Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study.

BACKGROUND: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING: Swiss Cancer Research foundation.

International survey on opinions and use of minimally invasive surgery in small bowel neuroendocrine neoplasms.

INTRODUCTION: Although minimally invasive surgery is becoming the standard technique in gastrointestinal surgery, implementation for small bowel neuroendocrine neoplasms (SB-NEN) is lagging behind. The aim of this international survey was to gain insights into attitudes towards minimally invasive surgery for resection of SB-NEN and current practices. METHODS: An anonymous survey was sent to surgeons between February and May 2021 via (neuro)endocrine and colorectal societies worldwide. The survey consisted of questions regarding experience of the surgeon with minimally invasive SB-NEN resection and training. RESULTS: A total of 58 responses from five societies across 20 countries were included. Forty-one (71%) respondents worked at academic centers. Thirty-seven (64%) practiced colorectal surgery, 24 (41%) endocrine surgery and 45 (78%) had experience in advanced minimally invasive surgery. An open, laparoscopic or robotic approach was preferred by 23 (42%), 24 (44%), and 8 (15%) respondents, respectively. Reasons to opt for a minimally invasive approach were mainly related to peri-operative benefits, while an open approach was preferred for optimal mesenteric lymphadenectomy and tactile feedback. Additional training in minimally invasive SB-NEN resection was welcomed by 29 (52%) respondents. Forty-three (74%) respondents were interested in collaborating in future studies, with a cumulative median (IQR) annual case load of 172 (86-258). CONCLUSIONS: Among respondents, 69% applies minimally invasive surgery for resection of SB-NEN. Arguments for specific operative approaches differ, and insufficient training in advanced laparoscopic techniques seems to be a barrier. Future collaborative studies can provide better insight in selection criteria and optimal technique.

Postoperative morbidity and mortality after surgical resection of small bowel neuroendocrine neoplasms: A systematic review and meta-analysis.

Although small bowel resection is generally considered a low risk gastrointestinal procedure, this might not be true for small bowel neuroendocrine neoplasms (SB-NEN) as a result of potential central mesenteric involvement. We aimed to determine the reported morbidity and mortality after resection of SB-NEN in the literature and assess the effect of hospital volume on postoperative morbidity and mortality. A systematic review was performed by searching MEDLINE and Embase in March 2021. All studies reporting morbidity and/or mortality after SB-NEN resection were included. Pooled proportions of overall morbidity (Clavien-Dindo I-IV), severe morbidity (Clavien-Dindo III-IV), 30-day mortality, 90-day mortality and in-hospital mortality were calculated, as well as the association with hospital volume (high volume defined as the fourth quartile). Thirteen studies were included, with a total of 1087 patients. Pooled proportions revealed an overall morbidity of 13% (95% confidence interval [CI] = 7%-24%, I2  = 90%), severe morbidity of 7% (95% CI = 4%-14%, I2  = 70%), 30-day mortality of 2% (95% CI = 1%-3%, I2  = 0%), 90-day mortality of2% (95% CI = 2%-4%, I2  = 35%) and in-hospital mortality of 1% (95% CI = 0%-2%, I2  = 0%). An annual hospital volume of nine or more resections was associated with lower overall and severe morbidity compared to lower volume: 10% vs 15% and 4% vs 9%, respectively. Thirty-day mortality was similar (2% vs 1%) and 90-day mortality was higher in high-volume hospitals: 4% vs 1%. This systematic review with meta-analyses showed severe morbidity of 7% and low mortality rates after resection of SB-NEN. The currently available literature suggests a certain impact of hospital volume on postoperative outcomes, although heterogeneity among the included studies constrains interpretation.

Update on Incidence, Prevalence, Treatment and Survival of Patients with Small Bowel Neuroendocrine Neoplasms in the Netherlands.

BACKGROUND: Small bowel neuroendocrine neoplasms (SB-NEN) are rare cancers, population-based studies are needed to study this rare indolent disease. The aim of this study was to explore trends in epidemiology, treatment and survival outcomes of patients with SB-NEN based on Dutch nationwide data. PATIENTS AND METHODS: Patients with grade 1 or 2 SB-NEN diagnosed between 2005 and 2015 were retrieved from the Netherlands Cancer Registry and linked to The Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands. Age-adjusted incidence rates were calculated based using the direct standardization method. Survival analyses were performed with the Kaplan-Meier method. RESULTS: A total of 1132 patients were included for epidemiological analyses. The age-adjusted incidence rate of SB-NEN increased from 0.52 to 0.81 per 100.000 person-years between 2005 and 2015. Incidence was higher for males than females (0.93 vs. 0.69 in 2015). Most patients had grade 1 tumours (83%). Surgery was performed in 86% of patients, with resection of the primary tumour in 99%. During the study period, administration of somatostatin analogues (SSAs) increased from 5 to 22% for stage III and from 27 to 63% for stage IV disease. Mean follow-up was 61 (standard deviation 38) months. Survival data were complete for 975/1132 patients and five-year overall survival was 75% for stage I-II, 75% for stage III and 57% for stage IV. CONCLUSIONS: This study shows an increase in the incidence of SB-NEN in the Netherlands. A predominant role of surgery was found in all disease stages. Use of SSAs has increased over time.

Evaluating Nationwide Application of Minimally Invasive Surgery for Treatment of Small Bowel Neuroendocrine Neoplasms.

AIM: Open resection of small bowel neuroendocrine neoplasms (SB-NEN) is still considered standard-of-care, mainly because of frequently encountered multifocality and central mesenteric masses. The aim of this study was to evaluate surgical approach for SB-NEN at a national level and determine predictors for overall survival. METHODS: Patients with SB-NEN who underwent resection between 2005 and 2015 were included from the Netherlands Cancer Registry. Patient and tumor characteristics were compared between laparoscopic and open approach. Overall survival was assessed by Kaplan-Meier and compared with the Log-rank test. Independent predictors were determined by Cox proportional hazards model. RESULTS: In total, 482 patients were included, of whom 342 (71%) underwent open and 140 (29%) laparoscopic resection. The open resection group had significantly more multifocal tumors resected (24% vs. 14%), pN2 lymph nodes (18% vs. 7%) and stage IV disease (36% vs. 22%). Overall survival after open resection was significantly shorter compared to laparoscopic resection (3-year: 81% vs. 89%, 5-year: 71% vs. 84%, p = 0.004). In multivariable analysis, age above 60-years (60-75, HR 3.38 (95% CI 1.84-6.23); > 75 years, HR 7.63 (95% CI 3.86-15.07)), stage IV disease (HR 1.86 (95% CI 1.18-2.94)) and a laparoscopic approach (HR 0.51 (95% CI 0.28-0.94)) were independently associated with overall survival, whereas multifocal primary tumor, grade and resection margin status were not. CONCLUSION: Laparoscopic resection was the approach in 29% of SB-NEN at a national level with selection of the more favorable patients. Laparoscopic resection remained independently associated with better overall survival besides age and stage, but residual confounding cannot be excluded.

Value of Laparoscopy for Resection of Small-Bowel Neuroendocrine Neoplasms Including Central Mesenteric Lymphadenectomy.

BACKGROUND: Literature on laparoscopic resection of small-bowel neuroendocrine neoplasms consists of single case descriptions or small selected case-series only, likely because of challenging mesenteric lymphadenectomy. OBJECTIVE: We evaluated an institutional change in approach from open to laparoscopic resection of small-bowel neuroendocrine neoplasm independent from lymph node involvement. DESIGN: This is a retrospective comparative cohort study. SETTING: This study was conducted at a tertiary referral center. PATIENTS: Patients with small-bowel neuroendocrine neoplasms were included. INTERVENTIONS: Laparoscopic or open segmental bowel resection with central mesenteric lymphadenectomy was the studied intervention. MAIN OUTCOME MEASURES: Complexity of lymphadenectomy was assessed by determining the distance between suspect lymph nodes and main mesenteric branches on preoperative CT. Number of (tumor-positive) lymph nodes, conversion to open surgery, and postoperative complications according to Clavien-Dindo classification and length of stay were measured. RESULTS: A total of 34 patients were identified, of whom 11 (32%) underwent open and 23 (68%) laparoscopic surgery. Distances between lymph nodes and main mesenteric branches and number of examined and tumor-positive lymph nodes did not differ significantly. Laparoscopy was converted in 7 patients (30%). Major postoperative complications (grades 3-5) occurred in 1 patient (9%) in the open surgery group (grade 5) and 2 patients (9%) in the laparoscopic surgery group (grade 3b). The length of stay was 8 days (range, 6-18 d) in the open surgery group and 4 days (4-8 d) in the laparoscopic group (p = 0.036). LIMITATIONS: Long-term outcomes could not reliably be assessed because of the relatively short follow-up time of the laparoscopy group. CONCLUSIONS: Laparoscopic bowel resection with central mesenteric lymphadenectomy for small-bowel neuroendocrine neoplasm appears safe and associated with similar pathologic outcome and shorter length of stay in the setting of a tertiary referral center. See Video Abstract at http://links.lww.com/DCR/B512. VALOR DE LA LAPAROSCOPIA PARA LA RESECCIN DE NEOPLASIAS NEUROENDOCRINAS DEL INTESTINO DELGADO, INCLUIDA LA LINFADENECTOMA MESENTRICA CENTRAL: ANTECEDENTES:La literatura sobre la resección laparoscópica de neoplasias neuroendocrinas del intestino delgado consiste en descripciones de casos únicos o en series de pequeños casos seleccionados, probablemente debido a la dificultad de la linfadenectomía mesentérica.OBJETIVO:Evaluamos un cambio institucional en el enfoque de la resección abierta a laparoscópica de SB-NEN independientemente de la afectación de los ganglios linfáticos.DISEÑO:Este es un estudio de cohorte comparativo retrospectivo.AJUSTE:Este estudio se realizó en un centro de referencia terciario.PACIENTES:Pacientes con neoplasias neuroendocrinas de intestino delgado.INTERVENCIONES:Resección intestinal segmentaria laparoscópica o abierta con linfadenectomía mesentérica central.PRINCIPALES MEDIDAS DE RESULTADO:La complejidad de la linfadenectomía se evaluó determinando la distancia entre los ganglios linfáticos sospechosos y las principales ramas mesentéricas en la TC preoperatoria. Número de ganglios linfáticos (tumor positivos), conversión a cirugía abierta, complicaciones postoperatorias según Clavien-Dindo y duración de la estancia.RESULTADOS:Se identificaron 34 pacientes, de los cuales 11 (32%) fueron sometidos a cirugía abierta y 23 (68%) laparoscópica. Las distancias entre los ganglios linfáticos y las principales ramas mesentéricas y el número de ganglios linfáticos examinados y con tumores positivos no difirieron significativamente. La laparoscopia se convirtió en 7 pacientes (30%). Se produjeron complicaciones posoperatorias importantes (grados 3-5) en un paciente (9%) en el grupo de cirugía abierta (grado 5) y en 2 (9%) pacientes en el grupo de cirugía laparoscópica (grado 3b). La estancia intrahospitalaria fue de 8 días (rango 6-18) en el grupo de cirugía abierta y 4 días (4-8) en el grupo laparoscópico (p = 0.036).LIMITACIONES:Los resultados a largo plazo no se pudieron evaluar de manera confiable debido al seguimiento relativamente corto del grupo de laparoscopia.CONCLUSIONES:La resección intestinal laparoscópica con linfadenectomía mesentérica central para SB-NEN parece segura y se asocia con un resultado patológico similar y una estadía más corta en el contexto de un centro de referencia terciario. Consulte Video Resumen en http://links.lww.com/DCR/B512.

Treatment of Liver Metastases from Midgut Neuroendocrine Tumours: A Systematic Review and Meta-Analysis.

Strong evidence comparing different treatment options for liver metastases (LM) arising from gastroenteropancreatic neuroendocrine tumours (GEP-NET) is lacking. The aim of this study was to determine which intervention for LMs from GEP-NETs shows the longest overall survival (OS). A systematic search was performed in MEDLINE, Embase and the Cochrane Library in February 2018. Studies reporting on patients with LMs of any grade of sporadic GEP-NET comparing two intervention groups were included for analysis. Meta-analyses were performed where possible. Eleven studies, with a total of 1108, patients were included; 662 patients had LM from pancreatic NETs (pNET), 164 patients from small-bowel NETs (SB-NET) and 282 patients of unknown origin. Improved 5-year OS was observed for surgery vs. chemotherapy (OR .05 95% CI [0.01, 0.21] p < 0.0001), for surgery vs. embolization (OR 0.18 95% CI [0.05, 0.61] p = 0.006) and for LM resection vs. no LM resection (OR 0.15 95% CI [0.05, 0.42] p = 0.0003). This is the largest meta-analysis performed comparing different interventions for LMs from GEP-NETs. Despite the high risk of bias and heterogeneity of data, surgical resection for all tumour grades results in the longest overall survival. Chemotherapy and embolization should be considered as an alternative in case surgery is not feasible.