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\begin{document}

\title{Endoscopic management of sinus neoplasia: case series of image-guided
surgery of inverted papillomata and recommended best practice for
managing cases.}



\author[1]{Gabi Klyvyte}%
\author[2]{Jeremy Wong}%
\author[1]{Shyam Gokani}%
\author[2]{Louis Luke}%
\author[2]{Lavandan Jegatheswaran}%
\author[1]{Carl Philpott}%
\affil[1]{University of East Anglia Norwich Medical School}%
\affil[2]{James Paget University Hospitals NHS Foundation Trust}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Key Points} Inverted papillomata are benign sinonasal tumours
with high recurrence rates. Inverted papillomata recurrence is increased
if operated on by a non-fellowship trained rhinologist. Inverted
papillomata recurrence can be detected earlier in cases managed by
specialist rhinology services. Inverted papillomata should be managed
through a clear treatment pathway for sinonasal tumours. Other risk
factors associated with increased recurrence include Krouse stage 3 and
involvement of the frontal or maxillary sinuses.%
\end{abstract}%



\sloppy


\emph{Endoscopic management of sinus neoplasia: case series of
image-guided surgery of inverted papillomata and recommended best
practice for managing cases.}

\textbf{Key Points}

\begin{itemize}
\tightlist
\item
  Inverted papillomata are benign sinonasal tumours with high recurrence
  rates.
\item
  Inverted papillomata recurrence is increased if operated on by a
  non-fellowship trained rhinologist.
\item
  Inverted papillomata recurrence can be detected earlier in cases
  managed by specialist rhinology services.
\item
  Inverted papillomata should be managed through a clear treatment
  pathway for sinonasal tumours.
\item
  Other risk factors associated with increased recurrence include Krouse
  stage 3 and involvement of the frontal or maxillary sinuses.
\end{itemize}



\textbf{Introduction}

Inverted papillomata (IP) are rare and benign sinonasal tumours that
account for 0.4-7\% of sinonasal tumours excised, with an estimated
annual incidence of 0.2-1.5 cases per 100,000. In patients, the highest
incidence is seen in the 5\textsuperscript{th} and
6\textsuperscript{th}decades of life, with a 2-5:1 male-to-female ratio
(1,2). Despite being benign tumours, IPs are locally aggressive and have
high recurrence rates of up to 78\% (1). There is also a known
association with malignancy, with a synchronous and metachronous
carcinomatous rate estimated at 7.1\% and 3.6\% respectively (2). The
aetiology of IP remains unknown, but evidence demonstrates an
association with Human Papilloma Virus (HPV), p53 and p21 oncogenes in
malignant transformation of IP (1).

Patients with IP can present with a variety of symptoms, including
unilateral nasal obstruction, rhinorrhoea, epistaxis, facial pain, or
hyposmia/anosmia (1,2). Conversely, IP can also present asymptomatically
in 4-23\% of cases with the IPs being an incidental finding (1).

On endoscopy, IPs appear as a reddish-grey, friable lobulated mass that
is firmer than an inflammatory polyp. IPs are predominantly unilateral,
with bilateral lesions accounting for 1-9\% of cases (2).
Histopathological diagnosis is essential for diagnosis and to rule out
associated malignancy. Characteristic features on microscopy include the
invagination of the superficial IP epithelium into the underlying
stroma, hence the `inverted' descriptor. The epithelium may be of the
stratified squamous, ciliated pseudostratified columnar epithelium or
transitional types (1,3).

Radiological assessment is essential to determine the tumour location
and extension for surgical planning. Computed Tomography (CT) of the
sinuses is widely used to evaluate sinonasal masses and assess for
underlying bony changes. Unlike malignant tumours that cause bony
destruction, IP causes hyperostosis or sclerosis. (1,2) Magnetic
resonance imaging (MRI) can be useful in addition to CT scans to
determine the lesion's exact location and decide upon the best surgical
approach. (2)

The optimal management of IP involves the complete surgical excision of
the diseased mucosa and mucoperiosteum. (2) Historically, gold-standard
management techniques involved external approaches such as a lateral
rhinotomy with medial maxillectomy. (1) With the progression of
minimally invasive techniques and high-quality imaging, endoscopic
management techniques have become the gold standard for IP resection.
Compared to external approaches, they result in lower recurrence rates
and reduce surgical morbidity. (1,4) Due to the high recurrence rates
associated with IP, a minimum follow-up period of five years is
recommended (4).

As many cases managed in our centre had already undergone a previous
procedure, the objective of this retrospective case series was to
evaluate the outcomes for primary and secondary cases of sinonasal IP
including recurrence rates and complication rates.

\textbf{Materials and methods}

\emph{Study design and setting}

We retrospectively reviewed clinical records for all patients with
histologically confirmed inverted papilloma who received surgical
management under the care of the senior author at a tertiary rhinology
referral centre. Records were reviewed between 01/01/2011 - 31/12/2022.

This project was a local service evaluation and did not require ethical
approval, following completion of the NHS Research Ethics Committee
Tool, provided by the Medical Research Council. The STROBE guidelines
were adhered to for reporting.

\emph{Participants}

Cases were identified from the operation logbooks of the Ears, Nose and
Throat (ENT) Department operating theatres. The following cases were
excluded:

\begin{itemize}
\tightlist
\item
  Pre-operative intracranial involvement -- these were referred
  externally to the local neurosurgical unit.
\item
  Features of alternative sinus neoplasia, such as squamous cell
  carcinoma, osteoma, or malignant melanoma.
\item
  Conservative or palliative management as the sole treatment modality.
\end{itemize}

Practice at our centre is for primarily endoscopic resection of inverted
papillomata with the use of intraoperative Medtronic computer-assisted
navigation software.

\emph{Main outcome measures, variables, and data sources}

Anonymised data was collected from patients' electronic clinic letters
and operation notes for age, histological diagnosis, site of the tumour,
date of operation, details of surgical management, postoperative
complications, need for revision surgery and outcome at five years
post-operatively (or most recent follow up if less than five years).

Surgical procedures were classified as primary if surgery was conducted
at our centre for the first time and secondary if a prior attempted
resection had been undertaken elsewhere.

Statistical analysis was done using a Chi-squared calculation with the
significance level of p\textless{}0.05.

\textbf{Results}

\emph{Participant characteristics}

Between 2010 to 2022 there were 40 cases of inverted papilloma - 22 were
primary and 18 were secondary. A consultant rhinologist did primary
cases, whereas secondary cases were operated on by a general ENT surgeon
at the first procedure. Our cohort included 26 males and 14 females. The
average age at surgery was 62.8 ranging from 22.4 to 89. In addition to
the endoscopic approach, 31\% of our participants had a medial
maxillectomy or Draf IIb/III as an adjunct.

\emph{Main results}

The most common area for IP in our cohort was the maxillary sinus (33\%)
which is displayed in Table 1. Recurrence was most common in the frontal
and maxillary sinuses and the most common procedure performed was a
medial maxillectomy (30\%).

After 5 years of follow-up, there were a total of 21 recurrences in our
cohort (figure 1) -- these consisted of 6 recurrences in primary cases
and 15 recurrences in secondary cases. When the number of recurrences
between primary and secondary cases was compared, the difference was
found to be statistically significant (X\textsuperscript{2}(1, n=40)=
19.1583, p = 0.000412). A range of 1-2 episodes of recurrence were seen
in each primary case, compared to 1-7 episodes in each secondary case.

On average, recurrence was detected within 20 and 39 months in primary
and secondary cases respectively. Most recurrences were treated with
local resection (50\%) or topical intranasal mitomycin (20\%). Regarding
complications, there was 1 case of intra-operative CSF leak (repaired
intra-operatively) and 1 case of temporary post-operative facial
numbness.

\emph{Krouse staging}

Sinonasal IPs were staged using the Krouse system. Most patients
(58.5\%) in our cohort presented with Krouse stage 3 -- this is when the
tumour invades lateral, inferior, superior, anterior, or posterior walls
of the maxillary sinus and/or frontal sinus. (1,2) Table 2 summarises
the rate of recurrences according to different Krouse stages. The
highest rates of recurrence were seen in stage 3, reflecting the more
advanced presentation of the cases, especially in secondary cases.
(Table 2)

\textbf{Discussion}

\emph{Key results}

Our patient cohort demographics were similar to other studies, with an
observed 2:1 male-to-female ratio and average age of presentation of
62.8 years. As in previous research, the maxillary sinus was the most
common site for primary IPs. (5) In literature, primary and secondary
cases have recurrence rates of 10\% and 29\% respectively (5,6), which
is comparable to our cohort's recurrence rates of 15\% (6/40) and 37.5\%
(15/40) for our primary and secondary cases.

The mean time of recurrence was 20 and 39 months for primary and
secondary cases, which is different to what has been found in previous
literature. (5) This difference could be explained by the faster
detection rate and the significantly smaller number of recurrences in
primary cases seen in our cohort (16\% vs 84\%), highlighting that
outcomes and recurrence rates for IP are better when managed by a
fellowship-trained rhinologist.

As in previous literature, patients with Krouse stage 3 cases and IPs
located in the frontal and maxillary sinuses had the highest rates of
recurrences. (5,6) This may be explained by the technical difficulty of
accessing the frontal sinus, limited visualisation of the tumour via
endoscopy, and the challenge of obtaining a margin when up against
critical structures. (8) Similarly, maxillary IPs are associated with
increased recurrence rates in literature; (6) due to the challenging
visualisation and access of the site (2,6), especially the floor of the
antrum and medial maxillary wall.

The worse outcomes seen in secondary cases may be explained by the
absence of landmarks due to previous dissections, scarring and distorted
anatomy. (9) However, our cohort further highlights that IPs have a
lower rate of recurrences when managed by a fellowship-trained
rhinologist. Thus, figure 2 contains the suggested gold-standard
treatment pathway for all sinonasal tumours.

\emph{Limitations}

Potential limitations of our study include the lack of information on
patient characteristics such as smoking, HPV and inflammatory disease
status since these were not well recorded in the electronic records. Our
population sample size was small and from a single centre, reflecting
the smaller regional population.

\emph{Conclusions}

This retrospective review suggests that recurrence rates of IPs may be
higher in cases operated on initially by a non-specialist surgeon. We
therefore recommend that all IP cases should be referred to a
fellowship-trained rhinologist using the suggested management
gold-standard flow chart (figure 2). Our study further demonstrates that
endoscopic approaches remain a beneficial technique in managing IPs
(2,5) by reducing morbidity, decreasing post-operative complications,
and inpatient stays. (4,6)

Word count -- 1433/1500

References:

\begin{enumerate}
\tightlist
\item
  Lisan, Q., Laccourreye, O., \& Bonfils, P. (2016). Sinonasal inverted
  papilloma: From diagnosis to treatment. In \emph{European Annals of
  Otorhinolaryngology, Head and Neck Diseases} (Vol. 133, Issue 5, pp.
  337--341). Elsevier Masson SAS.
  https://doi.org/10.1016/j.anorl.2016.03.006
\item
  Lund, V. J., Stammberger, H., Nicolai, P, Castelnuovo P, Beal T et al.
  (2010). \emph{European position paper on endoscopic management of
  tumours of the nose and paranasal sinuses and skull base Chronic
  Rhinosinusitis Burden of Disease View project Surgical versus medical
  treatment of CRS View project} .
  https://www.researchgate.net/publication/284882881
\item
  Wang, M. J., \& Noel, J. E. (2017). Etiology of sinonasal inverted
  papilloma: A narrative review. In \emph{World Journal of
  Otorhinolaryngology - Head and Neck Surgery} (Vol. 3, Issue 1, pp.
  54--58). KeAi Communications Co.
  https://doi.org/10.1016/j.wjorl.2016.11.004
\item
  Goudakos, J. K., Blioskas, S., Nikolaou, A., Vlachtsis, K., Karkos,
  P., \& Markou, K. D. (2018). Endoscopic Resection of Sinonasal
  Inverted Papillomas: Systematic Review and
  Meta-Analysis.\emph{American Journal of Rhinology and Allergy} .
  https://doi.org/10.1177/1945892418765004
\item
  Philpott, C. M., Dharamsi, A., Witheford, M., \& Javer, A. R. (2010).
  Endoscopic management of inverted papillomas: Long-term results - The
  St. Paul's sinus centre experience. \emph{Rhinology} , \emph{48} (3),
  358--363. https://doi.org/10.4193/Rhin09.105
\item
  Kim, D. Y., Hong, S. L., Lee, C. H., Jin, H. R., Kang, J. M., Lee, B.
  J., Moon, I. J., Chung, S. K., Rha, K. S., Cho, S. H., Kim, K. R.,
  Kim, S. W., Kim, D. W., Chung, Y. J., Kim, K. S., Won, T. bin, Shim,
  W. S., Park, C. H., Kang, I. G., \& Roh, H. J. (2012). Inverted
  papilloma of the nasal cavity and paranasal sinuses: A Korean
  multicenter study. \emph{Laryngoscope} , \emph{122} (3), 487--494.
  https://doi.org/10.1002/lary.22495
\item
  Walgama, E., Ahn, C., \& Batra, P. S. (2012). Surgical management of
  frontal sinus inverted papilloma: A systematic review.
  In\emph{Laryngoscope} (Vol. 122, Issue 6, pp. 1205--1209).
  https://doi.org/10.1002/lary.23275
\item
  Philpott C, Sama A. Endonasal Approaches to Maxillary Sinus. Int J
  Head Neck Surg 2018;9(1):26-31.
\item
  Sciarretta, V., Fernandez, I. J., Farneti, P., \& Pasquini, E. (2014).
  Endoscopic and combined external-transnasal endoscopic approach for
  the treatment of inverted papilloma: Analysis of 110
  cases.\emph{European Archives of Oto-Rhino-Laryngology} , \emph{271}
  (7), 1953--1959. https://doi.org/10.1007/s00405-013-2817-1
\end{enumerate}

\textbf{Tables and Figures:}

\textbf{Table 1: Location of Inverted Papilloma and Rate of Recurrence}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Area & Right & Left & Total & Percentage of total & Recurrence Rate
(Percentage)\tabularnewline
\midrule
\endhead
Nasal vestibule, septum & 0 & 4 & 4 & 10 & 0\tabularnewline
Frontal sinus & 3 & 3 & 6 & 15 & 31\tabularnewline
Maxillary sinus & 5 & 8 & 13 & 33 & 31\tabularnewline
Turbinates & 3 & 3 & 6 & 15 & 5\tabularnewline
Ethmoid sinus & 5 & 5 & 10 & 24 & 26\tabularnewline
Sphenoid sinus & 1 & 0 & 1 & 2 & 5\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2: The Rate of Recurrence according to Krouse stage}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Krouse Stage & Primary cases & Number of primary recurrences & Secondary
cases & Number of secondary recurrences\tabularnewline
\midrule
\endhead
T1 & 3 & 0 & 2 & 6\tabularnewline
T2 & 8 & 3 & 3 & 8\tabularnewline
T3 & 11 & 8 & 13 & 23\tabularnewline
T4 & 0 & 0 & 0 & 0\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure 1: The Rate of Recurrence Between Primary and Secondary
Lesions}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 2: A Recommended Patient Pathway for Sinonasal Tumours.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\selectlanguage{english}
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