Abstract
Aims
Smoking and human papillomavirus (HPV) are both distinct risk factors for head and neck cancer, but the nature of interaction between these 2 risk factors in the development of head and neck cancer remains unclear. The purpose of this review is to determine the potential effect of smoking in causation of HPV-related head and neck carcinoma.
Method
A literature search was carried out using the keywords human papillomavirus , head and neck cancer , smoking , tobacco , and cervical cancer . The English-language articles, references, and other relevant studies evaluating the association of smoking, HPV, and risk of head and neck cancer were collected and analyzed.
Conclusion
Overall, our review points to smoking tobacco posing an additional risk for development of head and neck cancer in the presence of HPV infection. This is consistent with available laboratory data that show evidence of biological plausibility for interaction between smoking and progression of HPV infection to carcinogenesis. It is therefore important that cessation of smoking is promoted in smokers with HPV infection.
1
Introduction
The evidence for a link between human papillomavirus (HPV) and head and neck squamous cell carcinoma (HNSCC) has been growing ever since it was first proposed . The literature, however, presents conflicting accounts about the nature of association between smoking and HPV in causation of HNSCC. In cervical cancer, a disease strongly associated with HPV, numerous studies point to a synergistic effect of smoking in the progression from cervical HPV infection to frank cervical cancer . Smoking has been found to prolong the cervical HPV infection resulting in the development of cervical dysplasia and progression of dysplasia toward higher grades of cervical intraepithelial neoplasia and, ultimately, invasive carcinoma . It has also been suggested that HPV infection alone may not be sufficient for causation of cancer, and other cofactors such as tobacco consumption may be required to evince its carcinogenetic effect . Although much of our understanding about HPV in HNSCC is based on the model of cervical cancer, the degree of interaction between smoking and HPV in HNSCC is not well delineated. Some authors have observed no association , whereas other studies demonstrate an additive or synergistic association . Our review critically appraises the current state of the literature and seeks to determine the effect of smoking in HPV-related head and neck cancer.
2
Methodology
We searched MEDLINE and Google Scholar electronic databases independently for the terms human papillomavirus , head and neck cancer , smoking , tobacco , and cervical cancer . We reviewed the articles available in English from 1980 through 2010 and their references. The related articles link and hand searching using key terms were used to locate additional relevant studies. The methodology, results, and conclusions sections of the studies were reviewed. Of more than 150 citations, we collected details on all studies that explored the association between HPV and smoking in development of HNSCC. Table 1 presents a summary of the selected studies included in our review. Based on their reported conclusions, we found the studies to be mainly of 3 categories: ( a ) studies with evidence that HPV is associated with an increased risk of HNSCC in nonsmokers, ( b ) studies with no difference in HPV-related HNSCC prevalence between smokers and nonsmokers, and ( c ) studies with evidence of an additive or synergistic effect between smoking and HPV-related HNSCC. These articles and their inferences about the interaction between smoking and HPV in HNSCC are analyzed below.
| Authors | Source of subjects and design | Cases | No. of cases/controls | HPV assay method | Relation between frequency of smoking and HPV status in cases (%) | OR (95% CI) for HNSCC (positive HPV infection and smoking) | Conclusion about interaction between smoking and HPV |
|---|---|---|---|---|---|---|---|
| Snijders et al, 1996 | Hospital-based prevalence study | Newly diagnosed patients with HNSCC sampled during surgical treatment | 63/0 | PCR of snap frozen tumor tissue and Southern blot analysis for multiple LR and HR | Of HPV-positive cases, 16.7% were nonsmokers, 28.6% were heavy smokers (>20/d), and 50% were former smokers | NR | No correlation between HPV and smoking status |
| Paz et al, 1997 | Hospital-based prevalence study | Treated patients with head and neck cancers | 167/0 | PCR of snap frozen tumor tissue for HPV 6, 16, and 18 and Southern blot hybridization | 81% smokers in HPV-positive cases vs 85.7% in HPV-negative cases (difference, NS) | NR | No difference in HPV-positive HNSCC prevalence in smokers and nonsmokers |
| Fouret et al, 1997 | Hospital-based prevalence study | Treated patients with oropharyngeal, hypopharyngeal, and laryngeal cancers | 187/0 | PCR and sequencing of paraffin-embedded samples using E6-directed primers | HPV positivity in 8.5% of smokers (95% CI, 0.5–1.4) vs 50% of nonsmokers (95% CI, 1.9–8.1) ( P = .003) | NR | HPV may play a role in HNSCC in nonsmokers |
| Schwartz et al, 1998 | Population-based case-control study | Newly diagnosed oral and oropharyngeal cases including treated cases | 284/477 | PCR and sequencing of tumor and exfoliated cells (brush) for HR and LR; ELISA for HPV L1 | 31.3% current smokers in HPV L1–seropositive cases vs 20.1% in HPV L1–seronegative cases | 8.5 (5.1–14.4) for smokers and HPV-16 L1 seropositivity | Synergistic association of smoking and HPV-16 L1 seropositivity (synergy index, 2.6; CI, 1.3–5.0) |
| Gillison et al, 2000 | Hospital-based retrospective study | Newly diagnosed or recurrent cases of HNSCC | 253/0 | PCR, Southern blot and in situ hybridization for HR and LR | 67% smokers in the HPV-negative vs 63% HPV-positive cases (difference, NS) | NR | No difference in HPV-positive HNSCC prevalence in smokers and nonsmokers |
| Herrero et al, 2003 | Hospital-based multicenter case-control study | Newly diagnosed patients with oral and oropharyngeal before treatment | 1670/1732 | PCR of tumor tissue and exfoliated cells by brushing; ELISA for antibodies to L1, E6, E7 | 24% nonsmokers and 76% smokers in cases with HPV E6/E7 positivity | 56.2 (22.5–140.4) for smokers who were positive for HPV-16 E6 or E7 (no stratification by dose duration) | Additive effect for HPV E6/E7 seropositivity and tobacco smoking or chewing |
| Smith et al, 2004 | Hospital-based case-control study | Newly diagnosed patients with oral and oropharyngeal cases before treatment | 201/333 | PCR and sequencing of oral exfoliated cells (rinse) for both HR and LR | 13% heavy smokers (>30 pack-years) in HPV HR cases vs 44% in HPV-negative cases | 5.5 (2.1–14.1) | Additive effect between tobacco use and detection of HPV DNA |
| D’Souza et al, 2007 | Hospital-based case-control study | Newly diagnosed oropharyngeal cancer cases before treatment | 100/200 | HPV-16 in situ hybridization; DNA analysis of both HR and LR types; ELISA for antibodies against L1 | NR | 27.8 (6.7–114.6) for HPV-16 L1 seropositivity and heavy smoking; 37.1 (15.6–88.4) for moderate smoker (<20) and 2.8 (1.2–6.4) for heavy smokers and seronegative cases | No additive/synergistic effect of tobacco with HPV (synergy index, 0.7; 0.5–1.1) |
| Applebaum et al, 2007 | Case-control study | Incident cases of HNSCC both before and after treatment | 485/549 | HPV competitive Luminex immunoassay for antibodies to HPV-16 L1 | In seropositive vs seronegative cases, never smokers (15% vs 5%); 0–20 pack-years (11% vs 7%); 20–45 (11% vs 15%); >45 (12% vs 24%) | HPV-16 seropositivity a/w 30-fold increased risk of pharynx cancer among never smokers (OR, 32.5; 95% CI, 13.3–79.5) | Tobacco use does not increase the risk of HPV-16–associated pharyngeal cancer |
| Gillison et al, 2008 | Hospital-based case-control study | Newly diagnosed patients with HNSCC before treatment | 240/322 | In situ hybridization system for HPV-16 DNA detection in paraffin-embedded tumor tissue for HR and LR | 52% never smokers; 29% former smokers; 18% current smokers among HPV-16–positive cases | Very heavy daily users of tobacco (>40/d) had nonstatistically significant increased odds of HPV-16 DNA-positive HNSCC (3.2; 95% CI, 0.73–13.9) | No additive/synergistic effect, positive trend noted for HPV and heavy smoking |
| Furniss et al, 2009 | Case-control study | Incident cases of HNSCC both before and after treatment | 486/548 | Competitive Luminex immunoassay for HPV 6, 11, 16, 18 | NR | For pharyngeal cancer cases with heavy smoking, OR = 3.1 (2.0–4.8) among HPV-6–seronegative cases and 1.6 (0.7–3.5) in HPV-6–seropositive cases | HPV-6 seropositivity independently associated with increased risk of pharyngeal tumors and is not associated with smoking |
| Smith et al, 2010 | Hospital-based case-control study | Newly diagnosed HNSCC cases | 201/324 | ELISA for antibodies to VLP and PCR of tumor tissue | 22% heavy smokers (>30 pack-years) in HPV VLP–seropositive cases vs 26% heavy smokers in seronegative cases | OR for heavy smoking (>30 pack-years) and HPV VLP seropositivity = 2.3 (1.1–4.8); for sereonegativity, OR = 2.6 (1.4–5.0) | Tobacco use increases risk of HNSCC in both HPV-seropositive and HPV-seronegative patients |
2
Methodology
We searched MEDLINE and Google Scholar electronic databases independently for the terms human papillomavirus , head and neck cancer , smoking , tobacco , and cervical cancer . We reviewed the articles available in English from 1980 through 2010 and their references. The related articles link and hand searching using key terms were used to locate additional relevant studies. The methodology, results, and conclusions sections of the studies were reviewed. Of more than 150 citations, we collected details on all studies that explored the association between HPV and smoking in development of HNSCC. Table 1 presents a summary of the selected studies included in our review. Based on their reported conclusions, we found the studies to be mainly of 3 categories: ( a ) studies with evidence that HPV is associated with an increased risk of HNSCC in nonsmokers, ( b ) studies with no difference in HPV-related HNSCC prevalence between smokers and nonsmokers, and ( c ) studies with evidence of an additive or synergistic effect between smoking and HPV-related HNSCC. These articles and their inferences about the interaction between smoking and HPV in HNSCC are analyzed below.
| Authors | Source of subjects and design | Cases | No. of cases/controls | HPV assay method | Relation between frequency of smoking and HPV status in cases (%) | OR (95% CI) for HNSCC (positive HPV infection and smoking) | Conclusion about interaction between smoking and HPV |
|---|---|---|---|---|---|---|---|
| Snijders et al, 1996 | Hospital-based prevalence study | Newly diagnosed patients with HNSCC sampled during surgical treatment | 63/0 | PCR of snap frozen tumor tissue and Southern blot analysis for multiple LR and HR | Of HPV-positive cases, 16.7% were nonsmokers, 28.6% were heavy smokers (>20/d), and 50% were former smokers | NR | No correlation between HPV and smoking status |
| Paz et al, 1997 | Hospital-based prevalence study | Treated patients with head and neck cancers | 167/0 | PCR of snap frozen tumor tissue for HPV 6, 16, and 18 and Southern blot hybridization | 81% smokers in HPV-positive cases vs 85.7% in HPV-negative cases (difference, NS) | NR | No difference in HPV-positive HNSCC prevalence in smokers and nonsmokers |
| Fouret et al, 1997 | Hospital-based prevalence study | Treated patients with oropharyngeal, hypopharyngeal, and laryngeal cancers | 187/0 | PCR and sequencing of paraffin-embedded samples using E6-directed primers | HPV positivity in 8.5% of smokers (95% CI, 0.5–1.4) vs 50% of nonsmokers (95% CI, 1.9–8.1) ( P = .003) | NR | HPV may play a role in HNSCC in nonsmokers |
| Schwartz et al, 1998 | Population-based case-control study | Newly diagnosed oral and oropharyngeal cases including treated cases | 284/477 | PCR and sequencing of tumor and exfoliated cells (brush) for HR and LR; ELISA for HPV L1 | 31.3% current smokers in HPV L1–seropositive cases vs 20.1% in HPV L1–seronegative cases | 8.5 (5.1–14.4) for smokers and HPV-16 L1 seropositivity | Synergistic association of smoking and HPV-16 L1 seropositivity (synergy index, 2.6; CI, 1.3–5.0) |
| Gillison et al, 2000 | Hospital-based retrospective study | Newly diagnosed or recurrent cases of HNSCC | 253/0 | PCR, Southern blot and in situ hybridization for HR and LR | 67% smokers in the HPV-negative vs 63% HPV-positive cases (difference, NS) | NR | No difference in HPV-positive HNSCC prevalence in smokers and nonsmokers |
| Herrero et al, 2003 | Hospital-based multicenter case-control study | Newly diagnosed patients with oral and oropharyngeal before treatment | 1670/1732 | PCR of tumor tissue and exfoliated cells by brushing; ELISA for antibodies to L1, E6, E7 | 24% nonsmokers and 76% smokers in cases with HPV E6/E7 positivity | 56.2 (22.5–140.4) for smokers who were positive for HPV-16 E6 or E7 (no stratification by dose duration) | Additive effect for HPV E6/E7 seropositivity and tobacco smoking or chewing |
| Smith et al, 2004 | Hospital-based case-control study | Newly diagnosed patients with oral and oropharyngeal cases before treatment | 201/333 | PCR and sequencing of oral exfoliated cells (rinse) for both HR and LR | 13% heavy smokers (>30 pack-years) in HPV HR cases vs 44% in HPV-negative cases | 5.5 (2.1–14.1) | Additive effect between tobacco use and detection of HPV DNA |
| D’Souza et al, 2007 | Hospital-based case-control study | Newly diagnosed oropharyngeal cancer cases before treatment | 100/200 | HPV-16 in situ hybridization; DNA analysis of both HR and LR types; ELISA for antibodies against L1 | NR | 27.8 (6.7–114.6) for HPV-16 L1 seropositivity and heavy smoking; 37.1 (15.6–88.4) for moderate smoker (<20) and 2.8 (1.2–6.4) for heavy smokers and seronegative cases | No additive/synergistic effect of tobacco with HPV (synergy index, 0.7; 0.5–1.1) |
| Applebaum et al, 2007 | Case-control study | Incident cases of HNSCC both before and after treatment | 485/549 | HPV competitive Luminex immunoassay for antibodies to HPV-16 L1 | In seropositive vs seronegative cases, never smokers (15% vs 5%); 0–20 pack-years (11% vs 7%); 20–45 (11% vs 15%); >45 (12% vs 24%) | HPV-16 seropositivity a/w 30-fold increased risk of pharynx cancer among never smokers (OR, 32.5; 95% CI, 13.3–79.5) | Tobacco use does not increase the risk of HPV-16–associated pharyngeal cancer |
| Gillison et al, 2008 | Hospital-based case-control study | Newly diagnosed patients with HNSCC before treatment | 240/322 | In situ hybridization system for HPV-16 DNA detection in paraffin-embedded tumor tissue for HR and LR | 52% never smokers; 29% former smokers; 18% current smokers among HPV-16–positive cases | Very heavy daily users of tobacco (>40/d) had nonstatistically significant increased odds of HPV-16 DNA-positive HNSCC (3.2; 95% CI, 0.73–13.9) | No additive/synergistic effect, positive trend noted for HPV and heavy smoking |
| Furniss et al, 2009 | Case-control study | Incident cases of HNSCC both before and after treatment | 486/548 | Competitive Luminex immunoassay for HPV 6, 11, 16, 18 | NR | For pharyngeal cancer cases with heavy smoking, OR = 3.1 (2.0–4.8) among HPV-6–seronegative cases and 1.6 (0.7–3.5) in HPV-6–seropositive cases | HPV-6 seropositivity independently associated with increased risk of pharyngeal tumors and is not associated with smoking |
| Smith et al, 2010 | Hospital-based case-control study | Newly diagnosed HNSCC cases | 201/324 | ELISA for antibodies to VLP and PCR of tumor tissue | 22% heavy smokers (>30 pack-years) in HPV VLP–seropositive cases vs 26% heavy smokers in seronegative cases | OR for heavy smoking (>30 pack-years) and HPV VLP seropositivity = 2.3 (1.1–4.8); for sereonegativity, OR = 2.6 (1.4–5.0) | Tobacco use increases risk of HNSCC in both HPV-seropositive and HPV-seronegative patients |
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