Abstract
All of the following are histologic characteristics of well-differentiated pancreatic neuroendocrine tumors (PNENs), except:
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Keywords
- Small Cell Carcinoma
- Vasoactive Intestinal Polypeptide
- Normal Pancreas
- Pancreatic Neuroendocrine Neoplasm
- Serum Gastrin Level
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Self-Assessment Questions
-
1.
All of the following are histologic characteristics of well-differentiated pancreatic neuroendocrine neoplasms (PNENs), except:
-
a.
Composed of uniform polygonal cells that resemble islet cells.
-
b.
Have round or ovoid nuclei that have stippled, salt-and-pepper chromatin and eosinophilic cytoplasm.
-
c.
Endocrine differentiation may be confirmed with chromogranin A.
-
d.
Amyloid may be identified in some insulinomas.
-
e.
Hormonal activity always correlates with immunohistochemical staining of the tumor.
-
a.
-
2.
All of these statements about imaging of PNEN are incorrect, except:
-
a.
Transabdominal ultrasound has a higher sensitivity in the detection of PNEN than intraoperative ultrasound.
-
b.
Usually, PNENs are best identified by computed tomography on the venous phase.
-
c.
PNENs are usually hyperattenuating on arterial and venous phase computed tomography images.
-
d.
These tumors are isointense to the normal pancreas on MR T2-weighted imaging.
-
e.
Overall sensitivity of octreotide scan in the detection of PNEN is between 60 and 50 %.
-
a.
-
3.
The following statements are correct regarding insulinomas, except:
-
a.
The most common location of insulinomas is the head of the pancreas.
-
b.
Insulinomas are the most common functioning PNEN.
-
c.
10 % of insulinomas demonstrate malignant behavior.
-
d.
Classic clinical triad of insulinomas: hypoglycemic symptoms, low blood glucose, and relief of symptoms after administration of glucose.
-
e.
Insulinomas are usually small at the time of diagnosis (<2 cm).
-
a.
-
4.
Which statement about gastrinomas is correct?
-
a.
Gastrinomas are as common as insulinomas.
-
b.
30 % of gastrinomas demonstrate malignant behavior.
-
c.
More common in the duodenum than in the pancreas.
-
d.
Zollinger-Ellison syndrome is responsible for 10 % of cases of peptic ulcer disease.
-
e.
Gastrinomas have a low concentration of somatostatin receptors.
-
a.
-
5.
Glucagonomas are associated with all of these, except:
-
a.
Dermatitis
-
b.
Diabetes
-
c.
Dizziness
-
d.
Deep vein thrombosis
-
e.
Depression
-
a.
-
6.
Watery diarrhea, hypokalemia, and achlorhydria are associated with:
-
a.
Somatostatinoma
-
b.
Glucagonoma
-
c.
Gastrinoma
-
d.
VIPoma
-
e.
Insulinoma
-
a.
-
7.
The following statements about somatostatinomas are true, except:
-
a.
These tumors most frequently occur in the pancreas or periampullary region of the duodenum.
-
b.
Duodenal somatostatinomas are more likely to be associated with neurofibromatosis type 1.
-
c.
These tumors inhibit the intestinal absorption and release of insulin, glucagon, gastrin, and pancreatic enzymes
-
d.
These tumors may be associated with cholelithiasis.
-
e.
At the time of diagnosis, the tumor metastases are rare.
-
a.
-
8.
The following tumors are associated with MEN-1 syndrome, except:
-
a.
Parathyroid adenoma
-
b.
Medullary thyroid carcinoma
-
c.
Carcinoid tumor of the lung
-
d.
Anterior pituitary adenoma
-
e.
Endocrine tumor of the pancreas
-
a.
-
9.
The following statements about PNEN treatment and prognosis are true, except:
-
a.
Most reliable indicators of malignancy and poor prognosis are tumor size and cytologic atypia.
-
b.
PNENs are classified under the same TNM staging as pancreatic ductal carcinoma.
-
c.
Poor prognostic factors are vascular or neural invasion, high mitotic rate, and high Ki-67 index.
-
d.
Surgical resection is the only curative treatment for PNEN.
-
e.
Metastatic disease may be managed medically with octreotide and/or α-interferon.
-
a.
-
10.
Which statement about von Hippel-Lindau syndrome (VHL) is true?
-
a.
PNEN occurs in 30–40 % of patients with VHL.
-
b.
PNENs in patients with VHL syndrome are nonfunctioning.
-
c.
Mean age of PNEN presentation in VHL is 20 years.
-
d.
PNENs are the most common pancreatic manifestations of VHL.
-
e.
Frequency of metastatic disease in patients with VHL and PNEN is high.
-
a.
Answers: 1. e, 2. c, 3. a, 4. c, 5. c, 6. d, 7. e, 8. b, 9. a, 10. b
2 Introduction
-
Pancreatic neuroendocrine neoplasms (PNENs) are predominantly well-differentiated pancreatic or peripancreatic tumors that demonstrate neuroendocrine differentiation.
-
Arises from multipotential epithelial cells in the pancreatic ductal epithelium.
-
Classified on the basis of clinical symptoms, size, biological behavior, and histologic parameters.
-
Clinically are categorized as nonfunctional or functional.
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PNENs smaller than 0.5 cm are defined as microadenomas.
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Prevalence: approximately 1 in 100,000 people.
-
3 % of all pancreatic neoplasms.
-
Most often occur in the third to sixth decades of life.
-
No significant gender predilection.
-
Most occur sporadically.
-
Hereditary endocrinopathies associated with PNEN (1–2 %)
-
Multiple endocrine neoplasia type 1 (MEN-1)
-
Von Hippel-Lindau (VHL)
-
Neurofibromatosis type 1 (NFT1)
-
Tuberous sclerosis (TS)
-
3 Histopathology
3.1 Macroscopic Appearance (Figs. 10.1 and 10.2)
-
Usually solitary, well-demarcated, tan to pink soft tissue tumors.
-
The masses may be hard and gray-white when they exhibit fibrosis or amyloid deposition.
-
Sizes range from a few millimeters up to 20 cm; average range 1–5 cm.
-
Cystic degeneration: due to necrosis 5–10 %; containing clear or hemorrhagic fluid.
-
Vascular invasion: adverse prognostic factor.
-
Obstruction of the pancreatic duct (benign or malignant tumors).
-
Obstruction of the common bile duct (malignant tumors).
3.2 Microscopic Appearance (Fig. 10.3)
-
Uniform polygonal cells arranged in a nested pattern.
-
Round to oval nuclei that have stippled, “salt-and-pepper” chromatin and scant eosinophilic granular cytoplasm.
-
Growth patterns: solid, trabecular, glandular, acinar, cystic, papillary, and angiomatoid.
-
Variable amounts of collagenous stroma and sclerosis.
-
Tumor differentiation refers to the extent of resemblance to the normal cellular counterpart (well or poorly differentiated).
-
Tumor grade refers to the degree of biologic aggressiveness (low, intermediate, and high grades) and is based on the mitotic count and the proliferative index by Ki-67 immunohistochemistry.
-
Tumor stage refers to the extent of spread of the tumor.
3.3 Immunohistochemical Endocrine Markers (Fig. 10.4)
-
Chromogranin A: positive (protein found in secretory granules)
-
Synaptophysin: positive (membrane glycoprotein found in presynaptic vesicles)
-
Ki-67: used to assess the proliferative rate
Practical Pearls
-
In functional PNEN, the hormonal activity does not always correlate with immunohistochemical staining of the tumor.
-
Most nonfunctioning PNENs can show focal immunohistochemical staining for several peptides.
Features of Well-Differentiated PNEN
-
Tumor confined to pancreas
-
Usually do not metastasize
-
No necrosis
-
Low grade: low mitotic rate (less than 2 mitoses per 10 high-power fields) and low Ki-67 proliferative index (less than 3 % of Ki-67 staining)
-
Intermediate grade: intermediate mitotic rate (between 2 and 20 mitoses per 10 high-power fields) and intermediate Ki-67 proliferative index (3–20 % of Ki-67 staining)
-
Strong positivity for chromogranin and synaptophysin
Mutations of Common Oncogenes or Tumor-Suppressor Genes
-
K-ras
-
PTEN
-
RET
-
BRAF
-
Rb
-
CDKN2a/p16 DNA mismatch repairs and P53 are absent
Features of Poorly Differentiated PNEN
-
Infiltrative growth pattern.
-
Areas of necrosis can be seen.
-
Cells are small or large in size with irregular nuclei, scant cytoplasm, and abundant mitoses (>20 per 10 high-power fields).
-
Positive stain for chromogranin and synaptophysin (sometimes only focally).
-
High Ki-67 proliferative index (>20 %).
3.4 World Health Organization (WHO) Classification (Fig. 10.5)
The 2010 WHO classification recommends to use the term “neuroendocrine carcinoma” in the absence of metastases, only for poorly differentiated neoplasms (small cell carcinomas and large cell carcinomas) (Table 10.1).
-
Well-differentiated endocrine neoplasm
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Low grade; grade 1
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Intermediate grade; grade 2
-
-
Poorly differentiated endocrine carcinoma
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High grade; grade 3
-
-
Classification is based on mitotic rate and cell proliferation (measured with the Ki-67 labeling index) (Fig. 10.6 ). Once the tumor shows cytologic features of high-grade carcinoma, it should be categorized as small cell carcinoma or large cell carcinoma.
4 Nonfunctional PNEN
4.1 Epidemiology
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Usually sporadic
-
More common than functional PNEN; representing up to 50–75 % of the cases
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Most common PNEN in MEN-1 and VHL syndrome
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Mean age of presentation: 55 years
-
Slight female predominance
-
60 % incidence of malignancy
-
Patients who have nonfunctional PNEN that are smaller than 2 cm are mostly cured by surgery
-
Many of these tumors secrete pancreatic polypeptide or other hormones without associated clinical symptoms.
-
May also produce an inert precursor hormone or low levels of an effective hormone.
4.2 Clinical Presentation
-
Nonfunctional PNENs remain clinically silent until they reach a noticeable size and provoke symptoms by tumor mass effect.
Associated Symptoms and Signs
-
Abdominal pain
-
Weight loss
-
Anorexia
-
Nausea
-
Abdominal mass
-
Jaundice (rare)
-
Pruritus
Practical Pearls
-
Silent, nonfunctional PNENs may eventually be discovered incidentally by abdominal imaging performed for another cause or during screening of a patient with MEN-1 syndrome.
-
Although nonfunctional PNENs secrete a number of substances such as chromogranin, neuron-specific enolase, pancreatic polypeptide, and ghrelin. They do not present clinically with a hormonal syndrome as compared to the functional neoplasms.
4.3 Laboratory Evaluation
-
Chromogranin A (CgA): most commonly secreted and measured hormone associated with all types of PNEN (normal value <93 ng/ml). Sensitivity of 50 %
-
Chromogranin A: useful marker for detecting residual or recurrent disease in treated patients
Practical Pearls
-
Chromogranin A can also be elevated in patients with carcinoid tumors, pheochromocytoma, neuroblastoma, medullary thyroid cancer, some pituitary tumors, and in amine precursor uptake and decarboxylation (APUD) tumors.
-
False-positive elevations of chromogranin A (CgA) are often seen in patients taking proton pump inhibitors or experiencing impaired hepatic or renal function or non-neuroendocrine tumors (i.e. testicular cancer).
4.4 Imaging
-
On average, nonfunctional PNENs are larger than functional PNENs
-
Average size: 5–6 cm
-
Usually solitary, except if they are associated with familial syndromes
-
Shape: round or oval, well-circumscribed or poorly defined margins
-
Calcifications and vascular invasion may be present
-
Even distribution throughout the pancreas
-
Diffuse involvement of the entire pancreas is rare
-
Metastases at the time of diagnosis (60–80 %), presenting as peripancreatic lymph nodes and/or liver masses
4.4.1 Ultrasound (US), Endoscopic Ultrasound (EUS), Intraoperative Ultrasound (IOUS) (Figs. 10.7–10.16)
Findings
-
Well-circumscribed, round or oval, hypoechoic mass with smooth margins
-
Color Doppler: hypervascular or hypovascular
Signs of Malignancy
-
Ill-defined margins
-
Enlarged peripancreatic nodes
-
Liver metastases: hyperechoic or hypoechoic
-
Pancreatic duct obstruction (rare)
-
Biliary obstruction (rare)
4.4.2 Computed Tomography (CT) (Figs. 10.17–10.43)
Contrast-Enhanced Computed Tomography (CECT) Protocol
-
Arterial phase images obtained at 20–25 s after the injection of nonionic intravenous contrast
-
Portal venous phase at 55–50 s after injection
Findings
-
Well-circumscribed margins, smooth or lobulated
-
Tumor enhancement:
-
Small lesion: homogeneous enhancement
-
Large lesion: heterogeneous enhancement (cystic degeneration, necrosis, fibrosis)
-
Calcifications (punctuate, coarse)
-
Signs of Malignancy
-
Large size
-
Poorly defined margins
-
Arterial vascular encasement (gastroduodenal, hepatic, splenic arteries)
-
Venous invasion: (splenic vein, portal vein)
-
Enlarged peripancreatic nodes: hypervascular, homogeneous or heterogeneous
-
Hepatic metastases: hypervascular, homogeneous or heterogeneous, or peripheral rim enhancing
-
Biliary obstruction
Practical Pearls
-
Pancreatic duct dilatation associated with parenchymal atrophy and/or pancreatic lipodystrophy distal to a PNEN is rarely seen. These findings may be associated with either benign or malignant tumors.
-
Intraductal PNENs without a pancreatic parenchymal lesion may also occur but are exceptionally rare (Fig. 10.41).
4.4.3 Magnetic Resonance Imaging (MRI) (Figs. 10.44–10.54)
MR Protocol
-
T1-weighted (T1WI) and T2-weighted (T2WI) images, with and without fat suppression
-
Diffusion weighted images (DWI)
-
Contrast-enhanced fat-suppressed gradient echo T1-weighted images (arterial phase 20–25 s and portal phase 55–50 s after injection of intravenous gadolinium)
Findings
-
T1WI: PNENs appear as round or oval, well-circumscribed masses with low signal intensity relative to the normal pancreatic signal intensity.
-
T2WI: PNENs typically show a high or heterogeneous signal intensity.
-
T1WIFS with contrast: small PNENs may have homogeneous, hyperintense signal relative to the normal pancreas. Large PNENs may have a heterogeneous signal intensity or ring-like peripheral signal intensity (central necrosis).
-
Hepatic metastases: hypervascular, homogeneous, heterogeneous, or peripheral rim enhancing.
-
Lymph node metastases: enlarged hyperintense nodes, homogeneous or heterogeneous signal intensity.
Practical Pearls
-
Presence of numerous stromal blood vessels contributes to a hypervascular appearance of PNEN on contrast-enhanced CT or MR.
-
Cystic PNENs may have a peripheral vascular rim which allows differentiation of PNENs from other cystic neoplasms.
-
MR diffusion sequences have great sensitivity in the detection of hepatic metastases and lymph node enlargement.
4.4.4 Differential Diagnosis (CT/MR)
-
Pancreatic adenocarcinoma
-
Pancreatic metastases
-
Solid pseudopapillary tumor
-
Intrapancreatic splenule
-
Peripancreatic paraganglioma
-
Pancreatic lymphoma
4.4.5 Nuclear Medicine Studies (Figs. 10.55 and 10.56)
4.4.5.1 111In-Octreotide Scan (Octreoscan)
-
Considered the gold standard for imaging PNEN.
-
Overall sensitivity of this method is 80 % and varies depending on the hormone produced by the tumor.
Findings
-
Accumulation of the radiotracer in the tumor
4.4.5.2 Positron Emission Tomography/Computed Tomography (PET/CT)
-
More precise in tumor localization than 111In-octreotide studies.
-
Increase 2-(fluorine-18) fluoro-2-deoxy-d-glucose (FDG) uptake is usually demonstrated in poorly differentiated PNEN.
5 Functional Pancreatic Neuroendocrine Tumors (PNENs)
-
Named after the predominant hormone secreted.
-
Most common functional PNENs are insulinoma, gastrinoma, glucagonoma, VIPoma, and somatostatinoma.
-
Related symptoms associated with functional PNEN are poorly specific.
-
Proper diagnosis depends on physician awareness. It can be delayed for months or years after the first symptoms appear.
-
With the exception of the insulinomas, functional PNEN are frequently malignant.
-
Characterized by vascular invasion, gross infiltration of adjacent organs, and synchronous or metachronous nodal involvement or distant metastases.
-
In some cases, the diagnosis of malignancy is made by the detection of metastases of a previously resected benign tumor.
5.1 Insulinomas
5.1.1 Epidemiology
-
Most common functional PNEN.
-
Arise from beta (β) cells of the pancreas.
-
This tumor produces hypoglycemia due to insulin secretion.
-
Incidence: 3 per million/year.
-
Usually sporadic.
-
Female to male predominance: 1.4:1.
-
Peak age: 30–60 years (mean age 45 years).
-
Malignant behavior: 10 %.
-
May be seen in patients with neurofibromatosis type 1.
-
Best prognosis among functional and nonfunctional PNEN.
5.1.2 Clinical Presentation
-
These tumors tend to manifest earlier and have a smaller size than other nonfunctional or functional PNEN.
-
Vast majority measure between 0.5 and 2 cm.
-
Patients present with classic triad (Whipple’s triad):
-
Low glucose level (40md/dl or less).
-
Symptoms and signs of hypoglycemia: dizziness or weakness, associated with fasting or exercise. Diplopia, blurred vision, confusion, and personality changes.
-
Symptoms are relieved by glucose.
-
Symptoms Related to Catecholamine Release (Less Frequent)
-
Tachycardia
-
Chest pain
-
Palpitations
-
Diaphoresis
5.1.3 Laboratory Evaluation
Biochemical Diagnosis
-
Monitored 72 h fasting with serial measurements of blood glucose and insulin levels
Parameters
-
Serum insulin levels of 10 μU/ml or more (normal <6 μU/ml)
-
Glucose levels of less than 40 mg/dl
-
C-peptide level exceeding 2.5 μ/ml (normal <6 μ/ml)
-
Proinsulin levels greater than 25 % (or up to 90 %) that of immunoreactive insulin
-
Screening for sulfonylurea negative
5.1.4 Imaging (Figs. 10.57–10.66)
-
Tumor size: 90 % is <2 cm; 40 % is <1 cm
-
Location: intrapancreatic, even distribution throughout the pancreatic head, body, and tail
-
Usually solitary lesion
-
Multiple in MEN-1 syndrome, 2–10 % of patients
5.1.4.1 Ultrasound: (US, EUS, and IOUS)
Findings
-
Well-circumscribed, hypoechoic, hypervascular mass
5.1.4.2 Computed Tomography (CT)
Findings
-
Small intrapancreatic or partially exophytic, well-circumscribed, hypervascular mass (arterial and venous phase)
-
Rare: cystic changes or calcifications
Malignant Insulinoma
-
Enlarged hypervascular nodes
-
Hypervascular hepatic metastases
5.1.4.3 Magnetic Resonance (MR)
Findings
-
T1WI: low signal intensity mass
-
T2WI: hyperintense to normal pancreas
-
T1WI post gadolinium: hyperintense to normal pancreas
5.1.4.4 Octreotide Scan
Finding
-
Poor radiotracer uptake (few somatostatin receptors)
Practical Pearls
-
Surgical exploration and intraoperative ultrasound are the gold standards for detecting pancreatic insulinomas.
-
CT and MR imaging, with multiple reformatted planes (sagittal, coronal, and oblique), are very useful techniques for detecting small, exophytic, pedunculated, or perivascular insulinomas.
-
Calcium stimulated angiography, portal venous sampling, and selective arterial secretagogue infusion are best used for insulinomas that are undetectable by all other imaging modalities.
-
With transhepatic portal venous sampling (THPVS), small peripancreatic veins can be accessed and tested for insulin levels.
5.2 Gastrinoma (Zollinger-Ellison Syndrome)
5.2.1 Epidemiology
-
Second most common functional PNEN
-
Arise from pancreatic islets stem cells
-
Associated with excessive amounts of gastrin which results in an overproduction of gastric acid
-
Peak of incidence: fifth decade of life
-
Male: 60 %
-
Most are sporadic
-
20–25 % associated with MEN-1 syndrome
-
Size: average diameter of pancreatic gastrinomas: 1–4 cm
-
Malignant behavior: 60–90 %
5.2.2 Clinical Presentation
Related to elevation of gastrin levels: hypersecretion of gastric acid
-
Intractable epigastric pain due to:
-
Atypical gastroduodenal ulcer disease is generally the hallmark to diagnose this condition
-
Solitary ulcer: 90 % of cases
-
Peptic ulcers in atypical location: 25 % (distal duodenum, proximal jejunum)
-
-
Diarrhea due to:
-
Malabsorption secondary to breakdown of lipase from excessive gastric acid
-
-
Dysphagia due to:
-
Esophagitis
-
Zollinger-Ellison Syndrome (Described in 1955)
-
Atypical peptic ulceration
-
Gastric hypersecretion/acidity
-
Non-insulin-producing islet cell tumor of the pancreas
Practical Pearls
-
Diarrhea is generally the first symptom to appear; frequently lasting several years before diagnosis becomes recognized.
-
Due to the overflow of gastropancreatic secretions, diarrhea is generally watery.
-
Zollinger-Ellison syndrome is responsible for approximately 0.1 % of peptic ulcer disease.
Clinical Situations Requiring Further Investigation for Gastrinoma
-
Multiple GI ulcers or ulcers in atypical locations
-
Recurrent peptic ulcers after appropriate medical or surgical therapy
-
Failure of peptic ulcer to heal on appropriate medical therapy
-
Peptic ulcer or GERD with diarrhea
-
Peptic ulcer in absence of H. pylori
-
Persistent diarrhea without clear etiology
-
Family history of peptic ulcer disease
-
Peptic ulcer disease (PUD) resulting in complication (bleeding, perforation, obstruction)
-
Personal or family history of MEN-1 tumors or endocrinopathies
-
Prominent gastric rugae with PUD
5.2.3 Laboratory Evaluation
-
Fasting serum gastrin level: elevation of serum gastrin levels over 1,000 pg/ml (normal level <100 pg/ml); 30 % of patients
-
Most patients present with gastrin levels between 200 and 1,000 pg/ml
-
A secretin stimulation test is recommended for patients with normal or mildly elevated serum gastrin levels
5.2.4 Imaging (Figs. 10.67–10.75)
-
Most gastrinomas are found in the gastrinoma triangle, limited by:
-
Superiorly: junction of the cystic duct and common bile duct
-
Inferiorly: second and third portions of the duodenum
-
Medially: neck and body of the pancreas
-
-
55 % of gastrinomas arise in the duodenum
-
Other sites: pancreas, peripancreatic nodes
Practical Pearls
-
Although most gastrinomas are located in the gastrinoma triangle, 10 % occur in very unusual locations, such as the kidney (Fig. 10.73), liver, ovary, mesentery, lungs, or heart.
-
In a small percentage of patients, the gastrinomas may be found only in peripancreatic lymph nodes harboring the primary tumor.
5.2.4.1 Ultrasound (US, EUS, IOUS)
EUS is the best imaging modality for identifying gastrinomas that arise in the duodenal wall and peripancreatic node.
Findings
-
Well-circumscribed, hypoechoic, hypervascular mass
5.2.4.2 Computed Tomography (CT)
Findings
-
Solid, well-circumscribed, hypervascular mass
-
Central necrosis and peripheral enhancement may be identified
5.2.4.3 Magnetic Resonance (MR)
Findings
-
T1WI: low signal intensity mass
-
T2WI: hyperintense to normal pancreas
-
T1WI post gadolinium: hyperintense to normal pancreas
5.2.4.4 Octreotide Scan
Finding
-
Uptake of the radiotracer by the tumors and metastases (high concentration of somatostatin receptors)
5.3 Glucagonoma
5.3.1 Epidemiology
-
Third most common functioning PNEN
-
Arise from pancreatic alpha (α) cells of the pancreatic islets
-
These tumors produce glucagon. Glucagon counteracts the effects of insulin on glucose metabolism resulting in glucose intolerance
-
Incidence: 1 in 20 million people per year
-
Age: 40–60 years of age
-
Equal gender distribution
-
Usually sporadic
-
Most are malignant (50 %)
5.3.2 Clinical Symptoms
-
Glucagonoma syndrome is referred to as the 4D syndrome (dermatitis, diabetes, deep vein thrombosis, and depression).
-
Dermatitis (necrolytic migratory erythema) in 2/3 of the patients, painful pruritic plaques that start in the abdomen and groin and spread to the trunk and extremities (pathognomonic sign)
-
Diabetes present in most of the patients (mild or severe)
-
Deep vein thrombosis (lower extremities and subsequent pulmonary embolism)
-
Depression
-
Other symptoms: diarrhea, glossitis, weight loss, and various neurologic and psychiatric symptoms.
Practical Pearl
-
Skin lesions are indirectly caused by hyperglucagonemia and may be due to zinc or amino acid deficiency.
5.3.3 Laboratory Findings
-
Elevated serum glucagon, usually 10–20 times above normal (normal: 0–150 pg/ml)
5.3.4 Imaging (Fig. 10.76)
-
Most glucagonomas originate in the body and tail of the pancreas
-
Size: average diameter is 5–6 cm
-
Most times, the diagnosis is delayed
5.3.4.1 Ultrasound (US, EUS, IOUS)
Findings
-
Hypoechoic, vascular mass
-
Hypoechoic, target-like liver lesions (metastases)
5.3.4.2 Computed Tomography (CT)
Findings
-
Small or large bulky mass, with homogeneous or heterogeneous enhancement
-
Hypervascular metastases (liver and/or lymph nodes)
5.3.4.3 Magnetic Resonance (MR)
Findings
-
T1WI: low signal intensity mass
-
T2WI: hyperintense to the pancreas
-
T1WIFS with gadolinium: homogeneous or heterogeneous enhancement
5.3.4.4 Octreotide Scan
Finding
-
Uptake of the radiotracer by the tumor/s and metastases
Practical Pearl
-
The diagnosis of glucagonoma may be suggested by the clinical presentation and biopsy of skin lesions but is confirmed by elevated levels of fasting serum glucagon and the presence of a pancreatic mass on CT.
5.4 Vasoactive Intestinal Peptide-Secreting Tumor (VIPoma)
5.4.1 Epidemiology
-
Very rare
-
Secretes vasoactive intestinal polypeptide (VIP)
-
VIP acts on cyclic adenosine monophosphate within the bowel epithelium to inhibit the absorption of and stimulate the secretion of water and electrolytes into the bowel lumen
-
Peak incidence: fifth and sixth decades
-
Equal gender distribution
-
Rarely associated with MEN-1 syndrome
-
Most present with malignant behavior
5.4.2 Clinical Syndrome (Verner-Morrison Syndrome)
-
Severe, intermittent, watery diarrhea (6–8 L per day)
-
Hypokalemia
-
Achlorhydria
Practical Pearl
-
The secretory-type diarrhea is secondary to a massive jejunal net secretion of water and electrolytes.
5.4.3 Laboratory Findings
-
Elevated fasting serum VIP level
-
Usually more than 200 pg/ml
-
Hypokalemia/achlorhydria
-
Elevated calcium levels during episodes of diarrhea
5.4.4 Imaging (Fig. 10.77)
-
Most frequently occur in the pancreatic tail
-
20 % extrapancreatic (sympathetic ganglia of retroperitoneum or mediastinum)
-
Other unusual locations: esophagus, small bowel, colon, liver, and kidney
-
Size: mean of 5 cm at diagnosis
-
60–80 % metastases at time of presentation
5.4.4.1 Ultrasound (US, EUS, IOUS)
Finding
-
Hypoechoic, hypervascular mass
5.4.4.2 Computed Tomography (CT)
Findings
-
Small masses: homogeneous enhancement.
-
Larger lesions: heterogeneous, hyperenhancing masses; cystic changes and/or calcifications may be present.
5.4.4.3 Magnetic Resonance (MR)
Findings
-
T1WI: low signal intensity mass
-
T2WI: hyperintense to the pancreas
-
T1WIFS with Gad: homogeneous or heterogeneous enhancement
5.4.4.4 Octreotide Scan
Findings
-
Uptake of the radiotracer by the tumor and metastases
5.5 Somatostatinoma
5.5.1 Epidemiology
-
Accounts for less than 2 % of all well-differentiated PNENs
-
Arise from delta (δ) cells of the pancreatic islet cells
-
These tumors produce somatostatin. Somatostatin inhibits the intestinal absorption and gut motility and release of insulin, glucagon, gastrin, and pancreatic enzymes
-
Mean age of presentation: 50 years
-
Equal sex distribution
-
Most are malignant (90 %)
Associated with
-
Neurofibromatosis type 1 (von Reckling-hausen’s disease)
-
MEN-1 syndrome
5.5.2 Clinical Symptoms
-
Nonspecific
-
Occur in 20 % of patients
-
Diabetes mellitus, steatorrhea, diarrhea, cholelitiasis, hypochlorhydria, and weight loss
Practical Pearl
-
Somatostatinomas detected in neurofibromatosis type 1 are usually asymptomatic and less frequently associated with metastases.
5.5.3 Laboratory Evaluation
-
Fasting serum somatostatin levels are 50-fold higher than normal
5.5.4 Imaging (Figs. 10.78 and 10.79)
-
The majority occur in the pancreatic head or duodenum (ampullary and periampullary regions).
-
Duodenal somatostatinomas are most likely related to neurofibromatosis, type 1.
-
Rare primary sites: small bowel and colon.
-
Metastases (liver, lymph nodes) are common at presentation.
5.5.4.1 Ultrasound (US, EUS, IOUS)
Findings
-
Hypoechoic or heterogeneous, hypervascular mass
5.5.4.2 Computed Tomography (CT)
Findings
-
Heterogeneous, hyperenhancing mass
-
Hypervascular metastases (liver and/or lymph nodes), homogeneous or with ring-like enhancement
5.5.4.3 Magnetic Resonance (MR)
Findings
-
T1WI: low signal intensity mass in relation to the pancreas
-
T2WI: high signal intensity
-
T1WIFS with Gad: homogeneous or heterogeneous enhancement
5.5.4.4 Octreotide Scan
Findings
-
Uptake of the radiotracer by the tumor and metastases
6 Other Functioning PNENs
-
Many other types of functioning PNEN have been described
-
Extremely rare
-
May secrete:
Practical Pearl
-
PNEN may cause symptoms related to more than one hormone. These symptoms may occur either synchronously or sequentially during treatment.
7 Syndromes Associated with PNEN
7.1 Multiple Endocrine Neoplasia Type I (Werner Syndrome) (Figs. 10.9, 10.14, 10.70, and 10.83)
-
Genetic disorder characterized by two or more endocrine tumors resulting in malignancy or increased glandular function
-
Most often associated with parathyroid, pancreatic, and pituitary tumors
-
Autosomal dominant condition
-
Prevalence: one person in every 30,000 people
-
Equal gender distribution
-
MEN-1 tumor suppressor gene is located on chromosome 11q13 encoding the protein menin, which suppresses cell proliferation
-
MEN-1 mutation present in 21 % of patients with sporadic PNEN
PNEN in MEN-1 Syndrome
-
Mean age of presentation: mid-30s
-
Gastrinomas: 60 % of patients (more common in duodenum)
-
Insulinomas: 20–30 % of patients
-
May have multiple microadenomas and nonfunctioning PNEN throughout the pancreas
Practical Pearl
-
MEN-1 is diagnosed in about 25 % of patients with gastrinomas and 5–10 % in patients with insulinomas.
7.2 Clinical Manifestations (3Ps: Parathyroid, Pancreas, Pituitary)
-
Hyperparathyroidism (parathyroid adenoma): 90 % of the patients
-
Hypercalcemia with elevated PTH
-
-
Endocrine tumors of the pancreas or duodenum: 30–80 % of the patients
-
Elevated serum gastrin or insulin levels
-
-
Anterior pituitary adenoma: 20–65 % of the patients
-
Elevated prolactin, GH, or ACTH
-
Practical Pearls
-
Parathyroid and pituitary lesions usually manifest before pancreatic lesions are found.
-
Patients with duodenal gastrinomas have a better prognosis than patients with pancreatic gastrinomas.
-
PNEN associated with MEN-1 have a lower rate of malignancy than sporadic tumors.
-
They have a higher rate of postoperative recurrence and are a common cause of death in patients.
-
Cutaneous tumors are also common in MEN-1: angiofibromas (face), collagenomas, and lipomas.
7.3 Von Hippel-Lindau Syndrome (VHL) (Figs. 10.10 and 10.84)
-
Autosomal dominant syndrome
-
Prevalence: 1 in 36,000–39,000 people
-
Caused by mutation of the VHL suppressor gene (located on chromosome 3p25)
-
Patients develop multiple clear cell, benign and malignant tumors in multiple organ systems
Hallmark of This Condition
-
Retinal and central nervous system hemangioblastomas
-
Clear cell renal cell carcinomas
-
Pheochromocytomas
-
Pancreatic serous cystadenomas
-
Pancreatic neuroendocrine neoplasms
PNEN in VHL
-
Occurrence: 5.6–15 %
-
Usually multiple neoplasms
-
Synchronous pheochromocytomas (40 %)
-
Synchronous cystic pancreatic disease (60 %)
-
Age range: 16–42 years; mean age: 31.5 years
-
Most of them are nonfunctional pancreatic neuroendocrine tumors (discovered on screening)
-
Slow growing
-
Frequency of metastatic disease is low
7.4 Neurofibromatosis Type 1 (NFT1)
-
Relatively common disorder occurring in 4,000–5,000 live births.
-
Occurs upon alteration of the NF-1 gene on chromosome 15q11.2 which encodes neurofibromin.
-
Neurofibromin acts as a tumor suppressor.
-
Signs and symptoms present by 5 years of age.
-
The most common manifestations are neurofibromas and café au lait skin macules, as well as functional neurological deficits and epilepsy.
-
Other lesions: ganglioneuromas, gastrointestinal stromal tumors, pheochromocytomas (rare), and precocious puberty.
-
Endocrine involvement: duodenal somatostatinomas (more common), pancreatic somatostatinomas, pancreatic gastrinomas, insulinomas, and nonfunctioning PNENs (rare).
7.5 Tuberous Sclerosis (TS)
-
Autosomal dominant neurocutaneous multisystem disorder.
-
Associated with mutations in two genes: the TSC1 gene at 9q34 that encodes hamartin and TSC2 at 16p13.3 that encodes tuberin.
-
Most cases are due to sporadic de novo mutations, with no family history of the disease.
-
Manifestations: apparent shortly after birth.
-
Hamartomas manifest in almost every organ: the brain, skin, eyes, heart, kidneys, lungs, and skeleton.
-
Disabling neurological features: epilepsy, mental retardation, and autism.
-
The association of TS and pancreatic neuroendocrine neoplasms (PNENs) is not clear.
-
Malignant PNENs have been reported in children.
-
Functional PNENs have been reported to produce insulin or gastrin.
8 Poorly Differentiated Neuroendocrine Carcinomas (High-Grade Neuroendocrine Carcinomas)
-
Rare
-
Prevalence: 2–3 % of all PNENs
-
Usually occur in older men (middle aged to elderly)
-
Fatal within less than 1 year
-
Usually large tumors at presentation: >5 cm in diameter
-
Histologically, they are classified as small cell carcinoma and large cell carcinoma
8.1 Clinical Symptoms
-
Abdominal pain
-
Back pain
-
Cachexia
-
Jaundice (obstruction of biliary system)
8.2 Imaging (CT/MR) (Figs. 10.85 and 10.86)
-
Large heterogeneous masses
-
Well or poorly defined margins
-
Obstruction of the pancreatic duct
-
Obstruction of the common bile duct
-
Liver metastases, hypervascular (homogeneous or heterogeneous)
9 Staging System of Pancreatic Endocrine Tumors
The AJCC TNM system specific for pancreatic adenocarcinoma should be used.
The American Joint Committee on Cancer (AJCC) TNM Stage System | |
---|---|
T-primary tumor | |
TX | Primary tumor cannot be assessed |
T0 | No evidence of primary tumor |
T1 | Tumor limited to the pancreas <2 cm |
T2 | Tumor limited to the pancreas <2 cm |
T3 | Tumor extends beyond the pancreas but without the involvement of the celiac axis or the superior mesenteric artery |
T4 | Tumor involves the celiac axis or the superior mesenteric artery (unresectable) |
N-regional nodes | |
NX | Regional nodes cannot be assessed |
N1 | No regional node metastases |
N2 | Regional node metastases |
M-distant metastases | |
MX | Distant metastases cannot be assessed |
M0 | No distant metastases |
M1 | Distant metastases (indicates the presence of any single or multiple metastases at any distant anatomic site including no regional nodes) |
Stage 1a | Stage 1b | Stage IIa | Stage IIb | Stage III | Stage IV |
---|---|---|---|---|---|
T1,N0 | T2,N0 | T3,N0 | T1–T3,N1 | T4, any N, MO | Any T, M1 |
10 Treatment of PNEN: Surgery
-
Remains the only curative treatment.
-
Only approach that can achieve a complete cure in patients with NE tumors.
-
In cases of metastases, surgery has been used to improve hormone-mediated symptoms, quality of life, and survival in certain groups of patients, as well as to reduce tumor bulk and prevent further local and systemic effects.
-
Surgical resection of primary tumors, as well as lymph nodes and liver metastases, can improve survival.
Surgical Procedures
-
Enucleation is the most common surgical procedure for sporadic, small, exophytic PNENs without metastases.
-
Distal pancreatectomy for deep lesions in the body or tail of the pancreas.
-
Pancreatoduodenectomy for lesions deep in the head of the pancreas.
-
Central pancreatectomy is an alternative procedure for lesions deep in the body of the pancreas.
-
Isolated metastatic disease can be excised.
-
Debulking surgery improves symptoms and survival in these patients.
-
Liver transplantation may provide palliation in young patients with metastatic disease (only to the liver).
Nonsurgical Procedures
-
Hormonally related symptoms in patients with metastatic disease may be managed medically with octreotide or analogs such as lanreotide (symptomatic response occurs in 60–90 %).
-
Alpha interferon may be helpful for refractory metastatic disease.
-
Patients with gastrinomas that cannot be removed can be treated with long-term omeprazole therapy to alleviate the symptoms.
-
Chemotherapy regimens for small cell carcinomas are used in patients with poorly differentiated PNEN.
-
Hepatic metastases can be treated with hepatic transarterial chemoembolization (doxorubicin or adriamycin).
-
Radiofrequency ablation and NanoKnife® of hepatic lesions are other alternatives used to treat hepatic metastases.
-
Radionuclide may be used to treat tumors with somatostatin receptors (combination of octreotide, octreotate, or lanreotide with DOTA and a radionuclide such as yttrium 90 or lutetium 155). Therapeutic agents may be administered intravenously or directly into the hepatic artery.
11 Prognosis of PNEN
-
Functioning tumors have a better prognosis than nonfunctioning tumors.
-
Poorly differentiated neuroendocrine carcinomas have the worst prognosis.
-
Prognosis of PNEN is much better than pancreatic adenocarcinomas.
Most Reliable Indicators of Malignancy and Poor Prognosis Are
-
Extrapancreatic invasion
-
Metastatic disease
Poor Prognostic Factors for PNEN
-
Size larger than 2–4 cm
-
Vascular or neural invasion
-
High mitotic rate
-
High Ki-67 proliferative index
-
Necrosis
-
Chromosomal loses or gains
Insulinomas Have the Best Prognosis
-
Small
-
No necrosis or invasion
-
Survival rate similar to that of the general population
Non-insulinoma PNEN
-
Recur or metastasize in 50–80 % of patients (survival rate 50–65 %)
-
After PNEN surgical resection: overall median survival is 58–95 months
-
Without surgical resection: overall median survival is 15–21 months
-
12 Teaching Points
Pancreatic neuroendocrine neoplasms (PNENs) | |
Classification | Nonfunctional PNEN Functional PNEN |
Pathology | Macroscopic appearance: well-circumscribed (majority) or poorly defined margins (malignant masses). Size 1–20 cm Microscopic appearance: cells with round or oval nuclei that have stippled, “salt-and-pepper” chromatin and eosinophilic granular cytoplasm Immunohistochemical markers: chromogranin A and synaptophysin positive. Hormonal markers: insulin, glucagon, somastostatin, gastrin, VIP, and/or PPP |
World Health Organization (WHO) classification | Well-differentiated neuroendocrine neoplasm grade 1: less than 2 mitoses per 10 high-power fields and less than 3 % Ki-67 proliferative index Well-differentiated neuroendocrine neoplasm grade 2: 2–20 mitoses per 10 high-power fields and 3–20 % Ki-67 proliferative index Poorly differentiated neuroendocrine carcinoma (small cell carcinoma and large cell carcinoma): more than 20 mitoses per 10 high-power fields and more than 20 % Ki-67 proliferative index |
Nonfunctional PNEN | |
General | Most common PNEN Usually sporadic Mean age at presentation: 55 years 60 % malignant Slight female predominance Most common PNEN in MEN-1 and von Hippel-Lindau syndromes |
Clinical presentation | Abdominal pain, weight loss, anorexia, nausea, abdominal mass, jaundice, pruritus Incidental finding on imaging |
Laboratory evaluation | Elevation of serum chromogranin A (sensitivity 50 %) |
Imaging | Average size: 5–6 cm Usually solitary, round or oval Preferred imaging modalities: CECT and octreoscan CT: hypervascular, homogeneous, or heterogeneous enhancement Rare: cystic changes or calcifications Signs of malignancy: poorly defined margins, vascular invasion, peripancreatic nodes, hypervascular hepatic metastases Octreoscan: radiotracer accumulation in tumor and/or metastases DD: pancreatic adenocarcinoma, metastases, solid papillary tumors of the pancreas, intrapancreatic spleen |
Treatment | Resectable masses: surgical resection Unresectable masses: chemotherapy, alpha interferon, radionuclide to treat tumors with somatostatin receptors Liver metastases: hepatic artery chemoembolization, radiofrequency ablation or NanoKnife, liver transplant (young patients) |
Functional PNEN | |
Insulinoma | Most common functional PNEN Arise from β-cells Produces insulin Usually sporadic Mean age: 45 years Most benign 10 % are malignant |
Clinical presentation | Whipple’s triad: Low glucose level Symptoms and signs of hypoglycemia: dizziness or weakness, associated with fasting or exercise Symptoms are relieved by glucose |
Laboratory | Inappropriately elevated insulin level (>5 mU/ml) in the presence of low glucose (<40 mg/dl) Insulin to glucose ratio >0.4 after an overnight fast May be found in MEN-1 and von Hippel-Lindau syndromes |
Imaging | Tumor size:<2 cm Usually solitary Even distribution throughout the pancreas Multiple in MEN-1 syndrome Preferred imaging modalities: CECT and intraoperative ultrasound (IOUS) CT: hypervascular mass IOUS: hypoechoic, hypervascular mass |
Treatment | Surgical resection |
Gastrinoma | Second most common functional PNEN Produces gastrin Peak of incident: fifth decade Malignant behavior: 60–90 % Most sporadic 20–25 % associated with MEN-1 syndrome |
Clinical presentation | Diarrhea (most common), epigastric pain, dysphagia, atypical ulcers, refractory to the treatment |
Imaging | Most located in gastrinoma triangle 55 % arise in the duodenum Preferred imaging modalities: Endoscopic ultrasound (EUS), intraoperative ultrasound (IOUS), CECT, octreotide scan CECT: hypervascular mass Octreotide: accumulation of radiotracer in the primary tumor Metastases: peripancreatic nodes, liver (hypervascular) |
Laboratory | Gastrin levels over 1,000 pg/ml |
Treatment | Surgical resection Unresectable lesions: somatostatin analog, chemotherapy |
Glucagonoma | Third most common PNEN Arise from α-cells Produces glucagon 40–60 years of age Usually sporadic Most malignant (50 %) |
Clinical presentation | 4Ds: dermatitis, diabetes, deep vein thrombosis, and depression |
Laboratory finding | Serum glucagon 10–20 times above normal |
Imaging | Most common location: body and tail of pancreas Size 5–6 cm Preferred imaging modalities: CECT and octreotide scan CECT: hypervascular mass, homogeneous or heterogeneous enhancement Octreotide: accumulation of radiotracer in the primary tumor Metastases: peripancreatic nodes, liver (hypervascular). |
Treatment | Surgical resection, chemotherapy |
Vasoactive intestinal peptide-secreting tumor (VIPoma) | Very rare Produces vasoactive intestinal polypeptide (VIP) Fifth and sixth decades Most malignant behavior Rarely associated with MEN-1 syndrome |
Clinical presentation | Severe diarrhea (6–8 L per day) |
Laboratory finding | Elevated fasting serum VIP level (>200 pg/ml) |
Imaging | Most occur in the body and tail of the pancreas Preferred imaging modalities: CECT and octreotide scan CECT: hypervascular mass, homogeneous or heterogeneous enhancement Octreotide: accumulation of radiotracer |
Treatment | Surgical resection Unresectable lesions: chemotherapy |
Somatostatinoma | Less than 2 % of functional PNEN Arise from δ-cells Produces somatostatin Associated with neurofibromatosis type 1 and MEN-1 syndrome |
Clinical presentation | Nonspecific (diabetes mellitus, steatorrhea, diarrhea, cholelithiasis, hypochlorhydria, and weight loss) |
Laboratory finding | Fasting serum somatostatin levels are 50-fold higher than normal |
Imaging | Most occur in the body and tail of the pancreas Preferred imaging modalities: CECT and octreotide scan CECT: hypervascular mass, homogeneous or heterogeneous enhancement Octreotide: accumulation of radiotracer |
Treatment | Surgical resection Unresectable lesions: chemotherapy |
Syndromes associated with PNEN | |
Multiple endocrine neoplasm MEN-1 | May have multiple microadenomas and nonfunctioning PNEN Gastrinomas (60 %); more common in the duodenum Insulinomas (20–30 %) |
Von Hippel-Lindau syndrome | Most of them are rare, nonfunctional PNEN |
Neurofibromatosis type 1 | Duodenal somatostatinomas are more common |
Tuberous sclerosis | Malignant PNEN in children Functional PNEN (gastrin, insulin) |
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Casillas, J., Levi, J.U., Lew, J.I., Ruiz-Cordero, R., Garcia-Buitrago, M.T. (2016). Pancreatic Neuroendocrine Neoplasms (PNENs). In: Multidisciplinary Teaching Atlas of the Pancreas. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46745-9_10
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