Principles of diagnosis, work-up and therapy The Gastroenterologist s role Dr. Christos G. Toumpanakis MD PhD FRCP Consultant in Gastroenterology/Neuroendocrine Tumours Hon. Senior Lecturer University College of London Neuroendocrine Tumour Unit - ENETS Centre of Excellence ROYAL FREE HOSPITAL, London,UK
Diagnosis of NEΝs History and clinical examination Biochemical tests (Biomarkers) Imaging studies ( for localization of primary and metastatic lesions) Histology - gold standard
Differential Diagnosis Diarrhoea + Abdominal pain Small bowel NENs associated diarrhoea + abdominal pain Diarrhoea always secretory (persists with fasting) Abdominal pain - Even during the night - Usually periumbilical - Occurring > 2 h after meals - Not settling after defecation - Features of sub-acute bowel obstruction Diarrhoea and abdominal pain due to IBS Usually young females Non-secretory diarrhoea Alternating with constipation Abdominal pain settling with defecation, not occurring during the night
Diagnosis of NEΝs History and clinical examination Biochemical tests (Biomarkers) Imaging studies ( for localization of primary and metastatic lesions) Histology - gold standard
Diagnosis of NEΝs History and clinical examination Biochemical tests (Biomarkers) Imaging studies ( for localization of primary and metastatic lesions) Histology - gold standard
The role of upper GI endoscopy for diagnosis of gastric NEΝs Type 2 gnen Type 1 gnen Type 3 gnen The surrounding mucosa should be ALWAYS biopsied especially in gastric NENs Type 4 gnec
Types of G-NENs Type I TypeΙΙ TypeΙΙΙ Relative frequency 70 80% 5 6% 14 25% Features Usually multiple (<10mm) Usually multiple (<10mm) Usually solitary (> 20mm) Ass. diseases Atrophic gastritis ΜΕΝ-1/ Gastrinoma No Histology G1 G1 G2 / G3 Serum Gastrin Raised Raised Normal MiNEN Gastric p H Alkaline Hyperacid (? type 4) Normal Metastases < 5 % 10 30% 50 100% Tumour related deaths 6 8% Very aggressive Mixed histological characteristics Metastases > 80% - < 10% 25 30%
The role of lower GI endoscopy for diagnosis of rectal NEΝs
Role of wireless small bowel capsule endoscopy Indications : - To detect the primary (-ies) in suspected small intestinal NENs - To identify source of small bowel bleeding in NENs Sensitivity : 75 83% (CT : 62.5 %, Push enteroscopy : 44%, colonoscopy : 22%) Specificity : 37.5% Positive Predictive Value : 55% Negative Predictive Value : 60% Nujaim et al, Gastroenterology Res 2017 Furnari et al, J Gastrointersin Liver Dis 2017
Role of double balloon enteroscopy Rarely, small bowel NENs can be diagnosed only with DBE Indications : - To precisely localize the primary (-ies) in suspected small intestinal NENs - To identify +/- treat the cause of small bowel bleeding in NENs * * * # + * DBE vs Capsule endoscopy DBE identified additional lesions in 62% of patients in a recent surgical series (82% of them confirmed in histology) Gangi et al, J Gastointerstinal Surg 2018 Rossi et al, United European Gastroenterology J 2017 Telese et al, UKI NETS 2017
The role of Endoscopic Ultrasound in G-I NENs Type 1 and 2 gastric NENs: to evaluate the depth of invasion and indication to endoscopic treatment that is reserved to lesions not infiltrating beyond the muscularis propria. Type 3 gastric NENs: to stage the disease by assessing the presence of regional lymph-node involvement. To stage duodenal NENs with diameter >2 cm. To exclude locoregional lymph node metastases and thus indication for endoscopic mucosal resection. To determine the indication of endoscopic removal in Rectal NENS versus transanal excision or radical surgery, in particular for those with diameter >2 cm, by assessing depth of invasion and the presence of lymph node metastases. To follow up patients after resection. Zilli at al, Dig Liver Dis 2018
The role of Endoscopic Ultrasound in pancreatic NENs To differentiate pancreatic NENs from adenocarcinoma To localize small pancreatic NENs, mainly insulinomas or gastrinoma, before surgery, especially if other non-invasive imaging studies are negative Diagnostic accuracy of EUS Pooled sensitivity: 87% Pooled specificity: 98% Mean detection rate: 90% in suspected p NENs (mean detection rate of CT/MRI : 73%) Increased pre-op p NEN detection by 25% Puli et al, World J Gastroenterol 2013 James et al, Gastrointest Endosc 2015 Manta et al, J Gastrointest Liv Dis 2016 To stage the NEN by evaluating the presence of vascular invasion or loco-regional lymph node To evaluate the distance between pancreatic lesion and the main pancreatic duct in a preoperative setting, thus predicting the risk of developing pancreatic fistula Zilli at al, Dig Liver Dis 2018
Endoscopic management of GEP NENs
Type I G-NENs 55-years female with hypothyroidism on levothyroxin, insulin-dependent diabetes, pernicious anemia on B12, underwent an upper GI endoscopy because of persistent dyspepsia - Atrophic mucosa, multiple polyps of body and fundus < 1 cm, CLO and biopsies were taken - Atrophic gastritis with ECL hyperplasia, and well differentiated, G1 NET with Ki67 < 2%. - CLO : + (H. pylori positive) - Serum Gastrin > 400 - Serum Chromogranin : 82 - Anti-parietal cell Ab : + - Anti-intrinsic factor Ab: +
Management suggestions Endoscopic polypectomy? Annual endoscopic surveillance? Commencement of somatostatin analogues or new agents? Gastrectomy?
Type I G-NEN 45 years old male Hypothyroidism Asthma Atrophic gastritis G1 NET Raised gastrin, Chromogranin-A Positive auto-antibodies One of the polyps is measuring 1.5 cm
Management suggestions Endoscopic polypectomy? Annual endoscopic surveillance? Commencement of somatostatin analogues or new agents? The overall metastatic risk is low in type 1 g-nens and has been directly correlated with tumor size (10 mm appearing to be the cut-off) Therefore, the minimal approach should be to resect tumors 10 mm. Resection should be performed by experienced endoscopists in gastric tumors using either Endoscopic Mucosal Resection or Endoscopic Submucosal Dissection (ESD); the latter has the benefit of an en bloc resection for complete histological appraisal. Delle Fave et al, ENETS Consensus Guidelines, Neuroendocrinology 2016
Endoscopic resection in G-NENs Snare polypectomy, Endoscopic Mucosal Resection (EMR) or Endoscopic Submucosal Dissection (ESD)? 33 pts, (polyps 2 20 mm), 45% polypectomy with snare. 63.6% had recurrence (within 8 months). Merola et al, Neuroendocrinology 2011 62 pts had either EMR or ESD. The overall ESD complete resection rate was higher than that of the EMR rate (94.9% versus 83.3%, P value = 0.174). A statistically lower vertical margin involvement rate was achieved when ESD was performed compared to when EMR was performed (2.6% versus 16.7%, P value = 0.038). The complication rate was not significantly different between the two groups. Kim et al, Gastroenterol Res Pract 2014
Role of EUS for treatment of p NENs 24 patients with EUS-guided Ethanol ablation (67% insulinomas) 7 patients with EUS-guided RFA (42% insulinomas) Encouraging results in the majority of patients Mild pancreatitis in 20% in ethanol ablation, no complications in RFA Lakhtakia, Clin Endoscopy 2017
Take Home messages Upper and lower GI endoscopy provide the diagnosis of gastric, duodenal and rectal NENs Wireless capsule endoscopy can identify the primary (-ies) and cause of obscure GI bleeding in small bowel NENs Double balloon enteroscopy can localize precisely the primary (-ies) in small bowel NENs EUS can assess the depth of invasion of G-I wall, from a G-I NEN prior to endoscopic treatment EUS can be very important in diagnosis, localization, staging and pre-op assessment of p NENs EMR & ESD are the methods of choice in endoscopic treatment of gastric and rectal NENs, when indicated, with ESD being associated with higher R0 resection rates EUS RFA seems promising for endoscopic treatment of localized /functional p NENs
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