Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / @xirurgi_2025 / @xirurgi_2025 - 436 - файл
.pdf
406 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
and chemoresistance. Implication of p42-44 MAPK, Akt, Bcl-2 and
MMP13 pathways. Biochem Biophys Res Commun 456: 757–762.
Truty, M.J., Kendrick, M.L., Nagorney, D.M. et al. (2021). Factors predicting
response, perioperative outcomes, and survival following total
neoadjuvant therapy for borderline/locally advanced pancreatic cancer.
Ann Surg 273: 341–349.
Tzeng, C.W., Katz, M.H., Fleming, J.B. et al. (2014). Morbidity and mortality
after pancreaticoduodenectomy in patients with borderline resectable type
C clinical classification. J Gastrointest Surg 18: 146–155; discussion 155-6.
Valle, J.W., Palmer, D., Jackson, R. et al. (2014). Optimal duration and
timing of adjuvant chemotherapy after definitive surgery for ductal
adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3
study. J Clin Oncol 32: 504–512.
Van Cutsem, E., Tempero, M.A., Sigal, D. et al. (2020). Randomized phase III
trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for
patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J
Clin Oncol 38: 3185–3194.
Van Laethem, J.L., Hammel, P., Mornex, F. et al. (2010). Adjuvant
gemcitabine alone versus gemcitabine-based chemoradiotherapy after
curative resection for pancreatic cancer: a randomized EORTC-40013-
22012/FFCD-9203/GERCOR phase II study. J Clin Oncol 28 (29): 4450–
4456. doi: 10.1200/JCO.2010.30.3446.
Versteijne, E., Dam, J.L.V., Suker, M. et al. (2022). Neoadjuvant
chemoradiotherapy versus upfront surgery for resectable and borderline
resectable pancreatic cancer: long-term results of the Dutch randomized
PREOPANC trial. J Clin Oncol 40: 1220–1230.
Versteijne, E., Suker, M., Groothuis, K. et al. (2020). Preoperative
chemoradiotherapy versus immediate surgery for resectable and
borderline resectable pancreatic cancer: results of the Dutch randomized
phase III PREOPANC trial. J Clin Oncol 38: 1763–1773.
Versteijne, E., Vogel, J.A., Besselink, M.G. et al. (2018). Meta-analysis
comparing upfront surgery with neoadjuvant treatment in patients with
resectable or borderline resectable pancreatic cancer. Br J Surg 105:
946–958.
Von Hoff, D.D., Ervin, T., Arena, F.P. et al. (2013). Increased survival in
pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med
369: 1691–1703.
Vonlaufen, A., Joshi, S., Qu, C. et al. (2008). Pancreatic stellate cells: partners
in crime with pancreatic cancer cells. Cancer Res 68: 2085–2093.
Waddell, N., Pajic, M., Patch, A.M. et al. (2015). Whole genomes redefine
the mutational landscape of pancreatic cancer. Nature 518: 495–501.
Walters, D.M., Lapar, D.J., De Lange, E.E. et al. (2011). Pancreas-protocol
imaging at a high-volume center leads to improved preoperative
staging of pancreatic ductal adenocarcinoma. Ann Surg Oncol 18:
2764–2771.
Wang, F., Gill, A.J., Neale, M. et al. (2014a). Adverse tumor biology associated
with mesenterico-portal vein resection influences survival in patients
with pancreatic ductal adenocarcinoma. Ann Surg Oncol 21: 1937–1947.
Wang, W., Shpaner, A., Krishna, S.G. et al. (2013). Use of EUS-FNA in
diagnosing pancreatic neoplasm without a definitive mass on CT.
Gastrointest Endosc 78: 73–80.
Wang, X.Y., Yang, F., Jin, C., and Fu, D.L. (2014b). Utility of PET/CT in
diagnosis, staging, assessment of resectability and metabolic response of
pancreatic cancer. World J Gastroenterol 20: 15580–15589.
Wang, Y., Timotin, E., Zia, W. et al. (2018). Pain palliation using
hypofractionated radiotherapy for unresectable pancreatic cancer. J Med
Imaging Radiat Sci 49: 293–300.
Westermann, A., Matrisian, L.M., and Rahib, L. (2019). The need for
improvement in the management of fatigue, depression and pain in
pancreatic cancer. J Clin Oncol 37: 429-429.
Whatcott, C.J., Diep, C.H., Jiang, P. et al. (2015). Desmoplasia in primary
tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res 21:
3561–3568.
WHO. Palliative care [Online]. (2020). World Health Organization. Available:
https://www.who.int/health-topics/palliative-care (accessed on 26th April
2022).
Wong, G.Y., Schroeder, D.R., Carns, P.E. et al. (2004). Effect of neurolytic
celiac plexus block on pain relief, quality of life, and survival in patients
with unresectable pancreatic cancer: a randomized controlled trial.
Jama 291: 1092–1099.
Xia, B.T., Fu, B., Wang, J. et al. (2017). Does radiologic response correlate to
pathologic response in patients undergoing neoadjuvant therapy for
borderline resectable pancreatic malignancy? J Surg Oncol 115: 376–383.
Xu, Z., Vonlaufen, A., Phillips, P.A. et al. (2010). Role of pancreatic stellate
cells in pancreatic cancer metastasis. Am J Pathol 177: 2585–2596.
Yamada, S., Fujii, T., Sugimoto, H. et al. (2013). Aggressive surgery for
borderline resectable pancreatic cancer: evaluation of National
Comprehensive Cancer Network guidelines. pancreas 42: 1004–1010.
Yamada, S., Shimada, M., Morine, Y. et al. (2021). Significance of frailty in
prognosis after surgery in patients with pancreatic ductal
adenocarcinoma. World J Surg Oncol 19: 94–94.
Yamada, S., Sugimoto, H., Kanazumi, N. et al. (2009). Prognostic factors for
survival after extended pancreatectomy for pancreatic head cancer:
influence of resection margin status on survival. Pancreas 38: 605–612.
Young, E.L., Thompson, B.A., Neklason, D.W. et al. (2018). Pancreatic
cancer as a sentinel for hereditary cancer predisposition. BMC Cancer
18: 697.
Zamboni, G.A., Kruskal, J.B., Vollmer, C.M. et al. (2007). Pancreatic
adenocarcinoma: value of multidetector CT angiography in preoperative
evaluation. Radiology 245: 770–778.
Zhang, Y., Huang, J., Chen, M., and Jiao, L.R. (2012). Preoperative vascular
evaluation with computed tomography and magnetic resonance imaging
for pancreatic cancer: a meta-analysis. Pancreatology 12: 227–233.
Zhou, Y., Zhou, Q., Li, Z. et al. (2012). The impact of internal or external
transanastomotic pancreatic duct stents following pancreaticojejunostomy.
Which one is better? A meta-analysis. J Gastrointest Surg 16 (12): 2322–
2335. doi: 10.1007/s11605-012-1987-2.
Zylberberg, H.M., Woodrell, C., Rustgi, S.D. et al. (2022). Opioid
prescription is associated with increased survival in older adult patients
with pancreatic cancer in the United States: a propensity score analysis.
JCO Oncol Pract 0: OP.21.00488.
21 Management of Intrahepatic and
https://t.me/medicina_free
Extrahepatic Cholangiocarcinoma
Nicholas Holt7, Joanna Lee6, Ngee Soon Lau3, Natalie Collier5, Oliver M. Fisher2,
3
Carlo Pulitano
1
Department of Medical Oncology, St. George Hospital Sydney and Clinical Trials Centre, University of Sydney, New South Wales, Australia
2
Department of Surgery, St. George Hospital Sydney and University of New South Wales, New South Wales, Australia
3
Department of Surgery, Royal Prince Alfred Hospital and University of Sydney, New South Wales, Australia
4
Department of Gastroenterology and Hepatology, St. George Hospital Sydney and University of New South Wales Medical School, New South
Wales, Australia
5
Department of Radiation Oncology, Wollongong Hospital and University of New South Wales, New South Wales, Australia
6
Clinical Trials Centre, University of Sydney, Sydney, Australia
7
Department of Gastroenterology and Hepatology, St. George Hospital Sydney, New South Wales, Australia
, Katrin Sjoquist1 & Philip I. Craig
4
Background
Nicholas Holt & Philip I. Craig
Anatomical Classification
The current anatomical classification of cholangiocarcinoma
(CCA) divides tumors into intrahepatic (iCCA; proximal to
secondary biliary radicles; 10–20% of CCA), perihilar
(pCCA; distal to secondary biliary radicles but proximal to
cystic duct insertion; 50–60% of CCA) and distal (dCCA;
below the cystic duct insertion; 20–30% of CCA). pCCA and
dCCA are often grouped as extrahepatic CCA (eCCA). This
classification has implications for presentation, diagnosis,
management, and prognosis.
The Bismuth-Corlette classification (Bismuth and Corlette
1975) further classifies pCCA, describing lesions that are confined to the hepatic duct (I), confluence (II), confluence and
right intrahepatic duct up to secondary biliary radicles (IIIA, see
Figure 2), confluence and left intrahepatic duct up to secondary
biliary radicles (IIIB) and multifocal (IV) (see Figure 1).
Presentation
The presentation of CCA often differs according to subtype.
The most common presenting symptom of eCCA is painless
jaundice. Associated symptoms may include pain, pruritis,
fever, or constitutional symptoms (Alvaro et al. 2011) . In
contrast, jaundice is less frequent in iCCA, with abdominal
pain being the most common presenting symptom (DeOliveira
et al. 2007). Importantly, 28–39% of iCCA subjects are
Gastrointestinal Oncology: A Critical Multidisciplinary Team Approach,
Second Edition. Edited by Janusz A. Z. Jankowski.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
asymptomatic at presentation with incidental abnormalities
identified on laboratory testing or imaging.
Although most CCAs arise de novo, predisposing conditions
exist. These relate to chronic biliary stasis and inflammation.
Primary Sclerosing Cholangitis (PSC) in particular is relevant
since as many as one in three patients ultimately succumb to CCA
(Boonstra et al. 2013). In this setting CCA may present with jaundice or constitutional symptoms. Alternatively, CCA may be suspected in the setting of progressive liver function test deterioration,
rising tumor markers (i.e. CA 19–9) or abnormal imaging as part
of a screening program. Screening is common and improves
survival (Ali et al. 2018). Choledochal cysts are another group susceptible to CCA development, with studies showing a risk of ranging between 0–17%, depending on the sampled population, and
duration of follow up. Younger subjects are managed with prophylactic resectional surgery (Baison et al. 2019). Pyogenic cholangitis
is a condition of intra-hepatic cholelithiasis that has been associated with a cumulative CCA incidence of approximately 5% over 5
years (M. Chen et al. 1993). In part this relates to an association
between pyogenic cholangitis and endemic infestations with the
liver fluke Opisthorchis viverrini and Clonorchis sinensis in East and
South-East Asia (Banales et al. 2020).
Laboratory Testing
Serum bilirubin levels are often elevated, predominantly the
conjugated fraction. Similarly, elevations of liver enzymes in a
predominantly cholestatic pattern is typical including serum
alkaline phosphatase and gamma glutamyl transferase levels. In
general, levels of liver function tests are lower for iCCA.
Similarly, in the setting of an extra-hepatic biliary stricture,
higher serum bilirubin levels are more likely to suggest a malignant versus benign biliary etiology, with levels >100 µmmol/L
having a sensitivity of 72% and specificity of 87% (Garcea et al.
407
408 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
2011). Biliary obstruction may induce fat-soluble vitamin malabsorption, particularly vitamin K resulting in a coagulopathy
which may be corrected with parenteral replacement.
The role of specific tumor markers being potentially elevated
in CCA including carbohydrate antigen 19–9 ( CA 19–9) are
addressed in Chapter 17.
Differential Diagnosis
The differential diagnosis for CCA depends on the clinical presentation. A patient presenting with painless jaundice with
imaging demonstrating a mass with biliary obstruction is likely
to have an underlying malignancy, although IgG4-related disease may also present in this manner. In patients without a
mass, the differential includes neoplastic and non-neoplastic
causes including post-surgical (including transplant) or radiotherapy-induced strictures, chronic pancreatitis, PSC, IgG4
cholangiopathy and other rare causes.
Figure 1 Cartoon of Bismuth Classification.
Figure 2 A likely Bismuth 3A stricture seen at ERCP; guidewires can be
seen in the Right anterior (arrowhead) and posterior (star) sectoral
ducts.
Imaging and Staging
Oliver M. Fisher
Imaging Modalities for Staging
Intra-hepatic and Perihilar
Cholangiocarcinoma
High-quality multiplane, fine-slice computed tomography
using IV-contrast arterial, portal-venous and delayed phases is
the baseline examination to asses CCA extent. To further characterize the extent of ductal involvement, contrast-enhanced
MRI with magnetic resonance cholangio-pancreatography
(MRCP) is often employed as an alternative to more invasive
endoscopic retrograde cholangiography (ERCP) or percutaneous transhepatic cholangiography (PTC). ERCP and PTC
have the added benefit of providing improved biliary drainage
and allow the facility to obtain cytological or biopsy sampling
of detected lesions.
Given that the main differential for mass-forming iCCA is
HCC, dynamic CT or MRI usually distinguish the two entities.
Over 80% of iCCAs have characteristic CT contrast-behavior with
progressive uptake during arterial and portal-venous and delayed
phases, whereby HCC is typically characterized by arterial contrast
uptake with washout during delayed phases (Rimola et al. 2009).
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 409
https://t.me/medicina_free
Whilst MRI may aid in satellite lesion detection, contrastenhanced CT scans are most helpful for assessment of vascular
involvement (Vilgrain 2008). PET-CT is helpful in larger (>1cm)
mass-forming iCCA with a sensitivity and specificity >90% (Van
Beers 2008). The principal role for PET is detection of nodal and
distant metastases with sensitivity and specificity of 100% and
94%, respectively (Corvera et al. 2008). However, unfortunately for
infiltrative CCA the sensitivity of PET is <20% (Van Beers 2008).
For pCCA CT has a reported accuracy of detecting portal
vein involvement of >80% with identification of arterial involvement in >90%, which is superior to MRI (H. Y. Lee et al. 2006).
Overall the accuracy of CT for determining resectability is
60–88%, however it’s sensitivity for local lymph node involvement detection is only 54% (Aloia et al. 2007; H. Y. Lee et al.
2006; Tillich et al. 1998; Vilgrain 2008). CT scanning may
underestimate the extent of proximal tumor extension (Blechacz
et al. 2011). MRI findings are complementary to CT in pCCA,
since its ability to assess tumor extent and resectability is similar
to ERCP at 95% (Lopera et al. 2001; Masselli et al. 2008; Vogl et
al. 2006). PET-CT is less helpful in staging p-CCA, with sensitivity and specificity <70% and poor lymph node detection rates
(Kato et al. 2002; Kluge et al. 2001). Endoscopic ultrasound may
be important in lymph node sampling (see advanced imaging).
Staging of intrahepatic
Cholangiocarcinoma
iCCA is typically staged according to the 8th edition of the
American Joint Committee on Cancer (AJCC) tumor-nodemetastases classification (Table 1) (Amin 2017). Herein,
solitary tumors involving only the liver without evidence of
vascular invasion are grouped into T1a if <5 cm or T1b if >5 cm
in diameter. T2 is solitary vascular invasion or multifocality
within the liver. T3 cancers invade through the visceral peritoneum not involving extrahepatic structures, and T4 cancers
grow by direct extension into surrounding structures.
For accurate nodal staging, AJCC requires at least six lymph
nodes to be sampled during resection allowing for accurate
Table 1 TNM-staging/AJCC prognostic staging groups.
T-stage N-stage M-stage AJCC stage group
Tis N0 M0 0
T1a N0 M0 IA
T1b N0 M0 IB
T2 N0 M0 II
T3 N0 M0 IIIA
T4 N0 M0 IIIB
Any T N1 M0 IIIB
Any T Any N M1 IV
Table 2
Criteria indicating potential unresectability in pCCA
1 Medical contraindications to surgery
2 Advanced cirrhosis/portal hypertension
3 Inadequate future liver remnant
4 Bilateral second-order biliary radical involvement
5 Bilateral hepatic arterial and/or portal venous involvement
6 Main portal vein involvement or encasement (unless suitable for
resection)
Lobar atrophy with contralateral portal venous or second-order
7
biliary radical involvement
8 Unilateral second-order biliary radical involvement with
contralateral venous/arterial encasement/occlusion
9 N2 nodal involvement
10 Distant metastases
1
Adapted from Jarnagin et al. (Jarnagin et al. 2001).
1
.
prognostication to select appropriate adjuvant treatment
(Mazzaferro et al. 2020). Involvement of at least one regional
node, renders patients N1. Extra-regional lymph nodes are
regarded as distant metastases (M1). Thus, for all iCCA spread
to para-aortic, coeliac, and pericaval lymph nodes are regarded
as M1-disease. AJCC also list the following with worse survival:
non-tumoral hepatic fibrosis, underlying PSC, and serum
CA19.9 levels >200 U/ml. Other factors that may determine
unresectability include locally advanced tumors affecting
hepatic/inflow bilaterally, multiple intra-hepatic tumors, multiple satellite lesions, extensive perihepatic lymphadenopathy,
the presence of portal hypertension and M1 disease (Table 2)
(DeOliveira et al. 2007).
Staging of Perihilar
Cholangiocarcinoma
The two most widely applied validated pCCA staging systems
are the Bismuth-Corlette classification (Figure 1) and AJCC
TNM staging system. The Bismuth-Corlette system implies
surgical resectability, but correlates poorly with patient outcomes (Table X). Whilst the 8th AJCC staging correlates with
patient outcomes, it is a pathology driven classification that
does not predict surgical resectability and the ability to achieve
a negative margin, which remains the main stage-independent
driver of patient outcomes. The AJCC staging however informs
postoperative risk stratification and adjuvant treatment selection. Earlier T-stages are still based on depth of penetration
while later T-stages include vascular involvement given that
these aspects of perihilar cholangiocarcinoma heavily
influence outcomes. T3 cancers are those that invade ipsilateral portal venous or hepatic arterial branches. T4 cancers
invade the main portal vein, or its branches bilaterally or, the
common hepatic artery or, unilateral second order biliary
410 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
radicals with contralateral portal venous or hepatic arterial
involvement. The extent of lymph node involvement is
inversely associated with patient survival (Aoba et al. 2013).
Therefore, N0 disease reflects no nodal involvement, N1 1–3
and N2 >3 positive lymph nodes (AJCC). Local lymph nodes
are classified as regional conversely, those distant to the hepato-duodenal ligament represent metastatic disease.
Importantly, N2 disease now indicates stage IVa, and surgery
is usually contraindicated due to poor survival.
Advanced Imaging and Diagnostic
Tissue Acquisition
Nicholas Holt & Philip I. Craig
Tissue diagnosis is the only way to definitively diagnose CCA.
In the setting of potentially resectable iCCA, cross-sectional
imaging findings may be enough for a putative diagnosis to be
made, without necessitating biopsy. Percutaneous ultrasound
or CT-guided biopsy may be undertaken, particularly in subjects not considered suitable for surgical resection. There is a
risk of tumor seeding (Heimbach et al. 2011) meaning the
patient’s ultimate therapeutic goals need to be carefully considered. Specific histological characteristics of CCA are addressed
in Chapter 15, of note, histological distinction between iCCA
and metastatic adenocarcinoma may be difficult thereby necessitating further imaging or endoscopy.
In contrast to iCCA, tissue diagnosis of dCCA and pCCA is
important and notoriously challenging. In the past surgery was
often undertaken in these situations without preceding tissue
confirmation, however this resulted in a substantial rate of
resections, for benign disease, unacceptable for procedures
which entail significant morbidity and mortality (Scheuermann
et al. 2016). Recently, considerable attention has been paid to
advanced means of interpreting tissue, with multiple nucleic
acid-based tests appearing to improve diagnostic accuracy.
These techniques are further addressed in Chapter 17. Moreover,
tissue diagnosis is required before commencing either chemotherapy or radiotherapy. Advanced imaging and tissue acquisition can be performed using the following techniques:
• Endoscopic Retrograde Cholangiopancreatography (ERCP)
allows both management of biliary obstruction and tissue
sampling. ERCP obtains detailed images of the biliary tree,
but with improvements in non-invasive biliary imaging, its
main role is tissue acquisition and biliary drainage. Cytological
specimens can be obtained from brushings of biliary stric-
tures and histological specimens may also be obtained under
ERCP guidance. Similar techniques can be employed during
percutaneous transhepatic approaches to biliary strictures. In
these settings cytological specimens and pathology each have
specificities over 95% for CCA, but sensitivities of only between 20–70% (Yoon et al. 2022). With this poor sensitivity,
often multiple attempts at tissue acquisition via different
modalities are required to obtain a firm diagnosis.
• Endoscopic ultrasound (EUS) – EUS allows high resolution
views of the biliary tree from the adjacent duodenum (Figure 3).
In the setting of eCCA, visualization of a mass or bile duct
wall thickening are usually identified. Under ultrasound
guidance, a needle can be passed through the echoendoscope
to puncture the area of concern. It is possible to collect either
cytological or core specimens for histological assessment.
The sensitivity of EUS fine needle aspiration/biopsy (FNA/
FNB) is 43–89%, with specificities over 95% (Khashab et al.
2012). Several analyses have stratified the accuracy of EUSguided tissue acquisition for proximal versus distal biliary
lesions, with increased sensitivities noted for distal lesions
(Raine et al. 2020). There is a risk of seeding tumor along the
needle tract during tissue sampling which is a particular concern for pCCA, where peritoneal seeding is a risk (Heimbach
et al. 2011), thereby limiting the utility of EUS for this indication. EUS can also be used for CCA staging, allowing
assessment of local vascular invasion and lymph node metastases (Gleeson et al. 2008).
• Cholangioscopy – modern digital single-operator cholan-
gioscopy is performed by passing a cholangioscope through
the instrument channel of a duodenoscope during ERCP.
This allows direct visualization of the biliary mucosa and
characterization of biliary strictures and masses (Figure 4).
The cholangioscope has an instrument channel allowing
passage of small caliber biopsy forceps to enable targeted
Figure 3 EUS FNA of an eccentric wall thickening of the distal bile duct;
CBD – common bile duct.
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 411
https://t.me/medicina_free
A
C
Figure 4 Biliary strictures seen at cholangioscopy. A & B – benign appearing; C & D – malignant appearing.
biopsies of biliary strictures. A recent meta-analysis reported
the sensitivity of cholangioscopic-guided biopsies at 74% in
this difficult cohort of indeterminate biliary strictures.
Several other studies have assessed the endoscopist’s, “visual
B
D
2 Laboratory and imaging features may be characteristic, but
lack specificity in diagnosing CCA
Definitive, tissue diagnosis of eCCA may be challenging
3
and includes use of ERCP, EUS and cholangioscopy
impression” of indeterminate biliary strictures compared
with the final diagnosis suggesting sensitivities ranging from
85–95% (Wen et al. 2020; Reynauld et al. 2021), though when
blinded to other factors these sensitivities was reduced
(Stassen et al. 2021) (Figure 5).
Surgery and Transplantation
• Less common techniques: include Intra-ductal ultrasound
(Krishna et al. 2007; Heinzow 2014; L. Chen et al. 2016), con-
Ngee-Soon Lau & Carlo Pulitano
focal laser endomicroscopy (CLE) (Slivka et al. 2015) and
optical coherence tomography (OCT) (Arvanitakis et al.
2009). These techniques are not in widespread use but may
have a role in expert centers.
Key Take Home Messages
1 The classic presentation of CCA is painless jaundice, but
pain, pruritis, or fever also occurs; iCCA may present with
either pain, abnormal LFTS or cross-sectional imaging
Perihilar Cholangiocarcinoma
Surgery represents the only chance at cure for patients with
pCCA (Cillo et al. 2019; Lauterio et al. 2021). The goal of surgery is R0 resection with clear margins, preservation of critical
vascular structures, and adequate future liver remnant. This
requires careful preoperative management to optimize biliary
drainage and future liver remnant, and a considered approach
412 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
Figure 5 Approach to the diagnosis of indeterminate biliary strictures.
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 413
https://t.me/medicina_free
to resection with selected use of aggressive approaches such as
extended liver resection and liver transplantation.
Preoperative Considerations
Preoperative Biliary Decompression
PCCA commonly presents with obstructive jaundice which is
associated with a proinflammatory state which impairs the
regenerative capacity of the liver (Kimmings et al. 1995;
Krähenbühl et al. 1998). For this reason, preoperative biliary
decompression is required in patients with cholangitis and
those with a planned extensive resection or small future liver
remnant requiring portal vein embolization (Farges et al. 2013;
Iacono et al. 2013; Kennedy et al. 2009; Ribero et al. 2016; Su
et al. 1996). Preoperative biliary decompression is associated
with an increased risk of cholangitis, observed in both retrospective studies of pCCA (Ferrero et al. 2009; Hochwald et al.
1999), and a randomized controlled trial of patients with
obstructive jaundice due to pancreatic cancer (van der Gaag et
al. 2010). Therefore, preoperative biliary decompression should
be used selectively in patients presenting with cholangitis or a
serum bilirubin >4 mg/dL (68 umol/L) or a future liver remnant of <40% (Cillo et al. 2019).
The methods of achieving biliary decompression are either percutaneous or endoscopic biliary stenting. At meta-analysis, a percutaneous approach resulted in less pancreatitis, cholangitis, or
failure than an endoscopic approach without significant
in postoperative complications or survival (Al Mahjoub et al.,
2017; Hameed et al. 2016). However, a percutaneous approach has
the additional risk of tumor seeding (Wang et al. 2019).
differences
Approach to Resection
Type of Resection
alone without hepatectomy is occasionally possible for cancers
arising below the confluence of the hepatic ducts (Bismuth I),
but this has been associated with a lower rate of R0 resection,
lower nodal yield and a lower five-year survival (30% vs 50%)
compared to resection of bile duct and liver en-bloc (de Jong
et al. 2012; Lim et al. 2013). Resection of the caudate lobe with
the hemi-hepatectomy or trisectionectomy is preferred because
perihilar cholangiocarcinoma commonly extends into the
caudate lobe either directly or through small biliary branches
from the confluence of the hepatic ducts (Nimura et al. 1990).
Margins
Achieving an R0 resection is important for optimal postoperative outcomes and is therefore the surgical goal (Tang et al.
2018; Xiang et al. 2015). This can be challenging because CCA
often spreads along the bile duct (Sakamoto et al. 1998).
Moreover, intraoperative diagnosis of an R1 resection through
frozen section may also be difficult (Mantel et al. 2016; Xiang
et al. 2015).
Future Liver Remnant
To achieve an adequate resection in pCCA an extended hepatectomy is often required. This may place patients at risk of
liver failure due to an inadequate future liver remnant. In
pCCA portal vein embolization has also been used with good
postoperative outcomes to improve the safety of liver resection
when future liver remnant is <40% (Ebata et al. 2012;
Glantzounis et al. 2017). Another strategy is the associating
liver partition and portal vein ligation for staged hepatectomy
(ALPPS) procedure which facilitates rapid hypertrophy over a
short period of time (Schnitzbauer et al. 2012). However, in
pCCA outcomes after ALPPS are inferior to standard extended
resections making portal vein embolization the preferred technique (Olthof et al. 2017).
The type of hepatectomy performed depends on the extent of
tumor invasion within the biliary tree and surrounding inflow
vascular structures. Typically, to achieve adequate margins,
patients require a right or left hemi-hepatectomy with resection of the bile duct (Nagino et al. 2013; Tran et al. 2019). If the
degree of biliary invasion involves both right and left hepatic
ducts (Bismuth IV), a right or left trisectionectomy is usually
required often with reconstruction of multiple segmental ducts
(Nagino et al. 2021; Neuhaus et al. 2012). A bile duct resection
Lymphadenectomy
Dissection of the regional nodes in the porta hepatitis including
the hepatoduodenal lymph node is recommended (NCCN
2021). Lymphadenectomy was not associated with survival
benefit, but overall lymph node status was an important prognostic indicator for long-term survival (Liang et al. 2021).
Excision of >5 lymph nodes improves lymph node staging and
prognostication (Liang et al. 2021).
414 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
Vascular Resection
Resection of the portal vein to improve the rate of R0 resection
in pCCA has been widely practiced (de Jong et al. 2012;
Neuhaus et al. 1999). More recently, portal vein resection when
combined with a hepatectomy and bile duct resection improves
long-term survival in selected patients (Abbas and Sandroussi
2013; de Jong et al. 2012). The benefits for resection of the
hepatic artery in pCCA are less clear since although this
improves R0 resection rates in advanced disease, survival is
unchanged (Abbas and Sandroussi 2013; Y. M. Li et al. 2022).
Minimally Invasive Surgery
Advances in technology and increasing experience with minimally invasive surgery have increased enthusiasm for this
approach for pCCA resections. The perceived benefits of less
pain, shorter length of stay and precise, magnified visualization
make this approach attractive (Hu et al. 2019; Ratti et al. 2020b).
In a series of 16 laparoscopic resections, a minimally invasive
approach resulted in a shorter length of stay and less blood loss
than an open approach with similar rates of R0 resection (Ratti
et al. 2020a). Another group have utilised a robotic-assisted
approach to perform 48 pCCA resections and reported a 10%
rate of major morbidity with no mortalities and an R0 resection
in 73% of patients (J. Li et al. 2020b). All series to date however
are limited by small numbers and therefore, this approach
should only be performed at expert centers in selected patients
(Hu et al. 2019).
Outcomes after Resection
Despite advances in resection for pCCA, long-term outcomes
remain poor. Reported rates of mortality are 1–14% and the
overall 5-year survival is 17–44% (Table 3).
Liver Transplantation
Using liver transplantation to treat pCCA has a number of
advantages. Firstly, it overcomes challenges associated with
attempting R0 resection by removing the liver and bile duct enbloc permitting resection of tumors previously considered unresectable. Secondly, it avoids concerns about postoperative liver
failure due to inadequate future liver remnant. Finally, it treats
any underlying predisposing conditions such as cirrhosis or primary sclerosing cholangitis (Cillo et al. 2019; Lauterio et al.,
2021). However, this impacts on transplant waiting lists therefore, due to donor shortages and historically poor outcomes after
transplant for pCCA, uptake is limited (Acher et al. 2021).
Development of the Mayo Clinic Protocol in 1993 demonstrated encouraging results with 82% 5-year survival in a 24
patient cohort (Heimbach et al. 2004; Rosen et al. 2010). This
protocol includes patients with unresectable disease and
tumors <3 cm without evidence of metastases and involves
neoadjuvant external beam radiation therapy, brachytherapy,
chemotherapy and then surgical exploration and liver transplantation (Figure 6) (Rosen et al. 2010). Using protocol variations, several centers have reported similar results with 5-year
overall survival 50–60% (Darwish Murad et al. 2012; Ethun
Table 3 Selected studies reporting outcomes after liver resection for pCCA.
Article, location Study period, type Number of patients Morbidity <90 days Mortality <90 days 5-year survival
Farges et al. (2013)
Europe
Nagino et al. (2013)
Japan
Yu et al. (2014)
China
Furusawa et al. (2014)
Japan
Tran et al. (2019)
USA
Franken et al. (2021)
Netherlands
Nagino et al. (2021)
Japan
1997–2008
Multi-center
1977–2010
Single-center
1998–2010
Single-center
1990–2012
Single-center
2000–2015
Multi-center
2000–2018
Single-center
2001–2018
Single-center
366 69% 11% -
574 57% 4% 33%
238 18% 1% 17%
144 73% 1% Early period: 33%
Late period: 35%
257 58% 6% 19%
178 77% 14% Left resection: 44%
Right resection: 38%
787 - 2% Left resection: 39%
Right resection: 42%
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 415
https://t.me/medicina_free
Figure 6 Mayo Clinic Protocol for neoadjuvant treatment followed by liver transplantation for pCCA. Adapted from Rosen et al. (2010).
et al. 2018; Tan et al. 2020; Zaborowski et al. 2020). A multicenter study of patients with “unresectable” disease undergoing
A treatment algorithm for perihilar cholangiocarinoma is
outlined in Figure 7.
liver transplantation found improved overall survival compared to patients undergoing resection for “resectable” disease
(5-year survival 64% vs 18%) (Ethun et al. 2018). Debate con-
Intrahepatic Cholangiocarcinoma
tinues about how to prioritize and select patients with p-CCA
for transplantation with some centers utilizing living donation
Overall Surgical Approach
liver transplantation with comparable results (Tan et al. 2020).
Intrahepatic cholangiocarcinoma is an aggressive malignancy
and although surgery is the only curative treatment, overall
Key Take Home Messages
1 Surgery is the only curative treatment for perihilar cholangiocarci-
noma
2 Preoperative biliary drainage is preferred in patients presenting with
cholangitis, a bilirubin >4 mg/dL (68 umol/L) or a future liver remnant of <40%
Portal vein embolization should be considered when the future liver
3
remnant is <40%
4 Resection should include caudate lobectomy, lymphadenectomy and
vascular resection if required
5 Liver transplantation can be considered in highly selected patients after
neoadjuvant treatment using the Mayo Clinic Protocol (or similar)
survival continues to be poor. The goal of surgery is an R0
resection with adequate future liver remnant but, due to late
presentation and rapid progression, most are unresectable at
diagnosis (Bridgewater et al. 2014; Lauterio et al. 2021;
Mazzaferro et al. 2020). With recent advances and a more
aggressive surgical approach, extended liver resections with
vascular resection and reconstruction is an option in selected
patients. (Lauterio et al. 2021; Mazzaferro et al. 2020). Liver
transplantation remains experimental with encouraging results
in small trials (Mazzaferro et al. 2020).
Соседние файлы в папке @xirurgi_2025