Nonfunctioning pancreatic neuroendocrine tumors

6 Interesting Facts of Nonfunctioning pancreatic neuroendocrine tumors

1. Nonfunctional pancreatic neuroendocrine tumors are a rare subset of neuroendocrine tumors originating from the ductal epithelial cells of the pancreas
   • Categorized as functional or nonfunctional based on hormone production and clinical manifestations; majority of tumors are nonfunctional
2. May be clinically silent and are usually discovered incidentally during surgery or imaging for another complaint
   • Uncommonly, they present at an advanced stage with nonspecific symptoms (eg, abdominal pain, weight loss, jaundice)
3. Diagnosis based on history, physical examination, serum biomarkers, and imaging studies; diagnosis confirmed with histopathologic findings
4. Management depends on size of tumor, presence of local or distant metastases, and general status of patient
5. Surgical resection is the mainstay of treatment in most cases and the only curative treatment; provides a significant survival advantage in patients with localized, regional, and metastatic disease
6. Systemic therapy, including treatment with somatostatin analogues or molecular targeted therapies, may prolong survival and improve quality of life in patients with progressive or recurrent disease

Pitfalls

• Diagnosis is often delayed until disease is at an advanced stage as the symptoms are nonspecific and disease course tends to be indolent 
• Proton pump inhibitors can cause false-positive elevations in chromogranin A levels; the biomarker pancreastatin is not affected by proton pump inhibitors and may be useful in these cases
• Some nonfunctioning pancreatic neuroendocrine tumors secrete low levels of peptide hormones but at such low concentrations that they do not result in clinical syndromes

Pancreatic neuroendocrine tumors are a rare subset of neuroendocrine tumors originating from pluripotent stems cells in the ductal epithelial cells of the pancreas

Categorized as functioning or nonfunctioning based on hormone production and clinical manifestations 

Majority of tumors are nonfunctional 

Nonfunctional tumors may still secrete hormones at very low levels, or produce peptides that do not cause symptoms 

Represent 1.3% of all pancreatic neoplasms; estimated incidence is less than 1 per 100,000 individuals 

Classification

• Classification of pancreatic neuroendocrine tumors according biologic activity
  • Nonfunctional pancreatic tumors (60%-90% of cases) 
    • Not associated with a clinical syndrome relating to hormone hypersecretion; however, these typically secrete a number of other peptides, including chromogranins, pancreatic polypeptide, neuron-specific enolase, subunits of hCG, neurotensin, and ghrelin 
  • Functional tumors (10%-30% of cases) include: 
    • Insulinoma
    • Glucagonoma
    • VIPoma
    • Gastrinoma
    • Somatostatinoma
    • Cholecystokinin-producing tumor
    • Other rare functional tumors produce hormones including adrenocorticotropic hormone, parathyroid hormone–related protein, and growth hormone–releasing hormone
• TNM staging system for pancreatic neuroendocrine tumors 
  • Primary tumor (T)
    • TX: primary tumor cannot be assessed
    • T0: no evidence of primary tumor
    • Tis: carcinoma in situ
    • T1: tumor limited to the pancreas, 2 cm or less in greatest dimension
    • T2: tumor limited to the pancreas, more than 2 cm in greatest dimension
    • T3: tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery
    • T4: tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)
  • Regional lymph nodes (N)
    • NX: regional lymph nodes cannot be assessed
    • N0: no regional lymph node metastasis
    • N1: regional lymph node metastasis
  • Distant metastases (M)
    • M0: no distant metastases
    • M1: distant metastases
  • Anatomic stage/prognostic groups
    • Stage 0: Tis, N0, M0
    • Stage IA: T1, N0, M0
    • Stage IB: T2, N0, M0
    • Stage IIA: T3, N0, M0
    • Stage IIB: T1, N1, M0; T2, N1, M0; T3, N1, M0
    • Stage III: T4, any N, M0
    • Stage IV: any T, any N, M1
• WHO histologic grading system 
  • Grade G1 (low): well differentiated, Ki-67 index 3% or less, mitotic count less than 2 per 10 high-power fields
  • Grade G2 (intermediate): well differentiated, Ki-67 index 3% to 20%, mitotic count 2 to 20 per 10 high-power fields
  • Grade G3 (high): poorly differentiated, Ki67 index greater than 20%, mitotic count greater than 20 per 10 high-power fields

Clinical Presentation

History

• Nonfunctional tumors are frequently clinically silent 
• May be found incidentally; uncommonly, may present at an advanced stage with nonspecific symptoms (eg, abdominal pain, weight loss) 
• Other infrequent symptoms include anorexia, nausea, or palpable abdominal mass 
• Symptoms often do not appear until metastases develop

Physical examination

• Examination may have normal findings
• May demonstrate abdominal tenderness or mass, hepatomegaly, or jaundice in advanced disease

Causes

• Causative factors of sporadic pancreatic neuroendocrine tumors are not fully defined
• Hereditary pancreatic neuroendocrine tumors can arise in the context of inherited genetic syndromes such as multiple endocrine neoplasia type 1 
• Many sporadic pancreatic neuroendocrine tumors have somatic mutations in chromatin remodeling genes (eg, MEN1, DAXX/ATRX) and genes within the mechanistic target of rapamycin pathway 

Risk factors and/or associations

Age

• Peak incidence is between ages 40 and 69 years 
  • However, a significant number of patients are diagnosed before age 35 years 

Sex

• Overall incidence is higher in males than in females 
  • According to the Surveillance, Epidemiology, and End Results Program (SEER) database from 1973 to 2000, the annual incidence of pancreatic neuroendocrine tumors was 1.8 in women and 2.6 in men per 1 million 

Genetics

• Most pancreatic neuroendocrine tumors are sporadic; however, some arise in the context of inherited genetic syndromes
  • Multiple endocrine neoplasia type 1 (OMIM #131100) 
    • Autosomal dominant, endocrine neoplastic predisposition disease caused by germline-inactivating mutations in the tumor suppressor gene MEN1
    • Characterized by predisposition to hyperparathyroidism (nearly 100%), pancreatic neuroendocrine tumors (50%), and pituitary adenomas (less than 50%)
      • Most common pancreatic neuroendocrine tumors include nonfunctioning type and insulinoma 
    • Note that a clinical diagnosis of multiple endocrine neoplasia type 1 requires the presence of 2 or more multiple endocrine neoplasia type 1–associated tumors; a confirmatory diagnosis is made with genetic testing 
  • von Hippel–Lindau syndrome (OMIM #193300) 
    • Autosomal dominant cancer predisposition disease caused by germline inactivating mutations in VHL gene
    • Characterized by a variety of malignant and benign neoplasms; most frequently, hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic neuroendocrine tumors
    • Pancreatic neuroendocrine tumors occur in approximately 5% to 10% of patients with von Hippel–Lindau syndrome and are usually clear cell nonfunctioning tumors 
  • Tuberous sclerosis complex (OMIM #191100) 
    • Autosomal dominant disorder caused by germline mutations in TSC1 or TSC2 genes
    • Characterized by hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, and lungs
      • Disorder is usually identified in infants and children based on characteristic skin lesions, seizures, and hamartomas in various organs
    • Pancreatic neuroendocrine tumors are uncommon but more likely to occur in individuals with TSC2 variants 

Ethnicity/race

• Majority of patients with neuroendocrine tumors (pancreatic and others) in a large series of patients in the United States were white (81% of all cases) 

Diagnostic Procedures

Primary diagnostic tools

• Nonfunctioning pancreatic neuroendocrine tumors are typically asymptomatic and discovered incidentally during surgery or through imaging performed to evaluate other conditions
• Initial work-up of an incidental pancreatic mass consists of imaging and measurement of tumor markers 
• Localize tumor (if presenting nonincidentally) and determine extent of disease by assessing nodal status and/or any metastatic spread 
  • Stage tumor using abdominal multiphasic CT or MRI
  • Somatostatin receptor–based imaging and endoscopic ultrasonography (often with biopsy) may be used if initial imaging does not have definitive results
• Obtain levels of neuroendocrine biomarkers (pancreatic polypeptide and chromogranin A) to confirm diagnosis and use as a baseline level for future tumor surveillance
  • Obtain additional laboratory (hormone) evaluation in patients with any symptoms and signs of hormone hypersecretion as needed to exclude a functioning tumor 
  • Note that laboratory testing for all pancreatic neuroendocrine hormones is not routinely recommended but should be guided by presence of symptoms of excess hormones 
  • Biomarker pancreastatin may also be helpful for suspected cases if chromogranin A is not elevated
• Evaluate patient and family history for the possibility of multiple endocrine neoplasia; may require additional diagnostic testing
• Obtain tissue specimen, either with endoscopic ultrasonography or at surgical resection, to identify (or confirm) histopathologic diagnosis; histology is the diagnostic determinant 
• Stage tumor according to the American Joint Committee on Cancer TNM staging criteria for primary tumor site and WHO gastroenteropancreatic neuroendocrine tumor grading system

Laboratory

• Serum chromogranin A level
  • Biomarker indicated for diagnostic evaluation of all suspected cases of pancreatic neuroendocrine tumors 
  • Elevated in 60% or more of patients with either functioning or nonfunctioning pancreatic endocrine tumors (threshold value depends on specific assay used) 
    • False-positive elevation can occur if patient has renal or hepatic impairment, Crohn disease, ulcerative colitis, rheumatoid arthritis, Parkinson disease, or is taking proton pump inhibitors 
      • Proton pump inhibitors should be discontinued at least 7 days before testing 
  • Can be used for diagnosis, to assess response to treatment, and to detect progression or recurrence 
• Serum pancreatic polypeptide level
  • Biomarker indicated for diagnostic evaluation of all suspected cases of pancreatic neuroendocrine tumors
  • Nonspecific biochemical marker; elevated levels found in most patients with nonfunctioning pancreatic neuroendocrine tumors 
    • Falsely elevated levels may be found with laxative misuse, advanced age, inflammatory processes of gut, or chronic renal disease 
• Serum pancreastatin level
  • Biomarker that is a derivative of chromogranin A; may be useful in diagnostic evaluation of patients with suspected pancreatic neuroendocrine tumors whose chromogranin A levels are within reference range 
  • Not affected by proton pump inhibitors; therefore, useful in patients using them 
  • Levels are often elevated in patients with diabetes or hyperparathyroidism 
• Serum gastrin level
  • Indicated when symptoms suggest gastrin excess (eg, recurrent gastric and duodenal ulcers, diarrhea)
  • Not routinely required for asymptomatic patients
  • Elevated fasting gastrin level (1000 ng/L or greater, or 10 times upper reference limit) and gastric pH level less than 2 or 2.5 is diagnostic of gastrinoma 
• Serum insulin, proinsulin, C-peptide, and fasting blood glucose levels 
  • Indicated when symptoms suggest hypoglycemia
  • Not routinely required for asymptomatic patients
  • Insulinoma is a likely diagnosis when laboratory evidence of hyperinsulinemic hypoglycemia exists 
• Serum glucagon level
  • Indicated when symptoms suggest excess glucagon (eg, flushing, diarrhea, hyperglycemia, dermatitis) 
  • Not routinely required for asymptomatic patients
  • Increased glucagon levels (usually 500-1000 pg/mL) are suggestive of glucagonoma when accompanied by typical symptoms 
• Serum vasoactive intestinal polypeptide level 
  • Indicated when symptoms suggest excess levels (eg, diarrhea, hypokalemia)
  • Not routinely required for asymptomatic patients
  • Plasma vasoactive intestinal polypeptide levels greater than 200 pg/mL in presence of large volume of secretory diarrhea is strongly suggestive of VIPoma

Tumor term	Symptoms and signs	Laboratory marker	Diagnostic threshold
Nonfunctional	Silent	Serum pancreatic polypeptide and chromogranin A	Chromogranin A level greater than 36.4 ng/mL; pancreatic polypeptide reference range varies by age and assay
Insulinoma	Hypoglycemia	Serum insulin, proinsulin, C-peptide, and fasting glucose	Hypoglycemia with nonsuppressed insulin
VIPoma	Diarrhea and hypokalemia	Serum VIP	VIP level greater than 200 pg/mL
Glucagonoma	Flushing, diarrhea, hyperglycemia, and dermatitis	Serum glucagon	Glucagon level 500 to 1000 pg/mL
Gastrinoma	Recurrent gastric and duodenal ulcers and diarrhea	Serum gastrin	Fasting gastrin level greater than 1000 pg/mL; gastric pH level less than 2.5

Caption: VIP, vasoactive intestinal peptide. Note that not all tests are routinely indicated; perform selected tests in the presence of symptoms.

• symptoms.

Imaging

• Multiphasic abdominal CT or MRI 
  • Standard imaging modes used to localize and stage pancreatic neuroendocrine tumors
  • Assess disease burden and possible primary location, delineate regional/mesenteric lymph nodes, and detect liver metastases
  • MRI has superior soft tissue contrast resolution for investigation of pancreatic neuroendocrine tumors and is optimal method for imaging hepatic metastases
  • Radiologic findings suggestive of a pancreatic neuroendocrine tumor include arterial enhancement, calcifications, and occasionally necrosis or cystic degeneration
• Somatostatin receptor–based imaging 
  • Uses overexpression of somatostatin receptors present on many nonfunctional pancreatic neuroendocrine tumors to identify tumor
  • Useful modality if initial imaging investigation fails to depict pancreatic neuroendocrine tumors
  • Also helpful for identifying additional metastases in regional lymph nodes, distant lymph nodes, and bone
  • 2 primary types of studies are available; method selected often depends on local availability and expertise
    • Somatostatin receptor scintigraphy with indium In 111 pentetreotide kit (Octreoscan)
    • Gallium Ga 68 DOTATATE PET/CT, which is preferred if available owing to high sensitivity (approximately 95%) and additional benefits of staging and detecting recurrence after treatment 
• Endoscopic ultrasonography 
  • May be performed if initial investigation fails to depict pancreatic neuroendocrine tumors 
  • Provides superior diagnostic sensitivity compared with CT and MRI
  • Particularly useful for localizing small (less than 2 cm) pancreatic tumors
  • Can provide guidance of biopsy needle for both fine-needle aspiration for cytology and core biopsy for histopathologic examination 

Procedures

Biopsy

General explanation

• Collection of tissue specimen for histopathologic examination, performed either via open surgical resection or percutaneously with CT guidance
• Octreotide should be administered before procedure

Indication

• Obtain tissue for diagnosis, histologic classification, and identification of biomarkers

Contraindications

• Uncontrolled bleeding diathesis

Interpretation of results

• Tumor is classified based on anatomic site and histologic characteristics
• Mitotic rate, level of Ki-67 (MKI67, a cell proliferation marker), and presence of nonischemic tumor necrosis are determined 
• Specific immunohistochemical markers may be used to establish neuroendocrine differentiation (eg, chromogranin A, synaptophysin, CDX2, CD56) 
• Tumor grade is assigned according to WHO tumor grading system for gastroenteropancreatic neuroendocrine tumors 
  • Grade 1 (low grade, well differentiated)
    • Mitotic count: fewer than 2 mitoses per 10 high-power fields
    • Ki-67 index: 3% or less
  • Grade 2 (intermediate grade, well differentiated)
    • Mitotic count: 2 to 20 mitoses per 10 high-power fields
    • Ki-67 index: 3% to 20%
  • Grade 3 (high grade, poorly differentiated)
    • Mitotic count: more than 20 mitoses per 10 high-power fields
    • Ki-67 index: greater than 20%

Differential Diagnosis

Most common

• Pancreatic adenocarcinoma
• Chronic pancreatitis
• Accessory spleens

Treatment Goals

• Eradicate or control tumor growth
• Prevent progression or recurrence

Admission criteria

• Admit patients for surgical resection of tumor

Recommendations for specialist referral 

• Refer patients to specialized centers with multidisciplinary team for all aspects of the disease: diagnosis, staging, treatment, and counseling
• Refer patients with resectable disease to an endocrine or oncologic surgeon
• Refer patients with metastatic or unresectable tumors to medical oncologist for systemic chemotherapy
• Refer patients with suspected genetic conditions to medical geneticist and genetic counselor

Treatment Options

Management strategy primarily depends on locoregional disease versus metastatic disease; other factors that influence treatment are anatomic size of tumor and general health status of patient

• For local or locoregional disease 
  • Surgical resection is cornerstone of treatment in most cases and is the only curative treatment 
  • Options for small tumors (2 cm or smaller):
    • Enucleation with or without regional lymph node resection
    • Distal pancreatectomy with or without regional node resection/splenectomy
    • Pancreatoduodenectomy with or without regional node resection
    • Observation in selected cases of small (1 cm or smaller), low-grade, incidentally discovered tumors
  • For larger (greater than 2 cm), invasive, or node-positive tumors, surgical procedure should include total removal of tumor to obtain negative margins (including adjacent organs) and resection of regional lymph nodes
    • Pancreatoduodenectomy plus regional node dissection if tumor involves head of pancreas
    • Distal pancreatectomy plus splenectomy plus regional node dissection if tumor involves distal portion of the pancreas
  • Note that there is no role for adjuvant systemic therapy after complete resection of tumors
• For unresectable locoregional and/or metastatic disease 
  • If complete or near complete resection is possible, consider curative surgery to remove both primary tumor and metastases
  • If patient is asymptomatic and has low tumor burden and apparently stable disease, consider observation with biomarker measurement and imaging every 3 to 12 months 
  • Consider lanreotide or octreotide as first line treatment for symptomatic, unresectable disease 
  • If disease is progressive, consider lanreotide or octreotide plus:
    • Molecular targeted therapy 
      • Everolimus
      • Sunitinib
    • Cytotoxic chemotherapy
      • Common regimens that may considered in patients with bulky, symptomatic, and/or progressive disease include: 
        • Temozolomide and capecitabine
        • Streptozocin, 5-fluorouracil, and doxorubicin
        • Streptozocin and doxorubicin
        • Streptozocin and 5-fluorouracil
    • Hepatic-directed therapies for patients with progressive hepatic-predominant metastatic disease
      • Options include arterial embolization, radioembolization, chemoembolization, ablative therapy, or cytoreductive surgery
    • Peptide receptor radionuclide therapy using radiolabeled somatostatin analogues, if somatostatin receptor–based imaging findings are positive and disease progresses while using somatostatin analogue drug therapy 
      • Yttrium Y 90 DOTATOC and lutetium Lu 177 DOTATATE are the most widely used agents 
    • Note that no data show superiority of a specific sequence of regional versus systemic therapy, and no data guide sequencing of systemic therapy (cytotoxic chemotherapy or molecular therapies) 

Rationale

• Surgical resection eradicates tumors and/or reduces tumor burden
• Treatment with somatostatin analogues may reduce symptoms and delay progression of disease

Outcomes

• Surgical resection
  • Provides a significant survival advantage in patients with localized, regional, and metastatic disease 
  • Surgical resection is optimal method of treatment for localized pancreatic neuroendocrine tumors and can result in excellent outcomes 
    • Median survival of 7 to 10 years is reported for patients undergoing resection of locoregional disease 
    • Overall, disease recurrence occurs in 21% to 42% of patients after resection of pancreatic neuroendocrine tumors; most recurrences are within 5 years 
  • Removal of primary tumor or reduction of tumor bulk and resection of hepatic metastases may improve progression-free survival and symptom control in advanced pancreatic neuroendocrine tumors; however, most patients will experience recurrence 
  • Hepatic-directed therapies may provide local control of unresectable hepatic metastasis
• Systemic therapy may prolong survival and improve quality of life in patients with progressive or recurrent disease
  • Targeted molecular therapies (sunitinib and everolimus) delay tumor progression in advanced/metastatic disease
  • Treatment with somatostatin analogues is recommended to manage any symptoms related to hormone secretion and may also delay progression in advanced disease 
  • Chemotherapy is reserved for patients with high-grade, poorly differentiated tumors or rapidly progressive, unresectable disease because indolent, well-differentiated forms are typically resistant to conventional therapeutic agents 

Drug therapy

• Somatostatin analogues 
  • Octreotide
    • Intramuscular injection (long acting)
      • Octreotide Acetate Suspension for injection; Adults who have responded to and tolerate SC octreotide: In adults with a response to subcutaneous use of octreotide, give 20 mg IM depot injection intra-gluteally every 4 weeks for 2 months. Continue the previous subcutaneous dosage for up to 2 weeks after initiating depot injections (some may require up to 4 weeks), as otherwise the patient may have symptom exacerbation. After 2 months, if response inadequate, may increase to 30 mg IM every 4 weeks. For maintenance, give a trial of 10 mg IM every 4 weeks if the patient responded to the initial dose. If increased symptoms occur, increase the dose. Max: 30 mg IM every 4 weeks. Dosing intervals greater than 4 weeks are not recommended. Some patients may require temporary management with subcutaneous octreotide for periodic symptom exacerbations, which may be halted once symptoms resolve.
  • Lanreotide
    • Lanreotide Solution for injection; Adults: 120 mg by deep subcutaneous injection every 4 weeks.
• Chemotherapy agents 
  • Molecular targeted agents
    • Everolimus (mechanistic target of rapamycin pathway inhibitor)
    • Sunitinib (receptor tyrosine kinase inhibitor)
  • Alkylating agents
    • Streptozocin
    • Temozolomide
  • Antimetabolites
    • Capecitabine
    • 5-fluorouracil
  • Anthracycline antibiotics
    • Doxorubicin

Nondrug and supportive care

Tailored to meet patient needs based on age, performance status, disease status, specific surgical approach and therapeutic agents used, and risk of complications; may include: 

• Presplenectomy trivalent vaccination for pneumococcus, Haemophilus influenzae type b, and meningococcal group C
• Prophylactic cholecystectomy at time of curative surgery to prevent cholelithiasis in patients who are anticipated to receive somatostatin analogues (octreotide or lanreotide)

Procedures

Surgical resection remains the primary curative modality in management of pancreatic neuroendocrine tumors 

Surgical management is individualized based on anatomic site and tumor stage

Relevant procedures include enucleation, pancreaticoduodenectomy, and distal pancreatectomy, with or without splenectomy or lymphadenectomy; may be performed via open or minimally invasive approach 

• May also include complete excision or debulking of hepatic metastases

Special populations

• Patients with multiple endocrine neoplasia type 1 
  • Tumors are more likely to be multifocal
  • Surgical management of an apparent single pancreatic neuroendocrine tumor in the setting of multiple endocrine neoplasia type 1 disease is similar to that of sporadically occurring pancreatic neuroendocrine tumors
  • Role of surgical resection in multifocal disease is controversial; may be appropriate if refractory to medical management, if tumor size is larger than 1 cm, or if tumor demonstrates rapid growth over 6 to 12 months 
  • Multiple endocrine neoplasia type 1–associated metastatic pancreatic neuroendocrine tumors often grow more slowly than sporadic tumors and observation may be considered for indolent nonfunctioning tumors 

Monitoring

• Surveillance measures apply to cases after surgical resection and to cases where observation has been chosen for metastatic disease
  • Measures include history, physical examination, measurement of chromogranin A and other biochemical markers (selecting ones that are elevated at baseline), and imaging 
    • Abdominal multiphasic CT or MRI, in combination with chest CT, are preferred imaging modalities for monitoring disease status and assessing for progression 
  • Intervals for surveillance
    • 3 to 12 months postresection (earlier if the patient shows symptoms)
    • Every 6 to 12 months for up to 10 years
    • Optimal duration of surveillance is unknown

Complications

• Locoregional recurrence
• Distant metastasis

Prognosis

• Single most important determinant of prognosis is histologic grade of tumor 
  • Histologic grade tends to surpass stage in prognostic capability, meaning that some patients with widespread distant metastasis may be asymptomatic for years, whereas others presenting with localized high-grade disease will frequently have early recurrence and disease progression within months of diagnosis
• Prognosis also varies according to histologic classification and stage at diagnosis
  • Older age at diagnosis, more advanced stage, and higher tumor grade are associated with worse survival rate 
  • Most patients have either metastatic or regionally advanced tumors at the time of diagnosis 
  • Overall 5-year survival ranges from 27% to 33%

Screening

At-risk populations

• Patients with known multiple endocrine neoplasia type 1 
• Carriers of a MEN1 mutation (ie, relatives of patients with multiple endocrine neoplasia type 1 who harbor a germline MEN1 mutation as identified through genetic testing) 

Screening tests

• Annual biochemical evaluation of a fasting gastrointestinal tract hormone profile that includes measurement of the following: 
  • Tumor biomarkers chromogranin A and pancreatic polypeptide
  • Laboratory studies should also include hormonal tests for functioning pancreatic neuroendocrine tumors, which would include:
    • Gastrin level
    • Glucagon level
    • Vasoactive intestinal polypeptide level
    • Insulin with an associated fasting glucose level
• Consensus for optimum radiologic screening for pancreatic neuroendocrine tumors has not been established and depends on clinical judgment and patient preferences 
  • Suggested minimum imaging protocol includes annual pancreatic (and duodenal) visualization with MRI, CT, or endoscopic ultrasonography

Sources

Aluri V et al: Biochemical testing in neuroendocrine tumors. Endocrinol Metab Clin North Am. 46(3):669-77, 2017 Reference