View source for Cancer of unknown primary origin

{{More medical citations needed|date=July 2015}} 
{{Infobox medical condition (new)
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'''Cancer of unknown primary origin''' ('''CUP''') is a [[cancer]] that is determined to be at the [[metastasis|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 tumor cancer.

CUP is found in about 3 to 5% of all people diagnosed with invasive cancer,<ref name="Stella">{{cite journal|last1=Stella|first1=GM|last2=Senetta|first2=R|last3=Cassenti|first3=A|last4=Ronco|first4=M|last5=Cassoni|first5=P|title=Cancers of unknown primary origin: current perspectives and future therapeutic strategies.|journal=Journal of Translational Medicine|date=24 January 2012|volume=10|pages=12|doi=10.1186/1479-5876-10-12|pmid=22272606|pmc=3315427 |doi-access=free }}</ref> and carries a poor [[prognosis]] in most (80 to 85%) of those circumstances.  The other 15 to 20% of people, however, have localized or small metastatic sites at the time of diagnosis, and is associated with a relatively long survival with appropriate treatment.<ref name="Stella" />

The worldwide incidence of CUP is estimated to be 2-15 cases per 100,000 person years and this incidence is declining as advances are made in diagnostic imaging, molecular markers and other cancer diagnostic tests such that it is easier to find a primary tumor.<ref name="Raghav 2025">{{cite journal |last1=Raghav |first1=Kanwal |title=Cancer of Unknown Primary Site |journal=New England Journal of Medicine |date=29 May 2025 |volume=392 |issue=20 |pages=2035–2047 |doi=10.1056/NEJMcp2402691|pmid=40435465 }}</ref> Risk factors for CUP are similar to other types of cancers and include tobacco use, alcohol misuse, a family history of cancer, and diabetes.<ref name="Raghav 2025"/>

Treatment usually involves empirical chemotherapy (most often with a [[Platinum-based antineoplastic|platinum agent]] with [[paclitaxel]] or [[gemcitabine]]) but clinical data does not support the superiority of one drug or class over others.<ref name="Raghav 2025"/>

==Signs and symptoms==
Most cancers typically present as a single [[primary tumor]].  Over the course of time—particularly if the primary tumor is left untreated—smaller "satellite" tumors will appear at other places in the body, a phenomenon known as [[metastasis]].  Less commonly, a metastatic tumor is found first; but in most such cases, the primary tumor can then be located via examination and testing.  Rarely (3–5% of the time), the primary tumor cannot be found because it is too small, or because it has [[Spontaneous regression|regressed]] due to [[immune system]] activity or other factors. In such situations a diagnosis of cancer of unknown primary origin (CUP) is made.

CUP usually comes to attention because of masses or swellings found somewhere in the body, either by [[physical examination]] or on [[medical imaging]] performed for another indication.{{citation needed|date=August 2014}} The disease typically develops rapidly, and metastases may occur in places in the body that are otherwise unusual.<ref name=Pavlidis2012>{{cite journal |vauthors=Pavlidis N, Pentheroudakis G |title=Cancer of unknown primary site |journal=Lancet |volume=379 |issue=9824 |pages=1428–35 |date=April 2012  |pmid=22414598 |doi=10.1016/S0140-6736(11)61178-1|s2cid=44385281 }}</ref> Comprehensive physical examination is part of the process to identify a possible primary source of cancer; this should include the [[breast]]s, [[lymph node]]s, the [[human skin|skin]], external genitals, as well as an [[Rectal examination|internal examination of the rectum]] and [[Pelvic examination|of the pelvic organs]].<ref name=NICE2010>{{NICE|104|Metastatic malignant disease of unknown primary origin|2010}}</ref>

The location of metastases may be a clue as to the underlying source, even if this cannot be found on investigations. For instance, a woman in whom there is [[axillary lymphadenopathy]] (swelling in the [[Axillary lymph nodes|lymph nodes of the armpit]]) it is likely that the [[breast cancer|cancer originated in the breast]], and men with lymph node deposits in the [[mediastinum]] of the chest and/or [[retroperitoneal space]] of the abdomen may have a [[germ cell tumor]].<ref name=Pavlidis2012/>

==Mechanism==
{{expand section|date=August 2014}}

Cancer of unknown primary source is not a single type of cancer, although researchers have attempted to find a common characteristic that explains why a cancer might spread very early without causing symptoms at the site of origin.<ref name=Pavlidis2012/> It is generally accepted that cancer of unknown primary site exists because the primary tumor is not identified due to clinical or technological inefficiencies, or because the primary tumor regresses or stays dormant after spreading the cancer cells that generate the metastases. This view is widely accepted in oncology; in fact, these cancers are also referred to as occult primary tumors. Because the site of the primary tumor usually dictates the treatment and expected outcome, this view may help create uncertainty and anxiety among health professionals and patients, who may feel that their evaluation has been incomplete.<ref>{{Cite web |title=Cancer of Unknown Primary Origin {{!}} Memorial Sloan Kettering Cancer Center |url=https://www.mskcc.org/cancer-care/types/cancer-unknown-primary-origin |access-date=2024-09-07 |website=www.mskcc.org |language=en}}</ref><ref>{{Cite web |title=Carcinoma of Unknown Primary—Patient Version - NCI |url=https://www.cancer.gov/types/unknown-primary |access-date=2024-09-07 |website=www.cancer.gov |language=en}}</ref>

Because stem cells have a natural ability to migrate and also play a key role in cancer development, it has been proposed that a cancer of unknown primary site may form when deregulated, premalignant or cancerous stem cells migrate away from their natural tissue and give rise to a cancer in the new site before or without generating a tumor in their original tissue.<ref name=LopezLarazo2015>{{cite journal | author=López-Lázaro | title=The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis | journal=Oncoscience | date=1 May 2015| volume=2 | issue=5 | pages=467–75 | pmid=26097879 | pmc=4468332 | doi=10.18632/oncoscience.159}}</ref> Forming a tumor in a tissue is not a prerequisite for stem cells to move away from that tissue. Stem cells can migrate from their natural tissue and initiate a cancer in the new site before generating a detectable tumor in their natural tissue. In this case, the primary tumor could be identified after some time. However, stem cells can also migrate away from their natural tissue without generating a cancer there. In this case, the "primary tumor" would never exist (see [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468332/figure/F1/ Figure]). This can explain why the primary site is not identified even on postmortem examination in many patients with these cancers.<ref name=LopezLarazo2015/> This view of CUP may provide relief to health professionals and patients. After a detailed imaging and pathologic analysis, oncologists can tell their patients with CUP that metastasis does not always involve the formation of a primary tumor, and that their diagnostic evaluation is complete.<ref name=LopezLarazo2015/>

==Diagnosis==
In recent years, microscopic and other diagnostic techniques have improved dramatically. However, the tissue of origin can be still determined only about in one in four cases of CUPs with these methods.<ref name=Varadhachary /> In some cases, the part of the body where cancer cells are first discovered helps the doctor decide which diagnostic tests will be most helpful.  Additional clues which may be helpful in determining the primary site include the pattern of spread, and the cell type, which is based on its appearance under a microscope ([[histology]]).<ref>{{Cite web |title=Tests for a Cancer of Unknown Primary |url=https://www.cancer.org/cancer/types/cancer-unknown-primary/detection-diagnosis-staging/how-diagnosed.html |access-date=2024-09-07 |website=www.cancer.org |language=en}}</ref>

The initial work-up of a cancer of unknown primary includes a [[CT scan]] of the chest, abdomen, and pelvis, with IV contrast.<ref name=Varadhachary />  Women with enlarged lymph nodes ([[lymphadenopathy]]) confined to the [[Axillary lymph nodes|axillary region]] with CUP should have a [[mammogram]] or [[ultrasound]] to evaluate for possible breast cancer.  If those imaging studies are normal, then an [[MRI]] of the breast may be appropriate.<ref name=Varadhachary />  A [[PET-CT scanning|PET CT scan]] should be done for squamous cell carcinoma involving lymph nodes of the neck region.<ref name=Varadhachary />  For other types of cancer of unknown primary, a PET-CT offers uncertain benefit.<ref name=Varadhachary />

The pattern of spread may suggest the location of the primary site.  For example, metastatic cancer found in the upper body is more likely to have an origin above the [[Thoracic diaphragm|diaphragm]], at sites such as the lung and breast. If the metastatic cancer appears first in the lower part of the body, the primary cancer is more likely to be at sites below the diaphragm, such as the pancreas and liver.<ref>{{Cite web |title=Cancer of unknown primary |url=https://www.macmillan.org.uk/cancer-information-and-support/cancer-of-unknown-primary |access-date=2024-09-07 |website=www.macmillan.org.uk |language=en}}</ref>

When the cancer cells are poorly differentiated (that is, they look less evolved than normal cells when viewed under a microscope), the cancer may be either a lymphoma or a [[germ cell tumor]]. Lymphomas begin in the [[lymphatic system]]. Germ cell tumors usually begin in the ovaries and testes. In patients in whom the primary cancer is eventually found, the lung and pancreas are the most common primary cancer sites. CUP also may be traced to the breast, prostate, colon, or rectum as the primary site.{{medical citation needed|date=July 2015}}
[[File:Histopathology of undifferentiated tumor cells.jpg|thumb|Histopathology of a biopsy of a lymph node with cancer of unknown primary origin, showing high-[[Grading (tumors)|grade]] tumor cells which are undifferentiated, that is, the primary tumor cannot be determined by their histologic appearance.]]
Sometimes, however, even when doctors use very sophisticated methods to try to identify the primary site, the part of the body the cancer cells came from cannot be determined. About 2 to 4 percent of all cancer patients have a cancer whose primary site is never found. Identifying the primary tumor site is important because knowing its location and type often helps doctors plan the best treatment. Treatment that is specific to the suspected type of cancer is likely to be more effective. Still, when diagnostic tests have not identified the primary site, doctors must decide whether the potential benefits of more extensive testing outweigh a patient's discomfort, possible complications, and the financial costs.{{medical citation needed|date=July 2015}}

===Immunohistochemical testing ===
[[File:CK7 and CK20 by body location.svg|thumb|300px|[[Immunohistochemistry]] including [[cytokeratin 7]] and [[cytokeratin 20]] can give a clue about possible origins of carcinomas of unknown primary site.<ref>Image by 
Mikael Häggström, MD. More info at [[Commons:File:CK7_and_CK20_by_body_location.svg|image description page in Wikimedia Commons]].</ref>]]
[[Antibodies]] may be used to determine the expression of protein markers on the surface of cancer cells.  Often the expression of these antigens is similar to the tissue that the cancer grew from, so [[immunohistochemical|immunohistochemical testing]] sometimes helps to identify the source of the cancer.  Individual tests often do not provide definitive answers, but sometimes patterns may be observed, suggesting a particular site of origin (e.g. lung, colon, etc.).  Immunohistochemical testing suggests a single source of cancer origin in about one in four cases of CUP.<ref name=Varadhachary />  However, there is a lack of definitive research data showing that treatment guided by information from immunohistochemical testing improves outcomes or long-term prognosis.{{medical citation needed|date=July 2015}}

===Classification===
CUP may be classified by its appearance under a [[light microscope]].  The majority of cancers of unknown primary, about 90%, are [[adenocarcinoma]]s, with 60% appearing as moderately to well-[[Differentiation (cellular)|differentiated]] adenocarcinoma, while about 30% are poorly differentiated adenocarcinoma.  The term ''adenocarcinoma'' refers to cancer that begins in the cells in glandular structures in the lining or covering of certain organs in the body.  Common primary sites for adenocarcinomas include the lung, pancreas, breast, prostate, stomach, liver, and colon.{{medical citation needed|date=July 2015}}

The remaining 10 percent are either poorly or undifferentiated malignant neoplasms (5%), or [[squamous cell carcinoma]]s (5%).<ref name="Varadhachary">{{cite journal|last1=Varadhachary|first1=Gauri R.|last2=Raber|first2=Martin N.|title=Cancer of Unknown Primary Site|journal=New England Journal of Medicine|date=21 August 2014|volume=371|issue=8|pages=757–765|doi=10.1056/NEJMra1303917|pmid=25140961|citeseerx=10.1.1.1019.2799}}</ref> Rarely, CUP may appear as [[neuroendocrine tumor]]s, or [[mixed tumor]]s, such as sarcomatoid, basaloid, or [[adenosquamous carcinoma]]s.{{medical citation needed|date=July 2015}}

==Management==
{{expand section|date=August 2014}}
Because CUP refers to many different cancers, treatment depends on where the cancer is found, the microscopic appearance of the cancer cells, the biochemical characterization of the cells, and the patient's age and overall physical condition. In women, who present with axillary lymph node involvement, treatment is offered along the lines of breast cancer. In patients, who have neck lymph node involvement, then treatment is offered along the lines of head and neck cancer. If inguinal lymph nodes are involved, then treatment may be offered along the lines of genitourinary cancer.{{citation needed|date=November 2014}}

If the site of origin is unknown or undiscovered, then the histology of the tumor (e.g., adenocarcinoma, squamous cell or mesenchymal) can usually be identified, and a probable origin may be assumed.  When this is possible, then treatment is based on the type of cell and probable origin.<ref name=":0">{{cite journal|first1 = David S.|last1 = Ettinger|first2 = Mark|last2 = Agulnik|first3 = Justin M. M.|last3 = Cates|first4 = Mihaela|last4 = Cristea|title = Occult primary|journal = Journal of the National Comprehensive Cancer Network|date = December 2011|issn = 1540-1413|pages = 1358–1395|volume = 9|issue = 12|doi = 10.6004/jnccn.2011.0117|pmid = 22157556|doi-access = free}}</ref> Based on histological subtype, combination chemotherapy may be selected. A combination of [[carboplatin]] and [[paclitaxel]] is often used. Advances techniques such as [[Fluorescence in situ hybridization|FISH]] and [[tissue of origin testing]] may also be employed. Germ cell tumors often carry abnormality of [[Chromosome 12 (human)|chromosome 12]], which if identified, directs treatment for metastatic germ cell tumors.{{medical citation needed|date=July 2015}}

No method is standard for all forms of CUP, but [[chemotherapy]], [[radiation therapy]], [[hormone therapy]], and [[Oncosurgery|surgery]] may be used alone or in combination to treat patients who have CUP. Even when the cancer is unlikely to be cured, treatment may help the patient live longer or improve the patient's quality of life.  Radiation may be used to shrink a variety of local tumors.<ref name=":0" /> However, the potential side effects of the treatment must be considered along with the potential benefits.
In CUP to secondary neck nodes, surgery followed by external beam radiotherapy is sufficient.<ref>{{cite journal |vauthors=Krishnatreya M, Sharma JD, Kataki AC, Kalita M | year = 2014 | title = Survival in carcinoma of unknown primary to neck nodes treated with neck dissection and radiotherapy | journal = Annals of Medical and Health Sciences Research| volume = 4 | issue = Suppl 2| pages = S165–S6 | doi = 10.4103/2141-9248.138050 | pmid = 25184090 | pmc=4145520 | doi-access = free }}</ref>
For CUP with an unfavorable prognosis, treatment with [[taxane]]s may provide a slight survival benefit.<ref>{{Cite journal|title = Evaluation of survival benefits by platinums and taxanes for an unfavourable subset of carcinoma of unknown primary: a systematic review and meta-analysis|journal = British Journal of Cancer|date = Jan 15, 2013|issn = 1532-1827|pmc = 3553519|pmid = 23175147|pages = 39–48|volume = 108|issue = 1|doi = 10.1038/bjc.2012.516|first1 = J.|last1 = Lee|first2 = S.|last2 = Hahn|first3 = D.-W.|last3 = Kim|first4 = J.|last4 = Kim|first5 = S. N.|last5 = Kang|first6 = S. Y.|last6 = Rha|first7 = K. B.|last7 = Lee|first8 = J.-H.|last8 = Kang|first9 = B.-J.|last9 = Park}}</ref> The uncertainties and ambiguity inherent in a CUP diagnosis may cause additional stress for the patient.<ref name=":0" />

==Prognosis==
Most people with cancer of unknown primary origin have widely disseminated and incurable disease, although a few can be cured through treatment.  With treatment, typical survival with CUP ranges from 6 to 16 months.<ref name=Varadhachary />  Survival rates are lower in cases with visceral metastatic disease, ranging from 6 to 9 months.<ref name=Varadhachary />  Survival rates are higher when the cancer is more limited to lymph nodes, pleura, or peritoneal metastasis, which ranges from 14 to 16 months.<ref name=Varadhachary />  Long-term prognosis is somewhat better if a particular source of cancer is strongly suggested by clinical evidence.<ref name=Varadhachary />

== Epidemiology ==
CUP sometimes runs in families.<ref name=":0" />  It has been associated with familial lung, kidney, and colorectal cancers, which suggests that these sites may often be the origin of unidentifiable CUP cancers.<ref name=":0" />

===UK===
Around 9,800 people were diagnosed with cancer of unknown primary in the UK in 2011, and around 10,625 people died from the disease in 2012.<ref>{{cite web|title=Cancer of unknown primary statistics|url=http://www.cancerresearchuk.org/cancer-info/cancerstats/types/cancer-of-unknown-primary/|website=Cancer Research UK|access-date=27 October 2014}}</ref>

== History ==
From 1980 to 1990, definition of unknown primary cancer was based on imaging results.<ref name="Varadhachary" /> Subsequently, research on immunohistochemistry allowed for the classification of cancer of unknown primary into sub-types.  From 2000 to 2010, tailored therapies began to evolve, targeting specific subtypes of unknown primary.<ref name="Varadhachary" />

==Further reading==
*{{Cite journal|title = Carcinoma of Unknown Primary Origin|journal = Gastrointestinal Cancer Research |date = 2007|issn = 1934-7820|pmc = 2631214|pmid = 19262901|pages = 229–235|volume = 1|issue = 6|first = Gauri R.|last = Varadhachary}}
*{{Cite web|title = Rarer cancers with unknown primary tumours diagnosed too late – Press releases – GOV.UK|url = https://www.gov.uk/government/news/rarer-cancers-with-unknown-primary-tumours-diagnosed-too-late|website = www.gov.uk|access-date = 2015-07-06}}

==References==
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== External links ==
{{Medical resources
|  DiseasesDB      = 
|  ICD10           = {{ICD10|C|80|0}}
|  ICD9            = {{ICD9|199.1}}
|  ICDO            = 
|  MedlinePlus     = 
|  MeSH            = D009382
}}
* {{eMedicine|med|1463}}
* [http://www.cancerhelp.org.uk/type/unknown-primary-cancer/ Clinically reviewed information on unknown primary cancer] for patients, from [[Cancer Research UK]]
* [http://www.cupfoundjo.org/ The CUP Foundation – Jo's Friends] – UK-based information and support for patients with CUP.
* [http://www.cancer.net/cancer-types/unknown-primary Cancer.Net: Unknown Primary Cancer]

{{Medicine}}

[[Category:Types of cancer|unknown primary origin]]