ROUTES &

Mechanisms OF

METASTASIS
Neetu Gupta
Roll No.17

Contents

Introduction
Routes of Metastasis
Lymphatic Route
Hematogenous Route
Direct Spread
Mechanism of Metastasis
Bibliography

INTRODUCTION
DEFINITIONS:
METASTASES : It refers to the tumor implant
discontinuous with the primary tumor.
METASTASIS (Distant Spread) : It is defined as
the formation of secondary tumor implant (i.e.
metastases) at a remote site, discontinuous
with the primary tumor.
Metastasis is the hallmark of malignancy
Benign tumors DO NOT metastasize(making
their local resection curative).
All the malignant tumors can spread.
Exception: 1. GLIOMAS(glial cells in CNS)
2. BASAL CELL CA of skin

Routes/Pathways of
Spread
Cancers may spread to distant sites by following
pathways:
1. Lymphatic spread
2. Haematogenous spread
3. Direct Spread through body cavities or surfaces.
NOTE: As a rule , CARCINOMAS metastasize through
lymphatic.
SARCOMAS metastasize via Blood.
EXCEPTIONS: 1. Hepatocellular CA
2. Renal Cell CA
3. Chorio CA
4. Follicular CA thyroid

1. LYMPHATIC ROUTE
This route of metastasis is preferentially used by CAs.
The pattern of lymph node involvement follows the
normal route of lymphatic drainage.
i.e. Tumor cells metastasize along the normal route of
drainage for that particular site.
For ex:
CA Breast- the tumor cells arising in the upper outer
quadrant, metastasize first into the axillary LNs., then
the infraclavicular and supraclavicular resp.
From lower quadrants to the sub diaphragmatic LNs
CA Lung - the bronchogenic tumor cells metastasize
first to perihilar ,tracheobronchial and mediastinal LN.

 SKIP METASTASIS:

Tumor cells may skip a proximal lymph

node to be deposited into the distal gp.
Reason:

Obliteration of the lymphatic vessel due to

inflammation or radiation
Arteriolymphatic anastomosis.
SENTINAL LYMPH NODE:
Defined as the first node in the regional lymphatic
basin to receive lymph drainage from the primary tumor.
IMPORTANCE:
If the biopsy of sentinel lymph node comes out to
be negative it virtually rules out involvement of
other LNs. In that region. Thus preventing massive
dissection/surgical morbidity.
Sentinel LN mapping can be done using
radiolabeled tracers and blue dyes.

 Tumor cells after arrest into a lymph node,

get destroyed due to tumor specific
immune response.
MORPHOLOGY OF THE LYMPH NODES:
On examination ,
Grossly, the LN is enlarged and firm to stony
hard.
Microscopically, LN may show reactive
hyperplasia, seen as
follicular hyperplasia & sinus histiocytosis
(in response to the draining tumor antigens, tumor
cell debris or it may show presence of metastatic
deposits known as metastatic lymphadenopathy.)

2. Hematogenous Route
This route is preferentially used by SACROMAS &
certain CAs as mentioned earlier.
Veins are preferentially involved than the Arteries.
Arterial spread of tumors is less likely because :
thick-walled & elastic tissue makes them resistant
to invasion.

arterial spread may occur when

tumor cells pass through pulmonary capillary bed or
through pulmonary arterial branches which have thin
walls.

(Cancer of the lung may, however, metastasize by pulmonary

arterial route to kidneys, adrenals, bones, brain etc.)

 The blood borne cells follow the venous flow

draining the neoplasm & come to rest in the
first capillary bed they encounter.
LUNGS and LIVER are the most common
sites of secondary implant.
Others Bones ( CA breast,
Neuroblastomas) and Brain( CA lung).
Tumors located in the vertebral plexus
(Batsons plexus) metastasize to the spine.
ex. CA thyroid & CA prostate.
Systemic veins drain blood into IVC from limbs,head and
neck and pelvis. Therefore, cancers of these sites more
often metastasize to the lungs.
Portal veins drain blood from the bowel, spleen and
pancreas into the liver. Thus, tumors of these organs
frequently have secondaries in the liver. rest in the first
capillary bed they encounter.

 Few organs such as spleen, heart, and skeletal

muscle generally do not allow tumor metastasis
to grow. (Spleen is unfavorable site due to open sinusoidal
pattern which does not permit tumor cells to stay there long
enough to produce metastasis.)

3. Direct Spread
This route of metastasis leads to tumor extension
into natural open fields or body cavities like
pleural cavity, pericardial cavity , peritoneal
cavity, subarachnoid space or joint spaces.
Most often involved is the PERITONIAL CAVITY.
Examples:
1. Mucin secreting adenocarcinoma of appendix or
ovary may rupture into the peritoneal cavity,
coating this neoplastic mass with mucilaginous
glaze . This is known as PSEUDOMYXOMA
PERITONEI.

2. CA of the stomach, intestine, appendix or breast

may seed into both the ovaries.
This bilateral metastatic mucin secreting
adenocarcinoma of the ovaries is called
KRUKENBERG TUMOR.
Features:
Ovarian stroma shows small metastatic glands.
Individual Tu. Cells with large anaplastic nucleus
pushed to the periphery by tumor cells known as
SIGNET RING CELLS.

MECHANISM OF
METASTASIS
Invasion and Metastasis are the biological
hallmarks of Malignant tumors.
Pathogenesis of metastasis is a multistep active
process which can be studied in two major steps:
1. INVASION OF Extracellular matrix
2. Vascular Dissemination & Homing of the
Cells.

Step 1 :Invasion of ECM

Tu.Cells in order to spread have to traverse through
following planes- BM of parent site

Interstitial CT. matrix

BM & Endothelial linning of the vessel.
Enter Circulation
Following steps occur during invasion:
1. Detachment of Tu. Cells from each other
2. Degradation of the Extracellular matrix
3. Attachment of the Tu.cells to the degraded
matrix
4. Migration of the Tu. Cells through the
degraded matrix.
Same steps repeated during extravasation

Details:
STEP 1. Detachment from each other.
Mutations cause - loss of E.Cadherin molecules
or
- increased expression of
beta-Catenin molecules
- increased expression of
SNAIL & TWIST Nuclear transcription Factor, it
down regulate expression of E.cadherin,
metastatic potential.

 STEP 2: Degradation of ECM(Invasion of BM & Interstitial

CT.)
Brought about by : 1.Matrix metalloproteinase
2.Catepsin D
3. Urokinase plasminogen activator.
- Importance of degraded matrix:
Cleavage of collagen and proteoglycans have angiogenic,
growth promoting & chemotactic effects.
Novel site for attachment of tumor cells.
- Benign tumors show little protease activity
STEP 3 : Attachment of Tumor cells to degraded matrix.
Tumor cells unlike normal epithelial cells express INTEGRIN
RECPTORS all over their surface.
STEP 4: Migration of Tumor cells from each other.
Tu. Cells produce AUTOCRINE MOTILITY FACTORS that along with
the growth factors produced by the degraded matrix help in the
migration.
GFs like Hepatocyte/Scatter GF, Insulin like GF

Step 2 : Vascular dissemination & Homing

of Cells
Once in the circulation, tumor cells are subjected
to host immune cells.
Therefore as a means of escape, these tumor
cells adhere to one another (HOMOTYPIC
ADHESINO), get coated upon by the lymphocytes
and platelets(HETEROTYPIC ADHESION) to formTumor-Lymphocyte-Platelet EMBOLUS.
This embolus now travels along the normal route
of lymphatic and vascular drainage.
Arrest and extravasation of tumor emboli at
distant site involves adhesion to the
endothelium & then egress through BM
For ex. Over expression of CD 44 may favour metastatic
spread

 ORGAN TROPISM:
The site of metastatic deposit may not always be
predicted by natural pathways of drainage.
Certain form of organ tropism is seen.
For ex.
o CA lung spreads to Adrenal and brain
o CA prostate preferentially spreads to bone
o Neuroblastomas spread to liver and bones.

Organ tropism can be explained by 3 features:

1. Adhesion molecules .
Tu. Cells express adhesion molecules on their
surface.
The ligands / receptors of these are preferentially
expressed on the surface of the target organs.

2. Role of Chemokine & Chemokine Receptors

Chemokines have an imp. Role In determining the
role of target tissue for metastasis.
For ex. Cells of CA breast express CXCR4 & CCR7
receptors. Chemokines that bind to these
receptors are highly expressed in tissues to which
breast cancers metastasize.
(BLOCKAGE of theses receptors can prevent
metastasis) in lymph node and lung)
Some target organs may liberate chemo
attractants that recruit Tu. Cells to the site.
For ex. IGFs I & II.

3. The target organ provides fertile soil for the

tumor cells.
Tissues with increased conc. Of protease inhibitors
prevent formation of metastatic deposits.
And some tissues maybe nonpermissive for
tu.growth .
for ex. Skeletal muscles are rarely site of
metastasis.

Molecular Genetics of
Metastasis Development
Various models have been developed to explain
the reason behind the metastatic process.
P53 gene(tumor suppressor) mutations favor
metastasis due to increased angiogenesis.
Metastatic suppressor have been discovered.
miRNAs & mir335 have been suggested to supress
metastasis of CA breast.

Bibliography
Class Notes
Robbins Pathologic Basis of Disease

THANK YOU