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16 Pancreatic Ductal Adenocarcinoma
74. Xiong J, Szatmary P, Huang W, et al. Enhanced recovery after surgery program in patients
undergoing pancreaticoduodenectomy: a PRISMA-compliant systematic review and metaanalysis. Medicine (Baltimore). 2016;95(18):e3497.
75. Pilgrim CH, Tsai S, Evans DB, Christians KK. Mesocaval shunting: a novel technique to
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76. Christians KK, Pilgrim CH, Tsai S, et al. Arterial resection at the time of pancreatectomy for
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77. Fortner JG.Regional resection of cancer of the pancreas: a new surgical approach. Surgery.
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Chapter 17
Pancreatic Neuroendocrine Neoplasms
AllenA.Razavi, JaewonLee, andAlexandraGangi
Introduction
Pancreatic neuroendocrine neoplasms (PNEN), also previously known as pancreatic neuroendocrine tumors (PNET), originate from islet cells of the pancreas and
represent a small percentage of pancreatic malignancies, around 1–3%. Interestingly,
their incidence is increasing and attributable to the improved detection with advances
in imaging technology [1]. PNEN as a group are quite heterogeneous and can be
classied based on functional status, biologic behavior, and risk for development
(sporadic vs secondary to inherited syndrome). Ninety percent of PNEN are sporadic but 10% are noted to occur in the setting of hereditary syndromes, most commonly multiple endocrine neoplasia type 1 (MEN1), von-Hippel-Lindau syndrome
(VHL), and neurobromatosis 1 (NF1) [2]. The age of onset for PNEN varies based
on hereditary (earlier in life) versus sporadic presentation, but most often occurs
between the ages of 40 and 60years [3]. The etiology of sporadic PNEN is unclear
but recently assumed to be secondary to point mutations commonly associated with
four main pathways: chromatin remodeling, DNA damage repair, activation of
mTOR, and telomere maintenance [2–4].
Diagnosis
PNEN can be classied as functional versus nonfunctional based on clinical manifestation. In general, PNEN typically have an indolent course and are difcult to
diagnose with mean time to diagnosis from symptom onset of approximately
A. A. Razavi · J. Lee · A. Gangi (*)
Department of Surgical Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
e-mail: Armin.Razavi@cshs.org; Jaewon.Lee@cshs.org; Alexandra.Gangi@cshs.org
Switzerland AG 2025
E. P. Ceppa et al. (eds.), The SAGES Manual of Evolving Techniques in
Pancreatic Surgery, https://doi.org/10.1007/978-3-031-78409-5_17
295© The Author(s), under exclusive license to Springer Nature
296
A. A. Razavi et al.
8–10years, especially for nonfunctional tumors [5]. Patients with functional PNEN
present with characteristic syndromes and physiologic derangements based on the
hormone(s) they secrete and will be described later in this chapter. Nonfunctional
PNEN are generally found incidentally on imaging but can present with symptoms
of local disease related to their size: mass effect, pain, bleeding, and/or sequela of
biliary obstruction. Once there is suspicion for a PNEN, patients should be thoroughly screened for tumor symptoms with detailed personal and family history to
assess for hereditary syndromes. Additionally, patients should have biochemical
testing to assist with diagnosis and be appropriately staged with cross-sectional
imaging (CT/MRI/Gallium DOTATATE scan) to localize primary tumor and evaluate for metastatic disease [6].
After a thorough history is obtained, if a functional PNEN is suspected, evaluation of elevated hormone or peptide levels is essential for the diagnosis of functional
PNEN (Table17.1). In the absence of symptoms to suggest a functional PNEN, a
full hormonal workup is not needed as is unlikely to assist with diagnosis.
Chromogranin A (CgA) is one of the most sensitive markers for nonfunctional
PNEN [7]. Elevated CgA has been correlated with tumor burden and can be useful
for surveillance in the postoperative state. Unfortunately, CgA is a nonspecic test
for PNEN as it may be inuenced by specic food intake, hepatic/renal insufciency, cardiac decompensation, as well as use of proton pump inhibitors. Therefore,
it is important to corroborate elevated CgA with imaging and not use the CgA level
as a diagnostic tool [8].
Table 17.1 Table of functional PNEN and their associated characteristics
Incidence
Tumor/syndrome
Insulinoma 1–3 Insulin Hypoglycemia after fasting with relief
Gastrinoma 0.5–2 Gastrin and gastric pH Zollinger-Ellison syndrome: GERD,
VIPoma 0.05–0.02 Vasoactive intestinal
Glucagonoma 0.01–0.1 Glucagon Necrotic migratory erythema, weight
Somatostatinoma Very rare Somatostatin Hyperglycemia, cholestasis, diarrhea/
ACTHoma Very rare Adrenocorticotropic
GRHoma Very rare Gonadotrophin-
Hypercalcemia Very rare Parathyroid hormone-
per 10
6
Biomarker Symptoms
peptide
hormone
releasing hormone
related protein
of symptoms with glucose
abdominal pain, diarrhea, duodenal
ulcers, PUD
Verner-Morrison syndrome: Watery
diarrhea, hypokalemia, achlorhydria
loss, hypoalbuminemia, diabetes/
glucose intolerance
steatorrhea
Cushing syndrome
Acromegaly
Hypercalcemia, abdominal pain,
constipation, kidney stones,
psychiatric disturbances, increased
urination
17 Pancreatic Neuroendocrine Neoplasms
297
Imaging
Tumor localization is the next step in workup after a thorough history and physical
exam and targeted diagnostic studies. As mentioned earlier, PNEN may be incidentally identied on imaging studies. For further imaging workup, a combination of
either dual/triple phase CT or MRI and DOTATATE PET/CT, with possible upper
endoscopic ultrasound (EUS), may be used to evaluate and diagnose PNEN.CT
triple phase with IV contrast is the most common initial imaging study and can
provide diagnostic data if obtained correctly. On CT, PNEN are typically well circumscribed and hyperattenuating because of their vascularity. They are best seen in
early arterial phases with a bright signal with early portal venous washout. The
sensitivity of localizing PNEN with a CT scan is reported to vary between 63% and
83%. MRI is also considered a rst-line imaging modality in detecting PNEN.On
MRI, PNEN are classically described as low signal intensity on T1-weighted images
and high signal intensity on T2-weighted images. The overall sensitivity of MRI for
PNEN detection is between 80% and 90% and related to tumor size [9]. If CT or
MRI does not yield adequate results, or if a biopsy is required, endoscopy with EUS
can be performed. On EUS, PNEN are described as well-dened hypoechoic homogeneous lesions with occasional cystic components. EUS’s prime utility is localizing lesions <2 cm, which is where conventional CT and MRI imaging may fall
short. In addition, at the time of EUS, tissue acquisition via ne needle aspiration
(FNA) can provide a diagnosis and histological grade prior to treatment. EUS limitations include operator skill and occasionally poorly visualized pancreatic masses
given the variations in pancreatic parenchyma in patients.
Somatostatin receptor scintigraphy (SRS) is another imaging modality that utilizes the prevalence of somatostatin receptors in most neuroendocrine neoplasms to
aid in targeting and visualization. The radiolabeled somatostatin that is administered is picked up by PNEN expressing somatostatin receptors and can theoretically
detect lesions with high sensitivity. Unfortunately, SRS is not accurate and may not
show the exact location of the tumor or adequately provide size. For these reasons,
DOTATATE PET/CT scan has now become the imaging study of choice for detecting PNEN with specicity climbing to 97%. The DOTATATE labeled radioisotope
binds with extremely high afnity to the somatostatin receptor and provides superior spatial resolution as compared to the prior modalities, allowing for improved
lesion identication [10]. If the aforementioned studies fail to localize the tumor,
selective angiography can be used. Angiography utilizes the hypervascular nature of
most PNEN, showing a characteristic blush on imaging, though this diagnostic
modality is rarely utilized [9, 11, 12].
298
A. A. Razavi et al.
Biology andInherited Syndromes
The majority of PNEN occur sporadically but some are associated with genetic
syndromes. Patients with genetic syndromes linked to the development of PNEN
are generally diagnosed earlier and often develop multiple neoplasms rather than
the solitary lesions seen in sporadic disease. In addition, patients with an inherited
syndrome tend to have a more prolonged indolent course when compared to sporadic tumors and may benet from specic treatment targets that are not suitable for
the sporadic subtypes [13].
MEN1 is an autosomal dominant disorder and the most common genetic syndrome linked to PNEN.MEN1 is caused by mutations in MENIN (a tumor suppressor on chromosome 11q13 that is key in control of G1 to S phase cell cycle
progression) and is characterized by development of parathyroid adenomas/hyperplasia, PNEN, and pituitary adenomas. Malignant PNEN have been reported as the
most common cause of death in patients with MEN1. Nonfunctional PNEN are the
most prevalent type of neoplasm in patients with MEN1. The most recent Endocrine
Society clinical practice guidelines for MEN1 recommend biochemical screening
for insulinoma at age 5 and gastrinoma at age 20, with annual imaging (MRI/CT/
EUS) for nonfunctional PNEN starting before 10years old [14].
Von Hippel-Lindau (VHL) is another autosomal dominant syndrome linked to
PNEN and characterized by mutations in the VHL gene leading to both malignant
and benign tumors and cysts of the central nervous system, retina, kidneys, pancreas, and gastrointestinal tract. The prevalence of PNEN in VHL patients is 5–17%,
and diagnosis of a PNEN has a favorable prognosis when compared to sporadic
PNEN.Current recommendations from the VHL Alliance guidelines include surveillance MRI of the abdomen starting at age 15 performed every 2years [15].
Another autosomal dominant condition that may lead to PNEN development is
neurobromatosis- 1 (NF-1). NF-1 results in lack of function of neurobromin, a
tumor suppressor protein, leading to increased risk for neurobromas, pheochromocytomas, and gastrointestinal stromal tumors. Somatostatinomas are the most common type of PNEN in patients with NF-1. Given the rarity of PNEN in NF-1, there
are no specic recommendations for surveillance, but clinicians should have a high
index of suspicion for symptoms to suggest PNEN in these patients [16].
Functionality
PNEN that are classied as functional are those that secrete a dominant hormone
which drives a clinical syndrome. Table17.1 lists all the types of functional PNEN,
the specic biomarker of interest, and related symptoms. Importantly, functional
PNEN can secrete more than one hormone and cause additional syndromes. The
majority of functional PNEN are well differentiated and diagnosed earlier than nonfunctional tumors given their clinical symptoms. Nonfunctional PNEN can
17 Pancreatic Neuroendocrine Neoplasms
represent three types: PNEN that do not secrete any hormone, PNEN that produce
hormones at a low enough level which does not cause symptoms, and PNEN that
secrete hormones which do not produce symptoms (CgA, pancreatic polypeptide,
neurotensin, and ghrelin). Nonfunctional PNEN are typically found incidentally but
can present with nonspecic symptoms secondary to mass effect. Prognostically,
tumor grade has a stronger inuence on prognosis rather than the functionality of
the tumor [2, 8, 17, 18].
299
Insulinoma
Insulinoma is the most common type of PNEN with a variety of symptoms stemming from hyperactivity of the sympathetic and central nervous system (hunger,
tremor, anxiety, irritability, diaphoresis, and weakness). Insulinomas are often sporadic (95%), found in the fourth decade of life and evenly distributed throughout the
pancreas. In addition, insulinomas tend to be small, nonmetastatic, thus amenable to
surgical resection. Although rare, MEN1 is the most common hereditary syndrome
associated with insulinomas and often present with multiple malignant tumors. The
gold standard for diagnosis of insulinomas is a 72h fast with subsequent testing
every 6h for glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate levels. It is important to differentiate an insulinoma from iatrogenic intake of hypoglycemic medications which will yield an elevated plasma insulin level but low
C-peptide and proinsulin [19]. The steps required to localize insulinomas are the
same for any PNEN with the caveat that SRS is not usually useful as they often lack
sufcient somatostatin receptors. As mentioned previously, surgical resection is the
mainstay and only curative option for insulinomas. Enucleation is usually the treatment of choice as the majority are benign, typically small (<2cm) and >2mm from
the pancreatic duct. In the event the insulinoma is identied within 2mm of the
pancreatic duct, formal anatomic resection may be required. Postoperatively, recurrence rates are low (3%) and more likely in patients with associated hereditary syndromes. In patients with metastatic disease, the median survival is approximately
5years [20, 21].
Gastrinoma
Gastrinomas are the second most common functional PNEN.Unlike insulinomas,
>50% of patients diagnosed with a gastrinoma have evidence of metastatic disease
at the time of diagnosis [2]. Gastrinomas typically originate within the gastrinoma
triangle (90%) and are diagnosed with gastrin levels >1000 and pH<2 from gastric
aspirate. Of note, PPIs must be stopped 2 weeks prior to testing gastrin levels
because they can falsely elevate gastrin levels. Gastrinomas may take an aggressive
300
or a benign course. The aggressive form is seen in 20–30% of patients with 90% of
tumors found in pancreas. Survival rates for benign and aggressive forms are 90%
and 30%, respectively. After diagnosis and localization, PPI is the rst-line treatment for symptomatic relief followed by curative surgical resection versus palliative
cytoreduction for symptom control [22]. PPI doses can be titrated to higher-thannormal ranges for symptom relief, especially in patients with unresectable metastatic disease. Somatostatin analogues have also been shown to help with symptom
control with PPIs. These large doses of PPIs have rendered debulking and acidreducing procedures exceedingly rare. Given a 50% chance of metastatic disease at
time of diagnosis, regional pancreatectomy is preferred. Patients with hereditary
syndromes may benet from pancreatoduodenectomy as most of the recurrent disease in this patient population is in the duodenum [2, 22, 23].
A. A. Razavi et al.
VIPoma
VIPomas are a rare type of PNEN with an incidence of one in ten million. VIPomas
secrete vasoactive intestinal peptide (VIP) and associated with the WDHA syndrome causing profuse watery diarrhea, electrolyte disturbances (hypokalemia,
hypomagnesemia, hypophosphatemia, and metabolic acidosis), weight loss, abdominal pain, and achlorhydria. Like gastrinomas, the majority of VIPomas are metastatic at time of diagnosis (70%). Diagnosis of VIPoma is suggested with VIP levels
>225pg/mL after an overnight fast. Of note, VIP may be secreted from other tumors
including neuroblastomas, ganglioblastomas, and ganglioneuromas; therefore,
tumor localization is imperative [24]. Management of VIPomas begins with preoperative resuscitation, electrolyte correction, and administration of somatostatin analogues. As with gastrinomas, anatomic resection with lymphadenectomy is
recommended and often warranted in the setting of resectable disease. Resection of
liver metastasis can be performed if surgically feasible [25]. In patients with unresectable disease, somatostatin analogues likely prolong progression-free survival
with secondary options including peptide receptor radiolabeled SSA, everolimus,
sunitinib, chemotherapy, or debulking. If there is evidence of extensive unresectable
liver dominant disease, embolization, radioembolization, radiofrequency ablation,
or brachytherapy are options to reduce tumor burden. No specic liver-directed
therapy has been proven to improve survival, but reduction of liver tumor burden is
associated with symptomatic improvement [24–26].
Glucagonoma
Glucagonomas are also exceedingly rare, with an incidence of one in 20 million.
They arise from the alpha cells of the pancreas and usually present in the body or
tail [27]. Patients can present with dermatitis (necrolytic migrating erythema),
17 Pancreatic Neuroendocrine Neoplasms
301
depression, DVTs, diabetes, weight loss, and vitamin/amino acid deciencies. The
diagnosis of glucagonoma is conrmed with elevated glucagon levels >1000pg/mL
after a fasting state [28]. Glucagonomas tend to be larger and malignant (50–80%)
at the time of diagnosis. Elevated glucagon can place patients in a severe state of
catabolism and malnourishment; therefore, treatment begins with optimizing nutrition with enteral supplements. In addition, DVT prophylaxis is imperative in these
patients to prevent pulmonary embolism. As with other functional PNEN, anatomic
resection is indicated for resectable disease. Postoperatively, patients without evidence of metastasis have an 85% 5-year survival rate, while patients with metastatic
disease have a 60% 5-year survival rate [26, 27, 29].
Histology Classications/Grading
The heterogeneity of PNEN has made it challenging to predict clinical behaviors
and prognosis. By this accord, classifying PNEN has also been difcult. In 2010,
the WHO released guidelines for stratifying patients with all digestive system neuroendocrine cancers that could be applied to PNEN.This system separated welldifferentiated neuroendocrine tumors into low grade (G1) and intermediate grade
(G2) depending on Ki67 and mitotic index [9]. High-grade tumors (G3) were considered poorly differentiated then. As expected, this wide application for all neuroendocrine tumors provided some discrepancies for PNEN which resulted in the
WHO creating a new classication system specically for PNEN.Briey, the WHO
2017 guidelines split PNEN into two broad categories: well-differentiated pancreatic neuroendocrine tumors (PNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PNECs). PNETs were further classied into grade 1 (G1),
grade 2 (G2), and grade 3 (G3) based on Ki-67 proliferation index and mitotic index
per high power eld (HPF). PNECs are now G3 with poorly differentiated tissue
architecture (Table17.2) [5]. A few key attributes should be noted in the new classication system: (1) the eighth edition system only applies to well-differentiated
PNETs G1-G3 while the poorly differentiated G3 PNECs are still classied by the
pancreatic adenocarcinoma staging system and (2) there is further emphasis on T
stage and location of metastatic site—liver vs extrahepatic vs both liver and extrahepatic [30]. The marked difference in phenotype between PNECs and PNETs is
believed to stem from genetic differences, with abnormalities of MEN1, DAXX,
Table 17.2 WHO eighth edition 2017 PNEN classication system
WHO 2017 classication Mitoses (# per high-powered eld) Ki-67 rate (%)
Well-differentiated PNET, grade 1 <2 <2
Well-differentiated PNET, grade 2 20 3–20
Well-differentiated PNET, grade 3 >20 >20
Poorly differentiated PNEC, grade 3 >20 >20
302
and ATRX molecular pathways among PNET but not for PNEC.On the other hand,
p53 genetic abnormalities have been noted in PNEC but not in PNET. Surgery
remains the only curable treatment approach for PNEN and typically recommended
when technically feasible. Exceptions to this include patients with widely metastatic disease, small and sporadic nonfunctional PNEN, and in patients with severe
comorbidities that would preclude surgery [31].
A. A. Razavi et al.
Staging/Surgical Decision-Making
Nonmetastatic Disease
Primary surgical resection should be offered for all functional or symptomatic
PNENs without evidence of distant metastatic spread and irrespective of size. Of
note, regional lymph node involvement does not preclude resection despite being a
negative prognostic indicator. In patients with locally advanced tumors, extended
organ resections with vascular reconstruction can be performed if need be. The
management of nonfunctional PNENs has been guided by size >2cm surgery is
recommended and <1cm observation given low likelihood of lymph node spread.
The controversy resides among PNENs 1–2cm [32]. European Neuroendocrine
Tumor Society (ENETS) and National Comprehensive Cancer Network (NCCN)
both endorse observation for nonfunctional PNENS <2cm while the North American
Neuroendocrine Tumor Society (NANETS) recommends an individualized
approach based on grade, growth rate, age, patient comorbidities/preference, and
the extent of surgery required for R0 resection. In lieu of these discrepancies, the
decision to watch or operate on a patient with nonfunctional PNENs between 1 and
2cm should be made on an individualized basis while taking account the tumor
grade, growth rate or radiographic progression, and morbidity associated with pancreatic resection [18]. If observation is chosen, guidelines mandate for repeat MRI/
CT every 6–12months with indication to re-evaluate the need for surgery if the
lesion increases by 0.5cm or more.
The goal of PNEN surgery is to resect the primary tumor and associated lymph
nodes while preserving as much pancreatic parenchyma as feasible. The surgical
approach and extent of resection are dictated by location, degree of local invasion,
presence of metastatic disease, grade, and patient factors [33]. Partial pancreatic
resection in the form of pancreatoduodenectomy, distal pancreatectomy, or enucleation are all options for resection. In general, PNEN located in the head/uncinate/
neck of pancreas require pancreatoduodenectomy and PNEN located in the body or
tail of pancreas require distal pancreatectomy with or without splenectomy.
Enucleation and central pancreatectomy are options for smaller lesions and have
gained wider acceptance to help minimize postoperative pancreatic insufciency
(endocrine/exocrine). Enucleation has the advantage of avoiding complications
17 Pancreatic Neuroendocrine Neoplasms
303
associated with a pancreatic anastomosis and has been shown to have less severe
pancreatic stulas despite having higher pancreatic leak rates [6, 34]. Importantly,
enucleation is not recommended in patients with nodal or metastatic disease, tumors
>3cm in size, or those near the common bile duct or pancreatic duct [6, 18, 32].
Metastatic Disease
At time of diagnosis, 40–80% of PNEN are metastatic. The most frequent site of
metastasis is the liver (40–90%) followed by bone (12–20%) and lung (5%). While
M1 disease is a negative prognostic indicator, long-term outcomes are signicantly
more favorable than for pancreatic adenocarcinoma. Metastatic disease is related to
several factors including histologic grade, size of primary tumor, mitotic index, and
vascular/lymphatic invasion [35]. The treatment of metastatic PNEN is complex
and in constant evolution and thus requires multidisciplinary expertise involving
surgery, interventional radiology, and medical oncology subspecialists on board.
Patients with metastatic PNEN should be presented at multidisciplinary tumor
board (MTD) or transferred to a center with high volume PNEN surgeons as there
are various treatment modalities for advanced PNEN.Given the indolent nature of
PNEN, it is likely that a patient with advanced PNEN will undergo multiple treatments over the course of their disease [36].
Metastatic PNEN should be classied as liver-only disease or those with presence of extrahepatic disease. For liver-only disease, the goal is resection of both
primary and hepatic metastatic lesions as it remains the only curative option when
the disease is resectable. Hepatic metastases are classied into three patterns: type
1—isolated single lesion, type 2—large focus of metastatic bulk with bilobar small
lesions, and type 3 with bilobar disseminated metastatic disease and with minimal
normal liver parenchyma. Patients with type 1 and 2 patterns of disease are candidates for resection. Unfortunately, 5-year recurrence rates are as high as 80–94%
given the likelihood of microscopic disease that is not visualized on preoperative
imaging [37]. Risk factors for recurrence include lymph node involvement and
microscopic positive surgical margins in the primary. If a patient’s disease pattern
after the index operation remains resectable, they may undergo multiple trips to the
operating room in combination with other locoregional treatments to obtain longterm disease control [38].
The high hepatic recurrence rate has also allowed liver transplantation to emerge
as an option for selected patients with favorable tumor grade. The criteria for liver
transplantation are quite strict and include: age <55years, well-differentiated PNEN
with hepatic disease burden <50% of liver, prior resection of primary tumor, absence
of extrahepatic disease, and stable disease for 6months [39]. Frequently, patients
eligible for transplant are also eligible for cytoreductive surgery or other liverdirected and systemic treatment options. Outcomes after transplantation in this