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Neuroendocrine neoplasms

Neuroendocrine neoplasms-general

Author: Danielle Hutchings, M.D.

Editorial Board Member: Wei Chen, M.D., Ph.D.

Deputy Editor-in-Chief: Catherine E. Hagen, M.D.

Last author update: 9 November 2021

Last staff update: 14 January 2022

Copyright: 2003-2022, PathologyOutlines.com, Inc.

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

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Table of Contents

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

1 - 5% of all pancreatic neoplasms; increasing incidence due to improved imaging techniques (Arch Pathol Lab Med 2019;143:1317, Cancer 2015;121:589)
Incidence of 1 per 100,000 persons (Cancer 2015;121:589)
Wide age range but most common in third to sixth decades (Arch Pathol Lab Med 2019;143:1317)
M = F (Arch Pathol Lab Med 2019;143:1317)
Most are sporadic
10 - 20% associated with syndrome (Arch Pathol Lab Med 2019;143:1317):
- 20 - 70% of multiple endocrine neoplasia 1 (MEN1) patients
- 20% von Hippel-Lindau (VHL) patients
- 10% neurofibromatosis type 1 (NF1) patients
- 1% of tuberous sclerosis complex (TSC) patients

Sites

WDNET is more common in tail and body (Arch Pathol Lab Med 2019;143:1317)
PDNEC is more common in head (Arch Pathol Lab Med 2019;143:1317)
See Clinical hormonal syndromes

Pathophysiology

Varies with clinical syndrome (see Clinical features)

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

WDNETs are usually slow growing with prolonged clinical course
PDNECs are usually aggressive and rapidly progressive
Ki67 index and mitotic count, as described for WHO grading
Prognostic immunohistochemical markers (not widely used in routine clinical practice):
- Expression of COX2, p27, CD99 and PR immunostains (Pathol Int 2001;51:770, Am J Clin Pathol 2003;120:685, Am J Surg Pathol 2006;30:1588, Cancer 1992;70:2268)
- Expression of CK19 is associated with aggressive behavior (Am J Surg Pathol 2006;30:1588, Histopathology 2007;50:597, Am J Surg Pathol 2004;28:1145)

Case reports

45 year old woman with possible VHL syndrome with mixed serous neuroendocrine neoplasm (World J Clin Cases 2019;7:4119)
48 year old man with cystic pancreatic WDNET radiographically mimicking cystic mucinous neoplasm (Autops Case Rep 2020;10:e2020171)
53 year old man with pancreatic WDNET with rhabdoid features (Virchows Arch 2018;473:247)
58 year old woman with systemic mastocytosis incidentally found to have pancreatic WDNET (Int J Surg Case Rep 2020;77:397)
73 year old woman with breast carcinoma with unrecognized neuroendocrine differentiation metastasizing to the pancreas (Int J Surg Pathol 2016;24:463)

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

Cribriform pattern

Pseudoacinar pattern

Organoid pattern

Ki67 staining

INSM1 immunostain

Spread to duodenum (H&E and synaptophysin)

Synaptophysin staining

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

Well differentiated pancreatic neuroendocrine tumor
(pap stained smears)

Round nuclei and scanty cytoplasm

Positive stains

Epithelial markers: CK8 / CK18, CAM 5.2, OSCAR, AE1 / AE3 (labels 50% of tumors) (Virchows Arch A Pathol Anat Histopathol 1986;409:609)
Neuroendocrine markers:
- Synaptophysin: strong and diffuse in WDNET; may be weak, patchy or negative in PDNEC (Hum Pathol 2020;96:8)
- Chromogranin A: may be more focal and 10 - 20% of WDNET may be negative; may be focal or negative in PDNEC (Hum Pathol 2020;96:8)
- INSM1: newer marker with high sensitivity and specificity (Am J Clin Pathol 2015;144:579)
- CD56, neuron specific enolase (NSE), CD57: less specific, limited utility (Hum Pathol 2020;96:8)
Panel to determine pancreatic origin for WDNET: Islet1+, PAX6+, TTF1-, CDX2 usually negative, SATB2-
- Panel is nonspecific in the setting of PDNEC
- TTF1 is positive in 40% of extrapulmonary PDNEC (Hum Pathol 2020;96:8)
Panel to differentiate WDNET, grade 3 from PDNEC (Arch Pathol Lab Med 2019;143:1317)
- WDNET: somatostatin receptor+, loss of DAXX / ATRX
- PDNEC: abnormal expression of p53, loss of RB1, loss of SMAD4 / DPC4
Hormone expression (insulin, glucagon, gastrin, somatostatin, VIP, pancreatic polypeptide): may be seen but does not indicate functional tumor
Trypsin: scattered positive cells may be seen but if > 25%, the tumor is classified as mixed (Am J Surg Pathol 1994;18:765, Am J Surg Pathol 2002;26:893, Dig Dis Sci 2002;47:2254)

Negative stains

Beta catenin (labels cell membrane only) (Arch Pathol Lab Med 2019;143:1317)
Trypsin (negative or only few positive cells) (Am J Surg Pathol 1994;18:765, Am J Surg Pathol 2002;26:893, Dig Dis Sci 2002;47:2254)
Chymotrypsin (Arch Pathol Lab Med 2019;143:1317)
BCL10 (Arch Pathol Lab Med 2019;143:1317)

Electron microscopy images

AFIP images

Enterochromaffin cell tumor: irregularly shaped

Molecular / cytogenetics description

WDNETs:
- MEN1 inactivation 44% (Arch Pathol Lab Med 2019;143:1317)
- DAXX / ATRX mutation or loss 43% (Arch Pathol Lab Med 2019;143:1317)
- mTOR pathway alterations (PTEN, TSC2, PIK3CA) 14% (Arch Pathol Lab Med 2019;143:1317)
- VHL small subset (Semin Diagn Pathol 2014;31:498)
Poorly differentiated neuroendocrine carcinomas and mixed neuroendocrine nonneuroendocrine neoplasms:
- TP53, RB, KRAS, APC, BRAF, SMAD4 / DPC4 (more like adenocarcinomas) (Arch Pathol Lab Med 2019;143:1317, Am J Surg Pathol 2012;36:173)

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

Solid pancreatic tumors:
- Acinar cell carcinoma:
  - Adults, high mitotic rate, labeling with BCL10, trypsin, chymotrypsin
  - May have focal positivity with synaptophysin but chromogranin is negative
- Pancreatoblastoma:
  - Children, squamoid nests
- Solid pseudopapillary neoplasm:
  - Women, degenerated pseudopapillae, hyaline globules
  - Nuclear labeling with beta catenin
  - May have focal positivity with synaptophysin but chromogranin is negative
- Usual ductal adenocarcinoma:
  - Desmoplastic stroma
  - Invasive mucin producing glands
- Paraganglioma:
  - Very rare, nested zellballlen architecture
  - Cytokeratin negative, S100 highlights sustentacular cells, GATA3 positive (Mod Pathol 2013;26:1365)
Clear cell tumors:
- Clear cell sarcoma:
  - Labels with melanoma markers and has t(12;22)
- Metastatic renal cell carcinoma:
  - PAX8+
- PEComa:
  - Labels with melanoma markers, inhibin, cathepsin K and TFE3, melanoma and other clear cell tumors
- Solid variant of serous cystadenoma:
  - Labels with inhibin (Am J Surg Pathol 2004;28:339)

Additional references

J Gastrointest Oncol 2020;11:548, Histopathology 2018;72:168, Am J Surg Pathol 2021;45:25, Clin Cancer Res 2016;22:1011, WHO Classification of Digestive System Tumours, 5th Edition, 2019

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?

Synatophysin-, chromogranin-, BCL10+, trypsin+, beta catenin cytoplasmic
Synatophysin-, chromogranin-, BCL10-, trypsin-, beta catenin nuclear
Synatophysin+, chromogranin+, BCL10-, trypsin-, beta catenin cytoplasmic
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?

Acinar cell carcinoma
Gastrinoma
Insulinoma
Pancreatic ductal adenocarcinoma
Well differentiated pancreatic neuroendocrine tumor, nonfunctional

Board review style answer #2

C. Insulinoma

Comment Here

Reference: Neuroendocrine neoplasms-general

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