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\begin{document}

\title{Therapeutic effect on pyriform sinus carcinoma resection via paraglottic
space approach: Results of a single-centre study of 93 patients}



\author[1]{lei wang}%
\author[1]{ruijie sun}%
\author[1]{zheng jiang}%
\author[1]{jian lin yue}%
\author[1]{da yu liu}%
\affil[1]{Qilu Hospital of Shandong University Qingdao}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective To analyse the surgical indications, surgical efficacy and key
influencing factors of prognosis of using a novel surgical approach for
pyriform sinus carcinoma resection utilising the paraglottic space.
Methods From 2014 to 2017, 93 patients with squamous cell carcinoma
originating in the pyriform sinus were resected through the paraglottic
space approach. The postoperative laryngeal function preservation,
complications, survival rate and prognostic factors were analysed.
Results The 2, 3 and 5 year overall survival rates of the patients were
77.2\%, 61.6\% and 47.4\%, respectively. The univariate analysis of
survival rate showed that primary tumour T stage and N stage had a
statistically significant effect on the survival rate of patients
(P=0.047 and P\textless{}0.001, respectively). Multivariate analysis
with the Cox regression model revealed that N stage is an independent
risk factor for postoperative survival (P=0.042). The preservation rate
of laryngeal function was 65.6\% (61/93). Pharyngeal fistula incidence
was 4.3\% (4/93). Systemic distant metastasis and second primary cancer
were found to be the main causes of death. Conclusions As a novel
surgical approach for the resection of pyriform sinus carcinoma, the
paraglottic space approach can better expose the tumour, effectively
improve the retention rate of laryngeal function, reduce the incidence
of pharyngeal fistula and result in the better recovery of postoperative
swallowing function with satisfactory long-term survival. This surgical
approach can be applied in patients with lesions that do not involve the
paraglottic space. N stage is an independent risk factor for
postoperative survival. Key Points: In this study, we present a novel
surgical approach for hypopharyngeal carcinoma resection utilizing the
paraglottic space. The paraglottic space is a natural anatomical
space.If the thyroid cartilage plate is cut obliquely and pulled
posterolaterally, the paraglottic space can be easily exposed. The
paraglottic space approach can help expose neoplasms under direct vision
and save mucosa during surgery while sufficiently preserving laryngeal
function. In our study, application of the paraglottic approach
significantly reduced one of the serious postoperative complications,
pharyngocutaneous fistula. This approach can be proposed as a promising
candidate for resection of early T stages of hypopharyngeal carcinoma.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Hypopharyngeal cancer is a highly malignant tumour of the head and neck
that accounts for approximately 3\%--5\% of all head and neck
malignancies {[}1{]}. The pyriform sinus is the most frequently affected
site and represents 70\% of hypopharyngeal carcinoma {[}2{]}. Given the
close location of the pyriform sinus to the larynx, piriform sinus
cancer easily invades the larynx, resulting in the destruction of
laryngeal structure and function. Considering that accurate tumour
resection is needed to achieve local control and improve survival rate,
how to preserve laryngeal function as much as possible to improve the
quality of life of patients after surgery is a difficult problem.
Previously, we explored and summarised a new surgical approach, namely,
the paraglottic space approach, through clinical practice to remove
pyriform sinus carcinoma. This approach achieved good results in
clinical practice. In this paper, we retrospectively analysed the
clinical data of patients admitted to our department from 2014 to 2017
who underwent pyriform sinus carcinoma resection via the paraglottic
space approach. The purpose of this study was to summarise and explore
the surgical indications, therapeutic effects, surgical advantages and
influencing factors of this approach for pyriform sinus carcinoma
resection.

\textbf{Materials and methods}

The clinical data of 93 patients who underwent primary pyriform sinus
carcinoma resection via the paraglottic space approach, from January
2014 to January 2017 were retrospectively analysed. All patients were
operated for the first time without preoperative chemoradiotherapy and
underwent electronic laryngoscopy, narrow band imaging, electronic
gastroscopy and cervicothoracic enhanced CT before surgery. Patients
with distant metastasis or second primary cancer and general anaesthesia
contraindications were excluded from this study. The age of the patients
ranged from 41 years to 87 years. Amongst the 93 patients, 91 were males
and 2 were females with an average age of 58.8\selectlanguage{ngerman}±9.51 years. The general
clinical data and tumour characteristics of all patients (in accordance
with the American Joint Committee on Cancer 2017 8th edition TNM staging
of hypopharyngeal carcinoma) are summarised in Tables 1--2. The STROBE
standard reporting guidelines for cohort studies were followed.

Table 1. T N Stage\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& N0 & N1 & N2 & N3 &\tabularnewline
T1 & 5 & 2 & 0 & 0 & 7\tabularnewline
T2 & 10 & 6 & 8 & 1 & 25\tabularnewline
T3 & 7 & 9 & 25 & 2 & 43\tabularnewline
T4 & 2 & 4 & 12 & 0 & 18\tabularnewline
& 24 & 21 & 45 & 3 &\tabularnewline
\bottomrule
\end{longtable}

Table 2. Population and Cancer Data\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Data & n (\%) & X\textsuperscript{2} & P\tabularnewline
Gender & & 1.545 & 0.214\tabularnewline
Male & 91 & &\tabularnewline
Female & 2 & &\tabularnewline
Age(y) & & 1.111 & 0.292\tabularnewline
<60 & 50 & &\tabularnewline
[?]60 & 43 & &\tabularnewline
Cigarette smoking & & 0.233 & 0.629\tabularnewline
Ever & 82 & &\tabularnewline
Never & 11 & &\tabularnewline
Alcohol drinking & & 1.304 & 0.253\tabularnewline
\textgreater{} 50 g/d & 84 & &\tabularnewline
\textless{} 50 g/d & 9 & &\tabularnewline
Tumour differentiation degree & & 3.909 & 0.142\tabularnewline
Well & 9 & &\tabularnewline
Moderately & 29 & &\tabularnewline
Poorly & 55 & &\tabularnewline
Initial location of cancer in the pyriform sinus & & 2.612 &
0.271\tabularnewline
Medial wall & 56 & &\tabularnewline
Lateral wall & 18 & &\tabularnewline
lateral and medial walls & 19 & &\tabularnewline
laryngeal function preservation & 61 & 1.661 & 0.197\tabularnewline
AJCC stage & & 7.017 & 0.071\tabularnewline
I & 5 & &\tabularnewline
II & 10 & &\tabularnewline
III & 24 & &\tabularnewline
IV & 54 & &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Description of the surgical procedure}

The neck dissection method was selected in accordance with the
preoperative examination, primary tumour extent and regional lymph node
metastasis. Patients with N0--N1 underwent ipsilateral II--IV selective
neck dissection, patients with N2 underwent ipsilateral II--V neck
dissection, and patients with N3 underwent ipsilateral I--V +
contralateral II--IV neck dissections. If the tumour crosses the midline,
bilateral neck dissection is performed; level VI and retropharyngeal
lymph node dissections were performed for patients with T3--T4 and N2b
or above.

\textbf{1. Tumour resection method}

After the neck lymph node dissection was completed, the free cervical
sheath was pulled outward, the ipsilateral thyroid lobe was separated,
and the ipsilateral great horn of the hyoid bone was removed. The
inferior constrictor of the pharynx was cut off on the surface of the
thyroid cartilage plate, and the thyroid cartilage plate was obliquely
incised so that the thyroid cartilage plate was divided into two parts:
anterior 2/3 and posterior 1/3. The piriform sinus was gradually
separated from the larynx by pulling the posterior part of the thyroid
cartilage plate outward and removing the connective tissue along the
lateral surface of the thyroarytenoid muscle, and the paraglottic space
was easily exposed (Fig. 1).

For the carcinoma of the lateral wall of the piriform sinus, the thyroid
cartilage plate was pulled outward, and the ipsilateral piriform sinus
can be separated from the larynx through the paraglottic space approach.
The tumour was fully exposed and resected under direct vision, and all
the cutting edges were sent for frozen pathology until the negative
margin was obtained. For the carcinoma of the medial wall of the
piriform sinus, the lateral surface of the thyroarytenoid muscle was
fully skeletonised until the arytenoid cartilage appeared. Firstly, the
resection of the deep margin of the tumour was completed. Subsequently,
the tumour was removed under direct vision by entering the pharyngeal
cavity naturally through the free edge of the aryepiglottic fold or
through the posterior incision of the thyroid cartilage plate into the
pharyngeal cavity (critical surgical steps were shown in Fig. 2, (Such
as~Video1).). If the paraglottic space was involved during the
operation, partial laryngectomy or total laryngectomy was performed
selectively.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure1 schematic diagram of paraglottic space approach}

Horizontal section of larynx at the level of the glotti

1=thyroid cartilage,2=cricoid cartilage,3=arytenoid cartilage,

4=thyroarytenoid muscle,5=vocal cord, 6= airway lumen,7=lumen of the
hypopharynx

black solid line=paraglottic space, double slash=Incision of thyroid
cartilage\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure2} Pictures of surgical procedures

\textbf{A} Exposure of lateral edge of thyroid cartilage
plate.\textbf{B} After the moderate outwards traction and lysis of the
surrounding tissue, the parglottic space was exposed. \textbf{C} Enter
the pharyngeal cavity from the paraglottic space and remove the tumour
under direct vision. \textbf{D} Remove the tumour along the safe
boundary of the tumour. \textbf{E} the mucosa of the posterior wall of
the hypopharynx is sutured up and down to widen the pharyngeal
cavity.\textbf{F} Suture the pharyngeal mucosa and close the pharyngeal
cavity

\textbf{2. Repair}

For stage T1 and T2 lesions, the pharyngeal cavity can mostly be closed
with local mucosal pulling sutures after tumour resection. For stage T3
and T4 lesions, such as the tumour of the lateral wall of the piriform
sinus invading the posterior wall of the hypopharynx or the tumour
invading the entrance of the oesophagus, the defect of the lateral wall
of the pharynx is so large that it is difficult to pull and suture
directly after tumour resection. The most common method we use to repair
the pharyngeal cavity is pedicled pectoralis major myocutaneous flap
(Such as~Video2). In addition, after the pharyngeal cavity was closed,
the ipsilateral uninvolved thyroid lobe was lifted and fixed on the
lateral side of the pharyngeal suture to strengthen the pharyngeal wall
and reduce the incidence of pharyngeal fistula.

\textbf{3. Postoperative adjuvant chemoradiotherapy}

Postoperative radiotherapy alone was performed in 70 cases, whereas
postoperative concurrent chemoradiotherapy was performed in 18 cases.
The target areas of radiotherapy included the primary focus and the
cervical lymphatic drainage area. All patients were treated with
intensity-modulated radiotherapy (IMRT). The dose of radiotherapy was
50--66 Gy/25--33 f, 1.8--2.0 Gy/f, 5 f/W. The concurrent chemotherapy
regimen was combined chemotherapy based on cisplatin.

\textbf{Follow-up and statistical analysis}

The survival stage and prognosis of all patients were followed up by
means of telephone return visits, outpatient reexaminations, and other
methods. Follow-up period was once every 3 months in the first and
second years and once every 6 months in the third to fifth years. The
re-examination included physical examination, laryngoscopy and imaging
examination (cervicothoracic enhanced CT). Patients with clinically
suspected tumour recurrence were examined by PET--CT. Survival rate was
analysed via Kaplan--Meier analysis. The difference between groups was
tested through log-rank method, and independent prognostic factors were
analysed by Cox regression model in multivariate survival analysis. The
statistical software SPSS 25 was used to analyse the data.
P\textless{}0. 05 was considered statistically significant.

\textbf{Results}

\textbf{Postoperative data of patients}

All patients were followed up for 5 years. Six patients were lost by the
end of follow-up. Survival analysis was performed in accordance with the
final follow-up time. The follow-up time was 6--82 months, and the
median follow-up time was 50 months. The patients who lost follow-up
participated in the survival analysis as censored data, and the survival
time was calculated according to the last follow-up time before the loss
of follow-up. The postoperative pathology of all patients was squamous
cell carcinoma. The metastasis rate of lateral cervical lymph nodes was
74.2\% (69/93). Seventy patients underwent level VI lymph node
dissection and retropharyngeal lymph node dissection. The positive rates
of region VI lymph nodes and retropharyngeal lymph nodes were 12.9\%
(9/70) and 15.7\% (11/70), respectively.

A total of 78 patients in this group had their larynges preserved. 11
patients underwent tongue root flap repair, 20 patients underwent
pectoralis major myocutaneous flap repair, and 5 patients underwent
subchin flap repair. Other patients performed local mucosal flap repair
of pharyngeal defects.

Pathological examination revealed that 81 patients (87\%) had negative
tumor margins without lesions. Twelve cases had positive or poorly
defined margins microscopically, and in these cases, the margins of the
frozen sections were expanded until the margins were negative.

By postoperational laryngeal function evaluation methods such as
subjective sensation, voice quality,electronic laryngeal endoscopy, and
X-ray barium meal examination, 65.6\% (61/93) cases showed complete
recovery of laryngeal functions (speech,respiration, and deglutition).
shown in Table 3.

Tracheal cannula removal time. Amongst the 78 patients with laryngeal
preservation, 63 patients were extubated after radiotherapy.
Unfortunately, 2 patients underwent tracheotomy and intubation again
with laryngeal edema.

During the perioperative period, four cases had internal pharyngeal
fistula, two cases experienced subcutaneous effusion, and one case
experienced bleeding at the tracheotomy, all of which were cured by
dressing change and pressure bandaging. One case of pulmonary infection
improved after switching to sensitive antibiotics. No death occurred
during the perioperative period.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
Table 3. & The preservation of laryngeal functions in different T stage
& The preservation of laryngeal functions in different T stage & The
preservation of laryngeal functions in different T stage & The
preservation of laryngeal functions in different T stage & The
preservation of laryngeal functions in different T stage & The
preservation of laryngeal functions in different T stage & The
preservation of laryngeal functions in different T stage\tabularnewline
\midrule
\endhead
T grade & & Laryngeal preservation & Laryngeal preservation & &
Laryngeal functions & Laryngeal functions & Laryngeal
functions\tabularnewline
& & Yes (78 cases) & No (15 cases) & & deglutition & speech &
respiration\tabularnewline
T1-T2 & & 32 & 0 & & 32 & 32 & 32\tabularnewline
T3 & & 37 & 6 & & 35 & 37 & 26\tabularnewline
T4 & & 9 & 9 & & 6 & 9 & 3\tabularnewline
Total & & 78 & 15 & & 73 & 78 & 61\tabularnewline
\bottomrule
\end{longtable}



\textbf{Survival and prognostic factor analyses}

The Kaplan--Meier survival curve method provided a 2-year survival rate
of 77.2\%, a 3-year survival rate of 61.6\% and a 5-year survival rate
of 47.4\%. Univariate analysis was carried out in accordance with the
general data, tumour characteristics and TNM stage of the patients. The
results of log-rank test showed that sex, age, history of smoking and
alcohol, degree of tumour differentiation, primary site, clinical stage
and preservation of laryngeal function were all P\textgreater{}0.05,
which indicates no statistical significance (Table 2). However,
significant differences in survival were found between stages T1--T2 and
T3--T4 (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}=3.959, P=0.047) and amongst N0--N3
(\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}=17.767, P\textless{}0.001; Fig.3). The Cox
regression analysis of tumour differentiation based on primary site,
clinical stage, T and N stages and preservation of laryngeal function
revealed that N stage is an independent risk factor of pyriform sinus
carcinoma resected via the paraglottic space approach (P=0.042, Fig.3).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image14/image14}

\end{center}
\end{figure}

\textbf{Figure3 Kaplan-Meier survival curves for different T-stages and
N-stages}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image16/image16}

\end{center}
\end{figure}

\textbf{Figure3 Multivariate regression analysis of factors influencing
overall survival.}

\textbf{Cause of death}

Fifty-one patients died as of the last follow-up date. The main causes
of death included systemic distant metastasis (18 cases, 35.3\%),
including lung metastasis (9 cases), liver metastasis (5 cases), bone
metastasis (3 cases) and brain metastasis (1 case); second primary
cancer (11 cases, 21.6\%), including middle and lower oesophageal
cancers (7 cases), central lung cancer (3 cases) and gastric cancer (1
case) and nontumour causes of death (9 cases, 17.6\%), including
respiratory failure (3 cases) and cardiogenic death (2 cases), severe
pneumonia (1 case), asphyxia caused by sputum thrombus (1 case) and
unknown causes (2 cases). Local metastases of cervical lymph nodes were
found in 7 cases (13.7\%). Local tumour recurrence was found in 6 cases
(11.8\%).

\textbf{Discussion}

The paraglottic space is a potential space containing adipose tissue and
blood vessels, bordered laterally immediately adjacent to the thyroid
cartilage, medially adjacent to the thyroarytenoid muscle and bordered
dorsally to the piriformis sinus {[}3{]}. The paraglottic space can be
easily exposed if the thyroid cartilage plate is cut obliquely during
the operation and the posterior part of the thyroid cartilage plate is
pulled outward (such as the description of the previous surgical
method). The advantages of the paraglottic space approach are as
follows. The paraglottic space is a natural anatomical space, and the
tissue is easily separated through the paraglottic space approach with
less intraoperative blood loss and a clear surgical field. The
hypopharynx is easier to separate from the larynx and the highly
wrinkled pharyngeal cavity is easily planarised to fully expose the
tumour and removing the tumour in a 3D way under the full dissociation
of the mucous membrane through the paraglottic space approach. The
tumour is not squeezes in the process of surgical resection, which is in
line with the principle of tumour resection. The surgical field of view
via the paraglottic space approach is well exposed. Combined with the
preoperative narrow band imaging examination, the tumour can be
accurately removed under direct vision, and the normal hypopharyngeal
mucosa can be preserved as much as possible, which is conducive to
pharyngeal cavity reconstruction and function preservation.

How to improve the retention rate of laryngeal function without
affecting the survival rate of patients has become the focus of clinical
attention. Relevant scholars also confirmed the feasibility of laryngeal
function-preserving surgery for pyriform sinus carcinoma and provided a
pathological basis {[}4-6{]}.The National Comprehensive Cancer Network
guidelines point out that surgery is feasible for patients with T1+N
positive and T2-3Nx hypopharyngeal cancer to preserve the laryngeal
structure, and partial laryngectomy (open or laser) combined with
postoperative radiotherapy can be considered. These patients are
expected to preserve laryngeal function. Although a part of pyriform
fossa carcinoma belongs to T4, only the posterior edge of the thyroid
cartilage, a small part of the cricoid cartilage, or the entrance of the
cervical esophagus are involved. After tumor resection, most of the
larynx can be preserved, the pectoralis major myocutaneous flap can be
used to reconstruct the pharyngeal cavity, and the preservation of
laryngeal function can be realised.

The paraglottic space of stage T1--T2 pyriform sinus carcinoma is rarely
invaded. It is the best indication for this surgical approach. In
addition, the paraglottic space approach can be used if the T3--T4
lesion does not involve the paraglottic space, because most cases of the
vocal cord fixation is caused by tumour compression and not by tumour
invasion of the paraglottic space {[}7{]}. For the carcinoma of the
lateral wall of the piriform sinus, the tumour rarely invades the larynx
because of its anatomical position. The approach through the paraglottic
space can fully separate the hypopharynx and larynx, that is, the entire
tumour can be directly exposed from the ventral side. The surgical field
of view is wide, and the tumour can be accurately removed. For the
primary tumour in the medial wall of the pyriform sinus, the
transglottic approach can firstly complete the resection of the deep
cutting edge of the tumour when entering the pharyngeal cavity, then
separate the tumour from the larynx by pulling the thyroid cartilage
plate outward and remove the tumour under direct vision. Preoperative
cervical enhanced CT and electronic laryngoscopic examination can
effectively determine the presence or absence of paraglottic space and
laryngeal cartilage involvement. If the paraglottic space is involved,
in the actual surgical operation, we can first enter through the
paraglottic space approach, separate the hypopharynx and larynx and then
combine the lateral pharyngeal approach, and observe the scope of tumour
invasion in multiple planes. Supraglottic hemilaryngopharygectomy,
partial pharyngectomy or total laryngectomy is performed according to
the actual extent of tumour invasion.

In addition, the incidence of pharyngeal fistula in this study was
4.3\%, which was considerably lower than those in other
studies{[}6,8{]}. As mentioned above, the paraglottic space approach can
retain more normal hypopharyngeal mucosa, dissociate the pharynx from
the larynx, effectively reduce the suture tension during pharyngeal
reconstruction and prevent mucosal avulsion during pharyngeal movement.
In addition, the lifting of the uninvaded lateral thyroid lobe to
strengthen the pharyngeal wall is another main reason to reduce the
occurrence of pharyngeal fistula. The lateral thyroid lobe has good
blood circulation and large tissue volume, which can be used as the
strengthening plane of the new pharyngeal cavity.

\textbf{Conclusion}

In summary, the paraglottic space approach is a novel surgical approach,
which can better expose the tumour. On the premise of ensuring a safe
tumour resection margin, this approach has obvious advantages in
preserving laryngeal function and reducing the serious postoperative
complications of pyriform sinus carcinoma. It is beneficial in improving
the quality of life of patients after surgery. This surgical approach
can be applied in patients with lesions that do not involve the
paraglottic space. N stage is an independent risk factor for
postoperative survival. This study still has the deficiency of a
relatively small sample size. Nonetheless, the resection method for
primary postcricoid carcinoma and posterior pharyngeal wall carcinoma
via the paraglottic space approach is worth further exploring and
trying.

\textbf{References}

{[}1{]}Cooper JS, Porter K, Mallin K, et al. National Cancer Database
report on cancer of the head and neck: 10-year update. Head Neck.
2009;31(6):748-758.

{[}2{]}Mura F, Bertino G, Occhini A, Benazzo M. Surgical treatment of
hypopharyngeal cancer: a review of the literature and proposal for a
decisional flow-chart. Acta Otorhinolaryngol Ita.2013;33:299-306.

{[}3{]}Reidenbach MM. The paraglottic space and transglottic
cancer:anatomical considerations.~Clin Anat. 1996;9(4):244-251.

{[}4{]} Hirano M, Kurita S, Tanaka H. Histopathologic study of carcinoma
of the hypopharynx: implications for conservation surgery.~Ann Otol
Rhinol Laryngol. 1987;96(6):625-629.

{[}5{]}Yoo SJ, Lee SH, Koh KS, Kim SY. Larynx preservation surgery in
pyriform sinus cancer. IntSurg. 2000;85(2):93--8.

{[}6{]} Plouin-Gaudon I, Lengel\selectlanguage{ngerman}é B, Desuter G, et al. Conservation
laryngeal surgery for selected pyriform sinus cancer.~Eur J Surg Oncol.
2004;30(10):1123-1130.

{[}7{]}Segas JV, Hantzakos AG, Tzagaroulakis AM, Adamapoulos GK. A novel
technique in the operative treatment of pyriform sinus carcinoma. Acta
Otolaryngol. 2001;121(4):529--33.

{[}8{]} Dirven R, Swinson BD, Gao K, Clark JR. The assessment of
pharyngocutaneous fistula rate in patients treated primarily with
definitive radiotherapy followed by salvage surgery of the larynx and
hypopharynx.~Laryngoscope. 2009;119(9):1691-1695.

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