HEGAZY SURGERY

1. ENOCRINETUMOURSOFTHEPANCREAS
Dr. MOUSTAFA HEGAZY

2. ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬
‫بخير‬ ‫وأنتم‬ ‫عام‬ ‫كل‬

3. The tumours of the pancreas can
be -
A. Non-Endocrineneoplasms
B. Endocrineneoplasms
TUMOURS OF THE PANCREAS

4. FUNCTIONING
ENDOCRINE TUMOURS
OF THE PANCREAS

5. Function of the endocrine pancreas
•The endocrine cells of the pancreas are grouped in the islets of
Langerhans, which constitute approximately 1–2% of the mass of
the pancreas .
•There are about one million islets in a healthy adult human
pancreas and their combined weight is 1–1.5 g.
•There are four main types of cell in the islets of Langerhans, which
can be classified according to their secretions:
•beta cells producing insulin (65–80% of the islet cells);
• alpha cells producing glucagon (15–20%);
•delta cells producing somatostatin (3–10%);
• pancreatic polypeptide (PP) cells containing polypeptide (1%).

6. ENDOCRINE NEOPLASMS:
These are less common than non-endocrine
tumours and generally benign and sometimes
multiple. They includes:
 Insulinoma
 Glucogonomas
 Others:
- Gastrinomas
- Somatostatatinomas
- Vipomas (Vasoactive Intestinal
Polypeptide)
common

7. EVALUATION OF PANCREATIC NEOPLASMS:
 History
 ClinicalExamination
 Investigations
The specific investigations:-
 Ultrasound Scan  Histology & cytology
 CT Scan  Angiography
 MR Imaging  Laparoscopy
 ERCP

8. PANCREATIC ENDOCRINE TUMOURS
Introduction
•They account for 5% of all clinically detected pancreatic tumours.
•They consist of single or multiple, benign or malignant neoplasm.
•They are associated in 10–20% of cases with multiple endocrine
neoplasia type 1 (MEN1).
•PETs present as either functional tumours, causing specific hormonal
syndromes, or non-functional tumours, with symptoms similar to those
in patients with pancreatic adenocarcinoma.
• insulinomas, gastrinomas and non-functioning tumours represent 90%
of all PETs

9. Neuroendocrine tumours of the pancreas
•Tumour (syndrome) n Incidence (%) Presentation Malignancy
(%)
------------------------------------------------------------------------------------
-
•Insulinoma 70–80 Weakness, sweating, tremor, <10
tachycardia, anxiety, fatigue, dizziness,
disorientation, seizures
---------------------------------------------------------------------------------
•Gastrinoma 20–25 Intractable or recurrent peptic 60-80
ulcer disease (haemorrhage, perforation),
complications of peptic ulcer, diarrhoea
---------------------------------------------------------------------------------
Non-functional tumours
30–50 Obstructive jaundice, pancreatitis, 60–90
epigastric pain, duodenal
obstruction, weight loss, fatigue
--------------------------------------------------------------------------------

10. •VIPoma 4 Profuse watery diarrhoea, hypotension, 80
abdominal pain
---------------------------------------------------------------------------------
•Glucagonoma 4 Migratory necrolytic skin rash, 80
glossitis, stomatitis, angular cheilitis,
diabetes, severe weight loss, diarrhoea
---------------------------------------------------------------------------------
•Somatostatinoma < 5 Cholelithiasis, diarrhoea, 50
neurofibromatosis
---------------------------------------------------------------------------------
•Carcinoid < 1 Flushing, sweating, diarrhoea, oedema 90
---------------------------------------------------------------------------------
•ACTHoma < 1 Cushing’s syndrome > 90
--------------------------------------------------------------------------------
•GRFoma < 1 Acromegaly 30

11. FUNCTIONING ENDOCRINE TUMOURS OF
THE PANCREAS:
 These are much less common than
adeno carcinoma. The beta cell
tumours secrete (Insulin) and called
INSULINOMAS. Another functioning
tumour secrete (Gastrin) called
GASTRINOMA which come from the
islets which cannot be classified
into either alpha or beta (non-beta).

12.  Other tumours are:
a. Vipoma (Werner-Morrisonsyndrome, Pancreatic cholera)
b. Somastatinoma
c. Glucagonoma
d. HPPoma(HumanPancreatic
Polypeptide tumours)
 Slow growing and therefore carry much
better prognosis.

13. Insulinoma
Definition
•This is an insulin-producing tumour of the pancreas causing Whipple’s
triad, i.e. symptoms of hypoglycaemia after fasting or exercise, plasma
glucose levels < 2.8 mmol l–1 and relief of symptoms on intravenous
administration of glucose.
Incidence
•Insulinomas are the most frequent of all the functioning PETs with a
reported incidence of 2–4 cases per million population per year.
•Insulinomas have been diagnosed in all age groups with the highest
incidence found in the fourth to the sixth decades.
•Women seem to be slightly more frequently affected.

14. Pathology
•The aetiology and pathogenesis of insulinomas are unknown.
• No risk factors have been associated with these tumours.
• Virtually all insulinomas are located in the pancreas and tumours
are equally distributed within the gland.
•Approximately 90% are solitary and about 10% are multiple and
are always associated with MEN 1 syndrome.
Prognosis and predictive factors
•No markers are available that reliably predict the biological
behaviour of an insulinoma. Approximately 10% are malignant.
•Insulinomas of < 2 cm in diameter without signs of vascular
invasion or metastases are considered benign.

15. Clinical features
•Insulinomas are characterised by fasting hypoglycaemia and neuroglycopenic
symptoms.
•The episodic nature of the hypoglycaemic attacks is caused by intermittent insulin
secretion by the tumour.
•This leads to central nervous system symptoms such as diplopia, blurred vision,
confusion, abnormal behaviour and amnesia. Some patients develop loss of
consciousness and coma.
•The release of catecholamines produces symptoms such as sweating, weakness,
hunger, tremor, nausea, anxiety and palpitations.
Biochemical diagnosis
•A fasting test that may last for up to 72 hours is regarded as the most sensitive test.
• Usually, insulin, proinsulin, C-peptide and blood glucose are measured in 1- to 2-
hour intervals to demonstrate inappropriately high secretion of insulin in relation to
blood glucose.
•About 80% of insulinomas are diagnosed by this test, most of them in the first 24
hours.
• Continuous C-peptide levels demonstrate the endogenous secretion of insulin and
exclude factitious hypoglycaemia caused by insulin injection.

16. Differential diagnosis
•The differential diagnosis of hypoglycaemia includes hormonal
deficiencies, hepatic insufficiency, medication, drugs and enzyme
defects.
• Occasionally, differentiating insulinoma from other causes of
hypoglycaemia can be difficult.
• Nesidioblastosis is a rare disorder, mainly encountered in children,
which is characterized by replacement of normal pancreatic islets by
diffuse hyperplasia of islet cells.

17. Medical treatment of insulinoma
•Medical management is reserved only for patients who
are unable or unwilling to undergo surgical treatment or
for unresectable metastatic disease.
• Diazoxide suppresses insulin secretion by direct action
on the beta cells and offers reasonably good control of
hypoglycaemia in approximately 50% of patients.
•When surgical options to treat malignant insulinomas
cannot be applied, chemotherapeutic options include
doxorubicin and streptozotocin.

18. Surgical treatment of insulinoma
Indications for operation
•After a positive fasting test and exclusion of diffuse abdominal
metastases by ultrasound or CT scan, all patients should undergo
surgical excision of insulinoma.
Preoperative localisation studies
•Intraoperative exploration of the pancreas is the best method to use for
localisation of insulinoma.
•Preoperative localisation in more than 40 patients has shown that
insulinomas are detected in 65% of cases by endoscopic ultrasound
(EUS), 33% of cases by CT scan and abdominal ultrasound, 15% of
cases by magnetic resonance tomography ,all tumours were identified
and resected after surgical exploration and intraoperative ultrasound
(IOUS) of the pancreas after extensive mobilisation of the gland.
•For preoperative localisation of an insulinoma, EUS has the highest
sensitivity and should be used if laparoscopic resection is considered.
• If no lesion is identified and one can rely on the biochemical tests for
diagnosis, laparotomy should follow.

19. Benign insulinoma
•Surgical cure rates in insulinoma range from 90% to 100%.
•At surgical exploration the abdomen is initially explored for evidence
of metastatic disease.
•Following this, an extended Kocher manoeuvre and mobilization of
the head and then the distal pancreas is performed to explore the whole
gland.
•IOUS should then be used to confirm the presence of a tumour, to find
non-palpable lesions and also to identify the relation of the tumour to
the pancreatic duct .
•Tumour enucleation is the technique of choice .
•For superficial tumours, laparoscopic enucleation is undertaken

20. Laparoscopic enucleation of an insulinoma

21. •Tumours located deep in the body or tail of the pancreas and those in
close proximity to the pancreatic duct require distal pancreatectomy.
•Postoperatively, blood sugar levels begin to rise in most patients within
the first few hours after removal of the tumour.
•To preserve pancreatic function and reduce the risk of iatrogenic
diabetes mellitus, patients in whom tumour localization is not
successful at operation should not undergo blind resection.
Malignant insulinoma
•Aggressive attempts at resection are recommended as these tumours
are much less virulent than adenocarcinomas.

22. INSULINOMA:
 The commonest islet cell tumour and arise
from the beta cell and situated anywhere
on the surface or within the substance
of the pancreas.
 Most tumours are benign adenomas but
15% are low grade carcinomas and
secrete (insulin).

23. CLINICAL FEATURES:
Whipple described a triad of features
which typify the (insulinomas):
1. Fastingproduces fainting.
2. Duringthese “attacks”there is
hypoglycaemia.
3. The attacksmay be relieved by ingestionof
glucose.

24. INVESTIGATIONS:
1. Measurementof blood sugar in an attack.
2. Overnight fasting serumglucose and insulin level (before & after
overnight). Insulin level are estimated byradio- immunoassay.
3. Pre-operativelocalization of the tumour very important
identification at operation can be difficult.
[Combination CT Scan and selective angiography]

25. TREATMENT:
1. If the tumourlocalized surgical resection is the TR of choice
also this apply to metastases.
2. If the tumoursnot localized during surgery (Intra operative USS
can be done to localize thetumour) than resected.
3. Sub total distal resection for multiple tumoursis appropriate.
Contn…

26. 4. With negative exploration it is appropriate to perform
pancreatectomy distal to the superior mesenteric vessels.
5. The Hypoglycemic attacks may be relieved by diazoxide or
streptazotocin.

27. Gastrinoma (Zollinger–Ellison syndrome)
Definition
•Zollinger–Ellison syndrome (ZES) is a condition that includes ;
•fulminating ulcer diathesis in the stomach, duodenum or atypical sites;
• recurrent ulceration despite adequate therapy; and
•non-beta islet cell tumours of the pancreas (gastrinoma).
Incidence
•Gastrinomas account for about 20% of PETs, second in frequency to
insulinomas.
• Approximately 0.1% of patients with duodenal ulcers have evidence of
ZES.
•The reported incidence is between 0.5 and 4 cases per million
population per year.
• ZES is more common in males than in females.
•The mean age at the onset of symptoms is 38 years, and the range 7–83
years.

28. Pathology
•The aetiology and pathogenesis of sporadic gastrinomas are unknown.
• At the time of diagnosis more than 60% of tumours are malignant.
•Pancreatic gastrinomas ,sporadic disease; found in the head of pancreas.
•More than 70% of the gastrinomas in MEN 1 syndrome and most
sporadic gastrinomas are located in the first and second part of the
duodenum.
•Therefore, the anatomical area comprising the head of the pancreas, the
superior and descending portion of the duodenum and the relevant lymph
nodes has been called the ‘gastrinoma triangle’
Prognosis and predictive factors
• progression of gastrinomas is relatively slow with a 5-year survival
rate of 65% and a 10-year survival rate of 51%.
• complete tumour resection 5- year survival rates (90-100%).
• Patients with pancreatic tumours have a worse prognosis than those
with primary tumours in the duodenum.
•There is no established marker to predict the biological behaviour of
gastrinoma.

29. Clinical and biochemical features
•Over 90% of patients with gastrinomas have peptic ulcer disease often
multiple or in unusual sites.
•Diarrhoea is another common symptom, caused by the large volume of
gastric acid secretion.
•Abdominal pain from either peptic ulcer disease or gastrooesophageal
reflux disease (GORD) remains the most common symptom, occurring
in more than 75% of patients.
Biochemical diagnosis
•If the patient presents with a gastric pH below 2.5 and a serum gastrin
concentration above 1000 pg ml–1 (normal < 100 pg ml–1) then the
diagnosis of ZES is confirmed.
• Unfortunately, the majority of patients have serum gastrin
concentrations between 100 and 500 pg ml–1 and in these patients a
secretin test should be performed.
•The secretin test is considered positive if an increase in serum gastrin of
> 200 pg ml–1 over the pre-treatment value is obtained; this also rules
out other causes of hypergastrinaemia (e.g. atrophic gastritis).

30. Differential diagnosis
•The most common misdiagnoses are idiopathic peptic
ulcer disease, chronic idiopathic diarrhoea and GORD.
•Other reasons for hypergastrinaemia are chronic atrophic
gastritis, gastric outlet stenosis and retained antrum after
gastric resection.
Medical treatment of gastrinoma
•In most patients with ZES, gastric hypersecretion can be
treated effectively with proton pump inhibitors.
•Octreotide can also help to control acid hypersecretion.
•Systemic chemotherapy is utilised in patients with diffuse
metastatic gastrinomas.
•Streptozotocin in combination with 5-fluorouracil or
doxorubicin is the first-line treatment.

31. Surgical treatment of gastrinoma
Indications for operation
•The only chance for cure is surgical resection and routine surgical
exploration increases survival.
• surgical exploration should be performed in all patients without
diffuse metastases.
Preoperative localisation studies
•Pancreatic gastrinomas are often larger than 1 cm in diameter whereas
gastrinomas of the duodenum are usually smaller.
•Therefore, it is nearly impossible to identify duodenal gastrinomas by
preoperative imaging.
• Pancreatic gastrinomas are detected by endoscopic ultrasound in 80–
90% of cases, and by CT in 39% of cases, and by MRI in 46% of cases.
• In approximately one third of patients the results of conventional
imaging studies are negative.
• On the basis of recent studies and the author’s experience, either
endoscopic ultrasound or CT and SRS should be performed
preoperatively for staging.

32. Pancreatic gastrinomas
•Most pancreatic gastrinomas are solitary, located in the head
of the gland or uncinate process, and can be identified at
operation.
•Enucleation with peripancreatic lymph node dissection is the
procedure of choice.
•Rarely, tumours are situated in the body or tail and should be
treated by enucleation or distal resection.
•Even if a tumour is found in the pancreas, duodenotomy is
recommended to detect additional tumours.
Duodenal gastrinomas
The duodenum should be opened with a longitudinal incision
and the posterior and anterior walls palpated separately.
Duodenal tumours smaller than 5 mm can be enucleated with
the overlying mucosa; larger tumours are excised with
fullthickness excision of the duodenal wall.

33. Non-functional endocrine pancreatic tumours
Definition
PETs are clinically classified as non-functioning (NF-PETs) when they
do not cause a clinical syndrome.
Incidence
•NF-PETs account for 30–50% of all PETs.
•They are most often diagnosed in the fifth to sixth decades of life.
Pathology
•NF-PETs cannot be differentiated from functional tumours by
immunocytochemistry because they may also express hormones such
as gastrin, insulin, etc.
•They usually stain positively for chromogranin A and synaptophysin.
•The tumours are usually large (> 5 cm) and unifocal except in MEN 1
syndrome.
•They are distributed throughout the pancreas with a head to body to
tail ratio of 7:1:1.5.

34. Prognosis and predictive factors
•About 70% of all NF-PETs are malignant.
•Overall 5- and 10-year survival rates of 65% and 49% respectively
have been described.
•When comparing NF-PETs with functioning PETs, the NF-PETs have
a worse prognosis.
Clinical features
•Patients usually present late because of the lack of a clinical/ hormonal
marker of tumour activity.
•Therefore, in contrast to functioning PETs, patients with NF-PETs
present with various non-specific symptoms, including jaundice,
abdominal pain, weight loss and pancreatitis.
•In some cases liver metastases are the first presentation.
Biochemical diagnosis
•Increased levels of chromogranin A have been reported in 50–80% of NF-
PETs; the level of chromogranin A sometimes correlates with the tumour
burden.
• The combination of elevated chromogranin A and PP measurements
increases the sensitivity of diagnosis from 84% to 96% in NF-PETs.

35. Differential diagnosis
•Differentiation from the more aggressive pancreatic adenocarcinoma is
extremely important.
•Recognition of NF-PETs is imperative because of their resectability and
excellent long-term survival compared with their exocrine counterparts.
*Differences between pancreatic cancer and non-functioning endocrine pancreatic tumours
(NF-PETs)
Pancreatic cancer NF-PETs
Tumour size < 5 cm > 5 cm
CT scan Hypodensity Hyperdensity
No calcifications Calcifications
Possible Chromogranin A in blood Negative Positive
Somatostatin receptor Negative Positive
Scintigraphy

36. Surgical treatment of non-functioning islet cell tumours
Indications for operation
•An aggressive surgical approach should be considered in malignant
NF-PETs, even in the presence of distant metastases.
Preoperative localisation studies
•Preoperative ultrasound or CT scan are the procedures of choice as
these tumours are relatively large.
•Also, SRS should be performed to differentiate endocrine from non-
endocrine pancreatic tumours.
Operative procedures
•The major goal is a potentially curative resection.
•This may require partial pancreaticoduodenectomy as well as the
synchronous or metachronous resection of liver metastases.
•Using an aggressive approach, curative resections are possible in up to
62% of cases and overall 5-year survival rates of around 65% can be
achieved.
•Repeated resections for resectable recurrences or metastases are
justified to improve survival.

37. NEUROENDOCRINE TUMOURS OF THE BRONCHI, STOMACH AND SMALL
BOWEL
Definition and physiology
•Neuroendocrine tumours (NET) of the gut and the pancreas arise from the
diffuse neuroendocrine cell system, which can be found as single or
clustered cells in the mucosa of the bronchi, stomach, gut, biliary tree,
urogenital system and in the pancreas (NET of the appendix, colon and
rectum).
•This cell system was first recognised as the ‘clear cell system’ by Feyrter in
the 1930s and is identical to the APUD (amine precursor uptake and
decarboxylation) system described by Pearse in 1970.
•All cells of the system secrete different neuroendocrine markers, such as
synaptophysin, chromogranin A and neurone-specific enolase (NSE), and
produce peptide hormones that are stored in granules, e.g. serotonin,
somatostatin, PP or gastrin.
•In clinical practice chromogranin A is utilised as a tumour marker
•The main functional test for NET of the jejunum and ileum (the NET that
are most often encountered) is the measurement of the serotonin metabolite
5-hydroxyindoleacetic acid (5-HIAA) in urine.

38. Pathology
•Neuroendocrine cells can form hyperplasias or tumours.
•Oberndorfer coined the term ‘carcinoids’ for tumours arising from
these cells in 1907.
•Although the term carcinoid continues to be used in clinical
practice, these tumours do not always grow in a well-differentiated
pattern reflecting the rather benign ‘carcinoma-like’, i.e.
‘carcinoid’, tumour.
• They can show different growth patterns, from benign tumours to
high-grade undifferentiated carcinomas having a poor prognosis
(neuroendocrine carcinomas).
•Therefore, they should always be addressed as NET, including a
description of their histological pattern (benign, lowor high-grade
malignant) and their anatomical site (e.g. stomach, ileum)
according to the World Health Organization (WHO) classification
(2000).

39. •Relative distribution of neuroendocrine tumours NET in
different organs
Site Distribution (%)
Lung 1 0
Stomach 5
Duodenum 2
Small bowel 25
Appendix 40
Colon 6
Rectum 15
•Another classification based on embryological principles
classifies NET as foregut (lung, stomach, pancreas), midgut
(small bowel and appendix) and hindgut (colon and rectum)
tumours.

40. Neuroendocrine tumours of the bronchi
Aetiology and clinical features
•About 1–2% of all lung tumours are NET.
•Their aetiology is unknown except in those diagnosed in
patients with MEN 1 syndrome.
• In centrally located tumours, symptoms can be coughing,
dyspnoea or fever if obstruction and pneumonia occur.
• NE situated in the peripheral parts of the lung do not cause
symptoms for a long time.
•The WHO classification should be used for these tumours and
should replace the former classification of typical or atypical
‘carcinoid’.

41. Diagnosis and treatment
•The diagnosis is made by radiography, CT scan, octreotide (SRS) scan
and bronchoscopy and biopsy .
•The treatment of choice is surgical resection.
•In benign or low-grade malignancy, a parenchyma-sparing resection
without regional lymph node dissection should be performed.
• In highly undifferentiated NET, patients should be treated as in ordinary
lung cancer.
•If there is metastatic disease, treatment with somatostatin analogues or
chemotherapy (e.g. cisplatin and etoposide or streptozotocin and
doxorubicin) is recommended.
•Even in advanced disease and in the presence of liver metastases,
patients do not suffer from ‘carcinoid’ syndrome (‘flushing’, etc.), as
NET of the foregut do not secrete serotonin.
• This is also the reason why a 5-HIAA urine test cannot be used to help
make a diagnosis.

42. Neuroendocrine tumours of the stomach
•These tumours are rare.
• They comprise about 5% of all NET of the gastrointestinal tract and
have an incidence of approximately 0.2 cases per 100 000 population
per year.
• There are four different types of gastric NET .
• Types 1 and 2 are small benign tumours that arise from the
enterochromaffin-like (ECL) cells in the gastric mucosa and grow in
either a linear or a nodular pattern.
•Hypergastrinaemia may cause symptoms and the treatment of choice
is endoscopic resection.
Types 3 and 4 are almost always malignant and surgical resection
should be undertaken if possible

43. Pathogenesis, diagnosis and treatment
•Type 1 tumours (ECLomas) are the most frequent NET of the stomach
(approximately 80%); they occur mostly in elderly women.
• Chronic hypergastrinaemia is the result of chronic atrophic gastritis and
achlorhydria, the alkaline pH being the stimulus for hypersecretion of
gastrin.
• They do not cause symptoms and are usually detected during gastroscopy
for other reasons.
•Endoscopic resection is the treatment of choice.
•Antrectomy and resection of ECLomas should be undertaken only if there
is recurrent disease and multiple (more than six) tumours, with at least one
measuring > 1 cm and infiltration of at least one into the submucosa.
•The pathogenesis, diagnosis and treatment of type 2 tumours is similar to
that of type 1.
•The only difference is the cause of the hypergastrinaemia, which in type 2
tumours is the result of MEN 1 syndrome, with multiple gastrinomas in the
duodenum or, rarely, in the pancreas.
•Type 3 tumours are rare, sporadic and solitary tumours of unknown origin.

44. •Serum gastrin is normal; upper gastrointestinal bleeding is the usual symptom that leads to
endoscopy.
• Type 3 tumours are usually larger than 2cm , and often have lymph node and liver
metastases at the time of diagnosis.
•Gastrectomy and lymph node dissection and resection of live metastases is the treatment of
choice.
•Liver metastases can also be treated by chemoembolisation.
Type 3 gastric neuroendocrine tumour discovered after upper gastrointestinal
bleeding.
•Type 4 tumours present as large ulcerating malignancies similar to adenocarcinomas and
should be treated accordingly.
•The prognosis of types 3 and 4 is poor .

45. Neuroendocrine tumours of the small bowel
Introduction
•These are the tumours that are most commonly referred to as‘carcinoid’
tumours, as most NET of the gastrointestinal tract are found in the small
bowel. They are also called ‘midgut’ tumours (together with NET of the
appendix and the right colon).
•These tumours produce serotonin and cause the ‘carcinoid’ syndrome,but
only in patients who have a large volume of liver metastases or if there is
advanced local tumour growth draining into the inferior vena cava and
thereby bypassing the liver.
•NET of the duodenum (gastrinomas in MEN 1 syndrome,
somatostatinomas and others) are very rare .
Pathology
•NET of the jejunum and ileum arise from a sub-group of cells of the diffuse
neuroendocrine system, the enterochromaffin (EC) cells, which secrete
serotonin and substance P.
• They are either solitary or more often multiple, are almost always
malignant and metastasise early to the regional lymph nodes and the liver
depending on the location of the primary tumour(s) .

46. Clinical symptoms
•Symptoms that lead to the diagnosis are caused by either the
primary tumour or its lymph node metastases.
• Acute or chronic, recurrent or persistent abdominal pain, ileus or,
rarely, lower gastrointestinal bleeding may occur.
• Symptoms may be due to liver metastases, such as sudden painful
reddening of the face and chest (‘flushing’), diarrhoea or bronchospasm.
•These symptoms constitute ‘carcinoid’ syndrome.
•About 60% of patients eventually develop cardiac symptoms because of
stenosis and insufficiency of the pulmonary and, more rarely, the
tricuspid valve, with enlargement and thickening of the wall of the right
atrium.
•The aetiology is unknown but local effects of serotonin and kinins
may contribute.

47. •Abdominal symptoms are caused either by obstruction of the appendix
by an appendiceal NET (leading to appendectomy) or by obstruction of
the mesentery or the bowel lumen by growth of lymph node metastases
in the mesentery near the bowel.
•Pain is caused by chronic ischaemia of the bowel , resulting not only
from mesenteric lymph node metastases but also from constriction of
mesenteric arteries and fibrosis of the mesentery by a so-called
desmoplastic reaction.
•Primary tumours in the jejunum and ileum rarely cause symptoms such
as bleeding or intussusception as they usually only measure from a few
millimetres up to 1 cm or at the most 2 cm in diameter .
•A polypoid NET of the terminal ileum may, however, cause ileocaecal
intussusception.

48. Diagnosis
=The diagnosis of NET of the small bowel is made by
history,
physical examination of the abdomen, imaging and an
assessment of 5-HIAA in a 24-hour urine sample. It is
positive in larger tumours only if metastases are present.
=Cross-sectional imaging, sonography, CT scan and MRI
will not show the primary tumour but will show mesenteric
lymph node and liver metastases.
=The best method for staging of NET is an octreotide (SRS)
scan.

49. Surgical procedure
•Surgery should be undertaken as soon as the diagnosis is made, even in the
presence of liver metastases.
•The main goal is resection of the bowel primary tumour(s) and mesenteric
lymph node metastases.
• This may entail resection of large amounts of bowel (100 cm or more),
particularly if stage III or IV lymph node masses are found in the mesentery.
•In the presence of liver metastases, extrahepatic disease should be resected
whenever possible.
* Metastatic disease in the mesenteric root will lead to long-term pain in the
abdomen or back and to a poor quality of life, whereas liver metastases can
be treated by chemotherapy or embolisation.
•Somatostatin and its analogues provide symptomatic treatment of the
‘carcinoid’ syndrome caused by a large volume of liver metastases. These
drugs may also have an antiproliferative effect.
•Surgery to remove liver metastases is possible in approximately 10% .
•In others, embolisation, chemoembolisation, SRS using radioactively
labelled octreotide, chemotherapy, biotherapy and also liver transplantation
can be performed.

50. MULTIPLE ENDOCRINE NEOPLASIAS
Introduction
Multiple endocrine neoplasias (MEN) are inherited syndromes characterised by a
different pattern of benign and malignant tumours in different endocrine glands.
There are two main types, type 1 (MEN 1) and type 2 (MEN 2).
The mode of inheritance is autosomal dominant in both.
MEN 1 is characterised by the triad of tumours in :
1- Anterior pituitary gland, mostly presenting as prolactinomas or
2- Parathyroid: nonfunctioning tumours, hyperplasia of the parathyroids causing
primary hyperparathyroidism (pHPT) and
3- Pancrease: pancreaticoduodenal endocrine tumours (PETs).
*The syndrome was first described by Wermer in 1954 and is therefore also called
Wermer’s syndrome.
*It is caused by germline mutations in the menin gene, located on
chromosome 11.
MEN 2 is divided into three subtypes:
familial medullary thyroid carcinoma (FMTC), MEN 2a and MEN 2b.
*Medullary thyroid carcinoma (MTC) plays the key role in all subtypes.
*MEN 2 is caused by germline mutations in the RET proto-oncogene, located on
chromosome 10.

51. MEN 2a is characterised by the combination of MTC, pHPT and mostly
bilateral phaeochromocytomas.
MTC combined with phaeochromocytoma alone is called Multiple
endocrine neoplasias Sipple’s syndrome.
FMTC is characterised by distinct mutations in RET and MTC alone as
the clinical manifestation.
MEN 2b comprises MTC, phaeochromocytoma and characteristic facial
and oral mucosal neurinomas and intestinal ganglioneuromatosis
accompanied by a marfanoid habitus .
The most important difference between MEN 1 and MEN 2, besides the
different clinical pictures, is that MEN 2 is characterised by a well-
understood genotype–phenotype correlation.
This means that depending on the particular mutation in the RET proto-
oncogene the phenotypic appearance and the onset of endocrine tumours
will be different and can be predicted from the type of mutation.
This is not the case in MEN 1 syndrome.

52. Multiple endocrine neoplasia type 1
Epidemiology
*The prevalence of the syndrome is estimated to be around 0.04–0.2 cases per 1000
population per year.
*The penetrance is high with almost 100% of mutation carriers developing the
syndrome.
*The disease is equally distributed between men andwomen.
Clinical presentation
The clinical presentation depends on the affected organs. Often
tumours occur synchronously .
Most of the mutation carriers identified in screening programmes are asymptomatic.
Parathyroids
* In total, 90–100% of patients suffering from MEN 1 develop pHPT and it is usually
the first manifestation of the disease.
MEN 1 pHPT is characterised by multiglandular disease so that all four parathyroids
become hyperplastic in the course of the disease.
*The clinical presentation of MEN 1 pHPT is similar to that of the sporadic disease. *
*Few patients have asymptomatic disease; most common in symptomatic disease is
nephrolithiasis.
* Diagnosis is established by determination of parathyroid hormone (PTH) and
calcium in serum.

53. Endocrine pancreas
* PETs occur in around 50–60% of MEN 1 patients. In patients
taking part in screening programmes, 70–90% are found to have
non-functioning and functioning PETs. This high rate of detection
of PETs is the result of the improvement in diagnostic procedures
in the last decade, including EUS.
•MEN 1 PETs are the most common syndrome-associated cause of
death. They are mostly multiple and often recur after surgery.
• Although most patients have multiple tumours, one hormone
syndrome is usually dominant. The most common functional tumour is
gastrinoma followed by insulinoma.
•VIPomas, glucagonomas and somatostatinomas are extremely rare.
•Non-functioning tumours can be asymptomatic for many years.
•The diagnostic work-up is similar to that for sporadic PETs and
includes laboratory tests, such as different hormone measurements,
e.g. gastrin, insulin, PP, etc., and imaging.

54. Anterior pituitary gland
Tumours of the anterior pituitary gland are found in 30–60% of
patients with MEN 1. These are mostly microadenomas that present
as prolactinomas or non-functioning tumours. Most prolactinomas
can be treated with anti-hormone medication.
Adrenal tumours and other organ manifestations
Adrenal involvement is common in MEN 1 patients and affects
nearly 40–50% of patients. Mostly non-functioning bilateral
adenomas are found. Very rarely adrenocortical carcinomas or
phaeochromocytomas may develop.
Although very rare, manifestations of MEN 1 include NET of
the lung, thymus, stomach, duodenum and small bowel. It is
important to check for NETs of the thymus, as they are mostly
malignant and are the main cause of death in MEN 1 patients.

55. Genetic screening
Identification of the MEN 1 (menin) gene in 1997 formed the
basis
for direct mutational analysis of the gene and for family
screening.
After genetic counselling of the index patient, family members
can
be screened. Mutation carriers can then be included in screening
programmes that make early detection of endocrine tumours
possible.
Screening programmes should follow the consensus guidelines
published by Brandi et al. in 2001. In cases of obviously
sporadic endocrine tumours in patients younger than 40 years,
genetic testing for MEN 1 seems to be useful.

56. Operative therapy
Parathyroids
The indications for surgery in MEN 1 pHPT follow the same
criteria as in sporadic disease but the choice of procedure is
different.
As multiglandular disease is present in all cases, resection
follows the same rules as in secondary HPT. Therefore, the most
common procedures are total parathyroidectomy, including
cervical
thymectomy and autotransplantation of parathyroid tissue in
the forearm, or 31⁄2-gland resection, leaving approximately 50 mg
of parathyroid tissue behind, and cervical thymectomy. Selective
resection of enlarged glands is obsolete because of the high rates
of recurrence.

57. Endocrine pancreas
Indications for surgery and its extent are controversial. Most
experts agree that MEN 1 gastrinoma and insulinoma have to be
operated on to prevent liver metastases and to control hormonal
excess, provided that diffuse liver metastases are not present.
MEN 1 gastrinomas are more often located in the duodenum as
multiple small tumours than in the pancreas. For gastrinomas
located in the duodenum or pancreatic head (gastrinoma triangle,
Fig. 49.17), pylorus-preserving partial pancreaticoduodenectomy
is recommended. In rare cases the gastrinoma is located in the
body or tail of the pancreas. In such cases distal pancreatectomy
with excision of tumours in the pancreatic head is the procedure
of choice. In MEN 1 insulinoma the standard operative procedure
is distal pancreatectomy with enucleation of tumours in the pancreatic
head. Non-functioning PETs are operated on if they reach
a size of 1 cm. Careful palpation and IOUS are essential in every
pancreatic procedure for MEN 1 PETs.

58. Anterior pituitary gland
The indications for surgery in tumours of the anterior pituitary
gland are the presence of symptomatic non-functional tumours or
if medical therapy of prolactinoma fails. Most procedures can be
performed through a trans-sphenoidal approach.
Adrenal tumours
Functional adrenal tumours in MEN 1 are rare and have to be
operated on. Non-functioning tumours should be resected if they
reach a size of 4 cm. Pre- and perioperative management follows
the same rules as in sporadic adrenal tumours; therefore,
phaeochromocytoma has to be ruled out in every patient. In most
cases a laparoscopic or retroperitoneoscopic approach can be
used. If there is evidence for a malignant tumour, open surgery is
preferred.

59. Multiple endocrine neoplasia type 2
In most patients with MEN 2a, the disease is caused by mutations
of the RET proto-oncogene in codon 634. MTC is almost always
the first manifestation of the syndrome. If phaeochromocytoma
and pHPT do not occur, one must suspect the presence of the
FMTC subtype. Patients with MEN 2b do not develop pHPT and
in 95% of cases mutations in codon 918 of the RET proto-oncogene
are causative (Table 49.8).
Medullary thyroid carcinoma
MTC is characterised by multicentricity and is often accompanied
by C-cell hyperplasia. These characteristics should lead to
molecular diagnostic work-up (mutational analysis of the RET
proto-oncogene) in patients with ‘sporadic’ MTC. In contrast to
sporadic MTC, the diagnosis in families with known mutation of
the RET gene is mostly made much earlier, possibly as the result
of mutational screening and calcitonin measurements. MTC is
most aggressive in MEN 2b. It occurs in early childhood, much
earlier than in MEN 2a, with lymph node metastases present in
the early stages.

60. Primary hyperparathyroidism
pHPT in MEN 2a is less common and has a milder clinical course
than MEN 1 pHPT. It occurs in about 20–30% of patients with
Multiple endocrine neoplasias
Phaeochromocytoma
The frequency of phaeochromocytoma in MEN 2 is around
10–50% and most tumours are bilateral. This can occur
synchronously
or metachronously. The tumours are almost always benign.
Diagnostic work-up includes measurement of urinary
catecholamines,
abdominal CT or MRI, and 131I-MIBG scintigraphy
(see above).

61. Operative therapy
Medullary thyroid carcinoma
Operative therapy for MEN 2 MTC in patients detected by
genetic screening is a good example of efficient prophylactic
surgery, as the likelihood of developing MTC is 100% for most
mutations. The mutation carriers can be operated on with no evidence
of tumour in the thyroid, protecting them from MTC for
the rest of their lives. Different RET mutations are associated
with early or late onset of the disease. Risk groups have been
defined to determine the appropriate age for thyroidectomy
(Table 49.9).
Phaeochromocytoma
The operative approach is open surgery or laparoscopy or
retroperitoneoscopy, depending on the manifestation of the disease
in a given patient. Unilateral or bilateral subtotal resection
may be feasible, which retains the healthy part of the gland and
prevents postoperative dependence on cortisol and mineralocorticoid
supplementation (see above) (Fig. 49.28).

62. Primary hyperparathyroidism
The clinical situation in MEN 2 pHPT is even more difficult than
in MEN 1 pHPT because of the association with MTC in MEN
2. During neck surgery for MTC in a eucalcaemic patient,
enlarged parathyroid glands should be removed. In cases in
which
neck surgery has already been performed for MTC, the surgical
approach to MEN 2a pHPT should be more tailored to the
individual
patient. For example, in an older patient after thyroidectomy
for MTC with mild asymptomatic hypercalcaemia,
localisation procedures and a targeted approach with
intraoperative
parathormone measurement may be worthwhile, if possible.

63. GASTRINOMA: (Zollinger-Ellison
Syndrome)
The tumour arising from the islets cell of
langhans in the pancreas and in the duodenal
wall.
The majority (60%) of these tumours are
malignant. They may be associated with (MEN
1) which are Parathyroid Hyperplasia, and
Pituitary Adenoma. Gastrinoma give rise to ZE
Syndrome which consist of triad
(hypersecretion of gastric acid, severe peptic
ulceration and the presence of non-beta cell
tumour of the pancreas or duodenum).

64. CLINICAL FEATURES:
 The disease present as peptic ulcer
disease in over 90%. They have typical
pain more severe and less response to
medical treatment.
 Co-existing diarrhoea.
 All complications of peptic ulcer disease
are present in (ZE-Syndrome) as acute
haemorrhage, perforation and recurrent
ulceration.

65. THE DIAGNOSIS OF ZE-SYNDROME:
 Severe peptic ulcerdisease doesn’t respond to
treatment.
 Multiplepeptic ulcersor ulcersin unusual locations such
as the distal duodenum or jejunum.
 Peptic ulcerdisease associated withdiarrhoea.
Contn…

66.  Recurrentpeptic ulcer disease following in acid reducing
operation (surgery).
 Peptic ulceris associated withMEN- 1 Syndrome.
 Markedelevation of serum gastrin.

67. TREATMENT:
 Medical therapy for control of the acid
hypersecretion in patient with ZE-
Syndrome Omprazole considered the
antisecretory drug of choice for all
gastrinoma patients.

68.  Surgical Treatment:
 Tumourexcision.
 Total gastrectomy.
 Patientwithmetastasesshouldhave medical therapy if
fail total gastrectomy.
 Gastrinomapatient withMEN1 Syndrome and
documented hyperparathyroidism should have
parathyroidsurgery performed prior to removal of
gastrinoma.