Pancreas
Neuroendocrine neoplasms
Well differentiated neuroendocrine tumor WHO grade 1 / 2 (carcinoid)

Author: Katrina Krogh, M.D.
Senior Author: Guang-Yu Yang, M.D. Ph.D.
Editorial Board Member Review: Raul S. Gonzalez, M.D.
Editor-in-Chief Review: Debra Zynger, M.D.

Revised: 13 November 2018, last major update September 2018

Copyright: (c) 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Well differentiated neuroendocrine tumor G1 G2 pancreas

Cite this page: Krogh, K. Well differentiated neuroendocrine tumor WHO grade 1 / 2 (carcinoid). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/pancreascarcinoid.html. Accessed November 17th, 2018.
Definition / general
  • Rare low to intermediate grade subset of neuroendocrine tumors (NET)
Essential features
Terminology
  • Synonyms: well differentiated neuroendocrine tumor (WD-NET), pancreatic neuroendocrine tumor (PanNET), pancreatic endocrine tumor, islet cell tumor
  • Specific functional terms (glucagonoma, insulinoma, gastrinoma) not recommended for use unless hormonal syndrome exists clinically
  • Microscopic lesions < 0.5 cm are termed microadenomas
  • Term "carcinoid" should be avoided if possible
ICD-10 coding
  • C25: malignant neoplasm of pancreas
Epidemiology
Sites
  • Most common in body or tail where there are more islets
Pathophysiology
Etiology
  • Majority sporadic and nonsyndromic
  • Minority associated with multiple endocrine neoplasia syndrome (80 - 100% incidence), tuberous sclerosis (rare) and von Hippel-Lindau (VHL, 10 - 17% incidence), among others (Cancer 2008;113:1807)
Clinical features
  • Demonstrate a spectrum of clinical behavior dependent on hormones produced
  • Commonly causes abdominal pain, jaundice
  • Asymptomatic pancreas neuroendocrine tumors increasingly common
  • Functional tumors may have elevated serum peptides corresponding to tumor cell type
  • May be associated with carcinoid syndrome (flushing, diarrhea) if metastatic to liver
  • Most nonfunctional tumors are large and detected at an advanced stage at diagnosis, with 60 - 85% having liver metastases (Endotext: Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors [Accessed 13 November 2018])
  • Liver is the most common site of metastasis
Diagnosis
Laboratory
  • Usually diagnosed by fine needle aspiration during endoscopic ultrasound or image directed core biopsy
Radiology description
  • Solid or cystic well circumscribed enhancing lesion
Radiology images

Images hosted on other servers:

Large mass in pancreas tail

Prognostic factors
  • Relatively indolent but with variable outcome
  • Features associated with adverse outcome (Am J Surg Pathol 2007;31:1677, HPB (Oxford) 2009;11:422):
    • Size > 2 cm
    • Tumor necrosis
    • 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 (Clin Cancer Res 2017;23:600)
Case reports
Treatment
  • Somatostatin analogs (octreotide and lanreotide) have shown tumor stabilizing effects in 50 - 60% of advanced or metastatic tumors (J Clin Oncol 2009;27:4656)
  • In addition, glucocorticoids can be used (Lancet Oncol 2014;15:e8)
  • Surgery or enucleation (< 2 cm) are possible if confined to the pancreas
  • Novel therapies include VEGF inhibitors, tyrosine kinase inhibitors and mTOR therapies
Gross description
  • Solid, well circumscribed mass
  • May show extensive fibrosis, calcification or ossification
  • 5% are cystic (both unilocular or multilocular)
Gross images

Images hosted on PathOut server:

Contributed by Katrina Krogh, M.D.

PanNET



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Invasion of large vessel

Tumor in isthmus / body

Microscopic (histologic) description
  • Architecture can be solid, gyriform / trabecular, glandular or nondescript
  • Small round monotonous cells with coarse, salt and pepper nuclear chromatin
  • Occasional small nucleoli most common; large nucleoli can be seen
  • Cytoplasm can be pale pink, oncocytic, lipid rich / vacuolated and rhabdoid
  • Presence of amyloid deposits indicative of insulinoma / beta cell tumor
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Katrina Krogh, M.D.

Trabecular growth

Neuroendocrine nuclei

Ki67

Synaptophysin

Chromogranin


PanNET (VIPoma) metastatic to liver

Ki67

Synaptophysin

Chromogranin

Cytology description
  • Single cell type; monotonous plasmacytoid cells with moderate amount of cytoplasm and distinctive neuroendocrine chromatin (Endocr Pathol 2014;25:65)
  • Can have rosette-like aggregates and eccentric nuclei
Cytology images

Images hosted on PathOut server:

Contributed by Katrina Krogh, M.D.

Diff-Quik

Positive stains
  • Chromogranin A (more specific) and synaptophysin (more sensitive): diffuse and strong
  • NSE, CD56, CD57, pankeratins
  • Immunohistochemistry for peptide hormones is rarely required and nonfunctional tumors may be positive
  • In metastatic setting:
    • ISL1 is supportive
    • PAX8 (polyclonal) is positive in 50 - 60% cases metastatic to the liver
    • NESP55+ and PDX1+, in the presence of negative CDX2 and TTF1, is 97% specific for pancreatic origin (Am J Surg Pathol 2009;33:626)
  • Strongly argentaffinic (contains catecholamines, indolamines or related substance that reduces silver and other metallic salts to metallic silver, staining brown or black) - includes Fontana-Masson, Schmorl
Negative stains
Molecular / cytogenetics description
  • Frequently mutated genes: (Science 2011;331:1199)
    • MEN1 (44.1%)
    • DAXX (death domain associated protein, 25%)
    • ATRX ([alpha] thalassemia / mental retardation syndrome X linked, 17.6%)
    • TSC2 (8.8%)
    • PTEN (7.3%)
Molecular / cytogenetics images

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MEN1 mutation

Differential diagnosis
Board review question #1
Which of the following statements about this pancreatic lesion is false?

  1. More common than pancreatic adenocarcinoma
  2. More likely to be nonsecreting than secreting
  3. Never contains ovarian stroma
  4. Serum insulin levels may be elevated
Board review answer #1
A. More common than pancreatic adenocarcinoma
Board review question #2
Which of the following statements about this Ki67 stain in a pancreatic neuroendocrine tumor is true?

  1. Can undergo transformation to squamous cell carcinoma
  2. Does not metastasize
  3. Has a high proliferation index
  4. Treatment depends on Ki67 interpretation
Board review answer #2
D. Treatment depends on Ki67 interpretation

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