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A. A. Razavi et al.
selected patient population are favorable with 5-year OS between 70% and 90%
[40]. For type 3 hepatic metastasis, initial non-surgical management with somatostatin analogue therapy, systemic chemotherapy, or peptide receptor radionucleotide therapy (PRRT) is generally recommended. Patients are followed closely to
determine if liver tumor burden downgrades and may qualify for resection. In
patients whose tumor does not become resectable, locoregional therapies play a key
role as resection of the primary tumor remains controversial given its unclear impact
on survival and a potential for increased morbidity and mortality. Transarterial
embolization (TAE), transarterial chemoembolization (TACE), and selective internal radiation therapy (SIRT) are among the options to control liver metastasis. The
choice among the three should be discussed within a multidisciplinary team as there
are no prospective studies yet that directly compare outcomes with the different
modalities. TACE and TAE have been shown to improve symptoms in 60–90% of
patients with low morbidity and mortality. Overall survival ranges from 12 to
84 months and 14 to 70 months for TAE/TACE and SIRT, respectively [35, 36,
38, 40].
Extrahepatic metastasis has been associated with poor prognosis when compared
to liver-only disease. Medical therapies such as SSA, everolimus, and sunitinib have
been loosely associated with tumor regression but may not improve symptoms as
they are unable to decrease the amount of hormone secretion to provide benet. The
evidence for PRRT is limited to the small bowel, and the ability to improve hormonal burden is questionable. Several systemic therapies are available and discussed later in this chapter. In certain scenarios, based on disease burden, utilization
of systemic therapy and cytoreductive surgery has been proposed as an option to
directly reduce tumor burden. Studies have shown this option to be benecial with
approximately 70% of patients receiving hormonal response rates in the largest
study to date. The authors believe it is necessary to discuss prospective cytoreductive candidates among the multidisciplinary team, particularly considering performance status, hormonal activity, symptomatic burden on life, anatomic location,
and volume of extrahepatic tumor. Cytoreductive surgery for asymptomatic disease
remains controversial, and more data is needed to provide guidance [41].
Multidisciplinary Decision-Making
Given that most PNEN are nonfunctional and diagnosed in late stages, a multidisciplinary approach to their treatment is essential in improving disease outcome. It is
important for clinicians to understand when surgical resection of primary and/or
metastatic PNEN is indicated, as well as types and indications of systemic therapies
available based on previous trials.
17 Pancreatic Neuroendocrine Neoplasms
305
Surgical Resection
Resection of the primary or metastatic PNEN has been associated with improved
survival, but surgery may not always be indicated. In patients with PNEN secondary
to inherited syndromes such as multiple endocrine neoplasia (MEN) type 1 and von
Hippel-Lindau (VHL) syndrome, tumors smaller than 2–3cm rarely progress or
metastasize [42]. Sporadic PNEN under 2 cm may also be observed given their
good prognosis [43], unless there are high-risk features such as patients older than
55 years of age, grade 3 tumor, or the presence of distant metastases [44, 45].
However, there is controversy in observing tumors under 2cm, as there have been
other studies showing improved survival in patients who underwent resection of
small nonfunctional PNEN [46–48]. Radiofrequency ablation of small PNEN has
been described as an alternative based on small series [49, 50].
In patients with liver metastases, both the primary and the metastatic lesions
should be resected if technically feasible [51]. However, if the primary tumor is not
resectable, the metastatic lesion(s) should not be resected [52]. There is no clear
data to suggest whether the primary tumor should be resected if the metastatic disease is unresectable. Even after resection of liver metastasis with curative intent,
recurrence rates up to 54% have been reported despite negative margins [53]. Liverdirected regional therapies such as transarterial embolization, chemoembolization,
or radioembolization may be an option for those patients with unresectable liver
metastases. However, current data demonstrates that surgical resection is superior to
intra-arterial therapies in terms of median survival in patients with NEN liver metastases [37, 54]. NANETs and ENETs guidelines suggest that treatment should be
individualized based on patient age and comorbidities, distribution of lesions and
volume of liver involvement, the presence of symptoms, and rate of progression.
Systemic Treatments
There are multiple systemic therapeutic options for locally advanced and metastatic
neuroendocrine neoplasms (NEN) of the gastrointestinal tract including those of the
pancreas. The use of somatostatin analog octreotide was shown to extend the time
to progression compared to placebo in the PROMID trial [55]. Similarly, the
CLARINET demonstrated prolonged progression-free survival in patients treated
with lanreotide, another somatostatin analog [56]. The follow-up CLARINET
FORTE trial looking at patients with disease progression on standard dosing of
lanreotide (every 28 days) who then underwent more frequent dosing (every
14 days) demonstrated some progression-free survival, although this study was
single arm [57].
As NEN demonstrate hypervascularity, inhibition of angiogenesis in the treatment of NEN has also been investigated. Sunitinib is a receptor tyrosine kinase
306
A. A. Razavi et al.
inhibitor that targets vascular endothelial growth factor (VEGF) receptors as well as
platelet-derived growth factor (PDGF) receptors which have shown to improve both
the progression-free survival and the overall survival of patients with advanced
well-differentiated PNEN compared to placebo in a phase III trial [58]. This study
was terminated early due to more deaths being observed in the placebo group. A
follow-up phase IV trial conrmed longer progression-free survival and objective
tumor response in PNEN treated with sunitinib [59]. Mammalian target of rapamycin (mTOR) represents another pathway that may be targeted in the treatment of
NEN.In the RADIANT-3 trial, patients with advanced PNEN receiving everolimus,
an oral mTOR inhibitor, demonstrated signicantly longer progression- free survival
compared to those receiving placebo [60]. The RADIANT-4 trial broadened the use
of everolimus to advanced NEN of the lung or the gastrointestinal tract and conrmed earlier ndings of prolonged progression-free survival with everolimus compared to placebo [61].
In recent years, immune checkpoint inhibitors have gained signicant clinical
interest as they have shown to improve outcomes in many cancer types. In the
KEYNOTE-028 trial, 25% of PNEN were positive for programmed death-ligand 1
(PD-L1). Of those, an objective response rate to pembrolizumab was 6.3% at
median follow-up of 21months [62]. Similarly, KEYNOTE-158 showed median
progression-free survival of 4.1months in NEN treated with pembrolizumab [63].
Of the four tumors with partial responses, three were PNEN, and all were PD-L1
negative.
Another study demonstrated a disease control rate of 24.1% in patients with
metastatic high-grade NEN who were treated with pembrolizumab, and there was
no difference in outcomes between PD-L1-positive and PD-L1-negative tumors
[64]. Current evidence shows limited utility of immune therapies in PNEN, but
more studies are needed to denitively conclude their utility.
Another option for systemic treatment of NENs is peptide receptor radionuclide
therapy using lutetium-177 (
improved progression-free survival in patients receiving
177
Lu)-Dotatate. The NETTER-1 trial demonstrated
177
Lu-Dotatate and octreotide compared to those receiving octreotide alone [63], although this trial only
included patients with midgut NENs. Despite longer progression-survival, a follow up analysis did not demonstrate an improved overall survival at 5years in patients
undergoing
177
Lu-Dotatate therapy [63].
Open Trials
There are multiple ongoing trials regarding PNEN, especially relating to outcomes
with different systemic therapy options. Some of these trials are summarized in
Table17.3.
17 Pancreatic Neuroendocrine Neoplasms
Table 17.3 Summary of select ongoing trials for systemic therapies for GEP NEN
Trial ID Phase Population Intervention
NCT04234568 1 GEP NEN Lu 177 with triapine (ribonucleotide
reductase inhibitor)
NCT05040360 2 High-risk well-differentiated
PNEN
NCT02893930 2 Metastatic or refractory
PNEN (unresectable)
NCT02595424 2 Metastatic or unresectable
GEP NEN
NCT05050942 3 Advanced well-differentiated
GEP NEN
NCT04919226 3 Well-differentiated grade 2–3
GEP NEN
Capecitabine and temozolomide after
surgery
Sapanisertib (mTOR inhibitor)
Temozolomade and capecitabine vs.
cisplatin and etoposide
CAM2029 (octreotide subcutaneous
depot)
Lu 177 and edotreotide (peptide
receptor radionuclide therapy)
307
Surveillance
In a review of 1020 patients who underwent curative-intent resection of PNEN
without liver metastasis at time of surgery, 15.1% developed recurrence, with 49.4%
of those patients having liver-only recurrence and 22.7% having pancreas-only
recurrence [65]. Pancreas-only recurrence decreased with time and was associated
with margin status, whereas liver-only recurrence increased with time and was
related to cancer characteristics such as Ki-67 index and presence of perineural
invasion. Given the heterogeneity of this disease and high recurrence rate, it has
been suggested that the surveillance strategies be individualized to each patient [33,
66]. Follow-up should include clinical examination, lab markers, and cross- sectional
imaging, and frequency should be based on risk factors based on patient and tumor
characteristics. The CommNETS group recommends a follow-up period of at least
10years [67]. The interim data from the ASPEN trial provides interesting information regarding surveillance for small (<2cm), sporadic, and asymptomatic nonfunctional PNEN [68]. Among the 406 patients who underwent surveillance over a
median follow-up of 2years, only 2% underwent surgery for increasing main pancreatic duct dilation, tumor size, or patient preference. This suggests that a nonoperative strategy may be a safe option, but long-term follow-up is needed to
provide more denitive guidance.
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A. A. Razavi et al.
Chapter 18
Secondary Malignant Neoplasms
RossMudgway , DanielJ.Oliveira, andDavidCaba Molina
Renal Cell Carcinoma
Introduction/Epidemiology
Metastasis from renal cell carcinoma (RCC) is common and already present during
diagnosis in approximately 25% of patients [1]. RCC metastasis is most common to
the lung, liver, bone, and adrenal tissue [1–3]. Of the malignant tumors that metastasize to the pancreas, the most common primary tumor site of metastasis is the
kidney, accounting for 70.5% [4]. Hematogenous and lymphatic spread have both
been considered as the underlying mechanism of RCC metastasis to the pancreas [1,
5, 6]. Studies have found no relation between site of the primary tumor and site of
the pancreatic metastasis, supporting a hematogenous spread, whereas a strong correlation between site and pancreatic localization would have suggested a lymphatic
spread [1, 5, 6]. Additionally, lymph-node positivity is rare, while a high rate of
vascular invasion has been observed during surgery [1, 5, 6]. However, systemic
spread would not explain the discrepancy between the relative frequency between
multiple pancreatic metastases and the absence of metastasis to other organs, suggesting there is some underlying biochemical mechanism [1, 6]. It has been observed
that RCC metastasis to the pancreas is predominantly in males, 62years old, and is
metachronous [3, 7, 8].
R. Mudgway · D. J. Oliveira
Loma Linda University, Loma Linda, CA, USA
e-mail: RMudgway@llu.edu; doliveir@sgu.edu
D. Caba Molina (
Loma Linda University, Loma Linda, CA, USA
Riverside University Health System/University of California-Riverside,
Loma Linda, CA, USA
e-mail: DCabamolina@llu.edu; d.cabamolina@ruhealth.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_18
*)
311© The Author(s), under exclusive license to Springer Nature
312
R. Mudgway et al.
Diagnosis/Radiology/Pathology
Common patient presentations include nonspecic symptoms, such as abdominal
pain, anemia, gastrointestinal (GI) bleeding, and jaundice, although 49–55%
patients are mostly asymptomatic [6, 7, 9]. There have also been cases of patients
presenting with pancreatitis due to pancreatic duct obstruction [6]. Typically,
patients will have a median disease-free survival of 6–12years after nephrectomy
[1, 3, 6–8, 10]. However, there have been some reports of disease-free intervals over
30years suggesting the necessity of long-term follow-up [6].
Tumor size in the pancreas ranges from 1.5 to 12cm [7]. Grossly, metastatic
tumor deposits are well-circumscribed, with bright yellow-orange to red-brown to
white-gray masses [7]. The most common location is the head of the pancreas, followed by the tail and then the body [7]. Clear cell renal cell carcinoma is the most
common RCC to metastasize to the pancreas; there are also cases of chromophobe
RCC and rarely sarcomatoid RCC [7].
Isolated pancreatic metastasis is often found incidentally on routine surveillance,
with computed tomography (CT) and magnetic resonance imaging (MRI) being the
most used initial diagnostic modality [6, 7, 11]. On CT and MRI, the pancreatic
metastasis will show intense enhancement on arterial and venous phase compared
to normal tissues (Fig. 18.1) [11]. Pancreatic ductal adenocarcinoma is nonenhancing and can be reliably distinguished, while nonfunctional pancreatic endocrine tumors (PNETs) share the same morphology and enhancement characteristics
of RCC [11]. Nuclear medicine testing like uorodeoxyglucose-positron emission
tomography (FDG-PET)/CT is useful for determining the need for surgery because
it can exclude distant extrapancreatic metastases [4, 10]. However, it is important to
Fig. 18.1 Contrastenhanced computed
tomography scan of renal
cell carcinoma (clear cell
type) metastasis to the
pancreas. An enhancing
soft tissue of the pancreatic
neck is demonstrated
ab
18 Secondary Malignant Neoplasms
313
note that the number of actual tumors in the resected pancreatic specimen are generally greater than the number determined by FDG-PET/CT [4].
In general, endoscopic ultrasound-guided ne needle aspiration (EUS-FNA) is to
be considered the best and most accurate modality and can be used when CT/MRI
cannot make a correct diagnosis [10, 11]. On endoscopic ultrasound (EUS), pancreatic RCC will appear as a hypoechoic, round, well-circumscribed homogeneous
lesion [11]. The hypervascularity nature of metastases can be appreciated using
Color Doppler imaging [11]. However, on EUS, PNET also has similar morphological features [11]; therefore, biopsy, when possible, allows for comparison to the
primary tumor.
Fine needle aspiration (FNA) will show cells in clusters, sheets, and often grow
along capillaries [7, 11]. There will be abundant pale and clear cytoplasm with centrally placed nuclei and prominent nucleoli (Fig. 18.2) [11]. Immunochemistry
plays an important role in the diagnosis of metastatic RCC to the pancreas [11].
RCC expresses pan-cytokeratin, vimentin, EMA, CD10, and PAX-8 [7, 11]. Also,
RCC metastasis to the pancreas is associated with cell clones that have a lower
aggressiveness and that can be distinguished from extrapancreatic metastases by a
lack of loss of 9p, lower weight genome instability index, low frequency of BAP1
alterations, and a high frequency of PBRM 1 loss [2, 12].
Treatment/Outcome
Current treatment options are surgical resection or biologic-targeted therapies [2,
8]. Surgical treatment includes pylorus-preserving or classic pancreatoduodenec-
tomy, distal pancreatectomy, or total pancreatectomy with or without splenectomy
Fig. 18.2 Renal cell carcinoma (clear cell type) involving the pancreas at 4X magnication (a)
and 20X magnication (b). In (a), the tumor is composed of malignant cells with prominent cytoplasmic clearing and enlarged nuclei with occasional prominent nucleoli and open chromatin. The
clusters of tumor cells are separated by a thin delicate vasculature which contributes to the hemorrhagic appearance of renal cell carcinoma grossly. In (b), the tumor is invading the glandular
parenchyma composed of acinar cells of the pancreas