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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_775_Библиотеки_им_академика_М_И_Перельмана.pdf
Surgical Approach toPancreas, Liver,
Biliary Physiologic Impairment
AlexandraW.Acher, AmirA.Rahnemai-Azar,
SharonM.Weber, andTimothyM.Pawlik
5
Abstract
The multi-disciplinary management of hepato-pancreatobiliary diseases involves the treatment of both benign and
malignant lesions. Benign liver lesions can be divided
into non-infectious and infectious lesions. The most common infectious lesions include abscesses, parasitic
lesions, fungal lesions, and granulomatous diseases. The
most common non-infectious primary benign liver lesions
include simple hepatic cysts, hepatic hemangiomas, focal
nodular hyperplasia, hepatic adenoma, and biliary cystadenoma. The most common liver malignancies include
metastatic disease from a non-hepatic primary followed
by hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and more rarely hepatic angiosarcoma. The treatment approach for liver malignancies should be rooted in
a multidisciplinary collaboration between medical and
radiation oncologists, interventional radiologists, pathologists, and hepatobiliary surgeons. Critically important to
treatment planning is the ability to contextualize the surgical and medical options relative to a patient’s disease
burden, comorbidities, and underlying liver function. We
herein review the pathophysiology and surgical management strategies of benign and malignant hepato- pancreatobiliary diseases.
A. W. Acher · S. M. Weber
Department of Surgery, Division of Surgical Oncology, University
of Wisconsin School of Medicine and Public Health,
Madison, WI, USA
A. A. Rahnemai-Azar
Department of Surgery, Division of Surgical Oncology, California
University of Science and Medicine, Colton, CA, USA
T. M. Pawlik (
Department of General Surgery, Division of Surgical Oncology,
The Ohio State University College of Medicine,
Columbus, OH, USA
e-mail: tim.pawlik@osumc.edu
*)
5.1 Benign Liver Disease:
Pathophysiology andIndications
forSurgical Treatment
Benign liver lesions can be divided into non-infectious and
infectious lesions. The most common infectious lesions
include abscesses (pyogenic, amebic abscess), parasitic
lesions (Echinococcus Granulosa or Hydatid cyst,
Echinococcus Multilocularis, Schistosomiasis), fungal
lesions (Candidiasis, Cryptococcus), and granulomatous diseases (Tuberculosis, Histoplasmosis) [1]. Depending on etiology and symptoms, the treatment of infectious lesions
largely involves medical therapy, sometimes aided by percutaneous drainage, and only rarely surgical intervention [1].
This review therefore focuses on non-infectious lesion
pathophysiology and surgical management strategies. The
most common non-infectious primary benign liver lesions
include simple hepatic cysts, hepatic hemangiomas, focal
nodular hyperplasia, hepatic adenoma, and biliary
cystadenoma.
5.1.1 Hemangioma
Hepatic hemangiomas are benign hepatic artery supplied
vascular lesions that can contain thick brous septations and
internal thromboses [2, 3]. Hepatic hemangiomas can be
solitary or multifocal and range in size from a few millimeters to >20 cm in diameter. Although hemangiomas have
been observed to grow in pregnancy and estrogen supplementation, targeted investigation has not demonstrated any
association between estrogen-enhanced states and hemangioma incidence or growth [4, 5]. Hemangiomas are hypothesized to result from dysregulated congenital intrahepatic
angiogenesis and although they rarely increase in size,
enlargement occurs secondary to ectasia or dilation of the
vessels rather than vessel hypertrophy or proliferation [2, 3].
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_5
31
32
ab
cd
A. W. Acher et al.
Although hemangiomas are highly vascular lesions, the risk
of spontaneous hemorrhage or rupture is very low due to the
thick walls and internal septations; the majority remain
asymptomatic over time [2, 3].
Management should be guided by the degree to which
symptoms affect a patient’s quality of life. Thorough evaluation should rule out other symptom etiology. There is no
indication for surgical intervention or regular surveillance in
asymptomatic or minimally symptomatic lesions.
Signicantly symptomatic lesions in healthy surgical candidates can be managed with either laparoscopic or open tumor
enucleation, wedge resection, or formal liver resection
depending on the tumor size and location. Giant hemangiomas and diffuse multifocal hepatic hemangiomatosis have
also been treated with liver transplantation, although the data
are limited to a few case reports [6]. In patients with symp-
tomatic lesions who are not surgical candidates, radiotherapy
and arterial embolization can be offered, although both have
transient response and should only be considered as palliative treatments to improve quality of life [7–9].
5.1.2 Focal Nodular Hyperplasia
Focal Nodular Hyperplasia (FNH) arises from hepatocyte
and cholangiocyte hyper-proliferation that represents a local
cellular response to congenital arteriovenous malformation
[4]. Although FNH lesions can be estrogen receptor positive,
estrogen-enhanced states (pregnancy or estrogen use) do not
increase the frequency or size of FNH lesions [10]. On axial
imaging, FNH often present with a central stellate scar but
this pathopneumonic characteristics can be absent (Fig.5.1)
Fig. 5.1 Stellate scar in association with focal nodular hyperplasia. In-
(a) and opposed-phase (b) GRE T1-WI, fat-suppressed FSE T2-WI (c),
pre (d) and post hepatocyte-specic contrast agent (Eovist
pressed 3D-GRE T1-WI at the arterial (e), portal venous (f), interstitial
(g) and hepatobiliary (h) phases. There is a lesion on the left hepatic
lobe (white arrow, a–h), showing isointense signal comparing to the
surrounding liver on non-contrast T1-WI (a, b and d) and on T2-WI (c).
The lesion also shows a central scar (black arrow, a–h), which is
hypointense on T1-WI (a, b and d) and hyperintense on T2-WI (c). The
lesion demonstrates homogeneous enhancement on early post-contrast
®
) fat-sup-
images (e), becoming isointense to the underlying liver parenchyma (f
and g). The progressive enhancement of the central scar is depicted on
the delayed post-contrast images (g). On the hepatobiliary phase,
20min after the administration the hepatocyte-specic contrast agent,
the lesion shows uptake of the contrast agent, becoming minimally
hyperintense comparing to the surrounding liver parenchyma. Since the
central scar has no hepatocytes, there is no uptake of the contrast agent,
becoming hypointense comparing to the liver and to the rest of the
lesion. GRE Gradient-echo, FSE Fast spinecho, T1-WI T1-weighted
images
ef
gh
5 Surgical Approach to Pancreas, Liver, Biliary Physiologic Impairment
33
Fig. 5.1 (contnued)
[4]. Interestingly, the formation of the stellate scar is secondary to oxidative stress caused by an over-abundance of oxygenated blood inherent in the arteriovenous malformation,
which activates stellate cells, the primary drivers of liver
brosis [11].
Due to their benign, largely asymptomatic and nonprogressive nature, management of FNH is observationbased with surgery rarely being indicated.
Management options include observation, aspiration with
or without sclerotherapy, cyst fenestration, or surgical resection [14, 15]. Aspiration (+/− sclerotherapy) has a high rate
of recurrence and has largely been replaced by cyst fenestration in patients t for surgery [14]. Although rare, hepatic
cystadenoma (discussed subsequently) can appear indistinguishable from a simple hepatic cyst on axial imaging, but
cystadenomas require resection due to associated risk of
invasive cancer [16]. Cyst fenestration is therefore the denitive treatment for large peripheral or symptomatic cysts, as it
5.1.3 Simple Hepatic Cyst
allows for intraoperative biopsy/cytology and the ability to
adjust the surgical plan if cystadenoma or cystadenocarci-
Simple cysts are thin walled and lined by cuboidal epithelium that can contain septa. Simple hepatic cyst size can
range from <1cm to more than 20 cm in diameter, and are
rarely symptomatic [12]. Simple cysts are thought to form
congenitally when intrahepatic ductules fail to merge with
the developing contiguous biliary system; over time, these
cysts can dilate and ll with yellow serous uid secondary to
epithelial cyst wall secretion of uid [12, 13].
noma is discovered. Cyst fenestration can be done safely
with either a laparoscopic or open approach. Laparoscopic
cyst fenestration has equivalent recurrence rates and less
perioperative morbidity than an open approach, however,
depending on the location of the cyst, an open approach may
facilitate a more complete fenestration [17–19]. An open
approach may also be preferred in the setting of a recurrent
cyst.
34
A. W. Acher et al.
5.1.4 Hepatic Adenoma
Hepatic adenomas are rare, soft, well-demarcated,
hepatocyte- based tumors supplied by hepatic artery-derived
arterioles, and occur as solitary or multifocal lesions. Hepatic
adenomas are largely considered as benign lesions, yet can
have malignant potential [20]. Solitary adenomas are associated with female gender, oral contraceptive use, obesity,
alcohol use, and anabolic steroids [20, 21]. In contrast,
hepatic adenomatosis (>10 lesions) can occur in association
with glycogen storage diseases [20, 22]. Adenoma rupture
and hemorrhage occurs in up to 20% of lesions and is associated with increasing tumor size (>4–5 cm), exophytic and
peripheral tumor location, left lateral sector tumor location,
and prominent supplying arteries on axial imaging [23]. The
overall rate of malignant transformation is around 4% and is
only associated with certain subtypes [24, 25]. Although
hepatic adenomas are difcult to distinguish from FNH and
hepatocellular carcinoma on routine imaging modalities, the
use of gadoxetic acid enhanced MRI has increased diagnostic sensitivity from 50% to 96%, enabling more accurate risk
stratication of these tumors [26, 27]. Small lesions (<2cm)
remain difcult, however, to distinguish; in turn, biopsy may
be benecial in some patients [28]. The clinical benet of
biopsy has increased with mutation-based subtyping of
hepatic adenomas given that each subtype has varying
degrees of malignant potential [28].
The most common hepatic adenoma subtype is associated
with a mutation in TCF1, the gene responsible for hepatocyte
nuclear factor-1 alpha (HNF-1a), a transcription factor
involved in hepatic cell homeostasis, metabolism, and cell
differentiation. This mutation inactivates HNF-1a, leading to
non-regulated cell differentiation [25, 29]. HNF-1a subtype
adenomas exhibit steatosis and have a frequency of malignant transformation of 7% [25, 30]. A second subtype results
from an activation mutation in CTNNB1 gene that encodes
beta-catenin, a transcriptional co-regulator protein that,
when aberrantly activated, promotes the transcription of
c-Myc and CycinD-1 oncogenes [25, 30, 31]. B-catenin subtype adenomas have pseudo-glandular cells with some cytological abnormalities and have a frequency of malignant
transformation of 46% [25, 30]. A third subtype is associated
with mutations in various oncogenes leading to uncontrolled
activation of the IL-6 inammatory pathway. Inammatory
hepatic adenomas are dened by inammatory inltrates and
dystrophic vessels and have not demonstrated malignant
potential [25, 30]. A fourth subtype, referred to as the unclassied subtype, is not associated with mutations or inammation. The unclassied subtype does not have any marked
steatosis, cytological abnormality, or inammatory inltration but is composed of stacked hepatocytes and has a 13%
frequency of malignant transformation [25, 30]. A nal subtype, referred to as the sonic hedgehog subtype, results from
activation of the sonic hedgehog pathway that is involved in
lipid metabolism and liver regeneration. This subtype is
associated with obesity and while it does not have increased
malignant potential, it is associated with a high risk of hemorrhage [25]. Independent of subtype, male gender and
tumor size (> 5cm) are associated with an increased risk of
malignant transformation [32, 33].
Given the diversity of subtype and presentation, management strategies for hepatic adenomas must weigh patient sex
and comorbidities, exogenous estrogen or androgen exposure, the genetic subtype, tumor size and the risks inherent in
surgery. Given the increased risk of malignancy in male
patients, discontinuation of androgen therapy and surgical
resection is recommended as rst line treatment [24, 25, 34].
For female patients with tumors <5cm, initial conservative
management may include discontinuation of any exogenous
estrogen or androgen therapy, weight loss, and 6–12months
of surveillance imaging [34]. Tumor regression can occur in
up to 79% of patients after discontinuation of OCPs [35]. In
female patients with tumor progression after hormone cessation or with tumors >5cm, surgical resection is the recommended rst line treatment [34]. Microwave ablation is an
alternative to surgical resection [36, 37]. With better understanding of malignant potential of certain hepatic adenoma
subtypes, many clinicians advocate for surgical resection of
B-catenin subtype tumors regardless of their size while
inammatory subtype or HFN1a subtype can be managed
more conservatively [25, 34].
In the event that a patient presents with adenoma rupture
and hemorrhage, transarterial embolization (TAE) of supplying vessels may be performed. Most patients who have
continued bleeding will eventually tamponade the site of
adenoma rupture and stabilize. The rate of complete tumor
regression associated with TAE is 10% while partial regression can approach 75% [38]. However, eventual surgical
resection is often necessary for denitive management [38].
5.1.5 Biliary Cystadenoma andthePotential
forCystadenocarcinoma
Biliary cystadenomas are rare multi-loculated cystic tumors
composed of biliary columnar epithelial cells. Interestingly,
spindle and ovarian stromal cells can also be present, which
may offer insight into an otherwise obscure etiology [39].
These lesions are mostly associated with the intrahepatic
biliary system and have a predominance in the left liver [39].
Biliary cystadenomas are slow growing lesions, which vary
in size, and can be radiologically difcult to distinguish from
5 Surgical Approach to Pancreas, Liver, Biliary Physiologic Impairment
35
simple hepatic cysts or biliary cystadenocarcinoma [39]. On
nal pathology, 10% of cystadenomas are found to have
transformed to biliary cystadenocarcinoma [39].
Historically, the management options of cystadenoma
varied from fenestration and wedge resection to formal hepatectomy. However, the current standard of care is to perform
cyst enucleation or formal hepatic resection to mitigate the
risk of recurrent disease and cystadenocarcinoma [40]. The
rate of cystadenoma recurrence is 49% in cyst fenestrations
versus 15% in partial hepatectomies/enucleations and 10%
in formal hepatectomies [39]. Other factors associated with
an increased risk of recurrence include an R1/R2 resection
and the presence of ovarian stromal and spindle cells (present in up to 90% of biliary cystadenomas) [39]. If biliary
cystadenocarcinoma is noted on nal pathology, a formal
hepatectomy may be considered as long as it is compatible
with patient comorbidities, cyst location, and the future liver
remnant (FLR). This is an especially relevant point as preoperative distinction of biliary cystadenoma from cystadenocarcinoma is limited by poor sensitivity (80%) and specicity
(21%) using axial imaging modalities (CT or MRI) [39].
Surgeons who advocate for partial hepatectomy or cystadenoma enucleation should counsel patients that a formal hepatectomy may be required if cystadenocarcinoma is found on
nal pathology.
5.2 Malignant Liver Disease:
Pathophysiology andIndications
forSurgical Treatment
The most common liver malignancies include metastatic disease from a non-hepatic primary followed by hepatocellular
carcinoma, intrahepatic cholangiocarcinoma, and more
rarely hepatic angiosarcoma. The treatment approach for
liver malignancies should be rooted in a multidisciplinary
collaboration between medical and radiation oncologists,
interventional radiologists, pathologists, and hepatobiliary
surgeons. Critically important to treatment planning is the
ability to contextualize the surgical and medical options relative to a patient’s disease burden, comorbidities, underlying
liver function, and FLR.Typically, the FLR should be >20%
for patients with normal liver, ≥ 30% for patients with brosis or steatosis, and≥40% for patients with cirrhosis [41].
The extent of resection, however, should also be assessed
relative to patient age, functional status, and response to any
neoadjuvant therapy exposure as these factors have been
shown to inuence post-hepatectomy outcome [41, 42].
Liver function can be assessed by the Child-Pugh scoring
system or the Model for End Stage Liver Disease (MELD)
scoring system [43, 44].
5.2.1 Hepatocellular Carcinoma
Hepatocellular carcinoma is the most common primary
hepatic malignancy. Its incidence varies with geographic
region, with a higher incidence in areas with endemic
hepatitis B infection (i.e. sub-Saharan Africa, Eastern Asia,
Mediterranean countries) [45]. Globally, the average 5-year
cumulative risk of developing HCC is 0.1–0.3% in inactive
HBV carriers, 0.6–2.4% in patients with chronic hepatitis B
virus (HBV), and 10–15% in patients with chronic HBV and
cirrhosis [46]. However, this risk is higher in areas with
endemic HBV [46]. Other conditions that predispose to
developing HCC include chronic hepatitis C infection with
cirrhosis (the most common etiology in North and South
America), alcohol liver disease with cirrhosis, non-alcoholic
fatty liver disease, toxin exposure (aatoxin, polyvinyl chloride, carbon chlorides), and non-alcoholic steatohepatitis
with cirrhosis [45]. The common denominator underlying all
these conditions is a state of chronic intrahepatic inammation (largely mediated through IL-6 inammatory pathway),
which is thought to promote dysplasia and malignant transformation of hepatocytes [45]. Additionally, there is likely a
synergistic and oncogenic relationship between underlying
inammation and genetic mutations that compound the risk
of HCC [47]. Examples of the most common hepatocarcinogenic gene mutations include those in telomerase reverse
transcriptase (TERT) promoter gene, CTNNB1 that encodes
B-catenin, and TP53 that encodes the tumor suppressor protein p53 [47, 48].
Treatment of HCC is complex and requires a multidisciplinary approach with input from medical and radiation
oncology, interventional radiology, pathologists, and hepatobiliary surgeons. Assessment of liver function and staging of
disease are crucial to the preoperative work up and have very
signicant prognostic implications that should be weighed
against the risks of surgery and the patient’s goals. Liver
function should be assessed by the Child-Pugh or the Model
for End Stage Liver Disease (MELD) scoring system. The
Barcelona Clinic Liver Cancer (BCLC) staging system is
one of the most commonly used tools to guide treatment
strategy by a summative assessment of tumor stage, liver
function, and patient functional status and includes estimated
prognosis of each treatment approach (Fig.5.2) [49]. In general, very early stage and early stage HCC can be considered
for tumor ablation, oncologic resection, or transplantation.
According to institutional practice, the Milan or San
Francisco Criteria may be used to guide transplant candidacy
based on the number and size of tumors (Table 5.1) [50].
BCLC intermediate stage are recommended to undergo chemoembolization while patients with advanced stages can be
enrolled in systemic therapy clinical trials [49]. Although
36
BCLC Staging and treatment schedule
A. W. Acher et al.
HCC
Stage 0
PST 0, Child-Pugh A
Very early stage (0)
Single<2cm
Carcinoma in situ
Single
Portal pressure/ bilirubin
Normal
Resection
Fig. 5.2 Barcelona-Clinic Liver Cancer (BCLC) staging classication and treatment schedule. PST performance status; CLT/LDLT cadaver liver
transplant/living donor liver transplant; RF/PEI radiofrequency ablation/percutaneous ethanol injection; TACE transarterial chemoembolization
Table 5.1 Milan and San Francisco criteria for liver transplantation in
the setting of hepatocellular carcinoma
Milan Criteria San Francisco Criteria
Single tumor <5cm
OR
1–3 tumors, each <3cm
Single or 3 nodules < 3cm, PS 0
Increased
Curative Treatments (30%)
5-yr survival : 50-70%
Early stage (A)
No Ye s
Liver Transplantation
(CLT / LDLT )
Single tumor <6.5cm
OR
1–3 tumors, each <4.5cm
OR
Total combined tumor diameter<8cm
Okuda 1-2, PST 0-2, Child-Pugh A-B
3 noudles <3cm
Associated diseases
PEI/RF Chemoembolization
Stage A-C
Intermediate stage (B)
Multinodular, PS 0
Randomized controlled trials (50%)
3yr survival: 20-40%
breast, skin, and lung cancers [51]. The most common indication for hepatic metastectomy is for colorectal liver metastases. In surgically-t patients with colorectal liver
metastasis, complete oncologic resection of metastases is
associated with a survival benet [52–59]. Appropriately
selected patients with hepatic metastases from primary pancreas or gastrointestinal neuroendocrine tumors may also
Okuda 3, PST >2, Child-Pugh C
Advanced stage (C)
Portal invasion, Na, M1, PS 1-2
Portal invasion, N1, M1
New
Agents
Stage D
Te rminal
stage (D)
Symptomatic Itc (20%)
1yr survival: 10-20%
benet from metastectomy [60]. The data supporting hepatic
some patients with BCLC intermediate stage HCC may also
be candidates for resection. Among surgical candidates, portal vein embolization can be used to induce contralateral
resection of other metastatic lesions from a primary breast
cancer, etc. are evolving; in turn, hepatectomy can be considered for appropriately selected patients [61].
liver hypertrophy prior to oncologic resection. Internal radiation therapy with Yttrium-90 can be used to treat the primary
tumor as well as induce contralateral hypertrophy in support
5.2.3 Intrahepatic Cholangiocarcinoma
of eventual curative intent oncologic resection. Despite these
treatment strategies, the 3year survival for intermediate and
advanced stage HCC is 20–40% [49].
Intrahepatic cholangiocarcinoma (ICC) is rare and arises
from malignant transformation of cholangiocytes lining the
intrahepatic biliary tree (Fig.5.3) [62]. Although biliary in
nature, ICC is considered a primary liver cancer [62].
5.2.2 Metastatic Disease
Primary sclerosing cholangitis, choledochal cyst disease,
chronic hepatitis B or C infection, cirrhosis, fatty liver dis-
The liver is a common site of metastatic spread for multiple
primary cancers. The majority of hepatic metastases originate from the gastrointestinal tract (70–75%) with nearly
50% originating from the colon or rectum [51]. However,
other common origins include stomach, pancreas, biliary,
ease, toxin exposure (asbestos), parasitic infection, obesity,
and diabetes are associated with increased risk of ICC development [63]. Similar to HCC, ICC is thought to result from
a synergistic relationship between chronic inammation and
genetic aberrancies. Associated mutations include: KRAS
bc
ype IIIb
5 Surgical Approach to Pancreas, Liver, Biliary Physiologic Impairment
37
Fig. 5.3 Anatomic
classication of
cholangiocarcinoma. “a: The
classication of
cholangiocarcinoma can be
based on anatomic location,
intrahepatic, hilar or
extrahepatic; b: Non-hilar
lesions can be described as
mass-like, periductal or
intraductal; c: Bismuth
classication for hilar
lesions.” Type I
cholangiocarcinoma involves
the common hepatic duct
only; Type II
cholangiocarcinoma involves
the common hepatic duct and
the conuence of the right
and left hepatic ducts; Type
IIIa and IIIb
cholangiocarcinoma includes
the common hepatic duct and
either the right or left hepatic
duct, respectively; and Type
IV cholangiocarcinoma
involves the biliary
conuence and extends to
both right and left hepatic
ducts or refers to multifocal
sites
a
Mass-like
Periductal
Intraductal
Intrahepatic
Hilar
Extrahepatic
Right hepatic
duct
Cystic duct
Distal common
bile duct
Left hepatic
Common
hepatic duct
Type I
Type IIIa
duct
Type II
T
gene which encodes K-Ras signaling protein of the RAS/
MAPK pathway crucial to cell proliferation and differentiation; TP53 which encodes tumor suppressor protein, P53;
IDH1 gene which encodes isocitrate dehydrogenase, an
enzyme critical for NADPH-dependent cellular metabolism
and sequestration of reactive oxygen species [64]. Other cell
signaling pathways, including Hedgehog (previously referenced relation to hepatic adenoma subtypes) and WNT/B- catenin (previously referenced in relation to hepatic adenoma
subtype malignant potential and HCC) are also altered [64].
As in HCC, IL-6 likely has a large role in linking a chronic
inammatory state and genetic alterations to facilitate malignant transformation of cholangiocytes [64].
Surgical resection provides the only option for potential
cure in patients with ICC.Unfortunately, most patients present with advanced disease not amenable to curative resection. Contraindications to resection include extrahepatic
disease, multiple bilobar or multicentric tumors, and lymph
node metastases [65]. As in HCC, as markers of tumor biology are discovered, tumor biology may play an increasing
role in helping to identify patients with the most potential to
benet from surgery; these advancements will undoubtedly
change the surgical landscape for this disease [66].
Type IV Type IV
5.2.4 Hepatic Angiosarcoma
Hepatic Angiosarcoma is a rare but aggressive vascular
tumor that can present as a solitary lesion with satellite
lesions or a diffuse inltrative mass. These tumors are formed
from malignant transformation of vascular endothelial cells
and are prone to hemorrhage. The pathogenesis of these
tumors is unclear, however, 25% may result from hemochromatosis or previous exposure to thorium dioxide, arsenic
based insecticides, or vinyl chlorides [67]. Most patients
present with metastatic disease and die within 6months of
presentation; unfortunately, even for patients who do undergo
treatment, 3year survival is only 3% [67].
Liver transplantation and liver resection have both been
utilized as potential treatment options, however, liver transplantation has been redacted given the high rate of recurrence and mortality. Liver resection can be offered to patients
with early stage disease, however, recurrence is exceedingly
likely. Transcatheter arterial chemoembolization has also
been employed as a palliative measure in patients who present with hemorrahge [67].
38
A. W. Acher et al.
5.3 Benign Biliary Disease:
Pathophysiology andIndications
forSurgical Treatment
The most common extrahepatic benign biliary diseases
include acute or chronic calculous cholecystitis, acalculous
cholecystitis, biliary dyskinesia, choledocolithiasis, ascending cholangitis, gallstone pancreatitis, and Sphincter of Oddi
dysfunction. Less common but potentially equally affecting
pathologies include choledochal cysts and benign biliary
strictures.
Calculous cholecystitis, choledocolithiasis, ascending
cholangitis, gallstone pancreatitis are all potential complications from gallstones. Gallstones form secondary to
imbalances in the three components of bile (phospholipids, bile salts, and cholesterols) and are either cholesterol
stones (70%) or pigment stones (30%). Cholesterol stones
form secondary to a relative abundance of cholesterol
compared to solubilizing phospholipid and bile salts which
leads to cholesterol crystallization [68]. Cholesterol stone
precipitation is also catalyzed by mucus glycoprotein,
secreted by gall bladder and biliary duct epithelial cells to
bind lipids and bile pigments, and gall bladder hypomotility [68, 69]. Pigment stones can be either black or brown;
black pigment stones precipitate in the gall bladder lumen
and are produced in hemolytic disorders (sickle cell anemia, hereditary spherocytosis, Gilbert syndrome) when
bilirubin polymers bind mucus glycoproteins [68, 70].
Brown stones precipitate in the bile ducts secondary to
bacterial byproducts that increase the concentration of
unconjugated bilirubin, which then complexes with calcium to form stones [68, 70].
5.3.1 Acute Calculous Cholecystitis
Acute calculous cholecystitis is an inammation of the gallbladder that most commonly results from a stone-dependent
outlet obstruction at either the infundibulum or cystic duct
[71]. The outlet obstruction leads to gall bladder distension,
wall edema and inammation with resulting vascular congestion, that if left untreated progresses to wall necrosis and
fundal perforation. Bactobilia occurs in 20% of patients with
acute cholecystitis [72] while bacteremia develops in a
minority of patients (<10%) but is associated with increased
mortality [73]. In 87% of bacteremic patients, a single bacterial isolate is identied and is most often either Escherichia
Coli or Klebsiella pneumonia [73].
The Tokyo Guidelines can be used to grade cholecystitis
severity with predicted 30-day mortality rate, which can aid
in guiding treatment options within the context of patient
presentation, comorbidities, and goals [74]. For patients who
are surgical candidates, standard of care treatment is urgent
laparoscopic cholecystectomy with or without intraoperative
cholangiogram to verify biliary anatomy and ensure common bile duct patency. Attaining a critical view of safety has
been demonstrated to reduce the risk of bile duct injury [75].
This is accomplished by clearing the hepatocystic triangle of
fat and brous tissue and dissecting the lower third of the
gall bladder from the cystic plate to visualize only two structures, the cystic duct and cystic artery, entering the gall bladder [76]. If severe pericholecystic inammation prevents
safe denition of the critical view of safety, conversion to an
open approach may be necessary [75, 77]. Risk factors for
conversion to an open approach include male gender, obesity, leukocytosis and elevated serum bilirubin, and history
of previous surgery [78–80]. Alternatively, if the critical
view of safety is not attainable, a subtotal fenestrating or
subtotal reconstituting cholecystectomy can be performed
[81]. A subtotal fenestrating cholecystectomy involves excising the peritonealized gall bladder, leaving the posterior gall
bladder wall in situ, and suture ligating the cystic duct [81].
A subtotal reconstituting cholecystectomy involves excising
the peritonealized gall bladder and closing the inferior gallbladder (sewing or stapling) to recreate a small lumen with a
patent cystic duct [81]. Fenestration is associated with a
higher incidence of postoperative bile leak (18% vs 7%),
wound infection (11% vs 3%), and longer hospitalization (5
vs 3 days); however, reconstitution is associated with a
higher risk of recurrent biliary pathology (18% vs 9%) [82].
Non-operative management of acute calculous cholecystitis
may be necessary for patients who are not surgical candidates
or whose pericholecystic inammation precludes safe dissection. Percutaneous cholecystostomy tube placement allows for
immediate clinical improvement in >80% of patients and can
be followed by interval cholecystectomy (performed at least
6weeks after placement) in select patients [83–85].
A more recently developed management option for
patients who are not surgical candidates (i.e. terminal cancer), includes internal drainage with lumen-apposing selfexpandable metallic stents (LASEMS), placed between the
stomach or duodenum and the gall bladder to facilitate
enteric drainage [86]. Although preliminary observational
studies report few complications and high rates of symptom
resolution, outcomes data and randomized studies are still
pending [86].
5.3.2 Chronic Cholecystitis
Chronic cholecystitis results from repeated transient gall
bladder outlet obstruction, most commonly from intermittent
stone impaction at the cystic duct or infundibulum. This
pathology appears to be more common in obese female
5 Surgical Approach to Pancreas, Liver, Biliary Physiologic Impairment
39
patients and is thought to be related to an increased biliary
cholesterol concentration in this patient population [87].
Xanthogranulomatous cholecystitis is a form of chronic
cholecystitis that can appear on ultrasound and axial imaging
similarly to gall bladder cancer. It is dened by signicant
inammation and brosis of the gall bladder wall with asymmetric wall thickening, mass formation, and bile extravasation into the gall bladder wall [88, 89]. Its exact pathogenesis
is unknown, but it is associated with gallstones and geography (higher incidence in India) and may be associated with
an increased risk of gall bladder cancer [89].
Management of chronic cholecystitis and xanthogranulomatous cholecystitis can be approached similarly to management of acute cholecystitis, however, given the chronicity
of symptoms, cholecystectomy may be less urgently
indicated.
5.3.3 Acalculous Cholecystitis
Acalculous cholecystitis occurs secondary to gall bladder
aperistalsis in the context of concomitant major illness (i.e.
sepsis, severe trauma or burns), severe vascular disease, or
advanced diabetes [90–93]. In these physiologically compromised states, it is hypothesized that lack of gall bladder contraction promotes bile stasis and biliary sludge, eventually
resulting in gall bladder wall edema, inammation, and
infection [94, 95].
Due to the concomitant severe illness, management of
acalculous cholecystitis is non-operative. Gall bladder
decompression is facilitated through percutaneous cholecystostomy tube placement with potential for interval cholecystectomy. Unfortunately, the mortality risk of patients who
undergo percutaneous cholecystostomy placement for acalculous cholecystitis is almost 15%, which likely reects the
impact of severe systemic illness rather than cholecystitisspecic mortality alone [96, 97].
5.3.4 Biliary Dyskinesia
Biliary dyskinesia is a symptomatic functional disorder of
the gall bladder with unclear etiology, but is hypothesized to
result from metabolic disturbance of gastrointestinal and/or
gall bladder motility. Patients have biliary symptoms (postprandial right upper quadrant pain with radiation to the right
shoulder, nausea, anorexia) without any evidence of gallstones or gall bladder inammation on ultrasound.
Hepatobiliary diacetic acid scan (HIDA) with ejection fraction has been used to aid in the diagnosis of biliary dyskinesia. In the presence of biliary pain but the absence of stones
or pericholecystic inammation, an ejection fraction <35%
may support a diagnosis of biliary dyskinesia [98, 99]. For
patients with convincing clinical symptoms, elective laparoscopic cholecystectomy is indicated.
5.3.5 Choledocolithiasis
Symptomatic choledocolithiasis occurs when gallstones
become impacted in the common bile duct.
Choledocolithiasis may be transient and clinically occult;
4% of patients undergoing cholecystectomy for cholelithiasis with patent biliary ducts in preoperative workup have
incidentally discovered choledocolithiasis [100]. However,
choledocolithiasis may also present as biliary colic or more
serious clinical sequelae such as obstructive jaundice with
or without ascending cholangitis and gall stone pancreatitis. Primary choledocolithiasis refers to stones that form in
the common bile duct and is more commonly seen with
pigment stones [101]. In contrast, secondary choledocolithiasis refers to stones, more commonly cholesterol stones,
that form in the gall bladder and then migrate via the cystic
duct to the common bile duct [101].
Surgical management of symptomatic choledocolithiasis requires common bile duct clearance and cholecystectomy. Common bile duct clearance can be achieved with
endoscopic retrograde cholangiopancreatography (ERCP)
with sphincterotomy and ductal balloon dilation, laparoscopic transcystic common bile duct exploration with choledocoscopy, laparoscopic choledocotomy and common
bile duct exploration, or less commonly, open cholecystectomy with duodenotomy and manual stone extraction. A
two-stage approach consists of either pre- or post-cholecystectomy ERCP with sphincterotomy and balloon dilation,
while a single stage approach refers to cholecystectomy
with common bile duct exploration and stone clearance
during the index operation. Both approaches are effective
strategies with equivalent duct clearance success rates and
morbidity [102].
A two stage approach, with ERCP prior to cholecystectomy, is preferred in patients who present with ascending
cholangitis (with or without gallstone pancreatitis) both for
source control and to increase safety of eventual cholecystectomy. However, for patients who present with obstructive
jaundice or gallstone pancreatitis without sepsis, a period of
observation may be benecial as up to 75% of stones will
pass spontaneously [103]. After symptom resolution, these
patients may undergo laparoscopic cholecystectomy with
intraoperative cholangiogram to ensure duct patency. This
sequence is particularly important to consider, as it avoids
ERCP and the potential for post-ERCP pancreatitis which
occurs in 10–15% of patients and can result in severe systemic illness [104].
40
A. W. Acher et al.
5.3.6 Sphincter ofOddi Dysfunction
Sphincter of Oddi dysfunction has an unclear etiology but is
hypothesized to occur secondary to impaired contractility of
the Sphincter of Oddi that results in recurrent biliary colic or
pancreatitis. Sphincter of Oddi dysfunction is most commonly diagnosed in patients with post-cholecystectomy biliary colic. Treatment remains controversial, as does the
diagnosis itself. In randomized trials of sphincterotomy versus sham procedure, patients with post-cholecystectomy
biliary symptoms who underwent sphincterotomy did not
have greater improvement in symptoms [105]. However, in
randomized trials comparing symptom resolution in patients
with manometry conrmed abnormal sphincter tone, greater
symptom improvement was demonstrated in patients with
RHD
LHD
CHD
abnormal sphincter who underwent sphincterotomy compared with individuals who underwent a sham procedure
[106, 107].
5.3.7 Choledochal Cysts
Choledochal cysts (CC) are dened by dilation of the intra
and/or extrahepatic biliary ductal system. While mainly considered benign lesions, certain subtypes of CC have signicant potential for malignant transformation. There are 5
subtypes of CC, classied by location and extent of biliary
involvement (Fig.5.4). Type I CC are the most common subtype (50–80% of CC) with fusiform dilation of the common
bile duct and lack of biliary mucosal cells [108, 109]. Type II
STOMACH
DUO
Type IType II Type III
Type IVAType IVB Type V
Fig. 5.4 Choledochal cyst classication. Type I cysts are fusiform dila-
tations of the common bile duct (CBD). Type II cysts are true diverticula of the CBD and type III CC (choledochoceles) are intraduodenal
dilations of the common channel. Type IVA CC consist of multiple
intrahepatic and extrahepatic biliary dilatations, while type IVB CC
have extra-hepatic biliary dilatation with a normal intrahepatic biliary
tree. Type V CC, or Caroli’s disease, consist of cystic dilation of the
intrahepatic biliary tree. RHD right hepatic duct, LHD left hepatic duct,
CHD common hepatic duct, DUO duodenum