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Update on Biliary Tumors
Jiaqi Shi, MD, PhD
University of Michigan
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Disclosure
I have not had a significant financial interest or other
relationship with the manufacturer(s) of the product(s) or
provider(s) of the service(s) that will be discussed in my
presentation.
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Biliary Neoplasms
Intrahepatic
Extrahepatic• Perihilar bile duct
• Distal bile duct
• Gallbladder
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Anatomy of extrahepatic biliary system
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Distal bile duct
Perihilar bile duct
Gallbladder
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WHO 4th Edition WHO 5th Edition
BilIN
-1: Low grade
-2: Intermediate grade
-3: High grade
BilIN
-low grade (low, intermediate)
-high grade
Intraductal/Intracystic papillary neoplasm (IPNB/ICPN)
-Low, intermediate, high-grade intraepithelial
neoplasia
Intraductal/Intracholecystic papillary neoplasm (IPNB/ICPN)
-low, high-grade intraepithelial neoplasia
-Intraductal tubular/tubulopapillary neoplasm (ITPN)-B
Adenoma
Tubular
Papillary
Tubulopapillary
Pyloric gland adenoma of the gallbladder
Signet ring cell carcinoma Poorly cohesive carcinoma with or w/o signet ring cells
NET G1, G2, NEC NET G1-G3, NEC
Mixed adenoneuroendocrine carcinoma Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)
Changes of Biliary Tumor Classifications in WHO 5th Edition
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Preinvasive lesions of the biliary tract
• Biliary intraepithelial neoplasia(BilIN)
• Pyloric gland adenoma
• Intraductal papillary neoplasm of bile duct (IPNB)/Intracholecystic papillary neoplasm (ICPN)
o Intraglandular neoplasms of the peribiliary glands?
o Intraductal tubulopapillary neoplasm of the bile duct (ITPN-B)
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BilIN
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Normal LG BilIN
HG BilIN LG+HG BilIN
Microscopic
KRAS-40%, early event
TP53—late event
Risk of recurrence:
extensive BilIN, RAS
involvement, pos margin
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Pyloric Gland
Adenoma
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Grossly visible
50-60% associated with stone
PJ, FAP syndrome
Paneth cells, NE cells
CTNNB1 mutation-60%
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Pyloric Gland
Adenoma with
“squamous
morules”
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~ 1/3 of PGA
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Pyloric Gland Metaplasia
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Pyloric Gland Adenoma
VS
VS
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IPNB with LGD
Gastric
Most unclear etiology,
associated with PSC, stone,
fluke
40-80% IPNB a/w invasive
carcinoma
Half IPNBs contain ≥2
epithelial types (PB most
common in US, Int/Gast in
Asia)
KRAS, p16, TP53,
GNAS/RNF43-intestinal
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ICPN with LGD
Gastric
More common in female
No known association
with stone
Invasive Ca in ~50% ICPN
More mixed than IPMN
KRAS
TP53, GNAS rare
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IPNB with
HGD
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Invasive
adenoCA
arising in
IPNB with
HGD
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Epithelial
phenotypes
Inv CA derived
from PB type
IPNB is a/w worse
outcome than CA
derived from
Int/Gast type
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PB Intestinal
Gastric Oncocytic
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Histol Histopathol (2017) 32: 1001-1015
No difference in
survival
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Cystic
micropapillary
neoplasm of
peribiliary glands
– flat branch duct
type IPNB?
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Virchows Arch. 2014 Feb;464(2):157-63
World J Gastroenterol. 2016 Feb 21;22(7):2391-7
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ICPN: noninvasive, overall uniform papillary architecture,
thin or edematous fibrovascular stalks
Papillary GBC: invasive cancers, grossly predominant
polypoid growth, histologically papillary or papillotubular
adenocarcinomas with an overall architecture that was more
complex than that expected in IPNBs
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Whole-exome and Sanger
sequencing
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Intraductal
tubulopapillary
neoplasm
(ITPN) of the
bile duct
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Histol Histopathol (2017) 32:
1001-1015
• Solid
• Tubular
• No/little mucin
• Necrosis
• Uniform HGD
Currently grouped under IPNB
Courtesy of Dr. Olca Basturk, MSK
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Precursor biliary lesions
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BilIN IPNB ITPN-B
Microscopic Macroscopic Macroscopic
Flat or micropapillary
(<3mm?)
Predominant papillary Predominant tubular
Mucin + Mucin + No mucin
No necrosis Necrosis rare Necrosis common
Low ~ high grade dysplasia Low ~ high grade
dysplasia
High grade dysplasia
KRAS, TP53, p21, cyclin D1,
SMAD4, S100P
KRAS, TP53, GNAS,
RNF43
CDKN2A, TP53
Histol Histopathol (2017) 32: 1001-1015
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Now on to the EVIL…
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Cholangiocarcinoma classifications
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• Anatomic location: Intrahepatic (ICC), extrahepatic (ECC)
• Macroscopic growth pattern: mass forming, periductal
infiltrating, intraductal, mixed
• Microscopic:
o Intrahepatic: small duct, large duct
o Extrahepatic: adenocarcinoma and variants
• Cell of origin: stem cells in canals of Hering, stem cells in
peribiliary glands
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Staging primary cancers of distal bile duct
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pTNM AJCC 7th Edition AJCC 8th Edition
Tis Carcinoma in situ Carcinoma in situ /HGD (BilIN3)
T1 Tumor confines to bile duct Tumor invades <5 mm
T2 Tumor invades beyond bile duct Tumor invades 5-12 mm
T3 Tumor invades adjacent organs w/o
involvement of celiac axis or SMA
Tumor invades >12 mm
T4 Tumor involves celiac axis or SMA Tumor involves celiac axis, SMA,
and/or CHA
N N1-regional LN met N1: 1-3 LNs; N2: ≥4 LNs
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Depth of tumor invasion better predicts prognosis
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Surgery. 2009 Aug;146(2):250-7
N=147
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N=370
Br J Surg. 2015 Mar;102(4):399-406.
The number of involved nodes
was a strong predictor of
survival
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Measuring tumor depth in cholangiocarcinoma
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Depth of invasion
- - - Invasive tumor thickness
Tumor depth measured from the basement membrane of adjacent normal or dysplastic epithelium
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The four‐tier ITT classification with cut‐off points of 1, 5 and
10 mm seems to be a better T system than those in the seventh
and eighth editions of the AJCC classification.
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Br J Surg. 2018 Jun;105(7):867-875
DOI could be
measured in only 182
(45%)
ITT can measure all
ITT:
<1 mm
≥ 1mm, <5 mm
≥5 mm, <10 mm
≥10 mm
N=404
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Staging primary cancers of perihilar bile duct
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pTNM AJCC 7th Edition AJCC 8th Edition
Tis Carcinoma in situ Carcinoma in situ /HGD (BilIN3)
T1 Tumor confines to bile duct up to muscle layer or
fibrous tissue
same
T2 Tumor invades beyond bile duct to adipose
tissue or liver
same
T3 Tumor invades unilateral PV or HA branches same
T4 Tumor invades main PV or its bilat branches,
or CHA, or 2nd order biliary radicals bilat, or
unilat 2nd order biliary radicals with contralat
PV/HA
Tumor invades main PV or its bilat
branches, or CHA, or unilat 2nd order
biliary radicals with contralat PV/HA
N N1:regional LN; N2: periaortic, pericaval,
SMA, CA LN
N1:1-3 LNs; N2:≥4 LNs
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Removal of Bismuth type IV tumors from the T4 determinants
enhance the prognostic prediction
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Br J Surg. 2014 Jan;101(2):79-88
N=1352Modified Bismuth-Corlette
classification of hilar
cholangiocarcinoma
Ann Surg. 1992 Jan;215(1):31-8
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The newly released classification American Joint Committee on Cancer 8th edition
staging system demonstrated a poor to moderate ability to predict prognosis of
patients undergoing liver resection for perihilar cholangiocarcinoma, which was
only slightly better than the previous edition
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Surgery. 2018 Aug;164(2):244-250N=214
7th Ed. 8th Ed.
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A four‐tier ITT classification with cut‐off points of 1, 5 and 8 mm is
an adequate alternative to the current layer‐based AJCC T
classification in perihilar cholangiocarcinoma
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Br J Surg. 2019 Mar;106(4):427-435
N=440AJCC ITT
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Staging primary cancers of gallbladder
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pTNM AJCC 7th Edition AJCC 8th Edition
Tis Carcinoma in situ Carcinoma in situ
T1 Tumor invades lamina propria or muscular layer same
T2 Tumor invades perimuscular connective
tissue, but not into liver or serosa
T2a: peritoneal side
T2b: hepatic side
T3 Tumor perforates serosa or invades
liver/other organ
same
T4 Tumor invades main PV or HA or ≥2
extrahepatic organs
same
N N1:regional LN; N2: periaortic, pericaval,
SMA, CA LN
N1:1-3 regional LNs; N2:≥4 LNs
(Recommend ≥6 LN be harvested)
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Ann Surg. 2015 Apr;261(4):733-9
Peritoneal side: only free serosal side
Hepatic side: any infiltration of liver part
Higher LVI, PNI, LN
metastasis in
hepatic side tumor
No difference in T1
& T3
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Genomics of gallbladder and extrahepatic bile duct carcinoma
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WHO 5th Edition
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Take Home Message
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• Yes, it went blue, but not too bad
• Dysplasia grading: 3-tiered to 2-tiered
• Adenomas: split into PGA or IPNB/ICPN
• NENs: unified with other GI NENs
• AJCC: find your
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Thank you for
your attention!
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