NET G1 Research Articles

HIGH-GRADE GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASMS. MODERN CLASSIFICATION, DIAGNOSTICS AND TREATMENT

Poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare malignancies, most of which are characterized by aggressiveness, a tendency to rapid metastasis and an unfavorable prognosis even when localized. In 2017 World Health Organization (WHO) updated classification of GEP NENs and recognized the category of well-differentiated pancreatic NET G3, associated with Ki‑67 index usually over 20%. The upper level of Ki‑67 is not defined. Usually it is 55%. Highgrade poorly differentiated pancreatic NENs are defined as pancreatic neuroendocrine carcinomas (panNECs). Although the NET G3 category is recognized for pancreatic neuroendocrine neoplasms only, many specialists consider it reasonable to apply this term to all well-differentiated GEP NETs with Ki‑67 index in the 20 to 55 percent range. Clinical behavior and therapeutic approaches for advanced GEP NECs and NETs G3 are different. Standard palliative chemotherapy for GEP NECs consists of cisplatin or carboplatin combined with etoposide. The second-line regimens include irinotecan-, oxaliplatin, fluoropyrimidine- and temozolomide-based regimens. Temozolomide-based chemotherapy regimens, as well as targeted therapy are more preferable as first line therapy for patients with NETs G3. The platinum-based chemotherapy regimens are considered at the time of disease progression. Further clinical studies with the inclusion of much more patients will determine the optimal treatment strategy for this category of patients.

Competitive Testing of the WHO 2010 versus the WHO 2017 Grading of Pancreatic Neuroendocrine Neoplasms: Data from a Large International Cohort Study

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell’s C statistics, and Royston’s explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

1317P - Treatment outcomes for well differentiated grade 3 neuroendocrine tumors (NET G3)

1317P - Treatment outcomes for well differentiated grade 3 neuroendocrine tumors (NET G3)

Expression of the phosphorylated variant of the AKT1-kinase (p-AKT1) in well-differentiated pancreatic neuroendocrine tumors: immunohistochemical evaluation

Background:Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a group of rare epithelial neoplasms with a highly variable clinical course. AKT1 is one of the most frequently activated protein kinases in pNETs, which promotes the tumor growth and is of interest as a prognostic factor and a target for new treatment approaches.Aim:To study the expression of the phosphorylated variant of AKT1-kinase (p-AKT1) in primary pNETs and their liver metastases and to correlate the results with various clinical and pathological parameters and the disease prognosis.Materials and methods:P-AKT1 expression was studied by the immunohistochemical analysis of the primary lesions and liver metastases in 52 pNETs patients.Results:A high level of cytoplasmic and/or nuclear immunoreactivity was detected in 24/52 of the primary pNETs (46.2%) and in 16/27 of their liver metastases (59.3%). p-AKT1 expression was observed in 3 (21.4%) of NET grade (G) 1, in 14 (46.7%) of NET G2, and in 7 (87.5%) of NET G3. p-AKT1 expression was more frequently identified in pNET G3 category and increased during the tumor progression in metachronous liver metastases, as compared to the corresponding primary tumor. In addition, p-AKT1 positivity was significantly associated with an increase of grade from G1 to G3 (p = 0.004), the Ki-67 index (p = 0.029), the pTNM stage (p = 0.0008), perineural invasion (p = 0.031) and a decrease in disease-free survival (p = 0.05).Conclusion:The results suggest that p-АКТ1 plays an important role in the pathogenesis of pNETs and may be an additional criterion for assessment of the prognosis and treatment effectiveness in this type of tumors.

Profiling the Tumour Immune Microenvironment in Pancreatic Neuroendocrine Neoplasms with Multispectral Imaging Indicates Distinct Subpopulation Characteristics Concordant with WHO 2017 Classification

We successfully determined the difference of immune microenvironments between pNENs and pancreatic ductal adenocarcinomas (PDACs), and the histology-dependent variability among pNENs using multispectral fluorescent imaging system. Tumour tissue samples including 52 pNENs and 18 PDACs were investigated. The tumour-infiltrating lymphocytes (TILs), their PD-1 and PD-L1 expression in the pNENs were comprehensively and quantitatively analysed and were subsequently compared with those in PDACs. A principal component analysis revealed that the tissue immune profile is related to tumour histology, with distinct groups being observed for NETs, NECs, and PDACs. While NECs and some PDACs had hot immune microenvironments with abundant TILs, NETs had a cold immune microenvironment with few TILs. Moreover, in NETs, the numbers of intraepithelial PD-1high T cells and PD-L1high Type-II macrophages were elevated according to the grade. Univariate analysis revealed that lymph node metastasis, grade, stage, PD-1high T cells, and PD-L1high Type-II macrophages were predictors for recurrence-free survival (RFS), while grade and PD-1high T cells were prognostic factors for overall survival (OS). We also showed that PD-1high T cells and PD-L1high Type-II macrophages were associated with worse outcome in pNENs. Our results support the WHO 2017 tumour classification criteria, which distinguish between G3 NETs and NECs.

A 0.8-cm clear cell neuroendocrine tumor G1 of the gallbladder with lymph node metastasis: a case report

BackgroundNeuroendocrine tumors (NETs) of the gallbladder are rare and generally considered low-grade malignancies. We herein describe a case of a patient with a 0.8-cm clear cell NET G1 of the gallbladder with nodal involvement.Case presentationA 65-year-old man with no medical history indicative of von Hippel-Lindau (VHL) disease underwent laparoscopic cholecystectomy for cholecystolithiasis. There was a 0.8-cm tumor in the neck of the gallbladder. Histologic examination revealed nests or trabecular growth of clear cells with small round-to-oval nuclei. Immunohistochemically, tumor cells showed positivity for chromogranin A and synaptophysin; Ki-67 index was < 1.0%. Based on the World Health Organization 2010 classification, we made a diagnosis of clear cell variant of NET G1 without VHL disease. The tumor invaded the muscular layer and had no extension to the perimuscular connective tissue but had metastasized to a cystic duct node. A radical second resection with regional lymphadenectomy of the gallbladder was performed, and there was no metastasis on histology. After the definitive surgery, he was followed up for 10 months without adjuvant therapy and is alive and well with no evidence of recurrence.ConclusionsOur experience suggests that, even when smaller than 1 cm, NET G1 of the gallbladder can metastasize. When NET G1 is incidentally identified in the gallbladder of a surgical specimen, detailed pathologic examination of the cystic duct node, when found, should be performed to guide whether a radical second resection with regional lymphadenectomy is appropriate.

Mo1208 - Even If small Size (Less than 10Mm) Net G1 Showed High Rates (More than 10%) of Lymphovascular Invasion on Microscopic Findings; Analysis of 156 Net Lesions in Japan

Mo1208 - Even If small Size (Less than 10Mm) Net G1 Showed High Rates (More than 10%) of Lymphovascular Invasion on Microscopic Findings; Analysis of 156 Net Lesions in Japan

A Case of Gastric Neuroendocrine Neoplasm with Mixed Grade: a Distinct Type of “High”-grade Well-Differentiated Neuroendocrine Neoplasm

Grade 3 neuroendocrine tumor (NET G3) is a rare new entity that has recently been introduced in the classification of neuroendocrine neoplasms of the pancreas. It is a well-differentiated form, with a high proliferative activity (Ki67 > 20%), and it represents a category whose prognosis is intermediate between NET G2 and poorly differentiated neuroendocrine carcinoma (NEC G3). In sites other than the pancreas, this new category is by far less coded. Herein is reported a case of NET G3 of the stomach, the 13th described in literature. The patient was a 71-year-old man with a mass in the gastric fundus. Histological examination revealed a neuroendocrine tumor that was mostly composed by areas with conventional well-differentiated features and intermediate proliferative rate (< 20 mitoses/10 HPFs and 7% Ki67); part of the tumor was characterized by increased nuclear atypia, a confluent growth pattern, intermediate mitotic activity, and high Ki67 value (25%). The tumor was studied immunohistochemically and molecularly, and the only alteration that came out was MEN1 gene mutation (Lau584SerfsTer5) in both the high- and low-grade components. According to the actual classification of gastric neuroendocrine neoplasms, this case is labeled as NEC G3 but it should be named NET G3, with a much better prognosis than the former. Overall, both morphological pattern and the Ki67 value should be mentioned in the histological report in cases of high-grade neuroendocrine neoplasms because of its clinical significance in defining the prognosis and for new potential therapeutic approaches.

Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study

IntroductionBesides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. AimTo evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. Patients and methodsRetrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th–75th IQR). ResultsEighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received ≥ 3 vs ≤ 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1–2 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. ConclusionsThe present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases.

Clinical outcome and long-term survival of 150 consecutive patients with pancreatic neuroendocrine tumors: A comprehensive analysis by the World Health Organization 2010 grading classification

The World Health Organization (WHO) has revised its grading system for pancreatic neuroendocrine tumors (PNETs) in 2010 into three main group, which has not been widely and comprehensively evaluated. We aimed to validate the clinical valve of this system associated with the clinical outcome and long-term survival when applied to PNETs, which were rare and heterogeneous. We retrospectively collected and analyzed the data of 150 consecutive patients with PNETs who underwent a resection. Sixty-four males and 86 females with PNETs were enrolled in our study. The clinical stage from I to IV by European Neuroendocrine Tumor Society were respectively defined in 53, 60, 19 and 18 patients. Seventy-two patients were pathologically diagnosed as neuroendocrine tumor G1 (NET G1), 48 as neuroendocrine tumor G2 (NET G2) and 30 as neuroendocrine carcinoma G3 (NEC G3). Patients with a radical resection obtained a notably higher overall survival (OS) than that of patients who underwent a palliative surgery (P=0.001). The 5-year OS of patients with NET G1 was significantly higher than that of patients with NET G2 (P=0.015) and NEC G3 (P<0.001); the comparison of OS for patients with NET G2 and NEC G3 was also statistically significant (P=0.005). In both univariate and multivariate analysis, clinical staging by ENETS (stage I and II vs. stage III and IV), resection (radical vs. palliative) and WHO 2010 grading classification (NET G1 and G2 vs. NEC G3) were validated to be independent predictors for the survivals of PNETs. The newly-updated WHO 2010 grading classification was prognostic for the OS of PNETs and could be widely adopted in clinical practice.

Changes in the pathomorphological diagnosis of gastrointestinal neuroendocrine neoplasms in 2017

The following changes were introduced in 2017 WHO and TnM classifications: 1. a new group of well-differentiated neuroendocrine tumors with the proliferation index of more than 20% and mitotic count of 20 per 10 hpf (NET G3), formerly classified under neuroendocrine carcinomas (NEC G3) 2. the division of poorly differentiated neuroendocrine tumors (PD NET) with the Ki-67 index of more than 20% into two groups in terms of the degree of differentiation and prognosis: NET G3 and NEC. 3. the replacement of MANEC with MINEN within the mixed group 4. the verification of histological grading (G) criteria 5. new TNM staging criteria, based on ENETS guidelines.

Clinicopathologic characteristics and prognosis of rectal neuroendocrine neoplasms

To study the clinicopathologic characteristics and prognosis of rectal neuroendocrine neoplasms (NENs). From January 2000 to May 2017, 84 patients were diagnosed as NENs by pathology and underwent surgical treatment in Peking University First Hospital. Their clinicopathological characteristics, surgial options and prognosis were analyzed retrospectively. Among these 84 cases, 67 cases were NET G1, 6 cases were NET G2, 10 cases were NEC G3 and 1 case was MANEC G3. The median size was 0.8 (0.2 to 18.0) cm. There were 60 cases of stage I(, 2 cases of stage II(, 12 cases of stage III(, 10 cases of stage IIII(. Forty-nine patients accepted examinations because of non-specific symptoms, including altered bowel habits(22/49), bloody stool (19/49) and abdominal pain(10/49); the other 35 cases including 2 patients with liver metastasis were diagnosed by endoscopy or CT during routine physical examination. Forty-four patients received endoscopic ultrasonography(EUS) with 100% of sensitivity and 90.9% of accuracy. Among 20 cases (23.8%) with lymph node metastasis (all ≥T2 stage), 12 cases were NET G1 and G2 (1 case of multiple NET G1) and 8 cases were NEC G3 and MANEC G3. The lymph node metastasis rate of stage T1 NET G1 and G2 was lower than that of stage T2 to T4 NET G1 and G2, also lower than that of NEC G3 and MANEC G3 (all P=0.000), however, stage T2 to T4 NET G1 and G2 showed the similar rate of lymph node metastasis with NEC G3 and MANCE G3(P>0.05). Synchronously distant metastasis was found in 10 (11.9%) patients at the first diagnosis, and ovarian metastasis was found in 1 case 9 years after curative resection of rectal NEN. Among 81 patients receiving operation, 57 patients underwent endoscopic mucosal resection (56 patients of stage T1 NET G1 and G2); 3 patients local excision without lymph node dissection; 13 patients curative resection; 1 patient curative resection with liver metastasis resection; 6 patients palliative surgery and 1 patient metastatic lesion resection only. Overall follw-up time was 1 month to 169 months, and the 3- and 5-year survival rates were 87.7% and 79.7% respectively. No recurrence or metastasis was observed in all the 62 patients with T1 G1 and G2, including 56 cases of ESD, 3 cases of local excision, 3 cases of curative resection, whose 3-year and 5-year survival rates were both 96%. The prognosis was closely associated with grade and stage of NENs (all P=0.000). The early symptoms of rectal NENs are insidious and atypical, therefore some patients are diagnosed as stage II( or higher at their first consultation. ESD is safe and effective for NET G1 and G2. The prognosis depends on grade and stage of NENs.

Prognoses in patients with primary gastrointestinal neuroendocrine neoplasms based on the proposed new classification scheme.

The aim of this study is to investigate the clinicopathological characteristics, as well as explore the prognostic accuracy of the proposed new classification in gastrointestinal NENs (GI-NENs) patients. Patients diagnosed with GI-NENs were retrospectively indentified from existing databases of the pathological institute at our institution from January 2009 to November 2015. We identified 414 patients with GI-NENs, 250 cases were diagnosed as neuroendocrine tumor G1 (NET G1), 25 as neuroendocrine tumor G2 (NET G2), 53 as neuroendocrine tumor G3 (NET G3), 55 as neuroendocrine carcinoma G3 (NEC G3), and 31 as mixed adenoneuroendocrine carcinoma (MANEC); the overall survival (OS) rate at three years were 94.9%, 91.7%, 74.3%, 62.7% and 38.1%, respectively. The difference in progression-free survival (PFS) duration among the patients with NET G1, NET G2, NET G3, NEC G3, and MANEC was statistically significant (P<0.001). However, the PFS of NEC G3 and MANEC was low and similar (P = 0.090). In multivariate analysis of patients with GI-NENs, surgical margin, comorbidity, proposed new classification and tumor location were useful predictors of OS (P<0.05). Our findings suggest that the proposed new classification can accurately reflect the clinical outcome, together with surgical margin, comorbidity, and tumor location may be meaningful prognostic factors for the OS of GI-NENs.

Mixed adenoneuroendocrine carcinoma: case report and review of literature

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare malignant neoplasm of a complex pathomorphological pattern combining the features of adenocarcinoma with a neuroendocrine component. According to the new classification of the World Health Organization (WHO) from 2010, the nomenclature of neuroendocrine neoplasms (NEN) was changed using this name for the entire group of neoplasms. The name ‘neuroendocrine tumours’ covers highly diversified neoplasms, determined in the pathomorphological comparison as G1 (NET G1) or G2 (NET G2). In addition, neuroendocrine carcinomas (NEC) and mixed adenoneuroendocrine carcinomas (MANEC) are differentiated. In a search of the the PubMed database, approximately 50 reports about this carcinoma were found, mainly with the location in the stomach, lymph nodes, intestines, liver, peritoneum, gallbladder, pancreas, oesophagus. We have not found a description of the metastatic lesions typical of MANEC in the meninges, brainstem, and lungs. We present the case of a 63-year-old patient who was admitted to the Department of Neurology due to increased dizzi­ness with accompanying diplopia, headache, nausea, and numbness of the hands. These symptoms appeared one day prior to admission, with intensification at night. The patient was initially diagnosed at the Department of Laryngology due to deafness of the right ear and deep hearing loss in the left ear four weeks prior to admission to our department. In the neurological examination, the following findings were detected: conscious, anxious, dysarthric speech, insignificant inspiratory dyspnoea, deafness of the right ear, deep hearing loss in the left ear, pharyngeal and palatal reaction, weak tension of the palato-pharyngeal fold, bilateral signs of central damage of the seventh nerve, insignificant deviation of the tongue to the left, muscle tone of the limbs without deficit, insignificantly decreased muscle tone in the left limbs, ataxia in the lower limbs, bilateral plantar reflex. In the admissions ward, CT examination of the head was performed and a hypodense focus in the left cerebral hemisphere, hypodense foci around the frontal horn of the lateral ventricles and small malacia cavities at the level of the subcortical nuclei were detected. A lumbar puncture was performed obtaining fluid with increased cytosis and a decreased glucose level. On the second day of hospitalisation, the general and neurological condition of the patient significantly worsened and a ‘sympathetic storming’ appeared followed by circulatory arrest. The patient was efficiently resuscitated, but then there was another sudden cardiac arrest and despite a long period of CPR, cardiac and respiratory action was not restored. After pathomorphological examination it was established that the whole image corresponded to MANEC located in the stomach, with dissemination mainly to the meninges, brainstem and lungs. In differential diagnosis rare causes of diseases must always be taken into consideration. An additional difficulty in diagnosing MANEC is a difference in the names depending on literature and country of the origin of the article, as well as the lack of Polish equivalents of some names of neoplasms. Only a reliable histopathological analysis is able to detect neoplasms from this group.

Results after surgical treatment of liver metastases in patients with high-grade gastroenteropancreatic neuroendocrine carcinomas

BackgroundGastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are generally characterized by synchronous metastases, high aggressiveness and a dismal prognosis. Current international guidelines do not recommend surgical treatment of liver metastases, however the existing data are scarce. The aim of this study was to evaluate the results of curatively intended resection/radiofrequency ablation (RFA) of liver metastases in patients with metastatic GEP-NEC. Methods32 patients with a diagnosis of high-grade gastroenteropancreatic neuroendocrine neoplasm (Ki-67 > 20%) and with intended curative resection/RFA of liver metastases, were identified among 840 patients from two Nordic GEP-NEC registries. Tumor morphology (well vs poor differentiation) was reassessed. Overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan–Meier analyses for the entire cohort and for subgroups. ResultsMedian OS after resection/RFA of liver metastases was 35.9 months (95%-CI: 20.6–51.3) with a five-year OS of 43%. The median PFS was 8.4 months (95%-CI: 3.9–13). Four patients (13%) were disease-free after 5 years. Two patients had well-differentiated morphology (NET G3) and 20 patients (63%) had Ki-67 ≥ 55%. A Ki-67 < 55% and receiving adjuvant chemotherapy were statistically significant factors of improved OS after liver resection/RFA. ConclusionThis study shows a long median and long term survival after liver surgery/RFA for these selected metastatic GEP-NEC patients, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population.

Clinical outcomes and prognostic factors of resected pancreatic neuroendocrine neoplasms: A single-center experience in China.

The aim of the present study was to investigate the clinical, pathological and prognostic characteristics of Chinese patients with resected pancreatic neuroendocrine neoplasms (p-NENs). Data from patients who were surgically treated and pathologically diagnosed with p-NENs at the Department of Pancreatic Oncology of the Fudan University Shanghai Cancer Center (Shanghai, China), between January 2003 and July 2015, were evaluated using univariate and multivariate analyses. A total of 162 patients with p-NENs met the criteria of the present study and were included in the analysis. Patients with poorly differentiated pancreatic neuroendocrine carcinoma (p-NEC) exhibited a significantly increased rate of lymph node metastasis, as compared with patients with grade (G)1/G2 pancreatic neuroendocrine tumors (p-NETs) (62.5 vs. 20.5%, P=0.003). Univariate analysis identified that the following factors led to decreased overall survival (OS): Lymph node metastasis (P=0.001, vs. the absence of lymph node metastasis); distant metastasis (P=0.043, vs. the absence of distant metastasis); resection margin R1/R2 (P=0.030, vs. R0 resection); NEC G3 (P<0.001, vs. NET G1). Following the multivariate analysis, NEC G3 remained a statistically significant risk factor (HR=12.593; 95% CI, 3.476-45.622; P<0.001, vs. NET G1/G2). Furthermore, according to the proliferation marker protein Ki-67 staining index, assigning a grade using the proliferative index (G1, ≤5%; G2, >5-20%; G3, >20%) was more efficient for prognostic stratification compared with the European Neuroendocrine Tumor Society (Berlin, Germany)/World Health Organization (Geneva, Switzerland) 2010 grading classification. The present study indicated that p-NEC was an important predictor of decreased OS in Chinese patients. Furthermore, a Ki-67 staining index of 5% represented a more efficient value for the distinction between G1 and G2.

Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future.

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1%–2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2; and neuroendocrine carcinoma: NEC) on the basis of the Ki-67 proliferation index and the mitotic count according to the 2010 World Health Organization (WHO) classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic background together with preclinical studies to develop new agents, including those already under investigation for small cell lung cancer (SCLC), will be needed to improve the prognosis.

Pancreatic neuroendocrine tumors: new aspects of morphological classification (World Health Organization, 2017)

The fourth edition of the World Health Organization (WHO) classification of endocrine tumors published in 2017 contains substantial new findings in the topics of pancreatic neuroendocrine neoplasms (PanNENs). In this edition, major modifications are mainly based on new molecular knowledge as well as the clinical behaviour of these tumors accommodated since the previous 2010 classification of degestive tumors was published. According to the new classification scheme PanNENs include malignant well-differentiated neuroendocrine neoplasms (NENs), which are called pancreatic neuroendocrine tumors (PanNETs), and poorly differentiated NENs, which are called pancreatic neuroendocrine carcinomas (PanNECs). PanNENs futher divided into three Grade (G) on the base of cell proliferation: G1 (&lt;2 mitoses on 10 HPF (high-power field) and Ki-67 Index &lt;3 %), G2 (2–20 mitoses on 10 HPF or Ki-67 Index 3–20 %), G3 (&gt;20 mitoses on 10 HPF or Ki-67 Index &gt;20 %). The new category NET G3 was first introduced in this edition of the WHO classification. PanNECs is classified as G3 neoplasms (&gt;20 mitoses on 10 HPF or Ki-67 Index &gt;20 %) and additionally divided into small cell NEC and large cell NEC. In this review we focus on some of the new features of PanNETs and recommended changes of their terminology and classification.

Alterations in Cancer-related Genes Associated with Grading of Well Differentiated Pancreatic Neuroendocrine Neoplasms

Objectives: Although recent advances in next-generation sequencing (NGS) have revealed some genetic alterations in various tumors, including pancreatic neuroendocrine tumors (PanNETs), their clinical significance is not fully understood. To investigate the clinical significance of gene alteration in PanNETs, we performed genetic analysis of well differentiated PanNETs using NGS. Methods: Twenty-nine resected primary PanNET tissue samples and three samples of metastatic liver tissues, obtained from 29 PanNET patients, were analyzed. DNA was extracted from laser-captured formalin-fixed paraffinembedded tissues, and 50 cancer-associated genes, including approximately 2,800 hotspots, were amplified by multiplex PCR. Amplified libraries were sequenced using NGS, and the results were analyzed in conjunction with respective clinicopathological features. Results: Among 50 investigated genes, somatic mutations were observed in four of 29 PanNET cases. We identified APC mutations in three cases, PTEN in two, and VHL and STK11 in one. The identified mutations were observed only in NET G2 tumors. All liver metastases contained at least one mutation, such as PTEN or TP53, which was not observed in the primary tumor. Conclusion: The cancer-related gene mutations observed in PanNETs were associated with G2 grade tumors. The mutations were more frequent in PanNET liver metastasis than in the primary tumors. Our analysis of liver metastasis cases suggested that cancer-related gene mutations might raise the tumor grade and promote liver metastasis. Further studies of associations between genetic alterations and clinicopathological features should help in the cancer diagnosis and prediction of therapeutic effects of molecular-target drugs.

The clinicopathological significance of angiogenesis in hindgut neuroendocrine tumors obtained via an endoscopic procedure.

BackgroundAs the World Health Organization grading system for gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) may not always correlate with tumor progression, it is imperative that other independent predictors of tumor progression be established. To identify such predictors, we conducted a retrospective histopathological study of hindgut NETs, obtained from endoscopic procedures, and used statistical analyses to evaluate predictive factors.MethodsWe first obtained clinicopathological data of cases of hindgut NETs. Tissue sections from tumor samples were prepared and subjected to pathological examination. In particular, we calculated the microvessel density (MVD) and lymphatic microvessel density (LMVD) values, and performed appropriate statistical analyses.ResultsA total of 42 cases of hindgut NETs were selected for the study, 41 from the rectum and 1 from the sigmoid colon. Based on the Ki-67 labeling index, 34 cases were classified as NET G1 tumors and 8 as NET G2 tumors. MVD values ranged from 1.4/mm2 to 73.9/mm2 and LMVD values from 0/mm2 to 22.9/mm2. MVD and LMVD were identified as risk factors for venous and lymphatic invasion of hindgut NETs. Moreover, MVD positively correlated with the maximum diameter of the tumor.ConclusionsTumor progression of NETs may cause angiogenesis and lymphangiogenesis, via an unknown mechanism, as well as lymphovascular invasion. Angiogenesis likely plays an important role in occurrence and progression in the initial phase of hindgut NETs.