Pathology of Peritoneal Metastases The Unchartered Fields
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Editors
Olivier Glehen
General and Oncologique Surgery, Centre Hospitalier Lyon-Sud, Lyon,
France
Aditi Bhatt
Department of Surgical Oncology, Zydus Hospital, Ahmedabad, India
ISBN 978-981-15-3772-1 e-ISBN 978-981-15-3773-8
https://doi.org/10.1007/978-981-15-3773-8
© Springer Nature Singapore Pte Ltd. 2020
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Preface
This is a book on pathology of peritoneal metastases that has been
edited and largely authored by surgeons which is unusual. Peritoneal
surface oncology is a field that has always been at the cross roads—in
the early years of evolution of surgical treatment, hyperthermia was
being increasingly used to potentiate cancer therapy and thus was
combined with the surgical treatment of peritoneal metastases, that is,
cytoreductive surgery. The surgery itself had to prove its merit over
systemic therapies and was burdened with proving the merit of another
treatment that added to the morbidity. Similarly, disease biology was
only partially understood and remains a major challenge for future
progresses. While the prognostic factors were still being identified, and
validated, oncology ushered into the era of genetics and molecular
biology. And the gaps in understanding the pathophysiology of
peritoneal metastases persisted. Pathological expertise has largely been
directed at the diagnosis and classification of uncommon tumors.
During cytoreductive surgery that comprises of peritonectomy
procedures and visceral resections, a large amount of tissue is
submitted for histopathological evaluation. This remains a potential
source of prognostic information regarding tumor biology. It provides a
good opportunity to also study the patterns and pathways of peritoneal
dissemination from various tumors.
In this book, we use these pathological findings to better explain the
patterns and pathways of peritoneal cancer dissemination and their
potential implications on clinical practice. We provide a rationale and
recommendations for standardizing CRS procedures and evaluation of
surgical specimens. In turn, we raise research question that can be
addressed in future studies.
Some of the other aspects of pathological evaluation like
pathological response to chemotherapy, diagnosis and classification of
rare peritoneal tumors have also been covered in different chapters.
Keeping in sync with the progress in molecular oncology, we look at the
role of molecular oncology in the current and future management of
peritoneal metastases.
We are grateful to all the contributors for lending their time and
expertise to this book. We are also grateful to our pathology colleagues
for their invaluable contribution to this work.
Olivier Glehen
Aditi Bhatt
3 December 2019
Contents
1 Mechanisms of Peritoneal Metastasis Formation
Yutaka Yonemura, Haruaki Ishibashi, Akiyoshi Mizumoto,
Kazuo Nishihara, Yang Liu, Satoshi Wakama, Syouzou Sako,
Nobuyuki Takao, Masumi Ichinose, Shun-ichi Motoi,
Keizou Taniguchi, Sachio Fushida, Yoshio Endou and
Masahiro Miura
2 Extent of Peritoneal Resection for Peritoneal Metastases:
Inferences from Pathophysiology
Aditi Bhatt and Olivier Glehen
3 Therapeutic Rationale and Data Set for Reporting Cytoreductive
Surgery Specimens
Aditi Bhatt, Nazim Benzerdjeb, Suniti Mishra and Olivier Glehen
4 Colorectal Peritoneal Metastases:Correlating Histopathological
Findings and Disease Biology
Aditi Bhatt and Olivier Glehen
5 Epithelial Serous Ovarian Cancer:Patterns of Peritoneal
Dissemination and their Clinical Implications
Aditi Bhatt, Loma Parikh, Suniti Mishra and Olivier Glehen
6 Peritoneal Mesothelioma:Disease Biology and Patterns of
Peritoneal Dissemination
Marcello Deraco, Nadia Zaffaroni, Federica Perrone,
Antonello Cabras, Shigeki Kusamura, Marcello Guaglio,
Matteo Montenovo and Dario Baratti
7 The Pathological Spectrum of Mucinous Appendiceal Tumours
and Pseudomyxoma Peritonei
Aditi Bhatt, Suniti Mishra, Loma Parikh and Olivier Glehen
8 Genomics in Pseudomyxoma Peritonei
Marco Vaira, Claudio Isella, Michele De Simone, Manuela Robella,
Alice Borsano and Enzo Medico
9 Peritoneal Regression Grading Score (PRGS) for Therapy
Response Assessment in Peritoneal Metastasis
Wiebke Solass
10 Rare Peritoneal Tumours:Histopathological Diagnosis and
Patterns of Peritoneal Dissemination
Suniti Mishra, Snita Sinukumar, Nutan Jumale, Loma Parikh,
Aditi Bhatt and Olivier Glehen
11 Approach to a Patient with Peritoneal Metastases with
Unknown Primary Site:Focus on Histopathological Evaluation
Aditi Bhatt, Loma Parikh, Suniti Mishra and Olivier Glehen
12 Biomarkers in the Management of Peritoneal Metastases
Ninad Katdare, Aditi Bhatt and Olivier Glehen
About the Editors
Olivier Glehen
is a world renowned expert in peritoneal surface oncology and a
member of the executive committee of the peritoneal surface oncology
group international (PSOGI). He is the head of the General and
Oncologic Surgery Department at Centre Hospitalier Lyon Sud
(Hospices Civils de Lyon) and at the Lyon Sud Charles Mérieux Medical
Faculty. His centre is one of centres that have pioneered the surgical
treatment of peritoneal metastases in the world. He is director of the
Peritoneal Carcinomatosis Research Group from the EMR 3738 (Claude
Bernard Lyon 1 University).
He has published extensively about peritoneal metastases. He is at
the head of RENAPE (French Network on rare peritoneal tumours) and
BIG-RENAPE groups (National Clinic-Biological Database on Digestive
Peritoneal Carcinomatosis). He is associate editor of European Journal
of Surgical Oncology, Journal of Surgical Oncology and Journal of
Peritoneum. Professor Glehen is one of the directors of the Inter-
University Diploma on Peritoneal Carcinomatosis in France and his
centre is a reference centre for the European Society of Peritoneal
Surface Oncology (ESPSO) certified fellowship in peritoneal surface
oncology. His centre performs more than 200 cytoreductive surgery
and HIPEC (Hyperthermic Intraperitoneal Chemotherapy) procedures a
year and is also one of the leading centers in the world that is
developing PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy).
Aditi Bhatt
is an Indian surgical oncologist specializing in the management of
peritoneal surface malignancies with an experience of 10 years in the
same. She is one of the founding members of the Society of peritoneal
surface oncology, India, the Indian HIPEC registry and serves as the
honorary secretary of the Asian Peritoneal Surface Malignancy Group.
She has published several scientific papers on the subject, edited
two special issues of the Indian Journal of Surgical Oncology on the
same and edited a book on peritoneal surface malignancies.
© Springer Nature Singapore Pte Ltd. 2020
O. Glehen, A. Bhatt (eds.), Pathology of Peritoneal Metastases
https://doi.org/10.1007/978-981-15-3773-8_1
1. Mechanisms of Peritoneal Metastasis
Formation
Yutaka Yonemura1, 2, 3 , Haruaki Ishibashi2, Akiyoshi Mizumoto3,
Kazuo Nishihara2, Yang Liu2, Satoshi Wakama2, Syouzou Sako2,
Nobuyuki Takao3, Masumi Ichinose3, Shun-ichi Motoi3,
Keizou Taniguchi4, Sachio Fushida5, Yoshio Endou6 and
Masahiro Miura7
(1) Asian School of Peritoneal Surface Malignancy Treatment, Kyoto,
Japan
(2) Department of Regional Cancer Therapy, Peritoneal Dissemination
Center, Kishiwada Tokushukai Hospital, Kishiwada, Osaka, Japan
(3) Department of Regional Cancer Therapy, Peritoneal Dissemination
Center, Kusatsu General Hospital, Kusatsu, Shiga, Japan
(4) Department of Surgery, Mizonokuchi Hospital, Teikyo University,
School of Medicine, Kawasaki, Kanagawa, Japan
(5) Department of Surgery, Kanazawa University, Kanazawa, Japan
(6) Central Research Resource Center, Cancer Research Institute,
Kanazawa University, Kanazawa, Japan
(7) Department of Anatomy, Oita Medical University, Oita, Japan
Yutaka Yonemura
Email: [email protected]
Keywords Peritoneal metastasis – Peritoneal dissemination –
Pseudomyxoma peritonei
1.1 Introduction
It has long been considered that the establishment of peritoneal
metastasis (PM) is a multi-step process, consisting of (1) detachment of
cancer cells from the primary tumor, (2) adhesion of peritoneal free
cancer cells (PFCCs) on the distant peritoneal surface, (3) invasion into
the submesothelial tissue, and (4) proliferation accompanying with the
angiogenesis and the induction of stromal tissue [1]. The process is
called “trans-mesothelial metastasis” by Yonemura et al. [2] or
“randomly proximal distribution” by Sugarbaker [3] (Fig. 1.1). Through
the process, cancer cells with high malignant potential can metastasize
on the peritoneum by concerted expression of metastasis-related genes
[1–3]. Recently, new concepts of the formation of PM were proposed:
i.e., (1) Trans-lymphatic metastasis and (2) superficial growing
metastasis (Table 1.1) [3].
Fig. 1.1 Trans-mesothelial metastasis as named by Yonemura et al. or randomly proximal
distribution by Sugarbaker. Peritoneal free cancer cells (PFCCs) exfoliated from the serosal surface
of primary tumors migrate into the peritoneal cavity, and adhere on the peritoneal surface
(Process 1). During the rolling of PFCCs on the peritoneal surface, peritoneal mesothelial cells
shrink by cytokines produced by PFCCs, resulting in the exposure of basement membrane and
macula cribriformis (Process 2). PFCCs then migrate into the inter mesothelial space, and invade
into the submesothelial tissue by degradation of extracellular matrix by matrix-digesting enzymes
and by locomotive activity using motility factors (Process 3). Finally, cancer cells proliferate near
the submesothelial blood vessels with introduction of tumor stromal tissues and neogenesis of
tumor blood vessels (Process 4)
Table 1.1 Three patterns of peritoneal metastasis according to the biological malignant potentials
and the morphological feature of peritoneal free cancer cells
Pattern of Biologic Cancer Morphological
metastasis malignant features of PFCCs
behavior
Trans-mesothelial High Gastric, colorectal, Single or small clusters
metastasis pancreatic, biliary ovarian
cancer
Trans-lymphatic High, moderate Gastric, colorectal, ovarian Single or small clusters
metastasis cancer
Omental milky
spots (OMS)
Initial
lymphatics outside
OMS
Superficial Moderate, low AMNa, GCSb, mesothelioma, Large with or without
growing metastasis mucinous material
MCMc, hepatoma
a
AMN low-grade appendiceal mucinous neoplasm
b
GCS granulosa cell tumor
c
MCM multicystic mesothelioma
In this chapter, mechanisms of the formation of PM will be
described in terms of the morphological, histological, and molecular
biological aspects.
1.2 Mechanisms of Trans-mesothelial
Metastasis
1.2.1 Mechanisms of Cancer Cell Spillage into the
Peritoneal Cavity
The first step of PM is detachment of cancer cells from the serosal
surface of the primary tumor in highly malignant tumors and the
rupture of appendix vermiformis or ovary by the increased intrinsic
pressure due to the proliferation on mucinous neoplasm. Additionally,
during surgery, blood or lymphatic fluid contaminated with cancer cells
may spill into the peritoneal cavity from damaged blood and lymphatic
vessels. The exfoliated cancer cells in the peritoneal cavity are called
peritoneal free cancer cells (PFCCs). PFCCs have high proliferative
activities and can grow in the distant peritoneum.
In the process of detachment of cancer cells from the primary
tumor, homophilic cell-cell adhesion molecules play important roles.
Epithelial cells tightly interconnect with a tight junction on the apical
membrane and an adherence junction on the basolateral membrane
side (Fig. 1.2). Tight junction components are transmembrane proteins,
claudin and occludin and the cytoplasmic scaffolding protein, ZO-1, -2,
and -3, which bind the actin bundles of the cytoplasmic protein. Tight
junction is mainly composed of claudin, which is observed as
continuous bead-like particles expressed on the lateral membrane of
cells [4]. The partition of the basilar membrane by the tight junction
functions as a barrier to control the movement of materials and as a
selective permeation channel [4]. However, dysfunction of the tight
junction causes the loosening of cell-cell adhesion, resulting in edema.
Disappearance of tight junction causes cells to disperse by the loss of
polarity. Vascular endothelial growth factor (VEGF) and some cytokines
reduce the function of tight junction, and cause edema [5].
Fig. 1.2 Molecules associated with homophilic cell-cell adhesion of epithelial cells. Epithelial cells
interconnect with tight junction, located at apical membrane of cells, and with adherence junction
on the basolateral membrane. Cancer cells showing the functional abnormalities of tight junction
and adherence junction tend to disperse and detach from the serosal surface, spill from the
primary tumor and migrate into the peritoneal cavity
Serial analyses of gene expression (SAGE) clarified the reduced
expression of claudin in poorly differentiated adenocarcinoma of the
stomach [6], in which reduced expression of claudin 4, 7 is found and
the patients with gastric cancer showing low expression of claudin have
a poor prognosis. In addition, ZO expression is also reduced in poorly
differentiated adenocarcinoma which tends to establish PM [6, 7].
In the components of the adherence junction, E-cadherin expression
is important. E-cadherin is a transmembrane glycoprotein, and cells
tightly connect with the extracellular domain of the molecule on the
basolateral membrane (homophilic adhesion). The intracellular domain
of E-cadherin connects with α-, β-, γ-catenin and the complex controls
the function of E-cadherin [8–10]. In gastric cancer, poorly
differentiated adenocarcinoma especially macroscopic type-4 has a
high potential of PM and the downregulation of E-cadherin expression
is an important feature [11, 12]. The causes of reduced expression of E-
cadherin are loss of the E-cadherin gene, point mutation, and the
methylation of the promoter region [12]. In addition, the function of E-
cadherin is reduced via the inhibition of the function of catenin
molecules by the loss of the α-catenin gene, and phosphorylation of the
tyrosine residue of β-catenin [13]. In colorectal cancer, downregulation
of E-cadherin level is associated with poorly differentiated type, higher
potential of metastasis, and progression [14]. The lower expression of
E-cadherin in poorly differentiated colorectal cancer may explain the
aggressive nature, and poorly differentiated adenocarcinoma is known
as a subtype that frequently metastasizes on peritoneum [14, 15].
Accordingly, cancer cells with the functional abnormalities of tight
junction and adherence junction tend to disperse and detach from the
serosal surface, spill from the primary tumor and migrate into the
peritoneal cavity.
1.2.2 Adhesion of PFCCs and Mesothelial Cells (Fig. 1.1,
Process 1)
PFCCs migrate on the distant peritoneal surface and adhere to
mesothelial cells during rolling on the mesothelial cell surface. PFCCs
express several kinds of integrin molecules and adhere with their
ligands expressed on mesothelial cells (Fig. 1.1, Process 1, 2). Peritoneal
mesothelial cells express immunoglobulin-like intercellular adhesion
molecules (ICAM-1, CD54) [16] and vascular cell adhesion molecules
(VCAM-1, CD106) [17], and interact with integrin αLβ2 (LFA-1α,
CD11a) expressed on PFCCs and inflammatory cells (heterotypic cell-
cell adhesion).
Platelet-endothelial cell adhesion molecules (PECAM-1, CD31) play
a role in the transmigration of white blood cells and PFCCs. After the
process of slowing down the passage of leukocytes and PFCCs over
activated vascular endothelium and peritoneal mesothelial cells
