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Differential survival trends for patients with tonsillar, base of tongue and tongue cancer in Sweden
Oral Oncology 47 (2011) 636–641
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Differential survival trends for patients with tonsillar, base of tongue and tongue cancer in Sweden Lalle Hammarstedt a,⇑, Yunxia Lu b, Linda Marklund a, Tina Dalianis c,d, Eva Munck-Wikland a, Weimin Ye b a
Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Karolinska University Hospital, Sweden Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden c Department of Oncology–Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden d Swedish Institute for Infectious Disease Control, Stockholm, Sweden b
a r t i c l e
i n f o
Article history: Received 10 November 2010 Received in revised form 18 April 2011 Accepted 19 April 2011 Available online 17 May 2011 Keywords: Tonsillar cancer Base of tongue cancer Tongue cancer Prognosis Relative survival rate
s u m m a r y Tonsillar, base of tongue and tongue cancer have similar anatomical and histopathological appearances but present differences in prognosis. Human papillomavirus (HPV) is a known risk factor for tonsillar and base of tongue cancer, and a survival benefit has been shown for these tumors; however, HPV prevalence in tongue cancer is low. Tonsillar, base of tongue and tongue cancer patients registered in the Swedish Cancer Registry between 1960 and 2004 were followed from the date of cancer diagnosis until death, emigration out of Sweden, or the end of a follow-up (5 years since cancer diagnosis), whichever occurred first. The relative survival rate was computed as the ratio of the observed to the expected survival rate, in which the latter was inferred from the survival of the entire Swedish population in the same age, sex and calendar year stratum. The relative survival rate has improved significantly over time for patients with tonsillar and base of tongue cancer although delineated by different patterns. However, the relative survival rate in tongue cancer patients exhibited only a very modest improvement during the same time period. Contrary to the overall improved survival for patients with tonsillar and base of tongue cancer, the patients with tongue cancer show a very modest improvement in Sweden since 1960. Further studies are warranted to elucidate more effective treatment options for tongue cancer patients. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction In Sweden, the incidence of tonsillar and base of tongue cancer has increased significantly over the last 30–40 years, while both the prevalence of known risk factors, such as smoking and heavy alcohol consumption, and the incidence of other smoking-related cancers have decreased.1,2 Human papillomavirus (HPV) has been hypothesized to be involved in the carcinogenesis of oropharyngeal cancer, and accumulating molecular and epidemiological data now show that high-risk types of HPV are responsible for a subset of oropharyngeal cancer.3–5 Based on these findings, the International Agency for Research on Cancer (IARC) now recognizes HPV as a risk factor for oropharyngeal cancer. HPV occurs in 45–93%6,7 of studied tonsillar cancer cases, and the prevalence of HPV in tonsillar cancer has increased significantly over the last decades. In fact, HPV is hypothesized to be responsible for a threefold increase observed ⇑ Corresponding author. Address: Department of Oto-Rhino-Laryngology, Karolinska University Hospital, S-171 76 Stockholm, Sweden. Tel.: +46 709 602549; fax: +46 8 51776267. E-mail address: [email protected] (L. Hammarstedt). 1368-8375/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2011.04.012
both in the incidence and proportion of HPV-positive tonsillar cancer in Sweden over the last few decades.7,8 Base of tongue cancer is the second most common oropharyngeal cancer in Sweden,9 and although base of tongue cancer resembles tonsillar cancer histopathologically, previous studies have shown that its prognosis is worse.10–12 Our group and others have shown that the prognosis for patients with HPV-positive tonsillar and base of tongue cancer is better than for patients with HPV-negative tumors, which is independent of nodal status, age, stage, tumor differentiation or gender.5,13–16 Cancer in the oral tongue is usually associated with poor prognosis. Using the SEER database, Rusthoven and colleagues17 found that the survival for this tumor group has not improved between 1988 and 2004, although some conflicting results have been reported.18,19 In contrast to tonsillar cancer, HPV prevalence in oral tongue tumors is still low, and no distinct correlation between HPV prevalence and the prognosis of tongue cancer patients has been observed.20,21 Hakulinen and colleagues assessed the changes of survival and incidence in oral and oropharyngeal cancers in the Nordic countries. However, they analyzed the trends for tongue and base of tongue cancer together and included nasopharynx and hypopharynx in the oropharyngeal group.22
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Chaturvedi and colleagues showed an improved survival in potentially HPV-positive oral squamous cell carcinomas in comparison to potentially negative carcinomas in a large cohort.23 To what extent the results of this study by Chaturvedi can be extrapolated to the Swedish population is yet unknown. In order to explore the survival trends of these cancer types, we used data from the Swedish Cancer Registry to assess the changes in the relative survival over time. Material and methods The Swedish Cancer Registry was established in 1958, and physicians throughout Sweden have been reporting all cancer cases to the registry. Because both clinicians and pathologists/cytologists report cancer cases based on biopsies, fine needle aspiration or surgically resected tissue, many cases have been verified twice. The Swedish Cancer Registry has been estimated to be 98% complete from 1960 onwards but not during its first two years (1958 and 1959).24,25 The registry has used the 7th version of the International Classification of Diseases (ICD-7) as its coding scheme during the entire study period. Data available in the registry include the following: a 10-digit personal registration number assigned to all Swedish residents, gender, date of diagnosis, age at diagnosis, basis of diagnosis, index for cancer found incidentally in autopsy, index for first or secondary cancers and pathology code. To avoid the effect due to the occurrence of other cancers on survival rates, we only included primary tonsillar cancer or tongue cancer, i.e., data on patients without any previously diagnosed cancer in the Cancer Registry. The inclusion criteria were the following: ICD-7 code 145.0 for tonsillar cancer, ICD-7 code 141 for tongue cancer and the pathology codes 146 and 196 for squamous cell carcinoma and undifferentiated carcinoma, respectively. The code 141.0 represents base of tongue cancer. The vital status of the cases was determined by linkage to the nationwide Swedish Causes of Death Registry, and any emigration out of Sweden was assessed by linkage to the nationwide Swedish Emigration Registry.
Statistical analyses For the nationwide cohort, to explore any secular trend of survival rates, patients were grouped by calendar period of diagnosis into five groups: 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000–2004. Patients were followed up from the date of cancer diagnosis until death, emigration out of Sweden, or at the end of a follow-up (5 years since cancer diagnosis), whichever occurred first. The observed survival rate for each group was estimated using the life-table method.26 The relative survival rate was computed as the ratio of the observed to the expected survival rate, in which the latter was inferred from the survival of the entire Swedish population in the same age, sex and calendar year stratum. The age-standardized relative survival rate27 was also estimated using age distribution (<50, 50–59, 60–69, and P70) at cancer diagnosis among all patients. To investigate independent effects of patient characteristics along with the calendar period, we also fit genderspecific Poisson regression models for excess mortality adjusting for follow-up time, period of diagnosis and age at diagnosis.28 This model was estimated in the framework of generalized linear models assuming a Poisson distribution for the observed number of deaths. Results A total of 2303 cases were diagnosed with tonsillar cancer between 1960 and 2004. After excluding 36 invalid cases, 2267 remained in the final cohort of tonsillar cancer patients. For base of tongue cancer, a cohort of 857 cases was initially identified. After excluding 82 cases with histopathology other than squamous cell carcinoma or undifferentiated carcinoma and 3 invalid cases, 772 remained in the final cohort of base of tongue cancer patients. Similarly, we excluded 119 cases with histopathology other than squamous cell carcinoma or undifferentiated cancer from the initially identified 3286 tongue cancer patients. We further excluded 26 invalid cases, leaving 3141 patients in the final tongue cancer cohort.
Table 1 Observed and relative 5-year survival for patients with tonsillar, base of tongue and tongue cancer, stratified by period and sex. Men Period of diagnosis
No. of patients
Tonsillar cancer 1960–1969 180 1970–1979 225 1980–1989 319 1990–1999 495 2000–2004 390 P value for trend Base of tongue cancer 1960–1969 45 1970–1979 113 1980–1989 136 1990–1999 147 2000–2004 135 P value for trend Tongue cancer 1960–1969 250 1970–1979 338 1980–1989 421 1990–1999 479 2000–2004 247 P value for trend
Women Mean age
Crude observed survival (%)
Age-standardized relative survival (%)
No. of mean
Patients age
Crude observed survival (%)
Age-standardized relative survival (%)
62.9 63.1 62.6 59.9 58.8
26.8 (20.6–33.5) 23.7 (18.3–29.4) 29.9 (24.9–35.0) 49.3 (44.8–53.6) 61.5 (56.5–66.2) p = 0.02
32.9 (19.2–49.6) 29.1 (16.8–43.0) 36.7 (25.1–48.3) 51.1 (41.8–60.1) 62.0 (51.1–71.7) p = 0.03
59 100 151 212 136
63.8 65.5 61.9 61.7 58.5
36.8 (24.7–48.9) 43.0 (33.2–52.4) 45.7 (37.6–53.4) 55.7 (48.7–62.1) 61.8 (53.1–69.3) p < 0.01
42.9 (17.1–65.4) 54.8 (30.7–72.1) 49.5 (32.9–64.2) 60.7 (45.9–72.9) 60.8 (40.5–73.5) p = 0.06
67.4 64.6 63.5 61.6 61.6
20.0 (9.9–32.7) 15.2 (9.3–22.4) 28.7 (21.3–36.4) 39.3 (31.4–47.1) 50.4 (41.7–58.4) p = 0.02
22.2 (10.3–50.5) 18.8 (6.1–36.7) 32.0 (16.5–49.5) 41.1 (24.7–57.5) 51.3 (32.7–67.8) p = 0.01
14 28 49 58 47
66.4 71.8 66.1 63.4 63.3
28.6 (8.8–52.4) 39.3 (21.7–56.5) 28.6 (16.8–41.5) 55.2 (41.6–66.9) 50.5 (35.5–63.8) p = 0.13
26.2 (14.1–70.0) 45.0 (32.5–71.4) 33.2 (9.0–60.2) 58.3 (29.8–77.7) 52.5 (22.1–76.2) p = 0.12
63.9 64.0 61.9 62.3 60.9
32.8 (27.1–38.7) 37.1 (32.0–42.2) 38.0 (33.4–42.7) 41.0 (36.6–45.4) 42.2 (35.9–48.2) p < 0.01
39.3 (25.7–53.2) 45.5 (32.7–58.1) 42.1 (31.7–52.7) 44.5 (34.8–54.1) 43.9 (30.8–56.7) p = 0.36
249 284 323 342 208
69.3 70.8 69.5 66.9 66.3
37.7 (31.6–43.7) 41.3 (35.6–47.0) 38.1 (32.8–43.4) 45.8 (40.5–51.0) 52.4 (45.4–58.9) p = 0.05
48.3 (33.0–62.1) 56.3 (41.3–68.3) 49.0 (35.8–61.1) 54.6 (42.5–65.2) 60.4 (44.4–73.6) p = 0.19
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Fig. 1a The age-standardized relative survival of tonsillar cancer diagnosed in Sweden during 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000–2004.
There was a strong male predominance (71%) in the tonsillar cancer group. The mean age at diagnosis in the male tonsillar cancer group was stable during the first three decades (62.6– 63.1 years) but decreased to around 59 years in the periods 1990–99 and 2000–2004. The trend was similar for women (Table 1). Among male tonsillar cancer patients, the 5 year agestandardized relative survival rate was 32.9% in 1960–1969, 29.1% in 1970–1979, 36.7% in 1980–1989, 51.1% in 1990–1999 and 62.0% in 2000–2004 (Table 1, Fig. 1a). The relative survival rates did not differ significantly in the first three decades. However, there was a significant improvement in prognosis for patients diagnosed since 1990 (Table 2). Compared to men, women had an overall better survival rate (observed 5 year survival rate, 51.0% vs. 42.3%). The improved prognosis among women had been observed
as early as the decade 1970–1979, and further improvement occurred during the last two decades (Table 2). Similarly, there was also a strong male predominance (75%) in the base of tongue cancer group, and the mean age at diagnosis was initially 67.4 years and decreased to 61.6 years during the last two decades. For women, a similar trend was observed: the mean age at diagnosis decreased from 66.4 years in the 1960s to 63.3 years in the period 2000–2004 (Table 1). The age-standardized relative survival rate increased from 22.2% in 1960–1969 to 51.3% in 2000–2004 for men. For women, the age-standardized relative survival increased from 26.2% in 1960–1969 to 52.5% in 2000–2004 (Table 1, Fig. 1b). The survival trend mimics the changes observed in tonsillar cancer for men with a gradually improved survival over time. For women, however, there was no
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L. Hammarstedt et al. / Oral Oncology 47 (2011) 636–641 Table 2 The relative hazards of mortality by diagnosis and gender during the first 5 years after diagnosis.a Variables
a
Relative hazards of mortality (95% CI) tonsillar cancer
Period of diagnosis
Men
1960–1969 1970–1979 1980–1989 1990–1999 2000–2004 P value for trend Age at diagnosis <50 50–59 60–69 P70 P value for trend
1.00 1.25 0.99 0.58 0.39 P < 0.01
Reference 0.97–1.60 0.78–1.26 0.46–0.73 0.30–0.51
1.00 0.57 0.61 0.44 0.49 P < 0.01
Reference 0.36–0.91 0.40–0.93 0.29–0.67 0.30–0.74
1.00 1.84 2.75 3.27 P < 0.01
Reference 1.40–2.40 2.13–3.57 2.48–4.31
1.00 1.62 2.71 5.39 P < 0.01
Reference 1.01–2.58 1.74–4.21 3.52–8.27
Variables
Relative hazards of mortality (95% CI) base of tongue cancer
Period of diagnosis 1960–1969 1970–1979 1980–1989 1990–1999 2000–2004 P value for trend Age at diagnosis <50 50–59 60–69 P70 P value for trend
Men 1.00 1.11 0.84 0.70 0.41 P < 0.01 1.00 1.85 2.13 2.75 P < 0.01
Variables
Relative hazards of mortality (95% CI) tongue cancer
Period of diagnosis 1960–1969 1970–1979 1980–1989 1990–1999 2000–2004 P value for trend Age at diagnosis <50 50–59 60–69 P70 P value for trend
Men 1.00 0.89 0.90 0.77 0.86 P = 0.09 1.00 1.54 1.70 2.61 P < 0.01
Women
Reference 0.72–1.69 0.55–1.29 0.45–1.08 0.26–0.64
Reference 1.21–2.84 1.42–3.18 1.83–4.13
Reference 0.71–1.12 0.72–1.12 0.64–0.99 0.67–1.10
Reference 1.22–1.96 1.36–2.14 2.09–3.27
Women 1.00 0.53 1.00 0.51 0.51 P = 0.13 1.00 1.81 2.69 4.57 P < 0.01
Women 1.00 0.85 0.93 0.85 0.70 P = 0.04 1.00 1.23 1.52 2.84 P < 0.01
Reference 0.21–1.31 0.45–2.20 0.22–1.19 0.22–1.19
Reference 0.70–4.69 1.06–6.82 1.90–10.99
Reference 0.65–1.11 0.72–1.20 0.66–1.10 0.52–0.94
Reference 0.85–1.78 1.09–2.11 2.12–3.80
The multivariable regression models included all variables listed in the table.
improvement seen in the last decade as compared to the 1990s, and this result was similar to the observed pattern for female tonsillar cancer patients. For the tongue cancer group, there were similar trends in gender and age to the tonsillar cancer patient group, with the exception of women being approximately 5 years older than men at diagnosis (Table 1). Regarding male tongue cancer patients, the age-standardized relative survival was 39.3% in 1960–1969, 45.5% in 1970–1979, 42.1% in 1980–1989, 44.5% in 1990–1999 and 43.9% in 2000–2004. Women had a more dramatic difference as compared to men: the age-standardized relative survival increased from 48.3% in 1960–1969 to 60.1% in 2000–2004 (Table 1, Fig. 1c). The relative hazard of mortality for male tongue cancer patients did not improve significantly (2000–2004 vs. 1960–69, HR = 0.86, 95% CI 0.67–1.10). For women, there was a slight improvement over time, particularly in the last period (2000– 2004 vs. 1960–1969, HR = 0.70, 95% CI 0.52–0.94) (Table 2).
Discussion This study reveals an overall improved survival in patients with tonsillar and base of tongue cancer in Sweden during the last decades, which is especially notable after the 1980s for men. In con-
trast, the relative survival rates in tongue cancer patients, particularly among men, showed a modest improvement with a borderline significance. We hypothesize that the reason for this improved survival is due to an increase in the proportion of HPV-positive tumors in the tonsillar and base of tongue cancer groups in Sweden. In general, many studies on tonsillar cancer and oropharyngeal cancer have explored HPV infection as a prognostic factor, and the majority have found that HPV is a favorable prognostic factor.5,6,14–16,29 Thus, the improved survival seen in patients with tonsillar and base of tongue cancer could be explained by an increased occurrence of HPV among recently diagnosed cases. In contrast, HPV prevalence in oral tongue cancer is low, if present at all,20,21,30 and survival among these HPV-negative cancers has only improved with borderline significance. In addition, the role of HPV in nonoropharyngeal tumors is still contradictory, and so far, the reported studies suggest no difference or even worse survival among patients with other HPV-positive head and neck tumors, indicating that HPV plays a more limited role outside the oropharynx.31,32 Because tumor stage is a major determinant in outcome of cancer, diagnosis at an earlier stage could explain the improved survival for patients with tonsillar and base of tongue cancer, and this issue should be scrutinized. Indeed, tonsillar, base of tongue and tongue cancer are in close proximity to one another anatomi-
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Fig. 1c The age-standardized relative survival of tongue cancer diagnosed in Sweden during 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000–2004. Fig. 1b The age-standardized relative survival of base of tongue cancer diagnosed in Sweden during 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000– 2004⁄. ⁄The sixties and seventies in women and the sixties in men is not presented due to small number of patients.
cally, and there is no reason to assume that the distribution of tumor stage at diagnosis for tongue cancer is different from that of the other two cancer types. However, there are studies indicating that HPV-positive tumors, i.e., the majority of the newly diagnosed cases of tonsillar cancer in the Stockholm area, have a higher stage at diagnosis.5,7,13–16 Thus, diagnosis at an earlier stage is not an additional reason for the improved clinical outcome in patients with tonsillar and base of tongue cancer. The age-standardized incidence for oral tongue cancer has remained almost unchanged since the 1960s, and only an increase among young patients has been noted.33,34 It is unlikely that HPV infection is responsible for the increase of this tumor noted among young patients.21 During the last few decades, new diagnostic techniques and advantages in the therapeutic field have been developed which could account for the improved survival of patients with tonsillar and base of tongue cancer. Since the 1960s, advances such as more intense and targeted radiotherapy, new oncologic agents, and modifications of surgical techniques, have been made in the therapeutic field. However, these technologies could sensitize both HPV-positive tonsillar and base of tongue cancer, which account for the majority of these tumors, to the new therapy modules as compared to oral tongue cancer. Hakulinen recently showed improved survival for tongue cancer patients but included base of tongue cancer patients,22 which could explain the differences seen in both survival and incidence.
The present study found a rapid increase in relative survival rates for both tonsillar and base of tongue but not for tongue cancer. Further, in the Hakulinen’s study, tonsillar cancer was grouped into cancer of the oropharynx, nasopharynx and hypopharynx which made direct comparison between the two studies impossible. The Chaturvedi study compared patients with potentially HPVrelated cancers to those HPV-unrelated and found an increased survival and incidence for HPV-related cancer patients. These data were analyzed from the SEER database and are not directly applicable to the Swedish population. Another difference of the present study from the Chaturvedi study is the analysis of HPV-related sites. Our present study analyzed tonsillar and base of tongue cancer separately whereas the Chaturvedi study analyzed base of tongue, oropharyngeal and tonsillar cancers together.23 The strengths of our study include the following: the nationwide setting, which includes all tonsillar, base of tongue and tongue cancer patients diagnosed in Sweden from 1960 to 2004, the completeness of follow-up, and the precision due to the large number of cases. Furthermore, to avoid the influence of other cancers on survival, we excluded patients with any other cancer diagnosed prior to the diagnosis of tonsillar, base of tongue, or tongue cancer. One limitation of our study is that although the Cancer Registry was started in 1958, and efforts have been made to record the order of primary cancers, we could not exclude the possibility that a few second or later primary cancers might have been misclassified as a first primary cancer. This error should primarily affect patients in the early 1960s, but the influence should be negligible. Another limitation of our study is that we could not collect any data about patients’ tumor stage, treatment, and HPV prevalence; therefore,
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we could not further elucidate the reasons for the differential secular trend of survival rate. In conclusion, we found an overall improved survival for patients with tonsillar and base of tongue cancer, but a very modest improvement in survival of tongue cancer patients during the last decades in Sweden. Further studies are needed to unveil the underlying mechanisms for this differential trend of survival. There is a clear difference in survival development between potentially HPV-related tumors and HPV-unrelated tumors. This study reveals a need for identifying predictive markers to select tongue cancer patients for more aggressive treatment. Conflict of interest statement None declared. Acknowledgment Grant sponsor: The Stockholm Cancer Society, The Laryngeal Foundation, Karolinska Institutet, Stockholm, Sweden. References 1. Hammarstedt L, Dahlstrand H, Lindquist D, Onelov L, Ryott M, Luo J, et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 2007;127(9):988–92. 2. Attner P, Du J, Nasman A, Hammarstedt L, Ramqvist T, Lindholm J, et al. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int J Cancer 2010;126(12):2879–84. 3. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Casecontrol study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356(19):1944–56. 4. Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001;344(15):1125–31. 5. Lindquist D, Romanitan M, Hammarstedt L, Nasman A, Dahlstrand H, Lindholm J, et al. Human papillomavirus is a favourable prognostic factor and its oncogenic role is supported by the expression by E6 and E7. Mol Oncol 2007;1(3):350–5. 6. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006;24(17):2606–11. 7. Nasman A, Attner P, Hammarstedt L, Du J, Eriksson M, Giraud G, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125(2):362–6. 8. Hammarstedt L, Lindquist D, Dahlstrand H, Romanitan M, Dahlgren LO, Joneberg J, et al. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer 2006;119(11):2620–3. 9. Cancer incidence in Sweden 2008: The National Board of Health and Welfare; 2008. 10. Pedruzzi PA, Kowalski LP, Nishimoto IN, Oliveira BV, Tironi F, Ramos GH. Analysis of prognostic factors in patients with oropharyngeal squamous cell carcinoma treated with radiotherapy alone or in combination with systemic chemotherapy. Arch Otolaryngol Head Neck Surg 2008;134(11):1196–204. 11. Johansen LV, Grau C, Overgaard J. Squamous cell carcinoma of the oropharynx – an analysis of treatment results in 289 consecutive patients. Acta Oncol 2000;39(8):985–94. 12. Makitie AA, Pukkila M, Laranne J, Pulkkinen J, Vuola J, Back L, et al. Oropharyngeal carcinoma and its treatment in Finland between 1995 and 1999: A nationwide study. Eur Arch Otorhinolaryngol 2006;263(2):139–43.
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Differential survival trends for patients with tonsillar, base of tongue and tongue cancer in Sweden Lalle Hammarstedt a,⇑, Yunxia Lu b, Linda Marklund a, Tina Dalianis c,d, Eva Munck-Wikland a, Weimin Ye b a
Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Karolinska University Hospital, Sweden Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden c Department of Oncology–Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden d Swedish Institute for Infectious Disease Control, Stockholm, Sweden b
a r t i c l e
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Article history: Received 10 November 2010 Received in revised form 18 April 2011 Accepted 19 April 2011 Available online 17 May 2011 Keywords: Tonsillar cancer Base of tongue cancer Tongue cancer Prognosis Relative survival rate
s u m m a r y Tonsillar, base of tongue and tongue cancer have similar anatomical and histopathological appearances but present differences in prognosis. Human papillomavirus (HPV) is a known risk factor for tonsillar and base of tongue cancer, and a survival benefit has been shown for these tumors; however, HPV prevalence in tongue cancer is low. Tonsillar, base of tongue and tongue cancer patients registered in the Swedish Cancer Registry between 1960 and 2004 were followed from the date of cancer diagnosis until death, emigration out of Sweden, or the end of a follow-up (5 years since cancer diagnosis), whichever occurred first. The relative survival rate was computed as the ratio of the observed to the expected survival rate, in which the latter was inferred from the survival of the entire Swedish population in the same age, sex and calendar year stratum. The relative survival rate has improved significantly over time for patients with tonsillar and base of tongue cancer although delineated by different patterns. However, the relative survival rate in tongue cancer patients exhibited only a very modest improvement during the same time period. Contrary to the overall improved survival for patients with tonsillar and base of tongue cancer, the patients with tongue cancer show a very modest improvement in Sweden since 1960. Further studies are warranted to elucidate more effective treatment options for tongue cancer patients. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction In Sweden, the incidence of tonsillar and base of tongue cancer has increased significantly over the last 30–40 years, while both the prevalence of known risk factors, such as smoking and heavy alcohol consumption, and the incidence of other smoking-related cancers have decreased.1,2 Human papillomavirus (HPV) has been hypothesized to be involved in the carcinogenesis of oropharyngeal cancer, and accumulating molecular and epidemiological data now show that high-risk types of HPV are responsible for a subset of oropharyngeal cancer.3–5 Based on these findings, the International Agency for Research on Cancer (IARC) now recognizes HPV as a risk factor for oropharyngeal cancer. HPV occurs in 45–93%6,7 of studied tonsillar cancer cases, and the prevalence of HPV in tonsillar cancer has increased significantly over the last decades. In fact, HPV is hypothesized to be responsible for a threefold increase observed ⇑ Corresponding author. Address: Department of Oto-Rhino-Laryngology, Karolinska University Hospital, S-171 76 Stockholm, Sweden. Tel.: +46 709 602549; fax: +46 8 51776267. E-mail address: [email protected] (L. Hammarstedt). 1368-8375/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2011.04.012
both in the incidence and proportion of HPV-positive tonsillar cancer in Sweden over the last few decades.7,8 Base of tongue cancer is the second most common oropharyngeal cancer in Sweden,9 and although base of tongue cancer resembles tonsillar cancer histopathologically, previous studies have shown that its prognosis is worse.10–12 Our group and others have shown that the prognosis for patients with HPV-positive tonsillar and base of tongue cancer is better than for patients with HPV-negative tumors, which is independent of nodal status, age, stage, tumor differentiation or gender.5,13–16 Cancer in the oral tongue is usually associated with poor prognosis. Using the SEER database, Rusthoven and colleagues17 found that the survival for this tumor group has not improved between 1988 and 2004, although some conflicting results have been reported.18,19 In contrast to tonsillar cancer, HPV prevalence in oral tongue tumors is still low, and no distinct correlation between HPV prevalence and the prognosis of tongue cancer patients has been observed.20,21 Hakulinen and colleagues assessed the changes of survival and incidence in oral and oropharyngeal cancers in the Nordic countries. However, they analyzed the trends for tongue and base of tongue cancer together and included nasopharynx and hypopharynx in the oropharyngeal group.22
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Chaturvedi and colleagues showed an improved survival in potentially HPV-positive oral squamous cell carcinomas in comparison to potentially negative carcinomas in a large cohort.23 To what extent the results of this study by Chaturvedi can be extrapolated to the Swedish population is yet unknown. In order to explore the survival trends of these cancer types, we used data from the Swedish Cancer Registry to assess the changes in the relative survival over time. Material and methods The Swedish Cancer Registry was established in 1958, and physicians throughout Sweden have been reporting all cancer cases to the registry. Because both clinicians and pathologists/cytologists report cancer cases based on biopsies, fine needle aspiration or surgically resected tissue, many cases have been verified twice. The Swedish Cancer Registry has been estimated to be 98% complete from 1960 onwards but not during its first two years (1958 and 1959).24,25 The registry has used the 7th version of the International Classification of Diseases (ICD-7) as its coding scheme during the entire study period. Data available in the registry include the following: a 10-digit personal registration number assigned to all Swedish residents, gender, date of diagnosis, age at diagnosis, basis of diagnosis, index for cancer found incidentally in autopsy, index for first or secondary cancers and pathology code. To avoid the effect due to the occurrence of other cancers on survival rates, we only included primary tonsillar cancer or tongue cancer, i.e., data on patients without any previously diagnosed cancer in the Cancer Registry. The inclusion criteria were the following: ICD-7 code 145.0 for tonsillar cancer, ICD-7 code 141 for tongue cancer and the pathology codes 146 and 196 for squamous cell carcinoma and undifferentiated carcinoma, respectively. The code 141.0 represents base of tongue cancer. The vital status of the cases was determined by linkage to the nationwide Swedish Causes of Death Registry, and any emigration out of Sweden was assessed by linkage to the nationwide Swedish Emigration Registry.
Statistical analyses For the nationwide cohort, to explore any secular trend of survival rates, patients were grouped by calendar period of diagnosis into five groups: 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000–2004. Patients were followed up from the date of cancer diagnosis until death, emigration out of Sweden, or at the end of a follow-up (5 years since cancer diagnosis), whichever occurred first. The observed survival rate for each group was estimated using the life-table method.26 The relative survival rate was computed as the ratio of the observed to the expected survival rate, in which the latter was inferred from the survival of the entire Swedish population in the same age, sex and calendar year stratum. The age-standardized relative survival rate27 was also estimated using age distribution (<50, 50–59, 60–69, and P70) at cancer diagnosis among all patients. To investigate independent effects of patient characteristics along with the calendar period, we also fit genderspecific Poisson regression models for excess mortality adjusting for follow-up time, period of diagnosis and age at diagnosis.28 This model was estimated in the framework of generalized linear models assuming a Poisson distribution for the observed number of deaths. Results A total of 2303 cases were diagnosed with tonsillar cancer between 1960 and 2004. After excluding 36 invalid cases, 2267 remained in the final cohort of tonsillar cancer patients. For base of tongue cancer, a cohort of 857 cases was initially identified. After excluding 82 cases with histopathology other than squamous cell carcinoma or undifferentiated carcinoma and 3 invalid cases, 772 remained in the final cohort of base of tongue cancer patients. Similarly, we excluded 119 cases with histopathology other than squamous cell carcinoma or undifferentiated cancer from the initially identified 3286 tongue cancer patients. We further excluded 26 invalid cases, leaving 3141 patients in the final tongue cancer cohort.
Table 1 Observed and relative 5-year survival for patients with tonsillar, base of tongue and tongue cancer, stratified by period and sex. Men Period of diagnosis
No. of patients
Tonsillar cancer 1960–1969 180 1970–1979 225 1980–1989 319 1990–1999 495 2000–2004 390 P value for trend Base of tongue cancer 1960–1969 45 1970–1979 113 1980–1989 136 1990–1999 147 2000–2004 135 P value for trend Tongue cancer 1960–1969 250 1970–1979 338 1980–1989 421 1990–1999 479 2000–2004 247 P value for trend
Women Mean age
Crude observed survival (%)
Age-standardized relative survival (%)
No. of mean
Patients age
Crude observed survival (%)
Age-standardized relative survival (%)
62.9 63.1 62.6 59.9 58.8
26.8 (20.6–33.5) 23.7 (18.3–29.4) 29.9 (24.9–35.0) 49.3 (44.8–53.6) 61.5 (56.5–66.2) p = 0.02
32.9 (19.2–49.6) 29.1 (16.8–43.0) 36.7 (25.1–48.3) 51.1 (41.8–60.1) 62.0 (51.1–71.7) p = 0.03
59 100 151 212 136
63.8 65.5 61.9 61.7 58.5
36.8 (24.7–48.9) 43.0 (33.2–52.4) 45.7 (37.6–53.4) 55.7 (48.7–62.1) 61.8 (53.1–69.3) p < 0.01
42.9 (17.1–65.4) 54.8 (30.7–72.1) 49.5 (32.9–64.2) 60.7 (45.9–72.9) 60.8 (40.5–73.5) p = 0.06
67.4 64.6 63.5 61.6 61.6
20.0 (9.9–32.7) 15.2 (9.3–22.4) 28.7 (21.3–36.4) 39.3 (31.4–47.1) 50.4 (41.7–58.4) p = 0.02
22.2 (10.3–50.5) 18.8 (6.1–36.7) 32.0 (16.5–49.5) 41.1 (24.7–57.5) 51.3 (32.7–67.8) p = 0.01
14 28 49 58 47
66.4 71.8 66.1 63.4 63.3
28.6 (8.8–52.4) 39.3 (21.7–56.5) 28.6 (16.8–41.5) 55.2 (41.6–66.9) 50.5 (35.5–63.8) p = 0.13
26.2 (14.1–70.0) 45.0 (32.5–71.4) 33.2 (9.0–60.2) 58.3 (29.8–77.7) 52.5 (22.1–76.2) p = 0.12
63.9 64.0 61.9 62.3 60.9
32.8 (27.1–38.7) 37.1 (32.0–42.2) 38.0 (33.4–42.7) 41.0 (36.6–45.4) 42.2 (35.9–48.2) p < 0.01
39.3 (25.7–53.2) 45.5 (32.7–58.1) 42.1 (31.7–52.7) 44.5 (34.8–54.1) 43.9 (30.8–56.7) p = 0.36
249 284 323 342 208
69.3 70.8 69.5 66.9 66.3
37.7 (31.6–43.7) 41.3 (35.6–47.0) 38.1 (32.8–43.4) 45.8 (40.5–51.0) 52.4 (45.4–58.9) p = 0.05
48.3 (33.0–62.1) 56.3 (41.3–68.3) 49.0 (35.8–61.1) 54.6 (42.5–65.2) 60.4 (44.4–73.6) p = 0.19
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Fig. 1a The age-standardized relative survival of tonsillar cancer diagnosed in Sweden during 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000–2004.
There was a strong male predominance (71%) in the tonsillar cancer group. The mean age at diagnosis in the male tonsillar cancer group was stable during the first three decades (62.6– 63.1 years) but decreased to around 59 years in the periods 1990–99 and 2000–2004. The trend was similar for women (Table 1). Among male tonsillar cancer patients, the 5 year agestandardized relative survival rate was 32.9% in 1960–1969, 29.1% in 1970–1979, 36.7% in 1980–1989, 51.1% in 1990–1999 and 62.0% in 2000–2004 (Table 1, Fig. 1a). The relative survival rates did not differ significantly in the first three decades. However, there was a significant improvement in prognosis for patients diagnosed since 1990 (Table 2). Compared to men, women had an overall better survival rate (observed 5 year survival rate, 51.0% vs. 42.3%). The improved prognosis among women had been observed
as early as the decade 1970–1979, and further improvement occurred during the last two decades (Table 2). Similarly, there was also a strong male predominance (75%) in the base of tongue cancer group, and the mean age at diagnosis was initially 67.4 years and decreased to 61.6 years during the last two decades. For women, a similar trend was observed: the mean age at diagnosis decreased from 66.4 years in the 1960s to 63.3 years in the period 2000–2004 (Table 1). The age-standardized relative survival rate increased from 22.2% in 1960–1969 to 51.3% in 2000–2004 for men. For women, the age-standardized relative survival increased from 26.2% in 1960–1969 to 52.5% in 2000–2004 (Table 1, Fig. 1b). The survival trend mimics the changes observed in tonsillar cancer for men with a gradually improved survival over time. For women, however, there was no
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L. Hammarstedt et al. / Oral Oncology 47 (2011) 636–641 Table 2 The relative hazards of mortality by diagnosis and gender during the first 5 years after diagnosis.a Variables
a
Relative hazards of mortality (95% CI) tonsillar cancer
Period of diagnosis
Men
1960–1969 1970–1979 1980–1989 1990–1999 2000–2004 P value for trend Age at diagnosis <50 50–59 60–69 P70 P value for trend
1.00 1.25 0.99 0.58 0.39 P < 0.01
Reference 0.97–1.60 0.78–1.26 0.46–0.73 0.30–0.51
1.00 0.57 0.61 0.44 0.49 P < 0.01
Reference 0.36–0.91 0.40–0.93 0.29–0.67 0.30–0.74
1.00 1.84 2.75 3.27 P < 0.01
Reference 1.40–2.40 2.13–3.57 2.48–4.31
1.00 1.62 2.71 5.39 P < 0.01
Reference 1.01–2.58 1.74–4.21 3.52–8.27
Variables
Relative hazards of mortality (95% CI) base of tongue cancer
Period of diagnosis 1960–1969 1970–1979 1980–1989 1990–1999 2000–2004 P value for trend Age at diagnosis <50 50–59 60–69 P70 P value for trend
Men 1.00 1.11 0.84 0.70 0.41 P < 0.01 1.00 1.85 2.13 2.75 P < 0.01
Variables
Relative hazards of mortality (95% CI) tongue cancer
Period of diagnosis 1960–1969 1970–1979 1980–1989 1990–1999 2000–2004 P value for trend Age at diagnosis <50 50–59 60–69 P70 P value for trend
Men 1.00 0.89 0.90 0.77 0.86 P = 0.09 1.00 1.54 1.70 2.61 P < 0.01
Women
Reference 0.72–1.69 0.55–1.29 0.45–1.08 0.26–0.64
Reference 1.21–2.84 1.42–3.18 1.83–4.13
Reference 0.71–1.12 0.72–1.12 0.64–0.99 0.67–1.10
Reference 1.22–1.96 1.36–2.14 2.09–3.27
Women 1.00 0.53 1.00 0.51 0.51 P = 0.13 1.00 1.81 2.69 4.57 P < 0.01
Women 1.00 0.85 0.93 0.85 0.70 P = 0.04 1.00 1.23 1.52 2.84 P < 0.01
Reference 0.21–1.31 0.45–2.20 0.22–1.19 0.22–1.19
Reference 0.70–4.69 1.06–6.82 1.90–10.99
Reference 0.65–1.11 0.72–1.20 0.66–1.10 0.52–0.94
Reference 0.85–1.78 1.09–2.11 2.12–3.80
The multivariable regression models included all variables listed in the table.
improvement seen in the last decade as compared to the 1990s, and this result was similar to the observed pattern for female tonsillar cancer patients. For the tongue cancer group, there were similar trends in gender and age to the tonsillar cancer patient group, with the exception of women being approximately 5 years older than men at diagnosis (Table 1). Regarding male tongue cancer patients, the age-standardized relative survival was 39.3% in 1960–1969, 45.5% in 1970–1979, 42.1% in 1980–1989, 44.5% in 1990–1999 and 43.9% in 2000–2004. Women had a more dramatic difference as compared to men: the age-standardized relative survival increased from 48.3% in 1960–1969 to 60.1% in 2000–2004 (Table 1, Fig. 1c). The relative hazard of mortality for male tongue cancer patients did not improve significantly (2000–2004 vs. 1960–69, HR = 0.86, 95% CI 0.67–1.10). For women, there was a slight improvement over time, particularly in the last period (2000– 2004 vs. 1960–1969, HR = 0.70, 95% CI 0.52–0.94) (Table 2).
Discussion This study reveals an overall improved survival in patients with tonsillar and base of tongue cancer in Sweden during the last decades, which is especially notable after the 1980s for men. In con-
trast, the relative survival rates in tongue cancer patients, particularly among men, showed a modest improvement with a borderline significance. We hypothesize that the reason for this improved survival is due to an increase in the proportion of HPV-positive tumors in the tonsillar and base of tongue cancer groups in Sweden. In general, many studies on tonsillar cancer and oropharyngeal cancer have explored HPV infection as a prognostic factor, and the majority have found that HPV is a favorable prognostic factor.5,6,14–16,29 Thus, the improved survival seen in patients with tonsillar and base of tongue cancer could be explained by an increased occurrence of HPV among recently diagnosed cases. In contrast, HPV prevalence in oral tongue cancer is low, if present at all,20,21,30 and survival among these HPV-negative cancers has only improved with borderline significance. In addition, the role of HPV in nonoropharyngeal tumors is still contradictory, and so far, the reported studies suggest no difference or even worse survival among patients with other HPV-positive head and neck tumors, indicating that HPV plays a more limited role outside the oropharynx.31,32 Because tumor stage is a major determinant in outcome of cancer, diagnosis at an earlier stage could explain the improved survival for patients with tonsillar and base of tongue cancer, and this issue should be scrutinized. Indeed, tonsillar, base of tongue and tongue cancer are in close proximity to one another anatomi-
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Fig. 1c The age-standardized relative survival of tongue cancer diagnosed in Sweden during 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000–2004. Fig. 1b The age-standardized relative survival of base of tongue cancer diagnosed in Sweden during 1960–1969, 1970–1979, 1980–1989, 1990–1999 and 2000– 2004⁄. ⁄The sixties and seventies in women and the sixties in men is not presented due to small number of patients.
cally, and there is no reason to assume that the distribution of tumor stage at diagnosis for tongue cancer is different from that of the other two cancer types. However, there are studies indicating that HPV-positive tumors, i.e., the majority of the newly diagnosed cases of tonsillar cancer in the Stockholm area, have a higher stage at diagnosis.5,7,13–16 Thus, diagnosis at an earlier stage is not an additional reason for the improved clinical outcome in patients with tonsillar and base of tongue cancer. The age-standardized incidence for oral tongue cancer has remained almost unchanged since the 1960s, and only an increase among young patients has been noted.33,34 It is unlikely that HPV infection is responsible for the increase of this tumor noted among young patients.21 During the last few decades, new diagnostic techniques and advantages in the therapeutic field have been developed which could account for the improved survival of patients with tonsillar and base of tongue cancer. Since the 1960s, advances such as more intense and targeted radiotherapy, new oncologic agents, and modifications of surgical techniques, have been made in the therapeutic field. However, these technologies could sensitize both HPV-positive tonsillar and base of tongue cancer, which account for the majority of these tumors, to the new therapy modules as compared to oral tongue cancer. Hakulinen recently showed improved survival for tongue cancer patients but included base of tongue cancer patients,22 which could explain the differences seen in both survival and incidence.
The present study found a rapid increase in relative survival rates for both tonsillar and base of tongue but not for tongue cancer. Further, in the Hakulinen’s study, tonsillar cancer was grouped into cancer of the oropharynx, nasopharynx and hypopharynx which made direct comparison between the two studies impossible. The Chaturvedi study compared patients with potentially HPVrelated cancers to those HPV-unrelated and found an increased survival and incidence for HPV-related cancer patients. These data were analyzed from the SEER database and are not directly applicable to the Swedish population. Another difference of the present study from the Chaturvedi study is the analysis of HPV-related sites. Our present study analyzed tonsillar and base of tongue cancer separately whereas the Chaturvedi study analyzed base of tongue, oropharyngeal and tonsillar cancers together.23 The strengths of our study include the following: the nationwide setting, which includes all tonsillar, base of tongue and tongue cancer patients diagnosed in Sweden from 1960 to 2004, the completeness of follow-up, and the precision due to the large number of cases. Furthermore, to avoid the influence of other cancers on survival, we excluded patients with any other cancer diagnosed prior to the diagnosis of tonsillar, base of tongue, or tongue cancer. One limitation of our study is that although the Cancer Registry was started in 1958, and efforts have been made to record the order of primary cancers, we could not exclude the possibility that a few second or later primary cancers might have been misclassified as a first primary cancer. This error should primarily affect patients in the early 1960s, but the influence should be negligible. Another limitation of our study is that we could not collect any data about patients’ tumor stage, treatment, and HPV prevalence; therefore,
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we could not further elucidate the reasons for the differential secular trend of survival rate. In conclusion, we found an overall improved survival for patients with tonsillar and base of tongue cancer, but a very modest improvement in survival of tongue cancer patients during the last decades in Sweden. Further studies are needed to unveil the underlying mechanisms for this differential trend of survival. There is a clear difference in survival development between potentially HPV-related tumors and HPV-unrelated tumors. This study reveals a need for identifying predictive markers to select tongue cancer patients for more aggressive treatment. Conflict of interest statement None declared. Acknowledgment Grant sponsor: The Stockholm Cancer Society, The Laryngeal Foundation, Karolinska Institutet, Stockholm, Sweden. References 1. Hammarstedt L, Dahlstrand H, Lindquist D, Onelov L, Ryott M, Luo J, et al. The incidence of tonsillar cancer in Sweden is increasing. Acta Otolaryngol 2007;127(9):988–92. 2. Attner P, Du J, Nasman A, Hammarstedt L, Ramqvist T, Lindholm J, et al. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int J Cancer 2010;126(12):2879–84. 3. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Casecontrol study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356(19):1944–56. 4. Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001;344(15):1125–31. 5. Lindquist D, Romanitan M, Hammarstedt L, Nasman A, Dahlstrand H, Lindholm J, et al. Human papillomavirus is a favourable prognostic factor and its oncogenic role is supported by the expression by E6 and E7. Mol Oncol 2007;1(3):350–5. 6. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006;24(17):2606–11. 7. Nasman A, Attner P, Hammarstedt L, Du J, Eriksson M, Giraud G, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125(2):362–6. 8. Hammarstedt L, Lindquist D, Dahlstrand H, Romanitan M, Dahlgren LO, Joneberg J, et al. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. Int J Cancer 2006;119(11):2620–3. 9. Cancer incidence in Sweden 2008: The National Board of Health and Welfare; 2008. 10. Pedruzzi PA, Kowalski LP, Nishimoto IN, Oliveira BV, Tironi F, Ramos GH. Analysis of prognostic factors in patients with oropharyngeal squamous cell carcinoma treated with radiotherapy alone or in combination with systemic chemotherapy. Arch Otolaryngol Head Neck Surg 2008;134(11):1196–204. 11. Johansen LV, Grau C, Overgaard J. Squamous cell carcinoma of the oropharynx – an analysis of treatment results in 289 consecutive patients. Acta Oncol 2000;39(8):985–94. 12. Makitie AA, Pukkila M, Laranne J, Pulkkinen J, Vuola J, Back L, et al. Oropharyngeal carcinoma and its treatment in Finland between 1995 and 1999: A nationwide study. Eur Arch Otorhinolaryngol 2006;263(2):139–43.
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