Cancer of unknown primary

Epidemiology
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.
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.

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.

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 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. 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.

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.

Prognosis

Patients in the favourable subgroup have limited disease that fits into standard patterns
and tend to have a better prognosis.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. Prognostic scoring systems
have been proposed to help guide treatment decisions but none have proven reliable
enough to be clinically useful.

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. Molecular profiling may
identify subsets that respond better to systemic treatments (see Table 1).

Table 1. Favorable Subsets Identified by Clinical and Pathologic Features

(Reproduced with permission)

Abbreviation: PSA, prostate-specific antigen.

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.

Screening and prevention

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