Background:Autoimmune gastritis (AIG) is characterized by chronic inflammation and represents a key step in the multistage precancerous process of the stomach. Patients with AIG are at increased risk of developing type I gastric neuroendocrine tumors (T1gNETs), but clinical and histological associated factors still remain incompletely defined. Aim:To evaluate the occurrence of T1gNETs in our AIG patients cohort and to identify clinical, biochemical, and histological factors associated with tumor development. Methods:Retrospective analysis of histologically confirmed AIG followed at Humanitas Research Hospital (from January 2020 to February 2025). Clinical, biochemical, and histological variables were extracted from a dedicated database. Associations between T1gNETs incidence and risk factors (smoking, BMI, gastrin,chromogranin- CgA levels, histology, clinical presentation) were tested using chi-square, Spearman and Mann-Whitney tests, with bootstrap-derived confidence intervals for effect sizes. Results:Among 175 AIG patients, 28 (16%) were diagnosed with T1gNETs. ECL cell hyperplasia emerged as the strongest histological factor associated with T1gNETs (82.1 vs 55.8; p= 0.0109, OR = 3.65). Conversely, dyspeptic symptoms showed a significant inverse correlation with tumor occurrence (21.4% vs 43.5%; p=0.035, OR = 0.35), suggesting that T1gNETs often develop in asymptomatic patients. No significant predictive value was found for smoking, alcohol, BMI, severe hypergastrinemia/CgA (>3x ULN) levels or degree of corpus atrophy, although a trend was observed for corpus metaplasia. Conclusions:Patients with AIG face significantly elevated occurrence of T1gNETs compared with the general population, with percentage being in line with recent studies. ECL hyperplasia was found as a factor associated with NET development, according to literature, confirming that the chronic stimulation of a cell with the ability to proliferate, results in tumors formation. Most patients with T1gNETs were asymptomatic and no correlation was found with smoking, alcohol and BMI. As a future perspective, these findings, even though preliminary, may help in the risk stratification of patients for more personalized endoscopic surveillance protocols, but further data are warranted to better standardize their use.

BACKGROUND:Primary intestinal B-cell (IBCL) and T-cell (ITCL) lymphomas are rare and poorly characterized entities. AIM:To compare clinical features and survival outcomes of IBCL and ITCL. METHODS:We conducted a multicentre, retrospective study including patients diagnosed with primary intestinal lymphoma between 2001 and 2024. Clinical and laboratory variables were analysed using univariate and multivariate logistic regression. Discriminatory accuracy was assessed through ROC analysis. Overall survival was estimated with Kaplan-Meier curves. RESULTS:Ninety-four patients (41 IBCL and 53 ITCL) were included. IBCL were more frequently diagnosed at Lugano stage I (90% vs 5.7%; p<0.01) and showed markedly lower lactate dehydrogenase and β2-microglobulin levels compared with ITCL (p<0.01). Coeliac disease (CD) was strongly associated with ITCL (p<0.01). In multivariable analysis, CD and biomarker levels independently differentiated IBCL from ITCL, with excellent model discrimination (AUROC 0.95). Median follow-up was 56 months for IBCL and 12 months for ITCL. IBCL demonstrated significantly greater survival (HR 0.21; log-rank p=0.01). CONCLUSIONS:IBCL and ITCL exhibit distinct clinical and prognostic profiles, with IBCL showing more favourable clinical profile and better survival. Tailored diagnostic and therapeutic approaches that reflect the divergent behaviour of these lymphomas are urgently needed.

BACKGROUND:Gender disparity has been documented in celiac disease (CD) with a female (F)-to-male (M) ratio of 2-2.5:1. Studies examining gender differences have yielded conflicting results. AIMS:To investigate gender differences in clinical presentation at diagnosis, adherence to gluten-free diet (GFD), and modification of clinical symptoms with the GFD in adult CD patients. METHODS:Single-center retrospective study, including all consecutive CD patients referred to our Center between September 2022-July 2024. RESULTS:One hundred and ninety-one patients, 141 F/50 M, mean age at diagnosis of 35.4/37.4 years, were included. In 59% F/54% M the diagnosis was prompted by gastrointestinal symptoms. At the diagnosis 13 F (9.1%) and 11 M (22%) were asymptomatic. Extra-intestinal manifestations were reported by 34 women (23.9%) and 6 men (12%). A low/absent adherence to GFD was reported by 17 women (12%) and 9 men (18%). Statistically significant differences were found regarding the prevalence of bone mineral density alterations (> in M, p-value = 0.017) and the degree of duodenal damage at the diagnosis (> in F, p-value = 0.021). CONCLUSIONS:Only slight discrepancies in the clinical presentation at CD diagnosis between the two genders were identified, which are mostly resolved with the GFD. No significant difference with regard to dietary adherence between F/M was found.

Background: Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are the most prevalent subgroup among NETs and include heterogeneous tumors characterized by different clinical behavior and prognosis. The NETest is a tool based on real-time PCR combined with deep learning strategies to specifically identify tumors with a neuroendocrine genotype. Despite the promising results achieved regarding its utility in the field of GEP-NETs, the NETest has not yet entered into routine clinical practice. Methods: We performed a systematic review aimed at summarizing available evidence on the application of the NETest in both the diagnosis and the prognostic stratification of GEP-NETs. Results: We identified five studies evaluating the diagnostic role of the NETest and nine studies evaluating its prognostic value. The NETest emerged as a reliable biomarker for GEP-NET diagnosis with an accuracy higher than 90%, regardless of tumor stage and grade. However, according to some studies, the NETest showed a low specificity, mainly attributed to interferences with other gastro-intestinal malignancies. In terms of prognostic value, the NETest correlated with the detection of residual disease after surgery in six studies. The NETest was also associated with patients’ survival outcomes, namely progression-free survival (PFS) and overall survival (OS) in three studies. Conclusions: According to current systematic review, the value of the NETest both for diagnosis and for prognosis of GEP-NET emerged as robust across different studies. Further prospective analysis on larger GEP-NET series is encouraged to validate this tool, improving patients’ diagnosis, management, and follow-up.

Bone metastases (BMs) are a rare and late event in patients with neuroendocrine tumors (NETs). The aim of our study was to investigate the clinical presentation and outcome of BMs in a large cohort of patients with NETs. A retrospective study was performed at two referral centers of Northern Italy (IRCCS Humanitas Research Hospital in Milan and Santa Maria della Misericordia University Hospital in Udine). Three hundred fifty-two consecutive patients with either gastroenteropancreatic or non-gastroenteropancreatic NETs were included: 52 patients with synchronous or metachronous BMs (BM-positive) and 300 patients with metastatic disease without BMs (BM-negative). Patients with BMs showed a higher prevalence of smoking habit (41.2 vs 21.8%, P = 0.004) and carcinoid syndrome (28.8 vs 5.7%, P <0.001) compared to patients without BMs. In addition, higher levels of chromogranin A (P = 0.001), urinary 5-hydroxyindoleacetic acid (P <0.001), parathyroid hormone (P = 0.022), and alkaline phosphatase (P = 0.018) were found compared to the BM-negative group. Patients with BMs had more frequently a primary lung NET compared to the BM-negative group (19.2 vs 0.7%, P = 0.001) and grade G2 or G3 gastroenteropancreatic tumors (P <0.001) compared to the BM-negative group. During a median follow-up of 4.2 years, a higher mortality rate was registered in the BM-positive group as compared to BM-negative group (42.3 vs 4.0%, P = 0.001). BMs were more common in patients with lung NETs, G2-G3 grade tumors, and in those with carcinoid syndrome. BMs affected patients' prognosis, highlighting the importance of investigating and managing this condition in patients with NETs.

INTRODUCTION:Helicobacter pylori (Hp)-related atrophic gastritis (AG) affects corpus and antral mucosa, resulting in multifocal AG (MF-AG); autoimmunity-driven AG is corpus-restricted (CR-AG). AG carries increased gastric dysplasia (GD) and gastric cancer (GC) risk, well established in MF-AG, but debated in CR-AG. This study aimed to assess clinical, endoscopic-histological characteristics of GD-GC in patients with MF-AG and CR-AG. METHODS:This was the multicenter cross-sectional study across 11 Italian gastroenterology centers on data of non-cardia GD-GC in adult patients with MF-AG or CR-AG based on clinical, endoscopic, and histological charts. RESULTS:Eighty-four patients were included with MF-AG and CR-AG in 45 (53.6%) and 39 (46.4%), respectively. Low-grade GD, high-grade GD, and GC were diagnosed in 31 (36.9%), 6 (7.1%), and 47 (56.0%), respectively. GD-GC similarly occurred in patients with MF-AG and CR-AG: high-grade GD in 4 (8.9%) vs 2 (5.1%), low-grade GD in 17 (37.8%) vs 14 (35.9%), and GC in 24 (53.5%) vs 23 (59.0%) ( P > 0.05). Compared with MF-AG, in patients with CR-AG, GD-GC were more commonly polypoid (51.6% vs 27.3%, P = 0.048) and more frequent in the corpus (55.3% vs 28.6%, P = 0.02), but occurred also in the antrum (34.2%) and incisura (10.5%). Surgery was more frequent in CR-AG than in MF-AG (48.6% vs 23.1%, P = 0.02). Corpus atrophy severity and intestinal metaplasia were not different ( P > 0.05), histological Hp positivity was low in both (2.3% vs 2.9%, P = 0.87), but in Hp negatives, active inflammation was present in the antrum in 26.7% and 7.7% ( P = 0.02), and in the corpus in 31.1% and 21.5% ( P = 0.27). DISCUSSION:Non-cardia GC and GD may occur in both MF-AG and CR-AG, displaying differences in topography and endoscopic presentation but similarities in nonlesional mucosa, differentiation, and staging. Surveillance should be considered in corpus AG, regardless of extension and supposed etiology. BACKGROUND:La gastrite atrofica (AG) Helicobacter pylori (Hp)-relata interessa la mucosa dell'antro e del corpo-fondo dando luogo alla gastrite atrofica multifocale (MF-AG); la gastrite atrofica autoimmune invece è limitata al corpo-fondo risparmiando l'antro (CR-AG). L'AG è ad aumentato rischio per displasia (GD) e cancro gastrico (GC). Questo rischio è ben stabilito nella MF-AG, ma ancor adibattuto nella CR-AG. Questo studio ha come scopo di valutare le caratteristiche cliniche e endoscopico-istologiche di pazienti affetti da GD o GC in MF-AG e CR-AG. METODI:E' stato condotto uno studio trasversale multicentrico in 11 centri gastroenterologici italiani su dati di pazienti adulti con GD o GC non cardiali in MF-AG o CR-AG basati su schede cliniche e referti endoscopici e istologici. RISULTATI:Sono stati inclusi 84 pazienti, di cui 45 (53.6%) con MF-AG e 39 (46.4%) con CR-AG. GD di basso (LG-GD) e di alto grado (HG-GD) e GC sono stati diagnosticati in 31 (36.9%), 6 (7.1%), and 47 (56.0%) pazienti, rispettivamente. GD e GC sono stati riscontrati con frequenza simile in pazienti con MF-AG e CR-AG: HG-GD in 4 (8.9%) vs 2 (5.1%), LG-GD in 17 (37.8%) vs 14 (35.9%), e GC in 24 (53.5%) vs 23 (59.0%) (p>0.05). Rispetto ai pazienti con MF-AG, nei pazienti con CR-AG GD e GC erano più frequentemente di aspetto polipoide (51.6% vs 27.3%, p=0.048) e più frequentemente localizzati nel corpo-fondo (55.3% vs 28.6%, p=0.02), ma venivano riscontrati anche nell'antro (34.2%) e a livello dell'incisura (10.5%). Il trattamento chirurgico era più frequente nei pazienti con CR-AG rispetto a coloro con MF-AG (48.6% vs 23.1%, p=0.02). La severità dell'atrofia del corpo-fondo e la presenza di metaplasia intestinale non erano differenti (p>0.05), mentre la positività istologica per l'Hp era bassa in ambedue i gruppi ((2.3% vs 2.9%, p=0.87), ma nei Hp negativi l'attività infiammatoria era presente nell'antro nel 26.7% e 7.7% (p=0.02), e nel corpo-fondo nel 31.1% e 21.5% (p=0.027). CONCLUSIONI:GD e i GC non cardiali possono sviluppare sia in pazienti con MF-AG che con CR-AG, con differenze nella topografia e nella presentazione endoscopica ma con similitudini nella mucosa non lesionale circostante, nella differenziazione e nella stadiazione. Pertanto, la sorveglianza dovrebbe essere considerata in tutti i pazienti con AG del corpo, a prescindere dall'estensione e dalla presunta eziologia.

BACKGROUND:The prognosis of neuroendocrine neoplasms (NENs) is traditionally driven by tumor grade, primary site, hormonal functionality, and disease staging; however, emerging evidence identifies tumor burden-encompassing the size, number, and anatomical spread of lesions-as an independent determinant of outcome. Despite its clinical relevance, tumor burden lacks a standardized definition across studies, with criteria ranging from liver involvement thresholds to metastatic site counts, extrahepatic spread, or surrogate biochemical markers, limiting cross-study comparability. METHODS:A comprehensive search on PubMed and ClinicalTrials.gov updated until June 2025 was conducted with the objective of investigating phase III trials on medical therapeutic options (chemotherapy, targeted therapy, somatostatin analogue, peptide receptor radionuclide therapy) for advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), thoracic, and unknown primary site origin in order to highlight the definition and application of tumor burden in well-differentiated NETs. RESULTS:After the screening process, a total of 23 completed and published phase III trials and 10 ongoing recruiting/not yet recruiting phase III trials were included in the final analysis. Our findings uncovered several critical issues regarding tumor burden staging, definition, and ethical implications. CONCLUSIONS:Harmonization of tumor burden definitions and integration into trial stratification frameworks are necessary to refine prognostic models, improve treatment evaluation in NETs, and ensure equity in care access.

Background and aimsType I gastric neuroendocrine tumors (gNETs) are known for their favorable prognosis. We aimed to present a real-life experience at a tertiary referral center.Materials and methodsRetrospective analysis of patients diagnosed with type I gNETs at our Institution between 2014 and 2024.ResultsA total of 36 lesions were identified in 23 patients, with a median tumor size of 7 mm (range 2-20 mm). There were 29 out of 36 lesions that were G1, and 7 were G2. In 13 cases, endoscopic ultrasound (EUS) was performed prior to resection, revealing lymph node involvement in one 20-mm G1 lesion that required surgery. A 15-mm G2 lesion underwent surgery. In the remaining 34 lesions, endoscopic resection was performed: forceps in 5, cold-snare polypectomy in 4, hot-EMR in 22, EMR-cap in 1, ESD in 1, hybrid-ESD in 1. Among those, one 5-mm G2 lesion, previously removed via simple polypectomy, required surgery due to the 14.5% Ki-67 index. The median follow-up was 14 months (range 1-120), with 10 cases of local recurrence in 6 patients, median tumor size 3 mm (range 2-8 mm), all G1. In three cases, endoscopic surveillance was indicated; seven NETs underwent endoscopic resection (three forceps, two EMR-cap, two EMR), with EUS being performed in four cases with negative results. No local/distant metastases nor tumor-related deaths occurred.ConclusionsPresent data confirm an indolent behavior for type I gNETs. Preoperative EUS staging led to a change in the management in one case, which highlights the need of dedicated studies to identify predictive factors to stratify risk and plan the management of these neoplasms.

Functional Motor Disorders (FMD) consists in symptoms of altered motor function not attributable to typical neurological and medical conditions. This study aimed to explore explicit and perceptual measures of Sense of Ownership, Agency, and Body Schema in FMD patients, and assess whether these alterations are specific to FMD or shared with other functional disturbances. Twelve FMD patients, ten with Irritable Bowel Syndrome (IBS, a functional gastrointestinal disorder) and fifteen healthy controls (HC) underwent: (i) the Mirror Box Illusion (MBI), requiring participants to perform tapping movements with their dominant hand concealed from sight, while visual feedback was provided by an alien hand under visuo-motor congruency or incongruency conditions; (ii) a Forearm Bisection Task before and after exposure to the MBI, and the Embodiment Questionnaire after the MBI, as perceptual and explicit indices of the embodiment illusion, respectively. At the Embodiment Questionnaire, all groups self-reported embodiment of the alien hand only under visuo-motor congruency; at the perceptual level, HC showed the expected distalized drift (an “elongated” arm in the Body Schema) under visuo-motor congruency, while FMD and IBS patients did not. FMD patients showed a proximalized drift when sensory feedback mismatched, possibly reflecting reliance on altered priors to avoid losing control over their movement. Results in IBS patients suggest Body Schema alterations differ across functional syndromes. In conclusion, we found that explicit Sense of Ownership and Agency are preserved in FMD and IBS patients, but dissociate from their implicit measures, differing in degree according to the specific disturbance.

PURPOSE: The incidence of inflammatory bowel diseases (IBDs) and gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) has increased, but their potential association remains unclear. Chronic inflammation in IBD may contribute to enteroendocrine cell hyperplasia and neoplasia, though evidence for a causal link is limited. This case series describes the characteristics and outcomes of patients with coexisting IBD and GEP-NETs at a tertiary referral center. METHODS: Retrospective case series including all consecutive IBD patients who were referred to the IBD Unit at the IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy, between January 2019 and December 2024 and who had been diagnosed with a GEP-NET. RESULTS: Nine Crohn’s disease patients (44.4% female, mean IBD diagnosis age: 51.1 years) also had GEP-NETs. The median interval between IBD and GEP-NET diagnoses was 39.3 months (0-180). In the totality of six cases that underwent surgical intervention, NETs diagnosis was incidental on the surgical specimen. Lesion sites included ileum (3), appendix (3), stomach (2), and rectum (1). Most NETs were G1 (88.8%); one required somatostatin analogues due to metastases. Treatments included surgery (6), endoscopy (2), and one pending. Over a median 24-month follow-up, no recurrences or disease-related deaths occurred. No cases of ulcerative colitis and concomitant GEP-NET ‘s diagnosis were observed in the patient cohort under consideration. CONCLUSIONS: Patients with Crohn’s disease may have a higher prevalence of GEP-NETs, possibly due to chronic inflammation and immune/microbiota dysregulation. This association does not appear to worsen disease outcomes. Larger studies are needed to explore underlying mechanisms.

BACKGROUND:Management of presumed branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) without worrisome features (WF) or high-risk stigmata (HRS) remains controversial, particularly regarding the duration of surveillance. METHODS:We conducted a retrospective single-center study including patients with presumed BD-IPMNs without WF or HRS at diagnosis, followed between 2014 and 2023. Clinical, radiological, and pathological data were collected. Outcomes included malignant progression, surgery, and mortality. Subgroup analyses assessed patients with ≥5years of follow-up, potentially meeting discontinuation criteria. RESULTS:413 patients met inclusion criteria. Median age at diagnosis was 65 years; 64 % were women. Median cyst size was 10 mm, and median follow-up 36 months. WF developed in 20 % of patients and HRS in 0.7 %. Four patients (0.26/100 person-years) experienced malignant progression, all within 30 months from diagnosis; two underwent surgery, revealing adenocarcinoma in both. In 108 patients followed ≥5 years, 89 remained stable. None developed cancer, required surgery, or died from BD-IPMN. Seven developed WF after 5 years. Depending on criteria, 49 % according to Marchegiani and 63 % according to Kyoto would qualify for discontinuation of surveillance. CONCLUSIONS:In real-world practice, malignant progression of presumed BD-IPMNs without WF/HRS is rare and tends to occur early. After 5 years of stability, surveillance discontinuation may be safe in selected subgroups, although prospective validation is needed.

BACKGROUND:The role of gender has gained attention in oncology. In the setting of lung neuroendocrine tumors (L-NETs), the existence of differences between male and females has been suggested, but no clear-cut data are available. We aimed to provide a critical analysis of the existing literature regarding sex roles in L-NETs. METHODS:We performed an extensive search of the available literature to provide a critical narrative review focused on key topics such as epidemiology, histopathological and molecular features, functioning syndromes, prognosis, and response/toxicity to treatments in L-NETs according to sex. RESULTS:Female patients are more likely to have an L-NET than males. The reasons underlying these gender differences are still unclear; a biologic mechanism for the sex difference is possible, through a role of hormones in regulating gene expression and promoting neuroendocrine cell proliferation. A difference in immunohistochemical biomarkers has been found; thyroid transcription factor-1 (TTF-1) expression appears to be associated with female gender; at the molecular level, in the majority of studies, L-NET mutational profile is not stratified for sex. In terms of prognosis, a correlation between male gender and a more aggressive disease has been found. Patient's gender has been recognized as a key modulator in the response/resistance to anticancer treatments; however, for L-NETs, the available data regarding the activity of different treatments and their toxicities are scarce, as in clinical trials designed for L-NETs, a stratified evaluation of drugs' activity according to patients' sex is largely missing. CONCLUSIONS:There is emerging evidence suggesting a gender role in L-NETs; however, further studies are needed to better understand the pathogenesis of these tumors and to plan tailored treatments. Graphical Abstract: for Graphical Abstract, see https://doi.org/10.1159/000546081.

Background. The optimal management of duodenal neuroendocrine neoplasms (dNENs) sized 10–20 mm remains controversial and although endoscopic resection is increasingly performed instead of surgery, the therapeutic approach in this setting is not fully standardized. We performed a systematic review of the literature and a meta-analysis to clarify the outcomes of endoscopic resection for 10–20 mm dNENs in terms of efficacy (i.e., recurrence rate) and safety. Methods. A computerized literature search was performed using relevant keywords to identify pertinent articles published until January 2023. Results. Seven retrospective studies were included in this systematic review. The overall recurrence rate was 14.6% (95%CI 5.4–27.4) in 65 patients analyzed, without significant heterogeneity. When considering studies specifically focused on endoscopic mucosal resection, the recurrence rate was 20.5% (95%CI 10.7–32.4), without significant heterogeneity. The ability to obtain the free margin after endoscopic resection ranged between 36% and 100%. No complications were observed in the four studies reporting this information. Conclusions. Endoscopic resection could be the first treatment option in patients with dNENs sized 10–20 mm and without evidence of metastatic disease. Further studies are needed to draw more solid conclusions, particularly in terms of superiority among the available endoscopic techniques.

The clinical presentation of celiac disease (CD) has changed over time with more patients presenting with non-classical symptoms, extra-intestinal manifestations (EIM) or no symptoms. We aimed to investigate the main symptoms/signs leading to the diagnosis of CD in adult patients. As secondary end-point, we evaluated the outcome of gastrointestinal (GI) symptoms following gluten-free diet (GFD). All consecutive CD adult patients referring to our University Hospital from September 2022 to February 2024 were included. Clinical data were retrospectively evaluated. 134 patients, 104 females/30 males, median age at diagnosis 35 years, were included. 79 patients reported GI symptoms (i.e., diarrhea, abdominal bloating, dyspepsia) as the main symptom leading to CD diagnosis. In 40 patients, the leading symptom/sign was an EIM (i.e., iron deficiency anemia, infertility/miscarriages, dermatitis, osteoporosis, elevated transaminase levels). Fifteen patients were asymptomatic, being diagnosed because of a positive family history or concomitant autoimmune hypothyroidism. Of the 79 patients reporting GI symptoms, 20 did not experience complete resolution with the GFD. Among the 17 patients who reported a strict adherence to GFD (vs 1 patient with low-adherence, 2 non-compliant), lactose intolerance and irritable bowel syndrome overlap were diagnosed in 2 and 15 patients, respectively. GI manifestations remain the main symptoms at presentation of CD, however clinicians should be aware of the EIM of CD and the association with other autoimmune disorders. In non-responsive CD patients, an overlap with functional disorders might be considered.

Aims Risk of branch duct intraductal papillary-mucinous neoplasms (BD-IPMNs) to harbor malignancy is not clearly understood, especially in relation to unfavorable evolutions after long periods of stability. Therefore, follow up (FU) is often continued indefinitely, resulting in significant healthcare costs. However, a recent multicenter study showed that the risk of developing cancer in presumed BD-IPMNs without worrisome features (WF) or high-risk stigmata (HRS) after 5 years of stability is equivalent to an age-matched population based on cyst size. The authors proposed to discontinue the FU after 5 years of stability in patients 75 years or older with cysts<30 mm and in patients 65 years or older with cysts≤15mm. Aim of this study is to evaluate the risk of malignant transformation, surgery and death related to BD-IPMN without WF/HRS at diagnosis, in a real-life cohort of patients under surveillance, particularly after 5 years of FU and among patients that potentially fulfilled criteria for discontinuing surveillance.

Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9–22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.