Conclusion: A broad diagnostic armamentarium can be offered to NEN patients and the improved diagnostic procedures have most likely caused a raising incidence in recent years. Among others, prognostic factors are Ki67 and NEN subtypes; these clinical determinants also have an impact on patient management., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Abstract: Neuroendocrine neoplasms (NENs) are rapidly evolving small bowel tumors, and the patients are asymptomatic at the initial stages. Metastases are commonly observed at the time of presentation and diagnosis. This review addresses the small bowel NEN (SB-NEN) and its molecular, histological, and imaging features, which aid diagnosis and therapy guidance. Somatic cell number alterations and epigenetic mutations are studied to be responsible for sporadic and familial SB-NEN. The review also describes the grading of SB-NEN in addition to rare histological findings such as mixed neuroendocrine-non-NENs. Anatomic and nuclear imaging with conventional computed tomography, magnetic resonance imaging, computed tomographic enterography, and positron emission tomography are adopted in clinical practice for diagnosing, staging, and follow-up of NEN. Along with the characteristic imaging features of SB-NEN, the therapeutic aspects of imaging, such as peptide receptor radionuclide therapy, are discussed in this review., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Appendiceal neuroendocrine neoplasm (NEN) is the most common adult appendiceal malignant tumor, constituting 16% of gastrointestinal NENs. They are versatile tumors with varying morphology, immunohistochemistry, secretory properties, and cancer genomics. They are slow growing and clinically silent, to begin with, or present with features of nonspecific vague abdominal pain. Most acute presentations are attributed clinically to appendicitis, with most cases detected incidentally on pathology after an appendectomy. Approximately 40% of them present clinically with features of hormonal excess, which is likened to the functional secretory nature of their parent cell of origin. The symptoms of carcinoid syndrome render their presence clinically evident. However, slow growing and symptomatically silent in its initial stages, high-grade neuroendocrine tumors and neuroendocrine carcinomas of the appendix are aggressive and usually have hepatic and lymph node metastasis at presentation. This review article focuses on imaging characteristics, World Health Organization histopathological classification and grading, American Joint Committee on Cancer/Union or International Cancer Control, European Neuroendocrine Tumor Society staging, European Neuroendocrine Tumor Society standardized guidelines for reporting, data interpretation, early-stage management protocols, and advanced-stage appendiceal NENs. Guidelines are also set for the follow-up and reassessment. The role of targeted radiotherapy, chemotherapy, and high-dose somatostatin analogs in treating advanced disease are discussed, along with types of ablative therapies and liver transplantation for tumor recurrence. The search for newer location-specific biomarkers in NEN is also summarized. Regarding the varying aggressiveness of the tumor, there is a scope for research in the field, with plenty of data yet to be discovered., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This article presents updates in the surgical management of non-functional sporadic pancreas neuroendocrine tumors NET, including considerations for assessment of biologic behavior to support decision-making, indications for surgery, and surgical approaches tailored to the unique nature of neuroendocrine tumors., Competing Interests: Disclosure J. Hallet has received speaking honoraria from Ipsen Biopharmaceuticals. A.W. Acher has nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: While males have dominated the physician lines over the last decades the recent female doctors' number increasing might progressively reduce this gender gap. This might be not fully true in the academic/research area. We aimed to analyze the gender distribution of first/senior Italian authors on neuroendocrine neoplasm papers published on peer reviewed journals., Methods: Publications from January 2019 to September 2023 were reviewed; only papers with first and/or senior Italian authors were included. First/senior author gender, type of article, co-authorship with foreign authors were the variable analyzed., Results: 742 papers with Italian first and/or senior authors were retrieved, 449 (60.5%) multicentric, 285 (38.4%) original articles. A female author was first and senior author in 386/742 (52%) and in 228/742 (31%) papers, respectively. 150 (20.2%) papers included foreign coauthors, being an Italian female researcher first author in 50 papers (33%), senior author in 28 (18.6%). The number of Italian female first/senior authors has been increasing over the years (22 in 2019, 113 in 2022; 16 in 2019, 62 in 2022, respectively). The first/senior female authors were mainly Oncologists/Endocrinologists/Pathologists rather than Gastroenterologists/Nuclear Medicine doctors/Surgeons/Radiologists., Conclusion: There has been an increase in the prevalence of female authorship of published research in the neuroendocrine setting over the last 5 years, which partially reflects the current distributions in this field, taking into account that several specialties with different gender distribution are involved. However, senior authorship continues to be primarily men. Efforts should be made to improve proportionate gender representation in both clinical and academic/research setting., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Pituitary neuroendocrine tumors (pitNETs) are the second most common primary brain tumors. Despite their prevalence, the tumor immune microenvironment (TIME) and its clinical implications remain largely unexplored. This review provides a comprehensive overview of current knowledge on the immune landscape and advancements in targeted immunotherapy for pitNETs. Macrophages and T cells are principal immune infiltrates within the TIME. Different subtypes of pitNETs display distinct immune patterns, influencing tumor progressive behaviors. PD-L1, the most extensively studied immune checkpoint, is prominently expressed in hormonal pitNETs and correlates with tumor growth and invasion. Cytokines and chemokines including interleukins, CCLs, and CXCLs have complex correlations with tumor subtypes and immune cell infiltration. Crosstalk between macrophages and pitNET cells highlights bidirectional regulatory roles, suggesting potential macrophage-targeted strategies. Recent preclinical studies have demonstrated the efficacy of anti-PD-L1 therapy in a mouse model of corticotroph pitNET. Moreover, anti-PD-1 and/or anti-CTLA-4 immunotherapy has been applied globally in 28 cases of refractory pitNETs, showing more favorable responses in pituitary carcinomas than aggressive pitNETs. In conclusion, the TIME of pitNETs represents a promising avenue for targeted immunotherapy and warrants further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: 177 Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical, biological, and imaging parameters may be used to establish a relative disease prognosis but none is able to predict early efficacy or toxicities. We investigated expression levels for mRNA and miRNA involved in radiosensitivity and tumor progression searching for correlations related to patient outcome during LuPRRT therapy., Methods: Thirty-five patients received LuPRRT for G1/G2 midgut NETs between May 2019 and September 2021. Peripheral blood samples were collected prior to irradiation, before and 48 h after the second and the fourth LuPRRT, and at 6-month follow-up. Multiple regression analyses and Pearson correlations were performed to identify the miRNA/mRNA signature that will best predict response to LuPRRT., Results: Focusing on four mRNAs and three miRNAs, we identified a miRNA/mRNA signature enabling the early identification of responders to LuPRRT with significant reduced miRNA/mRNA expression after the first LuPRRT administration for patients with progressive disease at 1 year ( p < 0.001). The relevance of this signature was reinforced by studying its evolution up to 6 months post-LuPRRT. Moreover, nadir absolute lymphocyte count within the first 2 months after the first LuPRRT administration was significantly related to low miRNA/mRNA expression level ( p < 0.05) for patients with progressive disease., Conclusion: We present a pilot study exploring a miRNA/mRNA signature that correlates with early hematologic toxicity and therapeutic response 12 months following LuPRRT. This signature will be tested prospectively in a larger series of patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jacques, Dierickx, Texier, Brillouet, Courbon, Guimbaud, Vija and Savagner.)

Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients., (© 2024. The Author(s).)

Background: Neuroendocrine neoplasm is a rare cancer of head and neck. This study aimed to evaluate clinical features, treatment outcomes, and prognostic factors of neuroendocrine neoplasm of head and neck treated at a single institution., Methods: Between Nov 2000 and Nov 2021, ninety-three patients diagnosed with neuroendocrine neoplasms of head and neck treated at our institution were reviewed retrospectively. The initial treatments included chemotherapy (induction, adjuvant, or concurrent) combined with radiotherapy in 40 patients (C + RT group), surgery followed by post-operative RT in 34 (S + RT group), and surgery plus salvage therapy in 19 patients (S + Sa group)., Results: The median follow-up time was 64.5 months. 5-year overall survival rate (OS), progression-free survival rate (PFS), loco-regional relapse-free survival free rate (LRRFS) and distant metastasis-free survival rate (DMFS) were 64.5%, 51.6%, 66.6%, and 62.1%, respectively. For stage I-II, the 5-year LRRFS for patients' treatment regimen with or without radiotherapy (C + RT and S + RT groups versus S + Sa group) was 75.0% versus 12.7% (p = 0.015) while for stage III-IV, the 5-year LRRFS was 77.8% versus 50.0% (p = 0.006). The 5-year DMFS values for patients with or without systemic therapy (C + RT group versus S + RT or S + Sa) were 71.2% and 51.5% (p = 0.075). 44 patients (47.3%) experienced treatment failure and distant metastasis was the main failure pattern., Conclusions: Radiotherapy improved local-regional control and played an important role in the management of HNNENs. The optimal treatment regimen for HNNENs remains the combination of local and systemic treatments., (© 2024. The Author(s).)

In the field of gynecologic cancer, low-grade serous ovarian cancer (LGSOC) has been poorly understood and underinvestigated until recently. Similarly, understanding of the distinct properties and therapeutic sensitivities of gynecologic melanoma and cervical neuroendocrine tumors has recently accelerated. For each of these rare cancers, we explore the epidemiology and natural history, discuss the prognosis, diagnostic testing, and contemporary molecular classification, and then deliberate existing and emerging therapeutic strategies. In LGSOC, we focus on the clinical relevance of recent molecular studies that shed light on the importance of mitogen-activated protein kinase (MAPK) pathway gene mutation and chromosome 1 copy-number change on prognosis and MEK inhibitor sensitivity. We also discuss the relative chemoresistance of this disease and the fact that attention is shifting to combinations of molecular therapies such as endocrine agents plus cyclin-dependent kinase 4/6 inhibitors or MEK inhibitors plus FAK inhibitors. Gynecologic tract melanomas harbor a lower frequency of canonical BRAF mutations, and have lower tumor mutational burden and immune cell infiltration than cutaneous melanomas (CMs). As a result, patients with this disease are less likely to respond to BRAF/MEK or immune checkpoint inhibition than patients with CM. Emerging strategies include the combination of antiangiogenic agents with immune checkpoint inhibitors and the use of adoptive cellular therapies. In cervical neuroendocrine cancer, we discuss the use of surgery in early-stage disease, and the uncertainties regarding the role of radiotherapy. We also explore the evidence for chemotherapy and emerging investigational strategies including the use of poly (ADP-ribose) polymerase inhibitors. For all situations, we explore the shared decision-making process with the patient.

Background: Nonalcoholic steatohepatitis (NASH) is an important etiology of hepatocellular carcinoma (HCC), and there is no established therapy for this syndrome. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD(NET)) is an extremely rare syndrome considered to be life-threatening, with death occurring around 10 years of age. We present the oldest known autopsy case of this syndrome that developed HCC. This case provided important information on not only improving the course of this syndrome, but also understanding the natural history and therapeutic modalities of NASH and HCC., Methods: The patient was diagnosed with ROHHAD(NET) syndrome in childhood, and liver cirrhosis due to NASH was diagnosed at age 17. HCC was detected at age 20, and embolization and irradiation were performed. At age 21, she died from accidental acute pancreatitis and subsequent liver failure and pulmonary hemorrhage., Results: Rapid onset of obesity, hypoventilation, and hypothalamic disturbance appeared in childhood and was diagnosed as this syndrome. At age 17, liver cirrhosis due to NASH was diagnosed by liver biopsy, and at age 20, HCC was diagnosed by imaging. Transarterial chemoembolization and irradiation were performed, and the HCC was well controlled for a year., Conclusion: At age 21, she died from accidental acute pancreatitis, subsequent liver failure and pulmonary hemorrhage. Autopsy revealed that the HCC was mostly necrotized. This case was valuable not only for other ROHHAD(NET) syndrome cases, but also in improving our understanding of the natural history of NASH and HCC., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Rectal neuroendocrine tumors (rNET) are rare and challenging to manage. While most patients with small rNET can be definitively treated with local excision, the role of chemotherapy in general and neoadjuvant therapy particularly in managing advanced rNET has not been well established. Therefore, this study aimed to determine which patients with rNET may gain a survival benefit from neoadjuvant chemotherapy., Methods: A retrospective cohort analysis of all patients who underwent surgical resection of rNET in the US National Cancer Database (NCDB) (2004-2019) was performed. First, univariate and multivariate Cox regression analyses were performed to determine the independent predictors of poor overall survival (OS) and define the high-risk groups. Afterward, stratified OS analyses were performed for each high-risk group to assess whether neoadjuvant chemotherapy had a survival benefit in each group., Results: A total of 1837 patients (49.8% female; mean age 56.6 ± 12.3 years) underwent radical resection of a rNET. Tumors > 20 mm in size, clinical T4 tumors, poorly differentiated tumors, and metastatic disease were independent predictors of worse OS and were defined as high-risk groups. Neoadjuvant chemotherapy did not have a significant survival benefit in any of the high-risk groups, except for patients with high-grade rNETs where neoadjuvant therapy significantly improved OS to a mean of 30.9 months compared with 15.9 months when neoadjuvant therapy was not given (p = 0.006)., Conclusions: Neoadjuvant chemotherapy improved the OS of patients with high-grade rNET by 15 months and may be indicated for this group., (© 2024. The Author(s).)

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10 -10 and p = 8.5 × 10 -9 , respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10 -4 ). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10 -8 ). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70-0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category., (© 2024. The Author(s).)

Background: Primary neuroendocrine neoplasms of the breast (Br-NENs) are rare. The classification has been updated in recent years making interpretation of the data published challenging. It is unclear whether neuroendocrine differentiation is associated with poorer prognosis and what treatment approaches should be applied., Methods: The database for breast cancer patients treated between 2009 and 2022 at the Maria Sklodowska-Curie National Research Institute of Oncology Branch Krakow was explored to search for Br-NENs. Patients' medical and pathological data were collected and analyzed., Results: We included 22 females with Br-NEN without metastases at the time of diagnosis. The median age was 64 years (range: 28-88), Of the cases, 18 were hormone receptor positive, all were HER-2 negative, the median Ki67 was 27% (10-100%). The median tumor size at the time of diagnosis was 29.5mm (7-75mm), 9 patients were N-positive. DCIS was present in 5 cases. Only one case was negative for chromogranin and synaptophysin staining, but data were missing for 4 cases. Nine patients received adjuvant chemotherapy, mainly based on anthracyclines and taxanes, while 16 received adjuvant hormonal therapy and 15 received postoperative radiotherapy. Radical surgery was performed in all patients, but two underwent suboptimal tumorectomy. One patient had local recurrence, three experienced metastatic disease, all involving the lungs, but these patients are still alive. The median follow-up was 96 months (8-153). Two patients died, with a follow up time of no recurrence >4 years. Our results were compared to twelve case series collecting clinical data on Br-NENs, with median patient number of 10.5 (range: 3-142)., Conclusion: Br-NENs represent a heterogenous group of diseases, lacking data from prospective studies or clinical trials. There are no established treatment standards tailored for Br-NENs. Our patients' cohort exhibited a favorable prognosis, potentially attributed to lower tumor stage and Ki67 index compared to other reported case series. We suggest that radical surgery and postoperative radiotherapy be administered akin to standard treatment for breast cancer of no special type. ESMO also advocates for this approach in systemic treatment, although we recommend considering platinum-based chemotherapy for patients with poorly differentiated Br-NENs exhibiting high Ki67., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Püsküllüoğlu, Grela-Wojewoda, Ambicka, Pacholczak-Madej, Pietruszka, Mucha-Małecka, Rudzińska, Ziobro, Ryś and Mituś.)

Background: Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs., Methods: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored., Results: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively)., Conclusions: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches., (© 2024. The Author(s).)