Endocrine Tumours

khaing zay aung

18.5.2015

Endocrine tumours of pancreas

Neuroendocrine tumours of the bronchi

Neuroendocrine tumours of the stomach

Neuroendocrine tumours of the small bowel

Multiple endocrine neoplasia

Endocrine tumours of the pancreas

Insulinomas (17%) Gastrinomas (15%) Non functioning tumours Rare functioning tumours (RFTs)

VIPomas (2%) Glucagonomas (1%) Carcinoid (1%) Somastinomas (1%)

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

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

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

Clinical feature and diagnosis contd:

Neuroglycopenia Headache Visual disturbances Dizziness Confusion Seizures Coma

Clinical feature and diagnosis contd:

Whipple's Triad low glucose level (<50 mg/dL) symptoms of hypoglycemia symptoms resolve with administration of glucose

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

Clinical feature and diagnosis contd:

Investigations

Laboratory Studieslow glucose levels (< 50 mg/dL)insulin levels > 7 U/mLinsulin/glucose ratio > 0.3C-peptide to confirm endogenous source of

insulin (>2.5 ng/ml)

Clinical feature and diagnosis contd:

LocalizationCT and MRI for larger tumorsEUS can detect small tumors (<2 cm in size)angiography showing a “blush”

Management:

Preoperative Administration of diazoxide to prevent

hypoglycaemic attacks Other agents such as verapamil, growth

hormone or corticosteroids can be given Perioperative

Glucose infusions

Management:

Operative Tumour enucleation Pancreatico duodenectomy Tumour debulking

Post operative Octeriotide infusion Systemic chemotherapy

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

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

90% of gastrinomas are located within Passaro's triangle

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

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

2. Imaging Endoscopy

multiple ulcerslarge gastric rugal foldsmucosal edemajejunal hypermotility

LocalizationCT (not for small tumors)MRI (liver metastases)SRS with radiolabeled octreotideEUS

Differential diagnosis

Idiopathic peptic ulcer disease Chronic idiopathic diarrhea GORD Chronic atrophic gastritis Gastric outlet stenosis Retained antrum after gastric resection

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)

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

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

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

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

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)

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

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

Management

Medical treatment When surgical excision is not possible Chemotherapy – streptozotocin, octreotide &

interferon

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

MEN-1

Hyperplasia of parathyroidsCausing primary hyperparathyroidism (90-100%)

Pancreaticoduodenal endocrine tumoursMost common syndrome-associated cause of

deathMost common functional tumour is gastrinoma

followed by insulinoma

Adrenal tumours and other organ manifestation Nearly 40-50% of patientsMostly non functioning adenomas are found Rarely adrenocortical carcinoma and

pheochromocytomas are found

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

Anterior pituitary gland Indicated for non functional tumours or medical

therapy for prolactinoma fails

Adrenal tumours Functional tumours and >4 cm non functional

tumours

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

MEN-2

MEN 2b MTC Pheochromocytomas Characteristic facial and oral mucosal neuromas

and intestinal ganglioneuromatosis accompanied by marfanoid habitus

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

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