Pancreatic neuroendocrine neoplasms

Section: Hepatobiliary Sub-section: Pancreas Curriculum: Curriculum, page 91

Epidemiology

• Rare, 0.2-0.4 per 100,000.
• 85% non-functional
  • Rest are syndromic with most common being carcinoid, insulinoma and gastrinoma

Aetiology

• Poorly understood. While majority sporadic, associations with hereditary syndromes:
  • Von Hippel Lindau Syndrome
  • MEN 1 syndrome
  • Neurofibromatosis Type 1
  • Tubular sclerosis

Stage/Grade

• Incidence of malignancy from 10% (insulinoma) to virtually 100 % (Glucagonoma/Somatostatinoma)
• Malignancy cannot be ascertained by histopathology
  • Can only be definitely determined by presence of metastasis
• Grade and differentiation also have important prognostic implications
  • Ki-67 proliferation index or mitotic index
    • Use higher of the two

Tumour Grade

Ki-67 Index (%)/ Mitotic Index Well-Differentiated PanNENs (NETs)

• PanNET G1 < 2
• PanNET G2 2 to 20
• PanNET G3 >20 Poorly Differentiated PanNENs: Pancreatic Neuroendocrine Carcinomas (PanNECs) PanNEC > 20 (Small Cell Type or Large Cell Type)

Tumor stage

	AJCC 8th edition
TX	Tumour cannot be assessed
T1	Tumour limited to pancreas, * < 2cm
T2	Tumour limited to pancreas, * 2 to 4cm
T3	Tumour limited to pancreas, * > 4cm; or tumour invading duodenum or CBD
T4	Tumour invading adjacent organs (stomach, spleen, colon, adrenal gland) or wall of large vessels (Coeliac Axis or SMA)

• Limited to pancreas means no invasion of adjacent organs or wall of large vessels Extension of tumour into peri-pancreatic adipose tissue is NOT a basis for staging

N Category	N Criteria
NX	Regional LN cannot be assessed
N0	No regional LN involvement
N1	Regional LN involvement

M Category	M Criteria
M0	No distant metastasis
M1	Distant metastases
M1a	Metastasis confined to liver
M1b	Metastases in ≥ 1 extra-hepatic site (e.g. lung, ovary, non-regional LN, peritoneum, bone)
M1c	Both hepatic and extra-hepatic metastases

Prognostic stage

When T is…	And N is…	And M is…	Then stage group is…
T1	N0	M0	I
T2-T3	N0	M0	II
T4	N0	M0	III
Any T	N1	M0	III
Any T	Any N	M1	IV

Clinical

Presentation

• Broad range of presenting symptoms
• Classic functional hormonal syndrome
  • Abdominal symptoms
  • Abdo pain, jaundice, anorexia, weight loss
• Incidental finding on imaging
• All suspected NETs need
  • Careful history screening for functional syndromes +/- biochemical evaluation if suspicious
  • Localisation of the lesion
  • Evaluation for metastatic disease

History

• History should screen for
• Neuroglycopenic symptoms
• Diarrhoea
• Ulcer diathesis
• Rash
• Other symptoms suggestive of a classic hormonal syndrome
• A family history should also be obtained to rule out the possibility of MEN1-associated PNET

Investigations

Bloods

• In the absence of symptoms, a full hormonal screen is unnecessary
• Diagnosis of functional PNETs can be made by elevated serum levels of the suspected peptide based on symptoms
  • Non-functional PNETs produce distinct gastrointestinal peptides including Chromogranin A, Neurotensin, and Pancreatic Polypeptide
    • Not associated with clinical symptoms or syndromes
    • Can aid in confirmation of the diagnosis
• Chromogranin A levels
  • Correlate with the presence of tumour in functional and non-functional PNETs
    • Useful for confirmation of the diagnosis in a patient with suspected PNET on imaging and post-treatment surveillance for recurrence
    • NB: Chromogranin A levels can also be elevated if taking PPIs, Atrophic Gastritis, and hepatic or renal insufficiency
  • C-peptide test:
    • Peptide that connects alpha and beta chains of proinsulin. Breakdown product when insulin is released. Half life of 30 min (compared to insulin 5-10 min)
    • Can differentiate between endogenous secretion and exogenous administration. It will be elevated in insulinoma and sulfonylurea therapy, but decreased in exogenous insulin therapy.
  • Calcium, PTH, calcitonin, TFTs considered esp if history suggestive of MEN-1

Imaging

Localisation

• First step is cross sectional imaging
• EUS
• Somatostatin Receptor Scintigraphy and SPECT/CT
• Angiography
• Surgical Exploration with Intra-op USS

Cross Sectional Imaging

• Contrast enhanced CT
  • Sensitivity for localisation 73-96% (directly related to size)
  • Hyperattenuating lesions (rich blood supply)
  • Arterial phase vascular blush differentiates PNETs from other pancreas lesions
  • Insulinomas/gastrinomas are small at presentation
    • Can be difficult to identify
    • Most other lesions easily seen on CT
  • Use fine slice CT and multiphase imaging
• MRI
  • Low intensity on T1, High intensity on T2
  • Sensitivity related to size (80-90%)

EUS

• Next step if can’t localise on CT/MRI
• Useful for imaging anatomy of duodenal wall, regional lymph nodes, pancreatic head and ducts.
• Sensitivity for all sized tumour localisation of 90%
  • Better than CT/MRI for tumours <3cm
• Best for detection/localisation of insulinomas
• Limited ability to detect small Duodenal Gastrinomas - Sensitivity 50%
• Also allows for FNA of suspicious non-functioning tumours

Somatostatin Receptor Scintigraphy (SRS) / SPEC CT

• Abundance of somatostatin receptors on PNETs
  • Except Insulinomas (and Adenocarcinomas)
• SRS good for Gastrin-secreting and Glucagon secreting tumours
• SRS limited by physiologic sites or benign conditions that may show tracer uptake
  • Also lack anatomic precision in localization
  • May only delineate to a few cms

Gallium-68 DOTATATE PET

• superior to octreotide scan

Angiography

• Use if failure to locate by other means
• Detects approximately 70% of insulinomas larger than 5 mm
  • Shows a characteristic vascular blush that corresponds to the highly vascular nature of insulinomas
• Portal venous sampling for insulin or gastrin levels may allow localization to a region of the pancreas (head, body, or tail) to aid in operative planning.
  • Portal venous sampling does not absolutely localize the tumour, but it provides accurate information on the region of the pancreas from which the high levels of hormones are released
• Arterial stimulation by injecting calcium or secretin into the Celiac and Superior Mesenteric Arteries can further increase the likelihood of localization with simultaneous portal venous sampling for appropriate hormone levels
  • Ca2+ stimulates Insulin release from Insulinomas
  • Secretin stimulates Gastrin release from Gastrinomas
• Arterial stimulation venous sampling has a sensitivity greater than 90%. However, with modern localization techniques, this is rarely necessary

Imaging by function

Non-functioning

• Localisation not an issue
• Arterial and portal venous phase CT
• Features include hypervascular or hyperdense lesion within pancreas; can appear cystic or contain calcifications

Functioning

• Somatostatinomas, VIPomas and glucagonomas tend to be large and easily identified on contrast CT.
  • Insulinomas and gastrinomas may not be, unless widespread mets.
    • Most insulinomas < 2cm and solitary.
      • CT - hypervascular with uniform or target enhancement. Detection of vascular blush essential to localise them.
      • MRI – low signal intensity on T1, well seen on fat suppressed images
    • Gastrinomas may be multiple and extrapancreatic.
      • Located within Gastrinoma Triangle
      • Less vascular than insulinoma. High rate of lymph node and hepatic mets
  • If unable to find on CT/MRI then EUS, DOTATE PET and finally angiography and selective arterial calcium (insulinoma) and secretin (gastrinoma) stimulation

Insulinoma

Gastrinoma

VIPoma

Glucagonoma

Somatostatinoma

Other Functional PNETs

• GFT
• PTHrP
• PP
• ACTH
• Calcitonin
• CCK

Non-functioning PNETs

Incidence and Presentation

• Rare, but more common than any functioning PNET
  • Increasing frequency with better imaging techniques
• Presentation
  • Incidental finding
• Symptomatic with mass effect (abdo pain, jaundice, obstruction) – typically larger

  • 60% have liver mets at diagnosis

Diagnosis

• Important to differentiate from pancreatic adeno
  • Biopsy
  • Somatostatin receptor scintigraphy
  • May produce hormones
    • Chromogranin A (increased in 60-100%)
    • Useful as tumour marker to follow progression
    • Pancreatic polypeptide
    • Neurotensin

PNETs in MEN 1 syndrome

• Gastrinoma (54%)
• Insulinoma (21%)
• Glucagonoma (3%)
• VIPoma (1%)
• PP-secreting pancreatic endocrine tumours occur in more than 80% of cases of MEN1
  • Not associated with a functional syndrome

Summary

Tumour type	Syndrome	Symptoms	Diagnosis	Medical treatment	Surgical treatment
Insulinoma - Most common - 90% benign	Whipple’s triad	Neuroglycaemic or neurogenic symptoms relieved with eating (+ low fasting plasma glucose)	72 hour monitored fast. Hypoglycaemia C-peptide.	Overnight feeding. Diazoxide. Somatostatin analogue.	Enucleation preferred surgery (90% benign)
Gastrinoma - Second most common - >50% present with metastatic disease	Zollinger-Ellison	Complicated peptic ulceration or GORD, diarrhoea, abdominal pain	Serum fasting gastrin > 1000 pg/mL (if gastric pH < 2.5). Secretin stimulation test	High dose proton pump inhibition (may need 60 mg bd)	Enucleation if small. Whipples if large/unincapsurlated
Glucagonoma - Malignant in 50-80%	Glucagonoma syndrome	Necrolytic Migratory Erythema, DVT, diabetes, depresseion	Plasma glucagon > 1000 pg/mL	Somatostatin analogue, hyperalimentation, thromboprophylaxis	Anatomic resection for resectable disease
VIPoma - >70% have metastatic diseas	Verner-Morrison syndrome	Profuse watery diarrhoea, hypokalaemia	Plasma VIP > 1000 pg/mL	Somatostatin analogue	Anatomic resection with lymphadenectomy rather than enucleation
Somatostatinoma		Gallstones, steatorrhoea, hypochlorhydria, glucose intolerance	Raised plasma somatostatin
Carcinoid	Carcinoid syndrome	Abdominal pain, if mets then flushing, palpitations, rhinorrhoea, diarrhoea, bronchospasm, pellagra	24h urinary 5-HIAA	Somatostatin analogue

Management

• Functional - resection for syx control

• First priority is controlling hormonal excess.

  • Somatostatin analogue infusions recommended pre- and intraoperatively for carcinoid (to prevent carcinoid crisis)
    • Not helpful insulinomas as can worsen glycemic control

• Insulinomas

  • 90% of insulinomas are solitary, benign and < 2 cm in size
  • Consider enucleation and laparoscopic resection
    • Enucleation possible if lesion clearly localised and relationship to pancreatic duct identified.
      • Can use intraoperative ultrasound.
    • Resection required if malignancy suspected (hard, infiltrating tumour, duct obstruction or lymph node involvement), if vascular involvement or large size.
  • Intraop localisation - duodenotomy and intraop USS combined with palpation

• Gastrinomas

  • PPI
  • For duodenal – small < 5mm tumours can be enucleated from submucosa while larger tumours require full thickness excision.
  • For pancreatic – similar intraop assessment to insulinoma to consider enucleation. If not suitable, need pancreatico-duodenectomy + lymph node dissection

Metastatic disease

• Surgery:
  • 10% with hepatic metastases suitable for potentially curative resection.
    • High recurrence rates but survival advantage.
    • Synchronous cholecystectomy to reduce complications from adjuvant therapy such as somatostatin analogues and hepatic artery embolization
• No evidence for debulking resections unless local symptoms from primary with low volume hepatic mets.
• If obstruction in well differentiated
  • Surgical bypass first line (given indolent nature)
• Cytoreductive approach (surgery or ablative) for patients with hormonal excess and hepatic mets if 90% of tumour bulk can be removed.
• Systemic chemotherapy based on combination streptozocin and .
• Protein kinase inhibitors (sunitinib and everolimus) have shown increase in overall and progression-free survival.
• Somatostatin analogs: Lanreotide has shown evidence of antiproliferative activity.
• Peptide receptor radioligand therapy (PRRT):
  • If tumour expresses somatostatin receptor, can use radiolabelled somatostatin analog e.g. lutetium Lu-177 dotatate.
  • Indications/criteria:
    • Inoperable/metastatic well differentiated (G1/2) NET
    • Sufficient tumour uptake on diagnostic somatostatin receptor-based imaging
    • Sufficient bone marrow reserve
    • CrCl > 50ml/min
    • Karnofsky performance status >50
    • Expected survival > 3 months
  • Limitations:
    • Complexity of administration
    • Lack of trials
    • Limited availability
    • Toxicity:
      • Myelotoxicity
      • Myeloid neoplasms
• Liver resection recommended if all tumours can be removed
• Alternatives include TACE and RFA
  • PNETs good for this due to highly vascular nature
• Liver transplantation
  • Criteria for Transplant
    • Age < 55
    • Well-differentiated tumour
    • Ki-67 index < 5%
    • Completely resected primary tumour with portal drainage
    • Less than 50% liver involvement
    • Absence of extrahepatic disease
• Systemic Therapy
  • Traditional cytotoxic agents poor for well differentiated tumours
    • Poorly differentiated tumours respond better
  • Octreotide when symptomatic or if high tumor burden and asymptomatic
    • Cholelithiasis can develop

Incidentally Found, Small PNETs (non functional)

• Smaller lesions
  • The 2023 European Neuroendocrine Tumor Society (ENETS) guideline
    • Surveillance <1cm
    • 1 and 2 cm (without dilation of the pancreatic duct) should be personalized based on patient characteristics
    • Surgery >2cm
  • Things to consider, grade, malignant vs benign, function and non function, location, proximity to structures i.e if it grows will it become an issue
  • NB: Histological grade (poor vs well differentiated) doesn’t correlate to prognosis
• Larger lesions
  • Formal resection and LN evaluation
  • Aggressive resection including localised liver mets indicated
    • Different to pancreatic adeno (reason why important to distinguish the two)

Endocrine Complications of Surgical Therapy

• Post–Gastric Bypass Hypoglycemia
  • Uncommon
  • Similar presentation to Non-insulinoma Pancreatogenous Hypoglycaemia Syndrome but distinct disease
    • Both will have postprandial hyperinsulinemic hypoglycemia, negative radiologic localization and positive calcium stimulation test
  • Thought to be due to obesity-induced B cell hypertrophy not reversed after RYGB inappropriate growth factor release, or persistent altered gut hormonal signalling.
  • Dietary modifications and medication are the first-line treatment for post-RYGB hypoglycaemia
    • Modifications include dietary restrictions or more complex nutritional supplementation
  • Medical management strategies
    • Continuous glucose monitoring
    • Acarbose
    • Calcium channel blockade
    • Diazoxide
    • Somatostatin analogues
  • Surgery, including reversal of the gastric bypass and distal pancreatectomy, should be evaluated in the context of the perioperative risk, long-term outcome, potential weight regain, and the potential effects on obesity-related comorbidity.
  • When surgical treatment is necessary, pancreatic resection is the most common surgical procedure used. However, the appropriate extent of resection is not defined, and symptoms often recur.
• Dumping Syndrome
  • Due to the rapid movement of hyperosmolar chyme from the stomach into the small intestine
  • Early dumping syndrome
    • Occur within 10 to 30 minutes after a meal
    • The rapid transit of hyperosmolar chyme from the stomach into the duodenum causes fluid to shift from the vasculature to the intestinal lumen, leading to increased volume in the small bowel.
    • Cause of abdominal cramps, tachycardia, nausea, and diarrhea.
  • Late dumping syndrome
    • Late dumping, also known as postprandial hyperinsulinemic hypoglycemia,
    • Occurs 1 to 3 hours after a high-carbohydrate meal.
    • There is an association with hypoglycemia, but the exact mechanism is unknown.
    • It is proposed that the rapid absorption of carbohydrates exaggerates the glucose-mediated insulin response.

Endocrine Insufficiency after Surgical Resection

• Destruction or removal of 80% of the pancreatic islet cell mass is necessary before endocrine dysfunction becomes clinically apparent
• Type 3c diabetes
  • Approximately 20% to 50% of pts develop diabetes after pancreatic resection
• Pancreatectomy, most commonly performed for pancreatic/periampullary cancer or chronic pancreatitis, is often preceded by pancreatic endocrine insufficiency, although this may be subclinical.
• Difficult to predict which patients will develop pancreatic endocrine insufficiency after pancreatectomy
• In patients with existing chronic pancreatitis, diabetes is very common post-op
• In the setting of total pancreatectomy, the resulting diabetes is extremely brittle
  • Because of the lack of endogenous glucagon to balance exogenously administered insulin