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Week 16 Learning Objectives
Pathology of Metastasis
1. Define the term metastasis
Metastasis is the transfer of disease from one part of the body to another. In cancer, metastasis is the
migration of cancer cells from the original tumor site through the blood, lymph vessels or through
seeding directly from surface to surface to produce cancers in other tissues. Metastasis also is the term
used for a secondary cancer growing at a distant body site.
2. Describe routes of metastatic spread
Metastatic spread is known to proliferate in three ways; through lymphatic, haematogenous or through
seeding. Seeding is seen in many “open” surfaces where the surfaces of different tissues are in direct
physical contact with one another or have an open passage through which malignant cells can travel to
other tissues. This frequently happens in peritoneal, pericardial and pleural surfaces. Ovarian tumors in
particular are quite prone to this method of spreading. When metastases seed, they break apart from
their original tumour and can travel to another tissue via physical contact or they can travel through a
fluid like the CSF in the subarachnoid spaces. Additionally, is possible to spread metastatic cells via
medical or surgical equipment during an invasive procedure. The idea comes from the concept that
touching a tumor with a piece of equipment may “shed” metastatic cells onto the equipment. Further
physical contact of that piece of equipment with another tissue or organ may then spread the
metastatic cells onto the new tissue or organ. This is a particular concern when attempting biopsies on
certain tumours, in these occasions, incidence of metastatic spread is known as ‘seeding by tract
implantation’.
Lymphatic spread occurs through the lymphatic system where metastases will be drained by and travel
through the lymphatic system and can pass on into the haematologic system. This method of spreading
is most frequently seen in carcinomas but may also be seen in sarcomas. Addressing the relationship
between carcinomas and the lymphatic tissue; a carcinoma is any cancer that arises from epithelial cells
of a tissue. As a result, many of these types of cancers are frequently spread through the lymphatic
system as it would be the first major passage way that many of them will encounter, though this is not
always the case. Additionally because of this carcinomas will frequently spread into lymph nodes. That
said sarcomas and other types of cancer can spread through the lymphatic system. In many cases,
regional nodes serve as a sort of barrier from further dissemination of metastases spreading through the
lymphatic system, though this effect can only be temporary. Nodes frequently enlarge when interacting
with cancers due to two reasons;
1) Either they are invaded by cancerous cells and grow from cancer
2) They grow due to reactive hyperplasia as they become more active in draining and destroying
cancer cells which have arrested within the node
Lymphatic spread can allow metastases to spread to the lymph nodes of the body, directly into the
circulatory system or seed out of the lymphatic system and into new tissues/organs.
Haematogenous spread occurs through the blood vessels where metastases will proliferate through the
vessel walls and travel to other tissues/organs. This method of spreading is most common with
sarcomas but carcinomas may also spread like this. Veins are more common passage ways for
metastases to spread because their walls are thinner and easily penetrated compared to arteries.
Because of this tendency to travel through the venous system, the liver and the lungs become prime
targets for hematogenous metastatic spread since portal area drainage flows to the liver and all caval
blood flows to the lungs. Metastatic penetration and spread through the arterial wall can still occur but
in addition, metastases can spread through the arterial system when tumors pass through the
pulmonary system or by passing through arteriovenous shunts. As the circulatory system is well
proliferated throughout the body, hematogenous spread is a way that metastases can disseminate to
numerous parts of the body.
3. Describe preferred metastatic sites for carcinoma, sarcoma and lymphoma (selected examples)
Carcinomas, because of their affinity towards the lymphatic system, frequently spread to lymph nodes
first. This however, is not always the case. The following are examples of carcinomas and their preferred
metastatic sites.
Squamous Cell Carcinoma – a cancer of the squamous epithelium present within many organs/tissues
within the body. Location will frequently determine the preferred site for metastatic spread:
Skin –> Lymphatic system
Prostate -> Bone through seeding in the pelvic region
Vaginal -> Liver and Lung (though there is a good chance it will not spread)
Adenocarcinoma – a carcinoma that originates from glandular tissues. Most adenocarcinomas including
colon, lung (non-small cell) and pancreatic (ductal) will frequently spread to nearby lymph nodes.
Basal Cell Carcinoma – a carcinoma that arises from the bottom (basal) layer of the outer skin. It is the
most common type of skin cancer. While it is malignant, it rarely metastasizes. If it does metastasize
however, spread to the lymph nodes is the most likely effect.
Sarcomas are cancers of the connective tissues (ie. bone, fat, cartilage). Though sometimes the term
sarcoma can be used instead of carcinoma to describe some epithelial cell cancers. Sarcomas have an
affinity for hematologic spread over lymphatic spread because they usually originate in places which will
have them encounter blood vessels before they reach the lymphatic system. Due to this affinity,
metastases are more likely to establish an invasion through organs and tissues with a large amount of
blood flow such as the liver and the lungs. The following are types of sarcomas and areas where they will
likely metastasize to:
Osteosarcoma – a malignant cancer of the bone whereas most bone cancers are benign. Osteosarcomas
are likely to spread to surrounding bones as well as the lungs if not treated effectively.
Chondrosarcoma – a very aggressive malignant cancer of the cartilage. This type of cancer can spread
very easily to into the bones themselves but will also spread to the lungs. Only 5% of known cases of
chondrosarcoma will spread to the lymphatic system.
Lymphomas are cancers that originate from lymphocytes, frequently within the lymph nodes
themselves. Spread from this cancer will most likely end up in surrounding lymphatic tissue and nodes.
The following are types of lymphomas and areas where they will likely metastasize to:
Hodgkin’s Lymphoma – a type of lymphoma that is characterized by a very systematic spread through to
other lymph nodes. It is also characterized by systematic symptoms are present in advanced stages of
the disease and the presence of Reed-Sternberg cells are present in affected lymph nodes upon
microscopy. As mentioned, this cancer will frequently spread to other lymph nodes.
Follicular Lymphoma – the most common form of non-Hodgkin’s lymphoma. It is a cancer of the B-Cells
and under microscopy, affected lymph nodes will show rounded structures called “follicles” hence the
name. Follicular lymphoma is slow to grow but can and does frequently spread to other lymph nodes.
4. Outline the molecular basis of metastatic spread
Note; it is important to remember that not all cells in a tumour are the same. Some cells exhibit more
“metastatic” characteristics than others. With a possibility that millions of cells can be released from a
primary tumour in a daily basis, metastatic spread is a probabilistic occurrence based on the qualities of
the cancer cells.
Metastatic spread is initiated by the creation of a neoplastic growth in or on a tissue. In order to
metastasize, cancerous cells must be able to break away from the growth. Cancer cells are held together
in a tumour by transmembrane proteins like cadherin. Some cells are less adhesive than others and will
tend to detach from the rest of the cancer. Many of these cells however, have fibronectin and laminin
receptors which allows them to attach to the basement membranes of tissues. From here, these cells
can directly seed into other tissues resulting in metastatic spread. In order to achieve hematological or
lymphatic spread however, the cancer must break through the surrounding tissue and infiltrate a
pathway for spreading. To break through surrounding tissue, the cells must degrade and invade the
extracellular matrix. In the body, the ECM is constantly broken down and restructured by a counteractive relationship between proteases and antipoteases. While in normal cells, this relationship is strictly
controlled, aggressive metastatic cells have a very strong affinity towards the production of proteases
which work to actively break down the ECM. Three types of proteases have been identified with
cancers; serine, cystine and matrix metalloprotinases (collagen cleaver). The breaking down of the ECM
will cause the release of angiogenic stimuli (an attempt to repair structures), which will only serve to
help the tumour grow. When elements of the ECM have been broken down, the cancer cells grow into
and invade this area. Aggressive cancer cells have very high amounts of autocrine motility factor - a
protein cytokine secreted by tumor cells which elicits increases in cell motility.
Given enough time, a cancer can break through enough ECM to puncture the basement membrane and
eventually enter a blood vessel. Once this happens, the cells will disseminate through the vessel and will
need to home into a suitable site for metastatic growth. This presents a problem for the cancer cells as
they may be actively attacked by the innate and adaptive immune system. In order to survive, these
cells may coagulate particularly with platelets. Cells can attach to T-Lymphocytes via the CD44 adhesion
molecule and effectively “ride” the lymphocyte to lymphoid tissue. As before, highly metastatic cells
have a strong affinity to basement membranes because of their fibronectin and laminin receptors. With
these, they will re-attach and break through the vessel walls to form another metastatic deposit. If this
can occur with a good amount of surviving cells, a new metastatic deposit can be formed.
5. Discuss the relationship between tumour grade with the spread of cancer and prognosis
Grading of a cancer is based on the degree of differentiation of the tumour cells and the number of
mitoses within the tumour as presumed correlates of the neoplasm’s aggressiveness. Essentially, the
more aggressive and more favorable the tumour’s characteristics are to metastasize, the higher the
grade. Low graded tumours have relatively uniform cells which are much less likely to break apart from
each other and metastasize. Highly graded tumours display a vast range of different mutated cells, some
of which may not be very adhesive to the rest of the tumour and will frequently disperse from their
origin. Also, as a principle of chance, the diversity of the tumour cells will increase the likelyhood that
cells which are highly adapted for metastatic spread will be formed. In addition, the cell activity level is
another important factor in tumor grading. Cell metabolism and turn-over rates are also graded as
indicators of tumour aggressiveness. High cell metabolism and turn-over rates will effectively cause
faster growing cancers. Therefore a higher graded tumour will grow faster and in turn it will also
disseminate metastatic cells at a higher rate. Because of this, higher graded tumours have a strong
tendency to metastasize and spread prolifically. These types of cancers are very difficult to treat once
they have spread. Lower grade tumours may be containable within a region and managed with
treatment. A low grade tumour is less likely to metastasize.
6. Describe the principles of cancer staging
The staging of cancers is based on the size of the primary lesion, its extent of spread to lymph nodes and
the presence or absence of blood-borne metastases. Essentially, the larger and more advanced the
primary lesion is, the higher the stage. Additionally, spreading to the lymph nodes will increase a
cancer’s stage as well as the presentation of blood-borne metastases.