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Patient delay and its clinical
significance among head and
neck cancer patients in Hungary
Kornél Dános
1
, Angéla Horváth
1
,
2
*, Judit Halász
2
, László Tamás
1
and Gábor Polony
1
1
Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Semmelweis
University, Budapest, Hungary,
2
Department of Pathology, Forensic and Insurance Medicine, Faculty of
Medicine, Semmelweis University, Budapest, Hungary
Introduction: Head and neck cancers represent a major health problem in Hungary.
With their high incidence and mortality rates, Hungary is one of the world leaders in
these indicators. The length of patient delay, defined as time from onset of symptoms
to first medical consultation, is unknown in Hungarian patients with head and neck
cancer. We aimed to use a representative sample of the Hungarian head and neck
cancer patient population to determine patient delay according to disease
localization and stage and to identify correlations with other clinical parameters.
Methods: In our retrospective study, we reviewed patient documentation. For
the inclusion, the patients had to be diagnosed with malignant tumors of the
oral cavity, oropharynx, hypopharynx or larynx at the Department Head and
Neck Surgery of Semmelweis University between 2012 and 2017.
Results: We identified 236 patients who met the inclusion criteria. The median delay
was9.5weeks(range0–209 weeks) and the mean delay of patients was 17.57 weeks
(SD 23.67). There was a significant difference in patient delay data by location. Among
glottic cancers, the most common diagnosis was an early stage (67%), compared with
other localizations, including most commonly the oropharynx (81%) and
hypopharynx (80%), where a locoregionally advanced stage was more frequent.
Discussion: Compared to data from different countries, the delay of Hungarian
patients with head and neck cancer is significantly longer, which may contribute
to the high mortality in Hungary. Screening and patient education in high-risk
groups could contribute to earlier diagnosis and thus improve prognosis.
KEYWORDS
survival, diagnosis, head and neck cancer, patient delay, symptom
Introduction
Hungary has the third highest incidence of head and neck squamous cell cancer
(HNSCC) and the second worst cancer-related mortality in the world, causing an
important health problem [1].
There are many articles in the international literature on patient delay as an important
factor in late diagnosis, but no data are available for Hungary [2].
OPEN ACCESS
EDITED BY
Anna Sebestyén,
Semmelweis University, Hungary
*CORRESPONDENCE
Angéla Horváth,
horvathangela11@gmail.com
RECEIVED 26 March 2023
ACCEPTED 01 August 2023
PUBLISHED 22 August 2023
CITATION
Dános K, Horváth A, Halász J, Tamás L
and Polony G (2023), Patient delay and
its clinical significance among head and
neck cancer patients in Hungary.
Pathol. Oncol. Res. 29:1611206.
doi: 10.3389/pore.2023.1611206
COPYRIGHT
© 2023 Dános, Horváth, Halász, Tamás
and Polony. This is an open-access
article distributed under the terms of the
Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms.
Pathology & Oncology Research Published by Frontiers01
TYPE Original Research
PUBLISHED 22 August 2023
DOI 10.3389/pore.2023.1611206
Diagnostic delay refers to the total period of time from the
onset of symptoms to (histological and radiological) diagnosis.
Diagnostic delay is generally separated into two phases: patient
delay defined as the time period from the beginning of symptoms
to the point where the patient seeks medical care and system
delay is the elapsed time between first contact with a healthcare
professional and the definitive diagnosis/treatment initiation [3].
In the case of suspected cancer, system delay can be
shortened by accurate patient pathways, as such the “14-day
rule,”established by the Hungarian Government in 2014, aiming
to reduce waiting times for staging-purpose imaging tests, and
the 21 (30)-day rule which aims to shorten the time in which
patients are referred to multidisciplinary tumor boards.
Nevertheless, it is known that the length of time a patient
waits from the first presentation of his/her first symptoms is
crucial in treatment success, head and neck cancer patients very
often seek medical attention for life-threatening symptoms only.
It is also known that patient delay is multifactorial, including
socioeconomic conditions, marital status, psychopathology,
denial, and is therefore difficult to influence the time to first
medical consultation [4]. No high-level evidence is available for
HNSCC screening in the general population. Screening of
patients with risk factors would be most recommended, but
this patient group is difficult to access to make them adopt
this awareness [5]. This underlines the importance of activities
such as the Make Sense campaign launched by the European
Head and Neck Cancer Society in 2013 to raise awareness of head
and neck cancer [6].
The present study aimed to evaluate the patient delay in this
specific and special Hungarian (based on incidence and
mortality) patient population, and its correlations with clinical
parameters.
Patients and methods
We aimed to enroll all patients in this retrospective, single-
institution study after being diagnosed (histologically) with
squamous cell cancer of the oral cavity, oropharynx,
hypopharynx, or larynx between September 2012 and August
2017 at the Department of Otolaryngology and Head-Neck
Surgery, Semmelweis University, Hungary.
The main exclusion criteria were: patients who were not
diagnosed (by biopsy) at our tertiary referral center or had
primaries in other head and neck sites (e.g., nasopharynx,
nasal cavity, paranasal sinuses, salivary gland, or skin,
furthermore those with unknown primaries) or had previous
treatment for head and neck tumor or/and underwent
oncological treatment in the last 5 years. Patients (22 cases)
who had been diagnosed in other hospitals were excluded.
In our study, we evaluated retrospectively the patients’
medical records (discharge summaries, multidisciplinary
tumor board reports, histological reports, and imaging studies).
The TNM stages were defined using the seventh edition of
the UICC TNM system [7].
To determine the HPV status in oropharyngeal cancers, as in
the clinical practice and current guidelines, we used
immunohistochemical (IHC) detection of the tumor
suppressor p16
INK4
(Vitro Master Diagnostics, mouse anti-
human p16-INK4A monoclonal antibody (MX007), 1:100).
We used the primary antibody at 37°C with an incubation
time of 10 min, at least 70% combined nuclear and
cytoplasmic staining of the tumor tissue was necessary for
positivity. This method is a reliable, surrogate marker for
testing human papillomavirus (HPV) in oropharyngeal
carcinoma [8].
For survival analyses, disease-specific survival was used:
the statistical event was defined as death due to cancer or the
presence of a tumor at the last check-up, while tumor-free
control or death due to other diseases was not defined as an
event.
Statistical analysis of the data—with descriptive statistics and
correlation analyses—was performed using the Kruskal-Wallis
test, Mann-Whitney U test, Chi-square test (Fisher’s exact test),
Kaplan-Meier estimates with log-rank tests.
We used SPSS Statistics for Mac v.28.0 (IBM Corp., Armonk,
NY) for the analyses.
Patient delays were reported using the median values. We
considered p<0.05 as statistically significant.
Our research was carried out with the ethical permission of
Semmelweis University (SE IKEB 105/2014).
Results
236 patients were identified meeting the criteria. We
examined 198 men and 38 women. The mean age of the
patients at the time of diagnosis was 61 years (40–92 years).
The patient data is presented in Table 1. The median delay
was 9.5 weeks (range 0–209 weeks), mean patient delay was
17.57 weeks (Std. deviation 23.67).
As for the tumor localizations in Table 2, the median delay
was the longest in patients with supraglottic cancer, followed by
glottic and transglottic tumors, while the patient delay was
8 weeks for oral and oropharyngeal cancers (p= 0.004).
Regarding the gender distribution of patient delay: we did
not find a significant difference between the median patient
delays by gender: men’s median patient delay was 9 weeks,
while it was 10 weeks among women (p= 0.237). In the
women group, there was one remarkable outlier, who
waited 209 weeks with her symptom, explaining the
difference in the mean value (Table 3).
An overview of the symptoms by region shows the following
(Table 4): in case of oral cancers, difficulty in swallowing (42.9%)
was the most frequent symptom, 28.6% of this patient group had
a sore throat and 14.3% reported weight loss, as significantly
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Dános et al. 10.3389/pore.2023.1611206
more common complaints than in other regions. We found that
dysphagia was common among oropharyngeal cancer patients
(40%), however, throat pain (48%) was even more frequent and
neck mass was significantly more common than in other
regions (32%).
Of all the regions, dysphagia was the most common among
patients with hypopharyngeal cancer (47.1%), which was also
found to be significant, but sore throat (25.5%), hoarseness
(21.6%), neck mass (27.5%) and earache (19.6%) were also
common symptoms in this group, of which earache showed to
be significant, compared to other regions. In case of supraglottic
tumors, the symptoms showed higher variability such as sore
throat (29.2%), hoarseness (29.2%), dyspnea (25%), and neck
mass (20.8%).
Patients with glottic and transglottic carcinoma presented
significantly more often with hoarseness. The only subglottic
cancer patient had hoarseness and dyspnea.
It is important to see what the median patient delay time was
per region in light of the characteristic complaints.
Patients with a main complaint of hoarseness or difficulty in
swallowing had significantly higher waiting times, compared to
those without either of these two symptoms (p<0.001 and p=
0.022, respectively). There were no differences in waiting times
for sore throat, neck lump or earache. Due to the small number of
patients, correlation analysis could not be performed for
hemoptysis and trismus (Table 5).
The clinical stage at the time of the diagnosis is of utmost
importance regarding the prognosis of head and neck cancers [9].
In our data, 67% of glottic cancers were diagnosed in the early
stage, while the tumors in other localizations were diagnosed
predominantly in a locoregionally advanced stage. In
oropharyngeal and hypopharyngeal cancers, distant metastasis
at the time of diagnosis occurred in 10% (Table 6).
Regarding survival data, we found a significant association
between stage and disease-specific survival for both T, N and M
status (Figures 1–3). Of particular note is the N status, where the
localization and number of neck metastases do not influence
survival as much as the presence or absence of cervical lymph
node metastases at all (Figure 2). In cases of distant metastases,
survival was significantly worse (Figure 3).
Asignificant correlation between tumor localization and
survival was found. It is noteworthy that laryngeal cancers
(with longer patient delay) have better survival rates
compared to the oral cavity and pharyngeal cancers. Based
on our previous data, it is remarkable that while the initial
stage certainly predicts a high survival rate, in contrast, we
found no significant direct association between the length of
patient delay and survival (Figure 4).
When correlating quartiles of patient delay time (longest to
shortest time interval in quartiles) to survival, we also found that
TABLE 1 Descriptive statistics of patients involved in our study.
Clinicopathological features All patients (N= 236)
Gender
Male 198 (84%)
Female 38 (16%)
Alcohol consumption
Never 59 (25%)
Previously 25 (10%)
Currently 105 (45%)
Not available 47 (20%)
Smoking
Never 11 (4.7%)
Previously 46 (19.5%)
Currently 163 (69%)
Not available 16 (6.8%)
Age 61 years (40–92 years)
Stage
T
1 36 (15.2%)
2 53 (22.5%)
3 52 (22%)
4a 55 (23.4%)
4b 26 (11%)
Not available 14 (5.9%)
N
N0 112 (47.4%)
N+ 110 (46.6%)
Not available 14 (5.9%)
M
M0 223 (94.5%)
M1 13 (5.5%)
Not available 0
Grade
1 13 (5.5%)
2 66 (28%)
3 53 (22.5%)
Not available 104 (44%)
Sites
Oral cavity 14 (5.93%)
Oropharynx p16 positive 28 (11.87%)
Oropharynx p16 negative 18 (7.63%)
Oropharynx p16 not available 29 (12.29%)
Hypopharynx 51 (21.62%)
Supraglottic larynx 24 (10.17%)
Glottic larynx 60 (25.42%)
Transglottic larynx 10 (4.23%)
Subglottic larynx 1 (0.42%)
Not assessable 1 (0.42%)
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TABLE 2 Delay in weeks according to the region (p= 0.004).
Localization Number Mean patient delay (weeks) Median patient delay (weeks)
Oral cavity 14 17.09 8
Oropharynx 75 11.18 8
Hypopharynx 51 13.9 11
Supraglottic larynx 24 27.75 17.5
Glottic larynx 60 25.9 15
Transglottic larynx 10 16.33 13
Subglottic larynx 1 Value = 4
TABLE 3 Delay in weeks according to the gender.
Gender Percent (%) Mean patient delay Median patient delay
Women 16.1 26.58 (1–209) 10
Men 83.9 15.79 (0–107) 9
TABLE 4 Symptoms (in percentage) with significance value and median patient delay (in weeks) according to the region.
Regions
Complaints
Oral
cavity
Oropharynx Hypopharynx Supraglottic
larynx
Glottic
larynx
Transglottic
larynx
Subglottic
larynx
p
Sore throat 28.6 48.0 25.5 29.2 3.3 0 0 <0.001
Hoarseness 0 4.0 21.6 29.2 96.7 60.0 100 <0.001
Neck mass 14.3 32.0 27.5 20.8 0 10.0 0 <0.001
Difficulty in
swallowing
42.9 40.0 47.1 25.0 0 20.0 0 <0.001
Weight loss 14.3 4.0 9.8 4.2 0 0 0 0.149
Earache 7.1 13.3 19.6 4.2 0 10.0 0 0.027
Hemoptysis 0 0 2.0 4.2 0 0 0 0.513
Trismus 0 2.7 0 0 0 0 0 0.636
Dyspnea 0 5.3 5.9 4.2 3.3 20.0 100 <0.001
Median patient delay
in weeks
8.0 8.0 11.0 17.5 15.0 13.0 4.0
TABLE 5 Patients’delay time according to complaint in weeks p<0.05.
Complaints Median patient delay in weeks p
With symptom Without symptom
Sore throat 10 9 0.985
Hoarseness 15 8 <0.001
Neck mass 8 10 0.215
Difficulty in swallowing 8 11.5 0.022
Weight loss 7 10 —
Earache 8 10 0.140
Hemoptysis 0 10 —
Trismus 32 9.5 —
Dyspnea 6.5 10 —
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patient waiting time did not significantly affect survival p= 0.214
(Figure 5).
We performed a multivariate regression analysis showing
that while the prognostic role of stage remained significant,
the patient delay was not a significant predictor of survival
(Table 7).
Role of p16 status in oropharyngeal
cancers
As for tumor biology, two groups of oropharyngeal
cancers can be distinguished: here we present an overview
of the symptoms according to the p16 status. In p16-positive
oropharyngeal cancer patients, neck mass as presenting
symptom was significantly more common than in p16-
negative tumor cases (p=0.003).Therewasnosignificant
correlation between the patient delay and HPV-positivity
status in the oropharyngeal cancer group (p= 0.524)
(Table 8).
The p16 immunohistochemistry was available in forty-six
out of seventy-six oropharyngeal cancer patients. Mean patient
delay was more for p16 positive patients 14.47 weeks versus
9 weeks, while median delay did not differ: 8 weeks for both
groups p= 0.524 (Table 9).
As expected, we found a significant correlation between HPV
status and survival: p16-negative oropharyngeal cancers were
associated with significantly worse survival (Figure 6).
TABLE 6 Cancer stage according to the cancer site: p<0.05.
Oral
cavity
Oropharynx Hypopharynx Supraglottic
larynx
Glottic
larynx
Transglottic
larynx
Early stage (T1-2N0M0) 3 7 5 8 38 3
23% 10% 10% 36% 67% 30%
Locoregionally advanced stage (T3-4N0M0,
T1-4N1-3M0)
10 55 40 13 18 7
77% 81% 80% 59% 32% 70%
Distant metastasis (T1-4N1-3M1) 0 65 110
0% 10% 10% 5% 2% 0%
FIGURE 1
T stage and survival analysis log-rank p<0.001. T1 vs. T2 p= 0.025; T1 vs. T3 p<0.001; T1 vs. T4a p= 0.003; T1 vs. T4b p<0.001; T2 vs. T3 p=
0.099; T2 vs. T4a p= 0.105; T2 vs. T4b p= 0.005; T3 vs. T4a p= 0.805; T3 vs. T4b p= 0.108; T4a vs. T4b p= 0.316.
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Discussion
Head and neck cancers can cause a diversity of symptoms.
These can be further classified into general symptoms, such as
fatigue, weight loss, or site-specific ones, e.g., hoarseness, and
sore throat.
Hoarseness can be due to the impaired function and structure
of the cover-body system of the vocal cords, vocal fold movement
problems associated with direct tumor spread to the paraglottic
space or the thyroarytenoid joint, or infiltration of the recurrent
laryngeal nerve [10]. Altered voice quality can also occur by
structural abnormalities (i.e., presence of the tumor mass) in the
FIGURE 2
N stage and survival analysis log-rank p<0.001. N0 vs. N1 p<0.001; N0 vs. N2a p= 0.005; N0 vs. N2b p<0.001; N0 vs. N2c p<0.001; N0 vs.
N3c p= 0.049; N1 vs. N2a p= 0.957; N1 vs. N2b p= 0.433; N1 vs. N2c p= 0.103; N1 vs. N3 p= 0.791.
FIGURE 3
M stage and survival analysis log-rank p<0.001.
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pharynx and oral cavity. In our data set, hoarseness was
significantly more common in cancers arising in the glottic
and subglottic larynx, interestingly, the symptom was also
significantly associated with longer patient delay. The latter
might be associated with the better biological behavior of
glottic cancers [11].
Referred ear pain can occur due to the involvement of
the 5th (mainly in oral cancers), more commonly by the 9th
and 10th cranial nerves [12]. We found a significant
association between otalgia and tumor localization:
hypopharyngeal cancers caused ear pain the most
frequently.
FIGURE 4
Primary tumor site and survival analysis log-rank p<0.001. oral vs. orophar. p= 0.906; oral vs. hypophar. p= 0.996; oral vs. supraglot. p= 0.860;
oral vs. glot. p= 0.013; oral vs. transglot. p= 0.185; orophar. vs. hypophar. p= 0.985; orophar. vs. supraglot. p= 0.723; orophar. vs. glot. p<0.001;
orophar. vs. transglot. p= 0.144; hypophar. vs. supraglot. p= 0.603; hypophar. vs. glot. p<0.001; hypophar. vs. transglot. p= 0.139; supraglot. vs.
glot. p= 0.012; supraglot. vs. transglot. p= 0.215; glot. vs. transglot. p= 0.986.
FIGURE 5
Patient delay and survival analysis log-rank p= 0.214.
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Sore throat and neck mass, as presenting symptoms were
significantly the most common in oropharyngeal cancers, and
further analyzed by p16-status, HPV-positive cancer patients
presented 3 times more common with neck lump as an initial
sign of disease, which phenomenon is due to the often rapidly
growing, cystic neck metastases of HPV-related head and neck
cancers [13].
Regarding patient delay, when comparing the results of
our study on a representative patient population in Hungary
(17.57 weeks) with international data (Table 10), similar times
were found (17.09 weeks) to the Canadian data [14]. However,
the data from Brazil (43.48 weeks, median) were longer than
our data [15]. This indicator was lower in the
United Kingdom, where the mean patient delay for oral
cancer patients was 7.4 weeks [16], another localization of
head and neck cancer was given as 12.3 weeks. In South India
the median delay was only 4.29 weeks [17]. In the
United States, from 1993 to 2004, this result (12.67 weeks)
was less than in Hungary, but from 2005 to 2013 it was close to
our rate (17.03 weeks) [18]. One-sample test was used to
compare whether the difference in the delay times was
significant. We found a significant difference between our
data and the Brazilian and South Indian results.
In reviewing the factors that determine patient survival,
one of the first to be mentioned is the size of the primary
tumor, the presence of lymph node metastases and distant
metastases. The TNM stage is a reliable predictor of survival,
which increases with time, and thus with delay time. In
advanced cancers, more drastic and radical surgery may be
performed, and often the general condition of the patient,
which also decreases with time, does not allow curative
surgery. In advanced cancers,thesideeffectsofchemo-
radiation are also more pronounced. Delay time therefore
indirectly determines patient survival [19].
Looking further at the components of survival, it is noted that
some localized tumors have been found to have better survival
rates despite longer waiting times. These were glottic and p16-
TABLE 7 Multivariate regression analysis (Cox regression).
pHR 95% confidence
interval (CI)
Lower Upper
Stage <0.001 5.075 2.756 9.347
Patient delay 0.265 0.990 0.974 1.007
TABLE 8 Oropharyngeal cancer symptoms according to p16 status.
Presence of symptoms in percent p
p16 positive OPC p16 negative OPC
Sore throat 38.9 64.3 0.091
Hoarseness 5.6 3.6 1.0
Neck mass 61.1 17.9 0.003
Difficulty in swallowing 16.7 42.9 0.064
Weight loss 0 7.1 0.513
Earache 0 17.9 0.140
Hemoptysis —— —
Trismus 5.6 3.6 1.0
Dyspnea 0 14.3 0.144
Median patient delay in weeks 8 weeks 8 weeks 0.524
TABLE 9 p16-positivity and patient delay in weeks in oropharyngeal cancers p= 0.524.
p16 status Numbers (available patient delay scores) Mean delay Median delay
Positive 18 (17) 14.47 (2–56) weeks 8.00 weeks
Negative 28 (26) 9.81 (2–42) weeks 8.00 weeks
Not available 29
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positive oropharyngeal cancers. This suggests that the variable
biological behavior of tumors with different localization is an
important factor for patient survival. Glottic cancers grow more
slowly and, due to their location, show obvious symptoms
(hoarseness) even when small, which may trigger the patient
to seek medical attention. However, our results show that they
wait for a long time, which may be because their hoarseness does
not cross their stimulus threshold, they probably think it is just a
normal part of smoking. Furthermore, due to their lymphatic
drainage, glottic tumors tend to metastasize only at an advanced
stage.
The better survival of p16 oropharyngeal cancers can be
explained by two factors: they have different tumor biology,
which makes them more responsive to chemo-radiation, and
they are younger, in a better general condition, with less smoking
and alcohol-related diseases, so they can tolerate treatment better.
Tumors with different localizations and behaviors
overlap in terms of symptoms, so this does not allow us
to screen out patients with a more favorable biological
behavior being likely to have a good chance in case of a
delayed diagnosis. Instead of population-wide screening,
the solution would be to screen patients with risk
factors—smoking and drinking—so that tumors can be
diagnosed and treated at an earlier stage.
A possible weakness of our study is the subjective matter of
the patients’self reported date of symptom onset, however, there
is no other option to assess the symptom onset which would be
more accurate.
FIGURE 6
p16 status and survival analysis log rank p= 0.032.
TABLE 10 Patient delay times by country.
Country Patient delay (weeks) Period Region p-value
Our data 17.57 (mean) 2012–2017
Canadian [14] 17.09 (mean) 2017–2018 All HNC 0.598
Brazil [15] 43.48 (median) 2011–2012 All HNC <0.001
United Kingdom [16] 7.4 (mean) 1995–1996 Oral 0.307
12.3 (mean) 1995–1996 All HNC ex. oral 0.002
South India [17] 4.29 (median) 2016–2017 All HNC <0.001
United States [18] 12.67 (not reported) 1993–2004 All HNC 0.001
17.03 (not reported) 2005–2013 All HNC 0.573
Iran [20] 23.05 (mean) 2004–2006 All HNC 0.002
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Data availability statement
The raw data supporting the conclusion of this article will be
made available by the authors, without undue reservation.
Ethics statement
The studies involving human participants were reviewed
and approved by SE IKEB 105/2014. Written informed
consent for participation was not required for this study in
accordance with the national legislation and the institutional
requirements.
Author contributions
KD: study design, statistics. AH: data management, manuscript
production. JH: immunohistochemistry, histopathology. LT and
GP: scientific oversee, consultation. All authors contributed to the
article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
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