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'{{dablink|For the musical composition, see [[Metastasis (Xenakis composition)]].}} {{Infobox Disease | Name = Metastasis | Image =| Caption = CT scan with metastatic tumour in lung (upper left lobe, seen on the right side of picture) | DiseasesDB = 28954 | ICD10 = | ICD9 = | ICDO = | OMIM = | MedlinePlus = 002260 | eMedicineSubj = | eMedicineTopic = | MeshID = | }} [[Image:Secondary tumor deposits in the liver from a primary cancer of the pancreas.jpg|thumb|200px|right|Cut surface of a [[liver]] showing multiple metastatic nodules originating from [[pancreatic cancer]]]] [[Image:Bone metastasis.jpg|thumb|200px|right|Cut surface of a [[humerus]] sawn lengthwise, showing a large [[cancer]]ous '''metastasis''' (the whitish tumor between the head and the shaft of the bone)]] '''Metastasis''' ([[Greek (language)|Greek]]: ''displacement, μετά=next + στάσις=placement'', plural: ''metastases''), or '''metastatic disease''', sometimes abbreviated '''mets''', is the spread of a [[disease]] from one [[Organ (anatomy)|organ]] or part to another non-adjacent organ or part. Only [[cancer|malignant]] [[tumor cell]]s and [[infection]]s have the established capacity to '''metastasize'''; however, this is recently reconsidered by new research.<ref>{{cite journal | author = Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H | title = Seeding and propagation of untransformed mouse mammary cells in the lung | journal = Science (New York, N.Y.) | volume = 321 | issue = 5897 | pages = 1841–4 | year = 2008 | month = September | pmid = 18755941 | pmc = 2694414 | doi = 10.1126/science.1161621 | accessdate = 2009-06-20 }}</ref><ref>{{cite journal | author = Klein CA | title = Cancer. The metastasis cascade | journal = Science (New York, N.Y.) | volume = 321 | issue = 5897 | pages = 1785–7 | year = 2008 | month = September | pmid = 18818347 | doi = 10.1126/science.1164853 | accessdate = 2009-06-20 }}</ref><ref>{{cite journal | author = Chiang AC, Massagué J | title = Molecular basis of metastasis | journal = The New England Journal of Medicine | volume = 359 | issue = 26 | pages = 2814–23 | year = 2008 | month = December | pmid = 19109576 | doi = 10.1056/NEJMra0805239 | accessdate = 2009-06-20 }}</ref> [[Cancer cell]]s can break away, leak, or spill from a [[primary tumor]], enter [[lymphatic vessel|lymphatic]] and [[blood vessel]]s, circulate through the [[bloodstream]], and be deposited within normal [[Tissue (biology)|tissue]] elsewhere in the body. Metastasis is one of three hallmarks of [[cancer|malignancy]] (contrast [[benign tumor]]s).<ref name="Robbins">{{cite book |last1=Kumar |first1=Vinay |last2=Abbas |first2=Abul K |last3=Fausto |first3=Nelson |last4=Robbins |first4=Stanley L |last5=Cotran |first5=Ramzi S |title=Robbins and Cotran pathologic basis of disease |edition=7th |year=2005 |publisher=Elsevier Saunders |location=Philadelphia |isbn=978-0-7216-0187-8 }} </ref> Most [[tumor]]s and other [[neoplasia|neoplasms]] can metastasize, although in varying degrees (e.g., [[glioma]] and [[basal cell carcinoma]] rarely metastasize).<ref name="Robbins"/> 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''. == Modes and sites of metastatic dispersal == Metastatic tumors 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 [[lung]]s, [[liver]], [[brain]], and the [[bone]]s.<ref>{{Cite web|url=http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic|title=Metastatic Cancer: Questions and Answers|accessdate=2008-08-28|publisher=National Cancer Institute}}</ref> There is also a propensity for certain tumors to seed in particular organs. This was first discussed as the "seed and soil" theory by [[Stephen Paget]] 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 metastasizes to the [[ovary]] in women, then it is called a [[Krukenberg tumor]]. 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. {{Fact|date=November 2008}} In 1928 [[James Ewing]] challenged the "seed and soil" theory and proposed that metastasis occurs purely by anatomic and mechanical routes. [[Image:Lymph node with papillary thyroid carcinoma.jpg|thumb|200px|right|[[Micrograph]] of thyroid cancer ([[papillary thyroid carcinoma]]) in a [[lymph node]] of the neck. [[H&E stain]]]] 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]].<ref>Robert Weinberg, The Biology of Cancer, cited in [http://www.nytimes.com/2007/04/03/health/03angi.html Basics: A mutinous group of cells on a greedy, destructive task,] by Natalie Angier, New York Times, April 3, 2007</ref> 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. <ref name="Robbins"/> In addition to the above routes, metastasis may occur by direct seeding, called transcoelomic spread. This is generally only seen in the [[peritoneal cavity|peritoneal]] or [[pleural cavity|pleural cavities]] by [[ovarian cancer|ovarian tumours]] and [[mesothelioma]]s respectively.<ref name="transcoelomic">{{cite journal |last=Bacac|first=M|coauthors=Stamenkovic, I |title=Metastatic cancer cell |journal=Annual Review of Pathology |date=February 2008|accessdate=June 2009|doi=10.1146/annurev.pathmechdis.3.121806.151523}}</ref> == 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 [[protein]]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.<ref>{{cite journal |author=Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW |title=Metastasis-suppressor genes: a review and perspective on an emerging field |journal=J Natl Cancer Inst. |volume=92 |issue=21 |pages=1717–30 |year=2000 |month=Nov |pmid=11058615 |doi= 10.1093/jnci/92.21.1717|url=http://jnci.oxfordjournals.org/cgi/content/full/92/21/1717}}</ref> 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]].<ref>{{cite journal |author=Weidner N, Semple JP, Welch WR, Folkman J |title=Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma |journal=N Engl J Med. |volume=324 |issue=1 |pages=1–8 |year=1991 |month=Jan |pmid=1701519 |doi= |url=http://content.nejm.org/cgi/content/abstract/324/1/1}}</ref> It has been found that [[angiogenesis inhibitor]]s would therefore prevent the growth of metastases. <ref name = "Robbins"/> == 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 unit]]s 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.<ref name="CUP-Oncologist">{{cite journal |author=Briasoulis E, Pavlidis N |title=Cancer of Unknown Primary Origin |journal=Oncologist |volume=2 |issue=3 |pages=142–152 |year=1997 |pmid=10388044 |doi= |url=http://theoncologist.alphamedpress.org/cgi/pmidlookup?view=long&pmid=10388044}}</ref> Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably [[lung cancer|lung]]", urinating blood—"probably [[bladder cancer|bladder]]"), complex imaging will not either.<ref name="CUP-Oncologist"/> 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. == Common sites of origin == {{Unreferenced section|date=September 2007}} * [[Lung cancer|Lung]] * [[Breast cancer|Breast]] * Skin: [[Melanoma]] (other skin tumors rarely metastasize) * [[Colon cancer|Colon]] * [[Renal cell carcinoma|Kidney]] * [[prostate cancer|Prostate]] * [[Pancreatic cancer|Pancreas]] * [[Cervical cancer|Cervical]] == Symptoms == [[Image:Symptoms of cancer metastasis.png|thumb|right|200px|Symptoms of cancer metastasis depend location of the tumor.]] The symptoms of metastasis varies with location of the tumors. Initially, nearby lymph nodes are struck early.<ref name=nci/> Lungs, bones, liver, and brain are the most common metastasis locations from solid tumors.<ref name=nci/> *In [[lymph nodes]], a common symptom is [[lymphadenopathy]] *Lungs: [[cough]], [[hemoptysis]] and [[dyspnea]]<ref name=nci/> (shortness of breath) *Liver: [[hepatomegaly]] (enlarged [[liver]])<ref name=nci/> and [[jaundice]]<ref name=nci/> *Bones: bone pain<ref name=nci>[http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic National Cancer Institute: Metastatic Cancer: Questions and Answers]. Retrieved on 2008-11-01</ref>, [[fracture]] of affected bones<ref name=nci/> *Brain: [[neurology|neurological]] symptoms such as headaches<ref name=nci/>, seizures<ref name=nci/>, and [[Vertigo (medical)|vertigo]]<ref name=nci/>. Although advanced cancer may cause [[pain]], it is often not the first symptom. Some patients, however, don't show any symptoms.<ref name=nci/> == Diagnosis of primary and secondary tumors == [[Image:MultipleLiverMets2008.jpg|thumb|200px|CT image of multiple liver metastases]] [[Image:LungMets2008.jpg|thumb|200px|CT image of a lung metastasis]] [[Image:Adenocarcinoma liver metastasis.jpg|thumb|200px|Metastasis proven by [[liver]] [[biopsy]] (tumor ([[adenocarcinoma]]) - lower two-thirds of image). [[H&E stain]].]] 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.<ref>{{cite journal | author = Poste G, Fidler IJ | title = The pathogenesis of cancer metastasis | journal = Nature | volume = 283 | issue = 5743 | pages = 139–46 | year = 1980 | month = January | pmid = 6985715 | doi = 10.1038/283139a0 | accessdate = 2009-06-20 }}</ref> 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.<ref name=signature>{{cite journal | author = Ramaswamy S, Ross KN, Lander ES, Golub TR | title = A molecular signature of metastasis in primary solid tumors | journal = Nature Genetics | volume = 33 | issue = 1 | pages = 49–54 | year = 2003 | month = January | pmid = 12469122 | doi = 10.1038/ng1060 | accessdate = 2009-06-20 }}</ref> 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.<ref name=signature /> 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."<ref name=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.<ref>{{cite journal | author = van 't Veer LJ, Dai H, van de Vijver MJ, ''et al.'' | title = Gene expression profiling predicts clinical outcome of breast cancer | journal = Nature | volume = 415 | issue = 6871 | pages = 530–6 | year = 2002 | month = January | pmid = 11823860 | doi = 10.1038/415530a | accessdate = 2009-06-20 }}</ref> 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.<ref name=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.<ref name=signature /> The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential with 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.<ref name=signature /> == Treatments for metastatic cancer == 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., [[leukemia]], 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 [[Cancer of unknown primary origin|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. == See also == {{Wiktionary}} *[[Disseminated disease]] *[[Brown-Sequard Syndrome]] (Sections on Cavernous malformation, Germinoma, Renal cell carcnomia and Lung Cancer) == References == {{reflist}} == External links == '''Medical information about metastatic cancer''' *[http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic Q&A: Metastatic Cancer] – from the [[National Cancer Institute]] *[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cmed.chapter.2030 Invasion and Metastases] – from ''Cancer Medicine'' e.5 *[http://www.childrenshospital.org/research/Site2029/mainpageS2029P23sublevel45.html How Cancer Grows and Spreads] – an interactive Flash presentation that explores the progression of a carcinoma from a single cell to metastasis; from the research department of [[Children's Hospital Boston]] '''Charities and advocacy groups dealing with metastatic cancer''' *[http://www.metacancer.org The MetaCancer Foundation] – resources and support for metastatic cancer survivors and their caregivers *[http://www.mbcnetwork.org Metastatic Breast Cancer Network] *[http://www.kidcancer.org Children's Cancer Research Charity for Metastatic Cancer in Kids] '''Not specifically about metastatic cancer''' *[http://cancerguide.org/basic.html Understanding Cancer Types and Staging] – a patients' guide at the ''CancerGuide'' website *[http://www.cancerforums.net Cancer Forums] – physicians answering questions about cancer *[http://cels-at-home-dev.dyndns.org/cels/ Cels@Home] – [[distributed computing]] project that is primarily concerned with cell adhesion. '''Research''' *[http://www.logikbase.com/website/techprofile.cfm?licid=2395 A Novel target for regulating lymphangiogenesis and lymph-node metastasis] {{Tumors}} [[Category:Oncology]] [[ar:نقيلة]] [[bg:Метастаза]] [[ca:Metàstasi]] [[cs:Metastáza]] [[da:Metastase]] [[de:Metastase]] [[es:Metástasis]] [[eu:Metastasi]] [[fa:متاستاز]] [[fr:Métastase (médecine)]] [[hr:Metastaze]] [[id:Metastasis]] [[it:Metastasi]] [[he:גרורה]] [[la:Metastasis]] [[lt:Metastazė]] [[hu:Áttét]] [[ms:Metastasis]] [[nl:Uitzaaiing]] [[ja:転移 (医学)]] [[no:Metastase]] [[pl:Przerzuty nowotworowe]] [[pt:Metástase]] [[ru:Метастаз]] [[simple:Metastasis]] [[sk:Metastáza]] [[fi:Etäpesäke]] [[sv:Metastas]] [[tr:Metastaz]] [[uk:Метастаз]] [[zh:遠端轉移]]'