Pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours/neoplasms (PNETs)

• Rare malignancies arising from pluripotent cells within the pancreas (not the same origin as GIT NETs)
• Tend to be more indolent than pancreatic adenocarcinoma
• Can secrete a variety of peptide hormones, although >50% are non-functioning
• Previously called 'islet cell tumours'

Epidemiology

• Accounts for <3% of pancreatic neoplasms
• Accounts for 75% of all gastroenteropancreatic NETs
• Incidence has increased 7x in past 20 years

Risk factors

• Genetic (minority of PNETs)
  • MEN 1
  • VHL
  • NFT-1
  • Tuberous sclerosis
• Non-specific family history of PNETs

Pathophysiology/staging

• Malignancy in PNETs can only be determined by the presence of metastases
• Grading - WHO staging system (includes all NETs regardless of site of origin or functional hormone secretion and classifies based on differentiation and grade)
  • Low grade - G1
  • Intermediate - G2
  • High grade - G3 (3% of all PNETs)
  • This is the most important prognostic indicator
  • If functioning, likely well-differentiated
• Tend to metastasise to the liver, and often does not spread beyond the liver
• The less common functional tumours tend to be more aggressive

Neuroendocrine tumours of the pancreas TNM staging AJCC UICC 8th edition

Primary tumour (T)
T category	T criteria
TX	Tumor cannot be assessed
T1	Tumor limited to the pancreas,* <2 cm
T2	Tumor limited to the pancreas,* 2 to 4 cm
T3	Tumor limited to the pancreas,* >4 cm; or tumor invading the duodenum or common bile duct
T4	Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery)
* Limited to the pancreas means there is no invasion of adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery). Extension of tumor into peripancreatic adipose tissue is NOT a basis for staging. NOTE: Multiple tumors should be designated as such (the largest tumor should be used to assign T category): If the number of tumors is known, use T(#); eg, pT3(4) N0 M0. If the number of tumors is unavailable or too numerous, use the m suffix, T(m); eg, pT3(m) N0 M0.
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node involvement
N1	Regional lymph node involvement
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastases
M1a	Metastasis confined to liver
M1b	Metastases in at least one extrahepatic site (eg, lung, ovary, nonregional lymph node, peritoneum, bone)
M1c	Both hepatic and extrahepatic metastases
Prognostic stage groups
When T is...	And N is...	And M is...	Then the stage group is...
T1	N0	M0	I
T2	N0	M0	II
T3	N0	M0	II
T4	N0	M0	III
Any T	N1	M0	III
Any T	Any N	M1	IV

Classification and treatment (functional vs non-functional)

Functional - 15-50% - only refers to those tumours associated with clinical symptoms

Insulinoma (most common)

• • • Summary
      • Most common
      • Typically small and benign - average size 1-1.5cm
      • >99% found in pancreas - uniformly distributed throughout pancreas
      • <10% are malignant
      • Majority sporadic
    • Presentation
      • Age 40-45
      • Symptoms caused by hypoglycaemia - headaches, confusion, visual disturbances, or catecholamines causing palpitations, sweating, tremors
      • Whipple's triad - symptoms of hypoglycaemia, BSL < 4, relief of symptoms with administration of glucose
    • Diagnosis
      • Elevated insulin to glucose ratio during fasting, with associated elevated levels of C-peptide
      • Gold standard is a 48 hour fasting test, with levels every 6 hours
      • Can be difficult to localise previously, but now fairly straightforward with EUS
        • Initial CT/MRI
        • Can try somatostatin receptor scan - but again often misses it
        • EUS positive in 70-95% of cases
      • Distributed equally throughout the pancreas, and can occur in duodenum, splenic hilum, or gastrocolic ligament

• Treatment
  • Medical - small, frequent meals and control of hypoglycaemia
  • Enucleation best surgery - cure 85-95%
    • Can be done safely if tumour is 2-3mm from PD
  • Pancreatic resection less common, generally unnecessary
  • Operative exploration - can find it via palpation and USS 92% of the time
    • Blind distal resection is not recommended if unable to find it

Gastrinoma (second most common)

• • See separate topic under UGIS

Glucagonoma (rare)

• • Presentation
    • '4 D's'
    • Dermatitis - necrolytic migratory erythema - primarily intertriginous locations like perineum, also trunk and legs
    • Diabetes (usually mild)
    • Depression
    • DVT
  • Diagnosis
    • High glucagon (fasting level >1000pg/mL is diagnostic)
    • CT/MRI to localise lesion
    • Tend to be larger than other PNETs, mostly in body or tail
  • Treatment
    • Resect when possible
    • Dermatitis resolves rapidly with treatment of hyperglycaemia
    • No effective chemotherapy against metastatic disease, but they are slow-growing and don't often kill

VIPoma - vasoactive intestinal polypeptide-secreting tumour - rare

• • Presentation
    • Verner-Morrison syndrome - watery diarrhoea, hypokalaemia, achlorhydria (WDHA)
    • Excessive VIP inhibits gastric acid secretion, bone resorption and glycogenolysis and causes vasodilation, resulting in respective symptoms of hypochlorhydria, hypercalcaemia, hyperglycaemia, and flushing
  • Diagnosis
    • Serum VIP
    • Majority are malignant, 70% have mets at diagnosis
    • Generally visible on CT/MRI
    • Somatostatin receptor scans generally work well for these
  • Treatment
    • Initially, fix the electrolytes and volume status - somatostatin analogues +/- glucocorticoids
    • Resection
    • Somatostatin analogues will give excellent symptomatic control with or without surgery

Somatostatinoma (rare)

• • Presentation
    • Classically diabetes, diarrhoea or steatorrhoea, and weight loss as a result of the inhibitory effect of somatostatin
  • Diagnosis
    • Fasting plasma somatostatin level > 3 ULN
    • If index of suspicion is high, but serum somatostatin level is normal, a stimulatory or inhibitory test can be performed
  • Treatment
    • Complete resection is ideal but often not possible
    • Consider debulking, chemoembolisation of primary and metastatic tumours, and chemotherapy
    • Octreotide is effective at suppressing symptoms

Other rare functional tumours (rare)

• • ACTH-producing
  • Parathyroid hormone-related peptide

Non-functional (50-85%)

• • Presentation
    • Either incidental or mass effect (pain, biliary obstruction)
  • Diagnosis
    • Pancreatic mass but no hormonal symptoms
    • Elevated CGA/PP
    • Positive somatostatin receptor scan
  • Management
    • Resection is primary method of achieving cure if >2cm or significant interval growth, since that group has higher risk of metastases
    • Observe <2cm without overt malignant features, or low-grade (based on Ki67 and mitotic index)
  • Palliation
    • Cytoreductive surgery of primary and mets

Diagnosis/workup

• History - carefully screen for functional tumour symptoms
  • Neuroglycopaenic symptoms
  • Diarrhoea
  • Ulcer diathesis
  • Rash
• Family history
• Bloods
  • Biochemical confirmation of functional symptoms
  • Chromogranin-A: often co-released in many PNETs (functional and non-functional), potential marker of secretory activity, especially in non-functional tumours (may be elevated with PPIs, atrophic gastritis, or CKD or liver dysfunction)
• Imaging - localise PNET and check for metastases
  • CT CAP - need early arterial phase
    • Hyper-enhancing
    • Can see arterial blush
    • Isodense pre-contrast, enhance arterial phase, washout PV phase
    • Distending duodenum with water can help for small duodenal gastrinomas
  • Gallium-68 DOTATATE PET, fused with CT
    • Sensitivity 80%, specificity 90%, and specificity nearly 100% for metastases seen outside pancreas
    • Lesions that take up tracer well, may respond better to somatostatin analogues
  • FDG PET
    • Better than DOTATATE PET for poorly-differentiated tumours, which tend to be high-grade and without somatostatin receptors
  • MRI
    • Low signal T1, high signal T2
    • Identifies all lesions >3cm, 50% of lesions 1-2cm, and no lesions <1cm
    • Useful for liver
  • EUS
    • Better sensitivity than CT or MRI
    • Good for pancreatic head and duodenal wall
  • Old - somatostatin receptor scintigraphy
    • Essentially replaced by DOTATATE PET
    • Useful adjunct in localisation if not seen on CT/MRI/EUS
    • Very good especially for gastrinomas, not as good for insulinomas and pancreatic adenocarcinoma
    • Lacks anatomic precision
    • Not very good if lesion <1cm
    • Overall sensitivity 70-90%, specificity nearly 100%
  • Angiography
    • Can sometimes be useful if other studies can't locate it
    • Detects 70% of insulinomas >5mm

Specific situations

• Patient presents with symptoms
  • Functional testing and localise the tumour
  • Surgical resection
  • Approach and extent dictated by tumour type and patient factors
  • Mostly perform partial pancreatic resection with lymph node sampling
• Patient presents with lesions found incidentally
  • Work up with imaging - local and systemic staging with CT CAP, DOTATATE PET, consider EUS +/- FNA
  • If <2cm and G1, observation may be an option - repeat CT/MRI at 6-12 months with surgery if increase in size by 0.5cm or more
  • If >2cm or G2 or G3, generally recommend resection in a good operative candidate
• Liver mets
  • Liver resection - either curative or palliative
  • Resection recommended if >90% of disease can be removed
  • 80% recurrence at 5 years, but 85% 5-year survival
  • Factors with better prognosis:
    • G1 or G2 tumours
    • Absence of distant lymph node metastases
    • Absence of extrahepatic or peritoneal metastases
  • Palliative: can do HAE/chemoembolisation/RFA, but outcomes appear to be worse, not curative
  • Liver transplant has been proposed under certain circumstances (unresectable neuroendocrine metastases) but this is controversial, and not done in Australia
  • Debulking is reasonable if >90% of tumour can be removed
• Metastatic PNETs in general
  • Somatostatin analogues - effective in controlling both hormone secretion and stabilising tumour growth
    • Can provoke cholelithiasis - if possible, cholecystectomy at initial operation
  • Knowing the type of somatostatin receptor expressed by the tumour can help guide therapy - there are 5 different types
  • Cytotoxic chemotherapy is also an option, especially for poorly-differentiated PNETs

Surveillance

• Chromogranin A