Accepted: 18 February 2017

DOI: 10.1111/coa.12860

ORIGINAL ARTICLE

Trans-oral robotic assisted tongue base mucosectomy for

investigation of cancer of unknown primary in the head and
neck region. The UK experience

S.C. Winter1 | E. Ofo2 | D. Meikle3 | P. Silva1 | L. Fraser1 | J. O’Hara3 | D. Kim2 |

M. Robinson3 | V. Paleri3,4

1
Oxford University NHS Trusts, Oxford, UK
2
St George’s University Hospitals NHS
Foundation Trust, London, UK
3
Newcastle upon Tyne Hospitals NHS
Trust, Newcastle upon Tyne, UK
4
Northern Institute for Cancer Research,
Newcastle University, Newcastle upon
Tyne, UK
Correspondence
S.C. Winter, Churchill Hospital, Oxford, UK.
Email: Stuart.winter@ouh.nhs.uk
Abstract
Objectives: The diagnosis of cancer of unknown primary (CUP) in head and neck
occurs when the treating clinicians have utilised all available diagnostic tests and
failed to identify the origin of the disease. There is no agreed consensus on which
diagnostic investigations to use, or the order in which to use them in, although
broad recommendations exist. Small tumours arising in the tongue base can be
below the limits of resolution of conventional diagnostic techniques. Given the diffi-
culty in targeting the tongue base, current practice involves blind random biopsies,
which leads to a variable detection rate. Robotically assisted surgical removal of the
tongue base, tongue base mucosectomy (TBM) has been shown to improve diagnos-
tic yield. This study reports the diagnostic hit rate for tongue base primaries using
this technique.
Design: Retrospective case review.
Setting: UK Head and Neck Centres.
Participants: Patients presenting as an unknown primary, investigated with clinical
examination, PET-CT and palatine tonsillectomy.
Main Outcome Measures: The detection of a primary site of head and neck cancer
in the otherwise unknown primary tumour.
Results: The primary tumour site was identified in the tongue base in 53% (n=17)
of patients. In 15 patients the tumour was in the ipsliateral tongue base (88%)
while in two cases (12%) the tumour was located in contra lateral tongue base.
Conclusions: Trans-oral robotic assisted TBM raises the possibility of identifying
over 50% of tumours that would otherwise be classified as CUP. Identifying these
in the contralateral tongue base has implications for treatment planning and out-
come.

1 | INTRODUCTION
Detection and assessment of the primary site remains a central strat-
egy in the diagnostic evaluation of head and neck squamous cell
cancer (HNSCC). Squamous cell carcinoma in a cervical lymph node
with no identifiable primary site occurs in 2-4% of new head and
neck cancer diagnoses.1 Techniques to find the primary site have
evolved over time as technologies and understanding of the disease
process have improved.2
The definition of cancer of the unknown primary (CUP) is not
fixed and reflects in part the number and type of investigations per-
formed to identify the tumour. Once a tumour has been identified it

Clinical Otolaryngology. 2017;42:1247–1251. wileyonlinelibrary.com/journal/coa © 2017 John Wiley & Sons Ltd | 1247
1248 | WINTER
is no longer a CUP. There is no internationally agreed consensus for
the diagnostic investigations that need to be used or the order to
use them in; however, recent NICE guidelines in the UK have rec-
3
ommended a diagnostic algorithm. All patients should undergo a
comprehensive physical examination including flexible nasendoscopy,
this may be supplemented by trans-nasal oesophagoscopy and
newer endoscopic modalities that use lights at different wavelengths
to enhance the submucosal vasculature, such as narrow band imag-
ing.4 Thereafter, a variety of radiological imaging modalities are
employed including CT, MR and PET-CT, each with increasing sensi-
tivity and specificity for identifying CUP.5,6 Cytology from a fine
needle aspiration biopsy and or tissue from a core biopsy are used
to establish the diagnosis of metastatic squamous cell carcinoma.
Clinical guideline documents recommend the use of high risk human
papillomavirus (HR-HPV) testing and Epstein Barr virus (EBV) test-
7
ing These laboratory tests can be used to establish the likely site
of the primary tumour: HPV, oropharynx: EBV, nasopharynx. Accu-
mulating clinical experience suggests that the majority of CUP are
HPV-related squamous cell carcinomas and are typically located in
the palatine tonsil or the lingual tonsils of the tongue base.8
Examination under anaesthesia ‘panendoscopy’ has been a main-
stay of the investigative workup for this patient group; preferably
performed after all radiological imaging and biopsies of the
nasopharynx, hypopharynx and oropharynx have been undertaken.
These biopsies can be directed if there is an identifiable area of
abnormal mucosa, but in other cases are directed at known ‘high
risk’ areas. Performing a palatine tonsillectomy rather than a deep
biopsy has also improved the diagnostic yield as a number of small
9
tumours are within the tonsil crypts. While some studies have
reported 10-17% of tumours arising in the contralateral tonsil there
remains no consensus on performing a unilateral or bilateral tonsil-
lectomy.10,11
These investigations will identify a primary tumour in around a
third of patients. For the other patients, classified as CUP, there is
the spectre of undetected disease, with potential impact on quality
of life and survival.12 Without identifying a primary tumour it is likely
the patient will receive wide field radiotherapy with or without
chemotherapy, with the extent of the irradiated mucosa varying
from ipsilateral oropharyngeal mucosa, to all oropharyngeal mucosa
sparing the nasopharynx, to complete upper aerodigestive tract
mucosal irradiation.13 The nodal groups in the neck, on one or some-
times both sides, are always in the radiation fields. The extent of
radiotherapy treatment has a direct impact on functional and long-
term outcomes.14,15
Trans-oral robotic assisted tongue base mucosectomy (TBM) has
emerged as a novel management strategy to further reduce the
number of patients classified as CUP.2 The improved vision and
manoeuvrability of the robotic instruments allows comprehensive
sampling of the tongue base mucosa in a way that has not been pre-
viously possible. To date all of the studies have been from North
American Institutions. This is the first study to report the UK experi-
ence for this technique from three centres that are early adopters of
trans-oral robotic surgery.
ET AL.
2 | DESIGN, MATERIALS AND METHODS
This is a prospective multicentre cohort study. Patients presenting
with metastatic HNSCC in a neck node and classified as CUP were
offered TBM as a diagnostic intervention at three tertiary head and
neck cancer centres (London, Newcastle and Oxford) between 2014
and 2016. While there was some variation in the pathway, only
patients in whom sequential clinical, radiological and examination
under anaesthesia did not identify a primary tumour were included. All
patients underwent PET-CT examination prior to surgical intervention.
All patients underwent comprehensive examination under anaes-
thesia, followed by a tonsillectomy if appropriate and a TBM. Based
on the diagnostic pathway at each centre, driven primarily by the
referral pattern, logistics of robotic availability, patients underwent
tonsillectomy at the same operation or at a later date. The patient
cohort in whom diagnostic efficacy of TBM was calculated included
only those in whom no primary tumour was identified following clini-
cal examination, imaging including PET-CT and a tonsillectomy with
or without biopsies. Patients, in whom a primary tumour was identi-
fied in the tonsil, even if they underwent a concurrent TBM, have
been excluded from this study.
The procedure was performed under general anaesthesia. The da
Vinci S was used in OX, the da Vinci Si was used in SGH. Both the
S and Si systems were used based on robotic availability at NuTH. In
all cases, the 5 mm monopolar spatula cautery was used to perform
the dissection, with the 5 mm Maryland forceps was used for retrac-
tion. The TBM specimen was bisected and orientated before being
sent for pathological examination Figure 1.
3 | RESULTS
Across the three centres, 35 TBM were performed in the time per-
iod. In three patients, SCC was confirmed in the palatine tonsils.
These three patients underwent synchronous TBM and palatine
tonsillectomy and were excluded from this analysis, as these
patients would have been identified using conventional techniques.
Of the 32 patients who form the subject of this report, the number
of patients at each site is as follows: Oxford University Hospital
(OUH; n=11), Newcastle upon Tyne Hospitals NHS Trust (NuTH;
n=12) and St Georges University Hospital (SGH; n=9). The sex dis-
tribution of this cohort was 27 male and five female patients with
a mean age of 57 years (range, 41-74 years). SCC was confirmed
after fine needle aspiration cytology or core biopsy in 23 of 32
patients, Table 1.
Of the 32 patients, 27 patients underwent a tonsillectomy con-
currently or prior to TBM; four patients had undergone a tonsillec-
tomy as a child and in these patients the tonsillar fossa was
rigorously inspected. One patient did not undergo tonsillectomy prior
to TBM. 13 patients underwent additional ‘blind’ biopsies from their
upper aerodigestive tract.
The primary tumour site was identified in the lingual tonsil in
53% (n=17) of patients. In 15 patients the tumour was in the
WINTER ET AL. | 1249

T A B L E 1 Investigations performed prior to tongue base

mucosectomy
Core Open
FNAC Biopsy Biopsy
Cytopathological 23 7 2
Investigations of
the neck node
MRI CT PET-CT
Imaging undertaken 13 17 32
Blind biopsies
from the
aerodigestive
Tonsillectomy tract
Tonsillectomy and 27 (four patients 13
biopsies of the had a
upper aerodigestive tonsillectomy
tract as a child)

F I G U R E 1 Intraoperative view after the left tongue base
mucosectomy(TBM) has been completed and pathological specimen
ipsilateral tongue base (88%) while in two cases (12%) the tumour
was located in contralateral tongue base.
In 23 of 32 (72%) patients were deemed to be HPV positive
based in p16 immunohistochemistry, 26% (8) were negative and 1
(3%) was not reported.
Complications were reported in three (9%) patients: one patient
developed postoperative chest infection and two others had postop-
erative bleeding that settled with conservative treatment The dura-
tion of hospital stay was not reported in all cases.
4 | DISCUSSION
Head and neck cancer represents sixth most common cancer in the
16
world with an estimated 6 00 000 cases per year. Worldwide the
incidence of oropharyngeal squamous cell carcinoma (OPSCC) has
increased with the largest increase in Western populations and
younger men. In the UK, over the last two decades the incidence
has increased from 2.9 per 1 00 000 males in 1992 to 3.5 per
1 00 000 in 2010.17,18
The rising incidence of OPSCC is attributed to an increasing role
of human papillomavirus (HPV). Evidence suggests that HPV-positive
OPSCC may represent a distinct disease entity, tending to occur in a
younger patient group, with an improved treatment response and
survival when compared to HPV-negative disease.
The ability to identify the primary tumour site has advantages
for the patient in terms of understanding their diagnosis and overall
survival.5,12,19 It also has advantages for the clinician as treating the
site of the primary tumour and likely nodal basin is the basis of head
and neck cancer care. Furthermore ipsilateral rather than bilateral
neck and mucosal radiotherapy has a significant beneficial impact on
long-term function in particular with respect to swallowing and saliva
function14.15 It is also recognised that radiotherapy to the neck
increases the risk of carotid artery atherosclerosis and therefore as
the patient demographics change long-term functional outcomes
become increasingly important.20
Strategies to improve identification of the primary site have been
evolving for a number of years. The increasing sensitivity and speci-
ficity of current imaging techniques has improved. PET-CT appears
to offer the highest sensitivity and specificity compared to CT alone
or MR scanning and is recommended in the 2016 NICE guidelines.3
However, it is recognised that the lowest sensitivity for PET-CT is in
the tongue base, reflecting the small volume of disease in occult
cases and the surrounding uptake of radio-labelled isotope in the
surrounding lingual tonsils.6
Dissection of the lingual tonsil (laser tongue base mucosectomy)
has been reported using the laser with diagnostic identification of
the primary site ranging fromm 75 to 89%. However, the improved
visualisation afforded by the robotic assisted technique combined
with the limitations of access and line of sight operating with the
laser limits this option to a smaller subset of patients.21
The use of robotic assisted tongue base mucosectomy has been
incorporated into a number of differing investigative pathways.
1250 | WINTER
Mehta et al.22 report a retrospective series of 10 cases in which
they performed a TBM after imaging, CT, MR or PET-CT followed
by endoscopy and bilateral tonsillectomy. In this series, 9 of 10
(90%) cases a primary tumour was identified in the base of tongue.
Patel et al.23 report a retrospective series of 47 patients. CUP
was defined after imaging, USS CT MR or PET-CT. 57% of patients
only underwent a PET-CT. TBM was combined with a variety of pro-
cedures and they report the primary site was identified in 72% of
cases. While the majority was in the base of tongue 13 tumours
were identified in the tonsil.
Durmus et al.10 report a series of 22 prospective cases. CUP was
defined after clinical examination and PET-CT. They carried out fro-
zen section biopsies and only proceeded to a diagnostic palatine and
lingual tonsillectomy when they were negative. In this series, they
identified a primary tumour in 78% of cases the majority in the pala-
tine tonsils.
The sensitivity and specificity of TBM reflects in part the investi-
gations that have been performed prior to the procedure, as these
will have diagnosed or raised the suspicion for the site of the pri-
mary in a number of cases. A recent systematic review on identifying
the unknown primary by Fu et al.8 has reported on eight studies
with 139 patients. Overall this review reported that 80% of the
unknown primaries were identified. In the subset of patients in
whom physical examination, direct visual examination and imaging
were all unremarkable there were 13/22 (59%) primary tumours
identified. The majority on the ipsilateral tongue base (96%) while
6% were in the contralateral tongue base. This systematic review
included patients from only North American institutions and yet
yields very similar diagnostic rates to this study.
Fu et al. report an overall 7% complication rate with postopera-
tive bleeding the most common complication. The slightly higher rate
reported in this study may reflect the later adoption of the tech-
nique in the UK compared to North America. While not measured
directly swallowing function has been reported to recover over
around 6 weeks24 and in the study by Fu et al.8 only 1% did not
return to a normal diet. It is yet to be demonstrated that identifying
the primary tumour will alter survival and functional outcomes as
adjuvant treatment can be tailored to the individual patient. How-
ever, the ability to treat a unilateral area may have significant affects
on swallowing in the long term.
Finally, it is likely that the discovery of a primary tumour in a
TBM specimen is dependent on pathology laboratory protocols. It is
conceivable that systematic examination of all the tissue using a step
serial section approach, similar to sentinel node examination, may
increase the rate of primary tumour detection.25 This suggestion
would require additional pathology resources and costs, but if effec-
tive, has the potential to influence patient care.
5 | CONCLUSION
This study provides further support for the use of tongue base
mucosectomy in identifying the primary tumour site. This is the first
ET AL.
study outside of North America to report on the sensitivity of the
procedure and demonstrates very similar diagnostic rates. Given the
relative rarity of the disease it may not be practical to perform a ran-
domised control trial exploring survival and functional outcomes for
different treatment strategies. However, the use of tongue base
mucosectomy should be further explored as this reflects a further
refinement in selecting appropriate care for these patients.
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How to cite this article: Winter SC, Ofo E, Meikle D, et al.
Trans-oral robotic assisted tongue base mucosectomy for
investigation of cancer of unknown primary in the head and
neck region. The UK experience. Clin Otolaryngol.
2017;42:1247–1251. https://doi.org/10.1111/coa.12860