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Histology of well and poorly differentiated aggressive neuroendocrine cancer. a-d High grade, G3, well-differentiated neuroendocrine tumor (NET) of the stomach, clinical-pathological Type 3; (a) solid-organoid structure void of necrosis, with abundant and thick hyaline stroma, composed by relatively monomorphic though highly atypical cells with evident mitoses (arrowhead), regular nuclei with evident nucleoli and abundant eosinophilic cytoplasm; at immunohistochemistry (IHC) cancer cells are strongly positive for synaptophysin (b), for the receptor subtype 2A for somatostatin (SSTR2A) with cell membrane reinforcement (c) and diffusely for Ki67 in their nuclei (d). e- i) High grade, poorly differentiated small cell carcinoma of the lung with organoid (e) and solid structure (f), evident necrosis (asterisks, f-i), few cell positive at IHC for chromogranin A (g, center of the micrograph), SSTR2A (g) and almost all cells with nuclei positive for Ki67 (i). (a, e, f) Hematoxylin and eosin; (b, c, d, g, h, i) immunoperoxidase; original magnification ×400
Source publication
The carcinoid as originally described is part of the relatively large family of neuroendocrine neoplasia found in almost every organ. Historical reasons back their current definitions. Neuroendocrine cancer is most frequently observed in the lung and the digestive tract. In the lung is defined as carcinoid (typical and atypical) for well differenti...
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Background
Neuroendocrine carcinoma (NEC) of gallbladder is a rare tumor. The clinical manifestation, treatment, and prognosis of gallbladder NEC are rarely reported.
Case presentation
Eight gallbladder NEC patients were admitted into our hospital. The major complaint was right upper quadrant pain. Two patients underwent a radical resection of gal...
Citations
... Neuroendocrine tumors are rare tumors comprising ~2% of all malignancies with the gastrointestinal tract and the lung as the most common sites. Neuroendocrine tumour express varied spectrum of proteins, shared with their normal cell counterparts at specific anatomical locations, including markers of general neuroendocrine differentiation such as chromogranin A, chromogranin B, and synaptophysin along with site-specific markers such as hormones and transcription factors [13]. In our case we found omental deposits for neuroendocrine tumour, we had thought process as these might came from pancreas so performed extensive sampling but no neuroendocrine tumour found in pancreas and the findings in omental tissue along with immunohistochemistry were suggestive of neuroendocrine tumour. ...
Cystic tumours of pancreas with malignant potential are very rare including serous cystic tumour, although mucinous cystic neoplasms of pancreas possess more frequent ability to transmute into mucinous cystadenocarcinoma. Neuroendocrine Tumors (NETs) are rare tumors comprising approximately 2% of all malignancies. The most common sites are gastrointestinal tract and the lung. Most of these tumors are well-differentiated and have an indolent course therefore an incidental finding.
... NENs have been shown to express general neuroendocrine differentiation markers (e.g., chromogranin, cytokeratin AE1/AE3, and synaptophysin) [3,4]. They additionally express hormones and transcription factors consistent with site-specific markers from where they originate [5]. The annual age-adjusted incidence of NENs is on the rise and was reported to be 6.98 per 100,000 persons in 2012 [6]. ...
Introduction
Neuroendocrine neoplasms (NENs) most commonly occur in the lungs or gastrointestinal (GI) tract and are a group of malignant neoplasms with high metastatic potential. Primary NENs of the salivary gland are extremely rare, with only 6 reported cases in the past 20 years. Diagnosis, treatment, and prognosis of these tumors are difficult due to the low incidence and lack of consensus in management guidelines. This article describes a likely case of primary neuroendocrine tumor (NET) of the submandibular gland (SMG) and summarizes the small pool of existing literature on this topic.
Case Presentation
A 54-year-old female with an unremarkable past medical history presented with a painless mass in the left submandibular region. Computed tomography (CT) scan and subsequent biopsy revealed a low-grade epithelial neoplasm with neuroendocrine features. The patient underwent surgical excision of the left SMG and final pathology confirmed a well-differentiated grade 2 (G2) NET. The patient was referred to medical oncology who recommended the following investigations: PET scan, abdominal, neck and chest CT, octreotide scan, and colonoscopy. All work-up returned negative for a primary tumor outside of the SMG. The patient was treated for a primary NET of the SMG and underwent complete neck dissection. Imaging was negative for additional neoplasms, and the patient is routinely monitored during follow-up.
Conclusions
Given its aggressive, malignant characteristic, and metastatic potential, timely and accurate management is critical to optimize patient outcomes. This rare case provides further discussion on the appropriate diagnosis and treatment of primary NENs occurring in the SMG.
... Regarding NETs, some studies supported that SATB2 expression is preferentially found in NETs of the lower GI tract, including colon, rectum, and appendix, while it is rare in NETs of the upper GI tract, pancreas, and lung [12,13,20]. On this account, SATB2 might be introduced in the immunohistochemical panel used to define the primary site of metastatic NETs, alongside TTF1 (marker of pulmonary NETs), CDX2 (marker of GI NETs), Islet 1 (Isl1), and PAX8 (markers of pancreatic NETs) [20,21]. ...
Neuroendocrine carcinoma (NEC) of the uterine cervix is less characterized than neuroendocrine neoplasms of other sites such as of the digestive system and the lung. Special AT-rich sequence-binding protein 2 (SATB2) recently emerged as a marker of well-differentiated neuroendocrine tumors of the lower gastrointestinal (GI) tract. Among NECs, SATB2 is more frequently expressed in cutaneous Merkel cell carcinoma than in NEC of other anatomical sites. In our study, we performed an immunohistochemical study of SATB2 in 16 NECs of the uterine cervix, where the expression of these markers is still undefined. SATB2 was expressed in 12/16 cervical NECs (75%), with 7/16 cases (44%) showing SATB2 positivity in ≥ 50% of cells. In 7 cervical NECs associated with a non-neuroendocrine component, the expression of SATB2 was restricted to the neuroendocrine component. SATB2 was positive in all cases that expressed CDX2 (n = 7) and TTF1 (n = 5), with no evident association with p16 and p53. Our study demonstrated that SATB2 is often expressed in NECs of the uterine cervix. This information should be taken into account when assessing the origin of a NEC.
... Key features for accurate broncho-pulmonary NENs diagnostics are characteristic organoid growth pattern (rosettes, trabeculae, ribbons, festoons, lobular nests, palisading); mitotic rate and necrosis that plays an important role in lung NENs grading and prognosis (Inzani, Petrone, & Rindi, 2017;Pelosi et al., 2017;Sugimoto et al., 2020). (see fig. 1). ...
... Also, biomarkers may help to exclude histologic mimics (poorly differentiated squamous cell carcinoma, small round cell tumor, hematologic malignancies, etc.), especially when facing with NECs. Briefly, IHC is used to characterize the aggressiveness of lung NENs by assessing the proliferation index (Ki-67), as well as NE differentiation (NE markers expression others than NSE -the best antibody panel here is Chr A, Syn, and CD56) and to find out NENs primary location (using TTF-1 and CK7) (Gkolfinopoulos et al., 2017;Inzani et al., 2017;Kriegsmann et al., 2021;Kyriakopoulos, Mayroeidi, & Alexandraki, 2018;La Rosa & Pelosi et al., 2017;Yatabe et al., 2019). ...
lung neuroendocrine neoplasms embrace rather heterogeneous and rare malignancies which are usually characterized by nonspecific, “blurred” clinical signs thus complicating correct diagnosis or seriously delays it. Pulmonary neuroendocrine neoplasms accurate diagnostics and classification need to be improved. Histological examination should be supplemented by immunohistochemical tests to verify the neuroendocrine component, assess proliferative index of tumor cells, and confirm its bronchopulmonary origin. Immunohistochemistry is especially important in case of small or crushed biopsies, which account more than 50% of all specimens in lungs neuroendocrine neoplasms. Modern classification of lung neuroendocrine neoplasms and their grading are based on morphological criteria. Immunohistochemical markers expression is quite variable in different histological subtypes of bronchopulmonary neuroendocrine neoplasms, often data are descriptive, and correlation with morphology is studied insufficiently. The aim of this study was to define any significant correlation between different immunohistochemical markers expression, necrosis, proliferative index (Ki-67 ratio), and tumor grade in broncho-pulmonary neuroendocrine neoplasms. Histological blocks of lung neuroendocrine neoplasms from 113 unique patients (36 resections and 77 biopsies (54.5% of biopsies appeared to be small or crushed) were used in this study. The sample comprised 91 male and 22 female patients; the mean age was 59.2, CI 95% (56.9–61.4) years (from 19 to 77 years). Histological examination (including neuroendocrine morphology, necrosis, and grade) was provided in all cases. Also, immunohistochemistry, using Chr A, Syn, CD56, TTF-1, CK7, and Ki-67 before chemotherapy was performed. All morphological and immunohistochemical data were assessed by two different independent pathologists without the access to patient’s clinical data. All the observations were classified based on 2021 WHO Thoracic Tumors Classification. The sample was censored. We used nonparametric statistics (Spearman’s rank correlation) for this study. In was found that Chr A expression strongly (p<0.05) correlated with immunohistochemical markers of primary lung malignancies (TTF-1 and CK7) that are mainly expressed in highly and moderately differentiated neuroendocrine neoplasms. Also, positive expression for TTF-1 and CK7 correlated with each other (p<0.01). There was a strong negative correlation (p<0.05) between Chr A staining and necrosis presence and it’s severity; between Chr A expression and tumor cells proliferation (Ki-67 ratio) (p<0.01); and between Chr A labeling and tumor grade (p<0.01). The correlation of immunohistochemical markers expression with necrosis, Ki-67 ratio and tumor grade was significant only for Chr A. All other tested options, for other markers were not statistically significant. It was defined that decrease or loss of Chr A expression reliably indicates tumors progression. Chr A expression can be used as an additional tool for grading of lung neuroendocrine neoplasms.
... Neuroendocrine neoplasms (NENs) occur at almost any anatomical site. Although they are characterized by the presence of neuroendocrine biomarkers [88], they comprise a heterogeneous group of tumors with widely differing etiologies, clinical features, morphological and genomic findings, and outcomes [10]. The 2022 WHO Classification of Endocrine and Neuroendocrine Tumors, following the WHO classification framework for NENs published in 2018 [10] as well as the 2019 WHO Classification of Digestive System Tumors [14], classifies epithelial NENs as well-differentiated (neuroendocrine tumor, NET) and poorly differentiated (neuroendocrine carcinoma, NEC). ...
In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.
... Two terminologies have been proposed within the NEN classification: the term NEC, which clearly indicates the malignant histology of a high degree and biological behavior of the tumor, and NET (neuroendocrine neoplasm), which refers to a family of well-differentiated neoplasms with the site-dependent potential for metastasis or invasion of adjacent tissues, type and degree of its advancement [1][2][3]. It should be noted that NENs are a group of relatively rare neoplasms, including heterogeneous tumors characterized by the presence of neurosecretory granules with a characteristic histology and immunological profile [1,4]. The statistical data available in the literature show that approximately 70% of the diagnosed cases of NETs concern the location of tumors in the digestive system, and the remaining 30% in the respiratory system [5,6]. ...
Simple Summary
Patients with neuroendocrine neoplasms (NETs) are a rare group of patients, 70% of which are diagnosed in the location of tumors in the digestive system, and the remaining 30% in the respiratory system. Building an appropriate therapeutic strategy in a patient with NET requires the involvement of a multidisciplinary team, which should include: oncology surgeon, clinical oncologist and radiation oncologist. One of the commonly used methods of treating lung NETs is the use of radiotherapy. However, the number of available recommendations for treatment of NET radiotherapy is negligible. This poses a significant problem for radiation oncologists when making qualification decisions for treatment with radiant energy. The aim of this article was to present the current knowledge on the use of radiotherapy in the treatment of lung NETs. In addition, we hope that the description of clinical cases in this publication will help radiation oncologists make the best, often personalized qualification decisions.
Abstract
The occurrence of neuroendocrine tumors among the diagnosed neoplasms is extremely rare and is associated with difficulties in undertaking effective therapy due to the histopathological differentiation of individual subtypes and the scarce clinical data and recommendations found in the literature. The choice of treatment largely depends not only on its type, but also on the location and production of excess hormones by the tumor itself. Common therapeutic approaches include surgical removal of the tumor, the use of chemotherapy, targeted drug therapy, peptide receptor radionuclide therapy, and the use of radiation therapy. This article reviews the current knowledge on the classification and application of radiotherapy in the treatment of lung NETs. Case reports were presented in which treatment with conventional radiotherapy, radical and palliative radiochemotherapy, as well as stereotactic fractionated radiotherapy in the treatment of typical (TC) and atypical (AT) lung carcinoids and large cell neuroendocrine carcinoma (LCNC) were used. We hope that the solutions presented in the literature will allow many radiation oncologists to make the best, often personalized decisions about the therapeutic qualifications of patients.
... From the sum of the individual items a score is obtained that ranges from 16 to 86. Based on their scores, individuals were categorized as morning (59-86), neither (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58), or evening chronotype. The selfreported duration of sleep was obtained from the answer to the question "How many hours did you usually sleep per day during the last month?". ...
... The mitotic rate and Ki67 index was obtained according to ENETS criteria [48], as previously reported [49]. Formalin-fixed paraffin-embedded tissue samples derived from biopsy or surgery of the primary tumor and/or metastases were used for immunohistochemistry analysis for chromogranin A, synaptophysin and Ki67 index [50]. After classifying the type of GEP-NET according to WHO classification [30], only patients with well-differentiated/low grade GEP-NET, graded as G1 (Ki67 index ≤ 2% and mitoses < 2) or G2 (Ki67 index 3-20% and mitoses [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] were enrolled in this study [30]. ...
Background
Chronotype is defined as a trait determining the subject circadian preference in behavioral and biological rhythms relative to external light–dark cycle. Although individual differences in chronotype have been associated with an increased risk of developing some types of cancer, no studies have been carried out in gastroenteropancreatic neuroendocrine tumors (GEP-NET).
Materials
We investigate the differences in chronotype between 109 GEP-NET and 109 healthy subjects, gender-, age-, and BMI-matched; and its correlation with tumor aggressiveness.
Results
GEP-NET patients have a lower chronotype score (p = 0.035) and a higher percentage of evening chronotype (p = 0.003) than controls. GEP-NET patients with morning chronotype had lower BMI, waist circumference, and higher percentage of MetS (p < 0.001) than evening type. Interestingly, considering the clinical pathological characteristics, patients with the presence of metastasis, grading G2, and in progressive disease presented the lower chronotype score (p = 0.004, p < 0.001, and p = 0.002; respectively) compared to other categories. Chronotype score was negatively associated with anthropometric measurements, metabolic profile, percentage of MetS, and Ki67 index (p < 0.001 for all).
Conclusions
GEP-NET patients have an unhealthy metabolic profile and present more commonly an evening chronotype. These results support the importance of including the assessment of chronotype in an adjunctive tool for the prevention of metabolic alterations and tumor aggressiveness of GEP-NET.
... Tumor grade followed WHO 2010 classification, and tumor stage was defined according to the ENETS criteria, and patients were classified with localized disease (stages I-III) or advanced d i s e a s e ( p r e s e n c e o f m e t a s t a s e s , s t a g e I V ) ( 6 0 ) . Immunohistochemistry for chromogranin A, synaptophysin, and Ki67 index was performed in all formalin-fixed paraffinembedded tissue samples from biopsy or surgery of the primary tumor and/or metastases (61). ...
Background
Obesity, mainly visceral obesity, and metabolic syndrome (MetS) are major risk factors for the development of type 2 diabetes, cardiovascular diseases, and cancer. Data analyzing the association of obesity and MetS with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are lacking. Fatty liver index (FLI) is a non-invasive tool for identifying individuals with non-alcoholic fatty liver disease (NAFLD). Visceral adiposity index (VAI) has been suggested as a gender-specific indicator of adipose dysfunction. Both indexes have been proposed as early predictors of MetS. This study aimed to investigate the association of FLI VAI as early predictors of MetS with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Methods
A cross-sectional, case–control, observational study was carried out at the ENETS Centers of Excellence Multidisciplinary Group for Neuroendocrine Tumors, University “Federico II”. VAI and FLI were calculated.
Results
We enrolled 109 patients with histologically confirmed G1/G2 GEP-NET (53 M; 57.06 ± 15.96 years), as well as 109 healthy subjects, age, sex- and body mass index-matched. Forty-four GEP-NET patients were G2, of which 21 were with progressive disease, and 27 patients had metastases. GEP-NET patients had a higher value of VAI ( p < 0.001) and FLI ( p = 0.049) and higher MetS presence ( p < 0.001) compared with controls. VAI and FLI values and MetS presence were higher in G2 than in G1 patients ( p < 0.001), in patients with progressive disease, and in metastatic vs non-metastatic patients ( p < 0.001). In addition, higher values of VAI and FLI and higher MetS presence were significantly correlated with the worst clinical severity of NENs. The cut-off values for the FLI and MetS to predict high grading of GEP-NETs and the presence of metastasis were also provided.
Conclusions
This is the first study investigating an association between VAI and FLI as early predictors of MetS and GEP-NET. Our findings report that the worsening of clinicopathological characteristics in GEP-NET is associated with higher presence of MetS, NAFLD, evaluated by FLI, and visceral adiposity dysfunction, evaluated by VAI. Addressing the clinical evaluation of MetS presence, NAFLD, and visceral adiposity dysfunction might be of crucial relevance to establish targeted preventive and treatment interventions of NEN-related metabolic comorbidities.
... found in brain tissue (https://www.uniprot.org); ii) neuroendocrine markers including SYT13, which is reported to be overexpressed in other neuroendocrine tumors, such as those of bowel and stomach, and is known to be associated with peritoneal metastases and to be a potential target for treatment [25,26], and SYP and CHGA, used for IHC diagnosis of neuroendocrine differentiation in breast and digestive system cancers [27,28]. In addition, microenvironment analysis detected a high proportion of the "neuronal component," which confirmed the upregulation of brain markers. ...
Epithelial sinonasal cancers (SNCs) are rare diseases with overlapping morphological features and a dismal prognosis. We aimed to investigate the expression differences among the histological subtypes for discerning their molecular characteristics.
We selected 47 SNCs: (i) 21 nonkeratinizing squamous cell carcinomas (NKSCCs), (ii) 13 sinonasal neuroendocrine cancers (SNECs), and (iii) 13 sinonasal undifferentiated cancers (SNUCs). Gene expression profiling was performed by DASL (cDNA-mediated annealing, selection, extension, and ligation) microarray analysis with internal validation by quantitative RT-PCR (RT-qPCR). Relevant molecular patterns were uncovered by sparse partial-least squares discriminant analysis (sPLS-DA), microenvironment cell type (xCell), CIBERSORT, and gene set enrichment (GSEA) analyses.
The first two sPLS-DA components stratified samples by histological subtypes. xCell highlighted increased expression of immune components (CD8⁺ effector memory cells, in SNUC) and “other cells”: keratinocytes and neurons in NKSCC and SNEC, respectively. Pathway enrichment was observed in NKSCC (six gene sets, proliferation related), SNEC (one gene set, pancreatic β-cells), and SNUC (twenty gene sets, some of them immune-system related). Major neuroendocrine involvement was observed in all the SNEC samples.
Our high-throughput analysis revealed a good diagnostic ability to differentiate NKSCC, SNEC, and SNUC, but indicated that the neuroendocrine pathway, typical and pathognomonic of SNEC is also present at lower expression levels in the other two histological subtypes. The different and specific profiles may be exploited for elucidating their biology and could help to identify prognostic and therapeutic opportunities.
... Poorly differentiated grade 3 (PD G3) gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are very rare malignancies that represent only 5%-10% of all neuroendocrine neoplasms (NENs) [1,2]. These tumors are characterized by aggressive histological features such as high Ki67 index, extensive necrosis, and nuclear atypia [2]. ...
... Poorly differentiated grade 3 (PD G3) gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are very rare malignancies that represent only 5%-10% of all neuroendocrine neoplasms (NENs) [1,2]. These tumors are characterized by aggressive histological features such as high Ki67 index, extensive necrosis, and nuclear atypia [2]. At the time of diagnosis, patients are generally in poor conditions, with aggressive and diffuse disease [3,4]. ...
There is a growing need for more accurate biomarkers to facilitate the diagnosis and prognosis of patients with grade (G) 3 neuroendocrine carcinomas (NECs). In particular, the discrimination between well-differentiated neuroendocrine carcinomas (WD-NECs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) is still an unmet need. We previously showed that ⁶⁸ Gallium-( ⁶⁸ Ga-) PET/CT positivity is a prognostic factor in patients with gastroenteropancreatic (GEP) G3 NECs, correlating with a better outcome in terms of overall survival. Here, we hypothesize that ⁶⁸ Ga-PET/CT could help to discriminate between WD-NECs and PD-NECs, adding complementary information to that obtained from morphologic and biologic factors. A retrospective, single-institution study was performed on 11 patients with histologically confirmed, measurable G3 large- or small-cell GEP-NECs according to the 2017 WHO classification. The staging procedures included a ⁶⁸ Ga-PET/CT scan. Results of ⁶⁸ Ga-PET/CT were correlated in univariate analysis with loss of tissue immunohistochemical expression of DAXX/ATRX or RB1 frequently associated with WD-NECs or PD-NECs, respectively. None of the patients with positive ⁶⁸ Ga-PET/CT showed loss of RB1 expression, whereas among those ( n=6 ) with negative ⁶⁸ Ga-PET/CT, 4 showed loss of expression. A trend towards a correlation between loss of RB1 expression and negative ⁶⁸ Ga-PET/CT was observed. Our preliminary data support the hypothesis that PD-NECs carrying RB1 mutation and loss of its expression may be associated with negative ⁶⁸ Ga-PET/CT. If confirmed in a larger clinical trial, ⁶⁸ Ga-PET/CT would help in the stratification of G3 NECs.
