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CANCER TREATMENT REVIEWS (2004) 30, 153164

www.elsevierhealth.com/journals/ctrv

TUMOUR REVIEWS

Cervical lymph node metastases of squamous cell


carcinoma from an unknown primary
Barbara A. Jereczek-Fossaa,*, Jacek Jassemb, Roberto Orecchiaa,c
a

Department of Radiation Oncology, European Institute of Oncology, via Ripamonti 435, Milan 20141,
Italy
b
Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland
c
Faculty of Medicine of the University of Milan, Italy

KEYWORDS

Summary Cervical lymph node metastases of squamous cell carcinoma from


occult primary constitute about 25% of all patients with carcinoma of unknown
primary site (CUP). Metastases in the upper and middle neck are generally
attributed to head and neck cancers, whereas the lower neck (supraclavicular area)
involvement is often associated with primary malignancies below the clavicles. The
diagnostic procedures include physical examination with thorough evaluation of the
head and neck mucosa using fiber-optic endoscopy, biopsies from all suspicious sites
or blindly from the sites of possible origin of the primary, computer tomography
and/or magnetic resonance. A systematic tonsillectomy in the absence of suspicious
lesions is often recommended since up to 25% of primary tumors can be detected in
this site. The thoracic primary (tracheal, bronchial, lung, esophagus) has to be
excluded, especially in the case of lower neck involvement. Positron emission
tomography (PET) with fluoro-2-deoxy-D -glucose allows detection of primary tumor
in about 25% of cases, but this procedure is still considered investigational.
Therapeutic approaches include surgery (lymph node excision or neck dissection),
with or without postoperative radiotherapy, radiotherapy alone and radiotherapy
followed by surgery. In early stages (N1), neck dissection and radiotherapy seem to
have similar efficacy, whereas more advanced cases (N2, N3) necessitate combined
approaches. The extent of radiotherapy (irradiation of bilateral neck and mucosa
versus ipsilateral neck radiotherapy) remains debatable. A potential benefit from
extensive radiotherapy should be weighted against its acute and late morbidity and
difficulties in re-irradiation in the case of subsequent primary emergence. The role
of other methods, such as chemotherapy and hyperthermia, remains to be
determined.
c 2003 Elsevier Ltd. All rights reserved.

Head and neck cancer;


Unknown primary;
Occult primary;
Radiotherapy;
Neck dissection;
Lymph node
metastases;
Squamous cell
carcinoma;
CUP

Introduction

* Corresponding author. Tel.: +39-02-5748-9607; fax: +39-02574-89036.


E-mail address: barbara.fossa@ieo.it (B.A. Jereczek-Fossa).

Carcinoma of unknown primary site (CUP) represents a heterogeneous group of malignancies presenting with lymph node or distant metastases, for
which a work-up fails to identify the site of origin.1

0305-7372/$ - see front matter c 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2003.10.001

154
CUP accounts for 0.510% of all tumors and, as a
result of recent improvement in imaging procedures, its number has decreased.13 Moreover, due
to progress in immunopathology, more individualized histology-based therapeutic options have
recently become available.13 A substantial fraction of CUP patients includes cases with cervical
lymph node metastases from unknown primary.4;5
Squamous cell carcinoma is the most common
histotype, followed by adenocarcinoma, undifferentiated carcinoma and other malignancies (for
example, lymphoma and melanoma).69 Patients
with cervical metastases other than squamous cell
carcinoma follow different treatment guidelines
and have different prognosis1012 therefore they
are not discussed here.
The management of cervical lymph node metastases of squamous cell carcinoma from unknown
primary remains a therapeutic challenge. Since
head and neck squamous carcinomas are characterized by mainly loco-regional progression and
relatively low risk of distant metastases, the priority is given to loco-regional control. Therefore,
local modalities including surgery and radiotherapy
remain cornerstones of treatment.
The optimal treatment of head and neck CUP has
not yet been defined. Randomized trials are
lacking. Published retrospective series include
heterogeneous patient populations (with different
histotypes, i.e., squamous cell, undifferentiated
carcinoma and adenocarcinoma),8;9;1318 managed
with various diagnostic and therapeutic procedures.8;11;15;16;1822 However, the recent publication
of several relatively large series of patients allows
for some conclusions to be drawn.7;13;2326
References for this review were identified by a
comprehensive search of MEDLINE for the years
19902003 (with no language restriction). References were supplemented with relevant citations
from older literature and from the reference list of
retrieved papers. Papers were selected on the basis
of their relevance to the topic. Data presented in
abstract form or non-English language articles
were included wherever they added significant
information.

Incidence
The incidence of cervical CUP varies between 2%
and 9% of all head and neck cancers.8;9;2629 In the
Danish national study, the annual incidence of
cervical metastases of squamous cell carcinoma
from unknown primary was 0.34 cases/100,000/
year, and has remained stable over the last 20

B.A. Jereczek-Fossa et al.


years.26 In the same period, the number of new
head and neck cancers has increased, suggesting
that the proportion of CUP cases has diminished.26
The most frequently involved nodal area are
level II, followed by level III, whereas levels I, IV
and V are less frequent.6;26;30;31 Unilateral lymph
node involvement is more common; bilateral adenopathy is present in about 10% of patients.12;21;30
In large series, the median nodal size was 5 cm
(range 214 cm)30 and there is an apparent prevalence of N2 cases.6;21;22;25;26
Metastases in the upper and middle neck are
generally attributed to cancers of the head and
neck region, whereas metastases limited to the
lower neck (supraclavicular area) are often associated with primary malignancies below the clavicles.8;19;28;32 As many patients with exclusive low
neck involvement are managed with palliative approaches,26 this group was excluded from some
analyses.11;14;24;25;32 .
Mean age at diagnosis varied in particular
series from 55 to 65 years and younger median age in some series may partially be explained by the inclusion of undifferentiated
tumors.6;7;18;22;24;25;27;3133 . As in other head and
neck carcinoma populations, the majority of patients are males.6;11;18;22;2427;3034 The reported
median interval between the first symptoms and
diagnosis and/or referral to oncology clinic was in
the range of 3 months.6;31

Diagnostic approaches
The diagnosis of a CUP requires accurate physical
examination including thorough evaluation of the
head and neck mucosa with a fiber-optic and rigid
endoscopy under general anesthesia. Usually biopsies are performed from all suspicious sites or
blindly from the sites of possible origin of the primary, including base of tongue, tonsil, pyriform
sinus and nasopharynx on the lesion side.35 If the
tonsil is not present, a biopsy of the tonsillar fossa
should be performed.35
Physical examination and evaluation under anesthesia, performed by experienced specialists,
allow detection of the primary head and neck
cancer in more than 50% of patients with cervical
lymph node metastases.36 Fine needle aspiration
for cytologic diagnosis preceding neck dissection is
recommended. Repetitive non-contributive fine
needle aspirations are an indication for planned
neck dissection to be performed. Another option is
open biopsy,25;37 although an increased risk of dis-

Cervical lymph node metastases of squamous


tant metastases following this procedure was suggested.15
Head and neck imaging includes computer tomography (CT) scan and/or magnetic resonance
(MRI). The detection rate with the use of CT scan is
about 1520%.38 In the case of suggestive findings
on clinical examination or on imaging studies,
panendoscopy with biopsies can reveal primary
tumor in up to 65% of patients, otherwise the primary tumor is disclosed in about 20% of cases.32
The most common sites of primary lesions (82%)
are tonsil/tonsillar fossa and base of tongue.32
Some patients present with synchronous primary
tumors.32 In the last years, the incidence of occult
primaries detected subsequently in the nasopharynx, hypopharynx, and supraglottic larynx has decreased.28 This can reflect more effective primary
detection of these lesions with the use of fiberoptic endoscopies and advanced radiographic
methods.28;32
A systematic tonsillectomy in the absence of
suspicious lesions is recommended by many authors
since up to 25% of primary tumors are detected in
this site.7;9;14;22;27;3942 The highest rate was observed in the case of involvement of subdigastric
lymph nodes, followed by submandibular and midjugular nodes.22 Some investigators limit recommendation to tonsillectomy to cases of suggestive
findings on physical examination and/or radiographic evaluation,32 or to the involvement of the
aforementioned high-risk lymph nodes.22 Only four
cases of bilateral synchronous tonsillar cancer in
CUP patients have been published in the literature.43 On the other hand, a 10% rate of contralateral spread from occult tonsil lesions seems to
justify bilateral diagnostic tonsillectomy.7;14;44
The thoracic primary (tracheal, bronchial, lung,
esophagus) has to be excluded with the use of
chest CT scan and endoscopic examinations (tracheo-broncoscopy, esophago-gastroscopy). This is
of particular relevance in patients with metastases
to the lower cervical (supraclavicular) lymph
nodes.
Despite numerous studies, the optimal diagnostic algorithm in head and neck CUP has not
yet been established. For example, in a series of
57 patients with upper and midneck nodes (all
histologies included), a diagnostic panel consisting of lymph node biopsy, rigid panendoscopy
with systematic biopsies of suspected regions including the tongue base and nasopharynx, and
bilateral tonsillectomy, led to the detection of 14
occult oropharyngeal (mainly submucosal or very
small lesions) and 5 nasopharyngeal tumors.14
Imaging procedures (X-ray, ultrasound, CT, MRI,
2-(F-18)-fluoro-2-deoxy-D -glucose positron emis-

155
sion tomography scan; FDG-PET) as well as
gynecological, urological and gastrointestinal
consultations did not reveal any additional
primaries.14 Multivariate analysis by Mendenhall
et al.32 showed high detection rate of CT and/or
MRI of the head and neck and no impact of
positive 2-(F-18)-fluoro-2-deoxy-D -glucose single
photon emission computed tomography scan
(FDG-SPECT). There was also no additional yield
related to the number of panendoscopies and
tonsillectomy in this analysis.

Positron emission tomography


In the case of negative morphologic examinations
(CT scan, MRI), primary tumor detection with the
use of functional imaging modality, such as PET,
seems to be a very attractive option. However,
based on the available data, the standard use of
FDG-PET cannot yet be recommended.39;4547 PET
has an overall staging accuracy of 6978%, a positive predictive value of 5683%, a negative predictive value of 7586%, a sensitivity of 63100%
and a specificity of 9094%.34;39;46 With negative
routine clinical examination, CT scan and MRI, PET
allows detection of primary tumors in 543% of
patients (Table 1),5;29;34;39;4650 Higher rates of primary tumor detection were observed if non-headand-neck CUP or histologies other than squamous
cell carcinoma were included in the analysis. In the
series including exclusively squamous cell head and
neck CUP, the detection rate did not exceed 25%.39
The resolution of the PET scan is usually limited
to 5 mm.46 The areas most difficult to be diagnosed
for primary tumor with FDG-PET include the supraglottic region and Waldeyers tonsillar ring.51
This can be explained by the low tumor volume in
small, superficial lesions, the presence of normal
lymphoid tissues, and the accumulation of FDG
secreted by salivary glands to saliva pools in the
valleculae and pyriform sinuses.45;51 Improved detection may probably be achieved with a 12-h
prestudy fast, which diminishes salivary gland excretion and enhances FDG uptake in tumors.52
In numerous series, all metastatic cervical
lymph nodes detected by CT were confirmed by
PET scan.34;49 Ideally, biopsies should be performed
after PET scan, since such a sequence allows for
sampling of the areas suspected in PET and avoids
false positive PET-scans at biopsy site. Apart from
the detection of primary tumor, other potential
advantages of PET include exclusion of other metastases, post-radiotherapy neck evaluation (selection of patients with residual disease) and
subsequent monitoring.34;45;53;54

156

B.A. Jereczek-Fossa et al.

Table 1 The role of PET in the detection of occult primary tumor


Author (reference)

Number of patients

Localization of
primary tumor (%)

Comments

Rades et al.5

42

43

Bohuslavizki et al.48

53

38

Regelink et al.34
Stoeckli et al.46
Jungehulsing et al.29
Johansen et al.50

50
18
27
42

32
28
26
24

Safa et al.49

14

21

All CUP included, irrespective of site


All CUP included, irrespective of site and histology (83
head and neck patients)
All histologies included
All histologies included
All histologies included
SCC and undifferentiated
carcinoma included
SCC N2N3 included, PET
performed after biopsy

Greven et al.47

14

PET, positron emission tomography; CUP, carcinoma of unknown primary site; SCC, squamous cell carcinoma.

Other diagnostic procedures


Recently, promising results have been reported
with laser-induced fluorescence imaging performed
in parallel to panendoscopy.55 Another diagnostic
method to identify the site of origin with higher
sensibility is FDG-SPECT, however its usefulness is
still debatable.32;56

Molecular assays
Some molecular assays have recently been proposed
to differentiate the potential primary site. Detection of the EpsteinBarr virus (EBV) with the use of in
situ hybridization in metastatic lymph nodes may be
suggestive for nasopharyngeal tumor.57 Human
Papilloma virus (HPV) detected by polymerase chain
reaction may indicate oropharyngeal cancer.58 Microsatellite mutation analysis of metastatic nodal
tissue and samples of normal pharyngeal mucosa was
also proposed.59 Despite these encouraging results,
little is known about the biology of CUP. It was hypothesized that in CUP the primary acquires a metastatic phenotype soon after transformation and
remains small, either by inborn errors leading to
involution of the primary, or due to extremely slow
growth rate. Another postulated mechanism was
inhibiting the growth of the primary by metastases
(reviewed in60 ). Definitely, more studies are needed
to evaluate the role of molecular investigations and
to understand the biology of CUP.

Management
Various therapeutic approaches are being employed for CUP, including exclusive lymph node

excision, neck dissection, node excision or neck


dissection followed by postoperative radiotherapy,
radiotherapy alone, and radiotherapy followed by
planned neck dissection or salvage surgery.

Surgery
Surgical therapy may include excisional biopsy or
neck dissection. In some series, exclusive surgery
provided overall survival similar to that following
surgery supplemented by irradiation.26 In the review by Nieder et al.,39 the emergence rate of the
primary tumor after surgery alone was about 25%,
the median nodal recurrence rate about 34%, and
the 5-year overall survival rate 66%.26;6163 Surgery alone was therefore postulated in selected
patients with N1 disease without extracapsular
extension and with no history of incisional or excisional biopsy.23;24;30;39;62;6466 In the case of a history of incisional or excisional biopsy for N1
disease, postoperative irradiation is indicated.67;68
Surgery (planned neck dissection) performed after
the irradiation showed persistence of nodal disease
in up to 44% of patients.20;27;30;32 Such a sequence
was associated with poorer survival and with higher
postoperative morbidity as compared to surgery
followed by radiotherapy.27;30 These outcomes
may, however, be related to selection bias, as radiotherapy is typically attempted in patients with
advanced, inoperable neck disease.27

Radiotherapy
The majority of patients managed with surgery
receive adjuvant irradiation.9;16;17;69 However, the
optimal extent of surgery and radiotherapy is still

Cervical lymph node metastases of squamous


controversial. Some authors recommend only diagnostic surgical procedure followed by radiotherapy.26 Salvage neck dissection is indicated in nodal
relapses26 or is performed routinely after irradiation (planned neck dissection)32 . French standards
recommend surgical node excision followed by radiotherapy in all operable patients, whereas radiotherapy alone is reserved for inoperable neck
disease.70
A review of the literature suggests most promising results with a strategy including nodal dissection and extensive irradiation (Table 2).
According to some authors, in early stages neck
dissection alone and radiotherapy alone are
equivalent and provide satisfactory nodal control.71 Thus, radiation alone or surgery alone were
proposed for N1 and selected N2a disease (without
persistent tumor after irradiation), whereas combined modalities were recommended for N2b, N2c

157
and N3 patients.71 In some centers most patients
are approached with radiotherapy alone.23;24;26
Others recommended this strategy only in patients
unfit for surgery and/or with advanced (fixed) nodal disease.23;24;39 In the Danish national study, the
observed survival following radiotherapy alone was
comparable with those observed in most reports
from the last decade.26
Various radiotherapy techniques have been employed in head and neck CUP. Portals may include
only ipsilateral neck, or bilateral neck including
head and neck mucosa (pharyngeal axis) as a potential site of primary. A review of the literature
shows that the majority of patients receive extensive bilateral neck irradiation including pharyngeal mucosa.6;7;13;25;26;31;72 The estimated
actuarial risk of emergence of head and neck
primary after extensive irradiation is up to 20% at
10 years.7;28 In the majority of series, extensive

Table 2 Treatment outcomes following various therapeutic approaches (reference numbers are given in superscript)
Outcome

Surgery alone
(mainly neck dissection)
(%)

Surgery and
ipsilateral neck
irradiation (%)

Surgery and bilateral


neck/mucosal
irradiation (%)

Primary emergence rate

3223
4476
5426a
6662

779
1227
4476

279
323
473
876
96
1025

Nodal relapse

2477
5069

2076c

076c
925
1477
1773
186

Radiotherapy
alone (%)

2177
4373

Distant metastases

116
1675
1825
2090
2169
2573
3372

Five-year disease free


survival

5472
666
7425

284526a;b

2278
4879
6025
5231
5376
678

08

Five-year overall survival

4776

4127
3779

Squamous cell and undifferentiated carcinoma included; surgery: excisional biopsy in the majority of cases.
28% for ipsilateral neck irradiation, 45% for irradiation of bilateral neck and mucosa.
c
Only N1 cases included.
b

158
radiotherapy resulted in reduced primary tumor
occurrence.2325;30;31;61;7377 In the large Danish
study, the risk of loco-regional relapse after extensive radiotherapy was reduced twofold as
compared to the ipsilateral therapy. This effect
was mainly due to the reduction of neck recurrences.26 The effectiveness of radiotherapy is illustrated by the fact that the risk of emergence of
a primary lesion after extensive irradiation is similar to the occurrence of second tumor in a patient
with overt head and neck cancer.21;26;30;39 The
predominant site of relapse after radiotherapy includes neck, followed by distant metastases.21;25;26;39;78 The crude risk of either nodal
recurrence or distant metastases is at least twofold
higher than the risk of developing a mucosal primary.39
The benefit from extensive radiotherapy to the
mucosa and bilateral neck should be weighted
against its acute and late morbidity (xerostomia,
dysphagia, etc.) and the difficulties in re-irradiation in the case of subsequent primary emergence.
In consequence, ipsilateral radiotherapy to the
involved
neck
side
is
commonly
practiced.20;21;26;27;61;65;76;7982 Based on the retrospective comparisons, some authors conclude that
ipsilateral neck radiotherapy is correlated with the
primary occurrence rate similar to that observed
after extensive radiotherapy.15;65;79;80 Importantly,
in some studies a part of the head and neck mucosa
was irradiated with ipsilateral neck, and this might
have contributed to the reduction of primary occurrence.79
Although in some series ipsilateral radiotherapy
was associated with higher risk of contralateral
neck relapse and/or emergence of the primary,
overall survival was not affected.76;79;80 It was
therefore postulated that after thorough initial
assessment with CT scan and panendoscopy, routine extensive mucosal irradiation may be avoided.
On the other hand, in some reports extended radiotherapy including mucosa and both sides of the
neck resulted in improved survival as compared to
ipsilateral neck treatment.6;26
In a systematic review of the papers published
before May 2000, the reported mucosal carcinoma
emergence rates following comprehensive radiotherapy and unilateral neck irradiation were 213%
(median, 9.5%) and 544% (median, 8%), respectively.39 The corresponding nodal relapse rates were
845% (median, 19%) and 3163% (median, 52%),
and 5-year survival rates were 3463% (median,
50%) and 2241% (median, 37%), respectively.39
In some conditions, the extent of radiotherapy
depends on the extent of nodal involvement. For
example, bilateral lymph node metastases neces-

B.A. Jereczek-Fossa et al.


sitate bilateral neck treatment, whereas exclusive
low neck involvement may be approached with
limited ipsilateral neck irradiation.6
Patients presenting with poor performance status, very extensive nodal involvement, distant
metastases or bilateral low neck involvement are
usually approached with palliative irradiation.28;33;83 This may include hypofractionated
schedules, such as 30 Gy in 10 fractions or 20 Gy in
2 fractions given one week apart.33 Palliative radiotherapy, independently of the radiotherapy
regimen, is associated with an objective response
rate of 65%, the symptomatic response rate of 57%
at one year, and 25% one-year survival.33 Importantly, these figures are similar to those obtained
with palliative chemotherapy, which would likely
be more toxic and more expensive.33
Radiotherapy applications
The curative radiotherapy dose to the mucosa
varied in different series from 50 to 70
Gy,6;11;26;27;30;84 and to the neck from 59 to 70
Gy.6;8;11;26;84 Similarly to current tendency in head
and neck cancer management, hyperfractionated
radiotherapy was used in CUP patients, although
its superiority over conventional irradiation remains to be established.30 Another innovative
strategy tested in CUP patients was combining
radiotherapy and hyperthermia. Amichetti et al.84
applied local microwave hyperthermia and radiotherapy (median 70 Gy to bilateral neck and
potentially primary sites) in a group of 15 patients with locally advanced squamous cell neck
carcinoma from unknown primary. Overall response rate was 87%, and actuarial 5-year local
control and overall survival rates were 65% and
29%, respectively. Both acute and late toxicities
were moderate, however longer follow-up and
larger patient groups are needed to evaluate the
role of this approach.
Ipsilateral irradiation may either include the
ipsilateral neck only (with electron beam) or both
ipsilateral neck and oral cavity, oropharynx and
larynx (with wedge anterior and posterior oblique
fields using photon beams).26;27 In the latter case,
the most probable sites of primary (ipsilateral
tonsillar fossa and base of tongue) are included in
the radiotherapy portals.
The portals of extensive irradiation depend on
the nodal involvement.28 Some authors do not
recommend radiotherapy to the mucosa in the case
of exclusive level I involvement, due to potential
morbidity and relatively effective follow-up and
treatment of subsequent primary in the oral
cavity.6;28;30;83

Cervical lymph node metastases of squamous


For patients with level II and V involvement,
radiation should include naso- and oropharynx.83 In
patients with level III, the irradiation of naso-,
oro- and hypopharynx, as well as larynx, is recommended.28 Some authors suggest, however, irradiation limited to naso- and oropharynx due to
the low probability of occult carcinoma located in
hypopharynx and larynx, and the potential complications of large-volume radiotherapy.6;30;32 Irradiation of nasopharynx may be avoided in patients
with level III involvement,6;27 however irradiation
of retropharyngeal nodes includes the base of skull,
and thus nasopharynx is included anyway.30;85 Importantly, in several series up to 17% of subsequent
squamous cell primaries were found in the nasopharynx.30

Chemotherapy
A combination of chemotherapy and extensive
irradiation was proposed by several authors.8;86
Platinum-based chemotherapy preceding radiotherapy is also recommended for N3 disease by
the European Society of Medical Oncology
(ESMO), whereas irradiation alone is suggested
for N1 and N2 patients.1 Some investigators advocate chemotherapy for supraclavicular lymph
node involvement13 or for undifferentiated tumors.9 However, according to the American
Physician Data Query (PDQ) recommendations,
both chemotherapy and hyperfractionated radiotherapy remain investigational approaches.35 Indeed, in the review of Nieder et al.39 no data
were found to support the benefit of chemotherapy. Future investigation should be directed
to the therapeutic approaches shown to be beneficial in locally advanced head and neck cancer,
such as postoperative radiochemotherapy87 or
definitive concomitant radiochemotherapy for inoperable tumors.88;89

Follow-up
Several authors recommend careful follow-up to
secure effective salvage treatment.20 Contrarily,
the ESMO Guidelines Task Force concludes that
there is no apparent benefit from follow-up in
asymptomatic patients, and suggests specific examinations as clinically indicated. However, these
guidelines concern all CUP patients, independently
of the metastasis site.1
In patients subjected to neck irradiation, thyroid
function testing should be considered prior to
therapy and as a follow-up procedure, since up to

159
30% of patients may develop subclinical or overt
radiation-induced hypothyroidism.35

Prognostic factors and prognosis


Several endpoints, including rates of overall survival, disease free survival, distant metastases,
loco-regional control, neck control and primary
occurrence, have been used to evaluate the outcome of patients with cervical squamous cell carcinoma metastases from unknown primary.
Numerous clinical and physical factors associated
with these endpoints were reported (Tables 35).
However, the impact of particular therapeutic
strategies is difficult to assess retrospectively. Selection bias is unavoidable; for example ipsilateral
irradiation is typically administered for advanced
disease or poor performance status patients,
whereas surgery is performed in early stages.
The nodal status is considered the most important prognostic factor. In fact, the prognosis seems
equivalent to that observed in patients with overt
primary and similar nodal stage.26 For patients
treated with neck dissection, other prognostic
factors include the number of lymph nodes, grading
and extracapsular extension.39
Over the last 30 years, probably due to better
pre-treatment evaluation and more effective
therapy, neck control and primary occurrence have
improved in head and neck CUP patients.69 The
question of whether these effects have been
translated into improved survival is debatable.24;69

Patterns of failure
The pattern of failure depends on the treatment
applied. After extensive radiotherapy, the predominant patterns of relapse include neck recurrence and distant metastases.21;2526;78 The latter
are observed in up to 33% of patients (Table
2)6;69;72;73;75;90 and usually occur shortly after the
treatment completion (median 0.9 years).30;72
The rate of emergence of the primary tumors
varies largely in particular series from 0% to 66%
(Table 2).6;23;25;26;27;39;62;73;76;79 The highest rate was
observed following exclusive surgery.26 The median
time to the occurrence of subsequent primary was
about 21 months,6;30 and the most common sites
included oral cavity, oro- and nasopharynx, and
supraglottis.26;30
Several authors observed poor prognosis after a
subsequent detection of the primary lesions

160

B.A. Jereczek-Fossa et al.

Table 3 Factors associated with poor outcome in terms of overall survival, disease free survival and distant failure
in patients with cervical metastases from unknown primary
Factor

Associated
(references)

Treatment-related variables:
Treatment (excisional biopsy, radical neck dissection, RT alone,
neck dissection followed by RT)
RT vs. surgery followed by RT
RT followed by surgery (vs. surgery followed by RT)
Split RT (vs. continuous RT)
Extent of RT (ipsilateral neck vs. mucosa and bilateral neck)
RT dose to the mucosa
RT dose to the neck
Overall treatment time
Overall RT time
Involved surgical margins/residual disease after surgery
Extent of neck surgery (node excision, modified, radical neck
dissection)
Planned neck dissection
No bilateral pre-treatment tonsillectomy
Treated in the 1970 vs. 1990
Patient-related variables:
Sex
Weight loss before treatment
Older patients
Hemoglobin level
Tumor-related variables:
Higher nodal stage
Extracapsular extension
Involvement of low neck nodes
Involvement lymph node regions (multiple vs. isolated)
Nodal size
Fixed lymph nodes
Histologic differentiation

Not associated
(references)
23, 11b

8, 91a
27
6
6m
30m

20m

30m
7a
24

19ma
27
26mb
26mb , 30m
26mb
30m,
26mb
6
25m

69
30m, 26mb

24
19a m, 24
26mb
9, 11b , 19ma , 23, 24, 26mb ,
27, 30m, 31, 63, 69, 75, 78
6, 23, 30m
8, 18a
25m
17a
17a
78

6, 20m, 25m,
16, 20m, 25m
30m
6
30m
6, 30m

m, multivariate analysis; RT, radiotherapy.


All histologies included.
b
Undifferentiated and squamous cell carcinoma included.
a

(median survival of 15 months after the diagnosis,


5-year survival of 20%)16;27;76 whereas others attributed poor outcome to nodal relapse, but not to
primary occurrence.17 In some series tumors arising
later than 5 years after primary treatment were
classified as second primaries,27 whereas in others
they were considered to be the site of origin.30

Conclusions and future directions


Despite many studies addressing cervical metastases from unknown squamous cell carcinoma, the
optimal diagnostic and therapeutic approach has
not yet been established. The role of new investigational methods, such as PET, SPECT or laser-

induced fluorescence, and the relevance of molecular assays still await critical evaluation. The
optimal extent of surgery and radiotherapy has to
be defined, both in terms of its efficacy and impact
on patient quality of life. The value of other therapeutic modalities (such as chemotherapy, hyperthermia) should be further investigated.
Recently, the first randomized study on squamous cell head and neck CUP patients has been
launched by the Intergroup including the European
Organization for Research on Treatment of Cancer
(EORTC), Radiation Therapy Oncology Group
(RTOG) and other cooperative groups from Australia, Canada, Denmark and Germany (study
2400122005). After surgery (radical neck dissection, modified or extended radical neck dissection,

Cervical lymph node metastases of squamous

161

Table 4 Factors associated with poor neck control in patients with cervical metastases from unknown primary
Factors

Associated
(references)

Treatment-related variables:
RT vs. surgery followed by RT
Extent of RT (ipsilateral neck vs. mucosa and bilateral neck)
Residual disease after surgery
Type of surgery (extirpation/biopsy of lymph node vs. neck
dissection)
RT dose to neck
Time interval between surgery and RT
Overall treatment time
Planned neck dissection
Treatment before 1977

Not associated
(references)

76
6
6
6

76

25, 30m
25
25, 30m
30m
69

Patient-related variables:
Sex

30m

Tumor-related variables:
Higher nodal stage
Histologic differentiation
Extracapsular extension
Involved lymph node regions (multiple vs. isolated)
Level of nodal involvement
Number of lymph nodes in the surgical specimen

30m

6
6, 30m
6, 30m
6
30m

25
25
17a

**, undifferentiated and squamous cell carcinoma included; m, multivariate analysis; RT, radiotherapy.
a
All histologies included.

Table 5 Factors associated with higher risk of subsequent primary tumor in patients with cervical metastases from
unknown primary
Factors
Treatment-related variables:
RT dose to the mucosa
Overall treatment time
Planned neck dissection
Treatment before 1977
Surgery vs. surgery and RT

Associated (references)

30m
30m
30m
69
69

Patient-related variables:
Sex
Tumor-related variables:
Higher nodal stage
Histologic differentiation
Level of nodal involvement

Not associated (references)

30m
30m
30m
30m

m, multivariate analysis; RT, radiotherapy.

or selective neck dissection), patients are randomized either to selective radiotherapy (ipsilateral neck node area) or to extensive irradiation
(naso-, oro, hypopharyngeal and laryngeal mucosa
and neck node areas on both sides of the neck).
Patients with single level IV, Vb or I lymph node are
excluded. The inclusion of pN1 patients depends on
institutional policy. Systematic ipsilateral tonsillectomy is obligatory. The primary endpoint is
disease-free survival, and the secondary endpoints
include control of the neck, incidence of sub-

sequent primary in the head and neck region,


overall survival, acute and late toxicity, and quality of life. The results will be available several
years from now, but they should elucidate many
questions regarding management of the head and
neck CUP patients.

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