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Epidemiology
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Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis
Article first published online: 1 JUN 2007
DOI: 10.1002/ijc.22851
Copyright © 2007 Wiley-Liss, Inc.
Additional Information
How to Cite
Ragin, C. C. R. and Taioli, E. (2007), Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int. J. Cancer, 121: 1813–1820. doi: 10.1002/ijc.22851
Publication History
- Issue published online: 14 AUG 2007
- Article first published online: 1 JUN 2007
- Manuscript Accepted: 17 APR 2007
- Manuscript Received: 2 MAR 2007
Funded by
- NIH. Grant Numbers: P50CA097190, 5P50CA097190
- GLMA
- Abstract
- Article
- References
- Cited By
Keywords:
- HPV;
- overall survival;
- disease-free survival;
- head and neck cancer
Abstract
Human papillomavirus (HPV) has been associated with head and neck squamous cell carcinomas (HNSCC), especially of the oropharynx, with highest distribution in the tonsils. HPV infection has been associated with improved outcome, although not all the studies show consistent results. The reason for this is not clear. We reviewed all published articles and conducted a meta-analysis on the overall relationship between HPV infection and overall survival (OS) and disease-free survival (DFS) in HNSCC. Patients with HPV-positive HNSCC had a lower risk of dying (meta HR: 0.85, 95% CI: 0.7–1.0), and a lower risk of recurrence (meta HR: 0.62, 95%CI: 0.5–0.8) than HPV-negative HNSCC patients. Site-specific analyses show that patients with HPV-positive oropharyngeal tumours had a 28% reduced risk of death (meta HR: 0.72, 95%CI: 0.5–1.0) in comparison to patients with HPV-negative oropharyngeal tumours. Similar observations were made for DFS (meta HR: 0.51, 95% CI: 0.4–0.7). There was no difference in OS between HPV-positive and negative non-oropharyngeal patients. The observed improved OS and DFS for HPV-positive HNSCC patients is specific to the oropharynx; these tumours may have a distinct etiology from those tumours in non-oropharyngeal sites. © 2007 Wiley-Liss, Inc.
The majority of head and neck tumours are differentiated squamous cell carcinomas (SCC), which occur in the oral cavity, oropharynx, hypopharynx and larynx. Approximately 45,660 new cases and 11,210 deaths from cancers of the oral cavity, pharynx and larynx are expected in the United States in 2007.1 The 5-year relative age-adjusted survival rate for these head and neck sites was 58% between 1973 and 2002 (58% for males and 60% for females),2 and have remained unchanged for more than 3 decades. This poor survival rate is primarily due to the late stage of diagnosis, and to a high frequency of recurrence and second primary tumours.3, 4, 5, 6, 7
Human papillomavirus (HPV) is associated with the development of most anogenital carcinomas, including cervical cancer and, has more recently been suggested to be a risk factor for a subset of head and neck squamous cell carcinoma (HNSCC).8 Most HPV-associated HNSCC tend to occur in the oropharynx, with highest distribution in the tonsils. HPV16 is the predominant genotype detected in head and neck tumours, with different prevalence between head and neck subsites. A recent review of the prognostic significance of HPV in survival of head and neck cancer patients has shown that the majority of studies have reported better survival in patients with HPV-positive head and neck tumours when compared to patients with HPV-negative tumours.9 However, the same review also reported that in some studies, HPV infection resulted in a worse prognosis or had no influence on prognosis.
We have reviewed all published articles that have addresses the impact of HPV infection on the outcome of patients with HNSCC, and have also conducted a meta-analysis of the published articles to evaluate the overall relationship between HPV infection and overall survival (OS) and disease-free survival (DFS).
Material and methods
Literature review and data extraction
A bibliographic search in the PubMed databases was conducted (from inception to January 30, 2007) to identify original articles that evaluated the outcome of patients with head and neck tumours in relation to HPV infection. The PubMed search term, (HPV OR ‘Human papillomavirus’ OR papillomavirus) AND (outcome OR survival OR prognosis) AND (oral OR buccal OR mouth OR tongue OR ‘head and neck’ OR pharyngeal OR pharynx OR oropharyngeal) AND (cancer OR neoplasms OR tumour OR carcinoma) yielded 196 articles. After manual review of each publication, 38 papers addressed the prognosis of patients with neck tumours in relation to HPV infection. The bibliographies of all publications as well as selected review articles9, 10, 11 were reviewed to ensure that other relevant publications were included, and 4 additional articles were identified with this process. From these 42 articles, 5 publications were excluded because they contained overlapping data12, 13, 14 or were review articles.9, 10 For each of the overlapping articles, only the article with the largest population and/or more complete information was used for this purpose. In total, 37 studies were included in this review. All of the studies determined HPV status for the tumours by a polymerase chain reaction (PCR) method and in most studies the HPV genotype was identified. From each study, information such as the number of subjects, HPV prevalence, tumour site, follow-up time in months and survival endpoints were extracted and tabulated.
Statistical analysis
All statistical analyses were performed using the Intercooled STATA (version 8.2) software (Stata LP, College Station, TX). The meta analyses were performed for OS and DFS comparing HPV-positive and HPV-negative patients. Although it would have been better to perform the meta-analysis of OS and DFS, by including patients with primary tumours only, it was not always possible to identify and exclude individual patients with recurrences or metastasis. Furthermore, a number of studies did not provide the status of the tumours that were included. Therefore, the meta-analysis included patients with primary, recurrent and metastatic tumours. Twelve of the 37 studies in this review were excluded from the meta-analysis because they did not provide complete data for calculating the log hazard ratio (HR) and standard error.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 Seven of them did not provide data on follow up time15, 16, 18, 19, 20, 22, 26; 3 described their findings in the text of the manuscript but did not show the survival data17, 23, 24 2 provided Kaplan–Meier plots but did not report in the actual number of patients at the start and end of each time interval.21, 25 Two other studies were excluded because they only provided data for disease-specific (DSS) survival.27, 28 Of the 14 excluded studies from the meta-analysis, 10 showed improved prognosis, 2 showed no difference and 2 a worse prognosis for patients with HPV-positive tumours. The log HR and standard error for the other 23 studies were calculated (a) by extracting the unadjusted HR and confidence intervals (CI) directly from each publication or (b) from individual patient data that was provided in some articles or (c) from extracting cumulative survival data from published Kaplan–Meier plots as described by Parmar et al.29 Three publications provided unadjusted HRs and CI for OS and/or DFS.30, 31, 32 The variance of the log HR was estimated from the CI as follows: [(log upper CI − log lower CI)/(2 × 1.96)]2 (Ref.29). The square root of the variance estimated the standard error. Four publications provided individual patient data.33, 34, 35, 36 A data set was created for each article by extracting follow-up time in months, vital status and/or disease-free status, HPV status of the tumour and tumour site for each patient. The univariate log HR and standard error for these studies were calculated using the maximum-likelihood proportional hazards model. Cumulative survival data, including Kaplan–Meier survival curves, were available from 15 articles.37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 For the study conducted by Reimers et al.,52 the maximum follow up time was obtained through a personal communication with the corresponding author. Therefore, 16 articles provided cumulative survival data and/or published survival curves from which the log HR and standard error were calculated.
A detailed description of the method used for estimating the log HR and its variance from survival curves was described by Parmar et al.29 Briefly, for each study, the overall log HR was calculated by combining the log HR for each nonoverlapping time interval of that study. For each nonoverlapping time interval, the log HR = ln [(number of deaths among HPV-positive patients during the time interval/number of HPV-positive patients at risk during the time interval)/(number of deaths among HPV-negative patients during the time interval/number of HPV-negative patients at risk during the time interval)]. The variance of the log HR was calculated by combining the variance of the log HR for each nonoverlapping time interval of that study. The variance of the log HR for each time interval = [(1/number of deaths among HPV-positive patients during the time interval) − (1/number of HPV-positive patients at risk during the time interval) + (1/number of deaths among HPV-negative patients during the time interval) − (1/number of HPV-negative patients at risk during the time interval)]. The number of patients at risk for any given time interval was calculated as the number of patients at risk at the start of the time interval − number of patients censored during the time interval. The assumption was made that the rate of censoring in a study is constant. Therefore, the number of patients censored during a time interval was equal to the number of patients at risk at the start of the time interval × [(time at the start of the interval − time at the end of the interval)/2(maximum follow up time − time at the start of the interval)]. Estimates of the standard error was calculated from the square root of the variance.
Meta analyses of HPV and overall or DFS were performed separately for patients with oropharyngeal and non-oropharyngeal tumours to evaluate site-specific differences in outcome. Only those studies that included 20 or more oropharyngeal or non-oropharyngeal patients were included in this subanalysis.
A survival benefit that favors patients with HPV-positive tumours is represented by a HR < 1.0, while a survival benefit that favors patients with HPV-negative tumours is represented by a HR > 1.0. Studies that reported data for recurrence and local control were include in the analysis for DFS.
The Q statistics were used to test for heterogeneity among the studies included in the meta analyses. A fixed effects model was used to calculate the summary HRs when there was no heterogeneity observed (i.e.Q-test p value < 0.05). Publication bias was determined by performing the Egger's test.
Results
Summary of studies and design characteristics
Table I shows a summary of the main design characteristics and findings of each study. There are variations among studies in the tissue type used (fresh vs. paraffin), tumour sites involved, HPV prevalence, as well as the treatment strategies for each patient. In addition, many studies reported the inclusion of patients with primary tumours only, while others included patients with recurrences and metastases as well. However, the definition of recurrence is not standardized between studies; for example, most tonsillar cancer patients may also present with neck metastases.
| Study | N | Tissue source | Tumor site (N) | HPV status | Follow up time (months) | Survival analysis reported, endpoints considered |
|---|---|---|---|---|---|---|
| ||||||
| %* (Type†) | ||||||
| Reimers et al.52 | 106 | Fresh frozen (primary) | Tonsil (63) | 28 (16, 33, 5, ADX1) | 98 (max) | n=80; 5-yr OS**; 5-yr DFS** |
| BOT (14) | ||||||
| Other oropharynx (29) | ||||||
| Na et al.38 | 108 | Paraffin§ | Tongue (70) | 9 (16) | 125 (total) | OS |
| Tonsil (38) | ||||||
| Sugiyama et al.15 | 66 | Paraffin§ | Alveolus/gingiva (27) | 36 (16) | n=62; 5-yr OS** | |
| Tongue (18) | ||||||
| Other (21) | ||||||
| De Petrini et al.40 | 44 | Paraffin§ | Oral cavity (23) | 46 (16) | 35.5 (mean) | DSS (oral cavity)**; DSS (oropharynx) |
| Oropharynx (21) | ||||||
| Licitra et al.39 | 90 | Paraffin§ | Tonsil/BOT (66) | 19 (16) | 69.9 (median) | OS††, tumor relapse††, second primaries†† |
| Other oropharynx (24) | ||||||
| Weinberger et al.26 | 77 | Paraffin: 68 (primary), 9 (recurrent) | Oropharynx | 61 (16) | 22 (median) | 5-yr OS‡‡, 5-yr DFS‡‡; 5-yr LR‡‡ |
| Hoffman et al.49 | 73 | Fresh frozen: (primary) | Tonsil (20) | 38 (16, 33) | 28 (median) | Recurrence**; DFS**, OS** |
| Oral Cavity (6) | ||||||
| Oropharynx (4) | ||||||
| Hypopharynx (24) | ||||||
| Larynx (19) | ||||||
| Kozomara et al.50 | 50 | Fresh tissue: 38 (primary); Paraffin: 12 (primary) | Tongue and/ or FOM | 64 (16, 18, 31) | 29 (median) | OS |
| Vlachtsis et al.24 | 100 | Fresh frozen: (primary) | Larynx | 40 (16, 18) | 40.6 (median) | OS** |
| Wittekindt et al.51 | 34 | Fresh frozen§ | Tonsil | 53 (16, 33) | 33 (median) | Recurrence, OS** |
| Azzimonti et al.33 | 34 | Paraffin§ | Larynx (25) | 56 (16. 18) | 37.5 (mean) | OS** |
| Tonsil (9) | ||||||
| Baez et al.41 | 118 | Fresh frozen§# | Oral Cavity (36) | 44 (16) | 60 (median) | 3-yr DFS, OS** |
| Pharynx (30) | ||||||
| Larynx (52) | ||||||
| Dahlgren et al.28 | 110 | Paraffin: (primary) | Mobile tongue (85) | 11 (16, 33, 31, X) | BOT: 38 (mean) | BOT: 3-yr DSS, 5-yr DSS |
| Base of tongue (25) | ||||||
| Koskinen et al.34 | 61 | Fresh frozen: (primary) | Hypopharynx (10) | 61 (16, 33, 6, 11, 51, 52) | 24.5 (mean) | OS** (n=59) |
| Tonsil (5) | ||||||
| Tongue (15) | ||||||
| Oral cavity (13) | ||||||
| Larynx (18) | ||||||
| Ritchie et al.42 | 139 | Paraffin: (primary) | Oral cavity (94) | 21 (16, 18, 33) | 58 (median) | OS, DSS** |
| Oropharynx (45) | ||||||
| Dahlgren et al.16 | 25 | Fresh frozen: (primary) | Tonsil | 60 (16, X) | 24 (max) | DSS |
| Li et al.37 | 67 | Paraffin§ | Tonsil | 46 (16, X) | 48 (median) | Recurrence, DSS |
| Ringstrom et al.18 | 89 | Fresh frozen: 86 (primary), 3 (recurrent) | Oral cavity (41) | 20 (16) | — | Recurrence, 5-yr OS, 5-yr DSS |
| Oropharynx (29) | ||||||
| Hypopharynx (4) | ||||||
| Larynx (10) | ||||||
| Other (5) | ||||||
| Mellin et al.17 | 22 | Fresh frozen: (primary) | Tonsil | 55 (16, 33) | — | n=20; OS**, DSS**, DSS¥ |
| Strome et al.46 | 52ρ | Paraffin: (primary) | Tonsil | 46 (16, 12, 59) | 44 (median) | 3-yr DFS**, 3-yr OS**, 3-yr CSS** |
| Sisk et al.13 | 32 | Fresh frozen§ | Oral cavity & oropharynx (22) | 47 (16, 18, X) | 23 (mean) | OS |
| Larynx (9) | ||||||
| Hypopharynx (1) | ||||||
| Lindel et al.19 | 99 | Paraffin: (primary) | Oropharynx: Tonsil (40), Nontonsil (59) | 14 (16, 33, 35, 45) | — | LFFS, OS, DFS** |
| Friesland et al.44 | 40 | Paraffin: (primary) | Tonsil | 41 (16) | 31 (mean) | n=34; OS (Stage IV only), DFS**, RT**, OS** |
| Schwartz et al.43 | 254 | Paraffin§ | Anterior tong (81) | 24 (16, X) | 55 (mean) | HPV16 only, OS, DSS; HPVX only, OS**, DSS** |
| Tonsil (44) | ||||||
| BOT (36) | ||||||
| FOM (30) | ||||||
| Other (63) | ||||||
| Mellin et al.17 | 60 | Paraffin§ | Tonsil | 43 (16) | 22 (median) | n=52, 3-yr RT; n=48, 5-yr DSS |
| Gillison et al.32 | 253 | Fresh frozen: 200 (primary), 53 (recurrent) | Nasopharynx (2) | 22 (16, 33, 31, 11, X) | 31 (median) | n=252, OS, DSS, DSS (oropharynx), DSS** (oral cavity) |
| Oral cavity (84) | ||||||
| Oropharynx (60) | ||||||
| Hypopharynx (21) | ||||||
| Larynx (86) | ||||||
| Shima et al.23 | 46 | Fixed/frozen§ | Tongue (27) | 74 (16, 18) | — | OS** |
| Buccal mucosa (3) | ||||||
| Gingiva (10) | ||||||
| FOM (3) | ||||||
| Palate (3) | ||||||
| Pintos et al.30 | 101 | Paraffin: (primary) | Oral cavity (29) | 17 (X) | — | Recurrence**, OS**, DFS** |
| Pharynx (20) | ||||||
| Larynx (52) | ||||||
| Koch et al.31 | 211 | Fresh frozen§ | HNSCCθ | 18 (16, 33) | — | OS |
| Portugal et al.20 | 100 | Paraffin: (primary) | Oral cavity (58) | 10 (16, 18, 33) | — | Recurrence**; 5-yr OS (tonsil), 5-yr OS**(oral cavity) |
| Tonsil (42) | ||||||
| Riethdorf et al.47 | 92 | Fresh frozen: 91 (primary), 1 (metastasis) | Oral Cavity (78) | 42 (16, 18, 6, 11) | 112 (max) | OS** |
| Pharynx (7) | ||||||
| Larynx (3) | ||||||
| Tonsil (2) | ||||||
| Lymph node (2) | ||||||
| Paz et al.48 | 167 | Fresh frozen: 121 (primary), 23 (recurrent), 23 (metastasis) | Esophagus (11) | 15 (16, 6, X) | 89.4 (max) | OS**, CSS** |
| Tonsil (15) | ||||||
| Tongue (39) | ||||||
| Larynx (28) | ||||||
| Oral cavity (32) | ||||||
| Supraglottic (21) | ||||||
| Other (21) | ||||||
| Haraf et al.21 | 66 | Paraffin#: (primary) | Oral cavity (14) | 18 (16, 33) | 111 (max) | OS (Stage IV only, n = 39) RT** |
| Oropharynx (26) | ||||||
| Hypopharynx (7) | ||||||
| Larynx (19) | ||||||
| Snijders et al.36 | 63 | Fresh frozen: (primary), (recurrent) | Oral cavity (25) | 21 (16) | 95 (max) | OS** |
| Hypopharynx (16) | ||||||
| Larynx (15) | ||||||
| Oropharynx (7) | ||||||
| Chiba et al.22 | 38 | Fresh frozen: (primary) | Oral cavity | 21 (16) | — | DFS |
| Brandwein et al.25 | 64 | Paraffin§ | FOM (13), | 25 (X) | 27.8 (mean) RT: 25 (mean) | DSS** (Stage III & IV only) |
| Tongue (19), | ||||||
| Tongue & FOM (6) | ||||||
| Tonsil (7) | ||||||
| Tonsil & tongue (5) | ||||||
| Tongue & vallecula (5) | ||||||
| Tongue, tonsil & pharynx (4) | ||||||
| RMT (3) | ||||||
| Pharynx (2) | ||||||
| Clayman et al.27 | 65 | Paraffin§ | Larynx (59) | 45 (X) | 63 (max) | DSS, LRC, DSS** (pts treated with radiotherapy) |
| Hypopharynx (6) | ||||||
The majority of studies (n = 24) reported a trend towards an improved overall (OS) and/or DSS and/or DFS for patients with HPV-positive head and neck tumours in comparison to patients with HPV-negative tumours.13, 15, 16, 17, 18, 19, 20, 21, 22, 26, 28, 31, 32, 37, 38, 39, 40, 41, 42, 43, 44, 45, 51, 52 However, more than half of these studies did not achieve statistical significance. The size of the study populations ranged from 25 to 254 subjects. Fifty-four percent of these studies (13/24) included patients with tumours from various combinations of head and neck subsites, such as the oral cavity, pharynx and larynx. Forty-two percent (10/24) included only patients with oropharyngeal tumours, the majority of which occurred in the tonsil. The other 2 studies included only patients with oral cavity tumours.
Ten studies reported that an HPV-positive head and neck tumour had no effect on OS, DFS or cause-specific survival.23, 24, 30, 33, 34, 36, 46, 47, 48, 49 The size of the study populations ranged from 34 to 167 subjects. The majority (80%, 8/10) included patients with tumours from various head and neck subsites. Two studies included patients with tumours from either the larynx or tonsil. Only 3 studies reported that patients with HPV-positive tumours had a worse overall or DFS.25, 27, 50 One included patients with oral cavity tumours only while the other 2 included patients with tumours from various combinations of head and neck subsites.
We compared the overall and site-specific HPV prevalence for each of the 3 outcome categories (Table II). Studies that report an improved prognosis reported an overall HPV prevalence of 28%. More than half of the tumours in this group were from the pharynx (55%, oropharynx = 53%) and as expected, a higher HPV prevalence was observed in this head and neck subsites (oropharynx 38%, tonsil 37.7%). In contrast, the studies that reported no differences in prognosis, or a worse prognosis, had an overall HPV prevalence that was higher than expected (42% and 44%, respectively). For studies reporting no difference in prognosis, the majority of the subjects had tumours from the oral cavity (35%) and larynx (36%). The studies that reported a worse prognosis included more than half of the subjects with tumours from the lip and oral cavity (51%).
| Number of tumors (%) | HPV prevalence, % | 95% confidence interval | |
|---|---|---|---|
| |||
| Studies that report an improved prognosis (number of studies = 21*) | |||
| Lip & oral cavity | 609 (34.9) | 13.5 | 10.9–16.4 |
| Pharynx | 964 (55.2) | 37.2 | 34.2–40.4 |
| Hypopharynx | 46 | 17.4 | 7.8–31.4 |
| Oropharynx | 918 | 38.2 | 35.1–41.5 |
| Tonsil | 425 | 37.7 | 33.0–42.4 |
| Larynx | 167 (9.6) | 25.1 | 18.8–32.4 |
| Nasopharynx‡ | 4 (0.2) | 0.0 | |
| Lymph nodes | 3 (0.1) | 0.0 | |
| Total | 1,747 (100.0) | 27.7 | 25.6–29.8 |
| Studies that report no difference in prognosis (number of studies = 9† | |||
| Lip & oral cavity | 212 (34.6) | 44.3 | 37.5–51.3 |
| Pharynx | 176 (28.8) | 40.9 | 33.6–48.6 |
| Tonsil | 90 | 54.4 | 43.6–65.0 |
| Larynx | 222 (36.3) | 39.6 | 33.2–46.4 |
| Nasopharynx | 0 (0.0) | 0.0 | |
| Lymph nodes | 2 (0.3) | 0.0 | |
| Total | 612 (100.0) | 41.5 | 37.6–45.5 |
| Studies that report worse prognosis (number of studies = 3) | |||
| Lip & oral cavity | 91 (50.8) | 45.1 | 34.6–55.8 |
| Pharynx§ | 29 (16.2) | 44.8 | 26.4–64.3 |
| Tonsil | 16 | 37.5 | 15.2–64.6 |
| Larynx | 59 (33.0) | 40.7 | 28.1–54.2 |
| Nasopharynx | 0 (0.0) | 0.0 | |
| Lymph nodes | 0 (0.0) | 0.0 | |
| Total | 179 (100.0) | 43.6 | 36.2–51.2 |
Meta-analysis
Of the 23 studies included in this meta-analysis, there were 19 studies that provided complete data for OS (Fig. 1). Patients with HPV-positive head and neck tumours had an 18% lower risk of dying than patients with HPV-negative tumours (combined HR: 0.85, 95% CI: 0.7–1.0). There was no heterogeneity observed between the studies (Q-test, p value = 0.206) and no evidence of publication bias (Egger's test, p value = 0.368). Nine of the 23 studies provided complete data for DFS (Fig. 2). Patients with HPV-positive tumours had a 38% lower risk of disease-failure (combined HR: 0.62, 95%CI: 0.5–0.8). Overall, the studies were not heterogeneous (Q-test, p value = 0.360) and no evidence of publication bias was observed (Egger's test, p value = 0.446).
Figure 1. (a) Overall survival, HPV-positive vs. HPV-negative tumours; meta hazard ratio: 0.85, 95% confidence interval: 0.7–1.0; Q-test for heterogeneity (p value = 0.206). (b) Funnel plot to test for publication bias (Egger's test p value = 0.368).
Figure 2. (a) Disease-free survival, HPV-positive vs. HPV-negative tumours; meta hazard ratio: 0.62, 95% confidence interval: 0.5–0.8; Q-test for heterogeneity (p value = 0.360). (b) Funnel plot to test for publication bias Egger's test (p value = 0.446).
To evaluate site-specific differences in outcome, meta analyses of HPV and overall or DFS were performed (Tables III and IV). Overall, 12 studies provided site-specific data for OS and DFS. Four studies included 224 patients with oropharyngeal tumours, while five studies included 201 patients with non-oropharyngeal tumours. Patients with HPV-positive oropharyngeal tumours had a 28% reduced risk of death (meta HR: 0.72, 95%CI: 0.5–1.0) in comparison to patients with HPV-negative oropharyngeal tumours, there was evidence of publication bias (Egger's test, p value = 0.011). There was no significant difference in the risk of death for patients with HPV-positive non-oropharyngeal tumours compared to patients with HPV-negative non-oropharyngheal tumours (meta HR: 0.79, 95% CI: 0.5–1.3). The studies were not heterogeneous (Q-test, p value = 0.706) and there was no evidence of publication bias (Eggers test, p value = 0.578).
| Study | N | HPV16 (%)‡ | Head and neck subsites | HR | 95% confidence interval |
|---|---|---|---|---|---|
| |||||
| Oropharyngeal tumors | |||||
| Friesland et al. (2001)44 | 34 | 100 | Tonsil | 0.86 | 0.6–1.3 |
| De Petrini et al. (2006)40 | 20 | 100 | Oropharynx | 0.20 | 0.0–1.0 |
| Licitra et al. (2006)39 | 90 | 100 | Oropharynx | 0.39 | 0.1–1.4 |
| Reimers et al. (2007)52 | 80 | 97 | Oropharynx | 0.61 | 0.3–1.4 |
| Total | 224 | ||||
| Meta* | 0.72 | 0.5–1.0 | |||
| p value, Q test | 0.240 | ||||
| p value, Egger's test | 0.011 | ||||
| Non-oropharyngeal tumors | |||||
| Snijders et al. (1996)36 | 51 | 100 | Oral cavity, hypopharynx, larynx | 0.39 | 0.1–1.7 |
| Koskinen et al. (2003)34 | 54 | 84 | Oral cavity, tongue, hypopharynx, Larynx | 0.69 | 0.3–105 |
| Azzimonti et al. (2004)33 | 25 | 79 | Larynx | 0.85 | 0.3–2.8 |
| Kozomara et al. (2005)50 | 50 | 31 | Tongue, FOM | 2.00 | 0.3–12.5 |
| De Petrini et al. (2006)40 | 21 | 100 | Oral cavity | 1.00 | 0.3–3.1 |
| TOTAL | 201 | ||||
| META* | 0.79 | 0.5–1.3 | |||
| p value, Q test | 0.706 | ||||
| p value, Egger's test | 0.578 | ||||
| Study | N | HPV16 (%)‡ | Head and neck subsites | HR | 95% confidence interval |
|---|---|---|---|---|---|
| |||||
| Oropharyngeal tumors | |||||
| Mellin et al. (2000)17 | 60 | 100 | Tonsil | 0.61 | 0.4–1.0 |
| Strome et al. (2002)46 | 52 | 88 | Tonsil | 0.44 | 0.2–1.3 |
| Li et al. (2003)37 | 67 | 90 | Tonsil | 0.43 | 0.2–1.0 |
| Wittekindt et al. (2005)51 | 34 | 94 | Tonsil | 0.36 | 0.2–0.9 |
| Reimers et al. (2007)52 | 80 | ≥96§ | Oropharynx | 0.55 | 0.2–1.4 |
| Total | 293 | ||||
| Meta* | 0.51 | 0.4–0.7 | |||
| p value, Q test | 0.846 | ||||
| p value, Egger's test | 0.135 | ||||
| Non-oropharyngeal tumors | |||||
| Azzimonti et al. (2004)33 | 25 | 79 | Larynx | 2.45 | 0.3–23.6 |
| TOTAL | 25 | ||||
For DFS, 5 studies included 293 patients with oropharyngheal tumours and only one study included 25 patients with non-oropharyngeal tumours from the larynx. The HPV-positive patients with oropharyngeal tumours had a 49% significantly lower risk of disease-failure than the patients with HPV-negative oropharyngeal tumours (meta HR: 0.51, 95% CI: 0.4–0.7). There was no evidence of publication bias (Egger's test, p value = 0.135). The risk of failure for HPV-positive patients with tumours from the larynx was more than 2 times greater than that of patients with HPV-negative tumours (unadjusted HR: 2.45, 95% CI: 0.3–23.6).
Discussion
To our knowledge, this is the first meta-analysis carried out to assess the effect of HPV status on overall and DFS for patients with head and neck cancer. We report a significantly improved OS (meta HR: 0.85, 95% CI: 0.7–1.0) and DFS (meta HR: 0.62, 95% CI: 0.5–0.8) for patients with HPV-positive tumours. While the majority of studies reported an improved prognosis, several reported no difference or worse outcome. For these 3 groups of studies, evaluation of HPV prevalence by tumour site (Table II) may have provided an explanation for the reported differences in outcome. When we summarized the prevalence of HPV for those studies that have reported an improved outcome, the HPV prevalence for all sites combined was 28%, and for tumours in the oropharynx it was 40%. These findings are consistent with earlier studies reporting that HPV prevalence in head and neck tumours is about 20–26%,8, 53 while a higher frequency of infection (∼36%) is observed in the oropharynx and more specifically in the tonsils.53 In contrast, studies reporting a worse prognosis or no difference in outcome had a much higher prevalence of HPV-positive tumours overall (42 and 44%, respectively). One explanation for the high prevalence of HPV infection reported in these studies may be because the majority of the HPV-positive tumours carried either low-risk or uncharacterized HPV types (studies that reported no difference in prognosis 5/9 (56%); and studies that reported a worse prognosis 2/3 (67%).
Furthermore, these studies included more than half of the patients with tumours from the oral cavity or larynx, while the studies that reported an improved outcome included more than half of the patients with tumours from the pharynx. This suggests that the prognostic significance of HPV may be site specific. This can be corroborated by our findings from the site-specific meta analyses, which suggest site-specific differences in overall and DFS for patients with HPV-positive tumours. Although the OS rate for patients with HPV-positive oropharyngeal tumours was only slightly better than those patients that had HPV-negative oropharyngeal tumours it may not be entirely clear from these data that HPV has no influence on survival for patients with non-oropharyngeal tumours. We observed evidence of publication bias for these studies, possibly because we were unable to include all of the articles in the site-specific meta-analysis since some did not provide specific site information.
In contrast to the patients with oropharyngeal tumours, OS for patients with non-oropharyngeal tumours did not differ by HPV status. We also observed that patients with HPV-positive oropharyngeal tumours had an even more significantly lower risk of recurrence than patients with HPV-negative oropharyngeal tumours (meta HR for DFS: 0.51, 95%CI: 0.4–0.7). The analysis for DFS for patients with non-oropharyngeal tumours (from the larynx) reported that the HPV-positive patients had more than doubled the risk of recurrence than did the HPV-negative patients. This observation should be interpreted with caution, since it was only a single study consisting of 25 patients. Therefore, further studies are required to evaluate the prognostic significance of HPV in non-oropharyngeal sites.
One possible limitation of our meta-analysis is the introduction of selection bias since only 23 out of the 37 original studies could be included in the meta-analysis because of lack of relevant data in the excluded publications. However, the excluded studies reported improved overall and/or DFS in 10 studies; no difference was reported in 2 studies, and in the other 2, a poor overall and/or DFS was reported.
This review suggests that there may not only be an improved overall and DFS for patients with HPV-positive tumours, but that this effect might be site specific. A recent systematic review and meta-analysis has shown that the association between HPV16 and cancer is strongest in the oropharynx and weakest in the oral cavity and larynx.54 Our review adds further support to earlier suggestions that HPV-positive oropharyngeal tumours may have a distinct etiology from the tumours in non-oropharyngeal sites. We report that the observed improved overall and DFS for HPV-positive patients is specific to the oropharynx. This finding may be attributed to the high frequency of HPV16 infections observed among patients with HPV-positive oropharyngeal tumours in this meta-analysis (range: 88–100% vs. 31–100%).
It is not entirely clear why there is an improved outcome for patients with HPV16-positive oropharyngeal tumours. We and others have shown that HPV16-positive head and neck tumours are more likely to carry wild-type TP53 and express p16.8, 39, 55 This characteristic is likely a result of a transcriptionally active HPV infection. Recent studies have shown that patients with HPV16-positive HNSCC that express wild-type TP53 and/or express p16 have an improved DFS,26, 51, 52 which supports the notion that the improved prognosis may in fact be attributed to HPV infection.
One explanation for the improved prognosis among patients with HPV-positive HNSCC might be that in contrast to tobacco-associated HNSCC, the presence of functional TP53 in HPV-positive HNSCC may render the tumour susceptible to radiation-induced apoptosis.56 However, the mechanism by which HPV infection attributes to the improved outcome may be less than simple. Studies have shown that not all HPV-positive head and neck tumours are transcriptionally active.55 Furthermore, nearly half of head and neck tumours express amplification at 11q13.57, 58 This molecular marker has been shown to be associated with a more rapid and frequent recurrence of disease59 and poorer survival.60, 61, 62 We recently reported that HPV-positive head and neck tumours are less likely to carry gene amplification at 11q13.8 The significance of this finding and how it might be related to outcome has not yet been investigated. Therefore, studies that further define the molecular characteristics of HPV-positive tumours using additional detection methods beside HPV-DNA PCR such as p16 staining or E6, E7 RT-PCR, TP53 status and 11q13 amplification status are necessary and might prove to be beneficial in identifying the pathways involved in the improved outcome of patients with HPV-positive HNSCC.
Acknowledgements
This work was supported in part by NIH grants P50CA097190 (Head and neck SPORE: Project 1) to E.T., 5P50CA097190 (Head and neck SPORE: Minority supplement) and a GLMA foundation grant to C.R.R.
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