Mixed Neuroendocrine-non-neuroendocrine Neoplasms Research Articles

Clinicopathological features and prognostic factors associated with gastroenteropancreatic mixed neuroendocrine non-neuroendocrine neoplasms in Chinese patients.

BACKGROUNDThe incidence of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) is low. To improve our understanding of this rare tumor type and optimally guide clinical treatment, associated risk factors, clinical manifestations, and prognosis must be explored.AIMTo identify risk factors that influence the prognosis of patients with gastroenteropancreatic MiNEN (GEP-MiNEN).METHODSWe retrospectively analyzed the clinical data of 46 patients who were diagnosed with GEP-MiNEN at the First Affiliated Hospital of Bengbu Medical College (Anhui, China) between January 2013 and December 2017. Risk factors influencing the prognosis of the patients were assessed using Kaplan-Meier curves and cox regression models. We compared the results with 55 randomly selected patients with gastroenteropancreatic GEP neuroendocrine tumors, 47 with neuroendocrine carcinomas (NEC), and 58 with poorly differentiated adenocarcinoma.RESULTSAmong the 46 patients with GEP-MiNEN, thirty-five had gastric tumors, nine had intestinal tumors (four in the small intestine and five in the colon and rectum), and two had pancreatic tumors. The median age of the patients was 66 (41-84) years, and the male-to-female ratio was 2.83. Thirty-three (71.7%) patients had clinical stage III and IV cancers. Distant metastasis occurred in 14 patients, of which 13 had metastasis to the liver. The follow-up period was 11-72 mo, and the median overall survival was 30 mo. Ki-67 index ≥ 50%, high proportion of NEC, lymph node involvement, distant metastasis, and higher clinical stage were independent risk factors affecting the prognosis of patients with GEP-MiNEN. The median overall survival was shorter for patients with NEC than for those with MiNEN (14 mo vs 30 mo, P = 0.001), but did not significantly differ from those with poorly differentiated adenocarcinoma and MiNEN (30 mo vs 18 mo, P = 0.453).CONCLUSIONA poor prognosis is associated with rare, aggressive GEP-MiNEN. Ki-67 index, tumor composition, lymph node involvement, distant metastasis, and clinical stage are important factors for patient prognosis.

Neuroendocrine neoplasms of the appendix: Characterization of 335 patients referred to the Copenhagen NET Center of Excellence

IntroductionNeuroendocrine neoplasms (NEN) of the appendix are often incidentally discovered after appendectomy. Appropriate management is debated. The purpose was to characterize a cohort of 335 appendix NEN and evaluate the risk of recurrence. MethodsRetrospective collection of data from 335 patients referred to the Neuroendocrine Tumor Center at Rigshospitalet 2000–2019. Appendix goblet cell carcinoids and mixed neuroendocrine non-neuroendocrine neoplasms were excluded.Patients were followed until December 31st, 2019. No patients were lost to follow-up. ResultsSixty-three percent of the patients were female. The median (range) age at diagnosis was 34 (9–92) years. Median follow-up was 66 (1–250) months. Median tumor size was 7 (1–45) mm with 10 (3%) tumors >20 mm. In 18 specimens (5%) resection margins were positive. Mesoappendiceal invasion was found in 113 (35%). Sixty-three (19%) patients underwent right-sided completion hemicolectomy (RHC) after appendectomy according to ENETS guidelines. Among these, 11 (17%) had lymph node metastases in the resected tissue. Further, one patient who underwent initial RHC due to colonic adenocarcinoma had lymph node metastases.All lymph node metastases were detected in patients with serotonin positive tumors. No patients with glucagon positive tumors (n = 85) had lymph node metastases. Mesoappendiceal invasion >3 mm and positive resection margins were associated with presence of lymph node metastases. No recurrences were recorded. ConclusionFollowing ENETS guidelines may lead to overtreatment of patients with respect to completion RHC. The risk of over- and undertreatment needs to be further evaluated.

Neuroendocrine neoplasms of the esophagus and stomach

SummaryEsophageal neuroendocrine neoplasms (E-NENs) are much rarer than other gastro-entero-pancreatic neuroendocrine neoplasms, the majority showing aggressive behavior with early dissemination and poor prognosis. Among E-NENs, exceptionally rare well differentiated neuroendocrine tumors (E-NET) and more frequent esophageal poorly differentiated neuroendocrine carcinomas (E-NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNEN) can be recognized. E-NECs usually exhibit a small cell morphology or mixed small and large cells. Esophageal MiNEN are composed of NEC component admixed with adenocarcinoma or squamous cell carcinoma. Gastric (G) NENs encompass a wide spectrum of entities ranging from indolent G-NETs to highly aggressive G-NECs and MiNENs. Among G-NETs, ECL-cell NETs are the most common and, although composed of histamine-producing cells, are a heterogeneous group of neoplastic proliferations showing different clinical and prognostic features depending on the patient’s clinico-pathological background including the morphology of the peri-tumoral mucosa, gastrin serum levels, presence or absence of antral G-cell hyperplasia, and presence or absence of MEN1 syndrome. In general, NET associated with hypergastrinemia show a better outcome than NET not associated with hypergastrinemia. G-NECs and MiNENs are aggressive neoplasms more frequently observed in males and associated with a dismal prognosis.

Neuroendocrine neoplasms of the appendix, colon and rectum.

SummaryNeuroendocrine neoplasms of the appendix, colon and rectum are classified according to the most recent WHO classification as neuroendocrine tumors (NET), neuroendocrine carcinomas (NEC) and mixed neuroendocrine-non neuroendocrine neoplasms (MiNENs). NECs and MiNENs are aggressive neoplasms requiring multimodal treatment strategies. By contrast, NETs are, in most cases, indolent lesions occurring as incidental findings in the appendix or as polyps in the rectum. While most appendiceal and rectal NETs are considered relatively non-aggressive neoplasms, a few cases, may show a more aggressive clinical course. Unfortunately, clinical/pathological characteristics to select patients at high risk of recurrence/metastases are poorly consolidated. Diagnosis is generally easy and supported by the combination of morphology and immunohistochemistry. Differential diagnostic problems are for NECs/MiNENs with poorly differentiated adenocarcinomas, when immunohistochemical neuroendocrine markers are not obviously positive, whereas for NETs they are represented by the rare appendiceal tubular and clear cell variants (which may be confused with non-neuroendocrine cancers) and rectal L-cell tumors which may be chromogranin negative and prostatic marker positive.

Neuroendocrine carcinoma and mixed neuroendocrine‒non-neuroendocrine neoplasm of the stomach: a clinicopathological and exome sequencing study

The gene mutation profiles of gastric neuroendocrine neoplasms are incompletely understood. The purpose of this study was to characterize the molecular pathology of poorly differentiated neuroendocrine carcinoma (NEC) and mixed neuroendocrine‒non-neuroendocrine neoplasm (MiNEN) of the stomach. Surgical cases of gastric NEC (n=7) and MiNEN (n=6) were examined by clinical review, immunohistochemistry, microsatellite instability (MSI) analysis and whole-exome sequencing. NEC cases consisted of small- (n=2) and large-cell types (n=4). All cases of MiNEN were histologically composed of large-cell type NEC and tubular adenocarcinoma. Whole-exome sequencing analysis detected recurrent mutations in TP53 in 8 cases (62%), and they were more frequently observed in MiNEN than in NEC (100% vs. 29%). Frameshift mutations of APC were observed in two cases of MiNEN. One case of large-cell type NEC had a frameshift mutation with loss of heterozygosity in RB1. The other mutated genes (e.g., ARID1 and KRAS) were detected in a single case each. A high level of MSI was confirmed in one case of MiNEN, which harbored mutations in two well-differentiated neuroendocrine tumor (NET)-related genes (MEN1 and ATRX1). In cases of MiNEN, two histological components shared mutations in TP53, APC and ZNF521, whereas alterations in CTNNB1, KMT2C, PTEN and SPEN were observed in neuroendocrine components only. In conclusion, TP53 is a single, frequently mutated gene in gastric NEC and MiNEN, and alterations in other genes are less common, resembling the mutation profiles of gastric adenocarcinomas. Gene mutations frequently observed in well-differentiated NET were uncommon but not entirely exclusive.

Primary MiNEN of the urinary bladder: an hitherto undescribed entity composed of large cell neuroendocrine carcinoma and adenocarcinoma with a distinct clinical behavior

Neuroendocrine carcinomas (NECs) of the urinary bladder are very rare and can be observed in the context of mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs), most frequently in association with urothelial carcinoma. Small cell NECs are far more common than large cell NECs (LCNECs), which are exceedingly rare. We describe a primary MiNEN of the urinary bladder, composed of a LCNEC and of an adenocarcinoma, in which the neuroendocrine component reached complete pathological regression after neoadjuvant M-VAC chemotherapy, whereas the non-neuroendocrine component of the tumor progressed to metastatic disease. Compared to mixed neuroendocrine/non-neuroendocrine neoplasms described in the literature until now, this appears to be a unique case that expands the spectrum of neuroendocrine neoplasia of the urinary bladder.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) of pancreas: a rare entity

Introduction: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) comprise of both epithelial and neuroendocrine component in which each element has to comprise at least 30% of the tumor. MiNEN usually involve various gastrointestinal organs, however it is very infrequent in pancreas. Case Presentation: We encountered an 81-year-old male patient who presented with pain in upper abdomen since 3 months. He noticed jaundice with cholestatic features for last 15 days which was associated with anorexia and weight loss. Liver function test revealed: Bilirubin-3.8mg/dl; AST- 76 U/L; ALT- 163 U/L; Alkaline phosphatase- 826 IU/L, while carbohydrate antigen 19-9 was 46.9 U/ml. CECT abdomen reported a mass in the pancreatic head with dilated common bile duct and pancreatic duct. He underwent pancreatoduodenectomy (PD) with uneventful post-operative course. Histopathological examination revealed two different tumours: ductal adenocarcinoma admixed with neuroendocrine tumour of pancreas which was confirmed with immunohistochemistry (CK-7, Chromogranin and Synaptophysin positive). He received adjuvant chemotherapy and at the end of six months follow up, he has no recurrence. Conclusion: MiNEN is a rare malignancy of pancreas for which pancreatoduodenectomy was performed and diagnosis confirmed on histopathology with immunohistochemistry. It is important to share all individual experience-based information of such anecdotal cases to get knowledge about their clinical and biological behaviour and to standardize optimal therapy.

Neuroendocrine cystic carcinoma in the pancreas tail. Asymptomatic

Introduction: Pancreatic neuroendocrine neoplasms are second most common neoplasm. Incidence are fewer than 1 per 100 000 individuals per year. 2017 World Health Organisation (WHO) classification: As well-differentiated pancreatic neuroendocrine tumours (PanNETs), poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the pancreas. PanNETs are much more common than PanNECs and present typically in adults between the fifth and sixth decades and may be asyntomatic or syntomatic due to inappropriate hormone secretion. Methods: INCIDENTAL FINDING DURING MAGNETIC RESONANCE A 60-year-old male patient presented with spondylolisthesis and underwent thoracoabdominal magnetic resonance, incidentally finding lumps in the pancreas tail measuring 10X12 centimeters. Laboratory tests and tumor markers were performed in normal range, he was sent to our service. Results: Was performed tail resection of pancreas of 10X12 centimeters, in the postoperative period it presented an acid base imbalance so it is handled in Intensive Care, it evolves favorably and it is discharged from the hospital 4 weeks after the surgery. Pathology report: Tumor in pancreas tail, cystic, well differentiated neuroendocrine, with focal invasion to the capsule and free edges of lesion of low malignant potential. Conclusion:1.Pancreatic neuroendocrine tumors are usually asymptomatic and are diagnosed by incidental findings.2.The success in the postoperative evolution is that they are treated by surgeons who are experts in liver, pancreas and biliary tract surgery.

Gastric Neuroendocrine Neoplasm : WHO Classification 2019

A B S T R A C TNeuroendocrine neoplasm (NEN) of gastric is a term that includes all tumour types withneuroendocrine differentiation of gastric, well differentiated or poorly differentiatedtumour. NEN is a new term in 2019 World Health Organization (WHO) classification ofdigestive system tumours. In WHO 2019 had many updates, one of them isneuroendocrine tumours (NET) grade 3 have been included in tumour category of welldifferentiated tumour or NET. Previously, NET G3 in WHO 2010 are included as poorlydifferentiated tumour or neuroendocrine carcinoma (NEC). This neoplasm is geneticallywell differentiated and because of that, WHO 2019 classification included them as a welldifferentiated tumour. For NEC, WHO 2019 subdivided them as NEC with small cells(SCNEC) and NEC with large cells (LCNEC). In WHO 2010, mixed type neuroendocrineneoplasms with other components of carcinoma are called mixed adenoneuroendocrinecarcinoma (MANEC). But, not all of non-neuroendocrine components areadenocarcinoma and it is possible that one of the components in not carcinoma. Becauseof that, in WHO 2019 the term has been changed to mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN).

Pancreatic neuroendocrine neoplasms: Clinicopathological features and pathological staging.

The nomenclature and classification of pancreatic neuroendocrine neoplasms has evolved in the last 15 years based on the advances in knowledge of the genomics, clinical behaviour and response to therapies. The current 2019 World Health Organization classification of pancreatic neuroendocrine neoplasms categorises them into three groups; pancreatic neuroendocrine tumours (PanNETs)(grade 1 grade 2, grade 3), pancreatic neuroendocrine carcinomas and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) based on the mitotic rate, Ki-67 index, morphological differentiation and/or co-existing tissue subtype. PanNETs are also classified into non-functional NET, insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, ACTH-producing NET and serotonin producing NET based on hormone production and clinical manifestations. A portion of the cases were associated with genetic syndromes such as multiple neuroendocrine neoplasia 1 (MEN 1), neurofibromatosis and Von Hippel-Lindau syndrome. In view of the distinctive pathology and clinical behaviour of PanNENs, the current 8th AJCC/UICC staging system has separated prognostic staging grouping for PanNETs from the pancreatic neuroendocrine carcinomas or MiNENs. Pancreatic neuroendocrine carcinomas and MiNENs are staged according to the prognostic stage grouping for exocrine pancreatic carcinoma. The new stage grouping of PanNETs was validated to have survival curves separated between different prognostic groups. This refined histological and staging would lead to appropriate selections of treatment strategies for the patients with pancreatic neuroendocrine neoplasms.

The clinical profiles, management, and prognostic factors of biliary mixed neuroendocrine nonneuroendocrine neoplasms: A systematic review of the literature.

Background:Mixed neuroendocrine nonneuroendocrine neoplasms (MiNENs) originating from the biliary system (gallbladder, biliary tract, or ampulla of Vater) are extremely rare and have not been discussed in detail or systematically. We aimed to present the demographics, clinicopathological characteristics, management, and prognostic factors of biliary MiNENs.Methods:A systematic search of electronic biomedical databases (Web of Science, PUBMED, and Embase) was performed to identify eligible studies. Survival was analyzed with the Kaplan–Meier method. Log-rank tests were used to evaluate the differences between groups, and the effects of various clinical and histopathological features on prognosis were analyzed by univariate and multivariate Cox regression.Results:Fifty-three publications (patients, n = 67) were included. The median overall survival time was 21.0 months. Fifty-one patients (76.1%) underwent radical surgery and median survival for 41 months (P < .001). Twenty-two patients who received adjuvant radiochemotherapy treatment after radical surgery had a median survival for 43 months (P = .076). Radical resection (P < .001), Ki-67 index (P = .011), tumor stage (P < .001), neuroendocrine (NEC) grade (P = .011), and non-NEC grade (P = .017) were independent statistically significant prognostic factors according to univariate analysis; radical resection (P = .010) and small morphological subtype (P = .036) were independent statistically significant prognostic factors associated with higher overall survival according to multivariate analysis, and radical resection (P = .005) and age < 65 years (P = .026) were associated with higher recurrence free survival time.Conclusion:Radical resection is essential for long-term survival. Aggressive multimodality therapy with adjuvant radiochemotherapy and biotherapy may improve survival of biliary MiNENs. Further randomized controlled trials are needed to determine the standard treatment.

Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas

Background/objectivesMixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) of the pancreas and periampullary region are extremely rare and heterogeneous malignancies. Literature is sparse, clinical management is not standardized and little is known about survival outcomes. The aim of this study was to identify pathological and radiological features of MiNEN and assess the outcome of surgical management. MethodsPatients undergoing surgery for pancreatic and periampullary MiNEN between 2001 and 2019 were retrospectively analysed based on a prospective database. Histological, radiological and clinical features were assessed. Survival was analysed in a nested case-control study and matched-pair analyses with pure neuroendocrine neoplasms (pNEN) and ductal adeno- or acinar cell carcinomas of the pancreas. A literature review with focus on survival after surgical resection was additionally performed. ResultsOf 13 patients with MiNEN, 5 had acinar-MiNEN and 8 adeno-MiNEN. Two of 5 (40%) acinar-MiNEN and one adeno-MiNEN patients had liver metastases. All but one adeno-MiNEN (88%) showed preoperative radiological features of pancreatic adenocarcinoma, 3 of 5 (60%) acinar-MiNEN exhibited mainly neuroendocrine features. No surgical mortality was observed. The 5-year overall survival rate in all MiNEN was 40%. Five-year survival rate was 58% in adeno-MiNEN and comparable to that of matched ductal adenocarcinomas (36%) and pNEN (48%). Five-year overall survival rate was 20% in acinar-MiNEN, compared to 39% in acinar carcinoma patients and 59% in matched pNEN patients. ConclusionsMiNEN are rare and difficult to distinguish from pure adenocarcinoma or neuroendocrine neoplasm preoperatively. Surgical resection would therefore be the treatment of choice in localized tumors.

Utility of contrast-enhanced harmonic endoscopic ultrasonography for predicting the prognosis of pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine neoplasms (PanNENs), including Grade 1 (G1) or G2 tumors, can have a poor prognosis. This study investigated the value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for predicting the prognosis of PanNENs. This single-center, retrospective study included 47 consecutive patients who underwent CH-EUS and were diagnosed with PanNEN by surgical resection or EUS-guided fine needle aspiration between December 2011 and February 2016. Patients were divided into aggressive and non-aggressive groups according to the degree of clinical malignancy. CH-EUS was assessed regarding its capacity for diagnosing aggressive PanNEN, the correspondence between contrast patterns and pathological features, and its ability to predict the prognosis of PanNEN. There were 19 cases of aggressive PanNEN and 28 cases of non-aggressive PanNEN. The aggressive group included three G1, four G2, three G3 tumors, three mixed neuroendocrine non-neuroendocrine neoplasms, and six neuroendocrine carcinomas. CH-EUS was superior to contrast-enhanced computed tomography for the diagnosis of aggressive PanNEN (P<0.001): hypo-enhancement on CH-EUS was an indicator of aggressive PanNEN, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94.7%, 100%, 100%, 96.6%, and 97.9%, respectively. Among G1/G2 PanNENs, cases with hypo-enhancement on CH-EUS had a poorer prognosis than those with hyper/iso-enhancement (P=0.0009). Assessment of 36 resected specimens showed that hypo-enhancement on CH-EUS was associated with smaller and fewer vessels and greater degree of fibrosis. Contrast-enhanced harmonic endoscopic ultrasonography may be useful for predicting the prognosis of PanNENs.

Chromosomal and molecular pathway alterations in the neuroendocrine carcinoma and adenocarcinoma components of gastric mixed neuroendocrine–nonneuroendocrine neoplasm

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive subtype of mixed neuroendocrine–nonneuroendocrine neoplasm (MiNEN) with unclear clonal origin. In this study, we analyzed high-resolution copy number (CN) profiling data using the OncoScan CNV Assay in the neuroendocrine carcinoma (NEC) and adenocarcinoma components of eight MANECs. Some common CNVs, including the gain of CCNE1 (19q12) and the loss of FAT1 (4q35.2), were frequently detected in both components; these CNVs were verified by FISH, qPCR and immunohistochemistry staining assays in samples with sufficient material. The identification of common CNVs in both components supports the likelihood of single clonal origin of morphologically heterogeneous tumor cells and suggests several novel genetic events potentially involved in the development of gastric MANEC. We also detected and validated some CNVs and alterations specific for the NEC component, such as MAPK1 loss and MAPK signaling pathway alterations, which could contribute to the neuroendocrine differentiation of gastric MANEC. In addition, we found that the NEC component presented more CNVs and greater CN loss than the adenocarcinoma component (P = 0.007 and P = 0.004, respectively); the NEC components from different cases were not clustered in the hierarchical clustering analysis, indicating the marked genetic heterogenicity of the NEC component in gastric MANEC. In summary, this study describes the cytogenetic characteristics of each component of gastric MANEC, providing some clues for further studies on the development and progression of gastric MANEC as well as providing some potential therapeutic targets.

Clinical implications of mismatch repair deficiency screening in patients with mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN)

IntroductionMixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are rare tumors, mainly encountered in the gastroenteropancreatic tract. Based on the limited available data, MiNEN is usually a highly aggressive neoplasm combining a high-grade neuroendocrine and a non-neuroendocrine component, associated with a poor prognostic outlook. Deficient DNA mismatch repair (MMR) results in microsatellite instability, which is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. Little information on MMR status in MiNEN is available in published studies. Therefore, the purpose of this study was to explore the status and putative role of MMR on MiNEN. MethodsWe investigated the MMR status in 44 cases and characterized their clinicopathological features and prognoses. Immunohistochemistry was performed for four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). ResultsMean age at diagnosis was 61 years, and 75% of the patients were male. Lymph node metastases were observed in 14 (35.9%) patients. The most common tumor localizations were gastric (28 patients, 63.6%). Lack of immunohistochemical expression of MMR proteins was shown in 38.6% of cases. The common deletion rates of one or more proteins were 29.4% (5/17) for MLH1/PMS2 and 23.5% (4/17) for MLH1. Correlation between clinicopathological parameters showed that MMR deficiency was significantly associated with early TNM stage and better prognoses in patients with MiNEN. ConclusionMiNENs showed frequent losses of MMR protein expression, which contributes to the knowledge of the pathological and clinical aspects of MiNEN tumors.

Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine

Over the past 5 years, a number of notable research advances have been made in the field of neuroendocrine cancer, specifically with regard to neuroendocrine cancer of the gastrointestinal tract. The aim of this Review is to provide an update on current knowledge that has proven effective for the clinical management of patients with these tumours. For example, for the first time in the tubular gastrointestinal tract, well-differentiated high-grade (grade 3) tumours and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are defined in the WHO classification. This novel classification enables efficient identification of the most aggressive well-differentiated neuroendocrine tumours and helps in defining the degree of aggressiveness of MiNENs. The Review also discusses updates to epidemiology, cell biology (including vesicle-specific components) and the as-yet-unresolved complex genetic background that varies according to site and differentiation status. The Review summarizes novel diagnostic instruments, including molecules associated with the secretory machinery, novel radiological approaches (including pattern recognition techniques), novel PET tracers and liquid biopsy combined with DNA or RNA assays. Surgery remains the treatment mainstay; however, peptide receptor radionuclide therapy with novel radioligands and new emerging medical therapies (including vaccination and immunotherapy) are evolving and being tested in clinical trials, which are summarized and critically reviewed here.

Survival Profile and Prognostic Factors for Appendiceal Mixed Neuroendocrine Non-neuroendocrine Neoplasms: A SEER Population-Based Study.

IntroductionMixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare form of neuroendocrine neoplasms (NENs). The purpose of this study was to investigate the characteristics and survival profile of appendiceal MiNENs, with a view of providing robust clinical features of this rare disease.MethodsPatients were selected from the Surveillance, Epidemiology, and End Results database (2004–2016). The prognosis of MiNEN (n = 315) was compared with other histological subtypes including neuroendocrine tumor (NETs) (n = 1734), neuroendocrine carcinoma (NECs) (n = 375), goblet cell carcinoid (GCC) (n = 968), signet ring cell carcinoma (n = 463), mucinous adenocarcinoma (MAC) (n = 2355), and non-mucinous adenocarcinoma (NMAC) (n = 1187) in the appendix. Age-adjusted incidence was calculated using Joinpoint regression. The Cox proportional hazards model and the Fine–Gray competing risk model were used to perform overall survival (OS) and cancer-specific mortality (CSM) analyses, respectively.ResultsThe age-adjusted incidence of MiNENs increased from 0.01/100,000 person-years in 2004 to 0.07/100,000 person-years in 2016. The 3-, 5-, and 10-year OS rates for MiNENs were 69.5, 57.4, and 43.7%, respectively, and the corresponding CSM rates were 23.1, 36.4, and 45.1%, respectively. Multivariate analysis revealed that the prognosis of MiNENs was worse than that of NETs, NECs, GCC, and MAC but better than that of NMAC and signet ring cell carcinoma. Tumor extension was the only independent factor influencing the prognosis of MiNENs, but tumor size, grade, and surgical approaches were not. Moreover, when compared with local excision or appendectomy, extensive surgery such as hemicolectomy or colectomy did not prolong the survival of individuals with MiNENs.ConclusionMiNEN is a rare but aggressive tumor with a poor prognosis differing from NENs, GCC and adenocarcinomas. To improve the prognosis of the disease, early diagnosis and comprehensive evaluation are necessary.

A case of primary hepatic mixed neuroendocrine-non-neuroendocrine tumor (MiNEN) associated with gallbladder carcinosarcoma

A woman in her seventies visited our hospital because of abdominal pain. Multiple hepatic tumors were detected and a liver biopsy revealed mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), which was composed of cholangiocellular carcinoma and neuroendocrine tumor (NET). Diagnostic imaging ruled out primary malignancies other than the liver and identified that the tumor originated from the liver. Because a predominant and aggressive part of the tumor was considered to be cholangiocellular carcinoma, gemcitabine and S-1 were used as first-line treatment. After the treatment, octreotide acetate was administered for the NET component, followed by transcatheter arterial embolization. Subsequently, her gallbladder (GB) rapidly swelled with biliary tract obstruction, and cholecystectomy revealed carcinosarcoma of the GB. She is still undergoing treatment at 44months after diagnosis. Herein we report this case of primary hepatic MiNEN consisting of cholangiocarcinoma and NET, followed by GB carcinosarcoma. This is the first case illustrating that a multidisciplinary treatment approach for MiNEN accompanied with carcinosarcoma, involving assessment and treatment targeting the most aggressive component, can result in a long survival time.

Does Mixed Neuroendocrine-Nonneuroendocrine Neoplasm (MiNEN) of the Parathyroid Gland Exist? First Description of a Possible Case

We describe the histological, histochemical, and immunohistochemical features of an unusual neoplasm of the parathyroid gland showing the histologic criteria of a mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN). To the best of our knowledge, this is the first report of such a tumor. A 43-year old male presented with acute and severe abdominal pain due to acute pancreatitis. On physical examination a painless lump in the right neck was detected and laboratory analyses revealed hyperparathyroidism (parathormone: 146 pmol/L, normal range 1.05–6.83) and hypercalcemia (calcium level: 3.02 mg/dL, normal range 2.25–2.5), which fell to 2.55 mg/dL after parathyroidectomy. Histologically, the tumor was a parathyroid carcinoma associated with a mucous secreting adenocarcinoma also confirmed by histochemical (Alcian blue—periodic acid Schiff) and immunohistochemical stainings. The present case expands the spectrum of MiNENs that can be found in endocrine organs.

Rectal neuroendocrine carcinoma: case report of a rare entity and perspective review of promising agents.

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.