GIT NET

1. GIT-Neuroendocrine Tumors/NET
Dr Gebrekirstos Hagos
Clinical Oncology R-I
AAU-SoM
October 30,2018

2. Outlines of presentation:
• Introduction
• NET-Distribution
-classification -Grade
-Epidemiology - Pathophysiology
-Molecular biology - Clinical features

3. Introduction
• Neuroendocrine cells are cells that receive
neuronal input (neurotransmitter) release
messaging molecules (hormone) to the blood.
• These hormones control many body functions.
• So they brings neural and endocrine
integration,a process know as neuroendocrine
integration.

4. Introduction…
• Pituitary gland, parathyroid glands and inner
layer of adrenal gland (adrenal medulla) are
almost made up of neuroendocrine cells.
• Other NEC are found scattered through out,
mainly GIT, Respiratory tract and pancreases.
• These NEC found scattered throughout these
organs are referred to as the diffuse
neuroendocrine system

5. Neuroendocrine cells/NEC

6. • This diffuse neuroendocrine cells don’t form
an actual organ like the adrenal or thyroid
glands(Instead scattered)
• GIT has more neuroendocrine cells than any
other part of the body so is commonest origin
of NET(64% of NET cases).

7. Neuroendocrine tumors/NET
• Derived from the diffuse neuroendocrine system
that is composed of peptide- and amine-
producing cells which secrete different hormones
depending on the site of origin.
• NETs are composed of monotonous sheets of
small round cells with uniform nuclei and
cytoplasm.
• Traditionally classified based on their embryonic
divisions (foregut, midgut, or hindgut) of the
alimentary tract

9. GIT-NET
• Gastroenteropancreatic NENs has evolved
over the past two decades & divided into two
major categories:
I) Well-differentiated neuroendocrine tumors
(NET)
II) Poorly differentiated neuroendocrine
carcinomas (NEC)

10. GIT-NET…Well differentiated
• Show a solid, trabecular, with fairly uniform
nuclei, coarsely stippled chromatin, and finely
granular cytoplasm.
• Traditionally referred to as carcinoid tumors in
GIT and pancreatic NETs (islet cell tumors) in
pancreases.

11. GIT-NET…Poorly differentiated
• Are high-grade carcinomas that resemble
small cell or large cell NEC of the lung.
• Often associated with a rapid clinical course,
so bad prognosis compared to well-
differentiated NET.

12. • Well-differentiated NETs, are further
subdivided into low grade and intermediate
grade based on proliferative rate.

13. Grading GIT-NET
• WHO classification of GIT-NET is based on
proliferative rate ,divided in to:
- Low-grade(G1) well-
-Intermediate-grade(G2) differentiated
-High-grade tumor(G3) poorly differentiated
Proliferative rate is measured using either
mitotic counts or Ki-67 labeling index.

15. GIT-NET
• progression from a lower grade (G1 or G2)
well-differentiated NET to a G3 NET can occur.
• Evidence of progression can be:
-increase in the proliferative rate
-change in tumor morphology(↑ nuclear
atypia, or development of significant necrosis)

16. Molecular pathogenesis
• Little is known about the induction & growth of
carcinoid tumors.
• Gastric NET ↑ hypergastrinemia conditions (pernicious
anemia, atrophic gastritis, ZES).
• other growth factors in some carcinoid tumors are :
- transforming growth factor-alpha
-insulin like growth factor- 1
-VEGF
-acidic and basic fibroblast growth factor
-epidermal growth factor

17. Epidemiology
• Generally GIT-NET are uncommon, but GIT
common primary site NETs(6.2/100,000)
• Incidence is increasing due to multifactorial
-increased awareness (if you don’t suspect
NET you will not Dx it!)
-improved endoscopic methods detection
Small bowel NETs (midgut carcinoids) are more
common than both foregut and hindgut

18. Esophageal NET
• Rare (<1% of GI NET)
• Common in men >60 yrs
• Seen in distal esophagus, proximal to GEJ
• On EUS they are sub mucosal mass, dimple
the mucosa.

19. Stomach-NET
• Subdivided into three categories which have different
biologic behavior and prognosis
• Type 1 -70-80 % all gastric NETs
-associated with chronic atrophic gastritis
-more common in women
-derived from enterochromaffin-like (ECL) cells
-non functioning
- Endoscopically →<1 cm
→multiple
→ polypoid lesions
→ small central ulceration

21. • Type 2 — associated with Zollinger-Ellison
syndrome, in the setting of MEN-1
-6-8% gastric NETs
-Men=women
-develop in a hyperplasia-dysplasia-neoplasia
sequence
-arise from ECL cells
-stimulated by elevated serum gastrin
levels

22. Gastric NET
• Type 3
-sporadic, no association with hypergastrinemia.
-15-20% of gastric NETs
-solitary, and grow more rapidly.
-Present with metastasis at Dx
-M:F,3:1

23. Small bowel NETs
Small bowel NETs — incidence increased in part
due to increased detection on endoscopy and
imaging studies
• NETs surpassed adenocarcinomas as the most
common small bowel tumor.
• Patients usually present in their 60s or 70s.
• Commonly located in the ileum within 60 cm of
the ileocecal valve & 42% of GI-NETs
• 25% patients will have more than one small
bowel NET at the time of discovery.

24. Small bowel NET…
• Many are asymptomatic at presentation and
are found incidentally.
• If symptomatic ,abdominal pain(51%) followed
bowel obstruction(31%),abdominal
mass(17)and GI bleeding(11%).
• Metastases to LN/liver are common, even if
the primary tumor is <2 cm in size.
• Commonly presented with carcinoid
syndrome.

25. Small bowel NET…
• Pts with metastatic NET with unknown
primary, they can harbor occult primary in
the ileum.
• So exploration and palpation of the bowel
can allow detection of the sub mucosal
primary which feel like little pea in the bowel
wall.

26. • Appendix — NETs are the most common
neoplasms in the appendix.
• NET is discovered incidentally (1 in 300
appendectomies, commonly at the tip).
• Common at age of 40s or 50s
• more common in women

27. Hind gut NET
• Includes NET of transverse,descending colon &
rectum.
• Are non secretory(not associated with
carcinoid syndrome, even when metastatic)
• If symptomatic, it is same CR adenocarcinoma
( changes in bowel habits, bleeding)

28. • Colon — in pts at their 70s during evaluation
for abdominal pain, anorexia, or weight loss.
• Incidence of functioning tumors is very low.
• More on Rt side of colon.

29. • Rectum — majority are asymptomatic .
• Found incidentally on colonoscopy that is
performed for other reason.
• Accounts 27% of GIT-NETs,1-2% rectal tumors
• 75-85% are localized at diagnosis

30. METASTATIC TUMORS
• Regardless of primary site, NETs are
characterized by metastasize to the liver.
• Patients with liver metastases may experience
symptoms related to tumor burden (eg, pain,
jaundice, early satiety) or hormonal symptoms
(eg, flushing and diarrhea, the main symptoms
of carcinoid syndrome).

32. PATHOPHYSIOLOGY
• Around 40 secretory products have been
identified in various NETs.
• The most prominent of these are:
-Serotonin - Tachykinins
-Histamine -Kallikrein
-Prostaglandin

34. Tryptophan metabolism
• Altered metabolism of tryptophan occurs in
almost all patients with the carcinoid
syndrome.
• In normal subjects, approximately 1 % of
dietary tryptophan is converted to serotonin;
(↑ to 70% in pts with carcinoid syndrome).
• Serotonin is then metabolized to 5-
hydroxyindoleacetic acid (5-HIAA)

36. Clinical features
• Can occur at any age, media age 63
• M:F, 48:52%
• Dx delayed for average 2yrs (can range for 20
yrs) due vague symptoms.
• The clinical presentation of carcinoid tumors far
underestimates their occurrence because many
are asymptomatic
• Symptoms are caused by local tumor growth,
metastatic spread or excess hormonal.

37. Carcinoid syndrome
• Symptoms mediated by various humoral factors.
Common in setting of liver metastasis b/c liver
failed to deactivate the products.
• Common mid gut, but lung & stomach NET
present with atypical carcinoid syndrome.
Flushing attack
Diarrhea
Cardiac manifestation
Wheezing and asthma like symptom
Retroperitoneal & intra-abdominal fibrosis

38. Cutaneous flushing
• Episodic flushing is the clinical hallmark of
carcinoid syndrome .
• occurs in 85 % of patients.
• Typical flush associated with midgut NET
• Begins suddenly and lasts for 30 sec to 30 min.
• Involves the face, neck, and upper chest,
which become red to violaceous or purple.

39. Cutaneous flush…
• Most episodes occur
spontaneously, but they
can be provoked by eating,
drinking alcohol, defecation,
emotional events, palpation
of the liver, and anesthesia.
• Carcinoid crisis:

40. Diarrhea
• present in 67% to 84%
• Occurs -with flushing(85% of cases)
-alone(15% of cases) .
• Described as watery and less commonly as
frothy bulky stool of steatorrhea.
• Number of stools ranges from 2 -30/day
• Most debilitating component of the syndrome

41. Cardiac valvular lesions
• occur i n 11-66%
• Carcinoid heart disease is characterized by
pathognomonic plaque-like deposits of fibrous
tissue.
• Common on right side of the heart because
inactivation of humoral substances by the lung
protects the left heart.
• Bronchospasm-10-20% of pts with the carcinoid
syndrome have wheezing and dyspnea, often
during flushing episodes.

43. References:
• Devita ------9th & 10th e
• Uptodate --2018
• NCCN------2017

44. Thank You!