Pancreas
Neuroendocrine neoplasms
General

Author: Sabrina Sopha, M.D. (see Authors page)
Editorial Board Member Review: Raul S. Gonzalez, M.D.

Revised: 26 June 2017, last major update June 2017

Copyright: (c) 2003-2017, PathologyOutlines.com, Inc.

PubMed Search: Pancreas[title] endocrine[title] tumors
Cite this page: Neuroendocrine Neoplasms - General. PathologyOutlines.com website. http://pathologyoutlines.com/topic/pancreaspen.html. Accessed September 19th, 2017.
Definition / general
  • Can be either well differentiated tumors or poorly differentiated carcinomas
  • Neoplasms which express neuroendocrine markers (synaptophysin, chromogranin A, NCAM / CD56, or Protein Gene Product (PGP))
    • Synaptophysin is strongly and diffusely expressed in most tumors
    • Chromogranin A is focal / patchy
    • CD56 and PGP are considered less specific
    • Site specific markers are PDX1 and ISL1
  • Mixed AdenoNeuroEndocrine Carcinomas (MANECs) express both exocrine and endocrine components, each > 30%
  • Functional tumors are associated with elevated serum hormone levels and are associated with a clinical hormonal syndrome (see Clinical features below)
  • Nonfunctional tumors are not associated with a clinical hormonal syndrome, but may still be associated with elevated serum hormone levels or tissue hormone expression on immunohistochemistry
    • Nonfunctional tumors which are < 0.5 cm are termed “pancreatic neuroendocrine microadenomas"
    • Neoplasms which secrete pancreatic polypeptide (PP), neurotensin or ghrelin are considered nonfuctional as there is no distinct clinical hormonal syndrome
Essential features
  • Well differentiated neuroendocrine tumors:
    • "Salt and pepper" nuclei
    • Cellular uniformity, central ovoid nucleus
    • A variety of architectures: ribbons / trabeculae, nesting, glands, gyriform, pseudorosettes
    • Amyloid deposition in insulinomas
    • Psammoma bodies in somatostatinomas (also associated with NF1)
    • May have hyaline globules (differential diagnosis includes solid pseudopapillary tumor, Am J Surg Pathol 2011;35:981)
    • Background of microadenomas in MEN1 and VHL syndromes
    • Clear cell morphology in von Hippel Lindau syndrome
Terminology
  • Antiquated terms: islet cell tumor, carcinoid, APUDoma
  • Classification based on Bosman: WHO Classification of Tumours of the Digestive System, Fourth Edition, 2010:
    • Well differentiated neuroendocrine tumor WHO grade 1: < 2 mitoses / 10 HPF or Ki67 index < 3%
    • Well differentiated neuroendocrine tumor WHO grade 2: 2 - 20 mitoses / 10 HPF or Ki67 index 3 - 20%
    • Poorly differentiated neuroencocrine carcinoma WHO grade 3: mitoses > 20 HPF or Ki67 > 20%
    • Due to grading discrepancies between mitotic count and Ki67 index, both mitotic count and Ki67 count must be done, larger value determines grade (Am J Surg Pathol 2013;37:1671)
    • Ki67 count should be done on 500 - 2000 cells in "hot spot" areas
  • WHO terminology to change in 2018 (addition of well differentiated neuroendocrine tumor WHO grade 3 for tumors which retain neuroendocrine morphology and have Ki67 indices ~ 20 - 50%; updates to follow)
Epidemiology
Sites
Pathophysiology
Etiology
  • No known environmental factors
  • 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)
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 (adapted from Arch Pathol Lab Med 2009;133:350)

  • Insulinoma:
    • Most common functioning pancreatic neuroendocrine tumor
    • Insulin secretion
    • Hypoglycemic syndrome
    • Solitary tumor < 2 cm
    • 5 - 10% of insulinomas are associated with MEN1 and are usually multiple
    • Benign in 90%

  • Gastrinoma:
    • Second most common functioning pancreatic neuroendocrine tumor
    • Gastrin secretion
    • Zollinger-Ellison syndrome (peptic ulcers, gastroesophageal reflux, diarrhea)
    • "Gastrinoma triangle" (common bile duct, duodenum, pancreatic head)
    • Duodenum affected more than pancreas
    • 20 - 30% of gastrinomas are associated with MEN1
    • Malignant in 80%

  • Glucagonoma:
    • 4Ds: 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, growth hormone
    • Usually malignant
    • Solitary, large
Laboratory
Radiology description
  • Solid or solid cystic lesion within any part of the pancreas
  • For very small masses, use a pancreatic mass protocol with a triple phase process: non contrast, late arterial (10 second delay from peak aortic enhancement) and portal venous (35 second delay) phases
  • Well circumscribed
  • Homogeneous enhancement (hypoenhancement is associated with aggressive tumor and worse prognosis, HPB (Oxford) 2014;16:304)
  • Intratumoral calcifications are associated with tumor grade, lymph node metastasis and worse prognosis (Ann Surg Oncol.2012;19:2295)
  • Hypervascular
Prognostic factors
Case reports
Treatment
  • Surgical resection is the mainstay, with resolution of both mass effect symptoms and symptoms associated with hormone secretion
  • Chemotherapy (no established protocol); tumors with lower Ki67 proliferation index have lower response to chemotherapy (Ann Oncol 2013;24:152)
Gross description
  • Firm, commonly well circumscribed, homogeneous
  • Tumors may have a cystic component
  • Color varies according to the degree of vascularity and amount of stroma and 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" is composed of intracytoplasmic lipfuscin and mimics metastatic melanoma
  • "Lipid-rich" pancreatic neuroendocrine tumor mimics adrenal cortical neoplasia (Arch Pathol Lab Med 2009;133:350)
  • Features of malignancy: invasion of fibroadipose tissue (as satellite nodules), invasion of adjacent organs, invasion of large vessels
Gross images
Images hosted on Pathout server:
Missing Image

Intrapancreatic adenoma, AFIP

Missing Image

Microadenomas in MEN 1 patients, AFIP

Missing Image

Carcinoma with hemorrhage, AFIP

Missing Image

Gut tumor in MEN 1, AFIP



Images hosted on other servers:
Missing Image

Various images

Missing Image

UPMC Case #172

Microscopic (histologic) description
  • Well differentiated neuroendocrine tumors:
    • Organoid architecture: solid nests, trabeculae, gyri, cords, festoons, ribbons, glandular, acinar, cribriform
    • 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 / inconspicuous cytoplasm
    • Rich vascular network
    • Amyloid deposition in insulinomas
    • Psammoma bodies in somatostatinomas
    • Hyaline globules (Am J Surg Pathol 2011;35:981)
  • Poorly differentiated neuroendocrine carcinomas:
    • Sheets or nests of atypical cells with pleomorphic, hyperchromatic nuclei and abundant mitotic figures
    • "Salt and pepper" chromatin is lost
    • Necrosis often present
    • May be small cell (molding nuclei, scant cytoplasm) or large cell (abundant amphophilic cytoplasm; may also have visible nucleoli)
Microscopic (histologic) images
Images hosted on Pathout server:

Surgical pathology images of pancreatic neuroendocrine tumors of pancreas, Contributed by Sabrina Sopha, M.D., FCAP
Missing Image Missing Image

Cribriform, pseudoacinar and organoid patterns

Ki67 staining


Missing Image

Spread to duodenum (H&E and synaptophysin)


Missing Image

Synaptophysin and chromogranin staining


Missing Image

Encapsulated growth of uniform cells, AFIP

Missing Image

Ill-defined nests of cells, AFIP

Missing Image

Blood vessel invasion, AFIP

Missing Image

Neoplastic thrombi in a lymphatic vessel, AFIP

Missing Image

Pancreatic enterochromaffin cell tumor, AFIP


Missing Image

Endocrine tumor immunostained, AFIP

Missing Image

Scattered Grimelius-positive tumor cells, AFIP

Missing Image

MEN 1 associated ZES

Missing Image

Pancreatic nonfunctioning endocrine tumor, AFIP



Images hosted on Other servers:
Missing Image

Abundant hyaline globules

Missing Image

Various images

UPMC Case #172


Missing Image

Ki67

Missing Image

CD31

Cytology description
  • Small / medium sized cells
  • Amphophilic, finely granular cytoplasm (neurosecretory capability)
  • Round / oval, uniform, centrally located nuclei without prominent nucleoli
  • May be plasmacytoid
Cytology images
Images hosted on Pathout server:
Missing Image

Well differentiated pancreatic neuroendocrine tumor (pap, cell block, synaptophysin, chromogranin), Contributed by Sabrina Sopha, M.D., FCAP


Missing Image

Tumor cells have round nuclei and scanty cytoplasm

Positive stains
Negative stains
Electron microscopy images
Images hosted on Pathout server:
Missing Image

Enterochromaffin cell tumor:
irregularly shaped
Molecular / cytogenetics description
Differential diagnosis