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Neuroendocrine neoplasms

Well differentiated neuroendocrine tumor


Jen Rytych, M.D.
David J. Escobar, M.D., Ph.D.

Last author update: 10 March 2023
Last staff update: 10 March 2023

Copyright: 2002-2023, PathologyOutlines.com, Inc.

PubMed Search: Well differentiated neuroendocrine tumor pancreas

Jen Rytych, M.D.
David J. Escobar, M.D., Ph.D.
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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 | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3
Cite this page: Rytych J, Krogh K, Yang GY, Escobar DJ. Well differentiated neuroendocrine tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasWDNET.html. Accessed June 7th, 2023.
Definition / general
  • Low, intermediate or high grade subset of neuroendocrine tumors (NET) that lack necrosis and express neuroendocrine markers (synaptophysin or chromogranin A)
Essential features
  • WHO Classification of Tumours of Endocrine Organs (2017) and WHO Classification of Tumours of the Digestive System (2019) classifies well differentiated pancreatic neuroendocrine tumors (PanNETs) as grade 1, grade 2 or grade 3 (see Diagnosis)
  • Classification uses criteria similar to other gastrointestinal neuroendocrine neoplasms
  • May be nonfunctioning or secrete 1 or more peptides; multiple tumors in the same patient may secrete the 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
  • Carcinoid is a term that should be avoided if possible
ICD coding
  • ICD-10: C25 - malignant neoplasm of pancreas
Epidemiology
Sites
  • Found throughout the pancreas
  • 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 (Ann Surg Oncol 2007;14:3492)
Pathophysiology
Etiology
  • Majority are sporadic and nonsyndromic
  • Minority are associated with multiple endocrine neoplasia syndrome (80 - 100% incidence), tuberous sclerosis (rare), von Hippel-Lindau (VHL, 10 - 17% incidence), among others (Cancer 2008;113:1807)
  • Hyperplastic and preneoplastic lesions were removed from the WHO 2017; PanNEN precursor lesions have not been clearly associated with sporadic neoplasms (but are described in MEN1 and VHL)
Clinical features
  • Demonstrate a spectrum of clinical behavior dependent on hormones produced
  • Commonly causes abdominal pain, jaundice
  • Asymptomatic pancreatic neuroendocrine tumors are increasingly common, likely because of an increase in detection due to increased imaging frequency and improvement in imaging modalities (Cancer 2015;121:589)
  • 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 (Cancer 2008;113:1807)
  • Liver is the most common site of metastasis
  • Insulinoma:
    • Composed of insulin producing cells with uncontrolled secretion of insulin
    • Clinical: Whipple triad (hypoglycemic symptoms, plasma glucose < 40 mg/dL and symptom relief after glucose administration)
    • Typically, small (< 2 cm diameter) and solitary (~10% multiple, usually in MEN1 patients) (Neoplasma 2015;62:484)
  • Gastrinoma:
    • Composed of gastrin producing cells with uncontrolled secretion of gastrin
    • Clinical: Zollinger-Ellison syndrome (reflux symptoms and duodenal ulcers)
    • Typically, large size (average 3.8 cm diameter), more common in the duodenum than in the pancreas (Wien Klin Wochenschr 2007;119:579)
  • VIPoma:
    • Composed of uncontrolled vasoactive intestinal peptide (VIP) secreting cells
    • Clinical: WDHA syndrome (watery diarrhea [persists when fasting], hypokalemia and achlorhydria)
    • Typically, large (average ~5 cm diameter) and solitary (Ann N Y Acad Sci 1988;527:508)
  • Glucagonoma:
    • Composed of cells with uncontrolled secretion of glucagon and preglucagon derived peptide
    • Clinical: triad of skin rash (necrolytic migratory erythema), diabetes mellitus and weight loss
    • Typically, variable in size (average 3 - 7 cm diameter) and solitary (Medicine (Baltimore) 1996;75:53)
  • Somatostatinoma:
    • Composed of cells that demonstrate D cell differentiation with uncontrolled secretion of somatostatin
    • Clinical: less distinctive than other functioning PanNETs (glucose intolerance, cholelithiasis and diarrhea)
    • Typically, large (average 5 - 6 cm diameter) and multinodular (J Exp Clin Cancer Res 1999;18:13)
  • ACTH producing neuroendocrine tumor:
    • Composed of cells secreting uncontrolled adrenocorticotropic hormone (ACTH)
      • Clinical: features of Cushing syndrome (central obesity, weight gain, moon face, hypertension, hyperglycemia, osteoporosis, hypokalemia and cutaneous hyperpigmentation)
    • Typically, large (average 4.8 cm diameter) and solitary (Am J Surg Pathol 2015;39:374)
  • Serotonin producing neuroendocrine tumor:
    • Composed of cells secreting uncontrolled serotonin
    • Clinical (usually only after metastasizing to the liver): carcinoid syndrome (abdominal pain, flushing, diarrhea and weight loss)
    • Typically large (average ~5 cm diameter) and solitary (Pancreas 2011;40:883)
Diagnosis
    • Requires neuroendocrine histology and positive staining for neuroendocrine and cytokeratin makers (and the presence of clinical symptoms if functional)
    • Contains < 30% of the neoplasm volume of a second tumor type (ductal, acinar etc.) (otherwise, see mixed neuroendocrine nonneuroendocrine neoplasms [MiNEN])
    • Does not contain necrosis or severe atypia (otherwise, see neuroendocrine carcinoma [PanNEC])
    • Well differentiated tumors are classified by mitotic count and proliferative index (Ki67):
      • 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
  • Elevated serum chromogranin A levels (> 15 ng/mL) show a sensitivity of 66% and a specificity of 95% for the diagnosis pancreatic neuroendocrine tumors (World J Gastroenterol 2020;26:2305)
  • Elevated serum neuron specific enolase (NSE) and pancreatic polypeptide (PP) are respectively seen in up to 30 - 50% and 50% of PNET patients (Front Oncol 2020;10:831)
  • Specific biomarkers for functional PNET are not currently recommended due to their poor sensitivity, specificity and lack of standardization between laboratories (Surg Oncol Clin N Am 2020;29:165)
Radiology description
  • 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 (Semin Ultrasound CT MR 2019;40:469)
  • 68Ga SRS (stimulated Raman scattering) is a type of PET imaging of somatostatin receptor, current gold standard for functional imaging of NETs (Nat Rev Endocrinol 2018;14:656)
Radiology images

Images hosted on other servers:

Large mass in pancreas tail

Prognostic factors
Case reports
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
  • Reference: Surg Clin North Am 2019;99:793
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 in well differentiated PanNETs
  • Reference: Arch Pathol Lab Med 2019;143:1317
Gross images

Contributed by Katrina Krogh, M.D.

Well circumscribed mass

Cut surface of mass



Images hosted on other servers:

Invasion of large vessel

Tumor in isthmus / body

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) (Am J Surg Pathol 2003;27:642)
  • Islet amyloid polypeptide (amylin) deposition is specific for insulinoma but is only seen in ~5% of cases
  • Psammoma bodies can be seen in somatostatinomas
Microscopic (histologic) images

Contributed by Katrina Krogh, M.D.

Trabecular growth

Neuroendocrine nuclei

PanNET (VIPoma) metastatic to liver

 

Ki67


 

Synaptophysin

 

Chromogranin



Contributed by @RaulSGonzalezMD on Twitter
Well differentiated neuroendocrine tumor   Well differentiated neuroendocrine tumor   Well differentiated neuroendocrine tumor

Well differentiated neuroendocrine tumor

Cytology description
  • Single cell type; monotonous plasmacytoid cells with moderate amount of cytoplasm and distinctive neuroendocrine chromatin (Clin Cancer Res 2017;23:600)
  • Can have rosette-like aggregates and eccentric nuclei
Cytology images

Contributed by Katrina Krogh, M.D.

Diff-Quik

Positive stains
Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:

MEN1 mutation

Sample pathology report
  • Distal pancreas and spleen, distal pancreatectomy and splenectomy:
    • Well differentiated neuroendocrine tumor, WHO grade 2, measuring 4.1 cm in greatest dimension (see comment)
    • Lymphovascular and perineural invasion identified
    • Pancreatic resection margin, negative for tumor
    • 2 of 10 lymph nodes, positive for metastatic tumor (2/10)
    • Spleen with no significant pathologic change
    • Pathologic stage: pT3, pN1
    • Comment: Immunohistochemical stains are performed and show the tumor cells are positive for cytokeratin AE1 / AE3, synaptophysin and chromogranin (patchy). The Ki67 proliferative index is 15%. Beta catenin shows membranous staining (negative result). Overall findings are consistent with 2019 WHO grade 2 (out of 3).
Differential diagnosis
Board review style question #1


Which of the following statements is true regarding the pancreatic lesion seen above?

  1. Commonly associated with familial adenomatous polyposis (FAP)
  2. Loss of DAXX / ATRX expression are associated with better outcomes
  3. More common than pancreatic adenocarcinoma
  4. More likely to be nonsecreting than secreting
Board review style answer #1
D. More likely to be nonsecreting than secreting

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Reference: Well differentiated neuroendocrine tumor
Board review style question #2


Which of the following statements is true about the Ki67 stain in a pancreatic neuroendocrine tumor seen above?

  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 style answer #2
D. Treatment depends on Ki67 interpretation

Comment Here

Reference: Well differentiated neuroendocrine tumor
Board review style question #3
A patient presents to his primary care doctor with a 1 month history of constant watery diarrhea that wakes him up several times each night. Laboratory values were remarkable for a potassium of 3.2 mmol/L (normal: 3.6 - 5.2 mmol/L). An abdominal CT showed a solitary, solid, well demarcated and vascular 5 cm lesion in the tail of the pancreas that is consistent with a neoplasm. What is the most likely gene mutation in this lesion?

  1. APC
  2. CTNNB1
  3. MEN1
  4. SMAD4
  5. STK11
Board review style answer #3
C. MEN1. The patient is presenting with WDHA syndrome (watery diarrhea that persists when fasting, hypokalemia and achlorhydria) and a pancreatic mass. This is likely due to a VIPoma, which is a type of pancreatic neuroendocrine tumor (PanNET). The most common mutation in these tumors is MEN1.

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Reference: Well differentiated neuroendocrine tumor
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