Principles of diagnosis, work-up and therapyThe Gastroenterologist’s role

Dr. Christos G. Toumpanakis MD PhD FRCPConsultant 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” associateddiarrhoea + 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

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 1 gNEN

Type 2 gNEN

Type 3 gNEN

Type 4 gNEC

The surrounding mucosa

should be ALWAYS biopsied

especially in gastric NENs

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 related

deaths

- < 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 2017Furnari 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 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 2018Rossi et al, United European Gastroenterology J 2017Telese 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

fistulaZilli 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 2015

Manta et al, J Gastrointest Liv Dis 2016

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 ?

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

Type I G-NEN

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

Thank you