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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.

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.

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.

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

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.

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) ...

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

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.

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.

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.

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.

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.

ObjectiveThis review aimed to critically analyse data pertaining to the clinical presentation and treatment of neuroendocrine carcinomas of the larynx.MethodA PubMed search was performed using the term ‘neuroendocrine carcinoma’. English-language articles on neuroendocrine carcinoma of the larynx were reviewed in detail.Results and conclusionWhile many historical classifications have been proposed, in contemporary practice these tumours are sub-classified into four subtypes: carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. These tumours exhibit a wide range of biological behaviour, ranging from the extremely aggressive nature of small and large cell neuroendocrine carcinomas, which usually have a fatal prognosis, to the less aggressive course of carcinoid tumours. In small and large cell neuroendocrine carcinomas, a combination of irradiation and chemotherapy is indicated, while carcinoid and atypical carcinoid tumour management entails conservation surgery.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations that irrespective of their primary site share features of neural and endocrine differentiation including the presence of secretory granules, synaptic-like vesicles, and the ability to produce amine and/or peptide hormones. NENs encompass a wide spectrum of neoplasms ranging from well-differentiated indolent tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. Most cases arise in the digestive system and in thoracic organs, i.e., the lung and thymus. A correct diagnostic approach is crucial for the management of patients with both digestive and thoracic NENs, because their high clinical and biological heterogeneity is related to their prognosis and response to therapy. In this context, immunohistochemistry represents an indispensable diagnostic tool that pathologists need to use for the correct diagnosis and classification of such neoplasms. In addition, immunohistochemistry is also useful in identifying prognostic and theranostic markers. In the present article, the authors will review the role of immunohistochemistry in the routine workup of digestive and thoracic NENs.

Undifferentiated endometrial carcinoma is an aggressive type of uterine cancer, which is occasionally associated with a low-grade endometrioid carcinoma component. This combination is referred to as "dedifferentiated endometrioid endometrial carcinoma." Neuroendocrine expression may occur in undifferentiated endometrial carcinoma, but its significance in dedifferentiated endometrial carcinomas is unknown. To gain insight into the pathogenesis of these tumors we have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, (beta-catenin, SMARCB1, synaptophysin, chromogranin A, and CD56) and mutational status (PTEN, KRAS, PIK3CA, TP53 and POLE) of 4 dedifferentiated endometrial carcinomas with strong and diffuse neuroendocrine expression. All tumors demonstrated neuroendocrine expression in >= 70% of the cells in the undifferentiated carcinoma areas. Loss of expression of at least 1 DNA mismatch repair protein was observed in 2 cases, and p53 immunoreaction was aberrant (mutated/inactivated) in one case. All carcinomas were negative for beta-catenin and maintained nuclear SMARCB1 (INI1) and ARID expression. Three tumors shared identical endometrioid molecular profile (PTENand/orP/K3CA mutations) in both components. One tumor had POLE exonuclease domain mutation in the undifferentiated component. In one case, TP53 mutation was found exclusively in the undifferentiated component. Two patients died with peritoneal carcinomatosis and abdominal metastases, respectively; one patient died of a renal failure without evidence of disease, and the last patient is alive and free of disease at 3.3 years. Dedifferentiated endometrial carcinomas with neuroendocrine features are clinically and molecularly heterogeneous tumors. Probably, these carcinomas might acquire undifferentiated phenotype through mutations in TP53 and POLE. (C) 2017 Elsevier Inc. All rights reserved.

The prevalence of premalignant and malignant endocervical glandular lesions is increasing in both relative and absolute terms. The majority of premalignant and malignant endocervical glandular lesions are aetiologically related to HPV infection. Neuroendocrine carcinomas of the cervix are also HPV related neoplasms that have an aggressive behaviour. This review concentrates on the latest classification and terminology of cervical glandular lesions and neuroendocrine carcinomas, their morphology and differential diagnosis and includes important practice points.

Originally large cell carcinoma was defined by the absence of visible glandular or squamoid features. Due to immunohistochemistry introduced into NSCLC diagnosis, this exclusion was extended. Solid carcinomas negative for either TTF1 or p40 without visible glandular or squamoid differentiation are now large cell carcinomas. In addition, as this requires whole tumor sections, this is restricted to resection specimen. The former variants are now splitted: LCNEC into the neuroendocrine carcinomas, lymphoepithelioma-like carcinoma into a separate entity, and rhabdoid carcinomas are now no longer regarded as a separate entity, but instead rhabdoid features should be reported. Clear cell changes are seen in different carcinoma types and are therefore also reported but do not comprise an entity.

Non-ductal tumors of the pancreas are relatively rare tumors and include pancreatic neuroendocrine tumors (PanNETs), poorly differentiated neuroendocrine carcinomas, acinar cell carcinoma, solid pseudopapillary neoplasm, and pancreatoblastoma. These tumors have a morphology and biology that is distinct from that of ductal neoplasms of the pancreas. PanNETs are the most common tumors among this group. A brief summary of each tumor is described here with an emphasis on the clinical presentation, cytological features, tumor histology, and immunohistochemical profile. Differential diagnoses for each entity are also discussed.

Neuroendocrine tumors are a spectrum of rare and highly heterogeneous neoplasms with distinct functional and biological behavior in relation to location, tumor size, and histological differentiation. Neuroendocrine tumors arise from the neuroendocrine cells of the diffuse neuroendocrine system located in almost every organ. Neuroendocrine tumors in the head and neck district are usually reported in sinonasal cavities and larynx. We present the case of a nasopharyngeal small-cell neuroendocrine carcinoma, which, as far as we know, is the 16th case reported in literature.

Next-Generation Sequencing (NGS) is being utilized with increasing frequency in the characterization of salivary gland tumours. The potential scenarios which may be encountered by using this technique in routine practice will be outlined in further text by drawing from our own clinical experience. These include oncocytic mucoepidermoid carcinomas with unusual variant morphology (and negative MAML2 fluorescent in-situ hybridization results), a diagnosis of ameloblastoma changed to adenoid cystic carcinoma (due to MYBL1 fusion presence), a salivary duct carcinoma with an ETV6-NTRK3 fusion (otherwise seen in secretory carcinomas) and novel fusion partners such as EWSR1-BEND2 (otherwise seen in pancreatic neuroendocrine carcinomas). As NGS continues to develop and more widespread clinical implementation increases, we must be cognisant of the need for proper interpretation and in some cases verification using a secondary technique, the limitations of this technique, and the ethical dilemmas one faces when encountering a novel fusion.

Extra-Pulmonary NeuroEndocrine Carcinomas (EP-NECs) are aggressive tumours (Ki-67>20%, poorly differentiated morphology), with a median overall survival Citation Format: Melissa Frizziero, Elaine Kilgour, Kathryn Simpson, Kristopher Frese, Juan W. Valle, Mairéad G. McNamara, Caroline Dive. Liquid biopsy-based precision medicine for extra-pulmonary neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 601.

Neuroendocrine tumours occur most frequently in the gastrointestinal tract, lungs, and pancreas. Primary malignant cardiac tumours are uncommon and are usually sarcomas, lymphomas, or, infrequently, mesotheliomas. Primary cardiac neuroendocrine carcinomas are exceedingly rare; only nine have been reported in the literature to date. We report the tenth case of this disorder in a 44-year-old man with a well-differentiated low-grade primary cardiac neuroendocrine carcinoma treated with surgery who remains in remission more than a year later. Our case and review of the literature demonstrate that surgical treatment for well-differentiated primary cardiac neuroendocrine carcinomas can be effective.

Gastrointestinal neuroendocrine neoplasms were recently reclassified into the 2019 World Health Organization schema into well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Among these, gastric MiNENs are exceedingly rare and often metastasize quickly without diagnostic clues. We present a refractory gastric MiNEN with unique presenting features. This case highlights the clinical spectrum of these tumors, the importance of accurate histochemical interpretation, and clinical management in the absence of formalized guidelines. Future therapies looking at novel targets and palliative symptom relief are needed.

Objectives To investigate the immunoreactivity of TTF-1 and PAX8 in neuroendocrine carcinoma of thymic (TNEC) and pulmonary origins (PNEC), and whether their immunophenotyping could be used to distinguish between NEC of the two sites, as well as prognosis of patients with TNEC. Methods Twenty-two cases of TNEC and 20 cases of PNEC were selected for immunohistochemical analysis using PAX8 and TTF-1. Clinical data and follow-up information were obtained for survival analyses. Results TTF-1 immunoreactivity was seen in 19 PNEC cases (95%) and 13 TNEC cases (59.1%). PAX8 was negative in all pulmonary tumors while positive in 19 thymic cases (86.4%). TTF-1 positivity was associated with high sensitivity but low specificity for PNEC, and adding PAX8 negativity significantly increased the specificity. PAX8 positivity alone showed essentially 100% specificity and 86.4% sensitivity for TNEC. Survival analysis showed lung metastasis as a significant prognostic factor in TNEC. Conclusion Our study demonstrated that TTF-1/PAX8 immunophenotyping may be helpful for differential diagnosis of NECs of pulmonary and thymic origins. TTF-1+/PAX8− immunophenotyping showed high specificity for PNECs, while PAX8+ alone showed a good diagnostic accuracy for TNEC. Lung metastasis was a predictive factor that associated with survival of TNEC patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

Context.—Gastrointestinal (GI) and pancreatobiliary tracts contain a variety of neuroendocrine cells that constitute a diffuse endocrine system. Neuroendocrine tumors (NETs) from these organs are heterogeneous tumors with diverse clinical behaviors. Recent improvements in the understanding of NETs from the GI and pancreatobiliary tracts have led to more-refined definitions of the clinicopathologic characteristics of these tumors. Under the 2010 World Health Organization classification scheme, NETs are classified as grade (G) 1 NETs, G2 NETs, neuroendocrine carcinomas, and mixed adenoneuroendocrine carcinomas. Histologic grades are dependent on mitotic counts and the Ki-67 labeling index. Several new issues arose after implementation of the 2010 World Health Organization classification scheme, such as issues with well-differentiated NETs with G3 Ki-67 labeling index and the evaluation of mitotic counts and Ki-67 labeling. Hereditary syndromes, including multiple endocrine neoplasia type 1 syndrome, von Hippel-Lindau syndrome, neurofibromatosis 1, and tuberous sclerosis, are related to NETs of the GI and pancreatobiliary tracts. Several prognostic markers of GI and pancreatobiliary tract NETs have been introduced, but many of them require further validation.Objective.—To understand clinicopathologic characteristics of NETs from the GI and pancreatobiliary tracts.Data Sources.—PubMed (US National Library of Medicine) reports were reviewed.Conclusions.—In this review, we briefly summarize recent developments and issues related to NETs of the GI and pancreatobiliary tracts.

Primary sino-nasal neuroendocrine carcinomas (PSNNECs) are rare, with a wide spectrum of histological differentiation. Advanced tumors may invade the surrounding structures, such as the skull base, orbit, or brain. Here, we present a rare case of PSNNEC and its management by concurrent chemoradiation (CCRT) followed by adjuvant chemotherapy with the radiological resolution of the tumor mass.

Introducción y objetivo: El 95% de las neoplasias malignas de laringe son de tipo carcinoma escamoso. Los carcinomas neuroendocrinos corresponden a menos del 1% de los tumores laríngeos. La localización laríngea más frecuente es la supraglotis. El diagnóstico se basa en las características histológicas e inmunohistoquímicas. Se dividen en cuatro tipos histológicos que tienen una evolución natural y pronóstico diferentes. Descripción: Exponemos dos casos de carcinomas neuroendocrinos de la laringe. Uno de ellos pertenece a la estirpe celular de carcinoma de células pequeñas y el otro a un carcinoma de células grandes, cuyo diagnóstico histológico generó controversias. Introduction and objective: 95% of the malignant neoplasm of the larynx are squamous carcinoma. Neuroendocrine carcinomas correspond to at least 1 % of laryngeal tumors. The supraglottic is the most frequent laryngeal localization. Diagnosis is based on histological and immunohistochemically characteristic. They are divided into four histological types, which have a different natural evolution and prognosis. Description: We present two cases of laryngeal neuroendocrine carcinomas. One of them belongs to a small cell neuroendocrine carcinoma and the other one to a large cell carcinoma, which diagnosis generated controversy.

Neuroendocrine carcinomas with distant metastases are rarely reported in the literature, with cutaneous metastases being among the most infrequently reported sites. The importance of distinguishing metastatic neuroendocrine carcinoma (NEC) from primary neuroendocrine carcinoma in the skin, or Merkel cell carcinoma (MCC), has been stressed in the literature, with CK20 positivity traditionally being reported as the key diagnostic feature of MCC. Our case not only serves as one of the few reported cases of cutaneous metastases of a visceral NEC, but also serves to caution providers as to the use of CK20 positivity as an absolute diagnostic feature. We present a case of a 67-year-old female with widespread cutaneous metastases of a pancreatic NEC. Immunohistochemical staining revealed CK20 positivity, despite visceral origin of the primary tumor. This case serves to highlight not only a rare presentation of cutaneous metastases of a pancreatic neuroendocrine carcinoma, which has yet to be reported in the literature, but also serves as the only report of a pancreatic NEC with CK20 positivity, providing evidence for cautionary use of CK20 staining for diagnostic purposes, particularly for visceral NECs which have been under-represented in the literature.

Aim of the study: To determine the significance of expression of synaptophysin, chromogranin A, and Ki-67 and their association with clinicopathological parameters, and to find out the possible prognostic factors in gastric neuroendocrine carcinoma (G-NEC). Material and methods: We investigated the immunohistochemical features and prognosis of 62 G-NECs, and evaluated the association among expressions of synaptophysin, chromogranin A, and Ki-67, clinicopathological variables, and outcome. Results : Chromogranin A expression was found more commonly in small-cell NECs (9/9, 100%) than in large-cell NECs (27/53, 51%) (p = 0.008). No statistical significance was found in Ki-67 (p = 0.494) or synaptophysin (p > 0.1) expression between NEC cell types. Correlation analyses revealed that Ki-67 expression was significantly associated with mid-third disease of stomach (p = 0.005) and vascular involvement (p = 0.006), and hada trend of significant correlation with tumour relapse (p = 0.078). High expression of chromogranin A was significantly associated with histology of small-cell NECs (p = 0.008) and lesser tumour greatest dimension (p = 0.038). The prognostic significance was determined by means of Kaplan-Meier survival estimates and log-rank tests, and as a result, early TNM staging and postoperative chemotherapy were found to be correlated with longer overall survival (p < 0.05). Univariate analysis revealed associations between poor prognosis in NECs and several factors, including high TNM staging (p = 0.048), vascular involvement (p = 0.023), relapse (p = 0.004), and microscopic/macroscopic residual tumour (R1/2, p < 0.001). In a multivariate analysis, relapse was identified as the sole independent prognostic factor. Conclusions : No significant correlation between survival and expression of synaptophysin, chromogranin A, or Ki-67 has been determined in G-NECs. Our study indicated that early diagnosis, no-residual-tumour resection, and postoperative chemotherapy were possible prognostic factors.

The prognosis and management of neuroendocrine carcinoma are largely driven by histologic grade as assessed by mitotic activity. The authors reviewed their institutional experience to determine whether the histologic grade of neuroendocrine carcinoma can differ between primary and metastatic tumors.This study examined patients who underwent operative resection of both primary and metastatic foci of neuroendocrine carcinoma. Resected tumors were independently reviewed and categorized as low, intermediate, or high grade as determined by mitotic count.The authors identified 20 patients with metastatic neuroendocrine carcinoma treated at their institution between 1997 and 2013 for whom complete pathologic review of primary and metastatic tumors was possible. Primary lesions were found in the small intestine (n = 12), pancreas (n = 7), ampulla (n = 1), stomach (n = 1), and rectum (n = 1). The timing of hepatic metastasis was synchronous in 15 cases and metachronous in 5 cases. The histologic grade was concordant between primary and metastatic tumors in 9 cases and discordant in 11 cases. Among the discordant cases, 7 had a higher metastatic grade than primary grade, and 4 had a lower metastatic grade than primary grade. Metachronous presentation was associated with a higher likelihood of grade discordance (p = 0.03). The histologic grade of all metachronous metastases differed from that of the primary tumors.There is a high prevalence of histologic grade discordance between primary and metastatic foci of neuroendocrine carcinoma, particularly among patients with a metachronous metastatic presentation. Given the importance of histologic grade in disease prognostication and treatment planning, this finding may be informative for the management of patients with metastatic neuroendocrine carcinoma.

Neuroendocrine neoplasms of the sinonasal region, which are relatively uncommon but clinically very important, are reviewed here in the light of current knowledge. Using a definition for neuroendocrine based on phenotypic, histologic, immunohistochemical, and electron microscopic features rather than histogenetic criteria, sinonasal neuroendocrine carcinomas are examined with a particular emphasis on the small-cell and large-cell subtypes. This is followed by revisiting olfactory neuroblastoma because it is also a tumor that shows a neuroendocrine phenotype. Kadish clinical and Hyams histologic grading systems as prognosticators of olfactory neuroblastoma are also considered in detail. Finally, controversies regarding sinonasal undifferentiated carcinoma as a neuroendocrine tumor are discussed and a possible relationship with high-grade olfactory neuroblastoma is explored. Genetic events and current management of these tumors are also outlined. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2259-E2266, 2016.

Primary neuroendocrine carcinomas (NECs) of the larynx and head and neck are an uncommon and heterogeneous group of neoplasms categorized by the 2017 WHO Classification of Head and Neck Tumors as: (a) well-differentiated (WD-NEC), (b) moderately-differentiated (MD-NEC), and (c) poorly-differentiated (PD-NEC) with small cell and large cell types. The classification incorporates elements of differentiation and grading and closely correlates to the 5-year disease specific survival of 100, 52.8, 19.3 and 15.3% for each diagnostic category. These survival rates are based on historical data limited by the previous lack of standard pathologic diagnostic criteria. The classification has de-emphasized the use of the terms "carcinoid" and "atypical carcinoid" as diagnostic categories. The adoption of uniform pathologic criteria for the classification of NECs of the head and neck should enable the design of high quality studies in order to understand the molecular alterations of these neoplasms.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of epithelial neoplastic proliferations arising in a large number of body organs, although most cases arise in the bronchopulmonary and gastroenteropancreatic (GEP) systems. Irrespective of their primary site, neoplastic cells share features of neural and endocrine differentiation and neoplasms encompass a wide spectrum of entities, from very indolent well-differentiated neuroendocrine tumors (NETs) to highly aggressive neuroendocrine carcinomas (NECs). They represent a challenge for oncologists and pathologists and a correct diagnostic approach is crucial for the management of patients. Indeed, although the diagnosis of GEP and lung NENs is generally simple in routine practice, there are critical aspects that need to be taken into account during the diagnostic workup. The most challenging tasks include the difficulty in achieving the correct prognostic evaluation of NETs by recognizing their metastatic/aggressive potential and the identification of NECs. To this aim, a comprehensive clinical, morphological, immunohistochemical, and molecular investigation represents the most reliable tool for pathologists. The present chapter examines current approaches to the diagnosis and prognostic classification of GEP and lung NENs, focusing on the classification and the critical use of morphological parameters, immunohistochemical stainings, and molecular markers in the pathology workup.

Neuroendocrine tumors are composed by a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. These tumors are generally slow growing and behave in an indolent fashion. However, they have the potential to spread, especially for poorly differentiated neuroendocrine carcinomas, and when they do, they can be very aggressive, with high propensity for distant metastases, and difficult to treat with current modalities. As poorly differentiated neuroendocrine carcinomas rarely occur in extrapulmonary sites, to the best of our knowledge, this is the first case report of a poorly differentiated duodenal neuroendocrine carcinoma with diffuse liver and bone metastases as the primary manifestation. Despite receiving a trial of chemotherapeutic regimen, the patient had progressive intrahepatic cholestasis and died of subacute hepatic failure.

Sinonasal tumors with neuroendocrine differentiation form a group of rare heterogeneous neoplasms of neuroectodermal and epithelial origin, consisting of olfactory neuroblastomas and neuroendocrine carcinomas. Because the natural history and biological behavior of this group of tumors vary, the morphological diagnosis coupled with grading/staging is important for prognostication, and the approach to treatment and rehabilitation is multidisciplinary. The identification of molecular abnormalities underlying these tumors is critical to the development of specific targeted therapies and the design of clinical trials.

Although rare cases of PAX-8-positive primary lung carcinoma have been reported, details of staining distribution and intensity in such cases are limited. The aim of this study was to determine whether strong and diffuse PAX-8 staining can occur in primary lung carcinoma. Immunohistochemical staining for PAX-8 (Rabbit polyclonal, 10336-1-AP; Proteintech) was performed on whole-tissue sections from 418 resected primary lung carcinomas. PAX-8 was positive in 5/418 (1.2%) cases, all of which were large cell neuroendocrine carcinomas. Staining was weak to moderate in all 5 cases, and was seen in 5% to 30% of tumor cells. All other primary lung carcinomas (413/418) were negative for PAX-8. This study-the largest series of PAX-8-stained whole-tissue sections of primary lung carcinoma to date-shows that strong and diffuse staining for PAX-8 does not occur in primary lung carcinoma of any type. This staining pattern in a carcinoma in a lung specimen provides strong evidence of nonpulmonary origin.

Background: Neuroendocrine carcinomas (NECs) and mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) in the gastrointestinal (GI) tract are both rare and malignant; however, it is unclear whether their prognosis is the same. Methods: In this cross-sectional study, a total of 12,878 patients with NEC or MiNEN in the GI tract were reviewed retrospectively by searching the Surveillance, Epidemiology, and End Results ( SEER) program database. Next, we compared the characteristics and survival between patients with NEC or MiNEN and further analyzed the prognostic factors for the patients. Results: The data showed that patients with MiNEN had a worse prognosis as compared with patients with pure NEC in the small intestine (SI) and appendix, whereas there was no significant survival difference between NEC and MiNEN in the other parts of the GI system. On the whole, age ⩾55 years ( p Conclusion: The prognostic differences between NECs and MiNENs in the GI tract are heterogeneous and site-related. Patients with appendiceal or SI MiNEN have a poorer prognosis than patients with pure appendiceal or SI NEC. Therefore, we should pay more attention to patients with MiNEN in the SI and appendix and monitor them more closely.

Contains fulltext : 171125.pdf (Publisher’s version ) (Closed access) Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.

Aims To determine HER2 amplification status and HER2 overexpression status in neuroendocrine carcinomas (NECs) of the stomach. Methods and results We analysed 51 gastric NECs, including 15 pure NECs and 36 NECs associated with adenocarcinoma and/or dysplasia, for HER2 amplification by dual-colour chromogenic in-situ hybridization, and for HER2 expression by immunohistochemistry. HER2 amplification was observed in three NECs (6%) and in seven (19%) cases of adenocarcinoma/dysplasia associated with NEC. Immunohistochemically, all of the NECs, including those showing HER2 amplification, lacked HER2 expression. On the other hand, positive and equivocal HER2 overexpression was observed in three (8%) and six (17%) cases of adenocarcinoma/dysplasia associated with NEC, respectively. Conclusions HER2 expression is consistently absent in gastric NECs, regardless of HER2 amplification status or association with HER2-positive adenocarcinoma/dysplasia components. Accordingly, HER2 is unlikely to be a valid therapeutic target in gastric NECs. Also, the absence of HER2 expression in NECs could be one of the causes of intratumoral heterogeneity of HER2 expression in gastric cancers.

Neuroendocrine carcinomas of the bladder (small cell, large cell, typical and atypical carcinoids) are rare and usually co exist with urothelial carcinoma. As in small cell carcinoma of the lung, various paraneoplastic neurologic disorders can occur although they are even less frequent. Here we report the case of a 63 year old man with small cell carcinoma of the urinary bladder and with a paraneoplastic neurologic disorder. © 2013 The Authors. 2 1 8 11

Pancreatic neuroendocrine neoplasms include well-differentiated pancreatic neuroendocrine tumors (PanNETs) and neuroendocrine carcinomas (NECs) with well-differentiated PanNETs accounting for most cases. Other pancreatic primaries and metastatic carcinomas from other sites can mimic pancreatic neuroendocrine neoplasms. Immunohistochemical studies can be used to aid in the differential diagnosis. However, no specific markers are available to differentiate PanNETs from NETs of other sites. Although NECs are uniformly deadly, PanNETs have variable prognosis. Morphology alone cannot predict the tumor behavior. Although some pathologic features are associated with an aggressive course, Ki67 is the only prognostic molecular marker routinely used in clinical practice.

Introduction: Small cell neuroendocrine carcinomas (SmCCs) of the salivary glands are rare high grade malignant neoplasms, and the identification of these lesions is often difficult. Histopathological features alone are not sufficient for the diagnosis of SmCCs, and immunohistochemical (IHC) staining is almost always mandatory for confirming the diagnosis. Case Presentation: We report one salivary SmCC case in a female who presented with swelling on the left side of the face. For a distinct diagnosis, histopathological and IHC evaluation was performed. Conclusions: The presentation of these cases can be helpful for the histopathological differential diagnosis of similar tumors

Ye-ye Chen,1 Shan-qing Li,1,2 Hong-sheng Liu,1,2 Ying-zhi Qin,1 Li Li,1 Cheng Huang,1 Ya-lan Bi,3 Yun-xiao Meng,3 Jia He,1 Xiao-yun Zhou,1 Dong-jie Ma11Department of Thoracic Surgery, 2Key Laboratory of Endocrinology,3Department of Pathology,Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People’s Republic of ChinaBackground and purpose: Thymic neuroendocrine carcinomas (TNECs) are extremely uncommon. Certain cases of TNECs can produce the adrenocorticotropic hormone (ACTH) and cause ectopic ACTH syndrome (EAS). The current literature on this topic consists mainly of case reports, and therapeutic guidelines are lacking. The aim of this study was to discuss the diagnosis, surgical management, and prognosis of EAS caused by TNECs to improve clinical experience with this rare disease.Methods: From June 1984 to June 2014, at the Peking Union Medical College Hospital, the surgical interventions and follow-up outcomes of 16 consecutive patients (eight men and eight women) with EAS caused by TNECs were retrospectively analyzed.Results: The median age was 32.5years (range: 13–47years), and the median disease duration was 8.5months (range: 1–150months). All patients presented with clinical and biochemical evidence indicating a diagnosis of Cushing’s syndrome. Contrast-enhanced thoracic computed tomography scans were critical to locating the ACTH-producing tumor and evaluating the feasibility of resection. All patients underwent surgery. One patient died of septicemia in the intensive care unit 2weeks after surgery. No other morbidity or mortality occurred during the perioperative period. The median overall survival (OS) was 41months (95% CI: 30.3–51.7months), and the progression-free survival was 28months (95% CI:21.6–34.3months). Both overall survival (P=0.002) and progression-free survival (P=0.030) improved significantly after complete resection.Conclusion: TNEC is an extremely aggressive disease that should be considered when treating patients with Cushing’s syndrome due to ectopic ACTH secretion. In particular, all suspected patients should undergo contrast-enhanced thoracic computed tomography scans to facilitate early diagnosis. The current first-line treatment is surgical resection, and complete resection is a favorable prognostic factor. However, additional patients and a longer follow-up will be needed to determine the variables that are predictive of survival and to improve patient prognosis.Keywords: ACTH syndrome, ectopic, neuroendocrine tumors, thymus gland, surgical procedures