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