Eur Arch Otorhinolaryngol DOI 10.1007/s00405-016-3922-8
LARYNGOLOGY
Epidemiology of laryngeal carcinoma in Germany, 1998–2011 Maximilian Peller1,5 • Alexander Katalinic2 • Barbara Wollenberg3 Ingo U. Teudt4 • Jens-E. Meyer5
•
Received: 31 October 2015 / Accepted: 3 February 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Abstract Constituting 25–30 % of all head and neck cancer cases, laryngeal carcinoma is the most prevalent entity. Major risk factors of laryngeal cancer are smoking and excessive alcohol consumption. This study presents the recent developments in the incidence of laryngeal cancer from 1998 to 2011 in Germany. Laryngeal carcinoma was identified using International Statistical Classification of Diseases and Related Health Problems (ICD10) from German population-based cancer registries. The incidence was provided by the Robert Koch Institute, and the mortality data were derived from German death statistics for further evaluation. Both descriptive and analytical analyses were conducted. From 1998 to 2011, a total of 14,847 laryngeal carcinoma cases were reported, in 13,195 men and 1652 women. Glottic carcinoma represented the main entity, constituting 69 % of male cases and 50 % of female cases. For men, a decline in incidence was observed starting in 2006. The incidence rate for women remained & Maximilian Peller [email protected] 1
Department of Radiology, Asklepios Klinik Altona, Paul-Ehrlich-Straße 1, 22763 Hamburg, Germany
2
Institute of Clinical Epidemiology, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
3
Department of Otolaryngology, Head and Neck Surgery, Medical University of Schlweswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
4
Department of Otolaryngology, Head and Neck Surgery, Asklepios Klinik Altona, Paul-Ehrlich-Straße 1, 22763 Hamburg, Germany
5
Department of Otolaryngology, Head and Neck Surgery, Asklepios Klinik St. Georg, Lohmu¨hlenstraße 5, 20099 Hamburg, Germany
stable for the period of observation. The incidence of laryngeal cancer resembles the development of smoking behaviour in Germany. To maintain the positive trend of the male population and to reduce the incidence in women, it is crucial to continue and to improve the prevention of smoking campaigns in Germany. Keywords Laryngeal cancer Epidemiology Incidence Smoking Development
Introduction Laryngeal carcinoma accounts for 25–30 % of head and neck cancer cases; therefore, it is the most common cancer site of the aero-digestive tract [1]. The larynx is anatomically divided into three levels: the glottic area, the supraglottic area and the subglottic area. In addition to these locations, there is carcinoma of the larynx overlapping at least two sections of the larynx and carcinoma with unspecified locations [2]. Two major risk factors for the development of laryngeal cancer are known, including tobacco use and excessive alcohol consumption [3, 4]. A meta-analysis of 15 case– control studies revealed that long-term smokers had a higher risk (OR 18; 95 % CI 7–47) of developing laryngeal cancer than non-smokers [5]. The odds ratio for heavy alcohol consumption is reported to be lower, and it depends on the amount of alcohol consumption; 25, 50 or 100 g of pure alcohol intake per day is associated with odds ratios of 1.38, 1.94 and 3.95, respectively, compared to non-drinkers [6]. If smoking and heavy drinking coincide, the effect is multiplicative [7]. Recently, the human papilloma virus (HPV) has been known to be a risk factor for the development of head and neck squamous cell cancer. Most
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important are high-risk HPV types 16 and 18. Although HPV-positive carcinoma is more frequently observed in the oropharynx (tonsils and the base of the tongue), a small proportion can also be detected in the larynx. However, HPV as a risk factor for the development of laryngeal cancer seems not to be comparable to high levels of cigarette and alcohol consumption [8]. Today, no valid data concerning the incidence and mortality of laryngeal cancer for the last two decades in Germany are available. The aim of this study is to evaluate the incidence and mortality of laryngeal cancer from 1998 to 2011 in Germany and to highlight trends in cancer development for further evaluation. The results are compared to the available national and international literature, identifying differences and similarities concerning the development of the incidence of laryngeal cancer.
Cases in which the registries noted the laryngeal carcinoma by death certificate are excluded from further investigation because the date of diagnosis and the date of death are the same and therefore are not usable for survival analyses. Statistics Statistical evaluation is performed using the statistical program SPSS Version 22.0 for Mac (IBM, New York, USA). The data are further processed using Excel 2011 (Microsoft, Washington, USA). All age-standardised incidence and mortality rates (old European standard population) are calculated using the program CARESS (OFFIS, Oldenburg, Germany).
Results
Data collection With the introduction of the federal cancer registry law in 1995, every federal state is obliged to establish populationbased cancer registries. The majority of registries in Germany, however, started to register continuously around the year 2000, and nationwide coverage was reached in 2009. The German Centre for Cancer Registry Data (ZfKD), Berlin, Germany is responsible for pooling the data of cancer epidemiology collected by all federal cancer registries in Germany. Additionally, the ZfkD has to verify the plausibility and completeness of the data every year. The set of data on laryngeal cancer from 1998 to 2011 has been transmitted for further evaluation. Covered epidemiological data The transmitted, anonymous data contain epidemiologic information such as gender, birth year, the state of residency and that of the incident case, disclosures on ICD 10 Code (C32.0, C32.1, C32.2, C32.8, C32.9), the year and month of diagnosis, the method of assuring the diagnosis (e.g., histological, clinical) and the TNM stage (5th, 6th and 7th edition). Moreover, in the case of death, information on the month and year of death is provided. Mortality data are provided by The Federal Statistical Office, Wiesbaden, Hessen (Destatis). For the analyses performed in this article, data from ten German registries covering approximately 30 % of the German population are included. A time bar on incidence and mortality from 1998 to 2011 is established.
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From 1998 to 2011, a total of 14,847 cases of laryngeal carcinoma were reported, 13,195 in men and 1652 in women. Age of the patient collective and sublocalisation The mean age of laryngeal cancer diagnosis increased both in males and females. Thus, the mean age of onset in 1998 for both men and women was 62 years. In 2011, the average age was 64 years in men and 65 years in women. Figure 1 shows the distribution of the absolute number of laryngeal carcinomas by sublocalisation and gender. In men, the glottic carcinoma represented the largest group, with 50 % of cases. The supraglottic and subglottic groups represented 21 and 2 %, respectively. The carcinomas that exceeded several laryngeal sections added up to 10 %, and those that were unspecified accounted for 18 % of all cases. In women, glottic carcinoma accounted for 36 % of cases, and supraglottic carcinoma accounted for 33 %. Subglottic carcinoma represented the lowest proportion with 2 %. Transglottic laryngeal carcinoma and unspecified carcinoma accounted for 8 and 21 %, respectively.
Total cases
Materials and methods
7000 6000 5000 4000 3000 2000 1000 0
Fig. 1 Distribution of localisation of laryngeal cancer
Men Women
Eur Arch Otorhinolaryngol Table 1 Summary of study patient characteristics by Union for International Cancer Control (UICC)—stage and by sublocalisation Localisation
UICC stages I
II
III
IVA ? B
IVC
Missing (n)
Glottic # (n = 6603)
61 % (n = 2241)
19 % (n = 775)
11 % (n = 457)
7 % (n = 288)
1 % (n = 50)
Glottic $ (n = 601)
63 % (n = 204)
17 % (n = 57)
9 % (n = 29)
9 % (n = 28)
2 % (n = 8)
275
Supraglottic # (n = 2712)
14 % (n = 238)
16 % (n = 300)
25 % (n = 438)
40 % (n = 711)
5 % (n = 92)
933
2592
Supraglottic $ (n = 542)
18 % (n = 61)
16 % (n = 53)
25 % (n = 83)
35 % (n = 116)
6 % (n = 19)
210
Subglottic # (n = 244)
11 % (n = 15)
19 % (n = 25)
32 % (n = 43)
35 % (n = 46)
4 % (n = 5)
110
Subglottic $ (n = 31)
20 % (n = 4)
0 % (n = 0)
32 % (n = 5)
44 % (n = 8)
4 % (n = 1)
13
Overlapping # (n = 1297) Overlapping $ (n = 126)
5 % (n = 38) 7 % (n = 5)
18 % (n = 141) 15 % (n = 10)
32 % (n = 253) 34 % (n = 23)
38 % (n = 299) 37 % (n = 25)
7 % (n = 57) 6 % (n = 4)
509 59
Unspecified# (n = 2340)
15 % (n = 145)
17 % (n = 161)
25 % (n = 238)
28 % (n = 261)
14 % (n = 131)
1404
Unspecified$ (n = 352)
14 % (n = 17)
18 % (n = 21)
30 % (n = 36)
30 % (n = 36)
8 % (n = 10)
232
Larynx # (n = 13,196)
38 % (n = 2877)
18 % (n = 1402)
19 % (n = 1429)
21 % (n = 1605)
4 % (n = 335)
5548
Larynx $ (n = 1652)
34 % (n = 291)
16 % (n = 141)
20 % (n = 176)
24 % (n = 213)
5 % (n = 42)
789
Fig. 2 Age-standardised incidence rate by sex in Germany, 1998–2011
8.00 7.00
per 100,000
6.00 5.00 4.00 3.00 2.00 1.00 0.00 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Men
UICC stage Table 1 depicts the Union for International Cancer Control (UICC) Stages by sublocalisation and gender. Looking at the sublocalisation of laryngeal carcinoma reveals only minor gender differences. The largest gender gap can be found in UICC stages I and II for subglottic carcinoma. For women, 20 % of subglottic cancer cases are diagnosed in UICC stage I. For men, it is only 11 %. Glottic carcinoma is primarily diagnosed in the early UICC stages, particularly in stage I. However, supra- and subglottic carcinoma are in most cases diagnosed in advanced UICC stages. To distinguish whether a T4 carcinoma and/or distant metastases are present at the time of diagnosis, stage IV is divided into stages IVa, IVb and IVc. Stages IVa and IVb represent cases in which locoregional metastases are detected at the time of diagnosis. Patients
Women
diagnosed with stage IVc already have distant metastases at the time of diagnosis. Glottic carcinoma barely presents with distant metastases (1–2 %), whereas subglottic carcinoma presents in 4 %, supraglottic carcinoma presents in 5–6 % and large, transglottic carcinoma accounts for 6–7 % of cases as stage IVc disease. Incidence and mortality The age-standardised incidence rate per 100,000 people is shown in Fig. 2. Gender-specific differences in incidence are obvious. For almost the entire period, the incidence rates for men were seven times higher than those of women. It was not until 2006 that the ratio decreased. The age-standardised incidence rate of female patients tends to remain constant, but the male age-standardised incidence rate decreases.
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Eur Arch Otorhinolaryngol Fig. 3 a, b Ranking of agestandardised incidence rate by sex, 1998–2011
Men
Women
Bremen
Hamburg
Hamburg
Muenster
Meckl-…
Saarland
Muenster Brandenburg Germany
per 100,000
Bremen
per 100,000
Saarland
Schleswig-…
Fig. 4 Age-standardised mortality rates by sex in Germany, 1998–2011
5
Brandenburg Rhineland-… Germany
Rhineland-…
Meckl.-…
Saxony
Saxony
Thuringia 10
Schleswig-…
Thuringia
0
0 0.5 1 1.5
3.50
3.00
per 100.000
2.50
2.00
1.50
1.00
0.50
0.00 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Men
Figure 3a, b show the average values of the age-standardised incidence rates of the included German states from 1998 to 2011 as a ranking. In the male population, the state of Bremen leads the ranking with an incidence of 8.5/100,000, ahead of the states of Saarland, with 8.2, and Hamburg, with 7.6 per 100,000 inhabitants. The lowest incidence can be found in the state of Thuringia, with 5.4/100,000. For women,
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Women
Hamburg is ranked highest, with an age-standardised incidence rate of 1.42/100,000, followed by Bremen, with a rate of 1.06/100,000 and the Region of Muenster, 1.01/ 100,000. The lowest incidence in women can also be found in Thuringia, with a rate of 0.39/100,000. Figure 4 depicts the development of age-standardised mortality rates in women and men. The changes in the mortality rates among women are similar to the
Eur Arch Otorhinolaryngol
development of age-standardised incidence over the same period. For men, the development is different. Mortality rates continuously decline starting in 1998.
Discussion In total, 14,847 case reports of laryngeal carcinoma from 01.01.1998 to 31.12.2011 were analysed using data provided by selected German registries. The development of laryngeal cancer in Germany is presented by showing epidemiological data and tumour parameters.
only 24 % of cases in men. The authors postulate that alcohol consumption, genetic predisposition and a different distribution of HPV status might have an influence on different distributions of sublocalisation in men and women. To investigate the influence of HPV and other possible risk factors on the sublocalisation of laryngeal cancer in Germany, further clinical studies are needed. A recent meta-analysis of 148 studies on HPV in head and neck cancer reported a total of 20 % cases of HPV-positive laryngeal cancer. These findings lead to the conclusion that the effect of HPV on the development of laryngeal cancer is not as large as it is in oropharyngeal cancer. For comparison, 46 % of oropharyngeal cancers have tested positive for HPV [13].
The mean age of onset increases Glottic carcinoma are recognised at early stages In both males and females, the mean age of onset has increased over the years. In 2011, patients diagnosed with laryngeal carcinoma were approximately 2 years older than patients who received a diagnosis in 1998. The reason for this development seems to be the demographic change in and the associated restructure of the population in Germany. Katalinic et al. linked the demographic shift to two factors. The increasing average life expectancy indemnifies the decline in birth. The birth rate decreased from 2.54 in 1955 to 1.45 in 1975 [9, 10]. An increase in mean age at tumour diagnosis was also found in the international literature [11]. It is expected that the mean age of onset will shift continuously in higher decades of life with the progress of demographic change in the coming years. Glottic sublocalisation is the most common laryngeal cancer site According to the literature, glottic laryngeal carcinoma is the most abundant laryngeal cancer in both men and women [4]. In line with the literature, glottic carcinoma in this study in both men and women represents the most common entity. However, there is a gender difference according to the three main entities (glottic, supra- and subglottic carcinoma) and their proportionality. In men, the glottic carcinoma is the most common group, representing 69 % of cases. For women, the proportion of glottic carcinoma accounts for 51 % of cases. In contrast, supraglottic carcinoma comprised 46 % of cases in women but only 28 % of cases in men. Women are more often affected by supraglottic carcinoma than men. The subglottic portion is the same for both sexes, 3 %. This ratio is in line with the retrospective study by Brandstorp-Boesen et al. [12]. The group analysed clinical data gathered from 1616 patients between 1983 and 2010 in Sweden. Supraglottic carcinoma was reported in 46 % of cases in women and
Glottic carcinoma is detected to a large extent in the early stages. It turns out that glottic carcinoma is diagnosed in more than 60 % of cases in the early UICC stage I. In 80 % of cases, there is no metastasis at the time of diagnosis; the tumour is thus restricted to the organ. Supra- and subglottic cancers are diagnosed in more advanced UICC stages. Only 14–20 % of these cancers are diagnosed in UICC stage I. At the time of diagnosis, 66–80 % of patients have advanced UICC stages with or without metastases. A possible explanation might be a difference concerning symptoms and symptom complexes. Patients with glottic carcinoma often feel persistent hoarseness and dyspnoea in the early stages. Due to these symptoms, the tumour is often diagnosed at a doctor’s visit [14, 15]. The complaints triggered by supraglottic and subglottic cancers are more likely noticeable only in more advanced stages. Patients seek medical advice because of tightness, dyspnoea, and/or stridor [16]. Lymphatic drainage also contributes to the described distribution of the UICC stages. In contrast to the supra- and subglottic floors, the glottic floor is barely dotted with lymphatic tissue. Thus, a lymphatic metastasis is less likely [17]. In general, it should be noted that regional or distant metastases are less frequent than hypopharyngeal cancers. Initially, only 25 % of men and 29 % of women are diagnosed with several small or a few large metastases. One possible explanation might be a high proportion of glottic carcinoma, which is detected in an early UICC stage. Stagnant evolution of incidence and mortality The development of incidence and mortality seem to have stagnated in recent years, with stable rates for men (7.1/ 100,000) and women (0.9/100,000). Unlike the female rate,
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the male rate decreased continuously in subsequent years and reached 5.5/100,000, the lowest rate during the entire observation, in 2011. When considering the age-standardised incidence, a convergence of the two sexes since 2006 can be observed. This trend is also evident in other countries, such as the Netherlands, the UK, the USA and the Scandinavian countries (Denmark, Faroe Islands, Finland, Iceland, Norway, Sweden; 18–21). The 30-day prevalence of smoking decreased for both males and females in Germany. Currently, people smoke less than they did 30 years ago [22]. For men, there was a decline in surveyed people in all age groups. For women, an increase in smoking among females could be seen, particularly in the class of 40–59-year-olds. In the UK, the prevalence of men smoking has decreased dramatically since the 1970s. As a result, the incidence of laryngeal cancer decreased since 2000. The smoking behaviour of women has changed to a lesser extent since the 1970s [23]. Within Germany, there are regional differences in the age-standardised incidence rates. Vo¨lzke et al. showed that people living in metropolitan regions such as Hamburg smoke more and more frequently than the inhabitants of rural regions [24]. The development of the mortality rate in Germany is based on the evolution of incidence and is likely also due to the change in the prevalence of major risk factors in Germany. Limitations Only data of state cancer registries were used, providing a completeness of data greater than 80 % since 1998. This requirement was fulfilled by 10 of the 16 state cancer registries at the start of the observation period and covered approximately 30 % of the German population. Another limitation of the study is the high proportion of missing values in the distribution of the UICC stages. However, despite the lack of data from six state cancer registries, the present study is characterised by a large number of cases. Acknowledgments This study used data from the German Centre for Cancer Registry Data. The interpretation and reporting of the data are the sole responsibility of the authors. We thank Nina ButtmannSchweiger and Dr. Klaus Kraywinkel at the German Centre for Cancer Registry Data for their kind assistance regarding data extraction and for providing valuable comments on the manuscript. Compliance with ethical standards Conflict of interest of interest.
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The authors declare that there are no conflicts
References 1. Strutz J, Mann W (2001) Praxis der HNO-Heilkunde, Kopf- und Halschirurgie, 2. Georg Thieme Verlag 2. ICD-10-GM Version 2015 [Internet]. Available from: DMDI Deutsches Institut fu¨r medizinische Information und Dokumentation; 2014. http://www.dimdi.de/static/de/klassi/icd-10-gm/ kodesuche/onlinefassungen/htmlgm2015/block-c30-c39.htm. abgerufen am 29 Sept 2014 3. Boffetta P, Hashibe M (2006) Alcohol and cancer. Lancet Oncol 7(2):149–156 4. Pantel M, Guntinas-Lichius O (2012) Laryngeal carcinoma: epidemiology, risk factors and survival. Hno 60(1):32–40 5. Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP et al (2007) Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 99(10):777–789 6. Altieri A, Garavello W, Bosetti C, Gallus S, La Vecchia C (2005) Alcohol consumption and risk of laryngeal cancer. Oral Oncol 41(10):956–965 7. Maier H, Dietz A, Gewelke U, Heller WD, Weidauer H (1992) Tobacco and alcohol and the risk of head and neck cancer. Clin Investig 70(3–4):320–327 8. Torrente MC, Rodrigo JP, Haigentz M Jr, Dikkers FG, Rinaldo A, Takes RP et al (2011) Human papillomavirus infections in laryngeal cancer. Head Neck 33(4):581–586 9. Pritzkuleit R, Beske F, Katalinic A (2010) Demographic change and cancer. Onkologie 33(Suppl 7):19–24 10. Krebs in Deutschland 2007/2008. 8 Ausgabe. Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg). Berlin, 2012 11. Reizenstein JA, Bergstrom SN, Holmberg L, Linder A, Ekman S, Blomquist E et al (2010) Impact of age at diagnosis on prognosis and treatment in laryngeal cancer. Head Neck 32(8):1062–1068 12. Brandstorp-Boesen J, Falk RS, Boysen M, Brondbo K (2014) Long-term trends in gender, T-stage, subsite and treatment for laryngeal cancer at a single center. Eur Arch Oto-Rhino-Laryngol 271(12):3233–3239 13. Ndiaye C, Mena M, Alemany L, Arbyn M, Castellsague X, Laporte L et al (2014) HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol 15(12):1319–1331 14. Raitiola H, Pukander J (2000) Symptoms of laryngeal carcinoma and their prognostic significance. Acta Oncol 39(2):213–216 15. Hansen O, Larsen S, Bastholt L, Godballe C, Jorgensen KE (2005) Duration of symptoms: impact on outcome of radiotherapy in glottic cancer patients. Int J Radiat Oncol Biol Phys 61(3):789–794 16. Bahar G, Nageris BI, Spitzer T, Popovtzer A, Mharshak G, Feinmesser R (2002) [Subglottic carcinoma]. Harefuah 141(10):914–8, 29 17. Werner JA, Dunne AA, Myers JN (2003) Functional anatomy of the lymphatic drainage system of the upper aerodigestive tract and its role in metastasis of squamous cell carcinoma. Head Neck 25(4):322–332 18. Cancer Research UK [Internet]. London: Laryngeal cancer statistics (2014). http://www.cancerresearchuk.org/cancer-info/ cancerstats/types/larynx/?script=true 19. Netherlands Cancer Registry [Internet]. Laryngeal cancer statistics (2014). http://www.dutchcancerfigures.nl/selecties/Dataset_ 3/img54d89aa75777a
Eur Arch Otorhinolaryngol 20. SEER Cancer Statistics Factsheets: Larynx Cancer. National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/statfacts/ html/laryn.html 21. NORDCAN: Cancer incidence and mortality in the Nordic countries 2014. http://www-dep.iarc.fr/NORDCAN/english/ frame.asp 22. Kraus L, Piontek D (2013) Epidemiologischer Suchtsurvey 2012 [2012 Epidemiological Survey of Substance Abuse]. Sucht 59(6):309–366
23. Office for National Statistics. Smoking and drinking among adults (2005) In: Goddard E (ed) Office of National Statistics, Crown Copyright; 2006 24. Volzke H, Neuhauser H, Moebus S, Baumert J, Berger K, Stang A et al (2006) Urban-rural disparities in smoking behaviour in Germany. BMC public Health 6:146
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LARYNGOLOGY
Epidemiology of laryngeal carcinoma in Germany, 1998–2011 Maximilian Peller1,5 • Alexander Katalinic2 • Barbara Wollenberg3 Ingo U. Teudt4 • Jens-E. Meyer5
•
Received: 31 October 2015 / Accepted: 3 February 2016 Ó Springer-Verlag Berlin Heidelberg 2016
Abstract Constituting 25–30 % of all head and neck cancer cases, laryngeal carcinoma is the most prevalent entity. Major risk factors of laryngeal cancer are smoking and excessive alcohol consumption. This study presents the recent developments in the incidence of laryngeal cancer from 1998 to 2011 in Germany. Laryngeal carcinoma was identified using International Statistical Classification of Diseases and Related Health Problems (ICD10) from German population-based cancer registries. The incidence was provided by the Robert Koch Institute, and the mortality data were derived from German death statistics for further evaluation. Both descriptive and analytical analyses were conducted. From 1998 to 2011, a total of 14,847 laryngeal carcinoma cases were reported, in 13,195 men and 1652 women. Glottic carcinoma represented the main entity, constituting 69 % of male cases and 50 % of female cases. For men, a decline in incidence was observed starting in 2006. The incidence rate for women remained & Maximilian Peller [email protected] 1
Department of Radiology, Asklepios Klinik Altona, Paul-Ehrlich-Straße 1, 22763 Hamburg, Germany
2
Institute of Clinical Epidemiology, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
3
Department of Otolaryngology, Head and Neck Surgery, Medical University of Schlweswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
4
Department of Otolaryngology, Head and Neck Surgery, Asklepios Klinik Altona, Paul-Ehrlich-Straße 1, 22763 Hamburg, Germany
5
Department of Otolaryngology, Head and Neck Surgery, Asklepios Klinik St. Georg, Lohmu¨hlenstraße 5, 20099 Hamburg, Germany
stable for the period of observation. The incidence of laryngeal cancer resembles the development of smoking behaviour in Germany. To maintain the positive trend of the male population and to reduce the incidence in women, it is crucial to continue and to improve the prevention of smoking campaigns in Germany. Keywords Laryngeal cancer Epidemiology Incidence Smoking Development
Introduction Laryngeal carcinoma accounts for 25–30 % of head and neck cancer cases; therefore, it is the most common cancer site of the aero-digestive tract [1]. The larynx is anatomically divided into three levels: the glottic area, the supraglottic area and the subglottic area. In addition to these locations, there is carcinoma of the larynx overlapping at least two sections of the larynx and carcinoma with unspecified locations [2]. Two major risk factors for the development of laryngeal cancer are known, including tobacco use and excessive alcohol consumption [3, 4]. A meta-analysis of 15 case– control studies revealed that long-term smokers had a higher risk (OR 18; 95 % CI 7–47) of developing laryngeal cancer than non-smokers [5]. The odds ratio for heavy alcohol consumption is reported to be lower, and it depends on the amount of alcohol consumption; 25, 50 or 100 g of pure alcohol intake per day is associated with odds ratios of 1.38, 1.94 and 3.95, respectively, compared to non-drinkers [6]. If smoking and heavy drinking coincide, the effect is multiplicative [7]. Recently, the human papilloma virus (HPV) has been known to be a risk factor for the development of head and neck squamous cell cancer. Most
123
Eur Arch Otorhinolaryngol
important are high-risk HPV types 16 and 18. Although HPV-positive carcinoma is more frequently observed in the oropharynx (tonsils and the base of the tongue), a small proportion can also be detected in the larynx. However, HPV as a risk factor for the development of laryngeal cancer seems not to be comparable to high levels of cigarette and alcohol consumption [8]. Today, no valid data concerning the incidence and mortality of laryngeal cancer for the last two decades in Germany are available. The aim of this study is to evaluate the incidence and mortality of laryngeal cancer from 1998 to 2011 in Germany and to highlight trends in cancer development for further evaluation. The results are compared to the available national and international literature, identifying differences and similarities concerning the development of the incidence of laryngeal cancer.
Cases in which the registries noted the laryngeal carcinoma by death certificate are excluded from further investigation because the date of diagnosis and the date of death are the same and therefore are not usable for survival analyses. Statistics Statistical evaluation is performed using the statistical program SPSS Version 22.0 for Mac (IBM, New York, USA). The data are further processed using Excel 2011 (Microsoft, Washington, USA). All age-standardised incidence and mortality rates (old European standard population) are calculated using the program CARESS (OFFIS, Oldenburg, Germany).
Results
Data collection With the introduction of the federal cancer registry law in 1995, every federal state is obliged to establish populationbased cancer registries. The majority of registries in Germany, however, started to register continuously around the year 2000, and nationwide coverage was reached in 2009. The German Centre for Cancer Registry Data (ZfKD), Berlin, Germany is responsible for pooling the data of cancer epidemiology collected by all federal cancer registries in Germany. Additionally, the ZfkD has to verify the plausibility and completeness of the data every year. The set of data on laryngeal cancer from 1998 to 2011 has been transmitted for further evaluation. Covered epidemiological data The transmitted, anonymous data contain epidemiologic information such as gender, birth year, the state of residency and that of the incident case, disclosures on ICD 10 Code (C32.0, C32.1, C32.2, C32.8, C32.9), the year and month of diagnosis, the method of assuring the diagnosis (e.g., histological, clinical) and the TNM stage (5th, 6th and 7th edition). Moreover, in the case of death, information on the month and year of death is provided. Mortality data are provided by The Federal Statistical Office, Wiesbaden, Hessen (Destatis). For the analyses performed in this article, data from ten German registries covering approximately 30 % of the German population are included. A time bar on incidence and mortality from 1998 to 2011 is established.
123
From 1998 to 2011, a total of 14,847 cases of laryngeal carcinoma were reported, 13,195 in men and 1652 in women. Age of the patient collective and sublocalisation The mean age of laryngeal cancer diagnosis increased both in males and females. Thus, the mean age of onset in 1998 for both men and women was 62 years. In 2011, the average age was 64 years in men and 65 years in women. Figure 1 shows the distribution of the absolute number of laryngeal carcinomas by sublocalisation and gender. In men, the glottic carcinoma represented the largest group, with 50 % of cases. The supraglottic and subglottic groups represented 21 and 2 %, respectively. The carcinomas that exceeded several laryngeal sections added up to 10 %, and those that were unspecified accounted for 18 % of all cases. In women, glottic carcinoma accounted for 36 % of cases, and supraglottic carcinoma accounted for 33 %. Subglottic carcinoma represented the lowest proportion with 2 %. Transglottic laryngeal carcinoma and unspecified carcinoma accounted for 8 and 21 %, respectively.
Total cases
Materials and methods
7000 6000 5000 4000 3000 2000 1000 0
Fig. 1 Distribution of localisation of laryngeal cancer
Men Women
Eur Arch Otorhinolaryngol Table 1 Summary of study patient characteristics by Union for International Cancer Control (UICC)—stage and by sublocalisation Localisation
UICC stages I
II
III
IVA ? B
IVC
Missing (n)
Glottic # (n = 6603)
61 % (n = 2241)
19 % (n = 775)
11 % (n = 457)
7 % (n = 288)
1 % (n = 50)
Glottic $ (n = 601)
63 % (n = 204)
17 % (n = 57)
9 % (n = 29)
9 % (n = 28)
2 % (n = 8)
275
Supraglottic # (n = 2712)
14 % (n = 238)
16 % (n = 300)
25 % (n = 438)
40 % (n = 711)
5 % (n = 92)
933
2592
Supraglottic $ (n = 542)
18 % (n = 61)
16 % (n = 53)
25 % (n = 83)
35 % (n = 116)
6 % (n = 19)
210
Subglottic # (n = 244)
11 % (n = 15)
19 % (n = 25)
32 % (n = 43)
35 % (n = 46)
4 % (n = 5)
110
Subglottic $ (n = 31)
20 % (n = 4)
0 % (n = 0)
32 % (n = 5)
44 % (n = 8)
4 % (n = 1)
13
Overlapping # (n = 1297) Overlapping $ (n = 126)
5 % (n = 38) 7 % (n = 5)
18 % (n = 141) 15 % (n = 10)
32 % (n = 253) 34 % (n = 23)
38 % (n = 299) 37 % (n = 25)
7 % (n = 57) 6 % (n = 4)
509 59
Unspecified# (n = 2340)
15 % (n = 145)
17 % (n = 161)
25 % (n = 238)
28 % (n = 261)
14 % (n = 131)
1404
Unspecified$ (n = 352)
14 % (n = 17)
18 % (n = 21)
30 % (n = 36)
30 % (n = 36)
8 % (n = 10)
232
Larynx # (n = 13,196)
38 % (n = 2877)
18 % (n = 1402)
19 % (n = 1429)
21 % (n = 1605)
4 % (n = 335)
5548
Larynx $ (n = 1652)
34 % (n = 291)
16 % (n = 141)
20 % (n = 176)
24 % (n = 213)
5 % (n = 42)
789
Fig. 2 Age-standardised incidence rate by sex in Germany, 1998–2011
8.00 7.00
per 100,000
6.00 5.00 4.00 3.00 2.00 1.00 0.00 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Men
UICC stage Table 1 depicts the Union for International Cancer Control (UICC) Stages by sublocalisation and gender. Looking at the sublocalisation of laryngeal carcinoma reveals only minor gender differences. The largest gender gap can be found in UICC stages I and II for subglottic carcinoma. For women, 20 % of subglottic cancer cases are diagnosed in UICC stage I. For men, it is only 11 %. Glottic carcinoma is primarily diagnosed in the early UICC stages, particularly in stage I. However, supra- and subglottic carcinoma are in most cases diagnosed in advanced UICC stages. To distinguish whether a T4 carcinoma and/or distant metastases are present at the time of diagnosis, stage IV is divided into stages IVa, IVb and IVc. Stages IVa and IVb represent cases in which locoregional metastases are detected at the time of diagnosis. Patients
Women
diagnosed with stage IVc already have distant metastases at the time of diagnosis. Glottic carcinoma barely presents with distant metastases (1–2 %), whereas subglottic carcinoma presents in 4 %, supraglottic carcinoma presents in 5–6 % and large, transglottic carcinoma accounts for 6–7 % of cases as stage IVc disease. Incidence and mortality The age-standardised incidence rate per 100,000 people is shown in Fig. 2. Gender-specific differences in incidence are obvious. For almost the entire period, the incidence rates for men were seven times higher than those of women. It was not until 2006 that the ratio decreased. The age-standardised incidence rate of female patients tends to remain constant, but the male age-standardised incidence rate decreases.
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Eur Arch Otorhinolaryngol Fig. 3 a, b Ranking of agestandardised incidence rate by sex, 1998–2011
Men
Women
Bremen
Hamburg
Hamburg
Muenster
Meckl-…
Saarland
Muenster Brandenburg Germany
per 100,000
Bremen
per 100,000
Saarland
Schleswig-…
Fig. 4 Age-standardised mortality rates by sex in Germany, 1998–2011
5
Brandenburg Rhineland-… Germany
Rhineland-…
Meckl.-…
Saxony
Saxony
Thuringia 10
Schleswig-…
Thuringia
0
0 0.5 1 1.5
3.50
3.00
per 100.000
2.50
2.00
1.50
1.00
0.50
0.00 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 Men
Figure 3a, b show the average values of the age-standardised incidence rates of the included German states from 1998 to 2011 as a ranking. In the male population, the state of Bremen leads the ranking with an incidence of 8.5/100,000, ahead of the states of Saarland, with 8.2, and Hamburg, with 7.6 per 100,000 inhabitants. The lowest incidence can be found in the state of Thuringia, with 5.4/100,000. For women,
123
Women
Hamburg is ranked highest, with an age-standardised incidence rate of 1.42/100,000, followed by Bremen, with a rate of 1.06/100,000 and the Region of Muenster, 1.01/ 100,000. The lowest incidence in women can also be found in Thuringia, with a rate of 0.39/100,000. Figure 4 depicts the development of age-standardised mortality rates in women and men. The changes in the mortality rates among women are similar to the
Eur Arch Otorhinolaryngol
development of age-standardised incidence over the same period. For men, the development is different. Mortality rates continuously decline starting in 1998.
Discussion In total, 14,847 case reports of laryngeal carcinoma from 01.01.1998 to 31.12.2011 were analysed using data provided by selected German registries. The development of laryngeal cancer in Germany is presented by showing epidemiological data and tumour parameters.
only 24 % of cases in men. The authors postulate that alcohol consumption, genetic predisposition and a different distribution of HPV status might have an influence on different distributions of sublocalisation in men and women. To investigate the influence of HPV and other possible risk factors on the sublocalisation of laryngeal cancer in Germany, further clinical studies are needed. A recent meta-analysis of 148 studies on HPV in head and neck cancer reported a total of 20 % cases of HPV-positive laryngeal cancer. These findings lead to the conclusion that the effect of HPV on the development of laryngeal cancer is not as large as it is in oropharyngeal cancer. For comparison, 46 % of oropharyngeal cancers have tested positive for HPV [13].
The mean age of onset increases Glottic carcinoma are recognised at early stages In both males and females, the mean age of onset has increased over the years. In 2011, patients diagnosed with laryngeal carcinoma were approximately 2 years older than patients who received a diagnosis in 1998. The reason for this development seems to be the demographic change in and the associated restructure of the population in Germany. Katalinic et al. linked the demographic shift to two factors. The increasing average life expectancy indemnifies the decline in birth. The birth rate decreased from 2.54 in 1955 to 1.45 in 1975 [9, 10]. An increase in mean age at tumour diagnosis was also found in the international literature [11]. It is expected that the mean age of onset will shift continuously in higher decades of life with the progress of demographic change in the coming years. Glottic sublocalisation is the most common laryngeal cancer site According to the literature, glottic laryngeal carcinoma is the most abundant laryngeal cancer in both men and women [4]. In line with the literature, glottic carcinoma in this study in both men and women represents the most common entity. However, there is a gender difference according to the three main entities (glottic, supra- and subglottic carcinoma) and their proportionality. In men, the glottic carcinoma is the most common group, representing 69 % of cases. For women, the proportion of glottic carcinoma accounts for 51 % of cases. In contrast, supraglottic carcinoma comprised 46 % of cases in women but only 28 % of cases in men. Women are more often affected by supraglottic carcinoma than men. The subglottic portion is the same for both sexes, 3 %. This ratio is in line with the retrospective study by Brandstorp-Boesen et al. [12]. The group analysed clinical data gathered from 1616 patients between 1983 and 2010 in Sweden. Supraglottic carcinoma was reported in 46 % of cases in women and
Glottic carcinoma is detected to a large extent in the early stages. It turns out that glottic carcinoma is diagnosed in more than 60 % of cases in the early UICC stage I. In 80 % of cases, there is no metastasis at the time of diagnosis; the tumour is thus restricted to the organ. Supra- and subglottic cancers are diagnosed in more advanced UICC stages. Only 14–20 % of these cancers are diagnosed in UICC stage I. At the time of diagnosis, 66–80 % of patients have advanced UICC stages with or without metastases. A possible explanation might be a difference concerning symptoms and symptom complexes. Patients with glottic carcinoma often feel persistent hoarseness and dyspnoea in the early stages. Due to these symptoms, the tumour is often diagnosed at a doctor’s visit [14, 15]. The complaints triggered by supraglottic and subglottic cancers are more likely noticeable only in more advanced stages. Patients seek medical advice because of tightness, dyspnoea, and/or stridor [16]. Lymphatic drainage also contributes to the described distribution of the UICC stages. In contrast to the supra- and subglottic floors, the glottic floor is barely dotted with lymphatic tissue. Thus, a lymphatic metastasis is less likely [17]. In general, it should be noted that regional or distant metastases are less frequent than hypopharyngeal cancers. Initially, only 25 % of men and 29 % of women are diagnosed with several small or a few large metastases. One possible explanation might be a high proportion of glottic carcinoma, which is detected in an early UICC stage. Stagnant evolution of incidence and mortality The development of incidence and mortality seem to have stagnated in recent years, with stable rates for men (7.1/ 100,000) and women (0.9/100,000). Unlike the female rate,
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the male rate decreased continuously in subsequent years and reached 5.5/100,000, the lowest rate during the entire observation, in 2011. When considering the age-standardised incidence, a convergence of the two sexes since 2006 can be observed. This trend is also evident in other countries, such as the Netherlands, the UK, the USA and the Scandinavian countries (Denmark, Faroe Islands, Finland, Iceland, Norway, Sweden; 18–21). The 30-day prevalence of smoking decreased for both males and females in Germany. Currently, people smoke less than they did 30 years ago [22]. For men, there was a decline in surveyed people in all age groups. For women, an increase in smoking among females could be seen, particularly in the class of 40–59-year-olds. In the UK, the prevalence of men smoking has decreased dramatically since the 1970s. As a result, the incidence of laryngeal cancer decreased since 2000. The smoking behaviour of women has changed to a lesser extent since the 1970s [23]. Within Germany, there are regional differences in the age-standardised incidence rates. Vo¨lzke et al. showed that people living in metropolitan regions such as Hamburg smoke more and more frequently than the inhabitants of rural regions [24]. The development of the mortality rate in Germany is based on the evolution of incidence and is likely also due to the change in the prevalence of major risk factors in Germany. Limitations Only data of state cancer registries were used, providing a completeness of data greater than 80 % since 1998. This requirement was fulfilled by 10 of the 16 state cancer registries at the start of the observation period and covered approximately 30 % of the German population. Another limitation of the study is the high proportion of missing values in the distribution of the UICC stages. However, despite the lack of data from six state cancer registries, the present study is characterised by a large number of cases. Acknowledgments This study used data from the German Centre for Cancer Registry Data. The interpretation and reporting of the data are the sole responsibility of the authors. We thank Nina ButtmannSchweiger and Dr. Klaus Kraywinkel at the German Centre for Cancer Registry Data for their kind assistance regarding data extraction and for providing valuable comments on the manuscript. Compliance with ethical standards Conflict of interest of interest.
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The authors declare that there are no conflicts
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