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Pancreatic Neuroendocrine Tumors (PNETs)

Introduction

  • PNETs are a group of heterogeneous neoplasms originating from the diffuse neuroendocrine cell system.
  • Commonly arise in the lung or gastrointestinal (GI) tract.
  • Incidence and prevalence are increasing; NETs are now the second most prevalent GI cancer.
  • PNETs originate from endocrine tissue of the pancreas (islets of Langerhans.
  • They are the second most common tumor arising from the pancreas.
  • Diagnosis relies on clinical symptoms, imaging, and histopathology.
  • Management is challenging due to tumor heterogeneity and clinical presentation.
    • Approximately 30% of PNETs are functional tumors, producing symptoms from hormone hypersecretion.
  • Treatment options include surgical resection, liver-directed therapies, and systemic treatments.
    • For metastatic PNETs, treatment is almost always noncurative.
    • Survival can be measured in years, but most patients will eventually die from the disease.

Epidemiology

  • PNETs account for approximately:
    • 7% of all NETs
    • 1ā€“2% of pancreatic tumors
  • Incidence has risen from 0.17 to 0.43 cases per 100,000 people over the past 30 years.
  • Affects males and females equally.
  • Most patients are diagnosed between the ages of 60 to 80 years.
  • Approximately 5% have an underlying familial syndrome (e.g., MEN1, VHL, TS, NF1).
  • Family history is the only well-established risk factor.
  • Risk factors for pancreatic adenocarcinoma (smoking, diabetes, chronic pancreatitis, obesity) are not associated with PNET development.

Molecular Biology and Somatic Alterations

  • Commonly mutated genes in PNETs:
    • Chromatin remodeling genes: MEN1, DAXX, ATRX
    • mTOR pathway genes: PTEN, TSC2, PIK3CA
  • Whole-genome sequencing revealed mutations in pathways involving:
    • Chromatin remodeling
    • DNA damage repair
    • mTOR pathway
    • Telomere maintenance
  • A significant germline contribution was identified, including mutations in DNA repair genes (MUTYH, CHEK2, BRCA2).
  • Poorly differentiated PNECs are distinct from PNETs and commonly have mutations in p53 (95%) and Rb (74%).

Pathology and Staging

  • PNETs are generally well-circumscribed, solitary masses that can occur anywhere in the pancreas.
  • The majority are well-differentiated.
  • All PNETs have the potential to grow and metastasize; therefore, they are considered malignant.
  • WHO 2017 Classification stratifies PNENs by:
    • Differentiation: Well-differentiated (NETs) vs. poorly differentiated (NECs)
    • Grade:
      • G1 (Low grade): Ki-67 index ā‰¤2%, mitotic count <2 per 10 HPF
      • G2 (Intermediate grade): Ki-67 index 3ā€“20%, mitotic count 2ā€“20 per 10 HPF
      • G3 (High grade): Ki-67 index >20%, mitotic count >20 per 10 HPF
  • AJCC TNM Staging System:
    • Stage I: Localized tumors
    • Stages II and III: Advanced local or regional disease
    • Stage IV: Distant metastases
  • 5-Year Overall Survival (OS) Rates:
    • Localized tumors: 62%
    • Regionally advanced disease: 54%
    • Distant metastases: 20%

Prognosis

  • Low- and intermediate-grade (G1 and G2) PNETs have better 5-year OS (75% and 63%) than G3 tumors (7%).
  • Functional tumors have a better survival rate than nonfunctional PNETs (68% vs. 60% 5-year OS).
  • Approximately 60% present with distant metastases, which is associated with decreased survival.
  • Older age at diagnosis correlates with worse survival outcomes.

Familial Syndromes Associated with PNETs

Multiple Endocrine Neoplasia Type 1 (MEN1)

  • Most common familial syndrome associated with PNETs (5ā€“7% of cases).
  • Autosomal dominant inheritance.
  • Characterized by:
    • Parathyroid adenomas causing hyperparathyroidism (90%)
    • Multiple functional or nonfunctional PNETs (75%)
    • Pituitary adenomas (40%)
  • Genetic testing for MEN1 is recommended for all first-degree relatives.
  • Complications from metastases are the most common cause of death.
  • Surgical management is complex due to multiple tumors.

Von Hippel-Lindau Disease (VHL)

  • Autosomal dominant syndrome caused by inactivation of the VHL gene.
  • Patients are at risk for:
    • Renal cell carcinoma
    • Pheochromocytoma
    • Hemangioblastomas (cerebellar and spinal)
    • Retinal angiomas
    • Pancreatic neoplasms
  • 10ā€“15% of VHL patients develop PNETs.

Neurofibromatosis Type 1 (NF1)

  • Characterized by benign neurofibromas in multiple locations.
  • PNETs may develop in the pancreas and duodenum.

Tuberous Sclerosis (TS)

  • Characterized by hamartomas in the brain, eyes, heart, lungs, skin, kidneys, and pancreas.
  • PNETs may develop in the pancreas and duodenum.

Types of Pancreatic Neuroendocrine Tumors

Functional Tumors

Insulinoma

  • Tumor of pancreatic beta cells that secrete insulin, leading to hypoglycemia.
  • Occurs in approximately 1 per million people per year.
  • Generally benign (90%); occasionally malignant (10%).
  • Uniformly distributed throughout the pancreas.
  • Whipple's Triad for diagnosis:
    • Neuroglycopenic symptoms
    • Low blood glucose levels (<45 mg/dL)
    • Relief of symptoms with glucose administration
  • Symptoms:
    • Anxiety, dizziness, confusion, seizures
    • Worsen after exercise or fasting
    • 80% of patients gain weight
  • Diagnosis:
    • Confirmed with a 72-hour fasting test
    • Elevated levels of insulin, C-peptide, and proinsulin during hypoglycemia
  • Preoperative Localization:
    • CT scan (noninvasive study of choice)
    • MRI
    • Endoscopic Ultrasound (EUS)
    • DOTA scan (preferred over Octreoscan)
  • Treatment:
    • Surgical removal is the only curative therapy
    • Medical management includes:
      • Frequent feeding with high-carbohydrate diet
      • Diazoxide to inhibit insulin release
    • Intraoperative Ultrasound (IOUS) improves localization during surgery

Somatostatinoma

  • Rare endocrine tumor of the pancreatic islet D cells or duodenum.
  • Secretes excessive amounts of somatostatin.
  • Somatostatin excess causes a syndrome characterized by:
    • Steatorrhea
    • Mild diabetes
    • Cholelithiasis
  • Somatostatin is an inhibitory hormone that:
    • Inhibits growth hormone
    • Decreases acid secretion, pancreatic enzyme secretion, and intestinal absorption
    • Reduces gut motility and transit time
  • Pancreatic somatostatinomas are not associated with von Recklinghausen syndrome.

Presentation

  • Typically in the sixth decade of life.
  • Equal proportion of men and women.
  • Initial symptoms:
    • Diabetes mellitus and glucose intolerance (60%)
    • Cholelithiasis (70%)
    • Diarrhea and steatorrhea (30ā€“68%)
    • Hypochlorhydria (86%)
  • Weight loss may be secondary to diarrhea and malabsorption.

Diagnosis

  • Often found incidentally during cholecystectomy or routine imaging.
  • 75% of cases are metastatic and larger than 5 cm at diagnosis.
  • Location:
    • Two-thirds in the head of the pancreas
    • One-third in the duodenum, ampulla, or small intestine
  • Diagnostic criteria:
    • Elevated tissue concentration of somatostatin.
    • Increased fasting plasma somatostatin levels (>14 pmol/L)
  • Imaging:
    • CT scan (sensitive for large tumors)
    • MRI, EUS with biopsy and cytology
    • Somatostatin receptor scintigraphy (SRS)
  • Early diagnosis may be possible with increased awareness and reliable somatostatin assays.

Therapy

  • Surgical resection is the treatment of choice for localized tumors and the only chance for cure.
  • Surgical debulking may be advocated for metastatic disease, though clear benefits are not demonstrated.
  • 5-Year Survival Rates:
    • Duodenal somatostatinomas: 30%
    • Pancreatic somatostatinomas: 15%

Vasoactive Intestinal Peptideā€“Producing Tumor (VIPoma)

  • Generally located within the pancreas, most commonly in the body and tail.
  • Initially characterized as Verner-Morrison syndrome:
    • Large-volume diarrhea
    • Severe hypokalemia with muscle weakness
    • Hypercalcemia
    • Hypochlorhydria
  • Typically occurs in adults.
  • Approximately 50% of VIPomas are benign.

Presentation

  • Diarrhea: Large volume (>5 L/day), 70% of patients.
    • Secretory diarrhea persists during a fast.
  • Hypokalemia: Present in nearly every patient, causing severe muscle weakness and debilitation.
  • Hypochlorhydria: Found in 75% of patients, due to inhibition of gastric acid secretion by VIP.
  • Flushing: Occurs in a minority of patients due to the vasodilatory action of VIP.
  • Hyperglycemia: Present in 25ā€“50% of patients, caused by the glycogenolytic action of VIP.
  • Hypercalcemia: Present in a significant proportion of patients.

Diagnosis

  • Fasting plasma VIP level should be measured in patients with secretory diarrhea and hypokalemia.
  • Imaging:
    • CT scan: Sensitive, especially since symptomatic tumors are usually >1 cm.
    • MRI, Ultrasound
    • Somatostatin receptor scintigraphy (SRS) for tumor localization.

Treatment

  • Correction of metabolic imbalance:
    • Aggressively correct electrolyte losses from diarrhea.
  • Medical management:
    • Long-acting somatostatin analogues to decrease diarrhea and correct hypokalemia and other metabolic derangements.
  • Surgical resection is the only chance for cure.
    • Intraoperative Ultrasound (IOUS) may aid in tumor identification.
  • If complete resection is not achievable:
    • Surgical debulking
    • Postoperative medical treatment with octreotide is recommended.

Glucagonoma

  • Endocrine tumor of the pancreas that secretes excessive amounts of glucagon.
  • Results in a characteristic syndrome including:
    • Necrolytic migratory erythema (NME): A migratory, red, scaling rash with intense pruritus.
    • Type 2 diabetes mellitus
    • Weight loss
    • Anemia
    • Stomatitis and glossitis
    • Pulmonary and venous thromboembolism
    • Other gastrointestinal and neuropsychiatric symptoms
  • Almost always malignant and usually not resectable for cure.
  • Tumor-related deaths occur in most patients after approximately 5 years.
  • Surgery is the only option for cure, leading to resolution of symptoms in many patients.

Presentation

  • Typically present between 50 and 60 years of age.
  • Necrolytic Migratory Erythema (NME):
    • Migratory, red, scaling rash
    • Commonly in intertriginous areas (groin, lower extremities)
    • Related to decreased plasma amino acids
    • Can be reversed with total parenteral nutrition or peripheral amino acid infusion.
  • Diabetes mellitus and glucose intolerance in 80% of patients.
    • Approximately 20% do not present with hyperglycemia.
  • Weight loss and cachexia are common.
  • Thromboembolic symptoms (e.g., deep venous thrombosis, pulmonary emboli) may lead to death.

Diagnosis

  • Elevated plasma glucagon levels:
    • >150 pg/mL suggest glucagonoma.
    • >1000 pg/mL are diagnostic.
  • Imaging:
    • CT scan: Identifies the location, usually >4 cm.
      • Body and tail of the pancreas are common locations.
    • Liver metastases present in 70% at diagnosis.

Therapy

  • Preoperative preparation:
    • Control of diabetes
    • Treatment of complications (e.g., venous thrombosis)
    • Nutritional support
  • Surgical treatment:
    • Subtotal pancreatectomy with splenectomy
    • If primary lesion is not fully resectable:
      • Debulking and resection of liver metastases may improve symptoms.
  • Other treatment options:
    • Hepatic artery embolization
    • Chemotherapy:
      • Bevacizumab (Avastin)
      • 5-fluorouracil
      • Oxaliplatin
      • Everolimus
    • Long-term octreotide (Sandostatin LAR) for symptom control
    • Liver and pancreas transplantation

Growth Hormoneā€“Releasing Factorā€“Producing Tumor (GRFoma)

  • Neuroendocrine tumor that secretes excessive amounts of GRF.
  • Common locations:
    • Lung (bronchus)
    • Pancreas
    • Jejunum
    • Adrenal glands
    • Retroperitoneum
  • Pancreatic GRFomas:
    • Typically large (>6 cm)
    • One-third have metastasized at diagnosis
  • Associated conditions:
    • Zollinger-Ellison syndrome in 50% of patients
    • MEN-1 in 33% of patients
  • Presentation:
    • Acromegaly
    • Pancreatic mass
    • Liver metastasis or peptic ulcer disease

Diagnosis

  • Plasma assay for GRF: Elevated levels confirm diagnosis.
  • Imaging:
    • CT scan: Sensitive for localization, especially for large tumors.

Therapy

  • Surgical resection:
    • Complete resection may be curative
    • Debulking may decrease symptoms and prolong survival
  • Medical management:
    • Octreotide therapy to relieve symptoms of acromegaly

Corticotropin-Producing Tumor (ACTHoma)

  • Malignant NETs may secrete ACTH (corticotropin), leading to Cushing syndrome.
  • Presentation:
    • Severe Cushing syndrome due to ectopic ACTH production.
  • Associated conditions:
    • MEN-1: Mild and clinically insignificant corticotropin production by pituitary tumors.
    • Zollinger-Ellison syndrome: 5% of patients may have Cushing syndrome.
  • Diagnosis:
    • Elevated blood cortisol levels
    • CT scan for tumor localization
  • Therapy:
    • Surgical resection is usually not feasible.
    • Debulking or bilateral adrenalectomy to control hypercortisolism.
    • Medical management of hypercortisolism is generally inadequate.

Tumor Releasing Parathyroid Hormoneā€“Related Protein (PTHrP)

  • Severe hypercalcemia due to PNETs releasing parathyroid hormoneā€“related protein (PTHrP).
  • Other causes of hypercalcemia in PNETs:
    • VIP release
  • Characteristics:
    • Pancreatic tumors are usually malignant and metastatic to the liver at diagnosis.

Neurotensinoma

  • Neuroendocrine tumors that secrete neurotensin.
  • Effects of neurotensin:
    • Hypotension
    • Tachycardia
    • Cyanosis
    • Pancreatic secretion
    • Intestinal motility
    • Small intestinal secretion
  • Presentation:
    • Diarrhea and hypokalemia
    • Weight loss
    • Diabetes
    • Cyanosis and hypotension
    • Flushing
  • Treatment:
    • Resection of the tumor can cure some patients.
    • Chemotherapy has been effective in others.
  • Controversy:
    • It is unclear whether neurotensinoma is a distinct syndrome, as patients with VIPoma and gastrinoma may have elevated neurotensin levels.

Ghrelinoma

  • Neuroendocrine tumor of the pancreas secreting ghrelin.
  • Ghrelin functions:
    • Promotes growth hormone release
    • Regulates energy balance
    • Increases appetite and food intake
    • Modulates insulin secretion
    • Stimulates gastric contractility and acid secretion
  • Characteristics:
    • Pancreatic ghrelinomas are a novel and rare finding.
    • Ghrelina not found in other neuroendocrine tumors of the pancreas.

Nonfunctional Tumors

  • Neuroendocrine tumors not associated with hormonal hypersecretion are referred to as nonfunctional.
    • Example: PPomas secrete pancreatic peptide (PP) but do not cause symptoms.
  • Prevalence:
    • 10ā€“25% of all pancreatic neuroendocrine tumors are nonfunctional.
    • Among the most frequent neuroendocrine tumors of the pancreas.

Presentation

  • Typically large at diagnosis (>5 cm).
  • 80% are malignant and metastatic.
  • Symptoms due to mass effect:
    • Cachexia
    • Abdominal pain
    • Intestinal bleeding
    • Blockage
    • Hepatomegaly
  • Pancreatitis may be a presenting symptom.
  • Incidental discovery on imaging for other reasons (e.g., trauma, kidney stones):
    • Usually <2 cm
    • May not be malignant or functionally important
    • Surgical excision recommended for young, healthy individuals
    • MRI follow-up may be better for older patients with comorbidities

Diagnosis

  • Imaging:
    • CT scan and MRI are effective diagnostic tools.
  • Tumor markers:
    • Pancreatic Peptide (PP)
    • Chromogranin A
  • Differentiation from pancreatic adenocarcinoma:
    • Immunohistochemical staining with chromogranin A
    • DOTA scan
  • Nonfunctional tumors are differentiated from PPomas based on serum PP assay results.

Therapy

  • Resection of the tumor:
    • Whipple procedure (pancreaticoduodenectomy) for tumors in the head of the pancreas
    • Pancreatectomy for other locations
  • Chemotherapy:
    • Everolimus and other regimens have shown effectiveness in some cases.
  • Debulking of hepatic tumor mass:
    • Hepatic embolization
  • Medical management:
    • Dopamine agonists to decrease PP and chromogranin A levels in large unresectable tumors
    • Somatostatin receptor analogues (PRRT) for partial responses
  • Liver transplantation:
    • Considered for patients with extensive disease localized to the liver

Prognosis

  • Nonfunctional tumors have a high incidence of malignancy.
  • Ki-67 rate is the most important predictor of outcome and survival.
    • Should be assessed pathologically in all cases.
  • Behavior:
    • No significant difference compared to functional tumors.
  • Survival rates may vary due to the small number of patients with this disease.

Diagnosis of PNETs

  • All PNETs produce Chromogranin A, which serves as a tumor marker.
    • Higher levels correlate with greater tumor burden.
  • Microscopic Features:
    • Sheets of small, round cells with uniform nuclei and cytoplasm
    • Mitotic figures are rare (Ki-67 index: 1ā€“2%)
    • Precise determination of malignancy cannot be made by histologic appearance alone.

Factors Predicting Aggressive Behavior

  • Aggressive PNETs include:
    • Glucagonoma
    • VIPoma
    • Somatostatinoma
    • Most nonfunctional tumors
  • Characteristics:
    • Short disease duration
    • Large tumor size
    • Presence of liver metastases
    • Reduced long-term survival
  • Predictors of Aggressive Growth:
    • Liver metastases
    • Lymph node metastasis
    • Local invasion
    • Primary tumor size >2 cm
    • Nonfunctional tumor
    • Incomplete tumor resection

Therapy for PNETs

Medical Management

  • Insulinoma:
    • Prevent hypoglycemia with:
      • Frequent feeding (high-carbohydrate diet)
      • Diazoxide to inhibit insulin release
    • Octreotide may be used but has unpredictable results.
  • Other PNETs:
    • Symptom control with hormone-specific medications.

Surgical Treatment

  • Surgical resection is the only potentially curative treatment.
  • Intraoperative Ultrasound (IOUS) aids in tumor localization.
  • Laparoscopic resection is an option for localized tumors with clear preoperative localization.
  • MEN1 Management:
    • Correct primary hyperparathyroidism before pancreatic surgery.
    • Pancreatic resection for tumors ā‰„2 cm.

Prognosis and Outcome

  • Variables Impacting Outcome:
    • Extent of disease
    • Location of primary tumor
    • Presence of liver or distant metastases
    • Familial vs. sporadic occurrence
    • Comorbid conditions
  • Success is not solely defined by cure:
    • Symptom control
    • Prolonged survival
  • Genetic counseling and screening are important for high-risk families (e.g., MEN1).

Important Keywords

PNETs, functional tumors, nonfunctional tumors, insulinoma, MEN1, VHL, NF1, TS, chromogranin A, Ki-67 index, intraoperative ultrasound (IOUS), surgical resection, prognosis, aggressive behavior predictors, somatostatinoma, VIPoma, glucagonoma, GRFoma, ACTHoma, PTHrPomas, neurotensinoma, ghrelinoma, Whipple's Triad, Verner-Morrison syndrome, necrolytic migratory erythema (NME), Zollinger-Ellison syndrome, parathyroid hormoneā€“related protein (PTHrP).