We searched Medline with the search terms “cancer”, “carcinoma”, or “adenocarcinoma”, in combination with “unknown primary” or “unknown origin”. We mostly selected publications from between 1981 and January, 2011, but did not exclude commonly referenced and highly regarded older reports. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Review articles and book chapters are cited to provide readers with more details and
SeminarCancer of unknown primary site
Introduction
Patients diagnosed with cancer of unknown primary site (CUP) present with histologically confirmed metastatic cancer for which clinicians are unable to identify a primary tumour after a standard diagnostic approach (panel 1).1
CUP accounts for 3–5% of all human cancers, is reported to be the seventh to eighth most frequent malignant tumour, and is the fourth most common cause of cancer death in both sexes. The overall age-standardised incidence per 100 000 people per year is 7–12 cases in the USA, 18–19 in Australia, 5–7 in the Netherlands, and 4–6 in Switzerland.1 Median age at presentation is 65–90 years.2 The disorder is slightly more common in men than in women, and predominantly affects adults (less than 1% of patients with diagnosed solid CUP are children).2
Section snippets
Pathophysiology
Some investigators believe that biologically distinct CUP cases exist. Such cases are thought to have a peculiar and poorly understood biology and a metastasis-causing genetic signature independent of that of the primary tumour.1, 3 Here we review the evidence for the existence of such a distinct biology.
Hedley and colleagues4 reported that 106 (70%) of 152 patients with CUP had aneuploid tumour cells. Additionally, several investigators have used immunohistochemistry to study the oncogenes MYC
Clinical features and clinicopathological subsets
Whether the clinical course of CUP—especially for patients with untreatable subsets—differs substantially from that of known primary tumours is unclear. CUP has several fundamental characteristics: short history with symptoms and signs associated with metastatic sites, early dissemination in the absence of primary tumour, aggressive clinical course, and occasionally an unpredictable metastatic pattern (frequency and location of metastases different from those of known primary tumours).
Histopathology
Three rules are of paramount importance to the diagnosis of CUP. First, the pathologist should receive an adequate tumour tissue or properly processed cytological samples. Second, a stepwise algorithm with immunohistochemical staining should be applied to provide a final diagnosis. Third, close contact with the clinical oncologist to retrieve necessary clinical and laboratory information is pivotal. The immunochemistry of a CUP biopsy should establish three things: whether the cancer is
Favourable subsets
For the past 50 years, chemotherapy has been the basis of CUP treatment. Generally, treatment recommendations are based mainly on type 3 evidence, and therapeutic modalities are thought to be suitable for individual clinical or investigational use.
Women with serous papillary adenocarcinoma of the peritoneal cavity should be managed similarly to patients with stage III and IV ovarian cancer. Best possible treatment includes maximum surgical cytoreduction followed by chemotherapy with a
Future prospects and research needs
CUP is a heterogeneous group of metastatic cancers with a distinct biology. However, although our inability to identify a primary tumour is because of clinical or technological inefficiencies in a substantial proportion of patients, sometimes the primary tumour will regress or stay dormant and the malignant clone will metastasise early to several secondary sites. For this subgroup of genuine CUP, research should be focused on the multigene prometastatic signature of these tumours, which might
Search strategy and selection criteria
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