Hepatic resections in the

treatment of hilar

cholangiocarcinoma (Klatskin

tumor)

Ph. D thesis’ abstract

Scientific coordinator:

Cristian Dragomir, MD, Ph.D, FRCS

(Hon Eng)

Ph.D student: Valeriu Gavrilovici

Iaşi, 2011

2

General Part

1. Introduction

Colangiocarcinoama (CC) is a tumour developed from biliary

epithelium duct.

Those interesting biliary confluence or hilar

cholangiocarcinoma (CCH) were firstly described by Gerald

Klatskin in 1965 and received afterwards this eponym.

During last three decades surgical treatment for CCH

changed dramatically, becoming more aggressive with better

results regarding patients’ survival. This has been obtained

performing hepatic resections besides bile duct excisions.

2. Epidemiology CC, both intra and extra hepatic, represents 3% of the

gastrointestinal cancers. Of those extrahepatic, CCH represents 40

to 60% in the series reported.

3. Natural history The majority of the untreated patients dies within 6 to 12

months from the moment of diagnosis by hepatic failure or

infectious complications due to biliary obstruction.

4. Pathology The synonyms describing the same entity are: proximal

biliary cancer, cancer of the biliary confluence, malignant stenosis

of the biliary confluence, hilar cholangiocarcinoma, Klatskin

tumour.

CCH are mainly adenocarcinoma. Non-epithelial tumours are

rarely encountered: carcinoid, sarcoma, lymphoma, metastases

from another primary cancer (colorectal).

3

5. Local, regional and systemic evolution The original article of Klatskin and the following ones

evidenced the progression of extra hepatic biliary tumours is very

slow. The extension is local and regional. Neural invasion is

constant and the regional extension is towards the lymphatic

nodes of the hepatic pedicle, portal vein and liver parenchyma.

Metastases, with the exception of those in the liver, are

exceptional.

6. Symptoms and clinical exams The symptoms are not specific. There are three main

categories of clinical aspects:

1) biliary obstruction: jaundice, pain in the right upper

quadrant, nausea, pruritus

2) general symptoms: anorexia, loss of weight, asthenia

3) signs and symptoms of metastatic disease: fatigue,

lethargy, loss of weight.

7. Staging and classification systems First classification was proposed in 1975 by Henri Bismuth

and Marvin B. Corlette; in a modified form it is largely used

today.

Bismuth-Corlette classification

Type I: tumour invades biliary confluence but right and left

channels communicate

Type II: tumour invades biliary confluence and right and left

channels do not communicate

Type III: tumour invades biliary confluence and extend on hepatic

channels

IIIa: extension on right hepatic channel

IIIb: extension non left hepatic channel

4

Type IV: tumor is either multicentric or invades right and left

hepatic channels

The most used system is the TNM (tumour, nodes, metastases)

proposed by UICC (Union Internationale Contre le Cancer).

The last edition (January 2010) introduces for the first time

the split of extra hepatic biliary cancers in proximal (including

CCH) and distal. It also changes some aspects of T and N

categories and eliminates Mx from all stages of solid tumours.

Staging of proximal extra hepatic biliary cancers

8. Diagnosis CCH are silent for long periods. Jaundice is the prominent

symptom and is, usually, progressive and unremissive.

Stage I T1 N0 M0

Stage II T2a-b N0 M0

Stage IIIA T3 N0 M0

Stage IIIB T1-3 N1 M0

Stage IVA T4 Any N M0

Stage IVB Any T Any N M1

5

8.1 Imagistic diagnosis

Radiologic studies are essential in the management of

patients with CCH, during the last decade, the selection of them

changed dramatically. MRI, MRCP and cholangio-MRI are the

first choice.

8.2. Diagnostic laparoscopy Laparoscopic staging is used to identify the patients with

metastatic disease in which surgical operation with curative intent

is not possible.

8.3 Differential diagnosis Includes: lymphatic nodes metastases, intrahepatic

cholangiocarcinoma with hilar extent, lymphoma, lythiasis of the

main hepatic duct, Mirizzi syndrome, granuloma, benign fibrosis,

tuberculosis, traumatic sequels, retroperitoneal fibrosis.

9. Preoperative management

It is very important to have a good functioning liver after

surgeon. For this and to increase curability, there were developed

techniques such as preoperative biliary drainage and portal vein

embolization.

Surgeon must assess resectability because only the resection

represents an effective therapy.

Criteria for non-resectability include:

Infiltration beyond second biliary branches in both

hemilivers;

Invasion of the great vessels (portal vein or hepatic artery),

invasion of the right and left branches of the portal vein,

invasion of a branch of the portal vein and of the

contralateral hepatic;

Vascular invasion on one side and contralateral biliary

invasion;

6

Lymphatic invasion beyond N1 stations

The presence of the metastases

10. Surgical options and techniques 10.1 Surgical anatomy

In the middle of the twentieth century, the French anatomist

Claude Couinaud described segmental anatomy of the liver, based

on the intrahepatic distribution of the vessels. Couinaud’s

classification of the hepatic anatomy divides the liver in eight

independent functional segments, each having its own biliary,

arterial and portal triad.

10. 2 Curative surgical options Surgical treatment of CCH has three objectives: complete

tumoural excision with negative histological margins, removal of

the symptoms related to biliary obstructions and the bilioenteral

restoration. Surgical strategy is based on the peroperative exploration,

including peroperative ecography. Curative surgical options are:

1. Bile duct resection

2. Hepatic and bile duct resection

3. Combined hepatic and vascular resection

4. Hepatopancreatoduodenectomy

5. Liver transplantation

11. Postoperative complications Japanese and American authors speak about minor and major

complications while European authors classify them as immediate

and late complications.

The rate of major complications varies between 33 and 50% in

the majority of the series published.

7

12. Prognostic factors for survival after

resectional surgery for CCH Many studies demonstrated survival of the patients after

surgery for CCH depends on some clinical land pathological

factors.

The most of them stated the negative impact on survival of

the: perineural invasion, lymphatic nodes invasion, involved

resected margins, vascular invasion, male gender, low tumoral

grading, absence of the caudate lobe resection, presence of the

lobar atrophy.

8

Personal part

CHAPTER I

AIM OF THE STUDY

Klatskin tumors represent a rare pathology encountered in

clinical practice. In the last two decades grew significantly the

number of series reported and changed dramatically their

management.

Surgery offers the only chance for cure and here emerged the

need for hepatic resection for better results.

I worked during 2003 and 2005 in Rennes, France in a

hepatic surgical service. Professor Karim Boudgema, chief of the

service proposed me to make a research on the surgical treatment

of hilar cholangiocarcinoma during the period 1994 to 2004.

CHAPTER II

STATISTIC METHODOLOGY

It was used STATISTICA for medical research program.

Were applied various tests for analysis (ANOVA, Scheffé,

Spjotvol/Stoline), and specific tests of correlation for variables

(Pearson, CHI – pătrat (2), Mantel-Haenszel, Fisher, Spearman,

Kendall tau (τ), Gamma) etc.

9

CHAPTER III

MATERIAL AND METHOD

For the study were retrospectively consulted the database and

archive of the Digestive Surgery service of CHU (Centre

Hospitalier Universitaire) of Rennes, France. There were 62

patients treated for Klatskin tumors from 01 January 1994 to 31

July 2004. 56 patients were operated on, 33 patients with curative

intent and 23 of them underwent palliative operations.

The study was performed on the 33 patients operated

on with curative intent (resectabiliry of 59%).

Patients were grouped in two categories, according to the type

of surgery:

1) 7 patients in which was performed resection of the

extrahepatic bile duct (RCBEH)

10

2) 26 patients in which was performed a hepatic associated

resection (RHA) besides RCBEH, more or less extended,

with or without resection of the segment 1 (caudate lobe).

Type of intervention No. of

cases

%

RCBEH & RHA 26 78.79%

RCBEH 7 21.21%

Total 33

There is a slight male gender predominance, not significant

statistically

11

Type of intervention

Total RCBEH RCBEH & RHA

Female 2 11

13 15.38% 84.62%

Male 5 15

20 25.00% 75.00%

Total 7 26 33

12

CHAPTER IV

RESULTS

Patients who underwent RCBEH associated more frequently

pruritus (β=0.62, p=0.009), anorexia (β=0.79, p=0.0073) and

weight loss (β=5.16, p=0.0071).

Some biological values were analysed (haemoglobin,

haematocrite, alkaline phosphatases, aspartat amino-transpherase

(ASAT), alanil amino-transpherase (ALAT), total and direct

bylirubinaemia).

Medium values of alkaline phosphatases and medium values

of ASAT and ALAT were significantly lower in patients receiving

RCBEH as treatment.

Medium values of total and direct bylirubinaemia were

significantly lower in the group receiving RCBEH and RHA as

treatment.

Bismuth-Corlette staging

13

RCBEH was the surgical option for all the cases classified

Bismuth-Corlette type I. RCBEH and RHA was applied in

Bismuth-Corlette type II, III and IV.

TNM staging

For the N factor were modified N2 lymph nodes into N1

according to the last definition in UICC seventh edition.

14

The analysis of the TNM staging in relation with operations

performed showed:

1. Referring to T factor

15

There is a significant association between the type of surgery

and T factor (χ2=7.79, p=0.02, r=-0.904, 95%CI).

2. Referring to N factor

Hepatic associated resections

16

Extension of hepatectomy (number of resected

segmnents)

Histogram: Extinderea hepatectomiei

Include condition: interventie chirurgicala curativa

1 1

3

6

13

2

1 2 3 4 5 6

numarul segmentelor rezecate

0

2

4

6

8

10

12

14

16

No

. o

f o

bs.

1 1

3

6

13

2

Type of resection (R0, R1)

The resected margins were found invaded in 33% of cases.

17

Resection of the segment 1 (caudate lobe)

Alte segmente,23.08%

Rezecţia segmentului 1,

76.92%

hepatectomie stanga, 30.77%

hepatectomie dreapta, 46.15%Alte segmente

Rezecţia segmentului 1

hepatectomie stanga

hepatectomie dreapta

Segmentele hepatice rezecate

hepatectomiestanga,11.54%

hepatectomiedreapta,3.85%

Segmetectomie izolata,3.85%

Hepatectomiecentrala,3.85%

Length of the operations

18

Categ. Box & Whisker Plot: Durata op. (min)

Durata op. (min): F = 8.7113, p = 0.0046;

Kruskal-Wallis-H = 7.851, p = 0.0051

Mean

Mean±SE

Mean±SD

278.57

381.52

278.57

381.52

RCBEH RCBEH & RHA

Felul interventiei

150

200

250

300

350

400

450

500

550

Du

rré

e o

p.

(min

)

278.57

381.52

RCBEH and RHA are significantly longer than RCBEH.

Arterial invasion

19

Portal invasion

Perineural invasion

20

Lymph nodes invasion

Tumoral vascular embolia

21

Peroperative transfusions

22

Postoperative transfusions

Postoperative complications, reoperations

23

There is a strong correlation between complications and the

group with RCBEH and RHA. The risk of complications is 8.33

bigger in this group.

Postoperative deaths

Length of hospital stay

24

Categ. Box & Whisker Plot: durata spitalizare

durata spitalizare: F(1,64) = 5.119, p = 0.0271;

Kruskal-Wallis-H(1,66) = 4.5696, p = 0.0325

Mean

Mean±SE

Mean±SD

15.7

24.5

15.7

24.5

RCBEH RCBEH & RHA5

10

15

20

25

30

35

40

du

rata

sp

italiz

are

(zi

le)

15.7

24.5

Analysis of factors influencing survival

Survival in group RCBEH & RHA

25

Survival Function - RCBEH & RHA

Complete Censored

Include condition: interventie=1

-10 0 10 20 30 40 50

Survival Time [LUNI]

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

Survival in group RCBEH

26

Survival Function - RCBEH

Complete Censored

Include condition: interventie=2

0 20 40 60 80 100

Survival Time [LUNI]

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

Influence of caudate lobectomy

27

Categ. Box & Whisker Plot: supravietuire

supravietuire: F(1,50) = 2.6911, p = 0.004097;

Kruskal-Wallis-H(1,52) = 0.9148, p = 0.3388

Mean

Mean±SE

Mean±SD

15.82

19.54

15.82

19.54

absenta prezenta

Rezectia segmentului 1

0

5

10

15

20

25

30

35

su

pra

vie

tuire

[lu

ni]

15.82

19.54

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

Include condition: Rezectia segmentului 1

cu rezect.segm.1

fara rezect.segm.1

0 5 10 15 20 25 30 35 40 45 50 55

Time [luni]

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

28

Influence of vascular invasion

29

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

Invazia arteriala hepatica

Cu invazie arteriala

hepatica

Fara invazie

arteriala hepatica

0 10 20 30 40 50 60 70 80 90 100

Time

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

Influence of portal invasion

30

.

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

cu invz.portala

fara invz.portala0 10 20 30 40 50 60 70 80 90 100

Time [luni]

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

Influence of perineural invasion

31

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

Invazia perineurala

Cu invazie

perineurala

Fara invazie

perineurala0 10 20 30 40 50 60 70 80 90 100

Time [luni]

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

Influence of lymph nodes invasion

32

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

Include condition: interventie chirurgicala

fara invaz.ggl.

cu invaz.ggl.

0 10 20 30 40 50 60 70 80 90 100

Time (luni)

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

33

Influence of complications

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

Include condition: interventie chirurgicala

fara complicatii

cu complicatii

0 10 20 30 40 50 60 70 80 90 100

Time (luni)

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

34

Analysis of the signs and symptoms as predictive

factors of the outcome

Complications vs. signs and symptoms

35

Mortality vs. signs and symptoms

36

The most important sign correlated to patients’ death was

weight loss.

Length of hospital stay vs. signs and symptoms

Signs and

symptoms

Medium

length of

stay

Media

Min Max Q25 Q75 -95% -95%

Jaundice 22.50 18.94 26.06 5.00 64.00 13.00 28.00

Pain 20.09 14.71 25.47 5.00 50.00 12.00 24.00

Nausea 23.20 11.84 34.56 5.00 50.00 14.00 24.00

Weight

loss 22.00 17.86 26.14 11.00 50.00 12.00 32.00

Asthenia 24.36 16.67 32.06 11.00 64.00 12.00 32.00

Anorexia 18.67 15.25 22.09 12.00 25.00 12.00 23.00

Feverus 22.00 3.63 40.37 12.00 32.00 12.00 32.00

Prurit 23.30 18.15 28.45 5.00 64.00 12.00 29.00

37

38

CHAPTER VI

DISCUTIONS

Surgical treatment of CCH has dramatically changed in the

last two decades. Complete surgical resection is now achieved

through aggressive approach, including extended hepatectomies.

This retrospective study reports on a series of 33 patient

operated on with curative intent from 01 January 1994 to 31 July

2004 in Digestive Surgical Service of Centre Hospitalier

Universitaire in Rennes, France. 26 of them had RCBEH and

RHA and 7 patients had only RCBEH.

Statistical research looked for factors which could influence

postoperative outcome or survival.

Patients in the group having RCBEH as operation had

preoperatively jaundice, anorexia and weight loss more frequently

when compared to the other group.

From the laboratory values were statistically significant total

and direct bylirubinaemia (bigger values in the group with

RCBEH) and alkaline phosphatases, ALAT and ASAT, with

bigger values in the group with RCBEH and RHA.

Bismuth-Corlette staging evidenced almost half of the cases

belonged to type III.

TNM staging showed 20 cases T2 and there were no cases

staged T4. N factor was N1 (metastases in regional lymph nodes)

in 12 patients. T factor was correlated with the type of resection.

Resectability was 58.9%; cases staged Bismuth/Corlette type I

(7 patients) received RCBEH and the other types RCBEH and

RHA. In 25 patients from this later group were performed major

hepatectomies.

The operations were significantly longer when hepatectomy

was associated.

39

Negative margins were obtained in 22 patients. In the group

with RCBEH negative margins had 42.86% of the patients while

in the other group the percentage was 73.08. This was statistically

significant.

Lymph nodes were found involved in 36.36% of the patients.

Survival was significantly shorter in these cases.

Resection of the caudate lobe (segment 1) was done in 20

patients, survival being slightly better in these cases.

Portal ipsilateral invasion was found in 30% of the patients, in

this group survival being significantly worse.

Arterial invasion was 27.27%, survival being slightly worse in

these cases.

Perineural invasion was found in 24 of the patients. There was

no significant difference regarding survival.

Morbidity was 66%, including minor and major

complications. When only major complications were taken,

morbidity came down to 19%, all appearing in the group with

RHA.

Statistics showed interesting correlation between preoperative

signs and symptoms and complications. Patients having jaundice,

nausea, anorexia or pain were more probably to have

complications in their postoperative outcome.

Mortality was 15.15% (5 cases), all in the group with RHA.

Weight loss preoperatively was a predictive factor for death.

Length of hospital stay was significantly shorter in patients

with anorexia and longer in the group with RHA. Preoperative

transfusions were 4 times more frequent in the patients with RHA.

40

CHAPTER VII

CONCLUSIONS

This study confirmed aggressive approach in patient with

Klatskin tumours is justified to obtain cure, morbidity and

mortality being acceptable. The following aspects were retained:

1. Pacients which received RCBEH as treatment had more

frequently jaundice, anorexia and weight loss.

2. It was a significant differences for total and direct

bylirubinaemia (bigger values in the group with RCBEH) and

alkaline phosphatases, ALAT and ASAT, with bigger values in

the group with RCBEH and RHA.

3. Half cases were Bismuth-Corlette type III and RCBEH was

applied only for Bismuth-Corlette type I.

4. TNM staging showed there was a correlation between T

factor and the type of resection.

5. From 26 cases with RHA, in 25 were performed major

hepatectomies. Curative resection was more frequently obtained

when segment 1 was resected, survival being better.

6. Curative resection (R0) was obtained more frequently in the

group with RHA.

7. Survival was better when was no arterial, portal or lymph

nodes invasion.

8. Interesting correlation was found between preoperative

signs and symptoms and complications; there were more

complications when jaundice, nausea, anorexia or pain were

present. It also has been found weight loss predicted death.

9. Morbidity and mortality rates were similar to literature. It

was significantly more complications in the group with RHA.

In conclusion, in patients with Klatskin tumours, surgery has

to associate hepatectomies and segment 1 resection. When this is

correctly indicated and performed by experienced teams, this

41

brings benefits in terms of survival and constitutes nowadays

standard for the surgical treatment for the majority of patients.

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