Dr. Christos G. Toumpanakis MD PhD FRCP AGAF

Consultant in Gastroenterology/Neuroendocrine Tumours

Honorary Associate Professor, University College of London

Neuroendocrine Tumour Unit - ENETS Centre of Excellence

ROYAL FREE HOSPITAL, London,UK

The role of Gastroenterologist

in the management of GEP - NEΝs

DISCLOSURE OF INTEREST

NOVARTIS: advisory board, research grants, educational grants, honoraria for lectures

IPSEN: advisory board, research grants, educational grants, honoraria for lectures

AAA: research grants, educational grants, honoraria for lectures

Lexicon: advisory board

PFIZER: advisory board, educational grants

DIAGNOSTIC APPROACH

• 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 abdominalpain due to IBS

• Usually young females• Non-secretory diarrhoea

• Alternating with constipation•Abdominal pain settling with defecation,

not occurring during the night

GEP – NETs

• Small bowel NETs (Carcinoid syndrome & other causes)

• VIPomas (chronic diarrhoea, dehydration and hypokalemia)

• Gastrinomas (chronic diarrhoea that responds to PPIs)

• Glucagonomas (+ other features of those tumours e.g migratory necrolytic erythema)

• Somatostatinomas (steatorrhoea)

Non-GEP NETs

• Bronchial NETs (carcinoid syndrome)

• Medullary Thyroid Carcinomas

NETS THAT CAN CAUSE CHRONIC DIARRHOEA

DIFFERENTIAL DIAGNOSIS OF

PERSISTENT DIARRHOEA IN SMALL BOWEL NETS

Refractory Carcinoid Syndrome

SteatorrhoeaBile acid malabsorption

Small bowel bacterial overgrowthMesenteric ischemia

DIAGNOSTIC APPROACH

• 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 1 gNEN

Type 2 gNEN

Type 4 gNEC

The surrounding mucosa should be ALWAYS biopsiedespecially in gastric NENs

Type 3 gNEN

Types of G-NENs

Type I Type ΙΙ Type ΙΙΙ

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

Gastric p H Alkaline Hyperacid Normal

Metastases < 5 % 10 – 30% 50 – 100%

Tumour relateddeaths

- < 10% 25 – 30%

MiNEN

(? type 4)

6 – 8%

Very aggressive

Mixed histological

characteristics

Metastases > 80%

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 (DBE)

� 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 endoscopyDBE 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 loco-regional 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

� 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 pre-operative

setting, thus predicting the risk of developing

pancreatic fistula

Zilli at al, Dig Liver Dis 2018

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 2015Manta et al, J Gastrointest Liv Dis 2016

Endoscopic resection in Gastric -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

EUS-guided RFA for pancreatic NENs

� Two devices are currently used:

- HabibTM EUS-RFA catheter; EMcision Ltd., London, UK)

- EUSRA from STARmed, Korea or HybridTherm Probe [HTP], from

ERBE) that resembles the conventional EUS FNA needle.

� The controlled heating of the target lesion can be visualized real-time

with EUS as the appearance of echogenic bubbles around the

needle tip.

� More than one zone in the lesion can be ablated depending on its

size .

Lakhtakia, Clin Endoscopy 2017

Results of EUS-RFA in p NENs

No of

ptsTumour Mean size

in mm

RF sessions Outcome Recurrence Complications

Armellini et al 1 P NET 20 1 Complete - None

Rossi et al 1 P NET 9 1 Complete None at 34 mo None

Pai et al 2 P NET 27 1,2 Necrosis None in 1 mo None

Lakhtakia et al 3 INSULINOMAS 18 2 Size reduction None in 12 mo None

Lakhtakia, Clin Endoscopy 2017

Take Home messages

� Many NETs can cause chronic diarrhoea

� Consider also other causes of diarrhoea, than refractory carcinoid syndrome, in small bowel

NETs

� 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

Thank you

very much