(5.51)--消化系统肿瘤消化系统肿瘤Biliarytractcancer.pdf

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1、Seminar428 Vol 397 January 30,2021Biliary tract cancerJuan W Valle,R Katie Kelley,Bruno Nervi,Do-Youn Oh,Andrew X ZhuBiliary tract cancers,including intrahepatic,perihilar,and distal cholangiocarcinoma as well as gallbladder cancer,are low-incidence malignancies in most high-income countries,but rep

2、resent a major health problem in endemic areas;moreover,the incidence of intrahepatic cholangiocarcinoma is rising globally.Surgery is the cornerstone of cure;the optimal approach depends on the anatomical site of the primary tumour and the best outcomes are achieved through management by specialist

3、 multidisciplinary teams.Unfortunately,most patients present with locally advanced or metastatic disease.Most studies in advanced disease have pooled the various subtypes of biliary tract cancer by necessity to achieve adequate sample sizes;however,differences in epidemiology,clinical presentation,n

4、atural history,surgical therapy,response to treatment,and prognosis have long been recognised.Additionally,the identification of distinct patient subgroups harbouring unique molecular alterations with corresponding targeted therapies(such as isocitrate dehydrogenase-1 mutations and fibroblast growth

5、 factor receptor-2 fusions in intrahepatic cholangiocarcinoma,among others)is changing the treatment paradigm.In this Seminar we present an update of the causes,diagnosis,molecular classification,and treatment of biliary tract cancer.IntroductionBiliary tract cancer refers to a spectrum of invasive

6、adenocarcinomas,including cholangiocarcinoma(cancers arising in the intrahepatic,perihilar,or distal biliary tree),and gallbladder carcinoma.In this Seminar we discuss epidemiology and risk factors,classification of the various subtypes of biliary tract cancer,diagnosis,and treatment(including surge

7、ry and adjuvant therapy in early-stage disease through to the latest developments in molecular profiling,targeted therapies,and immunotherapy for advanced disease)and provide some perspectives for the future.Epidemiology and risk factorsIncidence and causes vary between biliary tract cancer subgroup

8、s and geographical regions(figure 1).1,2 The incidence of cholangiocarcinoma is low in high-income countries(from 035 cases per 100 000 to 2 per 100 000 annually);however,in endemic regions of Thailand and China,the incidence is up to 40-times higher.3,4 The incidence of intrahepatic cholangiocar-ci

9、noma in high-income countries is rising;data from the UK,the USA,and other countries have shown a consistent and steady rise in incidence from 01 cases per 100 000 to 06 per 100 000 over the past 30 years.3,57 Surveillance,Epidemiology,and End Results Program data(19732012)have shown only a slight i

10、ncidence increase in extra hepatic cholangiocarcinoma from 095 cases per 100 000 to 102 per 100 000;however,intra-hepatic cholangiocarcinoma incidence has increased from 044 per 100 000 to 118 cases per 100 000;an average annual percentage change of 23%(44%over the past 10 years)8 even correcting fo

11、r the following coding errors.International Classification of Diseases and Related Health Problems(ICD)codes for cholangiocarcinoma have changed three times(ICD-01 to ICD-02 in 1993,and ICD-03 in 2001)with perihilar cholangiocarcinoma misclassified as intrahepatic chol angiocarcinoma during these ch

12、anges9 and with versions adopted inconsistently globally.The new ICD-11 classification10 includes specific codes for intrahepatic cholangiocarcinoma(2C12.10),hilar cholangiocarcinoma(2C18.0),adenocarcinoma of biliary tract,distal bile duct(2C15.0),and adenocarcinoma of the gallbladder(2C13.0);aiming

13、 to harmonise future epidemiological data.More over,cases of intrahepatic cholangiocarcinoma might be misclassified as metastatic cancer of unknown primary(CUP);11 a number of criteria and new tests,including the newly developed albumin in-situ hybridisation assay,can differentiate between intra-hep

14、atic cholangiocarcinoma and CUP.12Regarding gallbladder carcinoma,an estimated 219 420 new cases and 165 087 deaths were reported worldwide in 2018,13 with substantial variation by gender and geographical region globally.The highest rates are observed in women from southern Chile(27 cases per 100 00

15、0)followed by regions of northern India(215 cases per 100 000),Poland(14 cases per 100 000),south Pakistan(113 cases per 100 000),and Japan(7 cases per 100 000).The incidence is relatively uniform or decreasing in high-income countries,14 probably because of the increase in routine cholecystectomy.T

16、he varying regional incidence of cholangiocarcinoma reflects different underlying risk factors.In general,risk factors for the disease include primary sclerosing cholangitis,Carolis disease,hepatolithiasis,and liver fluke infections.Others include cirrhosis,hepatitis B and hepatitis C infection,obes

17、ity-associated liver disease,and Lancet 2021;397:42844Division of Cancer Sciences,University of Manchester,Manchester,UK(Prof J W Valle MD);Department of Medical Oncology,The Christie NHS Foundation Trust,Manchester,UK(Prof J W Valle);Helen Diller Family Comprehensive Cancer Center,University of Cal

18、ifornia,San Francisco,CA,USA(R K Kelley MD);Department of Hematology Oncology,School of Medicine,Pontificia Universidad Catlica de Chile,Santiago,Chile(B Nervi MD);Division of Medical Oncology,Department of Internal Medicine,Seoul National University Hospital,Cancer Research Institute,Seoul National

19、 University College of Medicine,Seoul,Korea(Prof D-Y Oh PhD);Massachusetts General Hospital Cancer Center,Harvard Medical School,Boston,MA,USA(Prof A X Zhu MD);Jiahui International Cancer Center,Jiahui Health,Shanghai,China(Prof A X Zhu)Correspondence to:Prof Juan W Valle,Division of Cancer Sciences

20、,University of Manchester,Manchester,M20 4BX,UK juan.vallemanchester.ac.uk Search strategy and selection criteriaWe searched MEDLINE and PubMed databases,using the terms“biliary tract cancer”,“cholangiocarcinoma”or“gallbladder cancer”,focusing on randomised trials and other high-quality studies publ

21、ished in English from Jan 1,1995,to March 31,2020.Publications within the past 5 years were prioritised,although older,relevant,high-quality studies were also selected.Meeting abstracts(from peer-reviewed congresses)were also included if deemed to be of high quality and could potentially change prac

22、tice.S Vol 397 January 30,2021 429diabetes.Underlying hepatic inflammation,fibrosis,or cirrhosis are risk factors for intrahepatic cholangio-carcinoma.15 A previous meta-analysis showed that stones,cirrhosis,hepatitis B and hepatitis C are the strongest risk factors for both intrahepatic cholan-gioc

23、arcinoma and extrahepatic cholangiocar cinoma.16 However,recognising that most patients with cholangio-carcinoma have no identifiable risk factors is important.Although in high-income countries cholangiocarcinoma is associated with chronic inflammation of the biliary tree and hepatic parenchyma,in T

24、hailand,chronic infection with liver fluke is the driving risk factor.Endemic liver fluke infection(Opisthorchis viverrini)is associated with eating raw or undercooked fish for 20 years or more.Endemic areas for Clonorchis sinensis are in China,Korea,Taiwan,and Vietnam.17Gallbladder carcinoma has a

25、different pathophysiology than does cholangiocarcinoma with a wide range of predisposing conditions,environmental exposures,and lifestyle behaviours linked to increased risk;gallbladder carcinoma increases with age and is more common in women.Predisposing conditions causing chronic irrita-tion or in

26、flammation of the gallbladder are associated with a higher incidence of gallbladder carcinoma,and cholelithiasis(gallstones)is one of the most strongly associated risk factors with 7090%of gallbladder carci noma cases having a history of cholelithiasis.How-ever,only 053%of gallstone cases result in

27、gallbladder carcinoma.18 Primary sclerosing cholangitis is associated with an increased risk of gallbladder carcinoma(esti-mated 2%lifetime incidence).1921 Structural biliary tree abnormalities,including congenital biliary dila tation and anomalous pancreaticobiliary ductal junction(also known as bi

28、liopancreatic or pancreaticobiliary maljunction),22 chronic Salmonella typhi or Helicobacter bilis infections,23 and obesity24 increase the risk of the disease.Choledochal cysts have a 115%lifetime risk of development into gallbladder carcinoma or cholangio carcinoma.Cancers arising from the ampulla

29、 of Vater(the junction of the pancreatic and distal common bile duct)are Figure 1:Global incidence of cholangiocarcinoma(A)and gallbladder cancer(B)Data for the global incidence of cholangiocarcinoma was reproduced from reference 1,by permission of Banales and colleagues.Data for the global incidenc

30、e of gallbladder cancer was reproduced from reference 2.AB2468101214Cases per 100 00002468101214Incident cases per 100 000Seminar430 Vol 397 January 30,2021sometimes included under the term biliary tract cancers;histologically,they can be pancreatobiliary,intestinal,or mixed and account for only 02%

31、of gastrointestinal cancers.25 They have a distinct clinical course and man agement(diagnostic tests,surgery,and adjuvant treatment)although they have often been included in studies of chemotherapy for advanced disease given their infrequency,but they are not discussed in further detail in this Semi

32、nar.Classificationanatomical and histopathologicalHistorically,biliary tract cancers are classified according to their anatomical primary site.Cancers arising from bile ducts proximal to the second-order ducts are classified as intrahepatic cholangiocarcinoma,those originating between the second-ord

33、er ducts and the insertion of the cystic duct are perihilar cholangiocarcinoma,and those arising from epithelium distal to the insertion of the cystic duct are termed distal cholangiocarcinoma.The term extrahepatic cholangiocarcinoma is used to refer to perihilar(previously referred to as Klatskin t

34、umours,although the use of this term is discouraged)and distal cholangiocarcinoma,collectively.Gallbladder cancers arise from the gallbladder itself or from the cystic duct(figure 2).Three growth patterns have been described for intrahepatic cholangiocarcinoma:mass-forming(78%of cases)consists of a

35、mass lesion within the liver parenchyma(these can be large and can have evidence of central necrosis or scarring as well as mucin production);periductal infiltrating(16%of cases)characterised by infiltration along the bile ducts and portal tracts;and intraductal growing(6%of cases),which feature pol

36、y-poidal growth within the bile ducts.26 Perihilar and distal cholangiocarcinoma can be flat or nodular sclerosing(corresponding to features of periductal infiltrating;73%of cases)or intraductal papillary type(27%of cases).Precursor lesions include biliary intra-epithelial neoplasia(graded 13 depend

37、ing on degree of cellular and nuclear atypia),associated with periductal infiltrating type of intrahepatic cholangiocarcinoma and flat or nodular sclerosing type of perihilar or distal cholangiocarcinoma;and intraductal papillary neoplasms of the bile duct(IPNB),associated with intraductal growing(i

38、ntrahepatic cholangio carcinoma)and intraductal papillary(perihilar and distal cholangiocarcinoma).27 However,the concept that cancers derived from IPNB are necessarily intraductal growing cholangiocarcinoma and intraductal papillary cholan giocarcinoma remains contentious.28 No precursor lesion has

39、 yet been shown for mass-forming intrahepatic cholan giocarcinoma.Most biliary tract cancers are well differentiated,moderately differentiated,or poorly differentiated adeno-carcinomas;rare subtypes include squamous or adeno-squamous,mucinous or signet ring cell,clear cell;undifferentiated,and lymph

40、oepithelial.26 Additionally,mixed tumours consisting of elements of both hepa-tocellular carcinoma and cholangiocarcinoma are well described,although only within the past 10 years has nomenclature been standardised setting the foundations for improved understanding of biliary tract cancer biology an

41、d clinicopathological behaviour.29This anatomical and histopathological classification is complemented by the identification of patient subgroups harbouring discrete molecular aberrations,some of which have therapeutic implications described later in this Seminar.Symptoms and diagnosis The presence

42、and nature of symptoms depends on the anatomical location of the primary tumour and associated metastases,if present(figure 2).Symptoms arise as a result of direct compression(eg,biliary obstruction),can be constitutional or due to underlying pathology(eg,chronic liver disease).Because of their non-

43、specificity,patients usually present with advanced stage disease.Patients can be asymptomatic,and malignancy is iden-tified incidentally,either through detection of deranged liver function tests or imaging undertaken for unrelated reasons.A medical history must include identification of risk factors

44、 and Eastern Cooperative Oncology Group(ECOG)performance status must be reported at physical examination.Liver function tests are essential with additional blood tests looking for evidence of infection,particularly in biliary obstruction(eg,raised white blood cell count,neutrophilia,elevated C-react

45、ive protein and blood cultures).Cross-sectional imaging could involve an ultrasound scan as the first examination.This imaging Figure 2:Clinical presentation of biliary tract cancerIntrahepatic cholangiocarcinoma arises proximal to the second-order bile ducts.Perihilar cholangiocarcinoma arises betw

46、een the second-order ducts and the insertion of the cystic duct.Distal cholangiocarcinoma is distal to the insertion of the cystic duct.Gallbladder cancer arises from the gallbladder itself or from the cystic duct.Extrahepatic cholangiocarcinoma refers to perihilar cholangiocarcinoma and distal chol

47、angiocarcinoma combined.*Biliary obstruction can occur from tumours arising in major bile ducts(perihilar cholangiocarcinoma or distal cholangiocarcinoma),or because of lymph node compression at the hilum.LiverCystic ductGallbladderIntrahepatic cholangiocarcinoma Abdominal pain Might be asymptomatic

48、,even if at advanced stageIncidental gallbladder cancerFound at routine cholecystectomyNon-incidental gallbladder cancerRight upper quadrant painBiliary obstruction*Obstructive jaundiceYellow scleraDark urinePale stoolsPruritusAmpulla of VaterIn patients with establishedchronic liver diseaseSplenome

49、galyAscitesSpider naeviGynaecomastiaCaput medusaeEncephalopathyConstitutional symptomsFatigueAnorexiaWeight lossAbdominal painNight sweatsIncidental findingsDeranged liver function testsFound on imaging for other causeIntrahepatic cholangiocarcinoma Perihilar cholangiocarcinoma Distal cholangiocarci

50、noma Common hepatic ductS Vol 397 January 30,2021 431technique excludes simple gallstone disease and identifies obstruction with upstream dilatation of the biliary tree,examines the gallbladder anatomy,and can identify space-occupying lesions within the liver.Ultrasound examination cannot be used fo