Search Results (211)

Neuroendocrine neoplasms (NENs) of the lung are a biologically and clinically diverse group of tumors that includes well-differentiated typical and atypical carcinoids (LNETs), as well as poorly differentiated large-cell neuroendocrine carcinoma and small-cell lung cancer. Despite their relative rarity, the incidence of LNETs is increasing, primarily due to advancements in diagnostic techniques and heightened clinical awareness. While the current World Health Organization (WHO) classification offers a morphological basis for diagnosis and prognosis, particularly for extrapulmonary neuroendocrine neoplasms (ep-NENs), it has limitations in predicting the clinical behavior of pulmonary carcinoids. Recent evidence highlights the inadequacy of traditional criteria in fully capturing the biological complexity and clinical heterogeneity of these tumors. This review explores the evolving landscape of LNETs, focusing on well-differentiated forms and analyzing current classification systems, clinicopathological features, and the emerging role of novel prognostic and predictive biomarkers. Advances in histopathology and molecular profiling have begun to elucidate distinct molecular subsets within carcinoids, offering potential avenues for improved risk stratification and therapeutic decision-making. Although there are limited treatment options for advanced disease, new insights into tumor biology could facilitate the development of personalized therapeutic strategies and pave the way for future innovations in LNET management. Full article

Background/Objectives: Pulmonary typical carcinoid (TC) is a rare type of primary neuroendocrine neoplasm of the lung with indolent behavior and a good prognosis. The main treatment strategy is surgery, the extent of which is controversial given the nature of the disease. The aim of this study is to assess whether the extent of resection influences survival and recurrence in patients undergoing lung resection and lymphadenectomy for TC and to investigate negative prognostic factors for OS. Methods: A single-centre retrospective study of 15 years’ experience was conducted. Data from all patients who underwent lung resection and lymphadenectomy for TC were collected. Patients were divided into two groups: anatomical and non-anatomical resections. Perioperative and long-term oncological results were analyzed. Results: In total, 115 patients were surgically treated for TC, of whom 83 (72%) underwent anatomical resection and 32 (28%) non-anatomical resection. Univariate analyses showed that age, left lower lobe, and many comorbidities had a detrimental effect on OS, whereas on multivariate analysis, only left lower lobe location and a high Charlson–Deyo comorbidity index (CCI) were confirmed as negative prognostic factors for OS. At a median follow-up of 93 months (IQR 57-129), the OS survival curves show a slightly lower trend for non-anatomical resections (p 0.152), while no differences were found for DFS. Conclusions: The results of this study confirm that in selected patients at risk for major resections, non-anatomical resection can be used to treat TC when R0 is achievable. These data, together with evidence from the literature, highlight the importance of patient-centred care in this rare disease. Full article

Drug repurposing or drug repositioning is the process of identifying new therapeutic uses for approved or investigational drugs beyond the original treatment indication. The discovery of new drugs for cancer therapy needs this cost-effective and time-saving alternative strategy to traditional drug development for a rapid clinical translation in Phase II/III studies, especially for unmet medical needs and rare diseases. Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms arising from cells of the neuroendocrine system that, though often indolent, can be aggressive and metastatic. In this context, drug repurposing has emerged as a promising strategy to improve treatment options due to the limited number of effective treatments and the heterogeneity of the disease. Indeed, a large number of non-oncology drugs have the potential to address more than one target that could be therapeutic for cancer patients. Although many repurposed drugs are used off-label, efficacy for the new use must be demonstrated in clinical trials. Within regulatory frameworks, both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have procedures to reduce the need for extensive new studies and to expedite the review of drugs for serious conditions when preliminary evidence indicates substantial clinical improvement over available therapy. In spite of several advantages, including reduced development time, lower costs, known safety profiles, and faster regulatory approval, difficulty in obtaining new patents for old drugs with limited protection for intellectual property may reduce commercial returns and disincentivize investments. This review aims to provide comprehensive information on some marketed drugs currently under investigation to be repurposed or used in clinical practice for NETs and to discuss the major clinical challenges. Although drug repurposing is a useful strategy for early access to medicines, the monitoring of the clinical benefit of oncologic drugs during the post-marketing authorization is crucial to support the safety and effectiveness of treatments. Full article

Background and Objectives: Peptide receptor radionuclide therapy (PRRT) using radiopharmaceuticals labelled with Lutetium-177 is currently a therapeutic option for patients with advanced neuroendocrine neoplasms overexpressing somatostatin receptors (SSTRs). One promising option that has gained interest for PRRT is using alpha-emitting radioisotopes such as Actinium-225. The aim of this study was to perform a systematic review and meta-analysis on the efficacy and safety of radioligand therapy with Actinium-225 DOTATATE in advanced, metastatic or inoperable neuroendocrine neoplasms. Materials and Methods: A comprehensive literature search of studies on radioligand therapy with Actinium-225 DOTATATE in neuroendocrine neoplasms was carried out. Three different bibliographic databases (Cochrane Library, Embase, and PubMed/MEDLINE) were screened up to May 2025. Eligible articles were selected, relevant data were extracted, and the main findings on efficacy and safety are summarized through a systematic review. Furthermore, proportional meta-analyses on the disease response rate and disease control rate were performed. Results: Five studies (153 patients) published from 2020 were included in the systematic review. The pooled disease response rate and disease control rate of radioligand therapy using Actinium-225 DOTATATE were 51.6% and 88%, respectively. This treatment was well-tolerated in most patients with advanced, metastatic or inoperable neuroendocrine neoplasms. Conclusions: Radioligand therapy with Actinium-225 DOTATATE in advanced, metastatic or inoperable neuroendocrine neoplasms is effective with an acceptable toxicity profile and potential advantages compared with SSTR-ligands labelled with Lutetium-177. Currently, the number of published studies on this treatment is still limited, and results from multicenter randomized controlled trials are needed to translate this therapeutic option into clinical practice. Full article

Background: Functioning gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors that secrete biologically active hormones, leading to complex clinical syndromes such as carcinoid syndrome, VIPoma, glucagonoma, gastrinoma, insulinoma, and somatostatinoma. These syndromes frequently induce profound metabolic, gastrointestinal, and nutritional disturbances. Objective: This review aims to provide a comprehensive overview of the physiopathology of malnutrition in functioning GEP-NENs and to highlight nutritional and supportive care strategies, including how medical, surgical, and locoregional treatments can indirectly improve nutritional outcomes. Methods: We analyzed the current literature and clinical guidelines to identify key mechanisms of malnutrition across different functioning syndromes and their clinical manifestations. Nutritional recommendations and the impact of treatment modalities on nutritional status were summarized. Results: The pathophysiology of malnutrition in functioning NENs is multifactorial and syndrome-specific. Hormonal hypersecretion may cause diarrhea, electrolyte imbalances, catabolic states, steatorrhea, or hypoglycemia, among other effects. These lead to nutrient loss, malabsorption, or altered intake. Tailored dietary interventions, micronutrient supplementation (e.g., niacin, calcium, vitamin B12), and symptom-guided nutritional support are essential. Somatostatin analogs, PRRT, and cytoreductive approaches often contribute to symptom control, thereby enhancing nutritional status and patient quality of life. Conclusions: Malnutrition in functioning GEP-NENs is a significant clinical issue that requires early recognition and a multidisciplinary, individualized management plan. Integrating nutrition into the comprehensive care of these patients is essential to improve outcomes and quality of life. Full article

Posterior pituitary tumors (PPTs) are rare, non-neuroendocrine neoplasms derived from pituicytes of the neurohypophysis or infundibulum. According to the 2025 WHO classification, PPTs comprise four distinct but related low-grade entities: pituicytoma, granular cell tumor of the sellar region, spindle cell oncocytoma, and ependymal pituicytoma. All share nuclear TTF-1 expression, confirming their common origin, but differ in morphology, immunophenotype, and ultrastructure. Histologically, pituicytomas consist of bipolar spindle cells in fascicles; granular cell tumors show polygonal cells with PAS-positive, diastase-resistant cytoplasmic granules; spindle cell oncocytomas display oncocytic change and abundant mitochondria; and ependymal pituicytomas exhibit perivascular pseudorosettes and EMA positivity in apical or dot-like patterns. Immunohistochemically, all are S100 and vimentin positive, and negative for pituitary hormones and lineage-specific transcription factors. Clinically, PPTs are typically non-functioning but may be associated with corticotroph or somatotroph hyperfunction. Imaging features are nonspecific. Surgical resection is the treatment of choice, although hypervascularity and adherence—especially in spindle cell oncocytomas—can hinder complete excision. Radiotherapy is reserved for recurrences. Molecular analyses reveal recurrent alterations in MAPK/PI3K pathways (e.g., HRAS, BRAF, FGFR1, NF1, TSC1) and suggest a shared histogenesis. Copy number imbalances correlate with reduced progression-free survival in some subtypes. Despite a generally favorable prognosis, recurrence—particularly in spindle cell oncocytomas—necessitates long-term follow-up. The WHO 2025 update provides a unified framework for classification, diagnosis, and prognostic stratification of these rare tumors. Full article

Cancer during pregnancy is a rare but complex clinical scenario that affects approximately 0.1% of pregnant individuals and is associated with increased maternal morbidity. With the trend of delayed childbearing, the incidence of pregnancy-associated cancers is expected to rise. Neuroendocrine neoplasms (NENs), although rare in pregnancy, present unique diagnostic and therapeutic challenges due to their hormonal activity, histological diversity, and limited data on management in the gestational context. Objectives: This manuscript reviews the current evidence on the diagnosis, staging, and management of NENs during pregnancy, focusing on maternal–fetal safety, therapeutic limitations, and multidisciplinary care strategies. Methods: A comprehensive narrative review was conducted using relevant case reports, retrospective studies, clinical guidelines, and expert consensus documents addressing cancer in pregnancy and NEN-specific management. Results: Pregnancy complicates the evaluation and treatment of NENs due to overlapping symptoms, contraindications to standard imaging and systemic therapies, and unreliable biomarkers such as chromogranin A and 5-HIAA. Most systemic therapies for NENs, including somatostatin analogs, tyrosine kinase inhibitors, and peptide receptor radionuclide therapy, are contraindicated or lack safety data in pregnancy. Surgical interventions and supportive care require careful planning. Decisions regarding pregnancy continuation or termination must be individualized and supported by a multidisciplinary team. Conclusions: The management of NENs during pregnancy demands a highly individualized approach, coordinated among oncology, maternal–fetal medicine, and supportive care teams. Given the paucity of robust data, future research is essential to establish evidence-based guidelines and improve outcomes for both mother and fetus. Full article

Background: Pancreatic neuroendocrine tumors (PanNETs) are relatively rare neoplasms with heterogeneous behavior, ranging from indolent to aggressive disease. The evolution of nuclear medicine has allowed the development of an efficient and advanced toolkit for the diagnosis and treatment of PanNETs. Case: A 45-year-old woman was diagnosed with a grade 1 PanNET and multiple liver metastases. She underwent distal pancreatectomy with splenectomy, extended liver resection, and radiofrequency ablation (RFA). Surgical planning was guided by [^99mTc]Tc-EDDA/HYNIC-TOC SPECT/CT (single-photon emission computed tomography/computed tomography) and preoperative [^99mTc]Tc-mebrofenin-based functional liver volumetry. Functional liver volumetry based on dynamic [^99mTc]Tc-mebrofenin SPECT/CT facilitated precise surgical planning and reliable assessment of the efficacy of parenchymal modulation, thereby aiding in the prevention of post-hepatectomy liver failure. Liver fibrosis was non-invasively evaluated using two-dimensional shear wave elastography (2D-SWE). Tumor progression was monitored using somatostatin receptor scintigraphy, chromogranin A, and contrast-enhanced CT. Recurrent disease was treated with somatostatin analogues (SSAs) and [¹⁷⁷Lu]Lu-DOTA-TATE peptide receptor radionuclide therapy (PRRT). Despite progression to grade 3 disease (Ki-67 from 1% to 30%), the patient remains alive 53 months post-diagnosis, in complete remission, with an ECOG (Eastern Cooperative Oncology Group) status of 0. Conclusions: Functional imaging played a pivotal role in guiding therapeutic decisions throughout the disease course. This case not only underscores the clinical utility of advanced nuclear imaging but also illustrates the dynamic nature of pancreatic neuroendocrine tumors. The transition from low-grade to high-grade disease highlights the need for further studies on tumor progression mechanisms and the potential role of adjuvant therapies in managing PanNETs. Full article

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a varied group of tumors that originate from neuroendocrine cells found throughout the gastrointestinal tract. These tumors encompass a broad spectrum of biological behaviors, ranging from slow-growing, well-differentiated neuroendocrine tumors (GEP-NETs) to aggressive and poorly differentiated neuroendocrine carcinomas (GEP-NECs), complicating their accurate classification and effective treatment. While advances in molecular research have refined our understanding of these tumors, their complexity, unpredictable progression, and differential response to therapies remain major clinical hurdles. A significant clinical challenge is the accurate grading and diagnosis of GEP-NENs, which is traditionally reliant on subjective methods. However, innovative technologies, such as artificial intelligence-based diagnostics, multi-omics approaches, and precision oncology, are now offering solutions for more precise and reliable classification. Meanwhile, emerging therapies aiming to activate the immune response or modify the tumor environment present promising avenues for improved outcomes. Realizing the full potential of these advances will require a thoughtful integration of molecular insights with standardized diagnostic practices and evolving therapeutic strategies, ensuring that progress in research meaningfully informs and enhances patient care across diverse clinical settings. This review discusses new advancements and explores future directions toward personalized and effective treatments for GEP-NENs. Full article

Neuroendocrine neoplasms (NENs) represent a heterogenous group of tumors with significant inter- and intra-patient variability. Once considered to be rare, neuroendocrine neoplasms are being increasingly recognized through the advent of advanced diagnostic techniques, which may be contributing to the significant increase in the incidence and detection rate of these tumors. NENs can be classified into well differentiated and poorly differentiated neuroendocrine tumors (NETs) or neuroendocrine carcinomas (NECs). The proliferation rate of NETs can vary from Ki-67 1–55%. In addition, the SSTR expression can vary significantly. Because of this high “heterogeneity”, their detection and characterization have become essential to disease management, leading to dual-tracer imaging, most commonly with FDG- and SSTR-targeted PET/CT. Because of the complexity of the disease, the optimal treatment of patients depends on a combination of imaging, serological biomarkers, and clinical information. There remains a significant portion of patients who do not respond as anticipated, and the management of their disease remains challenging with current techniques, necessitating the refinement of our technologies and the development of new ones. In addition to new biological targets, improved peptide vector targeting for the somatostatin receptor needs further development. This review aims to evaluate the existing imaging techniques utilized in the diagnosis, assessment, and treatment of NENs, as well as the emerging radiopharmaceuticals and technologies, which will expand our imaging repertoire as well as our management options. Full article

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) represent a challenging disease. Their large heterogeneity limits the possibility of providing accurate risk assessments or standardizing the most effective therapies for these patients. In recent years, artificial intelligence (AI), and in particular machine learning approaches, have shown real promise in addressing these complexities. By analyzing large volumes of clinical, imaging, and pathological data, AI-based tools can significantly improve the accuracy of survival predictions and guide more tailored treatment strategies. In this narrative review, we examine the potential applications of AI to develop effective prognostic models in GEP-NENs, and how these models may help clinicians in predicting survival and optimizing patient management. While early results are encouraging, important limitations remain, since available data stem from small, retrospective datasets, sometimes lacking external validation, and concerns around transparency and ethics still represent an open issue. Addressing these gaps will be key to moving from research applications to practical tools that can support everyday clinical decision-making. Full article

Background: Thymic carcinoids are rare neuroendocrine tumors arising in the anterior mediastinum, often diagnosed at an advanced stage due to nonspecific clinical manifestations. Their management remains challenging because of the paucity of data, rarity of occurrence, and aggressive biological behavior compared to other well-differentiated neuroendocrine neoplasms. Methods: We conducted a comprehensive review of the current literature focusing on the classification, clinical presentation, diagnostics, treatment options, prognostic factors, and emerging experimental therapies for thymic carcinoids. Emphasis was placed on integrating recent molecular and therapeutic advances into clinical practice. Results: Surgical resection remains the cornerstone of treatment for localized disease, while systemic therapies such as everolimus, somatostatin analogs, platinum-based chemotherapy, and peptide receptor radionuclide therapy (PRRT) are options for advanced cases. Novel diagnostic modalities, including NETest, 64Cu-DOTATATE PET, and 18F-FDOPA PET, offer promise in early detection and disease monitoring. Molecular insights, particularly involving MEN1, ATRX, and DAXX mutations, pave the way for individualized targeted therapies. Immunotherapy and radioimmunotherapy represent emerging, albeit still experimental, approaches. Prognosis largely depends on tumor stage, differentiation, resectability, and functional activity, with a high recurrence rate necessitating prolonged surveillance. Conclusions: Thymic carcinoids pose significant diagnostic and therapeutic challenges. Advances in molecular profiling, novel imaging techniques, and systemic therapies offer hope for improved outcomes. Given the disease rarity, continued collaboration through registries and multicenter studies is essential to refine evidence-based management strategies. Full article

Background/Objectives: Pancreatic neoplasms, including adenocarcinoma, pancreatic neuroendocrine tumors (pNETs), intraductal papillary mucinous neoplasms (IPMNs), and high-grade cystic lesions, often require surgical resection as a form of curative treatment. However, comorbidities and high-risk features may preclude surgery. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has emerged as a minimally invasive alternative with proven cytoreductive efficacy in solid tumors. This case series evaluates the safety and efficacy of EUS-RFA in patients with various unresectable, non-metastatic pancreatic neoplasms. Methods: A retrospective review was conducted on eight patients who underwent EUS-RFA at our institutions between July 2021 and February 2025. All patients were deemed unsuitable surgical candidates due to comorbidities such as advanced age, cardiovascular disease, renal insufficiency, and COPD or due to patient resistance to surgical intervention. EUS-RFA was performed using a 19-gauge RFA needle (Taewoong Corporation). Follow-up imaging was conducted 3 to 6 months after the completion of RFA treatment. Results: All eight patients demonstrated a good to excellent response in terms of tumor size reduction. The most notable response was observed in a patient with pNET, resulting in complete resolution from 15.6 × 12.0 mm to 0.0 × 0.0 mm after two RFA treatments. Other neoplasms, including pancreatic adenocarcinoma and intraductal papillary mucinous neoplasms (IPMNs), also demonstrated significant reductions. Mild post-procedure complications, including pancreatitis and abdominal pain, were noted in three cases. Conclusions: EUS-RFA is a promising alternative for managing unresectable pancreatic neoplasms in high-risk patients. Our findings support its use across various tumor types with favorable outcomes and minimal complications, reinforcing its role in expanding therapeutic options beyond surgery. Full article

Pancreatic neuroendocrine tumors (PNETs) are a rare subset of pancreatic neoplasms with diverse biological behavior and clinical presentations. Traditional treatment approaches, such as surgery and targeted therapies, have significantly improved outcomes. However, advancements in molecular biology, immunotherapy, and minimally invasive techniques have ushered in a new era of treatment possibilities. This manuscript explores the emerging modalities in PNET management, emphasizing the need for a multidisciplinary approach tailored to individual patient profiles. Full article

Pituitary neuroendocrine tumors (PitNETs) are slow-growing neoplasms with various clinical presentations, often leading to diagnostic challenges. While neuroimaging assessment and histopathological evaluation remain the gold standard for diagnosis, emerging research highlights the potential of liquid biopsy, mainly through the analysis of circulating non-coding RNAs (ncRNAs), as a promising diagnostic and prognostic tool. Recent studies have demonstrated distinct expression profiles in different types and subtypes of tumors, with implications in assessing tumor aggressiveness and predicting treatment response. The current article summarizes data about potential biofluid markers implicated in PitNET development, mainly circulating tumor DNA (ctDNA), cell-free RNAs (cfRNA), circulating tumor cells (CTCs), and exosomes. Many studies on genetic and molecular markers in PitNET tissue samples provide exciting information about tumor biology, but to date, specific studies on liquid biopsy biomarkers are still few. Over the past years, a certain understanding of the mechanisms involved in pituitary tumorigenesis has been gained, including the landscape of genomic alterations, changes in epigenetic profile, crucial molecules involved in specific signaling pathways, and non-coding RNA molecules with critical roles in malignant transformation. Genetic and molecular characterization of the PitNETs could help distinguish between functional and non-functional PitNETs, different types and subtypes of pituitary tumors, and invasive and non-invasive forms. Further studies are required to identify and validate innovative biomarkers or therapeutic targets for treating PitNET. Integrating liquid biopsy into clinical workflows could revolutionize the management of pituitary adenomas, enabling more personalized and less invasive diagnostic and therapeutic strategies. Full article