TABLE 2.
Representative studies demonstrating the existence of HPV-positive HNC as a distinct disease group.
| Study (year) | Sample size and HPV positivity | Study design | Anatomical sites examined | HPV-positive HNSCC | HPV-negative HNSCC |
|---|---|---|---|---|---|
| Pintos et al. (1999) | Archival specimens of UADT (n = 101), HPV positivity: 16.8% | Cross-sectional study | Pharynx, buccal, larynx | Gender bias [M:F::14:3 (4.7)] | Gender [M:F::66:18 (3.7)] |
| Younger age [<60:>60 years::12:8 (1.5)] | Age [<60:>60 years::30:54 (0.55)] | ||||
| Higher proportion of WDSCC [6/17 (0.35)] | WDSCC [14/84 (0.17)] | ||||
| Early stage [T1-2:T3-4::11:6 (1.8)] | Stage [T1-2: T3-4::41:43 (0.95)] | ||||
| Without lymph node metastasis [2/17 (0.12)] | Lymph node metastasis [29/84 (0.35)] | ||||
| Gillison et al. (2000) | Fresh tissues (n = 253), HPV positivity: 22% | Prospective analysis of tissues with patient follow-up and association with history | All sites of the HN region | HPV16 associated, viral integration, poor tumor grade (OR-2.4) | Moderate-to-heavy drinkers (OR- 5.88) |
| Over-representation in oropharynx | Smokers (OR- 6.25) | ||||
| Basaloid morphology (OR- 18.7) | TP53 mutations detected (OR- 16.7) | ||||
| Better DFS (HR- 0.26) | Age at diagnosis >60 years | ||||
| Better prognosis (59% risk reduction) | |||||
| Van Houten et al. (2001) | Fresh specimens of UADT (n = 84) | Prospective analysis | All sites of the HN region | p53 wild type, non-mutated in E6 positive tumor (9/9) | Frequent p53 mutations [40/64 (62.5%)] |
| HPV positivity: 23.8% | p53 mutations only in HPV E6RNA negative tumors [4/11 (36.4%)] | ||||
| Mork et al. (2001) | Serum from cohort studies (cases = 292; controls = 1,568) | Case–control retrospective study | All sites of the HN region | Seropositivity for HPV16–35/292 (12%) against control group—102/1,568 (7%) | Reference |
| HPV positivity: 12% | |||||
| Smith et al. (2004) | Patient biopsy (n = 193) | Prospective analysis | All sites of the HN region | Younger age (<55:>55 years; OR-3.4) | Reference |
| HPV positivity: 20% | More lifetime sex partners (OR-3.8), practiced oral-genital sex (OR-4.3), or oral–anal sex (OR-19.5) | ||||
| Mishra, et al. (2006) | Patient biopsy (n = 66) | Prospective analysis | All sites of the HN region | Selective participation of p65 subunit in the NF-κB complex | Constitutively active NF-κB complex with p50 homodimer |
| Mishra et al. (2006) | HPV positivity: 27% | ||||
| Hammarstedt et al. (2006) | Archival specimens (n = 203) | Retrospective study of cases b/w 1970–2002 | Tonsils | Younger patients [<60:>60 years::58:41 (1.41)] | Age [<60:>60 years::30:74 (0.41)] |
| HPV positivity: 49% | |||||
| Ragin and Taioli (2007) | Pooled analysis (n = 1747) | Meta-analysis | Oral cavity, oropharynx | Lower risk of dying (HR-0.85) | Reference |
| HPV positivity: 27.7% | Lower risk of recurrence (HR-0.62)DFS (HR: 0.51) | ||||
| Fakhry et al. (2008) | Fresh tissues (n = 96 patients) | Prospective clinical trial controlled for known factors of prognostic values | Oropharynx, larynx | Higher response after induction chemotherapy (82%) and chemoradiation (84%) | Moderate response after induction chemotherapy (55%) and chemoradiation (57%) |
| Increased 2-years survival (95%) with lower risk of progression and death | |||||
| — | Lower risk of dying (HR-0.36) | — | |||
| Lower risk of progression (HR-0.27) | |||||
| Chaturvedi et al. (2008) | SEER (1973–2004) (n = 45,769) | Cohort analysis for investigation of survival of OSCC patients | Oral cavity | Mean ages at diagnosis-61.0 years | Mean ages at diagnosis-63.8 years |
| HPV positivity: 38.5% | APC in incidence (1973–2004) - 0.80 Showed increased | APC in incidence (1973–2004)–(−)1.85 | |||
| 2-year survival from 9.9 to 18.6% | Showed 2-year survival from 5.6 to 9.9% | ||||
| Gillison et al. (2008) | Newly diagnosed HNSCC patient (n = 240) and 322 controls [HPV(16) positivity: 38.3%] | Case–control study to compare risk factors in HPV-positive vs HPV-negative tumors | Oral cavity, paranasal sinus, pharynx, larynx | Gender bias [M:F::78:14 (5.6)] association increased with the increasing number of oral sex partners, with increasing intensity (joints per month), duration (in years), and cumulative joint-years of marijuana use | Gender bias [M:F::111:37 (3.0)] |
| Associated with tobacco smoking, alcohol drinking, and poor oral hygiene | |||||
| Not associated with sexual behavior or marijuana use | |||||
| Golderberg et al. (2008) | FFPE (n = 84) [HPV(16) positivity: 87%] | Retrospective review of patients undergoing neck dissection between 2002 and 2004 | Oropharynx, oral cavity, larynx, hypopharynx | Related with cystic cervical lymph node | Associated with solid nodal metastasis |
| Ang et al. (2010) | Patients (n = 323) | Retrospective analysis for tumor HPV status and survival among patients | Oropharynx | 3-year rate of survival (82.4%) | 3-year rate of survival (57.1%) |
| 3-year rates of PFS (73.7%) | |||||
| Reduction in the risk of death (58%) | — | ||||
| Reduction in the risk of relapse or death (51%) | |||||
| Rischin et al. (2010) | Stage III and IV patients (n = 172) | Retrospective study | Oropharynx | Lower T and higher N categories and better ECOG performance status in p16 positive. 2-year overall survival [91% (HR-0.36)]. 2-year failure-free survival in p16 positive [87% (HR-0.39)] | 2-year overall survival (74%). 2-year failure-free survival (72%) |
| HPV positivity: 53.5%; p16 positivity a –59.3% | |||||
| Chaturvedi et al. (2011) | Archival tissue from year 1988 to 2004 (n = 271) | Retrospective time period study | Oropharynx | Median survival (131 months) | Median survival (20 months). Population-level incidence declined (50%; 2.0–1.0 per 100,000) |
| Increased prevalence from 1984 to 1989 (16.3%) to 2000 to 2004 (71.7%) | |||||
| Population-level incidence increased (225%; from 0.8 per 100,000 to 2.6 per 100,000) | |||||
| Posner et al. (2011) | Patients (n = 111) | Retrospective study to evaluate OS, PFS, and HPV | Oropharynx | Median age: 54 years | Median age: 58 years |
| T1/T2 primary: 49% | T1/T2 primary: 20% | ||||
| — | 5-year PFS: 78% | 5-year PFS: 28% | |||
| 5-year OS: 82% | 5-year OS: 35% | ||||
| De Martel et al. (2012) | GLOBOCAN data 2008 (sample size not described) | Synthetic analysis of HPV PCR positivity in tumor tissue with HPV E6 or E7 expression | Oropharynx | Geographical variations (north America: 56%, northern and western Europe: 39%, eastern Europe: 38%; southern Europe: 17%, Australia–45%, Japan: 52%, rest of world: 13% | Not assessed |
| Ndiaye et al. (2014) | Patients (n = 12,163) [overall HPV positivity: 31.54%; for oropharynx: 45.8%, for larynx (including hypopharynx): 22·1%, and for oral cavity: 24·2%] | Meta-analysis of 148 studies | Oropharynx, larynx, oral cavity | p16INK4a positivity in HPV-positive oropharyngeal cancer cases: 86·7% and E6/E7 mRNA positivity: 86·9% | Reference |
| HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was estimated as 39·8% and of p16INK4a was 39·7% | |||||
| Fakhry et al. (2014) | Patients (n = 181) | Retrospective evaluation of OS | Oropharynx | Improved 2-year OS in p16 positive patients (54.6%; median: 2.6 years) | OS in p16-negative patients (27.6%; median: 0.8 years) |
| p16 positivity a -58% | |||||
| Vermorken et al. (2014) | Patient samples-FFPE (n = 416) | Retrospective analysis of R/M HNSCC | All sites of the HN region | Better OS for HPV+/p16+. CT + cetuximab (median month-12.6). CT (median month-7.1) | OS for HPV-/p16-CT + cetuximab (median month-9.6). CT (median month-6.7) |
| HPV positivity: 6% | |||||
| The Cancer Genome Atlas Network (2015) | Tumor tissues (n = 279) | Cohort study | Oral cavity oropharynx, larynx | Helicase domain mutations of the oncogene PIK3CA. Novel alterations involving loss of TRAF3. Amplification of the cell cycle gene E2F1 | Near universal loss-of-function TP53 mutations and CDKN2A with frequent copy number alterations including a novel amplification of 11q22 |
| HPV positivity: 12.9% | |||||
| Gupta et al. (2015), Gupta et al. (2018) | Fresh biopsies (n = 50) [HPV(16) positivity: 28%] | Prospective study | Tongue | Well differentiated tongue carcinomas (78.5%) | Poorly differentiated carcinomas (72.2%) |
| Higher expression and DNA binding activity of AP-1 and NF-κB with c-fos and Fra-2; and p50 and c-rel as the major binding partners forming the functional AP-1 and NF-κB complex, and selective participation of p65 | Low expression and DNA binding activity of AP-1 with c-Jun as the major binding partners forming the functional AP-1 complex | ||||
| Induced expression of p65 and p27 leading to well differentiation and better prognosis | Participation of c-Rel with p50 that in crosstalk with AP-1/Fra-2 leading to poor differentiation and aggressive tumorigenesis | ||||
| Gaykalova et al. (2015) | Tissues from HNSCC patients (n = 195) and noncancer-affected patients (n = 63) [discovery- HPV(16) positivity: 29.5%] | Cohort study | All sites of the HN region | Described 5 top-scoring pair biomarkers from STATs, NF-κB and AP1 pathways that distinguished HPV + HNSCC based on TF activity | High expression of CCND1, CEBPD, ICAM1, IRF1, JAG1, JAK3, and NOS3 |
| Verma et al. (2017) | Fresh biopsies and FFPE tissues (n = 135) [HPV(16) positivity: 23%] | Prospective and archival study | Oral cavity oropharynx | Direct correlation with tissue immunopositivity for JunB and p65, whereas pSTAT3 were inversely correlated | Presence of STAT3/pSTAT3 with NF-κB irrespective immunopositivity for AP-1 members |
| Low pEGFRY1092 status | High pEGFRY1092 status | ||||
| Gletsou et al. (2018) | Patient samples-FFPE (n = 28) | Analytical study | Oropharynx | Bigger | Comparatively smaller |
| HPV positivity: 10.7% | Tumor diameter of 3.7 ± 1.5 cm, volume of 9.5 ± 5.8 cm3 | Tumor diameter of 2.7 ± 0.6 cm, volume of 5.4 ± 2.7 cm3 | |||
| Adjei Boakya et al. (2018) | Patient samples (n = 109,512) from SEER | Cohort study | All sites of the HN region | Low risk of second primary malignant neoplasms | High risk of second primary malignant neoplasms |
| HPV positivity: 38.1% | |||||
| Abdel-Rahman (2020), (Abdel-Rahman, 2020) | Patient records (n = 1,157) from SEER | Cohort analysis for investigation of survival of hypopharyngeal carcinoma patients | Hypopharynx | OS (HR: 1.76) | Reference |
| HPV positivity: 24% | Better OS with regional and distance disease | ||||
| Head and neck cancer–specific survival (HR: 1.54) |
a
p16 positivity was taken as surrogate marker for (transcriptionally active) HPV positivity.
Abbreviations: AP1, activator protein 1; APC, annual percentage change; CT, chemotherapy; DFS, disease-free survival; DNA, deoxyribose nucleic acid; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FFPE, formalin fixed paraffin embedded; HPV, human papillomavirus; HR, hazard ratio; HN, head and neck; HNSCC, head and neck squamous cell carcinoma; NF-κB, nuclear factor-kappa B; OS, overall survival; OR, odds ratio; OSCC, oral squamous cell carcinoma; OPSCC, oropharyngeal squamous cell carcinoma; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PCR, polymerase chain reaction; PFS, progression-free survival; R/M, recurrent and/or metastatic; STAT3, signal transducer and activator of transcription 3; SEER, surveillance, epidemiology, and end result program registries; TRAF3, TNF receptor-associated factor 3; UADT, upper aerodigestive tract; WDSCC, well-differentiated squamous cell carcinoma.