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Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 35% of all malignant
epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. Diagnostic
approaches to identify the primary site include detailed histopathological examination with specic immunohistochemistry and radiological assessment. Gene-proling microarray diagnosis has high sensitivity, but further
prospective study is necessary to establish whether patients outcomes are improved by its clinical use. Metastatic
adenocarcinoma is the most common CUP histopathology (80%). CUP patients are divided into subsets of favourable
(20%) and unfavourable (80%) prognosis. Favourable subsets are mostly given locoregional treatment or systemic
platinum-based chemotherapy. Responses and survival are similar to those of patients with relevant known primary
tumours. Patients in unfavourable subsets are treated with empirical chemotherapy based on combination regimens
of platinum or taxane, but responses and survival are generally poor.
Introduction
Patients diagnosed with cancer of unknown primary site
(CUP) present with histologically conrmed metastatic
cancer for which clinicians are unable to identify a primary
tumour after a standard diagnostic approach (panel 1).1
CUP accounts for 35% 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 712 cases in the USA,
1819 in Australia, 57 in the Netherlands, and 46 in
Switzerland.1 Median age at presentation is 6590 years.2
The disorder is slightly more common in men than in
women, and predominantly aects adults (less than 1% of
patients with diagnosed solid CUP are children).2
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 and RAS,
and human epidermal growth factor receptor-2 proteins,
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Panel 1: Investigations that should be done before diagnosis of CUP in patients with
suspected CUP
Clinicopathological data
Histologically conrmed metastatic cancer
Detailed medical history
Complete physical (including pelvic and rectal) examination
Histopathology review with specic immunohistochemical study
Laboratory test data for all patients
Full blood count
Biochemistry
Urinalysis
Testing for occult blood in stools
Chest radiography
CT scan of thorax, abdomen, and pelvis
Laboratory test data for selected patients only
Mammography (for all women)
Breast MRI
Testicular ultrasonography
PET or CT scan
Concentrations of serum -fetoprotein and human chorionic gonadotropin
Concentrations of serum prostate-specic antigen (for all men)
Concentrations of serum cancer antigen 125 and carcinoma antigen 15-3
Endoscopy
<50
52
70%/30%
0%/100%
UDF or PDF
Adenocarcinoma (WDF, MDF,
or PDF)
Cervical
5760
80%/20%
SCC
Inguinal
58
50%/50%
Peritoneal cavity
5565
0%/100%
Neuroendocrine tumours
63
60%/40%
62
61%/39%
Lungs
Pulmonary metastases
Pleural eusions
M>F
5155
Data taken from Pavlidis and Fizazi,1 and Pavlidis et al.2 M=men. F=women. UDF=undierentiated. PDF=poorly
dierentiated. WDF=well dierentiated. MDF=moderately dierentiated. SCC=squamous-cell carcinoma.
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Diagnosis
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 nal 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 carcinoma, melanoma,
lymphoma, or sarcoma; whether the subtype is adenocarcinoma, germ-cell tumour, hepatocellular, renal,
thyroid, neuroendocrine, or squamous carcinoma; and
the primary site of adenocarcinoma (ie, prostate, lung,
breast, colon, pancreas or biliary, or ovarian cancer;
table 2).
Cytokeratins are intermediate laments specic to
epithelial cells expressed in some normal human tissues.
They have 20 dierent subunits. Nowadays, cytokeratinantibody cocktails are widely used to predict the
anatomical origin of adenocarcinomas (table 3).2,24
Although the number of stains available is increasing,
immunohistochemistry probably pinpoints the epithelial
tissue or origin in less than 30% of CUP cases.
Molecular diagnosis
Every tissue has a dierent biological function and
therefore expresses specic genes. Conservation of this
www.thelancet.com Vol 379 April 14, 2012
tissue-specic gene-expression prole during carcinogenesis could potentially enable denition of CUP
according to primary site. Over the past decade, the
success of gene-expression proling in the classication
of tumour types25 has led to development of commercial
tests for biological denition of tissue of origin, with
accuracy rates of 3393%.26
Only one such assay, the 1550-gene microarray-based
Pathwork Tissue of Origin Test (Pathwork Diagnostics,
Redwood City, CA, USA), has been reviewed and cleared
by the US Food and Drug Administration.2630 Other
laboratory-developed tests are available. Theros CancerTYPE ID (BioTheranostics, San Diego, CA, USA) is a
92-gene real-time quantitative RT-PCR assay, and the
MiRview Mets test (Rosetta Genomics, Philadelphia, PA,
USA) is a 48-microRNA quantitative RT-PCR assay.
Another microarray-based test, the 1900-gene CupPrint
(Agendia BV, Amsterdam, Netherlands), is oered
clinically in Europe. Lastly, the CUP assay, a ten-gene
quantitative PCR assay (Veridex, La Jolla, CA, USA), has
been developed but is not yet clinically available.
Varadhachary and colleagues27 assessed use of the ten
gene CUP assay in a cohort of 120 patients and identied
a putative tissue of origin in 61% of patients. Greco and
co-workers28 retrospectively investigated the Cancer
Type ID RT-PCR platform in 20 patients with CUP who
had their primary tumours identied later in life or
during autopsy and reported correct biological diagnosis
in 15 cases. Horlings and colleagues29 applied the
CupPrint assay to tumour samples from patients with
CUP who were subdivided into three groups. For
patients presenting with CUP (n=16), the test agreed
with diagnosis of tissue of origin with immunohistochemistry in 94% of cases. For those with CUP with
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Diagnosis
Step one
AE1 or AE3 pan-cytokeratin
Carcinoma
Lymphoma
S100; HMB-45
Melanoma
S100; vimentin
Sarcoma
Step two
CK7 or CK20; PSA
Adenocarcinoma
Germ-cell tumour
Hepatocellular carcinoma
RCC; CD10
TTF1; thyroglobulin
Thyroid carcinoma
Neuroendocrine carcinoma
Step three
PSA; PAP
Prostate
TTF1
Lung
GCDFP-15; mammaglobulin; ER
Breast
CDX2; CK20
Colon
Pancreas or biliary
Ovary
Imaging
Step one detects broad type of cancer. Step two detects subtype. Step three detects origin of adenocarcinoma. Positive
results with any of these stains indicates a tumour is present, but without absolute certainty. PSA=prostate-specic
antigen. PLAP=placental alkaline phosphatase. OCT4=octamer-binding transcription factor 4. AFP=-fetoprotein.
pCEA=polyclonal carcinoembryonic antigen. RCC=renal-cell carcinoma antigen. ER=oestrogen receptor. PAP=prostatic
acid phosphatase.
Table 2: Immunohistochemical approaches for diagnosis of dierent types of cancer of unknown primary site
Cytokeratins
Colon
CK7/CK20+
Stomach
CK7/CK20+; CK7+/CK20+
Biliary
CK7+/CK20; CK7+/CK20+
Pancreas
CK7+/CK20; CK7+/CK20+
Lung
CK7+/CK20
Ovarian, non-mucinous
CK7+/CK20
Ovarian, mucinous
CK7/CK20+; CK7+/CK20+
Breast
CK7+/CK20
Urothelial
CK7+/CK20+
Endometrium
CK7+/CK20
Prostate
CK7/CK20
Renal
CK7/CK20
Liver
CK7/CK20
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Endoscopy
The detection accuracy, sensitivity and specicity of
endoscopic procedures are very low. Therefore, endoscopic procedures should be used only in patients
presenting with relevant symptoms or signs, or in the
presence of specic pathological changes. For example,
colonoscopy should be used when a patient has a CK7,
CK20+, or CDX2+ immunohistochemical prole, and
brochoscopy when positive for TTF1.
Treatment
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 combination regimen
of platinum and paclitaxel. Median response rate is about
80%, with 3040% patients having complete responses
and a median survival of 36 months.1,8,16
Patients with poorly dierentiated carcinoma with
midline distribution should be treated as having a poorprognosis germ-cell tumour and given platinum-based
combination chemotherapy. From ten available reports,10
the median response rate to this treatment is roughly
45%, with almost 20% of patients having complete
responses and a median overall survival of 12 months.
This subset is poorly dened, and constitutes a heterogeneous entity with a minority harbouring a typical
germ-cell cancer. It warrants further molecular genetic
investigation.8,10
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Unfavourable subsets
Most patients with CUP (80%) belong to prognostically
unfavourable subsets, and the most common subset is
visceral metastatic disease.1,2 In a systematic review of
more than 700 patients with poor-prognosis CUP and
liver metastases histologically diagnosed as adenocarcinoma or undierentiated carcinoma,44 response rates
were less than 20% and median survival was 67 months.
Data from non-randomised studies from the past 40 years
have shown that the introduction of platinum or platinumtaxane combinations is associated with a doubling of
response rates and overall survival. By contrast, a metaanalysis45 has shown that no type of chemotherapy has
been proven to lengthen survival.46
Targeted therapy
In one study,47 60 patients with CUP were given rstline treatment with carboplatin and paclitaxel, with or
without bevacizumab and erlotinib as maintenance
treatment. The response rate was 53% and overall
survival 13 months. In another investigation,48 47 patients
received bevacizumab and erlotinib as second-line
treatment, and the response rate was 10% and median
survival 7 months. Further investigation of targeted
treatment in patients with CUP is warranted.
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Conicts of interest
We declare that we have no conicts of interest.
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