Neuroendocrine Tumors Research Articles

Autoimmune Gastritis in Korean Patients with Gastric Tumors: Clinicopathologic Correlations and Diagnostic Histological Features.

Autoimmune gastritis (AIG) is a corpus-dominant atrophic gastritis in which patients are positive for antiparietal cell antibody (APCA) and/or anti-intrinsic factor antibody. The risk of developing gastric cancer in patients with AIG remains unclear, and reliable frequency data of AIG in patients with gastric cancer are lacking. We included 624 Korean patients with gastric tumors (612 gastric cancers and 12 neuroendocrine tumors) who had APCA results and were available for AIG evaluation. In patients with positive APCA results, endoscopy and histology findings were reviewed to diagnose AIG. Of the 624 patients, 37 (5.9%) tested positive for APCA, and ultimately, 11 (1.8%) met the diagnostic criteria for AIG (5 both endoscopy and histology findings, 4 endoscopy-only findings, 2 histology-only findings). The frequency of AIG in patients with gastric cancer was 1.3% (8/612), and that in patients with neuroendocrine tumors was 25.0% (3/12). Of the 11 patients with AIG, serum Helicobacter pylori antibody was positive in six patients (54.5%), all of whom had gastric cancer. Histologically, three patients showed pure AIG, four patients exhibited concurrent AIG and H. pylori gastritis, and the findings for four were indefinite for AIG. The pepsinogen (PG) I levels and PG I/II ratio were significantly lower in patients with gastric cancer with AIG than in patients with gastric cancer without AIG (p=0.042 and p=0.016, respectively). The frequency of AIG in gastric cancer patients was very low compared to that in patients with neuroendocrine tumors. Rather, concurrent AIG and H. pylori gastritis was common in patients with AIG with gastric cancer.

Neuroendocrine tumours and pregnancy: Real-world data from an European Neuroendocrine Tumour Centre of Excellence.

Neuroendocrine neoplasms (NENs) arise from the diffuse endocrine system and have been considered to be rare. However, the incidence and prevalence of these tumours have increased in recent years, and they are being seen in younger patients including women in the reproductive age group. Due to the paucity of data, diagnostic and therapeutic strategies in managing such tumours during pregnancy can be challenging to both treating physicians and patients. This article describes the experience and outcomes of managing pregnant women with NEN at a European Neuroendocrine Tumour Society (ENETS) Centre of Excellence. In this retrospective analysis, we evaluated a total of 22 pregnancies in 18 pregnant women with concurrent diagnoses of NENs who were managed at Royal Free Hospital ENETS Centre of Excellence throughout their pregnancy. These were identified from our tumour registry of 3500 NEN patients between 2015 and 2023. Cross-sectional imaging (computed tomography (CT)/magnetic resonance imaging (MRI)), pre- and post-pregnancy, for each patient was reviewed by an experienced radiologist. Tumour growth rate (TGR) was calculated using the formula: TGR = 100 × [exp (TG) - 1]; TG. [3 × log (D2/D1)]/time (months), where D1 is the tumour size at date 1; D2 is the tumour size at date 2; and time (months) = (Date 2 - Date 1 + 1)/30.44. Tumour growth rate pre-conception (TGRpc) and tumour growth rate post-partum (TGRpp) were calculated for each patient. In a sub-group of patients, positivity for oestrogen and progesterone receptors were analysed on the tumour tissue to evaluate whether the presence of these receptors affected tumour progression during the pregnancy. We also reviewed the pregnancy outcome in patients treated with somatostatin analogues during pregnancy. We analysed the data of a total 22 pregnancy encounters in 18 women: 15 pregnancies (68%) preceded the diagnosis of the NEN, whereas the diagnosis of NEN was made during pregnancy or in the post-partum period in 5 (23%) and 2 (9%) pregnancies respectively. Eight patients (44%) had a diagnosis of a pancreatic NEN, whereas 5 (28%) were diagnosed with mid-gut NENs, and a further 5 at other sites. The majority of the patients (n = 12, 67%) had evidence of metastatic disease at the time of diagnosis. Most pregnancies had a successful outcome (n = 19, 86%), whereas 3 patients (14%) had miscarriages in the 1st trimester. Five patients in total of 6 pregnancies were treated with somatostatin analogues as monotherapy during the pregnancy, and all of them had stable disease after pregnancy. All of them delivered healthy babies without any side effects or complications due to therapy. The average TGRpc was -0.8% (n = 5) and the average TGRpp was +0.96% (n = 6); 2 patients who did not have suitable targets for calculation of TGRpc developed new lesions suggesting disease progression. Moreover, 2 of the 4 patients who have had both pre-conception and post-pregnancy scans showed an increase in TGRpp compared to TGRpc. The management of NENs during pregnancy should be multidisciplinary with an individualised approach to each patient. Somatostatin analogues appear to be safe during pregnancy, though further robust studies are needed. Pregnancy per se may accelerate tumour progression, and patients should be counselled regarding this possibility.

Peptide Receptor Radionuclide Therapy Improves Survival in Patients Who Progress After Resection of Gastroenteropancreatic Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). We investigated a 2-decade experience with PRRT to determine whether PRRT confers a survival advantage to patients who progress after surgery versus other therapies. We identified patients from our clinic who had resection/cytoreduction of GEP-NETs, then disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The Kaplan-Meier method assessed progression-free survival (PFS) and overall survival (OS), calculated from progression after surgery (no-PRRT group) or the start of PRRT. Cox regression with time-dependent covariates controlled for immortal time bias and other confounders. Overall, 237 patients progressed after surgery; 95 received PRRT and 142 did not. No differences existed in sex, T or Nstage, tumor grade/differentiation, primary site, or time to progression; 94% of PRRT patients had metastases at diagnosis versus 77% in the no-PRRT group. Median PFS was longer in the PRRT group versus the no-PRRT group (32.4 vs. 11.0 months, p<0.001), as was median OS (49.8 vs. 38.4 months; p=0.009). In subgroup analysis, the PRRT group had improved PFS in small bowel NETs and pancreatic NETs. Time-dependent covariate analysis revealed a lower risk of death associated with PRRT (hazard ratio 0.61, p=0.028) after adjusting for sex, age, Mstage, tumor grade, and primary site. Surgical resection and cytoreduction is an effective treatment for patients with GEP-NETs, but most patients with metastatic disease develop recurrent disease. Surgery followed by PRRT after progression conferred superior PFS and OS over no PRRT/other therapies, and is an effective strategy for managing patients with GEP-NETs.

KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation.

Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma after endocrine treatment failure and implies lethality and limited therapeutic options. Deciphering the molecular mechanisms underlying transdifferentiation from adenocarcinoma to NEPC may provide valuable therapeutic strategies. We performed a pan-cancer differential mRNA abundance analysis and identified that Kinesin-like protein (KIF1A) was highly expressed in NEPC. KIF1A knockdown impaired neuroendocrine(NE) features, including NE marker gene expression, stemness, and epithelial-mesenchymal transition (EMT), whereas KIF1A overexpression promoted these processes. Targeting KIF1A inhibited the growth of NE differentiated prostate cancer (PCa) cells in vitro and in vivo. Mechanistically, KIF1A bound with O-linked N-acetylglucosamine transferase (OGT) and regulated its protein expression and activity. Nuclear accumulation of OGT induced by KIF1A overexpression promoted intranuclear O-GlcNAcylation of β-catenin and OCT4 in nucleus. More importantly, our data revealed that OGT was critical for KIF1A induced NE differentiation and aggressive tumor growth. An OGT inhibitor, OSMI-1, can significantly inhibited NE differentiated PCa cell proliferation in vitro and tumor growth in vivo. Our findings showed that KIF1A promotes NE differentiation to NEPC by regulating the OGT-mediated O-GlcNAcylation. Targeting O-GlcNAcylation may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.

Random survival forest algorithm for risk stratification and survival prediction in gastric neuroendocrine neoplasms.

This study aimed to construct and assess a machine-learning algorithm designed to forecast survival rates and risk stratification for patients with gastric neuroendocrine neoplasms (gNENs) after diagnosis. Data on patients with gNENs were extracted and randomly divided into training and validation sets using the Surveillance, Epidemiology, and End Results database. We developed a prediction model using 10 machine learning algorithms across 101 combinations to forecast cancer-related mortality in patients with gNENs, selecting the best model using the highest mean over a sequence of time-dependent area under the receiver operating characteristic (ROC) curve (AUC). The performance of the final model was assessed through time-dependent ROC curves for discrimination and calibration curves for calibration. The maximum selection rank method was used to determine the best prognostic risk score threshold for classifying patients into high- and low-risk groups. Afterward, Kaplan-Meier analysis and log-rank test were used to compare survival rates among these groups. Our study examined 775 patients with gNENs, dividing them into training and validation sets. A training set comprised 543 patients, with a median follow-up of 42 months and cumulative mortality rates of 40.0% at 1 year, 48.6% at 3 years, and 54.0% at 5 years. A validation set comprised 232 patients, with cumulative mortality rates of 29.1% at 1 year, 43.5% at 3 years, and 53.2% at 5 years. The optimal random survival forest (RSF) model (mtry = 4, node size = 5) achieved an AUC of 0.839 for survival prediction in the training set. Comprising 11 variables such as demographics, treatment details, tumor characteristics, T staging, N staging, and M staging, the RSF model revealed high predictive accuracy with AUCs of 0.92, 0.96, and 0.96 for 1-, 3-, and 5-year survival, respectively, which was consistently reflected in the validation set with AUCs of 0.88, 0.92, and 0.89, respectively. Moreover, patients were risk-stratified. Although our RSF model effectively stratified patients into different prognostic groups, it needs external validation to confirm its utility for noninvasive prognostic prediction and risk stratification in gNENs. Further research is required to verify its broader clinical applicability.

Histological transformation in lung adenocarcinoma: Insights of mechanisms and therapeutic windows

Abstract Histological transformation from lung adenocarcinoma (ADC) to small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma (SCC), and sarcomatoid carcinoma (PSC) after targeted therapies is recognized as a mechanism of resistance in ADC treatments. Patients with transformed lung cancer typically experience a poor prognosis and short survival time. However, effective treatment options for these patients are currently lacking. Therefore, understanding the mechanisms underlying histological transformation is crucial for the development of effective therapies. Hypotheses including intratumoral heterogeneity, cancer stem cells, and alteration of suppressor genes have been proposed to explain the mechanism of histological transformation. In this review, we provide a comprehensive overview of the known molecular features and signaling pathways of transformed tumors, and summarized potential therapies based on previous findings.

Primary Neuroendocrine Tumor of the Breast: A Case Report and Review of Current Guidelines

Primary Neuroendocrine Tumor of the Breast: A Case Report and Review of Current Guidelines

Ocular Manifestations in Neuroendocrine Tumors: A Review Article

Introduction: Neuroendocrine tumors (NETs) are a diverse group of tumors that arise from neuroendocrine cells and can synthesize and secrete neuropeptides or hormones. Although NETs usually originate from the gastrointestinal tract or bronchopulmonary tree, they can affect various organs, including the eye. The majority of ocular association with neuroendocrine tumors results from metastasis that affects the orbit, however, primary ocular tumors have been reported. Purpose of the study: The article reviews the presentation of ocular manifestations in neuroendocrine tumors including pheochromocytoma, ocular paraganglioma, gastrointestinal and bronchial NETs, Merkel cell carcinoma and neuroendocrine metastasis. Materials and methods: In order to summarize the current knowledge on the topic, a literature review of English language papers with a focus on the most current literature was performed. The review was conducted with the PubMed database with 43 works used, accessed before September 2024. Conclusions: Instances of neuroendocrine tumors leading to ocular manifestations have become increasingly prevalent. These nonspecific symptoms can make it challenging to diagnose ocular NETs. Ocular manifestations are not typically the primary symptom, but patients with tumors located in the eye may experience symptoms such as eye pain, blepharitis or exophthalmos. Ocular motility and vision may also be affected. It is crucial to study the association between those symptoms and NETs, in order to develop a more comprehensive understanding of the matter.

An automated pheochromocytoma and paraganglioma lesion segmentation AI-model at whole-body 68Ga- DOTATATE PET/CT.

Somatostatin receptor (SSR) targeting radiotracer 68Ga-DOTATATE is used for Positron Emission Tomography (PET)/Computed Tomography (CT) imaging to assess patients with Pheochromocytoma and paraganglioma (PPGL), rare types of Neuroendocrine tumor (NET) which can metastasize thereby becoming difficult to quantify. The goal of this study is to develop an artificial intelligence (AI) model for automated lesion segmentation on whole-body 3D DOTATATE-PET/CT and to automate the tumor burden calculation. 132 68Ga-DOTATATE PET/CT scans from 38 patients with metastatic and inoperable PPGL, were split into 70, and 62 scans, from 20, and 18 patients for training, and test sets, respectively. The training set was further divided into patient-stratified 5 folds for cross-validation. 3D-full resolution nnUNet configuration was trained with 5-fold cross-validation. The model's detection performance was evaluated at both scan and lesion levels for the PPGL test set and two other clinical cohorts with NET (n = 9) and olfactory neuroblastoma (ONB, n = 5). Additionally, quantitative statistical analysis of PET parameters including SUVmax, total lesion uptake (TLU), and total tumor volume (TTV), was conducted. The nnUNet AI model achieved an average 5-fold validation dice similarity coefficient of 0.84 at the scan level. The model achieved dice similarity coefficients (DSC) of 0.88, 0.6, and 0.67 at the scan level, the sensitivity of 86%, 61.13%, and 61.64%, and a positive predictive value of 89%, 74%, and 86.54% at the lesion level for the PPGL test, NET and ONB cohorts, respectively. For PPGL cohorts, smaller lesions with low uptake were missed by the AI model (p < 0.001). Anatomical region-based failure analysis showed most of the false negative and false positive lesions within the liver for all the cohorts, mainly due to the high physiologic liver background activity and image noise on 68Ga- DOTATATE PET scans. The developed deep learning-based AI model showed reliable performance for automated segmentation of metastatic PPGL lesions on whole-body 68Ga-DOTATATE-PET/CT images, which may be beneficial for tumor burden estimation for objective evaluation during therapy follow-up. https://www. gov/study/NCT03206060 , https://www. gov/study/NCT04086485 , https://www. gov/study/NCT05012098 .

High level of aneuploidy and recurrent loss of chromosome 11 as relevant features of somatotroph pituitary tumors

BackgroundSomatotroph neuroendocrine pituitary tumors (sPitNET) are a subtype of pituitary tumors that commonly cause acromegaly. Our study aimed to determine the spectrum of DNA copy number abnormalities (CNAs) in sPitNETs and their relevance.MethodsA landscape of CNAs in sPitNETs was determined using combined whole-genome approaches involving low-pass whole genome sequencing and SNP microarrays. Fluorescent in situ hybridization (FISH) was used for microscopic validation of CNAs. The tumors were also subjected to transcriptome and DNA methylation analyses with RNAseq and microarrays, respectively.ResultsWe observed a wide spectrum of cytogenetic changes ranging from multiple deletions, recurrent chromosome 11 loss, stable genomes, to duplication of the majority of the chromosomes. The identified CNAs were confirmed with FISH. sPitNETs with multiple duplications were characterized by intratumoral heterogeneity in chromosome number variation in individual tumor cells, as determined with FISH. These tumors were separate CNA-related sPitNET subtype in clustering analyses with CNA signature specific for whole genome doubling-related etiology. This subtype encompassed GNAS-wild type, mostly densely granulated tumors with favorable expression level of known prognosis-related genes, notably enriched with POUF1/NR5A1-double positive PitNETs. Chromosomal deletions in sPitNETs are functionally relevant. They occurred in gene-dense DNA regions and were related to genes downregulation and increased DNA methylation in the CpG island and promoter regions in the affected regions. Recurrent loss of chromosome 11 was reflected by lowered MEN1 and AIP. No such unequivocal relevance was found for chromosomal gains. Comparisons of transcriptomes of selected most cytogenetically stable sPitNETs with tumors with recurrent loss of chromosome 11 showed upregulation of processes related to gene dosage compensation mechanism in tumors with deletion. Comparison of stable tumors with those with multiple duplications showed upregulation of processes related to mitotic spindle, DNA repair, and chromatin organization. Both comparisons showed upregulation of the processes related to immune infiltration in cytogenetically stable tumors and deconvolution of DNA methylation data indicated a higher content of specified immune cells and lower tumor purity in these tumors.ConclusionssPitNETs fall into three relevant cytogenetic groups: highly aneuploid tumors characterized by known prognostically favorable features and low aneuploidy tumors including specific subtype with chromosome 11 loss.

ASCL1 Drives the Development of Neuroendocrine Prostate Cancer.

Therapeutic resistance to androgen receptor (AR)-targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence on androgen signaling and escape treatment. Although many known genetic alterations can predispose tumors to acquiring the NEPC phenotype, it remains unclear what, if any, drivers are essential to this progression. In this issue of Cancer Research, Rodarte and colleagues identified ASCL1 as one such essential regulator. Through the use of genetically engineered mouse models, the authors demonstrated that whereas ASCL1 was dispensable for tumor formation and growth, ASCL1 loss nearly completely abrogated the development of NEPC and instead redirected lineage trajectories toward a basal-like phenotype. This study provides an important new model for the study of NEPC, reveals the ability of ASCL1+ NEPC cells to also assume a NEUROD1+ state, and demonstrates the changes to tumor cell phenotypes following ASCL1 loss. See related article by Rodarte et al., p. 3522.

Role of non-coding RNA in lineage plasticity of prostate cancer.

The treatment of prostate cancer (PCa) has made great progress in recent years, but treatment resistance always develops and can even lead to fatal disease. Exploring the mechanism of drug resistance is of great significance for improving treatment outcomes and developing biomarkers with predictive value. It is increasingly recognized that mechanism of drug resistance in advanced PCa is related to lineage plasticity and tissue differentiation. Specifically, one of the mechanisms by which castration-resistant prostate cancer (CRPC) cells acquire drug resistance and transform into neuroendocrine prostate cancer (NEPC) cells is lineage plasticity. NEPC is a subtype of PCa that is highly aggressive and lethal, with a median survival of only 7 months. With the development of high-throughput RNA sequencing technology, more and more non-coding RNAs have been identified, which play important roles in different diseases through different mechanisms. Several ncRNAs have shown great potential in PCa lineage plasticity and as biomarkers. In the review, the role of ncRNA in PCa lineage plasticity and its use as biomarkers were reviewed.

Peptide Receptor Radionuclide Therapy and clinical associations with renal and hematological toxicities and survival in patients with neuroendocrine tumors: an analysis from two U.S. medical centers

PurposeRenal and hematological toxicity are side effects and dose-limiting factors of Peptide Receptor Radionuclide Therapy (PRRT). We aimed to assess the changes in renal and hematological function and associations with survival in neuroendocrine tumor (NET) patients treated with PRRT.MethodsA retrospective cohort of 448 NET patients treated with either 177Lu-DOTATATE or 90Y-DOTATOC were followed for changes of renal and hematological function. Renal function was assessed by monitoring changes in serum creatinine, blood urea nitrogen and estimated glomerular filtration rate. Hematological function was determined by examining changes in white blood cell counts (WBC), platelet counts, and hemoglobin levels over time. Piecewise linear mixed effect models were applied to model the longitudinal repeated measurements of renal and hematological function. Overall survival (OS) and progression-free survival (PFS) were modelled using Cox proportional hazard regressions.ResultsOf the 448 PRRT treated patients, 335 received 177Lu-DOTATATE (74.78%) and 113 were treated with 90Y-DOTATOC (25.22%). Comparing patients treated with 177Lu-DOTATATE to those treated with 90Y-DOTATOC, renal function did not differ significantly prior to, during or after PRRT. Compared with patients treated with 90Y-DOTATOC, significantly decreased indicators of hematological function were observed in those treated with 177Lu-DOTATATE prior to and during PRRT treatment (WBC: estimate, -0.10, 95% CI, -0.15 to -0.05; P < 0.001; platelet count: estimate, -2.53, 95% CI, -3.83 to -1.24; P < 0.001), and no significant recovery was observed in hematological function post PRRT. Individuals who received 177Lu-DOTATATE tended to have a longer PFS (hazard ratio, 0.47, 95%CI: 0.28–0.79, P = 0.004) compared with 90Y-DOTATOC, but there was no difference in OS.ConclusionThere was no significant renal, but minor hematological toxicity, in patients treated with 177Lu-DOTATATE compared with 90Y-DOTATOC. Compared to 90Y-DOTATOC, 177Lu-DOTATATE appears to enhance PFS, but not OS. Treatment with 177Lu-DOTATATE may necessitate follow-up for hematological toxicity irrespective of other therapies prior to PRRT.

The prognostic implications of podoplanin in cancer-associated fibroblasts and PD-L1 expression in high-grade neuroendocrine carcinoma of the lung.

Podoplanin (PDPN) expression in cancer-associated fibroblasts (CAFs) (CAF-PDPN) is considered a poor prognostic factor in nonsmall cell lung cancer, but little is known about its clinical significance in high-grade neuroendocrine carcinoma of the lung (HGNEC). This study examines the association between CAF-PDPN and stromal programmed death-ligand 1 (PD-L1) expression and the prognostic implications of CAF-PDPN and PD-L1 expression status in surgically resected HGNEC patients. Immunohistochemical analyses were performed on 121 resected HGNEC specimens using antibodies against PDPN and PD-L1. Correlations between CAF-PDPN, stromal PD-L1 expression, and clinicopathologic features and their implications for survival were analyzed statistically. There were substantially more large-cell neuroendocrine carcinomas in the stromal PD-L1-positive group and more vascular invasion in the tumoral PD-L1-positive group. PDPN expression in CAF was moderately correlated with stromal PD-L1 expression (ρ = 0.567, p < 0.001). In a survival analysis combining CAF-PDPN and stromal PD-L1 status, the 5-year RFS rates for Group A: CAF-PDPN (+)/stromal PD-L1 (+), Group B: CAF-PDPN (+)/stromal PD-L1 (-), Group C: CAF-PDPN (-)/stromal PD-L1 (+), and Group D: CAF-PDPN (-)/stromal PD-L1 (-) were 62.0%, 46.8%, 17.5%, and 20.2%, respectively, with corresponding 5-year OS rates of 76.6%, 69.2%, 27.0%, and 25.3%. The log-rank test showed statistically significant differences among the groups in RFS (p < 0.001) and OS (p < 0.001). There is a correlation between CAF-PDPN and tumoral/stromal PD-L1 expression, and positive status for either CAF-PDPN or stromal PD-L1 expression could be an independent favorable prognostic factor in surgically resected HGNEC patients.

Long-term outcomes and prognostic factors of metastatic or recurrent pheochromocytoma and paraganglioma: a 20-year review in a single institution

Pheochromocytoma and paraganglioma (PPGL) represent a group of rare neuroendocrine tumors known for their potential to metastasize. This study provides a comprehensive retrospective evaluation of 15 patients diagnosed with metastatic or recurrent PPGL at our institution over a two-decade span (2000–2020). Our primary objectives were to delineate the long-term clinical outcomes and pinpoint key prognostic determinants. Median duration from initial PPGL diagnosis to the onset of metastasis or recurrence stood at 5.8 years. Predominant sites for metastasis included the bone, lung, lymph nodes, and peritoneum. A salient finding was that surgical interventions targeting metastatic lesions significantly improved prognosis. Further analysis revealed that a Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) exceeding 7 closely associated with unfavorable outcomes. These insights not only underscore the clinical variability of PPGL’s progression but also highlight the pivotal role of surgical management for metastatic or recurrent cases. The value of the PASS score as an informative prognostic tool was evident, suggesting its utility in shaping future therapeutic approaches. Given the intricacies of PPGL, collaborative studies involving larger patient cohorts will be crucial to optimize management strategies and prognostication.

Liver metastasized pancreatic neuroendocrine tumor in a 17-year-old female: A case report.

Pancreatic neuroendocrine tumors (PNETs) are rare and often misdiagnosed due to their vague symptoms and tumor heterogeneity. Early detection using computed tomography (CT) is essential, particularly in regions without access to advanced diagnostic tools like immunohistochemistry and genetic testing. Neuroendocrine tumors (NETs) are rare tumors in adults and extremely rare in the pediatric population, as pancreatic NETs (pNETs) have an incidence rate of <0.1 per million. We present a case of a 17-year-old female with a liver metastasized pNET. A 17-year-old female with a history of intermittent abdomen-back pain presented to the clinic with severe upper abdominal pain radiating to the shoulder. The routine tests were normal. An ultrasound showed multiple lesions in the liver, which were confirmed by a computed tomography (CT) that uncovered a pancreatic lesion too. A liver biopsy proved it was a metastasized pNET with positive NET markers on IMC staining. The metaiodobenzylguanidine (MIBG) scan flared the liver lesion. The patient was started on Octreotide long-acting release (LAR) 30 mg once monthly. The rarity of these tumors makes their diagnosis difficult, but they should not be omitted and must be considered when there are long-lasting symptoms that are not compatible with common illnesses. These tumors are curable in their early stages.

Large cell neuroendocrine carcinoma in pancreatoblastoma with TP53 and SMAD4 mutations: a clinicopathologic study of a rare entity

Abstract Pancreatoblastoma, a rare pancreatic tumor, exhibits diverse differentiation pathways, including acinar, ductal, and neuroendocrine lineages, often with distinct squamoid nests [3]. We present a notable case of pancreatoblastoma coexisting with large cell neuroendocrine carcinoma in a 10-year-old boy, presenting with abdominal discomfort, weight loss, and lesions in the pancreas, spleen, and liver visible on imaging. A liver biopsy revealed a poorly differentiated carcinoma with neuroendocrine features, while a splenic biopsy showed acinar cell differentiation, raising possible diagnoses of pancreatoblastoma or acinar cell carcinoma. Subsequent surgical resection after chemotherapy revealed diverse components within the pancreatoblastoma, including well-differentiated acinar and neuroendocrine cells, squamoid nests, and a high-grade neuroendocrine carcinoma. Genetic analysis detected pathogenic variants in TP53 and SMAD4, rarely found in pancreatoblastomas. This juxtaposition of large cell neuroendocrine carcinoma and pancreatoblastoma suggests a potential evolution from well-differentiated neuroendocrine tumors to poorly-differentiated carcinomas within pancreatoblastomas.

"Vascular tuft sign" in neuroendocrine tumors of the pancreas.

The often well-developed microvasculature in pancreatic neuroendocrine tumors (PanNETs) has been studied from different perspectives. However, some detailed structural findings have received less attention. Our objective is to study an overlooked event in PanNETs: "enclosed vascular tufts" (EVTs). For this purpose, 39 cases of PanNETs were examined with conventional (including serial sections) and immunochemistry procedures. In typical EVTs, the results show: 1) an insulated terminal vascular area, with a globular (glomeruloid) aspect, formed by a cluster of coiled microvessels, presenting CD31-, CD34-positive endothelial cells, αSMA-positive pericytes, and perivascular CD34-positive stromal cells/telocytes, separated by a pseudoglandular space from the surrounding trabeculae of tumor neuroendocrine cells; and 2) a pedicle joining the insulated terminal vascular area, with connective tissue tracts around the enclosing tumor trabeculae. EVTs predominate in the trabecular and nested gyriform pattern of PanNETs, with tumor trabeculae that follow a ribbon coil (winding ribbon pattern) around small vessels, which acquire a tufted image. In EVTs, secondary modifications may occur (fibrosis, hyalinization, myxoid changes, and calcification), coinciding or not with those of the connective tracts. In conclusion, the typical characteristics of unnoticed EVTs allow them to be considered as a morphological sign of PanNETs (a vascular tuft sign). Further in-depth studies are required, mainly to assess the molecular pathways that participate in vascular tuft formation and its pathophysiological implications.

Molecular theranostics: principles, challenges and controversies.

Theranostics is a new term for long-established principles in nuclear medicine. The generalisability of the term means there is a very broad use of the term across the medical literature, not all of which is consistent with the intent in nuclear medicine. The term molecular theranostics better reflects the philosophy and application in nuclear medicine. Even with a clearer definition, there are a number of challenges or controversies whose debate provides a richer understanding of the principles and applications of molecular theranostics. Radioiodine imaging and therapy of hyperthyroidism and thyroid cancer provide the historical context for theranostics. The prototype molecular theranostic is the 68Ga/177Lu DOTATATE pair that targets somatostatin receptor subtype 2 in neuroendocrine tumors. The potential value of precision medicine of radiation dosimetry in molecular theranostics needs a balanced discussion with limitations of reactive dosimetry and the opportunities for predictive or pre-treatment dosimetry. Despite challenges and limitations, molecular theranostics is a powerful tool in the precision medicine landscape. Molecular theranostics is a vehicle for improved outcomes in cancer patients with a future-facing portfolio of opportunities.

The landscape of targetable gene mutations in neuroendocrine cervical cancer

The landscape of targetable gene mutations in neuroendocrine cervical cancer