Pancreas
Neuroendocrine neoplasms
Well differentiated neuroendocrine tumor
Editorial Board Member: Raul S. Gonzalez, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Topic Completed: 1 September 2018
Minor changes: 26 October 2020
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: Well differentiated neuroendocrine tumor G1 G2 pancreas
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Krogh K, Yang GY. Well differentiated neuroendocrine tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasWDNET.html. Accessed January 20th, 2021.
Definition / general
- Rare low to intermediate grade subset of neuroendocrine tumors (NET)
Essential features
- WHO 2017 Endocrine classifies well differentiated pancreatic neuroendocrine tumors (PanNETs) as grade 1, grade 2 or grade 3 (see Diagnosis)
- Classification uses criteria similar to other GI neuroendocrine neoplasms (IARC: 8249 / 3 Neuroendocrine Tumor, Grade 2 [Accessed 13 November 2018])
- May be nonfunctioning or secrete one or more peptides; multiple tumors in the same patient may secrete same or different peptides
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 coding
- C25: malignant neoplasm of pancreas
Epidemiology
- M = F
- Peak incidence: 30 - 60 years
- Neuroendocrine tumors of the pancreas are rare and comprise 1 - 2% of clinically apparent pancreas neoplasms; much less common than exocrine tumors (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
- Nonfunctional tumors represent 60 - 90% of all pancreas neuroendocrine tumors (Neuroendocrinology 2016;103:153, Biomed Res Int 2017;2017:9856140)
- Functional tumors: insulinoma / beta cell tumor, glucagonoma / alpha cell
tumor, somatostatinoma / delta cell tumor, gastrinoma / G cell tumor,
VIPoma
- Most common functioning islet cell tumor is insulinoma / beta cell tumor
- VIPomas are exceedingly rare, with a reported incidence of 1 in 10
million (La Rosa: Pancreatic Neuroendocrine Neoplasms, 2015)
- VIPomas represent just 6% of all functional pancreas neuroendocrine tumors (Lancet 2013;382:832)
- 5% are associated with multiple endocrine neoplasia type 1 (MEN1) (BMJ Case Rep 2015 Nov 12;2015)
Sites
- Most common in body or tail where there are more islets
Pathophysiology
- Theorized to arise from totipotent stem cells in the pancreatic ductal system (Endocr Pract 2014;20:1222, Endotext: Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors [Accessed 13 November 2018])
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])
- Though most nonfunctional tumors do not secrete peptides that cause a clinical syndrome, they can secrete other peptides, including chromogranin A and pancreatic polypeptide, though elevated levels of these are not specific (Gastroenterology 2008;135:1469, Neuroendocrinology 2006;84:196)
- Liver is the most common site of metastasis
Diagnosis
- In WHO 2017, pancreatic neuroendocrine neoplasms are separated into well differentiated neuroendocrine tumors (PanNETs - this topic) and poorly differentiated carcinomas (NECs)
- Tumors are classified by proliferative index (Ki67):
- G1 (NET G1): mitotic count < 2/10 high powered fields (HPF) or ≤ 2% Ki67 index
- G2 (NET G2): mitotic count 2 - 20/10 HPF or 3 to 20% Ki67 index
- G3 (NET G3): mitoses > 20 /10 HPF or > 20% Ki67 index (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)
- Can show progression from G1 primary tumors to G2 metastases and heterogeneity between grades can occur within individual tumor or sites of metastasis (Am J Surg Pathol 2011;35:853)
- Can contain focal regions of increased proliferation / G3 features (Clin Cancer Res 2016;22:1011)
- Neuroendocrine carcinomas rarely contain lower grade PanNET (Am J Surg Pathol 2014;38:437)
- Dedifferentiation has been proposed (Hruban: Tumors of the Pancreas, 6th Edition, 2007)
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
- 15 year old boy with tuberous sclerosis (Am J Surg Pathol 2012;36:149)
- 31 year old woman with VHL and PanNET with progression to NEC (Am J Case Rep 2017;18:1220)
- 36 year old woman with metastatic nonfunctioning PanNET (J Gastrointest Cancer 2011;42:257)
- 37 year old man with VIPoma (Lancet 2013;382:832)
- 62 year old man with metastases (J Med Life 2018;11:57)
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
Contributed by Katrina Krogh, M.D.
PanNET
Images hosted on other servers:
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
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
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
Molecular / cytogenetics description
- Frequently mutated genes: (Science 2011;331:1199)
- 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%)
Molecular / cytogenetics images
Images hosted on other servers:
MEN1 mutation
Differential diagnosis
- Acinar cell carcinoma
- PAS+ diastase resistant granules sometimes detected
- Positive stains: trypsin, chymotrypsin, lipase, cytokeratin 8 / 18
- Occasionally positive for synaptophysin or chromogranin
- Solid pseudopapillary neoplasm
- Positive stains: nuclear β-catenin, cytoplasmic / perinuclear CD10, nuclear PR, synaptophysin (sometimes), pankeratins (variable)
- Negative stains: membranous E-cadherin, ER, chromogranin (usually)
- Contains pseudopapillary architecture, which is rare in neuroendocrine tumors
- Neuroendocrine carcinoma (NEC)
- High mitotic rate (> 20 /10 HPF or Ki67 > 20%)
- Large or small cell with corresponding high grade morphology
Board review style question #1
Which of the following statements about this pancreatic lesion is false?
- More common than pancreatic adenocarcinoma
- More likely to be nonsecreting than secreting
- Never contains ovarian stroma
- Serum insulin levels may be elevated
Board review style answer #1
Board review style question #2
Which of the following statements about this Ki67 stain in a pancreatic
neuroendocrine tumor is true?
- Can undergo transformation to squamous cell carcinoma
- Does not metastasize
- Has a high proliferation index
- Treatment depends on Ki67 interpretation
Board review style answer #2
