Neuroendocrine Tumor G1 Research Articles

Combined Treatment of Patients with Neuroendocrine Liver Metastases Accompanied by High Hormonal Activity and Uncontrolled Carcinoid Syndrome

Introduction: The percentage of cases of neuroendocrine tumors (NET) is growing every year. Moreover, the diagnosis is often made in the later stages, when the disease manifests itself with manifestations of carcinoid syndrome (CS) and its accompanying indications. Today, there is a need to systematize approaches to diagnosis and individual groups of patients with unresectable metastatic lesions of NETs.Material and methods: A retrospective assessment of the results of treatment of patients with bilobar metastatic liver disease NET on the background of uncontrolled CS was performed in the period from 2010 to 2023. The study included 10 patients with NET G1 — 4 patients, G2 — 6. The sampling structure according to the location of the primary lesion was divided into: pancreas (n = 7), small intestine (n = 3). Before the start of regional chemotherapy, the primary lesion was removed in 1 patient. The average age of the patients in the sample was 31.3 years.In order to evaluate the results, patients underwent SCT of the abdominal cavity and chest with intravenous enhancement, PET/CT of the whole body with 68Ga-DOTA TATE/NOC. All patients in the group received therapy with long-acting somatostatin analogues. Two of them additionally received everolimus 10 mg per day.The leading method of embolization is oil TACE with a suspension of doxorubicin 50–100 mg or mitomycin C 10–20 mg with superfluid lipiodol 5–8 ml, then adding a collagen sponge 0.25–0.5 cm3 into the tumor vessels until blood flow is reduced. Courses were held once every 2 months. The evaluation of the treatment was carried out according to an objective examination (ECOG 0), the nature of the complaints, and instrumental diagnostic data (CT with intravenous contrast).Results: Evaluation after regional chemotherapy: partial response in one patient; stabilization in seven; progression in two patients (according to mRECIST). The average serotonin level before CEPA was 936.5 ng/ml; after two courses there was a significant decrease to 282.1 ng/ml (p < 0.05). After stabilization of the disease, the primary lesion was removed in 6 patients; patients underwent cytoreductive atypical liver resection (n = 4) and MVA (n = 1). Currently, three patients have died, the average life expectancy of the deceased is 64 months. Seven patients were alive for periods ranging from 30 to 134 (median 84) months.Conclusions : TACE in the treatment of patients with NETs that cause hyperproduction of hormones, manifested by CS and not relieved by somatostatin analogues, provides clinical and radiological improvements in 80 % of patients. Further cytoreductive interventions can extend the median overall-survival (OS) to 84 months.

Temozolomide and capecitabine regimen as first-line treatment in advanced gastroenteropancreatic neuroendocrine tumors at a Latin American reference center

BACKGROUND Numerous studies have indicated that the temozolomide and capecitabine regimen (TEMCAP) exhibits a certain level of efficacy in treating advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET). However, published data from Peru are limited. We hypothesize that this regimen could be a viable therapeutic option for advanced GEP-NET in the Peruvian population. AIM To evaluate overall survival (OS) in patients diagnosed with advanced GEP-NET treated with TEMCAP at the Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima-Perú. METHODS A retrospective review was conducted to identify patients with GEP-NEN treated with the TEMCAP regimen between 2011 and 2021 at the INEN. A total of thirty-eight patients were included in the final analysis: Thirty-five received TEMCAP as a first-line treatment, and three as a second-line treatment. The primary objective was to evaluate OS. The efficacy and safety of TEMCAP were assessed until the occurrence of unacceptable toxicity or disease progression. Survival outcomes were estimated using the Kaplan-Meier method. RESULTS The median age of the patients was 52 years (range 24-77 years), and 53.3% were female. The most common symptoms at diagnosis were abdominal pain in 31 patients (81.6%). Primary tumors included 12 in the rectum (31.6%), 11 in the pancreas (28.9%), 3 in the ileum (7.9%), 2 in the mesentery (5.3%), 2 in the small intestine (5.3%), 1 in the appendix (2.6%), 1 in the stomach (2.6%) and 6 cases of liver metastasis of unknown primary (15.8%). Five were neuroendocrine tumors (NET) G1 (13.2%), 33 were NET G2 (86.8%), five had Ki67 < 3% (13.2%), and 33 had Ki67 between 3% and 20% (86.8%). TEMCAP was administered to 35 (92.1%) patients as first-line treatment. OS at 12, 36, and 60 months was estimated in 80%, 66%, and 42%, respectively, with a median OS of 49 months. CONCLUSION TEMCAP therapy is a viable first-line option regarding efficacy and tolerability in areas where standard therapy is inaccessible.

Diagnostic relevance of p53 and Rb status in neuroendocrine tumors G3 from different organs: an immunohistochemical study of 465 high-grade neuroendocrine neoplasms.

The double inactivation of TP53 and RB1 is considered typical of neuroendocrine carcinomas (NECs) but is assumed to be rare in high-grade neuroendocrine tumors (NETs). The immunohistochemical determination of the p53 and Rb status has therefore been proposed as a diagnostic tool. We studied this status in a large series of high-grade neuroendocrine neoplasms, from multiple origins, in order to (a) assess the patterns observed in the different histopathological categories, (b) compare them between the various anatomic sites, and (c) evaluate their possible diagnostic relevance. Four hundred sixty-five cases from 9 organ systems (142 high-grade NETs -NET-G3-, 162 large-cell NECs -LCNEC-, 144 small-cell NECs -SCNEC-) and 60 cases of NET G1/G2 were included. The expression of both proteins was normal in 96.7% of NET G1/G2, 76.7% of NET-G3, and 5.8% of all NECs. p53 expression was abnormal in 12.7% of NET-G3 and 91.5% of NECs. Rb expression was lost in 10.6% of NET-G3 and 68.3% of NECs. Rb loss was significantly less frequent in LCNEC than in SCNEC (57.3% versus 80.6%); abnormal p53 expression was comparable in the two categories. Patterns were comparable between primary sites, except for head and neck NECs. For diagnostic purposes, taking into account, Rb status improved, but only marginally, the performances of p53 status. In conclusion, our study underlines the molecular heterogeneity of NET-G3 and LCNEC, irrespectively of the primary, and provides further insight on the diagnostic relevance of p53/Rb immunodetection in high-grade neuroendocrine neoplasms.

Automatic discrimination between neuroendocrine carcinomas and grade 3 neuroendocrine tumors by deep learning of H&E images

Neuroendocrine neoplasms (NENs) arise from diffuse neuroendocrine cells and are categorized as either well-differentiated and less proliferative Neuroendocrine Tumors (NETs), divided into low (G1), middle (G2), and high grades (G3), or poorly differentiated, and more proliferative Neuroendocrine Carcinomas (NECs). Low-grade NENs typically necessitate surgical intervention, whereas high-grade ones often require chemotherapy. However, low-grade NENs may exhibit aggressive behavior. Therefore, it is crucial to precisely refine the diagnosis of NENs. This refinement is achievable when differentiation/non-differentiation is evident or when the Ki-67 or mitosis index is low. The challenge arises in cases of morphologically undifferentiated instances with a high Ki-67 percentage and/or high mitotic index. To address this challenge, we developed a Deep Learning (DL) system named NEToC, designed to differentiate between NETs and NECs using exclusively morphological information from immunohistochemistry images, without relying on Ki-67 or mitosis assessments. NEToC was developed using 95 NEN cases from the period 2015 to 2018 at Parc Tauli Hospital in Spain, comprising 588 images. Implemented as a Graphical User Interface (GUI) system, NEToC is intended for deployment in pathological departments of hospitals to perform federated supervision. We tested the performance of NEToC with 119 images that were not used during the Artificial Neural Network (ANN) training phase, and evaluated its robustness across various resolutions: 64 × 64, 128 × 128, 256 × 256, and 512 × 512 pixels. The achieved accuracies for these resolutions were 74 %, 98 %, 98 %, and 100 %, respectively, for an underrepresented NET G3 experiment, and 66 %, 89 %, 95 % and 94 % for a represented NET G3 experiment. Based on several measured performance metrics, the optimal resolution appears to be between 128 × 128 and 256 × 256 pixels, considering computational resources and accuracy requirements. However, we found that the 256 × 256-pixel resolution is more robust to classify underrepresented classes in the learning phase. These results imply that the information to discriminate between NECs and Grade 3 NETs needs to be resolved in regions with a pixel resolution of no more than 4 μm/pixel. Most of the misclassifications were false negatives, where NET G1-type images were erroneously classified as NEC-type. Our results demonstrate that a DL-based diagnostic algorithm provides a more accurate diagnosis in NEN cases where physicians face challenges. NEToC has been initially trained with and used to classify gastrointestinal NENs. Since the NEN morphology does not change among the different organs, the use of NEToC can be extrapolated to NENs from different organs. NEToC facilitates federated supervision, allowing pathologists to collect interchangeable files based on NEToC classification predictions. NEToC is an easy-to-use, adaptable software that integrates multiple ANNs to improve standardization and accuracy NEN diagnosis, opening up possibilities for combining DL and histological diagnosis in federated supervision systems. A future goal is to classify not only NETs, but also the three-tier system (NET G1, NET G2, and NET G3) based solely on tissue differentiation information.

Progression of Low-Grade Neuroendocrine Tumors (NET) to High-Grade Neoplasms Harboring the NEC-Like Co-alteration of RB1 and TP53

AbstractHigh-grade or grade 3 epithelial neuroendocrine neoplasms (G3 NEN) are now divided into grade 3 well-differentiated neuroendocrine tumor (G3 NET) and neuroendocrine carcinoma (NEC), both defined by Ki-67 > 20% and/or > 20 mitoses per 2 mm2. NET and NEC are thought to be distinct tumors with different genetic profiles: NEC classically harbors co-alteration of TP53 and RB1, whereas NET genetics are site-dependent with frequent alterations in MEN1, ATRX, DAXX, and TSC1/2 in pancreatic NETs. Progression from NET to NEC is considered rare and is not well described. While both TP53 and RB1 alterations were initially thought to be rare in NET, recent work has demonstrated the former in up to 35% of high-grade G3 NET and the latter in rare high-grade NEN that progressed from NET. Here, we describe the clinical, pathologic, and molecular features associated with tumor evolution in a series of five patients that had low-grade NET that progressed to high-grade NEN with co-alteration of RB1 and TP53, similar to NEC. Morphology of the high-grade neoplasms remained well-differentiated in some cases despite RB1/TP53 co-alteration and had some NEC-like features in other cases. All five patients died of disease, with a mean overall survival of 41 months from the first metastatic disease and 12 months from acquisition of RB1/TP53 co-alteration. Our data demonstrate that low-grade NET can progress via the acquisition of both TP53 and RB1 alteration, similar to NEC, but whether this represents a transformation from NET to NEC remains unclear.

Diagnostic dilemma: a collision of pancreatic neuroendocrine tumor G3 and adenocarcinoma with extensive fibrosis.

An 82-year-old man presented with intermittent abdominal pain and elevated liver enzymes. Blood tests showed normal levels of tumor markers (CEA, CA19-9, NSE). Contrast-enhanced computed tomography (CE-CT) revealed a 20mm hypovascular mass in the pancreatic head. Magnetic resonance imaging indicated low intensity on both T1- and T2-weighted images and high intensity on diffusion-weighted images. Endoscopic ultrasonography visualized an irregular hypoechoic mass. Initially, it was diagnosed as pancreatic ductal adenocarcinoma (PDAC) based on imaging. Subsequent histopathological analysis via endoscopic ultrasound-guided fine-needle aspiration revealed a neuroendocrine tumor (NET). The preoperative diagnosis was changed to a pancreatic NET grade1. Consequently, a pancreaticoduodenectomy was performed. Histopathological examination of the resected specimen unveiled a mixed tumor-NET-Grade1/Grade3 and invasive PDAC. No clear transition between the NETs and PDAC was observed. The high grade of NET with significant fibrosis contributed to decreased enhancement of CE-CT. Finally, we diagnosed this case as a pancreatic collision tumor involving both NET and PDAC components, with lymph node metastases attributed to the NET components. In this case, achieving an accurate preoperative diagnosis was challenging despite utilizing both imaging and biopsy diagnostics. This unique case underscores the difficulties encountered in the preoperative assessment of mixed tumors.

Neuroendocrine Neoplasms of the Breast: Current Insights and Future Directions.

The breast neuroendocrine neoplasms (NENs) represent a heterogeneous group of tumors and account for less than 1% of all NENs. The 5th edition of the WHO Classification of Breast Tumors in 2019 introduced a more stringent definition for breast NENs including neuroendocrine tumors (NETs) (G1, G2) and neuroendocrine carcinomas (NECs) (small cell carcinoma, large cell neuroendocrine carcinoma). While the diagnostic criteria and treatment of breast NENs still have some unsolved issues. We aim to discuss the diagnosis, treatment progress, existing problems, and future development direction of breast NENs. We provide a comprehensive review and evaluation of the diagnostic criteria, pathological features, utilization of immunohistochemical markers, molecular characteristics, pathogenesis, clinical significance, treatment options for breast NENs. (1) Under the new definition, "pure" breast NENs are extremely rare. (2) Breast NETs are graded according to Nottingham grading System. Grading criteria utilized in other systems for NENs, such as mitotic count, ki67 proliferation index, and necrosis, have not been applied to breast NENs. (3) The WHO has not yet acknowledged the existence of NET G3 clearly. (4) The expression of NE markers may differ in breast NECs. (5) The treatment of breast NENs is still based on IBCs-NST, and without any difference from invasive carcinoma with NE features. (6) The prognosis of breast NENs remains unclear, while the prognosis for NECs is significantly poorer than invasive breast carcinomas of no special type (IBCs-NST) has been confirmed. Strict adherence to criteria is the key to correctly diagnose breast NENs with the exclusion of metastasis from other sites. Further exploration is required to determine the tissue origin of breast NENs and understand the pathogenesis. Efforts are still needed to establish unified diagnostic criteria and a unique diagnosis and treatment consensus for breast NENs.

ESR Essentials: role of PET/CT in neuroendocrine tumors-practice recommendations by the European Society for Hybrid, Molecular and Translational Imaging.

Neuroendocrine neoplasms (NEN) originate from the secretory cells of the neuroendocrine system, with the majority arising in the gastrointestinal tract and pancreas. Given the heterogeneity in the biological behavior and morphological differentiation of these tumors, advanced imaging techniques are crucial for supporting the suspected diagnosis, accurate staging, and monitoring therapy. As most well-differentiated NEN demonstrate overexpression of somatostatin receptors (SSR) on the cell surface, SSR-directed PET/CT is considered the reference standard for imaging of this particular entity. SSR-PET/CT should be the imaging method of choice in every NEN G1 or G2 and considered for re-staging after both potentially curative and non-curative surgeries. The extent of SSR expression is also crucial for determining a patient's eligibility for peptide receptor radionuclide therapy (PRRT). PRRT utilizes [177Lu]Lu-DOTA-TATE to target the SSR receptor and can significantly prolong progression-free survival in patients with advanced, progressive neuroendocrine tumor of the gastroenteropancreatic system (GEP-NET). PET/CT is a central component of the multidisciplinary management of NEN. Variable follow-up intervals are recommended, considering that tumors with higher proliferation rates or advanced metastatic disease require more frequent assessments. The combination with other imaging modalities, like MRI, complements SSR-PET/CT, further enhancing overall diagnostic accuracy. KEY POINTS: Somatostatin receptor-PET/CT (SSR-PET/CT) is the guideline-recommended reference standard for imaging well-differentiated neuroendocrine tumors (NET). SSR-PET/CT should be the diagnostic imaging of choice for staging and post-therapy re-staging of grade 1 or 2 NET (G1 or G2). Variable follow-up intervals are recommended for NET G1 and G2. Tumors with higher proliferation rates or advanced metastatic disease necessitate more frequent assessments.

Rapid Evolution of Metastases in Patients with Treated G3 Neuroendocrine Tumors Associated with NEC-Like Transformation and TP53 Mutation

Little is known about the morphomolecular features of G3 neuroendocrine tumors (G3NETs) under prolonged systemic treatments, although rapid progression is increasingly observed. This longitudinal study aims to elucidate the course and morphomolecular features of metastasized G3NETs with high-grade transformation. Clinical and histological findings in 40 patients with metastasized and treated G3NETs, which were histologically examined at least twice with an interval time of more than 6 months (median 27), were reviewed and the morphomolecular changes recorded and assigned to treatment. Neuroendocrine carcinoma (NEC)-like histology defined by high-grade atypia, diffuse growth pattern, and/or necrosis was identified in nine (22%) G3NETs (seven pancreatic, two rectal) patients. All NEC-like tumors showed a significantly higher Ki67 increase and longer interval time between first and last examination than non-NEC-like G3NETs (53 vs. 19% and 60 vs. 24 months, respectively). Moreover, all NEC-like G3NETs had TP53 (100%), but rarely RB1 (12%) mutations, and retained NET-typical mutations such as MEN1 or DAXX (five of the pancreatic NETs). The last treatments received prior to the NEC-like transformation included PRRT (n = 3), somatostatin analog, everolimus, sunitinib (n = 1 each), and alkylating agents (n = 2). Abrupt clinical progression in patients with metastasized G3NETs is associated with a significant increase in Ki67, accelerated growth, and NEC-like histology. These findings are most likely attributable to the novel TP53 mutation, which was detected in all nine cases at the last evaluation. However, none of the cases exhibited a complete transformation to a typical NEC, as the tumors retained partial histological and genetic features of NETs.

Less frequent radiological exams to avoid futile response assessments from 177-LuDOTATE therapy for patients with advanced neuroendocrine tumors.

177-LuDOTATE is an effective but expensive treatment for neuroendocrine tumors (NETs). Reducing treatment-related costs, such as the number of images, could improve access to 177-LuDOTATE. We evaluated early radiological tumor progression and prognostic factors in patients with NETs treated with 177-LuDOTATE. We retrospectively included all patients with NETs who received at least one cycle of 177-LuDOTATE. The primary endpoint was the rate of early radiological progression between cycles 2 and 3 (in 10-16 weeks). Secondary endpoints were progression-free survival (PFS) and overall survival (OS) according to prognostic factors (tumor grade, primary site, functioning syndrome, 177-LuDOTATE treatment line) in Cox proportional hazards models. The median number of 177-LuDOTATE cycles was 3 (range 1-6) among 59 patients included. Ten (17%) patients had early progression. Among 14 patients who received ≤2 cycles of 177-LuDOTATE, ten (72%) stopped treatment due to disease progression, with five patients having a G2 (ki67: 5-25%) and 4, a G3 (ki67: 25-90%) NET. In the Cox multivariable analysis, higher grade (G2 or G3 vs G1) were significantly associated with inferior PFS and OS. The median PFS of G1, G2 and G3 NET patients were: 34.1, 11.7 and 6.1 months (P = 0.015), respectively. It is feasible to perform imaging tests after 177-LuDOTATE completion for patients with indolent NETs with the intent to avoid futile assessments. For patients with more aggressive diseases, such as G3 NETs and G2 tumors with high tumor burden, we advise to perform more frequent images during 177-LuDOTATE therapy.

Long-term experience with octreotide and lanreotide for the treatment of gastroenteropancreatic neuroendocrine tumors.

The somatostatin analogs (SSA) octreotide and lanreotide are a mainstay in the treatment of neuroendocrine tumors (NET). The two pivotal trials differed considerably in terms of patient characteristics and are not directly comparable. Further comparative data are lacking. This retrospective chart review study included patients with gastroenteropancreatic NET grade 1 or 2 who were treated with octreotide LAR or lanreotide autogel. The main aim was to compare the two SSA based on progression-free survival (PFS) and overall survival (OS) from treatment start. In total, 129 patients were analyzed, 60% (n = 77) had a small intestinal NET and 31% (n = 40) a pancreatic NET. Histologically, 34% (n = 44) had NET G1, 55% (n = 71) a NET G2, and 11% (n = 14) a NET G1/G2 unclassified. Lanreotide was used in 90 patients (70%) and octreotide in 39 patients (30%). Overall, the median PFS was 32.2months (95%CI 23.0-42.9months). No PFS difference (p = 0.8) was observed between lanreotide (29.8months, 95%CI 18.7-48.5months) and octreotide (36.0months, 95%CI 23.2-68.2months). Median OS from treatment start was calculated at 93.5months (95%CI 71.1-132.9months). Again, the median OS following lanreotide (113.4months, 95%CI 62.3-NA months) or after octreotide (90.3months, 95%CI 71.1-NA months) did not differ significantly (p > 0.9). Our long-term experience with octreotide and lanreotide in NET did not reveal differences in antitumor effectiveness. This is consistent with previous reports and might suggest that both SSA can be used interchangeably if needed.

Incidence and survival of patients with malignant pancreatic neuroendocrine neoplasms in Germany, 2009–2021

BackgroundDue to the rarity of pancreatic neuroendocrine neoplasms, only few population-representative studies on incidence and survival have been conducted. The aim was to provide up-to-date nationwide incidence and relative survival estimates of neuroendocrine (NE) neoplasms overall, NE tumors (NETs), NE carcinomas (NECs), and mixed NE neoplasms (MiNEN). MethodsWe distinguished between pancreatic NETs (functioning versus non-functioning), NECs and mixed NE neoplasms and analyzed data from 2009 through 2021 from all German cancer registries covering a population of more than 80 million. We calculated crude and age-standardized incidence rates and 5-year relative survival estimates (RS). ResultsOverall 6474, 4217, and 243 patients with pancreatic NETs, NECs, and mixed NE neoplasms, respectively were registered. While the age-standardized incidence of NETs has increased (+16.4 % per year, 95 %CI 12.2;20.7), the incidence of NEC has fallen (about −6.4 % per year, 95 %CI −8.0; −4.8). The crude RS was 77.7 % (standard error [SE] 0.9) for non-functioning NETs, 90.3 % for functioning NETs (SE 3.9), and 18.5 % (SE 3.9) for MiNEN. Large and small cell NECs had a low RS (9.1 % and 6.9 %, respectively). RS for G1 NETs was 88.2 %, while it was only 36.6 % for G3 NETs. Localized NETs had a RS of 92.8 %, while distant metastatic NETs had a RS of 45.0 %. ConclusionsThe incidence of pancreatic NETs has increased markedly in Germany in the period 2009–2021. Subgroups of NETs (G1 grading or localized stage) have an excellent prognosis. RS of MiNEN is more similar to NECs than NETs.

Mixed hepatocellular carcinoma and high-grade neuroendocrine neoplasm with ambiguous histopathological features: a case report.

Well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC) are distinct entities with different biological behavior. However, difficult cases showing equivocal morphology have been reported in some organs. Herein, we report a case of primary hepatic neuroendocrine neoplasm (NEN) with ambiguous histopathological features admixed with conventional hepatocellular carcinoma (HCC). A 70-year-old man with untreated chronic hepatitis B underwent left medial sectionectomy because of two incidental liver masses. On pathological examination, one of the resected tumors had intermingling NEN and HCC components. The NEN component consisted of relatively uniform tumor cells proliferating in trabecular, cord-like, or solid patterns with peripheral nuclear palisading. The tumor cells were immunopositive for synaptophysin, chromogranin A, cluster of differentiation 56 (CD56), and focally hepatocyte paraffin 1. p53 showed wild-type expression. The Ki-67 labeling index was 27% at the hot spot. Eleven months after the surgery, he died of a cerebral hemorrhage without evidence of recurrent liver cancer. The intermediate degree of differentiation and the modest proliferative activity can challenge the distinction between NEC and NET G3. While the coexisting HCC indicates NEC rather than NET in a pathogenetic viewpoint, such ambiguous tumor may not be as aggressive as typical NECs.

Lateral pelvic lymph nodes dissection of rectal neuroendocrine neoplasms: A prospective case-series and literature review

BackgroundRectal neuroendocrine neoplasms are relatively rare. Patients with rectal neuroendocrine neoplasms undergoing radical surgery have a higher rate of lymph node metastases. Robust evidence on the status of lateral pelvic lymph node metastases and the role of lateral pelvic lymph node dissection in those patients is lacking. This case-series study aimed to explore and address these issues. MethodsThis single-center, prospective case series consecutively enrolled patients with biopsy-proven rectal neuroendocrine neoplasms in a tertiary referral hospital between June 2022 and January 2024. All eligible patients underwent laparoscopic total mesorectal excision surgery and bilateral lateral pelvic lymph node dissection under general anesthesia. The clinicopathologic features, surgical outcomes, and postoperative complications were presented. The last follow-up was conducted in March 2024. ResultsA total of 11 patients with rectal neuroendocrine neoplasms—3 female and 8 male—were enrolled. The average age was 60.0 years (range, 53.5–65.5 years), and the median tumor size was 2.0 cm (range, 1.6–2.5 cm). Tumors invaded the muscularis propria in 7 patients. There were 3 cases of neuroendocrine tumor G1, 6 cases of neuroendocrine tumor G2, and 2 cases of neuroendocrine carcinoma. Among these patients, 11 (100.0%) had lymph node metastases, and 6 (54.5%) had lateral pelvic lymph node metastases. In addition, in 2 patients, only lateral pelvic lymph node metastases were observed, without involvement of the mesenteric lymph nodes. Five patients had tumors located on the left wall of the rectum, and only left-sided lateral pelvic lymph node metastases were observed. The other patient had both sides of lateral pelvic lymph node metastases due to circumferential growth of the tumor around the rectum. Anal preservation was achieved in all patients. The median operating time was 235.0 minutes (range, 210.5–335.5 minutes), and the median estimated blood loss was 50.0 mL (range, 45.0–75.0 mL). Two patients experienced postoperative dysuria and recovered spontaneously within 2–4 months after surgery. ConclusionOn the basis of a prospective case series, we demonstrate, for the first time, the lateral pelvic lymph node metastasis status in patients with rectal neuroendocrine neoplasms requiring radical total mesorectal excision surgery. Simultaneous bilateral lateral pelvic lymph node dissection may be a feasible and beneficial procedure for preventing local recurrence in these patients due to the lack of definitive neoadjuvant or adjuvant therapy options.

Nivolumab plus platinum-doublet chemotherapy in treatment-naive patients with advanced grade 3 Neuroendocrine Neoplasms of gastroenteropancreatic or unknown origin: The multicenter phase 2 NICE-NEC trial (GETNE-T1913)

The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m2/d iv on days 1–3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H0 50%, H1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.

NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms.

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

Laryngeal Neuroendocrine Neoplasms: Analysis of 11 Cases in a Single-Center Study.

Objective: Laryngeal neuroendocrine neoplasms (LNEN) are rare, and there have been previous uncertainties regarding their classification and treatment modalities. This article aims to share our treatment experience, elucidate changes in LNEN classification, and discuss the treatment implications of different types and stages. Methods: A retrospective analysis was conducted on 11 cases of LNEN treated through surgical intervention at the Department of Otolaryngology, Qilu Hospital of Shandong University, Qingdao, from January 2014 to November 2023. Among the 11 cases, there were 9 males and 2 females, with ages ranging from 61 to 77 years. Pathological classifications included neuroendocrine tumors (NET) G1 (1 case), G2 (2 cases), G3 (5 cases), small-cell neuroendocrine carcinoma (2 cases), and large-cell neuroendocrine carcinoma (1 case). The follow-up period ranged from 1 to 115 months. Results: Treatment modalities varied among the cases: 5 patients underwent transoral laser microsurgery (TLM) without neck dissection, 1 patient underwent TLM with unilateral neck lymph node dissection, 1 patient underwent open partial supraglottic laryngectomy (OPSL) with ipsilateral neck lymph node dissection, and 4 patients underwent OPSL with bilateral neck lymph node dissection. Among the 11 patients, 4 died, with 2 succumbing to distant metastasis, 1 to local recurrence, and 1 to other diseases. Conclusion: The prognosis of LNEN is closely associated with the latest pathological classification and TNM staging. For a more detailed and specific clinical staging, further research involving multicenter large-scale data is needed.

Rare Nasopharyngeal Neuroendocrine Tumor in a 26-Year-Old Female: Case Report and Literature Review.

Neuroendocrine neoplasms (NENs) represent a collection of highly varied tumors that originate from neuroendocrine cells. They are considered rare tumors that predominantly affect the lungs. Epithelial NENs can be categorized into neuroendocrine tumors (NETs) and neuroendocrine carcinomas. It is extremely rare for NET grade 1 (NET G1) to exist in the nasopharynx, these tumors are slow-growing and the onset of symptoms and identification of the tumor may take several years. The majority of cases occur in ages between 60 and 65 years. In this article, we present a case of a 26-year-old female who presented with recurrent epistaxis and nasal obstruction for one and a half years. Magnetic resonance imaging revealed a substantial nasopharyngeal mass. Subsequently, a biopsy was conducted, and the histopathological results indicated a NET G1. Our literature review revealed 5 cases of NET G1 in the nasopharynx, with our patient being the youngest among all published cases.

Clinicopathological Findings and Treatment Outcomes of Patients with Primary Hepatobiliary Neuroendocrine Neoplasms: A Retrospective Single-institution Analysis.

Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.

Digital image analysis of Ki67 hotspot detection and index counting in gastroenteropancreatic neuroendocrine neoplasms

The Ki-67 proliferative index plays a pivotal role in the subclassification of neuroendocrine neoplasm (NEN) according to the WHO Classification of Digestive System Tumors (5th edition), which designates neuroendocrine tumor (NET) grades 1, 2, and 3 for Ki-67 proliferative index of <3 %, 3–20 %, and >20 %, respectively. Proliferative index calculation must be performed in the hotspot, traditionally selected by visual scanning at low-power magnification. Recently, gradient map visualization has emerged as a tool for various purposes, including hotspot selection. This study includes 97 cases of gastrointestinal neuroendocrine neoplasms, with hotspots selected by bare eye and gradient map visualization (GM). Each hotspot was analyzed using three methods: eye estimation (EE), digital image analysis (DIA), and manual counting.Of the NENs studied, 91 % were NETs (26 % for G1, 55 % for G2, and 10 % for G3). Only 9 cases were neuroendocrine carcinoma (NEC). Between two hotspot selection methods, GM resulted in a higher grade in 14.77 % of cases, primarily upgrading from NET G1 to G2. Among the counting methods, DIA demonstrated substantial agreement with manual counting, both for pathologist and resident. Grading by other methods tended to result in a higher grade than MC (26.99 % with EE and 8.52 % with DIA).Given its clinical and statistical significance, this study advocates for the application of GM in hotspot selection to identify higher-grade tumors. Furthermore, DIA provides accurate grading, offering time efficiency over MC.