Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_775_Библиотеки_им_академика_М_И_Перельмана.pdf
72
M. Kuang et al.
combination therapies can act on more targets, thus could
simultaneously treat multiple heterogeneous tumor clones.
Tumor heterogeneity means that different tumor cells can
have distinct morphological and phenotypic proles, including gene expression, metabolism, proliferation, metastatic
potential, and so on [11]. Tumor heterogeneity might be
more complex in multifocal HCC patients than that in
patients with single tumor [12–14]. Some recent studies have
evaluated genomic heterogeneity of multifocal HCC based
on mutational, copy number alterations (CNAs) proles,
structure variations (SVs), and HBV DNA integrations [15–
19]. In addition, transcriptional heterogeneity, especially
immune heterogeneity has been reported in multifocal HCC
recently and proved to be implicated in different immunotherapies response [18–20].
Here, we review genomic and transcriptional heterogeneity in multifocal HCC to elucidate the internodular heterogeneity of multifocal HCC at the molecular level and discuss
how we can leverage this information to improve the treatment and management of patients with multifocal HCC.
9.2 Heterogeneity ofMultifocal HCC
9.2.1 Genomic Heterogeneity ofMultifocal
HCC
Multifocal HCC may result from multicentric occurrence
(MO-HCC) or intrahepatic metastases (IM-HCC). Nextgeneration sequencing (NGS)-based studies have shown
substantial genomic heterogeneity in mutational proles,
CNAs, SVs, and tumor clonal evolution among tumors separated by anatomical locations within the same patient. The
extent of mutations shared by all tumor nodules in multifocal
HCC varied signicantly. Recent studies have revealed that
the actual shared mutation rates ranged from 8% to 97% in
IM-HCC, with nearly no common mutations in MO-HCC [3,
21, 22]. Extensive heterogeneity of copy number aberra-
tions, with highly variable percentages of genomic alteration
has also been reported among multifocal lesions. For example, the percentage of ubiquitous CNAs ranged from 22.2%
to 100% in IM-HCC and it could reach as high as 46.7% in
MO-HCC [23]. In our previous study, we have reported variable extent of heterogeneity in mutations and CNA patterns
among tumors of multifocal HCC patients by whole exome
sequencing [18]. For patients with HBV infection, HBVDNA was found to integrate into human host chromosomes
in the early stage of natural course of acute hepatitis B infection [13, 14], making the junctional information specic to
each tumor clone. As such, tumors with the same HBV DNA
integration site are supposed to be intrahepatic metastasis
nodules [21]. It has been reported that tumors in IM-HCC
exhibited the same HBV DNA integrations, while different
patterns of HBV DNA integration were found in tumors of
MO-HCC, which is consistent with what we found in our
research using whole genome sequencing [23, 24]. In parallel, different genomic structural variations (SVs) were
observed among multiple lesions [16]. Moreover, we found
that there was a tendency that the tumor with smaller size
had increased SV numbers as compared to the large tumor in
the same patient in our recent study [19].
Phylogenetic trees which were constructed based on all
somatic mutations also indicate great genomic heterogeneity
of multifocal HCC [18, 22, 23, 25]. Well-known driver alterations, including druggable targets were further mapped to
each phylogenetic tree. The result showed that only 9–85%
of the driver alterations were truncal events, indicating multiple tumors follow the scenario of branched tumor evolution
[21, 23]. Our recent study also showed that only 30% (18/60)
of the driver alterations were truncal events and only 20%
(3/15) of druggable alterations were mapped to trunks, rening the great heterogeneity of different tumors among multifocal HCC patient.
9.2.2 Transcriptional Heterogeneity
ofMultifocal HCC
In recent studies, RNA-sequencing is performed on multiple
tumor samples and their adjacent normal liver tissue samples
to characterize the transcriptomic prole of multifocal HCC
[18, 25]. The differentially expressed genes between all
tumors and normal samples are compared and up-regulated
genes and down-regulated genes in tumor samples are identied. Gene sets from Gene Ontology (GO) reveal downregulated genes in tumors are mainly concentrated in immune
response and protein/metabolic process pathways in our
recent study [18]. Consistently, Miao etal. found immune
response and metabolism pathways are enriched in multifocal HCC [25], which is supported by the results of a largescale liver cancer integrative research [26]. We also found
that proliferation-related pathways were enriched in the large
nodules in multifocal HCC, such as angiogenesis pathway,
VEGF signaling pathway, PI3K-AKT signaling pathway,
while more immune-related pathways were enriched in small
nodules, including TNFα signaling pathway, IFN-α signaling pathway, T cell and B cell receptor signaling pathway
[19]. This result partially explains the heterogeneity of clinical responses to targeted therapy or immunotherapy among
multiple tumor nodules within the same multifocal HCC
patient.
Moreover, RNA expression prole can also predict the
proliferation and invasion ability of multifocal HCC, providing new perspectives for postoperative adjuvant therapy [27].
9 Multifocal Hepatocellular Carcinoma: Genomic andTranscriptional Heterogeneity
73
In our recent study, after hierarchical clustering analysis of
34 HCC lesions in 6 patients based on RNA expression, we
found that patients with Edmondson−Steiner grade 2 and
grade 3 were clearly distinguished, suggesting that RNA
expression pattern is associated with tumor differentiation
[3]. Moreover, the authors in a retrospective study utilized
transcriptome sequencing to associate the sequencing data
with clinical outcomes in a cohort of Chinese patients with
HBV-related HCC.They found up-regulation of cytoskeletal
remodeling and extracellular matrix organization is associated with tumor metastasis, and worse prognosis may be
related to up-regulation of cell proliferation, nucleic acid
metabolism, protein translation, and macromolecular assembly, suggesting that RNA expression prole helps predict the
clinical characteristics of tumor [25].
Immunotherapy is emerging as a promising strategy in
HCC, but its relatively low response rate and mixed responses
among different tumor nodules remained to be a major challenge. Immune discrepancies among different nodules vary
within HCC patients, including cytokines, immunosuppressive cells, stromal cells, growth factors, which together shape
the heterogenous immune microenvironment of multifocal
HCC.Immune features of multifocal HCC are important for
understanding immune-escape mechanisms and developing
more effective immunotherapy [3].
A recent study based on immuno-transcriptomic analysis
divided multifocal HCC into three subtypes: immunocompetent subtype, immunodecient subtype, and immunosuppressive subtype. The compositions of immune cells in
different subtypes are quite different, which provides a good
classication reference for further study. The immunocompetent subtype has normal T cell inltration, but poor B cell
inltration; the lymphocyte inltration in immunodecient
subtype is lower, but has higher dendritic cells and natural
killing cells; the immunosuppressive subtype had higher frequencies of Treg cells, Breg cells, and M2 macrophages,
with up- regulated expressions of PD-1, PD-L1, CTLA-4,
and Tim-1 [21]. Besides, it has been reported that there are
fewer T cells and more M2 macrophage inltration, neoantigens, and TCR repertoires in IM-HCC, while more
immune checkpoint inhibitory molecules and immune editing are present in MO-HCC [3]. Our study also revealed that
there is signicant immune heterogeneity in multifocal HCC,
with various degrees of immune cell inltration among different nodules. Interestingly, in CD8
+
T cell-rich nodules, the
expression of inhibitory immune molecules such as CTLA4, PD-1, and PD-L1 is also up-regulated, making it difcult
for inltrating CD8+ T cells to exert antitumor function [18].
Therefore, for tumors with high inltrated CD8+ T cells,
PD-1/PD-L1 inhibitor treatment may be able to relieve
immunosuppression and enhance the killing effect of inltrating CD8+ T cells.
9.3 The Inuences ofGenomic
andTranscriptional Heterogeneity
onManagement ofMultifocal HCC
The number of tumors in multifocal HCC is signicantly correlated with patients’ overall survival [28, 29]. Surgical resection is recommended as the rst choice for multifocal HCC
patients with less than 3 nodules. For patients with more than 3
tumor nodules, if these tumors are conned to the same segment
or ipsilateral liver lobe, or intraoperative radiofrequency ablation can be performed simultaneously to remove lesions outside
the resection range, surgical resection may be more effective
than other treatment approaches [28, 30]. With the development
in surgical techniques and perioperative management, some
cancer centers in Asia advocate a relatively more active management of intermediate- stage HCC and have observed better
outcomes in patients [31–34]. Anatomical resection of HCC is
very important in surgical treatment, which was rst proposed
by the distinguished Japanese hepatic surgeon, Prof. Makuuchi
[35, 36]. This advanced concept has been widely applied in
multifocal HCC resection [37, 38], making it possible to analyze the clonal evolution and internodular heterogeneity of multifocal HCC with surgical specimens.
Based on the multi-omics analysis of surgical specimens
from multifocal HCC, the understanding of genetic heterogeneity has been deepened, and correspondingly, more insights
have been brought to the management of advanced unresectable multifocal HCC.Searching for truncal druggable targets
based on NGS sequencing data would help in prevention of
postoperative recurrence or treatment selection for multifocal
HCC.Our recent study revealed that sorafenib- targeted alterations (including BRAF amplication, PDGFRB amplication, and VEGFA amplication) were identied in the trunk
of only one out of six patients, which may explain the relative
low treatment response rate to sorafenib in clinical practice
[18]. These data indicate that the heterogeneity of druggable
targets might help interpret the clinical responsiveness to targeted drugs for multifocal HCC patients.
As the era of immune combination therapy has come in
the treatment of HCC, there is an increasing need for a precise analysis to choose the optimal immunotherapy strategy,
such as non-invasive imaging test combined with articial
intelligence, circulating tumor DNA, and other signatures to
predict therapeutic targets and monitor the treatment efcacy. Our multi-omics study revealed that the small nodules
had higher immune cell inltration and up-regulation of
immune pathways as compared to the large nodule of the
same multifocal HCC case, which may partially explain the
different responses of small and large nodules to anti-PD-1
treatment. We further demonstrated the synergistic effect of
combined immunotherapy and anti-proliferation/oncogenic
therapy such as tyrosine kinase inhibitors (TKIs) in multifo-
74
T5
M. Kuang et al.
T3
Mutation CNV Phylogenetic Tree
T2
T4
T1
Multifocal HCC
Immune Score
Heterogenetic Characteristics
Fig. 9.1 Genomic and transcriptional heterogeneity in multifocal HCC
cal HCC [19]. The heterogenous immune microenvironment
of multifocal HCC demands different or combinational
immunotherapies for different patients [19, 21]. As immune
checkpoint inhibitors can reactivate antitumor immunity in
an immunosuppressive microenvironment, it is very crucial
to adopt personalized immunotherapy strategies to patients
with multifocal HCC for better clinical response.
Moreover, the result of clinical trial IMbrave150 “atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma” brings hope to patients with advanced HCC [10].
This immune combination therapy was recently approved by
the National Medical Products Administration in China and
Food and Drug Administration in the USA as the rst- line
treatment of advanced HCC, highlighting the importance of
combination immunotherapy in advanced and multifocal
unresectable liver cancer. The success of clinical trial
IMbrave150 has shed light on future research to improve the
prognosis of multifocal HCC, emphasizing the importance
of immune combination therapy.
In conclusion, increasing studies have explored the
genomic and transcriptional heterogeneity among different
nodules in multifocal HCC through multi-omics sequencing.
The characteristics of the drug targets distribution and
immune microenvironment may help accurately predict the
efcacy of targeted drugs and immunotherapy in multifocal
HCC patients (Fig.9.1).
References
1. International Agency For Research On Cancer WHO.Cancer today.
https://gco.iarc.fr/today/home
2. Kudo M, Izumi N, Ichida T, Ku Y, Kokudo N, etal. Report of the
19th follow-up survey of primary liver cancer in Japan. Hepatol
Res. 2016;46:372–90.
T2
T3
T4
T5
T1
“HOT” “COLD”
3. Dong LQ, Peng LH, Ma LJ, Liu DB, Zhang S, etal. Heterogeneous
immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma. J Hepatol. 2020;72:896–908.
4. Xie DY, Fan HK, Ren ZG, Fan J, Gao Q.Identifying clonal origin
of multifocal hepatocellular carcinoma and its clinical implications.
Clin Transl Gastroenterol. 2019;10:e6.
5. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, etal. Lenvatinib versus
sorafenib in rst-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Lancet. 2018;391:1163–73.
6. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, et al.
Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.
2008;359:378–90.
7. Crocenzi TS, El-Khoueiry AB, Yau TC, Melero I, Sangro B, etal.
Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts
with advanced hepatocellular carcinoma (HCC): CheckMate 040
study. J Clin Oncol. 2017;15:4013.
8. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, et al.
Nivolumab in patients with advanced hepatocellular carcinoma
(CheckMate 040): an open-label, non-comparative, phase 1/2 dose
escalation and expansion trial. Lancet. 2017;389:2492–502.
9. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, et al.
Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224):
a non- randomised, open-label phase 2 trial. Lancet Oncol.
2018;19:940–52.
10. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, etal. Atezolizumab
plus bevacizumab in unresectable hepatocellular carcinoma. N
Engl J Med. 2020;382:1894–905.
11. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805:105–17.
12. Lin DC, Mayakonda A, Dinh HQ, Huang P, Lin L, etal. Genomic
and epigenomic heterogeneity of hepatocellular carcinoma. Cancer
Res. 2017;77:2255–65.
13. Huang A, Zhao X, Yang XR, Li FQ, Zhou XL, etal. Circumventing
intratumoral heterogeneity to identify potential therapeutic targets
in hepatocellular carcinoma. J Hepatol. 2017;67:293–301.
14. Torrecilla S, Sia D, Harrington AN, Zhang Z, Cabellos L, etal. Trunk
mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J Hepatol. 2017;67:1222–31.
15. Gao Q, Wang ZC, Duan M, Lin YH, Zhou XY, etal. Cell culture system for analysis of genetic heterogeneity within hepatocellular car-
Group A
Group B
Precision Medicine
9 Multifocal Hepatocellular Carcinoma: Genomic andTranscriptional Heterogeneity
75
cinomas and response to pharmacologic agents. Gastroenterology.
2017;152:232–42.
16. Furuta M, Ueno M, Fujimoto A, Hayami S, Yasukawa S, et al.
Whole genome sequencing discriminates hepatocellular carcinoma
with intrahepatic metastasis from multi-centric tumors. J Hepatol.
2017;66:363–73.
17. Zhai W, Lim TK, Zhang T, Phang ST, Tiang Z, etal. The spatial
organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat Commun.
2017;8:4565.
18. Xu LX, He MH, Dai ZH, Yu J, Wang JG, etal. Genomic and transcriptional heterogeneity of multifocal hepatocellular carcinoma.
Ann Oncol. 2019;30:990–7.
19. Huang ML, He MH, Guo Y, Li HP, Shen SL etal. The inuence of
immune heterogeneity on the effectiveness of immune checkpoint
inhibitors in multifocal hepatocellular carcinomas. Clin Cancer
Res. 2020.
20. Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C,
etal. Identication of an immune-specic class of hepatocellular
carcinoma. Based Mol Features Gastroenterol. 2017;153:812–26.
21. Zhang Q, Lou Y, Yang J, Wang J, Feng J, etal. Integrated multiomic
analysis reveals comprehensive tumour heterogeneity and novel
immunophenotypic classication in hepatocellular carcinomas.
Gut. 2019;68:2019–31.
22. Xue R, Li R, Guo H, Guo L, Su Z, et al. Variable intra-tumor
genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma. Gastroenterology. 2016;150:998–1008.
23. Duan M, Hao J, Cui S, Worthley DL, Zhang S, et al. Diverse
modes of clonal evolution in HBV-related hepatocellular carcinoma revealed by single-cell genome sequencing. Cell Res.
2018;28:359–73.
24. Chen XP, Long X, Jia WL, Wu HJ, Zhao J, etal. Viral integration
drives multifocal HCC during the occult HBV infection. J Exp Clin
Cancer Res. 2019;38:261.
25. Miao R, Luo H, Zhou H, Li G, Bu D, etal. Identication of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratication by integrative multi-omics analysis. J
Hepatol. 2014;61:840–9.
26. Comprehensive and Integrative Genomic Characterization of
Hepatocellular Carcinoma. Cell. 2017;169:1327–41.
27. Feo F, Pascale RM. Multifocal hepatocellular carcinoma: intrahepatic metastasis or multicentric carcinogenesis? Ann Transl Med.
2015;3:4.
28. Yin L, Li H, Li AJ, Lau WY, Pan ZY, et al. Partial hepatectomy
vs. transcatheter arterial chemoembolization for resectable multiple
hepatocellular carcinoma beyond Milan Criteria: a RCT.J Hepatol.
2014;61:82–8.
29. Zhao WC, Yang N, Zhu N, Zhang HB, Fu Y, et al. Patients with
multiple hepatocellular carcinomas within the UCSF criteria have
outcomes after curative resection similar to patients within the
BCLC early-stage criteria. World J Surg. 2012;36:1811–23.
30. Torzilli G, Belghiti J, Kokudo N, Takayama T, Capussotti L, etal.
A snapshot of the effective indications and results of surgery for
hepatocellular carcinoma in tertiary referral centers: is it adherent
to the EASL/AASLD recommendations?: an observational study of
the HCC East-West study group. Ann Surg. 2013;257:929–37.
31. Ohkubo T, Midorikawa Y, Nakayama H, Moriguchi M, Aramaki
O, et al. Liver resection of hepatocellular carcinoma in patients
with portal hypertension and multiple tumors. Hepatol Res.
2018;48:433–41.
32. Wada H, Eguchi H, Noda T, Ogawa H, Yamada D, etal. Selection
criteria for hepatic resection in intermediate-stage (BCLC stage B)
multiple hepatocellular carcinoma. Surgery. 2016;160:1227–35.
33. Liu W, Wang K, Bao Q, Sun Y, Xing BC.Hepatic resection provided long-term survival for patients with intermediate and
advanced-stage resectable hepatocellular carcinoma. World J Surg
Oncol. 2016;14:62.
34. Ho MC, Huang GT, Tsang YM, Lee PH, Chen DS, et al. Liver
resection improves the survival of patients with multiple hepatocellular carcinomas. Ann Surg Oncol. 2009;16:848–55.
35. Makuuchi M, Hasegawa H, Yamazaki S.Ultrasonically guided subsegmentectomy. Surg Gynecol Obstet. 1985;161:346–50.
36. Makuuchi M. Surgical treatment for HCC – special reference to
anatomical resection. Int J Surg. 2013;11(Suppl 1):S47–9.
37. Makuuchi M, Sano K.The surgical approach to HCC: our progress
and results in Japan. Liver Transpl. 2004;10:S46–52.
38. Ishizawa T, Hasegawa K, Aoki T, Takahashi M, Inoue Y, et al.
Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology.
2008;134:1908–16.
Intraductal Neoplasms ofthePancreas
ToruFurukawa
10
Abstract
Here described are denitions, epidemiology, etiology,
clinical features, radiology, pathology, and treatment and
prognosis of intraductal neoplasms of the pancreas,
namely, intraductal papillary mucinous neoplasms
(IPMNs), intraductal oncocytic papillary neoplasms
(IOPNs), and intraductal tubulopapillary neoplasms
(ITPNs). IPMNs are grossly visible intraductal epithelial
neoplasms of mucin-producing cells. IPMNs are fairly
common without known etiologic factors. Imaging studies show cystically dilated ducts involving branch ducts,
the main duct, or the both of ducts. Microscopically, the
neoplastic cells grow in papillae with various atypical
degree ranging from low-grade to high-grade. The papillae show various morphologic features with expression of
characteristic mucin proteins, which are classied into
gastric, intestinal, and pancreatobiliary types. Mutations
in KRAS and GNAS are frequently found. IPMNs often
become invasive, which show adenocarcinoma with ductal or mucinous elements. Disease-specic survivals of
patients with surgically resected IPMNs are fairly good in
low-grade IPMNs, modest in high-grade IPMNs, however, poor in invasive IPMNs. IOPNs show cystically
dilated mucinous ducts with arborizing papillae consist of
eosinophilic cells. IOPN is a rare tumor with an average
age of patients <65years. Imaging studies of IOPNs show
the same feature as those of IPMNs. Pathologically,
IOPNs show high-grade atypia occasionally with invasive
elements. IOPNs often harbor fusion genes of ATP1B1-
PRKACB, DNAJB1-PRKACA, and ATP1B1-PRKACA.
Disease-specic survival rates of patients with surgically
resected IOPNs are reported to be 84% for 5-year and
73% for 10-year. ITPNs are intraductal, grossly visible
solid neoplasms arising in the MPD or its branches. ITPN
is a rare tumor. Imaging studies show characteristic features called the two-tone duct sign and the cork-in-wine
bottle sign. Pathologically, ITPNs show packed tubulopaillary glands consist of cuboidal cells with enlarged
atypical nuclei and no visible mucin in cytoplasm. ITPNs
often harbor mutations in PIK3CA, KMT2C, KMT2D, and
BA P. ITPNs are often with invasion, and such cases show
poor prognosis.
10.1 Intraductal Papillary Mucinous
Neoplasm (IPMN)
10.1.1 Denition
IPMN is a grossly visible, intraductal epithelial neoplasm
of mucin-producing cells, found in the main pancreatic
duct (MPD), or its branches [1, 2]. The neoplastic epithelium is usually papillary, but may include tubular glands,
and the extent of mucin secretion, duct dilatation, and dysplasia can vary [3] (Fig. 10.1). Non-invasive IPMNs are
classied into two categories, based on the degree of cytoarchitectural atypia: low-grade and high-grade (carcinoma
in situ) [4]. If there is a component of invasive carcinoma,
these are designated as IPMN with associated invasive carcinoma [4].
10.1.2 Epidemiology
IPMNs are fairly common, particularly in the elderly.
Incidence was reported to be 1.7–2.8% in consecutive CT
scans [5, 6]. The incidence doubled among the patients in
their sixties, and tripled in the seventies [6].
T. Furukawa (*)
Department of Investigative Pathology, Tohoku University
Graduate School of Medicine, Sendai, Japan
e-mail: toru.furukawa@med.tohoku.ac.jp
© 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_10
77
78
ab
T. Furukawa
Fig. 10.1 Histological images of IPMN. (a) IPMN shows a cystically
dilated duct lled with mucin. Well-formed neoplastic papillae are
observed inside the dilated duct. (b) The neoplastic papillae are con-
10.1.3 Etiology
No denite etiological environmental factors associated with
IPMNs are known. However, patients with Peutz-Jeghers
syndrome, familial adenomatous polyposis, and McCune
Albright syndrome have a greater risk of IPMNs [7–9].
Individuals with familial predisposition to pancreatic cancer
often harbor cystic lesions in their pancreas that are presumably IPMNs [10].
sisted of mucin containing tall columnar cells. Grade of atypia may
vary from low-grade to high-grade. Hematoxylin and eosin staining.
Original magnications were × 20 (a) and ×100 (b)
10.1.6 Pathology
10.1.6.1 Macroscopic Appearance
IPMNs show dilated ducts containing mucin. Dilated branch
ducts are seen as cysts anywhere in the pancreas. IPMNs
involving the main duct can be identied as segmental/fusiform or diffuse/tortuous dilatation of the duct, often accompanied by dilated secondary branch ducts [3], containing
mural nodules or polypoid tumors.
10.1.6.2 Microscopic Appearance
10.1.4 Clinical Features
andVariations
Papillary proliferation of mucin-containing tall columnar
Clinical manifestations of the dilated main duct include epigastric pain, chronic pancreatitis, weight loss, diabetes mellitus, and jaundice [11–15], whereas the dilated branch ducts
are often discovered fortuitously during clinical evaluation
of some other conditions [16].
cells is a characteristic histopathological feature of IPMNs
[1] (Fig.10.1). Shapes of papillae are diverse, and cellular
atypia also vary. According to the shapes of papillae, IPMNs
are subdivided into gastric, intestinal, and pancreatobiliary
types [21–23]. Gastric-type IPMNs show thick, nger-like
papillae, resembling the gastric foveolar cells, or tubular
structures of the pyloric glands. Intestinal-type IPMNs show
10.1.5 Radiology
villous papillae mimicking a villous colonic tumor, whereas
pancreatobiliary-type show complex, arborizing papillae.
Radiological imaging reveals three distinct types of IPMN,
including branch duct-type, main duct-type, and mixed type
[16–18]. Branch duct IPMNs show dilated secondary pancreatic ducts of >5 mm size, without the dilatation of the
main duct, while the main duct IPMNs show segmental or
diffused dilation of the MPD, without any other causes of
obstruction. Mixed type IPMNs show the characteristics of
both these types of IPMNs [16, 18]. Mural nodules and/or
irregular ductal wall thickening can be the sign of high-grade
or invasive neoplasms [19, 20].
10.1.6.3 Immunohistochemistry
Ductal markers, including cytokeratins 7 and 19, CA19-9,
and CEA, are strongly expressed in most of the IPMNs [24,
25]. Mucin glycoproteins MUC1, MUC2, MUC5AC, and
MUC6, show subtype-specic expression patterns among
IPMNs [21, 26–28]. Gastric-type of IPMNs express
MUC5AC and MUC6, while those of the intestinal-type
IPMNs contain MUC2 and MUC5AC.Pancretobiliary-type
IPMNs express MUC1, MUC5AC, and MUC6 [22, 29].
10 Intraductal Neoplasms ofthePancreas
79
10.1.6.4 Grading
IPMNs can be low- or high-grade, based on the degree of
cytoarchitectural atypia [4]. A high-grade lesion corresponds
to carcinoma in situ. Existence of invasive carcinoma with
IPMN leads to designation of IPMN with associated invasive
carcinoma [4].
10.1.6.5 Dierential Diagnosis
Mucinous cystic neoplasm (MCN), oligocystic serous cystic
neoplasm (OSC), intraductal tubulopapillary neoplasm
(ITPN), lymphoepithelial cyst (LEC), and chronic pancreatitis (CP) with a retention cyst or pseudocyst should be differentially diagnosed from IPMN.MCNs have characteristic
ovarian-type stroma in the cyst wall [30]. OSCs are lined by
distinct glycogen-rich cuboidal cells [31]. ITPN is a solid
intraductal tumor clogging the duct, composed of high-grade
cuboidal cells that form tubulopapillae [32]. LECs are lined
by keratinized squamous epithelium with lymphoid stroma
[33]. When the cysts in CP have at epithelial lining, they are
identied as retention cysts, and when no lining cells are
present, they are called pseudocysts [34].
10.1.6.6 Molecular Pathology
Sixty to eighty percent of the IPMNs harbor somatic mutations in KRAS, while 50–70% have mutations in GNAS [35,
36]. Although KRAS mutations are prevalent in the pancre-
atic ductal adenocarcinomas (PDAC) as well, GNAS mutations are rarely found here, which makes them a specic
characteristic of IPMN [36–38]. In 14% of the IPMNs,
RNF43 also shows somatic mutations [36, 39, 40].
Overexression of p53, which presumably indicates missense
mutations of TP53, is found in 10–40% of the high-grade
IPMNs and in 40–60% of the associated invasive carcinomas
[29, 38, 41, 42]. While loss of SMAD4 is rare [43, 44],
nuclear expression of ß-catenin is seen in 18–39% of the
IPMNs [38, 45].
10.1.6.7 Treatment andPrognosis
IPMNs with high-grade dysplasia or invasive carcinoma
should be surgically resected. According to the international
consensus guidelines for management of patients with IPMN
[16], surgery is indicated by high-risk stigmata and worrisome features, such as cysts ≥3cm, enhancing mural nodules <5mm, thickened enhanced cyst walls, MPD with a size
of 5–9 mm, abrupt change in the MPD caliber with distal
pancreatic atrophy, lymphadenopathy, elevated serum level
of CA19–9, and a rapidly growing cyst at the rate of
>5 mm/2 years. High-risk stigmata are usually associated
with obstructive jaundice, an enhanced solid component, and
MPD with a size ≥10mm. IPMNs with high-risk stigmata
should be resected immediately, while those with worrisome
features should be evaluated by endoscopic ultrasound, to
further risk-stratify the lesions, whether they have mural
nodules or involvement of the MPD.High-grade lesions can
be evaluated with cyst uid or pancreatic juice cytology [16].
Five-year survival rate for patients with surgical resection of the low-grade IPMNs is 100%, and 95–85% with
high- grade IPMNs [22, 46, 47]. Survival rate varies
between 36–90% when the IPMNs are associated with
invasive carcinoma, depending on the stage [22, 46–48].
The morphological subtypes of IPMNs can be a prognostic
indicator; 5-year survival rate is 94% for the gastric-type,
90% for the intestinal- type, and 50% for the pancreatobiliary-type [22, 48].
10.2 Intraductal Oncocytic Papillary
Neoplasms (IOPN)
10.2.1 Denition
IOPN is an intraductal neoplasm of eosinophilic epithelial
cells that form arborizing papillae [49] (Fig.10.2). It is categorized as a variant of IPMNs, as it shows a grossly visible
intraductal neoplasm with mucin production [21], similar to
IPMN. However, a number of studies have reported that
IOPNs have distinct molecular features that distinguish
them from IPMNs in the current fth edition of the World
Health Organization classication of tumors of the digestive
system [50].
10.2.2 Epidemiology
IOPNs are fairly infrequent, making up only 4.5–8.4% of the
cystic neoplasms of the pancreas [22, 51]. They occur more
frequently in men than in women, between 20–80years of
age. With an average age of <65years, patients with IOPNs
are younger than those with IPMNs (> 65 years) [49,
51–53].
10.2.3 Etiology
No etiological factor associated with IOPN is known.
10.2.4 Clinical Features
Clinical manifestations of IOPN are the same as those of
IPMNs, including abdominal pain, weight loss, diabetes
mellitus, and jaundice [49, 51].
80
ab
T. Furukawa
Fig. 10.2 Histological images of IOPN. (a) IOPN shows mucinous
dilated ducts. Arborising papillae are seen inside them. (b) The neoplastic papillae of IOPN consist of eosinophilic cells with enlarged nuclei
10.2.5 Radiology
and prominent nucleoli, which show high-grade atypia. Intraepithelial
lumina are often seen in the cells. Hematoxylin and eosin staining.
Original magnications were × 20 (a) and ×100 (b)
serous cystic neoplasm, lymphoepithelial cyst, and solid
pseudopapillary neoplasm.
Like IPMNs, IOPNs show cystic dilatation of the pancreatic
duct, and can be of branch duct type, main duct type, and
mixed type. Mural nodules are often seen inside the dilated
duct [53].
10.2.6.5 Molecular Pathology
IOPNs infrequently show somatic mutations in KRAS and
GNAS unlike IPMNs [36, 40]. Instead, they carry fusion
genes of ATP1B1-PRKACB, DNAJB1-PRKACA, and
ATP1B1-PRKACA [55, 56]. Interestingly, these fusion genes
10.2.6 Pathology
upregulate the protein kinase A pathway, which is the main
target of GNAS that shows frequent gain-of-function muta-
10.2.6.1 Macroscopic Appearance
IOPNs show cystic dilation of ducts lled with mucin [49,
53], which is indistinguishable from IPMNs, and may
involve branch ducts or the main duct. Polypoid tortuous
tumors are often seen inside them.
tions in IPMNs, indicating that both IOPNs and IPMNs, are
driven by activation of the protein kinase A pathway. Aberrant
expression of p53 or SMAD4 is observed in up to 10% of
IOPNs [52], and about 30% of these show nuclear accumulation of ß-catenin [48],whereas RNF43 mutations are not
reported [40, 57]. A patient with a germline SMAD4 muta-
10.2.6.2 Microscopic Appearance
tion was reported to have developed IOPN [58].
In IOPNs, the dilated ducts are lined by arborizing papillae,
consisting of eosinophilic cells with enlarged nuclei and
prominent nucleoli [21, 49], and show high-grade atypia.
Intraepithelial lumina are often seen in the neoplastic papillae (Fig. 10.2). Occasionally, the neoplasm invades the
10.2.6.6 Treatment andPrognosis
IOPN should be surgically resected. Disease-specic survival rates of patients with surgically resected IOPNs are
reported to be 84% for 5-year and 73% for 10-year [22].
parenchymal stroma, resulting in a diagnosis of IOPN with
associated invasive carcinoma. The invading mass usually
shows clusters of eosinophilic cells in the mucin pools [54].
10.3 Intraductal Tubulopapillary
Neoplasms (ITPN)
10.2.6.3 Immunohistochemistry
Neoplastic cells frequently express HepPar1 and mesothelin
10.3.1 Denition
[54]. The expression of mucin proteins MUC5AC and MUC6
are consistently positive, while MUC1 and MUC2 are infrequently and focally positive [21, 54].
ITPN is an intraductal, grossly visible solid neoplasm arising
in the MPD or its branches [32]. Cystic lesions are infrequent
and are only focally and peripherally observed. The neoplas-
10.2.6.4 Dierential Diagnosis
IOPN should be distinguished from cystic neoplasms,
including IPMN, mucinous cystic neoplasm, oligocystic
tic epithelium has the mixture of tubular and papillary congurations, and the neoplastic cells show uniformly
high-grade atypia [32] (Fig. 10.3). The neoplasm is often
ab
10 Intraductal Neoplasms ofthePancreas
81
Fig. 10.3 Histological images of ITPN. (a) ITPNs show a solid tumor
clogged in dilated pancreatic ducts, without visible mucin. Cystic ducts
are occasionally seen in the periphery of a neoplasm-obstructed duct.
(b) ITPN consist of cuboidal to columnar cells with enlarged nuclei,
invasive, and is designated as intraductal tubulopapillary
neoplasm with associated invasive carcinoma.
10.3.2 Epidemiology
ITPN is rare, barely accounting for 0.9% of the exocrine
neoplasms and 3% of the intraductal neoplasms of the pancreas [32].
with little cytoplasmic mucin, exhibiting solid tubulopapillary growth.
Necrotic foci are often seen. Hematoxylin and eosin staining. Original
magnications were ×20 (a) and ×100 (b)
MPD show a sausage-like image in magnetic resonance
imaging [61].
10.3.6 Pathology
10.3.6.1 Macroscopic Appearance
ITPNs show a solid tumor packed in dilated pancreatic ducts,
without visible mucin. Cystic ducts are occasionally seen in
the periphery of a neoplasm-obstructed duct [32, 59].
10.3.3 Etiology
10.3.6.2 Microscopic Appearance
andVariations
No denite etiological factors of ITPNs are known.
Cuboidal to columnar cells with enlarged nuclei, with little
cytoplasmic mucin, exhibit solid tubulopapillary growth [32,
59]. Some may consist of tubular glands. The neoplastic cells
10.3.4 Clinical Features
show uniformly high-grade atypia (Fig. 10.3). Intraductal
comedo-like necrosis is often present. Stromal invasion can
Clinical manifestations include abdominal pain, nausea,
vomiting, jaundice, weight loss, and exacerbation of diabetes
mellitus [32, 59]. Some patients have a history of acute pan-
be seen in the periductal parenchyma, which shows clusters
of tubulopapillary glands. Tumor emboli are occasionally
evident in the veins [32].
creatitis [32].
10.3.6.3 Immunohistochemistry
10.3.5 Radiology
Cytokeratin (CK) 7 and CK19 are consistently positive.
Mucin glycoproteins, MUC1 and MUC6 are positive, while
MUC2 and MUC5AC are negative [32, 59]. Trypsin, an aci-
In CT scan, patients with ITPN show a solid enhanced mass,
nar marker, is negative.
packed in a dilated duct. Magnetic resonance cholangiopancreatography indicates a lling defect in a dilated duct or an
abrupt disruption of the dilated duct. Images of the dilated
duct packed with tumor, are known as the two-tone duct sign
and the cork-in-wine bottle sign [60]. ITPNs that involve the
10.3.6.4 Dierential Diagnosis
A solid intraductal neoplasm can be observed in the intraductal variant of acinar cell carcinoma and intraductal neuroendocrine tumors [62, 63]. Histologically, neuroendocrine
82
T. Furukawa
tumors can be easily differentiated; however, the intraductal
variant of acinar cell carcinoma may show solid tubular
growth with necrosis, mimicking ITPNs. Acinar cell carcinomas usually express trypsin, an immunohistochemical
marker of differentiation [32]. IPMNs occasionally show
solid nodules inside the dilated duct. IPMN of the pyloric
gland variant may particularly show a polypoid tumor in a
dilated duct, mainly consisting of tubular glands. However, it
can be distinguished from ITPNs by its well-formed tubular
glands with low-grade atypia and the expression pattern of
mucin which is negative for MUC1 and positive for
MUC5AC [64].
10.3.6.5 Molecular Pathology
ITPNs often show somatic mutations in PIK3CA, KMT2C,
KMT2D, and BAP1 [65, 66]. Some tumors also harbor
FGFR2 fusion genes [66]. KRAS or GNAS mutations that
are common in IPMNs, are not seen in ITPNs. Aberrant
expression of p16 and p53 is reported in up to 70% of the
cases [59], while the atypical expression of SMAD4 is rare
[32, 59].
10.3.7 Treatment andPrognosis
Surgery is the treatment of choice for patients with ITPN,
but some of them may experience a recurrence in the remnant tissue after pancreatectomy [32, 59]. ITPNs diffusely
involving the pancreatic duct, need total pancreatectomy
[32, 59, 67]. Efcacy of the adjuvant therapy is not known.
About 10% of the patients with ITPN die of the disease
[32, 59], and all of them are reported to have invasive
tumors.
References
1. Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra
J, Biankin AV, etal. An illustrated consensus on the classication of
pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2004;28(8):977–87.
2. Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi
M, Shimizu M, et al. International consensus guidelines for
management of intraductal papillary mucinous neoplasms and
mucinous cystic neoplasms of the pancreas. Pancreatology.
2006;6(1–2):17–32.
3. Furukawa T, Takahashi T, Kobari M, Matsuno S. The mucushypersecreting tumor of the pancreas. Development and extension
visualized by three-dimensional computerized mapping. Cancer.
1992;70(6):1505–13.
4. Basturk O, Hong SM, Wood LD, Adsay NV, Albores-Saavedra J,
Biankin AV, etal. A revised classication system and recommendations from the baltimore consensus meeting for neoplastic precursor
lesions in the pancreas. Am J Surg Pathol. 2015;39(12):1730–41.
5. Laffan TA, Horton KM, Klein AP, Berlanstein B, Siegelman SS,
Kawamoto S, etal. Prevalence of unsuspected pancreatic cysts on
MDCT.AJR Am J Roentgenol. 2008;191(3):802–7.
6. Chang YR, Park JK, Jang JY, Kwon W, Yoon JH, Kim
SW. Incidental pancreatic cystic neoplasms in an asymptomatic
healthy population of 21,745 individuals: large-scale, single-center cohort study. Medicine (Baltimore). 2016;95(51):e5535.
7. Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher
MC, etal. Germline and somatic mutations of the STK11/LKB1
Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol.
1999;154(6):1835–40.
8. Maire F, Hammel P, Terris B, Olschwang S, O'Toole D, Sauvanet
A, etal. Intraductal papillary and mucinous pancreatic tumour: a
new extracolonic tumour in familial adenomatous polyposis. Gut.
2002;51(3):446–9.
9. Wood LD, Noe M, Hackeng W, Brosens LA, Bhaijee F, Debeljak
M, et al. Patients with McCune-Albright syndrome have a broad
spectrum of abnormalities in the gastrointestinal tract and pancreas.
Virchows Arch. 2017;470(4):391–400.
10. Canto MI, Hruban RH, Fishman EK, Kamel IR, Schulick R, Zhang
Z, etal. Frequent detection of pancreatic lesions in asymptomatic
high-risk individuals. Gastroenterology. 2012;142(4):796–804;
quiz e14–5.
11. Kloppel G. Clinicopathologic view of intraductal papillarymucinous tumor of the pancreas. Hepato-Gastroenterology.
1998;45(24):1981–5.
12. Traverso LW, Peralta EA, Ryan JA Jr, Kozarek RA.Intraductal neoplasms of the pancreas. Am J Surg. 1998;175(5):426–32.
13. Yasuda H, Takada T, Amano H, Yoshida M. Surgery for
mucin-producing pancreatic tumor. Hepato-Gastroenterology.
1998;45(24):2009–15.
14. Salvia R, Fernandez-del Castillo C, Bassi C, Thayer SP, Falconi M,
Mantovani W, etal. Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and longterm survival following resection. Ann Surg. 2004;239(5):678–685;
discussion 85–7.
15. Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N,
Campbell KA, etal. Intraductal papillary mucinous neoplasms of
the pancreas: an updated experience. Ann Surg. 2004;239(6):788–
97; discussion 97–9.
16. Tanaka M, Fernandez-Del Castillo C, Kamisawa T, Jang JY,
Levy P, Ohtsuka T, et al. Revisions of international consensus
Fukuoka guidelines for the management of IPMN of the pancreas.
Pancreatology. 2017;17(5):738–53.
17. Kobari M, Egawa S, Shibuya K, Shimamura H, Sunamura M,
Takeda K, etal. Intraductal papillary mucinous tumors of the pancreas comprise 2 clinical subtypes: differences in clinical characteristics and surgical management. Arch Surg. 1999;134(10):1131–6.
18. Tanaka M, Fernandez-del Castillo C, Adsay V, Chari S, Falconi
M, Jang JY, et al. International consensus guidelines 2012 for the
management of IPMN and MCN of the pancreas. Pancreatology.
2012;12(3):183–97.
19. Furukawa T, Oohashi K, Yamao K, Naitoh Y, Hirooka Y, Taki T,
etal. Intraductal ultrasonography of the pancreas: development and
clinical potential. Endoscopy. 1997;29(6):561–9.
20. Koito K, Namieno T, Nagakawa T, Hirokawa N, Ichimura T, Syonai
T, et al. Pancreas: imaging diagnosis with color/power Doppler
ultrasonography, endoscopic ultrasonography, and intraductal ultrasonography. Eur J Radiol. 2001;38(2):94–104.
21. Furukawa T, Kloppel G, Adsay NV, Albores-Saavedra J, Fukushima
N, Horii A, etal. Classication of types of intraductal papillarymucinous neoplasm of the pancreas: a consensus study. Virchows
Arch. 2005;447(5):794–9.
22. Furukawa T, Hatori T, Fujita I, Yamamoto M, Kobayashi M,
Ohike N, et al. Prognostic relevance of morphological types of
intraductal papillary mucinous neoplasms of the pancreas. Gut.
2011;60(4):509–16.
23. Basturk O, Tan M, Bhanot U, Allen P, Adsay V, Scott SN, et al.
The oncocytic subtype is genetically distinct from other pancreatic