Cancer of unknown primary origin

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Clinical oncology for students > Cancer of unknown primary origin


In Australia, cancer of unknown primary origin (CUP) is the eighth most commonly diagnosed cancer (about 3000 per year) and makes up about 5% of all cancers diagnosed. Of all cancer deaths, CUP causes about 5% and is the fifth most common cause (AIWH). The median survival rate is about 6 months and the 5-year survival rate is about 16%. These figures are gradually changing. Each year, the incidence drops by about 2%, presumably reflecting better diagnostic methods, particularly the PET/CT scan which can identify a primary site in about 40% of patients in whom it would otherwise be unknown.[1] The risk of death also drops about 2% per year, probably due to better treatment. The incidence and mortality in Indigenous populations are both almost double that of the remainder of the population, possibly indicating delayed diagnosis and a lack of access to treatment. The incidence and mortality are both about 1.4 times higher in remote areas than in the cities.

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Risk factors

As the diagnosis of CUP requires exclusion of other known primary cancers and indicates many potential types of underlying primary cancer, risk factors have not been identified, except that the risk of CUP increases with age.

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Clinical presentation

By definition, CUP requires the presence of metastatic disease as indicated by a histologically confirmed type of cancer occurring in an organ or part of the body which would not normally generate that type of primary tumour. For example, if a cancer that usually arises in epithelial tissues, such as an adenocarcinoma, was found in a lymph node, it is likely to have spread there from some other organ. Many cancer patients present with metastatic disease anyway, but the term CUP is only for those in which a credible primary cancer cannot be found. There are favourable and unfavourable patterns of presentation.[2] The favourable presentation occurs in about 20% of patients and shows a pattern whereby a minimal amount of metastatic cancer in a particular location suggests a particular primary tumour may be present, but the likely primary tumour cannot be found despite investigations relevant to that location.

Sometimes a primary site is identified at autopsy and of these, the most common primary sites are lung, oropharynx and pancreas. However, most patients dying with metastatic cancer are not subjected to autopsy, as it would only be of academic interest. Patients with an unfavourable pattern are those with more widespread disease at presentation and are similar in presentation to those patients with metastatic disease of any of the known primary tumours. For example, the patients may have widespread painful bony metastases or constitutional symptoms and signs such as loss of appetite, generalised weakness and cachexia.

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Diagnosis and staging

As there are different types of CUP, a biopsy is required to determine the best treatment. Microscopy should be able to determine whether cancer is present and which broad type it is (most are carcinomas, but a few are sarcomas, melanomas, etc) and then identify which subtype (most are adenocarcinomas, but there are a few squamous cell cancers, neuroendocrine cancers, etc). These can lead to avenues of further investigation, e.g. a serous papillary carcinoma with a metastasis in the peritoneum in a female would suggest assessment of the ovaries could be worthwhile. Immunohistochemical staining may indicate a primary origin, as well as indicating potentially useful treatments, e.g. PSA or ER staining may indicate a role for hormone treatment, even if a primary tumour cannot be identified. Gene expression profiling of biopsy tissue may identify patterns of gene expression more in keeping with one type of primary cancer or another, e.g. colorectal cancer.

The extent of staging required is controversial and requires individual judgement. In patients showing a favourable pattern of presentation, potential primary sites can sometimes be deduced, e.g. adenocarcinoma in an axillary node in a female may be breast cancer and would lead to detailed breast imaging, including MRI scans where available. An SCC in a level II neck node may be an indication of a primary tumour in the upper aerodigestive tract and would lead to an endoscopic ENT assessment. PET/CT might identify more widespread disease in 10-20% of patients. If a primary tumour is still not identified, it may be possible to apply a curative style of treatment to a presumptive primary site in the absence of demonstrable tumour and obtain results similar to those with a primary cancer limited to regional nodes.

Raised tumour markers can sometimes indicate suitable treatment -- for example a raised serum PSA level is likely to respond to hormonal therapy suitable for metastatic prostate cancer. A raised CEA or CA19.9 serum tumour marker level may point towards a gastrointestinal primary and upper and lower endoscopies may be warranted to detect the primary. Elevated AFP and BHCG are suspicious of germ cell malignancy which may be potentially curable despite being disseminated.

Patients with the unfavourable pattern of presentation tend to have more advanced disease at diagnosis. If the disease is advanced, all of the information needed to select a suitable systemic treatment may be obtainable from the biopsy of a metastatic lesion. The further pursuit of a primary site by imaging, endoscopy or other procedures may be of little value as it may have no bearing on the chosen treatment and could delay effective palliative measures.

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Patients in the favourable subgroup have limited disease that fits into standard patterns and tend to have a better prognosis.[3] Each of these specific patterns has its own outlook and prognostic factors. However, most patients with CUP are in the unfavourable subgroup. The majority of these are poorly differentiated adenocarcinomas and have a poor prognosis, with the median survival 8-12 months. Prognostic factors include age, performance status, number of affected organs (particularly liver or adrenal glands) and elevated serum markers including ALP, albumin and LDH.[4] Prognostic scoring systems have been proposed to help guide treatment decisions but none have proven reliable enough to be clinically useful.

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Principles of management

Since CUP is a group of heterogeneous conditions, it would be inappropriate to consider one treatment suitable for all of them. Patients with limited disease may be suitable for resection and regional radiotherapy, while those with disseminated disease would be more suited to systemic treatment. Although institutional reports have indicated that survival rates improved when platinum chemotherapy was introduced, a meta-analysis of chemotherapy treatment has shown that there is no type of chemotherapy which is clearly better than any other, nor that any type is better than supportive care alone.[5] Molecular profiling may identify subsets that respond better to systemic treatments (see Table 1). Brief guidelines for treatment have been published.[6]

Table 1. Favorable Subsets Identified by Clinical and Pathologic Features (Reproduced with permission)[7]

Histology Clinical Subset Therapy Prognosis
Adenocarcinoma Women, axillary node involvement
Women, peritoneal carcinomatosis
Men, blastic bone metastases or high serum PSA/tumor PSA staining
Single metastasis

Colon cancer profile (IHC and/or molecular assay)
Treat as primary breast cancer
Treat as stage III ovarian cancer
Treat as metastatic prostate cancer

Surgical resection and/or radiotherapy ± chemotherapy
Treat as metastatic colon cancer
Survival improved
Survival improved
Survival improved

Survival improved

Survival improved
Squamous Carcinoma Cervical adenopathy
Inguinal adenopathy
Treat as locally advanced head/neck primary
Inguinal node dissection, radiation therapy, ± chemotherapy
25%–30% 5-yr survival
15%–20% 5-yr survival
Poorly Differentiated Carcinoma Extragonadal germ cell syndrome Treat as poor prognosis germ cell tumor 10%–20% cured
Neuroendocrine Carcinoma Aggressive (small cell or large cell, poorly differentiated)

Low grade
Treat as extensive-stage small cell lung cancer

Treat as advanced carcinoid tumor
High response rate/survival improved
Indolent biology/long survival

Abbreviation: PSA, prostate-specific antigen.

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Follow-up and survivorship

Survivorship issues for CUP are similar to those for incurable cancers generally, but also include dealing with issues surrounding the uncertainty of the diagnosis. During the course of follow-up, there may be new opportunities to further characterise the disease, for example if a more suitable lesion for biopsy becomes apparent then it may be possible to identify either a primary site or more suitable forms of treatment. An Australian CUP action group exists to provide support for patients.[8]

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Screening and prevention

There are no screening tests or prevention measures known for CUP.

Further reading

  1. Australian Institute of Health and Welfare. Cancer in Australia: In brief 2012. Canberra: AIHW; 2012 [cited 2014 May 29]. Report No.: Cancer series no. 72. Cat. no. CAN 69. Available from:
  2. Australian Institute of Health and Welfare. Cancer in Australia: An overview 2012. Canberra: AIHW; 2012 [cited 2014 May 29]. Report No.: Cancer series no. 74. Cat. no. CAN 70. Available from:
  3. Riihimäki M, Thomsen H, Hemminki A, Sundquist K, Hemminki K. Comparison of survival of patients with metastases from known versus unknown primaries: survival in metastatic cancer BMC Cancer 2013 Jan 28;13:36. Abstract available at:

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  1. Kwee TC, Basu S, Cheng G, Alavi A. FDG PET/CT in carcinoma of unknown primary. Eur J Nucl Med Mol Imaging 2009 Oct 31 [cited 2014 May 29];37(3):635–644 Available from:
  2. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet 2012 Apr 14;379(9824):1428-35 Available from:
  3. Greco FA, Oien K, Erlander M, Osborne R, Varadhachary G, Bridgewater J, et al. Cancer of unknown primary: progress in the search for improved and rapid diagnosis leading toward superior patient outcomes. Ann Oncol 2012 Feb;23(2):298-304 Available from:
  4. Ferté C, Penel N, Bonneterre J, Adenis A. Individual life expectancy estimation using validated prognostic scores for patients with cancer of unknown primary. Oncology 2010;78(2):87-93 Available from:
  5. Golfinopoulos V, Pentheroudakis G, Salanti G, Nearchou AD, Ioannidis JP, Pavlidis N. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: multiple-treatments meta-analysis. Cancer Treat Rev 2009 Nov;35(7):570-3 Available from:
  6. Fizazi K, Greco FA, Pavlidis N, Pentheroudakis G, ESMO Guidelines Working Group. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011 Sep;22 Suppl 6:vi64-8 Available from:
  7. Greco FA. Cancer of unknown primary site: improved patient management with molecular and immunohistochemical diagnosis. Am Soc Clin Oncol Educ Book 2013;:175-81 Available from:
  8. CUP Action. Cancer of unknown primary action. [homepage on the internet] Australia: Cancer of Unknown Primary Inc; 2014 [cited 2014 May 29; updated 2014 May 29]. Available from:

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