New insights in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are rare epithelial neoplasms derived from pluripotent endocrine cells along the gastrointestinal tract and pancreas.GEP-NENs are classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas.Despite overlapping morphological features,GEP-NENs vary in molecular biology,epigenetic,clinical behavior,treatment response,and prognosis features and remain an unmet clinical challenge.In this review,we introduce recent updates on the histopathologic classification,including the tumor grading and staging system,molecular genetics,and systemic evaluation of the diagnosis and treatment of GEP-NENs at different anatomic sites,together with some insights into the diagnosis of challenging and unusual cases.We also discuss the application of novel therapeutic approaches for GEP-NENs,including peptide receptor radionuclide therapy,targeted therapy,and immunotherapy with immune checkpoint inhibitors.These findings will help improve patient care with precise diagnosis and individualized treatment of patients with GEP-NENs.

Gastroenteropancreatic neuroendocrine neoplasms:A clinical snapshot

Our understanding about the epidemiological aspects,pathogenesis,molecular diagnosis,and targeted therapies of neuroendocrine neoplasms(NENs)have drastically advanced in the past decade.Gastroenteropancreatic(GEP)NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors.Most NENs are welldifferentiated,and slow growing.Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin,glucagon,vasoactive intestinal polypeptide,gastrin,somatostatin,adrenocorticotropin,growth hormone releasing hormone,parathyroid hormone-related peptide,serotonin,histamine,and 5-hydroxy indole acetic acid(5-HIAA).Biomarkers such as pancreatic polypeptide,human chorionic gonadotrophin subunits,neurotensin,ghrelin,and calcitonin are used in the diagnosis of non-functional NENs.5-HIAA levels correlate with tumour burden,prognosis and development of carcinoid heart disease and mesenteric fibrosis,however several diseases,medications and edible products can falsely elevate the 5-HIAA levels.Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs.Emerging novel biomarkers include circulating tumour cells,circulating tumour DNA,circulating micro-RNAs,and neuroendocrine neoplasms test(NETest)(simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood).NETest has high sensitivity(85%-98%)and specificity(93%-97%)for the detection of gastrointestinal NENs,and is useful for monitoring treatment response,recurrence,and prognosis.In terms of management,surgery,radiofrequency ablation,symptom control with medications,chemotherapy and molecular targeted therapies are all considered as options.Surgery is the mainstay of treatment,but depends on factors including age of the individual,location,stage,grade,functional status,and the heredity of the tumour(sporadic vs inherited).Medical management is helpful to alleviate the symptoms,manage inoperable lesions,suppress postoperative tumour growth,and manage recurrences.Several molecular-targeted therapies are considered second line to somatostatin analogues.This review is a clinical update on the pathophysiological aspects,diagnostic algorithm,and management of GEP NENs.

Current updates and future directions in diagnosis and management of gastroenteropancreatic neuroendocrine neoplasms

Gastroenteropancreatic neuroendocrine neoplasms are a heterogenous group of rare neoplasms that are increasingly being discovered,often incidentally,throughout the gastrointestinal tract with varying degrees of activity and malignant potential.Confusing nomenclature has added to the complexity of managing these lesions.The term carcinoid tumor and embryonic classification have been replaced with gastroenteropancreatic neuroendocrine neoplasm,which includes gastrointestinal neuroendocrine and pancreatic neuroendocrine neoplasms.A comprehensive multidisciplinary approach is important for clinicians to diagnose,stage and manage these lesions.While histological diagnosis is the gold standard,recent advancements in endoscopy,conventional imaging,functional imaging,and serum biomarkers complement histology for tailoring specific treatment options.In light of developing technology,our review sets out to characterize diagnostic and therapeutic advancements for managing gastroenteropancreatic neuroendocrine tumors,including innovations in radiolabeled peptide imaging,circulating biomarkers,and endoscopic treatment approaches adapted to different locations throughout the gastrointestinal system.

Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives

Although gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have always been considered rare tumors,their incidence has risen over the past few decades.They represent a highly heterogeneous group of neoplasms with several prognostic factors,including disease stage,proliferative index(Ki67),and tumor differentiation.Most of these neoplasms express somatostatin receptors on the cell surface,a feature that has important implications in terms of prognosis,diagnosis,and therapy.Although International Guidelines propose algorithms aimed at guiding therapeutic strategies,GEP-NEN patients are still very different from one another,and the need for personalized treatment continues to increase.Radical surgery is always the best option when feasible;however,up to 80%of cases are metastatic upon diagnosis.Regarding medical treatments,as GEP-NENs are characterized by relatively long overall survival,multiple therapy lines are adopted during the lifetime of these patients,but the optimum sequence to be followed has never been clearly defined.Furthermore,although new molecular markers aimed at predicting the response to therapy,as well as prognostic scores,are currently being studied,their application is still far from being part of daily clinical practice.As they represent a complex disease,with therapeutic protocols that are not completely standardized,GEP-NENs require a multidisciplinary approach.This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.

Current status of surgical management of patients with gastroenteropancreatic neuroendocrine neoplasms

Neuroendocrine neoplasms(NENs)of the gastroenteropancreatic system are rare and heterogeneous tumours,yet with increasing prevalence.The most frequent primary sites are the small intestine,rectum,pancreas,and stomach.For a localized disease,surgical resection with local lymph nodes is usually curative with good overall and disease free survival.More complex situation is the treatment of locally advanced lesions,liver metastases,and,surprisingly,small asymptomatic tumours of the rectum and pancreas.In this review,we focus on the current role of surgical management of gastroenteropancreatic NENs.We present surgical approach for the most frequent primary sites.We highlight the role of endoscopic surgery and the watch-and-wait strategy for selected cases.As liver metastases pose an important clinical challenge,we present current indications and contraindications for liver resection and a role of liver transplantation for metastatic NENs.

Role of surgical treatments in high-grade or advanced gastroenteropancreatic neuroendocrine neoplasms

Over the last 40 years,the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have continued to increase.Compared to other epithelial neoplasms in the same organ,GEP-NENs exhibit indolent biological behavior,resulting in more chances to undergo surgery.However,the role of surgery in high-grade or advanced GEP-NENs is still controversial.Surgery is associated with survival improvement of well-differentiated highgrade GEP-NENs,whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers.Additionally,surgery also plays an important role in locally advanced and metastatic disease.For locally advanced GEP-NENs,isolated major vascular involvement is no longer an absolute contraindication.In the setting of metastatic GEP-NENs,radical intended surgery is recommended for patients with low-grade and resectable metastases.For unresectable metastatic disease,a variety of surgical approaches,including cytoreduction of liver metastasis,liver transplantation,and surgery after neoadjuvant treatment,show survival benefits.Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control,prolonged survival,and improved sensitivity toward systemic therapies.Although there is no established neoadjuvant or adjuvant strategy,increasing attention has been given to this emerging research area.Some studies have reported that neoadjuvant therapy effectively reduces tumor burden,improves the effectiveness of subsequent surgery,and decreases surgical complications.

Clinicopathological features and survival analysis of gastroenteropancreatic neuroendocrine neoplasms: a retrospective study in a single center of China

Objective： To investigate the clinicopathological features, survival and prognostic factors for gastroenteropancreatic neuroendocrine neoplasms（GEP-NENs） in a Chinese population.Methods： We investigated 154 consecutive patients（88 males, 66 females; median age 56 years, age range 9-86 years） diagnosed with GEP-NENs between 2001 and 2013 at The Affiliated Hospital of Qingdao University. Demographic, clinical and pathological variables and survival data were retrieved.Results： The pancreas was the most common site of involvement（63/154, 40.9%）. Tumor size varied from 0.3 to 16.0 cm（median, 1.2 cm）. The patients were followed up for a median period of 22 months（range, 1-157 months）. The estimated 3- and 5-year overall survival（OS） rates for all patients were 84.0% and 81.9%, respectively. Multivariate analysis showed that larger tumor size, lymphatic metastases and distant metastases were significant predictors for poor survival outcome.Conclusions： Our data provide further information on the clinicopathological features of GEP-NENs in China. Additionally, we identified tumor size, lymphatic metastases and distant metastases as independent prognostic factors for long-term survival.

Utility of CT in differentiating liver metastases of well-differentiated gastroenteropancreatic neuroendocrine neoplasms from poorly-differentiated neuroendocrine neoplasms

Objective： To determine the capability of dynamic enhanced computed tomography（CT） to differentiate liver metastases（LMs） of well-differentiated from poorly-differentiated gastroenteropancreatic neuroendocrine neoplasms（GEP-NENs）.Methods： Patients with LMs of GEP-NENs who underwent dynamic enhanced CT examination in Peking University Cancer Hospital from January 2009 to October 2015 were included and data were retrospectively analyzed. We assessed the qualitative and quantitative CT features to identify the significant differentiating CT features of LMs of poorly-differentiated GEP-NENs from those of well-differentiated GEP-NENs using univariate analysis and a multivariate logistic regression model.Results： The study included 22 patients with LMs of well-differentiated GEP-NENs and 32 patients with LMs of poorly-differentiated GEP-NENs. Univariate analysis revealed statistically significant differences between the LMs of well-and poorly-differentiated GEP-NENs in terms of feeding arteries（36.4% vs. 75.0%, χ2=8.061,P=0.005）, intratumoral neovascularity（18.2% vs. 59.4%, χ2=9.047, P=0.003）, lymphadenopathy（27.3% vs. 81.2%,χ2=15.733, P〈0.001）, tumor-to-aortic ratio in the hepatic arterial and portal venous phase（T-A/AP： 0.297±0.080 vs.0.251±0.059, t=2.437, P=0.018; T-A/PVP： 0.639±0.138 vs. 0.529±0.117, t=3.163, P=0.003） and tumor-to-liver ratio in the hepatic arterial phase（T-L/AP： 1.108±0.267 vs. 0.907±0.240, t=2.882, P=0.006）. The LMs of poorlydifferentiated GEP-NENs showed more feeding arteries, more intratumoral neovascularity, more lymphadenopathy and a lower tumor-to-aortic ratio. Multivariate analysis suggested that intratumoral neovascularity [P=0.015, OR=0.108, 95% confidence interval（95% CI）, 0.018–0.646], lymphadenopathy（P=0.001,OR=0.055, 95% CI, 0.009–0.323） and T-A/PVP（P=0.004, OR=5.3 E–5, 95% CI, 0.000–0.044） were independent factors for differentiating LMs of poorly-differentiated from well-differentiated GEP-NENs.Conclusions： Dynamic enhanced CT features（intratumoral neovascularity, lymphadenopathy and T-A/PVP）are useful in the pathological classification of LMs of GEP-NENs.

Neuroendocrine neoplasms of liver-A 5-year retrospective clinico-pathological study applying World Health Organization 2010 classification

AIM To study the clinicopathological characteristics of neuroendocrine neoplasms(NEN) on liver samples and apply World Health Organization(WHO) 2010 grading of gastroenteropancreatic(GEP) NEN.METHODS Clinicopathological features of 79 cases of NEN of the liver diagnosed between January 2011 to December 2015 were analyzed. WHO 2010 classification of GEP NEN was applied and the tumors were graded as G1, G2 or G3. Two more categories, D1/2(discordant 1/2) and D2/3(discordant 2/3) were also applied. The D1/2 grade tumors had a mitotic count of G1 and Ki-67 index of G2. The D2/3 tumors had a mitotic count of G2 and Ki-67 index of G3. The follow up details which were available till the end of the study period(December 2015) were collected.RESULTS Of the 79 tumors, 16 each were G1 and G2, and 18 were G3 tumors. Of the remaining 29 tumors, 13 were assigned to D1/2 and 16 were D2/3 grade. Male preponderance was noted in all tumors except for G2 neoplasms, which showed a slight female predilection. The median age at presentation was 47 years(range 10-82 years). The most common presentation was abdominal pain(81%). Pancreas(49%) was the most common site of primary followed by gastrointestinal tract(24.4%) and lungs(18%). Radiologically, 87% of the patients had multiple liver lesions. Histopathologically, necrosis was seen in only D2/3 and G3 tumors. Microvascular invasion was seen in all grades. Metastasis occurred in all grades of primary NEN and the grades of the metastatic tumors and their corresponding primary tumors were similar in 67% of the cases. Of the 79 patients, 36 had at least one follow up visit with a median duration of follow up of 8.5 mo(range: 1-50 mo). This study did not show any impact of the grade of tumor on the short term clinical outcome of these patients.CONCLUSION Liver biopsy is an important tool for clinicopathological characterization and grading of NEN, especially when the primary is not identified. Eighty-seven percent of the patients had multifocal liver lesions irrespective of the WHO grade, indicating a higher stage of disease at presentation. Follow up duration was inadequate to derive any meaningful conclusion on long term outcome in our study patients.

Clinicopathological characterization of gastroenteropancreatic neu-roendocrine neoplasms： a retrospective study of 48 cases

Objective Gastroenteropancreatic neuroendocrine neoplasms （GEP-NENs） constitute a rare and heterogeneous group of tumors with varied biology and still constitute a diagnostic and therapeutic challenge for physicians of all specialties. In the present study, we aimed to review and study the clinicopathological characteristics of GEP-NENs applying the World Health Organization （WHO） 2010 grading criterion. Methods A total of 48 patients were enrolled in the study. The study included patients diagnosed with GEP-NENs who were treated and followed up at our Hospital from January 2013 to December 2017. Data regarding clinicopathological features of the patients were retrospectively evaluated. The expression of neuroendocrine markers was measured using the immunohistochemical Ultra SensitiveTM S-P method of staining in 48 cases of primary GEP-NENs; and serum levels of neuron-specific enolase, carbohydrate an-tigen 19-9, and carcinoembryonic antigen in 36 GEP-NEN patients were measured using the electrochemiluminescence method. Results The median age at presentation was 59.3 （range 48-82） years, and 39 cases （81.3%） were seen between the 5th and 6th decades. There was a male predilection （male： female=3：1）. In 79.2% cases （38/48）, tumors were hormonally nonfunctional. The most common presentation was abdominal pain, and the most frequent primary site of the tumor was the rectum, followed by the stomach （n = 15, 31.3%）, colon （n = 5, 10.4%）, and so on. Of the 48 tumors, 16 （33.3%） were G1,6 （12.5%） cases were G2, 16 （33.3%） were neuroendocrine carcinoma （NEC）, and 10 （20.8%） were mixed adenoneuroendocrine carcinoma （MANEC）. According to the AJCC/UICC classification, 45.8% （n = 22） were diagnosed at low stage （stage Ⅰ or Ⅱ） while 54.2% （n = 26） were diagnosed at high stage （stage Ⅲ or Ⅳ） （the majority of NEC, G3, and MANEC）. A male preponderance was noted for all tumors except for G2 neoplasms, which showed no gender predilection. Thirty-nine patients underwent endoscopic biopsy. The lesions in 18.8% （n = 9） of the patients were indentified only radiologically. After the surgical procedures, 36 had at least one follow-up visit with a median follow-up duration of 5 months; the mean follow-up period was 28 ± 16 months. The one- year and three-year survival rates were 72.2% （26/36） and 61.1% （22/36）, respectively. This study did not find an effect of grade 3 （G3） of tumor on the short-term clinical outcome of these patients. In the survival analysis, NEN G3, higher stage （stage Ⅲ or Ⅳ） according to the AJCC/UICC classification （P 〈 0.05）, and metastases at diagnosis （P 〈 0.05） were associated with poorer prognosis. Conclusion Most GEP-NENs are nonfunctional and nonspecific in presentation. The most frequent primary site of the tumor was the rectum and the commonest ages at diagnosis were the 5th and 6th decades. Endoscopic biopsy is the main diagnostic and histological grading method for GEP-NEN. In the survival analysis, NEN G3, a higher stage according to the AJCC/UICC classification, and metastases at diagnosis are associated with poorer prognosis.

Managing end-stage carcinoid heart disease:A case report and literature review

BACKGROUND Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)are rare tumors,often diagnosed in an advanced stage when curative treatment is impossible and grueling symptoms related to vasoactive substance release by tumor cells affect patients’quality of life.Cardiovascular complications of GEP-NENs,primarily tricuspid and pulmonary valve disease,and right-sided heart failure,are the leading cause of death,even compared to metastatic disease.CASE SUMMARY We present a case of a 35-year-old patient with progressive dyspnea,back pain,polyneuropathic leg pain,and nocturnal diarrhea lasting for a decade before the diagnosis of neuroendocrine carcinoma of unknown primary with extensive liver metastases.During the initial presentation,serum biomarkers were not evaluated,and the patient received five cycles of doxorubicin,which he did not tolerate well,so he refused further therapy and was lost to follow-up.After 10 years,he presented to the emergency room with signs and symptoms of right-sided heart failure.Panneuroendocrine markers,serum chromogranin A,and urinary 5-hydroxyindoleacetic acid were extremely elevated(900 ng/mL and 2178µmol/L),and transabdominal ultrasound confirmed hepatic metastases.Computed tomo-graphy(CT)showed liver metastases up to 6 cm in diameter and metastases in mesenteric lymph nodes and pelvis.Furthermore,an Octreoscan showed lesions in the heart,thoracic spine,duodenum,and ascendent colon.A standard trans-thoracic echocardiogram confirmed findings of carcinoid heart disease.The patient was not a candidate for valve replacement.He started octreotide acetate treatment,and the dose escalated to 80 mg IM monthly.Although biochemical CONCLUSION Carcinoid heart disease occurs with carcinoid syndrome related to advanced neuroendocrine tumors,usually with liver metastases,which manifests as right-sided heart valve dysfunction leading to right-sided heart failure.Carcinoid heart disease and tumor burden are major prognostic factors of poor survival.Therefore,they must be actively sought by available biochemical markers and imaging techniques.Moreover,imaging techniques aiding tumor detection and staging,somatostatin receptor positron emission tomography/CT,and CT or magnetic resonance imaging,should be performed at the time of diagnosis and in 3-to 6-mo intervals to determine tumor growth rate and assess the possibility of locoregional therapy and/or palliative surgery.Valve replacement at the onset of symptoms or right ventricular dysfunction may be considered,while any delay can worsen right-sided ventricular failure.

Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies?

Gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs) frequently present with distant metastases at the time of diagnosis and the liver is the most frequent site of spreading. The early identification of metastatic disease represents a major prognostic factor for GEP-NENs patients. Radical surgical resection, which is feasible for a minority of patients, is considered the only curative option, while the best management for patients with unresectable liver metastases is still being debated. In the last few years, a number of locoregional and systemic treatments has become available for GEP-NEN patients metastatic to the liver. However, to date only a few prospective studies have compared those therapies and the optimal management option is based on clinical judgement. Additionally, locoregional treatments appear feasible and safe for disease control for patients with limited liver involvement and effective in symptoms control for patients with diffuse liver metastases. Considering the lack of randomized controlled trials comparing the locoregional treatments of liver metastatic NEN patients, clinical judgment remains key to set the most appropriate therapeutic pathway. Prospective data may ultimately lead to more personalized and optimized treatments. The present review analyzes all the locoregional therapy modalities(i.e., surgery, ablative treatments and transarterial approach) and aims to provide clinicians with a useful algorithm to best treat GEP-NEN patients metastatic to the liver.