cancers

Article
T1 Glottic Cancer: Does Anterior Commissure
Involvement Worsen Prognosis?
Giuditta Mannelli 1, * , Lara Valentina Comini 2 , Roberto Santoro 1 , Alessandra Bettiol 3 ,
Alfredo Vannacci 3 , Isacco Desideri 4 , Pierluigi Bonomo 4 and Cesare Piazza 5
1 Head and Neck Oncology and Robotic Surgery, Department of Experimental and Clinical Medicine,
University of Florence, 50134 Firenze, Italy; [email protected]
2 University of Florence, 50134 Firenze, Italy; [email protected]
3 Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and
Toxicology, Tuscan Regional Centre of Pharmacovigilance and Phytovigilance, University of Florence,
50134 Florence, Italy; [email protected] (A.B.); [email protected] (A.V.)
4 Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy;
[email protected] (I.D.); [email protected] (P.B.)
5 Department of Otorhinolaryngology, Maxillofacial and Thyroid Surgery, Fondazione IRCCS,
National Cancer Institute of Milan, University of Milan, 20122 Milan, Italy; [email protected]
* Correspondence: [email protected]




Received: 9 April 2020; Accepted: 4 June 2020; Published: 6 June 2020


Abstract: Radiotherapy (RT) and transoral laser microsurgery (TLM) represent the main treatment
modalities for early glottic carcinoma. Local failure is notoriously more frequent in T1b glottic
cancer in comparison to T1a and T2 tumors. In this scenario, the role of anterior commissure (AC)
involvement is still controversial. The aim of the present study was therefore to determine its potential
prognostic power in worsening patients’ survival and outcomes. We categorized different tumor
glottic fold locations with respect to the involvement of one (T1a) or both vocal cords, with or without
AC involvement. We analyzed a retrospective cohort of 74 patients affected by Stage I glottic cancer,
treated between 2011 and 2018 by TLM or RT at a single academic institution. There were 22 T1a (30%)
and 52 T1b (70%) cases. The median follow-up period was 30 months (mean, 32.09 ± 18.738 months;
range, 12–79). Three-year overall survival (OS), disease-specific survival (DSS), recurrence-free
survival (RFS), and laryngectomy-free survival (LFS) were compared according to tumor location,
extension, and cT category. According to both uni- and multivariate analyses, an increased risk
for recurrence in T1b with AC involvement and T1a tumors was 7.31 and 9.45 times, respectively
(p-values of 0.054 and 0.030, respectively). Among the 17 recurrences, T1b with AC involvement
experienced 15 tumor relapses (88.2%), thus significantly affecting both the RFS and LFS in comparison
to the other two tumor subcategories (T1a, p = 0.028 and T1b without AC involvement, p = 0.043).
The deteriorating prognosis in the presence of AC involvement likely reflects the need to power the
hazard consistency and discrimination of the T1b category when associated with such a risk factor,
thus deserving an independent T category.

Keywords: early glottic cancer; anterior commissure involvement; prognosis; independent

prognostic factor

1. Introduction
Glottic squamous cell carcinoma (SCC) represents about 75% of laryngeal malignancies [1] and
arises from the glottic plane which, according to the staging manual of the American Joint Committee
on Cancer (AJCC), includes three different anatomical subsites: the vocal cords, anterior commissure
(AC), and posterior commissure (PC) [2].

Cancers 2020, 12, 1485; doi:10.3390/cancers12061485 www.mdpi.com/journal/cancers

Cancers 2020, 12, 1485 2 of 12

The five-year disease-specific survival (DSS) of T1 glottic SCC ranges between 94% and 100%,
with a five-year local control of 84% [3,4]. The AC is rarely the site of origin of these tumors, but it is
involved in up to 20% of early glottic cancers [5,6]. The AC’s complex anatomy constitutes a single
subsite of the larynx which, according to its embryonic origin, presents a vertical extension [7] as well
as a locus minoris resistentiae due to the absence of the inner perichondrium in correspondence to the
intermediate lamina of the thyroid cartilage [8,9]. In this setting, the AC has always been the object of
anatomic, diagnostic, and therapeutic controversies in laryngeal oncology. Furthermore, the pooled
difference in five-year local recurrence rates between T1 glottic SCC without (T1a) and with (T1b) AC
involvement has been reported to rise up to 12%, regardless of the type of treatment adopted (either
radiotherapy (RT) or transoral laser microsurgery (TLM), thus making the presence of AC involvement
an independent negative prognostic factor for Stage I glottic lesions [10–15]. Although several studies
have shown a significant association between AC involvement and a higher recurrence rate of glottic
SCC [8,10–17], the specific value of the AC anatomical partition is not taken into account by the current
TNM staging system as a structure whose involvement plays an independent prognostic role [18].
Since the binary variables for AC involvement has led to inconsistent results in the literature [10,19],
the purpose of this study was to propose a more detailed stratification for tumors involving the AC,
in order to better assess its prognostic role in early glottic carcinomas and consequently evaluate its
effect on survival. The final aim was to understand if early glottic SCC with AC involvement does
deserve a different staging category.

2. Materials and Methods

2.1. Study Population

A retrospective study on patients treated for T1a and T1b glottic SCC between June 2011 and
June 2018 at the Departments of Otorhinolaryngology—Head and Neck Surgery and Radiotherapy,
University of Florence, Italy, was carried out. This retrospective observational study was approved by
the local Ethical Committee with protocol number 16208_oss, and all the procedures were conducted
in accordance to the Helsinki Declaration of 1975, as revised in 1983. All of the patients’ clinical
charts were reviewed and tumors retrospectively restaged according to the 8th Edition of the AJCC
staging system [18]. All the participants provided informed consent before undergoing curative
treatment, either TLM or RT. The indications for both therapeutic approaches included the presence of a
biopsy-proven glottic primary SCC, staged as cT1aN0 or cT1bN0 (Stage I) according to the preoperative
fiberoptic evaluation, radiological imaging by CAT (computed assisted tomography) and/or MRI
(magnetic resonance imaging) with contrast medium administration, and intraoperative endoscopic
assessment performed to get a biopsy of the lesion. All patients and their therapeutic options were
discussed and shared among the members of the local multidisciplinary team (MDT).
The exclusion criteria were as follows: pre- and/or intraoperative clinical and radiological evidence
of glottic SCC different from Stage I; PC involvement; patients previously treated for other head and
neck cancers or already submitted to any kind of head and neck surgical procedures, including RT
and/or CRT (chemoradiation); patients who did not consent to be enrolled in the study; and patients
with incomplete clinical chart records and missing data.
The patients’ demographics, including their Charlson comorbidity index (CCI) [20], tumor and
treatment characteristics, and survival rates, were recorded and reviewed in a single dedicated database.
All patients underwent diagnostic preoperative assessment including videolaryngoscopy
coupled with narrow-band imaging (NBI) (Olympus Medical Systems Corporation, Tokyo, Japan),
and intraoperative panendoscopy with 0◦ , 30◦ , and 70◦ rigid telescopes, under general anesthesia in
the operating room. This allowed us to carefully examine the AC, with the specific aim of confirming or
excluding its potential involvement. In particular, special attention was devoted to 70◦ rigid endoscopy
to rule out potential subcommissural tumor extension. In the case of multiple glottic lesions, separate
biopsies were performed to confirm if they were malignant in nature or not. When surgical margins
Cancers 2020, 12,
Cancers 2020, 12, 1485
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12

lesions, separate biopsies were performed to confirm if they were malignant in nature or not. When
after TLM were close or positive (especially in the case of deep margin involvement), further re-excision
surgical margins after TLM were close or positive (especially in the case of deep margin involvement),
was generally planned. In selected cases, a wait-and-see policy was adopted after patient counseling if
further re-excision was generally planned. In selected cases, a wait-and-see policy was adopted after
the excision was believed to be radical and close/positive margins interpreted as an artifact of laser
patient counseling if the excision was believed to be radical and close/positive margins interpreted
diathermal effect or surgical specimen processing. Adjuvant radiotherapy (RT) was administered in
as an artifact of laser diathermal effect or surgical specimen processing. Adjuvant radiotherapy (RT)
the presence of clinical and/or pathological factors that increase the risk of tumor recurrence after
was administered in the presence of clinical and/or pathological factors that increase the risk of tumor
primary surgical treatment.
recurrence after primary surgical treatment.
On the other hand, primary RT was chosen upon patient request, major concerns regarding vocal
On the other hand, primary RT was chosen upon patient request, major concerns regarding vocal
outcomes, in cases with a preoperative Laryngoscore ≥9 [21], or whenever unfavorable laryngeal
outcomes, in cases with a preoperative Laryngoscore ≥9 [21], or whenever unfavorable laryngeal
exposure had been confirmed during the pretreatment general anesthesia for bioptic purposes alone.
exposure had been confirmed during the pretreatment general anesthesia for bioptic purposes alone.
In these cases, a CT scan (Big Bore, Philips Medical Systems, Cleveland, OH, USA) was acquired at
In these cases, a CT scan (Big Bore, Philips Medical Systems, Cleveland, OH, USA) was acquired at a
a 3-mm slice width for radiation treatment planning. Personalized thermoplastic head, neck, and
3-mm slice width for radiation treatment planning. Personalized thermoplastic head, neck, and
shoulder
shoulder masks
maskswerewerecreated for all
created forpatients. A three-dimensional,
all patients. conformal
A three-dimensional, techniquetechnique
conformal was employed:
was
radiation was delivered by means of opposing lateral fields with proper wedge filters
employed: radiation was delivered by means of opposing lateral fields with proper wedge filters using 6 MV
photons.
using 6 MVThephotons.
clinical target volume
The clinical (CTV)
target consisted
volume (CTV)of consisted
the wholeof larynx. A 5-mm
the whole larynx.CTV A to planning
5-mm CTV
target volume (PTV) was applied in order to compensate for potential systematic
to planning target volume (PTV) was applied in order to compensate for potential systematic and random errors.
and
The prescribed dose for the PTV was 70 Gray (Gy) given in 35 fractions of 2 Gy in 7 weeks.
random errors. The prescribed dose for the PTV was 70 Gray (Gy) given in 35 fractions of 2 Gy in 7
weeks.
2.2. Novel Classification Proposal
To better
2.2. Novel assess theProposal
Classification role of AC involvement in affecting Stage I survival and outcomes, we applied
a novel classification system for T1 glottic SCC. AC involvement here refers to all of Rucci’s categories
To better assess the role of AC involvement in affecting Stage I survival and outcomes, we
except for the AC0 class [7]. Our proposal is therefore articulated as follows:
applied a novel classification system for T1 glottic SCC. AC involvement here refers to all of Rucci’s
categories
1. exceptlimited
T1a, tumor for thetoAC0
oneclass
vocal[7]. Ourwithout
cord, proposal
ACisinvolvement,
therefore articulated as follows:
with normal vocal cord mobility
1(Figure
T1a,1);tumor limited to one vocal cord, without AC involvement, with normal vocal cord
mobility
2. T1b (Figure
without1);AC, tumor involving both vocal cords, without AC involvement, with normal vocal
2cordT1b without AC, tumor
mobility (Figure 2); involving both vocal cords, without AC involvement, with normal
vocalT1b
3. cordwith
mobility (Figure
AC, tumor 2);
involving one or both vocal cords, with AC involvement, with normal vocal
3cordT1b with AC, tumor
mobility (Figure 3). involving one or both vocal cords, with AC involvement, with normal
vocal cord mobility (Figure 3).

Figure 1.
Figure T1a cancer
1. T1a cancer of
of the
the right
right vocal
vocal cord
cord without
without anterior
anterior commissure
commissure (AC)
(AC) involvement.
involvement.
 2020, 12,
Cancers 2020, 12, 1485
x 44 of
of 12
Cancers 2020, 12, x 4 of 12

Figure 2. T1b without AC involvement.

Figure 2. T1b without AC involvement.

Figure 3. T1b with AC involvement.

Figure 3. T1b with AC involvement.
2.3. Statistical Analysis
2.3. Statistical Analysis
2.3. Statistical Analysis
The following endpoints
The following endpointswerewereconsidered:
considered:overall
overall survival
survival (OS),
(OS), defined
defined as the
as the timetime between
between the
the The of
following endpoints wereofconsidered: overall survival (OS), defined as(DSS),
the time between the
date of surgery and the date of death/last visit; disease-specific survival (DSS), defined as theastime
date surgery and the date death/last visit; disease-specific survival defined the
date of
time surgerythe
between and the ofdate of death/last visit; disease-specific survival (DSS),visit;
defined as the time
between the date ofdate
surgery surgery
and theand the
date of date of cancer-related
cancer-related death/last
death/last recurrence-free
visit; recurrence-free survival
between
survival the date of surgery and the date of cancer-related death/last visit; recurrence-free survival
(RFS), defined as the time between the date of surgery and the date of recurrence/last visit;visit;
(RFS), defined as the time between the date of surgery and the date of recurrence/last and
(RFS),
and defined as the time
laryngectomy-free between
survival (LFS), the date as
defined of surgery and the the
date of of
recurrence/last visit; and
laryngectomy-free survival (LFS), defined as thethetimetime between
between date
the date surgeryand
of surgery and the
the date
date of
of
laryngectomy-free
total survival (LFS), defined as the time between the date of surgery and the date of
total laryngectomy/death/last
laryngectomy/death/last visit.visit.
total The
laryngectomy/death/last visit.
The influence
influence ofof the
the three
three different
different abovementioned
abovementioned tumor tumor categories
categories on on the
the prognosis
prognosis was was
The
estimated influence of the three different abovementioned tumor categories on the prognosis was
estimated through the computation of the OS, DSS, RFS, and LFS curves using the Kaplan–Meier
through the computation of the OS, DSS, RFS, and LFS curves using the Kaplan–Meier
estimated
method through the computation of the OS, DSS,dichotomic
RFS, and LFS curvesMultivariate
using the Kaplan–Meier
method andand comparison
comparison by by the
the log-rank
log-rank test
test for
for the
the dichotomic variables.
variables. Multivariate analysis
analysis was
was
method
performed and comparison
using the Cox by the log-rank
proportional test
hazard for the
models dichotomic
and variables.
expressed as Multivariate
hazard ratios analysis
(HRs) was
with 95%
95%
performed using the Cox proportional hazard models and expressed as hazard ratios (HRs) with
performed using
confidence the Cox proportional hazard models and expressed as hazard ratios (HRs) with 95%
confidence intervals
intervals (CIs).
(CIs).
confidence intervals (CIs).
All
All the tests were 2-tailed,
the tests were 2-tailed, and p-values <
and p-values 0.05 were
< 0.05 were considered
considered toto be
be statistically
statistically significant. Data
significant. Data
were All the tests
analyzed wereStata
using 2-tailed,
14.0 and p-values
software < 0.05 were
(StataCorp LP, considered
College to beTX,
Station, statistically
USA). significant. Data
were analyzed using Stata 14.0 software (StataCorp LP, College Station, TX, USA).
were analyzed using Stata 14.0 software (StataCorp LP, College Station, TX, USA).
3. Results
3. Results
Among the 85 patients treated for Stage I glottic SCC by the Head and Neck MDT of our
Among the 85 patients treated for Stage I glottic SCC by the Head and Neck MDT of our
Institution, 74 were enrolled in the present study. Those excluded (n = 11) had already received
Institution, 74 were enrolled in the present study. Those excluded (n = 11) had already received
Cancers 2020, 12, 1485 5 of 12

3. Results
Among the 85 patients treated for Stage I glottic SCC by the Head and Neck MDT of our Institution,
74 were enrolled in the present study. Those excluded (n = 11) had already received previous head and
neck treatments (n = 4), presented with PC involvement (n = 3), had incomplete pretreatment diagnostic
data (n = 3), or did not give consent to be enrolled in the present study (n = 1). Table 1 summarizes
the study population characteristics. A total of 22 T1a (30%), 5 T1b without AC involvement (7%),
and 47 T1b with AC involvement (63%) were analyzed. The male to female ratio was 8:1 and the
median age at presentation was 68 years (mean, 67.83 ± 11.44; range, 38–90). We did not find any
statistical significance in the age categories (<50 years; 50–65 years; >65 years), or in the smoking and
alcohol habits among the three tumor categories (T1a, T1b without AC involvement, and T1b with AC
involvement). On the other hand, the CCI seemed to be slightly higher in T1b with AC involvement
(p = 0.049).
Thirty-six patients (48%) underwent TLM, whilst the remaining 38 (52%) received curative RT.
The vast majority of T1a patients (90.9%) had surgical treatment, while 66% of T1b with AC involvement
underwent RT. This treatment modality represented the preferred therapeutic approach in the presence
of AC involvement (p < 0.001). The incidence of post-treatment complications, as well as the need
for adjuvant RT after primary TLM, showed no statistically significant association with any of the
proposed T1 subcategories.
The median follow-up period was 30 months (mean, 32.09 ± 18.73 months; range, 12–79).
The three-year OS, DSS, RFS, and LFS were compared according to tumor location, extension, and
cT category.
The total number of recurrences was 17 out of 74 patients (22.9%) and salvage treatment was
represented by TLM in 7 patients out of 17 (41.2%), salvage total laryngectomy in 7 (41.2%), open
partial horizontal laryngectomy in 2 (11.7%), and RT in 1 (5.9%). The recurrence rate was significantly
higher among T1b with AC involvement (31.9%) in comparison to T1a (4.5%) and T1b without AC
involvement (20%), with a p-value of 0.028 (Table 2).

Table 1. Study population characteristics.

p-Value
T1b without AC T1b with AC
T1a n (%) (* Statistically
Involvement n (%) Involvement n (%)
Significant)
Number of patients 22 (30) 5 (7) 47 (63)
Male gender 21 (95.5) 4 (80.0) 42 (89.4) 0.405
Age at diagnosis
<50 years 0 1 (20.0) 4 (8.5) 0.56
50–65 years 5 (22.7) 3 (60.0) 19 (40.4)
>65 years 17 (77.3) 1 (20.0) 24 (51.1)
Charlson comorbidity index
3 (2–5) 2 (2–2) 3 (2–4) 0.049 *
(median (IQR))
Smoking habit
Yes 13 (59.1) 3 (60.0) 31 (66.0) 0.267
No 8 (36.4) 1 (20.0) 8 (17.0)
Missing data 1 (4.6) 1 (20.0) 8 (17.0)
Alcohol abuse
Yes 3 (13.6) 1 (20.0) 8 (17.0) 0.495
No 18 (81.8) 3 (60.0) 31 (66.0)
Missing data 1 (4.6) 1 (20.0) 8 (17.0)
Disease characteristics
Tumor location
Free margin 19 (86.4) 2 (40.0) 29 (61.7) 0.015 *
Superior aspect 3 (13.6) 3 (60.0) 8 (17.0)
Inferior aspect 0 0 10 (21.3)
Cancers 2020, 12, 1485 6 of 12

Table 1. Cont.

p-Value
T1b without AC T1b with AC
T1a n (%) (* Statistically
Involvement n (%) Involvement n (%)
Significant)
Treatment
Type of treatment
Transoral laser microsurgery
20 (90.9) 0 16 (34.0) <0.001 *
(TLM)
Radiotherapy (RT) 2 (9.1) 5 (100.0) 31 (66.0)
Resection margin
Negative 17 (85.0) - 12 (75.0) 0.530
Positive superficial, single 1 (5.6) - 0
Positive superficial, multiple 0 - 1 (6.3)
Positive deep, single 0 - 1 (6.3)
Positive deep, multiple 0 - 1 (6.3)
Missing data 2 (10.0) 1 (6.3)
Post-treatment complications
No 15 (68.2) 2 (40.0) 35 (74.5) 0.249
Yes 7 (31.8) 3 (60.0) 12 (25.5)
Dysphagia 2 (9.1) 1 (25.0) 6 (12.8)
Dysphonia 0 1 (25.0) 0
Dyspnea 0 1 (25.0) 0
Stenosis 0 0 1 (2.1)
Granuloma 5 (22.7) 0 1 (2.1)
Adjuvant RT
No 21 (95.5) 5 (100.0) 33 (70.2) 0.83
Yes 0 0 5 (10.6)
Missing data 1 (4.6) 0 9 (19.2)

Table 2. Disease recurrence and mortality rates.

p-Value
T1b without AC T1b with AC
T1a n (%) (* Statistically
Involvement n (%) Involvement n (%)
Significant)
Number of patients 22 (30) 5 (7) 47 (63)
Recurrence
No 21 (95.5) 4 (80.0) 32 (68.1) 0.028 *
Yes 1 (4.6) 1 (20.0) 15 (31.9)
Salvage treatment
for patients with
recurrence
Redo TLM 1 (4.6) - 6 (12.8) 1.000
Open partial
horizontal - - 2 (4.3)
laryngectomy
Total laryngectomy
- 1 (20.0) 6 (12.8)
+/- Neck dissection
RT - - 1 (2.1)
Disease-related
0 0 2 (4.3) 1.000
mortality
All-cause
1 (4.6) 0 2 (4.3) 1.000
mortality

In fact, T1b with AC involvement experienced 15 of 17 total recurrences (88.2%), significantly

affecting the RFS and LFS in comparison to the other two (T1a, p = 0.028 and T1b without AC
involvement, p = 0.043).
The OS was 95.5%, 100%, and 95.7% for T1a, T1b without AC involvement, and T1b with AC
involvement, respectively. The mortality rate did not show any statistically significant association
with either clinical and tumor characteristics or with the type of primary treatment. Specifically,
Cancers 2020, 12, 1485 7 of 12

disease-related
Cancers mortality was found only in the T1b with AC involvement group, although without
2020, 12, x 7 of 12
any statistical significance (p = 1.000) (Table 3).
Table 3. Survival outcomes.
Table 3. Survival outcomes.
OS DSS RFS LFS
T1a OS
21/22 (95.5%) DSS
22/22 (100%) RFS
21/22 (95.5%) 22/22LFS
(100%)
T1b
T1a without AC 21/22 (95.5%) 5/522/22 (100%) 21/22 (95.5%) 22/22 (100%)
5/5 (100.0%) (100%) 4/5 (80.0%) 4/5 (80.0%)
involvement
T1b without AC involvement 5/5 (100.0%) 5/5 (100%) 4/5 (80.0%) 4/5 (80.0%)
T1b
T1bwith
withAC
AC
45/47 (95.7%)
45/47 (95.7%) 45/4745/47
(95.7%)
(95.7%) 32/47
32/47(68.1%)
(68.1%) 37/47
37/47(76.6%)
(76.6%)
involvement
involvement
p-value
p-value 1.000 1.000 1.0001.000 0.028 *
0.028* 0.043**
0.043
OS:
OS: overall survival;DSS:
overall survival; DSS: disease-specific
disease-specific survival;
survival; RFS: recurrence-free
RFS: recurrence-free survival;survival; LFS: laryngectomy-
LFS: laryngectomy-free survival;
* p-value statistically significant.
free survival; * p-value statistically significant.

Accordingto
According toboth
boththe
theuni-
uni-and
andmultivariate
multivariateanalyses,
analyses,the
theincreased
increasedrisk
riskfor
forrecurrence
recurrenceininT1b
T1b
withAC
with ACinvolvement
involvementandandfor
forT1a
T1atumors
tumorswas was7.31
7.31and
and9.45
9.45times,
times,respectively
respectively(p-value
(p-valueof
of0.054
0.054and
and
0.030, respectively).
0.030, respectively). Conversely,
Conversely, the
therisk
riskofofrecurrence
recurrencewas
wascomparable
comparable among
among patients affected
patients by T1a
affected by
andand
T1a T1bT1b without AC AC
without involvement (p =(p0.304)
involvement (Figure
= 0.304) 4; Table
(Figure 4). 4).
4; Table

Figure 4. RFS Kaplan–Meier curves (T1b-w/: T1b with AC involvement; T1b-w/o: T1b without
Figure 4. RFS Kaplan–Meier curves (T1b-w/: T1b with AC involvement; T1b-w/o: T1b without AC
AC involvement).
involvement).
As reported above, the significant association between T1b with AC involvement and high
As
CCI was reported above, the
also confirmed forsignificant association
the recurrence between
risk at T1band
both uni- withmultivariate
AC involvement and (p
analyses high CCI
= 0.030
was
andalso confirmed
p = 0.023, for the recurrence
respectively). risk
Again, the at both
type uni- anddid
of treatment multivariate
not show analyses (p = 0.030
any statistically and p =
significant
0.023, respectively). Again, the type of treatment did not show any statistically significant difference
difference in the recurrence rate among the three tumor categories considered herein in the univariate
in the recurrence
analysis rate(Table
(p = 0.491) among 4). the three tumor categories considered herein in the univariate analysis
(p = 0.491) (Table
The LFS 4). a statistically significant difference (p = 0.043) among the three tumor classes
showed
(Figure 5 and Table 3).
Table 4. Univariate and multivariate analyses of risk of recurrence.

Univariate Analysis Multivariate Analysis

p-Value p-value
Hazard Ratio Hazard Ratio
(* Statistically (* Statistically
(95% CI) (95% CI)
Significant) Significant)
Tumor extension
T1a Ref.
T1b without AC
3.56 (0.22–57.01) 0.369 4.38 (0.26–73.28) 0.304
involvement
T1b with AC
7.31 (0.97–55.37) 0.054 9.45 (1.24–72.30) 0.030 *
involvement
Gender
Cancers 2020, 12, 1485 8 of 12

Table 4. Univariate and multivariate analyses of risk of recurrence.

Univariate Analysis Multivariate Analysis

p-Value p-Value
Hazard Ratio Hazard Ratio
Cancers 2020, 12, x (* Statistically (* Statistically
8 of 12
(95% CI) (95% CI)
Significant) Significant)
Male
Tumor extension Ref.
T1a
Female Ref.
1.24 (0.28–5.44) 0.772
T1b without
Age at diagnosisAC
3.56 (0.22–57.01) 0.369 4.38 (0.26–73.28) 0.304
<50involvement
years Ref.
T1b with AC
50–65 years 2.00 7.31 (0.97–55.37)
(0.25–16.06) 0.054
0.513 9.45 (1.24–72.30) 0.030 *
involvement
>65Gender
years 1.34 (0.17–10.74) 0.783
Charlson
Male Ref.
0.47 (0.25–0.87) 0.017 * 0.49 (0.26–0.91) 0.023 *
comorbidity
Female index 1.24 (0.28–5.44) 0.772
Age at habit
Smoking diagnosis 2.49 (0.56–11.13) 0.233
<50 years
Alcohol habit Ref.
2.85 (0.95–8.56) 0.062
50–65 years 2.00 (0.25–16.06) 0.513
Tumor location
>65 years 1.34 (0.17–10.74) 0.783
Free margincomorbidity
Charlson Ref.
Superior aspect 0.77 0.47 (0.25–0.87)
(0.22–2.69) 0.017 *
0.678 0.49 (0.26–0.91) 0.023 *
index
Inferior aspect
Smoking habit 0.36 2.49
(0.05–2.77)
(0.56–11.13) 0.328
0.233
Alcohol
Type of habit 2.85 (0.95–8.56) 0.062
Tumor location
intervention
TLMFree margin Ref. Ref.
Superior aspect 0.77 (0.22–2.69) 0.678
RT 1.40 (0.53–3.69) 0.491
Inferior aspect 0.36 (0.05–2.77) 0.328
Resection margin
Type of intervention
Negative
TLM Ref. Ref.
Positive
RT 1.74 (0.61–4.94)
1.40 (0.53–3.69) 0.299
0.491
Resection margin
The LFS showed a statistically
Negative Ref. significant difference (p = 0.043) among the three tumor classes
(Figure 5 and Table 3).
Positive 1.74 (0.61–4.94) 0.299

Figure 5. LFS Kaplan–Meier curves (T1b-w/: T1b with AC involvement; T1b-w/o: T1b without
Figure 5. LFS Kaplan–Meier curves (T1b-w/: T1b with AC involvement; T1b-w/o: T1b without AC
AC involvement).
involvement).
4. Discussion
4. Discussion
Although it is widely acknowledged that the presence of AC involvement can have a negative
Although
impact it is widely
on the oncologic acknowledged
outcomes that the
of early glottic presence
SCC, of AC
the results soinvolvement can
far reported in thehave a negative
literature about
impact on the oncologic outcomes of early glottic SCC, the results so far reported in the literature
about its predictive value have been inconsistent, and have generated much debate [19,22–25]. Even
though several reviews have analyzed this issue, none of them definitively solved the existing
controversy of the prognostic value of AC involvement [19]. In fact, the unique AC anatomical
characteristics make this laryngeal subsite a challenging area for adequate pretreatment endoscopic
 Cancers 2020, 12, 1485 9 of 12

its predictive value have been inconsistent, and have generated much debate [19,22–25]. Even though
several reviews have analyzed this issue, none of them definitively solved the existing controversy of
the prognostic value of AC involvement [19]. In fact, the unique AC anatomical characteristics make
this laryngeal subsite a challenging area for adequate pretreatment endoscopic and imaging workup
by either
Cancers 2020,CT or MR (with a high incidence of false negatives adequately assessed only intraoperatively,
12, x 9 of 12
after surgical resection, or at longer follow-up), difficult area for surgical resection due to laryngeal
surgical
exposure, resection
and prone duetototechnical
laryngealradiotherapy
exposure, and prone
issues to technical
at the air–tumorradiotherapy
interface within issues
theatACthedueair–to
tumor interface within the AC due to its variable degree of vascularization,
its variable degree of vascularization, ossification, and three-dimensional conformation/development ossification, and three-
dimensional conformation/development
further complicating its proper management further complicating its proper management [6,8].
[6,8].
To
Tofurther
furtherelucidate
elucidatethe theimpact
impactof ofAC
ACinvolvement
involvementin inearly
earlyglottic
glotticSCCSCCin inthis
thissetting,
setting,wewestarted
started
from
from thethe assumption that thatififthe
theextension
extension to to
thetheACAC represents
represents a worsening
a worsening prognostic
prognostic factor,factor,
it wouldit
would
definitelydefinitely
deservedeserve a specific
a specific T category
T category differentdifferent
from thefrom alreadytheexisting
alreadycategories
existing categories of T1ittois
of T1 to which
which
usually it associated
is usually associated
in terms ofin terms ofTosurvival.
survival. accomplish To accomplish
this purpose, this
wepurpose, we did
did not linger onnot
T1 linger on
spreading
T1 spreading
patterns or onpatterns
a proper orACon classification
a proper AC systemclassification system as
as previously previously
proposed proposed
by several by several
authors [7,22].
authors
Instead,[7,22].
we aimedInstead, we aimedthe
to highlight to potential
highlightpredictive
the potential value predictive value of ACby
of AC involvement involvement
differentiatingby
differentiating the existing T1b category, and looking for similarity in
the existing T1b category, and looking for similarity in prognosis among T1a and T1b without AC prognosis among T1a and T1b
without
involvement (p = 0.304) (Table
AC involvement (p =4),0.304)
based(Table
on our 4), based tumor
proposed on our proposed
staging tumor stagingforand
and independently the
independently
primary treatment for the primary
chosen, treatment
either surgicalchosen,
(TLM) either surgical (TLM)
or non-surgical (RT). or non-surgical (RT).
Our
Ourstudy
studypopulation
populationpresented
presenteddemographics
demographicsand andtherapeutic
therapeuticindications
indicationscomparable
comparabletotothosethose
reported
reportedininthe the literature
literature [10,12].
[10,12]. Even
Evenour ourreported
reportedrecurrence
recurrencerates ratesareareininaccordance
accordancewith withthe the
literature results, which usually range from 17% to 24%, depending on
literature results, which usually range from 17% to 24%, depending on the follow-up schedules and the follow-up schedules and
modality
modality[13,14,26].
[13,14,26].Interestingly
Interestingly enough,
enough, ourour
data confirm
data confirm thatthat
one one
of theoftwo
the T1b
twosubcategories
T1b subcategories(i.e.,
T1b
(i.e.,with
T1b AC withinvolvement)
AC involvement) represents an independent
represents an independent prognostic factor
prognostic for survival
factor andand
for survival resulted in
resulted
a significant association with a higher recurrence rate in comparison to T1a (p = 0.028). By analyzing
ainsignificant association with a higher recurrence rate in comparison to T1a (p = 0.028). By analyzing
this
this prognostic
prognostic impactimpactonon survival,
survival, we found
we found a trend a towards
trend towardsworse DSS worse DSSwith
for T1b forACT1b with AC
involvement,
involvement,
though without though without a statistically
a statistically significant significant
p-value due p-value
to thedue to the relatively
relatively small samplesmallsize
sample size3;
(Table
(Table 3;
Figure 6). Figure 6).

Figure 6. DSS Kaplan–Meier curves (T1b-w/: T1b with AC involvement; T1b-w/o: T1b without
Figure 6. DSS Kaplan–Meier curves (T1b-w/: T1b with AC involvement; T1b-w/o: T1b without AC
AC involvement).
involvement).
The predictive potential of the T1b with AC involvement category was reflected by an even
The predictive potential of the T1b with AC involvement category was reflected by an even more
more significant difference in the LFS, which was reported to be 100% in the T1a category, 80% in
significant difference in the LFS, which was reported to be 100% in the T1a category, 80% in the T1b
the T1b without AC involvement, and 76.6% in T1b with AC involvement (p = 0.043). These values
without AC involvement, and 76.6% in T1b with AC involvement (p = 0.043). These values are also in
accordance with the current literature [15–17,27,28]. Furthermore, as long as different treatment
strategies seem to result in equal clinical outcomes, the matter of post-treatment morbidity and long-
term sequelae should be emphasized even more within the decision-making process.
Interestingly, no statistically significant difference were revealed among the three tumor classes,
regardless of the respective therapeutic (surgical vs. non-surgical) modality applied, thus reflecting
Cancers 2020, 12, 1485 10 of 12

are also in accordance with the current literature [15–17,27,28]. Furthermore, as long as different
treatment strategies seem to result in equal clinical outcomes, the matter of post-treatment morbidity
and long-term sequelae should be emphasized even more within the decision-making process.
Interestingly, no statistically significant difference were revealed among the three tumor classes,
regardless of the respective therapeutic (surgical vs. non-surgical) modality applied, thus reflecting
the fact that tumor stage is per se an independent prognostic factor for survival and that choosing
the appropriate treatment regimen in the management of AC involvement should be guided by mere
functional considerations more than anatomical ones. Notwithstanding, an independent and specific
tumor category such as the T1b with AC involvement proposed here would play a role in alerting the
treating MDT about the potentially higher risk of suboptimal local control in such a condition.
We do believe that the present classification of T1, which does not take into proper account
the AC involvement, might not be fully consistent with the AJCC UICC staging system principles
which aim to distinguish the outcomes of tumors by a non-contradictory single prognostic language
(https://cancerstaging.org). For these reasons, we suggest that the T staging of glottic SCC should
consider AC involvement by a more detailed tumor subsite stratification. Further studies should
overcome the limitations of the present analysis, which are mainly due to a small sample size of T1b
without AC involvement (also due to their intrinsic rarity), disabling proper and significant statistics.
In addition, the application of a prospective study protocol design will give more consistency and allow
a more detailed and homogeneous diagnostic imaging acquisition, treatment modalities outcome, and
side effects analysis, which was not the main purpose of the current retrospective study.

5. Conclusions
In our study, the AC represents the glottic subsite with the greatest risk of local treatment failure
and tumor persistence after either TLM and RT [29,30]. Our proposed classification system for glottic T1
with AC involvement could represent a starting point to overcome the actual T1 staging and treatment
heterogeneity, where T1b with AC involvement could deserve a separate subcategory due to its evident
worse prognosis in comparison to T1a tumors. However, before including such an AC subclassification
system into future editions of the AJCC UICC staging system, multicenter, large-sampled cohorts
of T1 with different extensions, treated by either TLM or RT, need to be prospectively collected and
evaluated in order to confirm our preliminary data.

Author Contributions: Conceptualization, G.M. and C.P.; methodology, G.M., L.V.C., R.S., and C.P.; validation,
L.V.C., R.S., A.B., A.V., I.D., and P.B.; formal analysis, G.M., L.V.C., A.B., I.D., and P.B; investigation, G.M., L.V.C.,
R.S., I.D., and P.B.; data curation, A.B., A.V., I.D. and P.B.; writing—original draft preparation, G.M., L.V.C., and
P.B.; writing—review and editing, G.M. and C.P.; supervision, C.P. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflicts of interest.

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