Metastasis

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Metastasis
Synonymsmetastatic disease
Metastasis illustration.jpg
Illustration showing hematogenous metastasis
Pronunciation
Specialty Oncology

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; [1] it is typically spoken of as such spread by a cancerous tumor. [2] The newly pathological sites, then, are metastases (mets). [3] [4] It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues. [5]

Cancer disease of uncontrolled, unregulated and abnormal cell growth

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss and a change in bowel movements. While these symptoms may indicate cancer, they may have other causes. Over 100 types of cancers affect humans.

Contents

Cancer occurs after cells are genetically altered to proliferate rapidly and indefinitely. This uncontrolled proliferation by mitosis produces a primary heterogeneic tumour. The cells which constitute the tumor eventually undergo metaplasia, followed by dysplasia then anaplasia, resulting in a malignant phenotype. This malignancy allows for invasion into the circulation, followed by invasion to a second site for tumorigenesis.

Mitosis nuclear division cycle for eukaryotic cells in which the two resulting nuclei are genetically identical

In cell biology, mitosis is a part of the cell cycle when replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is often accompanied or followed by cytokinesis, which divides the cytoplasm, organelles and cell membrane into two new cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of an animal cell cycle—the division of the mother cell into two daughter cells genetically identical to each other.

A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass. Most cancers develop at their primary site but then go on to metastasize or spread to other parts of the body. These further tumors are secondary tumor

Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. This phenomenon occurs both between tumours and within tumours. A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication: whenever a cell divides, a few mutations are acquired—leading to a diverse population of cancer cells. The heterogeneity of cancer cells introduces significant challenges in designing effective treatment strategies. However, research into understanding and characterizing heterogeneity can allow for a better understanding of the causes and progression of disease. In turn, this has the potential to guide the creation of more refined treatment strategies that incorporate knowledge of heterogeneity to yield higher efficacy.

Some cancer cells known as circulating tumor cells acquire the ability to penetrate the walls of lymphatic or blood vessels, after which they are able to circulate through the bloodstream to other sites and tissues in the body. [6] This process is known (respectively) as lymphatic or hematogenous spread. After the tumor cells come to rest at another site, they re-penetrate the vessel or walls and continue to multiply, eventually forming another clinically detectable tumor.[ citation needed ] This new tumor is known as a metastatic (or secondary) tumor. Metastasis is one of the hallmarks of cancer, distinguishing it from benign tumors. [7] Most cancers can metastasize, although in varying degrees. Basal cell carcinoma for example rarely metastasizes. [7]

Circulating tumor cells (CTCs) are cells that have shed into the vasculature or lymphatics from a primary tumor and are carried around the body in the blood circulation. CTCs constitute seeds for the subsequent growth of additional tumors (metastases) in distant organs, a mechanism that is responsible for the vast majority of cancer-related deaths. The detection and analysis of CTCs can assist early patient prognoses and determine appropriate tailored treatments.

Lymphatic vessel any pathway for lymphiod fluids

The lymphatic vessels are thin-walled vessels (tubes) structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vessels are lined by endothelial cells, and have a thin layer of smooth muscle, and adventitia that bind the lymph vessels to the surrounding tissue. Lymph vessels are devoted to the propulsion of the lymph from the lymph capillaries, which are mainly concerned with absorption of interstitial fluid from the tissues. Lymph capillaries are slightly larger than their counterpart capillaries of the vascular system. Lymph vessels that carry lymph to a lymph node are called afferent lymph vessels, and those that carry it from a lymph node are called efferent lymph vessels, from where the lymph may travel to another lymph node, may be returned to a vein, or may travel to a larger lymph duct. Lymph ducts drain the lymph into one of the subclavian veins and thus return it to general circulation.

Blood vessel a tubular structure which carries blood

The blood vessels are the part of the circulatory system, and microcirculation, that transports blood throughout the human body. These vessels are designed to transport nutrients and oxygen to the tissues of the body. They also take waste and carbon dioxide and carry them away from the tissues and back to the heart. Blood vessels are needed to sustain life as all of the body’s tissues rely on their functionality.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 the tissues; and the veins, which carry blood from the capillaries back toward the heart. The word vascular, meaning relating to the blood vessels, is derived from the Latin vas, meaning vessel. Some structures -- such as cartilage, the epithelium, and the lens and cornea of the eye -- do not contain blood vessels and are labeled avascular.

When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in the original or primary tumor. [8] This means 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. Metastasis is a key element in cancer staging systems such as the TNM staging system, where it represents the "M". In overall stage grouping, metastasis places a cancer in Stage IV. The possibilities of curative treatment are greatly reduced, or often entirely removed, when a cancer has metastasized.

Breast cancer cancer that originates in the mammary gland

Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. In those with distant spread of the disease, there may be bone pain, swollen lymph nodes, shortness of breath, or yellow skin.

Cancer staging is the process of determining the extent to which a cancer has developed by growing and spreading. Contemporary practice is to assign a number from I to IV to a cancer, with I being an isolated cancer and IV being a cancer which has spread to the limit of what the assessment measures. The stage generally takes into account the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes it has spread to, and whether it has appeared in more distant locations (metastasized).

The TNM Classification of Malignant Tumors (TNM) is a globally recognised standard for classifying the extent of spread of cancer. It is a classification system of the anatomical extent of tumor cancers. It has gained wide international acceptance for many solid tumor cancers, but is not applicable to leukaemia and tumors of the central nervous system. Most common tumors have their own TNM classification.

Signs and symptoms

Cut surface of a liver showing multiple paler metastatic nodules originating from pancreatic cancer Secondary tumor deposits in the liver from a primary cancer of the pancreas.jpg
Cut surface of a liver showing multiple paler metastatic nodules originating from pancreatic cancer

Initially, nearby lymph nodes are struck early. [9] The lungs, liver, brain, and bones are the most common metastasis locations from solid tumors. [9]

Liver vital organ in vertebrates and some other animals

The liver, an organ only found in vertebrates, detoxifies various metabolites, synthesizes proteins, and produces biochemicals necessary for digestion. In humans, it is located in the right upper quadrant of the abdomen, below the diaphragm. Its other roles in metabolism include the regulation of glycogen storage, decomposition of red blood cells and the production of hormones.

Brain organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals

The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. The brain is located in the head, usually close to the sensory organs for senses such as vision. The brain is the most complex organ in a vertebrate's body. In a human, the cerebral cortex contains approximately 14–16 billion neurons, and the estimated number of neurons in the cerebellum is 55–70 billion. Each neuron is connected by synapses to several thousand other neurons. These neurons communicate with one another by means of long protoplasmic fibers called axons, which carry trains of signal pulses called action potentials to distant parts of the brain or body targeting specific recipient cells.

Bone rigid organs that constitute part of the endoskeleton of vertebrates

A bone is a rigid organ that constitutes part of the vertebrate skeleton. Bones protect the various organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and enable mobility. Bones come in a variety of shapes and sizes and have a complex internal and external structure. They are lightweight yet strong and hard, and serve multiple functions.

Lymphadenopathy disorder of lymph nodes

Lymphadenopathy or adenopathy is disease of the lymph nodes, in which they are abnormal in size, number, or consistency. Lymphadenopathy of an inflammatory type is lymphadenitis, producing swollen or enlarged lymph nodes. In clinical practice, the distinction between lymphadenopathy and lymphadenitis is rarely made and the words are usually treated as synonymous. Inflammation of the lymphatic vessels is known as lymphangitis. Infectious lymphadenitis affecting lymph nodes in the neck is often called scrofula.

Cough medical symptom, reflex to clear large breathing passages

A cough is a sudden, and often repetitively occurring, protective reflex which helps to clear the large breathing passages from fluids, irritants, foreign particles and microbes. The cough reflex consists of three phases: an inhalation, a forced exhalation against a closed glottis, and a violent release of air from the lungs following opening of the glottis, usually accompanied by a distinctive sound.

Hemoptysis is the coughing up of blood or blood-stained mucus from the bronchi, larynx, trachea, or lungs. This can occur with lung cancer, infections such as tuberculosis, bronchitis, or pneumonia, and certain cardiovascular conditions. Hemoptysis is considered massive at 300 mL. In such cases, there are always severe injuries. The primary danger comes from choking, rather than blood loss.

Although advanced cancer may cause pain, it is often not the first symptom.

Some patients, however, do not show any symptoms. [9] When the organ gets a metastatic disease it begins to shrink until its lymph nodes burst, or undergo lysis.

Pathophysiology

Metastatic tumors are very common in the late stages of cancer. The spread of metastasis may occur via the blood or the lymphatics or through both routes. The most common places for the metastases to occur are the lungs, liver, brain, and the bones. [10]

Factors involved

Metastasis involves 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, via the lymphatic system, or by direct extension. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissues. By degrading these proteins, cancer cells are able to breach the ECM and escape. The location of the metastases is not always random, with different types of cancer tending to spread to particular organs and tissues at a rate that is higher than expected by statistical chance alone. [11] Breast cancer, for example, tends to metastasize to the bones and lungs. This specificity seems to be mediated by soluble signal molecules such as chemokines [12] and transforming growth factor beta. [13] The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors, of which about a dozen are known. [14]

Human cells exhibit three kinds of motion: collective motility, mesenchymal-type movement, and amoeboid movement. Cancer cells often opportunistically switch between different kinds of motion. Some cancer researchers hope to find treatments that can stop or at least slow down the spread of cancer by somehow blocking some necessary step in one or more kinds of motion. [15]

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. [16] It has been found that angiogenesis inhibitors would therefore prevent the growth of metastases. [7]

Several different cell types are critical to tumor growth. In particular, endothelial progenitor cells have been shown to have a strong influence on the growth of tumor blood-vessels. Endothelial progenitor cells are also critical for metastasis and angiogenesis. [17] [18] Endothelial progenitor cells are important in tumor growth, angiogenesis and metastasis, and can be marked using the Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators gained the ability to track endothelial progenitor cells from the bone marrow to the blood to the tumor-stroma and even incorporated in tumor vasculature. Endothelial progenitor cells incorporated in tumor vasculature suggests that this cell type in blood-vessel development is important in a tumor setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow can lead to a significant decrease in tumor growth and vasculature development. Therefore, endothelial progenitor cells are important in tumor biology and present novel therapeutic targets. [19]

NFAT transcription factors are implicated in breast cancer, more specifically in the process of cell motility as the basis of metastasis formation. Indeed, NFAT1 (NFATC2) and NFAT5 are pro-invasive and pro-migratory in breast carcinoma [20] [21] and NFAT3 (NFATc4) is an inhibitor of cell motility. [22] NFAT1 regulates the expression of the TWEAKR and its ligand TWEAK with the Lipocalin 2 to increase breast-cancer cell invasion [23] and NFAT3 inhibits Lipocalin 2 expression to blunt the cell invasion. [22]

Epigenetic regulation also plays an important role in the metastatic outgrowth of disseminated tumor cells. Metastases display alterations in histone modifications, such as H3K4-methylation and H3K9-methylation, when compared to matching primary tumors. [24] These epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs. [25]

A recent study shows that PKC-iota promotes melanoma cell invasion by activating Vimentin during EMT. PKC-iota inhibition or knockdown resulted an increase E-cadherin and RhoA levels while decreasing total Vimentin, phophorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι is involved in signaling pathways which upregulate EMT in melanoma thereby directly stimulates metastasis. [26]

Recently, a series of high-profile experiments suggests that the co-option of intercellular cross-talk mediated by exosome vesicles is a critical factor involved in all steps of the invasion-metastasis cascade. [27]

Routes

Main sites of metastases for some common cancer types. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases". Metastasis sites for common cancers.svg
Main sites of metastases for some common cancer types. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases".

Metastasis occurs by the following four routes:

Transcoelomic

The spread of a malignancy into body cavities can occur via penetrating the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. For example, ovarian tumors can spread transperitoneally to the surface of the liver.

Lymphatic spread

Lymphatic spread allows the transport of tumor cells to regional lymph nodes near the primary tumor and ultimately, to other parts of the body. This is called nodal involvement, positive nodes, or regional disease. "Positive nodes" is a term that would be used by medical specialists to describe regional lymph nodes that tested positive for malignancy. It is common medical practice to test by biopsy at least one lymph node near a tumor site when carrying out surgery to examine or remove a tumor. This lymph node is then called a sentinel lymph node. Lymphatic spread is the most common route of initial metastasis for carcinomas. [7] In contrast, it is uncommon for a sarcoma to metastasize via this route. Localized spread to regional lymph nodes near the primary tumor is not normally counted as a metastasis, although this is a sign of a worse outcome. The lymphatic system does eventually drain from the thoracic duct and right lymphatic duct into the systemic venous system at the venous angle and into the brachiocephalic veins, and therefore these metastatic cells can also eventually spread through the haematogenous route.

Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin Lymph node with metastatic melanoma.jpg
Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin

Hematogenous spread

This is typical route of metastasis for sarcomas, but it is also the favored route for certain types of carcinoma, such as renal cell carcinoma originating in the kidney. Because of their thinner walls, veins are more frequently invaded than are arteries, and metastasis tends to follow the pattern of venous flow. That is, hematogenous spread often follows distinct patterns depending on the location of the primary tumor. For example, colorectal cancer spreads primarily through the portal vein to the liver.

Canalicular spread

Some tumors, especially carcinomas may metastasize along anatomical canalicular spaces. These spaces include for example the bile ducts, the urinary system, the airways and the subarachnoid space. The process is similar to that of transcoelomic spread. However, often it remains unclear whether simultaneously diagnosed tumors of a canalicular system are one metastatic process or in fact independent tumors caused by the same agent (field cancerization).

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 Paget in 1889. The propensity for a metastatic cell to spread to a particular organ is termed 'organotropism'. 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. [29] For example, breast tumor cells, which gather calcium ions 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 melanocytes arise from the same cell line in the embryo. [30]

In 1928, James Ewing challenged the "seed and soil" theory and proposed that metastasis occurs purely by anatomic and mechanical routes. This hypothesis has been recently utilized to suggest several hypotheses about the life cycle of circulating tumor cells (CTCs) and to postulate that the patterns of spread could be better understood through a 'filter and flow' perspective. [31] However, contemporary evidences indicate that the primary tumour may dictate organotropic metastases by inducing the formation of pre-metastatic niches at distant sites, where incoming metastatic cells may engraft and colonise. [27] Specifically, exosome vesicles secreted by tumours have been shown to home to pre-metastatic sites, where they activate pro-metastatic processes such as angiogenesis and modify the immune contexture, so as to foster a favourable microenvironment for secondary tumour growth. [27]

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). [32] It is estimated that 3% of all cancers are of unknown primary origin. [33] Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably lung", urinating blood—"probably bladder"), complex imaging will not either. [33] 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. In other cases, the tumor might just be too small and/or in an unusual location to be diagnosed.

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 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. [34] 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. [35]

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. [35] 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." [35] 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. [36] Recent work identified a form of genetic instability in cancer called chromosome instability (CIN) as a driver of metastasis. [37] In aggressive cancer cells, loose DNA fragments from unstable chromosomes spill in the cytosol leading to the chronic activation of innate immune pathways, which are hijacked by cancer cells to spread to distant organs.

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. [35] 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. [35]

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, identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis. [35]

Management

Treatment and survival is determined, to a great extent, by whether or not a cancer remains localized or spreads to other locations in the body. If the cancer metastasizes to other tissues or organs it usually dramatically increases a patient's likelihood of death. Some cancers—such as some forms of leukemia, a cancer of the blood, or malignancies in the brain—can kill without spreading at all.

Once a cancer has metastasized it may still be treated with radiosurgery, chemotherapy, radiation therapy, biological therapy, hormone therapy, surgery, or a combination of these interventions ("multimodal therapy"). The choice of treatment depends on a large number of factors, including the type of primary cancer, the size and location of the metastases, the patient's age and general health, and the types of treatments used previously. In patients diagnosed with CUP it is often still possible to treat the disease even when the primary tumor cannot be located.

Current treatments are rarely able to cure metastatic cancer though some tumors, such as testicular cancer and thyroid cancer, are usually curable.

Palliative care, care aimed at improving the quality of life of people with major illness, has been recommended as part of management programs for metastasis. [38]

Research

Although metastasis is widely accepted to be the result of the tumor cells migration, there is a hypothesis saying that some metastases are the result of inflammatory processes by abnormal immune cells. [39] The existence of metastatic cancers in the absence of primary tumors also suggests that metastasis is not always caused by malignant cells that leave primary tumors. [40]

History

In March 2014 researchers discovered the oldest complete example of a human with metastatic cancer. The tumors had developed in a 3,000-year-old skeleton found in 2013 in a tomb in Sudan dating back to 1200 BC. The skeleton was analyzed using radiography and a scanning electron microscope. These findings were published in the Public Library of Science journal. [41] [42] [43]

Etymology

Metastasis is a Greek word meaning "displacement", from μετά, meta, "next", and στάσις, stasis, "placement".

See also

Related Research Articles

Krukenberg tumor Human disease

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. Krukenberg tumors are often found in both ovaries, consistent with its metastatic nature.

Carcinoma A category of types of cancer that develops from epithelial cells

Carcinoma is a category of types of cancer that develop from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal or ectodermal germ layer during embryogenesis.

Small-cell carcinoma type of carcinoma that commonly arises within lung and sometime other body sites

Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell carcinoma, small cell carcinoma has a shorter doubling time, higher growth fraction, and earlier development of metastases.

Lymphadenectomy or lymph node dissection is the surgical removal of one or more groups of lymph nodes. It is almost always performed as part of the surgical management of cancer. In a regional lymph node dissection, some of the lymph nodes in the tumor area are removed; in a radical lymph node dissection, most or all of the lymph nodes in the tumor area are removed.

Intravasation is the invasion of cancer cells through the basal membrane into a blood or lymphatic vessel. Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites. Other mechanisms include invasion through basement membranes, extravasation, and colonization of distant metastatic sites. Cancer cell chemotaxis also relies on this migratory behavior to arrive at a secondary destination designated for cancer cell colonization.

Vulvar cancer is a malignant, invasive growth in the vulva, or the outer portion of the female genitals. The disease accounts for only 0.6% of cancer diagnoses but 5% of gynecologic cancers in the United States. The labia majora are the most common sites involved representing about 50% of all cases, followed by the labia minora. The clitoris and Bartholin glands may rarely be involved. Vulvar cancer is separate from vulvar intraepithelial neoplasia (VIN), a superficial lesion of the epithelium that has not invaded the basement membrane—or a pre-cancer. VIN may progress to carcinoma-in-situ and, eventually, squamous cell cancer.

A micrometastasis is a small collection of cancer cells that has been shed from the original tumor and spread to another part of the body through the lymphovascular system. Micrometastases are too few, in size and quantity, to be picked up in a screening or diagnostic test, and therefore cannot be seen with imaging tests such as a mammogram, MRI, ultrasound, PET, or CT scans. These migrant cancer cells may group together to form a second tumor, which is so small that it can only be seen under a microscope. Approximately ninety percent of people who die from cancer die from metastatic disease, since these cells are so challenging to detect. It is important for these cancer cells to be treated immediately after discovery, in order to prevent the relapse and the likely death of the patient.

Alveolar rhabdomyosarcoma (ARMS) is a sub-type of the rhabdomyosarcoma soft tissue cancer family whose lineage is from mesenchymal cells and are related to skeletal muscle cells. ARMS tumors resemble the alveoli tissue that can be found in the lungs. Tumor location varies from patient to patient, but is commonly found in the head and neck region, male and female urogenital tracts, the torso, and extremities. Two fusion proteins can be associated with ARMS, but are not necessary, PAX3-FKHR. and PAX7-FKHR. In children and adolescents ARMS accounts for about 1 percent of all malignancies, has an incidence rate of 1 per million, and most cases occur sporadically with no genetic predisposition. PAX3-FOXO1 is now known to drive cancer-promoting gene expression programs through creation of distant genetic elements called super enhancers.

MMP2 protein-coding gene in the species Homo sapiens

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

Cancer of unknown primary origin (CUP) is a cancer that is determined to be at the metastatic stage at the time of diagnosis, but a primary tumor cannot be identified. A diagnosis of CUP requires a clinical picture consistent with metastatic disease and one or more biopsy results inconsistent with a primary tumor.

C-fos-induced growth factor protein-coding gene in the species Homo sapiens

C-fos-induced growth factor (FIGF) is a vascular endothelial growth factor that in humans is encoded by the FIGF gene.

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 cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.

Uterine clear-cell carcinoma (CC) is a rare form of endometrial cancer with distinct morphological features on pathology; it is aggressive and has high recurrence rate. Like uterine papillary serous carcinoma CC does not develop from endometrial hyperplasia and is not hormone sensitive, rather it arises from an atrophic endometrium. Such lesions belong to the type II endometrial cancers.

Metastatic breast cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumours, secondaries or stage 4 breast cancer, is a stage of breast cancer where the disease has spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer. There is no stage after IV.

Brain metastasis Human disease

A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. The metastasis typically shares a cancer cell type with the original site of the cancer. Metastasis is the most common cause of brain cancer, with primary tumors that originate in the brain being less common. The most common sites of primary cancer which metastasize to the brain are lung, breast, colon, kidney, and skin cancer. Brain metastases can occur in patients months or even years after their original cancer is treated. Brain metastases have a poor prognosis for cure, but modern treatments are allowing patients to live months and sometimes years after the diagnosis.

Lewis lung carcinoma is a tumor that spontaneously developed as an epidermoid carcinoma in the lung of a C57BL mouse. It was discovered in 1951 by Dr. Margaret Lewis of the Wistar Institute and became one of the first transplantable tumors.

Lymphovascular invasion

Lymphovascular invasion is the invasion of a cancer to the blood vessels and/or lymphatics.

Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium. Recent ameliorations in maneuvering the mouse genome have provided the technology to induce mammary cancers in mice arising from genetic mutations that have been identified in human cancer. This means models can be generated based upon molecular lesions consistent with the human disease.

Carcinoma of the tonsil is a type of squamous cell carcinoma. The tonsil is the most common site of squamous cell carcinoma in the oropharynx. The tumors frequently present at advanced stages, and around 70% of patients present with metastasis to the cervical lymph nodes. . The most reported complaints include sore throat, otalgia or dysphagia. Some patients may complain of feeling the presence of a lump in the throat. Approximately 20% patients present with a node in the neck as the only symptom.

A pre-metastatic niche is an environment in a secondary organ conducive to the metastasis of a primary tumor. Such a niche provides favorable conditions for growth, and eventually metastasis, in an otherwise foreign and hostile environment for the primary tumor cells. The discovery of the pre-metastatic niche has fostered new research regarding the potential treatment of metastases, including attempts to stop the flow of vesicles from primary tumors to pre-metastatic niches in secondary organs and different combinations of previously-employed therapies.

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Classification
D
External resources

Medical information about metastatic cancer