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__NOTOC__
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{{SI}}                                                                 
{{CMG}} {{AE}} {{RAK}}{{MV}}
{{SK}} Occult cancer; CUP; Metastases of unknown primary origin; Unknown primary origin neoplasm; Cancers of unknown primary site; Neoplasms of unknown primary site;  Carcinoma of unknown primary; Cancer of unknown origin; Unknown primary tumors; UPT
==Overview==
'''Cancer of unknown primary origin''' or CUP is the diagnosis of metastatic cancer when the anatomic site of origin remains unidentified. Cancer of unknown primary origin is common, and it accounts for 2–5% of all cancers. Cancer of unknown primary origin may be classified according to pathology findings into 5 groups: well and moderately differentiated adenocarcinomas, poorly differentiated carcinomas, squamous cell carcinomas, undifferentiated neoplasms, and carcinomas with neuroendocrine differentiation. The majority of patients with cancer of unknown primary origin may be initially asymptomatic. Early clinical features include [[fatigue]], [[weight-loss]], and [[loss of appetite]].<ref name="wiki">Wikipedia.  https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin Accessed on April 4, 2016 </ref> If left untreated, the majority of patients with cancer of unknown primary origin may progress to develop multiple organ failure, heart failure, and death. Common complications of cancer of unknown primary origin, may include: [[hypercalcemia]], [[adrenal insufficiency]], [[Syndrome of inappropriate antidiuretic hormone|inappropriate antidiuretic syndrome]], [[Hematological malignancy|hematologic disorders]], and [[Pleural effusion|malignant effusions]].<ref name="pmid10697020">{{cite journal |vauthors=Nelson KA, Walsh D, Abdullah O, McDonnell F, Homsi J, Komurcu S, LeGrand SB, Zhukovsky DS |title=Common complications of advanced cancer |journal=Semin. Oncol. |volume=27 |issue=1 |pages=34–44 |year=2000 |pmid=10697020 |doi= |url=}}</ref> The treatment for cancer of unknown primary origin will depend on several factors, such as: metastatic origin, biopsy findings, patients age, and performance status.<ref name="wiki">Wikipedia.  https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin Accessed on April 4, 2016 </ref> The 5-year survival of patients with cancer of unknown primary origin is of less than 2%.
==Historical Perspective==
*Cancer of unknown primary origin was first described in 1980.
*From 1980 to 1990,  the definition of unknown primary cancer was based on imaging results.<ref name="pmid25140961">{{cite journal| author=Varadhachary GR, Raber MN| title=Cancer of unknown primary site. | journal=N Engl J Med | year= 2014 | volume= 371 | issue= 8 | pages= 757-65 | pmid=25140961 | doi=10.1056/NEJMra1303917 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25140961  }} </ref>
==Classification==
*Cancer of unknown primary origin may be classified into 4 groups initially according to light microscopy of the biopsy:<ref name="pmid19262901">{{cite journal |vauthors=Varadhachary GR |title=Carcinoma of unknown primary origin |journal=Gastrointest Cancer Res |volume=1 |issue=6 |pages=229–35 |year=2007 |pmid=19262901 |pmc=2631214 |doi= |url=}}</ref>
:*Adenocarcinomas
:*Squamous cell carcinomas
:*Poorly differentiated tumors
:*Carcinomas with neuroendocrine differentiation
==Pathophysiology==
*The exact pathogenesis of cancer of unknown primary origin is not fully understood.
*Cancer of unknown primary, like other cancers, arises from one cell that has managed to escape regulation and produces a tumor at a certain site (the site of origin) and consequently metastasizes to other parts of the body.
*It is thought that the site of origin of CUP remains unknown due to one of the following theories:<ref name="pmid19262901" />
**Remaining small and undetectable clinically
**Disappearing after metastasizing
**Elimination by body's defense
* It remains unknown whether cancers of unknown primaries are genetically or phenotypically distinct from metastasis with known origins.<ref name="pmid19262901">{{cite journal |vauthors=Varadhachary GR |title=Carcinoma of unknown primary origin |journal=Gastrointest Cancer Res |volume=1 |issue=6 |pages=229–35 |year=2007 |pmid=19262901 |pmc=2631214 |doi= |url=}}</ref>
==Causes==
*The cause of CUP has not been identified.
*Several studies have evaluated the chromosomal and molecular anomalies found in cancers of unknown primary; however, they could not identify unique causes of metastasis of unknown primaries relative to those with known primary origins.
*Overexpression of several genes has been noted in patients with cancer of unknown primary including Ras, p53, Bcl-2, and Her-2.<ref name="pmid10653878">{{cite journal| author=Hainsworth JD, Lennington WJ, Greco FA| title=Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. | journal=J Clin Oncol | year= 2000 | volume= 18 | issue= 3 | pages= 632-5 | pmid=10653878 | doi=10.1200/JCO.2000.18.3.632 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10653878  }} </ref><ref name="pmid9677443">{{cite journal| author=Briasoulis E, Tsokos M, Fountzilas G, Bafaloukos D, Kosmidis P, Samantas E et al.| title=Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: biological and clinical implications. A Hellenic Co-operative Oncology Group study. | journal=Anticancer Res | year= 1998 | volume= 18 | issue= 3B | pages= 1907-14 | pmid=9677443 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9677443  }} </ref>
==Differentiating Cancer of Unknown Primary Origin from Other Diseases==
*Cancer of unknown primary is a diagnosis of exclusion; hence, all other differentials in addition to primary tumor location must be ruled out prior to diagnosis.
*Cancer of unknown primary origin must be differentiated from other diseases that cause sudden weight-loss, fatigue, and loss of appetite, such as:<ref name="pmid19262901">{{cite journal |vauthors=Varadhachary GR |title=Carcinoma of unknown primary origin |journal=Gastrointest Cancer Res |volume=1 |issue=6 |pages=229–35 |year=2007 |pmid=19262901 |pmc=2631214 |doi= |url=}}</ref>
:*[[Incidentaloma]]
:*[[Anemia]]
:*[[Tuberculosis]]
:*[[Multiple myeloma]]


==Epidemiology and Demographics==
{{Cancer of unknown primary origin}}                                                                  
* The prevalence of cancer of unknown primary origin is approximately 10 cases per 100,000 individuals worldwide.<ref name="pmid23860528">{{cite journal |vauthors=Urban D, Rao A, Bressel M, Lawrence YR, Mileshkin L |title=Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities |journal=Br. J. Cancer |volume=109 |issue=5 |pages=1318–24 |year=2013 |pmid=23860528 |pmc=3778275 |doi=10.1038/bjc.2013.386 |url=}}</ref><ref name="lonco">Fong T, Govindan R, Morgensztern D. Cancer of unknown primary. J Clin Oncol 2008 ASCO Ann Meet Proc. 2008;26 (15S:22159.</ref>
{{CMG}}; {{AE}} {{RAK}}, {{MV}}
* Cancer of unknown primary origin is common, and it accounts for 3–5% of all malignant epithelial tumors.<ref name="pmid22414598">{{cite journal| author=Pavlidis N, Pentheroudakis G| title=Cancer of unknown primary site. | journal=Lancet | year= 2012 | volume= 379 | issue= 9824 | pages= 1428-35 | pmid=22414598 | doi=10.1016/S0140-6736(11)61178-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22414598 }} </ref>
* Cancer of unknown primary origin is the fourth most common cause of cancer-related death.<ref name="pmid23860528">{{cite journal |vauthors=Urban D, Rao A, Bressel M, Lawrence YR, Mileshkin L |title=Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities |journal=Br. J. Cancer |volume=109 |issue=5 |pages=1318–24 |year=2013 |pmid=23860528 |pmc=3778275 |doi=10.1038/bjc.2013.386 |url=}}</ref>
   
   
===Age===
{{SK}} Occult cancer; CUP; Metastases of unknown primary origin; Unknown primary origin neoplasm; Cancers of unknown primary site; Neoplasms of unknown primary site; Carcinoma of unknown primary; Cancer of unknown origin; Cancer of unknown primary; Unknown primary tumors; UPT; Metastatic malignant neoplasms
*Patients of all age groups may develop cancer of unknown primary origin.
*Cancer of unknown primary origin is more commonly observed among adults and elderly patients with a mean age of 59 upon presentation.<ref name="pmid8201389">{{cite journal| author=Abbruzzese JL, Abbruzzese MC, Hess KR, Raber MN, Lenzi R, Frost P| title=Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. | journal=J Clin Oncol | year= 1994 | volume= 12 | issue= 6 | pages= 1272-80 | pmid=8201389 | doi=10.1200/JCO.1994.12.6.1272 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8201389 }} </ref>
 
===Gender===
*Cancer of unknown primary origin affects men and women equally except for squamous cell carcinomas where males are affected twice as frequently as females.<ref name="pmid8001006">{{cite journal| author=Muir C| title=Cancer of unknown primary site. | journal=Cancer | year= 1995 | volume= 75 | issue= 1 Suppl | pages= 353-6 | pmid=8001006 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8001006  }} </ref>


===Race===
==[[Cancer of unknown primary origin overview|Overview]]==
*There is no racial predilection to cancer of unknown primary origin.


==Risk Factors==
==[[Cancer of unknown primary origin historical perspective|Historical Perspective]]==
*There are no established risk factors for cancer of unknown primary origin.
== Natural History, Complications and Prognosis==
*Early clinical features include fatigue, weight-loss, and loss of appetite.
*Cancers of unknown primary origin are characterized by their aggressiveness, early dissemination, and unpredictable metastasis.
*Upon presentation, around 60% of patients with cancer of unknown primary have two or more affected sites.<ref name="pmid8201389" />
*The most common sites of metastasis in cancer of unknown origin are lymph nodes, lungs, liver, bones, and pleura.
*If left untreated, the majority of patients with cancer of unknown primary origin may progress to develop multiple organ failure, heart failure, and death.
*Common complications of cancer of unknown primary origin, may include: hypercalcemia, adrenal insufficiency, and inappropriate antidiuretic syndrome, hematologic disorders, and malignant effusions.
*Prognosis is generally poor, and the average survival time of patients with cancer of unknown primary origin is approximately 6-12 months after diagnosis.<ref name="pmid10697020">{{cite journal |vauthors=Nelson KA, Walsh D, Abdullah O, McDonnell F, Homsi J, Komurcu S, LeGrand SB, Zhukovsky DS |title=Common complications of advanced cancer |journal=Semin. Oncol. |volume=27 |issue=1 |pages=34–44 |year=2000 |pmid=10697020 |doi= |url=}}</ref><ref name="pmid3940611">{{cite journal| author=Altman E, Cadman E| title=An analysis of 1539 patients with cancer of unknown primary site. | journal=Cancer | year= 1986 | volume= 57 | issue= 1 | pages= 120-4 | pmid=3940611 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3940611  }} </ref>
*The 1-year survival rate of patients with cancer of unknown primary origin is less than 10%
*The 5-year survival of patients with cancer of unknown primary origin is of less than 2%


== Diagnosis ==
==[[Cancer of unknown primary origin pathophysiology|Pathophysiology]]==
===Diagnostic Criteria===
*The diagnosis of cancer of unknown primary origin is made when the biopsy indicates malignancy and after ruling out known primary origins of tumors.
*On microscopic histopathological analysis findings will depend on tumor histology.<ref name="pmid19262901" />
*The initial approach to exclude known origins of the tumor must include:<ref name="pmid12915904">{{cite journal |vauthors=Bugat R, Bataillard A, Lesimple T, Voigt JJ, Culine S, Lortholary A, Merrouche Y, Ganem G, Kaminsky MC, Negrier S, Perol M, Laforêt C, Bedossa P, Bertrand G, Coindre JM, Fizazi K |title=Summary of the Standards, Options and Recommendations for the management of patients with carcinoma of unknown primary site (2002) |journal=Br. J. Cancer |volume=89 Suppl 1 |issue= |pages=S59–66 |year=2003 |pmid=12915904 |pmc=2753014 |doi=10.1038/sj.bjc.6601085 |url=}}</ref>
**Detailed medical history
**Full physical examination
**Liver and kidney function tests
**Complete blood count
**Chest radiography
**Abdomen and pelvis [[computed tomography]] (CT)
**Mammography in females
**Prostate-specific antigen (PSA) in males


=== Symptoms ===
==[[Cancer of unknown primary origin causes|Causes]]==
*Cancer of unknown primary origin may be asymptomatic.
*Symptoms of cancer of unknown primary origin may include the following:<ref name="pmid19262901">{{cite journal |vauthors=Varadhachary GR |title=Carcinoma of unknown primary origin |journal=Gastrointest Cancer Res |volume=1 |issue=6 |pages=229–35 |year=2007 |pmid=19262901 |pmc=2631214 |doi= |url=}}</ref>
:*[[Fatigue]]
:*[[Pain]]
:*[[Nausea]]
:*[[Vomiting]]
:*[[Diarrhea]]
:*[[Constipation]]
:*[[Insomnia]]


=== Physical Examination ===
==[[Cancer of unknown primary origin differential diagnosis|Differentiating Colorectal cancer from other Diseases]]==
*Patients with cancer of unknown primary origin usually appear cachectic.
*There are no remarkable findings in physical examination of patients with cancer of unknown primary origin.


=== Laboratory Findings ===
==[[Cancer of unknown primary origin epidemiology and demographics|Epidemiology and Demographics]]==
*Laboratory findings associated with cancer of unknown primary origin, may include:
:*Elevated levels of carcinoembryonic antigen
:*Elevated levels cancer antigen 125
:*Elevated levels cancer antigen 19-9
:*Elevated levels cancer antigen 27.29
:*Elevated levels of lactate dehydrogenase


===Imaging Findings===
==[[Cancer of unknown primary origin risk factors|Risk factors]]==
*CT scan is the imaging modality of choice for cancer of unknown primary origin.


=== Other Diagnostic Studies ===
==[[Cancer of unknown primary origin screening|Screening]] ==
*Cancer of unknown primary origin may also be diagnosed using [[Immunohistochemical staining|immunohistochemical testing]], [[FDG-PET]], and  [[Biopsy|biopsy (open and closed)]].<ref name="pmid15888766">{{cite journal |vauthors=Briasoulis E, Tolis C, Bergh J, Pavlidis N |title=ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) |journal=Ann. Oncol. |volume=16 Suppl 1 |issue= |pages=i75–6 |year=2005 |pmid=15888766 |doi=10.1093/annonc/mdi804 |url=}}</ref>


== Treatment ==
==[[Cancer of unknown primary origin natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
=== Medical Therapy ===
*There is no treatment for cancer of unknown primary origin; the mainstay of therapy is supportive care.<ref name="pmid15888766">{{cite journal |vauthors=Briasoulis E, Tolis C, Bergh J, Pavlidis N |title=ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) |journal=Ann. Oncol. |volume=16 Suppl 1 |issue= |pages=i75–6 |year=2005 |pmid=15888766 |doi=10.1093/annonc/mdi804 |url=}}</ref>
*The treatment for cancer of unknown primary origin will depend on several factors, such as: metastatic origin, biopsy findings, patients age, and performance status.<ref name="wiki">Wikipedia.  https://en.wikipedia.org/wiki/Cancer_of_unknown_primary_origin Accessed on April 4, 2016 </ref>
*Medical therapy for cancer of unknown primary origin should be adjusted on an individual basis  and according to well-defined clinicopathologic subsets.<ref name="pmid15888766">{{cite journal |vauthors=Briasoulis E, Tolis C, Bergh J, Pavlidis N |title=ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) |journal=Ann. Oncol. |volume=16 Suppl 1 |issue= |pages=i75–6 |year=2005 |pmid=15888766 |doi=10.1093/annonc/mdi804 |url=}}</ref>
*The table below summarizes different types of medical therapy strategies for cancer of unknown primary origin.


{| class="wikitable"
== Diagnosis ==  
! colspan="2" style="text-align: center;" |''' Treatment for cancer of unknown primary origin'''<br>
[[Cancer of unknown primary origin diagnostic study of choice|Diagnostic study of choice]] | [[Cancer of unknown primary origin history and symptoms|History and Symptoms]] | [[Cancer of unknown primary origin physical examination|Physical Examination]] | [[Cancer of unknown primary origin laboratory findings|Laboratory Findings]] | [[Cancer of unknown primary origin electrocardiogram|Electrocariogram]] | [[Cancer of unknown primary origin x ray|X-Ray Findings]] | [[Cancer of unknown primary origin MRI|MRI Findings]] | [[Cancer of unknown primary origin CT scan|CT Scan Findings]]  | [[Cancer of unknown primary origin echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Cancer of unknown primary origin other imaging findings|Other Imaging Findings]] | [[Cancer of unknown primary origin other diagnostic studies|Other Diagnostic Studies]]
<SMALL> Adapted from the European Society of Medical Oncology<ref name="pmid15888766">{{cite journal |vauthors=Briasoulis E, Tolis C, Bergh J, Pavlidis N |title=ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) |journal=Ann. Oncol. |volume=16 Suppl 1 |issue= |pages=i75–6 |year=2005 |pmid=15888766 |doi=10.1093/annonc/mdi804 |url=}}</ref></SMALL>
|-
| style="text-align:left; font-weight: bold;" | Sub-type
| style="text-align: left; font-weight: bold;" | Proposed treatment
|-
|
Poorly differentiated carcinoma,
predominately nodal disease
|
Platinum based combination
chemotherapy
|-
|
Peritoneal carcinomatosis
in female
|
Platinum based chemotherapy
|-
|
Isolated axillary nodal
metastases in female
|
Identical to breast cancer with similar
nodal involvement
|-
|  
Squamous carcinoma of
cervical lymph nodes
|
Irradiation for N1-N2 disease.<br>
For higher stages induction
chemotherapy with platinum-based
combination is suggested
|-
|
Liver, bone or multiple-site
metastases of adenocarcinoma
|
Low toxicity chemotherapy of
palliative orientation or best
supportive care are acceptable
|}


=== Surgery ===
==Treatment==
[[Cancer of unknown primary origin medical therapy|Medical Therapy]] | [[Cancer of unknown primary origin surgery|Surgery]] | [[Cancer of unknown primary origin primary prevention|Primary prevention]] | [[Cancer of unknown primary origin secondary prevention|Secondary prevention]] | [[Cancer of unknown primary origin follow up|Follow-up]] | [[Cancer of unknown primary origin cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Cancer of unknown primary origin future or investigational therapies|Future or Investigational Therapies]]


* Surgical intervention is not recommended for the management of cancer of unknown primary origin.
==Case Studies==


=== Prevention ===
[[Cancer of unknown primary origin case study one|Case #1]]{{Tumors}}
*There are no primary preventive measures available for cancer of unknown primary origin.<ref name="pmid15888766">{{cite journal |vauthors=Briasoulis E, Tolis C, Bergh J, Pavlidis N |title=ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) |journal=Ann. Oncol. |volume=16 Suppl 1 |issue= |pages=i75–6 |year=2005 |pmid=15888766 |doi=10.1093/annonc/mdi804 |url=}}</ref>
*There is no evidence that follow-up of asymptomatic patients is needed.<ref name="pmid15888766">{{cite journal |vauthors=Briasoulis E, Tolis C, Bergh J, Pavlidis N |title=ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) |journal=Ann. Oncol. |volume=16 Suppl 1 |issue= |pages=i75–6 |year=2005 |pmid=15888766 |doi=10.1093/annonc/mdi804 |url=}}</ref>
 
==References==
{{Reflist|2}}
[[Category: Oncology]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]

Latest revision as of 13:17, 21 October 2019


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2], Maria Fernanda Villarreal, M.D. [3]

Synonyms and keywords: Occult cancer; CUP; Metastases of unknown primary origin; Unknown primary origin neoplasm; Cancers of unknown primary site; Neoplasms of unknown primary site; Carcinoma of unknown primary; Cancer of unknown origin; Cancer of unknown primary; Unknown primary tumors; UPT; Metastatic malignant neoplasms

Overview

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Pathophysiology

Causes

Differentiating Colorectal cancer from other Diseases

Epidemiology and Demographics

Risk factors

Screening

Natural History, Complications and Prognosis

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Diagnostic study of choice | History and Symptoms | Physical Examination | Laboratory Findings | Electrocariogram | X-Ray Findings | MRI Findings | CT Scan Findings | Echocardiography and Ultrasound | Other Imaging Findings | Other Diagnostic Studies

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Case #1Template:Tumors