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62
Y. Nakanuma et al.
Invasion A surgical series demonstrated high rates of inva-
sive cancer arising from IPNB, with rates ranging from 40%
to 70% [7]. However, the incidence of invasion differs
according to the anatomical location of IPNB, with approximately 30% of cases of intrahepatic IPNBs invasive, while
many extrahepatic IPNBs show at least focal stromal invasion at the time of surgical resection [15, 19, 23], implying
that intrahepatic IPNBs are less aggressive than extrahepatic
IPNBs. The invasive parts of IPNBs usually show tubular
adenocarcinoma with a desmoplastic reaction and only occasionally show foci of colloid carcinoma. The oncocytic subtype shows invasion of oncocytic adenocarcinoma.
7.1.3 Pathogenesis: Molecular andGenetic
Alterations ofBIlINs andIPNBs
BilIN and IPNB share key pathogenetic and molecular pathways but show some differences.
7.1.3.1 Progression ofBilINs andIPNBs
The growth pattern of BilIN progresses from at/micropapillary projections to eventually develop the periductal growth
pattern of CCA showing tubular adenocarcinoma [2, 4].
IPNB may also sequentially progress from low-grade to
high-grade and then to invasive adenocarcinoma (IPNB
associated with invasive carcinoma) [3]. Chronic biliary
inammation may induce neoplastic changes of the biliary
epithelia including BilINs in chronic biliary diseases.
progression of BilIN and IPNB [19, 25]. The expression of
p16 INK4a was decreased in high-grade BilIN and invasive
carcinoma, while EZH2 expression showed a stepwise
increase from low-grade to high-grade BilIN to invasive carcinoma, suggesting that the overexpression of EZH2 may
induce hypermethylation of p16 INK4a promoter followed
by decreased expression of p16 INK4a in the progression of
BilIN in hepatolithiasis. The overexpression of EZH2 may
also be associated with malignant behavior in IPNB in parallel with the upregulated MUC1 expression and downregulated MUC6 expression [24, 25].
7.1.3.3 Genetic Changes inBilIN andIPNB
BilIN
KRAS mutations are already identiable in low-grade BilIN
and slightly increase during progression to high-grade BilIN
and invasive adenocarcinoma in hepatolithiasis cases [26]. In
contrast to IPNB, BilIN lesions do not seem to harbor
GNAS1 mutations. The downregulation of miR-451a and
miR-144-3p, a tumor suppressor, was recently reported
along with the progression of BilIN supporting the concept
of BilIN as a direct precursor of invasive dCCA [1].
IPNB
Yang et al. identied frequent mutations of KRAS (49%),
GNAS (32%), RNF43 (24%), APC (24%), TP53 (24%), and
CTNNB1 (11%) in IPNBs [21]. KRAS and p16 alterations
occur early and in tumors with low-grade IPNB and precede
the increased expression of PT53 [27].
7.1.3.2 Molecular Alterations inBilINs andIPNBs
BilIN and IPNB have shown the stepwise acquisition of
molecular alterations affecting common oncogenic pathways, such as cell-cycle related molecules [3, 14, 24]. For
example, p21, cyclin D1, and Dpc4 were shown to be
involved in the carcinogenesis of BilIN and IPNB, while the
p53 expression was regulated differently between BilIN and
IPNB. The loss of SMAD4 is a late molecular change in
BilIN lesions. A decreased membranous expression of
β-catenin and E-cadherin is an early event in the tumorigenesis of both BilIN and IPNB lineages. Cyclin D1 and c-myc,
target molecules of Wnt signaling, were frequently positive
in the IPNB lineage, and interestingly, nuclear β-catenin
staining was observed only in the IPNB lineage, suggesting
the importance of Wnt signaling in the tumorigenesis of the
IPNB lineage. The increased expression of autophagyrelated proteins in low- and high-grade BilIN, IPNB, and
invasive carcinoma suggests the role of dysregulated
autophagy at an early stage of BilIN and IPNB in hepatolithiasis [24].
The overexpression of the polycomb group protein
enhancer of zeste homolog 2 (EZH2) is also involved in the
Four Subtypes of IPNB
In eastern Asia, GNAS mutations
were detected in fewer than half of all cases of IPNB, and all
cases with GNAS mutations had intestinal differentiation
[22, 28–30]. Mutations in RNF43, a tumor suppressor gene,
were also frequent in the intestinal IPNB [29, 30]. When
divided into the intrahepatic and extrahepatic classications,
in intestinal IPNBs arising in the intrahepatic bile ducts,
GNAS and KRAS mutations are frequent, as is observed in
intestinal IPMN [28]. As for non-intestinal IPNBs, mutations
in APC or CTNNB1, both of which belong to the Wnt/β- catenin pathway, were observed in one-fourth of IPNBs and
were mutually exclusive [31]. Interestingly, APC and
CTNNB1 alterations were unique to IPNB [31]. Mutations of
genes also seen in colorectal neoplasms, such as SMAD4,
PIK3CA, APC, and CTNNB1, were frequent in intestinal
IPNBs of the extrahepatic bile ducts [28], and the pancreatobiliary subtype arising in the extrahepatic bile ducts also
showed a CTNNB1 mutation [30, 31]. Given these previous
ndings, the activation of the Wnt/β-catenin signaling pathway may be relevant to the development and progression of
non-intestinal-type IPNBs as well as iIPNBs arising in the
extrahepatic bile ducts [31].
7 Preinvasive Intraductal Biliary Neoplasm: Biliary Intraepithelial Neoplasm andIntraductal Papillary Neoplasm ofBile Duct
63
7.1.4 The Prognosis andOutcomes ofBilINs
andIPNBs
7.1.4.1 BilIN
Although high-grade BilIN group is a neoplasia with malignant potential, the prognostic signicance remains controversial. While the survival and recurrence outcomes of
patients with high-grade BilIN at the surgical margin were
shown to be similar to those without it in one report [32],
high-grade dysplasia of the bile duct margin in patients with
surgically resected node-negative perihilar CCA was associated with a poor survival in another study [33]. Yoon etal.
reported that the presence of BilIN lesions was not uncommon in CCA patients and was signicantly associated with a
better disease-free survival and overall survival in extrahepatic CCA patients [34]. A meta-analysis with unied criteria is necessary in order to evaluate the signicance of
high-grade BilIN at the surgical margin of nodular/sclerosing CCA.
7.1.4.2 IPNB
The median postoperative survival of IPNB patients is favorable compared with conventional CCA via BilIN carcinogenesis [7, 35, 36]. Luvira etal. reported that the median
postoperative survival of 102 IPNB patients was 1728days,
with 1-, 3-, and 5-year overall survival rates of 86.3%, 63.7%,
and 44.8%, respectively [8]. Factors that have been reported
to be associated with adverse outcomes include high serum
CA19-9, lymph node metastasis, R0 or R1/2 resection, invasive IPNB, tumor multiplicity, and the high expression of
MUC1in the tumor tissue [2, 7, 20]. The survival of IPNB
patients with cystic variant with micropapillary lesions was
shown to be favorable, and intrahepatic IPNB shows a favorable prognosis compared with IPNBs arising in the extrahepatic bile ducts. Type 1 is known to be associated with a
favorable prognosis, while type 2 is associated with a worse
prognosis [15], and recent studies have validated the signicance [22, 23]. Recurrence of IPNB or CCA after surgical
resection of IPNB may occur due to the implantation or cancerization of neoplastic cells.
7.2 Conclusion
BilIN and IPNB are main precursor lesions of CCA: BilINs
are microscopic lesions, while IPNBs are grossly visible
lesions. IPNBs are divided into intestinal, gastric, pancreatobiliary, and oncocytic subtypes, with the intestinal subtype
the most common followed by the other subtypes; in contrast, a majority of BilINs are of the pancreatobiliary type.
Both BilINs and IPNBs are graded by a two-tiered system:
low-grade and high-grade. In addition, IPNBs are subclassied into types 1 and 2, with type 1 composed of low-grade
IPNB and high-grade IPNB with regular structures and type
2 composed of high-grade IPNB with irregular structures.
Type 1 and 2 IPNBs show differing clinicopathological features, including a different mucus overproduction and postoperative survival and unique genetic alterations. Recognition
of these two intraductal preinvasive biliary epithelial neoplasms will encourage the better understanding of the clinicopathological features and therapeutic approach to CCA.
References
1. Loefer MA, Hu J, Kirchner M, et al. miRNA proling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in
distal cholangiocarcinoma via the miR-451a/ATF2 axis. J Pathol.
2020;252(3):239–51.
2. Nakanuma Y, Sudo Y.Biliary tumors with pancreatic counterparts.
Semin Diagn Pathol. 2017;34(2):167–75.
3. Nakanuma Y, Basturk O, Esposito I, et al. Intraductal papillary
neoplasm of the bile duct. In: The WHO Classication of Tumours
Editoral Board. WHO Classication of Tumors, Digestive System
Tumours . 5th ed., Lyon: International Agency for Research on
Cancer. 2019. pp. 279–82.
4. Basturk O, Aishima S, Esposito I. Biliary intraepithelial neoplasia. In: The WHO Classication of Tumours Editoral Board. WHO
Classication of Tumors, Digestive System Tumours. 5th ed., Lyon:
International Agency for Research on Cancer. 2019. pp. 273–5.
5. Hucl T.Precursors to cholangiocarcinoma. Gastroenterol Res Pract.
2019 Nov 13; eCollection 2019.
6. Nakanuma Y, Uchida T, Sato Y, et al. An S100P-positive biliary
epithelial eld is a preinvasive intraepithelial neoplasm in nodularsclerosing cholangiocarcinoma. Hum Pathol. 2017;60:46–57.
7. Gordon-Weeks AN, Jones K, Harriss E, et al. Systematic review
and meta-analysis of current experience in treating IPNB: Clinical
and pathological correlates. Ann Surg. 2016;263(4):656–63.
8. Luvira V, Pugkhem A, Bhudhisawasdi V, etal. Long-term outcome
of surgical resection for intraductal papillary neoplasm of the bile
duct. J Gastroenterol Hepatol. 2017;32(2):527–33.
9. Nakanuma Y, Kakuda Y. Pathologic classication of cholangiocarcinoma: New concepts. Best Pract Res Clin Gastroenterol.
2015;29(2):277–93.
10. Kubo S, Nakanuma Y, Takemura S, et al. Case series of 17
patients with cholangiocarcinoma among young adult workers of a printing company in Japan. J Hepatobiliary Pancreat Sci.
2014;21(7):479–88.
11. Siripongsakun S, Sapthanakorn W, Mekraksakit P, etal. Premalignant
lesions of cholangiocarcinoma: characteristics on ultrasonography
and MRI.Abdom Radiol (NY). 2019;44(6):2133–46.
12. Luvira V, Somsap K, Pugkhem A, etal. Morphological classication of intraductal papillary neoplasm of the bile duct with survival
correlation. Asian Pac J Cancer Prev. 2017;18(1):207–13.
13. Yoon HJ, Kim YK, Jang KT, etal. Intraductal papillary neoplasm
of the bile ducts: description of MRI and added value of diffusionweighted MRI.Abdom Imaging. 2013;38(5):1082–90.
14. Schlitter AM, Born D, Bettstetter M, etal. Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves
common molecular pathways. Mod Pathol. 2014;27(1):73–86.
15. Nakanuma Y, Jang KT, Fukushima N, et al. A statement by the
Japan-Korea expert pathologists for future clinicopathological and
molecular analyses toward consensus building of intraductal papillary neoplasm of the bile duct through several opinions at the present stage. J Hepatobiliary Pancreat Sci. 2018;25(3):181–7.
64
Y. Nakanuma et al.
16. Yokode M, Yamashita Y, Zen Y.Biliary intraductal papillary neoplasm with metachronous multiple tumors – true multicentric
tumors or intrabiliary dissemination: a case report and review of the
literature. Mol Clin Oncol. 2017;6(3):315–20.
17. Tsuyuguchi T, Sakai Y, Sugiyama H, etal. Endoscopic diagnosis of intraductal papillary mucinous neoplasm of the bile duct. J
Hepatobiliary Pancreat Sci. 2010;17(3):230–5.
18. Nanashima A, Sumida Y, Tamaru N, etal. Intraductal papillary neoplasm of the bile duct extending supercially from the intrahepatic
to extrahepatic bile duct. J Gastroenterol. 2006;41(5):495–9.
19. Sasaki M, Matsubara T, Yoneda N, et al. Overexpression of
enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct.
Histopathology. 2013;62(3):446–57.
20. Nakanuma Y, Kakuda Y, Uesaka K.Characterization of intraductal
papillary neoplasm of the bile duct with respect to the histopathologic similarities to pancreatic intraductal papillary mucinous neoplasm. Gut Liver. 2019;13(6):617–27.
21. Yang CY, Huang WJ, Tsai JH, et al. Targeted next-generation
sequencing identies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct. Mod Pathol.
2019;32(11):1637–45.
22. Aoki Y, Mizuma M, Hata T, Aoki T, etal. Intraductal papillary
neoplasms of the bile duct are consisted of two distinct types specically associated with clinicopathological features and molecular
phenotypes. J Pathol. 251(1):38–48.
23. Kubota K, Jang JY, Nakanuma Y, et al. Clinicopathological characteristics of intraductal papillary neoplasm of the bile duct: a
Japan-Korea collaborative study. J Hepatobiliary Pancreat Sci.
2020;27(9):581–97.
24. Sasaki M, Nitta T, Sato Y, Nakanuma Y.Autophagy may occur at
an early stage of cholangiocarcinogenesis via biliary intraepithelial
neoplasia. Hum Pathol. 2015;46(2):202–9.
25. Sasaki M, Yamaguchi J, Itatsu K, etal. Over-expression of polycomb group protein EZH2 relates to decreased expression of p16
INK4a in cholangiocarcinogenesis in hepatolithiasis. J Pathol.
2008;215(2):175–83.
26. Hsu M, Sasaki M, Igarashi S, etal. KRAS and GNAS mutations and
p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas. Cancer. 2013 May 1;119(9):1669–74.
27. Sasaki M, Matsubara T, Nitta T, etal. GNAS and KRAS mutations
are common in intraductal papillary neoplasms of the bile duct.
PLoS One. 2013 Dec 2, eCollection.
28. Nakanuma Y, Kakuda Y, Fukumura Y, et al. The pathologic
and genetic characteristics of the intestinal subtype of intraductal papillary neoplasms of the bile duct. Am J Surg Pathol.
2019;43(9):1212–20.
29. Tsai JH, Liau JY, Yuan CT, et al. RNF43 mutation frequently
occurs with GNAS mutation and mucin hypersecretion in
intraductal papillary neoplasms of the bile duct. Histopathology.
2017;70(5):756–65.
30. Tsai JH, Yuan RH, Chen YL, etal. GNAS Is frequently mutated in
a specic subgroup of intraductal papillary neoplasms of the bile
duct. Am J Surg Pathol. 2013;37(12):1862–70.
31. Fujikura K, Akita M, Ajiki T, etal. Recurrent mutations in APC and
CTNNB1 and activated Wnt/β-catenin signaling in intraductal papillary neoplasms of the bile duct: a whole exome sequencing study.
Am J Surg Pathol. 2018;42(12):1674–85.
32. Shin D, Lee S, Lee JH, et al. Prognostic implication of high
grade biliary intraepithelial neoplasia in bile duct resection
margins in patients with resected perihilar cholangiocarcinoma.
J Hepatobiliary Pancreat Sci. 2020;27(9):604–13.
33. Higuchi R, Yazawa T, Uemura S, etal. High-grade dysplasia/carcinoma in situ of the bile duct margin in patients with surgically
resected node-negative perihilar cholangiocarcinoma is associated
with poor survival: a retrospective study. J Hepatobiliary Pancreat
Sci. 2017;24(8):456–65.
34. Yoon KC, Yu YD, Kang WH, et al. Prevalence and clinical signicance of Biliary Intraepithelial Neoplasia (BilIN) in
Cholangiocarcinoma. Am Surg. 2019;85(5):511–7.
35. Kubota K, Nakanuma Y, Kondo F, etal. Clinicopathological features and prognosis of mucin-producing bile duct tumor and
mucinous cystic tumor of the liver: a multi-institutional study
by the Japan Biliary Association. J Hepatobiliary Pancreat Sci.
2014;21(3):176–85.
36. Paik KY, Heo JS, Choi SH, et al. Intraductal papillary neoplasm
of the bile ducts: the clinical features and surgical outcome of 25
cases. J Surg Oncol. 2008;97(6):508–12.
Pathology ofBiliary Tract Cancers
ClaudioLuchini, MicheleSimbolo, andAldoScarpa
8
Abstract
Biliary tract cancers are highly malignant tumors that
comprise bile duct cancers (so called cholangiocarcinoma, CCA) and gallbladder carcinomas. Based on their
anatomical location, bile duct cancers fall into two main
categories: intrahepatic and extrahepatic cholangiocarcinomas. Each type displays peculiar clinic-pathologic and
molecular features. Intrahepatic cholangiocarcinoma
(iCCA) is further subvided in small duct and large duct
iCCA.Small duct iCCA usually involves septal and interlobar bile ducts, produces mass-forming lesions, has a
better prognosis than large-duct iCCA and has no known
precursor lesions. Large duct iCCA usually involves the
rst to third branches of hepatic bile ducts, shows a
periductal- inltrating pattern of invasion, has a poorer
prognosis than the small duct counterpart and can derive
from two types of precursor lesions: biliary intraepithelial
neoplasia and intraductal papillary neoplasms.
Extrahepatic cholangiocarcinomas (eCCA) includes perihilar eCCA (so-called Klatskin tumors) and distal
eCCA.Histologically, eCCA display the morphology of a
classic pancreatico-biliary adenocarcinoma. Gallbladder
carcinomas (GBC) are malignant tumors mostly involving the gallbladder fundus (70% of cases), with the typical histology of a pancreatico-biliary adenocarcinoma.
From the molecular point of view, mutations affecting the
driver genes KRAS and TP53 can be found in all CCA
subtypes. Of note, mutations affecting IDH1 and IDH2
genes and the chromatin-remodelers ARID1A, BAP1 and
PBRM1 are typically enriched in iCCA, whereas ELF3
and ARID1B are more common in eCCA. In GBC, amplication of ERBB2 is more typical and also represent a
therapeutic target.
C. Luchini · M. Simbolo · A. Scarpa (*)
Department of Pathology, University of Verona, Verona, Italy
e-mail: Aldo.Scarpa@univr.it
8.1 Introduction
Biliary tract cancers are among the most deadly solid malignancies of the gastrointestinal tract [1], and are represented
by bile duct cancers and gallbladder carcinomas.
Based on their anatomical location, bile duct cancers fall
into two main categories: intrahepatic bile duct cholangiocarcinomas, furtherly subdivided into large duct and small
duct subtypes, and extrahepatic bile duct carcinomas [2].
Clinically, intrahepatic bile duct carcinomas are often
encountered in the context of differential diagnosis of liver
masses; extrahepatic bile duct carcinomas represent, along
with pancreatic head carcinomas, the deadliest cause of
obstructive jaundice. Gallbladder carcinomas represent the
most common biliary tract carcinomas, accounting for 80%
of biliary tract cancers, and are characterized by a subtle
clinical presentation, which unfortunately leads to late-stage
diagnosis [3].
Herein, we will describe the main pathological and
molecular features of biliary cancers. A specic focus will
regard the distinctive features that guide practicing pathologists in the histopathologic diagnostics of such
malignancies.
8.2 Intrahepatic Cholangiocarcinoma
8.2.1 Gross Features
Two main subtypes of intrahepatic cholangiocarcinoma
(iCCA) are recognized: small duct iCCA (Fig. 8.1a) and
large duct iCCA (Fig.8.1b).
Small duct iCCAs involve septal and interlobar bile
ducts, and are lodged deep inside the hepatic parenchyma;
large duct iCCAs involve from the rst to third branches of
hepatic bile ducts, and are therefore located near the
hepatic hilum [1].
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_8
65
66
ab
Fig. 8.1 Representative images of the two main subtypes of intrahepatic cholangiocarcinoma are here shown: small duct (a) and large duct (b).
Hematoxylin-Eosin, original magnication 10X
C. Luchini et al.
Two macroscopic patterns of growth are described: the
periductal inltrating (PI) type, characterized by whitish
sclerosing lesions which encase and obliterate the proximal
branches of the left and right hepatic ducts in a longitudinal
modality; the mass-forming (MF) type, characterized by
white-grayish solid nodular mass lesions involving the
hepatic parenchyma.
Large duct carcinomas mostly show a PI pattern, sometimes along with a MF component; small duct carcinomas
manifest almost exclusively as MF lesions [3].
ICCAs, particularly the MF types, should be distinguished
from other mass-forming malignancies involving the liver:
the main differential diagnosis is represented by hepatocellular carcinoma (HCC), followed by metastatic colorectal
adenocarcinoma. Cholangiocarcinomas are un-encapsulated
white-grayish sclerotic lesions, usually with very scant or
absent necrosis, mostly occurring in non-cirrhotic livers.
HCCs almost always occur in cirrhotic livers as solitary or
multiple nodules with a yellowish to green-brown color, and
are often partially or totally encapsulated and/or necrotic.
Furthermore, the so-called nodule-in-nodule pattern of
growth is characteristic of HCCs and is never seen in iCCAs.
Metastatic colonic adenocarcinomas may resemble iCCAs
due to their white-yellowish color and lobulated margins; the
frequent presence of necrosis and a simple clinical correlation are the most reliable tools for a gross differential diagnosis between these two entities.
desmoplastic reaction. However, differences are recognized
between the main subtypes.
Large duct iCCAs show mucin-secreting glands with
columnar to cuboidal epithelium; lymphatic and perineural
invasion are frequent, as are lymph node metastasis.
Therefore, they have a poorer prognosis compared to the
small-duct counterpart [1]. Moreover, large duct iCCAs have
two known precursor lesions: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile
ducts. Similarly to its pancreatic counterpart, BilIN is a
microscopic lesion of large bile ducts characterized by at or
micropapillary architecture; here the dysplasia is classied
as low-grade or high-grade, but a three-tiered system
(BilIN- 1,2,3) is also accepted [4]. Intraductal papillary neoplasm of the bile ducts is a grossly visible premalignant papillary lesion, which may progress from low-grade to
high-grade dysplasia, and eventually adenocarcinoma [5].
Small duct iCCAs have no known precursor lesions. Two
microscopic subtypes are recognized: i) cholangiolocarcinoma, which is characterized by a bland-looking proliferation of small ductular units resembling benign ductular
reaction, and ii) ductal plate malformation-like pattern, characterized by ectatic and irregular neoplastic glands, lined
with a single layer of cuboidal or low columnar carcinoma
cells and irregular protrusions [6, 7].
8.2.3 Molecular Features
8.2.2 Microscopic Features
Regardless of localization, iCCAs share a three-tiered grading system and a common microscopic appearance, which is
that of an invasive adenocarcinoma with tubular or ductal
pattern, accompanied by abundant brous stroma and intense
The most frequently mutated gene in iCCAs is TP53 [8]. This
gene is also altered with similar frequency in small duct
iCCA, extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC), and cannot be considered a
subtype- specic marker. Similarly, KRAS mutations can be
found in all types of CCAs. On the other hand, IDH1 and
ab
8 Pathology ofBiliary Tract Cancers
67
IDH2 mutations are highly subtype-specic, being altered
almost exclusively in iCCA [9–11]. Mutations in these two
genes are concentrated in specic hotspots (R132 for IDH1
and R172 for IDH2), with a mutation prevalence ranging
between 5% and 40% of iCCA.Another molecular hallmark
of iCCAs is represented by alterations of specic chromatinremodelling genes: ARID1A, BAP1 and PBRM1 (6–26%)
[12]. Interestingly, different studies have claried that altera-
tions in such genes are mutually exclusive with IDH1/2 mutations and in most cases with KRAS mutations [9, 11–14].
Furthermore, several tyrosine kinase receptors (TKIs) were
reported to be amplied in the iCCA subgroup; among them,
and in order of frequency: ERBB2 (4–22%), EGFR (2–12%),
ERBB3 (7%) and MET (2–7%). In addition, a small proportion of iCCA harbour amplications of CCND1 gene (13%)
[14]. Among the different subtypes of CCA, fusion genes
were mainly observed in iCCA. FGFR2 gene fusions (14–
23%) represent another hallmark of this subcategory, where
BICC1 is the most frequent rearrangement’s partner [15].
Other studies pointed out that iCCA can be divided according
to its etiologic environment and to the genomic alterations
developed during tumorigenesis. Infection by liver ukes
such as Opisthorchis viverrini and Clonorchis sinensis concurs to distinguish iCCA into two large genetic subgroups.
Specically, uke-positive iCCA had a higher rate of singlenucleotide variant, alterations of TP53 and other genes
involved in DNA repair, ERBB2 amplication and mutations
involving AKT1, CTNNB1 and WNT5B. In contrast, mutations in BAP1 and IDH1/2 genes and FGFR rearrangements
were observed almost exclusively in uke-negative samples,
which also had a higher rate of gene copy number alterations.
These alterations were observed to inuence also the meth-
positive tumours had a hypermethylation of the CpG islands
caused by a longer and multi-step process involving cytosine’s deamination and mutation [13].
8.3 Extrahepatic Cholangiocarcinoma
8.3.1 Gross Features
Extrahepatic cholangiocarcinomas (eCCAs) can involve the
extrahepatic segment of the hepatic ducts or, less commonly,
the common bile duct. Macroscopically, they tend to present
as a sclerosing lesion causing an ill-dened stricture of the
involved duct; nodular and papillary lesions are also recognized, albeit less common [3].
The main location of eCCAs is the perihilar region (perihilar eCCA), close to the conuence of the left and right
hepatic bile ducts [16]. These lesions are also denominated
Klatskin tumors, and have been subdivided by Bismuth etal.
into four main types, based on the stricture pattern [17]:
Type I: stricture does not interrupt the main hepatic
conuence.
Type II: stricture interrupts the main hepatic conuence.
Type III: (a) stricture interrupts the main and the right secondary hepatic conuence; (b) stricture interrupts the main
and the left secondary hepatic conuence.
Type IV: primary and both right and left secondary hepatic
conuence are interrupted.
Lesions located in the distal portion of the common
bile duct (distal eCCA) cause obstructive jaundice, and
may be amenable to surgical resection by Whipple’s
pancreatectomy.
8.3.2 Microscopic Features
In most cases, the histologic picture of eCCAs is that of a
classic pancreatico-biliary adenocarcinoma, with irregular
angulated glands embedded in a dense desmoplastic stroma
with frequent perineural and intravascular invasion
(Fig.8.2a).
Fig. 8.2 Representative images of an extrahepatic cholangiocarcinoma
(a), in this case extending from the intra-pancreatic choledochus to the
surrounding parenchyma, and of a gallbladder carcinoma (b), in which
it is usually associated with areas of high-grade dysplasia of the biliary
epithelium. Hematoxylin-Eosin, original magnication 10X
68
C. Luchini et al.
Multiple rare histological patterns have also been
described, such as intestinal-type, foveolar-type, pyloric
gland-type, hepatoid, micropapillary, and signet ring [18–
21]. Other rare non-adenocarcinoma tumor types are also
on record, albeit exceedingly rare, such as squamous, adenosquamous, sarcomatoid and undifferentiated carcinoma
[3, 22].
Extrahepatic CCAs can arise from the same precursor
lesions previously described in the context of iCCAs: biliary
intraepithelial neoplasia (BilIN) and intraductal papillary
neoplasm of the bile ducts.
Due to its striking resemblance to pancreatic ductal adenocarcinoma, eCCA arising in the distal portion of the choledochus may be difcult to distinguish from a pancreatic
primary; moreover, both cancers tend to express the same
pattern of cytokeratin (CK7, CK19) and mucins (such as
MUC1 and MUC4) [23]. The key to the differential diagnosis lies in the identication of precursor lesions in the surgical specimen: the presence of high grade PanIN favors the
hypothesis of a pancreatic primary; conversely, the presence
of high grade dysplasia in the biliary epithelium of the choledochus supports a biliary primary.
8.3.3 Molecular Features
To date, major molecular studies investigating the eCCAs
molecular landscape have combined perihilar and distal
eCCAs, without highlighting their differences. This subtypes
share genetic alterations in TP53 (18–45%), KRAS (8–47%),
ARID1A/B (5–16%), BRCA1/2 (1–4%), SMAD4 (11–25%)
ELF3 (8%) and PIK3CA (7–9%), with ELF3 and ARID1B
mutations showing a specically-higher frequency in distal
eCCAs [9]. Recurrent chromosomal amplications were
observed in YEATS4 (6%), MDM2 (5%), CCNE1 (3%),
CDK4 (1%) and ERBB2 (1%), where ERBB2 mutations and
amplications were more prevalent in tumors with papillary
histology (33%) [24]. Analysis of the fusion genes revealed
the presence of rearrangements involving PRKACA and
PRKACB genes, observed, in the biliary tumor spectrum,
only in eCCA [9]. Direct comparison between perihilar
eCCA and distal eCCA has shown conicting results and
needs to be claried [24]. The expression prole of these
tumors has recently been analyzed. The analysis conducted
with an unsupervised approach with respect to the anatomical site, highlighted the presence of 4 molecular groups: (i)
metabolic, (ii) proliferative, (iii) mesenchymal and (iv)
immune [24]. The Metabolic class presented an overexpression of hepatocyte markers and appears as enriched in gene
signatures linked to the deregulated metabolism of bile acids.
Conversely, overexpression of MYC targets, ERBB2 aberrations, and enrichment of oncogenic mTOR, DNA repair and
cell cycle pathways were observed in the Proliferation class.
In this subgroup a high prevalence of eCCA and papillary
histology samples was observed. Furthermore, the
Mesenchymal group showed aberrant Hedgehog and TNFalfa signaling, and was associated with a worse prognosis,
whereas the Immune class had several immune-related features, comprising overexpression of PD-1/PD-L1 and a
higher lymphocyte inltration.
8.4 Gallbladder Carcinoma
8.4.1 Gross Features
The most common location of gallbladder carcinomas
(GBCs) is the fundus, accounting for 70% of cases; approximately one third arises in the body and the remaining 10%
involves the neck.
GBCs are typically accompanied by calculi and tend to
grow with an inltrative pattern. Interestingly, up to 30% of
GBCs are grossly unapparent [25]; thus, an extensive sampling is strongly suggested in the case of a cholecystectomy
specimen characterized by calculi and by rm, thickened
walls with gritty consistency and whitish color. Nodular,
papillary and eshy polypoid lesions are less common; their
presence is more often associated with sarcomatoid and
undifferentiated variants [3].
8.4.2 Microscopic Features
The vast majority of GBCs are adenocarcinomas.
The most common pattern encountered is pancreaticobiliary adenocarcinoma, which shares the morphology and
the dismal clinical behavior with its pancreatic counterpart
(Fig.8.2b).
Pancreatico-biliary GBCs may have a wide range of differentiation: poorly differentiated cases show marked pleomorphism, bizarre nuclei and single-cell or sheet-like
pattern of inltration; well-differentiated cases may resemble benign lesions, sometimes with a foamy gland appearance [26]. However, most cases present a tubular pattern
akin to pancreatic adenocarcinoma. The presence of the
micropapillary pattern is typically associated with a more
aggressive course [3].
Other types of adenocarcinomas encountered in the gallbladder include: (i) intestinal-type adenocarcinoma, a diagnosis which requires the exclusion of a colonic primary; (ii)
mucinous adenocarcinoma, composed of >50% extracellular mucin and characterized by a poorer prognosis compared to ordinary GBCs; (iii) clear cell carcinoma, which is
virtually always accompanied by foci of conventional
GBCs; (iv) poorly cohesive carcinoma with or without signet-ring cells.
8 Pathology ofBiliary Tract Cancers
69
Adenosquamous carcinomas (dened by the presence of
>25% of squamous elements) and pure squamous cell carcinomas are extremely rare; they tend to show extensive keratinization and have a poorer prognosis compared to ordinary
GBCs [27]. Hepatoid carcinomas are very rare and must be
distinguished from hepatocellular carcinomas involving the
gallbladder; sarcomatoid carcinomas have also been
described, and may show cell pleomorphism or heterologous
differentiation [3].
The main differential diagnosis in the evaluation of well
differentiated GBCs is represented by benign entities mimicking inltration.
Rokitansky-Aschoff sinuses are the result of hyperplasia
and herniation of epithelial cells through the bromuscular
layer of the gallbladder wall, and are usually referred to as
adenomyomatosis. They can show glandular hyperplasia and
features mimicking a perineural invasion, and therefore must
be carefully evaluated and distinguished from foci of adenocarcinoma [28]. Luschka ducts are a development abnormality and can be found in up to 10% of cholecystectomy
specimens. They appear as biliary ducts measuring 1–2mm
in diameter, and are typically located within the gallbladder
fossa in the lower part of the right hepatic lobe. In the case of
a orid proliferation of the epithelium, they may closely
resemble a pancreatico-biliary GBC.Therefore, it is important to be aware of histologic aspects and typical anatomic
locations of these non-neoplastic entities [29].
8.4.3 Molecular Features
The molecular characterization of GBCs is still evolving.
The most recent studies have indicated the TP53 gene as the
most frequently altered (29–50%) [9, 30]. Like all biliary
tract cancers, a not-negligible proportion of cases show
KRAS mutations (up to 20% of cases) [11, 31, 32]. On the
other hand, alterations in the genes of the ERBB family and
of ELF3 were much more frequent in GBC (up to 11%) than
in other biliary cancers [9, 31, 32]. Fusion genes have also
been found in GBC.Most of them involve the breakpoint
between exon 1 of TPPP and intron 9 of BRD9, observed in
up to 19% of cases [30]. A supervised survival outcomebased approach showed the existence of 3 different molecular proles [30–32]. These three groups were related to a
different histo-morphology: (i) biliary-like, (ii) gastric
foveolar- like and (iii) intestinal-like. The gastric foveolarlike group showed the best survival and had a high frequency
of cases displaying TPPP-BRD9 fusions. The other two
show more frequently alterations affecting the hypoxia pathway. Furthermore, the intestinal-like group was distinguished
by a strong association with smoking and with an advanced
stage of the neoplasia at the time of diagnosis, indicating a
more aggressive behavior.
References
1. Aishima S, Oda Y. Pathogenesis and classication of intrahepatic
cholangiocarcinoma: different characters of perihilar large duct
type versus peripheral small duct type. J Hepato-Biliary-Pancreat
Sci. 2015;22:94–100.
2. Akita M, Fujikura K, Ajiki T, Fukumoto T, Otani K, Azuma T, Itoh
T, Ku Y, Zen Y. Dichotomy in intrahepatic cholangiocarcinomas
based on histologic similarities to hilar cholangiocarcinomas. Mod
Pathol Off J U S Can Acad Pathol Inc. 2017;30:986–97.
3. WHO Classication of Tumours Editorial Board: Digestive System
Tumours. International Agency for Research on Cancer; 2019.
4. Nakanuma Y, Sudo Y.Biliary tumors with pancreatic counterparts.
Semin Diagn Pathol. 2017;34:167–75.
5. Jung G, Park K-M, Lee SS, Yu E, Hong S-M, Kim J. Long-term
clinical outcome of the surgically resected intraductal papillary
neoplasm of the bile duct. J Hepatol. 2012;57:787–93.
6. Sempoux C, Fan C, Singh P, Obeidat K, Roayaie S, Schwartz M,
Fiel MI, Thung SN.Cholangiolocellular carcinoma: an innocentlooking malignant liver tumor mimicking ductular reaction. Semin
Liver Dis. 2011;31:104–10.
7. Nakanuma Y, Sato Y, Ikeda H, Harada K, Kobayashi M, Sano
K, Uehara T, Yamamoto M, Ariizumi S, Park YN, Choi JH, Yu
E. Intrahepatic cholangiocarcinoma with predominant «ductal
plate malformation» pattern: a new subtype. Am J Surg Pathol.
2012;36:1629–35.
8. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA,
Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C,
Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR,
Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni
M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens
JC, Moncsek A, Rizvi S, Heimbach J, Koerkamp BG, Bruix J,
Forner A, Bridgewater J, Valle JW, Gores GJ.Cholangiocarcinoma
2020: the next horizon in mechanisms and management. Nat Rev
Gastroenterol Hepatol. 2020;17:557–88.
9. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M,
Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H,
Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T.Genomic
spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10.
10. Churi CR, Shroff R, Wang Y, Rashid A, Kang HC, Weatherly J,
Zuo M, Zinner R, Hong D, Meric-Bernstam F, Janku F, Crane CH,
Mishra L, Vauthey J-N, Wolff RA, Mills G, Javle M.Mutation proling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9:e115383.
11. Simbolo M, Fassan M, Ruzzenente A, Mafcini A, Wood LD,
Corbo V, Melisi D, Malleo G, Vicentini C, Malpeli G, Antonello
D, Sperandio N, Capelli P, Tomezzoli A, Iacono C, Lawlor RT,
Bassi C, Hruban RH, Guglielmi A, Tortora G, de Braud F, Scarpa
A.Multigene mutational proling of cholangiocarcinomas identies actionable molecular subgroups. Oncotarget. 2014;5:2839–52.
12. Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas
DJ, Niknafs N, Guthrie VB, Maitra A, Argani P, Offerhaus GJA,
Roa JC, Roberts LR, Gores GJ, Popescu I, Alexandrescu ST,
Dima S, Fassan M, Simbolo M, Mafcini A, Capelli P, Lawlor
RT, Ruzzenente A, Guglielmi A, Tortora G, de Braud F, Scarpa A,
Jarnagin W, Klimstra D, Karchin R, Velculescu VE, Hruban RH,
Vogelstein B, Kinzler KW, Papadopoulos N, Wood LD. Exome
sequencing identies frequent inactivating mutations in BAP1,
ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat
Genet. 2013;45:1470–3.
13. Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN,
Padmanabhan N, Nellore V, Kongpetch S, Ng AWT, Ng LM, Choo
SP, Myint SS, Thanan R, Nagarajan S, Lim WK, Ng CCY, Boot A,
Liu M, Ong CK, Rajasegaran V, Lie S, Lim AST, Lim TH, Tan J,
Loh JL, McPherson JR, Khuntikeo N, Bhudhisawasdi V, Yongvanit
70
C. Luchini et al.
P, Wongkham S, Totoki Y, Nakamura H, Arai Y, Yamasaki S, Chow
PK-H, Chung AYF, Ooi LLPJ, Lim KH, Dima S, Duda DG, Popescu
I, Broet P, Hsieh S-Y, Yu M-C, Scarpa A, Lai J, Luo D-X, Carvalho
AL, Vettore AL, Rhee H, Park YN, Alexandrov LB, Gordân R,
Rozen SG, Shibata T, Pairojkul C, Teh BT, Tan P.Whole-genome
and epigenomic landscapes of etiologically distinct subtypes of
cholangiocarcinoma. Cancer Discov. 2017;7:1116–35.
14. Farshidfar F, Zheng S, Gingras M-C, Newton Y, Shih J, Robertson
AG, Hinoue T, Hoadley KA, Gibb EA, Roszik J, Covington KR,
Wu C-C, Shinbrot E, Stransky N, Hegde A, Yang JD, Reznik E,
Sadeghi S, Pedamallu CS, Ojesina AI, Hess JM, Auman JT, Rhie
SK, Bowlby R, Borad MJ, Cancer Genome Atlas Network, Zhu
AX, Stuart JM, Sander C, Akbani R, Cherniack AD, Deshpande
V, Mounajjed T, Foo WC, Torbenson MS, Kleiner DE, Laird PW,
Wheeler DA, McRee AJ, Bathe OF, Andersen JB, Bardeesy N,
Roberts LR, Kwong LN.Integrative genomic analysis of cholangiocarcinoma identies distinct IDH-mutant molecular proles.
Cell Rep. 2017;19:2878–80.
15. Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D,
Al-Rajabi R, Paulson AS, Borad MJ, Gallinson D, Murphy AG, Oh
D-Y, Dotan E, Catenacci DV, Van Cutsem E, Ji T, Lihou CF, Zhen
H, Féliz L, Vogel A. Pemigatinib for previously treated, locally
advanced or metastatic cholangiocarcinoma: a multicentre, openlabel, phase 2 study. Lancet Oncol. 2020;21:671–84.
16. Kondo S, Takada T, Miyazaki M, Miyakawa S, Tsukada K, Nagino
M, Furuse J, Saito H, Tsuyuguchi T, Yamamoto M, Kayahara M,
Kimura F, Yoshitomi H, Nozawa S, Yoshida M, Wada K, Hirano
S, Amano H, Miura F. Japanese Association of Biliary Surgery,
Japanese Society of Hepato-Biliary-Pancreatic Surgery, Japan
Society of Clinical Oncology: Guidelines for the management
of biliary tract and ampullary carcinomas: surgical treatment. J
Hepato-Biliary-Pancreat Surg. 2008;15:41–54.
17. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg.
1992;215:31–8.
18. Albores-Saavedra J, Chablé-Montero F, Méndez-Sánchez N,
Mercado MÁ, Vilatoba-Chapa M, Henson DE. Adenocarcinoma
with pyloric gland phenotype of the extrahepatic bile ducts: a previously unrecognized and distinctive morphologic variant of extrahepatic bile duct carcinoma. Hum Pathol. 2012;43:2292–8.
19. Wang Y, Liu Y-Y, Han G-P.Hepatoid adenocarcinoma of the extrahepatic duct. World J Gastroenterol. 2013;19:3524–7.
20. Yoshizawa T, Toyoki Y, Hirai H, Haga T, Toba T, Sakuraba S,
Okano K, Wu Y, Seino H, Morohashi S, Hakamada K, Kijima
H.Invasive micropapillary carcinoma of the extrahepatic bile duct
and its malignant potential. Oncol Rep. 2014;32:1355–61.
21. Ogata S, Kimura A, Hatsuse K, Yamamoto J, Shimazaki H,
Nakanishi K, Kawai T. Poorly differentiated adenocarcinoma
with signet-ring cell carcinoma of the extrahepatic bile duct in a
42-year-old Japanese female: a case report. Acta Med Okayama.
2010;64:63–5.
22. Goto T, Sasajima J, Koizumi K, Sugiyama Y, Kawamoto T,
Fujibayashi S, Moriichi K, Yamada M, Fujiya M, Kohgo Y.Primary
poorly differentiated squamous cell carcinoma of the extrahepatic
bile duct. Int Med Tokyo Jpn. 2016;55:1581–4.
23. Yonezawa S, Higashi M, Yamada N, Yokoyama S, Goto
M. Signicance of mucin expression in pancreatobiliary neoplasms. J Hepato-Biliary-Pancreat Sci. 2010;17:108–24.
24. Montal R, Sia D, Montironi C, Leow WQ, Esteban-Fabró R, Pinyol
R, Torres-Martin M, Bassaganyas L, Moeini A, Peix J, Cabellos L,
Maeda M, Villacorta-Martin C, Tabrizian P, Rodriguez-Carunchio
L, Castellano G, Sempoux C, Minguez B, Pawlik TM, Labgaa
I, Roberts LR, Sole M, Fiel MI, Thung S, Fuster J, Roayaie S,
Villanueva A, Schwartz M, Llovet JM.Molecular classication and
therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol.
2020;73:315–27.
25. Bal MM, Ramadwar M, Deodhar K, Shrikhande S. Pathology of
gallbladder carcinoma: current understanding and new perspectives. Pathol Oncol Res POR. 2015;21:509–25.
26. Adsay V, Logani S, Sarkar F, Crissman J, Vaitkevicius V. Foamy
gland pattern of pancreatic ductal adenocarcinoma: a deceptively
benign-appearing variant. Am J Surg Pathol. 2000;24:493–504.
27. Roa JC, Tapia O, Cakir A, Basturk O, Dursun N, Akdemir D, Saka
B, Losada H, Bagci P, Adsay NV.Squamous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis
of 34 cases identied in 606 carcinomas. Mod Pathol Off J US Can
Acad Pathol Inc. 2011;24:1069–78.
28. Albores-Saavedra J, Keenportz B, Bejarano PA, Alexander AAZ,
Henson DE.Adenomyomatous hyperplasia of the gallbladder with
perineural invasion: revisited. Am J Surg Pathol. 2007;31:1598–604.
29. Singhi AD, Adsay NV, Swierczynski SL, Torbenson M, Anders
RA, Hruban RH, Argani P.Hyperplastic Luschka ducts: a mimic
of adenocarcinoma in the gallbladder fossa. Am J Surg Pathol.
2011;35:883–90.
30. Nepal C, Zhu B, O’Rourke CJ, Bhatt DK, Lee D, Song L, Wang
D, Van Dyke A, Choo-Wosoba H, Liu Z, Hildesheim A, Goldstein
AM, Dean M, LaFuente-Barquero J, Lawrence S, Mutreja K,
Olanich ME, Bermejo JL, CGR Exome Studies Group(,), Ferreccio
C, Roa JC, Rashid A, Hsing AW, Gao Y-T, Chanock SJ, Araya JC,
Andersen JB, Koshiol J.Integrative molecular characterization of
gallbladder cancer reveals microenvironment-associated subtypes.
J Hepatol. 2020.
31. Li M, Zhang Z, Li X, Ye J, Wu X, Tan Z, Liu C, Shen B, Wang
X-A, Wu W, Zhou D, Zhang D, Wang T, Liu B, Qu K, Ding Q,
Weng H, Ding Q, Mu J, Shu Y, Bao R, Cao Y, Chen P, Liu T, Jiang
L, Hu Y, Dong P, Gu J, Lu W, Shi W, Lu J, Gong W, Tang Z, Zhang
Y, Wang X, Chin YE, Weng X, Zhang H, Tang W, Zheng Y, He L,
Wang H, Liu Y, Liu Y.Whole-exome and targeted gene sequencing
of gallbladder carcinoma identies recurrent mutations in the ErbB
pathway. Nat Genet. 2014;46:872–6.
32. Pandey A, Stawiski EW, Durinck S, Gowda H, Goldstein LD,
Barbhuiya MA, Schröder MS, Sreenivasamurthy SK, Kim S-W,
Phalke S, Suryamohan K, Lee K, Chakraborty P, Kode V, Shi
X, Chatterjee A, Datta K, Khan AA, Subbannayya T, Wang J,
Chaudhuri S, Gupta S, Shrivastav BR, Jaiswal BS, Poojary SS,
Bhunia S, Garcia P, Bizama C, Rosa L, Kwon W, Kim H, Han Y,
Yadav TD, Ramprasad VL, Chaudhuri A, Modrusan Z, Roa JC,
Tiwari PK, Jang J-Y, Seshagiri S. Integrated genomic analysis
reveals mutated ELF3 as a potential gallbladder cancer vaccine
candidate. Nat Commun. 2020;11:4225.
Multifocal Hepatocellular Carcinoma:
Genomic andTranscriptional
Heterogeneity
MingKuang, LixiaXu, SuiPeng, ManlingHuang, XinLiu,
andGuanruiLiao
9
Abstract
Hepatocellular carcinoma (HCC) often presents with multiple nodules within the liver, with limited effective intervention. The high tumor heterogeneity of multifocal HCC
might be the major cause of treatment failure. Studies
using next-generation sequencing identify genomic and
transcriptional heterogeneity among tumor nodules in
multifocal HCC patients including mutational proles,
copy number alterations (CNAs), structure variations
(SVs), tumor evolutionary trajectory, RNA expression patterns, and tumor immune microenvironment proles. In
addition, recent data indicate that the heterogeneity of
druggable targets and immune landscape might help interpret the clinical responsiveness to targeted drugs and
immunotherapy for multifocal HCC patients. Thus, a comprehensive and precise understanding of genomic and
transcriptional heterogeneity is crucial to improve the
treatment of patients with multifocal HCC and is particularly helpful to the development of personalized therapies.
This Chapter reviews previous studies of genomic and
transcriptional heterogeneity of multifocal HCC and discusses how we can leverage this information to improve
the clinical management of patients with multifocal HCC.
9.1 Introduction ofMultifocal
Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the fourth leading cause
of cancer death worldwide [1]. About 50–75% of HCC is
reported to be multifocal when diagnosed, of which only
20–30% can undergo surgical resection [2–4]. For advanced
multifocal HCC patients who have lost the chance of surgery, targeted therapy is the rst-line recommended treatment, offering a median progression free survival of only
3.6–7.3months [5, 6]. Immunotherapy represents a promis-
ing option for HCC. Targeting immune checkpoint programmed cell death protein-1 (PD-1) for advanced HCC
patients demonstrated an overall survival of 28.6months as a
rst-line treatment and 12.9–15 months as a second-line
treatment [7–9]. However, the overall response rate for the
anti-PD-1 treatment in advanced HCC patients is less than
20% [8, 9]. Recently, the results of clinical trial IMbrave150
are encouraging as they signicantly improve the overall survival in advanced liver cancer through combination of immunotherapy and VEGF inhibitor [10]. This nding further
underscores the importance of combination therapy in
HCC.Compared to previous single-agent strategy, emerging
M. Kuang (*)
Center of Hepatopancreatobiliary Surgery, The First Afliated
Hospital, Sun Yat-sen University,
Guangzhou, Guangdong Province, China
Cancer Center, The First Afliated Hospital, Sun Yat-sen
University, Guangzhou, Guangdong Province, China
Institute of Precision Medicine, The First Afliated Hospital, Sun
Yat-sen University, Guangzhou, Guangdong Province, China
e-mail: kuangm@mail.sysu.edu.cn
L. Xu
Cancer Center, The First Afliated Hospital, Sun Yat-sen
University, Guangzhou, Guangdong Province, China
Department of Gastroenterology and Hepatology, The First
Afliated Hospital, Sun Yat-sen University,
Guangzhou, Guangdong Province, China
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_9
S. Peng
Institute of Precision Medicine, The First Afliated Hospital, Sun
Yat-sen University, Guangzhou, Guangdong Province, China
Department of Gastroenterology and Hepatology, The First
Afliated Hospital, Sun Yat-sen University,
Guangzhou, Guangdong Province, China
Clinical Trials Unit, The First Afliated Hospital, Sun Yat-sen
University, Guangzhou, Guangdong Province, China
M. Huang
Cancer Center, The First Afliated Hospital, Sun Yat-sen
University, Guangzhou, Guangdong Province, China
X. Liu · G. Liao
Center of Hepatopancreatobiliary Surgery, The First Afliated
Hospital, Sun Yat-sen University,
Guangzhou, Guangdong Province, China
71