hello this is Dr Stanley Kim again currently I'm working at Guam Regional Medical City in Guam it's very nice to work in a tropical island during the winter time today we will discuss calendar carcinoma and the Goldwater cancer cholangiocarcinoma is a cancer of a bile duct and the incidence is not that high but recently the instance of intra hepatic cholangiocarcinoma is rising rather rapidly until recently we had a very limited options in treatment and the prognosis were not that good but for the past two three years tremendous progress was made in the diagnosis and the treatment of biliary cancer it's mostly due to Advanced advancements of technology and molecular science and the development of new targeted therapy and immunotherapy let's discuss more in detail and thank you for watching carcinoma rises from bile ducts and the gallbladder cancer from gallbladder and the cystic duct the cystic duct cancer is classified as gallbladder cancer they are mostly adenocarcinoma and the squamous of carcinoma is less common but the treatments are the same collagiocarcinoma is more common in men and the gallbladder cancer predominates in women the instance is about one to two cases per hundred thousand in the U.S each but they are much more common in agents Native Americans in the South Americans usually occurs in age group 50 to 70 but the age of onset is much younger when the cancer rises from primary sclerosing cholangitis or colodocal cyst the risk factors of cholangiocarcinoma include primary sclerosing cholangitis very important others are collodocosist hepatolithiasis the gallstone disease in the hepatic bile ducts alcohol and smoking hepatitis C liver cirrhosis genetic predisposition syndrome such as Lynch syndrome hereditary hemochromatosis cystic fibrosis and liver flukes commonly seen in Southeast Asia HIV infection diabetes and obesity or contraceptives the dpp4 Inhibitors are controversial issue the example of dpp4 inhibitor is Genovia used for diabetes treatment among gallbladder cancer risk factors gallstone is the most important it's seen in 80 percent of gall bladder cancer but gallbladder cancer occurs in very minute group of patients with the gallstones so not all patients with gallstone require uh cholecystectomy but the porcelain gallbladder is different it's a classified gallbladder walls about two to three percent of gallbladder porcelain gallbladder develops gallberry cancer so they need to have cholecystectomy large Global air polyps is strongly associated when the size of polyp is one centimeter or larger they require cholecystectomy because of 20 to 30 percent of them Harbor gallbladder cancer other factors are primary sclerosin colonialities chronic asymptomatic carrier for some other infection of gallbladder anomalous pancreatopillary Junction diabetes and obesity please look at this picture the anatomy of biliary system biles are produced in the liver a drained through the bile duct eventually into the duodenum to mix the fruit to digest them like a small Brooks Creeks become a streams and the river eventually the biles have drained through the intra hepatic ducts and then they become right and the left hepatic ducts when they uh United become a common hepatic dogs after cystic duct is uh added it become a common bile duct kolangiocarcinoma is classified by their locations into intrapatic and extra hepatic cholangiocarcinoma please look at this picture the cancer in the intrapatio bile ducts or intrapatical angiocarcinoma outside the laborer extra hepatic cholangiocarcinoma which are subclassified into perihila cholangiocarcinoma and the distal cholangiocarcinoma the perihila cancer in the hepatic duct and the distal in the common bile duct and the classical tumor indicate that it means that cancer Arise at the Confluence of right and the lab the hepatic duct bismuth Colette classification is for perihila cholangiocarcinoma which is the most common types of cholangiocarcinoma although the instance of intrapatical angiocarcinoma is arising there are four types type 1 cancer in the hepatic common hepatic duct type 2 it involves the Confluence of right and the left hepatic duct type 3 involves either right or left hepatic duct Type 4 both hepatic ducts or multiple locations on the location of clangiocarcinoma the clinical manifestations are different for example patients with the intrapatical angiocarcinoma they develop abdominal pain weight loss less commonly jaundice because it doesn't involve the artillery duct that much as as much as extra hepatic cholangiocarcinoma their symptoms are mostly biliary obstruction jaundice itching dark urine etc etc as disease progresses abdominal pain and the weight loss and fatigue when cholangitis develops patients can have fever pain and sweating but gallbladder cancer is different mostly they don't have any symptoms so most cases are diagnosed during or after cholecystectomy done for Cold Stone or acute cholecystitis or Chronicles about 10 are diagnosed before surgery so the symptoms and the signs are mostly gallstone or cholecystectomy abdominal pain nausea vomiting anorexia when the tumor invades the bile duct then they develop obstructive jaundice cover zero signed called palpable gallbladder in the jaundice patients was originally considered as a sign of gallbladder cancer or pancreatic cancer but now it now we know that it can be seen in benign conditions such as chronic pancreatitis or colodocal cyst meritsu syndrome is the symptom complex of compression of common bile common hepatic duct by impact and impacted Stone in the world of the neck they develop pain jaundice fever if cholangitis develops it can be the symptoms of gallbladder cancer Imaging studies are very important for hepatibility malignancy diagnosis and management that include ultrasound multi-phasic multi-detectoral cd CT scan MDC City MRI and MRCP ercp endoscopy ultrasound percutaneous transeptical angiography introduct ultrasound and for metastatic workups CT scan of the chest and the PET CT scan transabdominal ultrasound detects both intra and extra hepatobiliary duct dilatation and also it visualized the gallstone gallbladder polyps very well large polyps bigger than a one centimeter larger and the wall thickening without cholecystitis are suspicious Signs of gallbladder cancer gallbladder cancers are found in 23 percent of gallbl a large gallblower polyps one centimeter or larger this is the perihila colangiocarcinoma sent in the ultrasound the same cancer is seen in the um CT scan as a thickened enhancing bile duct this is ultrasound image of gallbladder cancer inside a gallbladder multi-phasic multi-detectoral City mdct and the MRIs are very useful for proximal uh Cola colangiocarcinoma detecting intraepatic tumor and also good for extra hepatic cholangiocarcinoma by locating the level of biliary obstruction please look at this multi-detector role CT scan of the intra hepatic cholangiocarcinoma the same tumor is much better visualized in the avocado septic acid enhance the MRI invading the liver fine parenchyma mdct is good in assessing vascular Invasion and there is receptability but not as good as for lymph node involvement and also patients with a primary sclerosis and cholangitis can have lymphadenopathy so sometimes lymph node biopsy is necessary to distinguish metastatic lymph node from reactive or lymph nodes mlcp look at this picture the MRCP visualize the proximal and the distal bile ducts it's not invasive because we don't use contrast interestingly the biles function as a contrast in this case it's very good in assessment the tumor extent and also MRCP accurately detects the common bile duct stone helpful to distinguish it from tumor but I like to mention that this MRCP should be done before ercp or uh or other polarity compression because when the bile is full in the uh biliary trick biliary ducts causing dilatation the image is much more clear ercp is more invasive you can use the uh uh to get the cytology and the biopsy and also we can place the stent or even sphincterotomy to release the obstruction the stent has two kinds metal stand like this picture or plastic stent the metal stance has a longer patent rate 6 to 12 months but cannot be removable because tumor or tissues can grow over this stent plastic stent is replaceable removable but the patent rate is very short three to four or five months this ercp can cause complications pancreatitis cholangitis bleeding preparation and even death in one percent or less surgical before surgical resection of many patients already had ercp or per contentious transparticle on geography too decompress stabiliary obstruction but usually not recommended unless patients have a very high bilirubin level over 10 milligram per ml or the surgery is delayed or for for example patients undergo neoadigment chemotherapy then you can decompress the biliary obstruction before surgery when ercp cannot decompress the bilio obstruction you use we use percutaneous transparatic cholangiography PCT and the biliary drainage please look at this picture by looking at the ultrasound images the Interventional Radiologists introduce the needle through the skin and the liver into the dilated bile duct and then you drain this spile through the catheter into the external bag we inject the Earth contrast you can see the uh cholangiography it may cause seeding of cancer cells in the draining tract so before surgery you need to discuss with the surgeon if it's okay or not endoscopic ultrasound is very useful in accurately assessed the tumor penetration depth of invasion lymph node status extra biliary uh organ involvement and also you can have fine needle aspiration biopsy or can obtain the bile specimen for cytology the intra-ductor ultrasound is one step further you introduce the small cath a cannuler into the common bile duct or even pancreatic duct to take up images of ultrasound of course you can obtain the uh bile specimen for the psychology and the fine needle aspiration at the same time now let's discuss tumor markers ca19-9 cea Alpha pherom protein for hepatocellular carcinoma IG G4 ca199 is elevated in about 80 percent of cholangiocarcinoma with a normal value less than 37 unit per ml it also elevated in gallbladder cancer pancreatic cancer and the benign conditions such as primary sclerosis and cholangitis pancreatitis biliary obstruction non-specific cholangitis and even in renal failure because patients with a primary sclerosis and cholangitis a little a little bit High ca12 ca19-9 doesn't necessarily means a patients have a or Colonial carcinoma so when you suspect that the cutoff level has to be much higher higher than 129 unit per ml Lewis blood group group negative patients have a false negative ca19-9 because even they have a cancer the Lewis because Lewis antigen is needed for to produce ca19-9 they have a zero ca19-9 about five to ten percent of general population have a lowest blood group negative very high level of ca199 more than one thousand unit indicate unresectable Advanced diseases especially peritoneal metastasis and the cea is a well-known non-specific tool marker and is elevated in 60 to 70 percent of calendula carcinoma so when both ca19-9 and the ca are high then it's very good uh in suspicious in diagnosis of colonial carcinoma Alpha fear of protein as we know is elevated in hepatocellular carcinoma and a mixed hepatocellular Colonial carcinoma not in pure Colonial carcinoma igg4 is a marker for autoimmune cholangitis such as primary sclerosis cholangitis but it also may be elevated in cholangiocarcinoma so it cannot use to distinguish primary sclerosis and cholangitis from cholangiocarcinoma let's in summary when the alpha Pharaoh protein is negative but ca19 H9 is positive and then you suspect galangiocarcinoma primary sclerosis and cholangitis when Alpha Pharaoh protein is positive and the ca19-9 then of course hepatocellular carcinoma when the alpha phero protein is positive and the ca19-9 is also positive then you'll suspect the mixed hepatocellular carcinoma cholangiocarcinoma and the C cea is a positive a very frequently positive metastatic cancer like a broncholocan colorectal cancer and in about 60 percent of cholangiocarcinoma or 20 of hepatocellular carcinoma have a positive CA levels when both ca19-9 and the ca are positive then of course we suspect the cholangiocarcinoma as well as gallbladder cancer and the biliary pancreatic cancer when you suspect to land your carcinoma like when you find the biliary retaliation into hepatic lesion and ultrasound or CT scan then we do a good history and physical lab tests the cbcmpca 19-9 and the cea alpha fear of protein only for intrapatic lesion to distinguish it from hepatocellular carcinoma and we know a pillar obstruction increased the direct conjugated bilirubin diagnosis of proximal lesions like a intrapatical angiocarcinoma we use MRI MRCP or mtct for tissue diagnosis City guided or MRI guided biopsy can be used percutaneous transeptical angiography and the bile aspiration for cytology may lead to a tissue diagnosis for distal chlangiocarcinoma in addition to the ercp to obtain the brushing psychology or tissue biopsy endoscopy ultrasound and the finial aspiration is very useful and much more sensitive than ercp in making a tissue diagnosis to rule of metastatic disease CT scan of the chest is always included as initial staging workout but not the Pet City is no Advantage for a staging of primary tumor over mdct or MRI MRCP so it's not routinely included in initial staging workup unless you suspect the metastatic disease especially before diagnostic laparoscopy or uh surgical resection and those proximal or digital lesions are kind of easier than perihila colangel carcinoma in terms of tissue diagnosis with the bile specimen you can send the Recon request fish test to detect abnormal chromosome which may increase the sensitivity but tissue diagnosis may not be necessary for certain cases patients who definitely have a resectable disease with a characteristic finding of cholangiocarcinoma and imaging studies or patients who just requires palliative care like a biliary drainage as we know most patients or gallbladder cancers are diagnosed during or after cholecystic cystectomy so still patients need to have a ca19-9 cea and imaging studies include ultrasound City MRI MRCP endoscopic ultrasound PET CT scan has a limitation due to high false positive rate with the core existing inflammation like a cholangitis cholecystitis large gallber Pollock has a high chance of risk of hovering gallbladder cancer porcelain gallbladder as you see the calcified gallbladder wall they need to have a cholecysterectomy the staging of calendula carcinoma is very complicated depending on the location the tnm systems are different I draw these pictures for better understanding for intrapatic cholangiocarcinoma tnm staging the T1 means solitary tumor if it's less than if five Center or or smaller is a t1a bigger than 5 centimeter t1b multiple tumors or tumor invading vascular system are T2 lesions T3 tumors perforates visceral peritoneum T4 invades the extra hepatic organs any Regional influent metastasis is N1 so stage one means T1 tumor without lymph node metastasis so stage two T2 and 0. stage 3 a T3 and zero stage three B is a T4 and 0 but stage C 3C means any size of tumor with the lymph node metastasis stage four means distant metastasis carcinoma has a different parameter T1 tumor confines to the bile duct T2 beyond the bile dog T3 invased portal vein hepatic artery branches T4 invades the main portal vein or bilateral portal vein branches with a three or less lymphoma metastasis classified as N1 N2 4 or more lymphoma metastases T1 means T a stage 1 means T1 and 0. stage 2 T2 and 0 stage three either T 3 4 without lymphomatostasis or N1 this is regardless of the uh uh tumor size which is stage 3C disconnected stage four for digital calendar carcinoma is also different T1 tumor means the tumor invades the bile duct wall less than five millimeter in depth T2 5 to 12 millimeter T3 more than 12 millimeter T4 invading cilia axis Superior mesenteric artery or common hepatic artery N1 and N2 in the stage this staging is kind of much more lenient because they have a better prognosis for example oh even N1 this is still stage one a stage two and the N3 uh and Stage 3A means or N2 disease and even with the T4 and 2 it's still stage 3B it reflects the better prognosis the key staging of gallbladder cancer depending on the depth of penetration into the gallbladder wall T1 divides into t1a and t1b T1 a means tumor invades the lamina propria and the t1b into the muscular layer and the t2a means the tumor invades the perimuscular connective tissue and on the side of on the side of the liver is a t2b and the T3 means tumor penetrates the gallbladder wall completely invading one adjacent organ such a duodenum when it invades the liver is a T3 also T4 diseases are much bigger deeply penetrates to the portal vein hepati artery biliary duct and the two or more adjacent organs I again emphasize that t1a means tumor in base the up to lamina propria the t1b up to a muscular layer and if the regional lymph nodes metastasis is N1 or 2 depending on the number one to three is the one four or more and two disease and the stage one means small tumor without lymphoma metastasis stage 2 2 T2 stage 3 T3 and then if the N1 disease is stage 3B and uh when it's N2 this is stage 4B and also this will metastasis stage 4B because surgical reception is the only curable treatments it's very important to evaluate patients for surgical resection and the resectability receptability with negative surgical margin in colangiocarcinoma is much higher in digital cholangiocarcinoma then intraepatic or perihilar cholangiocarcinoma have a better prognosis the contraindications include a coarse metastatic disease or Invasion to the major vascular system or local Invasion into extra hepatic organs but depending on the surgeon's skill Polo vein reconstruction or resection of extra hepatic lesion may be done routine pre-op polarity compression is not recommended we discussed in the previous slide unless patients have a very high bilirubin level over 10 then wait until bilirubin level drops below three before surgery gallbladder cancer receptability is similar the contraindication of course metastasis to the labor or peritoneum such as malignant ascitis or distant lymph nodes like a para aortic Pair cable cilia artery lymph nodes extensive involvement of heparodyl ligaments which contain common bile duct hepatic artery and the Prototype encasement of common bile dog I mean the hepatic artery or main portal veins direct involvement of colon judenum or liver is not absolute contraindication because depending on the surgeon skill can be resected if patients have a jaundice if those location of gallbladder cancers in the fundus is a relative conduct indication but not in the gallbladder cancer of infundibulum or cystic dog cancer diagnostic laparoscopies often recommended before surgery section to ensure no metastatic disease the surgical resection of intrapatic cholangiocarcinoma involves hepatic resection and extra hepatic bile duct resection and the poral lymphanectomy unless the tumor locates in the peripheral area then hepatic resection without lymphaden nectomy or extra hepatic bile that was section is sufficient five-year survival is for for to 40 to 60 percent carcinoma requires more extensive surgery or type 1 and the B A 1 and 2 N blood resection of extra hepatic bile ducts and the reception of the gallbladder Regional lymphoma Deck lymphadenectomy with or without codate hepatic lobectomy followed by Rue and oi a particle which is an ostomy and the type 3 tumors is even more extensive require more extensive hepatic lobectomy or dry section ectomy Type 4 is often unresectable but resection is possible depending on the surgeon's skill and the receptor will disease fiber survival 40 to 50 percent for digital cholangiocarcinoma requires Ripple procedure Polaris preserving surgeries preferred fiber survival 50 to 60 percent gallbladder cancer is a little bit different because we know most of gallbladder cancer found during or after cholecystectomy when the cancer is found during cholecystectomy the surgery is aborted and referred to an experienced surgeon unless the original surgeon is a hyperabilia Resurgence it found after cholecystectomy was done they referred to an expert surgeon for real resection of course after staging workup with the Imaging studies for t1a means the tumor invades the up to lamina propria simple cholecystectomy is sufficient but beyond that patience requires extended cholecystectomy which include cholecystectomy plus adjacent liver tissue resection Regional lymphadenectomy T2 region also extended cholecystectomy which resection is as good as a segmentectomy T4 is even more they need to have resection of involved extra hepatic organs such as colon to genome so they have a high reception rate because of in increased local recurrence the complications by bleeding infection some mortality there and the prognosis of resectable gallery cancer is better than cholangiocarcinoma 65 percent or five-year survival rate azurement therapy is usually given after resection when the patients have a positive margin or positive lymph nodes then concurrent chemoreadiation therapy or chemotherapy followed by concurrent reading chemo radiation therapies are given using 5fu or capsight again when you use the systemic chemotherapy after concurrent chemo radiation therapy gem cytapine with or without capsidobins are used American Society of clinical oncology recommends keptide being alone for all receptive kolangiocarcinoma for six months but if they have a positive surgical margin or gallbladder cancer chemo radiation therapy is recommended nccn guidelines a little bit different more lenient for extra hepatic cholangiocarcinoma with negative margin negative lymph node metastasis observation is an option along with 5 a few chemo or chemo radiation therapy but when the margins positive possible lymph nodes then vivipio chemotherapy alone or chemo radiation therapy or combination of both are recommended intra hepatic cholangiocarcinoma the same thing observation for negative margin negative lymph nodes or the chemotherapy chemo radiation or combination for margin positive or positive lymph node disease Gallery cancer has a high distance metastasis rate so single capsidamine for six months to all patients is recommended according to ESCO but NCC guidelines exclude the uh stage 1A disease which means tumoring base the laminar prayer only new instrument therapy is not our standard treatment but locally advanced non-receptable intraepedical angiocarcinoma was downstaged to resectable disease with a radio embolization and the chemotherapy liver transplantation is not a standard therapy for cholangiocarcinoma also due to lack of studies proving its benefit but receptable cholangiocarcinoma with the primary sclerosis in cholangitis or a non-resectable small hila calendula carcinoma may be referred to transplant center for concentration after resection patients are followed up every three months for two years with the CBC cbcc and PCA 19-9 and the cea and thereafter every six months Imaging studies are as needed for locally Advanced unresectable disease we used to use cisplatin and the gem cytamine as a gold standard with a not so good outcome until four or five months ago when FDA approved the volume at the immunotherapy drugs used in combination with cisplatin and Jim cytamine because this combination improved the oval survival over 12 months in addition to this systemic therapy we have many options for intrapatic cholangiocarcinoma concurrent chemo radiation therapy has a better local control when used with your high dose radiation Atrium 90 radio embolization concurrently with the cisplatin and Jim cytamine showed you a very impressive results median over survival about two years and the local ablation with radio frequency microwave ablations can be used stir tactic body radiotherapy has a better over survival than chemo radiation therapy or radio embolization and that proton beam therapy can be used for extra hepatic cholangiocarcinoma we don't use high dose radiation therapy or stereotactic patio body radiotherapy because they can hit the small bowel causing severe small bowel toxicity so we use the concurrent chemo radiation therapy with 5V on the cubic side I mean after the treatment patients need to be reassessed for resectability because resection is the best hope for cure liver transplantation is not a standard as we discussed but can be considered Case by case and the global cancer follow those principles of treatment of colandrocarcinoma I like to mention that gem cyta Bean is given after biliary decompression when the patients are deeply jaundiced because of its liver toxicity hyperbilirubinemia increases risk of clangitis and also a targeted therapy and the immunotherapy can be used the same as treatment of metastatic disease which will be described next slides for metastatic disease like a local Advanced a tumor the combination of tobalamet cisplatin and Gem cytomine is the choice patients still can have just chemotherapy with cisplatinum cytopene or Jim cytavine with oxaloclatine when a patients have a jaundice you can't use gem side of him because of liver toxicity then use cake pox or fall Fox for frail patients single capsidicine is sufficient when disease progressed over the first line therapy fallfox is the choice preferred second line chemotherapy but nowadays we have a Target therapy and the immunotherapy which provides less toxicity with a better efficacy most importantly fgfr2 Fusion rearrangement positive tumors fgf R2 stands for fibroblast growth factor receptor 2. there are three inhibitors in figurative and the futiva tinnipes especially this football team is very recently approved by FDA about six seven months ago over over response rate 42 and durational response 9.5 months specifically you need to check phosphate label because it can cause hyperphosphatemia it also can cause alopecia when the tumor is negative for f gfr2 Fusion or Gene rearrangement there are still many biomarkers to look for the fission MMR msih or high tea a t tumor mutational burden you use Pembroke Zuma pretty impressive response rate or trk Fusion rearrangement Laro tractinib with the oval survival rate oval response rate is 75 and tractinium is also another choice for prep v600e positive tumors we use the profanity with a traumatinum over response rate is almost 50 percent very recently approved for idh mutation we have either Sydney for idh1 inhibitor red Fusion tumors cell procatinine for her2 positive tumors perceptin with a projector easier positive we have inhibitor tarsiba with or without paper system when the tumor has a pdl1 positive nivolumab is Choice over kitruda pembrolazuma because piminalizumab it's the oval response rate is just about single digit provides the Disease Control where it is about 50 percent if pdl1 negative you still can use dual immunotherapy with nibolumet and the epilometer if nothing is positive we still have a option ramu serumab or cyrenza which is fiscalendothelial growth factor receptor to inhibitors according to the old Seer Database The Five-Year survival rates of clangiocarcinoma are not that good intraepatic locally disease 25 x-ray party even worse 17 percent although gallbladder cancer has a much better survival rate but when disease metastasized to distant organs The Five-Year survival rate is decimal two percent two percent two percent across the border however more recent data show better respond a better prognosis for example intrapatical angiocarcinoma after margin negative resuction five years survival is 63 percent even for metastatic disease with a newer a drug combination development with a cisplatin and Gem cytamine the two-year survival is over 25 percent please look at the survival curve of cholangiocarcinoma patients who received the development cisplatinum and Jim cytavin this is a red line after about two years the line become plateau indicating patients who lived up till like two years they continued to leave but those patients who received the uh cisplatin and Jim cytavin without development to grab just the falls I took this photo several days ago in Guam beautiful rainbow over the ocean I thought about Bible verse the God's peace peace I live with you my peace I give you I do not give to you as the world gives do not let your heart speed traveled in the do not be afraid John 14 27. I hope all cancer patients have a courage and the peace from God thank you for watching