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original papers
Adv Clin Exp Med 2010, 19, 4, 461–467
ISSN 1230-025X
© Copyright by Wroclaw Medical University
Maciej D. Zatoński1, Tomasz Kręcicki2, Agnieszka Jabłonka-Strom1,
Agnieszka Zatońska3, Agata Górecka4, Marek Bochnia1
Autofluorescence Endoscopy
in Diagnosis of Laryngeal Lesions
Endoskopia autofluorescencyjna w diagnostyce
zmian nabłonkowych krtani
Department of Otolaryngology, Faculty of Dentistry, Wroclaw Medical University, Poland
Department of Otolaryngology, Head and Neck Surgery, Wroclaw Medical University, Poland
3 Department of Otolaryngology, District Railway Hospital, Wroclaw, Poland
4 Department of Otolaryngology, University Hospital (ASK), Wroclaw, Poland
1 2 Abstract
Background. One of the most important problems in head and neck oncology is early diagnosis of laryngeal
cancer. Despite the introduction of new therapeutic methods and improvement of surgical techniques, patients’
5-year survival rate still depends primarily on the stage of the disease at the moment of introduction of appropriate
treatment.
Objectives. The goal of this study was to assess the efficacy of autofluorescence endoscopy (AFE) in diagnosis of
laryngeal lesions. AFE examinations were carried out on out-patient basis, without general anesthesia and without
using any photosensitizing agents (topical or systemic). Sensitivity and specificity of AFE alone, as well as AFE
combined with classic white-light endoscopy, were calculated.
Material and Methods. 129 patients (30 women and 99 men) at the age between 22–89 with various laryngeal
pathologies entered the study. Patients did not receive any photosensitizing agents. No tissue staining was used.
Occasionally, the patients received local 10% Xylocaine anesthesia before the examination. All examinations were
performed using modified laryngeal endoscopic setup. All patients underwent classical white-light endoscopy followed by AFE examination. Sites of possible pathologies were noted for further biopsy. The results obtained during
white-light endoscopy and AFE were then compared to histopathological findings. Sensitivity and specificity were
calculated.
Results. Suspected malignant lesions were confirmed in 63 out of 72 cases when using white-light endoscopy, and
in 71 out of 72 during AFE (p = 0.0087). In precancerous lesions, 9 out of 19 were identified during white-light
endoscopy, while AFE allowed to properly identify 16 out of 19 precancerous lesions (p = 0.0166). In all lesions,
histologically classified as benign, the authors received 18 false positive results (white-light endoscopy) and 7 false
positive results with AFE (p = 0.0072). Overall sensitivity of AFE was 95.6% and specificity was 81.6%. For whitelight endoscopy the results were 79.1% and 52.6% respectively. Combined specificity of both methods was 96.7%.
Conclusions. AFE is an effective, supplementary method of diagnosing pathologies of the glottic as well as supraglottic region of the larynx, that can be used in routine out-patient care. AFE is completely safe and has a very
high sensitivity in detecting invasive cancer as well as early precancerous lesions (starting from LIN II). It allows
to precisely visualize the extensions of the lesion and can be used to diagnose changes in supraglottic region. AFE
can also be used in monitoring patients after treatment and in early detection of possible recurrence (Adv Clin
Exp Med 2010, 19, 4, 461–467).
Key words: laryngeal cancer, autofluorescence, early diagnosis.
Streszczenie
Wprowadzenie. Diagnostyka i leczenie raka krtani jest dziś jednym z największych wyzwań w onkologii głowy
i szyi. Mimo rozwoju nowych metod terapeutycznych i wprowadzeniu nowoczesnych technik chirurgicznych,
w dalszym ciągu 5-letnie przeżycia w przypadku raka krtani zależą prawie wyłącznie od stanu zaawansowania
choroby w chwili rozpoczęcia leczenia.
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Cel pracy. Ocena skuteczności endoskopii autofluorescencyjnej (AFE) w diagnostyce zmian nabłonkowych w krtani. Opisana metoda pozwala na wykonywanie badania w trybie ambulatoryjnym, bez ogólnego znieczulenia i bez
konieczności stosowania środków fotouczulających (zarówno miejscowo, jak i ogólnie). Obliczono czułość i specyficzność badania z wykorzystaniem endoskopii autofluorescencyjnej jako samodzielnej metody diagnostycznej oraz
w połączeniu z klasycznym badaniem endoskopowym w białym świetle.
Materiał i metody. Badaniem objęto 129 pacjentów (30 kobiet i 99 mężczyzn) w wieku 22–89 lat, którzy zgłosili się
do pracowni endoskopowej Kliniki Otolaryngologii. Nie podawano żadnych środków fotouczulających ani barwników tkankowych. Sporadycznie stosowano znieczulenie miejscowe 10% roztworem Xylocainy przed rozpoczęciem
badania. AFE wykonywano z użyciem zmodyfikowanego zestawu do endoskopii krtani zaraz po klasycznym badaniu
endoskopowym. Z podejrzanych obszarów krtani pobierano następnie wycinki do badania histologicznego. Wyniki
otrzymane w czasie badań endoskopowych i AFE były porównywane do wyników badań histopatologicznych.
Wyniki. Podejrzenie zmian złośliwych potwierdziło się w 63 z 72 przypadków podczas klasycznej endoskopii
i w 71 z 72 przypadków w badaniu AFE (p = 0,0087). W przypadku zmian przedrakowych podczas badania w świetle białym zidentyfikowano 9 z 19 przypadków, a z użyciem AFE 16 z 19 (p = 0,0166). W zmianach zakwalifikowanych histologicznie jako łagodne otrzymano 18 fałszywie dodatnich wyników (endoskopia klasyczna) oraz 7 po
badaniu AFE (p = 0,0072). Czułość AFE wyniosła 95,6%, a specyficzność 79,1%. Dla klasycznej endoskopii wyniki
wynosiły odpowiednio 81,6% oraz 52,6%. Łączna czułość obu metod diagnostycznych (endoskopia w świetle białym
+ AFE) zastosowanych łącznie wyniosła 96,7%.
Wnioski. AFE jest skuteczną uzupełniającą metodą diagnostyczną, pozwalającą wcześnie rozpoznawać zmiany w krtani (zarówno w głośni, jak i nadgłośni). Może być używana podczas rutynowego badania w trybie ambulatoryjnym.
AFE jest całkowicie bezpieczna dla pacjenta. Charakteryzuje się bardzo wysoką czułością w rozpoznawaniu zmian
nowotworowych i przednowotworowych (już od LIN II). Pozwala na precyzyjną ocenę rozległości zmian i może być
używana do wczesnej diagnostyki zmian w nadgłośni. AFE może być także używana w monitorowaniu pacjentów po
leczeniu oraz do wczesnego wykrywania ewentualnej wznowy (Adv Clin Exp Med 2010, 19, 4, 461–467).
Słowa kluczowe: rak krtani, wczesna diagnostyka, autofluorescencja.
Cancer of the larynx makes 2–4% of all malignant tumors and is the 6th most common cause
of death out of all deaths caused by malignant tumors in men in Poland [1]. Prognoses and survival
rates depend strongly on the tumors’ advancement
(stage) at the introduction of appropriate therapy.
In Poland only 26% of all malignant laryngeal tumors is at early stages of development at the time
of initial diagnosis. Therefore early diagnostics and
treatment of laryngeal cancer is one of the most important challenges in the head and neck oncology.
Lesions that originate in the glottic region
usually present with hoarseness, which is often
noticed by patients, their families or their physicians. In other cases, often the first noticeable sign
of the neoplastic process is enlargement of regional
lymph nodes. Early diagnosis of laryngeal tumors
allows to introduce the treatment at early stages of
the disease and increases both – the chances of survival and the quality of life of patients treated from
laryngeal cancer.
Most of described in the literature autofluorescence diagnostic procedures requires general anesthesia or photosensitizing agents. The technique
described below lacks the above mentioned limitations. It allows to use autofluorescence endoscopy
(AFE) during routine endoscopic examination of
the larynx.
The goal of this study was to assess: a) the efficiency of AFE in diagnosing laryngeal pathologies
in comparison to classic white-light endoscopy;
b) specificity and sensitivity of AFE as a standalone method and combined with classic endo-
scopic examination; c) usefulness of AFE in treatment monitoring. The results were compared to
histopathological findings.
Material and Methods
Material included 129 patients (30 women and
99 men). The mean age of patients was 58.6 years
(22 to 89 years old). Ninety one patients with
suspected malignant lesions and 38 patients with
benign changes (Reinke’s Oedema, papillomas,
polyps, vocal nodules, granulomas, chronic hypertrophic laryngitis). The authors did not use general
anesthesia. Sporadically the patients were sprayed
with 10% Xylocaine solution. Patients did not receive any photosensitizing agents, neither topically
nor systemic. No tissue staining was used.
The examinations were performed using modified STORZ set-up for laryngeal endoscopy. It consisted of white-light source (xenon) with possibility to switch to blue-light during the examination,
optic fiber and rigid laryngeal 70o endoscope. The
endoscope was connected to high-sensitivity CCD
camera (Telecam PDD Storz). The set was equipped
with system of filters eliminating reflected excitation light (blue). The filters were able to pass the
light waves around 400 nm and over 450 nm. The
pictures from the camera obtained during white and
blue light examinations were recorded and stored
on a PC-class computer for further assessment.
The examination started with classic white light
endoscopy. The landmarks suspected of neoplastic
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AF Endoscopy in Laryngeal Pathologies
changes were noted for further biopsy. When necessary stroboscopic examination was performed.
AFE was performed right after white-light examination. The picture from the camera was observed
in real-time and stored on a PC computer.
All the patients suspected for malignant
changes underwent standard biopsy. The material
was sent for histopathological examination. The
spots for biopsy were identified during previously
performed white light and blue light examinations.
Further treatment of the patients was dependent
on histopathological findings. Material obtained
by removing benign lesions underwent histopathological evaluation post-operatively.
Digitally stored white and blue light examinations were then compared to the histopathological
findings. The endoscopic findings were classified
as positive, negative, false positive and false negative to assess sensitivity and specificity of AFE and
white-light endoscopy. These results were later
statistically tested with chi-square test (Statistics
Calculator 3, StatPac Inc.). Level of p < 0.05 was
considered to indicate significant difference between groups.
Results
The histopathological findings performed in
129 patients included 72 cases of invasive cancer,
19 pre-cancerous states and 38 benign pathologies.
The detailed diagnoses are presented in Table 1.
Malignancies that were initially suspected in
classic white-light videoendoscopy were histopathologically confirmed in 63 out of 72 cases,
while in AFE in 71 out of 72. Nine false negative
results in white light examination and only 1 in
AFE (Table 2). This difference was statistically significant (p = 0.0087).
AFE allowed to properly identify 16 out of
19 precancerous lesions confirmed in histopathological examinations, while white light videoendoscopy allowed for proper identification of 9 out
of 19 cases. The false negative results were 3 and
Table 1. Histological findings in the analyzed samples taken from 129 patients
Tabela 1. Rozpoznania histopatologiczne w materiale pobranym
od 129 pacjentów
Histopathological finding
(Rozpoznanie histopatologiczne)
Number of diagnoses
(Liczba rozpoznań)
Carcinoma planoepitheliale keratodes
52
Dysplasia (LIN I, II, III)
29
Carcinoma planoepitheliale akeratodes
14
Leucoplakia (without dysplasia)
13
Chronic hypertrophic laryngitis
9
Reinke’s oedema
8
Carcinoma keratoblasticum
5
Laryngeal polyposis
4
Pachydermia
4
Carcinoma in-situ
4
Laryngeal papilloma
3
Vocal nodules
2
Laryngeal tuberculosis
1
Total (Suma)
148
* The total number in the table exceeds 129 (the number of the patients), because
in some cases more than one pathology was diagnosed in the same patient (e.g.
dysplasia and invasive cancer, dysplasia and leucoplakia, leucoplakia and chronic
laryngitis, etc).
* Liczba rozpoznań przekracza 129 (liczbę pacjentów), ponieważ w niektórych
przypadkach rozpoznawano więcej niż jedną patologię u tego samego pacjenta
(np. dysplazja i rak inwazyjny, dysplazja i leukoplakia, leukoplakia i przewlekły
stan zapalny).
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M. Zatoński et al.
Table 2. Number of positive and false negative results
(laryngeal cancer) during white-light and AFE examinations
Table 4. Number of positive and false negative results
(LINs and laryngeal carcinomas) during white-light and
AFE examinations
Tabela 2. Liczba dodatnich i fałszywie ujemnych
wyników (rak krtani) dla AFE i klasycznej endoskopii
w świetle białym
Tabela 4. Liczba dodatnich i fałszywie ujemnych wyników
(LIN i raki krtani) dla AFE i klasycznej endoskopii
w świetle białym
LIN and Laryngeal Cancer
(n = 91)
(LIN i rak krtani) (n = 91)
Laryngeal carcinoma (n = 72)
(Rak krtani) (n = 72)
AFE
white light examination
Positive (+)
(Dodatni)
(+)
71
63
False negative (f-)
(Fałszywie
ujemny) (f-)
1
9
AFE
white light
examinations
Positive (+)
(Dodatni) (+)
87
72
False negative (f-)
(Fałszywie ujemny) (f-)
4
19
* AFE – autofluorescence endoscopy.
** LIN – laryngeal intraepithelial neoplasia.
* AFE – Autofluorescence Endoscopy.
* AFE – endoskopia autofluorescencyjna.
Table 3. Number of positive and false negative results
(precancerous lesions) during white-light and AFE examinations
Tabela 3. Liczba wyników dodatnich i fałszywie ujemnych
(stany przedrakowe) dla AFE i endoskopii w świetle
białym
Laryngeal intraepithelial neoplasia
(LIN) (n=19)
(Neoplazja śródnabłonkowa krtani
– LIN) (n=19)
AFE
white light examination
Positive (+)
(Dodatni)
(+)
16
9
False negative (f-)
(Fałszywie
ujemny) (f-)
3
10
* AFE – Autofluorescence Endoscopy.
** LIN – Laryngeal Intraepithelial Neoplasia.
* AFE – endoskopia autofluorescencyjna.
** LIN – neoplazja śródnabłonkowa krtani.
10 respectively (Table 3). This difference also
showed to be statistically significant (p = 0.0166,
Pearson).
Out of all 91 patients with precancerous or
cancerous pathologies AFE allowed to properly
identify 87 cases, while videoendoscopy 72 out of
91 (Table 4). The most significant difference was
observed for early pathologies (p = 0.00081).
* AFE – endoskopia autofluorescencyjna.
** LIN – neoplazja śródnabłonkowa krtani.
Table 5. Number of true negative and false positive results
(benign changes) obtained during white-light and AFE
examinations
Tabela 5. Liczba ujemnych i fałszywie dodatnich wyników
(zmiany łagodne) dla AFE I klasycznej endoskopii
w świetle białym
Benign changes (n = 38)
(Zmiany łagodne) (n=38)
AFE
white light
examinations
Negative (–)
(Ujemny) (–)
31
20
False positive
(f+)
(Fałszywie
dodatni) (f+)
7
18
* AFE – autofluorescence endoscopy.
* AFE – endoskopia autofluorescencyjna.
In the cases histologically classified as benign,
white light examination allowed to properly identify 20 out 38 cases (18 false positive results). AFE
allowed to properly identify 31 out of 38 cases
(7 false positive results) (p = 0.0072). Results are
presented in Table 5.
The above presented results were used to calculate sensitivity (Table 6) and specificity (Table 7)
of AFE and white light examination in diagnosing
malignant and premalignant lesions.
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AF Endoscopy in Laryngeal Pathologies
Table 6. Comparison of sensitivity of AFE and white-light endoscopy as a stand-alone and combined method of diagnosing
laryngeal neoplasms
Tabela 6. Porównanie czułości AFE i endoskopii w świetle białym jako samodzielnych metod diagnostycznych oraz zastosowanych łącznie w diagnostyce zmian nowotworowych i przednowotworowych w krtani
Sensitivity
(Czułość)
AFE
%
white-light endoscopy
%
AFE + white-light
endoscopy
%
Cancer (n = 72)
(Rak krtani) (n = 72)
98.6
87.5
100
LIN (n = 19)
(LIN) (n = 19)
84.2
47.3
  84.2
LIN + cancer (n = 91)
(LIN + raki krtani) (n = 91)
95.6
79.1
  96.7
* AFE – Autofluorescence Endoscopy.
** LIN – Laryngeal Intraepithelial Neoplasia.
* AFE – endoskopia autofluorescencyjna.
** LIN – neoplazja śródnabłonkowa krtani.
Table 7. Specificity of AFE and white-light endoscopy
Tabela 7. Specyficzność AFE i endoskopii w świetle
białym
Specificity
(Specyficzność)
Benign lesions
(Zmiany łagodne)
(n = 38)
AFE
%
white-light
endoscopy
%
81.6
52.6
* AFE – Autofluorescence Endoscopy.
* AFE – endoskopia autofluorescencyjna.
Discussion
Laryngeal cancer is the most common cancer
of upper respiratory tract in men [2, 3]. Prolonged
exposition to external carcinogens (such as tobacco smoke or alcohol abuse) causes damage to
large areas of upper airways mucosa, resulting in
development of cancerous changes. In the recent
years the authors have observed intensive development of methods of treatment of laryngeal cancer.
Beside numerous selective and preserving surgical
procedures, effective methods of radiotherapy and
chemoradiotherapy were introduced to offer the
patients treatment options that are more efficient,
more effective, less traumatizing and provide better quality of life.
Despite this progress in the treatment, 5-year
survival rate in the past 30 years did not change
and approximates at about 50% for all stages of
the disease [2, 4, 5]. Two major factors contribute
to this fact: delayed diagnosis and relatively high
percentage of developing a second primary focus
of the disease after treatment [6, 7]. Many head
and neck carcinomas are preceded by so-called
“precancerous lesions” (histologically defined as
laryngeal intraepithelial neoplasia – LIN, or previously – dysplasia). Clinically, they are possible
to detect only when accompanied by easy to spot
pathologies (such as leucoplakia or erythroplakia).
Diagnosis and treatment of laryngeal cancer presents a significant health problem, not only in Poland, but also worldwide. Non-invasive diagnostic
tool that would allow to detect dysplastic changes
would also allow to prevent or early diagnose laryngeal cancer. Early diagnosis enables to early
introduce appropriate therapy and improves the
chance of patients’ survival.
Many diagnostic techniques described in available literature are based on using 5-aminolevulinic
acid (5-ALA) to induce fluorescence of endogenic
protoporphyrin IX (PpIX). 5-ALA was usually
administered intravenously 1–4 hours prior the
examination. The most important drawback of
this method are the side effects of photosensitizers. Doses as low as 30 mg/kg of ALA can cause
nausea, vomiting, elevation of liver enzymes and
increase skin sensitivity to sunlight. Such side effects do not present a problem during photodynamic therapy (PDD) but cannot be accepted during routine examinations [8]. 5-ALA can also be
administered topically, right before the blue light
examination [9–12]. Cancerous tissues tend to accumulate PpIX. Achieved results are characterized
466
by strong, easy to spot, red fluorescence of cancerous tissues. In the literature, topical administration
of 5-ALA was done by inhaling 30 mg of 5-ALA
in 5 ml 0.9% NaCl solution 1–2 hours before the
microlaryngoscopy. Results allowed to assess sensitivity and specificity of this technique (95% and
80% respectively).
In the years 2000–2004 several reports on using Light-induced Fluorescence (LIF) for diagnosing laryngeal pathologies were published. Baletic et
al. used complete autofluorescence endoscopy system (designed to diagnose lower airways) to diagnose laryngeal epithelium. Patients were examined
with flexible bronchoscope in local anesthesia. The
authors assessed sensitivity of SAFE system to be
92.1% (and 73.7% in white light examination) [13].
Kulapaditharom and Boonkitticharoen showed
that sensitivity of LIF system in diagnosing laryngeal carcinomas was 100% with 87.5 specificity
(in a group of 25 patients) [14]. Other researchers
achieved similar results [15].
The main problems with introducing above
mentioned systems based on selective spectrum
enhancers or spectrometric analysis to the routine
examination are high costs and necessity to use
general anesthesia. The investigated tissue needs
to be examined from a very close distance (about
1 cm) for example by introducing an endoscope
through the Kleinsasser’s set. Using flexible bronchoscopes requires at least topical anesthesia (the
optics need to be close to the vocal cords) and significant patient’s cooperation.
The technique described in this paper lacks
the above mentioned limitations. It does not require general anesthesia. There is no need to use
any photosensitizing agents. It allows to examine
the larynx from much greater distance (with rigid
laryngoscope). The recorded image is of far greater
quality then image acquired from flexible optics.
Available laryngeal endoscopic systems can be easily adopted to perform AFE. The examination can
be quickly performed and repeated as often as necessary on out-patient basis.
The main drawback is caused by the limited
amount of light available for the CCD detector.
The image is too dark to be viewed by a naked
eye (directly through endoscope optics). Proper
exposure requires thus longer exposition time.
Practically it means that the pictures is refreshed
no more than 4 times per second (instead of normal 25/sec rate). In order to achieve a sharp, clear
picture of the larynx, the endoscope has to be held
firmly without any movement for this time. This
requires patient’s cooperation, although not as
much as during bronchoscopy. For the same reason a CCD camera and a computer with monitor
are required to perform the examination.
M. Zatoński et al.
Results achieved in own study rate the sensitivity of AFE at 95.6% and its specificity at 81.6% and
are comparable to results achieved by other authors
[15–18]. Technique described in this study is simpler to apply. The examination itself is also easier
to bear for the patient and can be performed completely on out-patient basis. This allows the present auhors to question the need of using 5-ALA in
diagnosing laryngeal cancer.
The big advantage of AFE is its high sensitivity in detecting early stages of neoplastic transformation. In own material false negative results
were almost exclusively found in early dysplastic
lesions (LIN I and II). However a strong, green
fluorescence can be observed in cases of severe
keratosis on the cancer’s surface, it is usually seen
in advanced tumors with accompanying lack of
fluorescence in the immediate area of keratosis.
Such picture does not present any diagnostic
difficulties. In the examined material there was
not any case that would lead to improper diagnosis, although it is (theoretically) possible that
the keratosis may completely cover the neoplastic
process (potential possibility of false negative results).
In own study the authors have found more
false-positive than false-negative results. The falsepositives were found mainly in laryngeal papillomas and chronic hypertrophic laryngitis, one falsepositive case of leucoplakia without accompanying
dysplasia, one vocal cord nodule and one case or
Reinke’s oedema. There was also one patient suspected of laryngeal cancer, with typical lack of
green fluorescence which was histopathologically
diagnosed as laryngeal tuberculosis.
Reassuming – in clinical practice false-positive
results present lesser problem than false-negative
ones, because the consequences of false-negative
results are far more dangerous for patients. High
sensitivity allows for precise and early diagnosis,
that in case of laryngeal cancers decides of the patient’s survival and quality of life after treatment.
Early detection is the key to successful treatment.
AFE allows to detect pathologies that are otherwise
clinically silent.
In the examined material most tumors were in
late stages of advancement (stage III and IV). In
those cases, AFE is of a little strictly diagnostic use,
since due to the size of the tumor, clinical diagnosis is relatively easy. However AFE allows for much
more accurate assessment of tumor’s size and its
borders; allows to precisely mark spots for biopsy,
and makes early detection of possible recurrence
much easier. In cases of very early detected pathologies, such as LIN I or II, it allows to decide
whether to schedule the patient for biopsy or continue observation.
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AF Endoscopy in Laryngeal Pathologies
Blue-light examination seems to be an excellent addition to the classic white-light endoscopy
of the larynx. Combining these two methods allows to significantly increase chances of proper
diagnosis of early laryngeal neoplasia. Popularization of this method may contribute to increased
survival and better results of treatment of patients
with laryngeal cancer.
The authors concluded that autofluorescence
endoscopy is an efficient, safe and easy to perform complementary diagnostic tool, that may be
regularly used in out-patient clinics during routine ENT examination of glottic and supraglottic
region of the larynx. AFE is characterized by very
high sensitivity and high specificity in diagnosing
laryngeal cancer and pre-cancerous lesions, starting from mid-grade dysplasia (LIN II). AFE allows
for precise biopsy and accurate assessment of the
spread of the lesion.
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Address for correspondence:
Maciej Dariusz Zatoński
Department of Otolaryngology, Faculty of Dentistry
Wroclaw Medical University
Borowska 213
50-556 Wrocław
Poland
Tel.: +48 507 082 765
E-mail: [email protected]
Conflict of interest: None declared
Received: 13.04.2010
Revised: 24.06.2010
Accepted: 27.07.2010