Neuroendocrine neoplasms-general

Pancreas

Neuroendocrine neoplasms

Author: Sabrina Sopha, M.D.

Editorial Board Member: Raul S. Gonzalez, M.D.

Topic Completed: 1 June 2017

Minor changes: 13 July 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: Pancreas[TI] neuroendocrine tumors[TI]

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Table of Contents

Cite this page: Sopha S. Neuroendocrine neoplasms-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreaspen.html. Accessed August 8th, 2020.

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 papillary neoplasm, 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 Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017:
- Diagnosis of well differentiated neuroendocrine tumor versus poorly differentiated neuroendocrine carcinoma determined purely by histologic (H&E) appearance
- 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%
- Well differentiated neuroendocrine tumor WHO grade 3: > 20 mitoses/10 HPF or Ki67 > 20%
- Poorly differentiated neuroendocrine carcinoma WHO grade 3: > 20 mitoses/10 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 - 2,000 cells in "hot spot" areas
- For more information, see: Gill: WHO 2017 Neuroendocrine Tumour Grading System [Accessed 7 November 2018]

Epidemiology

1 - 2% of all pancreatic neoplasms (Arch Pathol Lab Med 2009;133:350)
0.2 - 2 per million per year
Occur at any age but are rare in childhood (usually age 40 - 60, Arch Pathol Lab Med 2009;133:350)
No sex predilection (Arch Pathol Lab Med 2009;133:350)
Seen in multiple endocrine neoplasia type 1 syndrome (60% of patients have pancreatic neuroendocrine tumors and 80% have pancreatic microadenomatosis / hyperplasia), neurofibromatosis 1 syndrome (1% of patients have pancreatic neuroendocrine tumors, Arch Pathol Lab Med 2009;133:350), von Hippel-Lindau syndrome (16% of patients have pancreatic neuroendocrine tumors, Arch Pathol Lab Med 2009;133:350) and tuberous sclerosis complex (rare, Arch Pathol Lab Med 2009;133:350)
Approximately 10% of pancreatic neuroendocrine tumors are associated with one of these syndromes (Oncol Res Treat 2016;39:643)
Syndromic cases (MEN1, von Hippel-Lindau) present at younger age

Sites

Tumors may be anywhere in the pancreas (exceptions: see clinical hormonal syndromes below)

Pathophysiology

Varies with clinical syndrome, see clinical features below

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

Elevated serum chromogranin A in 60 - 80% (Arch Pathol Lab Med 2009;133:350)

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

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)
Ki67 index and mitotic count, as described for WHO grading

Case reports

37 year old woman with pancreatic gastrinoma associated with von Hippel-Lindau disease (Rev Esp Enferm Dig 2017;109:154)
38 year old man with pancreatic mixed serous neuroendocrine neoplasm (Pathol Res Pract 2016;212:747)
40 year old woman with ACTH producing neuroendocrine tumor (Ann Hepatobiliary Pancreat Surg 2017;21:61)
61 year old woman who had a well differentiated pancreatic neuroendocrine tumor (PNET) with lymph node metastasis (Intern Med 2016;55:2979)
62 year old man with insulinoma that was first diagnosed as hypersomnia (Mol Clin Oncol 2016;5:480)
67 year old woman with pancreatic neuroendocrine tumor secreting vasoactive intestinal peptide and dopamine with pulmonary emboli (J Clin Endocrinol Metab 2016;101:3564)
73 year old woman with breast carcinoma with unrecognized neuroendocrine differentiation metastasizing to the pancreas (Int J Surg Pathol 2016;24:463)
Case with two unusual variants of pancreatic neuroendocrine tumor (Diagn Cytopathol 2017;45:371)

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

AFIP images

Intrapancreatic adenoma

Microadenomas in MEN 1 patients

Carcinoma with hemorrhage

Gut tumor in MEN 1

Images hosted on other servers:

Various images

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

Surgical pathology images of pancreatic neuroendocrine tumors of pancreas, contributed by Sabrina Sopha, M.D.

Cribriform, pseudoacinar and organoid patterns

Ki67 staining

Spread to duodenum (H&E and synaptophysin)

Synaptophysin and chromogranin staining

AFIP images

Encapsulated growth of uniform cells

Ill defined nests of cells

Blood vessel invasion

Neoplastic thrombi in a lymphatic vessel

Pancreatic enterochromaffin cell tumor

Endocrine tumor immunostained

Scattered Grimelius positive tumor cells

MEN 1 associated ZES

Pancreatic nonfunctioning endocrine tumor

Images hosted on other servers:

Abundant hyaline globules

Various images

UPMC Case #172

Ki67

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

Contributed by Sabrina Sopha, M.D.

Well differentiated pancreatic neuroendocrine tumor (pap, cell block, synaptophysin, chromogranin)

AFIP

Tumor cells have round nuclei and scanty cytoplasm

Positive stains

CD56 (Am J Surg Pathol 2005;29:1194)
Chromogranin A: 20% stain and have patchy / variable positivity (Am J Surg Pathol 1984;8:607)
CK AE1 / AE3: labels 50% of tumors (Virchows Arch A Pathol Anat Histopathol 1986;409:609)
CK8 / CK18
Dupan-2 and CA 19-9: labeling with these markers of ductal differentiation can be seen in foci with pseudoglandular architecture but this is insufficient for a diagnosis of mixed ductal endocrine carcinoma (J Clin Oncol 2002;20:2633, Dig Dis Sci 2002;47:2254)
Hormone expression (insulin, glucagon, gastrin, somatostatin, VIP, pancreatic polypeptide): may be seen but is not sufficient for diagnosis of a specific tumor type
Neuron specific enolase (NSE): less specific, limited utility (Gastroenterology 1982;83:902)
Protein gene product 9.5: less specific, limited utility (Histopathology 1985;9:147)
S100 (Am J Surg Pathol 2005;29:1194)
Synaptophysin: generally diffuse (Proc Natl Acad Sci U S A 1986;83:3500)
Trypsin: labeling can be seen but if > 25%, the tumor is classified as mixed acinar endocrine carcinoma (Am J Surg Pathol 1994;18:765, Am J Surg Pathol 2002;26:893, Dig Dis Sci 2002;47:2254)
Useful panel for determining pancreatic origin is Islet1+, PAX8+, CDX2+, TTF1- (Am J Surg Pathol 2010;34:723, Mod Pathol 2011;24:412, Mod Pathol 2012;25:893, Am J Surg Pathol 2008;32:420, Am J Surg Pathol 2017;41:915)

Negative stains

Beta catenin (labels cell membrane only)
CK20
CK7

Electron microscopy images

AFIP

Enterochromaffin cell tumor: irregularly shaped

Molecular / cytogenetics description

DAXX (death domain associated protein) and ATRX (alpha thalassemia / intellectual disability syndrome X linked) have been identified in 45% of sporadic PanNETs (Endocr Pathol 2014;25:65)
15% of PanNets show mutations in mammalian target of rapamycin (mTOR) (Endocr Pathol 2014;25:65)
Deletion of VHL gene occurs in 25% of sporadic well differentiated PanNETs (Endocr Pathol 2014;25:65)
Syndromic cases described under etiology
Sporadic tumors are divided into two main groups: those with frequent allelic imbalances and those with few allelic imbalances
Total number of genomic changes correlates with tumor burden and stage of disease (Endocr Relat Cancer 2007;14:483)
In sporadic tumors, chromosomal losses occur more frequently than gains
Chromosomal losses include: 1p, 3p, 6q, 11q, Y and X
Chromosomal gains include: 5q, 7pq, 9q, 14q, 17pq and 20q (Am J Pathol 2000;157:1431, Genes Chromosomes Cancer 2000;29:83, Am J Pathol 1999;155:1787 and Cancer Res 2001;61:5186)
Loss of sex chromosome correlates with aggressive behavior (Int J Cancer 2002;98:532)
Microsatellite instability is very rare (Int J Cancer 2007;120:2157)
Pancreatic neuroendocrine tumors show global hypomethylation compared with adjacent uninvolved pancreas but this is less common than is seen in gastrointestinal neuroendocrine tumors (Mod Pathol 2007;20:802)
MEN1 mutations can be found in sporadic tumors
50% of all sporadic pancreatic neuroendocrine tumors show losses at 11q13, suggesting loss of one allele may be an initiating factor (Am J Pathol 1999;154:429, Cancer Res 2000;60:5536, J Clin Endocrinol Metab 2000;85:116)

Differential diagnosis

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 serous cystadenoma
Solid tumors:
- Acinar cell carcinoma: adults, high mitotic rate, labeling with BCL10, trypsin, chymotrypsin
- Pancreatoblastoma: children, squamoid nests
- Solid papillary neoplasm: women, degenerated pseudopapillae, nuclear labeling with beta catenin is a key diagnostic feature
- Usual ductal adenocarcinoma: marked nuclear atypia, abortive gland formation with luminal debris

Additional references

Cancer Treat Res 2010;153:253, Cancer Res 2001;61:285