Functioning Pancreatic Neuroendocrine Tumors

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Functioning Pancreatic Neuroendocrine Tumors

Urgent Action

Severe hypoglycemia in patients with insulinomas
- For conscious patients, administer 15-g rapid-acting carbohydrate and recheck blood glucose level 15 minutes later ²
  - If needed, repeat 15-g glucose doses until blood glucose level rebounds to more than 70 mg/dL
- For unconscious patients, administer 1-mg glucagon (available in glucagon emergency kits) subcutaneously, intramuscularly, or IV and recheck blood glucose level 15 minutes later ²
  - Be prepared to administer IV dextrose in hospitalized patients

Key Points

Pancreatic neuroendocrine tumors are a rare subset of islet cell tumors that arise from pluripotent stem cells in the ductal epithelial cells of the pancreas ¹
- Categorized as functional or nonfunctional based on hormone production and clinical manifestations
Functional pancreatic neuroendocrine tumors result in a variety of clinical syndromes relating to hormone hypersecretion; the presentation and disease course vary according to location of tumor and hormone produced
Pancreatic insulinomas are associated with symptoms of hypoglycemia; gastrinomas may present with symptoms related to peptic ulcers or esophagitis and diarrhea; glucagonoma present with symptoms of hyperglycemia, diarrhea, and skin and mucosal manifestations; and VIPomas (vasoactive intestinal peptide tumors) may present with large volume of watery diarrhea
Occasionally, pancreatic neuroendocrine tumors present at an advanced stage with nonspecific symptoms such as abdominal pain, weight loss, or jaundice
Diagnosis is based on demonstration of inappropriate elevation of a specific pancreatic hormone combined with imaging studies and histopathology
Management depends on anatomic site and size of tumor, presence of local or distant metastasis, secretory profile, and general status of patient
Surgical resection is the mainstay of treatment in most cases and is the only curative treatment; it provides a significant survival advantage in patients with localized, regional, and metastatic disease
Systemic therapy, including treatment with somatostatin analogues or molecularly targeted therapies, may prolong survival and improve quality of life in patients with progressive or recurrent disease

Pitfalls

Inappropriate use of octreotide or lanreotide can cause serious hypoglycemia in patients with insulinoma
- Use with caution; consider trial of short-acting octreotide before initiating long-acting formulation ³

Terminology

Clinical Clarification

Pancreatic neuroendocrine tumors are a rare heterogeneous subset of neuroendocrine islet cell tumors that originate from pluripotent stems cells in the ductal epithelial cells ¹ of the pancreas
Categorized as functional or nonfunctional based on hormone production and clinical manifestations
- Functional pancreatic neuroendocrine tumors present with manifestations reflecting an excess of the secreted hormone
- Most tumors are nonfunctional and asymptomatic; they are often found incidentally ⁴
Represent 1.3% of all pancreatic neoplasms; estimated incidence is less than 1 per 100,000 people ⁵

Classification

Classification of pancreatic neuroendocrine tumors according to biologic activity
- Functioning tumors (10%-30% of cases) ⁵
  - Insulinoma
    - Pancreatic β-cell tumor that secretes insulin, causing hypoglycemia
    - Accounts for up to 70% of functional tumors ⁶
    - Less than 10% of tumors are malignant ⁷
  - Glucagonoma
    - Pancreatic α-cell tumor that secretes excess glucagon causing hyperglycemia and blood glucose intolerance ⁷
    - Represents approximately 15% of the functioning tumors ⁸
    - Malignant in 50% to 80% of cases ⁷
  - Gastrinoma (Related: Zollinger-Ellison Syndrome)
    - Secretes gastrin and causes Zollinger-Ellison syndrome, a clinical syndrome characterized by refractory peptic ulcer disease, esophagitis, and diarrhea ⁵ ⁹
    - Together with somatostatinomas, accounts for 10% of the functional tumors ⁸
    - 60% to 90% of gastrinomas are malignant, making them the most common malignant functional islet tumor ⁷
    - May also arise from the duodenum
  - Somatostatinoma
    - Secretes somatostatin, resulting in diabetes, cholelithiasis, and diarrhea ⁷
    - Rare tumors that may also occur in extrapancreatic locations ⁷
    - More than 70% are malignant ⁷
  - VIPoma (vasoactive intestinal peptide tumor)
    - Secretes vasoactive intestinal polypeptide leading to diarrhea, dehydration, hypokalemia, and achlorhydria ⁷
    - Approximately 40% to 70% are malignant ⁷
  - Other very rare functional tumors produce the following hormones:
    - ACTH (causing Cushing syndrome)
    - Growth hormone–releasing hormone (causing acromegaly)
    - Serotonin (causing carcinoid syndrome)
    - Parathyroid hormone–related protein (rare cause of hypercalcemia)
    - Cholecystokinin (associated with diabetes, peptic ulcer disease, and cholelithiasis) ¹⁰
    - Renin (associated with hypertension)
    - Luteinizing hormone (associated with anovulation and virilization)
    - Erythropoietin (associated with polycythemia)
    - Insulinlike growth factor II (associated with hypoglycemia)
    - Glucagonlike peptide 1 (associated with hypoglycemia)
- Nonfunctioning pancreatic tumors (60%-90% of cases) (Related: Nonfunctioning Pancreatic Neuroendocrine Tumors)¹¹
  - Not associated with a clinical syndrome related to hormone hypersecretion; however, these typically secrete other peptides, including chromogranins, pancreatic polypeptide, neuron-specific enolase, subunits of hCG, neurotensin, and ghrelin ⁵
TNM staging system for pancreatic neuroendocrine tumors ¹²
- Primary tumor (T)
  - TX: primary tumor cannot be assessed
  - T1: tumor limited to the pancreas, less than 2 cm in greatest dimension
  - T2: tumor limited to the pancreas, 2 to 4 cm in greatest dimension
  - T3: tumor limited to the pancreas, greater than 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)
- 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 IA: T1, N0, M0
  - Stage II: T2, N0, M0 or T3, N0, M0
  - Stage IIB: T1, N1, M0; T2, N1, M0; or T3, N1, M0
  - Stage III: T4, N0, M0 or any T, N1, M0
  - Stage IV: any T, any N, M1
WHO histologic grading system ¹³
- Uses a combination of tumor differentiation, Ki-67 index (which estimates proliferative activity of cells), ¹⁴ and number of mitoses in a microscopic field
- Well-differentiated pancreatic neuroendocrine tumors
  - Grade G1 (low): Ki-67 index less than 3%, mitotic count less than 2 per 10 high-power fields
  - Grade G2 (intermediate): Ki-67 index 3% to 20%, mitotic count 2 to 20 per 10 high-power fields
  - Grade G3 (high): Ki-67 index greater than 20%, mitotic count greater than 20 per 10 high-power fields
- Poorly differentiated pancreatic neuroendocrine carcinomas
  - Grade G3 (high): Ki-67 index greater than 20%, mitotic count greater than 20 per 10 high-power fields
    - Small cell type
    - Large cell type

Diagnosis

Clinical Presentation

History

Symptoms and clinical course vary according to hormone secreted ⁵⁹
- Insulinomas are associated with symptoms of hypoglycemia (eg, tremors, palpitations, lightheadedness, hunger, diaphoresis, confusion, altered consciousness) ¹⁵
  - Symptoms are exacerbated by fasting and relieved by eating ¹⁵
  - Many patients report an increase in body weight ⁷
- Gastrinomas may present with dyspepsia or epigastric pain, usually accompanied by high-volume diarrhea (Related: Zollinger-Ellison Syndrome)
  - Symptoms are often attributed to peptic ulcer disease or gastroesophageal reflux and may be masked by use of proton pump inhibitors ⁷
  - Other symptoms may include hematemesis, melena, nausea, vomiting, and weight loss
- Glucagonoma may present with weight loss, diarrhea, abdominal pain, nausea, symptoms of hyperglycemia (eg, thirst, frequent urination, blurry vision), and skin rash ¹⁶
  - Skin rash may occur at presentation and be pruritic or painful, often affecting the extremities or mucous membranes ¹⁷
  - Patients may report new onset or worsening of diabetes ¹⁵
- Somatostatinomas may present with a history of diabetes, symptoms of hyperglycemia (eg, urinary frequency, thirst), abdominal pain, weight loss, diarrhea, and steatorrhea ¹⁸
  - Most common symptom for all somatostatinomas is abdominal pain, as these usually present at an advanced stage
  - Cholelithiasis is a frequent occurrence
- VIPoma (vasoactive intestinal peptide tumor) may present with profuse watery diarrhea, muscle weakness, numbness, lethargy, nausea, vomiting, abdominal pain, and weight loss
  - Eventually leads to severe electrolyte disturbances (eg, loss of bicarbonate and potassium in stool) ¹⁵
Some tumors present late with advanced disease and nonspecific symptoms (eg, abdominal pain, anorexia, nausea, weight loss, jaundice) ⁷

Physical examination

Physical findings vary according to specific hormone secreted
- Examination may be unremarkable
- In advanced disease, findings may include abdominal tenderness or mass, hepatomegaly, or jaundice
- Glucagonomas have peculiar findings, in particular the characteristic skin rash, necrolytic migratory erythema, which is an erythematous vesicular rash most often involving mucous membranes, genitals, buttocks, and lower legs ¹⁷
  - Rash initially appears as annular erythema with central pigmentation and scaly borders ¹⁷
  - Additional dermatologic findings of glucagonomas include stomatitis, glossitis, or angular cheilitis ¹⁵ ¹⁷

Causes and Risk Factors

Causes

Most pancreatic neuroendocrine tumors are sporadic and the cause is not fully defined ¹⁹
- Many sporadic pancreatic neuroendocrine tumors have somatic variants in chromatin remodeling genes, such as MEN1 and DAXX/ATRX, and genes within the mTOR pathway (mammalian target of rapamycin) ²⁰
Some pancreatic neuroendocrine tumors can arise in the context of inherited genetic syndromes (eg, multiple endocrine neoplasia type 1) ¹⁹

Risk factors and/or associations

Age

Peak incidence between age 40 and 69 years ⁶
- A significant number of patients are diagnosed before age 35 years ⁶

Sex

Overall incidence is higher in males than in females; however, insulinomas are more common in females ²¹²²
- Annual incidence of pancreatic neuroendocrine tumors was 1.8 in females and 2.6 in males per 1 million according to the SEER program database (Surveillance, Epidemiology, and End Results) from 1973 to 2000 ²³

Genetics

Most pancreatic neuroendocrine tumors are sporadic; however, some arise in the context of inherited genetic syndromes ⁶
- Multiple endocrine neoplasia type 1 (OMIM #131100 ²⁴)
  - Autosomal dominant endocrine neoplastic predisposition disease caused by germline-inactivating variants in the tumor suppressor gene MEN1
  - Characterized by predisposition to hyperparathyroidism (nearly 100%), pancreatic neuroendocrine tumors (50%), and pituitary adenomas (less than 50%) ⁶
    - Insulinomas are the most common functioning pancreatic neuroendocrine tumor in patients with multiple endocrine neoplasia type 1 ²⁵
    - If a patient is diagnosed with insulinoma before age 20 years or with multiple insulinomas at any age, suspect multiple endocrine neoplasia type 1 ⁷
  - Young patients with multiple endocrine neoplasia type 1 and an exon 2 variant appear to have a 2-fold greater risk for developing a pancreatic neuroendocrine tumor ²⁶
  - 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 ²⁷
- von Hippel-Lindau syndrome (OMIM #193300 ²⁸) ⁶
  - Autosomal dominant cancer predisposition disease caused by germline-inactivating variants in VHL gene
  - Characterized by a variety of malignant and benign neoplasms; most frequently, hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic neuroendocrine tumors
  - Most pancreatic neuroendocrine tumors that occur in von Hippel-Lindau syndrome are clear cell nonfunctioning tumors ²⁹
- Tuberous sclerosis (OMIM #191100 ³¹) ³⁰
  - Autosomal dominant disorder caused by germline variants in TSC1 or TSC2
  - Pancreatic neuroendocrine tumors are uncommon but are more likely to occur in people with TSC2 variants ³²
- Neurofibromatosis type 1 (OMIM #162200 ³³)
  - Autosomal dominant disorder caused by germline variants in NF2 gene
  - Most common manifestations are of cutaneous café au lait spots and neurofibromas (benign Schwann cell tumors)
  - Neurofibromatosis type 1 is characteristically associated with ampullary or duodenal somatostatinomas in up to 10% of cases ³⁴

Diagnostic Procedures

Necrolytic migratory erythema.From Wu BC et al: Necrolytic migratory erythema. In Lebwohl MG et al, eds: Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 5th ed. Elsevier; 2018:554-6.
Pancreatic neuroendocrine tumor imaging. – A, Pancreatic neuroendocrine tumor as seen on CT. B, Pancreatic neuroendocrine tumor as seen on MRI. C, Pancreatic neuroendocrine tumor as seen on somatostatin receptor scintigraphy. D, Pancreatic neuroendocrine tumor as seen on PET/CT.From White R et al: Endocrine pancreas. In: Townsend CM et al, eds: Sabiston Textbook of Surgery. 20th ed. Elsevier; 2017:941-62, Figure 38-5.

Primary diagnostic tools

Diagnosis is based on analysis of clinical features, results of biochemical hormone testing, imaging, and histopathology ⁷
- Diagnostic sequence varies among patients, depending on the presentation; those who present with hormonal symptoms may initially undergo blood testing, whereas more bulky tumors are found with imaging ³⁵
- Diagnosis of all pancreatic neuroendocrine tumors relies on immunohistochemical examination of tumor tissue for confirmation ³⁵
Biochemical evaluation for hormone hypersecretion is guided by clinical presentation ³⁶
- Note that laboratory testing for all pancreatic neuroendocrine hormones is not routinely recommended; focus testing on hormones that explain specific symptoms ³ ³⁶
- Neuroendocrine biomarkers (pancreatic polypeptide and chromogranin A) may be obtained but are not generally recommended as a diagnostic test or for posttreatment surveillance ³⁷
- A quantitative reverse transcriptase polymerase chain reaction measuring circulating tumor transcripts in blood may be useful in diagnosis, quantifying disease activity and tumor burden, and monitoring response to treatment but does not yet have an established role in clinical practice ³⁸ ³⁹
- Insulinoma-associated protein 1 is an emerging biomarker for gastroenteropancreatic neuroendocrine neoplasms with high sensitivity and specificity demonstrated in preliminary studies; requires confirmation to establish clinical usefulness ⁴

Table

Biochemical testing in pancreatic neuroendocrine tumors.

Tumor type	Symptoms and signs	Laboratory marker	Diagnostic threshold
Insulinoma	Hypoglycemia	Serum glucose, insulin, proinsulin, and C-peptide levels	Hypoglycemia (blood glucose level less than 55 mg/dL) with nonsuppressed insulin, nonsuppressed proinsulin, and elevated C-peptide levels; if hypoglycemia does not occur spontaneously, these laboratory studies are obtained during a 72-hour fast and then threshold for hypoglycemia is blood glucose level less than 40 mg/dL
VIPoma	Secretory diarrhea and hypokalemia	Serum VIP level	VIP level greater than 200 pg/mL
Glucagonoma	Flushing, diarrhea, hyperglycemia, and dermatitis	Serum glucagon level	Glucagon level 500-1000 pg/mL
Gastrinoma	Recurrent gastric and duodenal ulcers, and diarrhea	Serum gastrin level	Fasting gastrin level greater than 1000 pg/mL; on endoscopy, gastric fluid pH value is less than 2.5
Nonfunctioning	Silent	Serum pancreatic polypeptide and chromogranin A levels	Chromogranin A level greater than 36.4 ng/mL; pancreatic polypeptide reference range varies by age and assay

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

Localize and stage tumor using abdominal multiphasic CT or MRI ⁶
- Most noninsulinoma or nongastrinoma pancreatic endocrine tumors are identified on cross-sectional imaging; however, anatomic localization of very small lesions may be difficult because even with prominent symptoms tumors can escape detection
- Additional imaging modalities that may assist with localization include somatostatin receptor–based PET imaging (ie, gallium Ga 68 DOTATATE PET/CT or PET/MRI), somatostatin receptor scintigraphy, or endoscopic ultrasonography ⁴¹
Assess for metastases with chest CT ⁶
Evaluate patient and family history for the possibility of multiple endocrine neoplasia or other inherited cancer predisposition syndrome ⁶
Obtain tissue specimen, either with endoscopic ultrasonography or at surgical resection, to assign histopathologic diagnosis; histology is the diagnostic determinant ¹
Stage tumor according to the American Joint Committee on Cancer TNM staging criteria ¹²

Cancer TNM staging criteria ¹²

Laboratory

Serum chromogranin A
- Elevated in 60% or more patients with either functioning or nonfunctioning pancreatic endocrine tumors (threshold value depends on specific assay used) ⁶
  - False-positive elevation can occur if patients have renal or hepatic impairment or receive proton pump inhibitors ⁷
- Can be used to assess response to treatment and detect progression or recurrence ⁷
- Elevated serum chromogranin A level correlates with both disease burden and survival ³⁵
- Usefulness is now considered to be limited, and management should not be based solely on changes in value ⁶ ³⁷
Serum pancreatic polypeptide
- Sometimes measured along with chromogranin A, usually when a pancreatic tumor is found on imaging and neuroendocrine source is suspected
- Nonspecific biochemical marker; elevated levels, which are found in 50% to 100% of patients with pancreatic neuroendocrine tumors (all types), provide supportive information ⁴²
- Not routinely used in diagnosis or monitoring
Serum gastrin
- Indicated when symptoms suggest excess gastrin (eg, diarrhea, reflux)
  - Not routinely required for asymptomatic patients
- Markedly elevated fasting gastrin level (1000 ng/L or greater, or 10 times the upper reference limit) is characteristic of gastrinoma ⁴³
  - A gastric fluid pH value less than 2 to 2.5, obtained from sample taken at upper endoscopy with serum gastrin level 1000 ng/L or greater, is highly suggestive of gastrinoma ⁴³
  - Elevated serum gastrin levels can also be found in patients with achlorhydria or receiving proton pump inhibitors or antacids
  - Testing must be performed after washout period of at least 1 week after proton pump inhibitor therapy
- If fasting serum gastrin levels are not elevated sufficiently to make diagnosis, a secretin provocation test may be necessary ⁴³
Blood testing for insulinoma ⁶
- Includes serum insulin, proinsulin, C-peptide, β-hydroxybutyrate, and fasting blood glucose levels
- Indicated when symptoms suggest hypoglycemia
  - Not routinely required for asymptomatic patients
- To be drawn simultaneously either during an observed spontaneous episode of hypoglycemia or during a supervised 72-hour fast at the time symptoms of hypoglycemia are present or develop
- Proposed diagnostic criteria for insulinoma (must have evidence of endogenous hyperinsulinemic hypoglycemia) ⁴⁴
  - Blood glucose level less than 55 mg/dL ¹⁵
  - Elevated insulin level 3 μIU/mL or greater ⁴⁵ (usually 6 μIU/mL or greater) ⁴⁴
  - C-peptide level 0.6 ng/mL or greater ⁴⁴
  - Proinsulin level 5.0 pmol/L or greater ⁴⁴
  - β-Hydroxybutyrate level 2.7 mmol/L or less ⁴⁴
Serum glucagon
- Indicated when symptoms suggest excess glucagon (ie, flushing, diarrhea) ⁶
  - Not routinely required for asymptomatic patients
- Increased glucagon levels (usually 500-1000 pg/mL) are suggestive of glucagonoma when accompanied by hyperglycemia and other typical symptoms ⁴³
Serum vasoactive intestinal polypeptide ⁶
- Indicated when symptoms suggest excess vasoactive intestinal polypeptide (eg, watery diarrhea)
  - Not routinely required for all patients
- VIPoma is strongly suggested by plasma vasoactive intestinal polypeptide levels greater than 200 pg/mL in the presence of large volumes of secretory diarrhea ⁴⁶
Plasma somatostatin
- Indicated when there is suspicion for somatostatin excess, usually in the context of finding a pancreatic (or duodenal) mass on imaging or endoscopy
  - Given the rarity of somatostatinomas, it is not routinely required unless symptoms are highly suggestive (eg, urinary frequency, thirst, weight loss, diarrhea/steatorrhea)
- Fasting plasma somatostatin level of more than 30 pg/mL is diagnostic ¹⁸

Imaging

Multiphasic abdominal CT or MRI scan ⁶
- Standard imaging mode used to diagnose and stage pancreatic neuroendocrine tumors
- May identify location of primary lesion; evaluates regional/mesenteric lymph nodes and liver metastases, and assesses overall disease burden
- MRI has superior soft tissue contrast resolution for the investigation of pancreatic neuroendocrine tumors and is the optimal method for imaging hepatic metastases
- Radiologic findings suggestive of a pancreatic neuroendocrine tumor include arterial enhancement, calcifications, and occasionally necrosis or cystic degeneration ¹⁹
Endoscopic ultrasonography ⁶
- Recommended if the initial imaging investigation does not fully define or fails to identify pancreatic neuroendocrine tumors ⁶¹⁹⁴¹⁴⁷
  - Provides superior diagnostic sensitivity compared with that of CT and MRI
  - Particularly useful for localizing small pancreatic tumors (less than 2 mm)
- Can provide guidance for the biopsy needle during both fine-needle aspiration for cytology and core biopsy for histopathologic examination ⁴⁷
- Primary role is in determining multifocality in patients with MEN1 ⁴⁸
Somatostatin receptor scintigraphy ⁶
- Often used as an adjunct study; typically is considered if the initial investigation fails to identify pancreatic neuroendocrine tumors
- Helpful to identify additional metastases in regional and distant lymph nodes and in bone
  - Somatostatin receptor expression is low or absent in benign insulinomas, so the detection rate for these tumors is poor
    - Only perform in patients with insulinomas if octreotide or lanreotide is being considered to treat metastatic disease ⁶
- Method of choice is highly dependent on local availability and expertise ⁴⁷
  - Gallium Ga 68 DOTATATE PET/CT or PET/MRI is preferred if available owing to high sensitivity (approximately 95%) and additional benefits of staging and detecting recurrence after treatment ⁶ ⁴⁸
  - Somatostatin receptor scintigraphy with indium In 111 pentetreotide kit (Octreoscan) has been the primary modality used in the past ⁴⁸
CT or MRI of the chest
- Recommended at diagnosis for all pancreatic neuroendocrine tumors to assess for metastatic spread ⁶
- Generally performed for staging of regional and distant metastases

Procedures

Collection of tissue specimen for histopathologic examination, performed percutaneously under guidance from CT or endoscopic ultrasonography
Obtain tissue for diagnosis, histologic classification, and identification of biomarkers
Uncontrolled bleeding diathesis
Tumor is classified based on tumor morphology and assessment of proliferation
- Morphology is classified as well-differentiated or poorly differentiated; tumor grading (G1, G2, G3) is assessed by Ki-67 and mitotic count
Tumor grade, which is informative for treatment decisions and formulating a prognosis, is assigned according to WHO tumor grading system for gastroenteropancreatic neuroendocrine tumors ⁶¹³
- Grade G1 (low-grade, well-differentiated tumors)
  - Mitotic count: fewer than 2 mitoses per 10 high-power fields
  - Ki-67 index: less than 3%
- Grade G2 (intermediate-grade, well-differentiated tumors)
  - Mitotic count: 2 to 20 mitoses per 10 high-power fields
  - Ki-67 index: 3% to 20%
- Grade G3 (high-grade, well-differentiated tumors)
  - Mitotic count: more than 20 mitoses per 10 high-power fields
  - Ki-67 index: greater than 20%
- Grade G3 (high-grade, poorly differentiated carcinomas)
  - Mitotic count: more than 20 mitoses per 10 high-power fields
  - Ki-67 index: greater than 20%
Well-differentiated tumors are considered relatively indolent malignancies and are associated with a relatively favorable prognosis ⁴⁹
Specific immunohistochemical markers may also be used to establish neuroendocrine origin as opposed to exocrine pancreas (eg, chromogranin A, synaptophysin, CDX2, CD56) ³

Differential Diagnosis

Most common

Differential diagnosis depends on specific secretory profile of tumor and resulting clinical syndrome
- Each functioning pancreatic neuroendocrine syndrome is determined by the individual hormone profile
Differential diagnosis for insulinoma
- Noninsulinoma pancreatogenous hypoglycemia syndrome ⁵⁰
  - Pancreatic nesidioblastosis (islet hypertrophy, sometimes with hyperplasia, with enlarged and hyperchromatic β-cell nuclei) resulting in episodes of neuroglycopenia due to endogenous hyperinsulinemic hypoglycemia
  - Presents with episodes of hypoglycemia in an otherwise seemingly well person; however, unlike insulinoma, hypoglycemic episodes are typically postprandial
  - Similar to insulinoma, noninsulinoma pancreatogenous hypoglycemia syndrome shows a positive result after 72-hour supervised fast, with episodes of hypoglycemia associated with inappropriate elevation of insulin, C-peptide, and proinsulin levels
  - Pancreatic imaging studies are invariably negative for insulinoma
  - In some centers, selective arterial calcium administration and hepatic vein sampling are performed as a diagnostic aid, but this testing requires special expertise
    - Hepatic venous insulin levels after calcium injection are much higher in patients with insulinoma compared with those of in patients with noninsulinoma pancreatogenous hypoglycemia syndrome or nesidioblastosis ⁵¹
- Factitious hypoglycemia ⁴⁴
  - May occur in context of pharmacy errors (eg, substitution of a sulfonylurea for another medication), inadvertent use of oral hypoglycemic medications, or malicious administration of insulin or oral hypoglycemic agents
  - Presents with episodes of hypoglycemia in an otherwise seemingly well person; patient, family member, or caregiver may have access to hypoglycemic agents
  - Differentiated based on positive sulfonylurea screening or on findings obtained during a 72-hour fast
    - High serum insulin level with low serum C-peptide level obtained from samples collected during a hypoglycemic event is suggestive of factitious hypoglycemia
    - Insulinomas, on the other hand, have high serum insulin and C-peptide levels
- Nonislet cell tumors ⁵²
  - Nonislet cell tumors that overproduce incompletely processed insulinlike growth factor I or insulinlike growth factor II are unusual but can be a rare cause of hypoglycemia
    - Hypoglycemic episode is the presenting feature in 48% of cases, whereas tumor mass is the presentation in 52% ⁵³
  - In contrast to hypoglycemia due to insulinomas, hypoglycemia due to nonislet cell tumors causes suppression of endogenous insulin secretion, so measured insulin and C-peptide levels are low
  - Nonislet cell tumors that overproduce precursor insulinlike growth factors (eg, pro–insulinlike growth factors II) are usually associated with large, clinically apparent mesenchymal tumors
    - Hepatocellular carcinoma and gastric carcinoma are the most common causes ⁵³
Differential diagnosis for glucagonoma
- Other causes of hyperglycemia; no markedly elevated levels of serum glucagon (greater than 1000 pg/mL)
  - Standard type 2 diabetes (Related: Diabetes Mellitus Type 2 in Adults)
  - Drug-induced hyperglycemia
    - Drug classes include glucocorticoids, mechanistic target of rapamycin inhibitors, tyrosine kinase inhibitors, statins, antipsychotics, interferon alfa, and antiretroviral therapy ⁵⁴
- Other diseases associated with necrolytic migratory erythema, normal serum glucagon levels, and absence of a pancreatic mass ¹⁶
  - Cirrhosis (Related: Hepatic Cirrhosis)
  - Inflammatory bowel disease
  - Colorectal adenocarcinomas
  - Villous atrophy of the small intestine
  - Myelodysplastic syndrome
- Other dermatologic conditions that resemble necrolytic migratory erythema, distinguished based on skin biopsy along with absence of a pancreatic mass, include: ⁵⁵
  - Acrodermatitis enteropathica (with zinc deficiency)
  - Pellagra
  - Pemphigus
  - Pustular psoriasis (Related: Psoriasis)
  - Atopic dermatitis (Related: Eczema and Atopic Dermatitis)
Differential diagnosis for gastrinoma (Related: Zollinger-Ellison Syndrome)
- Helicobacter pylori–associated atrophic gastritis
  - Gastric condition caused by colonization of stomach with gram-negative bacteria Helicobacter pylori
  - As in gastrinomas, results in symptoms such as refractory heartburn and epigastric pain, with or without diarrhea, along with mild to moderately elevated gastrin levels ⁵⁶
  - Differentiation from gastrinoma is based on blood, breath, stool, or biopsy test result positive for Helicobacter pylori
- Chronic autoimmune atrophic gastritis (pernicious anemia) ⁵⁶
  - Autoimmune destruction of gastric glandular cells and replacement by intestinal-type epithelium, pyloric-type glands, and fibrous tissue
  - As in gastrinomas, patients may present with symptoms such as refractory heartburn and epigastric pain, with or without diarrhea
    - Also as in gastrinomas, patients with chronic autoimmune atrophic gastritis (pernicious anemia) have severe hypergastrinemia
  - Differentiated based on presence of megaloblastic anemia and intrinsic cell and parietal cell antibodies
- Antral G-cell hyperplasia ⁵⁶
  - Pseudo–Zollinger-Ellison syndrome characterized by hypergastrinemia associated with increase in number of gastric G cells
  - As in gastrinomas, patients have symptoms such as refractory heartburn and epigastric pain, with or without diarrhea
  - Differentiated based on equivocal response to secretin stimulation, exaggerated response to food ingestion (standard test meal), and absence of gastrinoma on diagnostic imaging tests ⁵⁶ ⁵⁷
Differential diagnosis for VIPoma
- Other causes of chronic watery secretory diarrhea (Related: Chronic Diarrhea)
  - Microscopic colitis
    - Chronic secretory diarrhea associated with autoimmune disorders, common in older adults
      - Diarrhea is refractory to fasting and often nocturnal
      - Biopsy of transverse colon confirms histopathologic findings consistent with microscopic colitis, differentiating it from glucagonoma
  - Infection involving enterotoxin-producing bacteria (eg, enterotoxigenic Escherichia coli, enteroaggregative Escherichia coli)
    - Differentiate from a pancreatic neuroendocrine tumor on the basis of stool cultures
  - Medication-induced secretory diarrhea (ie, diarrhea that occurs with therapeutic dosing) ⁵⁸
    - Numerous drugs can cause or contribute to secretory diarrhea, including: ⁵⁹
      - Antiarrhythmics
      - Amoxicillin-clavulanate
      - Chemotherapies
      - Metformin
      - Calcitonin
      - Olmesartan
      - Digitalis
      - NSAIDs
      - Proton pump inhibitors
      - Selective serotonin reuptake inhibitors
      - Ticlopidine
  - Prior gastrointestinal surgical procedures (eg, cholecystectomy with or without gastrectomy, vagotomy)
    - Differentiate from glucagonoma based on patient’s history and clinical context
  - Thyrotoxicosis
    - Similar to patients with VIPoma, patients with thyrotoxicosis often report loose bowel movements with some weight loss, but their appetite is increased and they display heat intolerance, insomnia, palpitations, tremors, and tachycardia ⁶⁰
    - Differentiate from glucagonoma based on thyroid function tests showing suppressed TSH and elevated free thyroxine and triiodothyronine ⁶⁰
Differential diagnosis for somatostatinoma
- Other causes of abdominal pain and pancreatic mass/inflammation
  - Pancreatic adenocarcinoma (Related: Pancreatic Cancer)
    - Malignant adenocarcinomas of the exocrine pancreas typically present with nonspecific gastrointestinal issues (eg, nausea, vague abdominal pain), obstructive jaundice, and unintentional weight loss
    - As in pancreatic neuroendocrine tumors, a pancreatic mass is found on abdominal imaging (CT or MRI)
    - Differentiate from glucagonoma based on surgical histologic analysis of tissue taken at the time of surgery or during endoscopic ultrasonography
  - Chronic pancreatitis (Related: Chronic Pancreatitis)
    - Irreversible fibroinflammatory disorder of the pancreas that presents with relapsing, remitting upper abdominal pain accompanied by features of malabsorption due to pancreatic exocrine insufficiency ⁶¹
    - Similar to the subset of large bulky pancreatic neuroendocrine tumors that present with mass effects, chronic pancreatitis is associated with nausea, vomiting, and weight loss
      - Furthermore, hyperglycemia, overt diabetes, and steatorrhea develop as complications, as can occur with somatostatinomas
    - Diagnosis is supported by history of pancreatitis or heavy alcohol use, along with abnormally low levels of chymotrypsin and elastase 1 in stool
    - However, differentiation from glucagonoma is usually based on pancreatic findings on abdominal CT; chronic pancreatitis will typically show a dilated pancreatic duct, calcifications, and parenchymal atrophy ⁶¹
  - Ampullary or distal cholangiocarcinomas (Related: Cholangiocarcinoma)
    - Relatively rare, malignant tumors originating from the bile duct epithelium that present with symptoms of biliary obstruction, with painless jaundice, often are accompanied by nausea and vomiting ⁶²
    - Endoscopic ultrasonography shows dilated intrahepatic ducts, and other abdominal imaging studies (CT and MRI) show bile duct dilation and possibly a perihilar mass ⁶³
    - Imaging will often delineate differences from glucagonoma; formal determination is based on results of tissue biopsy or cytologic brushing obtained during endoscopic or transhepatic procedures ⁶³
- Other diseases associated with steatorrhea
  - Chronic cholestasis
    - Cholestasis is a clinical syndrome that results from diminished bile formation by hepatocytes or impaired bile secretion due to choledocholithiasis, bile duct or pancreatic tumors, and parasitic infections ⁶⁴
      - Abdominal pain, jaundice, and steatorrhea are classic symptoms
    - Liver enzymes (alkaline phosphatase and γ-glutamyltransferase) are often very elevated with cholestatic diseases
    - Differentiate from somatostatinoma based on imaging and biopsy results, as indicated
      - Further abdominal imaging, including ultrasonography, CT, or MRI, usually establishes the cause of cholestasis; more advanced procedures using endoscopic techniques (using endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography, or magnetic resonance cholangiopancreatography) may be required to obtain more precise images and/or biopsy
  - Small intestinal bacterial overgrowth
    - Defined by increased density and/or abnormal composition of microbiota in the small bowel ⁶⁵
      - Associated with diverse clinical conditions (eg, irritable bowel syndrome, cirrhosis, nonalcoholic fatty liver disease) (Related: Irritable Bowel Syndrome)
    - Patients present with abdominal discomfort, diarrhea, or bloating; malabsorption of fat may cause steatorrhea (Related: Nonalcoholic Fatty Liver Disease)⁶⁶
    - Differentiate from somatostatinoma based on breath testing or jejunal aspiration ⁶⁵
  - Celiac disease (Related: Celiac Disease)
    - Autoimmune disorder that causes damage to small intestinal villi on ingestion of gluten, which ultimately causes malabsorption and steatorrhea
    - Abdominal pain, diarrhea, and steatorrhea are common to both somatostatinoma and celiac disease
    - Serologic testing for anti–tissue transglutaminase antibodies (plus antiendomysial antibodies if equivocal) will usually identify celiac disease ⁶⁷
    - Upper endoscopy with duodenal biopsy confirms a diagnosis of celiac disease ⁶⁷ and distinguishes it from other functioning pancreatic neuroendocrine tumors
Nonfunctioning pancreatic neuroendocrine tumor (Related: Nonfunctioning Pancreatic Neuroendocrine Tumors)
- Often asymptomatic, but they may also present with abdominal pain or weight loss
- In contrast to most functioning pancreatic neuroendocrine tumors, nonfunctioning pancreatic neuroendocrine tumors are hormonally silent, discovered incidentally during surgery or through imaging performed to evaluate other conditions
- Differentiate based on absence of endocrine symptoms and negative or very low levels of gastrointestinal or pancreatic hormones
  - Both chromogranin A and pancreatic polypeptide levels are nonspecifically elevated in both functioning and nonfunctioning pancreatic neuroendocrine tumor; therefore, levels of these biomarkers do not distinguish between them ⁶⁸

Treatment

Goals

Reduce pancreatic hormone secretion
Eradicate or control tumor growth
Prevent progression or recurrence

Disposition

Admission criteria

Surgical resection of tumor
Severe hypoglycemia refractory to conventional outpatient-based treatment (owing to insulinoma)
Uncontrolled hyperglycemia (in the setting of glucagonoma)

Recommendations for specialist referral ⁶⁹

Refer patients to endocrinologist or endocrine oncologist for diagnostic testing (hormone evaluation)
Refer patients with resectable disease to endocrine oncologist or surgical oncologist
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

Overview

For all functioning pancreatic neuroendocrine tumors, surgical resection is the only curative treatment approach, so it is typically attempted for localized disease whenever technically feasible ⁴⁸⁷⁰
- For some locally advanced or metastatic disease, tumor debulking may be used to alleviate symptoms secondary to local mass effect or excess hormone levels
- Surgical resection may not be advisable in patients with severe comorbidities, high surgical risk, or widely metastatic disease
- Endoscopic ultrasonography–guided ablation therapy may be a useful option for managing symptomatic hormonal syndromes in patients who are unfit for surgery ⁴¹
Management largely depends on secretory profile of the tumor; other determining factors include anatomic site and size of tumor, presence of local or distant metastasis, and general health status of patient
- Local or locoregional disease
  - Gastrinomas: the treatment approach depends on the location of the tumor (usually head of pancreas) and on the findings during exploratory laparotomy ⁶
    - Medical therapy
      - Prescribe proton pump inhibitors to manage gastric hypersecretion
      - Consider octreotide or lanreotide for hormone-related symptom control
    - Surgical approach depends on location of tumor
      - Gastrinomas in the head of the pancreas
        
        Enucleation and removal of paraduodenal nodes for exophytic or peripheral tumors (not immediately adjacent to the pancreatic duct)
        
        Pancreatoduodenectomy for deeper or invasive tumors and with proximity to the main pancreatic duct
      - Gastrinomas in the distal pancreas
        
        Distal pancreatectomy with or without splenectomy
  - Insulinomas
    - Medical therapy
      - Control blood glucose levels with diet (frequent feedings) and/or diazoxide or everolimus ⁶ ⁷¹
      - Octreotide or lanreotide can be used cautiously for blood glucose level control if somatostatin receptor–based imaging is positive ⁶
    - Surgical approach depends on location of tumor
      - Exophytic or peripheral tumors
        
        Perform enucleation
        
        Consider laparoscopic approach for patients with sporadic disease with imaged tumors
      - Deeper or invasive tumors and those in proximity to the main pancreatic duct
        
        Pancreatoduodenectomy if involving head of pancreas
        
        Distal pancreatectomy (spleen preserving for smaller tumors that do not involve splenic vessels) if involving distal pancreas
  - Glucagonomas and VIPomas ⁶
    - Medical therapy
      - Treat with octreotide or lanreotide for hormone-related symptom control
      - Treat hyperglycemia and diabetes with oral or injectable diabetes drug therapies
      - Correct any electrolyte imbalances (potassium, magnesium, or bicarbonate) for patients with VIPomas
      - Corticosteroids may be useful for VIPomas refractory to somatostatin analogues
    - Surgical approach depends on location of tumor
      - Distal pancreatectomy with splenectomy and resection of the peripancreatic lymph nodes if involving distal pancreas
      - Pancreatoduodenectomy with resection of the peripancreatic lymph nodes if involving head of pancreas (rare)
      - Enucleation or local excision with peripancreatic lymph node dissection may be considered for small peripheral tumors (less than 2 cm)
  - Other functional pancreatic neuroendocrine tumors
    - Treat with octreotide or lanreotide for hormone-related symptom control ⁷
    - Other agents may be added to control symptoms due to specific hormones (eg, ketoconazole or metyrapone for tumors producing ACTH, cabergoline for tumors producing growth hormone–releasing hormone, bisphosphates for tumors producing parathyroid hormone–releasing hormone) ⁷¹
    - Surgical approach depends on size and location of tumor
      - Distal pancreatectomy with splenectomy and resection of the peripancreatic lymph nodes if involving distal pancreas ⁶ ⁷
      - Pancreatoduodenectomy with resection of the peripancreatic lymph nodes if involving head of pancreas ⁶ ²²
      - Tumor enucleation with or without peripancreatic lymph node dissection if tumor is small and peripheral ⁶
Unresectable locoregional and/or metastatic disease
- Treatment depends on the extent, location, and distribution of disease and the tumor’s biological characteristics ⁷²
- First consideration is hormonal control, because hormone overproduction may cause significant morbidity and mortality ⁷⁰
  - Short- and long-acting somatostatin analogues may be used to alleviate symptoms of functional tumors (eg, diarrhea, flushing)
  - Consider somatostatin analogues (lanreotide ⁷³ or octreotide ⁷⁴) in the following settings:
    - Consider for symptomatic patients with unresectable disease, those who initially present with clinically significant tumor burden, or those with clinically significant disease progression ⁶
    - Consider for patients without hormone-related symptoms if somatostatin scintigraphy is positive ⁶
    - For patients with insulinoma, octreotide or lanreotide is only useful if somatostatin scintigraphy is positive; use with caution in this case, because somatostatin analogues may transiently worsen hypoglycemia ⁶
- Tumor debulking is not curative, and the main advantage of this approach is for symptom control in functional tumors and possibly to prolong survival
  - Surgical approach is based on the extent of tumor burden ⁶
  - Partial hepatectomy can be considered in patients with liver metastases ⁶
  - Consider cholecystectomy in patients anticipated to receive long-term octreotide therapy owing to the increased risk of biliary disease associated with somatostatin analogue therapy ⁷⁰
- Specific considerations for unresectable/metastatic disease according to tumor type
  - Gastrinoma ⁷⁰
    - High doses of proton pump inhibitors are required for most patients with gastrinoma with acid hypersecretion
    - H₂ receptor blockers are another option
  - Insulinoma ⁷⁰
    - Standard care is nutritional adjustment with frequent small meals and suppression of insulin secretion with diazoxide
    - Somatostatin analogues can be used cautiously for blood glucose level control, but these may paradoxically lead to more frequent hypoglycemic events owing to possible suppression of glucagon; use only if somatostatin receptor–based imaging is positive ⁶
    - Everolimus has been associated with increased blood glucose levels in these patients and may serve as a last line therapeutic option
    - Prescribe glucagon emergency kits if severe hypoglycemia is a concern
  - Glucagonoma ⁷⁰
    - Consider parenteral nutrition, including vitamin supplementation
    - Consider anticoagulation owing to increased risk of thromboembolism
  - VIPoma ⁷⁰
    - Maintain adequate hydration
    - Replete electrolytes
    - Control blood glucose level, using oral or injectable diabetes agents as needed in accordance with degree of hyperglycemia
    - Add somatostatin analogues to mitigate diarrhea
  - Somatostatinoma ⁷⁰
    - Maintain adequate hydration and replete electrolytes, parenterally if necessary
    - Use medications to control hyperglycemia
    - Supplement with pancreatic enzyme replacement to reduce diarrhea and steatorrhea
    - Somatostatin analogues are an option but may be less effective than those for other functional pancreatic neuroendocrine tumor types
- If disease is progressive, consider lanreotide or octreotide (if not already receiving), along with the following:
  - Molecularly targeted therapies ⁷⁵⁷⁶
    - Everolimus ⁷⁷ ⁷⁸
    - Sunitinib
    - Belzutifan (if germline VHL alterations) ⁶
  - Cytotoxic chemotherapy ⁷⁹
    - Common regimens that may be considered in patients with bulky, symptomatic, and/or progressive disease include: ⁶
      - Temozolomide-capecitabine
      - Streptozocin-fluorouracil-doxorubicin
      - Streptozocin-doxorubicin
      - Streptozocin-fluorouracil
      - Dacarbazine ⁷⁶
      - FOLFOX (leucovorin-fluorouracil-oxaliplatin)
      - CAPEOX (capecitabine-oxaliplatin)
  - Immunotherapy
    - Pembrolizumab ⁸⁰
  - Hepatic-directed therapies for patients with progressive hepatic-predominant metastatic disease include arterial embolization, radioembolization, chemoembolization, ablative therapy, or cytoreductive surgery ⁶
  - Peptide receptor radionuclide therapy using radiolabeled somatostatin analogues ⁶⁷⁸¹⁸²
    - Delivers targeted radiation to tumors
    - Option if somatostatin receptor–based imaging findings are positive and disease progresses while using somatostatin analogue therapy; generally second line after molecularly targeted therapies and chemotherapy ⁷⁵ ⁸³
    - Can reduce tumor size, improve hormonal symptoms, and improve progression-free survival when conventional therapy fails ⁸⁴
    - Yttrium Y 90 DOTATOC and lutetium Lu 177 DOTATATE are the most widely used agents ⁷¹

Rationale

Surgical resection eradicates tumors and/or reduces tumor burden
Treatment with somatostatin analogues controls symptoms related to hormone hypersecretion before surgery, or if surgery cannot be performed, may delay progression in advanced disease ⁷
Other forms of adjuvant therapy (eg, everolimus) have potential to delay progression in advanced disease, particularly when used in combination with somatostatin analogues ⁸⁵

Outcomes

Surgical resection is the mainstay of treatment in most cases and the only curative treatment ⁹
- Provides a significant survival advantage in patients with localized, regional, and metastatic disease
- Surgical resection is the optimal method of therapy for localized pancreatic neuroendocrine tumors and can result in excellent outcomes ⁶
  - Median survival of 7 to 10 years was reported for patients undergoing resection of locoregional disease ⁹
  - Surgical resection achieves long-term cure in most patients with insulinoma and about 60% of patients with gastrinoma ⁷
- Removal of primary tumor or reduction of tumor bulk, and resection or ablation of hepatic metastases, may control symptoms of hormone excess and improve progression-free survival in advanced pancreatic neuroendocrine tumors; however, some patients will experience recurrence ⁷
Systemic therapy may control symptoms of hormone excess, prolong survival, and improve quality of life in patients with progressive or recurrent disease
- Treatment with somatostatin analogues is recommended to manage any symptoms related to hormone secretion and may also delay progression in advanced disease ⁷¹
  - Used with caution in patients with insulinoma, because it can exacerbate hypoglycemia ³
- Targeted molecular therapies (sunitinib and everolimus) delay tumor progression in advanced/metastatic disease ⁷¹
- Chemotherapy is reserved for patients with progressive unresectable disease
Disease recurs in 21% to 42% of patients with pancreatic neuroendocrine tumors; most instances of recurrence are within 5 years ⁶

Drug therapy

Table

Drug Therapy: Functioning pancreatic neuroendocrine tumors.

Medications	Common regimens	Life-threatening or dose-limiting adverse reactions	Notable or nonemergent adverse reactions	Special considerations
Alkylating agent—nitrosurea
Streptozocin	• FAS • Streptozocin + doxorubicin • Streptozocin + fluorouracil	• Bone marrow suppression • Nausea/vomiting • Nephrotoxicity	• Confusion • Depression • Diarrhea • Hypoglycemia • Increased hepatic enzymes • Lethargy • Proteinuria • Secondary malignancy	• Avoid coadministering nephrotoxic agents • Ensure adequate hydration
Alkylating agent—platinum
Oxaliplatin	• CAPEOX • FOLFOX	• Anaphylaxis • Bleeding • Bone marrow suppression • Nausea/vomiting • PRES • Pulmonary fibrosis • QT prolongation and ventricular arrhythmias • Rhabdomyolysis	• Diarrhea • Fatigue • Increased hepatic enzymes • Peripheral sensory neuropathy • Stomatitis	• Effective contraception required during and after therapy for 9 months for females of reproductive potential and for 6 months for males with female partners of reproductive potential
Alkylating agents—triazene
Dacarbazine	• Dacarbazine monotherapy	• Anaphylaxis • Bone marrow suppression • Hepatotoxicity	• Anorexia • Nausea/vomiting
Temozolomide	• Temozolomide + capecitabine	• Bone marrow suppression • Hepatotoxicity • PCP • Secondary malignancy	• Alopecia • Anorexia • Constipation • Fatigue • Headache • Nausea/vomiting • Seizures	• Effective contraception required during and after therapy for at least 6 months for females of reproductive potential and for at least 3 months for males with female partners of reproductive potential
Antimetabolites—nucleoside metabolic inhibitor
Capecitabine	• CAPEOX • Temozolomide + capecitabine	• Bone marrow suppression • Cardiotoxicity • Dehydration • Dermatologic toxicity • Hyperbilirubinemia • Renal failure	• Abdominal pain • Diarrhea • Fatigue/weakness • Nausea • Vomiting	• Increased risk of serious or fatal adverse reactions in patients with low or absent dihydropyrimidine dehydrogenase activity • Effective contraception required during and after therapy for 6 months for females of reproductive potential and for 3 months for males with female partners of reproductive potential
Fluorouracil	• FOLFOX • FAS	• Bone marrow suppression • Cardiotoxicity • Diarrhea • Hyperammonemic encephalopathy • Mucositis • Neurotoxicity • Palmar-plantar erythrodysesthesia (hand-foot syndrome)		• Increased risk of serious or fatal adverse reactions in patients with low or absent dihydropyrimidine dehydrogenase activity • Effective contraception required during and after therapy for 3 months for females of reproductive potential and males with female partners of reproductive potential
Hypoxia-inducible factor inhibitor
Belzutifan	• Belzutifan monotherapy	• Anemia • Hypoxia	• Dizziness • Fatigue • Headache • Hyperglycemia • Increased creatinine • Nausea	• Effective nonhormonal contraception required during and after therapy for 1 week for females of reproductive potential and for 1 week for males with female partners of reproductive potential
Kinase inhibitors
Everolimus	• Everolimus monotherapy	• Anaphylaxis • Angioedema • Bone marrow suppression • Febrile neutropenia • Hypercholesterolemia • Hyperglycemia • Hyperlipidemia • Impaired wound healing • Infection • Pneumonitis • Radiation sensitization/recall • Renal failure • Stomatitis	• Abdominal pain • Anorexia • Asthenia • Cough • Diarrhea • Edema • Fatigue • Fever • Headache • Nausea • Rash	• Drug interactions: may need to avoid or adjust dosage of certain drugs • Avoid use of live vaccines and close contact with those who have received live vaccines; complete recommended childhood vaccinations before starting treatment • Withhold therapy for at least 1 week before elective surgery and for at least 2 weeks after major surgery and until adequate wound healing • Therapeutic drug monitoring may be indicated • Effective contraception required during and after therapy for 8 weeks for females of reproductive potential and for 4 weeks for males with female partners of reproductive potential
Sunitinib	• Sunitinib monotherapy	• Bleeding • Cardiotoxicity • Dermatologic toxicity • Hepatotoxicity • Hypertension • Hypoglycemia • Impaired wound healing • ONJ • Proteinuria • QT prolongation • RPLS • TMA • Thyroid dysfunction • Tumor lysis syndrome	• Abdominal pain • Anorexia • Asthenia/fatigue • Diarrhea • Dysgeusia • Dyspepsia • Hand-foot syndrome • Mucositis/stomatitis • Nausea/vomiting • Thrombocytopenia	• Drug interactions: may need to avoid or adjust dosage of certain drugs • Withhold therapy for at least 3 weeks before invasive dental procedure and until complete resolution to decrease the risk of development of ONJ • Withhold therapy for at least 3 weeks before elective surgery and for at least 2 weeks after major surgery and until adequate wound healing • Effective contraception required during and after therapy for 4 weeks for females of reproductive potential
PD-1 blocking antibody
Pembrolizumab	• Pembrolizumab monotherapy	• Adrenal insufficiency • Anaphylaxis • Colitis • Diabetic ketoacidosis • Exfoliative dermatitis • Hepatitis • Hyperthyroidism • Hypophysitis • Hypothyroidism • Myocarditis • Nephritis • Pneumonitis • Thyroiditis	• Abdominal pain • Anorexia • Constipation • Cough • Diarrhea • Dyspnea • Fatigue • Fever • Myalgia • Nausea • Pruritus • Rash	• Effective contraception required during and after therapy for at least 4 months for females of reproductive potential
Somatostatin analogues
Lanreotide	• Lanreotide monotherapy • Lanreotide + another functional pancreatic neuroendocrine tumor therapy	• Bradycardia • Cholelithiasis • Hyperglycemia • Hypoglycemia • Thyroid dysfunction	• Abdominal pain • Diarrhea • Dizziness • Headache • Hypertension • Injection site reactions • Muscle spasm • Musculoskeletal pain • Nausea/vomiting
Octreotide	• Octreotide monotherapy • Octreotide + another functional pancreatic neuroendocrine tumor therapy	• Bradycardia • Cardiac arrhythmia • Cholelithiasis • Hyperglycemia • Hypoglycemia • Thyroid dysfunction • Vitamin B₁₂ deficiency	• Abdominal pain • Back pain • Diarrhea • Dizziness • Fatigue • Flatulence • Headache • Nausea
Topoisomerase II inhibitor—anthracycline
Doxorubicin	• FAS	• Bone marrow suppression • Cardiac arrhythmias • Cardiomyopathy • Nausea/vomiting • Tumor lysis syndrome	• Alopecia • Prepubertal growth inhibition • Radiation recall and/or sensitization • Secondary malignancy	• Can cause red discoloration of urine for 1-2 days after administration • Effective contraception required during and after therapy for 6 months for females of reproductive potential

Caption: CAPEOX, capecitabine-oxaliplatin; FAS, fluorouracil-doxorubicin-streptozocin; FOLFOX, leucovorin-fluorouracil-oxaliplatin; ONJ, osteonecrosis of the jaw; PCP, pneumocystis pneumonia; PD-1, programmed cell death 1 (a receptor involved in immunotolerance); PRES, posterior reversible encephalopathy syndrome; RPLS, reversible posteriorleukoencephalopathy syndrome; TMA, Thrombotic microangiopathy.

Citation: Data from Zanosar (streptozocin). Package insert. Teva Parenteral Medicines USA Inc; 2007; Eloxatin (oxaliplatin). Package insert. Sanofi-aventis U.S. LLC; 2020; Dacarbazine injection. Package insert. Hospira Inc; 2016; Temodar (temozolomide) capsules and injection. Package insert. Merck and Co Inc; 2019; Xeloda (capecitabine). Package insert. Genentech Inc; 2021; Adrucil (fluorouracil injection). Package insert. Teva Parenteral Medicines USA Inc; 2007; Welireg (belzutifn) tablets. Package insert. Merck Sharp and Dohme Corp; 2021; Afinitor (everolimus) tablets. Package insert. Novartis Pharmaceuticals Corporation; 2022; Sunitinib (Sutent). Package insert. Pfizer Labs; 2020; Keytruda (pembrolizumab) injection. Package insert. Merck Sharp and Dohme Corp; 2022; Somatuline depot (lanreotide). Package insert; Ipsen Pharma Biotech; 2018; Sandostatin LAR depot (octreotide acetate) injection. Package insert. Novartis Pharmaceutials Corporation; 2021; and Doxorubicin injection. Package insert. Mylan Institutional LLC; 2016.

Nondrug and supportive care

Additional measures are tailored to meet individual needs based on age, performance status, disease status, specific surgical approach, therapeutic agents used, and risk of complications; these may include:

Antidiarrheal agents if clinically indicated ³
Medical alert bracelet in patients with insulinoma or gastrinoma ³
Perioperative anticoagulation in patients with glucagonomas, because they are associated with hypercoagulable state
Presplenectomy vaccination for pneumococcus, Haemophilus influenzae type b, and meningococcal group C ⁶
Prophylactic cholecystectomy at the time of curative surgery to prevent cholelithiasis in patients who are anticipated to receive somatostatin analogues (octreotide or lanreotide) ⁶

Offer genetic risk evaluation for multiple endocrine neoplasia in patients diagnosed with any of the following: ⁶

Gastrinoma
Multifocal pancreatic neuroendocrine tumors
Pancreatic neuroendocrine tumor and personal or family history of primary hyperparathyroidism, duodenal or pancreatic neuroendocrine tumor, pituitary adenoma, or foregut carcinoid tumor

Procedures

Pancreatic surgical resections

Surgical management is individualized based on anatomic site, tumor type, and stage

When surgery is indicated, a decision regarding the extent of surgery must be made

General explanation

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
Enucleation with peripancreatic lymph node dissection may be considered for a small tumor (less than 2 cm), peripheral glucagonoma, or VIPoma
For gastrinomas and some insulinomas, the National Comprehensive Cancer Network recommends enucleation of the tumor with periduodenal node dissection for exophytic or peripheral tumors in the head of the pancreas and pancreatoduodenectomy for tumors that are deeper, more invasive, or close to the main pancreatic duct ⁶
Distal pancreatectomy with excision of regional nodes is recommended for malignant tumors in the distal pancreas
Pancreaticoduodenectomy is commonly used for pancreatic neuroendocrine tumors in the pancreatic head that are not suitable for enucleation
Surgical exploration and removal of peritumoral lymph nodes are recommended for patients with sporadic gastrinoma
Partial hepatectomy can be considered in patients with liver metastases
For patients anticipated to receive long-term octreotide therapy, consider cholecystectomy owing to increased risk of biliary disease associated with somatostatin analogue therapy

Indication

Potentially resectable functioning pancreatic neuroendocrine tumor
- Tumor debulking is indicated and offered for symptom control in functional tumors that are not fully resectable or that have metastasized

Complications

Perioperative thromboembolism (particularly for glucagonomas)

Special populations

Patients with multiple endocrine neoplasia type 1
- Tumors are more likely to be multifocal in patients
  - There is also the potential for development of other malignant pancreatic tumors in patients with multiple endocrine neoplasia type 1
- Role of surgical resection in multifocal disease is controversial; may be appropriate if refractory to medical management, larger than 1 cm, or growing rapidly over 6 to 12 months ⁶
- For insulinomas in multiple endocrine neoplasia type 1, some experts recommend distal pancreatic resection up to the superior mesenteric vein along with enucleation of any additional tumors in the pancreatic head ⁸⁶
  - Aim is to perform parenchymal-preserving procedures
- Surgical intervention is controversial for gastrinomas in multiple endocrine neoplasia type 1
  - Some experts advocate explorative surgery as soon as a gastrinoma is discovered in a patient with symptomatic multiple endocrine neoplasia type 1; others suggest surgery only when a 2- to 3-cm lesion is preoperatively localized, because this tumor diameter has been reported to show a high risk of metastatic spread ⁸⁶
- Glucagonoma, somatostatinoma, VIPoma, and other tumors are uncommon in multiple endocrine neoplasia type 1, and there are no clear surgical guidelines for intervention ⁸⁷

Monitoring

Follow-up after surgical resection with history, physical examination, biochemical markers (chromogranin A, specific hormones if abnormal at baseline), and imaging as clinically indicated, at the following intervals: ⁶
- 3 to 12 months after resection (earlier if the patient shows symptoms)
- Every 6 to 12 months for up to 10 years
In functional pancreatic neuroendocrine tumors, the relevant biochemical tumor marker (hormone) is followed ⁷⁰
- For insulinoma: serum insulin, proinsulin, and C-peptide
- For gastrinoma: serum gastrin
- For glucagonoma: serum glucagon
- For VIPoma: serum vasoactive intestinal polypeptide
- For somatostatinoma: serum somatostatin
CT and MRI, in combination with biochemical tumor markers, are the preferred imaging modalities for surveillance and for monitoring disease progression ¹⁹
- Functional imaging may help to confirm recurrences observed on CT or MRI
  - Options include somatostatin receptor–based imaging (gallium Ga 68 DOTATATE PET/CT or somatostatin-receptor scintigraphy)

Complications and Prognosis

Complications

Hypoglycemia (insulinoma)
- For severe hypoglycemia in conscious patients, administer 15-g rapid-acting carbohydrate and recheck blood glucose level after 15 minutes; if needed, repeat glucose doses until blood glucose level normalizes ²
- For severe hypoglycemia in unconscious patients, administer 1-mg glucagon subcutaneously, intramuscularly, or IV, and recheck blood glucose level after 15 minutes ²
Hyperglycemia (glucagonoma)
Electrolyte imbalances and metabolic acidosis with hypokalemia and hypobicarbonatemia (VIPomas [vasoactive intestinal peptide tumors])
Perioperative pulmonary embolism (glucagonomas)
Locoregional recurrence
Distant metastasis

Prognosis

Prognosis varies according to tumor type, histologic classification, and stage at diagnosis
- Most insulinomas are benign and can be cured by surgical resection; however, median survival of those with metastatic disease (less than 10% of patients) is less than 2 years ⁸⁸ ⁸⁹
- Gastrinomas are associated with liver metastases at diagnosis in 20% to 25% of cases ⁷
  - 10-year survival rate for those with liver metastases is 10% to 20%
  - 10-year survival rate for those without liver metastases is 90% to 100%
- Most other functioning pancreatic neuroendocrine tumors present with advanced disease, and 5-year survival rate is less than 50% ⁹⁰

References

1.Kelgiorgi D et al: Pancreatic neuroendocrine tumors: the basics, the gray zone, and the target. F1000Res. 6:663, 2017

Functioning Pancreatic Neuroendocrine Tumors

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Classification

Diagnosis

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Causes

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Age

Sex

Genetics

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Laboratory

Imaging

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Treatment

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Disposition

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Recommendations for specialist referral 69

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Complications and Prognosis

Complications

Prognosis

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