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1240
GASTROINTESTINAL IMAGING

Pancreatic Neuroendocrine Neo-

plasms: 2020 Update on Patho-
logic and Imaging Findings and
Classification
Lokesh Khanna, MD
Srinivasa R. Prasad, MD Pancreatic neuroendocrine neoplasms (panNENs) are heteroge-
Abhijit Sunnapwar, MD neous neoplasms with neuroendocrine differentiation that show
Sainath Kondapaneni, BSA characteristic clinical, histomorphologic, and prognostic features;
Anil Dasyam, MD genetic alterations; and biologic behavior. Up to 10% of panNENs
Varaha S. Tammisetti, MD develop in patients with syndromes that predispose them to cancer,
Umber Salman, MD such as multiple endocrine neoplasia type 1, von Hippel–Lindau
Alia Nazarullah, MD disease, tuberous sclerosis complex, neurofibromatosis type 1, and
Venkata S. Katabathina, MD glucagon cell adenomatosis. PanNENs are classified as either func-
tioning tumors, which manifest early because of clinical symptoms
Abbreviations: ADC = apparent diffusion co- related to increased hormone production, or nonfunctioning tumors,
efficient, AJCC = American Joint Committee on
Cancer, FDG = fluorodeoxyglucose, MEN1 = which often manifest late because of mass effect. PanNENs are
multiple endocrine neoplasia type 1, MiNEN = histopathologically classified as well-differentiated pancreatic neu-
mixed neuroendocrine-nonneuroendocrine neo-
plasm, panNEC = pancreatic neuroendocrine
roendocrine tumors (panNETs) or poorly differentiated pancreatic
carcinoma, panNEN = pancreatic neuroendo- neuroendocrine carcinomas (panNECs) according to the 2010 World
crine neoplasm, panNET = pancreatic neuro- Health Organization (WHO) classification system. Recent advances
endocrine tumor, VHL = von Hippel–Lindau
syndrome, WHO = World Health Organization in cytogenetics and molecular biology have shown substantial hetero-
RadioGraphics 2020; 40:1240–1262
geneity in panNECs, and a new tumor subtype, well-differentiated,
high-grade panNET, has been introduced. High-grade panNETs
https://doi.org/10.1148/rg.2020200025
and panNECs are two distinct entities with different pathogenesis,
Content Codes: clinical features, imaging findings, treatment options, and prognoses.
From the Departments of Radiology (L.K., A.S., The 2017 WHO classification system and the eighth edition of the
U.S., V.S.K.) and Pathology (V.S.T.), University American Joint Committee on Cancer staging system include sub-
of Texas Health Science Center at San Antonio,
7703 Floyd Curl Dr, San Antonio, TX 78229; stantial changes. Multidetector CT, MRI, and endoscopic US help
Department of Radiology, University of Texas in anatomic localization of the primary tumor, local-regional spread,
M. D. Anderson Cancer Center, Houston, Tex
(S.R.P.); Department of Molecular Biosci- and metastases. Somatostatin receptor scintigraphy and fluorine 18–
ences, University of Texas at Austin, Austin, Tex fluorodeoxyglucose PET/CT are helpful for functional and metabolic
(S.K.); Department of Radiology, University
of Pittsburgh Medical Center, Pittsburgh, Pa
assessment. Knowledge of recent updates in the pathogenesis, clas-
(A.D.); and Department of Radiology, Univer- sification, and staging of panNENs and familiarity with their imaging
sity of Texas Health Science Center at Houston, findings allow optimal patient treatment.
Houston, Tex (A.N.). Recipient of a Certificate
of Merit award for an education exhibit at the ©
RSNA, 2020 • radiographics.rsna.org
2019 RSNA Annual Meeting. Received March
3, 2020; revision requested April 29 and received
May 25; accepted May 29. For this journal-
based SA-CME activity, the authors, editor, and
reviewers have disclosed no relevant relation-
ships. Address correspondence to L.K. (e- SA-CME LEARNING OBJECTIVES
mail: khannal@uthscsa.edu).
©
After completing this journal-based SA-CME activity, participants will be able to:
RSNA, 2020
Review changes in the 2017 WHO classification system and the eighth edition of the
„
AJCC TNM staging system for panNENs.
Discuss the pathogenesis of panNETs and panNECs, including the genetic muta-
„
tions that affect prognosis and treatment.
Describe cross-sectional imaging findings of functioning and nonfunctioning
„
panNETs and panNECs that help in identification of panNEN grades for diagnosis
and staging.
See rsna.org/learning-center-rg.
RG  •  Volume 40  Number 5 Khanna et al  1241
TEACHING POINTS
„ The 2017 WHO classification system describes panNENs as
two genetically distinct neoplasms that include well-differen-
tiated panNETs and poorly differentiated panNECs (small and
large cell types). PanNETs and panNECs differ significantly
in genetic changes, clinical presentations, imaging features,
prognosis, and therapeutic strategies.
„ For the eighth edition of the AJCC system, a separate staging
system that applies only to well-differentiated panNETs (WHO
system grades 1–3) was developed. Poorly differentiated pan-
NECs (WHO grade 3) are staged similarly to the staging of
pancreatic ductal adenocarcinoma. Size is the most important
criterion to assign the T category; invasion of peripancreatic
soft tissue has been removed from the staging criteria.
„ 68Ga DOTATATE PET/CT with 68
Ga-tetraazacyclododecane
tetraacetic acid (DOTA)–somatostatin analog has shown
promising results for detection of small tumors not seen with
111
In-pentetreotide imaging, CT, or conventional MRI. It is also
useful in staging and follow-up to identify recurrent disease
„ Well-differentiated grade 1 and grade 2 panNETs are typically
small (<3 cm) well-circumscribed hypervascular masses with
intense homogeneous enhancement in the arterial and portal
venous phases; the degree of homogeneity and enhance-
ment correlates with tumor grade.
„ DAXX and ATRX gene mutations are identified in up to 40%
of panNETs, which typically occur late in tumor development,
resulting in alternative lengthening of telomeres and posi-
tive phenotypes, and are associated with intermediate- and
high-grade tumors. Compared with those that are negative,
panNETs that are positive for alternative lengthening of telo-
meres are strongly associated with large tumor size (>3 cm),
pancreatic duct dilatation, and hepatic metastasis, and they
correspond to aggressive behavior, high tumor grade, and
resultant poor prognosis.
Introduction
Pancreatic neuroendocrine neoplasms (panNENs)
are rare tumors that originate from precursor cells
in the pancreatic ductal epithelium with neuroen-
docrine differentiation and constitute up to 2% of
all clinically detected pancreatic tumors. However,
the prevalence has been reported to be as high
as 10% in autopsy studies (1–4). On the basis of
histopathologic findings, panNENs are tradition-
ally divided into two broad categories that include
well-differentiated pancreatic neuroendocrine
tumors (panNETs) and poorly differentiated pan-
creatic neuroendocrine carcinomas (panNECs)
(1,2). PanNENs may also be classified into func-
tioning and nonfunctioning tumors on the basis of
the clinical manifestations (1,2). Functioning tu-
mors that account for up to 30% of panNENs are
defined by the clinical syndrome related to specific
hormone overproduction and are diagnosed earlier
than are nonfunctioning tumors; insulinomas and
gastrinomas are the most common functioning
panNENs (1,2). Neoplasms containing features
of nonendocrine carcinomas and neuroendocrine
neoplasms are classified as mixed neuroendo-
crine-nonneuroendocrine neoplasms (MiNENs)
(1,2). Although the majority of the panNENs are
sporadic, up to 10% may develop in patients with
hereditary syndromes that predispose them to can-
cer, including multiple endocrine neoplasia type 1
(MEN1), von Hippel–Lindau disease (VHL), tu-
berous sclerosis complex, neurofibromatosis type
1, and glucagon cell adenomatosis (Table 1) (6).
Evolving knowledge regarding pathogenesis,
cytogenetics, molecular biology, and clinical
outcomes of panNENs has necessitated substan-
tial changes in the staging and grading systems
that can impact diagnosis and management
(2,7). The 2017 WHO classification system is the
most updated classification of the panNENs and
addressed controversies regarding high-grade
panNETs and panNECs (5,8). The eighth edi-
tion of the American Joint Committee on Cancer
(AJCC) TNM staging system has made neces-
sary changes in T staging (2,9–11). The paradigm
shift in our understanding has led to significant
changes in management strategies and opened
new avenues for the development of novel mo-
lecular imaging techniques and therapeutic tar-
gets. Radiologists need to be cognizant of these
changes to play an important role in patient man-
agement. Anatomic imaging techniques, includ-
ing US, multidetector CT, and MRI, are helpful
in the initial diagnosis, treatment follow-up, and
long-term surveillance (12,13). Molecular imag-
ing techniques such as somatostatin receptor
scintigraphy (indium 111 [111In] and gallium 68
[68Ga] tetraazacyclododecane tetraacetic acid–oc-
treotate [DOTATATE] scanning) and fluorine
18 (18F)–fluorodeoxyglucose (FDG) PET/CT are
helpful in the functional assessment and detec-
tion of occult tumors (12). Endoscopic US helps
in the identification of smaller panNENs and
allows tissue sampling.
In this article, we review changes in the 2017
WHO classification system and the eighth edi-
tion of the TNM staging system for panNENs
and discuss genetics and pathogenesis of spo-
radic and syndromic tumors. We also describe
anatomic and functional imaging features of
panNENs and discuss the role of imaging in
their management.
2017 WHO Classification of PanNENs
The previous (2010) version of the WHO clas-
sification system (8) for panNENs primarily
used the Ki-67 proliferation index and mitotic
index to differentiate between panNETs and
panNECs. If these indices were greater than
20, tumors were classified as panNECs with-
out regard to the level of differentiation (14).
However, large patient studies (2,5,9) attested
to the existence of well-differentiated grade 3
panNETs with high Ki-67 and mitotic indices
1242  September-October 2020 radiographics.rsna.org
that portended a better prognosis. To address
these issues, both the degree of cellular differ-
entiation and cellular proliferation were taken
into consideration in the 2017 WHO classifica-
tion system (5) for panNENs to predict tumor
grade and behavior. With the use of the mitotic
index (number of mitoses per 10 high-power
fields) and the Ki-67 index, panNENs are
classified into three grades (Table 2) (1,9). In
addition, the 2017 WHO classification system
(9) describes panNENs as two genetically dis-
tinct neoplasms that include well-differentiated
panNETs and poorly differentiated panNECs
(small and large cell types). PanNETs and pan-
NECs differ significantly in genetic changes,
clinical presentations, imaging features, progno-
sis, and therapeutic strategies (2,9). PanNETs
are well-differentiated tumors with minimal to
moderate atypia and lack of necrosis, and they
express intense synaptophysin or chromogranin
A positivity (Fig 1). PanNECs are poorly dif-
ferentiated tumors that consist of atypical cells
with substantial necrosis that are faintly positive
for neuroendocrine markers (Fig 2) (15–17). In
the 2017 classification system, the WHO ac-
knowledges the existence of two distinct tumor
categories with high Ki-67 and mitotic indices:
well-differentiated high-grade tumors (panNET
G3) and poorly differentiated carcinomas (pan-
NEC G3) (2,5,9).
Eighth Edition of the AJCC Staging
System
Accurate clinical staging is the most important
step in the management of panNENs after the
appropriate WHO grade and/or differentiation is
assigned on the basis of pathologic findings. TNM
staging is the most commonly used clinical staging
system for assessment of mortality and prognosis
based on the anatomic extent of the panNENs (7).
There are two major TNM classification systems
available for panNENs: the European Neuroen-
docrine Tumor Society (ENETS) system and the
AJCC staging system (1,7). The eighth edition of
the AJCC system is the most recent TNM clas-
sification system. It includes multiple substantial
changes that address concerns about the previous
editions of the AJCC and ENETS systems and
was globally adopted on January 1, 2018 (Table 3)
(10). A recent study by You et al (18) supported
the use of the eighth edition of the AJCC staging
system and showed that it provides better discrimi-
nation compared with the ENETS and seventh
edition AJCC systems.
For the eighth edition of the AJCC system, a
separate staging system that applies only to well-
differentiated panNETs (WHO system grades
1–3) was developed. Poorly differentiated pan-
Table 1: 2017 WHO Classification of PanNENs
Well-differentiated panNETs
  Functioning tumors
  Insulinoma
  Gastrinoma
  Glucagonoma
  Somatostatinoma
   Vasoactive intestinal peptide tumor
  Serotonin-producing tumor
   Adrenocorticotropic hormone–producing tumor
  Nonfunctioning tumors
  Syndrome-associated panNETs
  MEN1
   VHL disease
   Neurofibromatosis type 1
   Tuberous sclerosis
   Glucagon cell hyperplasia and neoplasia
Poorly differentiated panNECs
  Large cell type panNEC
  Small cell type panNEC
 MiNEN
  Ductal MiNEN
   Acinar MiNEN
Sources.—References 1, 2, 5.
Note.—WHO = World Health Organization.
NECs (WHO grade 3) are staged similarly to
the staging of pancreatic ductal adenocarcinoma
(Table 3) (18,19). Size is the most important
criterion to assign the T category; invasion of
peripancreatic soft tissue has been removed from
the staging criteria (10). Although invasion into
the duodenum and the bile duct suggests assign-
ment of stage T3, the involvement of the adjacent
structures, including the spleen, stomach, colon,
adrenal gland, and major vessels (celiac artery and
superior mesenteric artery) has been categorized
as stage T4 (7,10). Finally, the M1 category has
been subdivided into three stages according to the
metastatic sites (hepatic vs extrahepatic locations
including the lungs, ovaries, nonregional lymph
nodes, peritoneum, and bones) (10).
PanNENs: Role of Imaging
The goals of imaging in patients with panNENs
are many and include detection, characteriza-
tion, and localization of tumors; identification of
malignancy and signs of aggressiveness, resect-
ability, and local-regional spread; and detection
of metastasis and the extent of disease (20,21).
Many small tumors are diagnosed incidentally
during imaging performed for an unrelated di-
agnosis, which has contributed to the increased
incidence of panNENs (22–24). In addition,
RG  •  Volume 40  Number 5 Khanna et al  1243

Table 2: Comparison of WHO 2010 and 2017 Classification Systems for PanNENs

Histopathologic Criteria

WHO 2017 Classification WHO 2010 Classification Mitoses (No.*) Ki-67 PR (%)
Well-differentiated panNET, grade 1 Well-differentiated panNET, grade 1 <2 ≤2
Well-differentiated panNET, grade 2 Well-differentiated panNET, grade 2 20 3–20
Well-differentiated panNET, grade 3 NA >20 >20
Poorly differentiated neuroendocrine Poorly differentiated neuroendocrine >20 >20
carcinoma (small cell carcinoma carcinoma (small cell carcinoma
or large cell endocrine carcinoma), or large cell endocrine carcinoma),
grade 3 grade 3
MiNEN Mixed adenoneuroendocrine carcinoma NA ≥30
Sources.—References 5,8,9.
Note.—NA = not applicable, PR = proliferation rate.
*Per 10 high-power fields.

Figure 1.  Well-differentiated panNET in a 40-year-old man. (a, b) Axial T2-weighted (a) and gadolinium-enhanced
T1-weighted (b) MR images show a well-defined heterogeneously enhancing focal mass (arrow) in the pancreas.
(c) Photograph of the sectioned gross specimen shows a well-defined intrapancreatic tumor with a few foci of hemor-
rhage (arrow). (d) Photomicrograph shows the uniform characteristic organoid and trabecular growth pattern of small
relatively uniform tumor cells, which is consistent with a low-grade tumor. The tumor cells were strongly positive for
chromogranin and had Ki-67 proliferation indices of less than 3 (not shown), which is consistent with a well-differenti-
ated grade 1 panNET. (Hematoxylin-eosin stain; original magnification, 40.)

imaging is pivotal to differentiation of panNENs Anatomic Imaging

from other pancreatic masses such as ductal ad- Both transabdominal US and endoscopic US
enocarcinomas, metastases, and intrapancreatic help in identification of primary tumors and
splenules (25–27). metastatic disease in the liver and lymph nodes
1244  September-October 2020 radiographics.rsna.org

Figure 2.  Poorly differentiated panNEC in a 42-year-old man. (a, b) Coronal T2-weighted MR image (a) and gad-
olinium-enhanced T1-weighted MR image acquired during the portal venous phase (b) show an ill-defined mildly
enhancing mass in the pancreatic head and uncinate process (arrow), with associated dilatation of the main pancre-
atic duct and an enlarged peripancreatic lymph node (arrowhead). The patient underwent pancreatoduodenectomy
(ie, Whipple surgery). (c) Photomicrograph shows irregularly arranged tumor cells with a scant cytoplasm, nuclear
pleomorphism, indistinct nucleoli, high nucleus-to-cytoplasm ratio, and nuclear molding in a background of increased
apoptotic debris. (Hematoxylin-eosin stain; original magnification, 40.) Inset photomicrograph shows that the Ki-67
proliferation index is 80% at immunohistochemical analysis. The pathology findings are consistent with a poorly dif-
ferentiated panNEC. (d) Follow-up coronal contrast-enhanced CT image shows a heterogeneously enhancing mass
in the surgical bed (arrow) and multiple enhancing liver lesions (arrowheads), findings consistent with recurrent and
metastatic disease.

Table 3: Well-differentiated PanNETs: Comparison of the Seventh and Eighth Editions of the AJCC
TNM Staging Systems

TNM
stage AJCC Seventh Edition AJCC Eighth Edition
T1 Tumor limited to the pancreas, ≤2 cm Tumor limited to the pancreas, <2 cm
T2 Tumor limited to the pancreas, >2 cm Tumor limited to the pancreas, 2–4 cm
T3 Tumor extends beyond the pancreas but Tumor limited to the pancreas, >4 cm; or tumor invading
without involvement of the celiac axis the duodenum or common bile duct†
or the superior mesenteric artery*
T4 Tumor involves the celiac axis or the Tumor invading adjacent organs (stomach, spleen, colon,
superior mesenteric artery adrenal gland) or the wall of large vessels (celiac axis or
superior mesenteric artery)
M1 Distant metastasis M1a: Metastasis confined to liver
M1b: Metastasis in at least one extrahepatic site
M1c: Both hepatic and extrahepatic metastases
Sources.—References 10 and 11.
*Includes peripancreatic soft-tissue extension.
†
Peripancreatic soft-tissue extension is not a basis for staging.
RG  •  Volume 40  Number 5 Khanna et al  1245

Figure 3.  Intraoperative US in management of panNEN. (a) Intraoperative US image in a 40-year-old man with an
insulinoma shows a well-defined hypoechoic mass (arrow) in the pancreas and its clear relationship to the adjacent
vessels (arrowheads). (b) Intraoperative US image in a 55-year-old man with hepatic metastasis from panNEC shows a
targetoid lesion in the liver with a central hyperechoic area and a peripheral hypoechoic halo (arrow).

(20,21,28,29). In addition, intraoperative US
is pivotal in surgical planning because it allows
accurate localization of nonpalpable tumors and
assessment of the relationship of the primary
tumor to the main pancreatic duct and adjacent
vessels for decision making regarding enucleation
or distal pancreatectomy and minimization of the
risk of postsurgical fistulas (Fig 3) (30–32).
At Doppler US, panNENs are identified as
well-defined hypoechoic masses with increased
vascularity. Hepatic metastases from panNENs
typically appear hyperechoic. However, hy-
poechoic and targetoid lesions may also be seen
(Fig 3) (33). Endoscopic US is considered the
imaging study of choice for diagnosis of small
occult panNENs that are not detected with
noninvasive modalities. It is also especially help-
ful for detection of insulinomas and gastrinomas
(34–36). In addition, endoscopic US allows
high-yield tissue sampling with adequacy of up to
85% for evaluation of the Ki-67 index and good
correlation with surgical specimen evaluation
results (up to 84%) (37,38). Other advantages
include endoscopically guided tumor ablation,
detection of cystic changes in small tumors, local-
regional staging including metastatic adenopathy,
and tumor relation to the main pancreatic duct
(36,39,40). Endoscopic US is useful in the sur-
veillance of patients with genetic syndromes, such
as MEN1 and VHL (41). Contrast-enhanced en-
doscopic US also helps to identify small tumors
and to allow hypervascular well-differentiated
panNETs to be distinguished from ductal adeno-
carcinomas and panNECs, which are typically
hypovascular (35). Patterns at contrast-enhanced
endoscopic US include uniform enhancement in
tumors with a low Ki-67 proliferation index and
inhomogeneous enhancement in tumors with a
high Ki-67 index (42).
Multidetector CT with the use of a pancreatic
mass protocol is an excellent modality for detec-
tion of panNENs and is preferred over MRI for
assessment of vascular invasion and resectability
(29). At our institution, nonenhanced CT images
are obtained first to allow identification of calci-
fications or hemorrhage. Subsequently, contrast-
enhanced images are acquired after injection of
iodinated intravenous contrast material at 4 mL/
sec in the arterial phase (25–30 seconds) or pan-
creatic parenchymal phase (40–45 seconds) and
portal venous phase (60–70 seconds).
Multiplanar reformation images are obtained
with a section thickness of 3 mm (43) (Table 4).
Sensitivity for detection is in the range of 64%–
81% and is affected by the tumor size and the de-
gree of arterial enhancement. Image acquisition
in different phases after intravenous administra-
tion of contrast material helps in identification of
the lesions based on their enhancement patterns
during different phases; panNENs and associated
metastases are typically hyperenhancing during
the arterial phase and remain mildly hyperat-
tenuating during the portal venous and delayed
phases (Fig 4) (28,29). Sensitivity for detection
of small functioning tumors is high during the
arterial phase (83%–88%) and is lower during
the portal venous phase (11%–76%) (29).
Smaller tumors are homogeneous, while
larger lesions tend to show heterogeneous
enhancement because of cystic degeneration,
necrosis, and calcification. Hepatic and lymph
node metastases are typically hypervascular dur-
ing the arterial phase and hypovascular during
the portal venous phase; ringlike enhancement
is also seen (33,44). Atypical patterns of iso- or
hypoenhancement during the arterial phase and
iso- to hyperenhancement during the portal
venous phase can be seen in some patients with
liver metastases (44). Large nonfunctioning
panNETs may undergo necrosis and degenera-
tive changes with subsequent calcification (45).
Multiplanar reformation is particularly helpful
1246  September-October 2020 radiographics.rsna.org

Table 4: CT and MRI Protocols for Diagnosis and Staging of PanNENs

Pancreatic Mass Protocol Details

Multidetector CT protocol
  Voltage (kVp)
  Effective amperage (mAs)
  Rotation time (sec)
  Detector collimation (mm)
  Section thickness (mm)
 Pitch
  Increment (mm)
 Coverage
  Oral contrast material
  Nonenhanced CT
  Contrast-enhanced CT
  Image acquisition phase
   Arterial (sec)
   Pancreatic parenchymal (sec)
   Portal venous (sec)
  Multiplanar reformation
MRI protocol
  Coronal T2-weighted MRI
  Axial T1-weighted MRI
  Axial T2-weighted MRI
  Diffusion-weighted MRI
  MR cholangiopancreatography
   Two-dimensional radial
  Three-dimensional
  Dynamic contrast-enhanced MRI
   T1-weighted MRI
   Axial contrast-enhanced MRI
   Coronal contrast-enhanced MRI
Sources.—References 29 and 43.
120
200
0.5
1.5
3.0
0.75
1.5
Image from the 11th vertebral body through the iliac crest
Negative oral contrast material (500 mL of water 30 minutes before
examination and 250 mL of water immediately before examination)
…
100–125 mL isomolar or osmolar iodinated contrast material (370 mg/
mL) at 4–5 mL/sec
25–30
40–45
60–70
Axial, sagittal, and coronal planes; section thickness, 3 mm
Single-shot fast spin-echo or steady-state free precession sequence
Dual-echo in- and opposed-phase spoiled gradient-echo sequence
Non–fat-suppressed and fat-suppressed imaging
(b = 0, 50, 400, and 800 sec/mm2)
Breath-hold, fast spin-echo thick-section imaging in multiple planes
Respiratory-gated fast spin-echo parallel imaging with maximum inten-
sity projection reconstructions
Fat-suppressed, three-dimensional gradient-recalled-echo sequences
before and after gadolinium-based contrast agent administration:
dose, 0.1 mmol/kg of body weight; injection rate, 1.5–2 mL/sec (in-
jection duration approximately 5–8 sec)
Arterial (20–40 sec), portal venous (45–65 sec), and equilibrium (3–5
min) phases after injection of contrast agent
Imaging between the portal venous and equilibrium phases (2 min after
injection of contrast agent), parallel to the portal vein bifurcation

for identification of pedunculated lesions, espe-
cially in the body and tail region (46). Improved
sensitivity of up to 95.7% has been reported
with dual-energy or low-energy monochromatic
CT with iodine material decomposition to
provide better contrast between the tumor and
parenchyma (7,29).
Multiphasic MRI before and after admin-
istration of intravenous contrast material and
diffusion-weighted MRI are essential to detec-
tion and characterization of lesions (Table 4).
The sensitivity of MRI in detection of panNENs
is affected by tumor size, with greater than 70%
sensitivity for tumors larger than 2.5 cm and
decreased sensitivity for lesions smaller than 1.5
cm (21,47). Diffusion-weighted MRI has greatly
improved sensitivity that is comparable to that
of PET/CT, for detection of primary lesions and
metastases (48–50). PanNENs are typically hy-
pointense at T1-weighted MRI, are hyperintense
at T2-weighted MRI, and show intense arterial
enhancement. They appear isointense compared
with the adjacent pancreatic parenchyma dur-
ing the portal venous and delayed phases (Fig 5)
RG  •  Volume 40  Number 5 Khanna et al  1247

Figure 4.  Well-differentiated grade 2 panNET in an 83-year-old man. Axial contrast-enhanced CT images of the pan-
creas in the arterial phase (a) and portal venous phase (b) show a well-defined focal mass (arrow) in the pancreas that
demonstrates intense enhancement in the arterial phase and becomes isointense compared with the pancreas in the
portal venous phase. This mass was proven to be a grade 2 panNET at pathologic evaluation.

Figure 5.  Well-differentiated grade 2 panNET in a

47-year-old man. (a, b) Axial T2-weighted (a) and gad-
olinium-enhanced T1-weighted (b) MR images show a
well-defined T2-hyperintense pancreatic mass (arrow)
with heterogeneous enhancement after administration of
contrast material and a T2-hyperintense focus in the liver
parenchyma (arrowhead in a). (c) Axial 68Ga DOTATATE
PET/CT image shows significantly increased uptake in
the mass (arrow) compared with the background, which
suggests the possibility of a well-differentiated mass. This
mass was proven to be a grade 2 well-differentiated pan-
NET during surgical resection.

mm2/sec (51). A higher tumor-to-background

(12,13,29). MRI is helpful in surgical planning
and assessment of the relationship of the tumor
to the main pancreatic duct if enucleation is
planned (13). The tumor size and shape; other
features including the enhancement pattern, vas-
cular invasion, and lymph node metastases; and
diffusion-weighted MRI can help in the predic-
tion of the tumor grade (13). Tumors larger than
2 cm with ill-defined margins that show het-
erogeneous enhancement or hypoenhancement
and low apparent diffusion coefficients (ADCs)
suggest the presence of a high-grade abnormal-
ity. Grades 2 and 3 panNETs can be recognized
by an absolute ADC cutoff value of 1.21  10-3
ADC ratio predicts a lower tumor grade, with
cutoff values of 1.03 for grade 1 tumors (52).
Dynamic contrast-enhanced MRI and diffu-
sion-weighted MRI with additional parameters
such as the volume transfer constant, rate con-
stant, and intravoxel incoherent motion can help
in assessment of change after antiangiogenic
treatment (7). Hepatic metastases typically ap-
pear hyperintense at T2-weighted MRI and show
hyperenhancement during the arterial phase.
A few atypical patterns include heterogeneous
isointensity to intermediate signal intensity at T2-
weighted MRI and hypoenhancement during all
phases or peripheral enhancement with gradual
fill in (53). Various interventions are used to treat
the primary tumor and hepatic metastases of
1248  September-October 2020 radiographics.rsna.org
Figure 6.  Well-differentiated panNET in a 44-year-old
man. (a, b) Axial contrast-enhanced CT images in the
arterial (a) and portal venous (b) phases show an isoat-
tenuating mass (arrow) in the region of the pancreatic
head. (c) Axial 111In-pentetreotide SPECT/CT image
shows increased uptake in the tumor (arrow) in the re-
gion of the head of the pancreas in comparison with
the background. This mass was proven to be a well-
differentiated grade 1 panNET at pathologic evaluation.
panNETs. However, discussion of those tech-
niques is beyond the scope of this article.
Functional Imaging
Although panNENs display a wide spectrum
of biologic behavior, from being functioning
to nonfunctioning and ranging from benign to
malignant, they express an adequate number of
somatostatin receptors, which allows imaging with
nuclear medicine techniques and radiotracers that
are somatostatin analogs. Somatostatin receptor
imaging with somatostatin analog radiotracers
has been at the forefront of imaging panNENs
and is the only validating imaging method that
allows selection of patients for peptide receptor
radionuclide therapy (54). 111In-pentetreotide
SPECT/CT imaging (OctreoScan; Mallinckrodt
Pharmaceuticals, St Louis, Mo) uses the affinity
of the radioactive labeled somatostatin analog to
G-protein–coupled glycoproteins that are associ-
ated with the somatostatin receptors expressed in
50%–80% of panNENs (Fig 6) (55). Studies show
overall sensitivity of 77% for 111In-pentetreotide in
detection of panNENs; however, among patients
with well-differentiated panNETs, sensitivity is
80%, and among patients with poorly differenti-
ated tumors, it is approximately 57% (56).
68
Ga DOTATATE PET/CT with 68Ga-tet-
raazacyclododecane tetraacetic acid (DOTA)–so-
matostatin analog has shown promising results for
detection of small tumors not seen with 111In-
pentetreotide imaging, CT, or conventional MRI.
It is also useful in staging and follow-up to identify
recurrent disease (55,57–60). Additional features
of PET/CT scanners, including improved spatial
resolution and higher sensitivity for photon detec-
tion, make them superior to 111In-pentetreotide
imaging, which has been historically used to
image panNENs and shows overall sensitivity of
77%, depending on the tumor size, the density of
tumor receptors, and the tumor grade (56,61).
DOTATATE PET/CT has 81%–100% sensitivity
and 90%–100% specificity, particularly for well-
differentiated tumors owing to high expression of
somatostatin receptors (Fig 5) (57,58).
Functional imaging with 18F-FDG PET/CT
has shown increased sensitivity for detection of
high-grade and poorly differentiated tumors that
lack adequate somatostatin receptors, with high
standardized uptake values associated with a
higher Ki-67 index (62,63). High-grade tumors
show higher 18F-FDG uptake than that of 68Ga
DOTATATE, with a median maximum standard-
ized uptake value of 11.7 versus 4.3 (Fig 7) (64).
Imaging with 18F-FDG PET/CT is considered
complementary to a 68Ga DOTATATE examina-
tion, and dual imaging may help to predict dis-
ease progression and prognosis (62). Dual-tracer
PET/CT with both 18F-FDG and DOTATATE
can be helpful to assess the tumor metabolic
phenotype and help to differentiate grade 3 pan-
NETs, which show increased uptake with 68Ga-
DOTATATE, from grade 3 panNECs, which
show high uptake at 18F-FDG PET/CT (65).
RG  •  Volume 40  Number 5 Khanna et al  1249

Figure 7.  Well-differentiated grade 3 panNET in a 36-year-old woman. (a) Axial contrast-enhanced CT image
shows a large heterogeneously enhancing mass (arrows) in the head of the pancreas that is causing substantial mass
effect on the adjacent structures. (b) Axial 18F-FDG PET/CT image shows increased FDG uptake in the tumor (arrows).
This mass was proven to be a grade 3 DAXX- or ATRX-mutated panNET at pathologic evaluation.

Figure 8.  Illustration shows the pathogenesis of panNENs. PanNETs develop from mutations in the MEN1, ATRX, DAXX, and mTOR
pathway genes (PTEN, PIK3CA, and TSC2). Mutations of KRAS (Kirsten rat sarcoma viral oncogene), Rb1 (retinoblastoma tumor sup-
pressor gene), SMAD4 (SMAD family member 4 gene), and TP53 (p53 suppressor gene) are seen in panNECs, and they are typically
absent in panNETs.

Genetics and Pathogenesis
of PanNETs
Recent gene-sequencing studies have helped to
broaden the understanding of oncogenic path-
ways that are involved in the development of
panNETs and panNECs and to fuel research
into identification of therapies and clarification of
prognoses (66). Mutations in the tumor suppres-
sor gene (MEN1, which encodes menin protein);
the chromatin-remodeling complex genes ATRX
(α thalassemia/intellectual X–linked disability
syndrome gene) and DAXX (death domain as-
sociated gene); and mTOR (mammalian target
of rapamycin gene) pathway genes PTEN (phos-
phatase and tensin homolog gene), PIK3CA
(phosphatidylinositol-4,5-bisphosphate 3-kinase
catalytic subunit alpha gene), and TSC2 (tuber-
ous sclerosis complex gene) are responsible for the
majority of panNETs (Fig 8). Mutation of DAXX
and ATRX genes results in a phenotype known as
alternative lengthening of telomeres, which increases
cell proliferation (67,68). DAXX mutations in
panNETs also lead to lower levels of TP53, result-
ing in tumor growth. PanNETs with DAXX and
ATRX mutations are associated with intermediate-
and high-grade tumors and show poor prognosis
(66). Hypoxia-inducible factor-1 pathway is the
main regulator of all these genes and is abnormal
in panNETs (69).
Genetics and Pathogenesis
of PanNECs
PanNECs are aggressive poorly differentiated
neoplasms composed of atypical cells with high
1250  September-October 2020 radiographics.rsna.org

Table 5: PanNENs Associated with Hereditary Cancer Syndromes

Familial Syndrome Pancreatic Manifestations

MEN1 syndrome (MEN1 tumor Nonfunctioning tumors (up to 80%)
suppressor gene [chromosome Multifocal gastrinomas (20%–60%)
11q13]) CT and MRI show well-circumscribed intensely enhancing masses
Zollinger-Ellison syndrome: extensive gastric rugal fold thickening
68
Ga DOTATATE PET/CT: highly sensitive, replaces 111In-pentetreotide
Cystic tumors (up to 15% of all panNETs in MEN1): larger, likely benign,
and mostly nonfunctioning
VHL syndrome (VHL gene Pancreatic cysts (50%–70%)
[chromosome 3p25]) Serous cystadenomas (12%)
PanNETs (9%–17%): multiple small (<2 cm) and mostly nonfunctioning tumors
CT and MRI: multiple enhancing solid masses in the pancreatic parenchyma
without involvement of the duodenum
15% of panNETs in patients with VHL are malignant
Neurofibromatosis type 1 Rare; periampullary or duodenal somatostatinomas
Tuberous sclerosis Rare; solid or cystic pancreatic masses in patients with tuberous sclerosis
should raise suspicion for panNETs
Glucagon cell hyperplasia and Multifocal pancreatic glucagon cell hyperplasia, microadenomas, and mac-
neoplasia roadenomas
Sources—References 71 and 72.

mitotic and Ki-67 indices that express general
markers of neuroendocrine differentiation, in-
cluding synaptophysin or chromogranin A, and
are categorized as grade 3 neoplasms per the
WHO classification system (9,15). Histologically,
they can be small cell or large cell types. Tumors
with large cells may be difficult to differentiate
from poorly differentiated pancreatic ductal ad-
enocarcinomas (70). PanNECs are characterized
by TP53 and Rb1 mutations, and less commonly
by KRAS and SMAD4 mutations, which differ-
entiates them from panNETs (Fig 8) (66).
Familial Syndromes Associated
with PanNENs
MEN1 Syndrome
MEN1 syndrome is an autosomal-dominant dis-
order that is caused by germline mutations in the
MEN1 gene and is the most common genetic syn-
drome that is associated with panNETs, account-
ing for approximately 10% of all tumors (Table
5) (71). Multifocal gastrinomas (20%–60%) and
nonfunctioning tumors (up to 80%) are the most
common panNETs in patients with MEN1, ap-
pearing as well-circumscribed intensely enhancing
masses (71). Patients with MEN1 and gastrinomas
may develop Zollinger-Ellison syndrome, which
is characterized by extensive thickening of the
gastric rugal folds at CT and MRI (Fig 9) (73).
PanNETs are the most common cause of disease-
associated mortality in patients with MEN1. 68Ga
DOTATATE PET/CT is sensitive for detection of
smaller panNETs and is replacing other imaging
techniques for the surveillance of MEN1 (Fig 9)
(73). Cystic tumors constitute up to 15% of all
panNETs in patients with MEN1. They are large,
likely benign, and mostly nonfunctioning (74). The
presence of pathologically proven cystic panNETs
should raise suspicion for MEN1 (Fig 10) (74).
VHL Syndrome
VHL syndrome is an autosomal-dominant
disease caused by mutations involving the VHL
gene located at chromosome 3p25 (74). Mul-
tiple simple pancreatic cysts (50%–70%), serous
cystadenomas (12%), and panNETs (9%–17%)
are the common pancreatic manifestations (74).
Approximately 50% of panNETs in patients with
VHL are small (<2 cm). Multiple panNETs are
often seen, and they are mostly nonfunctioning.
Patients with VHL present with panNETs at an
earlier age than do those with sporadic pan-
NETs (Table 5) (72). Multiple enhancing solid
masses in the pancreatic parenchyma, without
the involvement of the duodenum, are character-
istic of panNETs in an individual with a known
VHL mutation or with other manifestations of
VHL such as hemangioblastomas of the central
nervous system, renal cell carcinomas, pancreatic
cysts, and pheochromocytomas (Fig 11) (72).
Up to 15% of panNETs in patients with VHL are
malignant and show local invasion and distant
metastases (commonly to the liver) (Fig 11) (72).
Although small tumors (<2 cm) may be moni-
tored with imaging, masses larger than 3 cm,
rapidly growing tumors, and local-regional lymph
nodes warrant surgery (72).
RG  •  Volume 40  Number 5 Khanna et al  1251

Figure 9.  Multiple panNETs in a 38-year-old woman

with MEN1 and associated Zollinger-Ellison syndrome
due to gastrin overproduction. (a, b) Axial contrast-en-
hanced CT images of the abdomen show multiple hy-
perenhancing tumors (arrows in a) in the pancreatico-
duodenal groove (gastrinoma triangle) and irregularly
thickened gastric rugal folds (arrowheads in b), which
are suggestive of Zollinger-Ellison syndrome. (c) 68Ga
DOTATATE PET/CT image shows increased uptake in
the multiple pancreatic and duodenal masses (arrows),
which is consistent with well-differentiated panNETs.
The masses were proven to be gastrinomas at endo-
scopic US-guided biopsy.

Figure 10.  Cystic panNET in a 52-year-old woman with MEN1. Axial T2-weighted (a) and gadolinium-enhanced
T1-weighted (b) MR images show a T2-hyperintense cystic mass in the pancreatic tail, with an irregularly thickened
wall and irregular rim enhancement (arrow). This mass was proven to be a well-differentiated grade 1 cystic panNET
at pathologic evaluation.

Rare Hereditary Cancer Syndromes tion may be considered, as clinically warranted

PanNETs are rare manifestations of neurofibro-
matosis type 1, tuberous sclerosis, and glucagon
cell hyperplasia and neoplasia (Table 5) (74).
Although rare, periampullary and/or duodenal
somatostatinomas can be seen in patients with
neurofibromatosis type 1 (75). PanNETs, either
functioning or nonfunctioning, are the most
common pancreatic lesions in patients with
tuberous sclerosis; the presence of solid or cystic
pancreatic masses in tuberous sclerosis should
raise the suspicion of panNETs, and resec-
(76).Glucagon cell hyperplasia and neopla-
sia syndrome are characterized by the lack of
functional glucagon, which leads to multifocal
pancreatic glucagon cell hyperplasia, microad-
enomas, and macroadenomas (77).
Functioning PanNETs
Functioning panNETs are characterized by exces-
sive hormonal secretion and resulting clinical syn-
dromes. These are well-differentiated indolent tu-
mors, with a good prognosis (2). Clinical features
1252  September-October 2020 radiographics.rsna.org

Figure 11.  PanNENs in two patients with VHL syndrome. (a) Axial gadolinium-enhanced T1-weighted MR image in a
34-year-old man with VHL syndrome shows multiple hyperenhancing masses (arrows) that are suggestive of panNETs. A few
cysts (arrowhead) are also seen in the right kidney. (b) Axial gadolinium-enhanced T1-weighted MR image in a 25-year-old
man with VHL syndrome shows a heterogeneously enhancing mass (arrow) in the pancreas. This mass was proven to be a
high-grade panNEC at surgical resection.

and laboratory data are pivotal in their appropriate

diagnosis (9). Insulinomas are the most common
functioning panNETs and are usually detected
when they are small (<1 cm). Approximately 10%
of patients have multiple insulinomas, and they are
typically associated with MEN1 syndrome (1,2).
At CT or MRI, insulinomas are usually homo-
geneous and demonstrate intense enhancement
that is best seen during the arterial or pancreatic
parenchymal phase. Insulinomas may demonstrate
a pedunculated appearance (Fig 12) (12,33,46).
Insulinomas carry the best prognosis among the
panNETs (1,2). Gastrinomas are the second
most common functioning panNETs and are
usually located in the gastrinoma triangle, which is
bordered by the junction of the second and third
parts of the duodenum, the pancreatic head and
neck, and the confluence of the cystic duct and
the common bile duct (1,2). Multiple gastrino-
mas are the most common functioning panNETs
in patients with MEN1 syndrome (9). At CT or
MRI, gastrinomas show diffuse homogeneous or
ringlike enhancement. The presence of marked
thickening of the gastric fold and ulcers suggests
the presence of Zollinger-Ellison syndrome (Fig
9) (12,78). Up to 90% of tumors are malignant,
with metastases to the liver (74). 68Ga-DOT-
ATATE PET/CT is helpful and shows intense
uptake in gastrinomas (Fig 9) (12).
Nonfunctioning PanNETs
Up to 80% of panNETs are nonfunctioning
tumors and are being increasingly discovered at
imaging that is performed for other reasons. Al-
though they produce no clinical signs of hormonal
excess, tumors may secrete a precursor hormone
that is functionally inert or occurs in amounts that
are too small to be clinically relevant (7). These
tumors often manifest later in the course of the
Figure 12.  Insulinoma in a 35-year-old woman. Axial
contrast-enhanced CT image of the pancreas shows a small
well-defined hyperenhancing pedunculated mass (arrow)
in the pancreatic tail. This tumor was proven to be an insu-
linoma at surgical resection.
disease, with symptoms of local compression or
metastasis, and are commonly large (1). At CT or
MRI, tumors are larger and show heterogeneous
enhancement, with areas of necrosis and cystic
changes. A larger size correlates with aggressive
behavior, including local and vascular invasion and
metastases (Fig 13) (24,33).
Well-differentiated PanNETs:
Imaging Spectrum
Well-differentiated grade 1 and grade 2 panNETs
are typically small (<3 cm) well-circumscribed
hypervascular masses with intense homogeneous
enhancement in the arterial and portal venous
phases; the degree of homogeneity and enhance-
ment correlates with tumor grade (Figs 1, 4,
6) (79,80). They show signal hypointensity at
T1-weighted MRI and signal hyperintensity at
T2-weighted MRI, without substantial diffusion
restriction or distant metastases (21). Grade 1
panNETs show more arterial hypervascularity
RG  •  Volume 40  Number 5 Khanna et al  1253

Figure 13.  Well-differentiated grade 2 nonfunctioning panNET in a 40-year-old woman. Axial nonenhanced (a) and
contrast-enhanced (b) CT images of the pancreas show a relatively ill-defined isoattenuating to hypoattenuating mass
(arrow in a) in the pancreatic tail that shows homogeneous enhancement after administration of contrast material (ar-
row in b). This mass was proven to be a grade 2 well-differentiated nonfunctioning panNET at pathologic evaluation.

Well-differentiated grade 3 panNETs are

Figure 14.  Well-differentiated grade 3 panNET in a 48-year-
old man with VHL syndrome. Axial contrast-enhanced CT
image of the pancreas shows a heterogeneously enhancing
mass (arrow) involving the head and uncinate process of the
pancreas, with scattered areas of central necrosis that are
displacing adjacent structures. This mass was proven to be
a grade 3 well-differentiated panNET at surgical resection.
with higher CT perfusion parameters such as
blood flow and higher volume transfer constants
at perfusion MRI than do tumors of other grades,
which helps in differentiation of grades 1, 2, and 3
panNETs (20). In addition, grade 1 tumors show
higher ADCs than do grade 2 and grade 3 tumors
and show higher ADC ratios (ADC tumor/ADC
pancreas) at diffusion-weighted MRI (20,51,52).
Grade 1 and grade 2 panNETs are also typically
solid, with the exception of cystic panNETs that
commonly occur in patients with MEN1 syn-
drome (81). Although small tumors are not typi-
cally associated with pancreatic ductal obstruction
and dilatation, some panNETs may manifest with
fibrotic stricturing of the main pancreatic duct be-
cause of serotonin secretion, which results in up-
stream pancreatic ductal dilatation and parenchy-
mal atrophy (82,83). Pancreatic ductal dilatation
is more often seen with panNECs and pancreatic
ductal adenocarcinomas than with panNETs and
can be used as a distinguishing feature (84,85).
large (>3 cm) masses with irregular margins that
show low to moderate enhancement in the arte-
rial phase and appear hypointense in the portal
venous phase (Figs 7, 14) (21). They appear het-
erogeneous, with areas of necrosis, cystic change,
and ductal involvement. They demonstrate low
to intermediate signal intensity at T2-weighted
MRI, with increased diffusion restriction (21,86).
Peripancreatic lymphadenopathy and distant
metastases (commonly to the liver) are very com-
mon in grade 3 panNETs (7).
Poorly Differentiated PanNECs:
Imaging Spectrum
Poorly differentiated panNECs are typically large
hypoenhancing masses that show heterogeneous
enhancement, with ill-defined margins. Tumors
commonly show cystic changes, calcification, and
necrosis (Figs 2, 15) (7). Additional morphologic
features that are associated with panNECs include
vascular invasion with tumor extension into a vein,
upstream pancreatic ductal dilatation, and nodal
and hepatic metastases (21). Multiphasic pancre-
atic imaging shows atypical enhancement pat-
terns such as tumor hypovascularity in the arterial
phase, heterogeneous or rimlike enhancement in
the arterial phase, persistent enhancement in the
portal venous phase, and hyperenhancement in
the delayed phase (21,29). Tumors with early en-
hancement and a plateau or progressive enhance-
ment are more likely to be associated with a poor
prognosis and higher amounts of fibrosis than are
those with early rapid enhancement with washout
(7). Although atypical enhancement patterns and
morphologic features may overlap with those of
pancreatic ductal adenocarcinoma, contiguous tu-
mor extension into a vein is more commonly seen
in panNECs than in adenocarcinomas (21). Pan-
NECs show signal hypointensity at T1-weighted
1254  September-October 2020 radiographics.rsna.org

Figure 15.  Poorly differentiated high-grade panNEC in a 53-year-old man. Coronal T2-weighted (a) and axial diffusion-
weighted (b = 800 sec/mm2) (b) MR images, corresponding ADC map (c), and axial gadolinium-enhanced T1-weighted
MR images (d, e) show an ill-defined mass (arrow in a–d) with mild T2 signal hyperintensity (arrow in a) involving the
head and uncinate of the pancreas, which also show substantial diffusion restriction (arrow in b). The mass is diffusely
hypoenhancing (arrow in d) after administration of contrast material, and there are multiple liver metastases (arrowheads
in e). Also note the substantial pancreatic parenchymal atrophy and the main pancreatic ductal dilatation (arrowhead in
a), which mimic pancreatic ductal adenocarcinoma. The patient underwent Whipple surgery (pancreatoduodenectomy),
and the mass was proven to be a poorly differentiated grade 3 panNEC with Ki-67 proliferation of 70%.

MRI and moderate signal hyperintensity at T2-

weighted MRI in comparison with the pancreatic
parenchyma and are associated with lower ADCs
at diffusion-weighted MRI (29).

Well-differentiated Grade 3 PanNETs

versus Poorly Differentiated Grade 3
PanNECs
Although panNECs show aggressive biologic
behavior and have poor survival outcomes that
are not affected by the surgical approach, grade 3
panNETs with a lower Ki-67 index (21%–55%)
have a better prognosis with the use of an aggres-
sive surgical approach (47). Although differentia-
tion of grade 3 panNECs from grade 3 panNETs
based on imaging findings alone is difficult,
certain imaging characteristics favor a diagnosis
of panNEC over panNET (87). Compared with
grade 3 panNETs, panNECs are larger, with ir-
regular margins; appear invasive; and show ductal
dilatation, heterogeneous or rimlike enhance-
ment in the arterial phase, and hypoenhancement
in the portal venous phase, with a lower portal
enhancement ratio (attenuation of the tumor
compared with that of the pancreatic parenchyma
during the portal venous phase) of less than 1.02;
and are associated with lymph node and hepatic
metastatic disease (7). PanNECs show signal hy-
perintensity at diffusion-weighted MRI, with low
ADCs compared with grade 3 panNETs (86). Al-
though grade 3 panNETs have a low uptake rate
of 30% at 18F-FDG PET/CT, grade 3 panNECs
have an uptake rate of more than 80% (87). 111In-
pentetreotide reveals the expression of somatosta-
tin receptors in up to 90% of grade 3 panNETs,
compared with only 50% uptake in panNECs
(87). Given the lack of differentiation and low
RG  •  Volume 40  Number 5 Khanna et al  1255

Figure 16.  Well-differentiated grade 2 panNET in a 71-year-old woman. Axial contrast-enhanced CT images of the
pancreas in the arterial (a) and portal venous (b) phases show a pancreatic mass (arrows) with heterogeneous enhance-
ment in the arterial phase that demonstrates washout in the portal venous phase. The mass was proven to be a well-
differentiated grade 2 panNET with ATRX and DAXX mutations at pathologic evaluation.

somatostatin receptors, 68Ga DOTATATE PET/
CT also shows decreased uptake in panNECs
and moderate uptake in grade 3 panNETs (87).
Mixed Neuroendocrine-
Nonneuroendocrine Neoplasms
According to the 2017 WHO classification system,
mixed adenoneuroendocrine carcinomas have
been renamed as mixed neuroendocrine-nonneuroen-
docrine neoplasms (MiNENs) (7,88). These are rare
malignancies with aggressive biologic behaviors,
and they contain both endocrine and nonendo-
crine cell types, with each tumor cell type account-
ing for more than 30% of the overall tumor cell
population and both components classified as high
grade at pathologic evaluation (88). Ductal and
acinar type MiNENs are the most common (2)
and are aggressive entities with frequently poorly
differentiated high-grade neuroendocrine compo-
nents, resulting in poor survival (88).
Although the two components may have a
common monoclonal origin, with mutations of
tumor-associated genes such as TP53, BRAF, and
KRAS; microsatellite instability; and molecular
aberrations; the pathogenesis remains controver-
sial (88). Although their imaging appearance is
nonspecific, miNENs generally are large (>5 cm)
and manifest as local invasion, distant metastases,
and lymphadenopathy and mimic high-grade
panNECs (88). The management strategy is
based on the most aggressive component. Tissue-
sampling of the metastatic lesion is warranted,
because it usually arises from only one of the two
components. Additional biopsy of distant, recur-
rent, or rapidly progressing metastases is recom-
mended (88).
Radiogenomics of PanNETs
DAXX and ATRX gene mutations are identified
in up to 40% of panNETs, which typically occur
late in tumor development, resulting in alterna-
tive lengthening of telomeres and positive pheno-
types, and are associated with intermediate- and
high-grade tumors (3,66). Compared with those
that are negative, panNETs that are positive for
alternative lengthening of telomeres are strongly
associated with large tumor size (>3 cm), pan-
creatic duct dilatation, and hepatic metastasis,
and they correspond to aggressive behavior, high
tumor grade, and resultant poor prognosis (Figs 7,
16) (89). A lobulated or irregular shape, necrosis,
intratumoral calcifications, and vascular invasion
are also seen in panNETs that are positive for al-
ternative lengthening of telomeres (89). This infor-
mation can be useful for prognosis and is impor-
tant in guiding treatment and exploring specific
chemotherapeutic agents that target the alternative
lengthening of telomeres pathway (89).
Mimics of PanNENs
Hypervascular pancreatic and peripancreatic
neoplastic and nonneoplastic entities can mimic
panNENs at imaging. Also, given the irregular
margins and hypovascular appearance, poorly
differentiated panNECs mimic pancreatic ductal
adenocarcinoma.
Hypervascular metastases to the pancreas
from primary malignancies such as renal cell
carcinoma, thyroid cancer, and melanoma may
resemble panNENs at imaging (Fig 17) (25,26).
Serous microcystadenoma or cystadenocar-
cinoma with avidly enhancing hypervascular
stroma may appear solid at CT, mimicking pan-
NENs. The presence of a central scar and subtle
septa or a microcystic appearance at MRI and
the absence of uptake at 68Ga DOTATATE PET/
CT suggest the diagnosis of a serous cystic neo-
plasm (Fig 18) (27). Pancreatic cystic neoplasms
such as intraductal papillary mucinous neo-
plasms and mucinous cystic neoplasms mimic
1256  September-October 2020 radiographics.rsna.org

cystic panNETs; endoscopic US–guided fine

needle aspiration helps in the diagnosis (81).
An intrapancreatic-peripancreatic accessory
splenule is typically seen in or around the dis-
tal 3 cm of the pancreatic tail and can mimic
hypervascular panNETs. Splenules appear as
signal isointensity in comparison to the spleen
at T1-weighted, T2-weighted, and contrast-
enhanced MRI, with a serpiginous or arciform
enhancement pattern (Fig 19) (13). Increased
uptake at technetium 99m (99mTc)-labeled sulfur
colloid or 99mTc-labeled heat-damaged red blood Figure 17.  Hypervascular metastases to the pancreas from
cell–tagged imaging helps to identify splenic tis- renal cell carcinoma that mimic a panNET in a 68-year-old
man. Axial contrast-enhanced CT image shows a hyperen-
sue, although endoscopic US–guided fine needle hancing focal mass (arrow) in the head of the pancreas.
aspiration may be necessary in select cases with Also note the postnephrectomy changes on the left side.
inconclusive findings at MRI or nuclear imag- This mass was proven to be metastatic disease at endo-
ing (13). Peripancreatic gastrointestinal stromal scopic US-guided biopsy.
tumors that arise from the second portion of the
duodenum and peripancreatic paraganglioma
may also mimic panNENs at imaging (Fig 20)
(13). A splenic artery loop can also mimic solid
hypervascular lesions. However, enhancement
patterns that are similar to those of the artery and
its appearance on multiple planes at imaging is
diagnostic. A well-defined margin and hyperen-
hancement or isoenhancement in the portal ve-
nous phase are useful MRI features that are more
common in nonhypervascular panNETs and may
help in discrimination of them from pancreatic
ductal adenocarcinoma (90).
Figure 18.  Serous cystadenocarcinoma mimicking a pan-
Management of PanNENs NEC in a 35-year-old woman. Axial contrast-enhanced CT
Tumor grading and differentiation per the WHO image of the pancreas shows a large heterogeneously en-
classification system and the AJCC staging hancing mass (arrows) in the pancreas that is causing sub-
system are the most important determinants in stantial mass effect on the adjacent structures and is encas-
ing the superior mesenteric artery. This mass was proven to
selection of the appropriate treatment for patients
be serous cystadenocarcinoma at CT-guided biopsy.
with panNENs. The treatment options for well-
differentiated grade 3 panNETs are distinct from
those for poorly differentiated grade 3 panNECs of the tumor (7,12). Aggressive surgical resec-
(7). Based on the clinical features and pathologic tion and tumor debulking are also considered in
and imaging findings, active surveillance with symptomatic patients with advanced metastatic
follow-up imaging, surgical resection, chemother- disease (92). Liver transplantation should be
apy, and radiation therapy are the available treat- reserved for patients with widespread hepatic
ment options for panNENs. Partial hepatectomy, metastases (93).
image-guided ablation, transarterial chemoembo- The mTOR inhibitor everolimus and the
lization, and radioembolization with radioactive tyrosine kinase inhibitor sunitinib have shown
yttrium 90 (90Y) microspheres are helpful in the promise in progression-free survival in patients
treatment of hepatic metastases (Fig 21) (7,12). with grade 3 well-differentiated panNETs with
Complete surgical resection with regional metastatic disease (94). Chemotherapeutic
lymph node dissection is the treatment of choice regimens such as cisplatin with etoposide or
for well-differentiated grade 1 and grade 2 pan- cisplatin with irinotecan are recommended in
NETs and should be considered for all patients poorly differentiated panNECs (91,95). Hijioka
with early-stage disease (91). Although small et al (96) found a response rate of 61.3% to this
(<1.5 cm) low-grade nonfunctioning panNETs treatment regimen, which was significantly better
can be conservatively managed with follow-up in panNECs with loss of retinoblastoma protein
imaging, surgical resection is a preferred choice expression and KRAS mutation in comparison
for functioning and larger nonfunctioning pan- with those with preserved retinoblastoma expres-
NETs if possible, depending on the size and stage sion and no KRAS mutations.
RG  •  Volume 40  Number 5 Khanna et al  1257

Figure 19.  Intrapancreatic splenule mimicking a pan-

NET in a 50-year-old man. Axial T2-weighted image (a)
and gadolinium-enhanced T1-weighted MR images of
the pancreas in the arterial (b) and portal venous (c)
phases show a mildly T2-hyperintense well-defined
round lesion (arrows in a) in the pancreatic tail that
appears similar to the spleen. This lesion demonstrates
serpiginous enhancement in the arterial phase (arrow
in b) and homogeneous enhancement in the portal ve-
nous phase (arrow in c), similar to the adjacent splenic
parenchyma (arrowhead in b and c). These findings are
consistent with an intrapancreatic splenule.

a somatostatin analog, octreotide, is used as a

Figure 20.  Retroperitoneal paraganglioma mimicking
a panNEC in a 38-year-old woman. Coronal contrast-
enhanced CT image of the abdomen shows a hetero-
geneously enhancing mass (arrow) in the region of the
pancreatic head. At pathologic evaluation, this mass
was proven to be a retroperitoneal paraganglioma with
succinate dehydrogenase B (SDHB) gene mutation aris-
ing in the peripancreatic region.
PET/CT can help to guide the initial man-
agement of advanced or metastatic well-differ-
entiated panNETs. Depending on the degree
of differentiation, peptide receptor radionuclide
therapy with somatostatin analogs or chemo-
therapy is used frequently as the first choice of
treatment in these patients (97). Peptide receptor
radionuclide therapy is a novel concept in which
carrier molecule to deliver radionuclides such as
90
Y and lutetium 177 (177Lu) to the target tumor
cells with abundant somatostatin receptors. This
enables radioactivity in proximity to the nucleus,
leading to marked improvements in outcomes
compared with those of conventional therapies
(97,98). Peptide receptor radionuclide therapies
decrease tumor size and improve biochemical
and symptomatic manifestations in grade 3 pan-
NETs, with impressive outcomes, as shown in
progression-free survival and overall survival rates
compared with those of other therapies (99,100).
PanNECs may be less responsive to peptide
receptor radionuclide therapy because of lower
somatostatin receptors expression (101).
Natural History and
Prognosis of PanNENs
In comparison with pancreatic ductal adenocar-
cinoma, which shows a 5-year survival rate of less
than 7%, panNENs, including those in patients
with advanced disease, have a better prognosis,
likely because patients with panNENs tend to
have a higher proportion of well-differentiated
tumors and tend to be younger at diagnosis and
present earlier in the course of the disease than
do patients with pancreatic ductal adenocar-
cinoma (102). The tumor grade at pathologic
evaluation, the AJCC stage, and the presence
of metastatic disease are the most important
1258  September-October 2020 radiographics.rsna.org
Figure 21.  Flowchart demonstrates management of panNENs.
prognostic factors (7). Most small nonfunction-
ing panNENs do not increase in size and seldom
show metastasis during follow-up studies (103).
Tumors with early enhancement and a plateau
or progressive enhancement are more likely to
be associated with a poorer prognosis and higher
amounts of fibrosis compared with those that
show early rapid enhancement with washout (7).
Lymph node metastases, extrapancreatic exten-
sion, intratumoral calcifications, and hypoen-
hancement during the portal venous phase are
independent prognostic factors for poor survival
(104). Lobular shape, poorly defined margins,
cystic components, intratumoral blood vessels in
the early arterial phase and smooth rim enhance-
ment in the delayed phase, greater pancreatic
and bile duct dilatation, peripancreatic tissue
or vascular invasion, and lymphadenopathy and
distant metastasis were associated with higher-
grade tumors (105,106). Arterially hypoenhanc-
ing well-differentiated panNETs are associated
with an aggressive phenotype, including necrosis,
lymph node and liver metastases, and an overall
poor prognosis (107).
Future Directions
Identification and characterization of distinct
genetic mutations and clarification of specific
tumor pathways of panNENs have led to better
staging paradigms and improved patient triage,
treatment, and prognostication. Future areas
of research with profound clinical implications
include correlation of imaging findings with the
biologic aggressiveness of tumors, standardization
of quantitative and volumetric assessment of tu-
mor burden, optimization of imaging modalities
and techniques for screening and surveillance,
and identification of imaging findings to serve as
biomarkers of treatment response assessment.
Although 68Ga-DOTATATE has transformed
imaging of panNENs because of improved sensi-
tivity, it is limited by a low production yield, the
relatively short half-life of 68Ga, and low spatial
resolution. Radiolabeled tracers such as 68Ga-
satoreotide trizoxetan (OPS202) and curium
64 (64Cu)-1,4,8,11-tetraazacyclotetradecane-
1,4,8,11-tetraacetic acid (TETA)-octreotide may
be more effective because of higher affinity for so-
matostatin receptors, different biodistribution, and
reduced organ doses for the liver, the gastrointes-
tinal tract, the pancreas, the lungs, and the spleen,
leading to the improved tumor-to-background
ratio (108,109). Newer techniques and radiotrac-
ers may be important in future PET/CT imaging
and targeted radionuclide therapy.
Evolving knowledge about the genetics of pan-
NENs has fueled research in developing targeted
agents to treat these tumors. Various new che-
motherapeutic agents that target specific path-
ways are being tried to treat advanced tumors. A
multitargeted receptor tyrosine kinase inhibitor
(sunitinib) and an MTor inhibitor (everolimus)
RG  •  Volume 40  Number 5 Khanna et al  1259
have shown efficacy and safety in treatment of
patients with advanced or metastatic unresect-
able panNETs (110,111). New trials focusing on
tumors that are resistant to somatostatin analogs
are being explored. Additional treatment options,
including immunotherapy and targeted monoclo-
nal antibodies for bone metastases, are increas-
ingly pursued (112,113).
Conclusion
On the basis of recent advances in the genetics,
pathologic evaluation, and molecular biology of
panNENs, the 2017 WHO classification system
and the eighth AJCC staging system have made
substantial changes in the grading and staging
systems that guide appropriate therapeutic strate-
gies and better prognostication. Well-differentiated
panNETs differ substantively from poorly differ-
entiated panNECs in tumor genetics, histomor-
phologic and imaging findings, treatment strate-
gies, and prognoses. Imaging is essential to the
diagnosis, surveillance, and follow-up of patients
with panNETs and panNECs. New radioactive
isotopes such as 68Ga DOTATATE help in the
detection of occult disease and provide better
evaluation of the overall tumor burden. Radiola-
beled agents are being used to target tumor cells
that express specific receptors and deliver local-
ized radiation. Gene sequencing techniques have
improved our knowledge of tumor pathogenesis,
which has opened new avenues of research on
targeting oncogenic pathways with the use of new
therapeutic strategies. Imaging is crucial to testing
the efficacy of novel drugs. Knowledge of recent
updates in the pathogenesis, classification, and
staging of panNENs and familiarity with their
imaging findings permit optimal patient treatment.
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