Jurnal Inggris Empedu PDF

See discussions, stats, and author profiles for this publication at: https://www.researchgate.
net/publication/268233646
Gallbladder cancer
Article · October 2014

DOI: 10.3978/j.issn.2304-3881.2014.09.03 · Source: PubMed
CITATIONS READS
41 414
7 authors, including:
Mislav Rakić Mario Kopljar

Klinička bolnica Dubrava University Clinical Hospital Center "Sestre Milosrdnice"
16 PUBLICATIONS 114 CITATIONS 54 PUBLICATIONS 525 CITATIONS
SEE PROFILE SEE PROFILE
Robert Kliček Marijan Kolovrat

Klinička bolnica Dubrava Klinička bolnica Dubrava
56 PUBLICATIONS 555 CITATIONS 22 PUBLICATIONS 98 CITATIONS
SEE PROFILE SEE PROFILE
Some of the authors of this publication are also working on these related projects:
3rd Hepatobiliary and Pancreatic Surgery Congress View project
Systematic Review and Meta-Analysis View project
All content following this page was uploaded by Mislav Rakić on 08 March 2015.
The user has requested enhancement of the downloaded file.

HBSN
ISSN 2304-3881
Vol 3, No 5
OCT 2014
HEPATOBILIARY SURGERY AND NUTRITION
ISSN 2304-3881 Vol 3, No 5 OCT 2014

www.thehbsn.org
Focused Issue: Dedicated to the 2nd International Congress of Hepatobiliary and Pancreatic Surgery
Guest Editors: Leonardo Patrlj, Mario Kopljar and Yuman Fong
ed
b
Pu
in
d
xe
de
In
© AME Publishing Company 2014. All rights reserved. Contact: editor@asvide.com www.asvide.com
Editor-in-Chief Deputy Editors-in-Chief
Yilei Mao, MD, PhD J. Michael Millis, MD Xiang-Dong Wang, MD, PhD Timothy M. Pawlik, MD, MPH,
Department of Liver Surgery, (Liver Transplantation) (Nutrition and Liver Cancer) MTS, PhD
Peking Union Medical College Chicago, USA Boston, USA (Hepatobiliary Surgery)
Hospital, Chinese Academy of Woo-Jung Lee, MD, PhD Haitao Zhao, MD, PhD Baltimore, USA
Medical Sciences, Beijing, China (Robotic Surgery) (Hepatobiliary Research)
Seoul, Korea Beijing, China
Editorial Board Assistant Editor
René Adam, MD, PhD Norihiro Kokudo, MD, PhD, Frank Tacke, MD, PhD Zhiyong Guo, MD, PhD
Villejuif, France FACS Aachen, Germany Guangzhou, China
Stig Bengmark, MD, PhD Tokyo, Japan Tadatoshi Takayama, MD, PhD
Lund, Sweden Paul B.S. Lai, MD, BS Tokyo, Japan Managing Editor
Henri Bismuth, MD, FACS (Hon) Hong Kong SAR, China Wei Tang, MD, PhD Katherine L. Ji
Villejuif, France Masatoshi Makuuchi, MD, PhD Tokyo, Japan
William S. Blaner, PhD Tokyo, Japan Giuliano Testa, MD, FACS, MBA Senior Editors
New York, USA Jacques Marescaux, MD, FRCS, Texas, USA Eunice X. Xu
Ronald W. Busuttil, MD, PhD FJSES Haibo Wang, MD (Corresponding Editor)
Los Angeles, USA Strasbourg, France Hong Kong SAR, China Grace S. Li
William C. Chapman, MD, FACS Robert CG Martin, II, MD, PhD Roger Williams CBE, MD, FRCP, Elva S. Zheng
St. Louis, USA Louisville, USA FRCS, FRCPE, FRACP, FMedSci, Nancy Q. Zhong
Chao-Long Chen, MD, PhD (Hon.) Jeffrey B. Matthews, MD FRCPI (Hon), FACP (Hon)
Kaohsiung, Taiwan Chicago, USA London, UK Science Editors
N. Joseph Espat, MD, MS, FACS Donald N. Reed, Jr., MD, FACS Huttaporn Wongsiriroj, PhD Silvia L. Zhou
Providence, USA Ft. Wayne, USA Nakhon Pathom, Thailand Helen X. Seliman
Sheung-Tat Fan, MS, MD, PhD Edward Saltzman, MD Sien-Sing Yang, MD
Hong Kong SAR, China Boston, USA Taipei, Taiwan Executive Copyeditor
John Fung, MD, PhD Helmut K. Seitz, MD, AGAF Suh-Ching Yang, PhD Benti L. Peng
Cleveland, USA Heidelberg, Germany Taipei, Taiwan
Bengt W Jeppsson, MD, PhD Mary Simmerling, PhD Shou-Xian Zhong, MD, PhD Executive Typesetting Editor
Malmö, Sweden New York, USA Beijing, China Paula P. Pan
Michael D. Kluger, MD, MPH Robert J Smith, MD Thomas R. Ziegler, MD
New York, USA Providence, USA Atlanta, USA Production Editor
Emily M. Shi
Aims and Scope Note to NIH Grantees

HepatoBiliary Surgery and Nutrition (Print ISSN 2304-3881; Pursuant to NIH mandate, HepatoBiliary Surgery and Nutrition
Online ISSN 2304-389X; Hepatobiliary Surg Nutr; HBSN) (HBSN) journal will post the accepted version of contributions
is a bi-monthly peer-reviewed publication that is dedicated to authored by NIH grant-holders to PubMed Central upon
the advancement of hepatobiliary surgery and nutrition. The acceptance. This accepted version will be made publicly available
journal is now indexed in PubMed and PMC. The main focus 2 months after publication. For further information, see www.
of the journal is to describe new findings in hepatobiliary thehbsn.org
diseases, provide current and practical information on diagnosis,
prevention and clinical investigations. Specific areas of interest Conflict of Interest Policy for Editors
include, but not limited to, multimodality therapy, biomarkers, The full policy and the Editors’ disclosure statements are
imaging, biology, pathology, and technical advances related to available online at: www.thehbsn.org
hepatobiliary diseases. Contributions pertinent to hepatobiliary
diseases are also included from related fields such as nutrition, Disclaimer
surgery, public health, human genetics, basic sciences, education, The Publisher and Editors cannot be held responsible for
sociology, and nursing. Article categories of the journal include errors or any consequences arising from the use of information
original article, review, research highlight, editorial, case report contained in this journal; the views and opinions expressed
and a special section on nutrition will be featured. do not necessarily reflect those of the Publisher and Editors,
neither does the publication of advertisements constitute any
The official publication of: endorsement by the Publisher and Editors of the products
Society for Translational Medicine. advertised.
Editorial Correspondence For submission instruct ions, subscript ion and all ot her
Eunice X. Xu. HepatoBiliary Surgery and Nutrition. HK information visit www.thehbsn.org
office: 9A Gold Shine Tower, 346-348 Queen’s Road Central,
Sheung Wan, Hong Kong. Tel: +852 3488 1279; Fax: +852 3488 © 2014 HepatoBiliary Surgery and Nutrition
1279. Email: editor@thehbsn.org
Table of Contents
Preface
219 Maturation of HBP surgery: worldwide advances to address worldwide problems
Leonardo Patrlj, Mario Kopljar, Yuman Fong
Review Article
221 Gallbladder cancer
Mislav Rakić, Leonardo Patrlj, Mario Kopljar, Robert Kliček, Marijan Kolovrat, Bozo Loncar, Zeljko Busic
227 Pre-resectional inflow vascular control: extrafascial dissection of Glissonean pedicle in liver resections
Aleksandar Karamarković, Krstina Doklestić
238 Post-hepatectomy liver failure
Rondi Kauffmann, Yuman Fong
247 Pancreatic surgery: evolution and current tailored approach
Mario Zovak, Dubravka Mužina Mišić, Goran Glavčić
259 Potential use of Doppler perfusion index in detection of occult liver metastases from colorectal cancer
Mario Kopljar, Leonardo Patrlj, Željko Bušić, Marijan Kolovrat, Mislav Rakić, Robert Kliček, Marcel Židak, Igor
Stipančić
268 Pancreatic fistula and postoperative pancreatitis after pancreatoduodenectomy for pancreatic cancer
Miroslav Ryska, Jan Rudis
276 Techniques for prevention of pancreatic leak after pancreatectomy
Hans F. Schoellhammer, Yuman Fong, Singh Gagandeep
288 Robotic liver surgery
Universe Leung, Yuman Fong
295 “Vanishing liver metastases”—A real challenge for liver surgeons
Alex Zendel, Eylon Lahat, Yael Dreznik, Barak Bar Zakai, Rony Eshkenazy, Arie Ariche
303 Small for size liver remnant following resection: prevention and management
Rony Eshkenazy, Yael Dreznik, Eylon Lahat, Barak Bar Zakai, Alex Zendel, Arie Ariche
313 The laparoscopic liver resections—an initial experience and the literature review
Mislav Rakić, Leonardo Patrlj, Robert Kliček, Mario Kopljar, Antonija Đuzel, Kristijan Čupurdija, Željko Bušić
317 Complications after percutaneous ablation of liver tumors: a systematic review
Eylon Lahat, Rony Eshkenazy, Alex Zendel, Barak Bar Zakai, Mayan Maor, Yael Dreznik, Arie Ariche
324 The surgical treatment of patients with colorectal cancer and liver metastases in the setting of the “liver
first” approach
Leonardo Patrlj, Mario Kopljar, Robert Kliček, Masa Hrelec Patrlj, Marijan Kolovrat, Mislav Rakić, Antonija Đuzel
© Hepatobiliary Surgery and Nutrition. All rights reserved. HepatoBiliary Surgery and Nutrition, Vol 3, No 5 October 2014
Preface
Maturation of HBP surgery: worldwide advances to address

worldwide problems
The evolution of hepatobiliary pancreatic surgery in the last two decades has been remarkable. The improvements in technical
surgery, anesthesia, and technology now allow extraordinarily safe surgery. Whereas major hepatectomies or pancreatectomies
until recently were performed at few centers due to the enormous risk, they are now common place operations being
performed even on the elderly patient. Advances in neoadjuvant, adjuvant, and ablative therapies now allow for many more
patients to be eligible for life-prolonging surgeries and for better long-term outcome. Cancers such as cholangiocarcinoma,
gallbladder cancer, or metastatic colorectal cancer, which were largely incurable only three decades before are now routinely
resected and result in long-term survival and possibly cured. This progress and the current state of the treatment for many of
the hepatobiliary malignancies are summarized in this issue of the Hepatobiliary Surgery and Nutrition (HBSN) dedicated to the
proceedings of the Congress of Hepatobiliary Surgery about to be held in Croatia.
The advances in treatment of liver cancer have consequences throughout the world. Due to the high prevalence of
viral hepatitis and the associated liver cancers, hepatobiliary malignancies are some of the most common malignancies
globally. It is fitting that contributions to the improvement in surgical care of these malignancies have come from surgeons,
anesthesiologists, and scientists worldwide. The authorship of this journal issue includes many of the luminary and most
innovative investigators in this field, and include international expert surgeons and educators from Europe, Asia, and America.
We thank them for their contribution to this Journal, to the Congress, and for their dedication to these patients and to the
field. We also look forward to seeing these surgeons and physicians in beautiful Split for a few days of scholarship, of mutual
education, and of camaraderie.
Few solid tumors can be cured without surgical therapy. Thus, advances that result in safer operations increases potential
for cure. In order for this field to have moved so quickly in the last years is due not only to scientists, engineers, and clinicians,
but also due to those who have enrolled in the necessary trials. We therefore thank the patients who have contributed to the
advances, and whose diseases are the targets that push us to create new solutions.
Gratitude also goes to our post-docs, research fellows and colleagues that help us gather data, refine our hypothesis, and
design the next tools. We thank the editors and staff of HBSN, but particularly Editor-in-Chief Yilei Mao and Editor Eunice X.
Xu for their support. Finally, we thank our families for the patience and support they have given us to do our investigative and
clinical work, and for helping us put together this international meeting.
© Hepatobiliary Surgery and Nutrition. All rights reserved. www.thehbsn.org Hepatobiliary Surg Nutr 2014;3(5):219-220
220 Patrlj et al. Advances in HPB surgery
Leonardo Patrlj. Department of Abdominal Mario Kopljar, MD, PhD. Department Yuman Fong. City of Hope Medical Center,
Surgery, University Hospital Dubrava, Av. G. of Abdominal Surgery, University Hospital 1500 East Duarte Road, Duarte, CA 91010,
Šuška 6, HR-10000 Zagreb, Croatia. Dubrava, Av. G. Šuška 6, HR-10000 Zagreb, USA. (Email: yfong@coh.org.)
(Email: lpatrlj@kbd.hr.) Croatia. (Email: kopljar@yahoo.com.)
doi: 10.3978/j.issn.2304-3881.2014.09.11
Disclosure: The authors declare no conflict of interest.
View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.11
Cite this article as: Patrlj L, Kopljar M, Fong Y. Maturation

of HBP surgery: worldwide advances to address worldwide
problems. Hepatobiliary Surg Nutr 2014;3(5):219-220. doi:
10.3978/j.issn.2304-3881.2014.09.11
Review Article
Gallbladder cancer
Mislav Rakić, Leonardo Patrlj, Mario Kopljar, Robert Kliček, Marijan Kolovrat, Bozo Loncar, Zeljko
Busic
Department of Hepatobiliary Surgery, University Hospital Dubrava, Zagreb, Croatia

Correspondence to: Mislav Rakić, MD. Department of Hepatobiliary Surgery, University Hospital Dubrava, Avenija Gojka Šuška 6, 10000 Zagreb,
Croatia. Email: mrakic@kbd.hr; mislav78@gmail.com.
Abstract: Gallbladder cancer is the fifth most common cancer involving gastrointestinal tract, but it is the
most common malignancy of the biliary tract, accounting for 80-95% of biliary tract cancers. This tumor is
a highly lethal disease with an overall 5-year survival of less than 5% and mean survival mere than 6 months.
An early diagnosis is essential as this malignancy progresses silently with a late diagnosis. The percentage of
patients diagnosed to have gallbladder cancer after simple cholecystectomy for presumed gallbladder stone
disease is 0.5-1.5%. Patients with preoperative suspicion of gallbladder cancer should not be treated by
laparoscopy. Epidemiological studies have identified striking geographic and ethnic disparities—inordinately
high occurrence in American Indians, elevated in Southeast Asia, yet quite low elsewhere in the Americas and
the world. Environmental triggers play a critical role in eliciting cancer developing in the gallbladder, best
exemplified by cholelithiasis and chronic inflammation from biliary tract and parasitic infections. Improved
imaging modalities and improved radical aggressive surgical approach in the last decade has improved
outcomes and helped prolong survival in patients with gallbladder cancer. The overall 5-year survival for
patients with gallbladder cancer who underwent R0 curative resection was from 21% to 69%. In the future,
the development of potential diagnostic markers for disease will yield screening opportunities for those at
risk either with ethnic susceptibility or known anatomic anomalies of the biliary tract.
Keywords: Gallbladder carcinoma; gallstones; laparoscopic cholecystectomy; liver resection
Submitted Jul 28, 2014. Accepted for publication Sep 02, 2014.
doi: 10.3978/j.issn.2304-3881.2014.09.03
Introduction environmental exposure and intrinsic genetic predisposition

to carcinogenesis. For gallbladder cancer, several conditions
Biliary tract cancers are invasive adenocarcinomas that arise
associated with chronic inflammation are considered
from the epithelial lining of the gallbladder and intrahepatic
risk factors, which include gallstone disease, porcelain
and extra hepatic bile ducts. Although anatomically these gallbladder, gallbladder polyps, chronic Salmonella infection,
malignancies are related and have similar metastatic congenital biliary cysts, and abnormal pancreaticobiliary
patterns, each has a distinct clinical presentation, molecular duct junction (1,2).
pathology, and prognosis (1). The percentage of patients diagnosed to have gallbladder
Gallbladder cancer is the most common malignancy of cancer after simple cholecystectomy for presumed
the biliary tract, representing 80-95% of biliary tract cancers gallbladder stone disease is 0.5-1.5% (4-6).
worldwide (2,3). It ranks fifth among gastrointestinal cancers. In most instances, gallbladder cancer develops over 5 to
The global rates for gallbladder cancer shows differences, 15 years, when metaplasia progresses to dysplasia, carcinoma
reaching epidemic levels for some regions and ethnicities. in situ, and then, invasive cancer (1).
Gallbladder cancer has a particularly high incidence in A satisfactory outcome depends on an early diagnosis and
Chile, Japan, and northern India (2). surgical resection. Despite this potential for cure, less than
The basis for this variance likely resides in differences in 10% of patients have tumors that are resectable at the time
222 Rakić et al. Gallbladder cancer
of surgery, while nearly 50% have lymph node metastasis (4). term “porcelain gallbladder” (16). The porcelain gallbladder
Even with surgery, most progress to metastatic disease, is frequently (average 25%, range, 12-61%) associated with
highlighting the importance of improving adjuvant gallbladder cancer (17,18).
therapies (5). Chronic bacterial cholangitis poses a clear risk for biliary
This tumour is traditionally regarded as a highly lethal tract malignancy. The organisms that have been most
disease with an overall 5-year survival of less than 5% (5). implicated are Salmonella (e.g., S. typhi and S. paratyphi) and
The overall mean survival rate for patients with gallbladder Helicobacter (e.g., H. bilis) spp (19,20). Bacterial colonization
cancer is 6 months (6). may induce hydrolysis of primary bile acids forming.
Malignant transformation is further implicated via chronic
inflammation itself and alterations of tumor suppressor
Risk factors
genes [such as tumor protein 53 (p53)] or proto-oncogenes
The identification of risk factors is critical, providing insight [such as mutations of Kirsten ras oncogene homolog (K-ras)]
into the pathogenetic mechanism that drives geographic (15,21).
and ethnic variance, and yielding strategies for prevention Primary sclerosing cholangitis (PSC) is a chronic
and treatment. fibroinflammatory syndrome linking chronic inflammation
Gallbladder cancer rates tend to increase with advancing to carcinogenesis (22). Facilitating a metaplasia-dysplasia-
age. The median age was 67 years in a Memorial Sloan- carcinoma sequence (23,24).
Kettering report of 435 gallbladder cancer patients (5). Various environmental exposures have been hypothesized
Gender differences demonstrate a marked predominance to contribute to gallbladder cancer, such as: heavy metals,
of women over men worldwide (7). Women are affected tobacco, radon (25-28).
2-6 times more often than men (8). Obese people have an increased risk of developing
There is a widely variable geographic pattern for gallbladder cancer (29-31). The risk of developing gallbladder
gallbladder cancer, Asia is a high risk continent, while the cancer in those with diabetes mellitus is increased (32).
United States and most western and Mediterranean European Almost 5% of adults harbor gallbladder polyps (33,34).
countries (e.g., UK, France, and Norway) represent low risk Most of them are pseudopolyps, without neoplastic
areas (5,6,9,10). potential (35). Features that predict malignancy are: large
Ethnicity plays a role even in different geographic polyps (>10 mm), a solitary or sessile mass, associated
locations. The Korean people have the highest incidence gallstones, the patient’s age over 50 years old, and most
rate (per 100,000) of gallbladder cancer in Asia. Korean importantly, rapid polyp growth (7,29).
males living in Los Angeles County, California also carry Anomalous junction of the pancreaticobiliary duct is
the highest US ethnic incidence rate (10). a congenital malformation in which the pancreatic duct
Gallstones represent a most important association for drains into the biliary tract outside the papilae Vateri. Such
this malignancy, being present in most (~85%) patients with a long common channel defeats the gatekeeper function
gallbladder cancer. The incidence of gallbladder cancer in of the sphincter of Oddi, potentially allowing pancreatic
a population with gallstones varies from 0.3% to 3% (11). secretions to regurgitate into the bile ducts and gallbladder,
The higher risk of gallbladder cancer development in larger thus leading to malignant changes in the mucosa (36).
stones possibly reflects the greater duration and intensity Gallbladder cancer seems to result from a combination of
of mucosal irritation causing chronic inflamation (12,13). genetic predisposition and exposure to environmental risk
Prophylactic cholecystectomy would appear reasonable in factors (37). One proposed carcinogenic pathways suggest
these individuals (14). that: gallstone mediated inflammation → p53 mutation (↓)
Chronic inflammation causing deoxyribonucleic acid → K-ras mutation (↑) (21).
(DNA) damage, provoking repeated tissue proliferative
attempts at restoration, releasing cytokines and growth
Diagnosis
factors, and thus, predisposing cells to oncogenic
transformation (15). Chronic inflammation can also result Clinical presentation is similar to biliary colic or chronic
in calcium being deposited in the gallbladder wall. When cholecystitis. The most common symptoms are: persistent
calcium deposits become extensive, the gallbladder acquires right upper quadrant pain, jaundice, nausea and weight loss.
a bluish hue and becomes fragile, even brittle—hence the In some patients palpable mass is present (38,39).
HepatoBiliary Surgery and Nutrition, Vol 3, No 5 October 2014 223
Imaging can detect malignancy. Transabdominal gallbladder cancer who underwent R0 curative resection
ultrasound is a useful initial modality for investigating was reported to range from 21% to 69%, and 0% for
patients with upper abdominal pain and jaundice (40). patients who did not get R0 resection. So the R0 curative
Endoscopic ultrasound (EUS) is currently the definitive resection is objective of surgical management for gallbader
modality for staging gallbladder cancer. EUS also offers cancer (40).
sampling via fine needle aspiration (41). Type of liver resection for carcinoma of the gallbladder
Computerized tomography (CT) helps identify any varies from atipical resection of segments IVb at V to right
extension to lymph nodes, liver involvement, or distant hepatectomy.
metastases, performed preoperatively, determines gallbladder By the Union for internatonal Cancer Control (UICC)/
resectability with a high accuracy (up to 93%) (42) . AJCC are two types of regional lymphadenectomy for
Standard magnetic resonance imaging (MRI) is generally gallbladder cancer:
less valuable. Magnetic resonance (MR) cholangiography N1—lymphnodes of hepatoduodenal ligament (cystic
and MR angiography quite accurately detects bile duct duct, pericholedochal and hilar lymph nodes);
or vascular invasion, with sensitivity and specificity N2—peripancreatic, periductal, periportal, common
approaching 100%. hepatic artery, coeliac and superior mesenteric artery lymph
Positron emission computed tomography (PET) scans nodes.
are useful in differentiating malignant from benign disease, Laparoscopic cholecystectomy is absolutely contraindicated
in preoperative staging, and in detecting postoperative when gallbladder cancer is known or suspected pre-operatively.
residual disease (43). Patients with a pre-operative suspicion of gallbladder cancer
should undergo open exploration and cholecystectomy
after proper pre-operative assessment, or immediately
Staging system
with suspicion made during laparoscopy. If the diagnosis is
Gallbladder cancer staging, based on the American Joint confirmed on frozen section radical surgical resection should
Committee on Cancer (AJCC) guidelines, focuses on tumor be performed in the same session (5).
invasion and the extent of spread (44). Incidental gallbladder cancers are detected histologically
Adenocarcinoma is the most frequent histologic type, after the fact in 0.3-3% of laparoscopic cholecystectomies
accounting for 98% of all gallbladder tumors (45). The performed for cholelithiasis. For these patients a second
other histopathologic variants include the papillary, radical resection is indicated after adequate diagnostic and
mucinous, squamous, and adenosquamous subtypes. The treatment preparation, except for Tis and T1a disease.
disease stage determines the treatment options. The Port-site recurrences can follow laparoscopic
best outcomes are reserved for patients who qualify for cholecystectomies in up to 17% of cases where unsuspected
cholecystectomy. In stage I disease, according to AJCC gallbladder cancer is discovered (47). Here, accidental bile
criteria, tumor invades the lamina propria or the muscle spillage implants tumor cells at the trocar or incision site,
layer. Stage II is designated by the perforation of the leading to recurrence so the excision of the port sites are
serosa and/or involvement of adjacent organs or structures. indicated during the radical reoperation.
T1 to T3 tumor invasion with any nodal involvement Tis and T1a gallblader cancer (tumor is limited to
is automatically classified as stage II. Both stage I and mucosa) are usually diagnosed after cholecystectomy. There
II are potentially resectable with curative intent. Stage is consensus that simple cholecystectomy is an adequate
III generally indicates locally unresectable disease, as treatment which offers a surgical cure with 100% 5-year
a consequence of vascular invasion or the involvement survival (47).
of multiple adjacent organs. Stage IV represents In T1b gallbladder cancer (tumor invades the muscular
nonresectability because of distant metastases (46). layer) there is still controversy for the optimal management.
Reported incidence of occult lymphatic metastasis is 15-
25% in this stage with 10% incidence of residual disease
Surgical management
in liver bed (47,48). Given the frequency of positive lymph
Primary tumor invasion (T) is the most important factor nodes and residual disease in this stage, recommended
in the AJCC staging criteria; it determines the surgical procedure is cholecystectomy with radical resection which
approach (44). The overall 5-year survival for patients with encompasses 3 cm of liver parenchyma segment IVb and V,
plus adequate lymphadenectomy (48,49). The outcome after pathways, can impede tumor growth. Targeted therapy
simple cholecystectomy in this stage is 75% 10-year survival against epidermal growth factor receptor (EGFR) has
vs. 100% for radical operation. demonstrated an antiproliferative effect in vitro and provides
T2 lesions of gallbladder cancer invade perimuscular some optimism for a changing treatment paradigm in the
connective tissue with no extension beyond the serosa or future (53).
into the liver. The reported 5-year survival for patients with Unfortunately, the data supporting the use of adjuvant or
this stage of disease treated with simple cholecystectomy neoadjuvant chemoradiotherapy is largely based on Phase II
where 10-61% and 54-100% after radical resection. trials, with no conclusive evidence favoring benefit (46).
Yamaguchi reported that over 40% of these patients had
positive margins after simple cholecystectomy with rate of
Prognosis
positive lymph nodes of 19-62%. So radical resection is the
method of choice for these patients. This often requires a The most important prognostic factors that can predict
more formal resection of segments IVb and V (48-50). survival after resection are: T staging of the original lesion;
In T3 disease, the tumor may extend to the serosa, liver, extent of nodal involvement; metastasis; and jaundice (which
and/or adjacent organs/structures. Under these circumstances, can signify biliary invasion and possible obstruction) (46).
resection becomes more radical, including an extended The advent of gallbladder cancer staging has witnessed
right hepatectomy with possible caudate lobectomy (47), an improvement in overall 5-year survival rates, what is
regional lymphadenectomy, and extirpation of other the merit of radical and successful surgical curing and
affected structures (46). Some centers further advocate advances in diagnosis (2). Further improvement in the
pancreaticoduodenectomy to improve outcomes (47). There treatment of this disease is expected from the progress of
is 45-70% incidence of lymph node dissemination with 36% chemotherapy (53).
of residual disease (51). The AJCC “Cancer Staging Manual” assessed 10,000
T4 disease is widely disseminated through vascular patients diagnosed with gallbladder cancer from 1989 to
invasion and/or metastasis. Lesions here are commonly 1996. The 5-year survival rates start at 80% for stage 0,
unresectable and it is impossible to achieve R0 resection in then progressively fall to 50% for stage I, 28% for stage II,
this stage. Consequently palliative therapy which includes 8% for stage IIIa, 7% for stage IIIb, 4% for stage IVa, and
adequate pain control, surgical or non-surgical biliary finally, 2% for stage IVb (44).
drainage is more appropriate in this stage.
The goal of surgical intervention is to obtain R0
Conclusions
resection. Surgical resection for advanced gallbaldder cancer
is recommended only if a potentially curative R0 resection Gallbladder cancer is the fifth most common cancer
is technically possible (46,47,52). involving gastrointestinal tract, but it is the most common
malignancy of the biliary tract with a highly variable
prevalence in different parts of the world. Histopathological
Adjuvant therapy
type is almost always adenocarcinoma.
Patients with gallbladder cancer often present in advanced This distinctive malignancy has disastrous outcomes with
stage of disease. In these patients adjuvant therapy with an overall 5-year survival of less than 5% and mean survival
palliative therapy is the only way to treat though there is mere than 6 months.
still no effective adjuvant therapy for gallbladder cancer. Chronic inflammation caused with cholelithiasis is the
Three classes of chemotherapeutics may be used: most important risk factor.
gemcitabine, fluoropyrimidine, and platinum compounds. Diagnosis may come at the time of cholecystectomy
Monotherapy has limited effect (43). Combination for gallstones, although preoperative imaging with
chemotherapy using gemcitabine and cisplatin offers a transabdominal and EUS, multisliced computed tomography
significant survival advantage for patients with advanced (MSCT) and MR is providing an important advance.
disease (51). Surgery represents the only potential cure. Unfortunately,
Radiotherapy has proven to be marginally useful in the the usual late presentation means an advanced stage with
setting of advanced disease. potential nodal involvement and leads to recurrences despite
Therapeutic agents, targeting cellular and molecular attempted resection.
Laparoscopic cholecystectomy is contraindicated when gallstone disease in Chandigarh: a community-based study.

gallbladder cancer is suspected preoperatively. After J Gastroenterol Hepatol 2001;16:560-3.
incidental finding of gallbladder cancer on pathohistological 12. Csendes A, Becerra M, Rojas J, et al. Number and size of
review following cholecystectomy for cholelithiasis, a stones in patients with asymptomatic and symptomatic
second radical resection is indicated except for T1a stage. gallstones and gallbladder carcinoma: a prospective study
There is still no effective adjuvant therapy for gallbladder of 592 cases. J Gastrointest Surg 2000;4:481-5.
cancer so R0 surgical resection is the only treatment with 13. Mlinarić-Vrbica S, Vrbica Z. Correlation between
potential cure. Aggressive surgical approach should be cholelithiasis and gallbladder carcinoma in surgical and
based on a balance between the risk of surgery (morbidity, autopsy specimens. Coll Antropol 2009;33:533-7.
mortality) and the outcome. 14. Le MD, Henson D, Young H, et al. Is gallbladder
cancer decreasing in view of increasing laparoscopic
cholecystectomy? Ann Hepatol 2011;10:306-14.
Acknowledgements
15. Rashid A, Ueki T, Gao YT, et al. K-ras mutation, p53
Disclosure: The authors declare no conflict of interest. overexpression, and microsatellite instability in biliary tract
cancers: a population-based study in China. Clin Cancer
Res 2002;8:3156-63.
References
16. Berk RN, Armbuster TG, Saltzstein SL. Carcinoma in the
1. Zhu AX, Hong TS, Hezel AF, et al. Current management porcelain gallbladder. Radiology 1973;106:29-31.
of gallbladder carcinoma. Oncologist 2010;15:168-81. 17. Stephen AE, Berger DL. Carcinoma in the porcelain
2. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology gallbladder: a relationship revisited. Surgery
and outcome. Clin Epidemiol 2014;6:99-109. 2001;129:699-703.
3. Lazcano-Ponce EC, Miquel JF, Muñoz N, et al. 18. Cunningham SC, Alexander HR. Porcelain gallbladder
Epidemiology and molecular pathology of gallbladder and cancer: ethnicity explains a discrepant literature? Am J
cancer. CA Cancer J Clin 2001;51:349-64. Med 2007;120:e17-8.
4. Sheth S, Bedford A, Chopra S. Primary gallbladder cancer: 19. Kumar S. Infection as a risk factor for gallbladder cancer. J
recognition of risk factors and the role of prophylactic Surg Oncol 2006;93:633-9.
cholecystectomy. Am J Gastroenterol 2000;95:1402-10. 20. Gonzalez-Escobedo G, Marshall JM, Gunn JS. Chronic
5. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder and acute infection of the gall bladder by Salmonella
cancer (GBC): 10-year experience at Memorial Sloan- Typhi: understanding the carrier state. Nat Rev Microbiol
Kettering Cancer Centre (MSKCC). J Surg Oncol 2011;9:9-14.
2008;98:485-9. 21. Saetta AA. K-ras, p53 mutations, and microsatellite
6. Lai CH, Lau WY. Gallbladder cancer--a comprehensive instability (MSI) in gallbladder cancer. J Surg Oncol
review. Surgeon 2008;6:101-10. 2006;93:644-9.
7. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer 22. Razumilava N, Gores GJ, Lindor KD. Cancer surveillance
worldwide: geographical distribution and risk factors. Int J in patients with primary sclerosing cholangitis. Hepatology
Cancer 2006;118:1591-602. 2011;54:1842-52.
8. Konstantinidis IT, Deshpande V, Genevay M, et al. Trends 23. Lewis JT, Talwalkar JA, Rosen CB, et al. Prevalence and
in presentation and survival for gallbladder cancer during risk factors for gallbladder neoplasia in patients with
a period of more than 4 decades: a single-institution primary sclerosing cholangitis: evidence for a Metaplasia-
experience. Arch Surg 2009;144:441-7; discussion 447. Dysplasia-Carcinoma Sequence. Am J Surg Pathol
9. Curado MP, Edwards B, Shin HR, et al. eds. Cancer 2007;31:907-13.
incidence in five continents. IX. Lyon: International Agency 24. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and
for Research on Cancer Scientific Publications, 2007. management of primary sclerosing cholangitis. Hepatology
10. Surveillance, Epidemiology and End-Results Program 2010;51:660-78.
(SEER). The Four Most Common Cancers for Different 25. Pandey M. Environmental pollutants in gallbladder
Ethnic Populations 2013. Bethesda, MD: National Cancer carcinogenesis. J Surg Oncol 2006;93:640-3.
Institute; 2013. 26. Lubin JH, Boice JD Jr, Edling C, et al. Lung cancer in
11. Singh V, Trikha B, Nain C, et al. Epidemiology of radon-exposed miners and estimation of risk from indoor
exposure. J Natl Cancer Inst 1995;87:817-27. adenomyomatosis of the gallbladder from early-stage, wall-
27. Darby SC, Whitley E, Howe GR, et al. Radon and thickening-type gallbladder cancer using high-resolution
cancers other than lung cancer in underground miners: ultrasound. Eur Radiol 2013;23:730-8.
a collaborative analysis of 11 studies. J Natl Cancer Inst 41. Kim HJ, Lee SK, Jang JW, et al. Diagnostic role
1995;87:378-84. of endoscopic ultrasonography-guided fine needle
28. Jain K, Sreenivas V, Velpandian T, et al. Risk factors for aspiration of gallbladder lesions. Hepatogastroenterology
gallbladder cancer: a case-control study. Int J Cancer 2012;59:1691-5.
2013;132:1660-6. 42. Kumaran V, Gulati S, Paul B, et al. The role of dual-phase
29. Stinton LM, Shaffer EA. Epidemiology of gallbladder helical CT in assessing resectability of carcinoma of the
disease: cholelithiasis and cancer. Gut Liver 2012;6:172-87. gallbladder. Eur Radiol 2002;12:1993-9.
30. Calle EE, Rodriguez C, Walker-Thurmond K, et al. 43. Dutta U. Gallbladder cancer: can newer insights improve
Overweight, obesity, and mortality from cancer in a the outcome? J Gastroenterol Hepatol 2012;27:642-53.
prospectively studied cohort of U.S. adults. N Engl J Med 44. Edge SB, Byrd DR, Compton CC, et al. eds. AJCC Cancer
2003;348:1625-38. Staging Manual. New York: Springer, 2010.
31. Wolin KY, Carson K, Colditz GA. Obesity and cancer. 45. Goldin RD, Roa JC. Gallbladder cancer: a morphological
Oncologist 2010;15:556-65. and molecular update. Histopathology 2009;55:218-29.
32. Lai HC, Chang SN, Lin CC, et al. Does diabetes mellitus 46. Jayaraman S, Jarnagin WR. Management of gallbladder
with or without gallstones increase the risk of gallbladder cancer. Gastroenterol Clin North Am 2010;39:331-42.
cancer? Results from a population-based cohort study. J 47. Reid KM, Ramos-De la Medina A, Donohue JH.
Gastroenterol 2013;48:856-65. Diagnosis and surgical management of gallbladder cancer:
33. Hariharan D, Saied A, Kocher HM. Analysis of mortality a review. J Gastrointest Surg 2007;11:671-81.
rates for gallbladder cancer across the world. HPB (Oxford) 48. Cavallaro A, Piccolo G, Panebianco V, et al. Incidental
2008;10:327-31. gallbladder cancer during laparoscopic cholecystectomy:
34. Myers RP, Shaffer EA, Beck PL. Gallbladder polyps: managing an unexpected finding. World J Gastroenterol
epidemiology, natural history and management. Can J 2012;18:4019-27.
Gastroenterol 2002;16:187-94. 49. Fong Y, Brennan MF, Turnbull A, et al. Gallbladder cancer
35. Gallahan WC, Conway JD. Diagnosis and management discovered during laparoscopic surgery. Potential for
of gallbladder polyps. Gastroenterol Clin North Am iatrogenic tumor dissemination. Arch Surg 1993;128:1054-6.
2010;39:359-67. 50. Ouchi K, Mikuni J, Kakugawa Y, et al. Laparoscopic
36. Nomura T, Shirai Y, Sandoh N, et al. Cholangiographic cholecystectomy for gallbladder carcinoma: results of a
criteria for anomalous union of the pancreatic and biliary Japanese survey of 498 patients. J Hepatobiliary Pancreat
ducts. Gastrointest Endosc 2002;55:204-8. Surg 2002;9:256-60.
37. Dutta U, Nagi B, Garg PK, et al. Patients with gallstones 51. Pawlik TM, Gleisner AL, Vigano L, et al. Incidence
develop gallbladder cancer at an earlier age. Eur J Cancer of finding residual disease for incidental gallbladder
Prev 2005;14:381-5. carcinoma: implications for re-resection. J Gastrointest
38. Roa I, de Aretxabala X, Morgan R, et al. Surg 2007;11:1478-86; discussion 1486-7.
Clinicopathological features of gallbladder polyps and 52. Ogura Y, Mizumoto R, Isaji S, et al. Radical operations
adenomas. Rev Med Chil 2004;132:673-9. Spanish. for carcinoma of the gallbladder: present status in Japan.
39. Terzi C, Sökmen S, Seçkin S, et al. Polypoid lesions of the World J Surg 1991;15:337-43.
gallbladder: report of 100 cases with special reference to 53. Benson AB 3rd, Abrams TA, Ben-Josef E, et al. NCCN
operative indications. Surgery 2000;127:622-7. clinical practice guidelines in oncology: hepatobiliary
40. Joo I, Lee JY, Kim JH, et al. Differentiation of cancers. J Natl Compr Canc Netw 2009;7:350-91.
Cite this article as: Rakić M, Patrlj L, Kopljar M, Kliček

R, Kolovrat M, Loncar B, Busic Z. Gallbladder cancer.
Hepatobiliary Surg Nutr 2014;3(5):221-226. doi: 10.3978/
j.issn.2304-3881.2014.09.03
Review Article
Pre-resectional inflow vascular control: extrafascial dissection of

Glissonean pedicle in liver resections
Aleksandar Karamarković1,2, Krstina Doklestić1,2
1
Faculty of Medicine, University of Belgrade, Serbia; 2Clinic for Emergency Surgery, Clinical Center of Serbia, Belgrade, Serbia
Correspondence to: Prof. Aleksandar Karamarković, MD, Ph.D. Clinic for Emergency Surgery, Clinical Center of Serbia, Pasteur Str.2, Belgrade
11000, Serbia. Email: alekara@sbb.rs.
Background/aims: We are evaluated technique of anatomic major and minor hepatic resections using
suprahilar-extrafascial dissection of Glissonean pedicle with vascular stapling device for transection of hepatic
vessels intending to minimize operative time, and blood loss.
Methodology: We prospectively analyzed the clinical records of 170 patients who underwent hepatic
resection by suprahilar-extrafascial pedicle isolation and stapling technique in our clinic for emergency
surgery in Belgrade. Patients who underwent hilar extrahepatic intrafascial dissection were excluded from the
study.
Results: We performed 102 minor liver resections and 68 major hepatectomies. The minor liver resections
were associated with significantly shorter surgery duration (95.1±31.1 vs. 186.6±56.5) and transection time
(35.9±14.5 vs. 65.3±17.2) than major hepatectomies (P<0.001 for all). The mean blood loss was 255.6±129.9 mL
in minor resection and 385.7±200.1 mL in major resection (P=0.003). The mean blood transfusion requirement
was 300.8±99.5 mL for the patients with minor hepatectomy and 450.9±89.6 mL for those with major liver
resection (P=0.067). There was no significant difference in morbidity and mortality between the groups
(P=0.989; P=0.920). Major as well as minor liver resection were a superior oncologic operation with no
significant difference in the 3-year overall survival rates.
Conclusions: Extrafascial dissection of Glissonean pedicle with vascular stapling represents both an
effective and safe surgical technique of anatomical liver resection. Presented approach allows early and easy
ischemic delineation of appropriate anatomical liver territory to be removed (hemiliver, section, segment)
with selective inflow vascular control. Also, it is not time consuming and it is very useful in re-resection, as
well as oncologically reasonable.
Keywords: Liver resection; segmented orientated liver resection; Glissonean approach (GA); Glissonean pedicle
stapling; vascular stapler; extrafascial dissection
Submitted Aug 02, 2014. Accepted for publication Sep 02, 2014.
doi: 10.3978/j.issn.2304-3881.2014.09.09
Introduction dramatically (2-10). All improvements in liver surgery

have the same goals, to preserve the maximum amount of
Hepatic resection had an impressive growth, both by
liver parenchyma with minimum blood loss (1-10). The
broadening the range of its indications and the occurrence
of changes and technical tricks in order to reduce blunt liver dissection has been widely replaced by various
postoperative mortality and morbidity (1). Although the time-consuming methods, such as the cavitron ultrasonic
criteria for liver tumors resectability are expanded today, surgical aspirator (CUSA), followed by the development
hepatectomies are still demanding procedures due to risk of tools for safe approach, isolation and transection of
of hemorrhage and hepatic failure (2-6). During the last vascular and biliary structures during transection of liver
decades surgical techniques for hepatectomy have changed parenchyma (8,9).
228 Karamarković and Doklestić. Extrafascial Glissonean approach in liver resections
In 1949, Honjo (Kyoto University) and later in of vascular staplers in liver surgery (8,28-31). Vascular
1952, Lortat-Jacob and Robert were performed the first staplers offer speed and safety when dividing hepatic veins
anatomical right hepatectomy with classical intrafascial- and portal branches during hepatectomy, which minimizes
extrahepatic approach so-called “classic” hilar dissection blood loss (8,31). Previous studies compared classical HD
(HD) of the hepatic artery, portal vein and bile duct in vs. extrahepatic Glissonian stapling of the pedicle for major
the hepatoduodenal ligament (7,8,10). Nevertheless, the hepatectomies with acceptable morbidity (7,32).
potential disadvantages of this approach are reflected in Using technique of the suprahilar-extrafascial Glissonean
the cases of extensive scarring due to previous surgery, the pedicle dissection, with endo-GIA vascular stapling device
risk of incidental lesion of anomalous hepatic vessels or the transection of the pedicle, and appropriate hepatic vein,
contralateral biliary duct (11-14). we have performed 170 liver resections for malignant and
The observations of Glisson and Couinaud that elements benign tumors, with intent of minimal blood loss. Here
of portal triad are contained within a thick connective we review our experience gained with liver resections and
tissue and are surrounded by a fibrous sheet (Glissonean compare the clinical, perioperative and postoperative results
pedicle) were the basis for the initial proposal by Couinaud (complications, disease-free survival and overall survival) of
in 1957, that suprahilar vascular control of Glissonean the patients who have undergone either segmental resection
pedicle could serve as an important alternative to classical of different volume, or major hepatectomy.
HD for controlling vascular inflow to the liver. This
technique includes the extrafascial dissection of the whole
Methodology
sheath of the pedicle and its division “en masse” (15).
Anterior intrahepatic extrafascial approach proposed by We prospectively analyzed the clinical records of 170
Couinaud, Thung and Quang, uses anatomical fissures as patients who underwent hepatic resection by suprahilar-
door’s of the liver. By splitting the liver substance down extrafascial pedicle isolation and stapling technique in our
along the appropriate fissure could be approach to the clinic for emergency surgery in Belgrade, between January
pedicle of interest (15,16). The extrafascial dissection of 2007 and December 2011. Patients who underwent hilar
left Glissonean pedicle at the hepatic hilus without liver extrahepatic intrafascial dissection were excluded from the
transection, for the left hepatectomy, was previously study. All procedures were performed by the same operating
reported by Couinaud in 1985 and later by Lazorthes in 1993 team.
(17,18). Takasaki in 1986 described the surgical technique The protocol received the approval of the research review
called “Glissonean pedicle transection method”. Technique board of our hospital, and informed written consent was
is based on detachment of the hilar plate and extrafascial- obtained from each patient before surgery. Before operation,
extrahepatic dissection of the main left and right, as well all patients underwent a thorough physical examination,
as both right sectional pedicles, without opening the liver blood tests and radiologic evaluation. Liver function was
parenchyma (19,20). Galperin in 1989 described a digital evaluated by Child-Pugh-Turcotte (CPT) classification
“hooking” technique for the isolation of portal pedicles using prothrombin time (PT), albumin, bilirubin and
through an extrafascial-intrahepatic approach after division clinical findings of ascites and encephalopathy. CPT score
of a substantial amount of the hepatic tissue (21). In 1992 was stratified as classes A [5-6], B [7-9], and C [10-15]. Only
Launois and Jamieson proposed the posterior intrahepatic CPT class C is considered an absolute contraindication for
approach to the appropriate Glissonean pedicle, through surgical treatment. Liver resections were defined according
the dorsal fissure of the liver, after making proper perihilar to the International Hepato-Pancreato-Biliary Association
hepatotomies (22). Machado’s modifications of the posterior terminology derived from Couinaud’s classification (33).
approach include making small incisions around the hilar The amount of operative blood lost was measured by the
plate and strictly instrumental isolation of the pedicle volume (mL) of blood collected in the aspirator container
(23-25). It has been reported that the Glissonean approach and the ultrasonic dissector and by the weight of the soaked
(GA) can reduce the portal triad closure time, expedite gauzes.
the transection of the liver and reduce intraoperative Perioperative data were operative duration (min),
hemorrhage, as well as the risk of injury to the vasculature transection time (min), intraoperative blood loss (mL),
or the biliary drainage of the contralateral liver (26,27). transfusion requirement (intraoperative and postoperative
A step forward in achieving security is the introduction within the first 48 h) and intermittent vascular occlusion
through the catheter with a bilirubin content 2× higher than

the plasma levels.
Surgical technique
Makuuchi’s “J”-shaped laparotomy was used for all patients.

Liver was mobilized using standard technique. Intra-
operative ultrasound (IOUS) was performed to redefine
tumor localization in relation to major vascular structures
and to determine the transection plane. Extra hepatic
“outflow” control was performed after dissection and
isolation of major hepatic veins above the liver, whenever
it was possible. Ischemic preconditioning (IP) was done to
minimize ischemic-reperfusion injury of the liver (IRI). The
liver tissue was transected under intermittent hepatic inflow
Figure 1 Takasaki’s technique of extrahepatic-extrafascial dissection vascular occlusion (IVO) which involves periods of inflow
and isolation of the right main Glissonean (RMP) and both right clamping for 15 minutes followed by periods of unclamping
anterior (RAP) and right posterior (RPP) sectional pedicles. for five minutes (mode 15/5). In order to minimize bleeding
in minor hepatectomies, selective vascular clamping (SVO)
was used as the preferred method of inflow occlusion,
(IVO) duration (min). Transection time was defined as particularly in patients with underlying chronic liver disease.
the duration between the beginning and the end of the Central venous pressure (CPV) was maintained at 0-5 mmHg
liver parenchyma transection. The amount of operative to help reduce back bleeding from hepatic veins. After the
blood lost was measured by the volume (mL) of blood transectional line was marked, the liver capsule was divided
collected in the aspirator container and by the weight of with diathermy or harmonic scalpel. Transection of the liver
the soaked gauzes (assuming that 1 mL of blood =1 g). The tissue was performed using the cavitron ultrasonic dissecting
indications for blood transfusion were massive hemorrhage aspirator (“CUSA Excel”; Valleylab Inc., Boulder, CO, USA).
with hematocrit decreasing to approximately <25% or During dissection, small vessels/bile ducts were ligated,
hemoglobin level <70 g/L. Cumulative clamping time coagulated or clipped to achieved hemostasis and biliostasis.
was calculated according to cumulative period of vascular The major hepatic veins were divided extrahepatically
occlusion. using vascular surgical stapler (Endo GIA Ultra stapler
Postoperative data included postoperative liver injury, 3.0; Covidien, USA). Suprahilar vascular control of the
ICU and hospital stay (days), morbidity and mortality and appropriate Glissonean pedicle was achieved by Machado’s
disease-free survival and overall survival. The patients modification of the posterior intrahepatic approach
were subjected to postoperative follow-up by blood test, (23,24), or using Takasaki’s technique (19) (Figure 1).
ultrasonography or computed tomography (CT) scans. Clamping the taped Glissonean pedicle, demonstrated the
The degree of postoperative hepatic injury was assessed by further demarcation of the appropriate anatomical territory
measuring the postoperative serum values of the aspartate of the liver as well as delineation of resectional plan (Figure 2).
aminotransferase (AST), alanine aminotransferase (ALT), Pedicle was divided at the end of the resectional procedure
bilirubin, albumin, PT and international normalized ratio using endo-GIA vascular stapling device (Endo GIA Ultra
(INR) on postoperative days 1, 3, 5 and 7. stapler 3.0; Covidien) (Figure 3). Firm counter traction on
Postoperatively were followed in the outpatient clinic at the tape was applied during application of the stapler to
1, 3, and every 6 months thereafter with blood biochemistry ensure that the contralateral pedicle was not accidentally
and spiral CT scans of the abdomen. Post-operative mortality ligated.
was defined as any death occurring within 30 days after For the right main Glissonean pedicle (RMP) isolation
surgery. Postoperative bleeding, liver ischemia, bile leakage, maneuver, after cholecystectomy, “detachment” of the
or perihepatic abscess formation were considered surgical medial section of the liver (S4) was performed, by lowering
complications. Biliary leak was defined as any drainage the hilar plate and small anterior hepatotomy was made
Figure 2 Mesohepatectomy: resectional plan along the right sagital

fissure of the liver with isolated right anterior (RAP) and right
posterior (RPP) sectional pedicles.
Figure 3 Right hepatectomy: transection of the right main

Glissonean pedicle using endo-GIA vascular stapling device.
in front of the hilum. A second incision was performed
perpendicular to the hepatic hilum, between segment S7
and caudate lobe (S1). Curved clamp then was inserted
through the first hepatotomy with a 30° angle reaching main pedicle. This approach spared the caudate lobe (S1)
the second incision. Vascular tape was then placed around portal branches. The round ligament was retracted upward,
the RMP. Tape was pulled down and medially to provide exposing the umbilical fissure between segments S3 and
better exposure of the intrahepatic pedicle and to retract S4. If a parenchymal bridge connecting these two segments
the left biliary tree and portal vein away from the area to exists, it must be divided. Using the round ligament as a
be clamped or stapled. A third incision performed on the guide, two small incisions are performed on the left and
right edge of the gallbladder bed permitted access to the right margins of the round ligament where it is possible to
right anterior (RAP) and right posterior (RPP) sectional identify the anterior aspect of the Glissonean pedicle for
pedicles, by combining the previously mentioned incisions. segment S4 on its right side and segment S3 on its left side.
In short course of the right main pedicle, the RAP and With a clamp introduced through the anterior incision in
RPP were ligated and divided separately. The further, distal front of the hilum and the basis of the round ligament on
intrahepatic dissection of the isolated sectional pedicles, the right side, it is possible to isolate the Glissonean pedicle
allowed the parenchymal isolation of the appropriate (S5-S8) for the left medial section or segment S4. By combining
segmental pedicle. incisions from the caudal stump of the Arantius ligament to
For the left main Glissonean pedicle (LMP) isolation, the left side of the basis of the round ligament, it is possible
the lesser omentum was divided, exposing the Arantius to isolate the Glissonean pedicles for the left lateral section
venous ligament, which was then dissected and divided. The (segments S2 and S3).
proximal stump enabled the infero-posterior approach to During pedicle clamping, the color of the area changes
the left hepatic vein and common trunk. The caudal stump and the tumor location is confirmed by IOUS. Pedicle is
of the ligament was dissected towards the left portal vein. divided at the end of resectional procedure using vascular
This maneuver disclosed the posterior aspect of the left surgical stapler (Endo GIA Ultra stapler 3.0; Covidien).
Glissonean pedicle. A small anterior incision (4-5 mm) was After completed resection, the monopolar irrigated
performed on the left side of the hilum and a curved clamp electrocautery was applied to stop minor oozing. The raw
was introduced behind the caudal stump of the Arantius surface of the liver was sealed using fibrin glue. Closed
ligament, allowing the encircling and exposure of the left suction drainage was used in all patients.
Table 1 Type of minor liver resection Table 2 Type of major liver resection
Type of liver resection n (%) Type of liver resection n (%)
Segmentectomy 1 2 (1.9) Extended right hepatectomy 3 (4.4)
Segmentectomy 2 4 (3.9) Extended left hepatectomy 1 (1.5)
Segmentectomy 3 6 (5.8) Right hepatectomy 24 (35.3)
Left lateral sectionectomy 23 (22.5) Left hepatectomy 27 (39.7)
Left medial sectionectomy (segment 4) 8 (7.8) Mesohepatectomy 4 (5.8)
Segmentectomy 5 5 (4.9) Central transversal hepatectomy (S3,S4b,S5) 4 (5.8)
Segmentectomy 6 4 (3.9) Right inferior transversal hepatectomy (S4b,S5,S6) 5 (7.3)
Segmentectomy 7 4 (3.9) Total 68 (100.0)
Segmentectomy 8 2 (1.9)
Right posterior sectionectomy 15 (14.7)
Right anterior sectionectomy 8 (7.8) resection group (27.4%) were classified as CPT class B and
Bisegmentectomy 4b, 5 5 (4.9) 9 (13.2%) patients in major resection group as CPT class B.
Bisegmentectomy 3, 4b 4 (3.9) Indications for minor liver resection were metastases of
Right cranial bisegmentectomy 7, 8 4 (3.9) colorectal carcinoma (CRC) in 50 (49.02%), hepatocellular
carcinoma (HCC) in 10 (9.80%), cholangiocellular
Right caudal bisegmentectomy 5, 6 8 (7.8)
carcinoma in 4 (3.92%), non-colorectal liver metastases in 8
Total 102 (100.0)
(7.84%), gall bladder carcinoma in 7 (6.86%), hemangioma
hepatis in 13 (12.74%) and adenoma hepatis in 10 (9.80%)
patients. Indications for major hepatectomies were
Statistical analysis
colorectal liver metastases (CRC LM) in 33 (48.5%); non-
Data were expressed as mean with SD or median with colorectal liver metastases (non-CRC LM) in 7 (10.3%);
interquartile range, as appropriate. Categorical data HCC in 22 (32.3%); gall bladder carcinoma in 3 (4.4%)
are presented by absolute numbers with percentages. patients and liver hemangioma in 3 (4.4%).
Differences between groups were compared with parametric Intraoperative data for those patients undergoing
Student’s t-test or nonparametric Mann-Whitney test. hepatectomy, hospital stay and outcome are provided in Table 4.
Repeated measures of liver function indicated by serum level There were a significant difference in overall operative
of bilirubin, AST, ALT, albumin and PT was assessed by time, liver transection time and ischemic duration between
general linear model. For qualitative variables, comparisons minor and major resections (P<0.001 for all) (Table 4).
between groups were performed by the χ2 test or Fisher Intraoperative blood loss was significantly higher in the
exact test, when needed. In all tests, P value <0.05 was major resection group (P=0.003) (Table 4). Intraoperative
considered to be statistically significant. All the calculations transfusion was performed in 46 (27.1%) patients of all and
were performed with the SPSS 17.0 statistical package (SPSS, there was no significant difference between minor and major
Inc., Chicago, IL, USA). resections (P=0.395). The intraoperative blood transfusion is
expressed as the amount of blood volume (mL), there was no
significant difference between minor and major resections
Results
(P=0.067) (Table 4). In 124 (72.9%) patients of all liver
A total of 170 anatomical hepatectomies were performed resection were performed without any blood transfusion.
by suprahilar-extrafascial Glissonean pedicle dissection and Degree of liver damage presented by sequential
stapling technique, including 68 (40.0%) major and 102 postoperative serum values of AST, ALT, Bilirubin and PT.
(60.0%) minor liver resections (Tables 1 and 2). The changes in postoperative serum values of liver function
Demographics and preoperative data for all patients are markers were not significantly different between major and
shown in Table 3. There were no significant differences minor resection (P>0.05) Nevertheless, statistical analysis
between the two groups in terms of age, gender, comorbid of the total serum AST, ALT, bilirubin, and PT values
conditions, Child-Pugh score, indications and number of found significance in the specified period of time. Total
tumoral lesions (Table 3). Twenty-eight patients in minor AST and ALT values were significantly decreased on the
Table 3 Clinical characteristics and preoperative biochemical evaluations of patients included in the study
Characteristics Minor resections (n=102) Major resections (n=68) P
Male* 62 (60.78%) 36 (52.9%) 0.561
Age (years)** 62.52±15.29 61.65±13.58 0.778
Comorbidity* 54 (52.94%) 35 (51.5%) 0.881
Malignant indications* 79 (77.45%) 58 (85.3%) 0.345
No. of tumours lesions** 1.71±1.10 2.23±1.28 0.053
CPT score A 74 (72.5%) 59 (86.7%) 0.649
Bilirubin (μmol/L) 20.12±12.27 22.73±14.66 >0.05
AST (U/L) 35.89±13.21 33.36±15.81 >0.05
ALT (U/L) 59.04±35.40 49.66±28.54 >0.05
Albumin (g/L) 30.39±6.59 30.49±6.91 >0.05
†
INR 1.21±0.19 1.24±0.21 >0.05
PT (s) 13.72±1.68 13.22±2.32 >0.05
*, characteristics are presented as numbers of patients and percentage, n (%); **, characteristics are presented as mean ± SD,
standard deviation; †, international normalized ratio.
Table 4 Perioperative characteristics of patients included in the study

Characteristics Minor resections (n=102) Major resections (n=68) P
Operative time, (min)** 95.1±31.1 186.6±56.5 <0.001
Transection time, (min)** 35.9±14.5 65.3±17.2 <0.001
Blood loss, (mL)** 255.6±129.9 385.7±200.1 0.003
†
Ischaemic duration, (min) 15 [15] 30 [30] <0.001
CVP (0-5 mmHg)† 2.00 [2] 3.00 [2] 0.291
Blood transfusion inraop. (mL)** 300.8±99.5 450.9±89.6 0.067
Resection R0, n (%)* 96 (94.1%) 63 (92.6%) 0.833
Hospital stay (days)† 8 [3] 8 [4] 0.745
ICU stay (days) 1.00 [2] 1.00 [3] 0.441
Morbidity* 37 (36.3%) 25 (36.7%) 0.989
Mortality rate* 1 (0.9%) 2 (2.9%) 0.920
Overall survival rates for CRC° 53% 46% 0.744
Overall survival rates for HCC° 60% 69% 0.744
*, characteristics are presented as numbers of patients and percentage, n (%); **, characteristics are presented as mean ± SD; †,
characteristics are presented as median (range); °, follow-up 36 months.
third postoperative day (P˂0.001; P˂0.001). Total bilirubin complications were recorded in 27 (26.5%): 5 (4.9%)
value was significantly lower on the 5th postoperative day had cardiac complication, 10 (9.8%) had pleural effusion,
(P˂0.001). Total PT value was significantly reduced on the 5 (4.9%) had atelectasis, 6 of them (5.9%) had wound
5th postoperative day (P=0.001). infections and 1 (0.9%) bronchopneumonia. Total of 10
There was no significant difference in ICU stay, hospital (9.8%) patients experienced grade ≥3 surgery complications:
stay and complications rate between the groups (Table 4). 4 (3.9%) intra-abdominal fluid collection, 2 (1.9%) biliary
In minor resection group complications rate was 37 fistula, and 4 (3.9%) partial wound dehiscence. In major
(36.3%). According to Clavien’s classification, grade 1-2 resection group according to Clavien’s classification, grade
1-2 complications were recorded in 21 (30.9%): 5 (7.3%) than 20% for major liver resections, much effort has been
had cardiac complication, 11 (16.2%) had respiratory done to intraoperative control of blood loss and reduce
complications and 5 (7.3%) had wound infections. There intraoperative hemorrhage (34,35). Excessive blood loss is
were 4 (5.9%) grade ≥3 surgery complications: 2 (2.9%) associated with increased perioperative morbidity and, in
intra-abdominal fluid collection and 2 (2.9%) biliary fistula. cases of colorectal metastases, a shorter disease-free interval
The majority of complications were treated conservatively, (34,36). Technical refinements are focused on minimizing
or radiological intervention/percutaneous drainage and no hemorrhage during transection of hepatic parenchyma and
patients underwent reoperation. In all cases of the biliary safe dissection of the major hepatic veins and pedicles (34-36).
fistula there was spontaneous healing The extrafascial dissection of Glissonean pedicle is a
Mortality between groups did not reach a significant very important technique that can be extremely useful in
difference (P=0.920). The hospital morbidity rate in major particular circumstances during liver surgery, such as in
resection group was 2.9%. All deaths were caused by non- multi-operated patients or in patients with cirrhotic liver or
surgical complications. In both patients there were a history anomalous vascular and biliary variations. Regarding this
of cardiac disorders, and mortality was caused by an acute technique some terminology confusion still exists (Glissonean
myocardial infarction, after the seventh postoperative day in approach, extra-Glissonean approach, Glissonean pedicle
both cases. transection method, posterior intrahepatic approach, suprahilar
One patient who treated by minor liver resection died vascular control, perihilar posterior approach, superficialisation of
due to thromboembolic complications and pulmonary Glissonean pedicles) (20,37). Nevertheless, despite many titles
embolism, on postoperative day 3, despite regular the main surgical concept is the same, and it’s based on the
anticoagulant therapy. anatomical fact and observation of Couinaud that portal
The 1- and 3-year disease-free survival rates in group triad elements inside the liver substance, are enveloped with
with minor resections were 75% for patients with colorectal fibrous Glissonean sheet, thus representing an important
metastases (74% for patients with HCC) and 46% for structure of internal architecture of the liver (15,17). The
patients with colorectal metastases (49% HCC patients), extrafascial Glissonean pedicle approach in liver surgery
respectively. These results were similar to those observed in provides new knowledge of the surgical anatomy of the liver
group with major resections (76% for CRC patients; 80% and advances the technique of liver surgery (38). Opposite
for HCC patients) and (50% for CRC patients; 52% HCC to “classic” intrafascial dissection, this technique includes
patients), respectively. There was no significant difference extrafascial isolation of the whole sheet of Glissonean
in the disease-free survival rates between both groups pedicle and it’s division “en masse”. Glissonean pedicles
(P=0.066). can be approached intrahepatically or extrahepatically.
The overall survival rates after 1 year and 3 years were The use of vascular staplers in this situation allows quick
found to be 81% for patients with colorectal metastases and safe transection of the pedicle, as well as appropriate
(90% for patients with HCC) and 53% for patients with hepatic vein (39). The second advantage of this technique
colorectal metastases (60% for patients with HCC) in presents the quick and easy definition of the anatomic
group with minor liver resections and 83% for patients territory of the liver to be removed. Selective clamping of
with colorectal metastases (92% for patients with HCC) the appropriate isolated pedicle demonstrates the further
and 49% for patients with colorectal metastases (69% for ischemic demarcation of anatomical liver part of interest
patients with HCC) in group with major hepatectomies, (hemiliver, section or even segment) as well as delineation
respectively. There was no significant difference in the of resectional planes (21-25). Recent advances of presented
overall survival rates between both groups (P=0.744). surgical technique includes liver hanging maneuver and
some modifications with two tapes to control the main
fissure of the liver or various liver resections using hanging
Discussion
maneuver by three Glisson’s pedicles and three hepatic
Liver resections are complex procedures that requires veins (40,41). The first prospective randomized study
detailed knowledge of liver anatomy, precise “bloodless” which compared extrafascial GA vs. “classic” HD in major
surgical technique and sufficient volume of the remnant hepatectomies, was performed by the group of Figueras,
liver (1-8,34). showed that “en bloc” stapling transection of the pedicle was
Since the late 1970s, when operative mortality was more safe and faster than “classic” approach (7). The other studies
have shown similar results for the safety and operative greatest rate. The minor liver resections were associated
duration (42-46). Also, the aim of our previous study was to with significantly shorter surgery duration and transection
analyze the efficiency and safety of the Glissonean pedicle time than major hepatectomies. Intraoperative transfusion
approach vs. classical HD in major hepatectomies (32). rate was no significant difference between minor and
The extrafascial dissection was associated with significantly major resections. The changes in postoperative serum
shorter surgery duration, transection time and ischemic values of liver function markers were not significantly
duration than intrafascial HD, while amount of blood different between major and minor resections. There was
loss was significantly lower in GA (32). Extrafascial no significant difference in ICU stay, hospital stay and
isolation of Glissonean pedicle saves time comparing complications rate between the groups. Major hepatectomy
with difficult and some time hazardous intrafascial HD. as well as minor liver resection are a superior oncologic
Dissection above hepatic hilum significantly reduces operation with no significant difference in the 1- and 3-year
the risk of the potentially injury of the contra-laterally disease-free survival rates and overall survival rates between
sided vasculature and bile ducts (47). Smyrniotis et al. both groups in our study.
showed that intrahepatic dissection is safe as extrahepatic Stewart registered a significant difference between
hilar division in terms of intraoperative blood requirements the groups with extended resections and segmental ones
and morbidity; but biliary complications are more severe in terms of operative blood loss and post-operative stay
in patients undergoing extrahepatic division of the portal as major post-operative complications are less following
pedicle (43). segmental resection (48).
Advantages of anatomic segment orientated resections Intermittent Pringle maneuver (IPM) during transection
include prevention of postoperative liver failure especially in of liver parenchyma is simple and safe technique that may
elderly or patients with underlying liver disease, reduction reduce bleeding from hepatic inflow, and the total clamping
of blood loss as well as lower postoperative mortality time can be extended to 120 minutes in normal livers and
and morbidity rates. The question, whether to perform 60 minutes in pathological livers (30,36). The disadvantage
a segmental or a major resection if both procedures are of IPM is that bleeding occurs from the liver transection
technically feasible, is still under debate. The presented surface during the unclamping period and, thus, the overall
surgical technique of suprahilar extrafascial control of transection time is prolonged as more time is spent in
the Glissonean pedicle, is very useful in performing of achieving hemostasis. The presented surgical technique
sectionectomies and segmentectomies. Couinaud and, allows the use of SVO during parenchymal transection.
more recently, Takasaki, Galperin and Launois have noted Selective clamping it is also important from the
that the Glissonean capsule continues within the liver haemodynamic point of view because there is no splanchnic
parenchyma up to the segmental divisions (19-22). Although stasis and low fluid replacement. A previous randomized
the intersegmental planes were not visible on the surface of study demonstrated that the clinical advantages of selective
the liver, the segments were defined by occluding the inflow clamping are more significant in patients with chronic liver
pedicle to that segment. disease, particularly in very difficult resections in patients
This study describes our experiences with the extrafascial in whom lengthy pedicular clamping is anticipated as a
pedicle dissection and stapling technique during major result of portal hypertension or in whom very large areas
liver resection and minor hepatectomy: vascular staplers of transection are necessary (49). By contrast, selective
were used to divided pedicles and major hepatic veins while clamping or hemihepatic vascular occlusion, as described by
parenchyma transection was performed by CUSA, under Makuuchi et al. does not increase venous portal pressure or
IPM or selective vascular occlusion (SVO). The study was cause fluid overload or a consequent increase in CVP (50).
not designed to demonstrate the superiority of one major Expected, in our study results showed shorter operation
hepatic resection over the minor. Rather, it is the authors’ time, transection time, ischemic duration and less blood loss
intention to demonstrate the efficiency of the GA in major for minor hepatectomies compared to major liver resections.
as well as in minor hepatectomy. However our results showed that major hepatic resections
In our study, bisegmentectomies occupy the greatest are safe procedures with outcome results non-significantly
relative share in minor liver resection group, since left different from minor resections. Further development of
lateral sectionectomies dominates. In major liver resection sophisticated techniques and instruments in order to reduce
group, right hepatectomy and left hepatectomy had the bleeding during liver resection led to the introduction of
vascular stapler in liver surgery in the last decade of the fistulas, postoperative bleeding). Capussotti et al. published
twentieth century. Recent publications reporting a number a study on 610 patients with liver resection, where biliary
of techniques using stapling devices in liver surgery showed fistulas occurred in 3.6% of cases, and our rate of 2.3%
them to be extraordinarily useful in the safe ligation of of all being consistent with these data (53). Treatment
inflow and outflow vessels (51). Application of vascular is not easy and a number of non-surgical strategies have
staplers to selectively divide major intrahepatic blood vessels been proposed. However, surgical intervention should be
for hepatic inflow and outflow vascular control during considered for patients in whom non-surgical interventions
liver resection, has been shown to achieve excellent results, are either unsuccessful or not feasible. In this study no
reducing blood loss, warm ischemia time and operative time patients underwent reoperation, all complications treated
(24,26,29). However, there are a few of potential dangers successfully by non-operative interventional and radiological
in using the stapler. Serious blood loss can theoretically techniques. In our series, no hemorrhage, ischemic damage
occur when the stapler has sealed only half the diameter of or postoperative liver function was observed.
the vessel or after misfire of the devise although we did not Our experience in study of 170 patients who underwent
experience such a situation. hepatectomy with stapling of the pedicle shows that this
Another potential danger from the use of staplers in technique is applicable in a routine clinical setting based on
the liver is tearing a major hepatic vein or vena cava, both its feasibility and safety. Mortality of 1.7% seen in our
while placing the instrument. Usually after encircling of group is consistent with the data published in the literature.
the hepatic vein, the articulated and rotating Endo-GIA In the present series, both mortality and morbidity were as
vascular stapler is passed gently around the hepatic vein low as in a recently published large series of non-selected
to staple and divide it. The thinner blade of the stapler is patients who underwent liver resection in other high-
inserted in preference to the thicker blade because the space volume surgical centers (1,35,52).
available is limited. As the thinner blade is not on the same
axis as the instrument, difficulty may be encountered if the
Conclusions
tip of the blade and tearing of the vein may occur. In order
to avoid this complication, we used a right-angle clamp Extrafascial dissection of Glissonean pedicle with vascular
to grab the thinner blade and guide its insertion into the stapling represents both an effective and safe surgical
space between the liver parenchyma and major vein. This technique of anatomical liver resection. Presented approach
technique is also reported by other centers (28). allows early and easy ischemic delineation of appropriate
Morbidity and mortality are correlated with the anatomical liver territory to be removed (hemiliver,
amount of blood loss during hepatectomy (34,36). section, segment) with selective inflow vascular control.
Despite all technological advancing for liver resections, Also, it is not time consuming and it is very useful in re-
an intraoperative hemorrhage rate ranging from 700 to resection. From the oncological point of view technique is
1,200 mL is reported with a postoperative morbidity reasonable: early initial ligation of Glissonean pedicle avoid
rate ranging from 23% to 46% and a surgical death rate dissemination of neoplastic cells, while anatomical concept
ranging from 4% to 5% (34,36). Jarnagin et al. reported of of resection allows removal of micrometastases at the root
a moderate blood loss of 600 mL and in major hepatectomy of the pedicle with adequate resectional margin. We have
their investigations led to a blood loss of more than demonstrated that segment-orientated liver resections offers
1,000 mL; while 700 to 800 mL observed in the cases of disease-free and overall survival rates similar to those after
stapler hepatectomy (35,52). major resection. However, the patients should be judiciously
Specific complications after liver are all associated with selected. Finally, according to our opinion, extrafascial GA
high morbidity in terms of sepsis, liver failure, longer should be a part of knowledge and skills of HPB surgeon.
hospital stay, as well as postoperative mortality (53,54).
Complications such as biliary leaks continue to be reported
Acknowledgements
with incidences in the range of 2.6-15.6%, in our study
1.7% (53,54). Carefully checking the resection line and Funding: This study was supported by funding from the
completing hemo- and bilistasis, even in a modified Ministry of Education and Science of the Republic of Serbia
cirrhotic liver parenchyma, we obtained literature accepted (grant no III 45019).
percentages in resection line related complications (biliary Disclosure: The authors declare no conflict of interest.
References Paris: Masson, 1957.

16. Tung TT. Les Résections Majeures et Mineures du Fois.
1. Dan RG, Creţu OM, Mazilu O, et al. Postoperative
Paris: Masson & Cie, 1957.
morbidity and mortality after liver resection. Retrospective
17. Couinaud CM. A simplified method for controlled left
study on 133 patients. Chirurgia (Bucur) 2012;107:737-41.
hepatectomy. Surgery 1985;97:358-61.
2. Chirica M, Scatton O, Massault PP, et al. Treatment of
18. Lazorthes F, Chiotasso P, Chevreau P, et al. Hepatectomy
stage IVA hepatocellular carcinoma: should we reappraise
with initial suprahilar control of intrahepatic portal
the role of surgery? Arch Surg 2008;143:538-43;
pedicles. Surgery 1993;113:103-8.
discussion 543.
19. Takasaki K. eds. Glissonean pedicle transection method for
3. Pawlik TM, Schulick RD, Choti MA. Expanding criteria
hepatic resection. Tokyo: Springer, 2007.
for respectability of colorectal liver metastases. Oncologist
20. Takasaki K. Glissonean pedicle transection method for
2008;13:51-64.
hepatic resection: a new concept of liver segmentation. J
4. González HD, Figueras J. Practical questions in liver
Hepatobiliary Pancreat Surg 1998;5:286-91.
metastases of colorectal cancer: general principles of
21. Galperin EI, Karagiulian SR. A new simplified method
treatment. HPB (Oxford) 2007;9:251-8.
of selective exposure of hepatic pedicles for controlled
5. Minagawa M, Yamamoto J, Miwa S, et al. Selection
hepatectomies. HPB Surgery 1989;1:119-30.
criteria for simultaneous resection in patients with 22. Launois B, Jamieson GG. The importance of Glisson’s
synchronous liver metastasis. Arch Surg 2006;141:1006- capsule and its sheaths in the intrahepatic approach to
12; discussion 1013. resection of the liver. Surg Gynecol Obstet 1992;174:7-10.
6. Nuzzo G, Giuliante F, Ardito F, et al. Liver resection for 23. Machado MA, Herman P, Machado MC. A standardized
primarily unresectable colorectal metastases downsized by technique for right segmental liver resections. Arch Surg
chemotherapy. J Gastrointest Surg 2007;11:318-24. 2003;138:918-20.
7. Figueras J, Lopez-Ben S, Lladó L, et al. Hilar dissection 24. Machado MA, Herman P, Machado MC. Anatomical
versus the ‘Glissonian’ approach and stapling of the pedicle resection of left liver segments. Arch Surg 2004;139:1346-9.
for major hepatectomies: a prospective, randomized trial. 25. Machado MA, Herman P, Meirelles RF Jr, et al. How I
Ann Surg 2003;238:111-9. do it: bi-segmentectomy V-VIII as alternative to right
8. Aragon RJ, Solomon NL. Techniques of hepatic resection. hepatectomy: an intrahepatic approach. J Surg Oncol
J Gastrointest Oncol 2012;3:28-40. 2005;90:43-5.
9. Doklestic K, Karamarkovic A, Stefanovic B, et al. The 26. Fong Y, Blumgart L. Useful stapling techniques in liver
efficacy of three transection techniques of the liver resection: surgery. J Am Coll Surg 1997;185:93-100.
a randomized clinical trial. Hepatogastroenterology 27. Ramacciato G, Aurello P, D’Angelo F, et al. Effective
2012;59:1501-6. vascular endostapler techniques in hepatic resection. Int
10. Lortat-Jacob JL, Robert HG. Hepatectomie droite reglé. Surg 1998;83:317-23.
Press Med 1952;60:549-51. 28. Wang WX, Fan ST. Use of the Endo-GIA vascular stapler
11. Meunier B, Lakehal M, Tay KH, et al. Surgical for hepatic resection. Asian J Surg 2003;26:193-6.
complications and treatment during resection for 29. DeMatteo RP, Fong Y, Jarnagin WR, et al. Recent
malignancy of the high bile duct. World J Surg advances in hepatic resection. Semin Surg Oncol
2001;25:1284-8. 2000;19:200-7.
12. Lo CM, Fan ST, Liu CL, et al. Biliary complications after 30. Schemmer P, Friess H, Hinz U, et al. Stapler hepatectomy
hepatic resection: risk factors, management and outcome. is a safe dissection technique: analysis of 300 patients.
Arch Surg 1998;133:156-61. World J Surg 2006;30:419-30.
13. Miyagawa S, Makuuchi M, Kawasaki S, et al. Criteria for 31. Bagul A, McMahon G, Alam F, et al. Safely dealing with
safe hepatic resection. Am J Surg 1995;169:589-94. the right hepatic vein during a right hepectomy. Ann R
14. Icoz G, Kilic M, Zeytunlu M, et al. Biliary reconstructions Coll Surg Engl 2010;92:442-3.
and complications encountered in 50 consecutive right- 32. Karamarković A, Doklestić K, Milić N, et al.
lobe living donor liver transplantation. Liver Transpl Glissonean pedicle approach in major liver resections.
2003;9:575-80. Hepatogastroenterology 2012;59:1896-901.
15. Couinaud C. Le foie. Études Anatomiques et Chirugicales. 33. Pang YY. The Brisbane 2000 terminology of liver anatomy
and resections. HPB 2000; 2:333-39. HPB (Oxford) Extra-Glissonian approach in liver resection. HPB
2002;4:99; author reply 99-100. (Oxford) 2010;12:94-100.
34. Poon RT, Fan ST, Lo CM, et al. Improving perioperative 45. Mouly C, Fuks D, Browet F, et al. Feasibility of the
outcome expands the role of hepatectomy in management Glissonian approach during right hepatectomy. HPB
of benign and malignant hepatobiliary diseases: analysis (Oxford) 2013;15:638-45.
of 1222 consecutive patients from a prospective database. 46. Yamamoto M, Katagiri S, Ariizumi SI, et al. Tips for
Ann Surg 2004;240:698-708; discussion 708-10. anatomical hepatectomy for hepatocellular carcinoma by
35. Poon RT. Current techniques of liver transection. HPB the Glissonean pedicle approach. J Hepatobiliary Pancreat
(Oxford) 2007;9:166-73. Sci 2014;21:E53-6.
36. Belghiti J, Hiramatsu K, Benoist S, et al. Seven hundred 47. Launois B. General principles of liver surgery. In: Launois
fourty-seven hepatectomies in the 1990s: an update to B, Jamieson G. eds. The posterior intrahepatic approach
evaluate the actual risk of liver resection. J Am Coll Surg in Liver surgery. New York, USA: Springer, 2013.
2000;191:38-46. 48. Stewart GD, O’Súilleabháin CB, Madhavan KK, et al.
37. Bismuth H. Surgical anatomy and anatomical surgery of The extent of resection influences outcome following
the liver. World J Surg 1982;6:3-9. hepatectomy for colorectal liver metastases. Eur J Surg
38. Yamamoto M, Katagiri S, Ariizumi S, et al. Glissonean Oncol 2004;30:370-6.
pedicle transection method for liver surgery. J 49. Figueras J, Llado L, Ruiz D, et al. Complete versus
Hepatobiliary Pancreat Sci 2012;19:3-8. selective portal triad clamping for minor liver resections. A
39. Nanashima A, Sumida Y, Oikawa M, et al. Vascular prospective randomized trial. Ann Surg 2005;241:582-90.
transection using endovascular stapling in hepatic 50. Makuuchi M, Mori T, Gunvén P, et al. Safety of
resection. Hepatogastroenterology 2009;56:498-500. hemihepatic vascular occlusion during resection of the
40. Boudjema K, Veilhan LA, Dupont-Bierre E, et al. Two liver. Surg Gynecol Obstet 1987;164:155-8.
tapes to control the main fissure of the liver. Ann Chir 51. Delis SG, Bakoyiannis A, Karakaxas D, et al. Hepatic
2002;127:149-53. parenchyma resection using stapling devices: peri-operative
41. Kim SH, Park SJ, Lee SA, et al. Various liver resections and long-term outcome. HPB (Oxford) 2009;11:38-44.
using hanging maneuver by three Glisson’s pedicles and 52. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in
three hepatic veins. Ann Surg 2007;245:201-5. perioperative outcome after hepatic resection. Analysis
42. Cresswell AB, Welsh FK, John TG, et al. Evaluation of of 1803 consecutive cases over the past decade. Ann Surg
intrahepatic, extra-Glissonian stapling of the right porta 2002;236:397-406; discussion 406-7.
hepatis vs. classical extrahepatic dissection during right 53. Capussotti L, Ferrero A, Vigano L, et al. Bile leakage and
hepatectomy. HPB (Oxford) 2009;11:493-8. liver resection: where is the risk? Arch Surg 2006;141:690-
43. Smyrniotis V, Arkadopoulos N, Theodoraki K, et al. 4; discussion 695.
Association between biliary complications and technique 54. Nagano Y, Togo S, Tanaka K, et al. Risk factors and
of hilar division (extrahepatic vs. intrahepatic) in major management of bile leakage after hepatic resection. World
liver resections. World J Surg Oncol 2006;4:59. J Surg 2003;27:695-8.
44. Giordano M, Lopez-Ben S, Codina-Barreras A, et al.
Cite this article as: Karamarković A, Doklestić K. Pre-

resectional inflow vascular control: extrafascial dissection of
Glissonean pedicle in liver resections. Hepatobiliary Surg Nutr
2014;3(5):227-237. doi: 10.3978/j.issn.2304-3881.2014.09.09
Review Article
Post-hepatectomy liver failure

Rondi Kauffmann, Yuman Fong
Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
Correspondence to: Yuman Fong, MD. Department of Surgery, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010-8113,
USA. Email: yfong@coh.org.
Abstract: Hepatectomies are among some of the most complex operative interventions performed.
Mortality rates after major hepatectomy are as high as 30%, with post-hepatic liver failure (PHLF)
representing the major source of morbidity and mortality. We present a review of PHLF, including
the current definition, predictive factors, pre-operative risk assessment, techniques to prevent PHLF,
identification and management. Despite great improvements in morbidity and mortality, liver surgery
continues to demand excellent clinical judgement in selecting patients for surgery. Appropriate choice of
pre-operative techniques to improve the functional liver remnant (FLR), fastidious surgical technique, and
excellent post-operative management are essential to optimize patient outcomes.
Keywords: Post-hepatectomy liver failure (PHLF); prevention of liver failure; predictive factors for liver failure
Submitted Aug 01, 2014. Accepted for publication Aug 21, 2014.
doi: 10.3978/j.issn.2304-3881.2014.09.01
Introduction obscure laboratory tests, such as hepaplastin or hyaluronic

acid levels, limiting their utility (6). The Model for End-
Hepatic resections are among some of the most complex
Stage Liver Disease (MELD) score is one such definition
operative interventions performed, and are fraught with
that is widely used. The MELD score is calculated using
risk and the potential for complications. Mortality rates
serum creatinine, INR, and bilirubin, but requires a complex
after major hepatic resection have been reported to be
mathematical formula computation (7). The ‘50-50 criterion’
as high as 30% (1,2) with post-hepatectomy liver failure
(PT <50% and bilirubin >50 µmL/L) have also been
(PHLF) representing the major source of morbidity and proposed as a simple definition for PHLF (8). However,
mortality after liver resection. Despite great improvements this definition does not account for any clinical parameters,
in outcomes after major liver resection due to refinements and relies only on two laboratory values. In 2011, the
in operative technique and advances in critical care, PHLF International Study Group of Liver Surgery (ISGLS)
remains one of the most serious complications of major liver proposed a standardized definition and severity of grading
resection, and occurs in up to 10% of cases (3,4). Several of PHLF. After evaluating more than 50 studies on PHLF
studies report a lower rate of PHLF in East Asian countries after hepatic resection, the consensus conference committee
(1-2%), but when present, PHLF represents a significant defined PHLF as “a post-operatively acquired deterioration
source of morbidity and mortality (5). in the ability of the liver to maintain its synthetic, excretory,
and detoxifying functions, which are characterized by an
increased INR and concomitant hyperbilirubinemia on or
Definition
after postoperative day 5” (2). While other definitions of
The definition of PHLF has varied widely among groups, PHLF utilizing biochemical or clinical parameters are used
making comparison of rates between studies challenging. by some centers, the ease with which the ISGLS definition
Numerous definitions of PHLF exist in the literature, with can be calculated and used for comparison renders it the
variations by country and between hospitals within the same definition that ought to be standardized and used.
country. Many definitions include complicated formulas or While PHLF is the most feared complication, the
Table 1 ISGLS definition and grading of PHLF (2)

Grade Clinical description Treatment Diagnosis Clinical symptoms Location for care
A Deterioration in liver None • UOP >0.5 mL/kg/h None Surgical ward
function • BUN <150 mg/dL
• >90% O2 saturation
• INR <1.5
B Deviation from Non-invasive: fresh frozen • UOP ≤0.5 mL/kg/h • Ascites Intermediate unit
expected post- plasma; albumin; diuretics; • BUN <150 mg/dL • Weight gain or ICU
operative course non-invasive ventilatory • <90% O2 saturation despite • Mild respiratory
without requirement support; abdominal oxygen supplementation • Insufficiency
for invasive ultrasound; CT scan • INR ≥1.5, <2.0 • Confusion
procedures
• Encephalopathy
C Multi-system failure Invasive: hemodialysis; • UOP ≤0.5 mL/kg/h • Renal failure ICU
requiring invasive intubation; extracorporeal • BUN ≥150 mg/dL • Hemodynamic Instability
treatment liver support; salvage • ≤85% O2 saturation despite • Respiratory failure
hepatectomy; vasopressors; high fraction of inspired • Large-volume ascites
intravenous glucose for oxygen support • Encephalopathy
hypoglycemia; ICP monitor • INR ≥2.0
ISGLS, International Study Group of Liver Surgery; PHLF, post-hepatectomy liver failure.
Table 2 Predictive factors associated with increased risk of PHLF severity of its clinical manifestation ranges from temporary
Patient related hepatic insufficiency to fulminant hepatic failure. The
Diabetes mellitus ISGLS group advocated a simple grading system of PHLF,
Obesity in which laboratory values, clinical symptoms, and need for
Chemotherapy-associated steatohepatitis increasingly invasive treatments define severity of PHLF.
Hepatitis B, C
The mildest grade of PHLF, grade A, represents a minor,
temporary deterioration in liver function that does not
Malnutrition
require invasive treatment or transfer to the intensive care
Renal insufficiency
unit. The most severe, grade C, is characterized by severe
Hyperbilirubinemia
liver failure with multisystem failure and the requirement
Thrombocytopenia
for management of multi-system failure in the intensive
Lung disease
care unit (2) (Table 1). The peri-operative mortality of
Cirrhosis
patients with grades A, B, and C PHLF as determined by
Age >65 years
this grading schema is 0%, 12% and 54%, respectively (9).
Surgery related
EBL >1,200 mL
Intra-operative transfusions
Predictive factors
Need for vascular resection Patient factors
>50% liver volume resected
Various patient-related factors are associated with increased
Major hepatectomy including right lobectomy
risk of PHLF (Table 2). Operative mortality in patients with
Skeletonization of hepatoduodenal ligament
diabetes undergoing curative-intent hepatic resection for
<25% of liver volume remaining
treatment of colorectal metastases has been shown to be
Post-operative management
higher than comparable patients without diabetes mellitus (6).
Post-operative hemorrhage
In that series, operative mortality was 8% in diabetics
Intra-abdominal infection
compared to 2% in non-diabetics (P<0.02). Furthermore,
PHLF, post-hepatectomy liver failure. 80% of peri-operative deaths in diabetic patients were
240 Kauffmann and Fong. Post-hepatectomy liver failure
PHLF, with post-operative hemorrhage (15) and occurrence

of intra-abdominal infection (16) conferring increased risk
(Table 2).
Pre-operative risk assessment
Given the high mortality rate associated with PHLF, there

has been great interest in techniques to pre-operatively
identify patients at high risk for hepatic dysfunction or
failure. CT-based volumetric analysis is an effective tool that
utilizes helical CT scans to assess the volume of resection by
Figure 1 CT scan image of steatohepatitis, with liver attenuation semi-automated contouring of the liver. A study by Shoup
lower than that of the spleen. et al. utilized this technique to show that the percentage
of remaining liver was closely correlated with increasing
prothrombin time (>18 seconds) and bilirubin level
(>3 mg/dL) (24). In their analysis, 90% of patients
secondary to PHLF. Excess mortality seen in diabetic
undergoing trisegmentectomy with ≤25% of liver remaining
patients undergoing major hepatic resection is likely multi-
developed hepatic dysfunction, compared to none of the
factorial, with alterations in liver metabolism, decreased
patients who had >25% of liver remaining after the same
immune function, and hepatic steatosis contributing to
post-operative liver dysfunction (10). operation (24). Furthermore, the percentage of remaining
Chemotherapy-associated steatohepatitis (CASH) is an liver, as determined by volumetric analysis, was more
increasing challenge in the era of novel chemotherapeutic specific in predicting PHLF than the anatomic extent of
and biologic agents. Many commonly-used chemotherapy resection (24).
agents cause damage to hepatocytes, including 5-fluorouracil, Careful evaluation of pre-operative CT scan imaging
irinotecan, oxaliplatin, cituximab, and bevacizumab should focus on liver attenuation. Liver attenuation that
(11-14). Additionally, pre-operative malnutrition or renal is lower than that observed in the spleen indicates fatty
insufficiency, hyperbilirubinemia, thrombocytopenia, infiltration indicative of steatohepatitis (11,24,25) (Figure 1).
presence of co-morbidities (lung disease), and advanced age Similarly, splenomegaly, varices, ascites, or consumptive
are associated with increased risk of PHLF (15-18). thrombocytopenia should prompt the clinician to suspect
underlying cirrhosis (11) (Figure 2A,B).
Although ultrasound and 3-dimensional ultrasound has
Surgical factors been advocated by some as a means by which to assess the
In addition to patient-specific factors, the performance pre-operative volume of the liver, CT or MRI provide more
of the surgical procedure itself influences risk of PHLF. objective data that is less subject to operator-error. Both CT
Factors associated with increased risk are shown in Table 2 and MRI show excellent accuracy and precise quantification
and include operative estimated blood loss >1,200 mL of hepatic volume (26-28), and are particularly useful in
(19,20), intra-operative transfusion requirement, need for estimating the future liver remnant (FLR) (29).
vena caval or other vascular resection (21), operative time Numerous methods have been developed for calculating
>240 minutes (13), resection of >50% of liver volume, major liver volume, using either CT or MRI images. The first
hepatectomy including right lobe (22), and skeletonization of technique involved manual tracing of the outline of the
the hepatoduodenal ligament in cases of biliary malignancy liver (30), but has been criticized its time-intensity. Most
(23). In patients for whom <25% of the pre-operative liver recently, automatic or semi-automatic techniques have been
volume is left post-resection, the risk of PHLF is 3 times that developed that utilize mathematical formulas to measure
of patients with ≥25% of liver volume remaining (24). liver volumes obtained from CT scan images, utilizing
commercially-available software programming. These
software-based programs have been shown to correlate well
Post-operative factors
with manual volume estimation, but are performed in a
Issues of post-operative management influence the risk of fraction of the time (31).
A predictive value for post-operative liver dysfunction was

75%, and the negative predictive value was 90% (32). While
additional study is needed, this method appears to be a non-
invasive tool for prediction of PHLF.
There is increasing interest in the use of 99m Tc-
diethylenetriamine-pentaacetic acid-galactosyl human
serum albumin (GSA) scintigraphy for the pre-operative
evaluation of cirrhotic patients. In this technique, the
molecule is taken up by the liver, reflecting the volume of
functional liver (33). Uptake corresponds to bilirubin level,
INR, and ICG clearance (33). In 9-20% of patients, the
severity of liver disease is underestimated by ICG clearance
B
testing, and better represented by GSA scintigraphy. This
may be due to the fact that GSA scintigraphy is unaffected
by hyperbilirubinemia (33). Use of GSA scintigraphy pre-
operatively allows for highly accurate estimation of FLR (33).
Beyond imaging, a number of laboratory parameters
have been shown to correlate with risk of PHLF, including
prothrombin activity <70% and hyaluronic acid level
≥200 ng/mL. When elevated pre-operatively, these values
portend greater risk of PHLF (34), and can be used as
indications for or against major hepatectomy (Table 3).
Figure 2 (A) CT scan demonstrating evidence of cirrhosis, with Prevention

ascites, small liver, and splenomegaly; (B) CT scan demonstrating Treatment of PHLF hinges first on its prevention. In
evidence of cirrhosis, with ascites, small liver, splenic varices, and patients identified as high-risk by preoperative evaluation
splenomegaly. of underlying patient factors, presence of cirrhosis, pre-
operative laboratory values, volume of liver to be resected,
or estimated functional liver volume after resection,
Although pre-operative estimation of functional consideration should be given to techniques to minimize
liver volume after resection remains the most advanced the risk of PHLF. One such technique is portal vein
method for estimating hepatic functional reserve, newer embolization (PVE), which manipulates portal blood flow,
techniques, such as indocyanine green (ICG) clearance and by embolizing portal branches in the liver to be resected,
ICG retention rate (ICG R15) have been reported. Under directing blood flow to the intended remnant liver, and
normal conditions, nearly all ICG administered is cleared thereby inducing hypertrophy of the remnant liver before
by the liver. Because the ICG reflects intra-hepatic blood major hepatectomy (35). By increasing the volume of the
flow, it has long been used to assess liver functional reserve intended remnant liver, the risk for PHLF is decreased,
in patients with cirrhosis (32). Only recently, however, even after extended liver resection. Furthermore, pre-
have investigations begun into the application of ICG and operative PVE minimizes intra-operative hepatocyte injury
ICG R15 to estimating functional hepatic reserve after that would otherwise be caused by the abrupt increase
resection of normal livers in the setting of malignancy. in portal venous pressure at the time of resection (35).
In this method, ICG elimination is measured by pulse Current guidelines recommend PVE for patients with
spectrophotometry (32), and the indocyanine green plasma underlying cirrhosis and an anticipated FLR of ≤40%, or
disappearance rate (ICG PDR) is determined. The study by patients with normal liver function and intended FLR of
de Liguori Carino and colleagues reported that when the <20% (35). This procedure can be performed with minimal
pre-operative ICG PDR was less than 17.6%/min and the morbidity and mortality, and allows for improved safety
pre-operative serum bilirubin was >17 µmol/L, the positive of extended hepatectomies (36,37). Even when concurrent
Table 3 Determinants of low vs. high risk for PHLF

Risk Number of safe segments
Imaging Laboratory data Patient factors
category for resection
Low • Predicted FLR >25% • Prothrombin activity ≥70% • No history of cirrhosis Up to 6 (80% of
• Normal splenic size, no • Hyaluronic acid <200 ng/mL • No previous hepato-toxic functional liver volume)
vascular collaterals • Platelets >300,000/µL chemotherapy
• Indocyanine green plasma • Normal serum bilirubin level
disappearance rate
≥17.6%/min
High • Predicted FLR ≤25% • Prothrombin activity <70% • History of cirrhosis No more than 3 (60% of
• Splenomegaly, presence of • Hyaluronic acid ≥200 ng/mL • Previous administration of functional liver volume)
vascular collaterals • Platelets <100,000/µL hepato-toxic chemotherapy
• Steatohepatitis • Hyperbilirubinemia
• Indocyanine green plasma
disappearance rate
<17.6%/min
PHLF, post-hepatectomy liver failure.
A B
Figure 3 (A) Pre-portal vein embolization of right lobe of liver to induce hypertrophy of left lobe of liver; (B) six weeks post-portal vein
embolization of right lobe of liver to induce hypertrophy of left lobe of liver. Line marks middle hepatic vein, dividing right and left
hemilivers.
neoadjuvant chemotherapy is administered, sufficient ipsilateral approach spares the FLR from potential injury,
hepatic hypertrophy occurs after PVE to allow for major acute angulations of the portal branches may render this
liver resection (38). CT volumetry should be performed approach too technically difficult to be feasible (35). If an
3-4 weeks after PVE to assess the degree of hypertrophy (35). extended right hepatectomy is planned, segment 4 could be
A degree of hypertrophy >5% is associated with improved embolized first to minimize risk of dislodgement of embolic
patient outcomes (39) (Figure 3A,B). substances to the left liver during manipulation of the
Access to the portal system for PVE can be performed catheter (35).
via transhepatic contralateral or transhepatic ipsilateral Because PVE is not always technically feasible and some
approach. The transhepatic contralateral approach patients may experience disease progression during the
accesses the portal system through the intended FLR, waiting time between PVE and surgery, the associating liver
and is technically easier than an ipsilateral approach, but partition and portal vein ligation for staged hepatectomy
risks injury to the FLR. Additionally, access to segment 4 (ALPPS) procedure has been advocated by some, particularly
for embolization is technically difficult when performed for patients requiring trisectionectomy for bilateral liver
from a contralateral approach (35). While the transhepatic metastases, or intrahepatic cholangiocarcinoma. In this
Table 4 Techniques for preventing and minimizing the risk of PHLF

Period Techniques
Pre-operative Weight loss in obese patients
Nutritional supplementation
Aggressive management of co-morbid conditions
Portal vein embolization to enlarge FLR
Intra-operative Avoidance of skeletonization of hepatoduodenal ligament unless required for R0 resection
Minimize EBL (resection under low CVP conditions)
Avoidance of blood transfusions if able
Close attention to hemostasis to avoid post-operative hemorrhage
Post-operative Early recognition and treatment of post-op hemorrhage
Early recognition and treatment of biliary obstruction or leak
Early recognition and treatment of intra-abdominal infection
PHLF, post-hepatectomy liver failure; FLR, functional liver remnant.
procedure, blood supply to segments 4-8 is diminished identification of patients who are developing hepatic
by right portal vein branch ligation, combined with insufficiency after hepatectomy. A study by Rahman and
parenchymal transaction along the falciform ligament (40). colleagues showed that patients who developed PHLF had
This technique has shown a 74% increase in the volume of a lower CRP level on post-operative day 1 than patients
the FLR, but with high postoperative morbidity (68%) and who did not develop PHLF. A serum CRP <32 g/dL
mortality (12%) (41). Although there have been promising was an independent predictor of PHLF in multivariate
results in small series, with rapid liver hypertrophy and regression analysis (44). Other tools for predicting PHLF
enlargement of the FLR, this technique requires additional include the ‘50-50 criteria’, MELD system, and Acute
study to refine its indications and place in the repertoire of Physiology and Chronic Health Evaluation (APACHE)
techniques for minimizing the risk of PHLF (42). III. While the MELD system has a sensitivity of 55%
Beyond pre-operative techniques to enlarge the FLR, for morbidity and 71% for mortality, the ISGLS criteria
fastidious intra-operative technique and excellent post- for PHLF perform particularly well in assessing the
operative management contribute greatly to minimizing the risk of increased mortality after hepatectomy (45). The
risk of PHLF (Table 4). In cases of very heavy disease burden 50-50 criterion allows for early detection of PHLF, but is not
in the liver, when resection of all lesions would result in an a marker for increased morbidity after liver resection (45).
FLR too small to avoid PHLF, a combination of resection T h e A PA C H E I I I s c o r e p r e d i c t s m o r t a l i t y a f t e r
and ablation may be used to minimize the amount of liver hepatectomy, but has only been validated in patients with
resected. Additionally, wedge resections with minimal cholangiocellular carcinoma (46).
tumor-free margins may be used to treat multi-focal disease, The most effective treatment for PHLF is liver
leaving sufficient liver intact to avoid PHLF. transplantation, but this is typically reserved for patients
who have failed all other supportive therapies (47). Initial
treatment of PHLF includes supportive care of failing
Identification and management
systems, including intubation, pressors, or dialysis.
When present, PHLF is manifest by progressive multi- Treatment includes infusion of albumin, fibrinogen,
system organ failure, including renal insufficiency, fresh frozen plasma, blood transfusion, and initiation of
encephalopathy, need for ventilator support, and need nutritional supplementation (20).
for pressor support. As hepatic function worsens, patients Intra-hepatic cholestasis is a type of PHLF that warrants
develop persistent hyperbilirubinemia and coagulopathy (43). particular mention. It is characterized by a continued
The development of coagulopathy is a particularly increase in serum bilirubin, in the absence of biliary
poor prognostic indicator (20). Daily measurement of obstruction, with preservation of the synthetic function
serum C-reactive protein (CRP) may help with the early of the liver (48). Biopsy confirming this entity should be
obtained at 2 weeks post-operatively, if the diagnosis remains care unit patients. Ann Surg 2009;249:124-8.
uncertain. Although the course is protracted, PHLF nearly 4. Jaeck D, Bachellier P, Oussoultzoglou E, et al. Surgical
always occurs, with mortality rates approaching 90% despite resection of hepatocellular carcinoma. Post-operative
best supportive care. outcome and long-term results in Europe: an overview.
Liver Transpl 2004;10:S58-63.
5. Ren Z, Xu Y, Zhu S. Indocyanine green retention test
Conclusions
avoiding liver failure after hepatectomy for hepatolithiasis.
PHLF remains a severe complication of hepatic resection, Hepatogastroenterology 2012;59:782-4.
occurring in approximately 8% of patients undergoing 6. Eguchi H, Umeshita K, Sakon M, et al. Presence of active
major hepatectomy (49). It ranges from mild hepatic hepatitis associated with liver cirrhosis is a risk factor for
insufficiency, characterized by transient hyperbilirubinemia mortality caused by posthepatectomy liver failure. Dig Dis
that does not alter the expected post-operative course, to Sci 2000;45:1383-8.
liver failure resulting in multi-system failure requiring 7. Yoo HY, Edwin D, Thuluvath PJ. Relationship of the
invasive treatment in an intensive care unit. Multiple factors model for end-stage liver disease (MELD) scale to hepatic
increase the risk of PHLF, including obesity, diabetes, encephalopathy, as defined by electroencephalography
neoadjuvant treatment with chemotherapy, underlying and neuropsychometric testing, and ascites. Am J
cirrhosis, increased age, male gender, need for extended Gastroenterol 2003;98:1395-9.
liver resection, and long operation with high intra-operative 8. Balzan S, Belghiti J, Farges O, et al. The “50-50
EBL. Risk of PHLF can be minimized by accurate pre- criteria” on postoperative day 5: an accurate predictor
operative assessment of the FLR to be left after resection, of liver failure and death after hepatectomy. Ann Surg
and the induction of hypertrophy of the liver remnant 2005;242:824-8, discussion 828-9.
via PVE if the expected FLR is <20% in a person with a 9. Reissfelder C, Rahbari NN, Koch M, et al. Postoperative
normal liver, <30% in a patient with steatosis, or <40% in course and clinical significance of biochemical blood tests
a cirrhotic patient (50). Early recognition and initiation following hepatic resection. Br J Surg 2011;98:836-44.
of supportive care is crucial to improving patient survival 10. Little SA, Jarnagin WR, DeMatteo RP, et al. Diabetes
in the setting of PHLF. Despite great improvements in is associated with increased perioperative mortality but
morbidity and mortality, liver surgery continues to demand equivalent long-term outcome after hepatic resection for
excellent clinical judgement in selecting patients for surgery. colorectal cancer. J Gastrointest Surg 2002;6:88-94.
Appropriate choice of pre-operative techniques to improve 11. Fong Y, Bentrem DJ. CASH (Chemotherapy-Associated
the functional liver remnant (FLR), fastidious surgical Steatohepatitis) costs. Ann Surg 2006;243:8-9.
technique, and excellent post-operative management are 12. Karoui M, Penna C, Amin-Hashem M, et al. Influence
essential to optimize patient outcomes. of preoperative chemotherapy on the risk of major
hepatectomy for colorectal liver metastases. Ann Surg
2006;243:1-7.
Acknowledgements
13. Fernandez FG, Ritter J, Goodwin JW, et al. Effect of
Disclosure: The authors declare no conflict of interest. steatohepatitis associated with irinotecan or oxaliplatin
pretreatment on resectability of hepatic colorectal
metastases. J Am Coll Surg 2005;200:845-53.
References
14. Peppercorn PD, Reznek RH, Wilson P, et al.
1. Ong GB, Lee NW. Hepatic resection. Br J Surg Demonstration of hepatic steatosis by computerized
1975;62:421-30. tomography in patients receiving 5-fluorouracil-based
2. Rahbari NN, Garden OJ, Padbury R, et al. therapy for advanced colorectal cancer. Br J Cancer
Posthepatectomy liver failure: a definition and grading by 1998;77:2008-11.
the International Study Group of Liver Surgery (ISGLS). 15. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in
Surgery 2011;149:713-24. perioperative outcome after hepatic resection: analysis of
3. Paugam-Burtz C, Janny S, Delefosse D, et al. Prospective 1,803 consecutive cases over the past decade. Ann Surg
validation of the “fifty-fifty” criteria as an early and 2002;236:397-406; discussion 406-7.
accurate predictor of death after liver resection in intensive 16. Tzeng CW, Cooper AB, Vauthey JN, et al. Predictors
of morbidity and mortality after hepatectomy in elderly strategy to induce liver hypertrophy: role of MDCT-
patients: analysis of 7621 NSQIP patients. HPB (Oxford) volumetry to monitor and predict liver growth.
2014;16:459-68. Hepatogastroenterology 2013;60:337-42.
17. Golse N, Bucur PO, Adam R, et al. New paradigms 30. Soyer P, Roche A, Elias D, et al. Hepatic metastases from
in post-hepatectomy liver failure. J Gastrointest Surg colorectal cancer: influence of hepatic volumetric analysis
2013;17:593-605. on surgical decision making. Radiology 1992;184:695-7.
18. Aloia TA, Fahy BN, Fischer CP, et al. Predicting poor 31. Suzuki K, Epstein ML, Kohlbrenner R, et al. Quantitative
outcome following hepatectomy: analysis of 2313 radiology: automated CT liver volumetry compared with
hepatectomies in the NSQIP database. HPB (Oxford) interactive volumetry and manual volumetry. AJR Am J
2009;11:510-5. Roentgenol 2011;197:W706-12.
19. Tomuş C, Iancu C, Bălă O, et al. Liver resection for 32. de Liguori Carino N, O’Reilly DA, Dajani K, et al.
benign hepatic lesion: mortality, morbidity and risk Perioperative use of the LiMON method of indocyanine
factors for postoperative complications. Chirurgia (Bucur) green elimination measurement for the prediction and
2009;104:275-80. early detection of post-hepatectomy liver failure. Eur J
20. Jin S, Fu Q, Wuyun G, et al. Management of post- Surg Oncol 2009;35:957-62.
hepatectomy complications. World J Gastroenterol 33. Hoekstra LT, de Graaf W, Nibourg GA, et al.
2013;19:7983-91. Physiological and biochemical basis of clinical liver
21. Melendez J, Ferri E, Zwillman M, et al. Extended hepatic function tests: a review. Ann Surg 2013;257:27-36.
resection: a 6-year retrospective study of risk factors for 34. Nanashima A, Tobinaga S, Abo T, et al. Reducing the
perioperative mortality. J Am Coll Surg 2001;192:47-53. incidence of post-hepatectomy hepatic complications by
22. Nanashima A, Yamaguchi H, Shibasaki S, et al. preoperatively applying parameters predictive of liver
Comparative analysis of postoperative morbidity according function. J Hepatobiliary Pancreat Sci 2010;17:871-8.
to type and extent of hepatectomy. Hepatogastroenterology 35. Thakrar PD, Madoff DC. Preoperative portal vein
2005;52:844-8. embolization: an approach to improve the safety of major
23. Fujii Y, Shimada H, Endo I, et al. Risk factors hepatic resection. Semin Roentgenol 2011;46:142-53.
of posthepatectomy liver failure after portal vein 36. Shindoh J, Tzeng CW, Aloia TA, et al. Safety and efficacy
embolization. J Hepatobiliary Pancreat Surg of portal vein embolization before planned major or
2003;10:226-32. extended hepatectomy: an institutional experience of 358
24. Shoup M, Gonen M, D’Angelica M, et al. Volumetric patients. J Gastrointest Surg 2014;18:45-51.
analysis predicts hepatic dysfunction in patients 37. van Lienden KP, van den Esschert JW, de Graaf W,
undergoing major liver resection. J Gastrointest Surg et al. Portal vein embolization before liver resection:
2003;7:325-30. a systematic review. Cardiovasc Intervent Radiol
25. Panicek DM, Giess CS, Schwartz LH. Qualitative 2013;36:25-34.
assessment of liver for fatty infiltration on contrast- 38. Covey AM, Brown KT, Jarnagin WR, et al. Combined
enhanced CT: is muscle a better standard of reference than portal vein embolization and neoadjuvant chemotherapy
spleen? J Comput Assist Tomogr 1997;21:699-705. as a treatment strategy for resectable hepatic colorectal
26. D’Onofrio M, De Robertis R, Demozzi E, et al. Liver metastases. Ann Surg 2008;247:451-5.
volumetry: Is imaging reliable? Personal experience and 39. Ribero D, Abdalla EK, Madoff DC, et al. Portal vein
review of the literature. World J Radiol 2014;6:62-71. embolization before major hepatectomy and its effects
27. Tu R, Xia LP, Yu AL, et al. Assessment of hepatic on regeneration, resectability and outcome. Br J Surg
functional reserve by cirrhosis grading and liver 2007;94:1386-94.
volume measurement using CT. World J Gastroenterol 40. Li J, Girotti P, Königsrainer I, et al. ALPPS in right
2007;13:3956-61. trisectionectomy: a safe procedure to avoid postoperative
28. Torzilli G, Montorsi M, Del Fabbro D, et al. liver failure? J Gastrointest Surg 2013;17:956-61.
Ultrasonographically guided surgical approach to liver 41. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right
tumours involving the hepatic veins close to the caval portal vein ligation combined with in situ splitting induces
confluence. Br J Surg 2006;93:1238-46. rapid left lateral liver lobe hypertrophy enabling 2-staged
29. Ulla M, Ardiles V, Levy-Yeyati E, et al. New surgical extended right hepatic resection in small-for-size settings.
Ann Surg 2012;255:405-14. patients with biliary tract carcinoma. Acute Physiology
42. Vennarecci G, Laurenzi A, Levi Sandri GB, et al. The and Chronic Health Evaluation. Crit Care Med
ALPPS procedure for hepatocellular carcinoma. Eur J 1998;26:1671-6.
Surg Oncol 2014;40:982-8. 47. Chan SC, Sharr WW, Chan AC, et al. Rescue Living-
43. Roberts KJ, Bharathy KG, Lodge JP. Kinetics of liver donor Liver Transplantation for Liver Failure Following
function tests after a hepatectomy for colorectal liver Hepatectomy for Hepatocellular Carcinoma. Liver Cancer
metastases predict post-operative liver failure as defined 2013;2:332-7.
by the International Study Group for Liver Surgery. HPB 48. Chiarla C, Giovannini I, Giuliante F, et al. Plasma bilirubin
(Oxford) 2013;15:345-51. correlations in non-obstructive cholestasis after partial
44. Rahman SH, Evans J, Toogood GJ, et al. Prognostic utility hepatectomy. Clin Chem Lab Med 2008;46:1598-601.
of postoperative C-reactive protein for posthepatectomy 49. Vibert E, Pittau G, Gelli M, et al. Actual incidence and
liver failure. Arch Surg 2008;143:247-53; discussion 253. long-term consequences of posthepatectomy liver failure
45. Rahbari NN, Reissfelder C, Koch M, et al. The predictive after hepatectomy for colorectal liver metastases. Surgery
value of postoperative clinical risk scores for outcome after 2014;155:94-105.
hepatic resection: a validation analysis in 807 patients. Ann 50. Asencio JM, García Sabrido JL, Olmedilla L. How to
Surg Oncol 2011;18:3640-9. expand the safe limits in hepatic resections? J Hepatobiliary
46. Hamahata N, Nagino M, Nimura Y. APACHE III, unlike Pancreat Sci 2014;21:399-404.
APACHE II, predicts posthepatectomy mortality in
Cite this article as: Kauffmann R, Fong Y. Post-hepatectomy

liver failure. Hepatobiliary Surg Nutr 2014;3(5):238-246. doi:
10.3978/j.issn.2304-3881.2014.09.01
Review Article
Pancreatic surgery: evolution and current tailored approach

Mario Zovak, Dubravka Mužina Mišić, Goran Glavčić
Department of Surgery, University Clinical Hospital “Sisters of Charity”, Zagreb, Croatia

Correspondence to: Dr. Mario Zovak. Department of Surgery, University Clinical Hospital “Sisters of Charity”, Vinogradska 29, Zagreb, Croatia.
Email: mzovak73@gmail.com.
Abstract: Surgical resection of pancreatic cancer offers the only chance for prolonged survival. Pancretic
resections are technically challenging, and are accompanied by a substantial risk for postoperative
complications, the most significant complication being a pancreatic fistula. Risk factors for development
of pancreatic leakage are now well known, and several prophylactic pharmacological measures, as well as
technical interventions have been suggested in prevention of pancreatic fistula. With better postoperative
care and improved radiological interventions, most frequently complications can be managed conservatively.
This review also attempts to address some of the controversies related to optimal management of the
pancreatic remnant after pancreaticoduodenectomy.
Keywords: Pancreatic cancer; pancreatic resection; pancreatic fistula; total pancreatectomy; pancreatic
anastomosis
doi: 10.3978/j.issn.2304-3881.2014.09.06
Introduction pancreatectomy reported in 1944 (8), and Traverso and

Longmire with pylorus-preserving pancreaticoduodenectomy
Pancreatic cancer is an uncommon type of cancer, the
in 1978 (9) (Table 1). Despite the initially high mortality
incidence of which has been on the rise worldwide, likely
and morbidity following surgical treatment (12,13), with
correlated with an increased incidence of obesity. Pancreatic
the development of surgical technique and concentration of
cancer rates are highest in North America and Europe,
patients in high-volume centres, as well as with improvement
where the frequency of its occurrence puts it in the eighth in perioperative care, the rate of morbidity and mortality
place (1,2). Although it is not very common, its significance following pancreaticoduodenectomy has dropped to
lies in the fact that it is most often diagnosed in the late stage acceptable levels. Morbidity and mortality following total
of the disease, it is almost always fatal, surgical treatment is pancreatectomy have also become more acceptable, as well
rather complex and there is no adequate adjuvant treatment. as long term outcome with better blood glucose regulation
Moreover, it is the only type of cancer in Europe of which and exocrine insufficiency management which has been
increased mortality is anticipated in 2014 (3). Five-year made possible by developing novel insulin formulations and
survival rate in Europe and North America is around 6%, pancreatic enzyme supplements. Improved management
which makes it the fourth cause of death according to of endocrine and exocrine insufficiency following total
cancer mortality statistics (1,2). However, within the 10% pancreatectomy and the discovery of novel clinical entities,
of patients who have been diagnosed in the early, localised such as IPMN (intraductal papillary mucinous neoplasm),
stage, the 5-year survival rate rises to 25% (4,5). have revived what was once a rare surgery, with an increased
There has been immense progress in surgical treatment number of procedures and widened indications for surgical
of pancreatic cancer patients since Kausch and the first treatment.
pancreaticoduodenectomy of periampullary tumor (6), Despite its complications, curative resection is the single
Whipple and his modification of pancreaticoduodenectomy most important factor determining the outcome in patients
in the 1930’s (7), Priestley and the first successful total with pancreatic adenocarcinoma (14). Surgery remains the
248 Zovak et al. Pancreatic surgery: tailored approach
Table 1 History and evolution of pancreaticoduodenectomy

1909: Kausch 2-stage procedure, first cholecystectomy, followed 6 weeks later by resection of the head of pancreas, pylorus, first
and second half of duodenum, with gastroenterostomy, closure of common bile duct and anastomosis of pancreas and the third
part of duodenum (6)
1935: Whipple 2-stage procedure, first posterior gastroenterostomy, ligation and division of the common bile duct with
cholecystogastrostomy, followed by resection of the duodenum and pancreatic head, with closure of pancreatic stump (7)
1940: Whipple completed the procedure in a single stage, in 1942, modification of the procedure with pancreaticojejunostomy (10)
1946: Waugh and Clagett first used pancreaticogastrostomy (11)
1978: Taverso and Longmire reported pylorus preserving pancreaticoduodenectomy (9)
Table 2 Risk factors for pancreatic leak (20,23,24,30-34), infectious complications, most commonly
Pancreas related intra-abdominal abscesses, with prevalence from 1-17%
Soft pancreatic parenchyma (30,35) and hemorrhage. Postoperative bleeding occurs
in 3-13% of patients (5,17). Hemorrhage within the first
Small size pancreatic duct
24 hours is result of the inadequate hemostasis at the time of
Ampullary, duodenal, cystic and bile duct neoplasms
surgery, a slipped ligature, bleeding from an anastomosis or
Patient related
diffuse hemorrhage from the retroperitoneal operation field,
Male sex
most likely caused by underlying coagulopathy, frequently
Age >70 years seen in jaundiced patients (36,37). Late hemorrhage,
Cerebrovascular disease occurring 1-3 weeks after surgery, is often caused by an
Duration of jaundice anastomotic leak with erosion of retroperitoneal vessels (38)
Procedure related with mortality rates from 15%to 58% (39,40). Other causes
Type of pancreatic anastomosis of late hemorrhage are pseudoaneurysm and bleeding
Use of somatostatin from the pancreaticojejunostomy. Management includes
Surgeon’s experience completion pancreatectomy or formation of pancreatic
neoanastomosis (36). Other, not so common, complications
Intraoperative blood loss
are cholangitis, colonic and biliary fistulas. Within the
systemic complications group, cardiopulmonary and
principal treatment for pancreatic cancer and offers the only neurological complications prevail (34,36). Over the years the
chance for cure (15,16). most significant pancreaticoduodenectomy complication was
the development of pancreatic leak and fistula (33,41,42) due
to its frequency of occurrence and high mortality. However,
Complications of pancreaticoduodenectomy
with the refinement of surgical techniques, improved post-
Pancreaticoduodenectomy is indicated for patients with operative intensive care and concentration of patients in
neoplasma of the head of the pancreas, ampullary, duodenal high-volume centres decreased mortality, this also resulted
and distal bile duct neoplasms. It is also performed for chronic in decline of pancreatic fistula incidence. Depending on the
pancreatitis and rarely for trauma. Although high mortality definition used, the incidence of pancreatic fistula used to
rate approaching 25% and morbidity rates up to 60% be 10-29% (43). Nowadays, according to the International
(12,13) were initially related to pancreaticoduodenectomy, Study Group Pancreatic Fistula Definition the incidence
in the last few decades there has been a significant of pancreatic fistula is from 2% to 10% in the centres of
decline in mortality rates which is now 3-5% in highly excellence (30,34,41). The seriousness of pancreatic fistula
specialized centres (17-19). On the other hand, there are still can be seen in its possible consequences, such as septicaemia
numerous possible postoperative complications related to and hemorrhage, which makes it the leading risk factor
pancreaticoduodenectomy and morbidity rates are as high for postoperative death, longer hospital stay and increased
as 30-60% (20-24). Most common local complications are hospital costs after pancreaticoduodenectomy even today.
delayed gastric emptying with prevalence of 8-45% (25-30), Risks for developing the fistula can be divided into a few
pancreatic fistula with reported rates from 2% to 22% groups (Table 2). The first group is pancreas related. One
Table 3 Trials of pancreatic management

Varibles Authors Number of patients Pancreatic fistula (%)
Trials comparing Büchler et al. 1992 (53) 125 somatostatin vs. 121 control 17.6 vs. 38
outcomes of the use Friess et al. 1995 (54) 122 vs. 125 12 vs. 28
of somatostatin and Yeo et al. 2000 (55) 104 vs. 107 11 vs. 9
analogues Sarr et al. 2003 (56) 135 vs. 140 24 vs. 23
Suc et al. 2004 (57) 122 vs. 108 17 vs. 19
Trials comparing Yeo et al. 1995 (58) 73 PG vs. 72 PJ 12 vs. 11
outcomes of PG and PJ Duffas et al. 2005 (59) 81 vs. 68 16 vs. 20
Bassi et al. 2005 (60) 69 vs. 82 13 vs. 16
Trials comparing Winter et al. 2006 (61) 115 with stent vs. 119 no stent 11.3 vs. 7.6
outcomes after duct Poon et al. 2007 (62) 60 vs. 60 6.7 vs. 20
stenting Pessaux et al. 2011 (63) 77 vs. 81 26 vs. 42
Trials comparing Marcus et al. 1995 (64) 68 duct-to-mucosa vs. 18 invag 4.4 vs. 5.5
outcomes after different Bassi et al. 2003 (65) 144 duct-to-mucosa vs. invag 13 vs. 15
anastomotic technique Berger et al. 2009 (66) 97 duct-to mucosa vs. 100 invag 24 vs. 12
Peng et al. 2007 (67) 106 binding vs. 111 invag 0 vs. 7.2
Table 4 Solutions for pancreatic leak Prevention of complications

Use of Somatostatin & analogues A great deal of research has been conducted over the years
Pancreaticogastrostomy aimed at decreasing the risk of pancreatic fistula occurrence
Binding or invaginating pancreaticojejunostomy (Table 3). It has focused on the influence that somatostatin,
Pancreatic duct stenting pancreatic duct stenting and pancreatic occlusion have on
Pancreatic duct occlusion the reduction of PF rate. In addition, a number of studies
Total pancreatectomy have become available which compare pancreaticogastric
anastomosis versus pancreaticojejunal anastomosis and
different pancreaticojejunal anastomotic technique and their
of the most widely recognized risk factors is texture of influence on frequency of PF occurrence (Table 4).
the remnant pancreas; the relation between high rates of
pancreatic fistula up to 25% (42,44-47) in the presence of
Somatostatin and analogues
soft pancreatic parenchyma has been repeatedly reported.
The pancreatic duct size has been implicated as another Octreotide is a synthetic long acting analogue of
relevant factor. Pancreatic duct diameter under 3 mm is somatostatin, a potent inhibitor of pancreatic endocrine
related to a significantly higher risk of pancreatic fistula and exocrine secretion, and gastric and enteric secretion
development (42,44,46,47). Pancreatic fistula development as well. Somatostatin and its analogue are administered
is also predisposed by pancreatic pathology: ampullary, bile postoperatively as prophylaxis. The idea behind this is
duct, duodenal carcinoma and cystic neoplasms are correlated that the decrease of pancreatic secretion would result in
with an increased risk of pancreatic fistula (48,49). The the pancreatic fistula prevention. A number of RTC have
second group of risk factors are patient related, including examined the benefit of somatostatine in pancreatic leakage
male sex, advanced age (older than 70) (48,50), cardiovascular prevention, but the results were inconsistent (68). In 2005,
disease probably due to poor blood supply of anastomosis (30), Connor conducted meta-analyses of ten RTCs which showed
duration of jaundice (51). The last group is procedure related benefits of the use of somatostatin and its analog octreotide
and includes a type of pancreaticodigestive anastomosis, use in reducing the rate of biochemical fistula formation,
of somatostatin, surgeon’s experience and increased operative pancreas-specific complications and total morbidity. The
blood loss (20,21,23,24,30,43-47,52). incidence of clinical anastomotic disruption and mortality
rate was not reduced (69). Cochrane Database Systematic operation rate, length of hospital stay, overall complications
Review from 2013 involved 2,348 patients in 21 trials. and in-hospital mortality. In the subgroup analysis, it
Conclusion drawn from it was that there was no significant was found that the use of external stents is associated
difference in postoperative mortality, reoperation rate with lower incidence of pancreatic fistula, the incidence
or hospital stay between the group of patients who were of complications and length of hospital stay. The review
administered prophylactic somatostatin or its analogue and concludes that the external stenting can be useful, but
the group which received either placebo or nothing at all. In further RCTs on the use of stents are recommended (73).
the somatostatin analogue group, the incidence of pancreatic
fistula was lower, as was the overall number of patients with
Pancreatojejunal anastomosis technique
postoperative complications. On the other hand, when only
patients with clinically significant fistulas were considered, Ever since Whipple modified pancreaticoduodenectomy
there was no relevant difference between the groups. in 1942 by performing pancreaticojejunostomy instead of
Based on the current available evidence, somatostatin and occlusion of pancreatic remnant, this type of anastomosis
its analogues are recommended for routine use in people has been most commonly used for a reconstruction of
undergoing pancreatic resection (70). pancreaticodigestive continuity. There have been further
modifications over the years. For example, jejunal loop can
be positioned in antecolic, retrocolic or retro-mesenteric
Duct stenting
fashion, or the isolated Roux loop pancreaticojejunostomy
Internal, transanastomotic stent diverts the pancreatic can be performed. The anastomosis can be performed as an
juice from the anastomosis, and enables easier placement end-to-end anastomosis with invagination of the pancreatic
of sutures reducing the risk of iatrogenic duct occlusion. stump in the jejunum or as an end-to-side anastomosis with
Its drawbacks are possibility of migration of the stent and or without duct-to-mucosa suturing (Figure 1) (47,65,74,75).
occlusion which may lead to pancreatic fistula formation. In 2002, Poon et al. su compared duct-to-mucosa with
There are not enough studies on internal stenting and invagination anastomosis, and found that the duct-to-
their results have been contradictory (71,72). RTC from mucosa anastomosis was safer (49). In 2013, Bai et al.
Winter et al. (61), involving 234 patients, demonstrated conducted a meta-analysis of randomized controlled trials
that internal duct stenting did not reduce the rate or the comparing duct-to-mucosa (467 patients) and invagination
severity of pancreatic fistulas. The pancreatic fistula rates pancreaticojejunostomy (235 patients). Pancreatic fistula
were 11.3% in patients with internal stent and 7.6% in rate, mortality, morbidity, reoperation and hospital stay
patients without internal pancreatic stent. External stent were similar between techniques (76). Peng described a
has the possibility of a complete diversion of the pancreatic binding pancreaticojejunostomy technique with a pancreatic
juice away from the pancreaticojejunal anastomosis which fistula rate of 0%. This was further validated in an RTC
prevents the activation of pancreatic enzymes by bile. demonstrating that the binding pancreaticojejunostomy
The RTC by Poon et al., involving 120 patients, showed in comparison with end-to-end pancreaticojejunostomy
that the external stent group pancreatic fistula rate was demonstrated significantly decreased postoperative
significantly lower (6.7%) compared to the group which did pancreatic fistula rates, morbidity, mortality and shortened
not undergo the same procedure (20%) (62). In prospective the hospital stay (67,77). However, multiple authors
multicenter randomized trial from Pessaux et al., it was reported better results with binding or invaginating
shown that external drainage reduces pancreatic fistula rate pancreaticojejunostomy technique in patients with soft
(26% vs. 42%), morbidity and delayed gastric emptying pancreatic parenchyma and small size duct (42,64).
after pancreaticoduodenectomy in high risk patients (soft
pancreatic texture and a nondilated pancreatic duct) (63).
Type of pancreatic anastomosis
Cochrane database systematic Review from 2013 involved
656 patients in order to determine the efficacy of pancreatic I n 1 9 4 6 , Wa u g h a n d C l a g e t t f i r s t i n t r o d u c e d
stents, both external and internal, in preventing pancreatic pancreaticogastrostomy in clinical practice (11) (Figure 2).
fistula after pancreaticoduodenectomy. The use of external There are several advantages of this anastomosis—the
or internal stents was not associated with a statistically proximity of the stomach and the pancreas enables tension-
significant change in incidence of pancreatic fistula, re- free anastomosis, the excellent blood supply to the stomach
A enhances the anastomotic healing, the acidity of the stomach

content inactivates pancreatic enzymes, and the lack of
enterokinase in the stomach prevents the conversion of
trypsinogen to trypsin and subsequent activation of the
pancreatic enzymes, which reduces the risk of pancreatic
leakage due to anastomosis autodigestion (78). Yeo et al. were
first to conduct prospective randomized trial comparing
pancreaticojejunostomy and pancreaticogastrostomy, but this
trial failed in finding a significant difference in pancreatic
fistula incidence (58). Statistically relevant difference
regarding pancreatic fistula rates, postoperative complications
B or mortality has not been found in two RTCs from Duffas
et al. (59) and Bassi et al. (60) as well. In 2014 Menahem et al.
published their meta-analysis of seven randomized controlled
trials, involving 562 patients with pancreaticogastrostomy
and 559 patients with pancreaticojejunostomy after
pancreaticoduodenectomy. The pancreatic fistula rate was
significantly lower in the PG group (11.2%) then in the PJ
group (18.7%). The biliary fistula rate was also significantly
lower in the PG group (2% vs. 4.8%) (79). Liu et al. dealt
with the same RTCs, but focused also on morbidity,
C
mortality, hospital stay, reoperation and haemorrhage and
intra-abdominal fluid collection. As well as having lower
incidence of pancreatic and biliary fistula, the PG group
showed a significantly lower incidence of intra-abdominal
fluid collection and shorter hospital stay (80).
Figure 1 Different ways of doing the anastomosis for a Duct occlusion

pancreaticoduodenectomy. (A) End-to-side pancreaticojejunostomy;
In 1935 Whipple reported on the first series of results
(B) oversewing of the pancreatic remnant; (C) end-to-end
after pancreaticoduodenectomy, at which time he did not
pancreaticojejunal invagination
anatomize pancreas with digestive tract. Since there was a
high PF incidence rate, he abandoned the aforementioned
concept and implemented pancreaticojejunostomy as a
standard part of surgical procedure. Where there was suture
ligation of the pancreatic duct, without anastomosis, the
rates of pancreatic fistulas was as high as 80% (64,81,82).
In a randomized controlled trial, conducted by Tran et al.,
involving 86 patients with duct occlusion and 83 patients
with pancreaticojejunostomy, it was revealed that the da
ductal occlusion group had a significantly higher pancreatic
fistula rate (17% vs. 5%), but it failed to show any relevant
difference regarding other postoperative complications,
mortality and exocrine insufficiency. After 3 and 12 months,
there were significantly more patients with diabetes mellitus
Technique of
Pancreaticogastrostomy in the ductal occlusion group (83). Occlusion of the main
pancreatic with fibrin glue was also abandoned (83,84)
Figure 2 Pancreaticogastrostomy. based on results from several RCTs because of high fistula
rates and higher incidence of postoperative diabetes mellitus multicentric disease, total pancreatectomy was thought to
(83,85). be an oncologically more radical procedure (94,95). Later
reports revealed disadvantages of this procedure: long-term
survival after total pancreatectomy was similar or lower than
Treatment
after pancreatoduodenectomy (96), morbidity and mortality
Surgical interventions for complications after were as high as 37% (95-97), with obligatory development
pancreatoduodenectomy are nowadays rare, as low as 4% in of brittle diabetes mellitus and exocrine insufficiency.
centers of excellence (33,34) and 85-90% of patients with Development of steatohepatitis with progressive liver
pancreatic fistula can be treated conservatively by means of failure (98) is another potential long-term complication.
fluid management, parenteral nutrition, suspension of oral Without advantages of oncologic radicality and with
intake and antibiotics administration. Lower percentage diabetes mellitus and malabsorption difficult to control,
of surgical interventions can also be attributable to more total pancreatectomy was abandoned for treating pancreatic
advanced radiologic interventions for intrabdominal fluid tumors.
collections, fistulas and bleeding. Indications for surgical Number of total pancreatectomy procedures has been on
intervention are clinical deterioration of the patient, the rise over the last two decades, for which several reasons
disruption of pancreatic anastomosis, signs of spreading can be named. Concentrating patients in high-volume centres
peritonitis, abdominal abscess, haemorrhage, and wound and enhancements in surgical techniques have resulted in
dehiscence. Delayed hemorrhage can be managed, if morbidity and mortality decline, the rates of which are now as
a patient is stable, by angiographic embolization of low as 35% and 5% respectively (99-101) and are comparable
the bleeding vessel. In the remaining number of cases, to those following pancreatoduodenectomy. The second
emergency surgery is indicated (86,87). The type of surgical reason lies in the development of novel insulin formulations
procedure depends on the underlying cause, and includes and better pancreatic enzyme preparations. While exocrine
procedures such as peripancreatic drainage, control of insufficiency can be relatively easily managed using pancreatic
hemorrhage, disruption of the pancreatic anastomosis enzyme supplements, the control of endocrine insufficiency
without a new anastomosis or a conversion in another type demands intensive insulin programmers, extensive patient
of pancreatic anastomosis and a completion pancreatectomy education and continuing care (102). Total pancreatectomy
(68,78). is followed by not only insulin insufficiency, but also of
Completion pancreatectomy has nowadays become a glucagon and pancreatic polypeptide insufficiency, which
rare procedure, owing to improvements in conservative leads to development of diabetes mellitus with tendencies
treatment and radiologic interventions. Completion to severe hypoglycemia. However, with intensive insulin
pancreatectomy is indicated in patients with pancreatic programmers utilizing multiple daily insulin injections or
anastomotic leak accompanied by sepsis or bleeding (88). pumps, and with glucagon rescue therapy, glycemic control
Owing to the seriousness of the patient’s condition, this can be achieved with satisfactory levels of HBA1c, similar to
procedures postoperative mortality is between 38% and those in patients with insulin-dependent diabetes from other
52% (89,90). causes (99,102-104) and quality of life comparable to those of
the patients after PPPD (99,100).
The third reason is the existence of broader spectre
Total pancreatectomy
of indications which now include in situ neoplasia with
Total pancreatectomy was first performed in 1943 by malignant potential such as intraductal papillary mucinous
Rockey (91), but the patient died soon after it. In 1944 Priestley neoplasm and multifocal islet cell neoplasm; hereditary
performed the first successful total pancreatectomy (8). pancreatitis and familiar pancreatic cancer syndromes.
During the 1950’s this procedure was popularised by Ross (92) Other indications include locally advanced or multicentric
and Porter (93) who considered it to be safer than pancreatic adenocarcinoma, neuroendocrine tumors,
pancreatoduodenectomy with pancreatojejunostomy, because metastases in the pancreas, end-stage chronic pancreatitis
pancreatic anastomosis related morbidity and mortality was with disabling pain, trauma, unsafe pancreatic anastomosis
avoided. Because of high local recurrence rates and poor and completion pancreatectomy after dehisced pancreato-
long-term survival after Whipple operation, combined with enteric anastomosis (98,99,102).
the erroneous belief that pancreatic adenocarcinoma is a Given that the postoperative total pancreatectomy
morbidity and mortality outcomes do not differ significantly On the other hand, exocrine insufficiency will also develop
from those after pancreatoduodenectomy (17,33,34,98,99), in 9-20% of patients after Whipple procedure (116,117).
and the quality of life is fairly acceptable, there are no The underlying cause are probably stenosis of pancreatic
restrictions for performing total pancreatectomy on patients anastomosis and postoperative inflammation of the pancreas
with indication for total pancreatectomy (99,101). and fibrosis of pancreatic parenchyma (118,119). Other
factors include patient’s preexisting diabetes mellitus
or exocrine insufficiency, patient’s overall health and
Discussion
performance status and patient’s compliancy. A surgeon
After decreasing a 30-day mortality rate after has several possibilities. First option is to perform a
pancreaticoduodenectomy to about 5%, surgeons have pancreatoduodenectomy with pancreatogastrojejunostomy,
now focused their efforts on reducing morbidity, which is because of the lower incidence of pancreatic fistula with this
still as high as 30-60% (17,105-107). This mainly concerns type of anastomosis (79,80) or pancreatoduodenectomy with
reduction in incidence of pancreatic fistula, which is invagination pancreaticojejunostomy, recommended by a
regarded the main cause of other frequent complications number of authors in case of soft pancreatic parenchyma
such as delayed gastric emptying, septic complications and and small pancreatic duct (67,113). Second option is also
intraabdominal haemorrhage. pancreatoduodenectomy, but with occlusion of the pancreatic
Ever since Whipple’s first pancreaticojejunostomy remnant, either by ligation of the main pancreatic duct or by
after pancreatoduodenectomy, surgeons have paid special occlusion of the main pancreatic duct by Neoprene, Ethibloc
attention to anastomosis between pancreatic remnant and or fibrin glue injection. This procedure is related to a higher
digestive tract. In highly specialized centres pancreatic incidence of pancreatic fistula, but with more benign clinical
fistula incidence is from 0 to 18% (108), with death rate course, because pancreatic enzymes are not activated. The
of 5%. Among the reports classifying pancreatic fistulas last option is total pancreatectomy for initial treatment of
as A, B or C, following ISGPF grading system, incidence patients with multiple risk factors. With this procedure
of grade C pancreatic fistulas was 2-5% (109-111). potential risks of a pancreatic fistula are eliminated, but
Grade C pancreatic fistulas were associated with sepsis with establishment of a total pancreatic state. Because of
from intrabdominal collections and bleeding, with high glycemic instability, predisposition for severe, life-threating
reoperation rate, prolonged length of hospital stay hypoglycemia, and need for close glucose monitoring and
and with mortality rates from 35-40%. Soft pancreatic intense insulin programme, patient’s compliance after total
parenchyma is the most widely recognized risk factor pancreatectomy is essential.
for pancreatic fistula (112,113), along with three other When a surgeon encounters such a significant problem,
relevant factors: duct size smaller than 3 mm, excessive the decision about proper surgical management can be
intraoperative blood loss and specific pathology: difficult to make. Besides purely technical challenges,
ampullary, duodenal, cystic or islet cell neoplasms (111). patients overall health status, existing comorbidities,
The question is what to do when one or more risk factors pancreas pathology and expected survival are crucial in the
for development of pancreatic fistula are present. There decision-making process.
are multiple factors that will influence a decision which
procedure to perform. First, to preserve a sufficient
Acknowledgements
endocrine pancreatic function, approximately 50% of alpha
and beta cells must be preserved (114). Alpha and beta cells Disclosure: The authors declare no conflict of interest.
are located predominately in the tail of the pancreas (115),
so, theoretically, classical pancreaticoduodenectomy
References
procedure should not cause endocrine insufficiency. When a
pancreatic duct is occluded, without pancreatic anastomosis, 1. Howlader N, Noone AM, Krapcho M, et al. eds. SEER
pancreatic exocrine insufficiency will surely develop. Cancer Statistics Review, 1975-2011, National Cancer
Besides exocrine insufficiency, there is a significantly Institute. Bethesda, MD. Available online: http://seer.
higher incidence of diabetes mellitus in patients with cancer.gov/csr/1975_2011/
chemical occlusion of pancreatic duct in comparison 2. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN
with patients with a pancreaticojejunostomy (83). 2012 v1.0, Cancer Incidence and Mortality worldwide:
IARC CancerBase No.11 (Internet). Lyon, France: statement: epidemiology, diagnosis, and teratment of
International Agency for Research on Cancer; 2013. pancreatic ductal adenocarcinoma. Gastroenterology
Available online: http://globocan.iarc.fr 1999;117:1463-84.
3. Malvezzi M, Bertuccio P, Levi F, et al. European cancer 17. Büchler MW, Wagner M, Schmied BM, et al. Changes
mortality predictions for the year 2014. Ann Oncol in morbidity after pancreatic resection: toward the end of
2014;25:1650-6. completion pancreatectomy. Arch Surg 2003;138:1310-4;
4. Gaedcke J, Gunawan B, Grade M, et al. The mesopancreas discussion 1315.
is the primary site for R1 resection in pancreatic head 18. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital
cancer: Relevance for clinical trials. Langenbecks Arch volume and surgical mortality in the Unites States. N Engl
Surg 2010;395:451-8. J Med 2002;346:1128-37.
5. Yeo CJ, Cameron JL, Lillemoe KD, et al. 19. McPhee JT, Hill JS, Whalen GF, et al. Perioperative
Pancreaticoduodenectomy for cancer of the head of the mortality for pancreatectomy: a national perspective. Ann
pancreas: 201 patients. Ann Surg 1995;221:721-31. Surg 2007;246:246-53.
6. Kausch W. Das karzinom der papilla duodeni und seine 20. Schmidt CM, Powell ES, Yiannoutsos CT, et al.
radikale entfernung. Beitrage zur Klinischen Chirurgie Pancreaticoduodenectomy: a 20-year experience in 516
1912;78:29-33. patients. Arch Surg 2004;139:718-25; discussion 725-7.
7. Whipple AO, Parsons WB, Mullins CR. Treatment 21. Bassi C, Falconi M, Salvia R, et al. Management of
of carcinoma of the ampulla of Vater. Ann Surg complications after pancreaticoduodenectomy in a high
1935;102:763-79. volume centre: results on 150 consecutive patients. Dig
8. Priestley JT, Comfort MW, Radcliffe J. Total Surg 2001;18:453-7; discussion 458.
Pancreatectomy for Hyperinsulinism Due to an Islet- 22. Richter A, Niedergethmann M, Sturm JW, et al. Long-
Cell Adenoma: Survival and Cure at sixteen months after term results of partial pancreaticoduodenectomy for
operation, presentation of Metabolic studies. Ann Surg ductal adenocarcinoma of the pancreatic head: 25-year
1944;119:211-21. experience. World J Surg 2003;27:324-9.
9. Traverso LW, Longmire WP Jr. Preservation of the 23. Cameron JL, Riall TS, Coleman J, et al. One thousand
pylorus in pancreaticoduodenectomy. Surg Gynecol consecutive pancreaticoduodenectomies. Ann Surg
Obstet 1978;146:959-62. 2006;244:10-5.
10. Whipple AO. Observations on radical surgery for lesions 24. Bassi C, Dervenis C, Butturini G, et al. International study
of pancreas. Surg Gynecol Obstet 1946;82:623-31. group on pancreatic fistula definition. Post- operative
11. Waugh JM, Clagett OT. Resection of the duodenum and pancreatic fistula: an international study group (ISGPF)
head of the pancreas for carcinoma; an analysis of thirty definition. Surgery 2005;138:8-13.
cases. Surgery 1946;20:224-32. 25. Schäfer M, Müllhaupt B, Clavien PA. Evidence-based
12. Gilsdorf RB, Spanos P. Factors influencing morbidity pancreatic head resection for pancreatic cancer and chronic
and mortality in pancreaticoduodenectomy. Ann Surg pancreatitis. Ann Surg 2002;236:137-48.
1973;177:332-7. 26. Fernández-del Castillo C, Rattner DW, Warshaw AL.
13. Monge JJ, Judd ES, Gage RP. Radical Standards for pancreatic resection in the 1990s. Arch Surg
pancreatoduodenectomy: a 22-year experience with the 1995;130:295-9; discussion 299-300.
complications, mortality rate, and survival rate. Ann Surg 27. Patel AG, Toyama MT, Kusske AM, et al. Pylorus-
1964;160:711-22. preserving Whipple resection for pancreatic cancer. Is it
14. Wagner M, Redaelli C, Lietz M, et al. Curative resection any better? Arch Surg 1995;130:838-42.
is the single most important factor determining outcome 28. Lin PW, Lin Yj. Prospective randomized comparison
in patients with pancreatic adenocarcinoma. Br J Surg between pylorus-preserving and standard
2004;91:586-94. pancreaticoduodenectomy. Br J Surg 1999;86:603-7.
15. Beger HG, Rau B, Gansauge F, et al. Treatment of 29. van Berge Henegouwen MI, van Gulik TM, DeWitt
pancreatic cancer: Challenge of the facts. World J Surg LT, et al. Delayed gastric emptying after standard
2003;27:1075-84. pancreaticoduodenectomy versus pylorus-preserving
16. American Gastroenterological Association. American pancreaticoduodenectomy: an analysis of 200 consecutive
Gastroenterological Association medical position patients. J Am Coll Surg 1997;185:373-9.
30. DeOliveira ML, Winter JM, Schafer M, et al. Assessment 46. Shrikhande SV, D’Souza MA. Pancreatic fistula after
of complications after pancreatic surgery: A novel pancreatectomy: evolving definitions, preventive strategies
grading system applied to 633 patients undergoing and modern management. World J Gastroenterol
pancreaticoduodenectomy. Ann Surg 2006;244:931-7; 2008;14:5789-96.
discussion 937-9. 47. Lai EC, Lau SH, Lau WY. Meassures to prevent
31. Matsumoto Y, Fuji H, Miura K, et al. Sucsessfull pancreatic fistula after pancreaticoduodenectomy: a
pancreatojejunal anastomosis for pancreatoduodenectomy. comprehensive review. Arch Surg 2009;144:1074-80.
Surg Gynecol Obstet 1992;175:555-62. 48. Lin JW, Cameron JL, Yeo CJ, et al. Risk factors
32. Cullen JJ, Sarr MG, Ilstrup DM. Pancreatic anastomotic and outcomes in postpancreaticoduodenectomy
leak after pancreaticoduodenectomy: incidence, pancreaticocutaneous fistula. J Gastrointest Surg
significance and management. Am J Surg 1994;168:295-8. 2004;8:951-9.
33. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty 49. Poon RT, Lo SH, Fong D, et al. Prevention of pancreatic
consecutive pancreaticoduodenectomies in the 1990s: anastomosis leakage after pancreaticoduodenectomy. Am J
pathology, complications, and outcomes. Ann Surg Surg 2002;183:42-52.
1997;226:248-57; discussion 257-60. 50. Matsusue S, Takeda H, Nakamura Y, et al. A
34. Büchler MW, Friess H, Wagner M, et al. Pancreatic fistula prospective analysis of the factors influencing
after pancreatic head resection. Br J Surg 2000;87:883-9. pancreaticojejunostomy performed using a single
35. Halloran CM, Ghaneh P, Bosonnet L, et al. Complications method, in 100 consecutive pancreaticoduodenectomies.
of pancreatic cancer resection. Dig Surg 2002;19:138-46. Surgery Today 1998;28:719-26.
36. Ho CK, Kleeff J, Friess H, et al. Complications of 51. Yeh TS, Jan YY, Jeng LB, et al. Pancreaticojejunal
pancreatic surgery. HPB 2005;7:99-108. anastomotic leak after pancreaticoduodenectomy--
37. Rumstadt B, Schwab M, Korth P, et al. Haemorrhage after multivariate analysis of perioperative risk factors. J Surg
pancreatoduodenectomy. Ann Surg 1998;227:236-41. Res 1997;67:119-25.
38. Brodsky JT, Turnbull AD. Arterial hemorrhage after 52. Lowy AM, Lee JE, Pisters PW, et al. Prospective,
pancreatoduodenectomy. The ‘sentinel bleed’. Arch Surg randomized trial of octreotide to prevent pancreatic fistula
1991;126:1037-40. after pancreaticoduodenectomy for malignant disease. Ann
39. van Berge Henegouwen MI, Allema JH, Van Gulik TM, Surg 1997;226:632-41.
et al. Delayed massive hemorrhage after pancreatic and 53. Büchler M, Friess H, Klempa I, et al. Role of octreotide in
billiary surgery. Br J Surg 1995;82:1527-31. the prevention of postoperative complications following
40. Shankar S, Russell RC. Haemorrhage in pancreatic pancreatic resection. Am J Surg 1992;163:125-30;
disease. Br J Surg 1989;76:863-6. discussion 130-1.
41. Trede M, Saeger HD, Schwall G, et al. Resection of 54. Friess H, Beger HG, Sulkowski U, et al. Randomized
pancreatic cancer--surgical achievements. Langenbecks controlled multicenter study of the prevention of
Arch Surg 1998;383:121-8. complications by octreotide in patients undergoing surgery
42. van Berge Henegouwen MI, de Witt LT, Van Gulik TM, for chronic pancreatitis. Br J Surg 1995;82:1270-3.
et al. Incidence, risk factors, and treatment of pancreatic 55. Yeo CJ, Cameron JL, Lillemos KD, et al. Does prophylactic
leakage after pancreaticoduodenectomy: drainage versus octreotide decrease the rates of pancreatic fistula and other
resection of the pancreatic remnant. J Am Coll Surg complications after pancreaticoduodenectomy? Results of
1997;185:18-24. a prospective randomized placebo- controlled trial. Ann
43. Bassi C, Butturini G, Molinari E, et al. Pancreatic Surg 2000;232:419-29.
fistula rate after pancreatic resection: the importance of 56. Sarr MG; Pancreatic Surgery Group. The potent
definitions. Dig Surg 2004;21:54-9. somatostatin analogue vapreotide does not decrease
44. Callery MP, Pratt WB, Vollmer CM Jr. Prevention and pancreas-specific complications after elective
management of pancreatic fistula. J Gastrointest Surg pancreatectomy: a prospective, multicenter, double-
2009;13:163-73. blinded, randomized, placebo-controlled trial. J Am Coll
45. Yang YM, Tian XD, Zhuang Y, et al. Risk factors of Surg 2003;196:556-64; discussion 564-5; author reply 565.
pancreatic leakage after pancreaticoduodenectomy. World 57. Suc B, Msika S, Piccinini M, et al. Ocreotide in the
J Gastroenterol 2005;11:2456-61. prevention of intra-abdominal complications following
elective pancreatic resection: a prospective, multicenter 69. Connor S, Alexakis N, Garden OJ, et al. Meta- analysis
randomized controlled trial. Arch Surg 2004;139:288-94. of the value of somatostatin and its analogues in reducing
58. Yeo CJ, Cameron JL, Maher MM, et al. A prospective complications associated with pancreatic surgery. Br J Surg
randomized trial of pancreaticogastrostomy versus 2005;92:1059-67.
pancreatcojejunostomy after pancreaticoduodenectomy. 70. Gurusamy KS, Koti R, Fusai G, et al. Somatostatin
Ann Surg 1995;222:580-8. analogues for pancreatic surgery. Cochrane Database Syst
59. Duffas JP, Suc B, Msika S, et al. French association Rev 2013;4:CD008370.
for Research in Surgery. A controlled randomized 71. Yoshimi F, Ono H, Asato Y, et al. Internal stenting of
multicenter trial of pancreatogastrostomy or the hepaticojejunostomy and pancreaticojejunostomy in
pancreatojejunostomy after pancreaticoduodenectomy. patients undergoing pancreatoduodenectomy to promote
Am J Surg 2005;189:720-9. earlier discharge from hospital. Surg Today 1996;26:665-7.
60. Bassi C, Falconi M, Molinari E, et al. Reconstruction by 72. Imaizumi T, Hatori T, Tobita K, et al.
pancreaticojejunostomy versus pancreaticogastrostomy Pancreaticojejunostomy using duct-to-mucosa anastomosis
following pancreatectomy: results of a comparative study. without a stenting tube. J Hepatobiliary Pancreat Surg
Ann Surg 2005;242:767-71. 2006;13:194-201.
61. Winter JM, Cameron JL, Campbell KA, et al. Does 73. Dong Z, Xu J, Wang Z, et al. Stents for the prevention
pancreatic duct stenting decrease the rate of pancreatic of pancreatic fistula following pancreaticoduodenectomy.
fistula following pancreaticoduodenectomy? Results Cochrane Database Syst Rev 2013;6:CD008914.
of a prospective randomized trial. J Gastrointest Surg 74. Strasberg SM, Drebin JA, Mokadam NA, et al.
2006;10:1280-90. Prospective trial of a blood supply-based technique of
62. Poon RT, Fan ST, Lo CM, et al. External drainage of pancreaticojejunostomy: effect on anastomotic failure in
pancreatic duct with a stent to reduce leakage rate of the Whipple procedure. J Am Coll Surg 2002;194:746-58;
pancreaticojejunostomy after pancreaticoduodenectomy: a discussion 759-60.
prospective randomized trial. Ann Surg 2007;246:425-33; 75. Z’graggen K, Uhl W, Friess H, et al. How to do a safe
discussion 433-5. pancreatic anastomosis. J Hepatobiliary Pancreat Surg
63. Pessaux P, Sauvanet A, Mariette C, et al. External 2002;9:733-7.
pancreatic duct stent decreases pancreatic fistula rate 76. Bai XL, Zhang Q, Masood N, et al. Duct-to-mucosa
after pancreaticoduodenectomy: prospective multicenter versus invagination pancreaticojejunostomy after
randomized trial. Ann Surg 2011;253:879-85. pancreaticoduodenectomy: a meta-analysis. Chin Med J
64. Marcus SG, Cohen H, Ranson JH. Optimal management (Engl) 2013;126:4340-7.
of the pancreatic remnant after pancreaticoduodenectomy. 77. Peng S, Mou Y, Cai X, et al. Binding
Ann Surg 1995;221:635-45; discussion 645-8. pancreaticojejunostomy is a new technique to minimize
65. Bassi C, Falconi M, Molinari E, et al. Duct-to-mucosa leakage. Am J Surg 2002;183:283-5.
versus end-to-side pancreaticojejunostomy reconstruction 78. Crippa S, Salvia R, Falconi M, et al. Anastomotic leakage
after pancreaticojduodenectomy: results of a prospective in pancreatic surgery. HPB 2007;9:8-15.
randomized trial. Surgery 2003;134:766-71. 79. Menahem B, Guittet L, Mulliri A, et al.
66. Berger AC, Howard TJ, Kennedy EP, et al. Does type of Pancreaticogastrostomy is superior to
pancreaticojejunostomy after pancreaticoduodenectomy pancreaticojejunostomy for prevention of pancreatic fistula
decrease rate of pancreatic fistula? A randomized, after pancreaticoduodenectomy: an updated meta-analysis
prospective, dual-institution trial. J Am Coll Surg of randomized controlled trails. Ann Surg 2014. [Epub
2009;208:738-47. ahead of print].
67. Peng SY, Wang JW, Lau WY, et al. Conventional 80. Liu FB, Chen JM, Geng W, et al. Pancreaticogastrostomy
versus binding pancreaticojejunostomy after is associated with significantly less pancreatic fistula
pancreaticoduodenectomy: a prospective randomized trial. than pancreaticojejunostomy reconstruction after
Ann Surg 2007;245:692-98. pancreaticoduodenectomy: a meta- analysis of seven
68. Machado NO. Pancreatic fistula after pancreatectomy: randomized controlled trials. HPB (Oxford) 2014. [Epub
Definitions, Risk Factors, Preventive Measures, and ahead of print].
Management- review. Int J Surg Onc 2012;2012:1-10. 81. Sakorafas GH, Friess H, Balsiger BM, et al. Problems of
recontruction during pancreatoduodenectomy. Dig Surg morbidity and mortality after pancreaticoduodenectomy.
2001;18:363-9. Am J Surg 1986;151:141-9.
82. Papachristou DN, Fortner JG. Pancreatic fistula 97. McAfee MK, van Heerden JA, Adson MA. Is proximal
complicating pancreatectomy for malignant disease. Br J pancreatoduodenectomy with pyloric preservation superior
Surg 1981;68:238-40. to total pancreatectomy? Surgery 1989;105:347-51.
83. Yeo CJ, Cameron JL, Maher MM, et al. A prospective 98. Heidt DG, Burant C, Simeone DM. Total pancreatectomy:
randomized trial of pancreaticogastrostomy versus Indications, operative technique, and postoperative
pancreaticojejunostomy after pancreaticoduodenectomy. sequelae. J Gastrointest Surg 2007;11:209-16.
Ann Surg 1995;222:580-8; discussion 588-92. 99. Müller MW, Friess H, Kleeff J, et al. Is there still a role
84. Suc B, Msika S, Fingerhut A. French association for for total pancreatectomy? Ann Surg 2007;246:966-74;
Research in Surgery. Temporary Fibrin Glue Occlusion discussion 974-5.
of the main pancreatic duct in the prevention of 100. Billings BJ, Christein JD, Harmsen WS, et al. Quality-
intraabdominal complications after pancreatic resection. of-life after total pancreatectomy: is it really that bad on
Ann Surg 2003;237:57-65. long-term follow-up? J Gastrointest Surg 2005;9:1059-66;
85. Konishi T, Hiraishi M, Kubota K, et al. Segmental discussion 1066-7.
occlusion of the pancreatic duct with prolamine to prevent 101. Hartwig W, Gluth A, Hinz U, et al. Total pancreatectomy
fistula formation after distal pancreatectomy. Ann Surg for primary pancreatic neoplasms: Renaissance of an
1995;221:165-70. unpopular operation. Ann Surg 2014. [Epub ahead of
86. de Castro SM, Kuhlmann KF, Busch OR, et al. Delayed print].
massive hemorrhafe after pancreatic and biliary surgery. 102. Parsaik AK, Murad MH, Sathananthan A, et al. Metabolic
Embolization or surgery? Ann Surg 2005;241:85-91. and target organ outcomes after total pancreatectomy:
87. Yekebas EF, Wolfram L, Cataldegirmen G, et al. Mayo Clinic experience and meta-analysis of the literature.
Postpancreatectomy hemorrhage: diagnosis and treatment: Clinical Endocrinology 2010;73:723-31.
an analysis in 1669 consecutive pancreatic resections. Ann 103. Jethwa P, Sodergren M, Lala A, et al. Diabetic control
Surg 2007;246:269-80. after total pancreatectomy. Dig Liver Dis 2006;38:415-9.
88. Tamijmarane A, Ahmed I, Bhati CS, et al. Role of 104. MacLeod KM, Hepburn DA, Frier BM. Frequency and
compoletion pancreatectomy as a damage control option morbidity of severe hypoglycaemia in insulin-treated
for post- pancreatic surgical complications. Dig Surg diabetic patients. Diabet Med 1993;10:238-45.
2006;23:229-34. 105. Neoptolemos JP, Russell RC, Bramhall S, et al. Low
89. Gueroult S, Parc Y, Duron F, et al. Completion mortality following resection for pancreatic and
pancreatectomy for postoperative peritonitis after periampullary tumours in 1026 patients: UK survey of
pancreaticoduodenectomy: early and late outcome. Arch specialist pancreatic units. UK Pancreatic Cancer Group.
Surg 2004;139:16-9. Br J Surg 1997;84:1370-6.
90. Wittmann DH, Schein M, Condon RE. Management of 106. Stojadinovic A, Brooks A, Hoos A, et al. An evidence-
secondary peritonitis. Ann Surg 1996;224:10-8. based approach to the surgical management of
91. Rockey EW. Total pancreatectomy for carcinoma. Case resectable pancreatic adenocarcinoma. J Am Coll Surg
report. Ann Surg 1943;118:603-11. 2003;196:954-64.
92. Ross DE. Cancer of the pancreas; a plea for total 107. Cooperman AM, Schwartz ET, Fader A, et al. Safety,
pancreatectomy. Am J Surg 1954;87:20-33. efficacy, and cost of pancreaticoduodenal resection in a
93. Porter MR. Carcinoma of the pancreatico-duodenal specialized center based at a community hospital. Arch
area; operability and choice of procedure. Ann Surg Surg 1997;132:744-7; discussion 748.
1958;148:711-23. 108. Schäfer M, Müllhaupt B, Clavien PA. Evidence-based
94. ReMine WH, Priestley JT, Judd ES, et al. Total pancreatic head resection for pancreatic cancer and chronic
pancreatectomy. Ann Surg 1970,172:595-604. pancreatitis. Ann Surg 2002;236:137-48.
95. Sarr MG, Behrns KE, van Heerden JA. Total 109. Fuks D, Piessen G, Huet E, et al. Life-threatening
pancreatectomy. An objective analysis of its use in pancreatic postoperative pancreatic fistula (grade C) after
cancer. Hepatogastroenterology. 1993;40:418-21. pancreaticoduodenectomy: incidence, prognosis and risk
96. Grace PA, Pitt HA, Tompkins RK, et al. Decreased factors. Am J Surg 2009;197:702-9.
110. Pratt WB, Maithel SK, Vanounou T, et al. Clinical and pancreatectomy. J Clin Endocrinol Metab 2009;94:2857-63.
economic validation of the International Study Group of 115. Wittingen J, Frey CF. Islet concentration in the head,
Pancreatic Fistula (ISGPF) classification scheme. Ann Surg body, tail and uncinate process of the pancreas. Ann Surg
2007;245:443-51. 1974;179:412-4.
111. Callery MP, Wande BP, Kent TS, et al. Prospectively 116. Idezuki Y, Goetz FC, Lillehei RC. Late effect of
validated clinical risk score accurately predicts pancreatic pancreatic duct ligation on beta cell function. Am J Surg
fistula after pancreaticoduodenectomy. J Am Coll Surg 1969;117:33-39.
2013;216:1-14. 117. Shankar S, Theis B, Russell RC. Management of the
112. Mathur A, Pitt HA, Marine M, et al. Fatty pancreas: stump of the pancreas after distal pancreatic resection. Br J
a factor in postoperative pancreatic fistula. Ann Surg Surg 1990;77:541-44.
2007;246:1058-64. 118. Tran TC, van’t Hof G, Kazemier G, et al. Pancreatic
113. Suzuki Y, Fujino Y, Tanioka Y, et al. Selection of fibrosis correlates with exocrine pancreatic insufficiency
pancreaticojejunostomy techniques according to pancreatic after pancreatoduodenectomy. Dig Surg 2008;25:311-8.
texture and duct size. Arch Surg 2002;137:1044-7; 119. Nordback I, Parviainen M, Piironen A, et al. Obstructed
discussion 1048. pancreaticojejunostomy partly explains exocrine
114. Schrader H, Menge BA, Breuer TGK, et al. Impaired insufficiency after paancreatic head resection. Scand J
Glucose-Induced Glucagon Suppression after partial Gastroenterol 2007;42:263-70.
Cite this article as: Zovak M, Mužina Mišić D, Glavčić G.

Pancreatic surgery: evolution and current tailored approach.
j.issn.2304-3881.2014.09.06
Review Article
Potential use of Doppler perfusion index in detection of occult

liver metastases from colorectal cancer
Mario Kopljar, Leonardo Patrlj, Željko Bušić, Marijan Kolovrat, Mislav Rakić, Robert Kliček, Marcel
Židak, Igor Stipančić
Department of Abdominal Surgery, University Hospital Dubrava, Zagreb, Croatia

Correspondence to: Mario Kopljar, MD, PhD. Department of Abdominal Surgery, University Hospital Dubrava, Av. G. Suska 6, HR-10000 Zagreb,
Croatia. Email: kopljar@yahoo.com.
Abstract: Many clinical and preclinical studies demonstrated that measurements of liver hemodynamic
[Doppler perfusion index (DPI)] may be used to accurately diagnose and predict liver metastases from
primary colorectal cancer in a research setting. However, Doppler measurements have some serious
limitations when applied to general population. Ultrasound is very operator-dependent, and requires skilled
examiners. Also, many conditions may limit the use of Doppler ultrasound and ultrasound in general, such as
the presence of air in digestive tract, cardiac arrhythmias, vascular anomalies, obesity and other conditions.
Therefore, in spite of the results from clinical studies, its value may be limited in everyday practice. On
the contrary, scientific research of the DPI in detection of liver metastases is of great importance, since
current research speaks strongly for the presence of systemic vasoactive substance responsible for observed
hemodynamic changes. Identification of such a systemic vasoactive substance may lead to the development
of a simple and reproducible laboratory test that may reliably identify the presence of occult liver metastases
and therefore increase the success of adjuvant chemotherapy through better selection of patients. Further
research in this subject is therefore of great importance.
Keywords: Doppler perfusion index (DPI); liver; colorectal cancer; liver metastases; oncology; surgery; adjuvant
chemotherapy; ultrasound; Doppler ultrasound
doi: 10.3978/j.issn.2304-3881.2014.09.04
Introduction terms of their long-term prognosis (66.2% vs. 67.8%) (7).

Also, improvements in surgical technique resulted in less
According to epidemiological research, colorectal cancer
local recurrence (8).
is the second most common cancer and the second
Currently there is no reliable method for detecting
most common cause of death from malignant disease in
Europe, causing approximately 400,000 deaths annually small, occult liver metastases. Oncologists use various
worldwide (1-4). The main cause of death of patients with prognostic factors in deciding on adjuvant treatment. A
colorectal cancer is liver metastases (5). It is well known standard prognostic factor that is used routinely in selecting
that approximately 25% of patients with colorectal cancer patients for adjuvant treatment is the Dukes classification
already have liver metastases, and another 25% of patients of the primary colorectal cancer (9-11). The survival of
develop liver metastases during follow up, usually within patients with dukes C stage as well as one part of patients
the first 2 years after the diagnosis of the primary colorectal with dukes B stage can be improved by the application of
tumor (6). In rectal cancer, preoperative chemoradiotherapy adjuvant chemotherapy after potentially curative surgical
(CRT) significantly reduces the rate of local recurrence resection (12,13). Adjuvant chemotherapy (5-fluorouracil
(5.3% vs. 14.1%), but patients who were treated with with levamisole or 5-fluorouracil with folinic acid) leads to
preoperative CRT do not appear to benefit significantly in a 40% reduction in the rate of recurrence and metastases,
260 Kopljar et al. Doppler perfusion index in detection of liver metastases
and 33% reduction in mortality rates of patients with Dukes Although some research demonstrated that liver
C colon cancer (14). Despite that, approximately one third micrometastases indeed do derive some of their blood
of patients with Dukes C colon cancer will survive 5 years flow through the portal system, portal vascularization of
even without adjuvant chemotherapy. On the other hand, liver metastasis is generally considered insignificant in
approximately one third of patients with Dukes B colon comparison to vascularization derived through hepatic
cancer will develop recurrent disease or metastases. artery, especially considering the fact that the with the
However, today there is no clear recommendation for the growth of metastasis there is also an increase in arterial
application of adjuvant chemotherapy in patients with blood supply compared to a portal blood supply (23).
colorectal cancer stage Dukes B (9). Therefore, it is obvious In spite of the well-known thinking that only metastasis
that Dukes classification is insufficient for the selection of greater than one millimeter in diameter receive their
patients for the application of adjuvant chemotherapy after blood supply through newly formed blood vessels (22),
potentially curative resection for colorectal cancer (9). it has been demonstrated that even metastasis with only
Careful selection of patients is crucial to improve the half a millimeter have a defined vascularization derived
results of chemotherapy by applying it only to patients predominantly through the system of hepatic artery (23,25).
with the greatest impact on survival and avoiding harmful Hepatic neovascularization is a complex process during
effects of chemotherapy in patients with no risk off liver which the relative contribution of arterial and portal
metastasis (15). Therefore, the detection of those patients with blood flow changes during the growth of liver metastases
micrometastases that are not evident at the time of primary (24,25). In the earliest stage, liver metastasis depend on
tumor treatment still represents a significant challenge (16). perfusion from adjacent issue, until they reach a diameter
Current morphological methods for diagnosing liver of approximately 150-200 μm (26). Further growth of the
metastases from colorectal cancer obviously have the metastasis induces new vessel formation derived from those
limitation in detecting small focal liver lesions less than a arterial and portal system. As liver metastasis increases to
few millimeters in diameter (17). over two millimeters in size, arterial blood flow becomes
dominant (27). Angiographic research demonstrated a great
variability in the vascularization of liver metastasis. Some
Hepatic perfusion changes in patients with liver
metastasis demonstrate minimal accumulation of contrast
metastases
(hypovascularized metastases), while others are extremely
It has been known for a while now, that in patients with liver well vascularized with a marked arterial supply of the entire
metastasis there is an alteration of blood flow through the liver lobe (24). These variations in blood supply of liver
liver (18). Alterations of the hepatic flow in tumors were metastasis play a significant role in the choice and success
initially observed using dynamic scintigraphy. In 1983 Parkin of local therapeutic procedures such as locoregional arterial
et al. (19) proved that when malignant tumors are present chemotherapy, dearterialization and embolisation.
the arterial hepatic flow is elevated because tumors have a
predominantly arterial vascularity. Parkin also proposed the
Doppler perfusion index (DPI)
use of the hepatic perfusion index (HPI), which is increased
in patients with liver metastases. This well known change in liver perfusion in patients
Several papers consistently demonstrated that a relative with liver metastasis was further investigated by Leen and
blood flow through the common hepatic artery, expressed colleagues using Doppler ultrasound. In a series of papers
as a percentage of total hepatic blood flow is significantly he demonstrated that a Doppler ultrasound is a simple,
increased in patients with hepatic metastases in comparison non-invasive and reliable method in detecting changes in
to patients without liver metastases (9,20,21). liver perfusion, especially in patients with colorectal cancer
For a long time it has been considered that the observed liver metastases (9,28-30).
change of blood flow through the liver is exclusively the Some research demonstrated that DPI enables greater
consequence of increased neovascularization within the precision to determine the likelihood of the existence of
metastases themselves. Clinical and experimental studies occult metastases in the liver. The analysis of preoperative
demonstrated that liver metastases from colorectal cancer values of DPI on a sample of 120 patients with colorectal
establish their blood supply mostly through hepatic artery cancer confirmed the statistically significant predictive value
system (22-24). of DPI the detection of liver metastasis. The sensitivity,
Table 1 Doppler perfusion index—how to do it

Procedure How to do it
Prepare the patient Overnight fasting; supine position
Measure the diameter of the common In transverse plane, find the celiac trunk and locate the common hepatic artery. Set the
hepatic artery (AHC) size of the Doppler window to encompass AHC. Set the measurement point so that the
Doppler axis is as close as small as possible (should not be greater than 60 degrees to
minimize error). Measure the diameter (in centimeters) of the common hepatic artery
perpendicular to the longitudinal axis at the selected measurement point
Measure the cross sectional area of the Use built-in algorithm or calculate from the diameter of the AHC:
common hepatic artery cross sectional area (S) =
Measure the velocity of blood flow in the At the same measurement point, position the Doppler cursor in the middle of the artery
common hepatic artery and record Doppler waves for at least 3 cardiac cycles (more cycles may be required if
patient has arrhythmia). For each cycle determine the peak systolic velocity (PSV), end-
diastolic velocity (EDV) and mean velocity (MV) in centimeters per second. Calculate
mean PSV, EDV and MV across several cycles
Calculate resistance index (RI) RI =
Calculate blood flow in the common Use built-in algorithm or calculate blood flow in mL/s: fAHC = MV*S
hepatic artery (fAHC)
Measure the diameter of the portal vein Locate the portal vein before its bifurcation (adjacent to common hepatic duct). Set the
(PV) size of the Doppler window to encompass PV. Set the measurement point so that the
Doppler axis is as close as small as possible (should not be greater than 60 degrees to
minimize error). Measure the diameter (in centimeters) of the portal vein perpendicular
to the longitudinal axis at the selected measurement point
Measure the cross sectional area of the Use built-in algorithm or calculate from the diameter of the PV:
portal vein cross sectional area (S) =
Measure the velocity of blood flow in the At the same measurement point, position the Doppler cursor in the middle of the
portal vein portal vein and record Doppler waves for at least 3 cardiac cycles (more cycles may be
required if patient has arrhythmia). For each cycle determine the mean velocity (MV) in
centimeters per second. Calculate mean MV across several cycles (modern ultrasound
machines will do that automatically)
Calculate blood flow in the portal vein Use built-in algorithm or calculate blood flow in mL/s: fPV = MV × S
(fPV)
Calculate Doppler perfusion index (DPI) DPI =
specificity, positive and negative predictive values as well as 5-year disease free survival was only 22% in patients with
the accuracy of determining DPI for identification of patients elevated DPI (DPI ≥30%). Overall survival of patients with
in whom liver metastasis will be diagnosed during follow up normal values of DPI was as high as 91% and only 29% in
was found to be 95%, 69%, 73%, 94% and 81% (9). patients with abnormally elevated DPI (9).
Five-year follow-up of patients with colorectal cancer Measurement of blood flow through blood vessels
demonstrated that the blood flow redistribution through the by color Doppler is extremely dependent on a number
liver is strongly correlated to the survival (9). In a prospective of technical parameters, and even small errors in the
study, the 5-year follow-up of patients who underwent measurement of the diameter or cross-sectional area of
potentially curative resection of primary colorectal cancer blood vessels or the angle at which the measurements were
found that patients with normal values of DPI (DPI <30%) performed can produce large errors in the calculation of the
had a 5-year rate of disease free survival of 89%, while the blood flow through (Table 1) (31,32). Therefore, in most
Table 2 The equations that may be used for calculating body surface area in order to standardize blood flow
Author Formula
Du Bois and Du Bois (40) BSA = 0.007184 × H0.725 × W0.425
Gehan and George (41) BSA = 0.0235 × H0.42246 × W0.51456
Haycock (42) BSA = 0.024265 × H0.3964 × W0.5378
Mosteller (43) BSA = Square root [(H × W)/3,600]
2
H, height (cm); W, weight (kg); BSA, body surface area (m ).
clinical studies where Doppler measurements were used body surface area is used to achieve greater comparability
to measure blood flow, mean values of several consecutive of masses of different organs, such as liver, which mass,
measurements of diameters or cross sectional areas of expressed relatively according to body surface area can be
blood vessels were used to reduce the risk of errors in used in different researches (39). There are several formulas
measurements (9). Analyzing the maximum speed of blood that enable the calculation of the body surface area, such as
flow through the vessel in systole [peak systolic velocity those recommended by Mosteller or DuBois and DuBois
(PSV)], the speed of blood flow at the end of diastole [end- (Table 2) (40,43,44). The calculation of body surface area is a
diastolic velocity (EDV)] and calculating the resistance common procedure in many clinical and scientific branches
index (RI) can more precisely describe the hemodynamic of medicine (45), but surprisingly in most research this
status of the arteries than the calculation of blood flow method of standardization was not used (6).
volume, because the calculation of the above parameters Another possible downfall of determining DPI with
does not necessitate to knowledge the cross-sectional the purpose of detection of micrometastasis in the liver
surface of measured vessels. in patients with colorectal cancer is the factor that DPI
Despite the fact that ultrasonic Doppler technique is is increased in patients with cirrhotic liver. However,
dependent on the examiner, technically challenging and hemodynamic examination of hepatic blood flow
often requires significant time to perform, it has confirmed demonstrated that in patients with liver cirrhosis there is
good reproducibility and validity of the measurements also an increase in liver congestion index, defined as the
among multiple examiners (33,34). ratio of the cross sectional area of the portal vein and portal
Moreover, satisfactory accuracy and reproducibility mean blood flow velocity (30).
of measurements of the DPI of the liver was found when However, not all authors were able to prove the clinical
the measurements were performed by operators with no usefulness off DPI measurement in the detection of liver
classical medical education and after only a few months of metastasis. In a clinical study conducted by Roumen
training in this specific area (18). et al. (46), 133 patients with different stages of colorectal
In spite of the standardization of measurements, values cancer were examined. Reliable DPI measurements were not
of blood flow often demonstrate wide dispersion (6). In possible in 29 patients, mostly due to technical difficulties
order to maximize the extent of comparability and reduce caused by the presence of air or other contrast media,
the scattering of value, the flow can be expressed in relation obesity, scars or other reasons. In their study, they were
to body surface area. unable to detect a single cut-off value that could reliably
In histological examinations, the diameter of coronary discriminate patients with liver metastases. It has to be noted
arteries has been brought in correlation with age and body that in this study no preselection of patients was performed
surface area off young healthy people (35). Body surface and the focus was placed on the clinical usefulness of
area is also used as a method of standardization of the cross Doppler measurements in unselected population of patients.
sectional area of different arteries (36). Body surface area is Apart from technical difficulties, Doppler perfusion
routinely used in research of blood flow through different measurements are characterized by high variability,
vessels as well as for liver haemodynamics (37). Therefore, which has been reported to be as high as 26% (46).
utilizing body surface area and expressing the blood flow Especially important it is the intraobserver variability that is
through different vessels relative to body surface area is a not merely the result of the method or technique but rather
specially suitable to compare vascular parameters between a consequence of inherent subject variations.
groups with substantial morphological differences (38). Also, As the Doppler measurements may well prove not to be
Table 3 Possible etiology of change in flow

Main proposed etiology Studies
Increased hepatic arterial blood flow Parkin, 1983 (19); Ridge, 1987 (24); Archer, 1989 (25)
Decreased portal blood flow Nott, 1991 (48); Carter, 1994 (49); Yarmenitis, 2000 (47)
Decreased portal blood flow with compensatory increase in Kopljar, 2004 (6)
hepatic arterial blood flow
useful in everyday practice, the underlying hypothesis of experiment suggest that observed hemodynamic changes
the existence of a humoral vasoactive substance responsible are at least partly mediated by a circulating agent. Whether
for hepatic perfusion changes sheds the new light on the this circulating agent is produced by the tumor itself or is
clinical and preclinical research directed towards finding an an endogenous agent remains unclear (49).
easily and reliably measured systemic factor. In another animal experiment (47), liver metastases
were induced in 30 male Wistar rats by inoculating Walker
256 tumor subcutaneously. Hemodynamic changes were
Possibility of a humoral vasoactive factor
observed and correlated to the liver histology at the time of
Until now, the cause of this redistribution of hepatic blood measurement. By measuring the flow through the hepatic
flow is not clearly explained. According to one hypothesis, artery and portal vein in this animal model of spontaneous
this phenomenon is caused by splanchnic vasoconstriction liver metastases, Yarmenitis and colleagues have shown
and a consequent reduction of portal blood flow with a a statistically significant increase in blood flow through
simultaneous increase in common hepatic artery flow the common hepatic artery as early as the fourth day after
as a result of hemodynamic compensation (15). Some implantation of the primary tumor, when histological
experimental and clinical research indeed demonstrated examination of the liver demonstrated only single tumor
that in patients with liver metastases that are too small to cells or small clusters in the connective tissue of porta
be detected by conventional radiologic methods there is hepatis and periportal interlobular space (47).
already an alteration in the blood flow through the liver that DPI values were significantly increased as early as on
was shown to be highly sensitive in the detection of small, the fourth day after implantation of the primary tumor,
occult liver metastasis (9,18,20,47). This raises the question and did not significantly increase until the fifteenth day,
on the nature of these haemodynamic changes, since these when the histological examination showed metastatic
small, occult metastases are unlikely to be the cause of tumors in the liver with the largest diameter of 2 mm. Also,
sufficient neovascularization responsible for significant the flow through the portal vein was reduced in animals
changes in hepatic perfusion (Table 3). It was therefore with metastatic tumors in the liver on the fourth day, but
hypothesized that the primary cause of hepatic perfusion the difference was not statistically significant. Therefore,
changes in patients with colorectal cancer liver metastases is a statistically significant increase in DPI and blood flow
a circulating vazoactive factor causing primarily splanchnic through the hepatic artery was observed only four days
vasoconstriction and subsequent reduction in portal inflow after implantation of tumor cells, when the histological
to the liver. analysis of the liver in these animals was not able to
In order to prove the hypothesis of circulating vasoactive demonstrate any vascular component of either the hepatic
factor as a possible cause of liver hemodynamic changes in artery or portal vein.
patients with colorectal cancer and liver metastasis, a group This finding is consistent with the hypothesis of the
of researchers conducted a research on animal model (49). In existence of a humoral vasoactive factor that can lead to
this research, isolated intestinal loop of a healthy animal was hemodynamic changes in the liver in the earliest stages
perfused with blood from another animal with experimentally of the development of metastases, and that its effect
induced liver sarcoma (HSN sarcoma) (49). may manifest both locally, in the liver, as well as in the
The experiment showed that splanchnic vascular splanchnic circulation away from metastases (49). Opposite
resistance in healthy animals was significantly greater during to some other studies (48,49), in the experimental study
perfusion with blood from tumor bearing animals [91.6 conducted by Yarmenitis and associates, DPI changes were
(SE 21.5), vs. 51.7 (SE 7.41), P=0.036]. The results of this primarily attributed to a statistically significant increase in
the flow through the hepatic artery and without significant in increased blood pressure in the portal vein (52,53). Also,
changes in portal flow (47). it has been determined that endothelin-1 is synthesized and
In the research conducted by Nott and coworkers (48), released from several human epithelial carcinomas. Inagaki
the blood flow through the portal vein was significantly and coworkers demonstrated the existence of increased
reduced in animals with experimentally induced sarcoma quantities of endothelin-1 in the tissue of primary colorectal
of the liver (Walker carcinosarcoma). The results of this carcinoma (54). Furthermore, histochemical methods
study indicate that overt tumor derived from the intraportal demonstrated the presence of endothelin-1 in the cytoplasm
inoculation of Walker cells results in an increase in the HPI. of colorectal cancer cells metastatic to the liver, as well
The blood supply to the tumor was shown to be derived as in cytoplasm of adjacent myofibroblasts. These results
principally from the hepatic artery. However, hepatic indicate that endothelin-1 is not produced only in tumor
arterial flow did not change in the presence of tumor and cells but also in adjacent cells, thereby influencing the
the alterations in the HPI were found to be secondary to a growth of the tumor (51). Unfortunately, survival analysis
reduction in portal venous inflow. Moreover, the presence of did not demonstrate prognostic value of pre-operative
overt hepatic tumor was associated with gross derangement determination of the concentration of endothelin-1 in
of hepatic hemodynamic with a pronounced increase in patients with colorectal cancer (15).
intrahepatic arteriovenous shunting. It was concluded that In one clinical study (6) results showed that the DPI
hemodynamic changes accompanying the development of successively increased in patients with colorectal cancer
overt hepatic tumor are complex and must be taken into with no signs of liver metastases and in patients with liver
account when attempting to potentiate the distribution metastases. There was a statistically significant difference
of cytotoxics to the tumor by regional administration or in the blood flow through the portal vein between patients
through manipulation of liver blood flow (48). with colorectal cancer without signs of metastases in the
Other researchers also demonstrated significant liver and healthy control patients, but no statistically
reduction of portal flow in experimental models of liver significant differences in the flow through the common
metastasis, with no changes in arterial hepatic flow (50). An hepatic artery (6). However, the flow through the common
experimental and biomolecular research identified some hepatic artery and portal vein in patients with primary
systemic active factors that might, at least in theory, explain colorectal cancer with no signs of liver metastases and
the redistribution of blood flow through the liver in patients those with liver metastases, as well as between patients with
with colorectal liver metastasis (51). liver metastases and control subjects showed statistically
One possible causative agent might be endothelin-1 (15), significant differences in the absolute values of flow through
a potent vasoconstrictor with significant influence on common hepatic artery and portal vein as well as the values
the portal blood flow that is regularly produced by the of the flow through the same blood vessels expressed
colorectal cancer. Peeters and coworkers measured the relative to body surface area (6).
serum level of endothelin-1 in 68 patients with colorectal These results suggest that the early hemodynamic
cancer and 20 healthy volunteers without malignant disease. changes in patients with liver metastases are associated
The sera level of endothelin-1 was statistically significantly with a reduction of flow through the portal vein, while the
higher in patients with colorectal cancer compared to increase in blood flow through the common hepatic artery is
healthy participants. Further subgroup analysis was associated with the development of tumor neovascularization
performed and patients were divided into three groups: in larger metastases (6).
those with primary colorectal cancer without metastasis, Furthermore, clinical research demonstrated no
patients with colorectal cancer that developed metastasis statistically significant differences in the blood flow through
during follow up and patients with colorectal cancer and the superior mesenteric artery between patients with liver
synchronous liver metastasis. All three subgroups had metastases and those without metastases, and the difference
higher concentrations of endothelin-1 compared to healthy in RI was marginally statistically significant (6).
participants. However, no statistically significant difference These findings are certainly at least partly influenced
in preoperative concentration of endothelin-1 was found by the difficulties in measuring the cross-sectional area of
between healthy participants and patients with liver blood vessels and blood flow in general, which is why the
metastasis from previously resected colorectal cancer (15). measurements of vascular index have the advantage.
Animal models demonstrated that endothelin-1 results The hypothesis of the existence of systematic acting,
circulating humoral vasoactive factor in patients with liver systemic vasoactive substance responsible for observed
metastases is further supported by the analysis results hemodynamic changes. Identification of such a systemic
obtained by measuring the flow rate and RI of the superior vasoactive substance may lead to the development of a
mesenteric artery among the three groups of patients simple and reproducible laboratory test that may reliably
(patients with liver metastases, those with primary colorectal identify the presence of occult liver metastases and therefore
cancer and no detectable metastases and patients with no increase the success of adjuvant chemotherapy through
malignancy). If this hypothesis is correct, and if indeed a better selection of patients. Further research in this subject
humoral vasoactive factors can be found in the bloodstream is therefore of great importance.
of patients with metastases in the liver, then its actions
should be expressed also on remote vessels, outside of the
Acknowledgements
liver.
Indeed, the EDV in the superior mesenteric artery Disclosure: The authors declare no conflict of interest.
was higher in healthy subjects compared to patients
with colorectal cancer and no signs of liver metastases as
References
well as compared to patients with liver metastases, while
the difference in end-diastolic velocity in the superior 1. Boyle P, Langman JS. ABC of colorectal cancer:
mesenteric artery in patients with colorectal cancer without Epidemiology. BMJ 2000;321:805-8.
signs of metastases in the liver and patients with metastases 2. Jurisić I, Paradzik MT, Jurić D, et al. National program
was not statistically significant (6). Statistically significant of colorectal carcinoma early detection in Brod-Posavina
differences of RI were found among healthy subjects, County (east Croatia). Coll Antropol 2013;37:1223-7.
patients with colorectal cancer without signs of metastases 3. Milas J, Samardzić S, Miskulin M. Neoplasms (C00-D48)
in the liver and patients with metastases (6). These results in Osijek-Baranja County from 2001 to 2006, Croatia.
clearly indicate that even in patients with colorectal cancer Coll Antropol 2013;37:1209-22.
without clinical and radiological signs of metastases in the 4. Samardzić S, Mihaljević S, Dmitrović B, et al. First six
liver, there is a systemic alteration of blood flow, which is years of implementing colorectal cancer screening in the
reflected in the reduction of the end-diastolic velocity in the Osijek-Baranja County, Croatia--can we do better? Coll
superior mesenteric artery. Antropol 2013;37:913-8.
5. Doko M, Zovak M, Ledinsky M, et al. Safety of
simultaneous resections of colorectal cancer and liver
Conclusions
metastases. Coll Antropol 2000;24:381-90.
In the last three decades, many clinical and preclinical 6. Kopljar M, Brkljacic B, Doko M, et al. Nature of Doppler
studies demonstrated that DPI measurements may be used perfusion index changes in patients with colorectal cancer
to accurately diagnose and predict liver metastases from liver metastases. J Ultrasound Med 2004;23:1295-300.
primary colorectal cancer. However, Doppler measurements 7. Boras Z, Kondza G, Sisljagić V, et al. Prognostic factors
have some serious limitations when applied to general of local recurrence and survival after curative rectal cancer
population. Ultrasound is very operator-dependent, and surgery: a single institution experience. Coll Antropol
requires skilled examiners. Also, many conditions may 2012;36:1355-61.
limit the use of Doppler ultrasound and ultrasound in 8. Krebs B, Kozelj M, Potrc S. Rectal cancer treatment and
general, such as the presence of air in digestive tract, survival--comparison of two 5-year time intervals. Coll
cardiac arrhythmias (including rather common atrial Antropol 2012;36:419-23.
fibrillation), vascular anomalies (e.g., the origin of right 9. Leen E, Goldberg JA, Angerson WJ, et al. Potential role
hepatic artery from superior mesenteric artery), obesity and of doppler perfusion index in selection of patients with
other conditions (6,46). Therefore, in spite of the results colorectal cancer for adjuvant chemotherapy. Lancet
from clinical studies, its value may be limited in everyday 2000;355:34-7.
practice. 10. Cunningham D, Findlay M. The chemotherapy of
On the contrary, scientific research of the DPI in colon cancer can no longer be ignored. Eur J Cancer
detection of liver metastases is of great importance, since 1993;29A:2077-9.
current research speaks strongly for the presence of 11. Bosman FT. Prognostic value of pathological
characteristics of colorectal cancer. Eur J Cancer 26. Strohmeyer T, Haugeberg G, Lierse W. Angioarchitecture
1995;31A:1216-21. and blood supply of micro- and macrometastases in human
12. Haller DG. An overview of adjuvant therapy for colorectal livers. An anatomic-pathological investigation using
cancer. Eur J Cancer 1995;31A:1255-63. injection-techniques. J Hepatol 1987;4:181-9.
13. van Triest B, van Groeningen CJ, Pinedo HM. Current 27. Ackerman NB. Experimental studies on the role of the
chemotherapeutic possibilities in the treatment of portal circulation in hepatic tumor vascularity. Cancer
colorectal cancer. Eur J Cancer 1995;31A:1193-7. 1986;58:1653-7.
14. Moertel CG, Fleming TR, Macdonald JS, et al. 28. Leen E, Goldberg JA, Robertson J, et al. The use of
Fluorouracil plus levamisole as effective adjuvant therapy duplex sonography in the detection of colorectal hepatic
after resection of stage III colon carcinoma: a final report. metastases. Br J Cancer 1991;63:323-5.
Ann Intern Med 1995;122:321-6. 29. Robertson J, Leen E, Goldberg JA, et al. Flow
15. Peeters CF, Thomas CM, Sweep FC, et al. Elevated measurement using duplex Doppler ultrasound:
serum endothelin-1 levels in patients with colorectal haemodynamic changes in patients with colorectal liver
cancer; relevance for prognosis. Int J Biol Markers metastases. Clin Phys Physiol Meas 1992;13:299-310.
2000;15:288-93. 30. Leen E, Goldberg JA, Anderson JR, et al. Hepatic
16. Fong Y. Doppler perfusion index in colorectal cancer. perfusion changes in patients with liver metastases:
Lancet 2000;355:5-6. comparison with those patients with cirrhosis. Gut
17. Akhurst T, Kates TJ, Mazumdar M, et al. Recent 1993;34:554-7.
chemotherapy reduces the sensitivity of [18F] 31. Breyer B. Medicinski ultrazvuk - uvod u fiziku i tehniku.
fluorodeoxyglucose positron emission tomography in Zagreb: Školska knjiga; 1989. Available online: http://www.
the detection of colorectal metastases. J Clin Oncol skolskaknjiga.hr
2005;23:8713-6. 32. Burns PN. Physics and instrumentation: doppler. In:
18. Leen E. The detection of occult liver metastases of Goldberg BB. eds. Textbook of abdominal ultrasound.
colorectal carcinoma. J Hepatobiliary Pancreat Surg Baltimore: Williams & Wilkins; 1993, 24-9. Available
1999;6:7-15. online: http://www.lww.com
19. Parkin A, Robinson PJ, Baxter P. Liver perfusion 33. Oppo K, Leen E, Angerson WJ, et al. Doppler perfusion
scintigraphy. Method, normal range and laparotomy index: an interobserver and intraobserver reproducibility
correlation in 100 patients. Nuclear Medicine study. Radiology 1998;208:453-7.
Communications 1983;4:395-402. 34. Krüger S, Strobel D, Wehler M, et al. Hepatic Doppler
20. Leen E, Angerson WJ, Wotherspoon H, et al. Detection perfusion index--a sensitive screening method for detecting
of colorectal liver metastases: comparison of laparotomy, liver metastases? Ultraschall Med 2000;21:206-9.
CT, US, and Doppler perfusion index and evaluation of 35. Litovsky SH, Farb A, Burke AP, et al. Effect of age,
postoperative follow-up results. Radiology 1995;195:113-6. race, body surface area, heart weight and atherosclerosis
21. Leen E, Goldberg JA, Robertson J, et al. Early detection on coronary artery dimensions in young males.
of occult colorectal hepatic metastases using duplex colour Atherosclerosis 1996;123:243-50.
Doppler sonography. Br J Surg 1993;80:1249-51. 36. Huonker M, Schmid A, Schmidt-Trucksass A, et al. Size
22. Ackerman NB. The blood supply in liver metastases. In: and blood flow of central and peripheral arteries in highly
Weiss L, Gilbert HA. eds. Liver Metastases. Boston: Hall, trained able-bodied and disabled athletes. J Appl Physiol
1982:96-125. (1985) 2003;95:685-91.
23. Lin G, Lunderquist A, Hägerstrand I, et al. Postmortem 37. Bombelli L, Genitoni V, Biasi S, et al. Liver hemodynamic
examination of the blood supply and vascular pattern of flow balance by image-directed Doppler ultrasound
small liver metastases in man. Surgery 1984;96:517-26. evaluation in normal subjects. J Clin Ultrasound
24. Ridge JA, Bading JR, Gelbard AS, et al. Perfusion of 1991;19:257-62.
colorectal hepatic metastases. Relative distribution of 38. Zeppilli P, Vannicelli R, Santini C, et al. Echocardiographic
flow from the hepatic artery and portal vein. Cancer size of conductance vessels in athletes and sedentary
1987;59:1547-53. people. Int J Sports Med 1995;16:38-44.
25. Archer SG, Gray BN. Vascularization of small liver 39. Kuo PC, Li K, Alfrey EJ, et al. Magnetic resonance
metastases. Br J Surg 1989;76:545-8. imaging and hepatic hemodynamics: correlation with
metabolic function in liver transplantation candidates. index of the liver in detecting occult hepatic metastases:
Surgery 1995;117:373-9. histological findings related to the hemodynamic
40. Du Bois D, Du Bois EF. A formula to estimate the measurements in Wistar rats. Eur Radiol 2000;10:417-24.
approximate surface area if height and weight be known. 48. Nott DM, Grime SJ, Yates J, et al. Changes in hepatic
1916. Nutrition 1989;5:303-11; discussion 312-3. haemodynamics in rats with overt liver tumour. Br J
41. Gehan EA, George SL. Estimation of human body surface Cancer 1991;64:1088-92.
area from height and weight. Cancer Chemother Rep 49. Carter R, Anderson JH, Cooke TG, et al. Splanchnic blood
1970;54:225-35. flow changes in the presence of hepatic tumour: evidence
42. Haycock GB, Schwartz GJ, Wisotsky DH. Geometric of a humoral mediator. Br J Cancer 1994;69:1025-6.
method for measuring body surface area: a height-weight 50. Hemingway DM, Cooke TG, Grime SJ, et al. Changes
formula validated in infants, children, and adults. J Pediatr in hepatic haemodynamics and hepatic perfusion index
1978;93:62-6. during the growth and development of hypovascular HSN
43. Mosteller RD. Simplified calculation of body-surface area. sarcoma in rats. Br J Surg 1991;78:326-30.
N Engl J Med 1987;317:1098. 51. Shankar A, Loizidou M, Aliev G, et al. Raised endothelin 1
44. Wang Y, Moss J, Thisted R. Predictors of body surface levels in patients with colorectal liver metastases. Br J Surg
area. J Clin Anesth 1992;4:4-10. 1998;85:502-6.
45. Favier M, de Cazanove F, Saint-Martin F, et al. Preventing 52. Okumura S, Takei Y, Kawano S, et al. Vasoactive
medication errors in antineoplastic therapy. Am J Hosp effect of endothelin-1 on rat liver in vivo. Hepatology
Pharm 1994;51:832-3. 1994;19:155-61.
46. Roumen RM, Scheltinga MR, Slooter GD, et al. 53. Dugdale PE, Miles KA. Hepatic metastases: the value
Doppler perfusion index fails to predict the presence of of quantitative assessment of contrast enhancement on
occult hepatic colorectal metastases. Eur J Surg Oncol computed tomography. Eur J Radiol 1999;30:206-13.
2005;31:521-7. 54. Inagaki H, Bishop AE, Eimoto T, et al. Autoradiographic
47. Yarmenitis SD, Kalogeropoulou CP, Hatjikondi O, et localization of endothelin-1 binding sites in human colonic
al. An experimental approach of the Doppler perfusion cancer tissue. J Pathol 1992;168:263-7.
Cite this article as: Kopljar M, Patrlj L, Bušić Ž, Kolovrat

M, Rakić M, Kliček R, Židak M, Stipančić I. Potential use of
Doppler perfusion index in detection of occult liver metastases
from colorectal cancer. Hepatobiliary Surg Nutr 2014;3(5):259-
267. doi: 10.3978/j.issn.2304-3881.2014.09.04
Review Article
Pancreatic fistula and postoperative pancreatitis after

pancreatoduodenectomy for pancreatic cancer
Miroslav Ryska, Jan Rudis
Department of Surgery, 2nd Faculty of Medicine, Charles University and Central Military Hospital, Prague, Czech Republic
Correspondence to: Miroslav Ryska, MD, Ph.D. Surgery Department, 2nd Faculty of Medicine, Charles University and Central Military Hospital, U
Vojenske Nemocnice 1200, 160 00 Prague 6, Czech Republic. Email: miroslav.ryska@uvn.cz.
Abstract: The most serious complication after pancreatoduodenectomy (PD) is pancreatic fistula (PF) type
C, either as a consequence or independently from postoperative pancreatitis (PP). Differentiating between
these two types of complications is often very difficult, if not impossible. The most significant factor in early
diagnosis of PP after PD is an abrupt change in clinical status. In our retrospective study we also observed
significantly higher levels of serum concentrations of CRP and AMS comparing to PF without PP. Based
on our findings, CT scan is not beneficial in the early diagnosis of PP. Meantime PF type C is indication to
operative revision with mostly drainage procedure which is obviously not much technically demanding, there
are no definite guidelines on how to proceed in PP. Therefore the surgeon’s experience determines not only
whether PP will be diagnosed early enough and will be differentiated from PF without PP, but also whether
a completion pancreatectomy will be performed in indicated cases.
Keywords: Pancreatoduodenectomy (PD); pancreatic fistula (PF); postoperative pancreatitis (PP); drainage; total
pancreatectomy
doi: 10.3978/j.issn.2304-3881.2014.09.05
Introduction mortality rates of 4.9% in the 1980s, 1.5% in the 1990s and
1.3% in the 2000s (2). By the Nationwide Inpatient Sample
Pancreatoduodenectomy (PD) has its indication of radical
for 1994-1999 Birkmeyer et al. demonstrated wide variation
intent in the treatment of periampulary malignant tumors
in perioperative mortality based on hospital volume: 17.6%
as cephalopancreatic neoplasia, distal cholangiocarcinoma
for low volume compared to 3.8% for high volume (3).
or ampuloma. PD managing to provide a 5-year survival of Complications after PD affect a large part of patients
31.4% for tumors diagnosed in stage I and only 2.8% for stage and include a variety of clinical entities—internal (as
IV with a median of 24.1 and 4.5 months respectively (1). pneumonia, cardiovascular events, infection and others)
In patients with unresectable adenocarcinoma 5-year as well as surgical [bleeding, pancreatic fistula (PF),
survival reach only 0.6% for stage IV with a median survival postoperative pancreatitis (PP), infection-sepsis and others].
of 2.5 months and 3.8% for stage I with a median of The high rate of complications is due to multiple factors
6.8 months. Radical resection is the only chance for patients as comorbidity, technical complexity of the operation, frail
with this tumor. Unfortunately only 15-20% of them are patient population and remains as high as 31-60% (4).
suitable for it. The aim of this review is to present the occurrence of PF
Mortality of this type of resection has intermediate risk to and PP, the possibilities of their differentiation and some
compare to total pancreatectomy with highest and to distal aspects of treatment after PD as well as to present some
pancreatectomy with lowest risk. Retrospective review from aspects of the possibilities to differentiate PH and PP in our
a prominent high volume cancer center revealed 30-day retrospective study.
Table 1 New classification of pancreatic anastomosis failure (9)

Grade Classification
1 Any deviation from the normal postoperative course without the need for pharmacologic treatment or surgical,
endoscopic, and radiologic interventions. Allowed therapeutic regimens include: drugs as antiemetics, antipyretics,
analgetics, diuretics, electrolytes, and physiotherapy. This grade of complication applies to patients with fistula whose
only change in management other than use of allowed drugs in maintenance of the drain until the fistula has dried up
2 Requiring pharmacological treatment with drugs other than such allowed for grade 1 complications. Blood transfusions
and total parenteral nutrition are also included
3 Requiring surgical, endoscopic, or radiologic (invasive) intervention
3a Intervention not under general anesthesia
3b Intervention under general anesthesia
4 Life-threatening complication (including CNS complications) requiring IC/ICU management
4a Single organ dysfunction (including dialysis)
4b Multiorgan dysfunction
5 Death of a patient with PAF
CNS, central nervous system; IC, intermediate care; ICU, intensive care unit; PAF, pancreatic anastomosis failure.
Pancreatic fistula (PF) the general risk factors as age, gender, history of jaundice,
preoperative nutrition, type of resection and the length of
PF is the most feared complication after PD, being
postoperative stay seemed to be associated with PH (10,11).
considered the “Achilles’ heel” of this procedure (5). In
Two intraoperative risk factors—pancreatic duct size and
spite of previous studies with outstanding results with
parenchyma texture of the remnant pancreas—were found
almost no need for reoperation (6), actual rate of PF grade
to be significantly associated with PF. Pancreatic duct size
“C”—severe—(7) requiring operative re-intervention varies
>3 mm means only 4.88% of PF, and 38.1% in pancreatic
between 5% and 20% with mortality rate nearly 40% (8).
duct size <3 mm respectively. PH rate was less than 3% in
hard pancreatic tissue meanwhile in soft tissue reached more
Definition than 32%. French multicentric retrospective survey on
There is no universally accepted definition of PF. Most PD for ductal adenocarcinoma found that a soft pancreatic
of them rely on amylase content of the effluent from parenchyma, the absence of preoperative diabetes,
intraabdominal drain. International study group of PF pancreaticojejunostomy and low volume centers were
(ISGPF) organized by Bassi et al. (7) extended definition to independent risk factors for PF (12). Although anastomotic
standardizing of postoperative treatment by the adoption technique was not a significant factor, PH rate was much
and by the modification the definition based on clinical less in cases of duct-to-mucosa pancreaticojejunostomy
impact on the patient hospital course and the outcome and (10,13,14). On the other hand PH risk score for prediction
graded PF into A, B, C. The grading was based on nine of clinically-relevant PH after PD reflected intraoperative
clinical criteria: patient’s condition, use of specific treatment, blood loss (13). There are other factors apart from technical
US and/or CT findings, persistent drainage >3 weeks, consideration, of which increased intraoperative blood
reoperation, signs of infection, sepsis, readmissions and death. loss—more advanced stages of disease requiring portal or
Strasberg et al. proposed intraabdominal collection with superior mesenteric vein resection, patient obesity, jaundice
hemorrhage and peritonitis are also the result of PF (9) (Table 1). associated coagulopathy and others (11).
Moreover careful consideration should be given to
the larger pancreatic stumps, wide pancreatic remnant
Risk factors for PF
mobilization, and the duct decentralization on the stump in
Multivariate logistic regression analysis showed that none of anteroposterior axis (15).
270 Ryska and Rudis. Complication of pancreatoduodenectomy
Preventive measures from the 90’s showing reducing of the occurrence of the
typical postoperative complications (27). Current single-
Occlusion of pancreatic duct
center, randomized, double-blind trial of perioperative
To prevent complications following PD especially the
subcutaneous pasireotide in patients undergoing either PD
development of PF various techniques of managing the
or distal pancreatectomy showed similar results. Authors
pancreatic remnant have been proposed (11). Occlusion
presented that the perioperative treatment with pasireotide
of the pancreatic duct (chemical occlusion or simple duct
decreased the rate of clinically significant postoperative PF,
ligation) compared with pancreaticojejunostomy there
leak, or abscess (28).
is no significant difference found in the postoperative
According to the actual literature the administration of
complications, mortality and exocrine insufficiency.
Octreotide by principle is not recommended but only in
Moreover there were significantly more patients with
the case of low consistency pancreatic parenchyma or when
diabetes mellitus in the duct occlusion group. So there is
intraoperative handling of the pancreatic stump is more
no evidence to show that pancreaticojejunostomy can be
aggressive (10). Somatostatin administration may have
replaced by pancreatic duct occlusion (16). reduced the pancreas edema, protected the normal tissues
and improved the anastomosis quality, but on a daily basis,
Pancreaticogastrostomy the abdominal drainage fluid is not affected without any
Four RCTs comparing pancreaticogastrostomy to difference between preoperative and postoperative use (29).
pancreaticojejunostomy have failed to show any Moreover there is no statistical difference in the incidence
significant difference regarding to PF ratio, postoperative of PF between the patients who received the prophylactic
complications or mortality (17-20). The type of use of octreotide after surgery and the patients who did not
anastomotic fashion plays no role for the risk of PF. Results somatostatin therapy (30).
of one RCT has showed significantly lower rate and
severity of PF after pancreaticogastrostomy compared to Drain removal and other preventions
pancreaticojejunostomy (21). A prospective RCT by Bassi There is no standard regarding to the best time when
et al. revealed no significant difference in PF ratio between the intraabdominal drain should be removed. The most
duct-to-mucosa anastomosis and single layer end-to-side surgeons indicate drainage removal once the output
pancreaticojejunostomy (22). The use of isolated Roux-en-Y of amylase-rich fluid is low (31). Until now, there has
pancreaticojejunostomy cannot prevent the development of been no consensus on the optimal timing of the removal
PF formation (20,23). of prophylactic drainage after pancreatic surgery in
general. The similar situation is associated with poor or
Total pancreatectomy no agreement to the type of nutrition, use of antibiotics,
Total pancreatectomy allows not only more extensive imaging strategy and hospital discharge (32).
lympfadenectomy and decreases the risk of positive
resection margins but also obviates a leak from pancreatic
Treatment approaches
anastomosis. This type of procedures is however associated
with the development of diabetes mellitus, decreasing of The current treatment depends on the grade of PF. It is
immunity and loss of pancreatic exocrine function. So noteworthy that 70% of PH resolves spontaneously (33).
indication for total pancreatectomy is not corresponding to The best strategy for the management of PF is still highly
routine treatment of localized ductal adenocarcinoma of the debated. Actual rate of PF grade C requiring a relaparotomy
head of pancreas (24). varies between 5-20% even in experienced center with
Based on the current evidence it is unclear whether mortality rate as high as 39% (4,8). Different strategies
drainage of pancreatic duct with a stent (internal or include both preservation of the pancreatic remnant and a
external) can reduce PF rate (25,26). completion pancreatectomy (34). Pancreatectomy avoids
further PF but leads to complete pancreatic insufficiency
Pharmacologic prevention and to “brittle” diabetes (35). Preserving approach—
There were optimistic results of the multicentric study debridement and drainage of the pancreatic region or
regarding to the role of Octreotide in the prevention of resection the dehiscent jejunal loop followed by the
postoperative complications following pancreatic resection occlusion of the main pancreatic duct—is technically easier
and has the advantage of maintaining pancreatic function circulatory instability, especially in patients with replenished
but on the other hand leads to the risk of a persistent PH. blood supply (26). Early diagnosis of PP based on clinical
Balzano et al. presented better results with completion and laboratory results is very difficult from standard
pancreatectomy with splenectomy in the case of PH currently performed examinations, as is the evaluation of
grade C with autologous islet transplantation reducing preoperative findings during reoperation, especially after a
the metabolic consequences of total pancreatectomy (36). longer interval from the primary operation.
Moreover there is experience with other methods—the Nonetheless a similar condition may also be caused by
conversion to pancreaticogastrostomy and the bridging other postoperative complications. In a study by Wilson
stent technique but without evidence whether drainage of et al. (44) which clinically evaluated the postoperative
the pancreatic duct with a stent can reduce PF rate after course PP was only diagnosed at autopsy in 10 of 11 cases.
PD (37). Finally there is also the experience with resection Operative findings on revision also do not always correlate
of dehiscent jejunal loop and drainage of pancreatic region with the results of laboratory and imaging examinations.
followed by gastrofistulostomy (38). Pancreatic leak from PJA or PGA and peripancreatic
abscess may be clinical signs of PP. They may however
also develop due to technical error during sewing of the
Acute postoperative pancreatitis (PP)
anastomosis, where edge necrosis may occur in an otherwise
PP is a less frequent but very serious surgical complication undisturbed glandular parenchyma. During surgical
with often fatal results. It is most often seen following revision in a postoperatively changed terrain, pathological
surgery on the pancreas itself, but in rare cases has also been changes in the remaining pancreas and its surroundings are
described after surgical procedures on organs very distant often difficult to evaluate due to signs of superficial tissue
from the pancreas. The occurrence of PP according to digestion and the presence of necrosis, which develop due
Carter from 1956 depends upon the following condition (39): to digestion by activated pancreatic juice. Postoperative
mechanical injury direct to the pancreas and especially to the changes in cases of PF may easily be misinterpreted for
pancreatic ducts, vascular conditions, spasm of the sphincter signs of PP and vice-versa.
of Oddi and stagnation of duodenal contents. Regarding laboratory analysis, in addition to values of
The incidence of PP reported in the literature is amylase, lipase and trypsin levels, Büchler et al. also favors
approximately 8-10%, following PD ranges from 1.9-50% (40). analysis of CRP and calcium levels (45). In recent years,
But to analyze PP ratio by literature is difficult: PP is mostly diagnosis of PP has most often been reliant on CRP level
not evaluated as a separate complication of PD but in the along with the result of spiral contrast CT examination,
range of PH (40). Contrary to acute pancreatitis with 5-15% where necrotic changes in the parenchyma are evaluated
mortality, the mortality of PP is more than 30% (41). according to the Balthazar classification (46). In accordance
with current literary findings, CRP levels best reflect the
development and course of the disease. In contrast, CT
Diagnosis
examination performed prior to surgical revision has not
PP is clinically defined as abdominal pain which develops shown to be beneficial in terms of evaluating changes in the
during the postoperative course with a concurrent two- pancreatic gland.
to three-fold increase in the levels of specific pancreatic
enzymes in the blood. A non-standard postoperative course
Treatment approaches
accompanied by pain, distension of the abdominal muscles,
prolonged paralytic ileus and cloudy, often brownish, PJA disconnection and drainage procedures during surgical
discharge from the drains may signify developing PP revision after PD in cases of PP are usually insufficient
(26,42,43). Evaluation may however be complicated by the and do not lead to a better prognosis. An appropriate,
development of benign postoperative hyperamylasemia and although risky, solution during early revision with suspicion
the subjective perception of postoperative pain. Clinical of PP is a completion pancreatectomy with splenectomy.
symptoms may be hidden, especially if the patient remains However, after late revisions in an operating field devastated
under analgosedation, or even on artificial lung ventilation, by pancreatitis, the mortality of patients after completion
after a long operation with greater blood loss. The first pancreatectomy nears 100%, according to most authors
warning sign of the development of PP may be progressive (47,48). Is it desirable to proceed with the completion
pancreatectomy soon after the primary procedure (34)? significant benefit when performed as soon as possible after
However to perform a completion pancreatectomy in a diagnosis of potentially fatal PP (52). The longer the interval
patient with PF type C may be an unwarranted procedure, between primary operation and surgical revision, the lower
unjustifiably risky with subsequent significant worsening of the chance of performing completion pancreatectomy
quality of life. Early diagnosis of PP may therefore be a key without endangering the life of the patient. Due to the
moment in the treatment of PH type C in patients after PD. gradual postoperative development of inflammatory
Base on the current literature, very few firm statements peripancreatic infiltrate, the procedure becomes intolerable
can be made: the criteria for drain removal, imaging for the patient. In any case, the decision to perform
strategy and timing of hospital discharge in patients with PF completion pancreatectomy is very difficult for the surgeon.
remain unclear (31). In the case of PP after PD treatment In our set of patients who died in direct association
strategy is unclear yet and available standard is lacking. with a serious postoperative pancreatic leak from the
pancreaticojejunostomy, PP occurred in 4 out of 7 cases
(57%) based on autopsy histological findings. All of these
Our own experience
patients were suspected of having PP based on macroscopic
We retrospectively evaluated the postoperative clinical findings during revision surgery.
course, and radiological and laboratory data of 7/160 If we retrospectively evaluate our patient group and
patients underwent PD in the period of 2007-2011 in our reaction to the obtained values—markers—of PP, it is
our institution for ductal adenocarcinoma of the head of necessary to state that we rather underestimated the increasing
pancreas and died during primary hospitalization because values and was of the opinion that the values reflect developing
of PF type C with autopsy findings of PP in four cases (49). pancreatic leak and that we have time and will observe the
We compared this group of 4 (2.5%) patients to the group patient. We evidently missed the opportunity to perform early
of 10 (6.25%) patients with only a pancreatic leak type surgical revision and remove the remaining pancreas.
C and 12 (7.5%) patients with an uncomplicated clinical Another discovery was the evaluation of the postoperative
course. None of the patients with PP survived. We found finding on the remaining pancreas. We attributed superficial
significantly higher levels of serum pancreatic amylase necroses to developing PP; autopsy findings, however, did not
on the 1st postoperative day (POD) in 3 of these patients confirm PP. Evidently these were superficial changes caused
compared to the other groups. Significantly increasing by digestion of pancreatic tissue by activated pancreatic juice
levels of CRP during the first five POD were observed in from PJA dehiscence. In accordance with other authors, we
75% of these patients. Retrospectively analyzed contrast do not consider feature soft biopsy to be of value.
CT scans up to the 5th POD did not show PP. Only one Prior CT examinations did not describe structural
patient had findings of PP type E according to Balthazar on changes in the pancreas in any of the four cases of autopsy-
CT scan performed on the 9th POD. confirmed PP, not even on retrospective evaluation.
The results of our retrospective study confirmed the
Results commentary following:
A basic aim of our study was to confirm or rule out a (I) An abrupt increase in values of serum amylase and
diagnosis of PP in the interval from the primary surgical CRP from the 1st POD to 5th POD is indicative of
procedure to the surgical revision, with respect to our the development of PP following PD for ductal
standard type of surgical procedure (disconnection and adenocarcinoma;
closure of the feature stump and peripancreatic drainage). (II) CT examination may not be beneficial in diagnosing
Our retrospective evaluation showed that we were mistaken this complication;
in almost half of the patients. Subsequent decision to (III) When life-threatening PP is diagnosed, a completion
perform a disconnection of the pancreatojejunostomy pancreatectomy is recommended. The decision
with drainage of the resected area with planned external depends on the surgeon’s experience;
PF did not reflect the current view on treatment of this (IV) I n some patients, PP may not be confirmed on
complication. This error, in both diagnosis and type of biopsy or autopsy; changes on the remaining
surgical revision, has also been presented by other authors, pancreas may only be superficial, caused by digestion
who came to very similar conclusions based on retrospective of activated pancreatic juice leaking from dehiscence
analyses (50,51). Completion pancreatectomy can be of of the pancreaticojejunostomy.
Cost of pancreatic fistula (PF) volume and surgical mortality in the United States. N
Engl J Med 2002;346:1128-37.
Patients who experience any complications after pancreatic
4. Standop J, Glowka T, Schmitz V, et al. Operative re-
surgery are associated with a three-fold increase in costs
intervention following pancreatic head resection:
over those without complications (53). It is of note that one
indications and outcome. J Gastrointest Surg
of the most serious postoperative surgical complications
2009;13:1503-9.
is PF type C either as a consequence or independently
5. Stojadinovic A, Brooks A, Hoos A, et al. An evidence-
from PP. The hospital stay of these patients is significantly
based approach to the surgical management of
longer than that of patients without PF (53). A median total
resectable pancreatic adenocarcinoma. J Am Coll Surg
cost of the treatment depends on the type of PF: A, B and
2003;196:954-64.
C—100%, 170%, 620% respectively. There is no significant 6. Büchler MW, Wagner M, Schmied BM, et al. Changes
difference in total cost between patients without PF and in morbidity after pancreatic resection: toward the end of
with PF type A (54). completion pancreatectomy. Arch Surg 2003;138:1310-4;
discussion 1315.
Conclusions 7. Bassi C, Dervenis C, Butturini G, et al. Postoperative
pancreatic fistula: an international study group (ISGPF)
The most serious complication after PD is PF type C, either definition. Surgery 2005;138:8-13.
as a consequence or independently from PP. Differentiating 8. Fuks D, Piessen G, Huet E, et al. Life-threatening
between these two types of complications is difficult. postoperative pancreatic fistula (grade C) after
Meantime PF type C is indication to operative revision with pancreaticoduodenectomy: incidence, prognosis, and risk
mostly drainage procedure which is obviously not much factors. Am J Surg 2009;197:702-9.
technically demanding, there are no definite guidelines on 9. Strasberg SM, Linehan DC, Clavien PA, et al. Proposal for
how to proceed in PP. Therefore the surgeon’s experience definition and severity grading of pancreatic anastomosis
determines not only whether PP will be diagnosed early failure and pancreatic occlusion failure. Surgery
enough and will be differentiated from PF without PP, 2007;141:420-6.
but also whether a completion pancreatectomy will be 10. Werner J, Büchler MW. Resectional techniques:
performed in indicated cases. Pancreaticoduodenectomy, distal pancreatectomy,
Patients who experience any complications after segmental pancreatectomy, total pancreatectomy, and
pancreatic surgery are associated with a three-fold increase transduodenal resection of the papilla of Vater. In:
in costs over those without complications. Jarnagin WR, Blumgart LH. eds. Blumgart’s Surgery
of the Liver, Pancreas and Biliary Tract. 5th ed.
Philadelphia: Saunders, 2013.
Acknowledgements
11. Machado NO. Pancreatic fistula after pancreatectomy:
Supported by grant IGA MZCR NT 13 263 and by project definitions, risk factors, preventive measures, and
of MO1012. management-review. Int J Surg Oncol 2012;2012:602478.
Disclosure: The authors declare no conflict of interest. 12. Addeo P, Delpero JR, Paye F, et al. Pancreatic fistula after a
pancreaticoduodenectomy for ductal adenocarcinoma and
its association with morbidity: a multicentre study of the
References
French Surgical Association. HPB (Oxford) 2014;16:46-55.
1. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of 13. Yang YM, Tian XD, Zhuang Y, et al. Risk factors of
the 6th edition AJCC Pancreatic Cancer Staging System: pancreatic leakage after pancreaticoduodenectomy. World
report from the National Cancer Database. Cancer J Gastroenterol 2005;11:2456-61.
2007;110:738-44. 14. De Carlis L, Ferla F, Di Sandro S, et al. Pancreatico-
2. Winter JM, Brennan MF, Tang LH, et al. Survival after duodenectomy and postoperative pancreatic fistula: risk
resection of pancreatic adenocarcinoma: results from a factors and technical considerations in a specialized HPB
single institution over three decades. Ann Surg Oncol center. Updates Surg 2014;66:145-50.
2012;19:169-75. 15. Ridolfi C, Angiolini MR, Gavazzi F, et al.
3. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital Morphohistological features of pancreatic stump
are the main determinant of pancreatic fistula 2002;137:1289-93.

after pancreatoduodenectomy. Biomed Res Int 27. Büchler M, Friess H, Klempa I, et al. Role of octreotide in
2014;2014:641239. the prevention of postoperative complications following
16. Tran K, Van Eijck C, Di Carlo V, et al. Occlusion of pancreatic resection. Am J Surg 1992;163:125-30;
the pancreatic duct versus pancreaticojejunostomy: a discussion 130-1.
prospective randomized trial. Ann Surg 2002;236:422-8; 28. Allen PJ, Gönen M, Brennan MF, et al. Pasireotide
discussion 428. for postoperative pancreatic fistula. N Engl J Med
17. Yeo CJ, Cameron JL, Maher MM, et al. A prospective 2014;370:2014-22.
randomized trial of pancreaticogastrostomy versus 29. Wang W, Tian B, Babu SR, et al. Randomized, placebo-
pancreaticojejunostomy after pancreaticoduodenectomy. controlled study of the efficacy of preoperative somatostatin
Ann Surg 1995;222:580-8; discussion 588-92. administration in the prevention of postoperative
18. Duffas JP, Suc B, Msika S, et al. A controlled complications following pancreaticoduodenectomy.
randomized multicenter trial of pancreatogastrostomy or Hepatogastroenterology 2013;60:400-5.
pancreatojejunostomy after pancreatoduodenectomy. Am J 30. Connor S, Alexakis N, Garden OJ, et al. Meta-analysis
Surg 2005;189:720-9. of the value of somatostatin and its analogues in reducing
19. Bassi C, Falconi M, Molinari E, et al. Reconstruction by complications associated with pancreatic surgery. Br J Surg
pancreaticojejunostomy versus pancreaticogastrostomy 2005;92:1059-67.
following pancreatectomy: results of a comparative study. 31. Giovinazzo F, Butturini G, Salvia R, et al. Drain
Ann Surg 2005;242:767-71, discussion 771-3. management after pancreatic resection: state of the art. J
20. El Nakeeb A, Hamdy E, Sultan AM, et al. Hepatobiliary Pancreat Sci 2011. [Epub ahead of print].
Isolated Roux loop pancreaticojejunostomy versus 32. Melloul E, Raptis DA, Clavien PA, et al. Poor level of
pancreaticogastrostomy after pancreaticoduodenectomy: agreement on the management of postoperative pancreatic
a prospective randomized study. HPB (Oxford) fistula: results of an international survey. HPB (Oxford)
2014;16:713-22. 2013;15:307-14.
21. Figueras J, Sabater L, Planellas P, et al. Randomized 33. González-Pinto I, González EM. Optimising the
clinical trial of pancreaticogastrostomy versus treatment of upper gastrointestinal fistulae. Gut 2001;49
pancreaticojejunostomy on the rate and severity of Suppl 4:iv22-31.
pancreatic fistula after pancreaticoduodenectomy. Br J 34. Dellaportas D, Tympa A, Nastos C, et al. An ongoing
Surg 2013;100:1597-605. dispute in the management of severe pancreatic fistula:
22. Bassi C, Falconi M, Molinari E, et al. Duct-to-mucosa Pancreatospleenectomy or not? World J Gastrointest Surg
versus end-to-side pancreaticojejunostomy reconstruction 2010;2:381-4.
after pancreaticoduodenectomy: results of a prospective 35. Maeda H, Hanazaki K. Pancreatogenic diabetes after
randomized trial. Surgery 2003;134:766-71. pancreatic resection. Pancreatology 2011;11:268-76.
23. Lai EC, Lau SH, Lau WY, et al. Measures to prevent 36. Balzano G, Pecorelli N, Piemonti L, et al. Relaparotomy
pancreatic fistula after pancreatoduodenectomy: a for a pancreatic fistula after a pancreaticoduodenectomy: a
comprehensive review. Arch Surg 2009;144:1074-80. comparison of different surgical strategies. HPB (Oxford)
24. Karpoff HM, Klimstra DS, Brennan MF, et al. Results of 2014;16:40-5.
total pancreatectomy for adenocarcinoma of the pancreas. 37. Kent TS, Callery MP, Vollmer CM Jr. The bridge stent
Arch Surg 2001;136:44-7; discussion 48. technique for salvage of pancreaticojejunal anastomotic
25. Winter JM, Cameron JL, Campbell KA, et al. Does dehiscence. HPB (Oxford) 2010;12:577-82.
pancreatic duct stenting decrease the rate of pancreatic 38. Rudiš J, Ryska M. Postoperative pancreatic fistula
fistula following pancreaticoduodenectomy? Results management by gastrofistuloanastomosis - a set of case
of a prospective randomized trial. J Gastrointest Surg reports. Rozhl Chir 2012;91:620-4.
2006;10:1280-90; discussion 1290. 39. Carter Ae. Post-operative pancreatitis. Postgrad Med J
26. Ohwada S, Tanahashi Y, Ogawa T, et al. In situ vs 1956;32:248-58.
ex situ pancreatic duct stents of duct-to-mucosa 40. Kriger AG, Kubishkin VA, Karmazanovskiĭ GG, et al. The
pancreaticojejunostomy after pancreaticoduodenectomy postoperative pancreatitis after the pancreatic surgery.
with billroth I-type reconstruction. Arch Surg Khirurgiia (Mosk) 2012;(4):14-9.
41. Imrie CW, Dickson AP. Postoperative pancreatitis. In: 1997;185:18-24.

Howard JM, Jordan GL, Reber HA. eds. Surgical diseases of 48. Smith CD, Sarr MG, vanHeerden JA. Completion
the pancreas. Philadelphia: Lea and Febiger, 1987:332-41. pancreatectomy following pancreaticoduodenectomy:
42. Z’gragen K, Uhl W, Büchler MW. Acute postoperative clinical experience. World J Surg 1992;16:521-4.
pancreatitis. In: Beger HG, Warshaw AL, Büchler MW, 49. Rudis J, Ryska M. Pancreatic leakage and
et al. eds. The Pancreas. Oxford: Blackwell Science, acute postoperative pancreatitis after proximal
1998:283-90. pancreatoduodenectomy. Rozhl Chir 2014;93:380-5 .
43. Z’graggen K, Aronsky D, Maurer CA, et al. Acute 50. Cullen JJ, Sarr MG, Ilstrup DM. Pancreatic anastomotic
postoperative pancreatitis after laparoscopic leak after pancreaticoduodenectomy: incidence,
cholecystectomy. Results of the Prospective Swiss significance, and management. Am J Surg 1994;168:295-8.
Association of Laparoscopic and Thoracoscopic Surgery 51. Haddad LB, Scatton O, Randone B, et al. Pancreatic
Study. Arch Surg 1997;132:1026-30; discussion 1031. fistula after pancreaticoduodenectomy: the conservative
44. Wilson C, Imrie CW. Deaths from acute pancreatitis: why treatment of choice. HPB (Oxford) 2009;11:203-9.
do we miss the diagnosis so frequently? Int J Pancreatol 52. Farley DR, Schwall G, Trede M. Completion
1988;3:273-81. pancreatectomy for surgical complications after
45. Büchler MW, Gloor B, Müller CA, et al. Acute necrotizing pancreaticoduodenectomy. Br J Surg 1996;83:176-9.
pancreatitis: treatment strategy according to the status of 53. Vonlanthen R, Slankamenac K, Breitenstein S, et al.
infection. Ann Surg 2000;232:619-26. The impact of complications on costs of major surgical
46. Balthazar EJ. CT diagnosis and staging of acute procedures: a cost analysis of 1200 patients. Ann Surg
pancreatitis. Radiol Clin North Am 1989;27:19-37. 2011;254:907-13.
47. van Berge Henegouwen MI, De Wit LT, Van Gulik TM, 54. Čečka F, Jon B, Šubrt Z, et al. Clinical and economic
et al. Incidence, risk factors, and treatment of pancreatic consequences of pancreatic fistula after elective pancreatic
leakage after pancreaticoduodenectomy: drainage versus resection. Hepatobiliary Pancreat Dis Int 2013;12:533-9.
resection of the pancreatic remnant. J Am Coll Surg
Cite this article as: Ryska M, Rudis J. Pancreatic fistula and

postoperative pancreatitis after pancreatoduodenectomy for
pancreatic cancer. Hepatobiliary Surg Nutr 2014;3(5):268-275.
doi: 10.3978/j.issn.2304-3881.2014.09.05
Review Article
Techniques for prevention of pancreatic leak after pancreatectomy

Hans F. Schoellhammer, Yuman Fong, Singh Gagandeep
Division of Surgical Oncology, Department of Surgery; City of Hope National Medical Center, Duarte, CA, USA
Correspondence to: Singh Gagandeep, MD. Clinical Professor of Surgery; Head, Hepatobiliary and Pancreatic Surgery; Chief, Division of Surgical
Oncology, Department of Surgery, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
Email: gsingh@coh.org.
Abstract: Pancreatic resections are some of the most technically challenging operations performed by
surgeons, and post-operative pancreatic fistula (POPF) are not uncommon, developing in approximately
13% of pancreaticoduodenectomies and 30% of distal pancreatectomies. Multiple trials of various operative
techniques in the creation of the pancreatic ductal anastomosis have been conducted throughout the
years, and herein we review the literature and outcomes data regarding these techniques, although no one
technique of pancreatic ductal anastomosis has been shown to be superior in decreasing rate of POPF.
Similarly, we review the literature regarding techniques of pancreatic closure after distal pancreatectomy.
Again, no one technique has been shown to be superior in preventing POPF; however the use of buttressing
material on the pancreatic staple line in the future may be a successful means of decreasing POPF. We review
adjunctive techniques to decrease POPF such as pancreatic ductal stenting, the use of various topical biologic
glues, and the use of somatostatin analogue medications. We conclude that future trials will need to be
conducted to find optimal techniques to decrease POPF, and meticulous attention to intra-operative details
and post-operative care by surgeons is necessary to prevent POPF and optimally care for patients undergoing
pancreatic resection.
Keywords: Pancreaticoduodenectomy; distal pancreatectomy; pancreatic leak; post-operative pancreatic fistula

(POPF); prevention
doi: 10.3978/j.issn.2304-3881.2014.08.08
Introduction leak, or abscess have been found to have a 90-day mortality

of 5% in a single-institution report of pancreatectomy
Pancreatic resections, whether for benign or malignant
outcomes prospectively-collected over a five-year period (1).
disease processes, are some of the most technically
The magnitude of this complication is not insignificant;
challenging operations performed by surgeons. After
pancreatic resection the potential for the development in a large worldwide literature search, the incidence of
of serious complications exists. One of the most serious pancreatic fistula after pancreaticoduodenectomy was found
complications after pancreatic resection is the development to be 12.9% and 13% after distal pancreatectomy (2),
of a post-operative pancreatic leak or fistula, whereby and other reports detail fistula rates up to 31% for distal
digestive pancreatic enzymes leak out of the pancreatic pancreatectomies (3).
ductal system via an abnormal connection into the peri- Given the need to decrease the incidence of POPF as
pancreatic space or the peritoneal cavity, with resulting well as the resulting significant morbidity and mortality,
morbidity such as abdominal pain, ileus, fever, and various techniques have been attempted to prevent the
the possibility of abscess, sepsis, and hemorrhage and formation of pancreatic leak and fistula. In this report we
consequently prolonged hospitalization. Importantly, review techniques for the prevention of pancreatic leak after
patients with post-operative pancreatic fistula (POPF), pancreatectomy.
Definition reported on three cases of pancreatic duct ligation all

without fistula creation in 1952 (5), and in a large report by
A POPF is any abnormal connection between the
Goldsmith and colleagues the POPF rate was equivalent
pancreatic ductal system and the peri-pancreatic space, the
between 45 patients treated with pancreatic duct ligation
peritoneal cavity or other body cavities, or externally to the
and 34 treated with anastomosis to the jejunum (6).
skin. Leakage of enzyme-rich pancreatic fluid is typically
Pancreatic endocrine dysfunction in the form of diabetes
diagnosed in the post-operative period via percutaneous
may develop after pancreatic duct ligation (7), and since
drainage of a fluid collection that is found to be high in
approximately 1975 pancreatic duct ligation has been
amylase content or via continued drainage of amylase-
abandoned in favor of re-establishment of continuity of the
rich fluid through a drain placed at the time of surgery. In
pancreatic duct to the intestines (8,9).
the past, varying criteria for what constitutes POPF have
been published in the literature; however in an attempt to
standardize the definition of POPF an international study Pancreaticojejunostomy (PJ) anastomotic techniques
group (ISGPF) of pancreatic surgeons convened in 2005 (4).
Multiple techniques in anastomosing the pancreatic duct to
POPF was thus defined as drain output of any volume
the gastrointestinal (GI) tract after pancreaticoduodenectomy
occurring on or after post-operative day 3 with amylase
have been described in the literature. Two of the predominant
content at least three times that of serum amylase levels.
methods of creating a PJ are an end-to-side duct-to-mucosa
In order to standardize the reporting of POPF outcomes,
anastomosis or the invagination technique. Briefly, in the
the authors also defined three grades of POPF: Grade A
end-to-side duct-to-mucosa anastomotic technique, the
is a transient fistula that does not have any clinical impact,
jejunal limb is brought into the retroperitoneum adjacent to
does not delay hospital discharge, and is managed by slow
the pancreas in a retrocolic fashion. A two-layer anastomosis
removal of peri-pancreatic drains. Grade B POPF requires a
is constructed with interrupted absorbable suture material,
change in clinical management, such as making the patient
beginning with a posterior row of seromuscular sutures
NPO, administering TPN, or re-positioning drains, and
securing the jejunum to the pancreas (Figure 1). The
leads to a delay in hospital discharge or to a readmission.
pancreatic duct-to-mucosa anastomosis is performed to an
Grade C POPF is the most severe and requires a major
enterotomy in the jejunum with a second circumferential
change in clinical management such as ICU-level care,
layer of interrupted sutures, taking generous amounts of
percutaneous drainage of undrained fluid collections, or
pancreas and the full-thickness of the jejunum, followed
operative re-exploration for further drainage or attempted
by completion of an anterior layer of seromuscular sutures
anastomotic repair. Grade C POPF causes a major
again securing the anterior aspect of the opened jejunum to
increase in hospitalization time as well as increased rates of
the capsule of the pancreas. In a report by Z’graggen and
complications and the possibility of mortality (4).
colleagues using this technique, POPF was seen in 2.1% of
331 patients who underwent pancreatic head resection (10).
Techniques to prevent pancreatic leak The goal of creating an invagination PJ is to invaginate
or “dunk” all of the cut edge of the pancreatic parenchyma
Multiple trials using various operative techniques and
into the lumen of the jejunum (11). The performance of
pharmacologic agents have been conducted to evaluate for
invagination PJ anastomosis begins with a posterior row
a decrease in or prevention of POPF. Herein we review the
of interrupted seromuscular sutures bringing the jejunum
literature on techniques to decrease POPF.
into apposition with the pancreatic capsule (Figure 2). The
jejunum is opened, and an inner layer of running locking
Operative anastomotic construction techniques suture is then performed taking full-thickness jejunal bites
and large bites of the pancreatic parenchyma and capsule,
Historical technique: ligation of the pancreatic duct
but not of the pancreatic duct, with the goal of invaginating
Historically the creation of a pancreatic-enteric anastomosis all of the cut edge of the pancreatic tissue into the jejunum.
after pancreaticoduodenectomy was fraught with leak and An anterior layer of seromuscular sutures rolling the
complications, and thus some authors advocated simply jejunum onto the pancreatic capsule is then performed to
ligating the pancreatic duct without re-creating continuity complete the anastomosis.
to the GI tract as a means of fistula prevention. Brunschwig Berger and colleagues sought to compare rates of
278 Schoellhammer et al. Techniques to prevent pancreatic leak
Figure 1 Duct-to-mucosa pancreaticojejunostomy.
Figure 2 Invagination pancreaticojejunostomy.
POPF at the PJ with the use of the invagination technique more POPF in soft glands (27%) than in hard glands (8%).
versus the duct-to-mucosa technique to test the hypothesis The authors concluded that the pancreatic texture was the
that use of the duct-to-mucosa technique would lead greatest determinant in POPF and that further studies are
to a decreased POPF rate (12). To this end the authors needed to determine the optimal anastomotic technique.
performed a randomized prospective clinical trial at two
institutions and randomized 197 patients undergoing
Modified duct-to-mucosa PJ
pancreaticoduodenectomy to the invagination or the duct-
to-mucosa technique; patients were stratified in both groups One variation of the duct-to-mucosa technique that bears
by whether the pancreatic parenchyma was hard or soft. noting is the transpancreatic U-suture technique with a duct-
POPF occurred in 17.8% of all patients, with significantly to-mucosa anastomosis described by Grobmyer, Blumgart,
more POPF seen in the duct-to-mucosa group compared and colleagues at Memorial Sloan Kettering Cancer
with the invagination group (24% vs. 12%, P<0.05) and with Center and originally created by Dr. Leslie Blumgart (13).
Figure 3 Modified duct-to-mucosa pancreaticojejunostomy—Blumgart anastomosis.
In this technique an outer layer of polyglactin sutures are complications, and length of ICU stay. Proponents of this
first inserted full-thickness anterior-to-posterior through technique argue that the transpancreatic sutures minimize
the pancreas with subsequent seromuscular horizontal radial forces on the anastomosis, and that it is relatively
mattress stitches on the jejunum, followed again by a full- quick to construct and easy to teach to trainees.
thickness posterior-to-anterior bite coming up through the
pancreas (Figure 3). Care is taken not to pass the needle
Binding technique for PJ creation
through the pancreatic duct. The u-stitches are not tied yet,
and a duct-to-mucosa anastomosis is then created with fine Another technique for creating the PJ anastomosis is the so-
polydioxanone interrupted suture. The seromuscular sutures called “binding” PJ reported by Peng and colleagues (15),
are then tied bringing the jejunum into close apposition in which the distal 3 cm of the jejunal loop to be used for
anteriorly on the pancreas; however the suture is not yet cut. anastomosis are everted and the mucosa ablated either
Lastly, the sutures with the needles still on are used to create by electrocoagulation or by topical treatment with 10%
an anterior seromuscular bite on the jejunum with the needle carbolic acid followed by immediate rinsing in 75% ethanol
being brought through the pancreas under the previous and normal saline (Figure 4). The proximal 3 cm of the
knots. The sutures are then tied again, thus imbricating pancreatic stump is then anastomosed to just the mucosa of
the jejunum over the entire pancreas. In an audit of 187 the jejunum. The treated 3 cm of jejunum are then rolled
patients with PJ anastomoses constructed by this technique, out and intussuscepted back over the pancreas, sutured into
the authors report an overall POPF rate of 20.3%; however place, and lastly a catgut tie is looped around the entire
most of these were ISPGF Grade A, with only 6.9% of circumference of the anastomosis 1 cm from the cut edge of
patients with Grade B or C POPF. Soft pancreatic texture the pancreas. The authors reported a 0% POPF rate after
was significantly associated with leak, and patients with the completion of 150 cases using this anastomosis, with
POPF had significantly smaller diameter pancreatic an overall morbidity of 31.3% and a mean hospital stay of
ducts compared with patients without POPF (3 vs. 4 mm, 19.8±5 days (16). A subsequent prospective trial conducted
P=0.008). Kleespies and colleagues published their outcomes by Peng and colleagues randomized 217 patients undergoing
data using what they call the “Blumgart anastomosis” after pancreaticoduodenectomy to traditional PJ anastomosis
their department began to use this technique for PJ and or binding PJ anastomosis (17). Leak was seen in 8 of 111
abandoned the traditional duct-to-mucosa technique (14). (7.2%) conventional PJ patients compared with 0 of 106
They found significantly decreased leak rate with the binding PJ patients (P=0.014), and complications were
Blumgart anastomosis (13% vs. 4%, P=0.032), as well as reported in 36.9% of conventional PJ patients compared
significantly decreased rates of postoperative hemorrhage, with 24.5% of binding PJ patients (P=0.048), including 6.3%
A B C
Figure 4 Binding pancreaticojejunostomy.
Figure 5 Pancreaticogastrostomy.
perioperative mortality in the conventional group and 2.8% the rationale that a PG anastomosis is easier to perform and
mortality in the binding group (P=NS). Subsequent trials that the stomach has a more robust blood supply compared
of binding PJ conducted in Europe have not replicated the with the jejunum. Additional rationale for PG instead of
impressive rate of POPF. A case-control study 22 binding PJ in the case of pancreatic head resections that extend to
PJ and 25 conventional PJ patients found no difference in the left past the midline is that the increase in distance may
the rate of POPF, with longer delay in POPF healing as put the resulting jejunal limb and jejunal anastomosis under
well as increased postpancreatectomy hemorrhage in the tension, with increased risk for subsequent leak; however
binding group (18). Similarly, a recent prospective two- after such a resection the stomach will be immediately
institution trial of 69 binding PJ patients compared to 52 adjacent to the remnant pancreas with the opportunity
conventional PJ historical control patients demonstrated to create a tension-free PG anastomosis (Figure 5). In
significantly shorter hospital stay in the conventional PJ evaluating PG, an earlier report by Delcore and colleagues
patients. Soft pancreatic texture was significantly associated demonstrated no leaks of the PG anastomosis in 45 cases (20),
with POPF; however no significant difference in the rate of and a 0% leak rate over 38 cases was also reported by Mason
POPF between binding and conventional PJ anastomoses et al. (21). PG was later compared to PJ anastomosis in a
was seen (19). Binding PJ remains one of many options for prospective randomized trial conducted by Bassi and co-
creation of the pancreatic-enteric anastomosis. workers, in which 151 patients with soft pancreatic glands
were randomized to PG or end-to-side PJ anastomoses (22).
Pancreatic fistula occurred in 13% of PG patients and 16% of
Pancreaticogastrostomy (PG) creation
PJ (P=NS); however post-operative fluid collections, delayed
The creation of pancreatic duct anastomosis to the stomach gastric emptying, and biliary fistulae were significantly less
PG instead of to the jejunum has been studied as well, with in the PG group. A similar trial was conducted by Duffas
et al. who randomized 81 patients to PG and 68 patients to hypothesized that use of external drains more completely
PJ after pancreaticoduodenectomy and found POPF in 16% diverts pancreatic secretions away from the PJ anastomosis
of the PG group and 20% of the PJ group (23). The authors with decreased risk for leak formation.
concluded that the type of anastomosis does not influence the A recent Cochrane Review also examined the
development of POPF, and a meta-analysis of PG versus PJ efficacy of pancreatic stents in preventing POPF after
trials noted that there was no superiority of either technique pancreaticoduodenectomy in a review of randomly
and surgeons should continue to use the technique with controlled trials extracted the Cochrane Central Register
which they are most familiar (24). Interestingly, a recent of Controlled Trials (CENTRAL), MEDLINE, Excerpta
prospective randomized multi-center trial by Topal and Medica database (EMBASE), Web of Science, and other
colleagues from Belgium randomizing 329 patients to PJ major trials databases (29). A total of 655 patients were
or PG after pancreaticoduodenectomy, in which patients included in the systematic review, and the authors found that
were stratified by pancreatic duct diameter (≤3 or >3 mm), the use of external, but not internal stents was associated
reported significantly more POPF in the PJ group than the with a significant decrease in the incidence of POPF (RR
PG group (19.8% vs. 8%, OR 2.86, 95% CI: 1.38-6.17, 0.33, 95% CI: 0.11-0.98, P=0.002). These results are echoed
P=0.002) (25). The authors concluded that PG should be by another systematic review of the literature and meta-
the preferred anastomosis after pancreaticoduodenectomy, analysis performed by Xiong and colleagues, who examined
although further data from a multi-center international trial the literature from January 1973 to September 2011 and
will be needed to confirm this. included 1,726 patients from five randomized clinical
trials and 11 non-randomized clinical observation studies
in their analysis (30). The authors found that placement
Pancreatic duct anastomotic stenting
of internal or external stents in the pancreatic duct after
Pancreatic duct stenting at the time of anastomosis pancreaticoduodenectomy did not reduce the incidence of
creation has been proposed as a technique to decrease POPF; however on subgroup analysis placement of external
pancreatic leak and fistula, with the rationale that stenting stents significantly reduced the incidence of POPF compared
prevents the accumulation of pancreatic secretions in with no stent (OR 0.42, 95% CI: 0.24-0.76, P=0.004 for
the pancreatic stump and the pancreatic anastomosis is randomized clinical trials and OR 0.43, 95% CI: 0.27-0.68,
excluded from direct contact with the pancreatic juice (26). P<0.001 for observational studies). These recent data suggest
This was examined in a randomized trial by Winter and that if one intends to stent the pancreatic anastomosis, an
colleagues who randomized 238 patients undergoing external stent should be considered; however more data are
pancreaticoduodenectomy to internal pancreatic duct stent needed to suggest routine use of pancreatic stents, and many
or no-stent with the endpoint of POPF development (27). centers have moved away from the use of pancreatic duct
Patients were stratified by the texture of the pancreatic stents completely.
remnant (soft vs. normal/hard), with 6 cm pediatric feeding
tubes were used as stents. In the hard pancreas group 1.7%
Pancreatic stump closure after distal
stent patients and 4.8% non-stent patients developed POPF
pancreatectomy
(P=0.4), and in the soft pancreas group 21.1% stent patients
and 10.7% non-stent patients developed POPF (P=0.1) with Pancreatic leak after distal pancreatectomy occurs in
the conclusion that internal pancreatic duct stenting does approximately 30% of patients (31,32), which is a rate
not alter the rate of POPF. higher than is seen in pancreaticoduodenectomy. Many
Pancreatic duct drainage with external rather than studies have been conducted to determine the optimal
stents has also been studied. In a study from Hong Kong method for closing the pancreatic stump in order to
in 2007, Poon et al. prospectively randomized 120 patients prevent POPF. The two main techniques for closure of the
undergoing pancreaticoduodenectomy with PJ duct-to- pancreatic stump after distal pancreatectomy are suture
mucosa anastomosis to an external stent or not (28). Patients closure of the pancreatic duct or stapled closure of the
in the stented group had a significantly lower pancreatic parenchyma. A previous retrospective report by Bilimoria
fistula rate compared with the no stent group (6.7% vs. et al. in which the authors reviewed their institutional data
20%, P=0.032), and on multivariable analysis absence of of 126 patients who underwent distal pancreatectomy
stenting was a significant risk factor for POPF. The authors over a nine year period found that POPF rates in patients
who underwent suture closure of the pancreatic duct was distal pancreatectomy have been attempted as a means
significantly lower than patients who did not undergo suture of decreasing leak. In a small non-randomized single-
closure (9.6% vs. 34%, P<0.001) (33). On multivariable institution trial, Jimenez and colleagues reported rates of
analysis, failure to ligate the duct was significantly associated POPF with stapled pancreatic stump closure reinforced
with pancreatic leak (OR 5, 95% CI: 2-10, P=0.001). with bioabsorbable buttress sleeves mounted on the stapler
The other most prominent technique for pancreatic and compared a group of 13 patients treated in this manner
transection is to use a surgical stapler. A meta-analysis with 18 historical controls (37). Rates of POPF were 0%
conducted by Knaebel and co-workers in 2005 examined in the buttress group versus 39% in the control group
ten articles in the world literature (two randomized trials (P=0.025). A similar single-institution report from Thaker
and eight observational studies) that reported techniques and others of 40 patients undergoing distal pancreatectomy
to decrease POPF after distal pancreatectomy (34). Six and bioabsorbable mesh buttress staple line reinforcement
of the ten studies compared hand-sutured versus stapled with comparison to 40 historical controls of only stapled
pancreatic closure, and in this analysis the authors found closure found significantly decreased rate of POPF with
a trend towards decreased POPF with the use of staplers; mesh reinforcement (3.5%) compared with staple closure
however the results were not statistically significant only (22%, P=0.04) (38). In a subsequent single-institution
(OR 0.66, 95% CI: 0.35-1.26, P=0.21). Given this trend randomized prospective trial of stapled pancreatic
towards decreased POPF with stapled closure, Diener and closure with or without bioabsorbable mesh staple line
colleagues designed the multicenter prospective DISPACT reinforcement, Hamilton et al. found significantly fewer
trial in which patients undergoing distal pancreatectomy ISGPF Grade B/C leaks in 1/53 (1.9%) mesh reinforcement
were randomized to stapler or hand-sewn closure with the patients compared with 11/45 (20%) no-mesh patients
primary outcomes of POPF and mortality at one week; (P=0.007) (39).
the authors hypothesized that standardized closure with a Currently it appears that reinforcement of the
stapler would lead to decreased POPF (35). Of 450 patients pancreatic staple line with a bioabsorbable mesh is a
randomized, 352 were included in the final analysis (175 feasible method of decreasing POPF; however the previous
hand-sewn, 177 stapler). The rate of POPF in the stapler single-institution results still require confirmation in the
group was 32% compared with 28% in the hand-sewn form of multi-institution prospective randomized trials,
group, without any significant difference between the two preferably with international collaboration. Just as the
groups (OR 0.84, 95% CI: 0.53-1.33, P=0.56). There was rigorous methodology of the DISPACT trial appears
one death in the hand-sewn group and none in the stapler to have provided a definitive answer to the question of
group. The authors concluded that stapled closure was not stapled or hand-sewn closure, so is there a need for this
superior to hand-sewn closure for preventing POPF, and methodology regarding the question of bioabsorbable mesh
indeed the data demonstrate that these methods of closure reinforcement.
have equivalent POPF rates.
Given this equivalency, other methods to decrease POPF
Use of fibrin glue and other topical sealant agents
have been investigated. A prospective randomized trial of
prophylactic pancreatic duct stenting to decrease POPF The use of fibrin glue and other topical hemostatic agents
was conducted by Frozanpor et al. with the hypothesis applied to the pancreato-enteric anastomosis have been
that more efficient diversion of pancreatic secretions into proposed as adjuncts to help seal the anastomosis and
the duodenum away from the pancreatic transection line prevent POPF; however results have been disappointing. In
would lead to decreased POPF (36). A total of 58 patients a report from 1991, Kram and colleagues used fibrin glue
were analyzed (29 distal pancreatectomy only, 29 distal made from concentrated fibrinogen and clotting factors
pancreatectomy with stent); the rate of ISGPF Grade B/C which was applied topically to pancreatic wounds, staple/
POPF was 42.3% in the stent group and 22.2% in the no- suture lines, and pancreatic anastomoses in both trauma
stent group without a significant difference between the and non-trauma operations; the authors reported no
two (OR 2.57, 95% CI: 0.78-8.48, P=0.122). Decreasing pancreatic fistulae, abscesses, or pseudocysts in their series
resistance across the sphincter of Oddi with stenting does of 15 patients (40). In an early prospectively randomized
not appear to have a role in decreasing POPF rates. trial reported in 1994 by D’Andrea, 97 patients undergoing
Various methods of reinforcing the staple line after pancreatectomy for both benign and malignant conditions
were enrolled and randomized to intraoperative fibrin in an attempt to decrease POPF, with the hypothesis that
sealing of the pancreas or to no sealing (41). Pancreatic decreased pancreatic juice secretion will allow for improved
fistulae developed in 13.9% of the fibrin glue patients and healing of pancreatic ductal anastomoses and consequently
in 11.1% of the non-fibrin glue patients, with no significant decreased leak rates. The use of octreotide has been studied
difference seen between in two groups. in multiple randomized prospective trials in the United States
In a larger prospective randomized trial of fibrin glue and Europe; however the results have been mixed. Yeo and
conducted by Lillemoe et al., the authors randomized 125 colleagues conducted a prospective trial in which patients
patients, who were felt to be at high risk for pancreatic undergoing pancreaticoduodenectomy were randomized
leak after pancreaticoduodenectomy by their operating to saline control or octreotide 250 μg subcutaneously
surgeon, to either topical application of fibrin glue to the PJ every eight hours beginning 1-2 hours before surgery and
anastomosis (59 patients) versus no glue (66 patients) (42). continuing for seven days (48). Ultimately 211 patients made
The rate of POPF was 26% in the glue arm versus 30% up the entire study cohort; POPF was seen in 9% of control
in the control group (P=NS), and there was no difference group and 11% of octreotide group. The authors concluded
in length of hospital stay between the groups as well. that octreotide does not reduce incidence of POPF and
The authors concluded that the use of fibrin glue did that omission of this treatment may lead to a cost savings
not decrease the rate of POPF or of other complications for hospitals. Sarr and co-investigators in the Pancreatic
following pancreaticoduodenectomy. A recent large meta- Study Group conducted a prospective, randomized,
analysis evaluating the effectiveness of fibrin sealants in placebo-controlled trial of the long-acting somatostatin
pancreatic surgery systematically evaluated seven studies analogue vapreotide, hypothesizing that vapreotide would
including 897 patients and found that fibrin sealants had a decrease pancreas-related complications; 135 patients
non-significant impact on the development of POPF (43). received vapreotide and 140 received placebo (49).
The authors concluded that fibrin sealants cannot be No significant differences were seen in pancreas-related
recommended routinely in the setting of pancreatic complications between the two groups (placebo 26.4% vs.
resection. vapreotide 30.4%, P=NS), and the authors concluded that
Internal occlusion of the pancreatic duct with absorbable vapreotide offers no therapeutic benefit in terms of post-
fibrin glue after creation of a pancreatic duct anastomosis operative complications. Suc et al. conducted a French
has been proposed as a way to allow the anastomosis to multi-center prospective randomized trial in 230 patients
heal without being exposed to the enzyme-rich pancreatic undergoing pancreatectomy, with 122 patients randomized
fluid, although early prospective non-randomized trials to octreotide and 108 randomized to the control arm; the
did not demonstrate a decrease in POPF (44). To address primary endpoint was all intra-abdominal complications (50).
this, Suc and colleagues conducted a multi-institution, Intra-abdominal complications were seen in 22% of
single-blind, prospective randomized trial in France of octreotide patients versus 32% of placebo patients; however
pancreatic resection with or without fibrin glue occlusion this result was not statistically significant and the authors
of the pancreatic duct occlusion (45). The authors report concluded that octreotide cannot be routinely used to
an overall POPF rate of 16% in their trial; however no decrease intra-abdominal complications in pancreatectomy
difference in POPF rate was seen when comparing the patients.
fibrin glue to the control group. Fibrin glue occlusion Recently, Allen and colleagues reported their results of a
of the pancreatic duct appears to have no impact on the single-center, prospective, double-blind, placebo controlled
development of POPF. trial using the long-acting somatostatin analogue pasireotide,
which has a longer half-life than octreotide as well as a
broader receptor binding profile (51). Patients undergoing
Use of somatostatin analogues
pancreaticoduodenectomy or distal pancreatectomy were
The inhibitory peptide hormone somatostatin acts to randomized to pasireotide 900 μg subcutaneously given
decrease the output of secretions from the pancreas, GI twice daily beginning the morning of operation for seven
tract, and biliary tract, although the half-life is short at days (152 patients) or to placebo (148 patients). The
approximately two minutes (46). Synthetic analogues of primary endpoint was incidence of grade 3 pancreatic leak,
somatostatin with longer half-lives, such as octreotide (47), fistula, or abscess; grade 3 indicating that a radiologic,
have been developed and have been used in pancreatic surgery endoscopic, or surgical intervention was required, and
Table 1 Selected trials performed to evaluate rates of POPF

Study Trial arm(s) N Fistula (%) Conclusion
Berger, 2009 Duct-to-mucosa 100 12 (12%) Fewer POPF in invagination group
Pancreaticojejunostomy (PJ)
Invagination PJ 97 23 (24%)
Grobmyer, 2010 Modified duct-to-mucosa PJ 187 13 (6.7%) Grade B/C
(Blumgart anastomosis)
Kleespies, 2009 Duct-to-mucosa PJ 90 12 (13%) Fewer POPF with use of Blumgart
anastomosis
Modified duct-to-mucosa PJ 92 4 (4%)
(Blumgart anastomosis)
Peng, 2007 Binding PJ 111 0 Fewer POPF in binding group
Invagination PJ 106 8 (7.5%)
Maggiori, 2010 Binding PJ 22 8 (36%) No POPF difference with use of binding PJ
Invagination PJ 25 7 (28%)
Bassi, 2005 Pancreaticogastrostomy (PG) 69 9 (13%) No difference in POPF rates
PJ 82 13 (16%)
Topal, 2013 PG 167 13 (8%) PG decreases POPF rate
PJ 162 33 (19.8%)
Winter, 2006 Pancreatic duct stent 58 Hard pancreas 1.7%, No difference in POPF rates
soft pancreas 21.1%
No stent 63 Hard pancreas 4.8%,
soft pancreas 10.7%
Poon, 2007 External pancreatic duct stent 60 4 (6.7%) External stent decreases POPF
No stent 60 12 (20%)
Diener, 2011 Stapled distal pancreatectomy 175 32% No difference in POPF rates
Hand-sewn distal pancreatectomy 177 28%
Yeo, 2000 Octreotide 104 11 (9%) No difference in POPF rates
No octreotide 107 10 (11%)
Allen, 2014 Pasireotide 152 9% Pasireotide decrease POPF rates
No pasireotide 148 21%
POPF, post-operative pancreatic fistula.
the secondary endpoint was Grade B or C POPF. In total Conclusions

15% of patients met the primary endpoint; however the
Post-operative pancreatic leak and fistula are a major source
primary endpoint was significantly less in the pasireotide
group compared with placebo (9% vs. 21%, RR 0.44, 95% of morbidity and mortality after pancreatic resection.
CI: 0.24-0.78, P=0.006). In the pasireotide group 7.9% Many trials have been undertaken to identify techniques
of patients had Grade B POPF, and zero had Grade C, to reduce POPF (Table 1); however no one technique has
compared with 16.9% Grade B/C in the placebo group, been shown to definitively be the solution to the problem,
P=0.02; rates of adverse events were similar between the and indeed one of the major determinants of POPF is
two groups. Pasireotide significantly reduced risk of post- a factor over which the surgeon has very little control,
operative fistula/leak/abscess, and may have a role in the i.e., the consistency of the pancreatic parenchyma itself.
prevention of POPF in the future. Surgeons should continue to use the pancreatic duct
anastomotic technique with which they are most familiar analysis regarding 15 years of literature. Anticancer Res
and comfortable, and currently there is no evidence for 1991;11:1831-48.
routine use of stents or topical sealing products. For closure 9. Fromm D, Schwarz K. Ligation of the pancreatic duct
of the pancreatic stump after distal pancreatectomy, a during difficult operative circumstances. J Am Coll Surg
stapled closure in combination with bioabsorbable mesh 2003;197:943-8.
buttress may represent a reliable technique to decrease 10. Z’graggen K, Uhl W, Friess H, et al. How to do a safe
POPF; however high-quality data from multi-institutional pancreatic anastomosis. J Hepatobiliary Pancreat Surg
prospective trials are currently lacking. In the future, 2002;9:733-7.
novel somatostatin analogues may play a role in decreasing 11. Kennedy EP, Yeo CJ. Dunking pancreaticojejunostomy
POPF, but without question meticulous surgical technique versus duct-to-mucosa anastomosis. J Hepatobiliary
and attention to detail will remain the cornerstones of Pancreat Sci 2011. [Epub ahead of print].
decreasing pancreatic leak and patient morbidity/mortality. 12. Berger AC, Howard TJ, Kennedy EP, et al. Does type of
pancreaticojejunostomy after pancreaticoduodenectomy
decrease rate of pancreatic fistula? A randomized,
Acknowledgements
prospective, dual-institution trial. J Am Coll Surg
Disclosure: The authors declare no conflict of interest. 2009;208:738-47; discussion 747-9.
13. Grobmyer SR, Kooby D, Blumgart LH, et al. Novel
pancreaticojejunostomy with a low rate of anastomotic
References
failure-related complications. J Am Coll Surg
1. Vin Y, Sima CS, Getrajdman GI, et al. Management and 2010;210:54-9.
outcomes of postpancreatectomy fistula, leak, and abscess: 14. Kleespies A, Rentsch M, Seeliger H, et al. Blumgart
results of 908 patients resected at a single institution anastomosis for pancreaticojejunostomy minimizes severe
between 2000 and 2005. J Am Coll Surg 2008;207:490-8. complications after pancreatic head resection. Br J Surg
2. Alexakis N, Sutton R, Neoptolemos JP. Surgical treatment 2009;96:741-50.
of pancreatic fistula. Dig Surg 2004;21:262-74. 15. Peng S, Mou Y, Cai X, et al. Binding
3. Goh BK, Tan YM, Chung YF, et al. Critical appraisal of pancreaticojejunostomy is a new technique to minimize
232 consecutive distal pancreatectomies with emphasis leakage. Am J Surg 2002;183:283-5.
on risk factors, outcome, and management of the 16. Peng SY, Mou YP, Liu YB, et al. Binding
postoperative pancreatic fistula: a 21-year experience at a pancreaticojejunostomy: 150 consecutive cases without
single institution. Arch Surg 2008;143:956-65. leakage. J Gastrointest Surg 2003;7:898-900.
4. Bassi C, Dervenis C, Butturini G, et al. Postoperative 17. Peng SY, Wang JW, Lau WY, et al. Conventional
pancreatic fistula: an international study group (ISGPF) versus binding pancreaticojejunostomy after
definition. Surgery 2005;138:8-13. pancreaticoduodenectomy: a prospective randomized trial.
5. Brunschwig A. Pancreatoduodenectomy: a Ann Surg 2007;245:692-8.
curative operation for malignant neoplasms in the 18. Maggiori L, Sauvanet A, Nagarajan G, et al. Binding
pancreatoduodenal region; report of three over-five-year versus conventional pancreaticojejunostomy after
survivors. Ann Surg 1952;136:610-24. pancreaticoduodenectomy: a case-matched study. J
6. Goldsmith HS, Ghosh BC, Huvos AG. Ligation Gastrointest Surg 2010;14:1395-400.
versus implantation of the pancreatic duct after 19. Casadei R, Ricci C, Silvestri S, et al. Peng’s binding
pancreaticoduodenectomy. Surg Gynecol Obstet pancreaticojejunostomy after pancreaticoduodenectomy.
1971;132:87-92. An Italian, prospective, dual-institution study.
7. Tran K, Van Eijck C, Di Carlo V, et al. Occlusion of Pancreatology 2013;13:305-9.
the pancreatic duct versus pancreaticojejunostomy: a 20. Delcore R, Thomas JH, Pierce GE, et al.
prospective randomized trial. Ann Surg 2002;236:422-8; Pancreatogastrostomy: a safe drainage procedure after
discussion 428. pancreatoduodenectomy. Surgery 1990;108:641-5;
8. Bartoli FG, Arnone GB, Ravera G, et al. Pancreatic discussion 645-7.
fistula and relative mortality in malignant disease after 21. Mason GR, Freeark RJ. Current experience with
pancreaticoduodenectomy. Review and statistical meta- pancreatogastrostomy. Am J Surg 1995;169:217-9.
22. Bassi C, Falconi M, Molinari E, et al. Reconstruction by 34. Knaebel HP, Diener MK, Wente MN, et al. Systematic
pancreaticojejunostomy versus pancreaticogastrostomy review and meta-analysis of technique for closure of the
following pancreatectomy: results of a comparative study. pancreatic remnant after distal pancreatectomy. Br J Surg
Ann Surg 2005;242:767-71, discussion 771-3. 2005;92:539-46.
23. Duffas JP, Suc B, Msika S, et al. A controlled 35. Diener MK, Seiler CM, Rossion I, et al. Efficacy of stapler
randomized multicenter trial of pancreatogastrostomy or versus hand-sewn closure after distal pancreatectomy
pancreatojejunostomy after pancreatoduodenectomy. Am J (DISPACT): a randomised, controlled multicentre trial.
Surg 2005;189:720-9. Lancet 2011;377:1514-22.
24. Dixon E, Fingerhut A, Bassi C, et al. Meta-analysis of 36. Frozanpor F, Lundell L, Segersvärd R, et al. The effect
pancreaticojejunostomy versus pancreaticogastrostomy of prophylactic transpapillary pancreatic stent insertion
reconstruction after pancreaticoduodenectomy: authors’ on clinically significant leak rate following distal
comment (Br J Surg 2006; 93: 929-936). Br J Surg pancreatectomy: results of a prospective controlled clinical
2006;93:1435. trial. Ann Surg 2012;255:1032-6.
25. Topal B, Fieuws S, Aerts R, et al. Pancreaticojejunostomy 37. Jimenez RE, Mavanur A, Macaulay WP. Staple line
versus pancreaticogastrostomy reconstruction after reinforcement reduces postoperative pancreatic stump
pancreaticoduodenectomy for pancreatic or periampullary leak after distal pancreatectomy. J Gastrointest Surg
tumours: a multicentre randomised trial. Lancet Oncol 2007;11:345-9.
2013;14:655-62. 38. Thaker RI, Matthews BD, Linehan DC, et al. Absorbable
26. Kleespies A, Albertsmeier M, Obeidat F, et al. The mesh reinforcement of a stapled pancreatic transection
challenge of pancreatic anastomosis. Langenbecks Arch line reduces the leak rate with distal pancreatectomy. J
Surg 2008;393:459-71. Gastrointest Surg 2007;11:59-65.
27. Winter JM, Cameron JL, Campbell KA, et al. Does 39. Hamilton NA, Porembka MR, Johnston FM, et al.
pancreatic duct stenting decrease the rate of pancreatic Mesh reinforcement of pancreatic transection decreases
fistula following pancreaticoduodenectomy? Results incidence of pancreatic occlusion failure for left
of a prospective randomized trial. J Gastrointest Surg pancreatectomy: a single-blinded, randomized controlled
2006;10:1280-90; discussion 1290. trial. Ann Surg 2012;255:1037-42.
28. Poon RT, Fan ST, Lo CM, et al. External drainage of 40. Kram HB, Clark SR, Ocampo HP, et al. Fibrin glue
pancreatic duct with a stent to reduce leakage rate of sealing of pancreatic injuries, resections, and anastomoses.
pancreaticojejunostomy after pancreaticoduodenectomy: a Am J Surg 1991;161:479-81; discussion 482.
prospective randomized trial. Ann Surg 2007;246:425-33; 41. D’Andrea AA, Costantino V, Sperti C, et al. Human
discussion 433-5. fibrin sealant in pancreatic surgery: it is useful in
29. Dong Z, Xu J, Wang Z, et al. Stents for the prevention preventing fistulas? A prospective randomized study. Ital J
of pancreatic fistula following pancreaticoduodenectomy. Gastroenterol 1994;26:283-6.
Cochrane Database Syst Rev 2013;6:CD008914. 42. Lillemoe KD, Cameron JL, Kim MP, et al. Does fibrin
30. Xiong JJ, Altaf K, Mukherjee R, et al. Systematic glue sealant decrease the rate of pancreatic fistula after
review and meta-analysis of outcomes after pancreaticoduodenectomy? Results of a prospective
intraoperative pancreatic duct stent placement during randomized trial. J Gastrointest Surg 2004;8:766-72;
pancreaticoduodenectomy. Br J Surg 2012;99:1050-61. discussion 772-4.
31. Ferrone CR, Warshaw AL, Rattner DW, et al. Pancreatic 43. Orci LA, Oldani G, Berney T, et al. Systematic review and
fistula rates after 462 distal pancreatectomies: staplers meta-analysis of fibrin sealants for patients undergoing
do not decrease fistula rates. J Gastrointest Surg pancreatic resection. HPB (Oxford) 2014;16:3-11.
2008;12:1691-7; discussion 1697-8. 44. Lorenz D, Wolff H, Waclawiczek H. Pancreatic duct
32. Nathan H, Cameron JL, Goodwin CR, et al. Risk factors occlusion in resection treatment of chronic pancreatitis
for pancreatic leak after distal pancreatectomy. Ann Surg and cancer of the head of the pancreas. A 3-year follow-up
2009;250:277-81. study. Chirurg 1988;59:90-5.
33. Bilimoria MM, Cormier JN, Mun Y, et al. Pancreatic 45. Suc B, Msika S, Fingerhut A, et al. Temporary fibrin glue
leak after left pancreatectomy is reduced following main occlusion of the main pancreatic duct in the prevention of
pancreatic duct ligation. Br J Surg 2003;90:190-6. intra-abdominal complications after pancreatic resection:
prospective randomized trial. Ann Surg 2003;237:57-65. somatostatin analogue vapreotide does not decrease
46. Raptis S, Schlegel W, Lehmann E, et al. Effects of pancreas-specific complications after elective
somatostatin on the exocrine pancreas and the release of pancreatectomy: a prospective, multicenter, double-
duodenal hormones. Metabolism 1978;27:1321-8. blinded, randomized, placebo-controlled trial. J Am Coll
47. Meier R, Dierdorf R, Gyr K. Somatostatin analog Surg 2003;196:556-64; discussion 564-5; author reply 565.
(octreotide) in clinical use: current and potential 50. Suc B, Msika S, Piccinini M, et al. Octreotide in the
indications. Schweiz Med Wochenschr 1992;122:957-68. prevention of intra-abdominal complications following
48. Yeo CJ, Cameron JL, Lillemoe KD, et al. Does elective pancreatic resection: a prospective, multicenter
prophylactic octreotide decrease the rates of randomized controlled trial. Arch Surg 2004;139:288-94;
pancreatic fistula and other complications after discussion 295.
pancreaticoduodenectomy? Results of a prospective 51. Allen PJ, Gönen M, Brennan MF, et al. Pasireotide
randomized placebo-controlled trial. Ann Surg for postoperative pancreatic fistula. N Engl J Med
2000;232:419-29. 2014;370:2014-22.
49. Sarr MG, Pancreatic Surgery Group. The potent
Cite this article as: Schoellhammer HF, Fong Y, Gagandeep

S. Techniques for prevention of pancreatic leak after
pancreatectomy. Hepatobiliary Surg Nutr 2014;3(5):276-287.
doi: 10.3978/j.issn.2304-3881.2014.08.08
Review Article
Robotic liver surgery

Universe Leung1, Yuman Fong2
1
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Department of Surgery, City of Hope Medical Center,
Duarte, CA, USA
Correspondence to: Dr. Yuman Fong. City of Hope Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Email: yfong@coh.org.
Abstract: Robotic surgery is an evolving technology that has been successfully applied to a number of
surgical specialties, but its use in liver surgery has so far been limited. In this review article we discuss the
challenges of minimally invasive liver surgery, the pros and cons of robotics, the evolution of medical robots,
and the potentials in applying this technology to liver surgery. The current data in the literature are also
presented.
Keywords: Robotics; hepatectomy; minimally invasive surgery
doi: 10.3978/j.issn.2304-3881.2014.09.02
Overview of minimally invasive liver surgery such as the lateral sector and wedge resections from the
anteroinferior segments, to major hepatectomies (1).
Liver resection, once regarded as an operation with
However, certain scenarios are still considered prohibitively
prohibitively high mortality and morbidity, has now become
challenging, such the presence of extensive adhesions,
a routine operation in expert hands. As laparoscopic
resection of the caudate or posteriorly placed tumors, and
techniques for other major abdominal operations such as
bile duct resection and reconstruction. In 2008, a panel
splenectomy, colectomy, and fundoplication have matured,
of 45 international experts on laparoscopic liver surgery
the interest in applying minimally invasive techniques to gathered in Louisville, Kentucky to discuss the state of the
liver resection also developed. Technical developments art. There was a consensus that the best indications for
such as more sophisticated energy devices and articulated laparoscopic resection are in patients with solitary lesions,
laparoscopic staplers have enabled surgeons to tackle liver 5 cm or less, located in segments 2 to 6 (2). Of note, the
resection laparoscopically. participants of this consensus conference recommended
Some of the major technical challenges in liver surgery against routine laparoscopic resection of segments 7, 8, 1.
include the difficult access to the vena cava and major This is due to difficulties in visualizing and working in these
hepatic veins, precision required for dissection at the hilum, areas of the liver with straight laparoscopic instruments.
and propensity for the liver to bleed. These are made more Single incision laparoscopic surgery (SILS) has been
difficult with laparoscopy due to the limitations in depth touted as the next stage in minimally invasive surgery with
perception, restricted movement by rigid instruments enhanced cosmesis and possibly recovery compared to
and fixed fulcrum at the ports, unnatural ergonomics, and conventional laparoscopic surgery. Small series of single-
difficult suturing particularly in presence of hemorrhage. port laparoscopic hepatectomy have been published showing
There is a steep learning curve making its practice outside its feasibility (3,4). However, limited views, clashing of
high-volume centers difficult. the surgeons’ hands, “sword-fighting” of instruments
As a result, the uptake of minimally invasive hepatectomy and inability to triangulate remain significant limitations.
has been slow and cautious. But with increasing experience, Attempts have been made to reduce collision by creating
surgeons have gradually increased the difficulty and articulated instruments, however they may need to be used
complexity of surgery, from staging and deroofing cysts cross-handed, an unnatural and un-ergonomical operating
initially, to resecting readily accessible parts of the liver position (5).
in complex surgery is the shorter learning curve compared with

conventional laparoscopy. Port placement is more forgiving as
instruments are not completely restricted by a rigid fulcrum.
Currently complex laparoscopic liver resections are generally
performed by surgeons who are both expert hepatobiliary
surgeons and expert laparoscopic surgeons. Open techniques
are more readily translated to robotics and thus surgeons
who are expert in hepatobiliary but not necessarily advanced
laparoscopy may become proficient quickly.
An inherent imperfection in surgical training is the
need for inexperienced trainees to operate on real patients
while overcoming the learning curve of the procedure, thus
exposing patients to a degree of risk. Robotic surgery lends
itself well to computer based virtual reality training, similar
to how pilots train on flight simulators. Such training systems
have been developed and validated, such as the dV-Trainer
(Mimic Technologies, Inc, Seattle, WA, USA), and the da
Vinci Skills Simulator (Intuitive Surgical, Sunnyvale, CA,
USA). Studies have found that structured training exercises
improved simulator performance, although the translation to
actual surgical performance has not been well studied (6,7).
Figure 1 Typical room setup for a robotic hepatectomy.

Cons of robotic surgery
There are a number of disadvantages with robotic surgery.

The current generation of robots has a large footprint and
Pros of robotic surgery
bulky arms, in addition to the size of the operating console.
Robotic assistance was developed in part to compensate Spacious operating rooms are required, and dexterity is
for some of these limitations. The unfavorable ergonomics limited by collision of robotic arms (Figure 1). A skilled
of rigid laparoscopic instruments are partially overcome assistant is needed for suction, change of instruments,
by articulated ones to mimic the dexterity of the human application of argon plasma, and stapling. There is no
hand. This allows tissue manipulation and suturing in tactile feedback so the retraction pressure on the liver may
small spaces, at angles not possible with rigid instruments, be more difficult to gauge, and suture breakage may be
and facilitates curved transection lines for more complex more common, although experienced surgeons adjust to
resections. Tremor is filtered to allow precise suture it by visually judging the tension on sutures (8). Changing
placement useful for bleeding, and for creating biliary patient position requires the robot to be undocked and
and enteric anastomoses. The surgeon’s motions are redocked, adding time to the procedure and interrupting
scaled so that small, precise movements are effected at the the flow of the operation. The separation of surgeon
patient’s end. Operating via a console allows the surgeon and patient potentially leading to delays in managing
to work sitting down in a comfortable position, and the intraoperative complications and emergent conversion
3-dimensional projection of images partially overcomes can be a source of anxiety for the operating team. Studies
the lack of depth perception. The surgeon is in control have generally shown that robotic surgery take longer time
of the camera, which is mounted on a stable platform, than their laparoscopic counterparts, in part due to time
avoiding poor camera work due to a tired or inexperienced setting up and docking the robot, and time spent changing
assistant. Laparoscopic retractors are also controlled by the instruments (9-11). However, with increasing experience
surgeon and can be locked into position, further avoiding and proficiency this is likely to reduce.
inappropriate or ineffective retraction. The other recent advancements in the field that will
One of the big theoretical advantages of robotic assistance improve accessibility of robotic surgery for liver resection
290 Leung and Fong. Robotic liver surgery review
A B
Figure 2 Flexibility for multi-field robotic surgery for the Intuitive Xi Robot. Without moving the patient, or table, or robotic tower,
the working arms can be turned 180 degrees to swap from right upper quadrant work (A) to pelvic work (B). This will allow combined
hepatectomy and rectal resections.
include the range of new instrumentation that is now service cost of around $110,000, plus cost of disposable
available, including robotic suction devices, sealers, and instruments (15). In a systematic review, Turchetti et al.
staplers. That has eliminated the routine need for accessory analyzed 11 studies in the English literature which
ports and necessity of a skilled bedside assistant. The launch compared the cost of robotic surgery with the laparoscopic
of the Intuitive Xi robot has also allowed ease of multi-field approach for various abdominal operations. The cost of
surgery, and provides great ease in repositioning and re- the robotic approach was generally higher due to increased
docking (Figure 2). This robot is attached to a mobile boom operating time (particularly set-up time) and instruments,
that allows full 180 change in orientation of instruments while the costs of hospital stay were similar (16). However
without moving the patient, or table, or the robot. many studies did not include the purchase and maintenance
Robot malfunction in a variety of general surgical costs which are significant, particularly in lower volume
operations has been reported but appears to be relatively centers. None of the studies in this review evaluated the
uncommon, and rarely lead to significant consequences. potential economic benefits of robotics.
Approximately half of documented malfunction cases were
attributed to robotic instruments and were resolved by
Evolution of robots
replacing the instruments. Other sources of malfunction
included optical systems, robotic arms, and the console. Even though robotics in medicine have only recently caught
Agcaoglu et al. reported 10 cases of robotic malfunction in the attention of the public, the technology is not new. One
223 cases (4.5%), with no adverse outcomes (12). Buchs et al. of the first applications of robotics to modern medicine
reported 18 cases of malfunction in 526 cases (3.4%), with was the Puma 560 in 1985, an industrial robotic arm used
one conversion to laparoscopy due to light source failure (13). by Kwoh et al. to perform stereotactic brain biopsies. In
Kim et al. reported 43 malfunctions in 1,797 cases of general the 1990s, a number of robots were developed, including
and urological operations (2.4%), leading to conversion to the PROBOT at the Imperial College of London for
open in one patient and to laparoscopy in two patients, all transurethral resection of the prostate, the RoboDoc in
due to robotic arm malfunction (14). the USA for femoral coring for hip replacement, and the
One of the major disadvantages of robotic surgery ARTEMIS in Germany, a precursor to the modern master-
is the high cost. The purchase of a da Vinci robot has slave manipulator system. Subsequently the robots used in
been reported to be around US $1.5 million, with annual modern surgery were developed by two initially competing
companies (17,18). lines. As a result, laparoscopically lesions in these segments

One company was Computer Motion Inc based in may be more commonly resected via a right hepatectomy,
California. They were contracted by NASA to develop sacrificing a substantial volume of normal liver (21). Robotic
the AESOP, a voice-activated camera control system that hepatectomy helps overcome this problem and some authors
was compatible with standard 5 and 10 mm endoscopes. have reported success (22). Thus the greatest theoretical
Subsequently the ZEUS robotic system was developed advantage of robotic hepatectomy may lie in sectoral,
and became commercially available in 1998. The system segmental, or subsegmental resections in difficult-to-reach
consisted of a control console and table-mounted robotic positions, where patients may be spared the large incisions
arms incorporating the AESOP camera. In the 1980s, and extensive mobilization required in an open approach. On
the Stanford Research Institute conducted research the other hand, major hepatectomies for malignant conditions
funded by the U.S. Army to develop telesurgery in the where large incisions are required for specimen extraction
battlefield. Interest arose to extend its application to civilian may be better served by a traditional open approach. Difficult
surgery, and in 1995, Intuitive Surgical Inc was founded hepatic resections such as those for hilar cholangiocarcinoma
in California to further develop this technology. In 1999, requiring caudate lobectomy and bile duct anastomoses are
Intuitive Surgical released the da Vinci robot in Europe, generally not performed laparoscopically but the use of a robot
and in 2000 FDA approved its use in the USA. The da may allow these to be approached in a minimally invasive
Vinci robot consists of three parts: a control console, a 3- or manner.
4-armed surgical cart that is docked against the operating Image guided surgery is a developing field where pre-
table, and a vision system. Central to the technology are operative imaging is used to aid intraoperative maneuvers.
a high-definition 3-dimensional viewer, a footswitch to There is considerable experience in applying this
allow the surgeon to swap between camera, retractors, technology to neurosurgery and orthopedic surgery, but
and instrument control, and the Endowrist instruments, there is increasing interest in hepatobiliary surgery (23).
articulated instruments that mimic the seven degrees of Computer models built on CT or MRI are registered
motion of the human hand (18,19). In 2003, Intuitive onto the real-life organs by matching landmarks, which
Surgical and Computer Motion were merged. The ZEUS then allows intra-operative navigation to be guided. The
model was phased out and continued development was need for a computer console in robotic surgery makes it
focused on the da Vinci system, now the only commercially ideal for integration of image-guidance as an adjunct to
available robotic operating system in the world. The second intraoperative ultrasound, creating an augmented reality
generation da Vinci S was released in 2006, and in 2009, where images are superimposed onto the field of view which
the third generation Si model was released with dual- may help surgeons anticipate vascular structures and obtain
console capability and improved vision. In 2014, the fourth adequate margins. This is particularly suited to accurate
generation da Vinci Xi robot was approved by the FDA, probe placement for ablation of small, difficult to localize
with a redesigned surgical arm cart, smaller, longer arms, tumors. Image-guidance technology in hepatobiliary
and new camera system to allow more flexibility in cart surgery is still in its infancy with a number of technical
position and port placement (20). challenges such as deformation correction, and further work
is needed before augmented reality can be realized.
Robotic assistance can potentially overcome some of
Robotic liver surgery
the limitations of SILS, for example by swapping the
The indications for robotic hepatectomy are similar to those hand controls to eliminate cross-handed operating. Early
for laparoscopic hepatectomy. Both benign and malignant experiences with robotic single-port hepatectomy have
tumors can be resected robotically. Patients must have the been reported (24), but the technology will likely have to
physiological reserve to tolerate general anesthesia and a be modified to adapt to the unique challenges of SILS,
prolonged pneumoperitoneum. General contraindications particularly the propensity for the robotic arms to clash
to laparoscopy such as uncorrected coagulopathy should be with each other.
observed. In theory, robotic surgery is an ideal platform for
Laparoscopic hepatectomy for lesions in the superoposterior telesurgery. Indeed that was one of the driving forces
segments such as segment VII and VIII are particularly behind the development of the master-slave robotic system.
challenging due to their positions and the curved transection However, the latency between the surgeon’s movement and
the observed effect due to transmission of data to and back 6.2 days. R0 resection was achieved in 40 patients (93%).
from the patient is a significant limitation. Marescaux et al. Follow-up was relatively short at a median of 14 months.
reported the first transatlantic robot-assisted telesurgery in Six patients recurred within the liver and the 2-year overall
2001, where a robotic cholecystectomy was performed by survival was 94% (10).
surgeons in New York, USA, and the patient in Strasbourg, The hepatopancreatobiliary group at Memorial Sloan
France (25). The authors reported a total time delay of Kettering Cancer Center has performed over 70 robotic
155 ms; however this was performed on a dedicated high- hepatectomies (Kingham P and Fong Y, 2014, unpublished
speed terrestrial optical fibre network. Current satellite- data). Twenty-three percent of patients have had previous
based networks and public-internet based connections are abdominal surgery, including 5 re-operative hepatectomies.
inadequate for the widespread application of telesurgery Median operating time was 164 minutes, estimated blood
over long distances, particularly for complex procedures loss 100 mL, and four patients required conversion to open
with small margins of error (26). (6.1%). There were no mortalities and no re-operations
for complications. The major conclusion derived from this
series is: lesions in segment 1, 7, and 8 can be performed
Current data on robotic liver resection
safely. Unlike the prior series where investigators saw the
Early experiences with using a robot in cholecystectomy goal of robotic hepatectomy as trying to perform major
were reported by Gagner et al. and Himpens et al. hepatectomies, these investigators saw the robot as a means
(27,28). Chan et al. reported their experience with 55 to accomplish resection of ill places minor resections.
robotic HPB procedures, including 27 hepatectomies, 12 For major resections, it is unlikely that robotic resection
pancreatectomies (including 8 Whipple’s), and 16 biliary will change much the usual outcomes of hospital stay or
operations. Their experience with robotic liver resections complications, since the extent of the hepatic resection
for HCC was subsequently also published (29). and not the incision will be the greatest determinant of
The largest series of robotic hepatectomy to date was a outcome. For minor resections of ill placed tumors, the
single-surgeon series published by Giulianotti et al. from the incision usually dominates the clinical outcome. These are
University of Illinois, with 70 patients (60% malignant, 40% likely to be those resections where robotic surgery is likely
benign). Major hepatectomy was performed in 27 patients, to be proven superior. These are also those cases where
including 20 right hepatectomy, 5 left hepatectomy, and expert opinion has recommended against laparoscopic
2 right trisectionectomy. Of note, lesions in segments VII surgery (2). Positioning of patient and the robot has now
and VIII were only attempted if a right hepatectomy was been improved to facilitate safe robotic resection of tumors
performed. Three patients had a bile duct resection with in segments 7 and 8 (Figure 3).
biliary reconstruction, which is considered by most surgeons Few studies have compared robotic to laparoscopic liver
as a contraindication to laparoscopic hepatectomy because resections. Berber et al. found non-different operating time,
of the added complexity of a bile duct anastomosis. The blood loss, and resection margin (31). Ji et al. found that
median operative time was 270 min; for major resection robotic resections may have longer operating times than
it was 313 min, minor resection 198 min, and for biliary laparoscopic or open resections but comparable blood loss
reconstruction 579 min. Major morbidity occurred in four and complications (9). Lai et al. found a similar association
patients, and there were no mortalities. Median surgical for patients undergoing minor hepatectomy (<3 segments)
margin was 18 mm. No survival or oncological outcomes only (10). The largest matched comparison between
were reported (30). laparoscopic and robotic hepatectomy was published by
Lai et al. from Hong Kong reported their experience of Tsung et al. and the University of Pittsburgh group (11).
42 patients with HCC and non-cirrhotic liver or Child- In this retrospective study, 57 patients undergoing robotic
Pugh class A cirrhosis. The type of surgical operation hepatectomy were matched with 114 patients undergoing
included wedge resection in 10 patients, segmentectomy laparoscopic hepatectomy on background liver disease, extent
in 7, bisegmentectomy in 4, left lateral sectionectomy in of resection, diagnosis, ASA class, age, BMI, and gender.
12, right hepatectomy in 7, and left hepatectomy in 3. They found that operating times were significantly longer in
Mean operating time was 229 min and median blood loss the robotic group for both major and minor hepatectomies.
was 413 mL. Three patients developed complications, and There were no significant differences in complication
there were no perioperative deaths. Mean hospital stay was rates, length of stay, mortality, and negative margin rates.
of the technology has been a slow process. In a review article

in 2004, Lanfranco et al. outlined the pros and cons of robotic
surgery at its relative infancy (18). Ten years later we find
ourselves still facing similar limitations. Future directions may
include reducing the size of the robot, modifying the arm
mechanism to reduce clashing, multi-purpose instruments to
reduce the need for frequent instrument exchanges and for
an experienced assistant, development of hepatics to allow
tactile feedback, and integration of image guidance. There is
still skepticism outside the circle of robotic HPB enthusiasts
regarding the wide applicability of this technology. For many
centers the high cost will be a major deterrent. Despite all its
promises, until the benefits are more clearly defined, robotic
liver surgery will likely be practiced by a select group of
surgeons at high-volume centers.
Acknowledgements
Disclosure: The authors declare no conflict of interest.
References
Figure 3 Positioning for robotic hepatectomy for lesions in 1. Cherqui D, Husson E, Hammoud R, et al. Laparoscopic
segment 7 or 8. liver resections: a feasibility study in 30 patients. Ann Surg
2000;232:753-62.
2. Buell JF, Cherqui D, Geller DA, et al. The international
There was a trend towards less blood loss in the robotic position on laparoscopic liver surgery: The Louisville
major hepatectomies compared with laparoscopic major Statement, 2008. Ann Surg 2009;250:825-30.
hepatectomies, which the authors attributed to superior 3. Shetty GS, You YK, Choi HJ, et al. Extending the
inflow and outflow control, as well as magnified optics limitations of liver surgery: outcomes of initial human
allowing better identification of vessels during parenchymal experience in a high-volume center performing single-port
transection. Interestingly for the minor resections, the laparoscopic liver resection for hepatocellular carcinoma.
robotic approach was associated with a significantly higher Surg Endosc 2012;26:1602-8.
blood loss than laparoscopic approach. The authors also 4. Aikawa M, Miyazawa M, Okamoto K, et al. Single-port
noted that conversion to open rates were comparable, and laparoscopic hepatectomy: technique, safety, and feasibility
that patients in the robotic group were more likely to have in a clinical case series. Surg Endosc 2012;26:1696-701.
their surgery performed completely laparoscopically, without 5. Romanelli JR, Earle DB. Single-port laparoscopic surgery:
hand-assistance or a hybrid laparoscopic-open approach an overview. Surg Endosc 2009;23:1419-27.
(93% vs. 49% for the laparoscopic group) (11). 6. Hung AJ, Patil MB, Zehnder P, et al. Concurrent and
predictive validation of a novel robotic surgery simulator: a
prospective, randomized study. J Urol 2012;187:630-7.
Conclusions
7. Korets R, Mues AC, Graversen JA, et al. Validating
Current data show that with good patient selection and the use of the Mimic dV-trainer for robotic surgery
meticulous technique, robotic hepatectomy is a safe and skill acquisition among urology residents. Urology
effective operation that is likely to stay. The goal of robotic 2011;78:1326-30.
assistance is to mimic the techniques of open surgery delivered 8. Giulianotti PC, Coratti A, Angelini M, et al. Robotics in
through a minimally invasive approach. The theoretical general surgery: personal experience in a large community
advantages of robotic surgery are exciting but the evolution hospital. Arch Surg 2003;138:777-84.
9. Ji WB, Wang HG, Zhao ZM, et al. Robotic-assisted davinci_surgical_system/davinci_surgical_system_si/

laparoscopic anatomic hepatectomy in China: initial 21. Cho JY, Han HS, Yoon YS, et al. Feasibility of laparoscopic
experience. Ann Surg 2011;253:342-8. liver resection for tumors located in the posterosuperior
10. Lai EC, Yang GP, Tang CN. Robot-assisted laparoscopic segments of the liver, with a special reference to
liver resection for hepatocellular carcinoma: short-term overcoming current limitations on tumor location. Surgery
outcome. Am J Surg 2013;205:697-702. 2008;144:32-8.
11. Tsung A, Geller DA, Sukato DC, et al. Robotic versus 22. Casciola L, Patriti A, Ceccarelli G, et al. Robot-assisted
laparoscopic hepatectomy: a matched comparison. Ann parenchymal-sparing liver surgery including lesions
Surg 2014;259:549-55. located in the posterosuperior segments. Surg Endosc
12. Agcaoglu O, Aliyev S, Taskin HE, et al. Malfunction 2011;25:3815-24.
and failure of robotic systems during general surgical 23. Kingham TP, Scherer MA, Neese BW, et al. Image-guided
procedures. Surg Endosc 2012;26:3580-3. liver surgery: intraoperative projection of computed
13. Buchs NC, Pugin F, Volontl F, et al. Reliability of robotic tomography images utilizing tracked ultrasound. HPB
system during general surgical procedures in a university (Oxford) 2012;14:594-603.
hospital. Am J Surg 2014;207:84-8. 24. Kandil E, Noureldine SI, Saggi B, et al. Robotic liver
14. Kim WT, Ham WS, Jeong W, et al. Failure and resection: initial experience with three-arm robotic and
malfunction of da Vinci Surgical systems during various single-port robotic technique. JSLS 2013;17:56-62.
robotic surgeries: experience from six departments at a 25. Marescaux J, Leroy J, Gagner M, et al.Transatlantic robot-
single institute. Urology 2009;74:1234-7. assisted telesurgery. Nature 2001;413:379-80.
15. Steinberg PL, Merguerian PA, Bihrle W 3rd, et al. 26. Xu S, Perez M, Yang K, et al. Determination of the latency
A da Vinci robot system can make sense for a mature effects on surgical performance and the acceptable latency
laparoscopic prostatectomy program. JSLS 2008;12:9-12. levels in telesurgery using the dV-Trainer(®) simulator.
16. Turchetti G, Palla I, Pierotti F, et al. Economic evaluation Surg Endosc 2014;28:2569-76.
of da Vinci-assisted robotic surgery: a systematic review. 27. Gagner M, Begin E, Hurteau R, et al. Robotic interactive
Surg Endosc 2012;26:598-606. laparoscopic cholecystectomy. Lancet 1994;343:596-7.
17. Satava RM. Surgical robotics: the early chronicles: a 28. Himpens J, Leman G, Cadiere GB. Telesurgical
personal historical perspective. Surg Laparosc Endosc laparoscopic cholecystectomy. Surg Endosc 1998;12:1091.
Percutan Tech 2002;12:6-16. 29. Chan OC, Tang CN, Lai EC, et al. Robotic hepatobiliary
18. Lanfranco AR, Castellanos AE, Desai JP, et al. Robotic and pancreatic surgery: a cohort study. J Hepatobiliary
surgery: a current perspective. Ann Surg 2004;239:14-21. Pancreat Sci 2011;18:471-80.
19. Yates DR, Vaessen C, Roupret M. From Leonardo to da 30. Giulianotti PC, Coratti A, Sbrana F, et al. Robotic liver
Vinci: the history of robot-assisted surgery in urology. BJU surgery: results for 70 resections. Surgery 2011;149:29-39.
Int 2011;108:1708-13; discussion 1714. 31. Berber E, Akyildiz HY, Aucejo F, et al. Robotic versus
20. Intuitive Surgical. Da Vinci Surgical Si System. Available laparoscopic resection of liver tumours. HPB (Oxford)
online: http://www.intuitivesurgical.com/products/ 2010;12:583-6.
Cite this article as: Leung U, Fong Y. Robotic liver surgery.

j.issn.2304-3881.2014.09.02
Review Article
“Vanishing liver metastases”—A real challenge for liver surgeons

Alex Zendel1, Eylon Lahat2, Yael Dreznik2, Barak Bar Zakai3, Rony Eshkenazy3, Arie Ariche3
1
Department of Surgery C, 2Department of Surgery B, 3Department of HPB Surgery, Chaim Sheba Medical Center, Tel-Hashomer, Sackler School
of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Correspondence to: Arie Ariche. Department of HPB Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel. Email: Arie.ariche@sheba.health.gov.il.
Abstract: Expanded surgical intervention in colorectal liver metastasis (LM) and improved chemotherapy
led to increasing problem of disappearing liver metastases (DLM). Treatment of those continues to evolve
and poses a real challenge for HPB surgeons. This review discusses a clinical approach to DLM, emphasizing
crucial steps in clinical algorithm. Particular issues such as imaging, intraoperative detection and surgical
techniques are addressed. A step-by-step algorithm is suggested.
Keywords: Disappearing liver metastases (DLM); complete pathological response; liver imaging; contrast-
enhanced intraoperative ultrasound (CE-IOUS)
doi: 10.3978/j.issn.2304-3881.2014.09.13
Introduction improvement in chemotherapy treatment, there has been

an increasing evidence of “disappearing” liver metastases
Colorectal cancer (CRC) is one of the most common
(DLM) (27-31). DLM defined as a disappearance of liver
cancers in the world. Advances in treatment have led to a
metastases on cross-sectional imaging after administration
decrease in the death rate for CRC over past two decades (1).
of preoperative chemotherapy, which means a complete
Despite these advances, approximately half of all patients
radiological response. That phenomenon occurs in 5-38%
diagnosed with CRC will develop liver metastasis (LM)
of patients who undergo preoperative systemic therapy
during the course of their disease (2-5). When left untreated,
colorectal LM is rapidly and uniformly fatal with a median (27,29-32). The logic basis behind the decision-making
survival measured in months (6,7). Surgical resection algorithm for DLM built on understanding of correlation
provides the best opportunity for long-term survival and between the complete radiological response and complete
even the chance for cure, and so it is the current paradigm pathological response or durable complete clinical response.
of treatment (8-17). Unfortunately, only 10-25% of patients The complete pathological response defined as an absence
with LM are candidates for surgical resection at the time of residual tumor in the resection specimen. The durable
of presentation (18-20). In patients with unresectable complete clinical response means no recurrence during a
metastases, chemotherapy is the treatment of choice, either satisfactory period of time, when the site of disappearing
as a palliative treatment or in attempt to convert them into lesion in not resected (left in situ). Both are desirable
surgical candidates (21-24). Chemotherapy can also be outcomes promising a chance for cure.
administrated as a neoadjuvant strategy for selected cases In this review we propose a decision-making algorithm
of colorectal LM (23-25). Thus, an increasing number of for management of DLM which discuss step-by-step how to
patients receive chemotherapy prior to liver resection (26,27). improve a clinical approach to DLM, emphasizing upfront
The introduction of new, more effective systemic cytotoxic improvements in imaging, intraoperative detection and
and biologic agents have been an important advance in the surgical techniques.
management of CLM. Tumor response has significantly
improved with modern combination regimens, with up to
DLM prevention—Overtreatment is not advisable
50% response rates for unresectable LM and 20% proceeding
to liver resection with curative intent (28). Along with an The reported risk factors for the occurrence of DLM are:
296 Zendel et al. Vanishing liver metastases
small size of LM (<2 cm), initial number of metastasis (33,40). In that setting the background liver appears
(over 3) and a prolonged preoperative chemotherapy darker, allowing less contrast between the parenchyma
(26,30). Therefore, for those patients selected to receive and the hypovascular metastases, hindering their detection
neoadjuvant treatment for a resectable disease, preoperative (34,41,42).
chemotherapy should be given for a fixed short duration. Several risk factors have been reported causing an
There is no strict evidence for number of cycles to treat. inadequate staging of LM by CT, such as steatosis > 30%,
Van Vledder and colleagues showed that patients with DLM more than 3 LM and lesions smaller than 1 cm (32-34).
received 7.7 cycles of chemotherapy versus 5.5 cycles in Based on this evidence, we assume that all missing
patients without DLM (26). In addition, an 18 % increase in metastases on triple-phase CT should be confirmed by
chance of DLM with each additional cycle of treatment was another imaging modality.
noted. The majority of DLMs arose 3-6 months following
the start of chemotherapy (25). Based on that evidence,
PET-FDG and PET-CT
some writers proposed the numbers of 4-6 cycles (32,33).
After that initial course the clinician should reevaluate the That modality shows high sensitivity, up to 97%, for
patient in order to avoid disappearing and to promptly detecting LM in some series (43,44). Other publications
resect it. It is important to remember, that patients that reported wider range of sensitivities—51-90% (40,45-48).
receive chemotherapy for resectable disease do not need This data reflects several factors, which reduce the sensitivity
to demonstrate objective response, although radiological of FDG uptake, such as small lesions (especially less than
response is a good prognostic factor. As far as conversion 1 cm) and impaired glucose uptake in tumor cells due to
treatment for unresectable disease concerned, it should be chemotherapy (49,50). Nevertheless, some series emphasized
continued until the patient has a resectable disease, not until an important role of PET-FDG, changing the treatment
maximum response (28,33). plan in up to 30-40%, either by finding an extrahepatic
In fact, prolonged chemotherapy can cause liver disease or correctly predicting a complete pathological
toxicity, and thus to disturb the management of LM by response (51,52). In a prospective study of 104 patients
two mechanisms. First, it leads to decreased ability of with CRC, PET-CT revealed unsuspected disease in 19%,
preoperative imaging to detect LM, by increased fatty changed stage in 13.5% and resulted in modified surgery
content (26,33,34). Second, it makes the surgery more in 11.5% (53). As the likelihood of extrahepatic disease
difficult technically, causing an obvious increase in intra and increases along with the degree of liver involvement, PET-
postoperative morbidity (23). CT should be considered as a routine examination in staging
patients prior to surgical resection (34). This is important
when considering extensive surgery to avoid the morbidity
Preoperative imaging—Are the metastases
of futile laparotomies.
missing indeed?
In summary, remaining an important tool in primary
The rate of complete radiological response varies in different staging, PET scan is not a good test for looking at viable
series as much as 4% and 38% (25,26,28,33-37). It can be cancer within the liver after chemotherapy (54).
explained by differences in chemotherapy regimens and
by the quality and competence of preoperative imaging.
MRI
Numbers of modalities are in use to image patients with LM.
MRI appears to be the best hepatic imaging modality,
especially in the setting of chemotherapy-induced steatosis
Computed tomography (CT)
and for small lesions (28,55). Compared with CT, it has
Since its introduction into clinical practice in the 1970s, the better sensitivity and specificity (34). Recent advances
quality and accuracy of CT in detecting LM has continued in MRI techniques, such as diffusion-weighted imaging
to improve, with a sensitivity ranging currently between (DWI) and hepatobiliary contrast agents even strengthen
63% and 90%, and specificity between 85% and 90%, that superiority. DWI is a measure of the ability of water
approaching 100% in some series (26,33,34,38,39). molecules to diffuse freely between tissues and hence
Preoperative chemotherapy can induce parenchymal directly correlates with underlying cellular density.
changes to the liver, defined as steatosis or steatohepatitis Metastases tend to restrict diffusion and the addition of
DWI to the typical liver MRI protocol improves sensitivity preoperative imaging is significantly limited.
and specificity for lesion detection and characterization Using formal laparotomy, all patients with DLM
(56-60). In addition to DWI, hepatobiliary phase MRI should undergo a full liver mobilization, visual inspection,
using liver-specific contrasts has demonstrated improved palpation and finally intraoperative ultrasonography (IOUS).
sensitivity to metastasis detection over routine MRI (61-64). Systematic examination by IOUS can lead to an increase
Examples of such contrast agents are Gadoxetic acid and in the detection of DLM. In the published experience, a
super paramagnetic iron oxide (SPIO). These agents help macroscopic residual disease was observed in as much as 27-
to improve the contrast between hepatocytes and tumor 45% of the patients with DLM by combination of palpation
cells during the late hepatobiliary phase, in which peak and IOUS (25,26,36,37). As mentioned previously, that
parenchymal enhancement happens. frequency was lowered by the use of preoperative MRI
In summary, MRI is an optimal modality to image LM (26,28,36).
missing on CT scan. Moreover, in recent study an inability Contrast-enhanced intraoperative ultrasound (CE-
to observe a DLM on MRI was associated with an increased IOUS) is a novel technique that was proposed in 2004 for
chance for complete pathological or durable clinical both CLM and hepatocellular carcinoma detection. The
response (30). preliminary results were inconclusive for CLM (64-66).
Further investigations showed that it is capable of detecting
a larger proportion of CLM, in comparison with other
Following adequate imaging—Should we always
imaging modalities including IOUS (53,67,68). Arita et al.
operate?
assessed a usefulness of CE-IOUS in identifying DLM (69).
Since no preoperative imaging modality, including MRI, Out of 32 DLM, 4 were identified by IOUS, all confirmed
has a sensitivity of 100%, there is a subset of DLM that as tumor by pathology. Out of remaining 28, 12 we found by
will be found only at the time of surgical exploration. In CE-IOUS, all were resected and a vast majority (11 of 12)
other words, if we do not proceed to surgical exploration consisted of malignancy. The authors concluded that
in setting of DLM even after performing comprehensive CE-IOUS might be necessary for identifying DLM.
imaging, we may leave the tumor behind. So one should Possible factors influencing the surgeon ability to
always consider surgical exploration when feasible, especially discover DLM include the degree of hepatic steatosis,
in presence of DLM risk factors, mentioned previously, the depth of DLM, the location relative to anatomical
such as small and multiple lesions, prolonged chemotherapy landmarks and surgeon skill with IOUS (28,66,70).
and significant chemotherapy induced liver damage. The
literature hasn’t faced the difference between per patient
How to treat missing LM during surgery
versus per metastases approach to exploration. Obviously,
a patient with multiple metastases, which only part of When a surgeon cannot identify DLM during the
them disappeared on imaging, will undergo exploration, operation, he has two options to manage that situation. First
demanding resection of remaining lesions in any case. It is is to treat surgically the site of anatomical location of the
less clear how safe is a possibility to avoid surgery in rare metastases, and check for complete pathological response
patient with completely “clean” post-chemotherapy liver. in pathology regimen. Second, he can leave it in situ. In
Such specific cases should be discussed in a multidisciplinary that scenario the outcome will be assessed by the follow-
team, taking in consideration favorable prognosis in good up imaging, looking for recurrence al the site of DLM.
treatment responders. That fact promotes an aggressive The duration of the follow-up to define a complete clinical
approach with meticulous intraoperative assessment. response is not well defined. According to the fact that the
median time of recurrence is 6-8 months, it is makes sense
to define a durable clinical response as no recurrence at
Intraoperative assessment—Could we do better?
cross-sectional imaging at 1 year (26,28,30).
The role of exploratory laparoscopy as a first step in The literature is not is not convincing when facing the
operative approach to DLM is still being controversial. dilemma of resecting the site of metastasis versus leaving
The main importance of laparoscopy in such cases is it in situ. Several predicting factors for a good correlation
probably to rule out a disseminated peritoneal disease. The between a complete radiological and complete pathological
ability of laparoscopy to identify small lesions missing on response were described. Most significant of them were
initial higher number of LM, more metastases with partial are new software and applications that alleviate determining
response, young patients (<60 years), low initial CEA level surgical planes, evaluating FLR and depicting anatomy (34).
(<30) which normalizes during chemotherapy, small lesions Radiofrequency ablation (RFA) is a gaining momentum
(<3 cm) and an absence of lesion on preoperative MRI alternative for liver lesion resection (72). The idea of
(26,37). Another independent predicting factor was a use of ablating a previously marked site of DLM is promising in
hepatic artery infusion (HAI) therapy (28,36,37). avoiding massive resections. It is timely influencing the
Proponents of aggressive resection present high rates of debate about the necessity of DLM site resection. The
recurrence while left in situ (above 70%) and low rates of problem in analyzing that modality is to compare it to
complete pathological response when resected (20%) (27,28). surgical resections. Unlike in surgical resection, an evidence
van Vledder et al. showed a significant advantage in 3-year for complete response rates can be collected by looking for
intrahepatic recurrence-free survival rates for resection recurrence in follow-up imaging.
versus follow-up group (26). On the other hand, there In spite of its widespread use and noted efficacy, RFA has
was no difference in overall survival (26,27). The possible some limitations. Its dependence on heating of the tissue to
explanation is the fact that about a half of the patients denature proteins means adjacent thermosensitive structures
experience recurrence in any other location, different from such as colon, stomach, bile ducts, gallbladder, and hepatic
the DLM sites or even extrahepatic (33). The aggressive capsule can be damaged resulting in complications, and
biologic nature of disease in those patients may neutralize large vessels within or close to the treatment zone may
the local control of disease by DLM sites resection, thus cause thermal sinks (“heat-sink” effect) that will prevent
moderating overall survival benefit (25,26,33). complete treatment of the target lesion (72,73). Although
From the practical point of view, the decision should there are new thermal technologies such as microwave
be made based on aggressiveness of the disease, the ablation, which may potentially generate a larger ablation
patient condition and operative risk, an ability to treat all zone in a shorter time, they still have the limitations
sites surgically and predictive factors for true complete associated with thermal technologies. These limitations
pathological response as described above. have generated interest in other methods of ablation and
have forced an integration of irreversible electroporation
(IRE) method into treatment options list of hepatic tumors.
Advances in surgeon arsenal—From “blind”
IRE, commercially available as NanoKnife, is a new
hepatectomy to NanoKnife
ablative technology that uses high-voltage, low-energy
When the lesion cannot be identified, incorporation DC current to create nanopores in the cell membrane,
of the original site to hepatectomy or even performing disrupting the homeostasis mechanism and inducing cell
segmental hepatectomy for a DLM site alone should be death by initiating apoptosis (74). Its major advantage is
considered (26). The clear disadvantage of such “blind” the lack of heat-sink effect and the ability to treat zones
hepatectomy technique is an inadequate residual liver near vessels, bile ducts, and critical structures. IRE comes
volume and increased surgical risk. In fact, performing a with its own share of limitations. Human experiences are
major hepatectomy to resect the site of the DLM may not still limited, whereas thermal ablative techniques such as
decrease the recurrence rate (27). On the contrary, the RFA have been time-tested for nearly three decades. The
prognosis could be worsened by reducing the possibility procedure has a learning curve because multiple needle
of second hepatectomy. Along with the general trend of placements are required within a prescribed distance, which
liver sparing in hepatobiliary surgery, in the field of DLM can be challenging, and parallel placement of the probes
technological improvements allow more precise intervention. may be hindered by issues, such as intervening ribs. In
The key point is an exact site location. One option is to addition, this is a very expensive technology. We doubt a
mark the LM with coils using percutaneous interventional routine use of it when dealing with the lesion that is not
radiology techniques (71). Although discussed in the chapter even visible and the need for resection is controversial.
of operative treatment, its real place in decision-making Computer assisted liver surgery can be an elegant way to
algorithm is before starting chemotherapy. One can consider locate and ablate the site of DLM. Indeed, the integration
that tool, when dealing with an aggressive disease, which of the prechemotherapy imaging to the US imaging along
requires prolonged therapy, or when mentioned risk factors with the navigation system can allow the surgeon to locate
for DLM exist. Additional aids to assist in surgical planning and ablate precisely the metastatic site (75).
Neoadjuvant therapy Non resectable
Shrinkage Resectable
Consider MRI as Triple-phase CT

Consider marking first-line modality
when risk factors for DLM
DLM exist
MRI (DWI + HPB)
PET-CT – for
extrahepatic disease DLM
Surgical exploration:
inspection, Metastases
palpation, IOUS
DLM
Consider CE-IOUS
Local site treatment DLM
Segmental “blind”
Resection Ablation/NanoKnife Resection
hepatectomy
Figure 1 Algorithm for clinical approach to DLM. DLM, disappearing liver metastases.
Summary Rectum Cancer page. Available online: http://www.cancer.

org, accessed 4/15/2010.
Our review suggest an algorithm for clinical approach
2. Van Cutsem E, Nordlinger B, Adam R, et al. Towards a
to DLM (Figure 1). The most crucial steps are a
pan-European consensus on the treatment of patients with
comprehensive preoperative imaging, including MRI,
colorectal liver metastases. Eur J Cancer 2006;42:2212-21.
careful surgical exploration, using IOUS and possibly CE-
3. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005.
IOUS, and to be assisted by variety of operative techniques,
CA Cancer J Clin 2005;55:10-30.
such as local ablation of previously marked sites. The
4. Stangl R, Altendorf-Hofmann A, Charnley RM, et al.
algorithm might serve as a helpful tool, but it definitely does
not replace a multidisciplinary team, which should carry Factors influencing the natural history of colorectal liver
out the treatment of such a complicated patients. As the metastases. Lancet 1994;343:1405-10.
technology is improving fast, we look forward for the future 5. Leonard GD, Brenner B, Kemeny NE. Neoadjuvant
improvements. The desirable navigation system may give chemotherapy before liver resection for patients with
an answer for difficulties to locate previous sites of DLM. unresectable liver metastases from colorectal carcinoma. J
Clin Oncol 2005;23:2038-48.
6. Bengmark S, Hafström L. The natural history of primary
Acknowledgements
and secondary malignant tumors of the liver. I. The
Disclosure: The authors declare no conflict of interest. prognosis for patients with hepatic metastases from
colonic and rectal carcinoma by laparotomy. Cancer
1969;23:198-202.
References
7. Bengtsson G, Carlsson G, Hafström L, et al. Natural
1. American Cancer Society. Detailed Guide: Colon and history of patients with untreated liver metastases from
colorectal cancer. Am J Surg 1981;141:586-9. Surg 2004;240:644-57; discussion 657-8.

8. Alberts SR, Poston GJ. Treatment advances in liver- 23. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative
limited metastatic colorectal cancer. Clin Colorectal chemotherapy with FOLFOX4 and surgery versus surgery
Cancer 2011;10:258-65. alone for resectable liver metastases from colorectal cancer
9. Berri RN, Abdalla EK. Curable metastatic colorectal (EORTC Intergroup trial 40983): a randomised controlled
cancer: recommended paradigms. Curr Oncol Rep trial. Lancet 2008;371:1007-16.
2009;11:200-8. 24. Adam R, Wicherts DA, de Haas RJ, et al. Patients with
10. Kopetz S, Vauthey JN. Perioperative chemotherapy for initially unresectable colorectal liver metastases: is there a
resectable hepatic metastases. Lancet 2008;371:963-5. possibility of cure? J Clin Oncol 2009;27:1829-35.
11. Scheele J, Stang R, Altendorf-Hofmann A, et al. Resection 25. Allen PJ, Kemeny N, Jarnagin W, et al. Importance
of colorectal liver metastases. World J Surg 1995;19:59-71. of response to neoadjuvant chemotherapy in patients
12. Fortner JG, Silva JS, Golbey RB, et al. Multivariate undergoing resection of synchronous colorectal liver
analysis of a personal series of 247 consecutive patients metastases. J Gastrointest Surg 2003;7:109-15; discussion
with liver metastases from colorectal cancer. I. Treatment 116-7.
by hepatic resection. Ann Surg 1984;199:306-16. 26. van Vledder MG, de Jong MC, Pawlik TM, et
13. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for al. Disappearing colorectal liver metastases after
colorectal metastases. J Clin Oncol 1997;15:938-46. chemotherapy: should we be concerned? J Gastrointest
14. Hughes KS, Simon R, Songhorabodi S, et al. Resection Surg 2010;14:1691-700.
of the liver for colorectal carcinoma metastases: a multi- 27. Benoist S, Brouquet A, Penna C, et al. Complete response
institutional study of patterns of recurrence. Surgery of colorectal liver metastases after chemotherapy: does it
1986;100:278-84. mean cure? J Clin Oncol 2006;24:3939-45.
15. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical 28. Bischof DA, Clary BM, Maithel SK, et al. Surgical
resection of colorectal carcinoma metastases to the liver. A management of disappearing colorectal liver metastases. Br
prognostic scoring system to improve case selection, based J Surg 2013;100:1414-20.
on 1568 patients. Association Française de Chirurgie. 29. Elias D, Goere D, Boige V, et al. Outcome of
Cancer 1996;77:1254-62. posthepatectomy-missing colorectal liver metastases
16. Fong Y, Fortner J, Sun RL, et al. Clinical score for after complete response to chemotherapy: impact of
predicting recurrence after hepatic resection for metastatic adjuvant intra-arterial hepatic oxaliplatin. Ann Surg Oncol
colorectal cancer: analysis of 1001 consecutive cases. Ann 2007;14:3188-94.
Surg 1999;230:309-18; discussion 318-21. 30. Auer RC, White RR, Kemeny NE, et al. Predictors
17. Figueras J, Valls C, Rafecas A, et al. Resection rate of a true complete response among disappearing liver
and effect of postoperative chemotherapy on survival metastases from colorectal cancer after chemotherapy.
after surgery for colorectal liver metastases. Br J Surg Cancer 2010;116:1502-9.
2001;88:980-5. 31. Lubezky N, Geva R, Shmueli E, et al. Is there a survival
18. Scheele J. Hepatectomy for liver metastases. Br J Surg benefit to neoadjuvant versus adjuvant chemotherapy,
1993;80:274-6. combined with surgery for resectable colorectal liver
19. Petrelli NJ, Abbruzzese J, Mansfield P, et al. Hepatic metastases? World J Surg 2009;33:1028-34.
resection: the last surgical frontier for colorectal cancer. J 32. Thomay AA, Charpentier KP. Optimizing resection
Clin Oncol 2005;23:4475-7. for “responding” hepatic metastases after neoadjuvant
20. Adam R. Chemotherapy and surgery: new perspectives on chemotherapy. J Surg Oncol 2010;102:1002-8.
the treatment of unresectable liver metastases. Ann Oncol 33. Gaujoux S, Goéré D, Dumont F, et al. Complete
2003;14 Suppl 2:ii13-6. radiological response of colorectal liver metastases
21. Meric F, Patt YZ, Curley SA, et al. Surgery after after chemotherapy: what can we expect? Dig Surg
downstaging of unresectable hepatic tumors with intra- 2011;28:114-20.
arterial chemotherapy. Ann Surg Oncol 2000;7:490-5. 34. Fowler KJ, Linehan DC, Menias CO. Colorectal liver
22. Adam R, Delvart V, Pascal G, et al. Rescue surgery for metastases: state of the art imaging. Ann Surg Oncol
unresectable colorectal liver metastases downstaged by 2013;20:1185-93.
chemotherapy: a model to predict long-term survival. Ann 35. Chun YS, Vauthey JN, Ribero D, et al. Systemic
chemotherapy and two-stage hepatectomy for extensive enhanced CT, contrast-enhanced US, superparamagnetic
bilateral colorectal liver metastases: perioperative safety iron oxide-enhanced MRI, and gadoxetic acid-enhanced
and survival. J Gastrointest Surg 2007;11:1498-504; MRI. J Magn Reson Imaging 2011;34:326-35.
discussion 1504-5. 48. Kim YK, Park G, Kim CS, et al. Diagnostic efficacy
36. Elias D, Youssef O, Sideris L, et al. Evolution of missing of gadoxetic acid-enhanced MRI for the detection and
colorectal liver metastases following inductive chemotherapy characterisation of liver metastases: comparison with
and hepatectomy. J Surg Oncol 2004;86:4-9. multidetector-row CT. Br J Radiol 2012;85:539-47.
37. Tanaka K, Takakura H, Takeda K, et al. Importance 49. Fong Y, Saldinger PF, Akhurst T, et al. Utility of 18F-FDG
of complete pathologic response to prehepatectomy positron emission tomography scanning on selection of
chemotherapy in treating colorectal cancer metastases. patients for resection of hepatic colorectal metastases. Am
Ann Surg 2009;250:935-42. J Surg 1999;178:282-7.
38. Kamel IR, Choti MA, Horton KM, et al. Surgically staged 50. Tan MC, Linehan DC, Hawkins WG, et al.
focal liver lesions: accuracy and reproducibility of dual- Chemotherapy-induced normalization of FDG uptake
phase helical CT for detection and characterization. by colorectal liver metastases does not usually indicate
Radiology 2003;227:752-7. complete pathologic response. J Gastrointest Surg
39. Kim YK, Park G, Kim CS, et al. Diagnostic efficacy 2007;11:1112-9.
of gadoxetic acid-enhanced MRI for the detection and 51. Huebner RH, Park KC, Shepherd JE, et al. A meta-
characterisation of liver metastases: comparison with analysis of the literature for whole-body FDG PET
multidetector-row CT. Br J Radiol 2012;85:539-47. detection of recurrent colorectal cancer. J Nucl Med
40. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy- 2000;41:1177-89.
associated hepatotoxicity and surgery for colorectal liver 52. Ruers TJ, Wiering B, van der Sijp JR, et al. Improved
metastases. Br J Surg 2007;94:274-86. selection of patients for hepatic surgery of colorectal liver
41. Oliva MR, Mortele KJ, Segatto E, et al. Computed metastases with (18)F-FDG PET: a randomized study. J
tomography features of nonalcoholic steatohepatitis with Nucl Med 2009;50:1036-41.
histopathologic correlation. J Comput Assist Tomogr 53. Llamas-Elvira JM, Rodríguez-Fernández A, Gutiérrez-
2006;30:37-43. Sáinz J, et al. Fluorine-18 fluorodeoxyglucose PET in the
42. Albrecht T, Blomley MJ, Burns PN, et al. Improved preoperative staging of colorectal cancer. Eur J Nucl Med
detection of hepatic metastases with pulse-inversion US Mol Imaging 2007;34:859-67.
during the liver-specific phase of SHU 508A: multicenter 54. Akhurst T, Kates TJ, Mazumdar M, et al. Recent
study. Radiology 2003;227:361-70. chemotherapy reduces the sensitivity of [18F]
43. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal fluorodeoxyglucose positron emission tomography in
liver metastases: CT, MR imaging, and PET for diagnosis- the detection of colorectal metastases. J Clin Oncol
-meta-analysis. Radiology 2005;237:123-31. 2005;23:8713-6.
44. Kinkel K, Lu Y, Both M, et al. Detection of hepatic 55. Kulemann V, Schima W, Tamandl D, et al. Preoperative
metastases from cancers of the gastrointestinal tract by detection of colorectal liver metastases in fatty liver:
using noninvasive imaging methods (US, CT, MR imaging, MDCT or MRI? Eur J Radiol 2011;79:e1-6.
PET): a meta-analysis. Radiology 2002;224:748-56. 56. Kenis C, Deckers F, De Foer B, et al. Diagnosis of liver
45. Niekel MC, Bipat S, Stoker J. Diagnostic imaging of metastases: can diffusion-weighted imaging (DWI) be used
colorectal liver metastases with CT, MR imaging, FDG as a stand alone sequence? Eur J Radiol 2012;81:1016-23.
PET, and/or FDG PET/CT: a meta-analysis of prospective 57. Taouli B, Sandberg A, Stemmer A, et al. Diffusion-
studies including patients who have not previously weighted imaging of the liver: comparison of navigator
undergone treatment. Radiology 2010;257:674-84. triggered and breathhold acquisitions. J Magn Reson
46. van Kessel CS, Buckens CF, van den Bosch MA, et al. Imaging 2009;30:561-8.
Preoperative imaging of colorectal liver metastases after 58. Bruegel M, Holzapfel K, Gaa J, et al. Characterization
neoadjuvant chemotherapy: a meta-analysis. Ann Surg of focal liver lesions by ADC measurements using
Oncol 2012;19:2805-13. a respiratory triggered diffusion-weighted single-
47. Muhi A, Ichikawa T, Motosugi U, et al. Diagnosis of shot echo-planar MR imaging technique. Eur Radiol
colorectal hepatic metastases: comparison of contrast- 2008;18:477-85.
59. Bruegel M, Gaa J, Waldt S, et al. Diagnosis of hepatic 67. Torzilli G, Del Fabbro D, Palmisano A, et al. Contrast-
metastasis: comparison of respiration-triggered diffusion- enhanced intraoperative ultrasonography during
weighted echo-planar MRI and five t2-weighted hepatectomies for colorectal cancer liver metastases. J
turbo spin-echo sequences. AJR Am J Roentgenol Gastrointest Surg 2005;9:1148-53; discussion 1153-4.
2008;191:1421-9. 68. Takahashi M, Hasegawa K, Arita J, et al. Contrast-
60. Parikh T, Drew SJ, Lee VS, et al. Focal liver lesion enhanced intraoperative ultrasonography using
detection and characterization with diffusion-weighted perfluorobutane microbubbles for the enumeration of
MR imaging: comparison with standard breath-hold T2- colorectal liver metastases. Br J Surg 2012;99:1271-7.
weighted imaging. Radiology 2008;246:812-22. 69. Arita J, Ono Y, Takahashi M, et al. Usefulness of contrast-
61. Holzapfel K, Eiber MJ, Fingerle AA, et al. Detection, enhanced intraoperative ultrasound in identifying
classification, and characterization of focal liver lesions: disappearing liver metastases from colorectal carcinoma
Value of diffusion-weighted MR imaging, gadoxetic acid- after chemotherapy. Ann Surg Oncol 2014;21 Suppl
enhanced MR imaging and the combination of both 3:S390-7.
methods. Abdom Imaging 2012;37:74-82. 70. Takahashi M, Hasegawa K, Arita J, et al. Contrast-
62. Zech CJ, Herrmann KA, Reiser MF, et al. MR imaging enhanced intraoperative ultrasonography using
in patients with suspected liver metastases: value of liver- perfluorobutane microbubbles for the enumeration of
specific contrast agent Gd-EOB-DTPA. Magn Reson Med colorectal liver metastases. Br J Surg 2012;99:1271-7.
Sci 2007;6:43-52. 71. Zalinski S, Abdalla EK, Mahvash A, et al. A marking
63. Hammerstingl R, Huppertz A, Breuer J, et al. Diagnostic technique for intraoperative localization of small liver
efficacy of gadoxetic acid (Primovist)-enhanced MRI and metastases before systemic chemotherapy. Ann Surg Oncol
spiral CT for a therapeutic strategy: comparison with 2009;16:1208-11.
intraoperative and histopathologic findings in focal liver 72. Mahvi DM, Lee FT Jr. Radiofrequency ablation of
lesions. Eur Radiol 2008;18:457-67. hepatic malignancies: is heat better than cold? Ann Surg
64. Leen E, Ceccotti P, Moug SJ, et al. Potential value 1999;230:9-11.
of contrast-enhanced intraoperative ultrasonography 73. Nahum Goldberg S, Dupuy DE. Image-guided
during partial hepatectomy for metastases: an essential radiofrequency tumor ablation: challenges
investigation before resection? Ann Surg 2006;243:236-40. and opportunities--part I. J Vasc Interv Radiol
65. Fioole B, de Haas RJ, Wicherts DA, et al. Additional 2001;12:1021-32.
value of contrast enhanced intraoperative ultrasound for 74. Kingham TP, Karkar AM, D’Angelica MI, et al. Ablation
colorectal liver metastases. Eur J Radiol 2008;67:169-76. of perivascular hepatic malignant tumors with irreversible
66. Torzilli G, Botea F, Donadon M, et al. Criteria for electroporation. J Am Coll Surg 2012;215:379-87.
the selective use of contrast-enhanced intra-operative 75. Sakamoto T. Roles of universal three-dimensional
ultrasound during surgery for colorectal liver metastases. image analysis devices that assist surgical operations. J
HPB (Oxford) 2014. [Epub ahead of print]. Hepatobiliary Pancreat Sci 2014;21:230-4.
Cite this article as: Zendel A, Lahat E, Dreznik Y, Bar Zakai

B, Eshkenazy R, Ariche A. “Vanishing liver metastases”—
A real challenge for liver surgeons. Hepatobiliary Surg Nutr
2014;3(5):295-302. doi: 10.3978/j.issn.2304-3881.2014.09.13
Review Article
Small for size liver remnant following resection: prevention and

management
Rony Eshkenazy1, Yael Dreznik2, Eylon Lahat2, Barak Bar Zakai1, Alex Zendel3, Arie Ariche1
1
Department of HPB Surgery, 2Department of Surgery B, 3Department of Surgery C, Chaim Sheba Medical Center, Tel-Hashomer, Israel
Correspondence to: Dr. Arie Ariche. Department of HPB Surgery, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.
Email: Arie.Ariche@sheba.health.gov.il.
Abstract: In the latest decades an important change was registered in liver surgery, however the
management of liver cirrhosis or small size hepatic remnant still remains a challenge. Currently post-
hepatectomy liver failure (PLF) is the major cause of death after liver resection often associated with
sepsis and ischemia-reperfusion injury (IRI). ‘‘Small-for-size’’ syndrome (SFSS) and PFL have similar
mechanism presenting reduction of liver mass and portal hyper flow beyond a certain threshold. Few
methods are described to prevent both syndromes, in the preoperative, perioperative and postoperative
stages. Additionally to portal vein embolization (PVE), radiological examinations (mainly CT and/or
MRI), and more recently 3D computed tomography are fundamental to quantify the liver volume (LV)
at a preoperative stage. During surgery, in order to limit parenchymal damage and optimize regenerative
capacity, some hepatoprotective measures may be employed, among them: intermittent portal clamping and
hypothermic liver preservation. Regarding the treatment, since PLF is a quite complex disease, it is required
a multi-disciplinary approach, where it management must be undertaken in conjunction with critical care,
hepatology, microbiology and radiology services. The size of the liver cannot be considered the main variable
in the development of liver dysfunction after extended hepatectomies. Additional characteristics should be
taken into account, such as: the future liver remnant; the portal blood flow and pressure and the exploration
of the potential effects of regeneration preconditioning are all promising strategies that could help to expand
the indications and increase the safety of liver surgery.
Keywords: Liver surgery; small for size liver remnant; post-hepatectomy liver failure (PLF); liver resection
Submitted Sep 02, 2014. Accepted for publication Sep 09, 2014.
doi: 10.3978/j.issn.2304-3881.2014.09.08
Introduction function.
The term SFSS was first employed in liver transplantation
In the latest decades an important change was registered in
to describe the development of acute liver failure (ALF)
liver surgery, related to the progress of surgical techniques,
(hyperbilirubinemia, coagulopathy, encephalopathy and
anesthesiology and postoperative treatment, allowing
a sharp decrease in mortality and morbidity. However, refractory ascites) resulted from the transplantation of a
management of liver cirrhosis or small size hepatic remnant donor liver that was too small for a given recipient (2).
still remains a challenge (1). A similar syndrome, called ‘‘post-hepatectomy liver
The liver presents regenerative capacity, allowing failure (PLF)’’ was also described in hepatic surgery
performance of repeated resections. In certain cases, when involving extended resections of liver mass. The last one
this capacity is impaired, or where extensive resections were is characterized by postoperative liver dysfunction, with
performed with small remnant liver, these patients may clinical signs of prolonged cholestasis, coagulopathy, portal
develop small for size syndrome (SFSS) with the presence hypertension and ascites. PLF is the major cause of death
of reduced liver mass insufficient to maintain normal liver after liver resection often associated with sepsis and ischemia-
304 Eshkenazy et al. Small for size liver remnant
reperfusion injury (IRI) (3). alkaline phosphatase, gamma glutamyl transpeptidase,

The patho-physiological mechanisms of the SFSS and prothrombin time (PT) and platelet count;
PLF are very similar, both presenting reduction of liver Quantitative tests, i.e., aminopyrine breath test, antipyrine
mass and portal hyper flow beyond a certain threshold (4). clearance, caffeine clearance, lidocaine clearance, methacetin
The aim of this review is to discuss applicable peri- breath test, galactose elimination capacity, low-dose
operative methods to prevent the SFSS or PLF and highlight galactose clearance, clearance sorbitol, indocyanine green
the main treatment types. disappearance, albumin synthesis, urea synthesis and 99mTc-
GSA;
Scores, i.e., Child-Turcotte-Pugh and MELD.
Pathophysiology
One of the best tests today to check liver function before
The liver should contain minimum amount of parenchymal surgery is liver retention of indocyanine green. Widely used
hepatic cells to assure its functions and the maintenance of since the decade of the 70 in Asian countries, and not yet
its regeneration capacity. The hepatic parenchyma should be widespread in the west.
able to accommodate the hemodynamic changes that occur Based on the decisional tree [established by Seyama et al.
after liver resection, avoiding venous congestion. Factors (Figure 1)] identify before the operation which hepatic
such as decrease of hepatic parenchyma cells, infection and volume can be resected in cirrhotic patients depending on
different causes that might jeopardize regeneration should their liver function (9).
be absent (5).
Decrease in parenchymal volume results in a hyper Liver volume (LV) manipulation and liver parenchymal
perfusion of the liver, causing dilation of sinusoids, protection
hemorrhagic infiltration, shear stress, centro lobular necrosis, The ideal volume of the hepatic remnant was exhaustively
prolonged cholestasis impaired synthetic function and discussed in the literature and some formulas to calculate it
inhibition of cell proliferation (6). were described (10) (Table 1).
Hepatic resections have higher risks of infection The radiological examinations (mainly CT and/or
(above 50%). The number of Kupffer cells after hepatic MRI) before surgery are fundamental to quantify the LV.
resection decreased and thus the liver’s ability to fight More recently 3D computed tomography reconstructions
against infection as well. The sepsis possesses the ability could define more accurately the hepatic volume allowing
to complicate or precipitate PLF. A relative increase in the preoperative studies. Through this exam, the surgeon can
production of endotoxins in the remnant liver is beneficial, simulate a resection, making possible the planning and the
once it activates the Kupffer cells, trigging the liver choice of the best way to do the procedure (15,18).
regeneration. This prolonged state may cause Kupffer’s Measurement of volume ratios correlated with the
cellular dysfunction, resulting in difficulty of regeneration etiology and severity of chronic liver disease (CLD)
and even liver necrosis (7). constitute a reliable predictors of patient survival (19).
The parenchymal damage occurs following vascular Although, the reliability of this ratio might be compromised
occlusion or after hemorrhagic shock, causing IRI. After a by the presence of dilated bile ducts, multiple tumors,
period of ischemia, the complement cascade is triggered, undetected lesions. Additionally, due to cholestasis or
leading to the activation of Kupffer cells, reactive oxygen previous chemotherapy, cholangitis, vascular obstruction,
appearance of species (ROS) and endothelial cell lesion. steatosis or cirrhosis, or segmental atrophy and/or
During reperfusion a release of cytokines, cell adhesion, hypertrophy from tumor growth, negatively impacts the
activation and recruitment of T cell and polymorphonuclear liver function (16).
cell occurs, resulting in microvascular lesion, inflammation Values calculated from graft weight-to-recipient body
and cell death (8). weight ratio (GRBWR), or standardized liver volume
(SLV) based on recipient body surface area (BSA) are used
to predict minimum adequate graft volume (15). But in
Preoperative period-prevention
presence of steatosis, particularly >30%, graft weight alone
Liver function tests and scores (9) is not a suitable guide (10).
The liver function tests can be divided into three types: Extended resection of 80% of functional parenchyma
Conventional tests, i.e., serum bilirubin, albumin, can be performed in the absence of CLD for hepatobiliary
Figure 1 Decisional tree established by Seyama et al. (9).
Table 1 Formulas to calculate volume of the hepatic remnant hepatectomy (16,21). PVE is usually performed percutaneously
2
LV =706.2× BSA (m ) +2.4 (11) by transhepatic PVE, but may also be achieved by surgical
LV =[13 3 height (cm)] + [12 3 weight (kg)] –1530 (12)
ligation and injection of alcohol or others products to prevent
the recanalization of the portal vein. PVE increases the
LV =1072.8× BSA (m2) –345.7 (13)
functional capacity of the liver remnant and can increase
TLV =191.8+18.51× weight (kg) (14)
contralateral lobe volume by up to 20 per cent, with the peak
TLV =–794.41+1267.28× BSA (14)
in growth occurring within 2-4 weeks (22).
VR = (LV from reconstructed CT image/predicted volume) Patients, in which the liver does not have a good
×100 (12) result after PVE are selected as no good candidates for
SFLR = FLR (by CT volumetry) ÷ absolute LV (15) large resections due to the difficulty of regeneration (22).
ERFL = FRL ÷ (TLV – tumour volume) (16) Patients with bilateral tumors when proceeding PVE
ERFL = (resected volume – tumour volume) ÷ (TLV – tumour may stimulate of neoplastic cell growth in the non-
volume) (16) embolized lobes, in this cases surgical treatment or ablation
GRWR = graft weight ÷ recipient body weight (kg) (17) [radiofrequency (23,24), microwave (25) and NanoKnife®
(personal experience)] of such lesions prior to the embolization
are required (26). Neoadjuvant chemotherapy (27)
malignancies (20). Recommended minimal functional and intra-arterial chemotherapy (28) also can be used in
remnant LV following extended hepatectomy is 25% in a combination with PVE to control tumour load before
normal liver, and 40% in a “sick” liver, with moderate to resection (20,29).
severe steatosis, cholestasis, fibrosis, cirrhosis, or following Patients with bilateral liver lesions, where resection is not
chemotherapy (15). feasible under one procedure, the two stage hepatectomy
There are some strategies that allow volume manipulation, is applied, allowing the remaining liver to be resected to
such as portal vein embolization (PVE) and two-stage achieve the suitable LV at the second stage.
Intraoperative period-prevention mainly extra-hepatic location of metastasis in the patient’s

drop-out group. In addition, using PVE in this study
In order to limit parenchymal damage and optimize
yielded sufficient growth in 96.5% of the patients, with
regenerative capacity, two hepatoprotective measures may
median hypertrophy of 62%, comparable to the FLR
be employed: intermittent portal clamping and hypothermic
hypertrophy rates associated with the ALLPS approach (38).
liver preservation.
Although none of the studies published with this
Intermittent portal clamping with intervals allowed for
technique provide measurements of portal pressure
reperfusion is preferred to continuous clamping, usually
or portal blood flow, the clinical data suggest that the
applying a 15-min clamp-5-min release regimen (30-32).
acceleration of the hypertrophy of the residual parenchyma
Total vascular exclusion of the liver should be used when
occurs due to the reduction of intra-hepatic communicants,
we have no choice to do the resection without it. When
once the in situ split procedure leads to complete portal
chosen, we can utilized hepatic vascular exclusion with
devascularization of segment 4, preventing formation of
preservation of the caval flow (33).
collaterals between the left and the right liver that could
Hypothermic liver preservation in conjunction with total
otherwise undermine the completeness of right portal vein
vascular exclusion attenuates IRI. The future remnant is
infused with a preservative fluid and surrounded by crushed occlusion alone (41).
ice to maintain the liver at 4 ℃. This approach is a useful A second and not mutually exclusive explanation would
adjunct to complex resections when total vascular exclusion be the ‘‘regenerating liver’’ hypothesis proposed by Nagano
and vascular reconstructions are programmed (34). During et al. (42).
surgery it is still possible to apply techniques to prevent the
SFSS, if other procedures were not considered on the pre- Modulation of portal pressure
operative period. Intraoperative Doppler ultrasonography has been used
in combination with hepatic portal inflow modulation to
Association liver partition and portal vein ligation detect and offset hyperperfusion in a small-for-size graft.
(ALPPS) Importantly, numerous interventions that modulate the portal
ALPPS, a newer strategy to increase resectability of hepatic blood flow have been shown to prevent the development of
malignancies, has been described for the first time in 2010 (35). the SFSS in experimental models, such as: the performance
This method relies on the fact (proved in clinical trials) that of a portocaval anastomosis (43,44), the ligation of the splenic
any closure of portal branch will be followed by a reactive artery (45), banding of the portal vein (46) or the infusion
perfusion through intrahepatic branches and collaterals of adenosine (47), somatostatin (48), pentoxifylline (49) or
present between two lobes. Hence, partition of the liver endothelin-1 (50). It is important to highlight that the role
along the falciform ligament line, for example, will enhance for inflow modulation at the time of major liver resection or
regeneration compared to traditional methods. ALPPS as a salvage therapy in humans remains undefined.
has shown high hypertrophy rates compared to PVE/PVL After all these studies cited above we can conclude
(40% to 80% within a week compared to 8% to 27% within that the development of SFSS or PLF are not strictly
2 to 60 days by PVL/PVE), however it is associated with determined by the ‘‘size’’ of the liver graft or remnant. It is
high morbidity rates (16-64% of patients) and mortality determined by the hemodynamic parameters of the hepatic
rates (12-23% of patients), therefore a careful selection of circulation and, specifically, by a portal blood flow that,
surgical candidates should be done prior to surgery. Further when excessive for the volume of the liver parenchyma
investigation if ALPPS approach accelerates tumor growth leads to over-pressure, sinusoidal endothelial denudation
is still required (35-37). and hemorrhage. Perisinusoidal and periportal hemorrhage
Recently, a number of comparisons between ALLPS occurs in the first minutes after an extended hepatic
and standard methods (PVE followed by liver resections) resection as well as after the reperfusion of a small graft,
have been published (38-40). One of the proposed benefits while arterial vasoconstriction and ischemic cholangitis are
of ALLPS, for example, is rapid removal of tumor(s), thus observed at later stages (6).
preventing patient dropout due to disease progression of Also, experimental and clinical studies consistently show
existing liver tumors. This assumption, however, failed that an increased portal blood flow relative to the weight of
to achieve clinical relevance in a recent publication that the liver results in an inverse relationship between portal
compared right PVE + segment 4 to ALPPS, demonstrating and arterial blood flows that is known as the arterio-portal
buffer (51). The arterio-portal buffer occurs when the portal disciplinary approach, where it management must be
blood flow increases, the adenosine concentration in the undertaken in conjunction with critical care, hepatology,
space of mall decreases leading to arterial vasoconstriction microbiology and radiology services (1).
and decrease of arterial blood flow, which is responsible for After liver resection, clinical and laboratory assessment
the late damage (52). should be proceeded. Normally, the level of serum bilirubin
Studies performed in patients undergoing liver and the INR rises in the first 48-72 h after resection. It is
transplantation in which the portal and hepatic arterial possible to identify liver dysfunction, whenever bilirubin
blood flows were measured intra-operatively have provided concentration is above 50 µmol/L (3 mg/dL) or INR greater
further insights into the pathophysiology of the SFSS than 1.7 beyond 5 days of surgery (3). The most sensitive
(6,53,54). A portal blood flow of 300 mL/min/100 g was variable is serum bilirubin as predictor of outcome in PLF (62).
established by Jiang et al. as the threshold above that the PT and INR are also relevant, but the interpretation may be
incidence of the SFSS increases significantly (54). compromised if patients have received clotting factors.
In living donor liver transplantations involving grafts Serum albumin, although an indicator of hepatic
with GWRW below 0.8, Troisi et al. showed that the synthetic function, will vary in response to inflammation
construction of a portal-systemic shunt whenever the portal and administration of intravenous fluids (63,64). Increased
blood flow exceeded 250 mL/min/100 g was able to prevent levels of liver enzymes are common after liver resection and
the histological alterations characteristic of the SFSS and to do not predict outcome (3).
improve the overall patient and graft survival (43,54). Ascites and hepatic encephalopathy are important
Several studies indicate that additionally to blood flow, markers for liver failure, although it may be difficult to
portal pressure can also be considered a good parameter for assess in the immediate postoperative period. The first
predicting the failure of the graft. For example, patients with occurs as a result of surgery (portal hypertension, dissection,
a portal pressure higher than 20 mmHg show a decrease gross fluid overload), while the second is a result of mental
from 85% to 38% in their 6-month survival (55). Yagi et al. state as collateral effect of drugs such as opiates (62).
also described that a portal pressure above 20 mmHg was Several studies assessed the role of postoperative
associated with the development of ascites, coagulopathy functional of the liver. This task still consist a challenge,
and hyperbilirubinemia as well as with an early hypertrophy once the ICGR15 is capable to predicts PLF (65), but its
of the graft, higher values of hepatocyte growth factor value diminishes once liver failure is established, since the
(HGF) and diminished levels of vascular epithelial growth changes in hepatic blood flow impacts ICGR15. In the
factor (VEGF), suggesting that an increased portal pressure absence of controlled trials for PLF, management relies on
also influences liver regeneration (56). Kaido et al. reported data from experience with ALF, secondary to paracetamol
their experience with small grafts (GWRW of 0.6) in toxicity (66-68).
combination with portal pressure control (targeting final The pattern of organ dysfunction that occurs as a result
portal pressures below 15 mmHg), showing that the survival of PLF is similar to that in sepsis (1). Once the following
of recipients of small grafts and standard-size grafts was symptoms occur: cardiovascular failure, characterized by
similar and that the portal pressure control strategy resulted reduced systemic vascular resistance and capillary leak;
in a decreased rate of complications in the donors (57). acute lung injury, due to pulmonary edema and acute
As in liver transplantation, studies involving extended respiratory distress syndrome may ensue and acute kidney
hepatic resections also indicate that the increased portal injury can progress rapidly in PLF. In those cases, fluid
blood flow with diminished residual parenchyma are balance should be managed judiciously with avoidance
a critical factor determining the development of PLF of salt and water overload (64). Identifying and treating
(47,58,59). The performance of a portocaval anastomosis underlying sepsis is key in managing patients with PLF.
in a patient with liver cirrhosis undergoing a major Sepsis may exacerbate PLF, and bacterial infection is
hepatectomy effectively prevented the syndrome, probably present in 80 per cent of patients with PLF (69) and in 90
by reducing shear stress and damage to the sinusoids (60). per cent of those with ALF (70).
Therefore, any acute deterioration should be attributed
to sepsis until proven otherwise. Management of sepsis
Post-operative period-treatment (61)
should be in accordance with the surviving sepsis
PLF is a quite complex disease, that requires a multi- guidelines (71). A trial of prophylactic antibiotics after liver
resection failed to show a reduction in liver dysfunction the development of PLF. In these rare cases of inflow
or infective complications (72). A study of ALF have and outflow thrombosis with PLF, a decision must be
shown that prophylactic antibiotics reduce infections, but taken regarding the benefit of surgical or radiological
the impact on a long-term outcome is inconclusive (70). thrombectomy or dissolution versus anticoagulation (80,81).
In critically ill patients with PLF, chest radiography and The use of terlipressin also can reduce the portal venous
cultures of blood, urine, sputum and drain site/ascitic pressure helping to hepatic regeneration (82). Cerebral
fluid should be performed (68). Current guidelines for edema and intracranial hypertension may occur as a result
ALF propose that broad-spectrum antibiotics should be of PLF. It is unlikely in patients with grade 1 or 2 of liver
administered empirically to patients with progression to encephalopathy. When achieving grade 3 encephalopathy,
grade 3 or 4 of hepatic encephalopathy, renal failure and/ a head CT should be performed to exclude intracranial
or worsening SIRS parameters (68). hemorrhage or other causes of declining mental status.
Additionally coagulopathy may occur transiently In patients with established ALF and encephalopathy,
after major resection and is found in all patients with enteral lactulose might prevent or treat cerebral edema,
PLF. As in ALF, coagulation parameters can be used although the benefits remain unproven. Progression to
to chart the progress of PLF, provided blood products grade 3/4 encephalopathy warrants ventilation and may
have not been given. In the absence of bleeding it is not require intracranial pressure monitoring (68).
necessary to correct clotting abnormalities, except for The concept of hepatocyte transplantation has been
invasive procedures or when coagulopathy is severe. investigated as a strategy to boost residual liver function.
The level at which a coagulopathy should be corrected Intrahepatic hepatocyte transplantation (83) has been used
before an interventional procedure in ALF has yet to be successfully to treat patients with metabolic disorders of the
defined (66,68,73). Vitamin K may be given, but this is liver. However, results in liver failure (including patients
not supported by clinical trials (66). Thrombocytopenia with PLF) have been poor due to insufficient delivery of
may complicate liver failure (74). Indications for functional cells. The potential for stem cell therapies has
platelet transfusion in ALF include bleeding, severe yet to be established (84).
thrombocytopenia (less than 20×10 6 /L), or when an The use of salvage hepatectomy and orthotopic liver
invasive procedure is planned. A platelet count above transplantation for PLF has been reported in seven
70×106/L is deemed safe for interventional procedures (75). patients who underwent liver resection for cancer (85).
Recombinant factor VIIa (rFVIIa) has been used to Although the indications for transplantation in this study
treat coagulopathy in patients with ALF (76). In a large were questionable, overall 1-year (88 per cent) and 5-year
controlled trial of rFVIIa following major liver resection, (40 per cent) survival rates were promising.
no reduction in bleeding events was observed (77). Its role Extracorporeal liver support (ELS) devices fall into two
in PLF is yet to be defined. categories: artificial and bioartificial systems. Artificial
Gastrointestinal hemorrhage is a recognized complication devices use combinations of haemodialysis and adsorption
of liver failure. In ALF, H2-receptor blockers and proton over charcoal or albumin to detoxify plasma. Bioartificial
pump inhibitors (PPIs) reduce gastrointestinal ill patients devices use human or xenogenic hepatocytes maintained
ensuring euglycemia improves survival and reduces within a bioreactor to detoxify and provide synthetic
morbidity (78). function. These systems have not been evaluated extensively
The role of imaging in PLF is to assess hepatic blood in patients with PLF. A recent meta-analysis and systematic
flow, identify reversible causes of liver failure and locate review showed that ELS may improve survival in patients
sites of infection. Hepatic blood flow can be evaluated with ALF, but not acute-on-chronic liver failure, in
using non-invasive imaging. Doppler ultrasonography comparison with standard medical therapy (86).
may identify portal vein, hepatic artery and hepatic vein
thrombosis. Contrast CT or MRI can be used to establish
Conclusions
hepatic blood flow, provide more details of vascular
abnormalities and identify sites of infection. If patency of The increased use of small liver grafts and the expansion
hepatic vessels is still in doubt on cross-sectional imaging, of indications of curative liver surgery in patients with
angiography is the “gold standard” (79). hepatic tumors allows a step change in the knowledge of the
Portal vein thrombosis has also been implicated in mechanisms responsible for the development of the SFSS
and PLF. Hepatology 1995;21:1317-21.

It became evident that the size of the liver cannot be 12. Lin XZ, Sun Y, Liu Y, et al. Liver volume in patients with
considered the main variable in the development of liver or without chronic liver diseases. Hepatogastroenterology
dysfunction after extended hepatectomies. Additional 1998;45:1069-74.
characteristics should be taken into account, such as: the 13. Heinemann A, Wischhusen F, Püschel K, et al. Standard
future liver remnant; the portal blood flow and pressure liver volume in the Caucasian population. Liver Transpl
and the exploration of the potential effects of regeneration Surg 1999;5:366-8.
preconditioning are all promising strategies that could help 14. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface
to expand the indications and increase the safety of liver area and body weight predict total liver volume in Western
surgery. adults. Liver Transpl 2002;8:233-40.
15. Vauthey JN, Chaoui A, Do KA, et al. Standardized
measurement of the future liver remnant prior to extended
Acknowledgements
liver resection: methodology and clinical associations.
Disclosure: The authors declare no conflict of interest. Surgery 2000;127:512-9.
16. Azoulay D, Castaing D, Smail A, et al. Resection of
nonresectable liver metastases from colorectal cancer
References
after percutaneous portal vein embolization. Ann Surg
1. van den Broek MA, Olde Damink SW, Dejong CH, et 2000;231:480-6.
al. Liver failure after partial hepatic resection: definition, 17. Abdalla EK, Denys A, Chevalier P, et al. Total and
pathophysiology, risk factors and treatment. Liver Int segmental liver volume variations: implications for liver
2008;28:767-80. surgery. Surgery 2004;135:404-10.
2. Ikegami T, Shimada M, Imura S, et al. Current concept of 18. Mise Y, Tani K, Aoki T, et al. Virtual liver resection:
small-for-size grafts in living donor liver transplantation. computer-assisted operation planning using a three-
Surg Today 2008;38:971-82. dimensional liver representation. J Hepatobiliary Pancreat
3. Balzan S, Belghiti J, Farges O, et al. The 50-50 Criteria on Sci 2013;20:157-64.
Postoperative Day 5. Ann Surg 2005;242:824-8, discussion 19. Zhou XP, Lu T, Wei Y, et al. Liver volume variation in
828-9. patients with virus-induced cirrhosis: findings on MDCT.
4. Asencio JM, Vaquero J, Olmedilla L, et al. “Small-for-flow” AJR Am J Roentgenol 2007;189:W153-9.
syndrome: shifting the “size” paradigm. Med Hypotheses 20. Abdalla EK, Barnett CC, Doherty D, et al. Extended
2013;80:573-7. hepatectomy in patients with hepatobiliary malignancies
5. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. with and without preoperative portal vein embolization.
Hepatology 2006;43:S45-53. Arch Surg 2002;137:675-80; discussion 680-1.
6. Demetris AJ, Kelly DM, Eghtesad B, et al. 21. Adam R, Laurent A, Azoulay D, et al. Two-stage
Pathophysiologic Observations and Histopathologic hepatectomy: A planned strategy to treat irresectable liver
Recognition of the Portal Hyperperfusion or Small-for- tumors. Ann Surg 2000;232:777-85.
size-syndrome. Am J Surg Pathol 2006;30:986-93. 22. Farges O, Belghiti J. Portal Vein Embolization Before
7. Panis Y, McMullan DM, Emond JC. Progressive necrosis Right Hepatectomy Prospective clinical trial. Ann Surg
after hepatectomy and the pathophysiology of liver failure 2003;237:208-17.
after massive resection. Surgery 1997;121:142-9. 23. Elias D, Santoro R, Ouellet J. Simultaneous percutaneous
8. Jaeschke H. Molecular mechanisms of hepatic ischemia- right portal vein embolization and left liver tumor
reperfusion injury and preconditioning. Am J Physiol radiofrequency ablation prior to a major right
Gastrointest Liver Physiol 2003;284:G15-26. hepatic resection for bilateral colorectal metastases.
9. Seyama Y, Kokudo N. Assessment of liver function for safe Hepatogastroenterology 2004;51:1788.
hepatic resection. Hepatol Res 2009;39:107-16. 24. Akgül Ö, Çetinkaya E, Ersöz Ş, et al. Role of surgery in
10. Tucker ON, Heaton N. The “small for size” liver colorectal cancer liver metastases. World J Gastroenterol
syndrome. Curr Opin Crit Care 2005;11:150-5. 2014;20:6113-22.
11. Urata K, Kawasaki S, Matsunami H. Calculation of child 25. Bala MM, Riemsma RP, Wolff R, et al. Microwave
and adult standard liver volume for liver transplantation. coagulation for liver metastases. Cochrane Database Syst
Rev 2013;10:CD010163. remnant volume including a comparison to the ALPPS

26. Hoekstra LT, van Lienden KP, Doets A, et al. Tumor approach. J Am Coll Surg 2014;217:126-33; discussion
progression after preoperative portal vein embolization. 133-4.
Ann Surg 2012;256:812-7; discussion 817-8. 39. Tschuor Ch, Croome KP, Sergeant G, et al. Salvage
27. Adam R, Delvart V, Pascal G, et al. Rescue Surgery for parenchymal liver transection for patients with
Unresectable Colorectal Liver Metastases Downstaged by insufficient volume increase after portal vein occlusion --
Chemotherapy. A model to predict long term survival. Ann an extension of the ALPPS approach. Eur J Surg Oncol
Surg 2004;240:644-57. 2013;39:1230-5.
28. Selzner N, Pestalozzi BC, Kadry Z, et al. Downstaging 40. Schadde E, Ardiles V, Slankamenac K, et al. ALPPS
colorectal liver metastases by concomitant unilateral portal offers a better chance of complete resection in patients
vein ligation and selective intra-arterial chemotherapy. Br with primarily unresectable liver tumors compared with
J Surg 2006;93:587-92. conventional-staged hepatectomies: results of a multicenter
29. Wicherts DA, Miller R, de Haas RJ, et al. Long-Term analysis. World J Surg 2014;38:1510-9.
Results of Two-Stage Hepatectomy for Irresectable 41. Chan A, Chung PH, Poon RT. Little girl who conquered
Colorectal Cancer Liver Metastases. Ann Surg the “ALPPS”. World J Gastroenterol 2014;20:10208-11.
2008;248:994-1005. 42. Nagano Y, Nagahori K, Kamiyama M, et al. Improved
30. Brooks AJ, Hammond JS, Girling K, et al. The effect of functional reserve of hypertrophied contra lateral liver
hepatic vascular inflow occlusion on liver tissue pH, carbon after portal vein ligation in rats. J Hepatol 2002;37:72-7.
dioxide, and oxygen partial pressures: defining the optimal 43. Troisi R, Ricciardi S, Smeets P, et al. Effects of hemi-
clamp/release regime for intermittent portal clamping. J portocaval shunts for inflow modulation on the outcome of
Surg Res 2007;141:247-51. small-for-size grafts in living donor liver transplantation.
31. Belghiti J, Noun R, Malafosse R. Continuous Versus Am J Transplant 2005;5:1397-404.
Intermittent Portal Triad Clamping for Liver Resection. A 44. Takada Y, Ueda M, Ishikawa Y, et al. End-to-side
Controlled study. Ann Surg 1999;229:369-75. portocaval shunting for a small-for-size graft in living
32. Belghiti J, Noun R, Zante E. Portal Triad Clamping or donor liver transplantation. Liver Transpl 2004;10:807-10.
Hepatic Vascular Exclusion for Major Liver Resection. A 45. Luca A, Miraglia R, Caruso S. Effects of splenic artery
controlled study. Ann Surg 1996;224:155-61. occlusion on portal pressure in patients with cirrhosis and
33. Cherqui D, Malassagne B, Colau P. Hepatic Vascular portal hypertension. Liver Transpl 2006;12:1237-43.
Exclusion With Preservation of the Caval Flow for Liver 46. Reyal J, Uemoto S. Percutaneously adjustable portal vein
Resections. Ann Surg 1999;230:24-30. banding device could prevent post-operative liver failure-
34. Azoulay D, Eshkenazy R, Andreani P, et al. In situ -artificial control of portal venous flow is the key to a new
hypothermic perfusion of the liver versus standard total therapeutic world. Med Hypotheses 2009;73:640-50.
vascular exclusion for complex liver resection. Ann Surg 47. Kelly DM, Zhu X, Shiba H, et al. Adenosine restores the
2005;241:277-85. hepatic artery buffer response and improves survival in a
35. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right porcine model of small-for-size syndrome. Liver Transpl
portal vein ligation combined with in situ splitting induces 2009;15:1448-57.
rapid left lateral liver lobe hypertrophy enabling 2-staged 48. Matrella E, Valatas V, Notas G, et al. Bolus somatostatin
extended right hepatic resection in small-for-size settings. but not octreotide reduces hepatic sinusoidal pressure by
Ann Surg 2012;255:405-14. a NO-independent mechanism in chronic liver disease.
36. Andriani OC. Long-term results with associating liver Aliment Pharmacol Ther 2001;15:857-64.
partition and portal vein ligation for staged hepatectomy 49. Tian Y, Jochum W. Kupffer cell-dependent TNF- signaling
(ALPPS). Ann Surg 2012;256:e5; author reply e16-9. mediates injury in the arterialized small-for-size liver
37. de Santibañes E, Clavien PA. Playing Play-Doh to prevent transplantation in the mouse. PNAS 2006;103:4598-603.
postoperative liver failure: the “ALPPS” approach. Ann 50. Kawachi S, Shimazu M. Efficacy of intraportal infusion
Surg 2012;255:415-7. of prostaglandin E1 to improve the hepatic blood flow
38. Shindoh J, Vauthey JN, Zimmitti G, et al. Analysis of and graft viability in porcine liver transplantation.
the efficacy of portal vein embolization for patients with Transplantation 1997;64:205-9.
extensive liver malignancy and very low future liver 51. Eipel C. Regulation of hepatic blood flow: The hepatic
arterial buffer response revisited. World J Gastroenterol 64. Varadhan KK, Lobo DN. A meta-analysis of randomised
2010;16:6046. controlled trials of intravenous fluid therapy in major
52. Fondevila C, Hessheimer A. Portal hyperperfusion: elective open abdominal surgery: getting the balance right.
Mechanism of injury and stimulus for regeneration in Proc Nutr Soc 2010;69:488-98.
porcine small-for-size transplantation. Liver Transpl 65. de Liguori Carino N, O’Reilly DA, Dajani K, et al.
2010;16:364-74. Perioperative use of the LiMON method of indocyanine
53. Troisi R, de Hemptinne B. Clinical relevance of adapting green elimination measurement for the prediction and
portal vein flow in living donor liver transplantation in early detection of post-hepatectomy liver failure. Eur J
adult patients. Liver Transpl 2003;9:S36-41. Surg Oncol 2009;35:957-62.
54. Jiang SM, Zhou G, Zhang R. Role of splanchnic 66. Polson J, Lee WM. AASLD position paper: the
hemodynamics in liver regeneration after living donor management of acute liver failure. Hepatology
liver transplantation. Liver Transpl 2009;15:1043-9. 2005;41:1179-97.
55. Boillot O, Delafosse B, Méchet I, et al. Small-for-size 67. Jalan R. Acute liver failure: current management and
partial liver graft in an adult recipient; a new transplant future prospects. J Hepatol 2005;42 Suppl:S115-23.
technique. Lancet 2002;359:406-7. 68. Stravitz RT, Kramer DJ. Management of acute liver
56. Yagi S, Iida T, Hori T, et al. Optimal portal venous failure. Nat Rev Gastroenterol Hepatol 2009;6:542-53.
circulation for liver graft function after living-donor liver 69. Schindl MJ, Redhead DN, Fearon KCH, et al. The
transplantation. Transplantation 2006;81:373-8. value of residual liver volume as a predictor of hepatic
57. Kaido T, Mori A, Ogura Y, et al. Lower limit of the graft- dysfunction and infection after major liver resection. Gut
to-recipient weight ratio can be safely reduced to 0.6% 2005;54:289-96.
in adult-to-adult living donor liver transplantation in 70. Rolando N, Gimson A, Wade J. Prospective controlled
combination with portal pressure control. Transplant Proc trial of selective parenteral and enteral antimicrobial
2011;43:2391-3. regimen in fulminant liver failure. Hepatology
58. Hessheimer AJ, Fondevila C, Taurá P, et al. Decompression 1993;17:196-201.
of the portal bed and twice-baseline portal inflow are 71. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis
necessary for the functional recovery of a “small-for-size” Campaign: international guidelines for management of
graft. Ann Surg 2011;253:1201-10. severe sepsis and septic shock, 2012. Intensive Care Med
59. Farantos C, Arkadopoulos N, Theodoraki K, et al. Effect 2013;39:165-228.
of the portacaval shunt on reperfusion injury after 65% 72. Wu CC, Yeh DC, Lin MC, et al. Prospective randomized
hepatectomy in pigs. Eur Surg Res 2008;40:347-53. trial of systemic antibiotics in patients undergoing liver
60. Polacco M, Vitale A, Valmasoni M, et al. Liver resection resection. Br J Surg 1998;85:489-93.
associated with mini porto-caval shunt as salvage treatment 73. O’Shaughnessy DF, Atterbury C, Bolton Maggs P,
in patients with progression of hepatocellular carcinoma et al. Guidelines for the use of fresh-frozen plasma,
before liver transplantation: a case report. Transplant Proc cryoprecipitate and cryosupernatant. Br J Haematol
2010;42:1378-80. 2004;126:11-28.
61. Hammond JS, Guha IN, Beckingham IJ, et al. Prediction, 74. Schiødt FV, Balko J, Schilsky M, et al. Thrombopoietin in
prevention and management of postresection liver failure. acute liver failure. Hepatology 2003;37:558-61.
Br J Surg 2011;98:1188-200. 75. Drews RE, Weinberger S. Thrombocytopenic disorders
62. Mullen JT, Ribero D, Reddy SK, et al. Hepatic in critically ill patients. Am J Respir Crit Care Med
insufficiency and mortality in 1,059 noncirrhotic 2000;162:347-51.
patients undergoing major hepatectomy. J Am Coll Surg 76. Shami VM, Caldwell SH, Hespenheide EE, et al.
2007;204:854-62; discussion 862-4. Recombinant activated factor VII for coagulopathy in
63. Lobo DN, Stanga Z, Aloysius MM, et al. Effect of volume fulminant hepatic failure compared with conventional
loading with 1 liter intravenous infusions of 0.9% saline, therapy. Liver Transpl 2003;9:138-43.
4% succinylated gelatine (Gelofusine) and 6% hydroxyethyl 77. Lodge JP, Jonas S. Recombinant coagulation factor VIIa
starch (Voluven) on blood volume and endocrine responses: in major liver resection: a randomized, placebo-controlled,
a randomized, three-way crossover study in healthy double-blind clinical trial. Anesthesiology 2005;102:269-75.
volunteers. Crit Care Med 2010;38:464-70. 78. van Den Berghe G. Intensive insulin therapy in critically
ill patients. N Engl J Med 2001;345:1359-67. hepatectomy. Transplantation 2014;97:892-900.

79. DeLeve LD, Valla DC, Garcia-Tsao G. Vascular disorders 83. Fox IJ, Roy-Chowdhury J. Hepatocyte transplantation. J
of the liver. Hepatology 2009;49:1729-64. Hepatol 2004;40:878-86.
80. Adani GL, Baccarani U, Risaliti A, et al. Percutaneous 84. Stutchfield BM, Forbes S, Wigmore S. Prospects for stem
transhepatic portography for the treatment of early portal cell transplantation in the treatment of hepatic disease.
vein thrombosis after surgery. Cardiovasc Intervent Radiol Liver Transpl 2010;16:827-36.
2007;30:1222-6. 85. Otsuka Y, Duffy J, Saab S. Postresection hepatic failure:
81. Ozeki Y, Umemoto T. Partial portal arterialization successful treatment with liver transplantation. Liver
for dearterialized liver after hepatectomy. Br J Surg Transpl 2007;13:672-9.
1997;84:1011. 86. Stutchfield BM, Simpson K, Wigmore SJ. Systematic
82. Fahrner R, Patsenker E, de Gottardi A, et al. Elevated liver review and meta-analysis of survival following
regeneration in response to pharmacological reduction of extracorporeal liver support. Br J Surg 2011;98:623-31.
elevated portal venous pressure by terlipressin after partial
Cite this article as: Eshkenazy R, Dreznik Y, Lahat E, Bar Zakai

B, Zendel A, Ariche A. Small for size liver remnant following
resection: prevention and management. Hepatobiliary Surg Nutr
2014;3(5):303-312. doi: 10.3978/j.issn.2304-3881.2014.09.08
Review Article
The laparoscopic liver resections—an initial experience and the

literature review
Mislav Rakić, Leonardo Patrlj, Robert Kliček, Mario Kopljar, Antonija Đuzel, Kristijan Čupurdija, Željko
Bušić
Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka Šuška 6, 10000 Zagreb, Croatia
Correspondence to: Mislav Rakić, MD. Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka Šuška 6,
10000 Zagreb, Croatia. Email: mrakic@kbd.hr.
Abstract: The laparoscopic liver resection (LLR) represents a new pathway in hepatic surgery. Several
studies have reported its application in both malignant and benign liver diseases. The most common liver
resections performed laparoscopically are wedge, segmental resections and metastasectomy; although in
large centers the laparoscopic right and left hepatectomies have begun to perform more frequently. We
report the initial experience in LLRs at our department including a case of the first laparoscopic left lateral
liver bisegmentectomy performed in patient with follicular nodular hyperplasia and the 15 cases of wedge
laparoscopic resections of echinococcic liver cysts. According to literature the mortality rate in LLRs is up to
0.3% and morbidity rate up to 10.5%. The most common cause of the death is liver failure, while the most
frequent complication is the bile leakage. Advantages for patients include smaller incisions, less blood loss,
and shorter lengths of hospital stay. The LLRs in experienced hands were shown to be safe with acceptable
morbidity and mortality for both minor and major hepatic resections in benign and malignant diseases.
Keywords: Laparoscopic liver resection (LLR); segmental resections; left lateral bisegmentectomy; liver
echinococcic cyst laparoscopic treatment
doi: 10.3978/j.issn.2304-3881.2014.09.10
In general, liver surgery has seen significant advances in the At first the indications limited to easily accessible tumors
last decades, particularly associated with improvements in mostly placed at the peripheral portion of liver, the
anesthesia and critical care as well as surgical techniques. anterolateral segments (II, III, V, VI and the inferior part
The improved understanding of the vascular anatomy of the of IV liver segment) (6,7). The majority of initial reports
liver based on Couinaud segments, has also led to a great suggested that LLR is poorly indicated when the lesion
reduction in morbidity and mortality associated with liver is located in the posterior or superior part of the liver
resection (1). (segments I, VII and VIII, the same as the superior part of
Clearly challenging, the laparoscopic liver resections segment IV) (8,9).
(LLRs) were not accepted until recently due to the several The indications for LLRs widened from solitary, small,
reasons: the problem of intraoperative bleeding control, the easily approachable lesions, to more demanding procedures
technical difficulties, the learning curve and the fear of gas including the major liver resections such as left and right
embolism (2). Since the first reported cases of liver resection hepatectomies (10-14). The disease-related indications for
in 1991 and 1992 (3,4), more than 3,000 cases have been LLRs included various conditions of benign, but also the
reported in literature worldwide. malignant diseases especially the hepatocellular carcinoma
In general, LLR is associated with significant advantages: and colorectal liver metastases (15-21).
faster recovery, less post-operative pain, less morbidity, In our department the laparoscopic surgical procedures
easier subsequent surgery and better cosmetic results (5). are widespread. The laparoscopic cholecystectomies
314 Rakić et al. Laparoscopic liver resection
Figure 1 Magnetic resonance imaging (MRI) record of the operated patient with focal nodular hyperplasia (FNH). The tumor located in
segments II and III of the liver, shown with black arrows.
reports of laparoscopic operations of the echinococcic cysts

performed in our institution (1,10,11).
Through this paper we aim to report our initial
experience in laparoscopic liver surgery with the emphasis
on the first left lateral bisegmentectomy and to show a brief
literature review onto the main problems and concems
concerning the LLRs.
Report of a case
A 29 years old female patient was admitted to hospital

for operative therapy of a liver tumor found on a
magnetic resonance imaging (MRI) scan preformed as
gastroenterological workup for symptoms related to chronic
gastritis (Figure 1). There were no co-morbidities other
than mild ankylosing spondylitis and the general clinical
state was proper to the age of the patient. According to
Figure 2 Resected tumor along with the segment II and III of MRI record the tumor was situated at the left hepatic
liver. lobe and its diameters were 62×57 mm. There were no
other tumors found inside of the abdominal and thoracic
cavity. The patient underwent the laparoscopic left
and appendectomies are performed routinely and have lateral bisegmentectomy of the 2nd and 3rd liver segments
outnumbered the open cholecystectomies and appendectomies (Figure 2). The resection was performed throe three skin
that are done only in a narrow spectrum of indications. Apart incisions (Figure 3), using the harmonic scalpel and the
from that the explorations, the ulcer perforation and hernia vascular structures were ligated by the endoscopic vascular
repair are performed laparoscopically, as well. During last staplers (35 and 45 mm). The operation lasted for an hour.
10 years the elective splenectomies and colon resections are The patient spent a day in intensive care unit (ICU). There
performed laparoscopically in the high number of cases. were no any early complication found and the patient
On the other hand, more than 100 open liver resections was released home on the third postoperative day. The
are performed per year. The experience in laparoscopic pathology of the resected tumor had shown the follicular
surgery and open liver surgery encouraged our surgeons nodular hyperplasia. The consequent perioperative period
to start performing LLRs. There have already been some passed without complications.
history with comparable morbidity and mortality to those

in open surgical procedures (12). LLRs were concluded to
be comparable or even better than open liver resection in
the context of intraoperative blood loss and the length of
hospital stay (13). A similar or lower mortality (0.3%) and
morbidity (10.5%) were reported at LLR in comparison to
open operative technique of the liver resection (14). There
was no significant difference in overall and disease-free
5-year survival rate for hepatocellular carcinoma between
open and laparoscopic hepatectomies (15). The conversion
Figure 3 Postoperative skin incisions.
rates vary from 8.1% to 17.6% and the reported rate of
complications was 3.6% with the postoperative bile leakage
rate of 1.1% in 27 analyzed studies that included 619
patients (16).
Report of laparoscopically treated patients with
echinococcic liver disease
Conclusions
In our institution 15 laparoscopic pericistectomies were
performed to date. All patients were pre-operatively treated In our initial experience of operated patients the performed
with albendazole. Total pericystectomy without opening the laparoscopic surgical procedures were found safe and efficient
cyst cavity was performed laparoscopically in seven patients, with the acceptable operative time and hospital stay. The
while the partials pericystectomy was done laparoscopically data found in literature are encouraging, however the proper
five patients. In another three patients the procedure surgical training and experience the same as well technically
started laparoscopically but were converted and completed equipped centers are essential for performing LLRs.
as an open procedure. The median operative time was
67.5 minutes (range, 60.0-120.0 minutes) and the median
Acknowledgements
hospital stay 5.0 days (range, 4.0-7.0 days). In one patient
the echinococcic cyst was situated in 7th liver segment and Disclosure: The authors declare no conflict of interest.
another three cysts were found intraabdominaly. All of them
were removed laparoscopically. There were no complication
References
nor recurrences reported until now in laparoscopically
operated patients. During the same period of time 32 1. Busić Z, Lemac D, Stipancić I, et al. Surgical treatment of
patients underwent the open operation of the echinococcic liver echinococcosis--the role of laparoscopy. Acta Chir
liver cysts. In those patients the operation lasted longer [mean Belg 2006;106:688-91.
operative time 100.0 minutes (range, 60.0-210.0 minutes)]. 2. Cai X, Li Z, Zhang Y, et al. Laparoscopic liver resection
On the other hand, the hospital stay was longer in patient and the learning curve: a 14-year, single-center experience.
that underwent the open surgical procedure [median hospital Surg Endosc 2014;28:1334-41.
stay 8.0 days (range, 7.0-14.0 days)]. Also there was one case 3. Reich H, McGlynn F, DeCaprio J, et al. Laparoscopic
of recurrence in patient treated with the open procedure excision of benign liver lesions. Obstet Gynecol
3 years following the operation. There was no mortality 1991;78:956-8.
reported until now in both groups of patients. 4. Gagner M, Rheault M, Dubuc J. Laparoscopic partial
hepatectomy for liver tumor [abstract]. Surg Endosc
1992;6:99.
Discussion
5. Tranchart H, Dagher I. Laparoscopic liver resection: a
As the experience and technical improvement grow the review. J Visc Surg 2014;151:107-15.
spectrum of indications expands. According to recently 6. Gigot JF, Glineur D, Santiago Azagra J, et al. Laparoscopic
published study the LLR can be performed safely in selected liver resection for malignant liver tumors: preliminary
patients with both benign and malignant liver tumors results of a multicenter European study. Ann Surg
regardless to the dimensions, location or previous operating 2002;236:90-7.
316 Rakić et al. Laparoscopic liver resection
7. Kaneko H, Takagi S, Shiba T. Laparoscopic partial of laparoscopic liver resection-2,804 patients. Ann Surg
hepatectomy and left lateral segmentectomy: technique 2009;250:831-41.
and results of a clinical series. Surgery 1996;120:468-75. 15. Kaneko H, Takagi S, Otsuka Y, et al. Laparoscopic
8. Laurent A, Cherqui D, Lesurtel M, et al. Laparoscopic liver resection of hepatocellular carcinoma. Am J Surg
liver resection for subcapsular hepatocellular carcinoma 2005;189:190-4.
complicating chronic liver disease. Arch Surg 16. Laurence JM, Lam VW, Langcake ME, et al. Laparoscopic
2003;138:763-9; discussion 769. hepatectomy, a systematic review. ANZ J Surg
9. Dulucq JL, Wintringer P, Stabilini C, et al. Laparoscopic 2007;77:948-53.
liver resections: a single center experience. Surg Endosc 17. Jurisić I, Paradzik MT, Jurić D, et al. National program
2005;19:886-91. of colorectal carcinoma early detection in Brod-Posavina
10. Busić Z, Cupurdija K, Servis D, et al. Surgical treatment of County (east Croatia). Coll Antropol 2013;37:1223-7.
liver echinococcosis--open or laparoscopic surgery? Coll 18. Milas J, Samardzić S, Miskulin M. Neoplasms (C00-D48)
Antropol 2012;36:1363-6. in Osijek-Baranja County from 2001 to 2006, Croatia.
11. Busić Z, Lovrić Z, Kolovrat M, et al. Laparoscopic Coll Antropol 2013;37:1209-22.
operation of hepatic hydatid cyst with intraabdominal 19. Samardzić S, Mihaljević S, Dmitrović B, et al. First six
dissemination--a case report and literature review. Coll years of implementing colorectal cancer screening in the
Antropol 2009;33 Suppl 2:181-3. Osijek-Baranja County, Croatia--can we do better? Coll
12. Han HS, Yoon YS, Cho JY, et al. Laparoscopic liver Antropol 2013;37:913-8.
resection for hepatocellular carcinoma: korean experiences. 20. Boras Z, Kondza G, Sisljagić V, et al. Prognostic factors
Liver Cancer 2013;2:25-30. of local recurrence and survival after curative rectal cancer
13. Simillis C, Constantinides VA, Tekkis PP, et al. surgery: a single institution experience. Coll Antropol
Laparoscopic versus open hepatic resections for benign 2012;36:1355-61.
and malignant neoplasms--a meta-analysis. Surgery 21. Krebs B, Kozelj M, Potrc S. Rectal cancer treatment and
2007;141:203-11. survival--comparison of two 5-year time intervals. Coll
14. Nguyen KT, Gamblin TC, Geller DA. World review Antropol 2012;36:419-23.
Cite this article as: Rakić M, Patrlj L, Kliček R, Kopljar

M, Đuzel A, Čupurdija K, Bušić Ž. The laparoscopic liver
resections—an initial experience and the literature review.
j.issn.2304-3881.2014.09.10
Review Article
Complications after percutaneous ablation of liver tumors: a

systematic review
Eylon Lahat1, Rony Eshkenazy2, Alex Zendel3, Barak Bar Zakai2, Mayan Maor2, Yael Dreznik1, Arie
Ariche2
1
Department of Surgery B, 2Department of HPB Surgery, 3Department of Surgery C, Chaim Sheba Medical Center, Tel-Hashomer, Sackler School
of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Correspondence to: Dr. Arie Ariche, MD. Department of HPB Surgery, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, 52621, Israel.
Email: Arie.Ariche@sheba.health.gov.il.
Background: Although ablation therapy has been accepted as a promising and safe technique for treatment
of unrespectable hepatic tumors, investigation of its complications has been limited. A physician who
performs ablation treatment of hepatic malignancies should be aware of the broad spectrum of complications.
Proper management is possible only if the physician Performing ablation understands the broad spectrum of
complications encountered after ablation.
Objectives: To systematically review the complications after different ablation modalities: Radiofrequency
ablation (RFA), microwave ablation (MWA) and Nano knife for the treatment of liver tumors and analyze
possible risk factors that precipitate these complications.
Search methods: We performed electronic searches in the following databases: MEDLINE, EMBASE
and COCHARNE. Current trials were identified through the Internet (from January 1, 2000 to January 1,
2014). We included only studies who specific mentioned complications after liver ablation therapy (RFA/
MWA/Nano knife).
Main results: A total of 2,588 publications were identified, after detailed examination only 32 publications
were included in the review. The included studies involved 15,744 participants. According to the type of
technique, 13,044 and 2,700 patients were included for RFA and MWA. Analysis showed a pooled mortality
of 0.15% for RFA, and 0.23% for MWA.
Conclusions: This systematic review gathers information from controlled clinical trials and observational
studies which are vulnerable to different types of bias, never the less RFA and MWA can be considered safe
techniques for the treatment of liver tumors.
Keywords: Liver tumors; liver metastases; percutaneous ablation; systematic review
doi: 10.3978/j.issn.2304-3881.2014.09.07
Introduction of the lesions that often occurs in a background of chronic

liver disease, bad liver function, and deteriorating general
Hepatocellular carcinoma (HCC) and colorectal liver
condition (2,3).
metastases (CLM) are the two most common malignant liver Several alternative treatments to control and potentially
tumors. Hepatic resection (HR) is the only curative option, cure have been developed for use in patients with malignant
but only 15-20% of patients with liver metastases from CRC liver tumors, whether primary or metastatic. Interventional
(CRLMs) are suitable for surgical standard treatment (1). therapies, such as percutaneous ethanol injection (PEI),
For the HCC group, less than 30% of patients with HCC radiofrequency ablation (RFA), microwave ablation (MWA)
are eligible for surgery, mainly because of the multiplicity and Nano knife has been developed for treating malignant
318 Lahat et al. Percutaneous ablation of liver tumors
liver tumors. Search strategy

RFA has gained wide acceptance by showing superior
A literature search was conducted on PubMed and
anticancer effects with low complications and mortality
EMBASE to identify clinical series of RFA, MWA and
rate. Recently other emerging techniques such as MWA
Nano knife procedures for liver tumours published between
have attracted interest in clinical practice (4). However,
January 2000 and January 2014. Letters to the editors,
these procedures will always entail some risks. Information
supplements, review articles and case reports were excluded.
regarding mortality and complications is absolutely essential
The titles and abstracts of all potentially relevant trials
for every intervention to permit an accurate assessment of
were screened by one reviewer (LE). The full text articles
the risks and benefits (5).
of potentially relevant studies were obtained. Based on
One of the greatest persistent problems in hepatic
the full text article, another reviewer (HA) independently
ablation has been the inability to establish quality standards
determined whether the study meets the inclusion/exclusion
in ablation complications, success, local recurrence after
criteria.
ablation, and nonablation hepatic recurrence. Reports from
the literature are heterogeneous because of the study design,
sample size, different technical approaches, and number of Data collection
centers reporting complications and non-uniform terms
Information extracted from each study included: the number
as well as different parameters to calculate the rate of
of patients, age and Child-Pugh score. The type of study
complications (6-9).
were categorized as prospective, retrospective, observational
Major complications were defined as any symptom
or randomized trial and the type of intervention included
that developed after ablation and persisted for more
RFA/MWA, the tumor according to type (HCC or
than 1 week, or those that delayed hospital discharge,
metastasis). We extracted the data type for outcome
threatened the patient’s life, or led to substantial morbidity
measure using number of deaths, major complications
and disability (10). Major complication: included death,
and the description of the type of percutaneous ablative
hemorrhage, RFA needle-track seeding, intra hepatic
technique used.
arterial pseudo aneurysm, RFA lesion abscess, perforation of
gastrointestinal viscus, liver failure, biloma, biliary stricture,
portal vein thrombosis, and hemothorax or pneumothorax Assessment of complications
requiring drainage, and minor complications including pain,
In this study complications were reported in accordance
fever, and asymptomatic pleural effusion.
with the guidelines recommended by the Working Group
Our goal was to bring the most updated literature
on Image-Guided Tumor Ablation (10).
regarding current used techniques (“what we really do”).
The definition of major complication is an event that
The use of PEI has become less favorable in the face of new
leads to substantial morbidity and disability, increasing the
modalities such MWA and Nano knife, hence we decided to
level of care, or results in hospital admission or substantially
remove this technique from this review.
lengthened hospital stay (SIR classifications C-E) (Table 1).
Ablation can be done either percutaneous or by surgery,
This includes any case in which a blood transfusion or
in order to minimize bias related to surgery we decided to
interventional drainage procedure is required. All other
include only papers with percutaneous technique.
complications are considered minor. It is important to stress
that several complications, such as pneumothorax or tumor
Materials and methods seeding, can be either a major or minor complications.
Inclusion criteria
Results
Randomized controlled trials (RCTs) and nonrandomized
comparative studies assessing HCC or CRLM treated with The search on Medline and EMBASE databases provided
RFA, MWA or Nano knife treatment were considered a total of 2,588 citations (Figure 1). After screening title
for review. Only patients aged over 18 were included. In and abstract, 2,461 were discarded. The full text of the
order to exclude small studies, we only considered studies remaining 127 citations was examined in more detail, where
analyzing more than 50 patients for at least one technique. 95 studies did not meet the inclusion criteria as described.
Table 1 Procedure-related complication classification

Category I
No therapy, no consequence or adverse sequelae
Category II
Requires unplanned increase in level of care to a nominal degree, minimal consequence or adverse sequelae
Category III
Requires unplanned increase in level of care to intermediate degree, intermediate adverse sequelae, includes overnight
admission for observation only and minor hospitalization
Category IV
Requires unplanned increase in level of care to major degree, major adverse sequelae, prolonged hospitalization (>48 h)
Category V
Death directly or indirectly related to procedure
Print with authorization from publisher: John Wiley and Sons, License number: 3461161445472.
Records identified using mortality and complications were primary outcomes.

PubMed/EMBASE search
N=2,588
Specific outcomes
Excluded records
N=32 Death and adverse events were assessed as secondary
Records examined in detail outcomes in 16 studies. Mean follow-up after treatment
for eligibility ranged from 10 to 137 months. For all percutaneous
N=127 ablative techniques analyzed, mortality ranged from 0%
Excluded records failing to
to 0.88% and the pooled proportion was 0.16% (95%
meet inclusion criteria
CI, 0.10-0.24%) by the random effects model. Individual
Studies included in the N=32
analysis showed a pooled mortality of 0.15% for RFA, and
systematic review
0.23% for MWA.
N=32
Major complication rates were 4.1% and 4.6% for RFA
and MWA respectively.
Figure 1 Study flow diagram.
The most frequent major complication was hemorrhage
i n t r a p e r i t o n e a l , s u b c a p s u l a r, p l e u r a l , b i l i a r y a n d
retroperitoneal hemorrhage requiring blood transfusion
Finally 32 publications were included in the review. (Table 3). Meanwhile the minor complication rates were
5.9% and 5.7% for RFA and MWA. There was no
statistically significant difference in the mortality rates,
Characteristics
major complications, and minor complications between the
Study design, participants and interventions RFA and MWA groups (P>0.05).
Of the 32 studies selected for the review, one was
randomized trials and 31 were observational studies (Table 2).
Discussion
All the reports were published after 2000 (n=32). There
were 29 studies using RFA only and 2 using MWA only. Ablation techniques have gained wide acceptance as a safe
One observational study evaluated RFA versus MWA. alternative to surgery in the management of early HCC and
The included studies involved 15,744 participants. metastatic liver tumors (43,44).
According to the type of technique, 13,044 and 2,700 The effectiveness of RFA in the treatment of malignant
patients were included for RFA and MWA respectively. The liver tumors has been proven by a number of clinical
average age of patients ranged from 24 to 89 years. Mean studies and medical practice reports (45-48). Recently,
tumor size treated ranged from 1.8 to 5.0 cm. In 16 studies, developments in MWA technology have demonstrated its
Table 2 Baseline characteristics of studies included

Patients Child-Pugh class Tumor number Mean tumor
First author Country Year Age (years) Intervention
(N) A B C HCC Mets. size (cm)
Randomised trials
Shibata (11) Japan 2006 74 65 [41-83] 55 19 83 – 1.9 RFA
Observational studies
Livraghi (12) Italy 2000 114 64 [53-86] 100 14 – 126 – 5.4 RFA
Buscarini (13) Italy 2001 88 68 56 29 1 101 – NA RFA
Livraghi (14) Italy 2003 2,320 NA NA NA NA NA – 3.1 RFA
Guglielmi (15) Italy 2003 53 68 [48-88] 24 29 – 65 – 4 RFA
Rhim (16) Korea 2003 1,139 NA NA NA NA 1,303 360 NA RFA
Ruzzenente (17) Italy 2004 87 68 [41-88] 48 39 – 104 – 3.9 RFA
Gillams (18) Italy 2004 167 57 [34-87] – – – – 685 3.9 RFA
Chen (19) China 2004 110 24-78 26 38 5 74 47 4.7 RFA
Lu (20) US 2005 52 57 19 29 4 87 – 2.5 RFA
Lu (21) China 2005 102 RFA: 54 [20-74]; 69 33 – 170 – RFA: 2.6; RFA;
MWA: 50 [24-74] MWA: 2.5 MWA
Raut (22) US, Italy 2005 140 39-86 59 46 35 190 – 3 RFA
Chen (23) China 2005 338 24-87 96 95 13 430 333 NA RFA
Cabassa (24) Italy 2006 59 72 [47-88] 51 8 – 68 – 3.1 RFA
Solmi (25) Italy 2006 56 68 [45-81] 16 37 3 63 – 2.8 RFA
Choi (26) Korea 2007 102 54 [31-73] 77 10 – 119 – 2 RFA
Poggi (27) Italy 2007 250 63 NA NA NA NA NA 2.9 RFA
Choi (28) Korea 2007 570 58 359 160 – 674 – 2.5 RFA
Livraghi (29) Italy 2008 218 68 NA NA NA 218 – NA RFA
Kondo (30) Japan 2008 2,480 NA NA NA NA NA – NA RFA
Zavaglia (31) Italy 2008 63 58 46 13 4 71 – NA RFA
Chen (32) Taiwan 2008 104 58.6 [28-82] NA NA NA NA NA 3.9 RFA
Casaril (33) UK 2008 130 65 [33-85] 70 20 2 145 94 2.7 RFA
Sartori (34) Italy 2008 181 60 [36-85] NA NA NA 180 181 NA RFA
Gillams (35) UK 2008 309 64 [24-92] – – – – NA 3.7 RFA
Liang (36) China 2009 1,136 54 [23-83] 227 852 57 1,385 516 3.3 MWA
Solbiati (37) Italy 2012 99 65±11.8 NA NA NA – 202 2.2±1.1 –
Yu (38) China 2011 1,462 55±11.7 447 942 73 1102 331 3.3±1.9 MWA
Kondo (39) Japan 2010 589 68.4 396 B/C 151 – – 2.42-2.73 RFA
Chang (40) Korea 2010 2,630 61 NA NA NA – – 2.2 RFA
Francica (41) Italy 2012 365 67±8 277 86 – – – 2.3 RFA
Lee (42) Korea 2012 102 59.3±1 66 36 – 139 – 2.5±0.1 RFA
Age recorded as mean ± SD or median [range]. NA, not available; RFA, radio frequency ablation; MWA, microwave ablation; HCC,
hepatocellular carcinoma.
Table 3 Major complications of radiofrequency ablation (RFA) Prospective studies may report more accurately the
and microwave ablation (MWA) number of participants lost to follow-up, the timing of
Intra-peritoneal bleeding collecting complications and the adequate predefined
Portal vein thrombosis
definitions for harms.
It is well understood that the risk of complications can
Intra-hepatic hematomas
be reduced by proficiency in technique and refinement in
Bile leak
pretreatment assessments.
Biloma
There are several strategies for decreasing complications
Bile duct injury after ablation of hepatic tumors (51). The first key strategy
Liver dysfunction is prevention by not to perform ablation in patients at high
Liver abscess risk, meticulous pre evaluation of candidates should be
Intestinal perforation performed, especially in regard to coagulopathy, underlying
Diaphragmatic hernia hepatic reserve, and tumor proximity to major structures
Hemothorax such as the bile duct or intestine. In a patient with
Intractable pleural effusion correctable coagulopathy, ablation should be postponed
Tumour implantation
until all parameters are corrected.
Early detection cannot reduce the frequency of
complications such as infection or bleeding, but it can
unique advantage (49,50). Although we intended to include potentially minimize their clinical magnitude. Thus,
Nano knife in our review there are no publications up to the operator and other medical personnel should be
now that met our inclusion criteria and a solid conclusion knowledgeable about the spectrum of various complications
could not be excreted. after ablation because complications can be detected even
Post ablation complications such as liver failure, during the procedure in some cases. Close immediate
intraperitoneal bleeding, abscess, bile duct injury, tumor follow-up with clinical and laboratory data is also essential
seeding are very serious, and can be life threatening (51,52), for early detection of complications.
other complication can prolonged hospitalization and
increase morbidity. Being well aware of the complications
Acknowledgements
and the choice of treatment method will lead to a more
practical application and enable this procedure to be safer Disclosure: The authors declare no conflict of interest.
and more effective.
The results without heterogeneity show a mortality of
References
0.15% and 0.23% for RFA and MWA, respectively. The
prevalence of major complications in the reported studies 1. Vanagas T, Gulbinas A, Pundzius J, et al. Radiofrequency
ranged from 1.52% to 4.7%, calculated by using a random ablation of liver tumors (I): biological background.
effects model in the presence of significant heterogeneity, Medicina (Kaunas) 2010;46:13-7.
were 4.1% for RFA and 4.6% for MWA. 2. Verslype C, Van Cutsem E, Dicato M, et al. The
MWA-associated mortality was reported to occur in management of hepatocellular carcinoma. Current expert
0.002% according to a systematic review of this technique (53). opinion and recommendations derived from the 10th
Major complication rates have been reported to be higher World Congress on Gastrointestinal Cancer, Barcelona,
with MWA than with RFA in a randomized trial. Our 2008. Ann Oncol 2009;20 Suppl 7:vii1-vii6.
results indicated that MWA is a safe technique in terms 3. Zhu AX. Molecularly targeted therapy for advanced
of mortality and major complication rate. However, the hepatocellular carcinoma in 2012: current status and future
results should be interpreted with caution and more reports perspectives. Semin Oncol 2012;39:493-502.
including large number of patients are needed to make a 4. Lencioni R. Loco-regional treatment of hepatocellular
solid conclusion. carcinoma. Hepatology 2010;52:762-73.
The difference between the reported complication rates 5. Lencioni R, Crocetti L, De Simone P, et al. Loco-regional
can be explained by several factors: single/multicenter interventional treatment of hepatocellular carcinoma:
studies, prospective/retrospective studies. techniques, outcomes, and future prospects. Transpl Int
2010;23:698-703. application in 110 patients--mathematic model,

6. Curley SA, Marra P, Beaty K, et al. Early and late overlapping mode, and electrode placement process.
complications after radiofrequency ablation of malignant Radiology 2004;232:260-71.
liver tumors in 608 patients. Ann Surg 2004;239:450-8. 20. Lu DS, Yu NC, Raman SS, et al. Percutaneous
7. de Baère T, Risse O, Kuoch V, et al. Adverse events during radiofrequency ablation of hepatocellular carcinoma
radiofrequency treatment of 582 hepatic tumors. AJR Am as a bridge to liver transplantation. Hepatology
J Roentgenol 2003;181:695-700. 2005;41:1130-7.
8. Kasugai H, Osaki Y, Oka H, et al. Severe complications 21. Lu MD, Xu HX, Xie XY, et al. Percutaneous microwave
of radiofrequency ablation therapy for hepatocellular and radiofrequency ablation for hepatocellular carcinoma:
carcinoma: an analysis of 3,891 ablations in 2,614 patients. a retrospective comparative study. J Gastroenterol
Oncology 2007;72 Suppl 1:72-5. 2005;40:1054-60.
9. Tateishi R, Shiina S, Teratani T, et al. Percutaneous 22. Raut CP, Izzo F, Marra P, et al. Significant long-term
radiofrequency ablation for hepatocellular carcinoma. An survival after radiofrequency ablation of unresectable
analysis of 1000 cases. Cancer 2005;103:1201-9. hepatocellular carcinoma in patients with cirrhosis. Ann
10. Goldberg SN, Charboneau JW, Dodd GD 3rd, Surg Oncol 2005;12:616-28.
et al. Image-guided tumor ablation: proposal for 23. Chen MH, Yang W, Yan K, et al. Treatment efficacy
standardization of terms and reporting criteria. Radiology of radiofrequency ablation of 338 patients with hepatic
2003;228:335-45. malignant tumor and the relevant complications. World J
11. Shibata T, Shibata T, Maetani Y, et al. Radiofrequency Gastroenterol 2005;11:6395-401.
ablation for small hepatocellular carcinoma: prospective 24. Cabassa P, Donato F, Simeone F, et al. Radiofrequency
comparison of internally cooled electrode and expandable ablation of hepatocellular carcinoma: long-term experience
electrode. Radiology 2006;238:346-53. with expandable needle electrodes. AJR Am J Roentgenol
12. Livraghi T, Goldberg SN, Lazzaroni S, et al. 2006;186:S316-21.
Hepatocellular carcinoma: radio-frequency ablation of 25. Solmi L, Nigro G, Roda E. Therapeutic effectiveness
medium and large lesions. Radiology 2000;214:761-8. of echo-guided percutaneous radiofrequency ablation
13. Buscarini L, Buscarini E, Di Stasi M, et al. Percutaneous therapy with a LeVeen needle electrode in hepatocellular
radiofrequency ablation of small hepatocellular carcinoma: carcinoma. World J Gastroenterol 2006;12:1098-104.
long-term results. Eur Radiol 2001;11:914-21. 26. Choi D, Lim HK, Rhim H, et al. Percutaneous
14. Livraghi T, Solbiati L, Meloni MF, et al. Treatment of radiofrequency ablation for early-stage hepatocellular
focal liver tumors with percutaneous radio-frequency carcinoma as a first-line treatment: long-term results and
ablation: complications encountered in a multicenter study. prognostic factors in a large single-institution series. Eur
Radiology 2003;226:441-51. Radiol 2007;17:684-92.
15. Guglielmi A, Ruzzenente A, Battocchia A, et al. 27. Poggi G, Riccardi A, Quaretti P, et al. Complications
Radiofrequency ablation of hepatocellular carcinoma in of percutaneous radiofrequency thermal ablation of
cirrhotic patients. Hepatogastroenterology 2003;50:480-4. primary and secondary lesions of the liver. Anticancer Res
16. Rhim H, Yoon KH, Lee JM, et al. Major complications 2007;27:2911-6.
after radio-frequency thermal ablation of hepatic tumors: 28. Choi D, Lim HK, Rhim H, et al. Percutaneous
spectrum of imaging findings. Radiographics 2003;23:123- radiofrequency ablation for recurrent hepatocellular
34; discussion 134-6. carcinoma after hepatectomy: long-term results and
17. Ruzzenente A, Manzoni GD, Molfetta M, et al. prognostic factors. Ann Surg Oncol 2007;14:2319-29.
Rapid progression of hepatocellular carcinoma after 29. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete
Radiofrequency Ablation. World J Gastroenterol response and complications rates after radiofrequency
2004;10:1137-40. ablation of very early hepatocellular carcinoma in cirrhosis:
18. Gillams AR, Lees WR. Radio-frequency ablation of Is resection still the treatment of choice? Hepatology
colorectal liver metastases in 167 patients. Eur Radiol 2008;47:82-9.
2004;14:2261-7. 30. Kondo Y, Yoshida H, Tateishi R, et al. Percutaneous
19. Chen MH, Yang W, Yan K, et al. Large liver tumors: radiofrequency ablation of liver cancer in the hepatic dome
protocol for radiofrequency ablation and its clinical using the intrapleural fluid infusion technique. Br J Surg
2008;95:996-1004. carcinoma. Clin Mol Hepatol 2012;18:302-8.

31. Zavaglia C, Corso R, Rampoldi A, et al. Is percutaneous 43. Khan MR, Poon RT, Ng KK, et al. Comparison of
radiofrequency thermal ablation of hepatocellular percutaneous and surgical approaches for radiofrequency
carcinoma a safe procedure? Eur J Gastroenterol Hepatol ablation of small and medium hepatocellular carcinoma.
2008;20:196-201. Arch Surg 2007;142:1136-43; discussion 1143.
32. Chen TM, Huang PT, Lin LF, et al. Major complications 44. Guglielmi A, Ruzzenente A, Valdegamberi A, et al.
of ultrasound-guided percutaneous radiofrequency Radiofrequency ablation versus surgical resection for
ablations for liver malignancies: single center experience. J the treatment of hepatocellular carcinoma in cirrhosis. J
Gastroenterol Hepatol 2008;23:e445-50. Gastrointest Surg 2008;12:192-8.
33. Casaril A, Abu Hilal M, Harb A, et al. The safety of 45. Lau WY, Lai EC. The current role of radiofrequency
radiofrequency thermal ablation in the treatment of liver ablation in the management of hepatocellular carcinoma: a
malignancies. Eur J Surg Oncol 2008;34:668-72. systematic review. Ann Surg 2009;249:20-25.
34. Sartori S, Tombesi P, Macario F, et al. Subcapsular liver 46. Yan K, Chen MH, Yang W, et al. Radiofrequency ablation
tumors treated with percutaneous radiofrequency ablation: of hepatocellular carcinoma: long-term outcome and
a prospective comparison with nonsubcapsular liver tumors prognostic factors. Eur J Radiol 2008;67:336-347.
for safety and effectiveness. Radiology 2008;248:670-9. 47. Lencioni R, Crocetti L. Radiofrequency ablation of liver
35. Gillams AR, Lees WR. Five-year survival in 309 patients cancer. Tech Vasc Interv Radiol 2007;10:38-46.
with colorectal liver metastases treated with radiofrequency 48. Chen MS, Li JQ, Zheng Y, et al. A prospective randomized
ablation. Eur Radiol 2009;19:1206-13. trial comparing percutaneous local ablative therapy and
36. Liang P, Wang Y, Yu X, et al. Malignant liver tumors: partial hepatectomy for small hepatocellular carcinoma.
treatment with percutaneous microwave ablation-- Ann Surg 2006;243:321-8.
complications among cohort of 1136 patients. Radiology 49. Liang P, Wang Y. Microwave ablation of hepatocellular
2009;251:933-40. carcinoma. Oncology 2007;72 Suppl 1:124-31.
37. Solbiati L, Ahmed M, Cova L, et al. Small liver colorectal 50. Jones C, Badger SA, Ellis G. The role of microwave
metastases treated with percutaneous radiofrequency ablation in the management of hepatic colorectal
ablation: local response rate and long-term survival with metastases. Surgeon 2011;9:33-7.
up to 10-year follow-up. Radiology 2012;265:958-68. 51. Livraghi T, Solbiati L, Meloni MF, et al. Treatment of
38. Yu J, Liang P, Yu XL, et al. Needle track seeding after focal liver tumors with percutaneous radio-frequency
percutaneous microwave ablation of malignant liver ablation: complications encountered in a multicenter study.
tumors under ultrasound guidance: analysis of 14-year Radiology 2003;226:441-51.
experience with 1462 patients at a single center. Eur J 52. Giorgio A, Tarantino L, de Stefano G, et al. Complications
Radiol 2012;81:2495-9. after percutaneous saline-enhanced radiofrequency
39. Kondo Y, Shiina S, Tateishi R, et al. Intrahepatic bile duct ablation of liver tumors: 3-year experience with 336
dilatation after percutaneous radiofrequency ablation for patients at a single center. AJR Am J Roentgenol
hepatocellular carcinoma: impact on patient’s prognosis. 2005;184:207-11.
Liver Int 2011;31:197-205. 53. Ong SL, Gravante G, Metcalfe MS, et al. Efficacy and
40. Chang IS, Rhim H, Kim SH, et al. Biloma formation safety of microwave ablation for primary and secondary
after radiofrequency ablation of hepatocellular carcinoma: liver malignancies: a systematic review. Eur J Gastroenterol
incidence, imaging features, and clinical significance. AJR Hepatol 2009;21:599-605.
Am J Roentgenol 2010;195:1131-6.
41. Francica G, Saviano A, De Sio I, et al. Long-term
effectiveness of radiofrequency ablation for solitary small
Cite this article as: Lahat E, Eshkenazy R, Zendel A, Bar
hepatocellular carcinoma: a retrospective analysis of 363
Zakai B, Maor M, Dreznik Y, Ariche A. Complications after
patients. Dig Liver Dis 2013;45:336-41.
percutaneous ablation of liver tumors: a systematic review.
42. Lee HS, Park SY, Kim SK, et al. Thrombocytopenia
represents a risk for deterioration of liver function after
j.issn.2304-3881.2014.09.07
radiofrequency ablation in patients with hepatocellular
Review Article
The surgical treatment of patients with colorectal cancer and liver

metastases in the setting of the “liver first” approach
Leonardo Patrlj1, Mario Kopljar1, Robert Kliček1, Masa Hrelec Patrlj2, Marijan Kolovrat1, Mislav Rakić1,
Antonija Đuzel1
1
Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka Šuška 6, 10 000 Zagreb, Croatia; 2Department
of Childrens’ Surgery, Clinical Hospital for Childrens’ Disease, Zagreb, Klaićeva, 10 000 Zagreb, Croatia
Correspondence to: Robert Kliček, MD, PhD. Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka
Šuška 6, 10 000 Zagreb, Croatia. Email: rklicek@gmail.com.
Abstract: A surgical resection is the only curative method in the therapy of colorectal carcinoma and
liver metastases. Along with the development of interventional radiological techniques the indications
for surgery widen. The number of metastases and patients age should not present a contraindication for
surgical resection. However, there are still some doubts concerns what to resect first in cases of synchronous
colorectal carcinoma and liver metastases and how to ensure the proper remnant liver volume in order to
avoid postoperative liver failure and achieve the best results. Through this review the surgical therapy of
colorectal carcinoma and liver metastases was revised in the setting of “liver-first” approach and the problem
of ensuring of remnant liver volume.
Keywords: Colorectal liver metastases; liver resections; remnant volume; “liver-first” approach
doi: 10.3978/j.issn.2304-3881.2014.09.12
Introduction liver metastases will die of them (8). The 10-year survival
rate for patients with stage I disease is 90%, but for patients
Treatment of colorectal cancer and liver metastases are
with inoperable stage IV disease, it is currently only 5% (9).
an extremely important clinical issue since that there are
For patients with liver metastases, the treatment strategy
nearly a million newly diagnosed cases and nearly half
should be directed toward resectability (10).
of the million reported deaths worldwide (1). In large
The multidisciplinary therapeutic approach, consisting of
number of countries the incidence continue to rise (2), new and more effective chemotherapeutic agents in single
although the standardized prevention national programs of or combined therapy, an advanced role of interventional
early detection have developed and brought to an earlier radiology with portal vein embolization (PVE) and tumor
detection and diagnosed cases in early stage of tumor (3-5). ablation and new strategies and techniques for hepatic
In Asian countries, such as China, Japan, South Korea, and resections, brought improved resectability rate of metastases
Singapore, a 2-4-fold increase in the incidence of colorectal to 20-30% of cases and has resulted in 5-year survival
cancer in the past few decades is experienced (6). In of 35-50% for selected cases (11-13). A need has been
Western World the colorectal cancer is reported as the third recognized for a new staging system that acknowledges
the most frequent cancer and the most frequent cancer in the improvements in surgical techniques for resectable
population older than 75 years (7). metastases and the impact of modern chemotherapy on
Approximately 25% of newly diagnosed patients with rendering initially unresectable liver metastases from
colorectal cancer will have liver metastases at the time of colorectal carcinoma resectable while distinguishing
diagnosis, another 25% will develop liver metastases during between patients with a chance for cure at presentation and
the course of the disease and two-thirds of all patients with those for whom only palliative treatment is possible (14).
There have been presented the predictive factors for from CT the use of FDG-PET is widespread. A high quality
survival and local recurrence (15,16). Traditionally, a CT can detect the majority of extrahepatic disease, however
staged approach (colorectal first) has been used in the the FDG-PET may reveal additional signs of disease as high
management of patients with synchronous colorectal cancer metabolic activity. Although some studies showed a change
and liver metastases. This involves the initial extirpation in management in 10-20% of patients according to record
of the primary tumor. Systemic chemotherapy followed of FDG-PET (27,28), some reports lower percentage and
the operation, after which liver-directed operation was even seem to be more suspicious in its cost-effective role (29),
performed. The last 2 decades have brought an increased especially in the context of FDG-records following the
understanding of the biology of colorectal liver metastases, preoperative chemotherapy which reduces its sensitivity.
resulting in more effective targeted therapies in addition to
decreased mortality after liver-directed operations (17,18).
The surgical resection—what to resect first in
The goal of this review is to focus onto the doubts
synchronous metastases?
concerning the operators all around the world in the
context of reassuring the proper remnant liver volume and Surgical treatment of colorectal liver metastases remains
especially what to resect first in the cases of synchronous the only treatment associated with a long survival time in
liver metastases of colorectal carcinoma. patients with liver metastases from colorectal carcinoma,
with a 40% survival at 5 years and almost 25% postoperative
survival up to 10 years in specialized centers (30). The very
The preoperative imaging and planning the
important issue that the liver surgeon has to deal with is
surgical resection
to proceed decide what to resect first liver or colon and/or
The R0 resection is the ultimate goal of the surgical therapy. when to undertake simultaneous surgical resections of both.
However the proper indication is essential in order to achieve The perfect solution seems to be a single stage colon and
adequate result of resection. Resectability depends onto the liver operation. The advantage of the one stage procedure
multiple factors: the number and location of metastases, the could be less psychological stress for the patient, lower
remnant liver volume and quality of the liver tissue that is not financial cost and shorter hospitalization time. On the other
infiltrated by tumor. All lesions identified at the initial imaging hand the advantages of the staged procedure are that there
records (CT or MRI) before any therapy is performed have to is no accumulation of the risks of liver and bowel resections
be accounted during planning the liver resection in order to at the same time. Neoadjuvant chemotherapy may be given
predict the total risk and the outcome of surgical procedure. before liver resection, and an extended hepatectomy or
It is recognized that chemotherapy can induce toxic injury demanding bowel resection could be performed with the
of liver tissue, primarily steatohepatitis and sinusoidal injury. full attention of the surgical team focused on the liver or
Non-contrast CT and MRI could be used to assess steatosis bowel disease, although, the key point for decision-making
(19-21), but steatohepatitis cannot be diagnosed with imaging. is the patient’s safety (1). According to the reported initial
Sinusoidal injury can be judged by indirect signs of portal experience with simultaneous versus staged resections, a
hypertension, particularly spleen size (22), or by using the French multicenter study showed an operative mortality
liver-specific MRI contrast agent gadoxetic acid (23). The of 7% for simultaneous 2% for staged surgery (31), while
essential three points that are ultimate for complete resection in a single center US study the mortality was 12% for
are preservation of liver vascularity, the adequate remnant simultaneous and 4% for staged resections (32). Several
liver volume with reference to body weight and total liver studies reported simultaneous operations performed without
volume, and that the quality of the remnant liver parenchyma mortality, however patients were selected by experienced
is acceptable (24). The ultrasound (US), especially contrast hepatobiliary surgeons and the major hepatectomies
enhanced ultrasound (CEUS) presents a unique imaging were avoided in elderly patients the same as in those with
method for intraoperative assessment of unrevealed metastases, demanding colorectal surgery (33-36). In addition, since the
and the relation between tumor and vascular and biliar surgical mortality rate is significantly higher when surgery
structures (25), sometimes even significantly more sensitive of extensive hepatic resections is combined with colorectal
than CT and/or MRI preoperative imaging records (26). resection (37), this approach should be only performed in
For the detection of extra hepatic metastases and local carefully selected patients.
recurrence at the site of the initial colorectal surgery, apart The standard staged operative treatment recommendations
326 Patrlj et al. Order of surgical treatment of CRLM
in the literature suggest resection of the primary tumor How to achieve resectability without
followed by chemotherapy for 3-6 months and second stage chemotherapy?
of surgical treatment that includes liver surgery. The problem
A large number of liver metastases should not be an absolute
with this approach lies in the fact that liver metastases
contraindication to surgery combined with chemotherapy
determine survival more intensive than the primary colorectal
provided that resection can be complete, with preservation
tumor. Chemotherapy can sometime not be performed
of a functioning liver remnant of 25-30% (49). However,
after the surgical treatment of the primary tumor, especially
the problem is the loss of the proper functioning remnant
when complicated by anastomotic leak or dehiscence, which
volume of normal liver tissue, which presents an absolute
occurs in 6-12% of patients (38,39). In cases of advanced
contraindication for surgical resection. Advances in
rectal cancer usually a long term of radio-chemotherapy of
interventional radiology, particularly PVE in which the
5 weeks is recommended and the second stage of operative
hypertrophy of normal liver tissue is provoked in order to
treatment is planned 6-10 weeks following the neoadjuvant
ensure the proper remnant volume (50) and radiofrequency
therapy. Therefore the patients do not receive a therapy of
thermal ablation (RFA) widened the indications for surgical
liver metastases for almost 15 weeks, which brings to the
progress of liver metastatic disease (40). On the other hand treatment of patients with colorectal cancer and liver
some experimental studies have reported the rapid growth metastases. In patients planned for major hepatectomies
of metastases after removal of primary tumor (41,42). and with an otherwise normal liver, preoperative PVE is
The underlying mechanism for those experimental results recommended when the ratio of the remnant liver to total
could be the loss of primary tumor-induced inhibition of liver volume is estimated to be less than 30%, whereas
angiogenesis in the metastases, which supports the founding in patients with neoadjuvant chemotherapy this ratio is
of the increase of vascular density in humans after resection considered to be 40% (51,52). PVE is a safe procedure, but
of primary tumor (43). manipulation of the embolic material to the main portal
The reverse surgical approach onto the surgical vein or into branches that supply the future remnant liver
treatment of colorectal liver metastases known as “liver-first” remains a risk (1). RFA was initially anticipated for local
approach is reported as feasible and safe procedure with treatment of hepatocellular carcinoma but has recently
promising results, although it brings along the risk of bowel found application for the management of colorectal liver
obstruction following the growth of primary tumor, which metastases, where its indications are still under doubt.
can be avoided by Hartmanns procedure (39,44). Results Critical review of the results of RFA shows that it must be
from the Liver Met Survey, involving 13,334 patients restricted in cases with a maximum of 3 lesions with the size
from 330 centers in 58 countries who underwent surgery of the biggest lesion less than 3 cm (53). Another limitation
for liver metastases, reported a better survival outcome for the use of RFA in the management of colorectal liver
in patients who undergo first resection of liver metastases metastases is the anatomic location of the lesion near big
than in those who do not (45). A recent systematic review vessels, which increases the risk of incomplete ablation due
of studies published in 1999-2010 confirmed these results to reduced heat effect that is used (54). A great indication of
and revealed 5-year survival rates for patients with liver RFA is actually recurrence after resection, detected as small
metastases in the range of 16-74% (median, 38%) after liver lesions, so it is possible not to interrupt chemotherapy (55).
resection (46). A novel method in liver surgery that can solve the
The main idea of the “liver first” approach was to avoid problem of remnant volume is the associating of liver
the time loss between the operative therapy of primary partition and portal vein ligation (ALPPS) firstly reported
tumor and the oncological therapy. Since the patients 3 years ago (56). In ALPPS approach, the portal vein
with rectal cancer often require a complex oncological ligation associated with in situ splitting is able to
therapy (chemotherapy, radiotherapy, and a complex pelvic induce enormously accelerated hypertrophy (57). The
operation), they could be the most proper candidates for neovascularization and persistence of interlobar perfusion
such an approach (47). Despite liver-first patients usually are prevented by performing parenchymal dissection and
have a greater hepatic disease burden and undergoing major complete devascularization of segment IV (56). The nearly
resection more often, the reverse strategy was found safe total parenchymal dissection induced a median hypertrophy
and had long-term outcomes comparable to those of the of 74%, which is markedly above the range that can be
other approaches (48). achieved by portal vein ligation or PVE alone (58,59).
Conclusions 6. Sung JJ, Lau JY, Goh KL, et al. Increasing incidence
of colorectal cancer in Asia: implications for screening.
Surgical R0 resection still remains the only curative
Lancet Oncol 2005;6:871-6.
therapeutic tool in patients with colorectal cancer and liver
7. Boyle P, Leon ME. Epidemiology of colorectal cancer. Br
metastases. The proper diagnostic algorithm is ultimate.
Med Bull 2002;64:1-25.
The indications for surgical treatment are enlarged by
8. Khatri VP, Petrelli NJ, Belghiti J. Extending the frontiers
the progress in neoadjuvant chemotherapy, diagnostic
of surgical therapy for hepatic colorectal metastases: is
imaging, interventional radiology procedures especially the
there a limit? J Clin Oncol 2005;23:8490-9.
usage of PVE and radio frequent ablation. On the other
9. Van den Eynde M, Hendl isz A. Treatment of colorectal
hand the surgical techniques still develop producing the
liver metastases: a review. Rev Recent Clin Trials
new pathways of treatment such as “liver-first approach”
2009;4:56-62.
in the context of 2-stage operative therapy and ALPPS 10. Aloia TA, Adam R, Azoulay D, et al. Outcome following
for the ensuring the remnant liver volume. Simultaneous hepatic resection of metastatic renal tumors: the Paul
liver and colorectal operations are feasible at carefully Brousse Hospital experience. HPB (Oxford) 2006;8:100-5.
selected patients but should be avoided in cases of major 11. Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-
hepatectomies, in elderly patients, and in patients with term survival after hepatic resection for metastatic
too complex intraoperative asset of colorectal tumor. The colorectal cancer: a multifactorial model of 929 patients.
2-stage hepatectomies as well as the “liver first” approach Ann Surg 2008;247:125-35.
seem to become the new treatment strategies that improved 12. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in
the prognosis in patients in whom an R0 resection can be long-term survival following liver resection for hepatic
achieved with curative intention. The multidisciplinary colorectal metastases. Ann Surg 2002;235:759-66.
treatment therapeutic approach in patients with colorectal 13. Krebs B, Kozelj M, Potrc S. Rectal cancer treatment and
cancer and liver metastases is essential to make the proper survival--comparison of two 5-year time intervals. Coll
treatment plan and achieve the best results. Antropol 2012;36:419-23.
14. Poston GJ, Figueras J, Giuliante F, et al. Urgent need for
Acknowledgements a new staging system in advanced colorectal cancer. J Clin
Oncol 2008;26:4828-33.
Disclosure: The authors declare no conflict of interest. 15. Boras Z, Kondza G, Sisljagić V, et al. Prognostic factors
of local recurrence and survival after curative rectal cancer
References surgery: a single institution experience. Coll Antropol
2012;36:1355-61.
1. Dimitroulis D, Nikiteas N, Troupis T, et al. Role of 16. Fong Y, Fortner J, Sun RL, et al. Clinical score for
surgery in colorectal liver metastases: too early or too late? predicting recurrence after hepatic resection for metastatic
World J Gastroenterol 2010;16:3484-90. colorectal cancer: analysis of 1001 consecutive cases. Ann
2. Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Surg 1999;230:309-18; discussion 318-21.
Version 1.2, Cancer Incidence and Mortality Worldwide. 17. Mayo SC, Heckman JE, Shore AD, et al. Shifting trends
IARC Cancer Base No.10. Available online: http:// in liver-directed management of patients with colorectal
globocan.iarc.fr. accessed November 23, 2011. liver metastasis: a population-based analysis. Surgery
3. Jurisić I, Paradzik MT, Jurić D, et al. National program 2011;150:204-16.
of colorectal carcinoma early detection in Brod-Posavina 18. Asiyanbola B, Chang D, Gleisner AL, et al. Operative
County (east Croatia). Coll Antropol 2013;37:1223-7. mortality after hepatic resection: are literature-based rates
4. Milas J, Samardzić S, Miskulin M. Neoplasms (C00-D48) broadly applicable? J Gastrointest Surg 2008;12:842-51.
in Osijek-Baranja County from 2001 to 2006, Croatia. 19. Kodama Y, Ng CS, Wu TT, et al. Comparison of CT
Coll Antropol 2013;37:1209-22. methods for determining the fat content of the liver. AJR
5. Samardzić S, Mihaljević S, Dmitrović B, et al. First six Am J Roentgenol 2007;188:1307-12.
years of implementing colorectal cancer screening in the 20. Reeder SB, Sirlin CB. Quantification of liver fat with
Osijek-Baranja County, Croatia--can we do better? Coll magnetic resonance imaging. Magn Reson Imaging Clin
Antropol 2013;37:913-8. N Am 2010;18:337-57.
328 Patrlj et al. Order of surgical treatment of CRLM
21. van Werven JR, Marsman HA, Nederveen AJ, et al. multiple bilobar hepatic metastases from colorectal
Assessment of hepatic steatosis in patients undergoing liver carcinoma. Ann Surg 2000;231:743-51.
resection: comparison of US, CT, T1-weighted dual-echo 33. Weber JC, Bachellier P, Oussoultzoglou E, et al.
MR imaging, and point-resolved 1H MR spectroscopy. Simultaneous resection of colorectal primary tumour and
Radiology 2010;256:159-68. synchronous liver metastases. Br J Surg 2003;90:956-62.
22. Overman MJ, Maru DM, Charnsangavej C, et al. 34. Chua HK, Sondenaa K, Tsiotos GG, et al. Concurrent vs.
Oxaliplatin-mediated increase in spleen size as a biomarker staged colectomy and hepatectomy for primary colorectal
for the development of hepatic sinusoidal injury. J Clin cancer with synchronous hepatic metastases. Dis Colon
Oncol 2010;28:2549-55. Rectum 2004;47:1310-6.
23. Shin NY, Kim MJ, Lim JS, et al. Accuracy of gadoxetic 35. Tanaka K, Shimada H, Matsuo K, et al. Outcome
acid-enhanced magnetic resonance imaging for the after simultaneous colorectal and hepatic resection for
diagnosis of sinusoidal obstruction syndrome in patients colorectal cancer with synchronous metastases. Surgery
with chemotherapy-treated colorectal liver metastases. Eur 2004;136:650-9.
Radiol 2012;22:864-71. 36. Minagawa M, Yamamoto J, Miwa S, et al. Selection criteria
24. Zorzi D, Laurent A, Pawlik TM, et al. Chemotherapy- for simultaneous resection in patients with synchronous liver
associated hepatotoxicity and surgery for colorectal liver metastasis. Arch Surg 2006;141:1006-12; discussion 1013.
metastases. Br J Surg 2007;94:274-86. 37. Reddy SK, Pawlik TM, Zorzi D, et al. Simultaneous
25. Chami L, Lassau N, Malka D, et al. Benefits of contrast- resections of colorectal cancer and synchronous liver
enhanced sonography for the detection of liver lesions: metastases: a multi-institutional analysis. Ann Surg Oncol
comparison with histologic findings. AJR Am J Roentgenol 2007;14:3481-91.
2008;190:683-90. 38. Chiappa A, Biffi R, Bertani E, et al. Surgical outcomes
26. Leen E, Ceccotti P, Moug SJ, et al. Potential value after total mesorectal excision for rectal cancer. J Surg
of contrast-enhanced intraoperative ultrasonography Oncol 2006;94:182-93; discussion 181.
during partial hepatectomy for metastases: an essential 39. Tran CL, Udani S, Holt A, et al. Evaluation of safety
investigation before resection? Ann Surg 2006;243:236-40. of increased time interval between chemoradiation and
27. Necib H, Garcia C, Wagner A, et al. Detection and resection for rectal cancer. Am J Surg 2006;192:873-7.
characterization of tumor changes in 18F-FDG PET 40. Verhoef C, van der Pool AE, Nuyttens JJ, et al. The
patient monitoring using parametric imaging. J Nucl Med “liver-first approach” for patients with locally advanced
2011;52:354-61. rectal cancer and synchronous liver metastases. Dis Colon
28. Hendlisz A, Golfinopoulos V, Garcia C, et al. Serial FDG- Rectum 2009;52:23-30.
PET/CT for early outcome prediction in patients with 41. O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin:
metastatic colorectal cancer undergoing chemotherapy. a novel angiogenesis inhibitor that mediates the
Ann Oncol 2012;23:1687-93. suppression of metastases by a Lewis lung carcinoma. Cell
29. Moulton C, Levine MN, Law C, et al. An Ontario Clinical 1994;79:315-28.
Oncology Group (OCOG) randomized controlled trial 42. O’Reilly MS, Holmgren L, Chen C, et al. Angiostatin
(RCT) assessing FDG PET/CT in resectable liver induces and sustains dormancy of human primary tumors
colorectal adenocarcinoma metastases (CAM). J Clin in mice. Nat Med 1996;2:689-92.
Oncol 2011;29:abstr 3520. 43. Peeters CF, de Waal RM, Wobbes T, et al. Outgrowth
30. Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long- of human liver metastases after resection of the primary
term survival after hepatic resection for metastatic colorectal tumor: a shift in the balance between apoptosis
colorectal cancer: a multifactorial model of 929 patients. and proliferation. Int J Cancer 2006;119:1249-53.
Ann Surg 2008;247:125-35. 44. Mentha G, Roth AD, Terraz S, et al. ‘Liver first’ approach
31. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical in the treatment of colorectal cancer with synchronous
resection of colorectal carcinoma metastases to the liver. A liver metastases. Dig Surg 2008;25:430-5.
prognostic scoring system to improve case selection, based 45. Registry of patients operated for Colorectal Liver
on 1568 patients. Association Française de Chirurgie. Metastasis. Available online: http://www.livermetsurvey.
Cancer 1996;77:1254-62. org. International livermetsurvey.org, accessed November
32. Bolton JS, Fuhrman GM. Survival after resection of 23, 2011.
46. Kanas GP, Taylor A, Primrose JN, et al. Survival after Surgery 2000;127:512-9.
liver resection in metastatic colorectal cancer: review 53. Berber E, Pelley R, Siperstein AE. Predictors of survival
and meta-analysis of prognostic factors. Clin Epidemiol after radiofrequency thermal ablation of colorectal cancer
2012;4:283-301. metastases to the liver: a prospective study. J Clin Oncol
47. Andres A, Toso C, Adam R, et al. A survival analysis of the 2005;23:1358-64.
liver-first reversed management of advanced simultaneous 54. Terraz S, Constantin C, Majno PE, et al. Image-guided
colorectal liver metastases: a LiverMetSurvey-based study. multipolar radiofrequency ablation of liver tumours: initial
Ann Surg 2012;256:772-8; discussion 778-9. clinical results. Eur Radiol 2007;17:2253-61.
48. Mayo SC, Pulitano C, Marques H, et al. Surgical 55. Mentha G, Majno P, Terraz S, et al. Treatment strategies
Management of Patients with Synchronous Colorectal for the management of advanced colorectal liver metastases
Liver Metastasis: A Multicenter International Analysis. J detected synchronously with the primary tumour. Eur J
Am Coll Surg 2013;216: 707-16. Surg Oncol 2007;33 Suppl 2:S76-83.
49. Adam R, De Gramont A, Figueras J, et al. The 56. Baumgart J, Lang S, Lang H. A new method for induction
oncosurgery approach to managing liver metastases of liver hypertrophy prior to right trisectionectomy: A
from colorectal cancer: a multidisciplinary international report of three cases HPB (Oxford, England) 2011;13:71-2.
consensus. Oncologist 2012;17:1225-39. 57. Torres OJ, Moraes-Junior JM, Lima e Lima NC, et al.
50. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative Associating liver partition and portal vein ligation for
portal embolization to increase safety of major staged hepatectomy (ALPPS): a new approach in liver
hepatectomy for hilar bile duct carcinoma: a preliminary resections. Arq Bras Cir Dig 2012;25:290-2.
report. Surgery 1990;107:521-7. 58. de Santibañes E, Alvarez FA, Ardiles V. How to avoid
51. Abdalla EK, Barnett CC, Doherty D, et al. Extended postoperative liver failure: a novel method. World J Surg
hepatectomy in patients with hepatobiliary malignancies 2012;36:125-8.
with and without preoperative portal vein embolization. 59. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right
Arch Surg 2002;137:675-80; discussion 680-1. portal vein ligation combined with in situ splitting induces
52. Vauthey JN, Chaoui A, Do KA, et al. Standardized rapid left lateral liver lobe hypertrophy enabling 2-staged
measurement of the future liver remnant prior to extended extended right hepatic resection in small-for-size settings.
liver resection: methodology and clinical associations. Ann Surg 2012;255:405-14.
Cite this article as: Patrlj L, Kopljar M, Kliček R, Hrelec Patrlj

M, Kolovrat M, Rakić M, Đuzel A. The surgical treatment
of patients with colorectal cancer and liver metastases in the
setting of the “liver first” approach. Hepatobiliary Surg Nutr
2014;3(5):324-329. doi: 10.3978/j.issn.2304-3881.2014.09.12
View publication stats

Jurnal Inggris Empedu PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Jurnal Inggris Empedu PDF

Uploaded by

Copyright:

Available Formats

See discussions, stats, and author profiles for this publication at: https://www.researchgate.

Article · October 2014

Mislav Rakić Mario Kopljar

SEE PROFILE SEE PROFILE

Robert Kliček Marijan Kolovrat

SEE PROFILE SEE PROFILE

3rd Hepatobiliary and Pancreatic Surgery Congress View project

Systematic Review and Meta-Analysis View project

The user has requested enhancement of the downloaded file.

HEPATOBILIARY SURGERY AND NUTRITION

ISSN 2304-3881 Vol 3, No 5 OCT 2014

Aims and Scope Note to NIH Grantees

Maturation of HBP surgery: worldwide advances to address

Cite this article as: Patrlj L, Kopljar M, Fong Y. Maturation

Department of Hepatobiliary Surgery, University Hospital Dubrava, Zagreb, Croatia

Keywords: Gallbladder carcinoma; gallstones; laparoscopic cholecystectomy; liver resection

Introduction environmental exposure and intrinsic genetic predisposition

Laparoscopic cholecystectomy is contraindicated when gallstone disease in Chandigarh: a community-based study.

Cite this article as: Rakić M, Patrlj L, Kopljar M, Kliček

Pre-resectional inflow vascular control: extrafascial dissection of

Introduction dramatically (2-10). All improvements in liver surgery

through the catheter with a bilirubin content 2× higher than

Makuuchi’s “J”-shaped laparotomy was used for all patients.

Figure 2 Mesohepatectomy: resectional plan along the right sagital

Figure 3 Right hepatectomy: transection of the right main

Table 4 Perioperative characteristics of patients included in the study

References Paris: Masson, 1957.

Cite this article as: Karamarković A, Doklestić K. Pre-

Post-hepatectomy liver failure

Introduction obscure laboratory tests, such as hepaplastin or hyaluronic

Table 1 ISGLS definition and grading of PHLF (2)

PHLF, with post-operative hemorrhage (15) and occurrence

Pre-operative risk assessment

Given the high mortality rate associated with PHLF, there

A predictive value for post-operative liver dysfunction was

Figure 2 (A) CT scan demonstrating evidence of cirrhosis, with Prevention

Table 3 Determinants of low vs. high risk for PHLF

Table 4 Techniques for preventing and minimizing the risk of PHLF

Cite this article as: Kauffmann R, Fong Y. Post-hepatectomy

Pancreatic surgery: evolution and current tailored approach

Department of Surgery, University Clinical Hospital “Sisters of Charity”, Zagreb, Croatia

Introduction pancreatectomy reported in 1944 (8), and Traverso and

Table 1 History and evolution of pancreaticoduodenectomy

Table 3 Trials of pancreatic management

Table 4 Solutions for pancreatic leak Prevention of complications

A enhances the anastomotic healing, the acidity of the stomach

Figure 1 Different ways of doing the anastomosis for a Duct occlusion

Cite this article as: Zovak M, Mužina Mišić D, Glavčić G.

Potential use of Doppler perfusion index in detection of occult

Department of Abdominal Surgery, University Hospital Dubrava, Zagreb, Croatia

Introduction terms of their long-term prognosis (66.2% vs. 67.8%) (7).

Table 1 Doppler perfusion index—how to do it

Table 3 Possible etiology of change in flow

Cite this article as: Kopljar M, Patrlj L, Bušić Ž, Kolovrat

Pancreatic fistula and postoperative pancreatitis after

Table 1 New classification of pancreatic anastomosis failure (9)

are the main determinant of pancreatic fistula 2002;137:1289-93.

41. Imrie CW, Dickson AP. Postoperative pancreatitis. In: 1997;185:18-24.

Cite this article as: Ryska M, Rudis J. Pancreatic fistula and

Techniques for prevention of pancreatic leak after pancreatectomy

Keywords: Pancreaticoduodenectomy; distal pancreatectomy; pancreatic leak; post-operative pancreatic fistula

Introduction leak, or abscess have been found to have a 90-day mortality

Definition reported on three cases of pancreatic duct ligation all