Pancreas

Neuroendocrine neoplasms

Neuroendocrine neoplasms-general


Editorial Board Member: Wei Chen, M.D., Ph.D.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Danielle Hutchings, M.D.

Last author update: 9 November 2021
Last staff update: 14 January 2022

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PubMed Search: Pancreas[TI] neuroendocrine neoplasms[TIAB]

Danielle Hutchings, M.D.
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Cite this page: Hutchings D. Neuroendocrine neoplasms-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreaspen.html. Accessed May 18th, 2022.
Definition / general
  • Includes well differentiated neuroendocrine tumors (WDNET) and poorly differentiated neuroendocrine carcinomas (PDNEC)
  • Express neuroendocrine markers (synaptophysin and chromogranin A) (see Positive stains)
  • Mixed neuroendocrine nonneuroendocrine neoplasms (MiNEN) includes both neuroendocrine and nonneuroendocrine component (e.g., adenocarcinoma, acinar carcinoma), each ≥ 30%
  • Functional tumors are associated with elevated serum hormone levels and a clinical hormonal syndrome (see Clinical features)
  • Nonfunctional tumors are more common and are not associated with a clinical hormonal syndrome
    • May still be associated with elevated serum hormone levels or tissue hormone expression on immunohistochemistry
    • Nonfunctional tumors < 0.5 cm are termed pancreatic neuroendocrine microadenomas
Essential features
  • Well differentiated neuroendocrine tumors (WDNET):
    • Clumped chromatin (salt and pepper) nuclei
    • Cellular uniformity, central ovoid nucleus
    • Organoid architecture: ribbons / trabeculae, nesting, glandular, gyriform, pseudoacinar
    • Necrosis is rare
    • Amyloid deposition in insulinomas
    • Psammoma bodies in somatostatinomas (also associated with NF1)
    • Background of microadenomas in multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) syndromes
    • Clear cell morphology in von Hippel-Lindau syndrome
  • Poorly differentiated neuroendocrine carcinomas (PDNEC):
    • Diffuse sheets or solid nests of markedly atypical malignant cells with small cell or large cell morphology
    • Abundant mitoses and apoptotic bodies
    • Necrosis is frequent
Terminology
  • Antiquated terms: islet cell tumor / carcinoma, carcinoid, APUDoma
  • Classification based on WHO system:
    • Per WHO 2019, neuroendocrine neoplasms with Ki67 > 20% are now regarded in 2 distinct groups, WDNET grade 3 or PDNEC, based on the morphologic characteristics
    • Well differentiated neuroendocrine tumor grading:
      • WHO grade 1: < 2 mitoses/2 mm2 or Ki67 index < 3%
      • WHO grade 2: 2 - 20 mitoses/2 mm2 or Ki67 index 3 - 20%
      • WHO grade 3: > 20 mitoses/2 mm2 or Ki67 > 20%
    • Ki67 count should be done on a minimum of 500 cells in hot spot areas
    • Both mitotic count and Ki67 should be performed and grade is assigned based on largest value; usually Ki67 is higher than mitotic count (Am J Surg Pathol 2013;37:1671)
Epidemiology
Sites
Pathophysiology
Etiology
  • Risk factors include smoking, diabetes and first degree relative with history of cancer (Sci Rep 2016;6:36073)
  • Subset associated with MEN1 (MEN1 gene on 11q13), von Hippel-Lindau (VHL tumor suppressor gene on 3p25), neurofibromatosis 1 (microdeletion in neurofibromin gene on 17q11.2) and tuberous sclerosis complex (TSC1 tumor suppressor gene on 9q34 or TSC2 tumor suppressor gene on 16p13.3) (Arch Pathol Lab Med 2019;143:1317)
Clinical features
  • Nonfunctional tumors are encountered incidentally and are usually larger at time of diagnosis
  • Local obstruction / mass effect, if located in the pancreatic head
  • Other clinical features of MEN1, VHL, NF1 or TSC (if applicable)
  • Clinical hormonal syndromes in functioning tumors, 10 - 30% of tumors (Arch Pathol Lab Med 2009;133:350)
  • Insulinoma:
    • Most common
    • Insulin secretion
    • Whipple triad: symptoms of hypoglycemia, low plasma glucose, relief of symptoms with glucose administration
    • Solitary tumor < 2 cm
    • 5 - 10% MEN1 and are usually multiple
    • Generally indolent
  • Gastrinoma:
    • Second most common functioning pancreatic neuroendocrine tumor
    • Gastrin secretion
    • Zollinger-Ellison syndrome (peptic / duodenal ulcers, gastroesophageal reflux, diarrhea)
    • Located in gastrinoma triangle (common bile duct, duodenum, pancreatic head)
    • More commonly found in duodenum than pancreas
    • 20 - 30% associated with MEN1
  • Glucagonoma:
    • 4 Ds: diabetes, dermatitis (necrolytic migratory erythema), deep vein thrombosis, depression
    • Solitary, large
    • Tail > head
    • > 50% have metastasis at presentation
  • VIPoma:
    • Verner-Morrison syndrome: watery diarrhea, hypokalemia, achlorhydria / hypochlorhydria
    • Solitary, large
    • Tail > head
  • Somatostatinoma:
    • Diabetes mellitus, diarrhea or steatorrhea, anemia, malabsorption, cholelithiasis
    • Very rare
    • Solitary, large
    • > 50% have metastasis at presentation
  • Ectopic hormone producing neuroendocrine tumor:
    • ACTH (Cushing syndrome), serotonin (atypical carcinoid syndrome), growth hormone
    • Solitary, large
Laboratory
  • Elevated serum hormone in functional tumors (see Clinical features)
  • Elevated serum chromogranin A in 50 - 100%; correlates with tumor burden and metastasis but has limited utility due to low specificity and sensitivity (Arch Pathol Lab Med 2019;143:1317)
Radiology description
  • Round, solid, hypervascular
  • Subset may be cystic
  • Well circumscribed
  • Contrast enhanced computed tomography (CT) has decreased sensitivity in smaller (< 2 cm) tumors (Clin Endosc 2017;50:537)
  • Magnetic resonance imaging (MRI) has better sensitivity, especially for small tumors compared with CT (Clin Endosc 2017;50:537)
  • Gallium 68 dotatate positron emission tomography (PET) (Clin Endosc 2017;50:537):
    • Uses radiolabeled somatostatin analog
    • Useful for WDNETs, most of which express somatostatin receptor
    • High sensitivity and specificity for somatostatin receptor expressing tumors
Radiology images

Images hosted on other servers:

MRI demonstrating small WDNET

CT and Gallium 68 Dotatate PET showing WDNET

Prognostic factors
Case reports
Treatment
  • Surgical resection is the mainstay for WDNET, with resolution of both mass effect symptoms and symptoms associated with hormone secretion (Surg Clin North Am 2019;99:793)
    • Benefit for both localized and metastatic disease
  • Other therapies for metastatic WDNET (Surg Clin North Am 2019;99:793):
    • Somatostatin analog therapy
    • Molecular therapies: tyrosine kinase inhibitor, sunitinib; mTOR inhibitor, everolimus
    • Chemotherapy (capecitabine and temozolomide [CAPTEM])
    • Peptide receptor radionuclide therapy (PRRT)
    • Liver directed therapy: ablation or hepatic artery embolization of liver metastasis
  • PDNECs usually treated with platinum based chemotherapy (Surg Clin North Am 2019;99:793)
Gross description
  • Usually well circumscribed, homogeneous
  • May have cystic change
  • Color and consistency varies according to degree of vascularity and stroma, ranges from white to pink to tan to brown; may be yellow if necrosis present (Arch Pathol Lab Med 2009;133:350)
  • Pigmented black pancreatic neuroendocrine tumor contains intracytoplasmic lipfuscin and mimics metastatic melanoma (Arch Pathol Lab Med 2009;133:350)
  • Lipid rich pancreatic neuroendocrine tumor appears yellow and may mimic adrenal cortical neoplasia (Arch Pathol Lab Med 2009;133:350)
  • Large tumors may appear lobulated and infiltrative
  • Can invade adjacent fibroadipose tissue, other organs and large vessels
Gross images

Contributed by Danielle Hutchings, M.D.

Well circumscribed, solid tumor in pancreatic tail

Tumor with hemorrhage

Invasion into spleen

Large vessel invasion

Pancreatic duct obstruction

Cystic degeneration

Microscopic (histologic) description
  • Well differentiated neuroendocrine tumors:
    • Organoid architecture: solid nests, trabeculae, gyri, cords, festoons, ribbons, glandular, tubuloacinar
    • Small to medium cells with eosinophilic to amphophilic and finely granular cytoplasm; nuclei are uniform, central, round / oval, with salt and pepper (finely stippled) chromatin; no or inconspicuous nucleoli
    • Rich vascular network
    • Amyloid deposition in insulinomas
    • Psammoma bodies in somatostatinomas
    • May have hyaline globules (Am J Surg Pathol 2011;35:981)
    • Variants include clear cell, lipid rich, oncocytic, rhabdoid and pigmented black neuroendocrine neoplasm (Arch Pathol Lab Med 2019;143:1317, Virchows Arch 2018;473:247, Cancer 2001;92:1984)
  • Poorly differentiated neuroendocrine carcinomas:
    • Diffuse sheets or solid nests of markedly atypical malignant cells
    • Salt and pepper chromatin is lost
    • Abundant mitoses and apoptotic bodies
    • Necrosis is frequent
    • May be small cell (high N/C ratio, nuclear hyperchromasia and molding) or large cell (moderate to abundant amphophilic cytoplasm, may have prominent nucleoli) morphology
Microscopic (histologic) images

Contributed by Danielle Hutchings, M.D. and Sabrina Sopha, M.D.

Amyloid deposition

Poorly differentiated neuroendocrine carcinoma, small cell type

Poorly differentiated
neuroendocrine
carcinoma, large
cell type

Calcification


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Cribriform pattern

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Pseudoacinar pattern

Organoid pattern

Ki67 staining

INSM1 immunostain


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Spread to duodenum (H&E and synaptophysin)

Synaptophysin staining


Synaptophysin staining

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Chromogranin staining


Well differentiated pancreatic neuroendocrine tumor
(cell block, synaptophysin, chromogranin)

Cytology description
  • Well differentiated neuroendocrine tumors (Diagn Cytopathol 2006;34:649):
    • Cellular specimen with clean background
    • Clusters and individual cells
    • Uniform round oval, small / medium sized cells
    • Frequently plasmacytoid
    • Amphophilic, finely granular cytoplasm (neurosecretory capability)
  • Poorly differentiated neuroendocrine carcinomas (Diagn Cytopathol 2006;34:649):
    • Overtly malignant cells with small cell or large cell morphology
    • Necrosis
Cytology images

Contributed by Sabrina Sopha, M.D. and AFIP images
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Well differentiated pancreatic neuroendocrine tumor
(pap stained smears)

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Round nuclei and scanty cytoplasm

Positive stains
Electron microscopy images

AFIP images
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Enterochromaffin cell tumor: irregularly shaped

Molecular / cytogenetics description
Videos

Solid tumors of the pancreas

Sample pathology report
  • Pancreas, distal pancreatectomy:
    • Well differentiated neuroendocrine tumor, WHO grade 1 of 3 (3 cm) (see comment)
      • Ki67 proliferation index: 2%
      • 1 mitosis per 2 mm2
      • Tumor confined to the pancreas
    • Lymphovascular and perineural invasion identified
    • Proximal pancreatic parenchyma margin is uninvolved
    • Metastatic tumor in 2/17 lymph nodes
    • Comment: The tumor cells are positive for synaptophysin and chromogranin A.
Differential diagnosis
Board review style question #1

A 58 year old man presents with a 2.8 cm solid mass in the tail of the pancreas. Based on the morphology below, you suspect a well differentiated neuroendocrine tumor (WDNET). Which of the following immunoprofiles would be most characteristic of pancreatic WDNET?

  1. Synatophysin-, chromogranin-, BCL10+, trypsin+, beta catenin cytoplasmic
  2. Synatophysin-, chromogranin-, BCL10-, trypsin-, beta catenin nuclear
  3. Synatophysin+, chromogranin+, BCL10-, trypsin-, beta catenin cytoplasmic
  4. Synatophysin+, chromogranin-, BCL10-, trypsin-, cytokeratin-
Board review style answer #1
C. Synatophysin+, chromogranin+, BCL10-, trypsin-, beta catenin cytoplasmic

Comment Here

Reference: Neuroendocrine neoplasms-general
Board review style question #2


A 45 year old woman presents recurrent episodes of dizziness, palpitations and sweating, which she reports usually resolve with drinking orange juice. She is found to have a 2.0 cm solid mass in the body of the pancreas. Resection specimen is shown in the image above. What is the most likely diagnosis based on H&E and congo red stains?

  1. Acinar cell carcinoma
  2. Gastrinoma
  3. Insulinoma
  4. Pancreatic ductal adenocarcinoma
  5. Well differentiated pancreatic neuroendocrine tumor, nonfunctional
Board review style answer #2
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Image 01 Image 02