NECK METASTASIS FROM AN UNKNOWN PRIMARY - RECENT ADVANCES

1. NECK
METASTASIS
FROM AN
UNKNOWN
PRIMARY Recent advances
Dr MANU S BABU
MBBS MS ENT

2. The term carcinoma of unknown
primary (CUP) represents a
heterogeneous disease entity
characterized by the presence of
clinically overt metastatic disease in the
absence of a clinically or radiologically
obvious primary tumour.

3. CUP is diagnosed in a patient who presents with biopsy
proven squamous cell carcinoma (SCC) in one or more
cervical lymph nodes and in the absence of an obvious
primary tumour despite rigorous clinical examination,
appropriate cross-sectional imaging and examination under
anaesthesia including an ipsilateral tonsillectomy and
biopsy of tongue base mucosa (or formal mucosectomy) +/−
biopsy of the mucosa of the post nasal space and/or
ipsilateral piriform fossa

4. It is important to distinguish between true CUP cases in which a primary site
tumour never becomes evident and the case where, on initial presentation, a
primary tumour is present but remains undetected.
In the latter case, it is presumed that there has been early metastasis from a
small primary tumour following which the growth of the cervical metastasis
has proceeded at a considerably faster rate than that of the primary tumour.
 It is inevitable that, left untreated, the primary tumour would eventually
become clinically evident.
 However, as will be seen later, the sites at highest risk of harbouring a
primary tumour are often treated in any case such that the primary tumour
never becomes clinically evident.

5. 1. The microscopic primary tumour lies undetected in the mucosal
folds of Waldeyer’s ring and is too small to be detected by conventional
diagnostic methods and is ultimately successfully treated either by
design or coincidental (by inclusion in radiation fields designed
primarily to treat the neck).
2. The primary tumour is removed by the patient`s innate or adaptive
immune system, but not before early metastasis to the cervical lymph
nodes has occurred with subsequent evasion of the host immune
response

6. In the 1970s and early 1980s, prior to the universal availability of crosssectional imaging, the
incidence ranged between 10% and 30%. Many of these historical cases may have been
incorrectly diagnosed as CUP as they represented distant metastases from lung and abdominal
primaries
The incidence reported in the literature subsequently plateaued over the last decade to around
5% of HNSCC due to standardized diagnostic protocols.
It is increasingly recognized that high-risk HPV related HNSCC tends to present with regional
disease and clinically unrecognized primary focus, and most patients with CUP presentation
will have a primary site in the oropharynx.

7.  1. History -A history of excessive alcohol consumption and heavy smoking may suggest a
primary
 tumour outside the nasopharynx, while a history of multiple sexual partners and orogenital
contact may suggest a primary tumour within the oropharynx.
 2. Fibre-optic nasolaryngoscopy - with special attention to sites where a small primary
focus can be missed, such as the nasopharynx, tongue base, the infrahyoid epiglottis and the
pyriform sinus.
 3. The site of the node is an indicator of the primary site. For instance, level I nodes are
almost never seen with nasopharyngeal primaries and level V nodes never with laryngeal
cancer.

8. Based on the modication of the standard white light endoscope in which white light is
transmitted through optical filters absorbing all but two wavelengths; one band centred at 415
nm and another at 540 nm.
The former wavelength penetrates the supercial mucosa and highlights submucosal capillaries
as a brown colour while the latter penetrates through the submucosal layer and identifes
prominent vessels as cyan in colour.
 SCCs arising from the upper aerodigestive tract mucosa are accompanied by neo angiogenesis,
NBI identies neoplastic tissue at an earlier stage than conventional endoscopy.
A meta-analysis31 of four studies where NBI was performed on 115 patients with CUP
demonstrated a high level of diagnostic accuracy(sensitivity (74.1%; 95% condence interval [CI]
52.5%–100%) and specicity (94.1%; 95% CI 5 23.7% –100%)).

9. This should be followed by cross–sectional imaging such as multi-planar
computed tomography (CT) or and magnetic resonance imaging (MRI) and
FDG PET-CT before the patient is subject to an assessment under general
Anaesthesia
If the primary is not identied following the above sequence of investigations,
then the patient should undergo pandendoscopy under general anaesthesia
which should include biopsies based on the results of the core biopsy and
imaging. Sites to be sampled include the nasopharynx, tongue base and
ipsilateral tonsillectomy.
Using this protocol, most CUP cases turn out to be either tonsil or tongue
base primary cancers

10. Blind biopsies of the nasopharynx have proven to be
unsatisfactory as they often provide a poor yield of
primary site diagnosis.
It is therefore recommended that biopsies on this site
should be guided using rigid telescopes, especially where
abnormalities have been noted on imaging.
 In instances where high-resolution imaging does not
identify pathology, even telescope-guided biopsies are
unlikely to pick up a malignant focus.

11. There is evidence from selected series that bilateral tonsillectomy should be
employed as the primary resides in the contralateral tonsil in up to 10% of cases.
 In the high-risk HPV era, there is greater recognition that these tumours can be
multifocal at presentation, providing further basis for a bilateral tonsillectomy .
It has been suggested that bilateral tonsillectomy could reduce the need for
bilateral irradiation to the neck, thus leading to reduced morbidity.
 In patients who have undergone previous tonsillectomy but they have tonsillar
remnants, the search for the primary should also include the excision of the
remnants as primary tumours can be found within them.

12. Blind biopsies of the base of tongue (BOT) are often unsatisfactory as occult carcinomas rarely
arise from the mucosal surface.
 It is therefore advisable to target the deep tissue of the BOT.
 The superior manoeuvrability and access provided by transoral robotic techniques have led to the
design of the procedure called tongue base mucosectomy.
This procedure samples the entire tongue base mucosa and has been shown to identify a primary
site in over 50% of patients who are PET negative and have no primary site in the tonsil.
Interestingly, around 10% can be contralateral foci.
However, the morbidity of this procedure cannot be underestimated, with the risk of bleeding,
need for tube feeding and the very small risk of pharyngeal stenosis

13. key modality in the evaluation of the unknown primary.
It is combined with a CT scan to provide anatomical localization of the avid lesion (fusion or co-
localized PET scanning).
A recent meta-analysis of FDG-PET-CT from the Netherlands has reported data from 11 studies
including 433 patients with CUP. Overall primary detection rate was 37%, with equal sensitivity
and specicity of 84%.
A negative PET-CT result does not preclude the requirement for panendoscopy and multiple site
biopsies.
Other studies have identied the sensitivity and specicity of PET scanning in identifying the
primary in HNSCC to be as high as 87% and 92% respectively.
It should be noted that this investigation is only useful if it is performed before the
panendoscopy and biopsies, as the post-biopsy inammatory response may increase the uptake of
the FDG tracer, causing a false positive result

14.  1. Consider adding ultrasound guidance to ne-needle aspiration cytology or core
biopsy.
 2. Consider having a cytopathologist or a biomedical scientist to assess the
adequacy of the cytology sample.
 3. Consider a FDG PET-CT scan as the first investigation to detect the primary
site.
 4. Consider using NBI (in clinic or during general anaesthetic assessment) in
cases where PET-CT has led to identify a primary site.
 5. Offer surgical diagnostic assessment if the FDG PET-CT does not identify a
primary site, including guided biopsies, tonsillectomy and TBM

16. CUP management can be organized into the treatment of early disease (N1 with no extracapsular
spread) and advanced disease (extracapsular spread, N2 and N3).
In early disease, single-modality therapy can be considered in the form of neck dissection alone or
radiotherapy alone.
 Radiation therapy alone has been reported for small N1 stage disease with some success and can
be considered in patients with comorbidities that can pose a high surgical risk.
Similarly, some authors have adopted neck dissection surgery alone without radiotherapy for N1
neck disease with a ‘watch & wait’ approach to the primary.
Advanced cases require combined modality therapy

17. Traditionally, either radical neck dissection or modied radical neck dissections
have been employed in the management of CUP.
Selective neck dissection has been suggested as a valid option for patients with
N2a and N2b disease as the risk of metastases in levels I and V has proven to be
rare in patients with CUP unless they present with N3 neck disease,
Traditionally, most units favour neck dissection upfront followed by either RT or
chemoradiotherapy (CRT) as indicated.
 This allows adequate pathological staging of the neck and therefore tailoring
treatment accordingly

18.  There is also an advantage of performing surgery in a non-irradiated neck and
therefore minimizing morbidity.
 This approach could potentially cause a treatment delay if any unexpected
complications from the surgery occur.
 Primary RT or CRT will reduce the need for but may render surgery difcult
and with an increased risk of complications
 However, recent randomized trials48 have reported that PET-CT-guided active
surveillance after radical CRT showed similar survival outcomes to upfront neck
dissection followed by CRT and lead to considerably fewer NDs, fewer
complications and lower costs.
 Although this is in the setting of the known primary, the data is robust enough to
warrant a re-examination of current approach for primary surgery in CUP,
especially when a rm diagnosis of the neck lump can be established by non-
surgical means.

19. In the past many patients underwent excisional and incisional biopsies as first-line diagnosis.
 Earlier reports identified poor prognosis in these patients, which has been attributed to
inadequate definitive treatment and advanced stage at presentation.
With current, centralized, multidisciplilnary team (MDT) driven practices, smaller numbers of
patients with lateral neck masses undergo open surgical interventions for diagnosis, primarily
due to non- diagnostic FNAC or owing to suspicion of non-SCC pathology such as lymphoma.
 In the era of adequate surgical management of the neck and good (chemo)radiation practices,
open cervical biopsy does not signify a poorer prognosis provided adequate and timely treatment
is given.
 A high proportion of HPV positive oropharyngeal tumours may also explain the favourable
outcomes observed.
 The treatment of the violated neck can be upfront surgery or CRT followed by PET-CT
surveillance and surgery as needed.

20. The evidence for the existence of branchial cyst or branchiogenic carcinoma is tenuous.
Many reported series have failed to meet the criteria set by Hayes Martin and in many cases
elective tonsillectomies were not performed.
 Many patients with CUP may present with lateral neck cystic masses mimicking branchial
cysts.
 There is enough evidence to recommend that all patients over the age of 35years with lateral
cystic masses must be presumed to have cancer until proven otherwise.
 these people should be entered into a CUP investigation protocol even if the FNAC is not
suggestive of metastatic SCC

21. The external beam radiotherapy (EBRT) fields recommended remains
controversial, with some centres offering unilateral radiation to the neck and
ipsilateral likely primary sites, whilst others propose bilateral neck treatment,
so-called ‘total mucosal irradiation’.
Results for bilateral neck irradiation tend to show improved local control rates
and disease-free survival compared to unilateral neck treatment.
The improvement on overall survival however is not always seen,
Unfortunately, the superior survival results seen with bilateral EBRT are at
the expense of increased morbidity in terms of pain, xerostomia and long-term
dysphagia with increased feeding tube dependence.

22. Intensity-modulated radiotherapy treatment (IMRT) with bilateral neck radiation has
the potential for reduced acute and late toxicity as the parotid glands may be spared,
with robust data to suggest that IMRT signicantly reduces morbidity.
IMRT is currently the standard of care for head and neck cancers in several countries.
For CUP patients receiving total mucosal radiation,
IMRT appears to provide improved radiation coverage of the mucosa including the
nasopharynx with significant reduction of dose to the parotid gland contralateral to the
involved neck and therefore reducing the risk of severe xerostomia

23.  1. bcT0N1M0
 cT0N1M0 WITHOUT ENE FOUND ON HISTOPATHOLOGICAL OR RADIOLOGICAL STUDIES
 Patients can be treated with single-modality treatment either with selective neck dissection or
involved field radiotherapy alone.
 If treated surgically, the upper aerodigestive tract mucosa should be carefully inspected during
surveillance visits.
 2. PT1N0M0 WITH ENE
 Patients should be treated with post-operative RT if ENE is identified
 3. T0N2M0 AND T0N3M0
 Patients should be treated with primary CRT followed by PET-CT guided surveillance or combined
modality treatment including neck dissection followed by RT or CRT.

24. Most series show improved overall and disease-free survival with combined modality treatment.
Survival results are dependent upon the N stage at presentation with worsening outcome observed
with increased stage.
The outcome and survival of patients with CUP has been variable as the published series are mainly
retrospective and represent diverse patient populations.
We would however expect a 5-year survival of between 70% and 100% for N1 stage cancers and 30%
and 60% for stage N3.
The overall 5-year survival for all stages of HNSCC with unknown primary site would be in the range
of 52% and 75%.39–49
A 10-year single-centre uncontrolled retrospective case series of 25 patients with complete records,,
showed an excellent overall survival for N1 disease of 100% and a 60% survival for patients with N2
and N3 neck disease
In a recent series of patients with CUP treated with IMRT by the Memorial Sloan Kettering Cancer
Center showed 2-year regional progression-free survival, distant metastases-free survival and overall
survival of 90%, 90% and 85% respectively

25. The pattern of failure largely depends on the initial treatment protocol.
 If EBRT is used, disease recurrence is usually in the neck and in form of distant metastasis.
Recurrent disease is often difcult to diagnose and it often shows extracapsular spread and
presents in advanced stages.
FDG-PET-CT scan is probably the best method of detection and diagnosis of recurrences.
 Distant metastases often occur within a year of treatment completion and are most common
in the lung.
 The incidence of recurrence in the potential primary sites is extremely variable and may
occur from 0% to 66%.
 It occurs mainly in those patients treated initially with surgery alone.
The emergence of aprimary tumour often occurs within the rst 24 months and usually
presents in the oral cavity, oropharynx and nasopharynx

26.  The unknown primary in HNSCC is becoming an increasingly rare entity due to better diagnostic protocols and now
accounts for fewer than 5% of cases.
 However, the raw numbers may be on the increase owing to the higher number of HPV-positive cancers.
 The diagnostic workup should include panendoscopy, bilateral tonsillectomy,biopsies of nasopharynx, tongue base and any
other potential suspicious lesions in the upper aerodigestive tract. Investigations should employ cross-sectional imaging CT
and or MRI as well as PET-CT imaging; the latter must be performed before the biopsies are taken.
 Recent modalities being used in the clinical and operative setting allow for a higher primary pickup rate. Most of these
cases identify the primary in the oropharynx.
 Treatment of CUP should be based on the stage of the disease process, with single modality sufcing for patients with early
stage disease.
 A combination of neck dissection and EBRT may be needed for patients with advanced disease.
 Bilateral neck irradiation increases overall and disease-free survival at the expense of increased morbidity
 Molecular analysis of the metastatic cervical neck nodes can potentially locate previously occult oropharyngeal or nasopharyngeal
primaries.
 The survival outcomes are generally good for early and late-stage disease but whether less intensive or singlemodality therapy
could be adequate in patients who are HPV-positive is yet to be determined

27.  Several questions in the aetiology and management of CUP remain unresolved.
These include:
 ➤ Is definitive neck dissection sufficient for patients with N1, N2a and selected
N2b disease, avoiding the need for elective total mucosal irradiation?
 ➤ Should definitive RT or CRT should be offered as a primary modality of
treatment with salvage neck dissection for persistent
 disease?
 ➤ Which extent of neck dissection patients should have foreach stage?
 ➤ What are the optimal fields for elective irradiation? Ipsilateral,versus bilateral
vs total mucosal unilateral or bilateralirradiation

28.  • CUP is an increasingly rare clinical scenario and accounts for only up to 5% of patients with head
and neck malignancy.
 • Involvement of nodal levels I to IV is almost exclusively associated with occult upper aerodigestive
tract primary SCC with level II being the most common site
 • Patients should be evaluated with CT, MRI or FDG-PET-CT prior to biopsy in order to guide
biopsy site and to avoid imaging artefacts or false positive results with PET-CT.
 • FDG-PET-CT has now a clear role on the management of CUP and should be employed whenever
possible..
 • The only tumour marker of clinical value is Epstein–Barvirus serology as will indicate origin from
the nasopharynx.HPV16 status can be determined in tumour cells aspiratedfrom the necks of
patients with metastatic HNSCCand its presence is a reliable indicator of origin from
theoropharynx.
 • Bilateral tonsillectomy may be recommended as diagnostictool in the evaluation of CUP. Transoral
laser and transoralrobotic mucosectomies of the tongue base have showedpromising results in
detecting primary tumours at this site.

29. • Definitive neck dissection should be performed in all patients with CUP.
The extent of the neck dissection requires further evaluation especially on those
patients with N1, N2a and limited N2b disease where selective neck dissection
could be considered.
• Total mucosal irradiation has demonstrated a reduction in primary site recurrence
without any improvement in overall survival. Associated mucositis and xerostomia
rates are high.
• Radiotherapy-related morbidity can be reduced if selective mucosal irradiation is
undertaken, most commonly by exclusion of nasopharynx especially in patients
presenting with II to IV nodal disease.
• IMRT should be considered as the optimal technique for radiation dose delivery.
• For total mucosal irradiation, a dose of 50 Gy in 25 daily fractions, five fractions
per week is sufficient for control of
occult primary disease.
• Nodal stage is the most important risk factor for local recurrence.
• CRT in patients with CUP should be considered in N3 disease and in those
patients with definitive ECS or when
resection margins are positive for example around the common carotid artery

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cancer incidence in the United States. J Clin Oncol 2011; 29: 4294–301.
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and nonoropharyngeal head and neck cancer: systematic review
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