cancer spread within peritoneal cavity - · pdf filecancer spread within peritoneal cavity...
TRANSCRIPT
Cancer spread within
peritoneal cavity
M.Carnelli
L.Frigerio, D.Bornaghi, L.Busci, G.
Grosso, D. Rossetti, G. Trezzi
Ostetricia e Ginecologia
Ospedali Riuniti Bergamo
Type I is composed of low-grade serous, low-grade endometrioid, clear cell,
mucinous and transitional (Brenner) carcinomas.
Behave in an indolent fashion, are confined to the ovary at presentation and,
as a group, are relatively genetically stable.
They lack mutations of TP53, but each histologic type exhibits a distinctive
molecular genetic profile.
Exhibit a shared lineage with the corresponding benign cystic neoplasm, often
through an intermediate (borderline tumor) step, supporting the morphologic
continuum of tumor progression.
Type II, is highly aggressive, evolves rapidly and almost always presents in
advanced stage. Type II tumors include conventional high-grade serous
carcinoma, undifferentiated carcinoma, and malignant mixed mesodermal tumors
(carcinosarcoma). They display TP53 mutations in over 80% of cases and rarely
harbor the mutations that are found in the type I tumors.
75%
PERITONEUM
The term peritoneum derives from the Greek
peritonaion, meaning to stretch around.
The first known recorded reference of the
peritoneal cavity appears in the Ebers papyrus in
1550 BC.
The peritoneal membrane became of
physiological interest to anatomists after the
discovery of cells.
Von Recklinghaussen was the first to describe the
anatomy of the peritoneum in 1862.
Peritoneum
Baron 1941
5 layers of fibrous and
elastic connective tissue
and the layer of mesothelial
cells : thickness of 90 μm.
Very few blood vessels �40
�μm from the surface.
Mesothelial cells secretion
of lubricant solutions made
of primarily phospholipids
and glycosaminoglycans.
Peritoneum permits
quantitatively important passive
and active exchange of
substances between the
peritoneal fluid, blood vessels
and lymphatics.
Permeability of the
peritoneal membrane depends on
molecular size, charge, weight,
and hydrophobicity of the
molecules
Peritoneum
Peritoneum is the large serous
membrane of the body, with an
extimated area of more than 2 m2 .
It lines the inside the abdominall
wall and is reflected over the
viscera (liver, gallbladder, spleen,
stomach, small and large intestines,
ovaries and uterus).
The space between the parietal and
visceral portion of the membrane is
called the peritoneal cavity.
PERITONEAL CARCINOMATOSIS
Sampson 1931
First to describe peritoneal carcinomatosis in humans
implantation(spread)/dissemination(metastasis)
Described “life hystory of peritoneal carcinomatosis
implants”:
-escape/migration/reaction of the peritoneal
surface/progression
Weiss L 1986
“Metastatic inefficiency”
Cancer cells disseminate with great efficiency within
peritoneal in contrast to hematogenous route.
PERITONEAL CARCINOMATOSIS
The tumor dissemination starts from the primary tumor
and consists of a multistep process.
The most widely explanation of peritoneal metastasis
is that individual or cluster of tumor cells become
detached from the primary tumor mass and are
transported throughout the peritoneal cavity by
peritoneal fluid befor seeding intraperitoneally
TRANSCOELOMIC JOURNEY
Resistance to anoikis
and cell detachment
Development of resistence to anoikis is a vital step for metastatic progression
(upregulation of RAB25, B7-h4)
Epithelial -mesenchimal transition
(epithelial cell depolarise, disassemble cell-cell contacts, acquire fibroblast-like morphological features, adopt an invasive migratory phenotype)
Overexpression of endothelin1 and its receptor
Downregulation of expression/function of E-cadherin
Overexpression hepatocyte growth factor/ receptor c-Met
Overexpression UPA/UPAR system
Adaptive
mechanism
First mechanism
Random-proximal spread
In the absence of intraperitoneal fluid cancer cells
metastasize in a random fashion immediately adjacent to the
primary neoplasm which has penetrated the serous surface.
(Invasive - non mucinous cancer)
Sugarbaker PH, Cancer Treat Res. 1996; 82: 79-100.
Four specific sites are
evident:
- the pouch of Douglas at the
rectosigmoid level;
- the right lower quadrant at the lower
end of the small bowel mesentery;
- the left lower quadrant along the
superior border of the sigmoid
- mesocolon and colon;
Cancer cells dissemination in the
presence of ascitic fluid was neither
random nor limited to the immediate
area of the primary neoplasm
If ascites...
The distribution is determined by:
- mesenteric reflections
- peritoneal recesses
- action of gravity
- hydrostatic pressure
The changes in the intraperitoneal hydrostatic
pressure and the anatomic arrangement of the
peritoneal recesses result in transcelomic migration
of fluid toward the undersurface of the diaphragm.
Second mechanism
“redistributed” pattern
of implants
Clockwise direction
of intraperitoneal
flow
The dominant regions for
redistrubuted cancer
progression would be:
the space between the right
diaphragm and liver
the lower part of the left
paracolic sulcus
the cul-de-sac of Douglas.
Ascites-a metastatic milieu
Association of peritoneal seeding with
accumulation of ascites
Hypotesis: cancer cells involved in production of
a carrier solution and growth medium
(clinical observation that reduction of tumor in responce
to chemotherapy---reduction in volume of ascites)
Ascites :
hypoaalbuminnaemia secondary to cachexia/dietary
def.
Reduced lymphatic drainage
Hyperpermeability of microvessels lining the per.
cavity
tumor neoangiogenesis
Ascites-a metastatic milieu
Soluble components in ascites:
VEGF upregulated by tumor hypoxia, induces
angiogenesis and increase vascular permeability
Lysophosphatidic acid upregulates protease
expression and activity
ascites contains vesicles rich in
extracellular-matrix-degrading proteinases like
MMPs and UPA.
increases adhesive and invasive properties
(upregulating CD 44 expression)
Spheroid formation
Evidence of adaptive methastatic process
Spheroids = to survive humoral immunological
response
Detached tumor cells
aggregate (chemotactic signals , upregulation
cells adhesion molecules)
disaggregate (haptotactic forces)
Evasion of immunologic
surveillance
EOC in ascitic fluid might have evolved to evade I.S.
Presence of Immunomodulators IL2, TNF, IFN in ascitic
fluid = malignant ascites = immunogenically induced
host responce to intraperitoneal metastases
Immunologically privileged tumor microenvironment
FAS ligand
Complement C1 complex inhibitor
Factor H e FH like protein1
Recruitment regulatory T cells
Transmesothelial route
Cells directly attach on distant mesothelium and this
process is mediated by adhesion molecules such as
CD44, integrin, selectins, leukocyte adhesion
molecules
Cytokines induce contraction / exfoliation of
mesothelial cells exposing the submesothelial basement
membrane (Studies in animal model)
Other possibility is postulated by studies in vitro
with use of three dimensional model of human
peritoneum. Invasion of mesothelial invasion is
accompanied by changes in mesothelial cell morphology
suggestive of apoptosis.
Peritoneal implantation
Once attached....
Haptotactic migration (up regulation E-Cadherin)
Dynamic regulation EOC cell's adhesiveness
Interaction with underlying peritoneal mesothelium
Importance of MMP family proteinases (MMP2 , MMP9 ,MMP14)
VEGF and neoangiogenesis
Translymphatic processcPeritoneal free cancer cells migrate into lymphatic
orifices (lymphatic stomata) on the peritoneal surface
and proliferate in the submesothelial lymphatic space.
High density of lymphatic stomata in:
the greater omento, appendices epiploicae of the
colon, inferior surface of the diaphragm,
falciform ligament, Douglas pouch and small bowel
mesentery (all areas where peritoneal seeding is
commonly found)
(also presence of milky spots : consist of
submesothelial lymphoid tissue clustered around a
vessel)
Close correlation between
infiltrating cancer cells
and the density of lymhoid
aggregates
Shimoutsuna et al 1993
Lymphology.26,90-91.
It is primarily composed of fatty tissue with
associated nerves, vessels, and lymphatic tissues
invested by serosal layers which make up the
ligaments and mesenteries associated with the major
abdominal organs and viscera. It thus represents a
significant conduit for the spread of disease
within the peritoneal cavity.
Subserous thoracoabdominal
continuum
Subserous space : a continuum composed of the
subperitoneal space and the subpleural space
It is an anatomic plane formed in the embryo that
persist during development into the adult
During the division of the coelomic cavity into the
torax and abdomen, the integrity of the subserous
space is maintened.
Subserous continuum within
the aortic and esophageal
hiatuses are potential avenues
for direct spread of disease
The pleural cavities remain in continuity dorsally
with the peritoneal cavity due to the incomplete dorsal
development of the diaphragm at this time. The subserous
space defined by the area subjacent to the membraneous
lining of these cavities also remains in continuity between
the thorax and abdomen.
Small apertures lie between the sternum and costal
cartilage, anteriorly transmitting the superior epigastric
branch of the internal mammary artery and lymphatics
within the subserosal space at this site, thereby providing
a potential pathway for direct spread of disease.
Third mechanism
Tumor cell entrapment
Cancer dissemination caused by surgical dissection
Anatomic sites associated with an increased incidence of
cancerous implants would be all surgically traumatized
peritoneal surfaces.
Cancer implants at:
- anastomotic sites
- sites where bowel was repeatedly handled
- within abdominal closure
- within raw tissues created by retroperitoneal dissection
Sugarbaker PH, Cancer Treat Res. 1996; 82: 79-100.
The movement of an intra-abdominal structure largely
determines the volume of malignancy that is associated
with its peritoneal surface.
Small bowel and its mesentery free to move by
peristalsis had a reduced incidence of implants as
compared to the ileocecal area, which is fixed to the
retroperitoneum.
Fourth mechanism
“motion hypotesis”
Transcoelomic dissemination
or metaplasia
Hypothesis of metaplasia of presumed pluripotent
mullerian stem cells in the peritoneum.
Metaplasia might also
address the controversy of
bilaterality in ovarian
cancer.
Can explain the
pathogenesis of primary
ovarian-type peritoneal
carcinomas.
Transcoelomic dissemination
or metaplasia
The peritoneal metaplasia hypotesis does not explain
the full picture when the peritoneal distribution of
ovarian carcinomatosis is taken into account
IA EOC fewer relapse than stage IC (capsular rupture,
surface tumor or W+)
Desease removed befor it is exposed to the peritoneum
Counterintuitive to the metaplasia hypotesis
A comprehensive understanding of events involved in
the peritoneal carcinomatosis is of paramount
importance and should be systematically pursued...
To give a rationale for curative surgical approach
To identify novel strategies for the prevention of
the condition
To obtain therapeutic advances, through the
identification of the surrogate markers of
prognosis and development of future targeted
therapies.
Conclusion