Neuroendocrine tumors (Gastroduodenal)

1. NEUROENDOCRINE TUMORS
(GASTRODUODENAL)
PRESNTOR – Dr Jairaj V Bomman

2. Introduction
Molecular pathogenesis
Classification/Grading
Gastric NET
Duodenal/Ampullary NET
• Biomarkers
• Tumor Localisation
• Imaging
Diagnosis
Treatment

3. Introduction
• Neuroendocrine tumors (NET) originate from the cells of diffuse neuroendocrine system.
• Gastroenteropancreatic NETs (GEP-NETs) constitute –
• GI-NETs, also known as carcinoid tumors, originating from GI tract, and
• pNETs, originate within the pancreas
• GI NET originate from Enterocremaffin cells and pNET from islands of Islets of Langerhans
• The origin of these cells is thought to be from Neural crest cells, currently now the source
is proposed to be from both Neural crest cells and also from Endodermal lineage cells.

4. • GEP-NETs are characterized by a propensity to produce hormones and other vasoactive
substances.
• Tumors that secrete hormones resulting in a clinical syndrome are known as “functional
tumors”
• Tumors that are non secretory or secrete inactive proteins/peptides are termed
“nonfunctional.”

5. Molecular pathogenesis
• Less well understood than pNET
• CDKN1B mutations are noted in 8%
• Epigenetic changes are fundamental
• Global DNA hypomethlation is characteristic feature of SINET
• Dysregulated mTOR pathway
• Over expression of angiogenic factors – VEGF, FGF, PDGF
• Poorly Differentiated – Mutations in KRAS/MYC/FOS and suppression of p53, RB gene (as
these mutations are common in Non NET )

6. Classification
• ENET 2006/2007
• WHO 2010
• WHO 2017
• AJCC 8TH STAGING

7. ENETS 2006/2007
Grading
Later endorsed by the
WHO 2010
classification
Grade Mitotic
count (per
10 HPF)
Ki-67
(%)
G1 (low) <2 ≤2
G2 (intermediate) 2–20 3–20
G3 (high) >20 ≥20

9. TNM STAGING(8th AJCC)
• Tumor size
• Tx: Primary tumor cannot be assessed
• T0:No evidence of primary tumor
• T1:Invades lamina propria or submucosa and less than or equal to 1cm in size
• T2:Invades muscularis propria or>1cm in size
• T3: Invades through the muscularis propria into subserosal tissue without
penetration of overlying mucosa
• T4: Invades visceral peritoneum(serosal) or other organs or adjacent structures

10. • Regional lymph nodes
• Nx: Regional lymph nodes cannot be assessed
• N0: No regional lymph node involvement occurred
• N1: Regional lymph nodes metastasis <12 in number
• N2: Large mesenteric masses(>2cms) and/or extensive nodal deposits(12 or greater),
especially those that encase the superior mesenteric vessels
• Metastasis
• M0: No distant metastasis
• M1: Distant metastasis
• M1a: Metastasis confined to liver
• M1b:Metastasis in at least 1 extra hepatic site
• M1c: Both hepatic and extra hepatic Metastasis

11. Gastric NET
• GI-NETs (carcinoid tumors) comprise nearly 70% of all carcinoid tumors (≈25% are in the
respiratory tract)
• GI-NETs most commonly occur in the small intestine (Ileum, followed by duodenum and
jejunum), rectum, appendix or stomach
• Gastric NETs comprise 2% to 6% of all carcinoid tumors and 0.3% of all gastric tumors

12. Classification of Gastric NET
• Gastric NETs are classified into 3 types –
• Type 1
• Type 2
• Type 3
• The mucosa of the gastric antrum and the
body/fundus should be sampled, along with removal
or biopsy of the lesions (for appropriate
classification.)

13. Type 1 Gastric NET
• Represent 70-80% of Gastric NETs
• Chronic atrophic gastritisHigh gastrin(>1000pg/ml)Trophic effect on
ECL cellPolyp and tumor formation
• Small, multiple and appear as polypoidal with mucosal atrophy
• Random mucosal biopsyadditional intramucosal carcinoid
• Well differentiated and minimally invasive
• Histology – Mucosa (27%), Submucosa (64%) and muscularis propria (9%)

14. Type 2 Gastric NET
• Least common
• Almost always associated with MEN-1 (Wermer Syndrome)
• Rarely is found in patients with sporadic form of ZES
• Multiple and polypoidal but larger than type 1
• A/w ECL cell hyperplasia with hyperplastic gastric mucosa
• Well differentiated – mucosa (15%), Submucosa (60%) and Muscularis
propria (10%)
• More invasive and increased metastasis than type 1

15. Type 3 Gastric NET
• Not a/w hypergastrinemia/alterations in acid secretion
• Solitary, sporadic and not a/w other diseases of stomach
• On EGD - Single, large, infiltrative>ulcerative
• Histologically - Well differentiated
• More invasive and malignant than other types
• May present with GI bleeding or advanced malignancy, prompting
EGD.
• Most of them are already invasive.

17. Carcinoid Syndrome in Gastric NET
Seen in a small percentage of patients with type 2 and type 3 gastric NETs.
The gastric NETs may lack l-amino acid decarboxylase, and thus instead of producing
serotonin, they secrete its unprocessed precursor, 5-hydroxytryptophan (5-HTP)
The patients may present with atypical flush, c/b prolonged red-purple flush
involving the trunk and extremities.
Rare gastric NETs can also release histamine, which can result in bronchospasm,
itching, cutaneous flushing, and lacrimation.

18. Duodenal and Ampulla
of Vater NET
• Comprise 5% of all GI-NETs
• Accounts to 4 % of total and 22 % of small intestinal
carcinoids
• 90% are solitary and are multiple in 9% to 13%.
• Mean age sixth decade
• Duodenal NETs are generally small, with a mean
diameter of 1.2 to 1.5 cm; 75% of them are smaller
than 2 cms.
• 63% limited to mucosa/submucosa, still can
metastasize to lymph nodes (19% to 60% of cases),
and liver metastases occur in less than 10%.
Duodenal Ampullary
Incidence >90% in D1/D2
of duodenal
NET
18-20% of
duodenal NET
Type Gastrinoma is
more cmmon
Somatostatinomas
and Gangliomas
are more common
Ass. Syndrome 6% of all are
Ass. With
MEN1
25% Ass. With NF1
Clinical
features
Asymptomatic,
ZES (10%),
Carcinoid
Syndrome (4%)
Obstructive
jaundice

19. • In MEN-1/ZES patients, 80% to 90% of Gastrinomas are in the duodenum, and they invariably are
multiple.
• 50-75% are well differentiated
• Duodenal NETs can be divided into 5 subtypes –
• Duodenal gastrinomas (48% to 66%),
• Somatostatinomas (15% to 43%),
• Nonfunctioning NETs (i.e., not associated with a clinical syndrome; 19% to 27%)
• Gangliocytic paraganglioma (<2%), and
• Poorly differentiated neuroendocrine carcinomas (<3%).
• Carcinoid syndrome is almost never observed with duodenal NETs
• 5 year survival 80-95%

20. Diagnosis
• To assess –
localisation of primary tumor,
depth of mucosal invasion,
histological grading and differentiation,
Biomarkers (serological and cytological),
lymph node status,
liver metastasis and distant metastasis.

21. Biomarkers
• Non specific markers
• Specific markers
Pathomorphological/Histological
• Well differentiated
• Poorly Differentitaed
• Grading
• Mitosis / 10HPF
• Ki-67/ Proliferative Index
Localisation
• Panendoscopy
• Abdominal US
• EUS
• Enteroscopy
• Capsule endoscopy
• CT/MRI
Radioisotope diagnostics
• Radioisotope labelled SST analogue
• Indium 111In (Octreoscan)
• Technecium 99mTc (HYNTITAC)
• Positron emitting tracer labelled SST
analogue (DOTANAC, DOTATOC,
DOTATATE)
• Intraoperative Imaging
• 18FDG PET SCAN
• Dihydroxyphenylalanine 18F-DOPA
• Meta Iodobenzylguanide 123/131I-MIBG

22. Biomarkers (Neuroendocrine markers) –
• Synaptophysin-Most sensitive
• Chromogranin-Most specific
• Non specific markers
• CD56/NCAM1
• Leu7/CD 57/B3GAT1
• PGP9.5
• Neuron specific enolase

23. • Site specific markers
• Intestinal/Pancreatic: CDX2
• Pancreatic/Rectal NETs: PDH1, ISL-1, and PAX8
• Duonedal Gangliocytic paraganglioma – S-100

24. *Zhu F, Wang M, Wang X, Tian R, Shi C, Xu M, et al. Modified technique of pancreaticogastrostomy for soft pancreas with two continuous hemstitch
sutures: a single-center prospective study. J Gastrointest Surg. 2013 Jul;17(7):1306-11.
**Yang X, Yang Y, Li Z, et al. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLos One
2015;10:e0124884
• Chromogranin A* -
• Most important marker
• Polypeptide present in the secretory granules
• Its sensitivity varies between 53% and 68%
• Specificity varies between 84% and 98%
• In a recent metanalysis
• sensitivity of 73% and specificity of 95% for the diagnosis of NETs**
• G3 NETs: Normal Plasma CgA levels

25. • Level of CgA correlates with tumor volume
• Prognostic significance in well-differentiated tumors
• False positive measurements
• Decreased renal function, liver or heart failure, chronic gastritis, inflammatory bowel
disease, hyperthyroidism, PPI use, and even benign essential hypertension and
exercise-induced physical stress.
• Also, elevations of CgA are reported in malignant non-NETs like breast cancer and
hepatocellular carcinoma.

26. *Zhu F, Wang M, Wang X, Tian R, Shi C, Xu M, et al. Modified technique of pancreaticogastrostomy for soft pancreas with two continuous hemstitch
sutures: a single-center prospective study. J Gastrointest Surg. 2013 Jul;17(7):1306-11.
Urinary 24-hour 5-HIAA -
• In small intestinal NETs (carcinoids).
• Certain common food items like bananas, eggplant, walnuts, tomatoes etc. should be
avoided for at least 48-hours prior to urine collection.
• Foregut and hindgut carcinoids: lack dopa decarboxylase thus 5-HIAA levels not much
raised

27. *Tellez MR, Mamikunian G, O’Dorisio TM, et al. A single fasting plasma 5-HIAA value correlates with 24-hour urinary 5-HIAA values and other biomarkers
in midgut neuroendocrine tumors (NETs). Pancreas 2013;42:405–10.
Plasma 5-HIAA –
• Measuring a single fasting plasma 5-HIAA level is much more convenient
• A recent study compared the 2 assays
• 115 individuals with all types of NETs (among which 72 had midgut tumors) and 47
patients with midgut tumors metastatic to the liver.
• A statistically significant correlation found between the urine and plasma assays,
indicating that these are equivalent.
• Overall, CgA seems a better tumor marker than 5-HIAA.

28. Pancreastatin –
• A posttranslational processing product of CgA
• An alternative biomarker to CgA
• Level is less susceptible to nonspecific effects
• Correlates with the number of liver metastases and also shown to be a better predictor of
tumor growth than CgA, useful for follow-up
• Increasing levels during somatostatin analogue therapy is associated with poor survival
• It has negative prognostic value, higher levels are associated with worse progression-free
and overall survival in midgut and pancreatic NETs independent of age, site, and presence
of metastases.

29. Neurokinin –
• Important marker for prognosis
• When NKA levels continue to increase despite treatment with somatostatin analogues,
patients have poorer prognosis:
• 1-year survival decreases from 87% to 40%.

30. Neuron Specific Enolase –
• NSE is elevated in only 30% to 50% of patients with NETs, especially the poorly
differentiated ones.*
• 100% sensitive but very low specificity of 32.9%
• It a useful marker for follow-up of patients with a known diagnosis of NET but is not
very useful as a diagnostic tool.

31. Histology -
• Well differentiated –
• Abundant secretory granules
• Intense expression of neuroendocrine
markers
• Arranged as well developed organoid shape
• Small cells with uniform round to oval
nuclei with salt and pepper appearance
• Poorly differentiated (NEC) –
• Solid sheetlike proliferation with irregular
nuclei
• High mitotic figures
• Less cytoplasmic secretory granules
• Limited IHC staining for neuroendocrine
markers
• Diffuse expression of Syn
• Faint or focal staining of CgA

32. Localisation –
Transabdominal USG Non-specific. Well-circumscribed, hypoechogenic, sometimes with a hyperechoic capsule, foci of
necrosis, and calcifications.
EUS GI NET – To assess depth of mucosal involvement
pNET – Sensitivity Head and Neck – 90%, Peripheral – 75-80%. Specificity 98%.
Rectal – Helpful in staging, Sens. Wall  76-93%, LN  61-88%
CT Arterial enhancement and portal venous washout
pNET – Sens 73%, Spec  96%
Hepatic Metastsis – Sens  82%, Spec  92%
Extrahepatic Mets - Sens  75%, Spec  99%
MRI Hyperintense on T1, enhance strongly after administration of contrast.

33. Radiolabelled/Radioisotope Imaging (Scintigraphy)
• Clinical indications for SRI are:
• location of the primary tumour,
• determination of the stage of the disease,
• monitoring of the patient following radical surgical treatment,
• assessment of the effectiveness of the applied treatment and
• qualification of patients for antiproliferative treatment with SSA and targeted
radioisotope therapy.

34. Isotope diagnostics using indium-labelled
111In-pentreotide (OctreoScan®)
• High affinity to SSTR2
• Lower affinity to SSTR5 and SSTR3
• No affinity to SSTR1 and SSTR4.
• The sensitivity is 54–86%, with an average of 80%.
• Disadvantage –
• High radiation exposure
• High cost
• Long duration
• New scans have high resolution and sensitivity

35. Diagnostics imaging with technetium-labelled
somatostatin analogues (99mTc) –
HYNICTOC/HYNICTATE
• The physical properties of 99mTc significantly increase the quality of imaging,
compared to 111In-pentreotide.
• Scintigraphy of choice if PET facility is not available
• Advantage –
• Low exposure
• Better quality
• Low time consuming

36. Diagnostics imaging with positron emitting tracer-
labelled somatostatine analogues –
DOTATOC, DOTANOC, DOTATATE
• Test of choice when PET facility is available
• Tracer – 68 Gallium ;
• SST Analogue –
• DOTATOC  92% Sens
• DOTANOC  96% Sens
• DOTATATE  97% Sens with specificity of 90% for all
• SUVmax α Density of SST receptor on cells
• Best of results for PRRT is when SUVmax is >2.2 times liver or >16.4
• Advantage –
• Most sensitive in detecting occult primary and also osseous metastasis (4th MC)
• 64Cu Tracer – newer method, longer half life of more than 24 hrs, still in trail

37. Intra-operative imaging of somatostatin
analogues
• Done by using intra-operative scintillation probes, detects the receptors on organs,
lymph nodes.
• Helps in accurate assessment of lymphnode status and excision

38. Radioisotope diagnostics with
radioisotope- labelled
dihydroxyphenylalanine 18F-DOPA
• Sensitivity of 65–96% in the diagnosis of NETs.
• Appears to be useful in the case of functional pancreatic tumours and in other
GEP NETs, if SRI is negative.

39. Radioisotope-labelled Meta-
Iodobenzylguanidine 123/131I-MIBG
• It accumulates in cells via the VMAT1 and VMAT2 mechanism.
• Imaging with the use of 123/131I-MIBG is performed primarily in
pheochromocytoma and neuroblastoma.
• Low sensitivity ⁓ 50%, i.e, lower than OctreScan
• May be useful in SRI Negative NET

40. Treatment
• Gastric NET
• Duodenal NET
• Treatment of Distant metastasis
• Poorly Differentiated NET

41. Gastric NET
• Small (<1 cm) type 1 and 2 carcinoids should in most cases be
treated endoscopically.
• EGD surveillance should be at least yearly.
• Type 1 and 2 gastric carcinoids 1 to 2 cm in size, there is not
complete agreement on the best treatment.
• In patients with high-risk tumors (e.g., size > 2 cm, relatively high
Ki-67 index), a surgical wedge resection can be considered.
• In patients with numerous type 1 gastric carcinoids, antrectomy
eliminates the hypergastrinemia driving ECL cell growth and is
effective in over 80% of patients.
• Type 3 gastric NETs require imaging for disease staging.
• Small (<1 cm) type 3 gastric carcinoid without any risk factors may be
treated conservatively by endoscopic mucosectomy.
• If no distant metastases, these patients should be managed
surgically.
• Patients with advanced metastatic gastric carcinoids of type 1
(rare), 2 (uncommon), or 3 require systemic antitumor therapies.

42. GASTRIC NET
G1/G2 NET
Fnal
Resection irrespective
of size
Non Fnal.
Size
<1cms
EMR/ESD
1-2cms
EUS
Beyond
Surgical resection
Limited to submucosa
EMR/ESD
>2cms/High Pri.
Surgical resection
G1 with
multiple Mets
Antrectomy may be
helpful
G3
No distant metastasis
1-2cms
Surgical resection
< 1cms
EMR/ESD
Distant
metastasis/Advanced
Carcinoma*

43. Duodenal/Ampullary
NET
• Duodenal NET –
• <1cms – EMR/ESD
• 1-2cms – Surgical resection
• > 2cms – Surgical resection
• Ampullary NET –
• Surgical resection with LN dissection irrespective
of size
• Gastrinoma –
• Duodenotomy with LN dissection

44. DUODENAL/AMPULLA OF VATER NET
AMPULLARY NET
Surgical resection
with LN status
NON AMPULLARY
<1 cms
EMR/ESD
1-2 cms
Surgical
Resection
>2 cms
Surgical
resection
LN Positive
Irrespective of
size
Surgical
resection
GASTRINOMA
Duodenotomy
with LN
dissection

45. Treatment of
Distant
Metastasis
Metastatic NETs are relatively slow-growing (compared with
more common adenocarcinomas). Poorly differentiated
neuroendocrine carcinomas are highly aggressive
• Cytoreductive surgery
• Liver directed nonsurgical therapies
- Ablation
- Embolisation of Hepatic artery
- Hepatic radioembolization
• Liver transplant
• Anti proliferative treatment
• Somatostatin analogs, INF α
• Everolimus
• Sunitinib
• PRRT
• Cytotoxic chemotherapy

46. Cytoreductive Surgery -
• Removal of resect able metastatic tumor by - cytoreductive surgery, debulking,
and metastasectomy
• Hepatic cytoreductive surgery is recommended if more than 90% of liver
metastases can be resected.
• 5-year survival rates of 75% to 80% and occasional cures are noted.
• Possibility seen in only 5% to 15% of patients.

47. Liver directed nonsurgical therapies –
• Ablation –
• RFA, PEI, Crytherapy performed either during surgery or percutaneously
• Embolisation of Hepatic Artery –
• TAE or TACE with Cisplatin, Doxorubicin, 5-FU, Streptozocin
• 60% to 100% of patients have symptomatic improvement,
• 25% to 86% have an objective tumor response for variable period of time.
• In patients with the carcinoid syndrome, symptom reduction is seen in 64% to 75%, and 5-
HIAA excretion/tumor markers in 50% to 70%.
• Hepatic Radioembolization –
• Radioembolization using 90Yttrium (90Y) microspheres, referred to as selective internal
radiation therapy (SIRT)
• Two types of 90Y microspheres can be used: resin (SIR-spheres) and glass (Thera Spheres)

48. Liver Transplantation –
• In one review, the overall 5-year survival rate after transplantation was 52%, and disease- free survival was 30%.
• In the UNOS database, over all 1, 3, and 5 - year survival rates were 81%, 65%, and 49%, respectively
• Factors predicting a poor outcome –
• Major resective surgery concurrent with the liver transplant, poor tumor differentiation, and
hepatomegaly
• age older than 45,
• hepatomegaly, and major or minor resective surgery concurrent with liver transplantation.
• may include a primary NET in the duodenum or pancreas,
• extrahepatic metastases at the time of transplantation,
• extensive (>50%) liver involvement, and
• Ki67 index above 10%.

49. Somatostatin Analogues –
• SSAs control hormone release from functional NETs and also have an inhibitory effect on tumor
growth.
• Except for insulinomas, over 90% of all well-differentiated GEP-NETs possess somatostatin
receptors.
• Mechanism –
• Exact mechanism is not known
• Activates intracellular cascades that reduce cell proliferation.
• Inhibit the release of growth factors from the NET or from adjacent cells, and
• Possess anti growth effects on other cells that may contribute to cancer growth (e.g., vascular,
stromal, immune cells).

50. • PROMID (placebo-controlled, prospective, randomized study in patients with metastatic
neuroendocrine midgut tumors), Phase III trail, well-differentiated, low-grade metastatic
midgut NETs to receive octreotide LAR 30 mg every 4 weeks versus placebo.
• Median time to progression, the primary endpoint, improved from 6 months on placebo
to 14.3 months with octreotide LAR (P < .001).
• There was no significant effect on overall survival.

51. • CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine
tumors) Phase III trail.
• Enteropancreatic NETs (somatostatin receptor positive, ki-67 index ≤10%) were
randomized to receive lanreotide 120 mg every 4 weeks versus placebo.
• Median progression-free survival (PFS) was 18 months with placebo but had not been
reached with lanreotide (HR 0.47; P < .001).

52. Interferon – α –
• Effective at controlling symptoms of hormone excess states in functional GI-NETs, also has
antiproliferative effects that primarily result in disease stabilization (30% to 80%) rather than
causing a decrease in tumor size (<15%).
Sunitinib –
• GEP-NETs are highly vascular tumors, expressing both VEGF and its receptor (VEGFR).
• Inhibitor of a number of tyrosine kinase receptors including PDGFRs, VEGFR-1, VEGFR-2, c-KIT,
and FLT-3.
• In a placebo-controlled trial, patients with progressive, unresectable, metastatic, well-
differentiated pNETs were randomly assigned to receive either oral sunitinib (37.5 mg/day) or
placebo.
• Median PFS increased from 4.5 to 11.4 months (HR 0.42; P = 0.001) and was associated with a OS
benefit.

53. Everolimus –
• mTOR cascade plays an important role in the growth of NETs, especially pNETs.
• RADIANT 3* study, oral Everolimus 10mg/day V/s placebo. PFS ↑ 4.6 to 11 months with no
improvement OS (p<0.0001)
• RADIANT 2 study, (Oct LAR 30mg/month + Everolimus) V/s (Oct LAR + placebo). PFS 16.4 V/s
11.3 (p=0.026)
• RADIANT 4 study, evaluated everolimus V/s placebo in 302 patients with nonfunctional GI and
lung NETs. Improvement in median PFS from 3.9 months on placebo to 11.0 months with
everolimus (HR 0.48, P < .001).
• After this study Everolimus was approved for NET management.
* RAD001 in Advanced Neuroendocrine Tumours (RADIANT)

54. Peptide Receptor Radionuclide Radiotherapy 177Lutetium-
Dotatate –
• Radioisotopes like 90 yttrium and 177Lutetium are used with SSA like Octreotide or
Octreotate.
• 90Y have penetrance range of 12mm, and that of 177Lu of 2mm.
• NETTER – 1 (Neuro Endocrine Tumor Therapy Trail 1) phase III study, included well
differentiated mid gut NET. ( 4 cycles of 177Lu – Dotatate 200 mCu q8 weekswith Oct LAR
30mg V/s Oct LAR 60mg q4 weeks) Median PFS was 8.4 months high dose Oct arm and
was not reached with other group.
N Engl J Med 2017;376:125-35.

55. Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 6; 10.6004/jnccn.2018.0056

56. Thank you