endocrine tumours in surgical aspect....

1. Endocrine Tumours
khaing zay aung
18.5.2015

2.  Endocrine tumours of pancreas
 Neuroendocrine tumours of the bronchi
 Neuroendocrine tumours of the stomach
 Neuroendocrine tumours of the small bowel
 Multiple endocrine neoplasia

3. Endocrine tumours of the pancreas
 Insulinomas (17%)
 Gastrinomas (15%)
 Non functioning tumours
 Rare functioning tumours (RFTs)
 VIPomas (2%)
 Glucagonomas (1%)
 Carcinoid (1%)
 Somastinomas (1%)

4. Insulinomas
 The most frequent cause of primary hyperinsulinism
 80% are benign solitary tumours
 An even distribution of tumour in head, body and tail of
pancreas
 rarely, they may be located in the duodenum, splenic
hilum, or gastrocolic ligament
 90% < 2 cm in size

5.  Multiple tumours in 10%, associated with MEN I syndrome
 they are encapsulated, firm, yellow-brown nodules that are typically
hypervascular
 release large amounts of proinsulin (C-peptide and insulin) which cause
hypoglycemia
 Carcinoma in 5-10%
 Characterized by local invasion and metastatic spread to regional lymph
node and liver

6. Clinical feature and diagnosis
 Hypoglycaemia
 Symptoms reflecting the activation of ANS and release of
epinephrine together with cerebral dysfunction
 Symptoms of adrenergic overactivity
 Weakness
 Sweating
 Hunger
 Palpitation
 Tremulousness

7. Clinical feature and diagnosis contd:
 Neuroglycopenia
 Headache
 Visual disturbances
 Dizziness
 Confusion
 Seizures
 Coma

8. Clinical feature and diagnosis contd:
 Whipple's Triad
 low glucose level (<50 mg/dL)
 symptoms of hypoglycemia
 symptoms resolve with administration of glucose

9. Clinical feature and diagnosis contd:
 The most important clue to early correct diagnosis is
 The relationship of symptoms to periods of food
deprivation, exercise
 And relieve of symptoms after taking food

10. Clinical feature and diagnosis contd:
 Investigations
 Laboratory Studies
low glucose levels (< 50 mg/dL)
insulin levels > 7 U/mL
insulin/glucose ratio > 0.3
C-peptide to confirm endogenous source of insulin
(>2.5 ng/ml)

11. Clinical feature and diagnosis contd:
 Localization
CT and MRI for larger tumors
EUS can detect small tumors (<2 cm in size)
angiography showing a “blush”

12. Management:
 Preoperative
 Administration of diazoxide to prevent hypoglycaemic
attacks
 Other agents such as verapamil, growth hormone or
corticosteroids can be given
 Perioperative
 Glucose infusions

13. Management:
 Operative
 Tumour enucleation
 Pancreatico duodenectomy
 Tumour debulking
 Post operative
 Octeriotide infusion
 Systemic chemotherapy

14. Gastrinomas
(Zollinger-Ellison syndrome ZES)
 About 20% of all PETs
 Second common after insulinoma
 Male > female (3:2)
 Definition
1. Fulminating ulcer diathesis in the stomach,
duodenum or atypical sites
2. Recurrent ulceration despite adequate therapy
3. Non-beta islet cell tumour of the pancreas

15.  ¼ of ZES pations have gastrinomas as part of MEN-1
syndrome
 Gastrinoma in MEN-1 are less malignant but frequently
multifocal
 Whereas sporadic types are more malignant and solitary
 Arises in pancreas in about 75%
 Extrapancreatic sites
 Duodenum – most common
 Omenta
 Liver
 Gastric antrum

16.  90% of gastrinomas are located within Passaro's triangle

17. Clinical feature and diagnosis:
 Present with severe peptic ulcer disease
 Typical dyspeptic pain which is more severe and less
responsive to medical treatment
 May complaint of co-existing diarrhea
 Or steatorrhoea
 Peptic ulcers in duodenum or even in jejunum because of
mucosal injury
 May present with ulcer complications

18.  Investigations
1. Laboratory
 Gastric pH below 2.5
 Serum gastrin concentration >1000 pg/ml
 Secretin test – positive when serum gastrin of >200
pg/ml over pretreatment value
1. Imaging
 Endoscopy
multiple ulcers
large gastric rugal folds
mucosal edema
jejunal hypermotility

19. Localization
CT (not for small tumors)
MRI (liver metastases)
SRS with radiolabeled octreotide
EUS

20. Differential diagnosis
 Idiopathic peptic ulcer disease
 Chronic idiopathic diarrhea
 GORD
 Chronic atrophic gastritis
 Gastric outlet stenosis
 Retained antrum after gastric resection

21. Management
 Medical treatment
 Proton pump inhibitors
 Octreotide – to control acid hypersecretion
 Systemic chemotherapy – in patients with diffuse
metastatic gastrinomas
(streptozotocin in combination with 5-FU or doxorubicin
is the first line of treatment)

22. Management contd:
Surgical treatment
Indications for surgery
 Surgical exploration should be performed in all
patients without diffuse metastases, to remove known
malignant gastrinomas or benign ones

23. Management contd:
 Pancreatic gastrinomas
 Most are solitary
 Located in the head of the gland or uncinate process
 Enucelation with peripancreatic lymph node dissection is the
procedure of choice
 Body or tail – enucleation with distal resection
 Duodenotomy is indicated in patients with MEN-1 syndrome

24. Management contd:
 Duodenal gastrinomas
 Smaller tumours <5mm can be enucleated with the
overlying mucosa
 Larger ones are excised with full thickness of the
duodenal wall

25. Non-functional endocrine
pancreatic tumours
 NF-PETs – when they do not cause clinical syndrome
 Incidence
 30-50% of all PETs
 5th
to 6th
decade of life

26.  Pathology
 Cannot differentiated from functional ones by
immunohistochemistry
 Usually larger (>5cm)
 Unifocal
 May distribute throughout the pancreas (head to tail
ratio of 7:1:1:5)

27.  Clinical features
 Usually late
 May present with various non-specific symptoms
 Jaundice, abdominal pain, weight loss and pancreatitis
 Biochemical diagnosis
 Increased level of chromogranin A (50-80%)
 Chromogranin combined with PP (sensitivity 84-96%)
 Differential diagnosis
 Important to differentiate from exocrine counterpart
 Because of their good prognosis

28. Differences between pancreatic cancer and NF-
PETs
Pancreatic cancer NF-PETs
Tumour size <5 cm >5 cm
CT scan Hypodense & no calcifications Hyperdense & calcifications
possible
Chromogranin A in blood Negative Positive
Somatostatin receptor
scintigraphy
Negative Positive

29. Management
 Medical treatment
 When surgical excision is not possible
 Chemotherapy – streptozotocin, octreotide &
interferon

30.  Surgical treatment
 Should be considered in malignant NF-PETs, even with
distant metastasis
 Pre-op tumour localization by USG or CT as they are
usually large
 Major goal is the potentially curative resection
 Partial pancreaticoduodenectomy as well as the
synchronous or metachronous resection of liver
metastases

31. RFTs
Tumour Incidence
(%)
Presentation Malignancy
(%)
VIPoma 4 Profuse watery diarrhea, hypotension, abd
pain
80
Glucagonoma 4 Migratory necrolytic skin rash, glossitis,
stomatitis, angular cheilitis, diabetes,
severe wt loss, diarrhea
80
Somatostatinoma <5 Cholelithiasis, diarrhea, neurofibromatosis 50
Carcinoid <1 Flushing, sweating, diarrhea, oedema 90
ACTHoma <1 Chushing’s syndrome >90
GRFoma <1 Acromegaly 30

32. Neuroendocrine tumours of stomach &
small bowel
 All cells of the system secret
 neuroendocrine markers such as synaptophysin,
chromogranin A and neurone-specific enolase (NSE)
 Peptide hormones that are stored in granules s/a
serotonin, somatostatin, PP or gastrin

33. Neuroendocrine tumours of stomach
 5% of all NETs of the GIT
 ~0.2 cases per 100,000 population
 4 different types of gastric NETs
 Type 1 & 2 are small benign tumours
 Arise from endochromaffin cells of gastric mucosa

34. Neuroendocrine tumours of stomach
contd:
 Type 1
 Most frequent of all gastric NETs
 ~ 80%
 Mostly in elderly women
 Chronic atrophic gastritis and achlorhydria resulting in chronic
hypergastrinaemia
 Usually no symptoms
 Usually detected during gastroscopy for other reasons

35. Neuroendocrine tumours of stomach
contd:
 Endoscopic resection is the treatment of choice
 Antrectomy and resection of ECLomas - only when recurrent disease
and multiple ( at least >1 cm & infiltration into submucosa)
 Type 2
 Pathogenesis & treatment is similar to that of type 1
 Hypergastrinaemia in type 2 is the result of MEN-1 syndrome
 With multiple gastrinomas in the duodenum or rarely in the pancreas

36.  Type 3
 Rare
 Sporadic
 Solitary tumours of unknown origin
 Usually larger than 2 cm
 Serum gastrin level is usually normal
 Gastrectomy and lymph node dissection and resection
of liver metastases is the treatment of choice

37. Neuroendocrine tumours of stomach
contd:
 Type 4
 Present as large ulcerative malignancies
 Resemble to adenocarcinomas
 Should be treated accordingly
 Type 3 & type 4 tumours usually carries poor prognosis

38. Neuroendocrine tumours of the small
bowel
 Mostly refered to as carcinoid tumours
 Also called midgut tumours
 Secrete serotonin and substance P
 Almost always malignant
 Metastasize early to regional lymph nodes and to the
liver

39.  They produce serotonin causing carcinoid syndrome
 But only in the patients with large volume of liver
metastases
 Or tumour infiltrating into IVC bypassing the liver

40. Clinical features
 Acute/chronic, recurrent/ persistant abdominal pain
 Ileus or
 Rarely lower GI bleeding may occur
 Sudden painful reddening of the face & chest
 Diarrhoea
 Bronchospasm
Carcinoid
syndrome

41. Clinical features cont:
 Abdominal symptoms are also caused by obstruction of
the lumen of appendix and undergone appendicectomy
for symptoms of acute appendicitis
 Polypoid NET of terminal ileum may cause intussception
 Pain is caused by chronic ischaemia of the bowel
 Resulting from mesenteric lymph node metastasis
 Or constrition of the mesenteric arteries and fibrosis
of the mesentery
 So called desmoplastic reaction

42. Clinical features cont:
 Diagnosis
 Assessment of 5-HIAA in 24 hr urine sample
 CT or MRI may show the primary tumour, mesenteric
lymph node and liver metastasis
 Best method for staging NET is octerotide scan
 Will show all the tumour deposits if they are large
enough and have a high somatostatin receptor density

43. Management
 Surgical procedure
 Should be undertaken as soon as the diagnosis is made
 The main goal is resection of the primary tumour and
lymph node metastases
 Liver metastases can be treated by chemotherapy of
tumour embolization
 Also liver transplation can be performed
 Symptoms of carcinoid syndrome can be treated by
somatostatin and its analog

44. Bronchopulmonary carcinoid tumours
 80% are found in main bronchi
 Slow growing and highly vascular
 Mostly benign but ~ 15% are metastasize
 Patient may present as recurrent pneumonia or haemoptysis or
rarely with carcinoid syndrome
 Surgical excision is preferred because of excellent prognosis
after complete excision
 Small peripheral tumours – segmental or wedge resection is
sufficient
 Lobectemy or pneumonectomy may be needed in central
tumours

45. Multiple Endocrine Neoplasia
 An inherited syndrome
 Characterized by a combination of benign and malignant
tumours in different endocrine glands
 Two main types
 MEN-1
 MEN-2

46. MEN-1
 Wermer’s syndrome
 Caused by germline mutations in the menin gene located
on chromosome 11
 Tumours in anterior pituitary gland
 Mostly prolactinoma or non functioning tumours
 Or microadenomas

47. MEN-1
 Hyperplasia of parathyroids
 Causing primary hyperparathyroidism (90-100%)
 Pancreaticoduodenal endocrine tumours
 Most common syndrome-associated cause of death
 Most common functional tumour is gastrinoma
followed by insulinoma

48.  Adrenal tumours and other organ manifestation
 Nearly 40-50% of patients
 Mostly non functioning adenomas are found
 Rarely adrenocortical carcinoma and
pheochromocytomas are found

49. Operative therapy for MEN 1
 Parathyroids
 Total parathyroidectomy including cervical
thymectomy or 3 ½ gland resection leaving
approximately 50 g of gland
 Endocrine pancreas
 Should be operated to prevent liver metastasis
 Pylorus preserving pancreaticoduodenectomy is
recommended

50.  Anterior pituitary gland
 Indicated for non functional tumours or medical
therapy for prolactinoma fails
 Adrenal tumours
 Functional tumours and >4 cm non functional tumours

51. MEN-2
 Subdivided into FMTC, MEN 2a & MEN 2b
 MEN 2 is caused by mutations in RET proto-onco gene
located on chromosome 10
 MEN 2a
 MTC
 pHPT
 Mostly bilateral pheochromocytoma
 MTC + pheochromocytoma alone is called Sipple’s
syndrome

52. MEN-2
 MEN 2b
 MTC
 Pheochromocytomas
 Characteristic facial and oral mucosal neuromas and
intestinal ganglioneuromatosis accompanied by
marfanoid habitus

53. MEN-2
 Medullary thyroid carcinoma
 Multicentricity and often accompanied by C-cell
hyperplasia
 More aggressive in MEN 2b
 Primary hyperparathyroidism
 Less common in MEN 2b
 Milder clinical course
 Phaeochromocytoma
 10-15%
 Almost always benign
 Can be bilateral

54. Operative therapy for MEN 2
 Medullary thyroid carcinoma
 Mutation carriers can be operated on before the
disease develops
 Pheochromocytoma
 Unilateral or bilateral subtotal resection is feasible
 Primary hyperparathyroidism
 More difficult because associated with MTC
 Localization procedures should be done with targeted
approach