Cholangio and Hepato‐ cholangiocarcinoma: Update Emma E. Furth, M.D. Professor of Pathology and Laboratory Medicine University of Pennsylvania Medical Center WHO, What, Where, How, Why The WHO • Combined hepatocellular and cholangiocarcinoma “A rare tumour containing unequivocal elements of both hepatocellular and cholangiocarcinoma that are intimately admixed.” • Cholangiocarcinoma “An intrahepatic malignant tumour composed of cells resembling those of bile ducts. Intrahepatic (or peripheral) cholangiocarcinoma (ICC) arises from any portion of the intrahepatic bile duct epithelium, i.e. from intrahepatic large bile ducts (the segmental and area ducts and their finer branches) or intrahepatic small bile ducts. Cholangiocarcinoma arising from the right and left hepatic ducts at or near their junction is called hilar cholangiocarcinoma and is considered an extrahepatic lesion.” The “What?” “Cholangiocarcinoma is a highly malignant and heterogeneous adenocarcinoma of biliary epithelial cells with limited understanding of its molecular pathogenesis.” J Hepatobiliary Pancreat Sci (2014) The “Where” Hepatocellular carcinoma Intra‐hepatic Hepato‐ Cholangiocarcinoma cholangiocarcinoma “Extra”‐hepatic Cholangiocarcinoma The “How/Why” Why Care! • Prognoses • Treatment – Chemotherapy choice – Transplant candidate? • Prevention • Pathogenesis Outline • Model of stem cells and neoplastic progression • Embryology and cell lineage determination • Carcinomas – Types – Genetics – Outcomes Outline • Model of stem cells and neoplastic progression • Embryology and cell lineage determination • Carcinomas – Types – Genetics – Outcomes Model of Normal Unit Terminally differentiated cells Stem Daughter cell cells Relative half life: 1 10‐5 10‐20 Given: • Cancers are genetic/mutation events/hits(i) • > 1 event/hit is required • These hits (i,j,k…) are, for the most part, independent events • Non‐stem cells are quickly lost and therefore mutations gained in this population lost …then: • Therefore, the most probable cell population to acquire and keep/”fix” multiple mutations over time are the stem cells. Example pij = pi x p(survival) x pj x p(survival) Stem Cell(pij) = pi x 1 x pj x 1 = pi x pj Non‐Stem Cell(pij) = pi x 10‐5 pj x 10‐5 = 10‐10 x pi x pj Stem Cell(pij) = 1010 Non‐Stem Cell(pij) Model of Neoplastic Progression Extra‐hepatic cholangiocarcinoma Intra‐hepatic cholangiocarcinoma: bile duct type j,m Bile duct stem cell Intra‐hepatic cholangiocarcinoma: j cholangiolar type i,k,l,j,p Hepato‐cholangiocarcinoma i,k,l,j CK19 + Hepatocellular carcinoma i,k,j i i,k i,k Hepatocellular carcinoma Intrahepatic stem cell Outline • Model of stem cells and neoplastic progression • Embryology and cell lineage determination • Carcinomas – Types – Genetics – Outcomes Bile DuctBile Development Duct Development 7 weeks 8 weeks 12 weeks PV PV PV Hepatoblasts Ductal Plate CK 7/19 Regeneration: Stem Cell(s) Niche(s)? Portal Triad ? ? ? ? e.g. Hepatic Duct ? Key Lineage Determination Pathways • Wnt Hepatocyte • Notch Biliary Allagilles Ck7/19 Outline • Model of stem cells and neoplastic progression • Embryology and cell lineage determination • Carcinomas – Types – Genetics – Outcomes Pathogenesis, Staging, Epidemiology, Outcomes, etc Intra‐hepatic Cholangiocarcinoma 33% Extra‐hepatic 67% Cholangiocarcinoma Staging T1 Solitary, no LVI T2a Solitary, with LVI T2b Multiple T3 Perf peritoneum Tis T1 confined to wall T2a beyond wall T2b hepatic invasion T3 unilateral PV or HA invasion Large duct: Small duct: Stem cells in stem cells peri‐biliary in canals of glands? Hering? perihilar large duct type peripheral small duct J Hepatobiliary Pancreat Sci (2014) DOI: 10.1002/jhbp.154 bile duct cholangiolar 59% 41% Modern Pathology (2014) 27, 1163–1173 Features Bile duct Cholangiolar 59% 41% Association Stones Cirrhosis BIN 45% 4% Kras mutation 23% 1% IDH1/2 mutations 5% 17% Five year survival 20% 40% Adapted from: Modern Pathology (2014) 27, 1163–1173 and other sources referenced below. Type: Survival Kras & P53 Mutations: Survival Churi CR, Shroff R, Wang Y, Rashid A, et al. (2014) Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications. PLoS ONE 9(12): e115383. doi:10.1371/journal.pone.0115383 Whole‐genome mutational landscape of liver cancers displaying biliary phenotype reveals hepatitis impact and molecular diversity Hepatitis ‐ Hepatitis + ICC HCC ICC Combo FLC NATURE COMMUNICATIONS 2015| 6:6120 | DOI: 10.1038/ncomms7120 AJCC 7th T1 Solitary, no LVI T2a Solitary, with LVI T2b Multiple T3 Perf peritoneum Stage: Survival Months Cancer May 15, 2011 Bile duct type Background Liver: Diagnoses?? Background Liver: Diagnoses?? Background Liver H&E Trichrome Hepar Ck19 Cholangiocarcinoma: Stroma H&E Trichrome Hepar CK19 Model of Neoplastic Progression Extra‐hepatic cholangiocarcinoma Intra‐hepatic cholangiocarcinoma: bile duct type j,m Bile duct stem cell Intra‐hepatic cholangiocarcinoma: j cholangiolar type i,k,l,j,p Hepato‐cholangiocarcinoma i,k,l,j CK19 + Hepatocellular carcinoma i,k,j i i,k i,k Hepatocellular carcinoma Intrahepatic stem cell Cholangiolar Type Cholangiolar type: Idh1 mutation (gain of function) Inhibits TET CpG Methylation Me Hnf CpG x 1 1 0 | N AT U R E | VO L 5 1 3 | 4 S E P T E M B E R 2 0 1 4 TET (ten–eleven translocation) 1. Family of a‐ketoglutarate (a‐KG)‐dependent dioxygenases. 2. Isocitrate dehydrogenase (IDH1 and IDH2) mutations result in simultaneous loss and gain of activities in the production of a‐KG and 2‐ hydroxyglutarate (2‐HG), respectively. 3. 2‐HG functions as an a‐KG antagonist by binding to the same space in the catalytic site and competitively inhibiting the activity of a‐KG‐dependent dioxygenases. Epigenetics! Me Me Me CpG CpG CpG CpG DNMP TET TDG ten eleven translocation thymine‐DNA glycosylase dioxygenases Me CpG x CpG Repression Expression Model of Neoplastic Progression Extra‐hepatic cholangiocarcinoma Intra‐hepatic cholangiocarcinoma: bile duct type j,m Bile duct stem cell Intra‐hepatic cholangiocarcinoma: j cholangiolar type i,k,l,j,p Hepato‐cholangiocarcinoma i,k,l,j CK19 + Hepatocellular carcinoma i,k,j i i,k i,k Hepatocellular carcinoma Intrahepatic stem cell Hepato‐cholangiocarcinoma Staged as Intra‐hepatic cholangiocarcinoma hepar ck19 Hepato‐ cholangiocarcinoma with “Stem cell features” Diagnoses • Morphology! • Pitfalls of Immunohistochemistry Case History • 72 year old male with history of hypertension hypertension – Pain radiating to right upper quadrant – 30‐40 lb unintentional weight loss – Nausea and occasional vomiting Liver Mass: FNA TTF‐1 Napsin‐A Patient Developed Biliary Obstruction: Bile duct biopsy TTF‐1 Final Diagnosis Adenocarcinoma, moderately differentiated, morphologically compatible with biliary primary, involving bile duct; see note. NOTE: …TTF‐1+, CK19+, Napsin‐A ‐…. Morphologically, a hepato‐biliary origin is favored, although TTF‐1 positivity is not typical. TTF‐1 is Expressed in a Subset of Cholangiocarcinomas HCC (0%) Intra‐hepatic Cholangiocarcinoma (50%) (66%) Distal extra‐hepatic cholangiocarcinoma (0%) Pancreatic adenocarcinoma (0%) Am J Surg Pathol, 38(2), 224‐227. (2014). H & E TTF‐1 Napsin‐A 40x 40x 100x HepaticDuct CholangioCA 50x 200x 200x Gallbladder CholangioCA SUMMARY • 42.1% of extrahepatic cholangioCA expressed TTF‐1, 37.5% of which also co‐ expressed NapA. • TTF‐1 reactivity was more common in patients >60 years of age with extrahepatic tumors (p=0.01). Outline • Model of stem cells and neoplastic progression • Embryology and cell lineage determination • Carcinomas – Types – Genetics – Outcomes HCC CTNNB1 Normal CTNNB1 TP53 Cholangiocarcinoma: intra and extra APC CTNNB1 ERBB4 FGFR2 GNAS IDH1 KIT KRAS Normal NRAS PIK3CA SMAD4 STK11 TP53 Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications • intrahepatic and extrahepatic CCA had equal types and frequency of genetic aberrations • Intrahepatic TP53 (29%), KRAS (24%), ARID1A (20%), IDH1 (24%), DNA repair (16%) and PBRM1 (11%) • ExtrahepaticTP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4(25%), FBXW7 (15%) and CDKN2A (15%). PLOS ONE DOI:10.1371/journal.pone.0115383 December 23, 2014 Dramatic response to dabrafenib and trametinib combination in a BRAF V600E‐mutated intra‐ hepatic cholangiocarcinoma • 47 year old woman • Intrahepatic cholangiocarcinoma • Progressed on chemo rx • Mutation found in BRAF p.V600E c.1799T > A (allele frequency of 53%) • Regressed on Braf and MEK inhibitors ecancer 2014, 8:479 DOI: 10.3332/ecancer.2014.479 .