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Chapter 16 / Neuroendocrine and Noncolorectal Liver Metastases 191
FIGURE 16.3 A. Computed tomography revealing numerous enhancing metastases in the
liver.
with moderately dierentiated grade 2 NEC have a less predictable and
more aggressive course though are often still candidates for operative treat-
ment. Operative intervention in patients with poorly dierentiated grade
3 NEC is rarely indicated as these NECs are typically highly aggressive and
are characterized by rapid dissemination and resistance to most therapeu-
tic interventions. Currently, NEC is most frequently staged by the AJCC
TNM staging system. Staging is crucial for planning overall management.
As patients with hepatic metastases harbor by denition stage IV disease,
the site and extent of local–regional disease and the site, extent, and dis-
tribution of other distant metastases to the peritoneum, lung, and bone
signicantly inuence treatment planning.
Imaging
Radiolabeled somatostatin receptor scintigraphy (SRS) is the most sensitive
and accurate imaging modality for diagnosis and initial staging particularly
for identication of occult extrahepatic disease. Positive scintigraphy is
dependent upon the presence of active somatostatin receptors (SR) on the
NEC (Fig. 16.3). Current agents do not bind to all SRS receptors nor do all
NEC harbor all SRs. In addition, SRS also predicts response to somatostatin
analog therapy. More recently, udeoxyglucose positron emission tomog-
raphy (18-FDG-PET) also has been used as an alternative staging adjunct.
However, contrast-enhanced CT remains the primary imaging study for
assessing resectability of hepatic metastases from NEC. Metastases are
hypervascular and are best visualized during the arterial phase of contrast
administration. In patients with iodinated contrast allergies or signicant
steatosis, gadolinium-enhanced MRI is indicated; the contrast-enhanced
T2-weighed sequences are most sensitive (Fig. 16.4). In our experience, MRI
is complementary to CT with particular utility in detection of very small
hepatic metastases that may alter treatment strategies. Liver-specic con-
trast agents such as gadoxetate disodium (Eovist) increase the sensitivity
for detecting small NEC hepatic metastases. Such agents preferentially are
taken up by hepatocytes; thus, small contrast-negative metastases not visi-
ble on CT are more readily identied. Additionally, contrast-enhanced cross-
sectional imaging is essential to assess resectability of the primary NEC, if
present, and to assess residual or recurrent regional disease if previously
(Continued )
Section II / Liver192
resected. Most patients with hepatic metastases from NEC harbor multifo-
cal bilobar disease, though 25% of patients have isolated lobar disease.
In potentially resectable patients, radiologic data should estimate the
future liver remnant volume in patients considered for extended or comp lex
hepatectomy or in patients with bulky parenchymal disease. Formal upper
and lower endoscopy and endoscopic ultrasound are also important tools
with which to identify primary NECs. Patients with carcinoid syndrome
FIGURE 16.3 (Continued) B. In-111 octreotide scan revealing multiple large foci of
intense radiotracer uptake in the liver as well as pancreatic tail, conrming metastatic
(arrow) pancreatic NEC. C. Gross specimen of resected liver tumors.
Chapter 16 / Neuroendocrine and Noncolorectal Liver Metastases 193
should have a formal cardiac evaluation including echocardiography to
evaluate the extent of right heart valvular disease. If present, valvular
disease should be corrected prior to any major liver resection.
Potentially Curative Resection
Although NEC is considered indolent, metastatic disease can be associ-
ated with severe, life-threatening endocrinopathies or symptoms from
locally invasive nonfunctional NEC. e leading cause of mortality aside
from hormonal complications is extensive hepatic progression and hepatic
failure. e timing and type of treatment should be considered in a multi-
disciplinary setting. Ideally, the rst-line treatment for well-dierentiated
hepatic metastases from NEC without extrahepatic spread and unilobar
alone or unilobar and limited contralobar metastases is resection with or
without concomitant ablation. Potentially curative resection (R0) is dened
as resection/ablation of all gross disease with an adequate functional liver
remnant. Fewer than 50% of patients undergoing hepatic resection of meta-
static NEC with hepatic metastases have R0 resection due to the extent of
FIGURE 16.4 Neuroendocrine liver metastases. A. Enhancing right lobe mass on the arte-
rial phase of computed tomography. B. Diffuse bilobar metastases on T2-weighted MRI
imaging.
Section II / Liver194
hepatic metastases. e historical 5-year survival for unresected patients
with NEC liver metastases is approximately 30%. In contrast, the expected
5-year survival for patients after R0 resection of hepatic metastases based
on retrospective series ranges from 60% to 80%. Factors correlating with
long-term survival include size and site of metastases, tumor grade, extent
of hepatic resection and baseline hepatic disease, presentation with stage
IV disease, and impact of endocrinopathy such as carcinoid heart disease.
Importantly, regardless of the apparent completeness of resection, disease
progresses in most patients, either extra- or intrahepatically. Most patients
will manifest disease progression within 5 years; the median identica-
tion of disease progression is 18 months. Perioperative octreotide is rec-
ommended to prevent the carcinoid crisis in patients with the carcinoid
syndrome and other patients with demonstrable clinical control of endo-
crinopathies. Additionally, cholecystectomy is performed routinely during
hepatic resection to avert cholelithiasis associated with somatostatin ana-
log treatment and to potentially avoid ischemic cholecystitis or gallbladder
necrosis associated with future arterial embolization and ablation, respec-
tively. Adjuvant systemic chemotherapy is not established as the standard
of care, but participation in clinical trials where available is recommended.
Palliative Resection
QOL related to endocrinopathies can be improved signicantly through
appropriate hepatic resection provided that residual disease is minimized.
In general, durable relief of endocrine symptoms is obtained when nearly all
radiographic metastases are resected even in the presence of gross residual
disease. Palliative cytoreductive resection should be considered primarily
in patients with endocrinopathies, particularly in patients who have failed
medical management. Whether survival in patients without endocrinopa-
thies is improved by palliative resection remains unproven. e complete-
ness and duration of response to palliative resection are primarily based
on residual metastatic volume and not resected metastatic volume. Given
the growth kinetics of NEC, at least 90% or more of the hepatic metastases
should be resected. In general, R2 resections are single-stage operations
and are parenchymal sparing because disease progression is inevitable.
Resection of the primary NEC may be undertaken concomitantly or at a
staged procedure (Fig. 16.5). Palliative resection has limited applicability
in patients with high-grade NEC or those with unresectable extrahepatic
FIGURE 16.5 Synchronous carcinoid metastasis. A. Computed tomography of large atypi-
cal carcinoid metastases replacing the left lateral sector.
(Continued )
Chapter 16 / Neuroendocrine and Noncolorectal Liver Metastases 195
metastases. Importantly, no high-level evidence has shown that debulking
improves survival or QOL compared to nonsurgical therapies. Palliative
resection can be enhanced by subsequent percutaneous ablative thera-
pies after hepatic regeneration. Notably, palliative resection does not
FIGURE 16.5 (Continued) B. Gross intraoperative photo of this lesion. C. CT with inltra-
tive primary carcinoid arising in the terminal ileum and involving the small bowel mesentery
(arrow). D. Gross intraoperative photo of this ileum tumor and the sclerotic adjacent mesentery.
Section II / Liver196
preclude subsequent liver-directed therapies, antihormonal treatment, or
chemotherapy.
Liver Transplantation
e role of liver transplantation for metastatic NEC is limited. As may be
expected, complete resolution of endocrine symptoms is achieved after
liver transplant, but disease progression is typical, and survival has not
exceeded that of hepatic resection. Liver transplantation in patients har-
boring completely unresectable hepatic metastases who have controlled
primary and regional disease is clearly reasonable; however, selection cri-
teria are currently unclear. Patients who are young, have had resection of
the primary NEC without progression of extrahepatic disease for at least
6 months, and have low-grade NEC may be potential transplant candi-
dates (Fig. 16.6). Fewer than 1% of liver transplants in the United States are
performed for metastatic NEC.
FIGURE 16.6 A. Contrast-enhanced CT with numerous bilobar ileal carcinoid metastases
in a 26-year-old female. B. Intraoperative photos of liver lesions at the time of staged
primary tumor resection.
(Continued
)
Chapter 16 / Neuroendocrine and Noncolorectal Liver Metastases 197
FIGURE 16.6 (Continued) C. Intraoperative photo of resected ileal carcinoid and mesen-
tery during staged primary tumor resection. D. Gross photo of liver explant following liver
transplantation 18 months after primary staged tumor resection and no evidence of interval
extrahepatic disease. E. Computed tomography 3 years following transplantation showing
no evidence of recurrent disease.
Section II / Liver198
Ablative Therapy
Ablation as a single therapy is applicable in patients with limited unresect-
able hepatic NEC metastases. Ablation is most frequently employed as an
adjunct during resection or for progressive disease following resection.
Ablative techniques are either thermal—cryotherapy, radiofrequency abla-
tion (RFA), microwave, or chemical—alcohol or acetic acid. Metastatic NEC
is quite sensitive to ablative therapy. Ablation has been shown to eectively
control disease progression and palliate symptoms whether performed
during laparotomy, laparoscopically, or percutaneously with image guid-
ance. In general, ablation should be considered as an adjunct to hepatic
resection for deep-seated metastases during hepatic resection and as an
adjunct to R2 hepatic resection postoperatively to further reduce residual
disease. Ablation should be considered as a primary liver-directed therapy
in patients with limited hepatic disease progression after prior hepatic
resection and as the initial liver-directed therapy for limited deep small
metastases to avoid major hepatic resection at the initial presentation
of the NEC. Ablative therapy should be avoided in patients with numer-
ous metastases, large metastases (>
5 c
m), or juxtahilar metastases or in
patients with prior bilioenteric anastomoses because of the risk of chronic
intrahepatic infection.
Transarterial Therapies
Because NECs are hypervascular, hepatic metastases from NEC are well
suited for transarterial embolization therapies. is locoregional treatment
should be considered in patients with hepatic dominant disease where
resection and ablation are not tenable. Transhepatic arterial embolization
(TAE) may either be “bland” or use particles loaded with various additional
chemotherapeutic agents (transarterial chemoembolization—TACE). Both
TAE and TACE eectively control symptoms for up to 1 year and result in
signicant decrease in biochemical markers and objective tumor responses
in about 50% of patients. Response to TACE is greater for high-grade NEC;
however, treatment of high-grade tumors is associated with greater toxicity.
Selective peripheral percutaneous embolization has replaced proxi-
mal hepatic arterial embolization to minimize hepatic ischemia– and
procedure –related liver failure. Moreover, embolization is frequently
staged; the lobe harboring the dominant metastatic burden is embolized
initially. Both TAE and TACE should be performed in experienced centers
that have developed clear-cut treatment algorithms. e most common
side eect of TAE/TACE is postembolization syndrome (PES), an inam-
matory reaction triggered by tumor necrosis and/or hepatocellular injury.
is reaction occurs in up to 80% of patients either immediately following
the procedure or up to 2 weeks after the procedure. Typically, PES includes
fever, pain, extreme fatigue and malaise, and nausea/vomiting. A chemical
and/or ischemic cholecystitis may also occur if the cystic artery is inad-
vertently embolized. Contraindications to TAE/TACE include ipsilateral or
complete portal vein thrombosis, hepatic insuciency, and previous bil-
ioenteric anastomoses such as after pancreaticoduodenectomy. Although
embolization can be repeated, eventually the arterial supply to residual
metastases becomes pruned with development of alternative arterial col-
laterals that become inaccessible to further embolization.
An alternative to TAE or TACE is selective internal radiation therapy
(SIRT). In SIRT, radioactive
90
Yttrium is incorporated into microbeads that
are delivered transarterially to lodge within the neovasculature of the metas-
tases. is treatment delivers irradiation locally and concomitantly reduces
tumor blood supply. Although embolic in concept, the major arterial sup-
ply remains intact, which permits subsequent TAE/TACE. Candidates for
Chapter 16 / Neuroendocrine and Noncolorectal Liver Metastases 199
SIRT must harbor hepatic dominant disease and have angiographic proof
of limited extrahepatic arterial shunting. SIRTs should be considered in
patients with miliary hepatic metastases in particular. Repeat SIRT is pos-
sible. Current data suggest that SIRT is equally ecacious as TAE in achiev-
ing symptom control.
Radiation Therapy
External beam irradiation for the treatment for hepatic metastases has
been limited by the inability to deliver eective cytotoxic radiation doses
to tumors without associated signicant parenchymal damage. Because
NECs have SRs that bind endogenous somatostatin, radiolabeled soma-
tostatin analogs potentially can deliver radioactive compounds directly to
the metastases. Peptide receptor radionuclide therapy (PRRT) combines
octreotide with various radionuclides. Radiopeptides are typically deliv-
ered through selective arterial perfusion as in SIRT. e radioparticles are
retained preferentially in the metastases due to selective receptor binding
delivering high-dose local irradiation while sparing normal liver tissue.
Radionuclides vary (
90
Yttrium,
111
Indium,
177
Lutetium); each emits radia-
tion of diering type and depth of tissue penetration. Although conceptu-
ally attractive, most agents are still investigational. Selective radiolabeled
therapies have shown signicant benets, specically in patients with
recalcitrant tumor and symptoms after TAE/TACE. Objective response to
PRRT has been seen in up to 50% of patients. Furthermore, PRRT has been
shown to be eective treating the hypoglycemia of metastatic insulinoma
and is recommended after failure of standard treatments. e overall role
for radiolabeled receptor therapy in conjunction with other liver-directed
therapies including surgery is evolving.
Hormonal Therapy
Somatostatin analog treatment is the gold standard medical therapy for
patients with inoperable carcinoid cancer. In most patients with the car-
cinoid syndrome, control is often urgently required, and somatostatin
analogs provide prompt relief. Treatment is initiated with short-acting ana-
logs to conrm response because octreotide only binds to some SR. Once
response is conrmed, long-acting analogs are used to maintain response
with monthly injections. Randomized trial data support octreotide use for
control of symptoms and improved QOL. Additionally, octreotide has an
antiproliferative, apoptotic eect. Although used as a rst-line treatment in
patients with advanced, unresectable midgut NEC, response in this setting
is frequently partial (< 10%) and typically stabilizing (50%). Other soma-
tostatin analogs that bind with higher anity to various SRs are emerging
and will likely play a greater role in primary and adjuvant therapy in the
future. Interferon alpha has also been utilized however carries signicant
and often poorly tolerated side eects. Somatostatin analogs are also typi-
cally used as adjuncts in combination therapy. Eventual treatment failures
occur after 1 to 2 years due to tachyphylaxis from the larger doses that are
required. Gastric antisecretory agents such as H2 blocker and PPI should
be used in all patients with gastrin-secreting tumors; similar cumulative
tachyphylaxis is also seen with these agents (Fig. 16.7).
Chemotherapy
e role of systemic chemotherapy for metastatic NEC is limited, though
chemotherapy ecacy has been seen in well-dierentiated NEC. Regardless
of agents, response to chemotherapy is dependent on the site of NEC ori-
gin and tumor grade. Chemotherapy is considered second-line therapy
for midgut NEC because response rates are typically only 10% to 15%.
Section II / Liver200
FIGURE 16.7 A. Computed tomography of a hypodense duodenal gastrinoma metastasis.
B. In-111 octreotide scan revealing left medial sector gastrinoma metastasis with normal
physiologic uptake of indium-111 in the gallbladder, spleen, and kidneys.
In contrast, various combinations of streptozocin and doxorubicin/5-FU,
temozolomide and thalidomide, or single-agent dacarbazine may be con-
sidered in patients with advanced unresectable or progressive low-grade
metastatic pancreatic NEC. Objective response rates approach 30%, and
overall survival is improved compared to no therapy. More than 50% of
patients with poorly dierentiated NEC (regardless of origin) respond to
combinations of etoposide and cisplatin. Systemic
treatment failure in
(Continued )