Oropharyngeal squamous cell carcinoma (OPSCC) originating from human papillomavirus infection has emerged as a new entity in head and neck cancer, defining a subset of patients with distinct carcinogenesis, risk factor profiles, and clinical presentation that show markedly improved survival than patients with classic OPSCC. De-escalation of therapy and identification of relevant biomarkers to aid in patient selection are actively being investigated. This review addresses the implications of these findings in clinical care.
| CRT | Chemo-radiotherapy |
| CT | Chemotherapy |
| HNSCC | Head and neck squamous cell carcinoma |
| HPV | Human papillomavirus |
| IC | Induction chemotherapy |
| ISH | In situ hybridization |
| OPSCC | Oropharyngeal squamous cell carcinoma |
| OS | Overall survival |
| PFS | Progression free survival |
| RT | Radiotherapy |
| TLM | Transoral laser microsurgery |
| TORS | Transoral robotic surgery |
Key points
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Human papillomavirus (HPV)-positivity defines a subset of patients with oropharyngeal squamous cell carcinoma (OPSCC) with distinct carcinogenesis, risk factors, clinical presentation and prognosis, representing a different disease from other head and neck squamous cell carcinomas (HNSCC).
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Cancer in these patients is mainly driven by the viral E6 and E7 oncoproteins, which interfere with p53 and pRb tumor-suppressor pathways.
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Patients are typically younger, nondrinkers, and nonsmokers, with risk factors associated with sexual exposure to HPV.
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Patients with HPV-positive OPSCC show better response to treatment, overall survival, and progression-free survival than those with HPV-negative tumors.
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Reasons for improved survival are unknown. Current hypotheses include decreased field cancerization, decreased genetic instability and tumor heterogeneity, reactivation of p53 by chemotherapy and radiotherapy, and improved immune response in HPV-positive cancers.
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The improved outcomes found in HPV-positive OPSCC have confounded clinical trial results in the recent past. Ongoing trials need to include assessment of HPV status in their design.
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Clinical trials are under way to determine whether de-escalation of therapy is possible in HPV-positive patients with OPSCC to achieve similar survival with reduced short-term and long-term morbidity.
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Biomarkers that may direct different therapeutic approaches are actively being investigated.
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Prevention should be focused on modification of risk factors, with a special emphasis on HPV vaccination.
Introduction
Within the recent epidemic of oropharyngeal squamous cell carcinoma (OPSCC), human papillomavirus (HPV) has been found to play a pivotal role in defining a subset of patients with distinct carcinogenesis, risk factors, clinical presentation, and prognosis. HPV-positive OPSCC patients, OPSCC seems to be a wholly different disease to that classically described for HPV-negative tumors, which are typically driven by the carcinogenic effects of tobacco and alcohol exposure. Although much effort has been put into describing the subset of HPV-positive patients, research has not yet translated into therapies that address the different biology and its associated better outcomes. The identification of biomarkers to aid in prognostic and therapeutic decisions, the potential for de-escalation of therapy, and the incorporation of therapies targeted to relevant HPV-related pathways are areas that are actively being evaluated in clinical trials. In this review, the implications of these findings in clinical care are addressed.
Introduction
Within the recent epidemic of oropharyngeal squamous cell carcinoma (OPSCC), human papillomavirus (HPV) has been found to play a pivotal role in defining a subset of patients with distinct carcinogenesis, risk factors, clinical presentation, and prognosis. HPV-positive OPSCC patients, OPSCC seems to be a wholly different disease to that classically described for HPV-negative tumors, which are typically driven by the carcinogenic effects of tobacco and alcohol exposure. Although much effort has been put into describing the subset of HPV-positive patients, research has not yet translated into therapies that address the different biology and its associated better outcomes. The identification of biomarkers to aid in prognostic and therapeutic decisions, the potential for de-escalation of therapy, and the incorporation of therapies targeted to relevant HPV-related pathways are areas that are actively being evaluated in clinical trials. In this review, the implications of these findings in clinical care are addressed.
HPV basics
The causal role of HPV in carcinogenesis was first described in cervical cancer, but the virus has also been implicated in oropharyngeal, penile, anal, vaginal, and vulvar cancer. It is estimated that 5.2% of all cancers worldwide are attributable to HPV, and the burden of incidence and costs is increasing for noncervical HPV-related cancers, especially in the oropharynx. The incidence of OPSCC increased from 1988 to 2004, mainly driven by an increase in HPV-positive OPSCC of 225%, whereas HPV-negative disease has declined by 50%. HPV now accounts for 45% to 90% of cases of OPSCC in developed countries, and more than 90% of these are caused by the HPV-16 subtype. HPV status has important implications in OPSCC tumor biology, clinical presentation, prognosis, and potential treatment options, but its importance in other subsites is unclear. HPV has been detected in laryngeal (6%), hypopharyngeal (3%), oral cavity (4%), and paranasal (14%) cancers, but the significantly lower rates of HPV positivity and inconsistent findings among the studies suggest that HPV may not be playing a causative role in these subsites.
HPV and Carcinogenesis
Human papillomaviruses are small, nonenveloped, double-stranded DNA viruses that show tropism for squamous epithelium. They are classified into high risk (HR, HPV-16, HPV-18, HPV-51, HPV-53) and low risk (LR, HPV-6, HPV-11) based on the ability of the virus to promote progression to cancer. The process of HPV carcinogenesis is well characterized in cervical cancer, in which infection is established in the basal cell layer of the epithelium and leads to either a subclinical infection or a benign or malignant lesion. Although most women have a cervical HPV infection over their lifetime, about 10% of these become persistent and only a few may progress to cancer. For OPSCC, it is now known that 1% of the population has an oral HPV-16 infection, and that this confers a 50-fold increased risk for HPV-positive OPSCC, but the intermediate steps in progression have not been described. The cryptic epithelium that covers the tonsil and tongue base serves as a viral reservoir and facilitates infection through increased access to its basal layer, with an apparent predilection of this anatomic site to transformation by HPV similar to the cervical transformation zone.
The process of malignant transformation arises from the continued function of the E6 and E7 oncoproteins expressed by HR-HPV. These oncoproteins target several critical cellular pathways, providing multiple simultaneous oncogenic hits and leading to deregulation of proliferation, evasion of apoptosis, and induction of invasive and metastatic properties. As a result, HPV infection reduces the number of subsequent mutations needed to develop invasive carcinoma. The difference in oncogenic potential between HR-HPV and LR-HPV may rely on more efficient disruption of the biological activities of E6 and E7 proteins. Specifically, E7 inhibits the retinoblastoma tumor suppressor protein (pRb) and targets it for degradation, whereas E6 inactivates the p53 tumor suppressor. Inhibition of pRb function by viral proteins allows cells to continue dividing, despite signals for cell cycle arrest caused by oncogenic stress, such as those mediated by p53 or p16. High-risk HPV-E6 also induces the expression of vascular endothelial growth factor (VEGF) and activates telomerase, an essential step in immortalization. The combined effects of E6 and E7 on the p53/pRb pathways create an environment of genomic instability, which is highly conducive to cancer development.
Carcinogenesis in HPV-positive OPSCC is a process of cell cycle deregulation mediated by viral oncoproteins, which is specific to the epithelium under transformation. In contrast, HPV-negative OPSCC usually results from exposure to environmental carcinogens such as tobacco and alcohol, leading to disruption of those same cancer-promoting signaling pathways targeted by HPV. This disruption occurs via the process of field cancerization, or the progressive accumulation of mutations over large regions of aerodigestive mucosa, and leads to a higher probability of developing additional primary tumors. The highly localized carcinogenesis in HPV-positive OPSCC represents a profound difference in tumor biology.
Clinical implications of HPV-positive OPSCC
The distinct carcinogenesis of HPV-positive OPSCC leads to important differences in the population at risk for this disease, their clinical presentation, and prognosis. From the physician’s standpoint, this information is highly relevant in patient education and counseling. In the future, this information may soon translate into differential workup and tailored treatments for this patient population.
Clinical Presentation
Clinical presentation of HPV-positive OPSCC is different from that of HPV-negative patients. Patients tend to be younger and are more likely to be white, married, and college educated and typically present without a history of smoking or drinking. Given that HPV is a sexually transmitted disease, factors that increase oral or genital HPV exposure increase the risk of OPSCC, such as increasing age, increasing number of lifetime vaginal or oral sexual partners, ever having participated in casual sex, infrequent use of barriers during vaginal or oral sex, and ever having had a sexually transmitted disease. Oral HPV infection increases the risk for HPV-positive OPSCC, and this risk is higher among individuals who first performed oral sex at 18 years or younger or with increasing number of cigarettes smoked per day. Other risk factors for HPV-positive OPSCC include immunosuppression, seropositivity for HR-HPV, history of an HPV-associated malignancy, and being the partner of a woman with cervical cancer. Patients tend to present with low T and high N stage tumors on the American Joint Committee on Cancer TNM staging system, and histologically, these are usually nonkeratinizing, poorly differentiated, and of basaloid morphology.
HPV Status Determination
There is no general consensus on which method for diagnosing HPV-positive cancer should be used in HNSCC, because the techniques differ in sensitivity, specificity, and other technical considerations. Real-time polymerase chain reaction (RT-PCR) performed on microdissected tumors can detect small quantities of HPV DNA and describe the subtype, but it gives no information on host cell integration or activity, which are critical for carcinogenesis, and is not available in most clinical laboratories. In situ hybridization (ISH) localizes HPV DNA integrated into the host cell genome with high specificity, indicating viral presence and activity, but is less sensitive and more time consuming than RT-PCR and is available only at selected centers. Immunohistochemistry (IHC) of p16 has been suggested as a surrogate marker for HPV infection because of the simplicity, low cost, high sensitivity, and good correlation to HPV RT-PCR and ISH. However, because p16 has been reported to be constitutively expressed in tonsillar epithelium, can rarely be overexpressed in HPV-negative tumors, and the practice and reporting of IHC varies, its clinical application as a single assay may occasionally be misleading. With these considerations, an expert panel recommends a cost-efficient algorithm for HPV detection. Initial testing should include p16 IHC with HPV-16 ISH performed concurrently or after a positive IHC for confirmation. In case of discrepancy, a consensus ISH probe that detects an extended panel of HPV types or RT-PCR can be used to determine HPV status and subtype. However, to allow for standardized detection and robust clinical investigations, a true consensus has to be reached on the method of HPV detection in OPSCC.
Prevention
The distinct pathogenesis of HPV-positive OPSCC raises important public health considerations aiming to decrease the increasing incidence of this disease through health promotion and primary prevention strategies. The prevalence of oral HPV-16 infection is 1% in the United States and has been associated with a 50-fold increased risk for HPV-positive OPSCC. Infection is more common in smokers, and its increasing incidence has been related to the changing sexual behaviors among the population. In the primary care setting, efforts toward the modification of risk factors should be directed to reducing high-risk sexual behavior, decreasing oral HPV infection, and smoking cessation.
Because HPV-positive OPSCC is related to only a few HR-HPV subtypes, there is potential for the prevention of this disease through vaccination targeting those subtypes. Vaccination is effective only before infection is established, because it induces neutralizing antibodies that prevent virion entry but do not halt the progression of existing lesions. The 2 vaccines (HPV bivalent and quadrivalent vaccines) approved by the US Food and Drug Administration prevent persistent cervical HPV-16 infection. The bivalent vaccine is indicated for the prevention of cervical cancer in women, whereas the quadrivalent vaccine has in addition been approved for the prevention of genital warts and genital cancers in both sexes up to age 26 years. Vaccination may have higher impact in OPSCC than in cervical cancer, given that, unlike cervical cancer, there is no screening strategy for OPSCC and incidence is estimated to surpass that of cervical cancer by 2020. Parents of children of both sexes should be informed that vaccination is available and, although not approved for this indication, it may reduce the risk of other HPV-related cancers, including OPSCC.
Implications of HPV for treatment and outcomes
Survival in HPV-positive OPSCC
Over the last few decades, there has been improved survival in OPSCC and a resultant move toward organ preservation therapy as the primary treatment choice for these patients. Older studies looking at the effect of HPV on survival had mixed results, but the data that have accrued over the intervening years are increasingly convincing that HPV-positive OPSCC has a more favorable prognosis. A recent historical demographic analysis of patients with OPSCC at a single institution by Dahlstrom and colleagues ( Table 1 ) showed that, after 1995, patients with OPSCC were more likely to be male, white, never-smokers or former smokers, and have low T and high N stage tumors. These characteristics are now known to be closely associated with HPV-positive tumors. Thus, it seems that the changing demographics are caused by the increase in the proportion of HPV-positive OPSCC, and that survival also improved in their cohort of patients. However, the external validity of these results is limited by the inability to control for confounders, such as treatment regimens, in this historical analysis.
| Study | Study Design | Results | ||
|---|---|---|---|---|
| HR (95% CI) or % | P | |||
| Dahlstrom et al, 2013 | Retrospective study comparing patients before and after 1995 in 1 center N = 3891 HR: overall survival analysis with the earlier cohort as reference | Tumor subsite | ||
| BOT | 0.6 (0.5–0.8) | .001 | ||
| Tonsil | 0.6 (0.5–0.8) | <.001 | ||
| CRT | 0.4 (0.3–0.6) | <.001 | ||
| N status | ||||
| N1 | 0.5 (0.4–0.8) | .001 | ||
| N2 | 0.5 (0.4–0.6) | <.001 | ||
| TNM stage | ||||
| Stage III | 0.5 (0.4–0.8) | <.001 | ||
| Stage IV | 0.5 (0.4–0.6) | <.001 | ||
| Ang et al, 2010 | Retrospective analysis (RTOG 0129 trial: accelerated vs standard fractionation RT each with concurrent cisplatin) N = 323 patients with HPV data | OS at 3 y | ||
| HPV+ | 82 | |||
| HPV− | 57.1 | |||
| 0.42 (0.27–0.66) | <.001 | |||
| PFS at 3 y | ||||
| HPV+ | 73.7 | |||
| HPV− | 43.4 | |||
| 0.49 (0.33–0.74) | <.001 | |||
| LR recurrence | ||||
| HPV+ | 13.6 | |||
| HPV− | 35.1 | <.001 | ||
| Second primary tumors | ||||
| HPV+ | 5.9 | |||
| HPV− | 14.6 | .02 | ||
| Rischin et al, 2010 | Retrospective analysis (TROG 02.02 trial. CRT with or without tirapazamine) N = 185 patients with HPV data | OS at 2 y | ||
| HPV+ | 91 | |||
| HPV− | 74 | |||
| 0.36 (0.17–0.74) | .004 | |||
| PFS at 2 y | ||||
| HPV+ | 87 | |||
| HPV− | 72 | |||
| 0.39 (0.2–0.74) | .003 | |||
| LR recurrence | ||||
| HPV+ | 93 | |||
| HPV− | 86 | |||
| 0.43 (0.17–1.11) | .091 | |||
| Posner et al, 2011 | Retrospective analysis (TAX 324 trial: IC TPF vs PF, both followed by CRT) N = 111 patients with HPV data | OS at 5 y | ||
| HPV+ | 82 | |||
| HPV− | 35 | <.0001 | ||
| PFS at 5 y | ||||
| HPV+ | 78 | |||
| HPV− | 28 | <.0001 | ||
| LR recurrence | ||||
| HPV+ | 13 | |||
| HPV− | 42 | .0006 | ||
| Fakhry et al, 2008 | Prospective analysis (ECOG 2399 trial. Sequential therapy to CRT or surgery) N = 101, includes larynx cancer | Response to IC | ||
| HPV+ | 82 | |||
| HPV− | 55 | .01 | ||
| Response to CRT | ||||
| HPV+ | 84 | |||
| HPV− | 57 | .007 | ||
| OS at 2 y | ||||
| HPV+ | 95 | |||
| HPV− | 62 | |||
| 0.36 (0.15–0.85) | .02 | |||
| PFS at 2 y | ||||
| HPV+ | 86 | |||
| HPV− | 53 | |||
| 0.27 (0.10–0.75) | .01 | |||
| O’Rorke et al, 2012 | Meta-analysis N = 42 studies, 4834 patients | OS | 0.47 (0.35–0.62) | .08 |
| PFS | 0.48 (0.33–0.69) | .87 | ||
Randomization to treatment regimens
Only recently have clinical trials begun to include HPV status in their patient stratification, but retrospective subgroup analyses have been performed in several phase III, multicenter trials involving the prospective randomization of patients with HNSCC to different treatment regimens. In each, a post hoc analysis has been performed to investigate the effect of HPV status on patient survival. Ang and colleagues investigated the RTOG (Radiation Therapy and Oncology Group) 0219 trial, which randomized patients to concurrent chemoradiation with either standard fractionation or accelerated fractionation radiotherapy (RT). The subgroup of patients with OPSCC had an increase in overall survival (OS) and progression-free survival (PFS) for HPV-positive compared with HPV-negative OPSCC ( Table 1 ). Rischin and colleagues had similar results in their analysis of the HeadSTART trial, which compared the effect of the addition of tirapazamine with chemoradiotherapy (CRT) on outcome in OPSCC. These investigators also noted improved survival at 2 years in the HPV-positive subgroup as well as lower rates of locoregional failure compared with the HPV-negative subgroup (see Table 1 ). More recently, Posner and colleagues looked at HPV-related outcomes in the TAX 324 trial, which compared the addition of docetaxel to a standard induction chemotherapy (IC) regimen. Their results show increased OS and PFS in HPV-positive compared with HPV-negative OPSCC, along with a decreased risk of death and a significant reduction in locoregional failure rates (see Table 1 ). Overall, these retrospective analyses of prospectively treated patients strongly suggest that there is a survival benefit in HPV-positive OPSCC. However, the generalizability of these results is limited by their retrospective nature and post hoc analysis; in addition, the ability of all 3 studies to determine HPV status was limited by tissue availability.
Oropharyngeal and laryngeal cancer
Published data on the effect of HPV on survival have been provided in a prospective fashion in a single study. In 2008, Fakhry and colleagues reported the results of a substudy in ECOG 2399, a phase II trial on the use of sequential therapy for organ preservation in resectable advanced stage oropharyngeal and laryngeal cancer. HPV status was determined prospectively in both subsites, and none of the laryngeal tumors was HPV positive. These investigators found that HPV-positive patients had higher response rates to IC and CRT, as well as improved OS and PFS (see Table 1 ). However, this effect did not reach statistical significance for the oropharyngeal subsite alone, because it was underpowered for subgroup analysis. At the time of the study design, it was believed that HPV was a cause of laryngeal cancer as well, so those patients were included in the trial. By the time of the data analysis, this hypothesis had largely been disproved, but the number of oropharyngeal patients alone was insufficient for the results of the multivariate analysis to remain statistically significant.
Survival disparity
Awareness of the increase in incidence of HPV-positive OPSCC has also solved one of the survival conundrums in OPSCC. Multiple studies had reported a disparity in survival rates between African American and white patients, despite controlling for tumor site, age, and other risk factors. However, using data from the TAX 324 trial, Settle and colleagues concluded that the disparity in survival between African American and white patients with OPSCC was entirely caused by significant differences in rates of HPV infection between the 2 groups. A more recent report confirms that the shorter PFS in African American patients with OPSCC may be caused by HPV status, treatment type, and higher T stage at presentation but is not caused by race.
HPV-positive OPSCC has improved survival, lower rate of disease progression, and lower chance of locoregional recurrence when compared with HPV-negative OPSCC. There have not been significant differences in the rates of distant failure, which may or may not be related to insufficient power to detect a difference. Furthermore, a recent meta-analysis by O’Rorke and colleagues, the most comprehensive to date, reported a 53% better OS and 74% better disease-specific survival for HPV-positive OPSCC, as well as statistically significant improvement in PFS and disease-free survival (DFS). Prospective data are limited; however, there are ongoing clinical trials that include HPV status stratification in their trial design ( Table 2 ). Several of the recent trends observed in OPSCC (improved survival, change in patient demographics, and suspected racial outcome disparities) are likely caused by differences in incidence of HPV-positive OPSCC.
