Pancreatic Neuroendocrine Tumors (PanNETs)

• Well differentiated pancreatic neuroendocrine tumors (PanNETs) are a subset of neuroendocrine tumors (NET) with low, intermediate, or high grade, lacking necrosis, and expressing neuroendocrine markers like synaptophysin or chromogranin A.
• The WHO Classification of Tumours of Endocrine Organs (2017) and Digestive System (2019) classifies PanNETs as grade 1, 2, or 3, using criteria similar to other gastrointestinal neuroendocrine neoplasms.
• PanNETs may be nonfunctioning or secrete one or more peptides, and multiple tumors in the same patient may secrete the same or different peptides.
• Microscopic lesions less than 0.5 cm are termed microadenomas.
• The term "carcinoid" should be avoided when possible.
• ICD-10 code for malignant neoplasm of pancreas: C25

Epidemiology

• Incidence is equal in males and females.
• Peak incidence occurs between 30-60 years of age.
• PanNETs comprise approximately 2-5% of pancreatic neoplasms.
• Most cases are sporadic, with risk factors including family history of cancer, elevated BMI, diabetes, cigarette smoking, and elevated alcohol consumption.
• 10-20% are associated with syndromes like multiple endocrine neoplasia type 1 (MEN1), von Hippel-Lindau (VHL), neurofibromatosis type 1, and tuberous sclerosis.
• Nonfunctional tumors account for 60-90% of all PanNETs.
• Functional tumors account for 10-40% of PanNETs.
• Insulinoma is the most common functional tumor, accounting for 4-20% of PanNETs.
• Gastrinoma is the second most common functional tumor, accounting for 4-8% of PanNETs.
• VIPoma accounts for less than 2% of PanNETs.
• Glucagonoma accounts for 1-2% of PanNETs.
• Somatostatinoma and ACTH producing neuroendocrine tumors both account for less than 1% of PanNETs.
• Serotonin producing neuroendocrine tumors account for up to 3.9% of PanNETs.
• Nonfunctional, gastrinomas, or serotonin producing tumors are more likely to be found in the head of the pancreas.
• Insulinomas, glucagonomas, and VIPomas are more likely to be found in the tail.

Pathophysiology & Etiology

• The tumors are theorized to arise from totipotent stem cells in the pancreatic ductal system and islets of Langerhans.
• The majority of cases are sporadic and nonsyndromic.
• A minority are associated with multiple endocrine neoplasia syndrome, tuberous sclerosis, and von Hippel-Lindau (VHL).
• Hyperplastic and preneoplastic lesions were removed from the WHO 2017 classification.

Clinical Features

• Clinical behavior varies depending on hormones produced.
• Common symptoms include abdominal pain and jaundice.
• Asymptomatic tumors are increasingly common due to increased detection from imaging.
• Functional tumors may have elevated serum peptides corresponding to tumor cell type.
• Metastasis to the liver may be associated with carcinoid syndrome.
• Most nonfunctional tumors are large and detected at an advanced stage, with 60-85% presenting with liver metastases.
• Liver is the most common site of metastasis.

Functional Tumor Types

• Insulinoma: Uncontrolled secretion of insulin, leading to Whipple triad (hypoglycemic symptoms, plasma glucose < 40 mg/dL, and symptom relief after glucose administration); typically small (< 2 cm) and solitary.
• Gastrinoma: Uncontrolled secretion of gastrin, leading to Zollinger-Ellison syndrome (reflux symptoms and duodenal ulcers); typically large (average 3.8 cm), more common in the duodenum than in the pancreas.
• VIPoma: Uncontrolled secretion of vasoactive intestinal peptide (VIP), leading to WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria); typically large (average ~5 cm) and solitary.
• Glucagonoma: Uncontrolled secretion of glucagon, leading to a triad of skin rash (necrolytic migratory erythema), diabetes mellitus, and weight loss; typically variable in size (average 3-7 cm) and solitary.
• Somatostatinoma: Uncontrolled secretion of somatostatin, leading to glucose intolerance, cholelithiasis, and diarrhea; typically large (average 5-6 cm) and multinodular.
• ACTH producing neuroendocrine tumor: Uncontrolled secretion of adrenocorticotropic hormone (ACTH), leading to Cushing syndrome features (central obesity, weight gain, moon face, hypertension, hyperglycemia, osteoporosis, hypokalemia, and cutaneous hyperpigmentation); typically large (average 4.8 cm) and solitary.
• Serotonin producing neuroendocrine tumor: Uncontrolled secretion of serotonin, leading to carcinoid syndrome (abdominal pain, flushing, diarrhea, and weight loss) usually after metastasizing to the liver; typically large (average ~5 cm) and solitary.

Diagnosis

• Requires neuroendocrine histology, positive staining for neuroendocrine and cytokeratin markers, and the presence of clinical symptoms if functional.
• Contains < 30% of a second tumor type.
• Lacks necrosis or severe atypia.
• Well differentiated tumors are classified by mitotic count and Ki67 index:
  • G1 (NET G1): mitotic count < 2/2 mm2 and < 3% Ki67 index
  • G2 (NET G2): mitotic count 2 - 20/2 mm2 or 3 - 20% Ki67 index
  • G3 (NET G3): mitoses > 20/2 mm2 or > 20% Ki67 index

Laboratory Findings

• Elevated serum chromogranin A levels (> 15 ng/mL) show a sensitivity of 66% and a specificity of 95% for the diagnosis pancreatic neuroendocrine tumors
• Elevated serum neuron specific enolase (NSE) and pancreatic polypeptide (PP) are respectively seen in up to 30 - 50% and 50% of PNET patients
• Specific biomarkers for functional PNET are not currently recommended due to their poor sensitivity, specificity and lack of standardization between laboratories

Radiology

• General: highly vascular, well circumscribed enhancing lesion that can be solid or cystic
• Ultrasound: circumscribed masses with smooth margins, suboptimal visualization of the body and tail due to bowel gas obstruction, sensitivity of 20 - 80%
• CT: well defined, uniformly hypervascular masses on arterial phase CT, most widely available technique
• MRI: hyperintense on T1 weighted imaging due to an abundance of proteinaceous material and variable signal on T2 weighted images; better resolution than CT
• 68Ga SRS (stimulated Raman scattering) is a type of PET imaging of somatostatin receptor, current gold standard for functional imaging of NETs

Prognostic Factors

• Size > 2 cm
• Tumor necrosis
• Lymph node positivity
• Mitoses > 2/10 high powered fields
• Vascular invasion
• Perineural invasion
• High Ki67 index
• CK19 positivity
• Loss of DAXX / ATRX expression and alternative lengthening of telomeres suggest poor outcome

Treatment

• Primarily surgical (benefits shown for primary and metastatic disease)
• Enucleation can be used for small and localized tumors
• First line treatments for metastatic disease are somatostatin analogs (octreotide and lanreotide)
• Second line treatments include tyrosine kinase inhibitors (sunitinib) and mTOR inhibitors (everolimus)
• Novel chemotherapy regime of capeciabine and temozolomide (CAPTEM) and peptide receptor radionuclide therapy (PRRT) has been approved

Gross Description

• Solid, well circumscribed mass, typically 2 - 5 cm in diameter
• Larger tumors often show heterogenous and lobulated cut surfaces
• Color can range from red-tan to brown-yellow
• May show extensive fibrosis, calcification or ossification
• 5% are cystic (unilocular, less commonly multilocular) but necrosis is uncommon

Microscopic (Histologic) Description

• Architecture can be solid, organoid, nesting, gyriform, trabecular or glandular
• Small, round monotonous cells with coarse, salt and pepper nuclear chromatin and minimal atypia
• Occasional small nucleoli are most common; large nucleoli can be seen
• Cytoplasm can be pale pink, oncocytic, granular or lipid rich / vacuolated
• Rarely, nuclei can be eccentrically located (rhabdoid cell appearance)
• Islet amyloid polypeptide (amylin) deposition is specific for insulinoma but is only seen in ~5% of cases
• Psammoma bodies can be seen in somatostatinomas

Cytology Description

• Single cell type; monotonous plasmacytoid cells with moderate amount of cytoplasm and distinctive neuroendocrine chromatin
• Can have rosette-like aggregates and eccentric nuclei

Positive Stains

• Chromogranin A (more specific) and synaptophysin (more sensitive): diffuse and strong
• NSE, CD56, CD57
• AE1 / AE3, CAM5.2 and CK8/18
• Somatostatin receptor is positive in 80 - 90% and PR is positive in 58% of PanNETs
• Immunohistochemistry for peptide hormones (insulin, glucagon, VIP, etc.) is rarely required and nonfunctional tumors may be positive
• SMAD4 and Rb retained
• In metastatic setting: Isl1 (most sensitive) and PAX6 positivity is supportive
• PAX8 (polyclonal) is positive in 50 - 60% of cases metastatic to the liver (monoclonal PAX8 is negative)
• NESP55+ and PDX1+, in the presence of negative CDX2 and TTF1, is 97% specific for pancreatic origin

Negative Stains

• CDX2, SATB2 and TTF1
• Nuclear beta catenin
• Trypsin / chymotrypsin
• BCL10
• SMA

Molecular / Cytogenetics

• Frequently mutated genes:
  • MEN1 (44.1%)
  • DAXX (death domain associated protein, 25%)
  • ATDX ([alpha] thalassemia / intellectual disability syndrome X linked, 17.6%)
  • TSC2 (8.8%)
  • PTEN (7.3%)
  • PI3KCA (1%)
  • VHL (up to 25% including deletion by promoter methylation)