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\begin{document}

\title{Prevalence of occult nodal metastases in squamous cell carcinoma of the
temporal bone: A systematic review and meta-analysis}



\author[1]{Daniele Borsetto}%
\author[2]{Ananth Vijendren}%
\author[3]{Gianni Franchin}%
\author[4]{Neil Donnelly}%
\author[5]{Patrick Axon}%
\author[6]{Liam Masterson}%
\author[1]{Manohar Bance}%
\author[7]{Athanasios Saratziotis}%
\author[8]{Jerry Polesel}%
\author[9]{Paolo Boscolo-Rizzo}%
\author[5]{James Tysome}%
\affil[1]{Addenbrooke's Hospital}%
\affil[2]{Colchester Hospital University NHS Foundation Trust}%
\affil[3]{Aviano AB, Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS Pordenone, Friuli Venezia Giulia, IT}%
\affil[4]{Cambridge University Hospital NHS Foundation Trust}%
\affil[5]{Cambridge University Hospitals}%
\affil[6]{Addenbrookes Hospital}%
\affil[7]{University Hospital of Larissa}%
\affil[8]{Aviano AB}%
\affil[9]{University of Padua}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objectives : Primary : To determine the rate of occult cervical
metastasis in primary temporal bone squamous cell carcinomas (TBSSC).
Secondary : to perform a subgroup meta-analysis of the risk of occult
metastasis based on the clinical stage of the tumour and its risk based
on corresponding levels of the neck Design : A systematic review and
meta-analysis of papers searched through Medline, Cochrane, Embase,
Scopus and Web of Science up to January 2021 to determine the pooled
rate of occult lymph node/parotid metastases. Quality assessment of the
included studies was assessed through the Newcastle-Ottawa scale.
Setting : Centres around the world that perform surgery for TBSCC
Participants : Patients with TBSCC Results : Overall, 9 out of 1034
screened studies met the inclusion criteria, for a total of 907 patients
of which 388 had TBSCC. Out of the 191 patients who underwent a neck
dissection, 21 had positive lymph nodes giving a pooled rate of occult
metastases of 11\% (95\% CI: 7\%-17\%). When analysed using the Modified
Pittsburg staging system, 21 pT2 cases had a pooled occult metastases
rate of 3\% (95\% CI: 0\%-21\%), 27 pT3 cases had a pooled occult
metastases rate of 12\% (95\% CI: 1\%-60\%), and 65 pT4 cases had a
pooled occult metastases rate of 14\% (95\% CI: 7\%-25\%). Data
available showed that most of the positive nodes were in Level II.
Conclusion: The rate of occult cervical metastases in TBSCC increases
based on the tumour (T) staging of the disease with majority of nodal
disease found in level 2 of the neck.%
\end{abstract}%



\sloppy


\textbf{Abstract}

\textbf{Objectives :} Primary : To determine the rate of occult cervical
metastasis in primary temporal bone squamous cell carcinomas (TBSSC).
Secondary : to perform a subgroup meta-analysis of the risk of occult
metastasis based on the clinical stage of the tumour and its risk based
on corresponding levels of the neck

\textbf{Design :} A systematic review and meta-analysis of papers
searched through Medline, Cochrane, Embase, Scopus and Web of Science up
to January 2021 to determine the pooled rate of occult lymph
node/parotid metastases. Quality assessment of the included studies was
assessed through the Newcastle-Ottawa scale.

\textbf{Setting} : Centres around the world that perform surgery for
TBSCC

\textbf{Participants :} Patients with TBSCC

\textbf{Results :} Overall, 9 out of 1034 screened studies met the
inclusion criteria, for a total of 907 patients of which 388 had TBSCC.
Out of the 191 patients who underwent a neck dissection, 21 had positive
lymph nodes giving a pooled rate of occult metastases of 11\% (95\% CI:
7\%-17\%). When analysed using the Modified Pittsburg staging system, 21
pT2 cases had a pooled occult metastases rate of 3\% (95\% CI:
0\%-21\%), 27 pT3 cases had a pooled occult metastases rate of 12\%
(95\% CI: 1\%-60\%), and 65 pT4 cases had a pooled occult metastases
rate of 14\% (95\% CI: 7\%-25\%). Data available showed that most of the
positive nodes were in Level II.

\textbf{Conclusion:} The rate of occult cervical metastases in TBSCC
increases based on the tumour (T) staging of the disease with majority
of nodal disease found in level 2 of the neck.

\textbf{Key Words:} lymph node metastases, squamous cell carcinoma,
elective neck dissection, meta-analysis, temporal bone carcinoma.

\textbf{Key points}

\begin{itemize}
\tightlist
\item
  Temporal bone squamous cell carcinomas (TBSCCs) are rare cancers of
  the head and neck with overall poor prognosis.
\item
  As they tend to spread locally, there is a dilemma if prophylactic
  neck dissections should be performed in clinically staged N0 necks.
\item
  We identified 9 studies containing 907 patients of which 388 had TBSCC
\item
  21 out of 191 patients who underwent elective neck dissection were
  found to have positive lymph nodes giving a pooled occult metastases
  rate of 11\%
\item
  As the rate of occult metastases increased with T- staging of the
  tumour (pT2: 3\%, pT3: 12\%, pT4: 14\%) and were most commonly found
  in level 2 of the neck, we would recommend dissecting a minimum of
  level II of the neck in pT3 and pT4 TBSCC.
\end{itemize}



\textbf{Introduction}

Temporal bone cancers account for around 0.2\% of head and neck
malignancies and squamous cell carcinoma (SCC) represents the commonest
histopathological subtype (1).

Despite its low incidence, temporal bone squamous cell carcinomas
(TBSCC) are aggressive with poor survival outcomes and high morbidity.
Patients usually present with a troublesome discharging ear, hearing
loss, pain, head and neck lumps and not infrequently a facial palsy(2).
A combination of biopsies and CT as well as MRI imaging is essential to
investigate, diagnose and stage the disease for treatment options.
Although there is no Union for International Cancer Control (UICC) or
American Joint Committee on Cancer Control (AJCC) on TBSCC, the modified
Pittsburgh staging is commonly employed(3).

TBSCC tend to spread locally rather than metastasize to regional lymph
nodes or distant sites, making radical resection of the primary lesion
the mainstay of treatment. Therefore, while neck dissections (ND) are
generally advocated in the presence of nodal disease, although survival
of patients with neck metastases is very poor(4), its role in a
clinically N0 neck (cN0) has been a subject of debate, mainly due to the
lack of evidence and because many units will routinely treat at least
the upper neck as well as the primary site with adjuvant radiotherapy.
The UK national multidisciplinary guidelines on the management of head
and neck cancer(5, 6) have recommended that all TBSCC with cN0 undergo
neck dissection of levels 2-5 based on Rinaldo et al.'s narrative
review, which estimated that the risk of occult metastases lies between
17-25\%.(7) Others may decide on the extent of neck dissection based on
the clinical staging, or on performing no neck dissection given that
radiotherapy may be planned post-operatively to the neck.

With these discrepancies in mind, the aim of this systematic review and
meta-analysis is to estimate the rate of occult cervical metastasis in
primary TBSSC and to analyse the evidence on the indication and extent
of elective neck dissection in these tumours.



\textbf{Methods}

\emph{Ethical consideration}

As the meta-analyses did not involve any direct patient care within or
outside the NHS, Research Ethics Committee approval was not necessary.
The project did not constitute a form of audit nor research and hence
local audit and research department approval were not required either.

\emph{Outcome measures}

The primary outcome of this meta-analysis is the prevalence of occult
cervical metastases in primary TBSSC. The secondary outcome is a) to
perform a subgroup meta-analysis of the risk of occult metastasis based
on the clinical stage of the tumour and b) the rate of occult metastasis
in each level in the neck.

\emph{Search strategy}

This systematic review and meta-analysis~were~conducted following the
preferred reporting items for systematic reviews and meta-analyses
(PRISMA) checklist(8).~Medline (via Ovid), Cochrane, Embase~(via Ovid),
Web of Science (Core Collection) and Scopus were searched from inception
through to January 2021 (Appendix 1).~The research was conducted
according to PRISMA criteria. A combination of MeSH terms and free-text
words were utilized to search for ``temporal bone squamous cell
carcinoma'' or ``temporal bone'' or ``squamous cell carcinoma'' AND
``Neck dissection'' OR ``Elective'' OR ``Node'' OR ``Lymphnode'' OR
``Lymph node'' OR ``N0''.

The reference lists of articles included in this review as well as
narrative reviews published in the last 10 years~were also manually
searched to minimize the risk of missing data. Two authors (DB and AV)
independently screened all titles and abstracts generated by the search
and then evaluated the full texts of all the relevant articles
identified against the inclusion criteria (Figure 1);~a third author
(PBR) settled discordances when present.

\emph{Selection criteria}

Studies were included in the analysis if they met the following
criteria:

(a) population study including previously untreated primary squamous
cell carcinoma involving the temporal bone

(b) neck staging carried out by performing ultrasound (US) and/or
computerized tomography (CT) and/or magnetic resonance imaging (MRI)
and/or positron emission tomography (PET)

(c) studies reporting complete or extractable data on the number of
patients with cN0 parotid tumours, number of elective neck dissections
and cases of occult metastases.

The exclusion criteria were

(a) studies that did not declare precisely how they staged the neck
(palpation or imaging) before elective dissection

(b) studies with fewer than 5 patients

(c) non-English language studies

(d) reviews, editorials and letters.

(e) studies containing aggregated and non-extractable data, or
duplicated data from previously published work

e) non-squamous cell carcinoma or metastasis

f) recurrent disease.

We defined occult metastases (pN+/cN0) as lateral cervical lymph node
metastases identified upon elective neck dissection of patients with
clinically uninvolved cervical lymph nodes (cN0) at preoperative
staging.

\emph{Data extraction and statistical analysis}

An electronic data-collection form was used to extract the following
data from each of the included studies: author, year of publication,
study design, country and period of conduction, number of patients,
demographic characteristics, staging, grading of the tumours, type of
imaging used to stage the neck, criteria used for elective neck
dissection and dissected levels if specified, number of cN0 patients who
underwent elective neck dissection and cases of occult metastases
identified (pN+/cN0). The authors of the selected studies were contacted
in order to gather missing information about individual patient data and
attempt to perform subgroup meta-analysis. Two authors (DB, AV)
independently assessed the quality of the included studies with the
Newcastle-Ottawa Scale(9).

The pooled proportion of occult metastases and corresponding 95\%
confidence interval (CI) were calculated according to random-effects
models of DerSimonian and Laird(10), using the logit transformation and
weighting through the inverse variance method. Statistical heterogeneity
among studies was evaluated using the I\selectlanguage{ngerman}² and
t\textsuperscript{2}statistics. Influence analysis was performed when
pooled proportions were estimated from five or more studies: pooled
proportion was calculated by omitting one study at a time. Publication
bias was assessed through a funnel plot(11).

The results of the meta-analysis were presented graphically using forest
plots, plotting the individual paper, pooled proportions and
corresponding 95\% CI. Analyses were conducted using R 3.6, and
statistical significance was claimed for p \textless{} 0.05 (two sided).



\textbf{Results}

\emph{Literature search}

The literature review yielded 1034 articles. From the review of the
titles and abstracts, 1008 articles were excluded for being irrelevant
to the topic, non-English language, non-original, case reports,
editorials or duplicated studies (Figure 1). Twenty-six full-text
articles were examined reporting elective neck dissection in the
therapeutic management of cN0 in squamous cell carcinoma of the temporal
bone. Of these, 17 were excluded as they did not meet the inclusion
criteria, or because there were no available data on clinically N0
patients, the data were secondary, or because the authors were contacted
but were unable to provide the data requested (authors of the studies
were contacted where required for information about individual patient
data to ensure a subgroup meta-analysis could be performed for specific
tumour histology of squamous cell carcinoma). From the articles included
in the systematic review, it was determined that nine studies fully
satisfied the inclusion criteria.

\emph{Demographics}

The nine articles(4, 12-19) that satisfied the criteria for inclusion in
the systematic review and meta-analysis were retrospective case series
published between 2009 and 2018. All the studies focused on management
of squamous cell carcinoma of the temporal bone. Patient demographics
were only available in six studies(4, 12-15, 18). The total population
of the included studies was 907 patients, 388 of whom had squamous cell
carcinoma. Studies ranged from 6 to 125 patients with an overall median
of 43.1 patients. The median age was 65.08 years (range, 3.8-92 years).
Gender was reported in six articles, with 140 (57.8\%) male and 102
(42.14\%) female.

\emph{Core data}

Data on positive SCC histology was available for all 388 patients; of
which 191 patients had undergone a neck dissection. Positive metastatic
lymph nodes were found in 21 of these 191 patients (Table 1). Only three
studies reported the level of the positive lymph nodes(13, 14, 18). Ng
et al, Gidley et al. and Cristalli et al. had reported a total of 33
cases undergoing prophylactic neck dissections of which 5 patients had
positive nodal involvement. 3 of these patients were found to have nodes
in level II of the neck with the levels not reported in the remaining 2
patients(13, 14, 18). The data on tumour grading based on Modified
Pittsburgh classification were available in 128 out of the 191 patients
with the following percentages; T1 = 4.68\%, T2 = 24.21 \%, T3 =
20.31\%, and T4 = 50.78\%.

\emph{Meta-analysis pN+/cN0}

In the nine studies, neck staging was determined by a combination of
PET, MRI, US and/or CT. Of these 191 patients with TBSCC and cN0 necks,
there were 21 cases were pN+/cN0, with a pooled rate of occult
metastases of 11\% (95\% CI: 7\%-17\% -- Figure 2); with corresponding
levels of neck dissected known in 11 patients. No publication bias
emerged by inspection of funnel plot (Supplementary Figure 1.A).
Influence analysis did not report substantial modification when one
study was omitted at a time, with pooled proportion ranging from 9\%
when McRackan was excluded to 14\% when Masterson was excluded
(Supplementary Figure 1.B). Of the 191 patients included in the
meta-analysis, 121 patients had data available on the Tumour stage
according to the Pittsburgh classification: 21 cases were pT2 with a
pooled rate of occult metastases of 3\% (95\% CI: 0\%-21\%), 27 cases
were pT3 with a pooled rate of occult metastases of 12\% (95\% CI:
1\%-60\%), and finally 65 cases were pT4 with a pooled rate of occult
metastases of 14\% (CI: 7\%-25\%) (Figure 3).

\emph{Quality of studies assessed and risks of biasness}

Four out of the nine studies reported a Newcastle-Ottawa Scale (NOS)
score \selectlanguage{english}[?]7, meaning they are high quality studies, but the NOS median of 6
establishes an overall high risk of bias in the meta-analysis. A
detailed report on the quality of included studies according to the
Newcastle-Ottawa Scale is reported in Supplementary~Table 1.



\textbf{Discussion}

\emph{Summary of findings}

Our meta-analyses of 191 cN0 TBSCC patients estimated an overall rate of
occult lymph nodes metastases of 11\% with level II being the only
affected neck region, although the level was only known in 5 patients..

\emph{Comparison to other studies}

The treatment of TBSCC remains a multidisciplinary challenge. The
treatment of a clinical N0 neck has been fraught with controversies and
differing opinions, particularly on the benefits of a prophylactic neck
dissection, the extent of dissection and the role of postoperative
radiotherapy. Regional lymph node involvement has negative impact on
prognosis. Morris (17) reported a 5-year disease-specific survival (DSS)
of 18.8\% and 80.8\% in node-positive and node-negative patients while
Nakagawa (20) found a 5-year estimated survival rate of 70\% in patients
with negative regional lymph node involvement, but a significant decline
in estimated survival to 19\% in patients with positive lymph node
involvement. Masterson et al(4) reported a 5-year overall survival of
0\% in his cohort of TBSCC with positive lymph node involvement. The
negative impact of nodal metastasis on survival supports the argument
that complete surgical clearance of the tumour both at primary site and
in the neck is required irrespective of the presence of nodal
involvement.

.

Historically, elective neck dissections have been advocated for cN0
necks in patients with head and neck SCC thought to have a 20\% risk of
occult cervical metastases. This recommendation was based on
risk-benefit analyses performed in the 1970s by authors such as Ogura et
al.(21) and Lee et al.(22). It was commonly accepted then that radical
neck dissections were the main surgical approaches of choice for total
disease clearance, which in effect also carries a higher morbidity with
the associated removal of the accessory nerve, internal jugular vein
and/or the sternocleidomastoid muscle. It is understandable why a 20\%
cut off was a reasonable historic choice to balance the pros and cons of
the surgery. Since then, the surgical procedures for cN0 have evolved
from radical neck dissections to functional, selective and highly
selective procedures with consequent reduction in morbidity. These more
selective approaches have been shown to adequately remove pathology
while minimising morbidity such as shoulder dysfunction and have become
the more mainstay form of prophylactic treatment of cervical disease.
With the change in surgical technique over the years, it seems
reasonable to re-evaluating the 20\% cut off point and accept a lower
risk of metastases as an indication for a selective neck dissection to
achieve adequate disease removal and pathological neck staging.

\emph{Clinical applicability}

While previous studies have included diffferent approaches to slelective
neck dissection, the little data available has only showed occult
metastases at level 2. As no level V found metastases were found and
given the increased risk of damage to the accessory nerve, this data
does not support inclusion of level V in a selective ND for a cN0 neck.
While some authors have suggested a that frozen section samples are sent
for Level 2 prior to proceeding to dissect other levels in the neck
based on the results, it seems reasonable to perform a supra-omohyoid or
level II and III neck dissection in cN0 necks given that this also
facilitates vessel preparation for a microvascular free flap as is often
required in these cases (23, 24).

Based on our meta-analysis's findings of an 11\% occult risk of TBSCC
cervical metastases, specifically 12\% for T3 and 14\% for T4 tumours
predominantly confined to level II, we would advocate a selective level
2 and 3 neck dissection in T3 and T4 TBSCC patients after taking into
account the low morbidity of the procedure and the aggressiveness of the
cancer. This approach can be beneficial in a number of ways: by removing
the cervical lymph nodes, one would be able to accurately stage the neck
of and remove metastases not apparent on clinical staging, potentially
avoiding adjuvant treatment completely if histological outcomes are
favourable for this option. (24). Elective neck dissection has proved to
improve the prognosis in head and neck cancers patient(25) as only a
single modality treatment of the neck is required if pathologically N0,
avoiding adjuvant radiotherapy of the regional lymph nodes and its
related complications.(26) The low rate of occult metastases found in
our pT2 (3\%) analysis and relatively small rare occurrence of T1 and T2
TBSCC would suggest that an elective neck dissection is not required
echoing the recommendations from Morris et al(17).

The~role of adjuvant prophylactic radiotherapy as well as the total dose
of radiation for elective neck treatment in TBSCC patients remains
debatable. Although most clinicians would agree that radical surgery
should be followed by postoperative radiation therapy (PORT) in cases
with adverse histopathological features (eg. advanced tumours, multiple
nodal involvement, extracapsular spread, perineural invasion, positive
margins)(27, 28), the overall survival of patients with stage III-IV
disease remains low despite dual modality of treatment(29, 30).
Intensity-modulated radiotherapy (IMRT) has been shown to reduce the
severity of toxicity and significantly improve quality of life in head
and neck cancer patients (31). However, even treatment regimens
incorporating doses of IMRT with 54-63 Gy of adjuvant radiotherapy,
which is considered adequate in intermediate-risk disease management
according to NCCN guidelines (32) may be excessive in clinical N0 necks
of TBSCC patients. As there is a general consensus that single modality
of treatment should be advocated for TBSCC patients where possible, we
feel that surgical excision of the TBSCC should be accompanied by a
selective neck dissection after a multidisciplinary decision has been
made to treat the cN0 neck.

\emph{Strength and limitations of the study}

The strength of this meta-analysis is represented by its systematic and
quantitative assessment of the role of prophylactic neck dissections in
TBSCC using a strict inclusion and exclusion criteria. Our limitations
include the low number of cases reporting the level of metastasis in the
neck and the fact that the rates of occult nodal metastasis reported in
the literature could be underestimated as not all cN0 patients underwent
a neck dissection. From a statistical point of view, this meta-analysis
has the limitation of having only observational and retrospective
studies included. Furthermore, there are a relative low number of cases
in some of the studies predominantly as a result of the rarity of these
malignancies. Further limitations of our study include:

(a) Insufficient of data for a statistical analysis on the prevalence of
occult metastases in each of the different lymph node levels

b) Inability to determine whether selective neck dissection is better
than radiotherapy.

c) The inclusion criteria for many studies were not specified. This
resulted in the exclusion of 17 studies in the final phase of review.

It would be helpful to perform a prospective multicentre study to
compare the effectiveness of elective neck dissection and radiotherapy
in TBSCC cN0 necks as data from individual units are unlikely to be
sufficiently powered to influence overall management.

\textbf{Conclusion}

This meta-analysis estimated a pooled rate of occult lymph node
metastases of 11\% (99\% CI: 0.07-0.17), with specific rates of 12\% for
pT3 tumours and 14\% of pT4 tumours. Taking into account other pertinent
factors such as the aim of single modality of treatment, the need to
access the neck for reconstructive purposes, and the low morbidity for
highly selective neck dissections, we would advocate that a selective
neck dissection of at least level II should be considered in locally
advanced (T3 and T4) TBSCC or radiotherapy to the upper neck.

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