Metastasis
Encyclopedia
Metastasis, or metastatic disease (sometimes abbreviated mets), is the spread of a disease
from one organ
or part to another non-adjacent organ or part. It was previously thought that only malignant
tumor cells and infection
s have the capacity to metastasize; however, this is being reconsidered due to new research. The word metastasis means "displacement" in Greek, from μετά, meta, "next", and στάσις, stasis, "placement". The plural is metastases.
Cancer
occurs after a single cell in a tissue
is progressively genetically damaged to produce a cancer stem cell
possessing a malignant
phenotype
. These cancer stem cells are able to undergo uncontrolled abnormal mitosis
, which serves to increase the total number of cancer cells at that location. When the area of cancer cell
s at the originating site becomes clinically detectable, it is called a primary tumor
. Some cancer cells also acquire the ability to penetrate and infiltrate surrounding normal tissues in the local area, forming a new tumor. The newly formed "daughter" tumor in the adjacent site within the tissue is called a local metastasis.
Some cancer cells acquire the ability to penetrate the walls of lymphatic and/or blood vessel
s, after which they are able to circulate through the bloodstream (circulating tumor cell
s) to other sites and tissues in the body. This process is known (respectively) as lymphatic or hematogeneous spread.
After the tumor cells come to rest at another site, they re-penetrate through the vessel or walls, continue to multiply, and eventually another clinically detectable tumor is formed. This new tumor is known as a metastatic (or secondary) tumor. Metastasis is one of three hallmarks of malignancy
(contrast benign tumors). Most tumor
s and other neoplasms
can metastasize, although in varying degrees (e.g. basal cell carcinoma
rarely metastasize).
When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are like those in the original tumor. This means, for example, that, if breast cancer
metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called metastatic breast cancer, not lung cancer.
The symptoms of metastasis varies with location of the tumors.
Initially, nearby lymph nodes are struck early. Lungs, bones, liver, and brain are the most common metastasis locations from solid tumors.
Although advanced cancer may cause pain
, it is often not the first symptom.
Some patients, however, don't show any symptoms.
s, liver
, brain
, and the bone
s.
s that make up the surrounding extracellular matrix
(ECM), which separates the tumor from adjoining tissue. By degrading these proteins, cancer cells are able to breach the ECM and escape. When oral cancer
s metastasize, they commonly travel through the lymph system to the lymph node
s in the neck. The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressor
s, of which about a dozen are known.
Cancer researchers studying the conditions necessary for cancer metastasis have discovered that one of the critical events required is the growth of a new network of blood vessels, called tumor angiogenesis
. It has been found that angiogenesis inhibitor
s would therefore prevent the growth of metastases.
There are several different cell types critical to tumour growth. In particular endothelial progenitor cell
s are a very important cell population in tumour blood vessel growth. This finding was demonstrated in the high impact factor journals of Science (2008) and Genes and Development (2007) which also showed that endothelial progenitor cells are critical for metastasis and angiogenesis. This importance of endothelial progenitor cells in tumour growth, angiogenesis and metastasis has been confirmed by a recent publication in Cancer Research (August 2010). This seminal paper has demonstrated that endothelial progenitor cells can be marked using the Inhibitor of DNA Binding 1
(ID1). This novel finding meant that investigators were able to track endothelial progenitor cells from the bone marrow to the blood to the tumour-stroma and even incorporated in tumour vasculature. This finding of endothelial progenitor cells incorporated in tumour vasculature proves the importance of this cell type in blood vessel development in a tumour setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow lead to a significant decrease in tumour growth and vasculature development. Therefore endothelial progenitor cells are very important in tumour biology and present novel therapeutic targets.
, pleural
, pericardial or subarachnoid spaces. For example, ovarian tumours
spreads transperitoneally to the surface of the liver. Mesothelioma can spread through the pleural cavity.
Cancer cells may spread to lymph node
s (regional lymph nodes) near the primary tumor. This is called nodal involvement, positive nodes, or regional disease. ("Positive nodes" is a term that would be used by medical specialists to describe a patient's condition, meaning that the patient's lymph nodes near the primary tumor tested positive for malignancy. It is common medical practice to test by biopsy at least two lymph nodes near a tumor site when doing surgery to examine or remove a tumor.) Localized spread to regional lymph node
s near the primary tumor is not normally counted as metastasis, although this is a sign of worse prognosis
. Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas.
over a century ago in 1889. For example, prostate cancer
usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer
often metastasises to the ovary
in women, then it is called a Krukenberg tumor
.
According to the "seed and soil" theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics. For example, breast tumor cells, which gather calcium ion
s from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma
spreads to the brain, presumably because neural tissue and melanocyte
s arise from the same cell line in the embryo
.
In 1928 James Ewing
challenged the "seed and soil" theory and proposed that metastasis occurs purely by anatomic and mechanical routes.
", urinating blood—"probably bladder
"), complex imaging will not either. In some of these cases a primary tumor may appear later.
The use of immunohistochemistry
has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma
), no primary tumor is found, even on autopsy
. It is therefore thought that some primary tumors can regress completely, but leave their metastases behind.
For instance, breast cancer
cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry
, FISH (fluorescent in situ hybridization
), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified.
Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor.
It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop the ability to metastasize through the development of somatic mutations. According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy
) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential.
The somatic
mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that the genetic state of the primary tumor reflects the ability of that cancer to metastasize. Research comparing gene expression between primary and metastatic adenocarcinomas identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a "metastatic signature." Up-regulated genes in the signature include: SNRPF, HNRPAB
, DHPS
and securin
. Actin
, myosin
and MHC class II
down-regulation was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor.
Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature. Additionally, the expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma
. Metastases of breast cancer
, medulloblastoma
and prostate cancer
all had similar expression patterns of these metastasis-associated genes.
The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within the primary tumor and hope for improving the prognosis of these metastatic-associated cancers. Additionally, by identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis.
, a cancer of the blood) that can kill without spreading at all.
When cancer has metastasized, it may be treated with radiosurgery
, chemotherapy
, radiation therapy
, biological therapy, hormone therapy
, surgery
or a combination of these. The choice of treatment generally depends on the type of primary cancer
, the size and location of the metastasis, the patient's age and general health, and the types of treatments used previously. In patients diagnosed with CUP
, it is still possible to treat the disease even when the primary tumor cannot be located.
The treatment options currently available are rarely able to cure metastatic cancer, though some tumors, such as testicular cancer
and thyroid cancer
, are usually still curable.
Charities and advocacy groups dealing with metastatic cancer
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
from one organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
or part to another non-adjacent organ or part. It was previously thought that only malignant
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
tumor cells and infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s have the capacity to metastasize; however, this is being reconsidered due to new research. The word metastasis means "displacement" in Greek, from μετά, meta, "next", and στάσις, stasis, "placement". The plural is metastases.
Cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
occurs after a single cell in a tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
is progressively genetically damaged to produce a cancer stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
possessing a malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. These cancer stem cells are able to undergo uncontrolled abnormal mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
, which serves to increase the total number of cancer cells at that location. When the area of cancer cell
Cancer cell
Cancer cells are cells that grow and divide at an unregulated, quickened pace. Although cancer cells can be quite common in a person they are only malignant when the other cells fail to recognize and/or destroy them. In the past a common belief was that cancer cells failed to be recognized and...
s at the originating site becomes clinically detectable, it is called a primary tumor
Primary tumor
A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass....
. Some cancer cells also acquire the ability to penetrate and infiltrate surrounding normal tissues in the local area, forming a new tumor. The newly formed "daughter" tumor in the adjacent site within the tissue is called a local metastasis.
Some cancer cells acquire the ability to penetrate the walls of lymphatic and/or blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s, after which they are able to circulate through the bloodstream (circulating tumor cell
Circulating Tumor Cell
Circulating tumor cells are cells that have detached from a primary tumor and circulate in the bloodstream. CTCs may constitute seeds for subsequent growth of additional tumors in different tissues....
s) to other sites and tissues in the body. This process is known (respectively) as lymphatic or hematogeneous spread.
After the tumor cells come to rest at another site, they re-penetrate through the vessel or walls, continue to multiply, and eventually another clinically detectable tumor is formed. This new tumor is known as a metastatic (or secondary) tumor. Metastasis is one of three hallmarks of malignancy
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
(contrast benign tumors). Most tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s and other neoplasms
Neoplasia
Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
can metastasize, although in varying degrees (e.g. basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
rarely metastasize).
When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are like those in the original tumor. This means, for example, that, if breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called metastatic breast cancer, not lung cancer.
Signs and symptoms
Initially, nearby lymph nodes are struck early. Lungs, bones, liver, and brain are the most common metastasis locations from solid tumors.
- In lymph nodes, a common symptom is lymphadenopathyLymphadenopathyLymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
- Lungs: coughCoughA cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...
, hemoptysisHemoptysisHemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
and dyspneaDyspneaDyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
(shortness of breath) - Liver: hepatomegalyHepatomegalyHepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
(enlarged liverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
) and jaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid... - Bones: bone pain, fractureFractureA fracture is the separation of an object or material into two, or more, pieces under the action of stress.The word fracture is often applied to bones of living creatures , or to crystals or crystalline materials, such as gemstones or metal...
of affected bones - Brain: neurologicalNeurologyNeurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
symptoms such as headaches, seizures, and vertigoVertigo (medical)Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
.
Although advanced cancer may cause pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
, it is often not the first symptom.
Some patients, however, don't show any symptoms.
Pathophysiology
Metastatic tumours are very common in the late stages of cancer. The spread of metastases may occur via the blood or the lymphatics or through both routes. The most common places for the metastases to occur are the lungLung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, and the bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
s.
Factors involved
Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream or the lymphatic system. To do so, malignant cells break away from the primary tumor and attach to and degrade proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s that make up the surrounding extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM), which separates the tumor from adjoining tissue. By degrading these proteins, cancer cells are able to breach the ECM and escape. When oral cancer
Oral cancer
Oral cancer is a subtype of head and neck cancer, is any cancerous tissue growth located in the oral cavity. It may arise as a primary lesion originating in any of the oral tissues, by metastasis from a distant site of origin, or by extension from a neighboring anatomic structure, such as the...
s metastasize, they commonly travel through the lymph system to the lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s in the neck. The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressor
Metastasis suppressor
A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal attributes of cancer. This attribute is responsible for about ninety percent of human cancer deaths...
s, of which about a dozen are known.
Cancer researchers studying the conditions necessary for cancer metastasis have discovered that one of the critical events required is the growth of a new network of blood vessels, called tumor angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. It has been found that angiogenesis inhibitor
Angiogenesis inhibitor
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels . Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet....
s would therefore prevent the growth of metastases.
There are several different cell types critical to tumour growth. In particular endothelial progenitor cell
Endothelial progenitor cell
Endothelial progenitor cells are a population of rare cells that circulate in the blood with the ability to differentiate into endothelial cells, the cells that make up the lining of blood vessels. The process by which blood vessels are born de novo from endothelial progenitor cells is known as...
s are a very important cell population in tumour blood vessel growth. This finding was demonstrated in the high impact factor journals of Science (2008) and Genes and Development (2007) which also showed that endothelial progenitor cells are critical for metastasis and angiogenesis. This importance of endothelial progenitor cells in tumour growth, angiogenesis and metastasis has been confirmed by a recent publication in Cancer Research (August 2010). This seminal paper has demonstrated that endothelial progenitor cells can be marked using the Inhibitor of DNA Binding 1
ID1
DNA-binding protein inhibitor ID-1 is a protein that in mice and humans is encoded by the ID1 gene.. The protein encoded by this gene is a helix-loop-helix protein that can form heterodimers with members of the basic HLH family of transcription factors...
(ID1). This novel finding meant that investigators were able to track endothelial progenitor cells from the bone marrow to the blood to the tumour-stroma and even incorporated in tumour vasculature. This finding of endothelial progenitor cells incorporated in tumour vasculature proves the importance of this cell type in blood vessel development in a tumour setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow lead to a significant decrease in tumour growth and vasculature development. Therefore endothelial progenitor cells are very important in tumour biology and present novel therapeutic targets.
Routes of metastasis
Metastasis occurs by four routes:1. Transcoelomic
The spread into body cavities occurs by the seeding surface of the peritonealPeritoneal cavity
The peritoneal cavity is a potential space between the parietal peritoneum and visceral peritoneum, that is, the two membranes that separate the organs in the abdominal cavity from the abdominal wall...
, pleural
Pleural cavity
In human anatomy, the pleural cavity is the potential space between the two pleura of the lungs. The pleura is a serous membrane which folds back onto itself to form a two-layered, membrane structure. The thin space between the two pleural layers is known as the pleural cavity; it normally...
, pericardial or subarachnoid spaces. For example, ovarian tumours
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
spreads transperitoneally to the surface of the liver. Mesothelioma can spread through the pleural cavity.
2. Lymphatic spread
Invasion into the lymphatic system is followed by the transport of tumor cells to regional nodes and ultimately to other parts of the body. This is the most common route of metastasis for carcinomas.3. Haematogenous spread
This is typical of all sarcomas but it is the favored route in certain carcinomas (e.g. those originating in kidneys). Because of their thinner walls veins are more frequently invaded than arteries and metastasis follows the pattern of the venous flows.4. Transplantation or implantation
Mechanical carriage of fragments of tumor cells by surgical instruments during operation or the use of needles during diagnostic procedures.Cancer cells may spread to lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s (regional lymph nodes) near the primary tumor. This is called nodal involvement, positive nodes, or regional disease. ("Positive nodes" is a term that would be used by medical specialists to describe a patient's condition, meaning that the patient's lymph nodes near the primary tumor tested positive for malignancy. It is common medical practice to test by biopsy at least two lymph nodes near a tumor site when doing surgery to examine or remove a tumor.) Localized spread to regional lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s near the primary tumor is not normally counted as metastasis, although this is a sign of worse prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
. Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas.
Organ-specific targets
There is a propensity for certain tumors to seed in particular organs. This was first discussed as the "seed and soil" theory by Stephen PagetStephen Paget
Stephen Paget was an English surgeon, the son of the distinguished surgeon and pathologist Sir James Paget. Stephen Paget has been long credited with proposing the "seed and soil" theory of metastasis, even though in his paper “The Distribution Of Secondary Growths In Cancer Of The Breast”, The...
over a century ago in 1889. For example, prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer
Stomach cancer
Gastric cancer, commonly referred to as stomach cancer, can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs, lymph nodes, and the liver...
often metastasises to the ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
in women, then it is called a Krukenberg tumor
Krukenberg tumor
A Krukenberg tumor refers to a malignancy in the ovary that metastasized from a primary site, classically the gastrointestinal tract, although it can arise in other tissues such as the breast. Gastric adenocarcinoma, especially at the pylorus, is the most common source...
.
According to the "seed and soil" theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics. For example, breast tumor cells, which gather calcium ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
spreads to the brain, presumably because neural tissue and melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s arise from the same cell line in the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
.
In 1928 James Ewing
James Ewing
James Stephen Ewing was an American pathologist. He was the first Professor of pathology at Cornell University and became famous with the discovery of a form of malignant bone tumor that later became known as Ewing's sarcoma.-Life:James Ewing, was born in 1866 to a prominent family of Pittsburgh....
challenged the "seed and soil" theory and proposed that metastasis occurs purely by anatomic and mechanical routes.
Metastasis and primary cancer
It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients presenting to oncology units will have metastases without a primary tumor found. In these cases, doctors refer to the primary tumor as "unknown" or "occult," and the patient is said to have cancer of unknown primary origin (CUP) or Unknown Primary Tumors (UPT). It is estimated that 3% of all cancers are of unknown primary origin. Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably lungLung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
", urinating blood—"probably bladder
Bladder cancer
Bladder cancer is any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis...
"), complex imaging will not either. In some of these cases a primary tumor may appear later.
The use of immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
), no primary tumor is found, even on autopsy
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
. It is therefore thought that some primary tumors can regress completely, but leave their metastases behind.
Common sites of origin
- LungLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
- BreastBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
- Skin: melanomaMelanomaMelanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
(other skin tumors rarely metastasize) - Colon
- KidneyRenal cell carcinomaRenal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
- ProstateProstate cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
- PancreasPancreatic cancerPancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
- CervixCervical cancerCervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
Diagnosis
The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken.For instance, breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
, FISH (fluorescent in situ hybridization
Fluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified.
Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor.
It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop the ability to metastasize through the development of somatic mutations. According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential.
The somatic
Somatic
The term somatic means 'of the body',, relating to the body. In medicine, somatic illness is bodily, not mental, illness. The term is often used in biology to refer to the cells of the body in contrast to the germ line cells which usually give rise to the gametes...
mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that the genetic state of the primary tumor reflects the ability of that cancer to metastasize. Research comparing gene expression between primary and metastatic adenocarcinomas identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a "metastatic signature." Up-regulated genes in the signature include: SNRPF, HNRPAB
HNRPAB
Heterogeneous nuclear ribonucleoprotein A/B, also known as HNRPAB, is a protein which in humans is encoded by the HNRPAB gene. Although this gene is named HNRNPAB in reference to its first cloning as an RNA binding protein with similarity to HNRNP A and HNRNP B, it is not a member of the HNRNP A/B...
, DHPS
DHPS
Deoxyhypusine synthase is an enzyme that in humans is encoded by the DHPS gene.-Further reading:...
and securin
Securin
Securin is a protein involved in control of the metaphase-anaphase transition and anaphase onset. Following bi-orientation of chromosome pairs and inactivation of the spindle checkpoint system, the underlying regulatory system, which includes securin, produces an abrupt stimulus that induces highly...
. Actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
, myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
and MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
down-regulation was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor.
Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature. Additionally, the expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
. Metastases of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, medulloblastoma
Medulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
and prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
all had similar expression patterns of these metastasis-associated genes.
The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within the primary tumor and hope for improving the prognosis of these metastatic-associated cancers. Additionally, by identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis.
Management
Treatment and survival is determined by whether or not a cancer is local or has spread to other locations. If the cancer spreads to other tissues and organs, it may decrease a patient's likelihood of survival. However, there are some cancers (i.e., some forms of leukemiaLeukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, a cancer of the blood) that can kill without spreading at all.
When cancer has metastasized, it may be treated with radiosurgery
Radiosurgery
Radiosurgery is a medical procedure that allows non-invasive treatment of benign and malignant tumors. It is also known as stereotactic radiotherapy, when used to target lesions in the brain, and stereotactic body radiotherapy when used to target lesions in the body...
, chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
, biological therapy, hormone therapy
Hormone therapy
Hormone therapy, or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also referred to as hormonal therapy...
, surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
or a combination of these. The choice of treatment generally depends on the type of primary cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, the size and location of the metastasis, the patient's age and general health, and the types of treatments used previously. In patients diagnosed with CUP
Cancer of unknown primary origin
Cancer of unknown primary origin is the diagnosis when metastatic cancer is found but the place where the cancer began cannot be determined. About two to four percent of all cancer patients have a cancer whose primary site is never identified...
, it is still possible to treat the disease even when the primary tumor cannot be located.
The treatment options currently available are rarely able to cure metastatic cancer, though some tumors, such as testicular cancer
Testicular cancer
Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...
and thyroid cancer
Thyroid cancer
Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...
, are usually still curable.
See also
- Disseminated diseaseDisseminated diseaseDisseminated disease refers to a diffuse disease process, generally either infectious or neoplastic, but sometimes also referring to connective tissue disease....
- Brown-Sequard SyndromeBrown-Séquard syndromeBrown-Séquard syndrome, also known as Brown-Séquard's hemiplegia and Brown-Séquard's paralysis, is a loss of sensation and motor function that is caused by the lateral hemisection of the spinal cord...
(Sections on Cavernous malformation, Germinoma, Renal cell carcinoma and Lung Cancer) - Brain metastasisBrain metastasisA brain metastasis is a cancer that has metastasized to the brain from another location in the body. Brain metastases are the most common cause of intracranial mass lesions, and up to 45% of cancer patients eventually develop brain metastases during the course of their illness, with 98,000 to...
External links
Medical information about metastatic cancer- Q&A: Metastatic Cancer – from the National Cancer InstituteNational Cancer InstituteThe National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
- Invasion and Metastases – from Cancer Medicine e.5
- How Cancer Grows and Spreads – an interactive Flash presentation that explores the progression of a carcinoma from a single cell to metastasis; from Children's Hospital BostonChildren's Hospital BostonChildren's Hospital Boston is a 396-licensed bed children's hospital in the Longwood Medical and Academic Area of Boston, Massachusetts.At 300 Longwood Avenue, Children's is adjacent both to its teaching affiliate, Harvard Medical School, and to Dana-Farber Cancer Institute...
Charities and advocacy groups dealing with metastatic cancer
- The MetaCancer Foundation – resources and support for metastatic cancer survivors and their caregivers
- Metastatic Breast Cancer Network
- Children's Cancer Research Charity for Metastatic Cancer in Kids