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TUMOUR REVIEWS
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
Introduction
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
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-
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.
156
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
Greven et al.47
14
PET, positron emission tomography; CUP, carcinoma of unknown primary site; SCC, squamous cell carcinoma.
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
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
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 (%)
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
5472
666
7425
284526a;b
2278
4879
6025
5231
5376
678
08
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-
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
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
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
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,
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
30m
30m
30m
30m
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-
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