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UDC 616.361-006.4-036.22-08
CHOLANGIOCARCINOMA: TRENDS IN EPIDEMIOLOGY AND TREATMENT
Shumeyko V., Rela M., Heaton N.
HPB and Liver Transplant Unit, King's College Hospital, London, United Kingdom
Cholangiocarcinoma (CC) is a relatively infrequent malignant tumor arising from the biliary epithelium anywhere within the biliary tract. Its incidence is rising and the prognosis is considered poor. The incidence increases exponentially with age, and the majority of CC patients are over 65 years old. Further increases should be expected due to the population ageing. Most patients clinically present with painless obstructive jaundice. Other common symptoms are weight loss and upper abdominal pain. Patients should be offered an extensive diagnostic and staging workup in high-volume high-expertise tertiary centres before definitive treatment can be offered. Surgical resection offers the only prospect of cure with improving results over the last 2 decades. The majority of patients have advanced unresectable disease at presentation and a poor prognosis. Chemotherapy has yet to prove effective. Modern mainstream palliation is nonsurgical relief of biliary obstruction (endoscopic and/or percutaneous stenting). Other modalities such as radiotherapy, photodynamic therapy, high intensity ultrasound are being evaluated for the purposes of palliation and as an adjunct to surgery. UK national consensus guidelines for the diagnosis and treatment of cholangiocarcinoma were published in November 20021. We review mortality statistics, management and outcome data for CC since the document was published.
Key words: cholangiocarcinoma, epidemiology, surgical and nons
Anatomy, Histology and Classification
Yamagiwa in 1911 identified microscopic characteristics which divider primary liver cancers into 2 groups: hepatoma and cholangioma, denoting their cellular origin (not necessarily carcinoma). Goldzie-her and von Bokay further suggested the use of "hepatocellular carcinoma" and "cholangiocellular carcinoma" for malignant tumors originating from these cells.2 Semantic confusion widened with the use of terms "cholangioma", "malignant cholan-gioma", "bile duct cancer", "biliary adenocarcinoma", "Klatskin tumor", etc, and with the proposals to use different terms depending on the anatomical position of the tumor. Nowadays the term "Cholangiocarcinoma" regarded as cancer originating from
urgical treatment
the biliary epithelium anywhere in the biliary tract: intrahepatic, perihilar, gall bladder and distal extra-hepatic.
CC is anatomically classified into three main categories: perihilar CC (also known as Klatskin tumor3), distal CC and intrahepatic CC4 (Figure 1). Perihilar CC is further subclassified depending on the degree of the proximal tumor extension within the intrahepatic biliary radicles according to the classification proposed and later modified by Bismuth5 (Figure 1). Perihilar CC is the most common form of CC accounting for approximately 50-60% of all CC cases. Both Distal and Intrahepatic CC account for approximately 20-25% each.4
Cholangiocarcinoma: Anatomical Classification and ICD-10 Statistical Codes
Intrahepati Cholangiocarcipoma C22.1
Bismuth Types of Perihilar Tumor Extention
Bladder !
Carcinoma.....'
C23 I
Perihilar CC
Type I Type II Type II Ia (Klatskin Tumor) Type IIIb ' C221 Type IV
\
Distal Extrahepatic
Cholangiocarcinoma
1 C24 I
/
Tumor within the Common Hepatic Duct Involves Bifurcation of Common Hepatic Duct Involves the Right Hepatic Duct Involves the Left Hepatic Duct Involves both Right and Left Hepatic Ducts
World Health Organisation (WHO) International Classification of Diseases (ICD) was introduced for statistical purposes in the UK: ICD-9 in 1979 and ICD-10 in 2001. In an attempt to avoid reclassification / diagnosis transfer and double coding during our statistical analysis, correlations between anatomo-histological and WHO statistical classifications of HPB tumors are summarised in the Table 1.
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Table 1. Correlations between anatomo-histological and statistical classifications of HPB cancer
Anatomo-histological classification WHO Statistical classification
ICD-9 ICD-10
All malignant liver tumors 155 C22
Liver cell carcinoma (mainly Hepatocellular Carcinoma, HCC) 155.0 C22.0
Intrahepatic / unspecified site Cholangiocarcinoma (IHCC) 155.1 C22.1
Perihilar Cholangiocarcinoma (Klatskin Tumor, included in IHCC) 155.1 C22.1
Gall Bladder Carcinoma (GB Ca) 156.0 C23
Extrahepatic Bile Duct Tumors (excluding GB Ca) 156.1 C24
All Extrahepatic Biliary Tumors (EHCC) 156 C23+C24
Cholangiocarcinoma of all anatomical sites (CC) 155.1+156 C22.1+C23+C24
Pancreatic Cancer (Pan Cr) 157 C25
Epidemiology and Aetiology
Incidence of Cholangiocarcinoma, predominantly intrahepatic, increases slowly worldwide and almost resembles the mortality figures, as prognosis is extremely poor despite recent diagnostic and treatment advances. In England and Wales there has been a steady rise in the mortality figures from IHCC between 1968 and 1996, with CC becoming primary liver tumor-related cause of death in the UK.6 IHCC is distinctly uncommon in the USA with reported incidence of 0,8 per 105 population7, but continues to rize, especially after 1985. Stable proportion of early stage, unstaged disease, tumour size <5cm and microscopic confirmation suggest a true increase of IHCC rather then a reflection of improved detection or reclassification.8
In the year 2003 in England and Wales there were 1568 reported cases of death due to CC, of which 528 (34%) were of Gall Bladder and Distal Extrahepatic Duct location. The quote of IHCC rose from only 68 (3% of all CC) in 1968, doubling every 7 years, to 1040 (66% of all CC) in 2003. The cause of such a sharp rise is unknown, but several factors are likely to contribute. Hilar cholangiocarcinoma generally regarded by surgeons as Extra-hepatic CC (EHCC), but listed in the WHO International Statistical Classification of Diseases as Intrahepatic (Klatskin's tumor C22.1), confusing incidence and anatomical site - related statistics. This diagnosis transfer / reclassification (EHCC into IHCC) may well contribute to the issue of predominant IHCC rise in many countries.6, 8
Intermediate (combined) hepatocellular-cholangiocarcinoma (bearing immunohistochemical characteristics of both hepatocyte and cholangio-cyte) may be morphologically and phenotypically distinct type of primary liver carcinoma originating from transformed hepatic progenitor cells,9 but is genetically closer to CC than HCC and as such it could share common with CC carcinogenesis path-ways,10 be more often diagnosed as IHCC and as a result contribute to the IHCC incidence increase.
Comparison of mortality figures from HPB tumors over the past 35 years (for which reliable UK na-
tional data available at www.statistics.gov.uk), demonstrates 20% overall increase (Figure 2, top line), with Liver tumors, especially IHCC being a major contributor to this trend (Figure 2, bottom line), followed by Pan Cr. Interestingly, mortality from EHCC decreased at the same time by 50%. Sharp rise of IHCC, decline of EHCC with overall increasing CC mortality could mean that "Cholangiocarcinoma migrates into the Liver". Age-specific mortality followed similar for HCC, CC and PanCr pattern with the peak of deaths occurring in patients' late 70s (Figure 3). In the year 2003 in England and Wales the CC mortality rised to 3 per 105 of general population, retaining stable in decades male/female ratio: equal for IHCC and 1 to 2 for EHCC.11, 12
CC mortality was predictably rising in age groups: doubled for those older than 50 years old, increased 5 fold (15 per 105) for those more than 65, and 8 times (24 per 105) for population in their 80s (Figure 4).
The UK has an ageing population, which grew by 6.5 per cent in the last thirty years or so, from 55.9 millions in 1971 to 59.6 millions in mid-2003. Population increases have not occurred at all ages. Whereas the proportion of the population aged 65 and over has increased, the proportion below the age of 16 is less now than thirty years ago. The percentage of people aged 65 and over increased from 13 per cent in mid-1971 to 16 per cent in mid-2003 (Figure 5). Over the same period, the percentage of the population under 16 fell from 25 per cent to 20 per cent. Over the last three decades, the median age rose from 34.1 years in mid-1971 to 38.4 in mid-2003.11 Continued population ageing is inevitable during the first half of this century, since the number of elderly people will rise as the relatively large numbers of people born after the Second World War and during the 1960s baby boom (55-59 age group, Figure 3) become older, further increasing the incidence of cancers. Why Intrahepatic Cholangiocarcinoma demonstrates so dramatic growth, or rather why Cholangiocarcinoma moves into the Liver, remains to be answered.
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1968 1975 1982 1989 1996 2003
Age-specific mortality from HPB Cancer Figure 3
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45 40 35 30 25 20 15 10 5 0
Age group analysis: Population and Mortality from Cholangiocarcinoma in England and Wales in 2003
Figure 4
Population, hundreds of thousands
Mortality per 10A5 population of same age
35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80 >
Age Groups
Ageing: 16% of UK population are aged 65 or over
100
80
60
40
20
0
Percentages
iiiii
1971 1981 1991 2001 ■ 0-15 ■ 16-64 D65 and over Population: by age, UK
2003
Figure 5
Aetiology of CC is not well understood, but there are several known risk factors, triggering biliary stasis and chronic inflammation of the biliary epithelium, leading to fibrosis, and eventually carcinoma. Worldwide these risk factors include primary sclerosing cholangitis (PSC, 8-14% eventually develop CC13, 3), Caroli's disease and choledochal cysts (10% transform to CC if unresected14), cholangio-lithiasis15, biliary-enteric bypass16, parasitic infestation of the biliary tree (Clonorchis sinensis and Opistorchis viverrini in certain parts of South-East
Asia17,18), HCV-related cirrhosis (increases the risk of CC 1000 fold compared to general population in Japan19). Thorium dioxide, intravascular contrast agent used until 1950's, still echoes with the reports of Thorotrast-induced Cholangiocarcinoma20. Di-oxin-like substances proved to induce both HCC and CC in animal models in a dose-dependant manner, therefore human dioxin cancer risk assessment by WHO dioxin toxic equivalency factor (TEF) was suggested21. Other environmental and industrial exposures (low levels of radionuclides,
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asbestos, polychlorinated biphenyls, nitrosamines, tobacco smoke, isoniazid, oral contraceptives) and their combinations have also been reported to be associated with CC22. However, most patients with CC do not have any identifiable risk factors.
Diagnostics and Staging.
Clinical and laboratory features depend on the location of tumor within the biliary system and the stage of the disease. Most patients with EHCC present with the clinical picture of the progressive biliary obstruction: painless increasing jaundice, pale stools, dark urine and pruritis1. Cholestatic biochemical profile (rised bilirubin, alkaline phosphatase and y-glutamyl transferase) is common, aminotransferases are usually normal but may be rised in acute obstruction or cholangitis, serum CA19.9 values greater than 100 U/L in the absence
1 23
of cholangitis are highly suggestive of CC , . Cholangitis symptoms (right upper quadrant pain, fewer, rigors) may occur, mainly after invasive biliary procedures1,2 . IHCC patients' clinical presentation is that of a liver mass with variable symptoms. Cholestatic biochemical profile in the absense of jaundice may indicate unilobar bile duct obstruction. Non-specific systemic cancer manifestations (abdominal pain, anorexia, weight loss, malaise, night sweats) evolve with tumor progression and often indicate the advanced stage of the disease, in which the majority of CC patiens present24. Seldom CC cases are detected incidentally in early stage by imaging or laboratory tests performed for other indications.
There is an ongoing search for reliable tumor markers, which could be used for diagnostics as well as screening of population at risk. The sensitivity and specificity of serum IL-6 for distinguishing benign from malignant biliary strictures were reported as 71% and 90% respectively35. Biliary isoenzyme of alkaline phosphatase (BALP) in non-jaundiced patients differentiated CC from other malignancies with 85% sensitivity and 79% specificity35. High levels of serum sialyl Lewis (a) marker (sLea) have been demonstrated to denote mass-forming type of tumor growth, vascular invasion, and poorer prognosis32.
Diagnostics of CC requires a multidisciplinary approach and is not always straightforward. When suspition of CC is raised on the clinico-laboratory basis, ultrasonography is usually the initial imaging modality, most commonly obtained by primary care physicians. It can exclude gall stone disease, evaluate the extent of biliary system dilatation and sometimes spot intrahepatic lesions; Dopler scan allow assessing blood flow in the portal vein (PV) and hepatic artery (HA), which can be compressed by the tumor. Intraductal ultrasonography (IDUS) is a reliable method for the evaluation of cholangio-carcinoma, and accurate staging is the most significant role of IDUS (3D tumor volume calculation, assessment of the tumor extension and the relationship with surrounding organs, especially portal vein
and pancreas)25. Quantification of contrast-enhanced ultrasound offers the possibility of an investigator-independent characterization of lesions and should be evaluated in further studies26. Conventional CT may help detect the primary tumor, dilated bile ducts, lympadenopathy and systemic spread (lung metastases). However, contrast-enhanced thin-cut spiral CT and/or liver MRI/MRCP can provide much more information on the hepatic parenchymal abnormalities and small liver lesions, ductal architecture and site of obstruction, liver vas-culature involvement and abdominal lymphade-nopathy. Three-dimensional computerized image reconstruction, offered by MRI/MRCP, may be a useful addition in planning surgical resection or palliative stenting, but the overall diagnostic performance of MRI is comparable to CT in identifying primary liver malignancies27. Positron emission tomography (PET) can be useful in assessing the extent of the disease and metastases in difficult cases, although false-positive results have been reported28. The test of choice to evaluate suspected cholan-giocarcinoma is cholangiography: magnetic resonance cholangiopancreatography (MRCP), endo-scopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholan-giogram (PTC). Each modality has its own advantages as well as limitations. Noninvasiveness of MRCP allowed recommending it as an optimal initial investigation1 if available. ERCP / PTC provide biliary tree images and facilitate cytological diagnosis (fine needle aspiration / brushing), endoscopic IDUS and treatment (stenting), but expose patient to the risk of postprocedure cholangitis / pancreatitis.
Histological confirmation of EHCC is notoriously difficult because of the intense desmoplastic nature of the tumor, leading to variable sensitivities with routine tissue acquisition techniques such as brush cytology and fine needle aspiration. Newer cytological analysis techniques such as digital image analysis (DIA) and fluorescent in situ hybridization (FISH), which appear promising in improving the sensitivity in diagnosing malignant biliary strictures, are currently been evaluated13. Confirmation of IHCC is less problematic: a needle biopsy specimen of a liver mass demonstrating an adeno-carcinoma in the absence of an alternative primary tumor (excluded clinically, by chest x-ray and ab-domino-pelvic CT).
Staging / Preoperative evaluation for re-sectability
Patients usually present to tertiary referral centres having had some preliminary evaluation, most commonly US, CT scan and cholangiography (ERCP, PTC or MRCP), in many cases histological verification have been attempted and endobiliary stents have been placed29.
Patients with suspected CC first assessed for medical fitness in anticipation of a major abdominal operation. Then the resectability is evaluated once they are deemed medically fit. Staging of CC is ac-
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cording to the American Joint Committee on Can-
30
cer TNM staging scheme, revised in 2002 . Intrahepatic CC is staged as primary liver cancer similar
As many as 50% of CC patients are stage III and 10-20% stage IV upon presentation (60-70% are unresectable upon presentation)31. This staging system does not take into account all surgically important details, therefore D'Angelica, Jarnagin and Blumgart in 2004 proposed to adjust T-stage criteria for hilar CC by introducing few more tumor-related factors influencing resectability and survival (the extent of contralateral biliary tree and vasculature involvement + atrophy of potential liver remnant).
Unresectable CC, summary:
• Non-local disease: remote systemic / peritoneal / liver metastases M1
• Extensive local disease: major invasion of adjacent organs / vasculature T4
• Vital structures of potential liver remnant invaded with no surgical reconstruction possible T3adj2004
Resectable tumor is defined as amenable to complete resection, while preserving a well-perfused sufficient size hepatic remnant with adequate biliary drainage29.
If the staging evaluation does not demonstrate evidence of locally advanced (T4) or metastatic (M1) disease and the patient has no other comor-bidities precluding surgical intervention, the patient should be referred for consideration of curative re-
to HCC. Extrahepatic CC staging is outlined in the table 2.
Table 2
section.
When, based on preoperative imaging, an extended hepatectomy is anticipated, ipsilateral Portal Vein Embolisation (PVE) can be utilised to induce contralateral hypertrophy of suggested hepatic remnant and thus decrease postoperative hepatic dysfunction in selected patients (especially if the predicted liver remnant volume is less than 25% of total liver volume)33. Transhepatic Right PVE including SIV appears to be safe, increase future liver remnant volume by up to 80% and reduce pospop-erative complications rate after extended right hepatectomy34.
Laparoscopy is increasingly recognised as a useful tool to clarify the resectability of liver malignancies. For hilar cholangiocarcinoma laparoscopy can correctly identify unresectable disease in 1/3 of patients and therefore recommended before attempting at resection36.
Treatment
Surgery is the only curative treatment for patients with CC. Table 3 summarises main results of series of surgical resections and orthotopic liver transplantations (OLTx) for cholangiocarcinoma, published within the last 3 years.
American Joint Committee on Cancer TNM staging for Extrahepatic Bile Duct Tumors (revised 2002)
Primary Tumor T TX Primary tumor can not be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor confined to the bile duct histologically
T2 Tumor invides beyond the bile duct
T3 Tumor invades the liver, gall bladder, pancreas and/or unilateral branches of the portal vein (right or left) or hepatic artery (right or left)
T4 Tumor invades one of the following: main portal vein or its branches bilaterally, common hepatic artery, or other adjacent structures, such as the colon, stomach, duodenum or abdominal wall
Regional Lymph Nodes N NX Regional lymph nodes can not be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastases
Distant Metastases M MX Distant metastases can not be assessed
M0 No distant metastases
M1 Distant metastases
Stage 0 Tis N0 M0
IA T1 N0 M0
IB T2 N0 M0
IIA T3 N0 M0
IIB T1-3 N1 M0
III T4 Any N M0
IV Any T Any N M1
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Table 3
Authors, year published Number of cases presented, main results Predictors of outcome, author's conclusion
Ohtsuka M, I to H et al, 200237 62 pts underwent laparotomy for IHCC, 48 hepatectomies (resectability 77%). 1-, 3-, 5-year survival - 62%, 38%, 23%. All pts with intraductal growth - alive. Multiple hepatic lesions, high level of CA19-9 were significant negative prognostic factors. Recurrence in 30 patients, most common site - remnant liver.
Nakagohri T, Asano T et al, 200338 40 pts IHCC. 5-year survival: perihilar CC - 43%, hilar-invasive CC - 4%. Hilar-invasive CC had 100% perineural invasion and 85% nodal involvement. Perineural invasion, positive resection margin and lymph nodes involvement associated with worse survival. Tumor-free margins - aim of curative resection.
Abdalla EK, Barnett CC et al 200339 42 pts -marginal candidates for extended hepatectomy because of small liver remnant size. Overall 3-year survival 65%, similar in PVE and non-PVE pts. Portal vein embolization enables safe and potentially curative extended hepatectomy in marginal (small liver remnant) candidates with non-increased morbidity and mortality.
Chi-Leung Liu, Sheung-Tat Fan et al, 200240 12 pts with combined HCC-CC. 7 (58%) were HBV positive, 9 (75%) had underlying chronic liver disease. After hepatic resection median disease-free survival was 10, overall - 17 months. Clinico-pathological features of HCC-CC pts were close to those of HCC pts, but survival after hepatic resection was significantly worse and similar to CC outcomes. Postop adjuvant therapy and further studies needed.
Rea DJ, Munoz-Juarez M et al, 200441 46 pts underwent partial hepatectomy, bile duct resection and lymphadenectomy for Hilar CC. Perioperative mortality 9%, surgical morbidity 52%. 1-, 3-, 5-year survival - 80%, 39%, 26%. Male sex, lymph node meta, tumor grade 3 or 4, high bilirubin and APTT at diagnosis, transfusion of more than 4 units of blood perioperatively - negative survival prognosis. Frequent local and regional recurrence.
Kelley ST, Bloomston M et al, 200442 94 pts (32-distal tumor, 10-midduct, 52- proximal/intrahepatic lesions) had resections for CC: 34 pancreato-duodenectomies, 23 bile duct resections, 37-bile duct + hepatic resections. Mean survival 27-32 months, with negative margins - 34, positive - 24-24 months. Tumor location and type of operation did not influence survival. TNM stage failed to predict survival. Margin status influenced duration of survival. Adjuvant treatment prolonged survival. Aggressive surgical approach followed by adjuvant therapy advocated.
Zervos EE, Pearson H et al, 200443 31 pts had concomitant biliary and hepatic resections for hilar CC. 5 (16%) died perioperatively. 16 (52%) had one or more complications. 1-, 3-, 5-year survival was 69%, 33% and 26% respectively. AJCC stage and margin status did not impact long-term survival after resection. Concomitant hepatic and biliary resections for Klatskin tumors carry relatively high risk but offer hope for long-term survival.
Lang H, Soti-ropoulos GC et al, 20 0544 27 pts underwent extended hepatectomy for locally advanced intrahepatic CC (>4 segments). Following resection, the overall 1- and 3-year-survival rates were 69% and 55%. R0-resection can provide prolonged survival, even in patients with advanced IHCC. Improved preoperative assessment of resectability + aggressive surgical approach help to achieve complete tumor resection.
Dixon E, Vollmer CM Jr et al, 20 0545 99 pts with GB Ca treated, 38 underwent surgery with curative intent. Perioperative mortality 2%, morbidity 49%. Margin-negative resections in both times associated with better survival rates. A margin-negative resection leads to improved survival in patients with gallbladder cancer. Later introduced radical surgical approach facilitated improved median survival time.
Shimada H, Endo I et al, 20 0346 39 pts had hepatectomy for advanced CC (perihilar or GB), of which 15 with vascular (PV and/or HA) reconstructions. Morbidity in the vasoreconstructive group was 33,3-66.7-83.3% for PV-HA-both reconstruction and 70.8% without, mortality 13.3%, without - 8.3%. 3-year survival 33% vs 42%, 5-year 18% vs 25% Hepatectomy with vascular reconstruction extends the potential curability of the operation with acceptable morbidity and mortality, but is not recommended for advanced GB Ca.
Stein DE, Heron DE et all, 20 0547 28 pts underwent resection for CC, 23 of whom adjuvant radiotherapy. Median and 5-year survival were 21.5 months and 18.4% in the margin-negative group and 26 months and 15% in margin- Positive microscopic resection margins in lymph node negative resected hilar cholan-giocarcinoma may not represent a negative prognostic factor when resection is combined with postoperative radiotherapy.
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positive.
Wakai T, Shirai Y et al, 20 0548 84 pts who underwent curative surgery for extrahepatic / hilar CC, analysed on how carcinoma in situ or invasive residual carcinoma at the ductal resection margin influence survival. Median survival time after R0 - 45 months, Ris - 99 months, R1 - 21 months. Invasive CC at resection margins has a strong adverse effect on pts survival, whereas carcinoma in situ - does not. Positive microscopic resection margins in lymph node negative resected hilar CC may not represent a negative prognostic factor when resection is followed by radiotherapy.
Jitsma AJ, Appeltans BM et al, 200449 42 patients underwent a combined extrahepatic bile duct resection (EHBDR) and liver resection (LR) for hilar CC. The 1-, 3-, and 5-year actuarial patient survival was 72%, 37%, and 22%, respectively. Median survival was 19 months. Hospital mortality, all due to septic complications, was 12%. Morbidity was observed in 32 patients (76%). Over 20% of the patients with hilar cholan-giocarcinoma can survive more than 5 years after a combined EHBDR and LR at the cost of 12% perioperative mortality and 76% morbidity. Results might improve with the prevention of infectious complications and improved selection of patients to avoid vascular reconstruction and to predict a negative nodal state.
Kondo S, Hi-rano S et al, 200450 40 consecutive pts, no positive resection ductal margins, 2 periarterial invasions. 0% postoperative mortality and 48% morbidity, 3 year survival rate 40% and median survival time 27 months. No postop mortality and no positive ductal margins achieved in a high-volume expert centre, however long-term survival have not been significantly improved. Need for increased radicality suggested.
Otto G, Ro-maneehsen B et al, 200451 82 pts with Hilar CC. Resection rate 75%, hospital mortality 7%. 3-year survival after curative en-block resection was 61%, hilar resection - 25%, palliative -15%. Tumor-free resection margin was the only significant prognostic factor of survival. Sophisticated diagnostic workup is not an absolute prerequisite for adequate surgery.
Sudan D, DeRoover A et al, 200252 17 pts underwent neoadjuvant biliary brachytherapy for non-resectable CC, 5 shown progression of tumor, 11 underwent OLTx 1-26 months post diagnosis. 6 deaths post-OLTx, 2 due to tumor recurrence, 3 - sepsis, 1 -retransplanted for chronic rejection, then graft failure due to HA trombosis. Brachytherapy + orthotopic liver transplantation for unresectable CC achieved long-term tumor-free survival in 5 (45%) of patients. Complications of percutaneous transhepatic biliary catheter placement for brachytherapy associated with poor outcome. CC should not be considered an absolute exclusion criterion for OLTx.
Heimbach JK, Haddock MG et al, 200413 Pts with PSC have 8-12% risk of developing CC. Survival following OLTx for unresectable perihilar CC mass lesion if present <3 cm, is greater than 80% at 5 years. Pts with IHCC are not eligible for OLTx.
Brandsater B, Isoniemi H et al, 200453 CC was found in 14% of explanted livers of 223 patients who had OLTx for PSC. 1-, 3- and 5-year patient survival rates were 65%, 35% and 35% respectively.
Axel rod D, Koffron A et al, 20 0554 5 pts had neo-adjuvant chemoradiation and living-donated OLTx for otherwise inoperable CC as a primary indication with 100% recurrence-free survival at a mean follow up of 18 months.
surgical approach
centres show modest improvement in the outcomes struction46 extend the potential curability of the op-
of surgery for CC: 1-, 3- and 5-year overall survival of 686 CC patients was 70%, 42% and 22% respectively with median postoperative survival of 23 months, overall surgical morbidity of 58% and perioperative mortality 8.5%. Hepatic resections for CC are associated with a higher operative morbidity and mortality, than that for other disorders - a fact likely to be related to infective complications of preoperative biliary stenting29. Major factors influencing survival after curative surgery: resection margin
,. ,. 38,42,44,45,47,48,50,51 * 38,41,48 , u
status......., tumor grade , , , lymph
node status38,41; most common recurrence site -resection margin / liver remnant37. TNM and AJCC stage fail to predict outcome after surgery42,43. Pre-operative portal vein embolisation39, aggressive
eration. Adjuvant treatment prolonges survival40,42,47. Spectrum of procedures: pancreatoduodenectomy, extrahepatic bile duct excision, partial hepatectomy or their combinations. Latest results of OLTx for CC are encouraging13,53,54, clearly indicating that carefully selected patients can benefit from liver transplantation.
Palliative procedures
The majority of patients diagnosed with CC (6070%) are not candidates for surgical resection with curative intent because of either advanced stage of disease or comorbid medical conditions precluding surgery, with survival expectancy usually less than 18 months. In this large group, palliation of obstructive jaundice becomes the first priority. It primarily
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involves relief of cholestasis and can be achieved surgically (mainly when attempted laparotomy reveals unresectable disease), endoscopically (mainstream palliation with high success rate and low cost) and percutaneously (usually when endoscopic attempts failed). Important considerations, when contemplating palliative therapy in patients with un-resectable CC, are life expectancy, quality of life, complication rate, minimal invasiveness and cost. Self-expanding metal stent (SEMS) placement is the most effective palliation of malignant biliary stricture, but cost-effective only if no liver metastases and life expectancy at least 3-6 months55. It allows for a much longer duration of stent patency because of the larger diameter of the SEMS comparing to plastic stent. Latter, especially when of smaller calibre, becomes covered by a biofilm of bacteria and proteinaceous material with median time to obstruction of 5 months. Many endoscopists recommend preemptive replacement of plastic stent to avoid complications of it's obstruction 556. It is known that only 25-30% of the liver needs to be drained to achieve sufficient palliation of obstructive jaundice57. In patients with complex hilar stricture involving both hepatic ducts, unilateral SEM stent-ing of dominant lobe, detected by preprocedure MRCP or CT, provides sufficient palliation with fewer complications rate than bilateral58,59,60. In an attempt to control local tumor growth in patients with inoperable CC and/or as an adjuvant therapy after surgical resection of CC, intraluminal brachy-therapy (ILBT) was tried with no obvious benefit but increased incidence of complications61.
Photodynamic therapy (PDT) involves the intravenous administration of a photosensitizer that preferentially accumulates in malignant cells and subsequent its photoactivation by endoscopically applying laser light directly to the malignant biliary stricture. This results in the formation of oxygen radicals in the tumor tissue and destruction of the tumor cells. Randomised prospective study by M.E. Ortner and colleaques demonstrated significant efficacy of PTD as adjunction to biliary stenting in palliating of hilar CC and actually prolonging survival: median survival was 493 days in a stent+PTD group versus 98 days in stent-only group62. This study is extremely encouraging, and PTD could prove to be an important modality in the palliation of patients with unresectable CC, a group for whom there is little else to offer.
Other studies demonstrated benefit of PTD for palliation and safe addition to surgical resection of CC with positive ductal margins63,64,65. Localised ablation of tumor cells by high intensity intraductal ultrasound is another new modality currently being evaluated as a potential therapeutic and palliative addition..
Oncologic approaches in cholangiocarcinoma treatment
Neither radiotherapy nor chemotherapy proved to be effective for the treatment of CC1. Although 5-fluoruracil- and Gemcitabine-based regimens have
partial response rate of 20-30% with well tolerable toxicity66,6 , improval of patients' survival has yet to be demonstrated24. Takada and colleaques68 published the results of multicenter prospective randomised controlled trial on the effect of postoperative adjuvant chemotherapy for pancreatic and biliary cancer. There was a clear benefit of mitomycin C and 5-fluoruracil adjuvant chemotherapy for GB cancer, but not for other biliary or pancreatic cancer survival. The results of other trials were less encouraging so far69,70. New therapeutic modalities, targeting tyrosine kinase and epidermal growth factor receptors24,71, are being preclinically evaluated. Hepatic arterial infusion chemotherapy has a potential to deliver high concentrations of therapeutic agents to the locus morbi, and indeed report from Japan of 2 stage IV CC cases responding to this treatment was quite optimistic72.There is a need for futher randomised controlled trials with survival to be the primary aim.
References
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2. Okuda K, Nakanuma Y and Miyazaki M. Cholangiocarcinoma: recent progress. Part 1: Epidemiology and etiology. J Gastroenterol Hepatol 2002; 17: 1049-1055.
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Реферат
ХОЛАНГИОКАРЦИНОМА: ТЕНДЕНЦИИ В ЭПИДЕМИОЛОГИИ, ДИАГНОСТИКЕ И ЛЕЧЕНИИ
Шумейко В., Рела М., Хитон Н.
Ключевые слова: холангиокарцинома, эпидемиология, хирургическое и нехирургическое лечение
Холангиокарцинома (ХК) - относительно редкая злокачественная опухоль, возникающая из билиар-ного эпителия в любом отделе желчного тракта. Заболеваемость ею медленно увеличивается в ОК и во всем мире, и почти соответствует смертности, поскольку прогноз однозначно неблагоприятный. Заболеваемость возрастает экспоненциально с возрастом, большинство ХК пациентов старше 65 лет. Ожидается дальнейший рост заболеваемости в связи со старением популяции. Большинство пациентов обращаются с безболезненной обструктивной желтухой. Другие характерные симптомы - потеря веса и боль в верхнем этаже живота. Хирургическая резекция - это единственная надежда на излечение, с улучшающимися в течение последних десятилетий морбидностью, смертност1 и частотой выживаемости, хотя большинство пациентов на момент обращения имеют позднюю, нерезекта-бельную стадию болезни и соответственно очень неблагоприятный прогноз. Химиотерапии еще предстоит доказать свою эффективность в лечении ХК. Современной основой паллиативной тактики является нехирургическое устранение билиарной обструкции (эндоскопическое или чрескожное стен-тирование). Другие виды лечения, такие как радиотерапия, фотодинамическая терапия, высокоинтенсивный ультразвук в настоящее время оцениваются для целей паллиации и сочетания с хирургией. Основываясь на лучших доступных доказательствах и дискуссии экспертов, национальное руководство ОК по диагностике и лечению холангиокарциномы было опубликовано в ноябре 2002 года, признано и принято многими центрами. В настоящем обзоре мы попытались пересмотреть недавнюю статистику, отметить прогресс в диагностике и лечении ХК с момента опубликования документа и представить это в клиническом контексте.
Реферат
ХОЛАНГЮКАРЦИНОМА: ТЕНДЕНЦ11У ЕП1ДЕМЮЛОПТ, Д1АГНОСТИЦ1 I Л1КУВАНН1
Шумейко В., Рела М., Х1тон Н.
Ключов1 слова: холанпокарцинома, епщемюлопя, х1рурпчне та не х1рурпчне лкування
Холангюкарцинома (ХК) - вщносно нечаста злоякюна пухлина, що виникае з бт1арного еп1тел1ю в будь-якому вщдт1 жовчного тракту. Захворюванють нею повтьно збтьшуеться у ОК \ в усьому свт, \ майже вщповщае смертности осктьки прогноз однозначно несприятливий. Захворюванють зростае експоненц1ально з вком, бтьшють пац1ет1в з ХК старше 65 роюв. Очкуеться подальший рют захво-рюваност1 у зв'язку з1 старнням популяци. Бтьшють пац1ент1в звертаються з безболюною обструктив-ною жовтяницею. 1нш1 характеры симптоми - утрата ваги \ бть у верхнм частиы живота. Х1рурпчна резекця - це едина над ¡я на лкування з позитивними показниками морбщност1, смертност1 та частотою виживаност1, хоча бтьшють пац1ет1в на момент звертання мають тзню, нерезектабельну стад1ю хвороби \ вщповщно дуже несприятливий прогноз. ХЫотерапи ще мае довести свою ефективнють у лкуваны ХК. Сучасною основою пал1ативноТ тактики е нех1рурпчне усунення 51л1арноТ обструкци (ендоскопнне або черезкожне стентовання). 1нш1 види лкування, так1 як рад1отерап1я, фотодинам1чна тератя, високо1нтенсивний ультразвук у наш час оцнюються для ц1лей пал1ац1Т у сполучены з х1рург1ею. ^рунтуючись на кращих доступних доказах \ дискус1| експерт1в, нац1ональне кер1вництво ОК з д1агностики та л1кування холанг1окарциноми було опублковано у листопад! 2002 року, визнане \ прийнято багатьма центрами. У огляд1 ми спробували переглянути недавню статистику, вщм1тити про-грес у д1агностиц \ л1куванн1 ХК ¡з моменту опублкування документа \ представити це в кпннному контекст!.
