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Rectal neuroendocrine carcinomas (rNECs) are poorly characterized and, given their aggressive nature, optimal management is not well-established. We therefore sought to describe clinicopathologic traits, treatment details, and survival patterns for patients with rNECs. Patients captured in the National Cancer Database (NCDB; 2004–2016) with rNECs managed with observation, chemotherapy, or proctectomy ± chemotherapy were considered for analysis. The inclusion criteria were met by 777 patients. Mean age was 62.4 years, 45% were male, 80% were Caucasian, 40% presented with lymph nodes metastases, and 49% presented with distant metastases. Chemotherapy and surgical resection were administered in 72 and 19% of cases, respectively. Median overall survival (OS) was 0.83 years (1 year, 41%; 3 years, 13%; 5 years, 10%). During the study interval, 659 (85%) patients died, with a median follow-up of 0.79 years. On multivariable analysis, age ≥60 years, male sex, and distant metastases were associated with worse survival; surgical resection and administration of chemotherapy were associated with a reduced risk of death. Among non-metastatic patients treated with surgical resection, administration of chemotherapy was protective, while a positive lymph node ratio (LNR) ≥42% (median value) was associated with an increased risk of death. There was no difference in the number of examined lymph nodes between LNR cohorts. Patients with rNECs experience dismal survival outcomes, including those with non-metastatic disease treated with curative-intent surgical resection. Neoadjuvant therapy can serve as a useful biologic test, and surgical resection should be judiciously employed.

Neuroendocrine neoplasms of the breast (Br-NENs) are rare tumors of the mammary gland. Their definition and classification have been a matter of discussion for more than half a century, as they present some degree of overlap with other malignancies in the mammary gland. The recent evolutions in the understanding of the pathogenesis of neuroendocrine neoplasms (NENs) as well as the novel tools in the diagnostic arsenal of the pathologists, and a better correlation with clinical data, have led to improved classification schemes for these entities, beginning from those arising in digestive and thoracic organs. These new classification concepts have been recently expanded to NENs arising in every anatomical site, with the proposal of a common classification framework that has been applied in the 5th edition of the WHO classification of tumors. These concepts include the recognition of two distinct families of NENs (neuroendocrine tumors, NETs, and neuroendocrine carcinomas, NECs), the identification of mixed neuroendocrine/non-neuroendocrine neoplasms, and the application of definite morphological and immunohistochemical criteria for the diagnosis of NENs. The last WHO classification of Br-NENs, however, still seems to leave several unanswered questions and unmet needs in the understanding of diagnostic and clinical features of these entities. This review will critically revise the current classification of Br-NENs, underlining its lights and shadows and focusing on the identification of diagnostic histopathological criteria that can help the univocal recognition of Br-NET, Br-NEC, and Br-MiNEN.

Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous malignancies, arising from the neuroendocrine system. These neoplasms are divided into two distinct groups, the low-proliferating, well-differentiated neuroendocrine tumors (NETs), and the highly-proliferating, poorly-differentiated neuroendocrine carcinomas (NECs). Recent data demonstrate that the incidence of gastroenteropancreatic (GEP) neuroendocrine neoplasms, GEP-NETs and GEP-NECs, has increased exponentially over the last three decades. Although surgical resection is considered the best treatment modality, patients with GEP-NETs often present with advanced disease at diagnosis associated with a 5-year survival rate of 57% for well-differentiated tumors, and only 5.2% for small-cell tumors. Immunotherapy is a novel treatment approach, which has demonstrated effective and promising therapeutic results against several types of cancers. In the present study, we review the current ongoing clinical trials and to evaluate the efficacy of immunotherapy in GEP-NENs. Furthermore, we analyze the importance of tumor genetic profiling and its clinical implications in immunotherapy response.

Endometrial neuroendocrine carcinoma is a rare disease with unknown clinicopathological and molecular characteristics. Therefore, we conducted the present study to elucidate the clinicopathological and molecular characteristics of endometrial neuroendocrine carcinoma, as compared to conventional endometrial carcinoma, and to determine the origin of the former. We analyzed 22 endometrial neuroendocrine carcinomas and 22 conventional endometrial neoplasia cases with respect to clinical, histological and genetic features. Of these, 21/22 neuroendocrine carcinoma cases were admixed carcinomas, with 15 admixed with endometrioid adenocarcinoma. Genetic analysis of hotspot mutations in 50 cancer-related genes revealed that the neuroendocrine carcinoma group carried mutations in PIK3CA (12/22 cases; 54%) and PTEN (8/22 cases; 36%), commonly encountered in endometrioid adenocarcinoma. Comparative statistical analysis of neuroendocrine carcinoma and conventional endometrial neoplasia cases showed a significant trend only in PIK3CA mutation. Moreover, in six mixed-type neuroendocrine carcinoma cases, macrodissection was used to separate the neuroendocrine carcinoma and endometrioid adenocarcinoma components for next-generation sequencing, which revealed several mutations common among the two. These findings suggest that endometrial neuroendocrine carcinoma could originate from conventional endometrial neoplasia, especially endometrioid adenocarcinoma.

Purpose of review Neuroendocrine neoplasms (NENs) are rare and heterogeneous malignancies whose natural evolution may be defined according to various prognostic factors, including localization of the primitive tumour, hormone secretory status, histological grade, tumour burden, tumour growth rate, expression of somatostatin receptors and fluorodeoxyglucose-avidity. The treatment of these tumours in an advanced setting is based on relatively little robust data. Recent findings A recent pathological classification introduced a new category of high-grade but well differentiated neuroendocrine tumours (NET G3), with markedly different behaviour from neuroendocrine carcinomas (NECs). Yet, the optimal treatment of those tumours is still uncertain. Advances are needed in molecular subtyping of NENs to understand better their heterogeneity and inform personalized therapies. Summary The current review summarizes the current knowledge, indicates some exciting future directions and outlines the most interesting ongoing clinical trials likely to impact current practice.

Aims To gather the best available evidence regarding Ki-67% values in large-cell neuroendocrine carcinoma (LCNEC) and determine whether certain cut-off values could serve as a prognostic feature in LCNEC. Methods and results Aperio ScanScope AT Turbo, eSlide Manager and ImageScope software (Leica Biosystems) were used to measure Ki-67% in 77 resected LCNEC diagnosed by World Health Organisation (WHO) criteria. Cases were stratified into six classes by 10% Ki-67 increments. Using the Kaplan-Meier method, overall (OS) and disease-free survivals (DFS) were compared by AJCC stage, by six Ki-67% classes and with Ki-67% cut-points ≥20% and ≥40%. Tumours were from 0.9 to 11.5 cm and pathological stages 1-3. The system measured Ki-67% positivity using 4072-44 533 tumour nuclei per case (mean 16610 ± 8039). Ki-67% ranged from 1 to 64% (mean = 26%; median = 26%). Only 16 (21%) tumours had Ki-67% ≥40%. OS ranged from 1 to 298 months (median follow-up = 25 months). DFS ranged from 1 to 276 months (median follow-up = 9 months). OS and DFS differed across AJCC stage (overall log-rank P = 0.038 and P = 0.037). However, neither OS nor DFS significantly correlated with Ki-67% when six or two classes were used with either ≥20% Ki-67 or ≥40% Ki-67 as cut-point. A literature review identified 14 reports meeting our inclusion criteria with ≥10 LCNEC. Reported Ki-67% ranged from 2% to 100%. Problems contributing to variability in Ki-67% measurements are discussed. Conclusion Our findings caution against a blanket use of 20%, 40% or other Ki-67% cut-points for LCNEC diagnosis or prognostication.

Background Gastric neuroendocrine carcinomas (NECs), consisting of both large- and small-cell NECs, and mixed adenoneuroendocrine carcinomas (MANECs), including mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), are a group of high-grade malignancies. Few studies to date have reported clinical outcomes, including prognosis, in patients with these tumors. This study therefore evaluated the clinicopathologic outcomes and prognosis in patients with NECs and MANECs. Methods This study included 36 patients diagnosed with gastric NECs, including 23 with large-cell and 13 with small-cell NECs, and 85 with MiNENs, including 70 with high-grade and 15 with intermediate-grade MiNENs. Clinical outcomes, including overall survival (OS) and disease-free survival (DFS), were assessed. Results DFS was significantly poorer in patients with NEC than in patients with intermediate-grade MiNEN ( P < .05), whereas both OS and DFS were similar in patients with NEC and high-grade MiNEN ( P > .05). Patients with large-cell NEC were more likely to undergo aggressive surgery than patients with high-grade MiNEN ( P < .05). Lymphovascular invasion was more frequent and DFS poorer in patients with large-cell than small-cell NECs ( P < .05 each). Conclusion DFS is significantly poorer in patients with NEC than in patients with intermediate-grade MiNEN and significantly lower in patients with large-cell than small-cell NECs.

Although neuroendocrine neoplasms (NEN) were once thought to be rare and mostly "benign" diseases, they are now being redefined in light of recently discovered molecular information. NENs constitute a spectrum of variably differentiated neoplasms, ranging from well-differentiated tumors with a protracted course over many years to very aggressive neuroendocrine carcinomas. Although the majority of NEN are non-functional lesions, some of these tumors, do produce a hormonal hypersecretion syndrome. Their reappraisal has led scientist to unveil previously unknown oncogenic pathways and connections that resulted in a new category in the International Classification of Diseases (ICD-11) and a revised version of the World Health Organization Classification (WHO 2018). Complex diseases like NEN require a multidisciplinary approach that includes the perspectives of endocrinologists, medical and surgical oncologists, radiation oncologists, imaging specialists and pathologists. There are currently virtually thousands of ongoing trials evaluating the efficacy and safety of several molecular targeted therapies. The purpose of this review was to critically evaluate recent information regarding the pathogenesis, diagnosis and treatment of NEN.

The purpose of the study was to summarize the available data on etiology, diagnosis, clinical symptoms and signs as well as on various approaches to the treatment of neuroendocrine cervical tumors.Material and Methods. The relevant sources were searched in the PubMed and cochrane Library systems, and publications from 1980 to 2019 were analyzed, 53 of which were used to write this review. We also included 6 case reports from N.N. Petrov National Research Center of Oncology.Results. Neuroendocrine tumors (NETs) are extremely rare and aggressive malignancies of the female genital tract, among which NETs of the cervix are the most common. Due to the rarity of these tumors, there are currently no treatment standards based on prospective, well-planned clinical trials. For these reasons, NETs present a significant therapeutic challenge for clinicians. Case reports. Six patients ranged in age from 32 to 71 years, with a median age of 46 years, were diagnosed with large-cell neuroendocrine carcinoma (4 patients) and small-cell neuroendocrine carcinoma (2 patients). One patient with stage IIIA dropped out of the follow-up schedule. Out of 5 followed up patients, 2 patients with stage IIIA and IIB died of disease progression after 6 and 11 months, respectively. One patient with stage IB1 is in remission for 16 months. Two patients with stage IIB continue to receive primary treatment.Conclusion. Neuroendocrine carcinoma of the cervix is a rare variant of cervical cancer. The choice of treatment options is decided only by a multidisciplinary team of doctors, and further research is required.

The neuroendocrine carcinomas (NECs) of the head and neck are rare. The purpose of this article is to explore the diagnosis and treatment of NECs in the ear and larynx. We report a case of a patient with NECs found in the ear and throat simultaneously, and the relevant literatures are reviewed. It is difficult to identify which is the original site. There is no specific clinical manifestation of NECs in the ear and throat, and carcinoid syndrome is a rare situation. Surgery is still the preferred treatment for this disease. For patients with metastasis, radiotherapy and/or chemotherapy are required.

In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.

Skull-based neuroendocrine carcinomas are rare tumors with only a few case reports in literature. Here we present an unusual case of primary neuroendocrine carcinoma of the skull in 60-year-old male which was proven on surgical biopsy. The imaging features of this rare tumor along with differential diagnosis are discussed with brief review of the literature.

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumours, which can be classified into neuroendocrine tumours (NETs), neuroendocrine carcinomas (NECs) and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). To date, there is no consensus regarding the optimal therapy, which usually depends on the primary location and classification, according to morphological features of differentiation and proliferation rates. Nevertheless, multidisciplinary strategies combining medical treatments and locoregional strategies have yielded better efficacy results. Here, we report the case of a patient diagnosed with a nonfunctional rectal NECs with metastatic widespread to pelvic lymph nodes and bilateral lung metastases. The patient received three cycles of platinum-etoposide, concomitantly with palliative radiotherapy. Although CT scan after three cycles showed a significant partial response, there was an early fatal progression only 3 months after having stopped systemic therapy. As formerly described in the literature, this case highlights the aggressive behaviour of NECs, rare tumours that often present in advanced stages at diagnosis. Lately, new insights into the molecular biology of NECs have unveiled the possibility of using novel drugs, such as targeted agents or immunotherapy, in molecularly selected subgroups of patients. In this review, we discuss the current management of this rare entity and provide an overview of the most relevant molecular findings, whilst illustrating the potential value that prescreening panels can offer, searching for actionable targets (MSI/dMMR, PD-L1, BRAFv600E) to guide therapy with promising agents that could fill a void in this disease.

Acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MAcNECs) of the pancreas are extremely rare carcinomas with a significant component with acinar differentiation. To date, the clinicopathological behaviours of these neoplasms remain unclear. In this study, we evaluated the histopathological and molecular characteristics of 20 ACCs and 13 MAcNECs and compared them to a cohort of 269 well-differentiated pancreatic neuroendocrine tumours (PanNETs). Compared to PanNETs, both ACCs and MAcNECs had an advanced pT classification (p

Gallbladder neuroendocrine carcinomas are rare tumors with a prognosis poorer than that of other gallbladder carcinomas. These tumors are often detected late and are difficult to treat. We present the case of a 68-year-old woman with small-cell gallbladder neuroendocrine carcinoma. Abdominal sonography and dynamic contrast-enhanced MRI performed at different points in time showed rapid growth. Treatment with surgical resection and adjuvant chemotherapy was instituted. In view of the rapid growth of these tumors, suspicious cases should at least be considered for close follow-up with appropriate imaging studies. Keywords: Neuroendocrine carcinoma, Gallbladder, Ultrasonography, Magnetic resonance imaging, Computed tomography

Objective: We analyzed the clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas (NECs) in order to provide further guidance for the clinical treatment of small-cell lung cancer, which is a type of advanced intrapulmonary NECs. Methods: The clinical data and survival of 123 patients with advanced intra- and extra-pulmonary NECs in the Fujian Medical University Union Hospital, Fujian Province, China, between January 2013 to November 2019 were collected. We retrospectively analyzed the corresponding clinical diagnosis and treatment, and explored the relevant factors affecting the survival prognosis of patients with intra- and extra-pulmonary NECs. Results: The data of 123 patients were collected. There were 90 cases of intra-pulmonary NECS (including 81 cases of small-cell lung cancer, SCLC), 25 cases of extra-pulmonary NECs involving in the gastrointestinal tract, and 8 cases of extra-pulmonary NECs in other regions. The median overall survival (OS) of intra-pulmonary NECs was 13.53 months, of which the median OS of SCLC was 12.97 months, and the median OS of other intra-pulmonary NECs was 27.07 months. The median OS of extra-pulmonary NECs in the gastrointestinal tract was 9.42 months, and the OS of extra-pulmonary NECs in the other regions was 8.69 months. The median OS of intra-pulmonary NECs was significantly longer than that of the extra-pulmonary NECs in the gastrointestinal tract and in the other regions (P < 0.05). Multivariate analysis showed that age, liver metastasis, number of cycles of first-line chemotherapy, and chest radiotherapy were risk factors affecting OS in patients with NECs (P < 0.05). Conclusions: The survival of intra-pulmonary NECs was significantly longer than that of extra-pulmonary NECs of the gastrointestinal tract and in other regions. However, patients with advanced intra- and extra-pulmonary NECs who were older and had liver metastases had a poorer prognosis. Multi-disciplinary treatments such as multi-cycle chemotherapy and combination of chemotherapy and radiotherapy should play an important role in prolonging the survival of NECs.

Introduction In the literature, results after surgical treatment of non-colorectal non-neuroendocrine liver metastases (NCNNLM) are reported that are often inferior to those from colorectal liver metastases. The selection of patients with favorable tumor biology is currently still a matter of discussion. Materials/methods The retrospective data analysis was based on data that were collected for the multicenter study “Role of surgical treatment for non-colorectal liver metastases” in county Thuringia. Results For the study, 637 patients were included from 1995 to 2018. 5 and 10-year survival of R0 resected patients were 33% and 19%, respectively. In the multi-variate analysis of the entire group, sex, timing, disease-free interval, number of metastases, R-classification as well as lymph node status of the primary lesion showed an independent statistical influence on the 5-year survival. In the group of R0 resected patients, disease-free interval, number of metastases and lymph node status of the primary lesion influenced the 5-year survival in the multi-variate analysis. In kidney malignancies, R-classification, timing and number of liver metastases were statistically significant in the multi-variate analysis of the 5-year survival, in mamma carcinomas only the R-classification. Conclusion The Adam score identifies some risk factors which influence prognosis in most but not in all tumor entities. For kidney cancer and breast cancer it can be simplified.

Background: Colonic neuroendocrine carcinomas (co-NECs) are heterogeneous and aggressive, especially with regard to metastasis. Whether co-NECs on the right and left sides of the colon have different characteristics from colon adenocarcinoma is unknown. Methods: The co-NEC patients were selected from the 2010–2017 Surveillance, Epidemiology, and End Results Program (SEER) database. The right and left sides of the colon were separated by the splenic flexure. Coarsened exact matching (CEM) was performed to adjust for relevant factors before regression models were constructed. Results: A total of 669 pathologically diagnosed co-NEC patients with sufficient baseline data were identified from the SEER database. A total of 80.72% of the patients had co-NEC that originated from the right side of the colon, and their mean overall survival (mOS) was similar to that of the patients with left-sided co-NECs (right versus left: 22.30 m versus 22.55 m). A total of 44.84% of the patients were diagnosed with liver metastasis (46.68% right side versus 37.98% left side). In patients with liver metastasis, those with right-sided co-NECs had better survival than those with left-sided co-NECs (mOS right versus left: 15.37 m versus 9.62 m; adjusted hazard ratio (HR) = 0.69, 95% confidence interval (CI): 0.49–0.98, p = 0.035). To further investigate the survival benefits of primary site resection, we separated the patients who had liver metastasis according to the primary site and performed CEM to balance the groups (no patients underwent liver metastasis resection or intervention). The results suggested that primary surgery could benefit patients with both left- and right-sided co-NECs (adjusted HR = 0.50, 95% CI: 0.33–0.77, p = 0.001 on the right side; HR = 0.38, 95% CI: 0.16–0.89, p = 0.026 on the left side). Conclusions: Co-NECs frequently originate on the right side and commonly develop liver metastasis. Right-sided co-NECs are associated with better survival than left-sided co-NECs after liver metastasis has occurred. Primary site resection is associated with prolonged survival in co-NEC patients with liver metastasis, regardless of the side from which the co-NEC has originated.

Neuroendocrine carcinomas (Merkel cell carcinomas) of the vulva are extremely rare tumours, with very few cases reported to date. Herein, a primary neuroendocrine carcinoma (Merkel cell carcinoma) ...

Neuroendocrine carcinomas (NECs) of the urinary bladder are rare and aggressive, without an effective treatment approach. Immune checkpoint inhibitor agents targeting the interaction of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have been approved for urothelial carcinoma, but their use for small-cell carcinoma (SmCC) of the urinary bladder is unclear. Thus, we analyzed PD-1 and PD-L1 expression in NECs, particularly in SmCC of the urinary bladder. We used PD-1 antibody and two different biomarkers for PD-L1 antibodies, Ventana SP263 (Ventana Medical Systems, Inc.) and AM26531AF-N (Acris Antibodies GmbH). Among the 12 SmCC cases, 16.7% stained positive on immune cells for PD-1 and 33.0% for PD-L1. PD-L1 positivity on tumor cells was 25.0% of SmCC cases. The overall survival was shorter in PD-L1-positive patients compared with PD-L1-negative patients (15.4 months vs. 27.6 months). Large cell carcinoma (n = 1) was strongly and diffusely stained with PD-L1, and this case had the longest survival (68 months) in the group. Immune checkpoint inhibitors may be an alternative treatment option in SmCC of the urinary bladder. Furthermore, the absence of PD-L1 may be a good prognostic parameter.

Background High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. Method Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative ( 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%). Results In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. Conclusion Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria—as defined largely based on early-stage carcinoids—in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed. We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) at metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by (1) well-differentiated morphology, (2) conventional proliferation rates in other samples from same patient, (3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n = 19), and (4) median overall survival of 2.7 years, compared to

Objective We aimed to evaluate the diagnostic impact of 18F-FDG PET/CT in staging apocrine breast carcinoma (ABC) and primary breast neuroendocrine carcinoma (PBNEC) and to demonstrate possible alterations of the 18F-FDG uptake in these histopathologic subtypes. In addition, we aimed to compare 18F-FDG PET/CT findings between ABC, PBNEC and invasive ductal carcinoma (IDC). Material and methods A total of 570 patients and 585 breast lesions were retrospectively included in this study. After patients were classified into molecular subtypes according to the histopathological analysis, 18F-FDG PET/CT imaging was performed. The SUVmax findings of primary tumors obtained from 18F-FDG PET/CT were compared between the groups. Results IDC was the most prevalent breast carcinoma (77.7%, n = 446), with a low proportion of ABC (4.1%, n = 24) and PBNEC (2.4%; n = 14) diagnosed. The highest mean SUVmax was calculated in HER2 subtype of ABC and 18F-FDG uptake ratio in HER2 and TN subtypes were found statistically higher than Luminal B type of ABC (p = 0.038 and p = 0.019, respectively). Although 18F-FDG uptake in Luminal B subtype of PBNEC was higher than Luminal A subtype, difference was not statistically significant. Additionally, the axillary metastasis rate was significantly higher in the ABC group (p = 0.015). Conclusions The histopathological ABC subtype group showed different 18F-FDG uptake than the IDC group. Even if 18F-FDG uptake was lower in the PBNEC group than in the other groups, PET/CT showed and adequate performance in detecting primary tumors and metastases. The 18F-FDG PET/CT scan results may contribute to the initial staging and management of ABC and PBNEC patients.

All neuroendocrine neoplasms (NENs) are characterized by the expression of synaptophysin and chromogranin A (or B). Yet, they are not a homogeneous group of tumors. Paradigmatic for these tumors are the NENs of the gastroenteropancreatic (GEP) system. Two NEN families can be distinguished: predominantly well differentiated and low-proliferative NENs, called neuroendocrine tumors (NET), and poorly differentiated and high-proliferative NENs, called neuroendocrine carcinomas (NECs). Based on their proliferative activity, GEP NETs are further classified into G1, G2, and G3 tumors. NECs are per definition G3 carcinomas. The morphological NEN dichotomy is supported by differences in epidemiology, genetics, clinics, and prognosis, and potentially has its cause originating from different progenitor cells. Genetically, NECs are distinguished by TP53 and RB1 alterations, which are lacking in NETs and are helpful in the distinction of NETs from NECs. Comparison of the GEP NEN WHO classification with extragastroenteropancreatic NEN classifications commonly reveal differences in terminology and categorization. In addition, they lack a grading system. However, common to all NEN classifications is the recognition of two tumor families differing in histological differentiation and prognosis. This allows the construction of a uniform classification frame for all NENs.

Background: Large-cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are categorized as high-grade neuroendocrine carcinoma (HGNEC). We analyzed the efficacy of perioperative chemotherapy for HGNEC and the prognostic factors. Methods: We retrospectively reviewed the medical records of patients who underwent tumor resection and were diagnosed with HGNEC between January 2001 and December 2014. The overall survival (OS) was estimated by the Kaplan-Meier method. Propensity score matching was performed to compare the OS between the treatment groups. Multivariate analyses using a Cox proportional hazards model were performed to search for prognostic factors for HGNEC. Results: We analyzed 146 HGNEC patients (LCNEC n=92, SCLC n=54) without synchronous multiple cancers, who underwent complete resection. Seventy patients (LCNEC n=31, SCLC n=32) received perioperative chemotherapy and all of them received a platinum-based anticancer drug. Perioperative chemotherapy significantly improved the 5-year OS rates of HGNEC patients (all stages: 74.5% vs. 34.7%, P

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms with neuroendocrine phenotype. They range from well differentiated neuroendocrine tumors (NETs) to aggressive poorly differentiated neuroendocrine carcinomas (NECs). Esophageal neuroendocrine carcinomas (NECs) are rare and aggressive type of esophageal carcinoma with positive neuroendocrine immunohistochemical markers and usually involve lower esophagus. The esophageal NECs present most commonly with gastrointestinal symptoms such as dysphagia and/or abdominal discomfort. They have the potential for distant metastasis. The present case series delineate the recent classification of neuroendocrine neoplasm of esophagus. All the patients present with symptoms of dysphagia and ulcerative growth pattern with positive neuroendocrine immunohistochemical markers.

3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]

Neuroendocrine carcinomas are a spectrum of rare and highly heterogeneous malignant tumors. Neuroendocrine carcinomas mainly arise from neuroendocrine cells scattered throughout the body. They mainly occur in the lung and gastrointestinal tract. Atypical carcinoid of the larynx is a rare type of neuroendocrine carcinoma, which is easily misdiagnosed as hemangioma in appearance. We mainly feature the disease to you through the diagnosis and treatment of a case of atypical carcinoid of the larynx.

We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer 68Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard 18F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent 18F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. 68Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while18F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, 18F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to 68Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard 18F-FDG PET/CT.

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%, TP53, 24%) and distinct (SMAD4, 20%, RET, 16%, EGFR, 12%, APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.

Objective: Neuroendocrine neoplasms (NEN) are frequently located in the lung and gastroenteropancreatic (GEP) system organs. Neuroendocrine carcinoma (NEC) constitutes 5% of GEP NENs and has a very high malignancy potential. In this study, it is aimed to determine a new threshold value in addition to the 20% Ki-67 proliferation index that was specified as a threshold value for predicting survival in patients with grade (G) 3 tumors according to World Health Organization (WHO) 2010 classification. Method: Demographic, clinicopathologic features and survival rates of 34 patients diagnosed with GEP NEC between 2008-2015 in İzmir Katip Celebi University Atatürk Training and Research Hospital Medical Pathology Clinic were evaluated retrospectively. Results: Most of the 34 (76.5%) cases were male and the average age was 63.9 years. Median survival rates were 15, and 7 months in patients with Ki-67 indexes of ≤65% and >65%, respectively (p=0.232). Conclusion: Recent studies have shown heterogeneity of high-grade NENs, identified as NEC and foreseen their subdivision into biological subgroups. The researchers suggest that the NECs should be divided into two categories as patients with Ki-67 indexes of 20-55% and >55%. In our study, the most significant difference in survival rates was observed when 65% was selected as threshold value for Ki-67 index which supports the results of other studies in the literature. Since the number of our cases is limited and it is a single-center study, the findings obtained needs to be further investigated in studies with greater number of case series.

Primary lung neuroendocrine tumors (NETs) represent a rare but diverse set of neoplasms occurring with increasing frequency. Well-differentiated NETs, also known as bronchial carcinoids, are classified as either typical carcinoids or intermediate-grade atypical carcinoids and are best treated with formal anatomic lung resection with systematic lymphadenectomy. Small-cell and large-cell neuroendocrine carcinomas represent more aggressive histologies though surgical resection with adjuvant chemotherapy remains the standard approach for well-selected patients with localized disease. This chapter reviews the diagnosis and surgical management of primary lung NETs.

High-grade neuroendocrine neoplasms (HG-NENs) are clinically aggressive diseases, the classification of which has recently been redefined. They now include both poorly differentiated NENs (neuroendocrine carcinoma, NECs) and high proliferating well-differentiated NENs (called grade 3 neuroendocrine tumors, G3 NETs, in the digestive system). In the last decade, the "molecular revolution" that has affected all fields of medical oncology has also shed light in the understanding of HG NENs heterogeneity and has provided new diagnostic and therapeutic tools, useful in the management of these malignancies. Considering the kaleidoscopic aspects of HG NENs in various anatomical sites, this review systematically addresses the genomic landscape of such neoplasm throughout the more common thoracic and digestive locations, as well as it will consider other rare but not exceptional primary sites, including the skin, the head and neck, and the urogenital system. The revision of the available literature will then be oriented to understand the translational relevance of molecular data, by analyzing conceptual issues, clinicopathological correlations, and unmet needs in this field.

Considerable confusion surrounds neuroendocrine neoplasms, as terminology and understanding of their biological behavior continues to evolve. In this chapter, a series of questions and answers is presented addressing what features define neuroendocrine neoplasms; definitions of neuroendocrine tumors, neuroendocrine carcinomas, and other rarer neuroendocrine neoplasms; and how to diagnose, grade, and stage neuroendocrine neoplasms. Particular attention is paid to current concepts and updates regarding high-grade neuroendocrine tumors, mixed adenoneuroendocrine carcinomas and mixed neuroendocrine-nonneuroendocrine neoplasms, updated tumor staging criteria, and novel insights into the genomic landscape of neuroendocrine neoplasms. Finally, examination of five real-world cases walks the reader through the approach to neuroendocrine neoplasms and explores many of the concepts introduced earlier in the chapter.

Mixed hepatocellular carcinoma-neuroendocrine carcinomas (HCC-NECs)11 HCC-NECs: hepatocellular carcinoma-neuroendocrine carcinomas. are rare, and they usually carry a poor prognosis. We report a fascinating case of mixed HCC-NEC — the neuroendocrine component of the tumor was diagnosed retrospectively after discovery of the metastatic neuroendocrine carcinoma (NEC).22 NEC: neuroendocrine carcinoma. A 50-year-old man with cirrhosis underwent resection of a 2.7 cm hepatocellular carcinoma (HCC)33 HCC: hepatocellular carcinoma. at the segment II of the liver. Thirteen months after the surgery he had local recurrence in the liver that was treated with radio-embolization. Eighteen months after the initial diagnosis, he was found to have metastatic NEC in the left shoulder. Later, re-evaluation of the previously resected liver tumor revealed a small focus of tumor cells with neuroendocrine morphology within the tumor, which were negative for HepPar1 and positive for synaptophysin, whereas the majority of the tumor cells were positive for HepPar1 and negative for synaptophysin that reclassified the liver tumor as a combined type of mixed HCC-NEC tumor. Upon discovery of the metastatic NEC, the patient was treated with eight cycles of cisplatin and etoposide with a partial response. Nonetheless, his disease progressed two months after finishing chemotherapy, and he was treated with nivolumab for two cycles. In addition, he received palliative radiation to different skeletal metastases. The patient died of sepsis thirty-three months after the initial diagnosis of liver tumor. In conclusion, mixed HCC-NECs are rare and aggressive— an accurate diagnosis may require a high degree of clinical suspicion and re-evaluation of the pathological specimen, especially when one of the components is scarce. Strategic use of multiple modalities of treatment may prolong the life of patients with this type of aggressive tumor.

Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a rare tumor type, and a standard therapy for EP-NEC has not yet been established. The purpose of this research was to explore the overall survival (OS) and therapeutic effects of platinum-etoposide combination therapy in EP-NEC.This retrospective study was conducted based on the medical records from January 2010 to March 2020. Eligible patients had been pathologically diagnosed with EP-NEC.Forty-seven patients were included in the study. About 72.3% (n=34) of the patients were diagnosed with metastatic disease at the first diagnosis. The most common primary tumor site was the stomach. The median progression-free survival (PFS) of the patient group, who received the combination of platinum/etoposide, was 5.83 months (95% CI 4.46-7.20), whereas the median OS of the patients, who were found to have metastatic disease at the first diagnosis, was 13.6 months (95% CI 9.01-18.18). There was no difference in PFS and OS between patients with and without liver metastasis.The outcome of advanced EP-NECs with platinum/etoposide chemotherapy remains poor. Obviously, there is a need for new, more effective treatment options.

Large cell neuroendocrine carcinomas (LCNEC) are rare, aggressive high-grade neuroendocrine neoplasms within the neuroendocrine cell lineage spectrum. This manuscript provides a detailed review of published literature on LCNEC of gynecological origin. We performed a PubMed search for material available on gynecologic LCNEC. We analyzed 104 unique cases of gynecologic LCNECs, of which 45 were cervical primary, 45 were ovarian, 13 were uterine, and 1 was vaginal. A total of 45 cases of cervical LCNEC were identified with a median age of 36 years. Median overall survival was 16 months. We identified 45 ovarian LCNEC cases in the published literature with a median age of 54 years. Median overall survival was 8 months. 13 LCNEC cases of uterine origin were identified; 12 out of 13 were of endometrial origin and the median age was 71 years. The majority of patients presented with Stage III/IV disease (stages I–IV were 31%, 8%, 38%, and 23%, respectively). Gynecologic LCNEC is an aggressive malignancy. Our current understanding of the disease biology is very limited. Efforts are required to better understand the genomic and molecular characterizations of gynecological LCNEC. These efforts will elucidate the underlying oncogenic pathways and driver mutations as potential targets.

Primary gynecologic neuroendocrine carcinomas (gNECs) are a heterogeneous spectrum of rare and highly aggressive neoplasms, accounting for about 2% of all gynecologic malignancies, which mostly resemble the small cell lung carcinoma (SCLC). Due to the lack of standardized treatment guidelines, their management poses a noteworthy clinical challenge. Currently, cumulative data retrieved from the management of SCLC and from retrospective studies supports a multimodality strategy, based on surgery, chemotherapy, and radiotherapy. Nevertheless, the prognosis remains poor and recurrences are extremely frequent. Hence, there is an urgent need for novel treatment options and promising molecular targets. Recently, there has been an increasing interest on the potential role of immune checkpoint inhibitors, especially in the recurrent setting. However, only scant evidence exists and there is still a long road ahead. A solid collaboration between gynecologists and oncologists worldwide is required to improve the treatment of these puzzling tumors.

Background: Few data are available on programmed cell-death-protein-1–ligand-1 (PD-L1) expression on large-cell neuroendocrine carcinomas of the lung (LCNECs). We analyzed PD-L1 expression on tumor (TCs) and inflammatory cells (ICs) from LCNEC patients to assess relationships between this expression, clinical characteristics, and disease outcomes. Methods: PD-L1 expression was determined by immunohistochemistry with monoclonal antibody 22C3 in consecutive LCNEC patients managed in 17 French centers between January 2014 and December 2016. Results: After centralized review, only 68 out of 105 (64%) patients had confirmed LCNEC diagnoses. Median overall survival (OS) (95% CI) was 11 (7–16) months for all patients, 7 (5–10), 21 (10–not reached) and not reached months for metastatic, stage III and localized forms ( p = 0.0001). Respectively, 11% and 75% of the tumor samples were TC+ and IC+, and 66% had a TC–/IC+ profile. Comparing IC+ versus IC– metastatic LCNEC, the former had significantly longer progression-free survival [9 (4–13) versus 4 (1–8) months; p = 0.03], with a trend towards better median OS [12 (7–18) versus 9.5 (4–14) months; p = 0.21]. Compared to patients with TC– tumors, those with TC+ LCNECs tended to have non-significantly shorter median OS [4 (1–6.2) versus 11 (8–18) months, respectively]. Median OS was significantly shorter for patients with TC+/IC– metastatic LCNECs than those with TC–IC+ lesions (2 versus 8 months, respectively; p = 0.04). Conclusion: TC–/IC+ was the most frequent PD-L1–expression profile for LCNECs, a pattern quite specific compared with non-small-cell lung cancer and small-cell lung cancer. IC PD-L1 expression seems to have a prognostic role.

Objectives.With targeted agents, characterizing carcinomas of the gastrointestinal (GI) tract has become more important. We aim to determine the usefulness of p40 in classifying GI tract carcinomas.Methods.Seventy-five GI carcinomas including 28 squamous cell carcinomas (SCC), 2 adenosquamous carcinomas (ASCA), 21 poorly differentiated carcinomas (PDCA), and 24 adenocarcinomas (AdCA; control group) were stained for p40, p63, and CK5/6. Tumors were scored from 0 to 5 based on extent of staining and marked as positive (score >2) or negative.Results.p63 was positive in 100% of SCC/ASCA and 12.5% of AdCA. p40 was positive in 92.5% of SCC/ASCA and 4.1% of AdCA. In the PDCA subset, a panel including p63, p40, and MOC31 was the best way to accurately classify most cases.Conclusions.p63 and CK5/6 are more sensitive but less specific than p40 for SCC/ASCA in GI carcinomas. In PDCA, a panel approach including p63, CK5/6, and p40 may be best in classifying these cases.

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.

Purpose To evaluate the diagnostic value of 99mTc-HYNIC-TOC SPECT/CT in the detection of primary small cell neuroendocrine carcinomas of the nasal cavity and paranasal sinuses. Methods From September 2005 to November 2015, 19 patients (mean age 53.9 years, range 37–77; male 6, female 13) with sinonasal small cell neuroendocrine carcinoma (SNEC) underwent whole-body 99mTc-HYNIC-TOC SPECT/CT scan. Results All 19 primary lesions were detected by 99mTc-HYNIC-TOC SPECT/CT. A total of 212 metastatic lesions were identified by organ-based analysis, and the sensitivity and specificity of 99mTc-HYNIC-TOC SPECT/CT were 90.5% and 92.3%, respectively. The application of 99mTc-HYNIC-TOC SPECT/CT resulted in the detection of a higher number of lesions in 11 patients (57.9%) and in the successful alteration of the treatment in 7 patients (36.8%) compared with the morphological imaging methods. Conclusion 99mTc-HYNIC-TOC scintigraphy is an effective method for the detection of the sinonasal SNEC.

Purpose: Neuroendocrine tumors of the lung (LNETs) encompass a heterogeneous group of lesions, including tumors with no or low metastatic potential, such as typical (TCs) and atypical (ACs) carcinoids, and highly aggressive neuroendocrine carcinomas. To date, only a few biomarkers with prognostic impact have been identified in LNETs. Previous experimental studies have suggested that the cytokine CXCL12 might have a role in stratifying the outcome of lung cancer as well as LNET patients. However, the reliability of immunohistochemical (IHC) tissue expression of CXCL12 in evaluating the prognosis of resected LNETs is currently not known. Methods: Here, we subjected a cohort of 112 resected LNETs specifically enriched for ACs to IHC for CXCL12 and Ki67 using routine procedures. The clinical value of CXCL12 was assessed by applying the Cox proportional-hazards model to overall and disease-free survival rates. Results: We found that CXCL12 was expressed in 8.3 to 38% of LNETs, depending on the different diagnostic categories. Upon survival analysis, when considering the whole cohort, we found that CXCL12-positive cases exhibited shorter disease-free survival rates compared to CXCL12-negative cases. Among ACs, tumors overexpressing CXCL12 showed significantly shorter disease-free survival rates. Finally, we found that the Ki67 index in ACs was higher in the CXCL12-positive cases. Conclusion: CXCL12 immunohistochemistry may serve as a potentially useful tool to better stratify LNETs, and more specifically ACs, in clinical practice.

High-grade gastroenteropancreatic neuroendocrine neoplasms are well-differentiated neuroendocrine tumors or poorly differentiated small/large cell neuroendocrine carcinoma. Distinguishing these entities relies on different genetic backgrounds and resulting different biology. The new classification creates several problems. Almost all clinical treatment data on neuroendocrine neoplasms do not stratify between well and poorly differentiated, providing insufficient help in treatment selection. Treatment of gastroenteropancreatic neuroendocrine neoplasms should separate between well-differentiated neuroendocrine tumors and neuroendocrine carcinoma, and depends on primary tumor site, stage, proliferation rate, and clinical course. This article addresses how to diagnose and treat gastroenteropancreatic neuroendocrine neoplasms, focusing on well-differentiated neuroendocrine tumors versus neuroendocrine carcinomas.

Our aim of this research was to determine the value of SPECT/CT with 99mTc-HYNIC-TOC for evaluation of the pancreatic masses which were suspected as neuroendocrine neoplasms and follow-up of patients with pancreatic neuroendocrine neoplasms. We retrospectively analyzed 184 patients who performed 99mTc-HYNIC-TOC SPECT/CT. All the patients were divided into two groups: one for assessment of diagnostic efficiency for pancreatic suspected masses (n = 140) and another for monitoring recurrence after surgery (n = 44). The image findings acquired at 2 h postinjection were compared to final diagnoses from pathological results and clinical follow-up. Then, the correlation between ratios of tumor-to-background (TBR) and tumor grade was analyzed. In group 1, 95/140 (67.9%) patients were confirmed as neuroendocrine neoplasms including 85 neuroendocrine tumors and 10 neuroendocrine carcinomas. Patient-based analysis showed that the sensitivity, specificity and accuracy of diagnosing neuroendocrine neoplasms with SPECT/CT were 81.1, 84.4 and 82.1%. There was significant difference of TBRs among G1, G2 and G3 (F = 3.175, P = 0.048). In group 2, 22/44 (50.0%) patients occurred metastasis mainly in liver. The sensitivity, specificity and accuracy of monitoring recurrence were 87.0, 100 and 93.2%. 99mTc-HYNIC-TOC SPECT/CT is a reliable method of diagnosing and monitoring of pancreatic neuroendocrine neoplasms, especially neuroendocrine tumors.