Introduction
Head and neck cancers (HNCs) are the ninth most
prevalent cancers in the world and are associated with high
mortality rates (1). Recent research
has shown that the incidence of several of these cancers has
significantly increased in both men and women over the past few
years in Germany (2). The study also
found that the five-year overall survival rate was lower than 50%,
underlining the major impact of HNCs on the global health in this
country.
HNCs involve a variety of symptoms which can also be
found in non-malignant disorders (e.g., dysphagia, dysphonia, and
oral ulceration) (3). For example, a
2000 study including more than 350 HNC patients discovered that
almost 60% of the population reported difficulties swallowing prior
to treatment (4). Another work
estimated that mild to severe dysphagia affected between 5 and 52%
of patients diagnosed with oral, laryngeal, oropharyngeal, or
hypopharyngeal tumors (5). In the
case of dysphonia, Cohen and colleagues recently found that this
symptom was reported by nearly 1% of individuals in a study
involving 55 million people, and that in most cases it was related
to acute laryngitis, nonspecific dysphonia, benign vocal fold
pathology, chronic laryngitis, or laryngeal cancer (6). These findings suggest that the clinical
presentation of HNCs is very unspecific, thus rendering these
cancers difficult to diagnose (7,8).
Regrettably, little is known about how HNCs are
diagnosed in specialized practices and about initial suspicions
among otolaryngologists concerning a potential tumor based on the
symptoms affecting their patients. Therefore, the goal of the
present study was to estimate the prevalence of suspected HNC
diagnoses made by otolaryngologists in a population with
subsequently confirmed cancer diagnoses in Germany.
Materials and methods
Database
The present retrospective study used data from the
Disease Analyzer database (IQVIA). This database compiles
demographic, clinical, and pharmaceutical data obtained in an
anonymous format from computer systems of clinical practices
(9). IQVIA regularly assesses the
quality and exactness of the data (e.g., diagnoses and drug
prescriptions), and the Disease Analyzer database has been found to
be representative of clinical practices in Germany (9). Finally, this database has already been
used for previous studies focusing on cancer (10–12).
Study population
This study included patients with an initial
documentation of confirmed cancer diagnosis from 137 otolaryngology
practices made between January 2012 and December 2016 (index
date).
Study outcome and variables
The main outcome of the study was the prevalence of
diagnoses of suspected cancer in otolaryngology practices within
one year prior to the first documentation of a confirmed cancer
diagnosis. The suspicion of cancer was defined using several ICD-10
codes for cancer (malignant neoplasms of lip (C00), base of tongue
(C01), other and unspecified parts of tongue (C02), gum (C03),
floor of mouth (C04), palate (C05), other and unspecified parts of
mouth (C06), parotid gland (C07), other and unspecified major
salivary glands (C08), tonsil (C09), oropharynx (C10), nasopharynx
(C11), pyriform sinus (C12), hypopharynx (C13), other and
ill-defined sites in the lip, oral cavity and pharynx (C14), nasal
cavity and middle ear (C30), accessory sinuses (C31), larynx (C32),
thyroid gland (C73), and non-Hodgkin lymphoma (C85)) in combination
with the phrase ‘suspicion of’ or ‘exclusion of’. Additionally, the
following diagnoses were included and classified as ‘suspected
cancer’: Granuloma, leukokeratosis and leukoplakia of vocal cords
(J38.3), leukoplakia and other disturbances of oral epithelium,
including tongue (K13.2), neoplasm of uncertain behavior of oral
cavity and digestive organs (D37), neoplasm of uncertain behavior
of middle ear and respiratory and intrathoracic organs (D38),
neoplasm of uncertain behavior of thyroid gland (D44.0), neoplasm
of uncertain behavior of parathyroid gland (D44.2), neoplasm of
uncertain behavior of craniopharyngeal duct (D44.4), neoplasm of
uncertain behavior of carotid body (D44.6), neoplasm of uncertain
or unknown behavior of other and unspecified sites (D48).
Statistical analyses
The demographic variables included age and gender.
The association between defined demographic and clinical variables
and diagnoses of suspected cancer was analyzed using a logistic
regression model. A P-value <0.05 was considered statistically
significant. All analyses were carried out using SAS 9.3 (SAS
Institute, Cary, USA).
Results
This retrospective study included 6,446 patients
with documentation of a confirmed cancer diagnosis (Table I). The mean age was 62.1 years
(SD=14.3 years), and 63.2% of patients were men. The three most
frequent cancer diagnoses were neoplasms of larynx (23.3%),
non-Hodgkin lymphoma (13.8%), and neoplasms of oropharynx (12.0%).
Approximately 23.1% of the population received a diagnosis of
suspected cancer within 12 months prior to the first documentation
of a confirmed cancer diagnosis. The results of the logistic
regression model are displayed in Table
II. Patients over the age of 50 were more likely to receive a
diagnosis of suspected cancer compared to patients aged 50 or under
(ORs ranging from 1.44 to 1.55). In addition, these odds were also
significantly higher in men than in women (OR=1.52). Compared to
laryngeal cancers, cancers of pyriform sinus (OR=3.00) and of
hypopharynx (OR=1.64) were associated with an increase in the
probability of having received a diagnosis of suspected cancer,
whereas cancers of floor of mouth (OR=0.74), of unspecified major
salivary glands (OR=0.39), of ill-defined sites in the lip, oral
cavity and pharynx (OR=0.39), of accessory sinuses (OR=0.35), of
thyroid gland (OR=0.27) and non-Hodgkin lymphoma (OR=0.62) were
associated with a decrease in this probability.
 | Table I.Baseline characteristics of the
population (IQVIA, Disease Analyzer Database). |
Table I.
Baseline characteristics of the
population (IQVIA, Disease Analyzer Database).
| Variable | Patients with
confirmed cancer diagnosis (N, %) |
|---|
| Total | 6,446 |
| Demographic
variables |
|
| Age
(Mean, SD) | 62.1 (14.3) |
| ≤50
years | 1,192 (18.5) |
| 51–60
years | 1,543 (23.9) |
| 61–70
years | 1,709 (26.5) |
| 71–80
years | 1,502 (23.3) |
| >80
years | 500 (7.8) |
| Men | 4,074 (63.2) |
|
Women | 2,372 (26.8) |
| Cancer diagnoses (ICD
codes) |
|
| Malignant
neoplasm of lip (C00) | 83 (1.3) |
| Malignant
neoplasm of base of tongue (C01) | 242 (3.8) |
| Malignant
neoplasm of other and unspecified parts of tongue (C02) | 400 (6.2) |
| Malignant
neoplasm of gum (C03) | 28 (0.4) |
| Malignant
neoplasm of floor of mouth (C04) | 310 (4.8) |
| Malignant
neoplasm of palate (C05) | 76 (1.2) |
| Malignant
neoplasm of other and unspecified parts of mouth (C06) | 89 (1.4) |
| Malignant
neoplasm of parotid gland (C07) | 190 (3.0) |
| Malignant
neoplasm of other and unspecified major salivary glands (C08) | 54 (0.8) |
| Malignant
neoplasm of tonsil (C09) | 422 (6.6) |
| Malignant
neoplasm of oropharynx (C10) | 773 (12.0) |
| Malignant
neoplasm of nasopharynx (C11) | 106 (1.6) |
| Malignant
neoplasm of pyriform sinus (C12) | 14 (0.2) |
| Malignant
neoplasm of hypopharynx (C13) | 420 (6.5) |
| Malignant
neoplasm of other and ill-defined sites in the lip, oral cavity and
pharynx (C14) | 51 (0.8) |
| Malignant
neoplasm of nasal cavity and middle ear (C30) | 89 (1.4) |
| Malignant
neoplasm of accessory sinuses (C31) | 137 (2.1) |
| Malignant
neoplasm of larynx (C32) | 1,491 (23.3) |
| Malignant
neoplasm of thyroid gland (C73) | 582 (9.0) |
|
Non-Hodgkin lymphoma
(C85) | 889 (13.8) |
| Table II.Association between
demographic/clinical variables and diagnoses of suspected cancer in
patients followed in otolaryngology practices (logistic regression
model). |
Table II.
Association between
demographic/clinical variables and diagnoses of suspected cancer in
patients followed in otolaryngology practices (logistic regression
model).
| Variables | Proportion of
patients with diagnoses of suspected cancer within one year prior
to the date of confirmed cancer diagnosis (N,%) | Odds ratio (95%
CI)a |
P-valuea |
|---|
| Total | 1,490 (23.1) |
|
|
| Demographic
variables |
|
|
|
| ≤50
years | 183 (15.4) | Reference |
|
| 51–60
years | 390 (25.3) | 1.54 (1.26–1.89) | <0.001 |
| 61–70
years | 436 (25.5) | 1.52 (1.25–1.85) | <0.001 |
| 71–80
years | 362 (24.1) | 1.44 (1.18–1.77) | <0.001 |
| >80
years | 119 (23.8) | 1.55 (1.18–2.02) | 0.001 |
| Male | 1,097 (26.9) | 1.52 (1.33–1.75) | <0.001 |
|
Female | 393 (16.6) | Reference |
|
| Cancer diagnoses |
|
|
|
| Malignant
neoplasm of lip (C00) | 24 (28.9) | 1.11 (0.68–1.81) | 0.679 |
| Malignant
neoplasm of base of tongue (C01) | 54 (22.3) | 0.74 (0.54–1.03) | 0.073 |
| Malignant
neoplasm of other and unspecified parts of tongue (C02) | 111 (27.8) | 1.07 (0.85–1.38) | 0.588 |
| Malignant
neoplasm of gum (C03) | 6 (21.4) | 0.77 (0.31–1.93) | 0.580 |
| Malignant
neoplasm of floor of mouth (C04) | 68 (21.9) | 0.74 (0.55–0.99) | 0.040 |
| Malignant
neoplasm of palate (C05) | 17 (22.4) | 0.81 (0.47–1.42) | 0.468 |
| Malignant
neoplasm of other and unspecified parts of mouth (C06) | 18 (20.2) | 0.71 (0.42–1.21) | 0.208 |
| Malignant
neoplasm of parotid gland (C07) | 46 (24.2) | 0.97 (0.68–1.38) | 0.850 |
| Malignant
neoplasm of other and unspecified major salivary glands (C08) | 6 (11.1) | 0.39 (0.16–0.92) | 0.031 |
| Malignant
neoplasm of tonsil (C09) | 111 (26.3) | 0.95 (0.74–1.21) | 0.672 |
| Malignant
neoplasm of oropharynx (C10) | 174 (22.5) | 0.84 (0.69–1.04) | 0.109 |
| Malignant
neoplasm of nasopharynx (C11) | 20 (18.9) | 0.68 (0.41–1.13) | 0.135 |
| Malignant
neoplasm of pyriform sinus (C12) | 7 (50.0) | 3.00 (1.03–8.76) | 0.044 |
| Malignant
neoplasm of hypopharynx (C13) | 161 (38.3) | 1.64 (1.31–2.07) | <0.001 |
| Malignant
neoplasm of other and ill-defined sites in the lip, oral cavity and
pharynx (C14) | 7 (13.7) | 0.39 (0.18–0.88) | 0.024 |
| Malignant
neoplasm of nasal cavity and middle ear (C30) | 20 (22.5) | 0.86 (0.51–1.44) | 0.568 |
| Malignant
neoplasm of accessory sinuses (C31) | 15 (11.0) | 0.35 (0.20–0.61) | 0.002 |
| Malignant
neoplasm of thyroid gland (C73) | 43 (7.4) | 0.27 (0.20–0.39) | <0.001 |
|
Non-Hodgkin lymphoma
(C85) | 157 (17.7) | 0.62 (0.51–0.77) | <0.001 |
| Malignant
neoplasm of larynx (C32) | 425 (28.5) | Reference |
|
Discussion
To the best of our knowledge, this is the only study
to investigate initial suspicions among specialists regarding
potential malignant diagnoses. The major finding yielded by this
study is that cancer was suspected by otolaryngologists only in a
relatively small proportion of patients subsequently diagnosed with
HNCs. Before proceeding, one must consider that the rate of
suspected cancer diagnoses made by general practitioners in Germany
is even lower (5%) (12). The most
likely hypothesis to explain the primary result of the present
analysis is that symptoms associated with HNCs can also be found in
other benign disorders. In 2012, researchers demonstrated that
536,943 patients out of nearly 55 million individuals from the U.S.
received diagnoses of dysphonia (0.98% of the population) (6). Additionally, the authors estimated that
laryngeal cancer was only the fifth most frequent cause of
dysphonia (2.2%) following acute laryngitis (42.1%), nonspecific
dysphonia (31.2%), benign vocal fold pathology (10.7%), and chronic
laryngitis (9.7%). In a later study, Bhattacharyya found that 9.5
million adults reported symptoms of dysphagia in the U.S. in 2012
(13). Interestingly, only one out
of four patients sought medical help and only one out of three of
these individuals were given a final diagnosis. Stroke (11.2%),
neurological disorders (7.2%), and HNCs (4.9%) were the three most
common causes of dysphagia. These two studies clearly underline the
lack of specificity of the symptoms associated with tumors of the
head and neck.
Another important finding of our work is that the
probability of having received a diagnosis of suspected cancer was
associated with several demographic and clinical variables. First,
diagnoses of suspected cancer were more frequent in men and in
older individuals than in women and younger individuals. This
result might be explained by the fact that HNCs are more often
diagnosed in older men (1,14,15).
Therefore, it is possible that otolaryngologists are more likely to
suspect cancer when dysphagia, dysphonia and other HNC-related
symptoms are present in men and older patients compared to women
and younger patients. Second, we showed that the probability of
having received a diagnosis of suspected cancer varied with the
type of cancer. Of particular importance was cancer of the pyriform
sinus, the most common malignant tumor of the hypopharynx (16), and other cancers of the hypopharynx
which were associated with a higher chance of having received this
diagnosis compared to laryngeal cancers. In 2008, Hall and
colleagues studied a population of nearly 600 individuals and
estimated that the typical patient with squamous cell carcinoma of
the hypopharynx was an unemployed man around 65 years of age with a
low socioeconomic status, high comorbidity level, and frequent
drinking habit (17). The presence
of this specific sociodemographic profile in patients affected by
common symptoms might have triggered suspicions among
otolaryngologists regarding the potential malignant etiology of
these symptoms. Another explanation is that cancers of the
hypopharynx are difficult to detect in non-specialized practices
due to the localization of this anatomical region. Thus, general
practitioners might directly refer patients displaying
hypopharyngeal symptoms to otolaryngologists for further
examination. On the other hand, it is possible that a significant
proportion of cancers of the mouth and of major salivary glands are
diagnosed in general practices. In line with this hypothesis, we
found that the probability of having received a diagnosis of
suspected cancer in otolaryngology practices was significantly
lower for malignant neoplasms of the floor of the mouth and of
major salivary glands. Finally, cancers of the thyroid gland were
associated with the lowest probability of having received a
diagnosis of suspected cancer. This last finding might be explained
by the fact that thyroid cancers are often diagnosed by
endocrinologists in Germany (18,19).
There are several limitations which should be
mentioned at this point. The major limitation of the present
retrospective study is that suspected and confirmed HNC diagnoses
relied only on ICD 10 codes and texts entered by otolaryngologists.
It is possible that in some cases, no diagnoses of suspected cancer
were documented even if the physician did indeed suspect cancer,
but that patients were instead referred to hospitals with
unspecified diagnoses. Of particular importance is the lack of TNM
information as well as data concerning molecular markers which
could have potentially increased the internal validity of the
study. Second, there was no information concerning the diagnosis of
HNCs in other practices (e.g., general or endocrinological
practices) and in hospitals. Therefore, we were unable to
investigate the prevalence of diagnoses of suspected cancer in HNC
patients followed in other settings in Germany. Finally, data on
socioeconomic status and lifestyle-related risk factors were also
unavailable. The two main strengths of this works are the number of
patients and the various types of cancer available for
analyses.
Overall, approximately 23% of individuals received a
diagnosis of suspected cancer within a year prior to the first
documentation of confirmed HNC. Age, gender, and the type of cancer
were associated with the probability of receiving this suspected
diagnosis.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current
study are available from the corresponding author on reasonable
request.
Authors' contributions
KK, ML, LS, ID, AS and LJ contributed substantially
to the conception, design, and interpretation of the data, revised
the manuscript critically for important content and gave the final
approval of the version to be published.
Ethics approval and consent to
participate
German law allows the use of anonymous electronic
medical records for research purposes under certain conditions.
According to this legislation, it is not necessary to obtain
informed consent from patients or approval from a medical ethics
committee for this type of observational study that contains no
directly identifiable data. Therefore, no waiver of ethical
approval was obtained from an Institutional Review Board or ethics
committee. The authors had no access to any identifying information
at any moment during the analysis of the data.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
References
|
1
|
Gupta B, Johnson NW and Kumar N: Global
epidemiology of head and neck cancers: A continuing challenge.
Oncology. 91:13–23. 2016. View Article : Google Scholar : PubMed/NCBI
|
|
2
|
Guntinas-Lichius O, Wendt T, Buentzel J,
Esser D, Lochner P, Mueller A, Schultze-Mosgau S and
Altendorf-Hofmann A: Head and neck cancer in Germany: A
site-specific analysis of survival of the Thuringian cancer
registration database. J Cancer Res Clin Oncol. 136:55–63. 2010.
View Article : Google Scholar : PubMed/NCBI
|
|
3
|
Mehanna H, Paleri V, West CM and Nutting
C: Head and neck cancer-Part 1: Epidemiology, presentation, and
prevention. BMJ. 341:c46842010. View Article : Google Scholar : PubMed/NCBI
|
|
4
|
Pauloski BR, Rademaker AW, Logemann JA,
Stein D, Beery Q, Newman L, Hanchett C, Tusant S and MacCracken E:
Pretreatment swallowing function in patients with head and neck
cancer. Head Neck. 22:474–482. 2000. View Article : Google Scholar : PubMed/NCBI
|
|
5
|
Nguyen NP, Vos P, Moltz CC, Frank C,
Millar C, Smith HJ, Dutta S, Alfieri A, Lee H, Martinez T, et al:
Analysis of the factors influencing dysphagia severity upon
diagnosis of head and neck cancer. Br J Radiol. 81:706–710. 2008.
View Article : Google Scholar : PubMed/NCBI
|
|
6
|
Cohen SM, Kim J, Roy N, Asche C and Courey
M: Prevalence and causes of dysphonia in a large treatment-seeking
population. Laryngoscope. 122:343–348. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
7
|
Yu T, Wood RE and Tenenbaum HC: Delays in
diagnosis of head and neck cancers. J Can Dent Assoc.
74:612008.PubMed/NCBI
|
|
8
|
Lee SC, Tang IP, Avatar SP, Ahmad N, Selva
KS, Tay KK, Vikneswaran T and Tan TY: Head and neck cancer:
Possible causes for delay in diagnosis and treatment. Med J
Malaysia. 66:101–104. 2011.PubMed/NCBI
|
|
9
|
Dombrowski S and Kostev K: Use of
electronic medical records in the epidemiological research.
Cuvillier Verlag; Göttin: 2017
|
|
10
|
Jacob L, Kalder M, Arabin B and Kostev K:
Impact of prior breast cancer on mode of delivery and
pregnancy-associated disorders: A retrospective analysis of
subsequent pregnancy outcomes. J Cancer Res Clin Oncol.
143:1069–1074. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
11
|
Kostev K, Jacob L and Kalder M: Risk of
depression, anxiety, and adjustment disorders in women with a
suspected but unconfirmed diagnosis of breast or genital organ
cancer in Germany. Cancer Causes Control. 28:1021–1026. 2017.
View Article : Google Scholar : PubMed/NCBI
|
|
12
|
Kostev K, Meister U, Kalder M and Jacob L:
Suspected cancer diagnoses made by general practitioners in a
population with subsequently confirmed cancer diagnoses in Germany:
A retrospective study of 31,628 patients. Oncotarget.
8:84540–84545. 2017. View Article : Google Scholar : PubMed/NCBI
|
|
13
|
Bhattacharyya N: The prevalence of
dysphagia among adults in the United States. Otolaryngol Head Neck
Surg. 151:765–769. 2014. View Article : Google Scholar : PubMed/NCBI
|
|
14
|
Döbrossy L: Epidemiology of head and neck
cancer: Magnitude of the problem. Cancer Metastasis Rev. 24:9–17.
2005. View Article : Google Scholar : PubMed/NCBI
|
|
15
|
Rettig EM and D'Souza G: Epidemiology of
head and neck cancer. Surg Oncol Clin N Am. 24:379–396. 2015.
View Article : Google Scholar : PubMed/NCBI
|
|
16
|
Krstevska V: Early stage squamous cell
carcinoma of the pyriform sinus: A review of treatment options.
Indian J Cancer. 49:236–244. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
17
|
Hall SF, Groome PA, Irish J and O'Sullivan
B: The natural history of patients with squamous cell carcinoma of
the hypopharynx. Laryngoscope. 118:1362–1371. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
18
|
Paschke R, Lincke T, Müller SP, Kreissl
MC, Dralle H and Fassnacht M: The treatment of well-differentiated
thyroid carcinoma. Dtsch Ärztebl Int. 112:452–458. 2015.
|
|
19
|
Wendler J, Kroiss M, Gast K, Kreissl MC,
Allelein S, Lichtenauer U, Blaser R, Spitzweg C, Fassnacht M,
Schott M, et al: Clinical presentation, treatment and outcome of
anaplastic thyroid carcinoma: Results of a multicenter study in
Germany. Eur J Endocrinol. 175:521–529. 2016. View Article : Google Scholar : PubMed/NCBI
|
