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\begin{document}

\title{Head and neck squamous cell carcinoma of unknown primary - Who can be
offered surgery as the sole treatment modality? A systematic review}



\author[1]{Arunjit Takhar}%
\author[2]{Mark Wilkie}%
\author[3]{Devraj Srinivasan}%
\author[4]{Emma King}%
\affil[1]{St George's University Hospitals NHS Foundation Trust Department of ENT Surgery}%
\affil[2]{Royal Adelaide Hospital}%
\affil[3]{NHS Lothian}%
\affil[4]{University Hospitals Dorset NHS Foundation Trust}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Objective} Evaluate the role of neck dissection (ND) as the sole
treatment modality for patients with cervical head and neck squamous
cell carcinoma of unknown primary (HNSCCUP). \textbf{Design} Systematic
review of observational cohort studies with qualitative synthesis.
\textbf{Setting} PubMed, Ovid EMBASE, and Cochrane Controlled register
of Trials (CENTRAL) were screened from January 2000 up to October 2021.
\textbf{Participants} HNSCCUP patients undergoing ND. \textbf{Main
Outcome Measures} The primary outcome was 3-year overall survival (OS).
Secondary outcomes included disease-free survival (DFS), primary
emergence, regional recurrence, and distant metastasis. \textbf{Results}
Fourteen eligible studies were identified, including 1,780 patients, of
whom 294 received ND as their sole treatment (seven studies) with 3-year
OS ranging from 43.9\% to 100\%. 3-year DFS was reported in four studies
(n=62) ranging from 42.8\% to 67.0\%. 5-year OS and DFS were available
in three studies (n=31), ranging from 36.6\% to 75.0\%, and 43.6\% to
67.0\%, respectively. The rate of primary emergence ranged from 11.1\%
to 33.3\% (seven studies, n=157), regional relapse from 0.0\% to 50.0\%
(five studies, n=60), and distant metastasis from 0.0\% to 3.3\% (three
studies, n=45). Patients undergoing ND as a sole treatment had
predominantly p16 positive N1 (TNM7) disease without ECS.
\textbf{Conclusion} Outcomes for HNSCCUP patients undergoing ND alone
range widely in the literature but appear reasonable in a subset of
patients with early stage p16 positive disease. Data is lacking for p16
negative disease where the potential primary site is more varied and
primary emergence appears more common.%
\end{abstract}%



\sloppy


\textbf{TITLE PAGE}

\textbf{Title:}

Head and neck squamous cell carcinoma of unknown primary - Who can be
offered surgery as the sole treatment modality? A systematic review

\textbf{Objective}

Evaluate the role of neck dissection (ND) as the sole treatment modality
for patients with cervical head and neck squamous cell carcinoma of
unknown primary (HNSCCUP).

\textbf{Design}

Systematic review of observational cohort studies with qualitative
synthesis.

\textbf{Setting}

PubMed, Ovid EMBASE, and Cochrane Controlled register of Trials
(CENTRAL) were screened from January 2000 up to October 2021.

\textbf{Participants}

HNSCCUP patients undergoing ND.

\textbf{Main Outcome Measures}

The primary outcome was 3-year overall survival (OS). Secondary outcomes
included disease-free survival (DFS), primary emergence, regional
recurrence, and distant metastasis.

\textbf{Results}

Fourteen eligible studies were identified, including 1,780 patients, of
whom 294 received ND as their sole treatment (seven studies) with 3-year
OS ranging from 43.9\% to 100\%. 3-year DFS was reported in four studies
(n=62) ranging from 42.8\% to 67.0\%. 5-year OS and DFS were available
in three studies (n=31), ranging from 36.6\% to 75.0\%, and 43.6\% to
67.0\%, respectively. The rate of primary emergence ranged from 11.1\%
to 33.3\% (seven studies, n=157), regional relapse from 0.0\% to 50.0\%
(five studies, n=60), and distant metastasis from 0.0\% to 3.3\% (three
studies, n=45). Patients undergoing ND as a sole treatment had
predominantly p16 positive N1 (TNM7) disease without ECS.

\textbf{Conclusion}

Outcomes for HNSCCUP patients undergoing ND alone range widely in the
literature but appear reasonable in a subset of patients with early
stage p16 positive disease. Data is lacking for p16 negative disease
where the potential primary site is more varied and primary emergence
appears more common.

\textbf{KEY WORDS}

Cancer of unknown primary, head and neck cancer, human papillomavirus,
squamous cervical carcinoma, treatment of cancers of unknown primary

\textbf{KEY POINTS}

\begin{itemize}
\tightlist
\item
  True unknown primary head and neck squamous cell carcinoma is
  increasingly rare with the evolution in diagnostic paradigms. In
  addition, changes in oncogenesis (Human papillomavirus related) have
  improved prognosis and led to a trend towards treatment de-escalation.
\item
  Due to these issues, there is a paucity of relevant data on treatment
  outcomes, which is currently limited to historic observational studies
  only.
\item
  Lower survival figures along with higher primary emergence and
  regional recurrence rates were observed in patients with p16- (or
  undefined p16 status) disease.
\item
  Where populations of studies had higher rates of p16 positivity;
  outcomes from early-stage nodal disease (N1 without ECS) were
  favourable and there were lower primary emergence and regional
  recurrence rates. Primary emergences were often successfully treated
  with further curative intent.
\item
  ND alone may be a reasonable treatment in a subset of HNSCCUP, namely
  p16+ N1 (TNM7) disease without ECS. For p16- disease it appears
  multi-modality treatment is required for optimal survival outcomes.
\end{itemize}

\textbf{INTRODUCTION}

As alluded to throughout this special issue, diagnostic and treatment
paradigms for head and neck squamous cell carcinoma of unknown primary
(HNSCCUP) are vexed issues, reflecting a dearth of robust contemporary
evidence on the topic. This is largely because true unknown primary
disease is relatively uncommon (1-5 \% of all HNSCC cases (1)),
resulting in small study cohorts, particularly in single-centre
settings, compounded by a lack of uniformity between studies on the
definition of what constitutes an `unknown primary', making inter-study
comparisons or pooled-analyses challenging or indeed unfeasible.
Furthermore, the relatively recent realisation of the importance of
human papillomavirus (HPV) in HNSCC oncogenesis (2), the particular
pertinence this has to HNSCCUP given the typical clinical presentation
(that p16 positive HNSCCUP is considered oropharyngeal in the most
recent edition of TNM/AJCC Classification for Head and Neck Cancer
attests to this) (3), together with the dramatic upsurge HPV-related
HNSCC (4), casts aspersion on the relevance of many historic studies to
modern day practice.

An issue of contemporary interest in the management of HNSCCUP is in
which specific circumstances can patients be managed by surgery as a
single modality, thus avoiding adjuvant treatment and associated
toxicity. The increased traction of this notion in recent years is
underpinned, firstly, by advances in diagnostic surgical work-up
resulting in more comprehensive oropharyngeal sampling, with tongue base
mucosectomy becoming a standard of care in many centres internationally,
and secondly, by a shift towards treatment de-escalation in HPV-related
oropharyngeal SCC, something which is the subject of several
international clinical trials currently recruiting (5,6)

Current guidelines internationally recommend that in HNSCCUP
single-modality treatment can be considered in the presence of N1 or
``small-volume'' disease in the absence of extra-nodal extension (7--9).
However, such recommendations are relatively tentative, suggesting
multi-disciplinary discussion on an individual case basis; and are
largely derived from consensus and expert opinion and/or extrapolation
from contemporary oropharyngeal SCC data. To this end, to the best of
our knowledge there have been no prior attempts to formally synthesise
data on this topic to inform such decision-making.

Cognisant of these issues, the purpose of this systematic review was to
collate and interrogate in detail the evidence for HNSCCUP patients
treated with neck dissection (ND) alone with respect to oncological
outcomes.

\textbf{METHODS}

This systematic review was conducted in accordance with preferred
reporting items for systematic reviews and meta-analysis (PRISMA)
statement (10). As this study was a systematic review there was no
requirement for local ethics approval or institutional board review.

\textbf{Study Characteristics}

\emph{Type of studies to be included}

All types of observational and experimental study designs will be
eligible for inclusion.

\emph{Setting}

All countries and health systems will be considered.

\emph{Report Characteristics}

\begin{itemize}
\tightlist
\item
  Publications from 1\textsuperscript{st} January 2000 up until the date
  search conducted.
\item
  English Language.
\item
  Any publications status, including grey literature.
\item
  Conference abstracts were excluded.
\item
  Minimum 5 patients per report undergoing ND as sole treatment
  modality.
\end{itemize}

\textbf{Participants}

\emph{Inclusion criteria}

\begin{itemize}
\tightlist
\item
  Patients with squamous cell carcinoma of unknown primary in cervical
  lymph nodes after clinical examination, radiological investigations
  +/- diagnostic surgery (biopsies, tonsillectomy, tongue base
  mucosectomy)
\item
  Aged over 18
\item
  Both sexes
\item
  Treated with curative intent ND as their primary and sole therapeutic
  intervention
\end{itemize}

\emph{Exclusion criteria}

Other tumour types of unknown primary in cervical lymph nodes (e.g.,
adenocarcinoma, melanoma, thyroid, salivary)

\emph{Intervention}

Neck dissection (selective, modified radical, radical, extended)

\emph{Comparator}

None selected

\textbf{Outcome Measures}

\emph{Primary Outcome}

3- year survival (overall (OS), disease-free (DFS))

\emph{Secondary Outcomes}

\begin{itemize}
\tightlist
\item
  Any other reported survival data (2- and 5- year survival, regional
  control rates)
\item
  Primary emergence rates and sites of emergence
\item
  Regional recurrence and distant metastasis
\end{itemize}

\textbf{Information Sources}

Sources to be searched: Databases PubMed, Ovid EMBASE, and Cochrane
Controlled register of Trials (CENTRAL). References from previous review
articles were also citation checked against the search results.

\textbf{Search Strategy}

Searches were limited to English Language entries reported from
1\textsuperscript{st} January 2000 onwards and were last conducted on
7\textsuperscript{th} October 2021. Searches were based around 3 broad
search terms with expansions and synonyms for each database summarised
in appendix 1:

\begin{itemize}
\tightlist
\item
  Squamous cell carcinoma of head and neck
\item
  Neoplasms, unknown primary
\item
  Neck dissection
\end{itemize}

\textbf{Data Extraction}

\emph{Selection of studies}

The titles and abstracts of all studies were screened independently by
two authors (AT/MDW) against the inclusion and exclusion criteria. Where
there was uncertainty regarding eligibility, or there was disagreement
between authors, the full texts of articles were obtained and reviewed.
There were no differences of opinion that were not resolved through
discussion. Where title and abstracts were identified in English
language, but the main report was in a foreign language, they were
subsequently excluded from analysis.

\emph{Data collection and items}

Both authors independently extracted data using a standardised proforma
with data entered to a Microsoft excel spreadsheet and final approval
ratified by consensus of the first two authors.

Data items included: patient demographics, smoking history, diagnostic
interventions performed prior to therapeutic ND, pathological nodal and
p16 status. Further data items to reflect the primary and secondary
outcomes were collected and are detailed in the table 1 and 2 below.

\textbf{Risk of Bias}

A study level risk of bias assessment was performed for all studies
using the MINORS tool (11) as all studies eligible for inclusion were
observational. Scores are summarised in table 1 and risk of bias
cumulatively is commented upon.

\textbf{Data Synthesis}

Summary data are presented in table format from the studies. Given the
heterogeneity in presentation and reporting of data in the studies, a
statistical meta-analysis of these results was not possible, and the
results were presented descriptively, with findings grouped according to
outcome measures set out above.

\textbf{RESULTS}

\emph{Study Selection}

A total of 390 potentially relevant records were identified, reducing to
290 after duplicates were removed. A PRISMA flowchart is demonstrated in
figure 1. On review of full text articles 17 were removed as the series
contained less than five patients that were treated with ND alone
(12--28). A further 15 were removed as they comprised conference
abstracts only (29--43) while six were non-English language (44--49). A
total of 14 studies have met the eligibility criteria and are presented
herein. (50--63).

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/315585/articles/646094-head-and-neck-squamous-cell-carcinoma-of-unknown-primary-who-can-be-offered-surgery-as-the-sole-treatment-modality-a-systematic-review}

\textbf{Figure 1. Preferred reporting items for systematic reviews and
meta-analysis (PRISMA) flowchart with results for searches, screening,
and application of eligibility criteria.}

\emph{Study Characteristics}

The characteristics of the studies included in this systematic review
are summarised in table 1. The studies were published between 2002 and
2021 and originate from centres in the USA (51,53,55,57), Europe
(50,52,56,64), Asia (58,59,61--63) and Australia (54). There were no
eligible studies from the UK. One of the studies was based on extraction
of data from a national cancer database (51), while the remainder were
single institution or multi-centre studies from a single geographical
region. Three studies were based on prospective databases (53--55) that
were retrospectively analysed, and the remainder were all retrospective
studies. All the studies identified patients based on diagnosis and
reported outcomes with respect to treatments given, and as such, were
observational cohort studies. None of the studies directly compared ND
alone to radiotherapy alone in a prospective or matched cohort manner,
although some retrospectively commented on outcomes for both groups.

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/315585/articles/646094-head-and-neck-squamous-cell-carcinoma-of-unknown-primary-who-can-be-offered-surgery-as-the-sole-treatment-modality-a-systematic-review}

\textbf{Hosted file}

\verb`image3.emf`  available at \url{https://authorea.com/users/315585/articles/646094-head-and-neck-squamous-cell-carcinoma-of-unknown-primary-who-can-be-offered-surgery-as-the-sole-treatment-modality-a-systematic-review}

The 14 eligible studies included a total of 1780 patients, of which 294
underwent ND as their single primary treatment for HNSCCUP. There were
on average 17.5 (5-63) (median(range)) cases per study. Although all
studies met the initial eligibility criteria and presented outcome data
relevant to the primary and / or secondary aims, there was significant
heterogeneity in reporting parameters, precluding any meta-analysis.
There was a male preponderance, ranging from 76-88\% across the studies,
with an average age of 55-65 years. Four (28.6\%) of the studies
reported on p16 status, with one (7.1\%) also reporting on high-risk HPV
status by in situ hybridisation. In these studies, data were incomplete,
with anywhere between 19.1\% and 86.7\% of included patients having
status recorded.

The studies were evaluated for quality of diagnostic investigations
compared to perceived `gold standards' (FDG PET-CT, MRI, panendoscopy,
tonsillectomy, tongue base mucosectomy). No single study included all
investigations prior to treatment. PET-CT was performed on all patients
in two studies (53,58) and on a proportion (20.0-58.6\%) of patients in
a further eight studies (50,54,56,57,59--62). Three studies (51,55,63)
made no mention of cross-sectional imaging being performed, with the
remainder confirming all patients underwent either CT or MRI scan prior
to treatment. One study (51) didn't state if panendoscopy was performed
and in two further studies only a proportion (45.1-64.0\%) underwent
panendoscopy (56,63). Tonsillectomy was undertaken for all patients in
nine of the studies; a proportion of patients (5.8-41.7\%) in three of
the studies (50,56,63), and was not stated in two studies (51,55). Only
one study reported on tongue base mucosectomy, stating that all patients
had this procedure (52).

All the studies reported data on the nodal status (AJCC/UICC TNM7) of
patients treated; however only half provided discernible data on nodal
status for patients undergoing ND alone, totalling 132 of the 294
patients (44.9\%). Of these, the breakdown of nodal status was: N1 (n=
35,26.5\%), N2a (n= 28, 21.2\%), N2b (n =58, 43.9\%), N2c (n=4, 3.0\%),
and N3 (n=7, 5.3\%).

Follow up duration was reported in 10 studies (n=800), but none
specified follow up timeframes for ND only patients, median follow up
duration ranged from 31.1 to 83.5 months, 6 studies reported a lower end
range of follow up \textless{}12 months post treatment, which may impact
interpretation of this data. Data for survival, primary emergence,
recurrence, or metastasis was not stratified by p16 status in any of the
studies.

\emph{Risk of bias in studies}

MINORS scores are presented in table 1. The median MINORS score was 9
(range 6-13) out of a maximal score of 16. In general studies presented
clearly stated aims, however lack of clarity on whether consecutive
patients were included was a frequent issue. Endpoints were typically
well defined, and reporting was unbiased. None of the studies
prospectively calculated a study size and there was variable reporting
on minimal follow-up periods and attrition rates, thus impacting
reliability of extracted survival data.

\emph{Survival}

A summary of survival data is presented in table 2. 3-year OS was
reported on patients undergoing ND only in five studies (n=89) and
ranged from 43.9\% to 100\%. 3-year DFS was available in four studies
(n=62) for the same and ranged from 42.8-67.0\%. 5-year OS and DFS was
available in three studies (n=31) and ranged from 36.6-75.0\% and
43.6-67.0\% respectively.

\textbf{Hosted file}

\verb`image4.emf`  available at \url{https://authorea.com/users/315585/articles/646094-head-and-neck-squamous-cell-carcinoma-of-unknown-primary-who-can-be-offered-surgery-as-the-sole-treatment-modality-a-systematic-review}

\textbf{Table 2: Survival outcomes}

\emph{Primary emergence, regional recurrence, and distant metastasis}

A summary of primary emergence, recurrence and distant metastasis is
presented in table 3. Twelve of the studies reported on primary
emergence with reported rates between 1.5\% and 21.8\%. These studies
included a total of 117 emergences in 1007 patients (11.6\%). Primary
emergence rates in patients having ND only were reported in seven
studies (n=157) and ranged from 11.1-33.3\%. Sites of primary emergence
were reported on in 10 studies; but only three studies discerned sites
of primary emergence in patients receiving ND only from the whole
cohort. There were 95 primary site emergences reported in 823 patients,
sites were as follows: 32 oropharynx (3.9\%), 19 hypopharynx (2.3\%), 18
nasopharynx (2.2\%), 7 larynx (0.9\%), 5 oesophagus (0.6\%), 4
supraglottic (0.5\%), 4 oral cavity (0.5\%), 3 sino-nasal (0.4\%), 3
lung (0.4\%). Amongst those reporting on site of primary emergence for
ND alone (n=82) there were: 8 hypopharynx (7.2\%), 6 nasopharynx
(7.3\%), 6 oropharynx (7.3\%), 3 larynx (3.7\%), and 1 oral cavity
(1.2\%).

Eleven studies reported on nodal relapse rates overall, with rates
varying from 8.7\% to 42.0\%. These studies included a total of 184
regional recurrences in 932 patients (19.7\%). Five studies (n=60)
reported on nodal relapse rates for ND alone and rates varied from 0.0\%
to 50.0\%. 11 studies reported on distant metastasis with overall rates
ranging from 1.5\% to 36.2\%, amongst the ND only patients, only three
studies (n=45) reported, with rates of 0-3.3\%.

\textbf{Hosted file}

\verb`image5.emf`  available at \url{https://authorea.com/users/315585/articles/646094-head-and-neck-squamous-cell-carcinoma-of-unknown-primary-who-can-be-offered-surgery-as-the-sole-treatment-modality-a-systematic-review}

\textbf{Table 3: Primary emergence and recurrence data}

\textbf{DISCUSSION}

In this systematic review we sought to identify if there is a subset of
HNSCCUP patients that can be treated with ND as single modality therapy
and provide acceptable oncological safety. Despite broad search
criteria, only 294 patients were identified as eligible for inclusion
across 14 studies, none of which reported exclusively on patients
treated with ND alone. Patients in these studies were recruited over a
protracted time frame (1969-2018) during which the oncogenesis, risk
factors and diagnostic approaches have evolved considerably. In
addition, the nodal status of those receiving ND alone was only reported
for 44.9\% patients, of which 52.2\% had N2b disease or above (table 1).
As such, the results need to be approached with caution, as they do not
reflect treatment within the framework of current international
guidelines (7--9). The lack of granularity regarding p16 status and
limited diagnostic work-up compared to contemporary practice further
confounds the interpretation of this review.

\emph{Survival}

In general, studies with a greater proportion of early N-stage patients
treated with ND only tended to have improved survival. In Miller\emph{et
al.} (53) 88.9\% of ND only patients had N1 or N2a disease, with a 3-yr
DFS and OS of 66.7\% and 100\%, respectively. Furthermore, they report
that in the 7 patients that were treated for N1 disease without evidence
of extracapsular spread (ECS) progression-free survival (PFS) was 100\%.
In Mizuta \emph{et al} . (58) 55.5\% of ND only patients had N1 or N2a
disease with 3-year disease specific survival (DSS) of 81.8\% and 3-yr
distant metastasis free survival (DMFS) of 88.6\%. Whilst Iganej
\emph{et al.} (55) and Patel \emph{et al} . (54) do not provide as
detailed data the authors summarised that there was a `5-yr tumour
control rate of 81\% for N1 and N2a disease without ECS' and a `100\%
ipsilateral regional control for pN1' respectively. In contrast to this,
Dou \emph{et al} . (61) and Wongsritrang \emph{et al} . (63) report only
10.4\% and 17.3\% of their whole cohort had N1 disease respectively,
whilst the authors do not report on the N-stage for surgery only, we
surmise that the lower 3-yr DFS \& OS observed for ND only is reflective
of this (42.8\%, 87.5\% and 54.5\%, 43.9\% respectively). Furthermore,
these studies were conducted in China and Thailand, respectively, where
a putative primary site is more likely to be nasopharyngeal (65),
further limiting the interpretation of these findings in Western
practice.

None of the studies included in this review could identify a survival
benefit for primary radiotherapy over primary surgery, and some could
not find a survival benefit for any particular combination of treatment
modalities (51,58). However, four of the studies demonstrated improved
survival when ND formed part of initial multi-modality treatment
(50,59,60,62).

\emph{Primary site emergence, recurrence, and distant metastasis}

Despite the heterogeneity in data reporting between studies, it appears
that primary emergence was consistently higher amongst patients treated
with ND only. For the whole cohort of patients 66.3\% of primary
emergences were from non-oropharyngeal sites, and where data was
available for ND only emergences, 75.0\% were non-oropharyngeal. For the
three studies that report on both p16 status and primary emergence
(50,57,60), rates of p16 positive disease were 43.5\%, 69.5\% and
76.3\%, with emergence rates of 7\%, 1.5\% and 5.3\% respectively. This
suggests that primary emergence rates may be lower in p16 positive
disease compared to p16 negative disease where the primary site is more
likely to be non-oropharyngeal and less prognostically favourable.

The 3-yr mucosal control rate for ND only was observed to be 67\% in one
study compared to 100\% with the addition of adjuvant radiotherapy (to
neck and putative primary site based on nodal basin)(61). However, this
did not translate into a difference in 3-yr OS between groups (83.5\%
vs. 84.7\%, p=0.591). Several studies additionally reported on outcomes
after primary emergence. In Mizuta \emph{et al} . (58) where there were
six emergences after ND only (3 hypopharynx, 2 oropharynx, 1 oral
cavity), three were treated with chemoradiotherapy, one with surgery and
radiotherapy, and two with surgery alone. Four of the six remained
disease free at the time of reporting with two of the hypopharynx
cancers being alive with recurrent disease (distant metastasis). In
Miller \emph{et al} . (53), the sole primary emergence ND only (N2b)
patient (oropharynx) was successfully treated with chemoradiotherapy 16
months after initial treatment.

The data with respect to primary emergence highlights three pertinent
points. Firstly, the patterns and rates of emergence likely reflect the
heterogeneity of patients included in these studies, and thus the
variability in applicability and reliability of the data to contemporary
practice. Secondly, the sites of emergence reported in these studies
indicate a likely high incidence of p16 negative disease, conferring a
poorer prognosis than p16 positive disease. Finally, consideration
should be given to `salvageability' when considering ND only as primary
treatment, from the limited data presented, outcomes appear to be
acceptable when considering the OS of ND only to the whole cohorts in
these studies.

Due to the limited reporting and sample size for regional recurrence and
distant metastasis it is difficult to draw any more meaningful
conclusions from the data beyond what has been discussed with regards to
survival and primary emergence.

\emph{Limitations}

Several limitations must be considered in addition to those already
discussed. Firstly, diagnostic and treatment protocols varied
considerably both within and between studies. In some, treatment
approaches varied upon likely putative primary site (61), and others
reported a change in practice during the study period (60). Whilst some
studies identified which patients were not treated `per protocol'
(53,54) (usually due to patient refusal of adjuvant treatment), the
majority gave no explanation for decision making regarding treatments
given, leading to potential selection bias. The lack of clarity
regarding patients excluded, small sample sizes, and attrition rates in
several studies leads to potential concerns for reporting bias within
the studies. The geographical differences in incidence of disease (65)
and prognostic impact of p16 (66) mean that the tumour biology both
within and between these studies is likely to be variable, impacting on
the results and interpretability.

\emph{Summary}

This review has highlighted the paucity of evidence relevant to
contemporary practice for HNSCCUP. The studies identified are
heterogenous and span a timeframe from 1969-2018 during which
oncogenesis and diagnostic strategies have evolved considerably,
limiting interpretability of the findings. Crude interpretation of the
data may suggest ND alone is a reasonable treatment consideration for
select patients with p16 positive N1 (TNM7) disease without ECS. For
patients with p16 negative disease the potential primary site is more
varied, and outcomes were inferior with ND alone, given the high rates
of primary emergence. For p16 negative patients it is likely that
multi-modality treatment is nearly always indicated for optimal survival
outcomes.

Whilst a prospective randomised control trial would prove highly
valuable in further defining optimal management strategies, given the
rarity and heterogeneity of this disease entity, patient accrual is
likely to be a significant barrier. Multi centre studies examining
treatment outcomes in a contemporary era of practice may be more
informative. Given the recent updates to AJCC/UICC TNM8 guidelines where
p16 positive HNSCCUP is to be treated along oropharynx paradigms;
extrapolation from relevant studies may be appropriate. For example,
recent randomised control trial data from ECOG 3311(6) report a 2-yr PFS
of 96.9\% for a group of patients with T1-2, N0-1 (TNM 7) oropharynx
cancer treated with surgery alone (27/38 patients N1 disease, no ECS)

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\textbf{Appendix 1: Search Terms}

\textbf{PUBMED}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Squamous Cell Carcinoma of head and neck {[}mh{]} OR} &
\textbf{Neoplasms, unknown primary {[}mh{]} OR} & \textbf{Neck
Dissection {[}mh{]} OR}\tabularnewline
\midrule
\endhead
Squamous cell carcinoma of head and neck OR & Neoplasms, unknown primary
OR & Neck dissection {[}tw{]} OR\tabularnewline
Head and Neck Cancer OR & Unknown primary OR & Cervical lymphadenectomy
{[}tw{]}\tabularnewline
Head and Neck SCC OR & Carcinoma of unknown primary &\tabularnewline
Squamous cell carcinoma & &\tabularnewline
\bottomrule
\end{longtable}

\textbf{EMBASE}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{''Squamous Cell Carcinoma of head and neck''/syn OR} &
\textbf{''Neoplasms, unknown primary''/syn OR} & \textbf{''Neck
Dissection'' /syn OR}\tabularnewline
\midrule
\endhead
''Squamous cell carcinoma of head and neck''/exp OR & ''Neoplasms,
unknown primary''/exp OR & ''Neck dissection'' /exp OR\tabularnewline
''Head and Neck Cancer'':ti,ab OR & ''Unknown primary'' :ti,ab OR &
''Cervical lymphadenectomy'':ti,ab\tabularnewline
''Head and Neck SCC'':ti,ab OR & ''Carcinoma of unknown primary'' :ti,ab
&\tabularnewline
''Squamous cell carcinoma'':ti,ab & &\tabularnewline
\bottomrule
\end{longtable}

\textbf{CENTRAL}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{''Squamous Cell Carcinoma of head and neck''ti,ab,kw OR} &
\textbf{''Neoplasms, unknown primary'' ti,ab,kw OR} & \textbf{''Neck
Dissection'' ti, ab, kw OR}\tabularnewline
\midrule
\endhead
Squamous Cell Caricinoma'' ti,ab,kw & ''Unknown primary'' :ti,ab, kwOR &
''Cervical lymphadenectomy'':ti,ab,kw\tabularnewline
''Head and Neck Cancer'':ti,ab,kw OR & ''Carcinoma of unknown primary''
:ti,ab, kw &\tabularnewline
''Head and Neck SCC'':ti,ab'kw OR & &\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-1-8-14/Table-1-8-14}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-1-study-1-7/Table-1-study-1-7}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-2--Survival-Outcomes/Table-2--Survival-Outcomes}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-3---primary-emergence-and-recurrence/Table-3---primary-emergence-and-recurrence}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

