Clin Transl Oncol (2011) 13:88-97

DOI 10.1007/s12094-011-0624-y

E D U C AT I O N A L S E R I E S Purple Series

MULTIDISCIPLINARY APPROACH TO CANCER TREATMENT

Unknown primary cancer of the head and neck: a multidisciplinary

approach
Laura Cerezo · Eduardo Raboso · Ana Isabel Ballesteros

Received: 15 November 2010 / Accepted: 20 December 2010

Abstract The management of patients with cervical lymph
node metastases from an unknown primary cancer (CUP)
remains a matter of controversy. Although new advanced
diagnostic tools, such as positron emission tomography,
have recently been introduced in oncology, the frequency
of this tumour entity in clinical practice means it is still
relevant. Recently introduced molecular profiling platforms
may provide biological classification for the primary tis-
sue of origin as well as insights into the pathophysiology
of this clinical entity, including the characterisation of the
Epstein-Barr virus and human papilloma virus genomas
in the metastatic cervical nodes. Due to the lack of ran-
domised trials, a standard therapy has not been identified
yet. Although neck dissection followed by post-operative
radiotherapy is the most generally accepted approach,
there are other curative options that can be used in some
patients: neck dissection alone, nodal excision followed
by post-operative radiotherapy or radiotherapy alone. A
major controversy remains in the target radiation volumes
L. Cerezo (쾷)
Servicio de Oncología Radioterápica
Hospital Universitario de la Princesa
C/ Diego de León, 62
ES-28011 Madrid, Spain
e-mail: lcerezo.hlpr@salud.madrid.org
E. Raboso
Servicio de Otorrinolaringología
Hospital Universitario de la Princesa
Madrid, Spain
A.I. Ballesteros
Servicio de Oncología Médica
Hospital Universitario de la Princesa
Madrid, Spain
that range from ipsilateral neck irradiation to prophylactic
irradiation of all potential mucosal sites and both sides of
the neck. Finally, the administration of concurrent chemo-
therapy is currently being advised for patients with adverse
prognostic factors.
Keywords Unknown primary cancer ·
Head and neck cancer · Cervical lymph node metastases ·
Molecular biology · Neck dissection · Radiotherapy ·
Chemotherapy
Background
Unknown primary cancer (CUP) of the head and neck pres-
ents as cervical lymph node metastases without an obvious
mucosal lesion. Its estimated incidence ranges from 3% to
9% of all head and neck cancers, with squamous histology
constituting 75% of these tumours [1]. In recent years a de-
crease in the incidence of cervical CUP has been observed,
due to a more accurate diagnosis of the primary tumour by
means of a thorough fibreoptic endoscopy of the pharynx
and larynx, and also to examination under anaesthesia in
most patients [2]. Cervical CUP preferentially affects male
patients of 55–60 years with a history of alcohol and to-
bacco abuse, though a proportion of cases may be related
to chronic infection of the oropharynx by human papilloma
virus [3, 4].
In case of squamous cell carcinoma (SCC), routine
work-up of CUP patients includes physical examination,
CT or MRI of the head and neck area, CT of the chest, and
panendoscopy under general anaesthesia of the whole up-
per aerodigestive tract, with or without random biopsies
Clin Transl Oncol (2011) 13:88-97
[5]. Recent developments in imaging (PET) and pathology
(immunohistochemistry, hybridisation) have increased our
diagnostic spectrum considerably, but the impact of these
procedures on decision-making has not been well docu-
mented.
The management of patients with CUP is a major chal-
lenge in oncology. Recommendations include surgery
alone [6], limited field radiotherapy [7, 8] and extensive
prophylactic irradiation of all potential mucosal sites as
well as both sides of the neck with or without concomitant
chemotherapy [9–11]. However, morbidity of these com-
bined treatments might be high, decreasing the quality of
life of these relatively young patients. No randomised or
prospective studies are available to support either of these
approaches specifically, and such a study would also be
difficult to undertake since the disease is so rare.
The aim of the present study is to revise the adequate
diagnostic work-up of this entity, including molecular biol-
ogy, and to better define the multidisciplinary approach of
patients with cervical node metastases from CUP, includ-
ing the extent of the neck surgery, volumes and doses of
irradiation, and the addition and type of systemic therapy.
The questions still not answered about cervical CUP,
which we will try to answer in this review, are the following:
– Is there a biological explanation for the existence of
cervical metastases without evidence of a primary tumour?
– What are the most common histopathological types
of cervical CUP?
– Can the location of the lymph node indicate the site
of origin of the primary tumour?
– Would it be possible to determine the site of the pri-
mary tumour using molecular diagnostic panels?
– What is the recommended study work-up?
– What is the general therapeutic management?
– Which surgical procedure should be performed on
the neck?
– Is limited radiotherapy equal to extended irradiation?
– What mucosal sites should be included in the radio-
therapy volume?
– What are the required doses of irradiation?
– Is IMRT beneficial for cervical CUP patients?
– What is the role of chemotherapy and targeted ther-
apy?
– Are there any predictive or prognostic factors in these
patients?
– What are the recommended procedures and timing
for the follow-up of these patients?
– What is the primary tumour emergence rate after
treatment?
– Are there any topics for future research?
Answers to the questions proposed
Is there a biological explanation for the existence of cervi-
cal metastasis without a primary tumour?
89
There are several explanations for a cervical metastasis
in the absence of a primary tumour. One is the difficulty
in the diagnosis of an occult primary tumour. Small le-
sions in redundant areas, such as the tonsillar fossa or the
base of tongue, can be easily missed, both on physical and
radiographic exams, due to the anatomical complexity of
the region and to intrinsic limitations of the diagnostic
techniques.
The second possibility is to consider CUP as a distinct
clinical entity characterised by regression/dormancy of the
primary and early high-volume lymphatic spread. A small
lesion hidden in the crypts of the lymphoid tissue of the
pharynx can acquire an early metastatic phenotype and
spread to the regional lymph nodes while remaining dor-
mant at the primary site [12].
Furthermore, immunosurveillance can play a role in the
natural history of this disease. Malignant cells, which have
reached the draining lymph node, can activate T lympho-
cytes that would be able to inhibit, in a feedback manner,
the growth of the small foci of malignant cells at the prima-
ry site, while the growth of the phenotypically transformed
malignant cells in the lymph node continues [13].
On the other hand, they may represent a separate group
of cancers harbouring genetic and phenotypic characteristics
that underline their unique clinical presentation [12, 14].
Advances in the understanding of the basic biology of
CUP syndrome may have a direct impact on clinical care.
If we regard CUPs as common metastases of an unrecogn-
ised primary, then diagnostic evaluation should concentrate
on the identification of the primary origin of the tumour. If,
finally, a primary is not found, treatment will encompass
all the potential primary sites. On the contrary, if we ac-
cept the concept of a specific natural history and biology
of unknown primary tumours, research should focus on the
characterisation of the metastatic genotype and phenotype,
and treatment should be directed to the neck.
What are the most common histopathological types
of cervical CUP?
SCC is the most common histology, representing 75% of
cases, followed by undifferentiated carcinoma and adeno-
carcinoma. Within the squamous cell histology, the poorly
and moderately differentiated carcinomas are predominant.
Lymphoepithelioma is a form of undifferentiated, non-
keratinising carcinoma, with a rich infiltrate of reactive T
lymphocytes, that often originates in the nasopharynx, but
sometimes can be found in the oropharynx. Other histologi-
cal types, such as melanoma or sarcoma, are very rare [15].
In the head and neck mucosa, keratinising stratified epi-
thelia include the gingival and hard palate tissue of the oral
cavity and tongue, while non-keratinising stratified epithe-
lia include the buccal and soft palate tissue of the oral cav-
ity, hypopharynx, oesophagus and true vocal cords [5].
Patients with adenocarcinoma in the metastatic lymph
nodes almost always have a primary lesion below the clav-
90
icles, although if the nodes are located in the upper neck,
salivary gland, thyroid or parathyroid primary tumours
must be excluded [5].
Can the location of the lymph node indicate the site
of origin of the primary tumour?
Patients with tumour involving the upper or mid-level cer-
vical nodes are likely to have a primary cancer of the head
and neck. In contrast, a lung primary should be suspected
in those with the bulk of the disease in the lower cervical
lymph nodes.
The metastatic spread of head and neck tumours into
cervical lymph nodes is rather consistent and follows pre-
dictable pathways, at least in the neck that has not been vi-
olated by previous surgery or radiotherapy [16]. According-
ly, a primary site can sometimes be suspected if a specific
node location is affected. For instance, an isolated posterior
cervical node, in level IIb or V, indicates a possible primary
in the nasopharynx, especially if the histology shows lym-
phoepithelioma or poorly differentiated carcinoma, or if
Epstein-Barr virus (EBV) genome is found in the lymph
node. Levels Ia and Ib are indicative of a possible tumour
in the oral cavity, especially if keratinising SCC carcinoma
is demonstrated in the node biopsy. Also, the parotid and
retroauricular lymph nodes indicate a parotid gland tumour
or a skin tumour as the most probable occult site of origin.
But these patients represent a small subset in most studies,
compared to the most frequent invasion of level IIa, which
is the main lymph node station of nearly all head and neck
mucosal sites, including Waldeyer’s ring, where most of
the occult primaries are eventually found [16–18].
Most patients present with unilateral disease, although
bilateral lymph nodes can be found in 10% of cases [8, 9,
19]. For SCC, jugulodigastric, level II nodes are the most
commonly affected cervical lymph nodes (71%), followed
by mid-jugular, level III (22%), level IV and level I [20].
Would it be possible to determine the site of primary
using molecular diagnostic panels?
CUP represents the main entity in which molecular analy-
sis, including immunohistochemistry, is of primordial
interest for the characterisation of the disease and for
choice of treatment. However, its molecular biology has
not been extensively investigated and any insights into its
pathophysiology come from extrapolated data from known
primaries of the head and neck cancer. In general, the CUP
syndrome constitutes a heterogeneous group of tumours
with aggressive behaviour. Its unusual natural history with
early regional spread suggests that this tumour progresses
through exclusive molecular and biochemical pathways
[12, 14].
Among head and neck cancers, the EBV genome has
been found only in nasopharyngeal carcinoma. As a result,
Clin Transl Oncol (2011) 13:88-97
its identification in a metastatic cervical node could lead to
the identification of an unsuspected primary site within the
nasopharynx. In situ hybridisation for EBV-encoded RNA
or polymerase chain reaction for EBV genomic DNA can
be performed on tissue obtained by fine-needle aspiration
(FNA) biopsy and should be considered, particularly in
young patients with poorly differentiated squamous histol-
ogy in a cervical lymph node [21].
High-risk HPV has been advocated recently as an
important aetiologic factor for a subset of head and neck
SCC. These are believed to have a special predilection for
the oropharyngeal tonsils and are characterised by non-
keratinising basaloid morphology and a strong reactivity to
p16 immunostain [22]. Identifying HPV DNA or RNA in
the lymph nodes may thus provide a means for localising
the primary tumour site in the oropharynx [23].
Recent studies suggest that it would be possible to de-
termine the site of primary tumours using an immunohis-
tochemical diagnostic panel in metastatic cervical lymph
nodes. Park et al. [24] evaluated the expression profiles of
cytokeratins 5/6, 8/18, 10, 13, 14, 19, p16 and pRb in 101
patients with SCC of head and neck cancer. They found
that cytokeratin 10 was more frequently expressed in oral
cavity primary tumours, whereas cytokeratin 19 staining
was more frequently observed in tumours originated from
the pharynx and larynx. The expression of p16 and altered
pRb status were more frequently observed in oropharyn-
geal tumours.
Microsatellite analysis may represent a clinically useful
tool for determining the site of origin of unknown primary
SCC. Califano et al. [25] performed microsatellite analy-
sis on nodal metastatic tumours and histologically benign
surveillance biopsy specimens obtained from 18 patients
with unknown primary SCC treated with neck dissection
and radiation therapy. Three patients harbouring genetic
alterations in the oropharynx subsequently developed a
carcinoma in the same mucosal region. The authors con-
cluded that histopathologically benign mucosa of the upper
aerodigestive tract may harbour foci of clonal, preneo-
plastic cells that are genetically related to metastatic SCC
in cervical lymph nodes and that such mucosal sites are
the sites of origin of unknown primary SCC. The genetic
alterations represent an early clonal population of cells on
the progression pathway to clinically detectable cancer and
a corresponding cervical metastasis. The metastatic lymph
nodes contain additional genetic alterations related to the
progression of cancer.
These molecular findings used in conjunction with
histology, clinical history and radiological findings can be
useful for distinguishing the primary site of cervical lymph
node metastases of CUP of the head and neck.
What is the recommended study work-up?
When a patient presents with a mass in the neck, the first
diagnostic procedure consists of complete head and neck
Clin Transl Oncol (2011) 13:88-97
exam with attention to skin, mirror and endoscopic ex-
ploration as indicated, to visualise the nose, nasopharynx,
oropharynx, hypopharynx and larynx, including biopsy of
any suspicious areas. Most patients are diagnosed after an
efficient examination by an otolaryngologist in the clinic
[26].
A FNA of the metastatic node should be performed
to establish an initial histological diagnosis. The FNA
has a diagnostic accuracy of 95% [27]. Repeat FNA, core
or open biopsy may be necessary for uncertain or non-
diagnostic histologies. An open biopsy is controversial due
to the high incidence of local recurrence. However, it is in-
dicated if there is a high suspicion of lymphoma, sarcoma,
melanoma or adenocarcinoma. Patients should be prepared
for neck dissection at the time of open biopsy.
In the mean time, a computed tomography (CT) scan or
a magnetic resonance imaging (MRI) of the neck should be
performed to define the extent of disease and to occasion-
ally detect the primary tumour. A full blood count, basic
biochemistry battery and a chest X-ray would complete
the basic work-up for all patients. If the node is situated in
level IV or lower V, a chest/abdominal/pelvic CT should
be obtained. Serum thyroglobulin, CA15.3 and CA125 are
useful in certain UPC subsets such as suspected thyroid
cancer [28].
Those patients whose primaries remain undetected
in spite of a thorough clinical and radiological diagnos-
tic procedure should undergo direct laryngoscopy and
examination under anaesthesia with directed biopsies of
the nasopharynx, base of tongue, supraglottic larynx and
pyriform sinuses, as well as a bilateral tonsillectomy, all
of which are anatomical sites with a recognised ability to
generate submucosal microscopic primaries with meta-
static lymph nodes. This invasive procedure should only be
performed when thorough clinical and radiological studies
have yielded no results. Any further surgery, for instance
neck dissection, should be delayed until the results of the
blind biopsies and the tonsillectomy are available. If the
node is located on level IV or lower V, an oesophagoscopy
should be included [27]. Bronchoscopy is not routinely
performed if the chest CT is negative and the patient lacks
pulmonary symptoms.
Ipsilateral or bilateral tonsillectomy is recommended
as part of the diagnostic work-up in patients with unknown
primary site who have adequate lymphoid tissue in their
tonsillar fossae, particularly in those with a single node
involving the subdigastric (level II), mid-jugular (level III)
or submandibular (level Ib) areas, or in patients presenting
with bilateral subdigastric adenopathy [29, 30]. In a study
of 87 patients who underwent tonsillectomy as a part of
the work-up for cervical node metastases presenting as an
unknown primary cancer, 26% had a tonsillar primary [31].
Contralateral tonsil has been identified as the location of
the primary tumour in 10% of cases [30]. This technique
must always be offered if p16 in biopsied tissue is positive,
due to the proven relationship between VPH infection and
oropharyngeal tumours.
91
Positron emission tomography (PET), using fluorodeox-
yglucose (FDG), may permit the identification of metaboli-
cally active, small or superficial lesions that are not seen
on CT or MRI. PET scanning provides useful information
frequently enough to be considered part of a standard eval-
uation. The utility of PET in evaluating the primary tumour
was assessed in a meta-analysis based upon 16 studies that
included 302 patients with cervical lymph node metastasis
from an unknown primary [32]. PET detected the primary
tumour in 25% of patients in whom panendoscopy and CT
failed to identify a primary tumour. Kwee et al. [33] have
recently published a meta-analysis with 11 studies and 433
CUP patients with PET/CT. The global rate of tumour de-
tection was 37%, with sensitivity and specificity of 84%. In
four of the studies, which included only patients with CUP
of the head and neck, the rate of detection of the primary
tumour ranged from 27 to 57%. Accordingly, most recent
clinical guidelines include PET-CT in the diagnostic work-
up of CUP patients.
What is the general therapeutic management?
The optimal therapeutic management of patients with cer-
vical CUP remains controversial as a result of the absence
of randomised studies comparing treatment options. As a
general rule, these patients should be treated with aggres-
sive multimodal therapy similar to patients with locally
advanced head and neck cancer. The type of treatment can
be individualised depending on the patient’s age, site, his-
tology and extent of metastatic lymph node involvement of
the tumour (Fig. 1).
The most frequently recommended approach by the
majority of authors consists of surgical removal of the neck
disease followed by comprehensive post-operative radio-
therapy [2, 5, 34–36].
Surgery alone is not recommended except in patients
with pN1 or N2a neck disease in level I, with no extra-
capsular extension. In these patients radiotherapy can be
reserved for salvage [6].
Radiation alone has been used extensively, with ac-
ceptable results [2, 11, 19]. One potential advantage of ra-
diation compared to surgery in this setting is that potential
primary sites in the head and neck can be included in the
radiation field. A neck dissection following radiation will
be necessary for nodal residual disease [37]. A nodal exci-
sion can be sufficient when radical, comprehensive irradia-
tion to the neck and mucosal sites is planned [5, 9].
Concurrent chemoradiotherapy seems to be beneficial
in N2 disease with multiple nodes, patients with N3 dis-
ease or in operated patients with evidence of extranodal
extension in the soft tissues of the neck [38].
Patients with SCC involving lower cervical or su-
praclavicular lymph nodes can also benefi t from radical
treatment if a lung primary has not been identified. A neck
dissection, or nodal excision, followed by localised post-
operative radiation is indicated in this situation.
92
Fig. 1 Management algorithm in cervical unknown primary cancer
CRT: chemoradiation
Which surgical procedure should be performed
on the neck?
Dealing with a metastatic lymph node in the neck from
CUP requires complying with two requirements: the surgi-
cal procedure must be oncologically sound and the damage
inflicted to the anatomical structures of the neck should
be kept to a minimum. Open biopsies of a positive lymph
node or isolated adenectomy must be discouraged unless
there is strong cytological evidence of a lymphoma. But if
the cytology is compatible with SCC, opening the capsule
of an infiltrated lymph node or breaking the lymphatic
drainage net can increase the risk of tumour dissemina-
tion. From this point of view, the minimum procedure
considered for the surgical treatment of a metastatic lymph
Clin Transl Oncol (2011) 13:88-97
node in the neck should be a selective neck dissection of
the lymphatic levels affected. The extent of the dissection
will be determined by the radiological and clinical find-
ings. It must involve the entire lymphatic chain where the
metastatic lymph nodes are situated, avoiding an oversized
surgical procedure. A radical neck dissection should only
be considered in cases with radiological signs or intraoper-
ative findings of extracapsular disease involving the jugular
vein or the sternocleidomastoid muscle.
Neck dissection in a patient with an unknown primary
should be understood as the final step in the diagnostic ef-
fort aiming to locate the primary site of the tumour, as well
as the first therapeutic procedure. Therefore, neck dissection
in a patient with an unknown primary must be performed
only after all other diagnostic resources have been exhaust-
Clin Transl Oncol (2011) 13:88-97
ed. The cervical specimen will render enough tumoral tis-
sue to perform full immunohistochemical studies that might
eventually yield decisive data about the site of origin.
Patients with pN1 or pN2a disease without extracapsu-
lar extension could be treated with surgery alone. Locore-
gional control rates range from 80% to 90% and 5-year
overall survival rate is about 66% [2, 6, 36].
Is limited radiotherapy equal to extended irradiation?
The two radiotherapy strategies adopted for the treatment
of this patient population are comprehensive irradiation of
bilateral neck nodes plus the pharyngeal axis or irradiation
of the ipsilateral cervical nodes. The rationale for giving
mucosal irradiation is to treat the undetectable primary. In
contrast, the rationale for treating only the affected side of
the neck is assuming that the primary tumour has disap-
peared or that it is not malignant enough to progress in the
following years.
In the absence of comparative trial results, the potential
gain with comprehensive radiotherapy in controlling the
putative primary carcinoma should be weighed against its
effect on quality of life resulting from increased acute and
persistent morbidity, such as dysphagia and xerostomia.
Many authors have observed that mucosal irradiation re-
duced both the emergence of the primary tumour and region-
al recurrence, without impact on overall survival [6, 9, 19].
Weir et al. [8] compared the outcomes in 85 patients treated
with involved field radiation alone to 59 patients treated with
radiation to both the nodes and to potential primary sites
in the head and neck. There was no difference in five-year
survival between the two treatment groups, although some
more primaries (six vs. one) subsequently became evident in
the group treated with nodal irradiation only.
In the series by Grau et al. [2], 26 patients received
irradiation to the ipsilateral neck only and 277 patients re-
ceived elective irradiation to the bilateral neck and mucosal
sites. In multivariate analyses, there was no significant dif-
ference in the rates of mucosal primary emergence, nodal
failure, disease-specific survival or overall survival between
the two groups. However, combining all relapses above the
clavicle, patients treated with unilateral neck irradiation
had a relative increased risk of 1.9 (p=0.05) compared with
those receiving more comprehensive irradiation.
Ligey et al. [11] also reported similar overall survival
rates at 5 years after unilateral or bilateral post-operative
radiotherapy (22% and 23%, respectively) in a group of 95
patients (59 unilateral/36 bilateral). The nodal relapse was
34% after unilateral neck irradiation and 25% after bilat-
eral radiotherapy, without significant difference (p=0.21).
The occult primary occurred in 12% after unilateral and
6% after bilateral irradiation.
In our experience, the regional recurrence rate was sim-
ilar using ipsilateral or bilateral plus mucosal irradiation in
31 patients treated over a period of 13 years, as well as the
appearance of the primary tumour [39].
93
In view of these retrospective comparisons, the ques-
tion of whether mucosal sites should be irradiated remains
open. In case of a young patient with good general health,
comprehensive irradiation should be considered, using a
precise technique and adjusting the volumes as much as
possible to the location of the node. In contrast, exclusive
ipsilateral irradiation can be recommended for unfit older
patients.
In case of an isolated lower cervical node, local irra-
diation after excisional biopsy or neck dissection is better
suited than extended irradiation, since the chances of an
occult primary tumour in the head and neck area are lower.
These patients occasionally have long-term disease-free
survival (DFS).
The benefit of extended mucosal irradiation must out-
weigh its morbidity. Radiation-induced toxicity might be
more severe and more debilitating after volume-extended
radiotherapy when larger volumes receive higher doses.
What mucosal sites should be included in the radiotherapy
volume?
If comprehensive radiation therapy to putative mucosal sites
is decided, it is possible to tailor the radiotherapy volumes
according to the location of the metastatic lymph node.
When the initial disease is located in level II or upper V,
most occult primaries would be hidden within the lymphat-
ic tissue of Waldeyer’s ring. Accordingly, the usual volume
will encompass the nasopharynx, tonsillar fossae, base of
tongue and both sides of the neck. The hypopharynx and
larynx can be avoided, because they are rarely the site of
the primary cancer and because irradiation of these sites
significantly increases the morbidity of treatment [35].
It is not necessary to irradiate the oral cavity unless the
patient has submandibular adenopathy (level I). In that case
the oral cavity should be included in the irradiated volume,
but not the nasopharynx [5].
Level III (mid-jugular) metastatic nodes are more com-
mon in tumours arising in the larynx and hypopharynx.
The exclusive affectation of this level, without invasion of
level II, is rare for other locations such as the oropharynx
or nasopharynx. Sometimes carcinomas of the tip of the
tongue can produce skip metastases to the mid- or low
jugular levels.
When the bulk of the disease is in the supraclavicular
fossa, there is agreement that irradiation should be restrict-
ed to that side of the neck, since the primary is not assumed
to be located in the head and neck region, but in the thorax
or pelvis instead [3].
What are the required doses of irradiation?
The dose usually given is 65–70 Gy, with standard fraction-
ation of 1.8–2 Gy per fraction to the enlarged non-resected
lymph nodes, and 50–56 Gy for the uninvolved neck and
94
potential mucosal sites. In case of particularly suspicious
mucosal sites, a dose of 60–66 Gy is recommended [5, 11].
If a neck dissection has been performed, the minimum
dose for post-operative radiotherapy to the surgical nodal
bed would be 54–60 Gy, at 2 Gy per fraction, whereas
64–66 Gy is recommended when extracapsular extension is
demonstrated.
When intensity-modulated radiotherapy (IMRT) is
used, the fractionation can vary between the different areas,
thus elective dose to non-involved (contralateral) lymph
nodes can be 56 Gy, at 1.75 Gy per fraction, while dose to
the enlarged non-resected lymph nodes would be 69 Gy at
2.16 Gy per fraction, and dose to the putative mucosal sites
66 Gy at 2.06 Gy per fraction [35].
Is IMRT beneficial for cervical CUP patients?
Given the superiority of IMRT in target coverage and spar-
ing of organs at risk, it can be beneficial for cervical CUP
patients, especially if bilateral neck and elective mucosal ir-
radiation is prescribed. IMRT can deliver multiple doses si-
multaneously to different targets, e.g., clinical metastases in
cervical lymph nodes and elective neck nodes, while at the
same time minimising the irradiation of salivary glands and,
therefore, decreasing the late xerostomia, which is the main
complication of patients treated with extended radiotherapy.
Madani et al. [35] have recently reported on 23 patients
with cervical CUP treated with IMRT, and compared them
retrospectively with 18 patients treated with conventional ra-
diotherapy. The incidence of acute grade 3 dysphagia was sig-
nificantly lower in the IMRT group (4.5% vs. 50%, p=0.03),
as well as the late grade 3 xerostomia (11.8% vs. 53.4%,
p=0.03), while the efficacy in terms of overall survival and
distant disease-free probability was the same in both groups.
Furthermore, the precision of the radiation technique
can positively influence the outcome of CUP patients
treated with radiation therapy. Ligey et al. [11] report bet-
ter locoregional control using 3D-CRT or IMRT techniques
compared to 2D radiation in 95 patients treated between
1990 and 2007 (40% vs. 78%, p=0.026). Nevertheless,
there may be a selection bias in these retrospective re-
views: most patients who received 2D radiotherapy were
treated 20 or more years ago when diagnostic procedures
were less sophisticated and distant metastases could have
been undetected.
What is the role of chemotherapy and targeted therapy?
Patients with SCC of unknown primary site that involves
the upper or mid-cervical nodes should be treated accord-
ing to the guidelines for locally advanced SCC of the head
and neck. The incidence of distant metastases is high in
CUP syndrome, ranging from 10% to 33% [2, 34]. This
highlights the potential for inclusion of chemotherapy in
the treatment strategy.
Clin Transl Oncol (2011) 13:88-97
Concomitant chemotherapy and radiotherapy in locally
advanced head and neck cancer improves local control and
overall survival, both in the radical and in the adjuvant
setting [40]. However there are no randomised studies for
patients with cervical CUPs and the rationale of treatment
is based on the results of primary known cancer of the head
and neck and small series of patients with SCC of unknown
primary [34, 41, 42]. In the recent report by Shehadeh et al.
[42], 37 patients were managed with neck dissection fol-
lowed by concurrent high-dose cisplatin and irradiation of
bilateral neck/mucosal sites. At a median follow-up of 42
months, 89% of the patients were alive. Only two regional
and four distant relapses were observed. Based on this da-
ta, a reasonable approach would be to administer systemic
therapy in N2b or N3 patients [43].
The choice of chemotherapy should be individualised
based on patient characteristics, such as histology and per-
formance status, and also on the goals of therapy. Cisplatin
and its derivates are the most commonly used drugs, based
on its interaction with radiation. The standard scheme of
concomitant cisplatin 100 mg/m2 every three weeks on
days 1, 22 and 43 of concomitant chemotherapy is based
on Al-Sarraf et al.’s study for stage N2b-N3, non-resectable
disease [44].
When the suspected primary tumour is an oral, oropha-
ryngeal or laryngeal carcinoma, the preferred treatment is
cisplatin or cetuximab. The combination of cisplatin or car-
boplatin with paclitaxel or infusional 5-FU can be useful
in selected patients with good performance status. In the
post-operative setting, cisplatin concomitant with radiation
is usually given for high-risk patients [38]. If a nasopharyn-
geal tumour is suspected, the first option is chemoradiation
followed by adjuvant cisplatin/5-FU [45].
There is no evidence about neoadjuvant treatment in pa-
tients with CUP, however the European Society of Medical
Oncology suggests platinum-based chemotherapy before
radiotherapy in some patients with N3 disease [43]. Doc-
etaxel-cisplatin-5-FU is the preferred scheme for induction
therapy [46, 47]. Following induction, agents to be used
with concurrent chemoradiation typically include weekly
platinums, taxanes or cetuximab.
In recurrent or metastasic cancer, a combined scheme
with taxanes or cetuximab in addition to cisplatinum is
preferred [15]. There are only two completed studies using
bevacizumab and erlotinib as second-line treatment in CUP
patients, with slightly superior results to those obtained
with the standard treatment [48].
Are there any predictive or prognostic factors in these
patients?
The prognosis of cervical CUP is more favourable than
the prognosis of other subsets of CUP, such as inguinal
or axillary lymph nodes. The 5-year survival ranges from
25 to 75%, depending on the various reported series, and
the median overall survival is around 24 months [3, 9, 11,
Clin Transl Oncol (2011) 13:88-97
34]. Survival might be influenced by different patient and
tumour factors, as well as treatment factors.
Among patient-related variables, good performance sta-
tus, female gender, young age and absence of weight loss
were favourable prognostic factors [2, 49].
The most important prognostic factors are nodal stage
and extracapsular spread. Three-year DFS rates following
surgery and/or radiation therapy for unknown squamous
primaries range from 40% to 50% for patients with N1 dis-
ease to 38% and 26% for patients with N2 and N3 disease,
respectively [3, 9, 49]. In a large series of 352 consecutive
CUP patients treated with radical intent, Grau et al. [2]
confirmed nodal stage as the most important factor for neck
control, with 5-year actuarial survival estimates of 69% for
N1, 58% for N2 and 30% for N3 disease. Extracapsular
spread was a significant prognostic factor in the retrospec-
tive analysis on 113 patients treated with surgery and post-
operative radiotherapy reported by Beldi et al. [34], with
5-year overall survival of 57.5% vs. 31.2% for patients
with and without extracapsular spread (p<0.05).
Location of the nodes has proven to be of prognostic
significance in some series. Patients with enlarged lymph
nodes in the upper neck have a good prognosis when
treated aggressively compared with those with enlarged
lymph nodes in the lower neck or in the supraclavicular
fossa. The latter patients are more likely to have primary
lesions located in the lung or in the oesophagus. Issing et
al. [3] reported a 5-year tumour-specific survival rate of
30% for patients with metastases in levels II or III, com-
pared with 0% for patients with metastases in the supra-
clavicular region (p=0.005). This remarkable worsening of
the prognosis seemed to be due to the rapid development
of further metastases from carcinomatous supraclavicular
lymph nodes.
Jereczek-Fossa et al. [50] reviewed published prognos-
tic information in patients with SCC of unknown origin and
reported negative resection margin, neck surgery followed
by radiotherapy, bilateral irradiation of the neck and head
and neck mucosa, and avoidance of delays in radiotherapy
as the most important treatment-related variables predicting
for superior patient outcome. In two recent papers by Beldi
et al. [34] and Huang et al. [49], the prognostic importance
of bilateral irradiation of neck and mucosa, early nodal
stage, absence of extracapsular extension and curative
treatment (surgery and/or irradiation) was confirmed.
Finally, several authors have observed a significant
worsening of the prognosis after subsequent detection of
the primary lesions [3, 49]. This fact has been particularly
described for patients in whom a large primary tumour is
discovered.
What are the recommended procedures and timing
for the follow-up of these patients?
Despite definitive treatment, between 10 and 15% of af-
fected patients will develop an evident mucosal head and
95
neck primary site within five years and an equal number
will develop distant metastatic disease. But retrospective
studies have shown that neck relapse is more common than
emergence of mucosal primary tumours, ranging from 30%
to 40%. According to Issing et al. [3], 52.3% of locore-
gional tumour recurrences and 50% of the primary tumours
are diagnosed within 24 months of follow-up.
The primary objective of the clinical follow-up in CUP
patients is to improve survival. This can be achieved by
detecting and treating the appearance of the primary tu-
mour or a recurrence in the neck. A secondary objective
is to palliate possible late complications of the treatment.
Accordingly, follow-up care of CUP patients necessitates
interdisciplinary clinical cooperation.
As for other head and neck sites, Guidelines of the Na-
tional Comprehensive Cancer Network recommend history
and physical examination every 1–3 months during the first
year, every 2–4 months during the second year, every 4–6
months until five years and every 6–12 months thereafter.
Post-treatment baseline imaging with CT or MRI of head
and neck is recommended within 6 months of treatment
and, depending on symptoms, thereafter. Chest imaging is
clinically indicated. Endoscopy is an essential part of the
clinical examination in CUP patients, since it can lead to
the discovery of the primary tumour or a second treatable
primary. Close follow-up is advised in those patients irradi-
ated only on one side of the neck.
In case of appearance of a primary tumour, surgical
resection or re-irradiation to doses 60 Gy, with or with-
out chemotherapy, are therapeutic possibilities associated
with cure in selected patients. Endocavitary brachytherapy
or stereotactic radiosurgery for nasopharyngeal primary
tumours in patients previously irradiated can be very effec-
tive and will produce fewer late sequelae [51]. However,
the majority of patients will present with locoregional dis-
ease that cannot be treated radically or with distant metas-
tases. In these patients, chemotherapy would be the main
palliative treatment.
The main complication of radiation therapy for patients
treated for a CUP is xerostomia, which can be significantly
avoided using IMRT [35]. The complications of treatment
of the neck depend on whether a neck dissection is added,
and consist mainly in cervical fibrosis and shoulder pain.
Rehabilitation of these patients is of extreme importance in
order to reintegrate them into daily life.
What is the primary tumour emergence rate after
treatment?
Between 10 and 15% of affected patients will develop
an evident mucosal head or neck primary site within five
years of the initial treatment. The oropharynx, particularly
the base of tongue, has been reported as the most common
location of mucosal site failure in the large series [2, 9, 19].
Other sites of appearance of primary tumours include the
nasopharynx, tonsil and pyriform sinus. Several authors
96 Clin Transl Oncol (2011) 13:88-97

consider primary tumours arising later than 5 years after
first diagnosis as second primaries.
Radiotherapy is very effective in reducing the rate of
appearance of a potential primary site. Iganej et al. [52]
compared 41 patients treated with exclusive neck surgery
with 65 patients treated with surgery and/or radiotherapy.
Only two patients (3%) who had received radiotherapy
as part of their initial treatment developed a primary site
inside the irradiated field vs. 13 patients (32%) who had
not received radiotherapy (p=0.006). Similarly, Grau et al.
[2] reported a higher frequency of primary emergence in
patients treated with surgery alone than in patients treated
with radiotherapy (54% vs. 15% actuarial risk at 5 years,
p<0.0001).
Colletier et al. from MD Anderson [9] reported on 136
patients treated with neck dissection followed by radiother-
apy to pharyngeal mucosal sites and bilateral lymph nodes.
Six percent of patients developed carcinomas in mucosal
sites within radiotherapy portals, and an additional 4% of
patients developed carcinomas in head and neck mucosal
sites outside radiotherapy portals.
The incidence of subsequent mucosal primary lesions
was reported by Erkal et al. [19] for 126 patients treated for
CUP at the University of Florida and compared with 1112
patients treated for a known primary cancer (oropharynx,
hypopharynx and supraglottis). The incidence of a subse-
quent mucosal head and neck cancer was similar in both
groups (13% and 9%, respectively), suggesting that mu-
cosal irradiation significantly reduced the risk of primary
site failure. This author and some others have suggested
that the incidence of primary tumours in patients treated
for CUP was similar to that of metachronous second head
and neck malignancies [19, 36]. This is probably related to
the same participating risk factors and the field cancerisa-
tion in these individuals [3, 19].
Are there any topics for future research?
The discovery of the primary site using molecular plat-
forms constitutes an investigational topic of interest. In re-
cent years, molecular profiling technologies have provided
extensive data on expression of multiple genes in several
human tumours. A typical multigene expression profile can
be identified for each solid tumour. Accordingly, gene ex-
pression in metastatic lymph nodes from an unknown pri-
mary may be studied by the same methods and compared
with the typical genetic profiles of known cancers [54].
The question of whether CUPs are really different from
tumours of known primaries is another topic of interest.
Further research on the biology of CUP should concern
the determination of whether this group of tumours share
unique genetic, chromosome and/or phenotypic anomalies.
It is postulated that new molecular techniques, such as
DNA and gene expression profiling as well as proteomics,
are going to play an important role in this research [14,
15].
Optimal extension of radiotherapy volumes remains
an open issue. A randomised trial proposed recently by
the European Organization for Research on Treatment of
Cancer Radiotherapy Group and the Radiation Therapy
Oncology Group testing whether the DFS achievable by ip-
silateral neck irradiation could be equivalent to that achiev-
able by a more extensive irradiation including mucosal and
bilateral neck nodes, was prematurely closed because of
insufficient accrual. The answer to this question would lead
to important management decisions for the vast majority of
patients with cervical CUP.
The use of immunohistochemical markers can predict
response to treatment as in other head and neck cancers.
EGFR overexpression has been described in more than
70% of cases of SCC, suggesting the possibility of treat-
ment with cetuximab, gefitinib or panitumumab. Over-
expression of MET and activation of cyclin D1, Ras and
AKT occur in one third to one quarter of head and neck
cancers, resulting in increased cellular proliferation, apop-
tosis inhibition, invasion and metastases. Angiogenesis is
particularly active in head and neck cancer and microvessel
density and VEGF expression by immunohistochemistry or
PCR have been associated with aggressive disease course
and poor outcome [15, 53].
But the main issue to be investigated is the natural his-
tory of CUP. Insights into the molecular biology of CUP
are needed in order to identify the cellular signalling path-
ways responsible for primary tumour dormancy and early
metastatic spread. This will eventually guide the best diag-
nostic and therapeutic management of these patients.
Conflict of interest The authors declare that they have no conflict of
interest relating to the publication of this manuscript.

References
1. Pavlidis N, Briasoulis E, Hainsworth J, Hains-
worth J (2003) Diagnostic and therapeutic man-
agement of cancer of unknown primary. Eur J
Cancer 39:1990–2005
2. Grau C, Johansen LV, Jakobsen J et al (2000)
Cervical lymph node metastases from unknown
primary tumours. Results from a national survey
by the Danish Society for Head and Neck Oncol-
ogy. Radiother Oncol 55:121–129
3. Issing WJ, Taleban B, Tauber S et al (2003) Diag-
nosis and management of carcinoma of unknown
primary in the head and neck. Eur Arch Otorhino-
laryngol 260:436–443
4. Vidal L, Gillison M (2008) Human papillomavirus
in HNSCC: recognition of a distintc disease type.
Hematol Oncol Clin N Am 22:1125–1142
5. Mendenhall WM, Amdur RJ, Hinerman RW et
al (2008) Management of the neck including un-
known primary tumor. In: Halperin EC, Perez
CA, Brady LW (eds) Principles and practice of
radiation oncology, vol. 1, Lippincott Williams
and Wilkins, Philadelphia, PA, pp 1035–1054
6. Coster JR, Foote RL, Olsen KD et al (1992) Cer-
vical nodal metastasis of squamous cell carcinoma
of unknown origin: indications for withholding
radiation therapy. Int J Radiat Oncol Biol Phys
23:743–749
7. Glynne-Jones RG, Anand AK, Young TE, Berry
RJ (1990) Metastatic carcinoma in the cervical
lymph nodes from an occult primary: a conserva-
tive approach to the role of radiotherapy. Int J
Radiat Oncol Biol Phys 18:289–294
8. Weir L, Keane T, Cummings B et al (1995) Radia-
tion treatment of cervical lymph node metastases
from an unknown primary: an analysis of outcome
by treatment volume and other prognostic factors.
Radiother Oncol 35:206–211
9. Colletier PJ, Garden AS, Morrison WH et al
(1998) Postoperative radiation for squamous cell
Clin Transl Oncol (2011) 13:88-97
carcinoma metastatic to cervical lymph nodes
from an unknown primary site: outcomes and pat-
terns of failure. Head Neck 20:674–681
10. Reddy SP, Marks JE (1997) Metastatic carcinoma
in the cervical lymph nodes from an unknown pri-
mary site: results of bilateral neck plus mucosal
irradiation vs. ipsilateral neck irradiation. Int J
Radiat Oncol Biol Phys 37:797–802
11. Ligey A, Gentil J, Créhange G et al (2009) Impact
of target volumes and radiation technique on loco-
regional control and survival for patients with
unilateral cervical lymph node metastases from an
unknown primary. Radiother Oncol 93:483–487
12. Van de Wouw AJ, Jansen RLH, Speel EJM, Hillen
HFP (2003) The unknown biology of the un-
known primary tumour: a literature review. Ann
Oncol 14:191–196
13. Karlsson M, Lindberg K, Karlen P et al (2010)
Evidence for immunosurveillance in intestinal
premalignant lesions. Scand J Immunol 71:362–
368
14. Pentheroudakis G, Briasoulis E, Pavlidis N (2007)
Cancer of unknown primary site: missing primary
or missing biology? Oncologist 12:418–425
15. Pavlidis N, Pentheroudakis G, Plataniotis
G (2009) Cervical lymph node metastases of
squamous cell carcinoma from an unknown pri-
mary site: a favourable prognosis. Clin Transl
Oncol 11:340–348
16. Gregoire V, Coche E, Cosnard G et al (2000)
Selection and delineation of lymph node target
volumes in head and neck conformal radiotherapy.
Proposal for standardizing terminology and pro-
cedure based on the surgical experience Radiother
Oncol 56:135–150
17. Lindberg R (1972) Distribution of cervical lymph
node metastases from squamous cell carcinoma of
the upper respiratory and digestive tracts. Cancer
29:1446–1449
18. Shah JP (1990) Patterns of cervical lymph node
metastasis from squamous carcinomas of the up-
per aerodigestive tract. Am J Surg 160:405–409
19. Erkal HS, Mendenhall WM, Amdur RJ et al
(2001) Squamous cell carcinomas metastatic to
cervical lymph nodes from an unknown head-and-
neck mucosal site treated with radiation therapy
alone or in combination with neck dissection. Int
J Radiat Oncol Biol Phys 50:55–63
20. Haas I, Hoffmann KT, Enger R et al (2002) Di-
agnostic strategies in cervical carcinoma of an
unknown primary (CUP). Eur Arch Otorhinolar-
yngol 259:325–333
21. Lee WY, Hsiao FR, Jin JT, Tsai ST (2000) Ep-
stein-Barr virus detection in neck metastases by
in-situ hybridization in fine-needle aspiration cy-
tologic studies: an aid for differentiating the pri-
mary site. Head Neck 22:336–340
22. Guillison ML, Koch W, Capone RB et al (2000)
Evidence for a casual association between human
papillomavirus and a subset of head and neck can-
cer. J Natl Cancer Inst 92:709–720
23. El-Mofty SK, Zhang MQ, Davila RM (2008)
Histologic identification of human papillomavirus
(HPV)-related squamous cell carcinoma in cervi-
cal lymph nodes: a reliable predictor of the site of
an occult head and neck primary carcinoma. Head
Neck Pathol 2:163–168
24. Park JM, Jung CK, Choi YJ et al (2010) The use
of an inmunohistochemical diagnostic panel to
determine the primary site of cervical lymph node
metastases of occult squamous cell carcinoma.
Hum Pathol 41:431–437
25. Califano J, Westra W, Koch W et al (1999) Un-
known primary head and neck squamous cell
carcinoma: molecular identification of the site of
origin. J Natl Cancer Inst 91:599–603
26. Cianchetti M, Mancuso AA, Amdur RJ et al
(2009) Diagnostic evaluation of squamous cell
carcinoma metastatic to cervical lymph nodes
from an unknown head and neck primary site.
Laryngoscope 119:2348–2354
27. Varadchary GR, Abbruzzese JL, Lenzi R (2004)
Diagnostic strategies for unknown primary cancer.
Cancer 100:1776–1785
28. Waltonen JD, Ozer E, Hall NC et al (2009) Meta-
static carcinoma of the neck of unknown pri-
mary origin. Evolution and efficacy of the mod-
ern workup. Arch Otoloryngol Head Neck Surg
135:1024–1029
29. Righi PD, Sofferman RA (1995) Screening uni-
lateral tonsillectomy in the unknown primary.
Laryngoscope 105:548–550
30. Koch WM, Bhatti N, Williams MF, Eisele DW
(2001) Oncologic rationale for bilateral tonsillec-
tomy in head and neck squamous cell carcinoma
of unknown primary source. 124:331–333
31. Lapeyre M, Malissard L, Peiffert D et al (1997)
Cervical lymph no de metastasis from an un-
known primary: is a tonsillectomy necessary? Int
J Radiat Oncol Biol Phys 39:291–296
32. Rusthoven KE, Kosky M, Paulino AC (2004) The
role of fluorodeoxyglucose positron emission
tomography in cervical lymph node metastases
from an unknown primary tumor. Cancer 101:
2641–2649
33. Kwee TC, Kwee RM (2009) Combined FDG-
PET/CT for the detection of unknown primary
tumors: systematic review and a meta-analysis.
Eur Radiol 19:731–744
34. Beldi D, Jereczek-Fosa BA, D’Onofrio A et al
(2007) Role of radiotherapy in the treatment of
cervical lymph node metastases from an unknown
primary site: retrospective analysis of 113 pa-
tients. Int J Radiat Oncol Biol Phys 69:1051–1058
35. Madani I, Vakaet L, Bonte K et al (2008) Inten-
sity-modulated radiotherapy for cervical lymph
node metastases from unknown primary cancer.
Int J Radiat Oncol Biol Phys 71:1158–1166
36. Nieder C, Gregoire V, Ang K (2001) Cervical
lymph node metastases from occult squamous cell
carcinoma: cut down a tree to get an apple? Int J
Radiat Oncol Biol Phys 50:727–733
37. López M, Cerezo L, Martín M, Couñago F (2008)
Neck dissection after radiochemotherapy in pa-
tients with locoregionally advanced head and neck
cancer. Clin Transl Oncol 10:812–816
38. Bernier J, Cooper JS, Pajak TF et al (2005) Defin-
ing risk levels in locally advanced head and neck
cancers: a comparative analysis of concurrent
postoperative radiation plus chemotherapy tri-
als of the EORTC (#22931) and RTOG (#9501).
Head Neck 27:843–850
39. Rios P, Martin M, Cerezo L et al (2007) Impacto
del volumen de irradiación en las metástasis gan-
97
glionares cervicales de origen desconocido. Patrón
de recidiva. Clin Transl Oncol 9:63 (abstract)
40. Aldestein DJ, Li Y, Adams GL et al (2003) An
Intergroup phase III comparison of standard ra-
diation therapy and two schedules of concurrent
chemoradiotherapy in patients with unresectable
squamous cell head and neck cancer. J Clin Oncol
21:92–98
41. Argiris A, Smith SM, Stenson K et al (2003)
Concurrent chemoradiotherapy for N2 or N3
squamous cell carcinoma of the head and neck
from an occult primary. Ann Oncol 14:1306–1311
42. Shehadeh NJ, Ensley JF, Kucuk O et al (2006)
Benefit of postoperative chemoradiotherapy for
patients with unknown primary squamous cell
carcinoma of the head and neck. Head Neck
28:1090–1098
43. Briasoulis E, Pavlidis N, Felip E (2009) Cancer
of unknown primary site: ESMO Clinical Recom-
mendations for diagnosis, treatment and follow-
up. Ann Oncol 20:1306–1311
44. Al-Sarraf M, Pajak TF, Byhard RW et al (1997)
Postoperative radiotherapy with concurrent cispla-
tin appears to improve locoregional control of ad-
vanced, resectable head and neck cancers: RTOG
88-24. Int J Radiat Oncol Biol Phys 37:777–782
45. Chitapanarux I, Iorvidhaya V, Kamnerdsupaphon
P et al (2007) Chemoradiation comparing cis-
platin versus carboplatin in locally advanced na-
sopharyngeal cancer: randomised, non-inferiority,
open trial. Eur J Cancer 43:1399–1406
46. Vermorken JB, Remenar E, Van Herpen C et al
(2007) EORTC 24971/TAX 323 Study Group.
Cisplatin, fluoracil and docetaxel in unresectable
head and neck cancer. N Engl J Med 357:1695–
1704
47. Posner MR, Hershock DM, Blajman CR et al
(2007) Cisplatin and fluorouracil alone or with
docetaxel in head and neck cancer. N Engl J Med
357:1705–1715
48. Hainsworth J, Spiegel DR, Thompson DS et al
(2009) Paclitaxel/carboplatin plus bevacizumab/
erlotinib in the first-line treatment of patients
with carcinoma of unknown primary. Oncologist
14:189–197
49. Huang CC, Tseng FY, Yeh TH et al (2008) Prog-
nostic factors of unknown primary head and neck
squamous cell carcinoma. Otolaryngol Head Neck
Surg 139:429–435
50. Jereczek-Fossa BA, Jasse J, Orecchia R (2004)
Cervical lymph node metastases of squamous
cell carcinoma from an unknown primary. Cancer
Treat Rev 30:153–164
51. Suarez C, Rodrigo JP, Rinaldo A et al (2010) Cur-
rent treatment options for recurrent nasopharynge-
al cancer. Eur Arch Otorhinolaryngol 267:1811–
1824
52. Iganej S, Kagan R, Anderson P et al (2002) Meta-
static squamous cell carcinoma of the neck from
an unknown primary: management options and
patterns of relapse. Head Neck 24:236–246
53. Seiwert T, Cohen E (2008) Targeting angiogenesis
in head and neck cancer. Semin Oncol 35:274–285
54. Pentheroudakis G, Golfinopulos V, Pavlidis N
(2007) Switching benchmarks in cancer of un-
known primary: from autopsy to microarray. Eur J
Cancer 43:2026–2036