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\begin{document}

\title{Surface vascular and epithelial anatomy of the vocal folds in
leukoplakia and cancer}



\author[1]{Pavlos Pavlidis}%
\author[2]{Vasilios Tseriotis}%
\author[3]{Ioulia Katsikari}%
\author[3]{Aimilios Chatzinikolaou}%
\author[4]{Haralampos Gouveris}%
\affil[1]{University Medical Centre of Mainz, Mainz, Germany}%
\affil[2]{Aristotle University of Thessaloniki, Thessaloniki, Greece}%
\affil[3]{General Hospital Veria, Veria, Greece}%
\affil[4]{Johannes Gutenberg University Hospital Mainz}%


\vspace{-1em}



  
  \date{March 14, 2025}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\selectlanguage{english}
\begin{abstract}
Objective: To investigate the features of the superficial mucosa and
microvascular network of the vocal cords in patients with suspected
laryngeal cancer using contact endoscopy (CE). Design: A retrospective
review of patients with leukoplakia and cancer of vocal cords. Main
outcome measure: Fourty-two patients (mean age = 57.2 \selectlanguage{ngerman}±7.6 years), were
prospectively evaluated. Eighteen had malignant lesions and 24 had
leukoplakia, proven on histologic exam. Eight cancer patients and 8
patients with leukoplakia had bilateral lesions. Therefore, a total of
58 lesions (26 malignant and 32 non-malignant) was found.
Contact-endoscopic imaging findings were classified into five types (I
to V) based on the features of the mucosal intraepithelial capillary
loops. Results: The CE-based intraepithelial papillary capillary loop
classification was strongly correlated with the histological findings.
Smoking habits didn't significantly differ between patients with
unilateral and bilateral lesions. Conclusions: CE imaging of the vocal
cord mucosal capillaries may be useful in the early detection of
laryngeal cancer and precancerous lesions.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Surface vascular and epithelial anatomy of the vocal folds in
leukoplakia and cancer}

Vascular and morphological changes of vocal folds in leukoplakia and
cancer

\textbf{Abstract}

\textbf{Objective: T} o investigate the features of the superficial
mucosa and microvascular network of the vocal cords in patients with
suspected laryngeal cancer using contact endoscopy (CE).

\textbf{Design:} A retrospective review of patients with leukoplakia and
cancer of vocal cords.

\textbf{Main outcome measure:} Fourty-two patients (mean age = 57.2 \selectlanguage{ngerman}±7.6
years), were prospectively evaluated. Eighteen had malignant lesions and
24 had leukoplakia, proven on histologic exam. Eight cancer patients and
8 patients with leukoplakia had bilateral lesions. Therefore, a total of
58 lesions (26 malignant and 32 non-malignant) was found.
Contact-endoscopic imaging findings were classified into five types (I
to V) based on the features of the mucosal intraepithelial capillary
loops.

\textbf{Results:} The CE-based intraepithelial papillary capillary loop
classification was strongly correlated with the histological findings.
Smoking habits didn't significantly differ between patients with
unilateral and bilateral lesions.

\textbf{Conclusions:} CE imaging of the vocal cord mucosal capillaries
may be useful in the early detection of laryngeal cancer and
precancerous lesions.

\textbf{Key words:} Vascular patterns, epithelium, hyperplasia, contact
endoscopy, leukoplakia

\textbf{Key points:}

\begin{enumerate}
\tightlist
\item
  Leukoplakia is an anatomical term for thick white or grey patches that
  can be associated with a variety of histological diagnoses ranging
  from hyperplasia to malignant transformation.
\item
  According to our findings, malignancy is associated with a single
  abnormal vascular pattern on the surface of the vocal cords, whereas
  leukoplakia might be associated with either normal or many abnormal
  vascular patterns.
\item
  Capillaries in the surface lamina propria, smaller arteries and veins
  characterize the vascular microanatomy of human vocal folds.
\item
  Age may be related to the development of this disease.
\item
  Two inherent limitations of CE are the inability to detect very early
  dysplasia and the inability of differentiation of carcinoma in situ
  from invasive carcinoma.
\end{enumerate}

\textbf{1 INTRODUCTION}

Leukoplakia is a macroscopic anatomical term for thick white or grey
patches that can be associated with a variety of histological diagnoses
ranging from hyperplasia to malignant
transformation.\textsuperscript{1-4} Endoscopic (white light, WL)
examination combined with stroboscopy is currently the «main-stream''
approach for detecting and assessing vocal fold leukoplakia (VFL) or
other vocal fold lesions.\textsuperscript{5-7} Andrea et al. described
using contact endoscopy to examine the vocal folds and nasal mucosa in
the 1990s.\textsuperscript{8,9}

The goal of this study was to evaluate distinct vascular patterns in
patients with VFL and glottis cancer using contact endoscopy (CE) and
see if there were any correlations with histologic abnormalities in the
mucosa of the vocal cord.

\textbf{2 MATERIALS AND METHODS}

2. 1 \emph{Clinical data}

For the purposes of this study, 42 consecutive participants were
prospectively recruited: 24 (7 female, 17 male; \textbf{Group A} ) had
leukoplakia and 18 (4 females and 14 males) had glottic cancer (pT1,
n=6; p T2, n=8; pT3, n=8; \textbf{Group B} ). Regarding the patients
with malignancies, 8 had bilateral lesions and thus 26 malignant lesions
were totally detected by narrow band imaging. Between patients with
non-malignant lesions ,8 of them had bilateral lesions of the vocal
cords, therefore we have examined a total of 32 nonmalignant lesions.
Regarding basic characteristics, there was no difference in age, number
of cords affected, cigarettes smoked per year and years smoking between
male and female patients (\textbf{Table 1} ). For the purposes of our
study we have also examined 42 non-smokers (Control Group-\textbf{Group
C} ), who received total anesthesia for surgeries, such as hernias,
colectomies etc, which had nothing to do with otolaryngological
diseases..

2.2 \emph{Contact endoscopy}

For contact endoscopy the Andrea-Dias Contact Micro Laryngoscope (with
HOPKINS Straight Forward Telescope 0° and 30°, with diameter 5.5 mm,
length 23 cm, magnification 60 × and 150×); a 3 chip camera (Tricam SL
II); a Xenon 175 watt light source and a video recording system (AIDA)
were used, all manufactured by Karl Storz, (Tuttlingen, Germany).

The entire larynx was initially visualized with standard white light,
followed by visualisation using the narrow band imaging (NBI) mode.
Endoscopically guided biopsy of laryngeal lesions was also performed;
tissue was fixed in 10\% formalin for histological
analysis.\textsuperscript{10,11} The recorded findings were examined by
two persons (PP and VST), who evaluated separately the pictures before
discussing together the results. All of them were blinded to the
histological results. The interrater reliability was also calculated
with the use of Kappa test was estimated at 0.89 (Cohen's kappa
statistic).

2.3 \emph{Morphological types of the surface of the vocal cords}

The morphological types of vocal fold leukoplakia assessed by
preoperative rigid laryngoscopy were categorized as: flat and smooth,
elevated and smooth, and rough type.\textsuperscript{11}

The definition is presented as the following:

\textbf{Flat and smooth type:} Surface: smooth; Margin: lesion without
raised margins, being continuous with the surrounding mucosa; Texture:
homogeneous, regular, the lesion with even coloration.

\textbf{Elevated and smooth type:} Surface: smooth; Margin: lesion with
raised margins, sharply demarcated from the surrounding mucosa; Texture:
homogeneous, regular, the lesion with even coloration.

\textbf{Rough type: Surface:} wrinkled, corrugated; Margin: lesion with
raised margins, sharply demarcated from the surrounding mucosa; Texture:
non-homogeneous, irregular, the lesion with uneven coloration and is
usually accompanied with erosion or ulceration.

2.4 \emph{Patterns and changes}

The Ni categorization was used for the purposes of our
research.\textsuperscript{12} Intraepithelial capillary loop alterations
seen with Contact Endoscopy (CE) can be categorized into five categories
(I to V) according to this classification. Intraepithelial papillary
capillary loops are nearly inconspicuous in type I, while oblique and
arborescent capillaries of small diameter are discernible. The
intraepithelial papillary capillary loops are nearly invisible in type
II, while the diameter of the clearly apparent oblique and arborescent
capillaries is increased. The mucosa is white in type III, and the
intraepithelial papillary capillary loops are invisible; if the white
patch is thin, the oblique and arborescent vessels can be seen
indistinctly, but if the white patch is thick, the vessels are obscured.
The mucosal intraepithelial papillary capillary loops appear as
scattered, small, dark brown spots in type IV, with a relatively regular
arrangement and low density; the capillary terminals are bifurcated or
slightly dilated, and the intraepithelial papillary capillary loops
appear as scattered, small, dark brown spots; the oblique and
arborescent vessels are usually not visible.\textsuperscript{12}

\textbf{Type V} changes are subdivided into \textbf{types Va, Vb}
and\textbf{Vc} according to the shape, regularity and distribution of
vessels. In type Va, intraepithelial papillary capillary loops are
significantly dilated and of relatively high density, and appear to be
solid or to have hollow, brownish, speckled features and various
shapes.\textsuperscript{12} In type Vb, the intraepithelial papillary
capillary loop itself is destroyed, with its remnants presenting in a
snake-, earthworm-, tadpole- or branch-like shape, and the microvessels
are dilated, elongated and `woven' in appearance. In type Vc, the lesion
surface is covered with necrotic tissue, and the intraepithelial
papillary capillary loops present as brownish speckles or tortuous
shapes of uneven density which are irregularly scattered on the tumor
surface.\textsuperscript{12}

According on the shape, regularity, and distribution of vessels, type V
changes are split into types Va, Vb, and Vc. Intraepithelial papillary
capillary loops in type Va are highly dilated and of relatively high
density, appearing solid or hollow, brownish, speckled, and of varied
shapes.\textsuperscript{12} The intraepithelial papillary capillary loop
is disrupted in type Vb, with remains resembling a snake, earthworm,
tadpole, or branch, and microvessels that are dilated, elongated, and
'woven' in appearance. The lesion surface is coated with necrotic tissue
in type Vc, and the intraepithelial papillary capillary loops appear as
brownish speckles or sinuous shapes of uneven density spread irregularly
on the tumor surface.\textsuperscript{12,13} Type is depicted
in\textbf{Images 1, 2,} and \textbf{3} .

2.5 \emph{Histologic examination}

All the tissues were processed for pathological testing on a regular
basis. The same pathologist evaluated and graded histologically graded
formalin-fixed and paraffin-embedded slides independently. Squamous cell
hyperplasia with non-dysplasia, mild dysplasia, moderate dysplasia,
severe dysplasia, carcinoma in situ, and squamous cell carcinoma were
all assessed histologically according to the World Health Organization's
2017 guidelines.\textsuperscript{14} The new WHO 2017 classification is
a two-tier system. Laryngeal precursor lesions are classified as
low-grade dysplasia (previous categories squamous hyperplasia, mild
dysplasia), and high-grade dysplasia (previous categories of moderate
and severe dysplasia, carcinoma in situ).\textsuperscript{14} Carcinoma
in situ, is distinguished from high-grade dysplasia, showing features of
conventional carcinoma.\textsuperscript{14}

2.6 \emph{Statistical analysis}

Parameters were evaluated using the Jamovi project (2021; Jamovi,
software Version 1.6, Sydney, Australia. Retrieved from www.jamovi.org).
A p-value less than 0.05 was considered statistically significant for
all analyses. Independent samples t-test, Mann-Whitney U test and Chi
square test were used for basic characteristics' comparisons between
male and female patients' features (age, years of smoking, number of
cigarettes/day) as well as for comparisons between patients with
unilateral or bilateral lesions and patients with or without
histologically confirmed malignancies. The ANOVA and the nonparametric
Kruskal-Wallis tests were used to detect possible statistically
significant differences between lesions with different vascular
patterns.

\textbf{3 RESULTS}

3.1 \emph{Smoking status and age between patients with unilateral and
bilateral lesions}

The number of cigarettes smoked per day didn't appear significantly
different between patients with unilateral and bilateral lesions (U =
56.9, p = .109 and though it seemed to be higher in the malignancies
group, that was not statistically significant (U = 56, p = .064). The
years of smoking were found to be similar between patients with
unilateral and bilateral lesions (t = 0556, p = .956) and although
patients who developed malignancies reported having smoked for more
time, there was no significant difference when comparing their years of
smoking with those of the patients with non-malignant lesions (t =
-1.24, p = .227). It was age however that was found to be of true
importance, since in our group malignancies were identified in older
rather than younger subjects (t = -2.23, p = .034), but that was not
observed as regards the bilateral presence of lesions (t = -0.98, p =
.332). \textbf{Table 2} presents the comparison of smoking status and
age between patients with and without malignancies.

3.2 \emph{Smoking habits and age in different types of vascular
classification}

Moreover, a Kruskal-Wallis test showed no significant statistical
difference in cigarettes smoked per day between lesions that had
different types of intraepithelial papillary capillary loop
classification, \selectlanguage{greek}χ\selectlanguage{english}2 (5) = 9.93, p = .077 (\textbf{Figure 1} ). No such
difference was found in years smoking either, as determined by a one-way
ANOVA that was also performed, F (5, 9.95) = 2.52, p = .100. Age however
presented a significant effect regarding the vascular classification, F
(5, 12.9) = 3.71, p = .027. Post-hoc comparisons using the Games-Howell
test showed significant difference particularly between the age of
patients in the group of type I lesions (M = 52.7, SD = 1.15) and the
age in the group of type Vb lesions (MD = 63.7, SD = 8.50). Our results
suggest that malignancies had significantly higher chances of developing
in older individuals, when compared to the mildest type I lesions of
vascular classification.

3.3 \emph{Smoking habits and age in different types of morphological
classification}

A Kruskal-Wallis test showed no significant statistical difference in
cigarettes smoked per day between different types of morphological
classification, \selectlanguage{greek}χ\selectlanguage{english}2 (5) = 4.84, p = .089. In the same way a one-way ANOVA
did not indicate statistical difference in the years smoking either F
(2, 14) = 2.02, p = .170. Age, according to a one-way ANOVA, was
significantly different among different types of morphological
classification types, F (2, 35) = 7.72, p = .002. The significant
difference in age was detected between the ``flat and smooth'' type of
lesions (M = 51.4, SD = 6.33),p=.002 and the ``rough'' type of lesions
(M = 61.5, SD = 6.83), p = .001 as indicated by post-hoc comparisons
using the Tukey correction. The results are depicted in \textbf{Table 3}
.

3.4 \emph{Classification of leukoplakia and smoking habits}

As mentioned above we have examined a total of 32 vocal cords with
leukoplakia. By 22 of them a low-grade dysplasia has been found. The
rest of them have been diagnosed with a high-grade dysplasia. A
Kruskal-Wallis test showed no significant statistical difference in
cigarettes smoked per day between different types of morphological
classification, \selectlanguage{greek}χ\selectlanguage{english}2 (5) = 4.64, p = .088. In the same way a one-way ANOVA
did not indicate statistical difference in the years smoking either F
(2, 08) = 2.02, p = .1640. The application of Kendal-tau criterion has
shown the grade of dysplasia is correlated to age. By patients with
low-grade dysplasia (n=18) this was estimated by \selectlanguage{greek}τ\selectlanguage{english}=0.73. By those with
high-grade dysplasia (n=14) the correlation was stronger (\selectlanguage{greek}τ\selectlanguage{english}=0.82).

3.5 \emph{Contact Endoscopy in non-smoking and smoking subjects}

We also tested if there was statistical significance between the
vascularization type of the vocal cords of the healthy subjects (control
group) and the vascularization type of patients suffering from
leukoplakia and malignancy. Vocal cords with type I or type II
vascularization pattern were more likely to belong to patients who have
non-malignant contralateral vocal cords, whereas healthy cords of type
III or IV were more likely to be associated with contralateral
malignancies, according to a Fisher's exact test that showed statistical
significance, p = .002. In non-smoking subjects we have found that 18 of
them had a type I vascularization. By the rest a type II vascularization
on both sides has been documented.

\textbf{4 DISCUSSION}

According to our findings, malignancy is associated with a single
abnormal vascular pattern on the surface of the vocal cords, whereas
leukoplakia might be associated with either normal or many abnormal
vascular patterns. In addition, we discovered that in patients with
leukoplakia, the length of time spent smoking (in years) had a
detrimental impact on the surface and vascularization of the voice
cords. The number of cigarettes smoked each day did not seem to make a
difference.

Capillaries in the surface lamina propria, smaller arteries and veins,
as well as arterioles and venules in the deeper layers, characterize the
vascular microanatomy of human vocal folds. Arterioles and venules have
direct vascular anastomoses.\textsuperscript{15}

Under rigid laryngeal endoscopy, vocal cord leukoplakia presents as a
white or grayish confined patch, distributed granule, or verrucous
structure. It may have one or more
localizations.\textsuperscript{10}Leukoplakia is a chameleon-like
epithelial transformation that can range from benign thickening to
malignant tumors. As a result, the name ''leukoplakia'' is insufficient
to characterize the lesion's histological
identity.\textsuperscript{10-13}

There are previous reports on a tissue-specific classification of
vascular changes associated with laryngeal leukoplakia. They finally
have found that age, non-homogenous lesion texture and existence of
hyperemia are independent predictors of
malignancy.\textsuperscript{14-16} Their results support the findings of
the present study to some extent because they also have found that age
and lesion texture may predict prognosis. However, these authors have
not further explored the impact of age on leukoplakia lesions. Our study
provides evidence that age may be related to the development of this
disease. Moreover, a further novelty of the present study is that a very
detailed study on the lesion texture has been conducted. Leukoplakia
lesions have traditionally been divided into two categories from their
appearances which were individually homogenous and heterogeneous in many
reports.\textsuperscript{17}

Although new endoscopic tools, such as narrow band imaging, optical
coherence tomography and contact endoscopy have been developed to
improve the diagnosis of vocal fold leukoplakia, WL laryngoscopy is most
applied in clinical practice.\textsuperscript{18-21} The ability of
rigid or flexible laryngoscopy to visualize and characterize lesions of
vocal cords continues to improve.

Many researchers have reported high efficacy of CE in diagnosis of
mucosal lesions not only of larynx, but in other sites of head and neck
as well.\textsuperscript{10,12,23-25} These results have been obtained
taking the histopathological examination as the gold standard. However,
the technique of CE has definite advantages and limitations. Contact
endoscopy enables visualization of tumor margins, dysplasia, and normal
epithelium, thus offering the possibility of more precise complete
removal of laryngeal lesions in a single sitting. Along with in vivo
studies, contact endoscopy can also be used to analyze the excised
segment of the lesion and hence ensure whether the lesion has been
completely resected. The grade of dysplasia is indicated by the impaired
nucleus/cytoplasm ratio, nuclear hyperchromasia, and variation in the
number and appearance of the nucleoli. \textsuperscript{21,23}

Of course, there are limitations in the use of CE, which should be also
considered in the interpretation and validation of the results of the
present study. Two inherent limitations are the inability to detect very
early dysplasia and the inability of differentiation of carcinoma in
situ from invasive carcinoma.

\textbf{5 CONCLUSION}

Vascular changes may play an important role as one of the most prominent
features in endoscopic work-up of laryngeal lesions. Further validation
of our preliminary findings, especially in combination with further
standardized morphologic endoscopy findings (together with macroscopic
appearance, mucosal vibration, vocal cord stiffness and others) should
be undertaken to increase reliability of pre- and intraoperative
diagnosis of leukoplakia and malignant glottic lesions.

\textbf{LEGENDS}

\textbf{Table 1.} Comparison of demographic features between patients
with malignant and non-malignant lesions. \textbf{Information on s}
moking status (cigarettes per day and years smoking) and age in
different types of vascular classification is also provides.

\textbf{Table 2.} Smoking status (cigarettes per day and years smoking)
and age in different types of vascular classification.

\textbf{Table 3} . Smoking status (cigarettes per day and years smoking)
and age in different types of morphological classification. The meanings
of the abbreviations are the following: fs = Flat and smooth type:
Surface: smooth; Margin: lesion without raised margins, being continuous
with the surrounding mucosa; Texture: homogeneous, regular, the lesion
with even coloration; es=elevated and smooth type: Surface: smooth;
Margin: lesion with raised margins, sharply demarcated from the
surrounding mucosa; Texture: homogeneous, regular, the lesion with even
coloration; r = Rough type.

\textbf{Images 1, 2} and \textbf{3.} The figures depict type I, II and
III patterns of vascularization correspondingly. In type I, the
intraepithelial papillary capillary loops are almost invisible; oblique
and arborescent vessels of small diameter can be clearly seen. In type
II, the intraepithelial papillary capillary loops are also almost
invisible, but the diameter of the clearly observed oblique and
arborescent vessels is enlarged. In type III, the mucosa is whitish and
the intraepithelial papillary capillary loops cannot be seen; if the
whitish patch is thin, the oblique and arborescent vessels may be seen
indistinctly, but if the whitish patch is thick the vessels will be
obscured.

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\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/313079/articles/580866-surface-vascular-and-epithelial-anatomy-of-the-vocal-folds-in-leukoplakia-and-cancer}

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