Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy images | Molecular / cytogenetics description | Differential diagnosis | Additional referencesCite this page: Sopha S. Neuroendocrine neoplasms-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreaspen.html. Accessed January 22nd, 2021.
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
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
Contributed by Sabrina Sopha, M.D.
AFIP images
Images hosted on other servers:
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
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
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