Sage Journals: Discover world-class research

Abstract

The human papilloma virus (HPV) is one of several viral pathogens linked to human cancer. This article reviews the current worldwide cancer burden related to this pathogen. The article also examines the role of HPV in oropharyngeal and gynecological malignancies, current treatment implications, and future directions in the treatment and prevention of HPV-related disease.

Keywords

HPV Oropharyngeal cancer gynecologic cancer papilloma virus

‘The implementation of HPV vaccines and the association of HPV and oropharyngeal cancer in nonsmokers are examples of recent developments that have raised many questions and, occasionally, caused controversy.’

Background

Human-Associated Viruses and Cancer

Today, approximately 15% to 20% of the cancer burden worldwide has been attributed to infectious agents.¹ It is estimated that 26% of cancer in developing countries is related to infectious causes, compared with 8% in developed countries.¹ Agents such as Epstein-Barr virus, hepatitis B virus, human T-lymphotropic virus-1, Kaposi’s sarcoma–associated herpes virus, and human papilloma virus (HPV) have been linked to cancer. In the past few years, there has been much written regarding HPV in both the lay and medical literature. The implementation of HPV vaccines and the association of HPV and oropharyngeal cancer in nonsmokers are examples of recent developments that have raised many questions and, occasionally, caused controversy. Because of the breadth of the topic of HPV-related malignancy, this review article will mainly focus on oropharyngeal and gynecological neoplasms.

HPV and Cancer

The different HPV subtypes are divided into those with a predilection for infecting the skin versus the mucosal surfaces—the former being associated with wart formation and the latter with cancer (therefore termed high risk).¹ Approximately 15 HPV types are considered high risk,^2-6 and infection with these agents has been associated with induction of carcinoma of the cervix, vulva, vagina, penis, anus, and oropharynx (tongue base and tonsil).^1,7 The high-risk HPV types (HPV-16, -18, -31, -33, -35, -45, -52, and -58) are associated with nearly all cases of cervical cancer in the world.¹ HPV 16 and 18 are the high-risk subtypes responsible for more than 70% of HPV-infection-related cancer.⁷ HPV-associated cancers in the oropharynx and anogenital tract are typically squamous cell carcinomas (SCCs).

HPV Carcinogenesis

HPV viruses infect the basal epithelial cells and lie dormant until they reach differentiated cells in the surface layers of the skin or mucosa (stratum spinosum and granulosum).^7,8 We must keep in mind that the events of viral upregulation, replication, and release occur in cells that are terminally differentiated and have exited the cell cycle.⁸ These terminally differentiated keratinocytes are no longer able to support DNA synthesis. Therefore, the viruses must disrupt the cellular machinery to create an environment where DNA synthesis can take place.

To overcome the problem of noncycling host cells, the virus particles encode proteins, which reactivate DNA synthesis, inhibit apoptosis (programmed cell death), and delay differentiation.⁸ The E6 protein binds p-53, a tumor suppressor protein, often called the “guardian of the genome.” This tumor suppressor protein is involved in cell cycle arrest, DNA repair enzyme activation, and initiation of apoptosis.^8,9 The E7 viral oncoprotein binds and destabilizes the retinoblastoma protein (Rb) and related proteins.⁸ The retinoblastoma protein is also a tumor suppressor protein that prevents the cell from progressing into the initial part of the cell cycle.¹⁰ Together, the effects of these viral oncoproteins (ie, cancer-causing proteins) are to promote cell cycle progression and viral DNA replication in terminally differentiated keratinocytes. Unfortunately, a rare consequence of this process is deregulation of cellular growth control and cancer formation.

Risk Factors and Incidence

The known risk factors for the acquisition of an HPV infection are early age of sexual debut, multiple sexual partners, immunodeficiency caused by HIV infection, autoimmune disorders, organ transplantation, intravenous drug use, and tobacco use. HPV is the most common sexually transmitted infection in the United States. It is transmitted via skin-skin and mucosa-mucosa contact and does not require penetrative sex.

What is the impact of HPV on anogenital diseases worldwide? This is a widely disseminated family of viruses with geographical variations in the HPV types involved. For example, HPV-45 is abundant in West Africa and HPV-16 is abundant in North America.⁵ One study has estimated that the lifetime risk of acquiring an HPV infection is 79% for women, and the prevalence among men is similar.¹¹ These infections will lead to approximately 530 000 new cases of cervical cancer annually, making it the third most common malignancy in women worldwide (23 000 in Europe, 35 000 in Latin America, 18 000 in North America, and 12 340 in the United States.^11,12 These numbers likely underestimate the infection burden because HPV infections can be transient; there are no requirements to report these infections to the Centers for Disease Control (CDC); and cervical cancer screening procedures vary greatly around the globe.

Oncogenic or high-risk HPV plays a significant role in the development of vulvar, vaginal, penile, anal, and oropharyngeal cancers.¹³ According to the CDC, an average of 33 369 HPV-associated cancers were diagnosed annually between 2004 and 2008. With respect to anogenital malignancies in 2013, the CDC predicts the following: 12 340 new cervical cancer diagnoses; 4700 new vulvar cancers; 2800 new anal cancers; and 2890 new vaginal cancer diagnoses. HPV is the cause of 91% of all cervical cancers, 70% of all cancers of the vagina, and 40% to 47% of vulvar cancers.¹⁴ SEER data suggest that the incidence and number of deaths related to cervical cancer in the United States have been relatively stable over the past decade

The association of HPV and oropharyngeal squamous cell carcinoma (OPSCC) is a relatively recent discovery. The predominant risk factor for OPSCC is persistent pharyngeal infection with oncogenic strains of HPV.¹⁵ The incidence of HPV-associated OPSCC is increasing in epidemic proportions. Between 1988 and 2004, the incidence of HPV-associated OPSCCs increased by 225%, whereas the incidence of HPV-negative OPSCCs decreased by 50%.¹⁶ The number of HPV-positive OPSCCs is projected to surpass the number of HPV-associated cervical cancers by the year 2020 if the current trend continues.¹⁷

The prevalence of HPV in oropharyngeal cancer increased from 16.3% in the 1980s to 71.7% during the 2000s, with a corresponding improvement in survival of patients with OPSCCs.¹⁷ The decrease in incidence of HPV-negative OPSCCs corresponds to decreases in smoking incidence in the United States. The median tobacco exposure among HPV-positive patients with OPSCC in US cooperative group studies declined from 29 pack-years during 1991-1997 to 14 pack-years from 2001 to 2005.¹⁸ HPV-associated OPSCC is clinically a unique disease entity compared with HPV-negative OPSCC.

HPV and Gynecological Malignancies

Genital HPV Infection and Cancer

The development of invasive cancer is preceded by a spectrum of intraepithelial abnormalities. In the cervix, the spectrum of intraepithelial abnormalities ranges from (1) low-grade cervical intraepithelial neoplasia (CIN1); (2) to moderate cervical intraepithelial neoplasia (CIN2); to (3) high-grade cervical intraepithelial neoplasia (CIN3). CIN3 is the obligate precursor lesion for cervical cancer, and 90% of these lesions contain high-risk HPV DNA sequences (most frequently HPV-16).^19,20

The natural history of cervical dysplasia has been widely studied. In 1999, Holowaty et al²¹ evaluated cervical dysplasia in 17 000 women who had mild, moderate, and severe disease.²¹ The relative risks of progression from severe or moderate dysplasia to invasive cancer in this study were 4.2 and 2.5, respectively. The incidence of progression from Carcinoma in situ (CIS) to invasive cancer in patients with persistently abnormal cytology after initial treatment was 24.8 times greater than in those who had normal cytology after initial diagnosis.²² Overall, the reported rate of progression from CIS to invasive cancer ranges from 12% to 22%.

Treatment of Preinvasive Disease

Preinvasive lesions may be treated with topical therapies such as topical medical therapy (Imiquimod), carbon dioxide photoablative techniques, and surgical excisional techniques. In many women, a combination of these modalities may be used. Retrospective data have revealed that up to 30% of patients treated for Vaginal Intraepithelial Neoplasia (VIN) will develop recurrences regardless of the treatment modality chosen. The reported risk factors for recurrence in the vulva, vagina, and perianal areas include positive margins, multifocal disease, and history of tobacco abuse.²³ Whatever the modality used to treat women with this disease, recurrences may occur after 5 years in up to as many as 35% of patients.²⁴ Therefore, close and long-term follow-up is recommended in these patients.

Treatment of Invasive Disease

In the case of cervical cancer, the standard surgical treatment for stage 1A2 to IIA disease is radical hysterectomy and complete pelvic lymphadenectomy. The pelvic lymphadenectomy removes all the nodal-bearing tissues from the bifurcation of the aorta down to the deep circumflex iliac vein over the external iliac artery and the internal iliac artery above the obturator nerve. After surgical treatment, high-risk pathological features include close margins, positive lymph nodes, and lymphovascular space invasion. If these features are present after resection, patients may be candidates for treatment with postoperative radiation or the combination of chemotherapy and radiation. For patients with IIB to VA disease, a combination of chemotherapy and radiation therapy (in lieu of surgery) is preferred.²⁵

Invasive vulvar cancer is generally treated with primary surgery and groin lymphadenectomy based on depth of invasion of the primary cancer. Patients who have close resection margins or lymph node metastases after surgery will often undergo adjuvant radiation. Vaginal cancer is usually treated with a combination of primary surgery and/or radiation.

HPV and Head and Neck Cancer

Oral HPV Infection and Cancer

Traditionally, SCC of the upper-aerodigestive tract has been strongly associated with tobacco and alcohol exposure.²⁶ The association of HPV infection with oropharyngeal cancer has been widely recognized in the past decade. It is almost certain that oral HPV infection is a necessary event in the development of OPSCCs.²⁶ The current literature suggests that approximately 7% of the US population, at any given time, has a prevalent oral/oropharyngeal HPV infection.²⁷ The majority of these infections are cleared by the immune system and do not progress to cancer.²⁸

The stepwise changes in the epithelium of cervical mucosal cells from normal, to dysplastic, to cancerous have been well documented. However, precursor lesions of the oropharynx have not been identified. Thus, the changes induced from persistent oral HPV infection leading to OPSCC are largely unknown.²⁸ In fact, our current knowledge of the epidemiology, natural history, and prevention of oral HPV infection is limited.

Recent evidence indicates that HPV-associated OPSCC (HPV-OPSCC) is a biologically and clinically unique disease entity compared with HPV-negative OPSCC. Patients with HPV-positive OPSCCs are generally younger than patients with HPV-negative cancers, have no (or light) history of smoking, and have minimal or absent history of ethanol use.²⁹ HPV-positive tumors are more likely to be poorly differentiated, be nonkeratinizing, and show basaloid morphology compared with HPV-negative tumors.^2,15 HPV-positive OPSCC cases typically present as TNM stage III and IV disease, with earlier T stage and more advanced N stage.^30,31 In addition, these cases tend to be associated with Caucasian race and higher socioeconomic status.³²

Increased sexual behavior has been associated with a greater risk of developing HPV-OPSCCs.³³ The factors associated with an increased odds ratio of developing HPV-OPSCCs include (1) earlier age of sexual debut, (2) higher number of vaginal sex partners, and (3) higher number of lifetime oral sex partners. Generally, these behaviors are associated with oral HPV transmission. Although the natural history of anogenital HPV infections and its transmission is well understood, less is known about the natural history of oral HPV infection.

Treatment of OPSCC

The increasing prevalence of HPV-OPSCC likely accounts for the improvement in overall survival rates for patients with oropharyngeal cancer. The overall survival for patients with HPV-OPSCC has improved across calendar periods over the decades; however, the magnitude of this improvement has been greater in patients with HPV-OPSCCs.¹⁶ The standard treatment for OPSCC consists of either concurrent chemoradiation or surgery and adjuvant radiotherapy. Concurrent chemotherapy plus radiation became a new standard of care based on the results of multiple studies showing improved survival with the addition of chemotherapy concurrently with radiation and improvement in functional organ preservation.^34-37 A number of studies showed improvements in locoregional and overall survival of approximately 15% to 20% with the addition of cisplatin- or carboplatin-based chemotherapy to radiotherapy.^34-37 However, these early studies were not stratified for HPV status, and therefore, the proportion of patients with HPV-positive cancers in these early studies is unknown.

In a retrospective analysis using SEER data, patients with HPV-positive tumors had a significantly better long-term overall survival (median 131 months vs 20 months).¹⁷ After adjustment for age, advanced stage of disease, lack of surgery or radiotherapy, chemotherapy delivery, and diagnosis in an earlier time period, HPV-positive patients had a 69% decrease in risk of death compared with HPV-negative patients.¹⁷

A number of studies have been reported recently looking at the impact of HPV on treatment outcomes and disease.^18,38 Taken together, these studies clearly demonstrate that patients with HPV-positive tumors have superior response rates, clinical outcomes, and survival. Patients with HPV-positive disease seem to have progression-free survival of approximately 70% to 90%, compared with 50% in patients with HPV-negative disease.^18,38,39 The overall survival statistics are 90% versus 60% to 70% for patients with HPV-positive versus HPV-negative disease.^18,38,39

The Radiation Therapy Oncology Group conducted a post hoc recursive partitioning analysis showing that HPV status was the strongest determinant of overall survival, followed by tobacco use, lymph node status, and tumor stage.¹⁸ The low-risk group included HPV-positive patients with a tobacco use history of less than 10 pack-years and N0 to N2a nodal disease; this group had the most favorable 3-year overall survival rate of 93%.¹⁸ The intermediate-risk group included HPV-positive patients with a tobacco use history of greater than 10 pack-years and higher nodal stage (N2b to N3); this group had intermediate prognosis with a 3-year overall survival of 73%.¹⁸ These data clearly demonstrate that HPV is one of the most powerful prognostic biomarkers in Head and Neck Squamous Cell Carcinoma(HNSCC) and is clearly strongly associated with both response to radiotherapy and chemotherapy as well as with survival.

HPV Vaccines

Prophylactic HPV vaccines have been developed on the basis of recombinant expression and self-assembly of the major capsid protein L1 into immunogenic virus-like particles.^40,41 The quadrivalent vaccine protects against HPV types 6, 11, 16, and 18 and was approved in June 2006 for administration to girls and women 9 to 26 years old. The bivalent vaccine was approved in October 2009, protects against HPV types 16 and 18, and was approved for use in girls and women 10 to 26 years old. Although this vaccine does not include HPV types 6 and 11, a clinical trial demonstrated that the bivalent vaccine induced higher antibody titers against the high-risk viral types compared with the quadrivalent vaccine.⁴² Currently, the CDC Advisory Committee on Immunization Practices guidelines recommend that girls receive either the quadrivalent or bivalent vaccine at age 11 to 12 years and the catch-up vaccine through age 26 years.

Prophylactic vaccines work based on the concept of antibody responses to L1 capsid proteins of the virus^40,41; however, the prophylactic vaccines are not able to control or eliminate established infection.⁴³ The efficacy of the 2 available vaccines against oncogenic HPV is greater than 90% for cervical and anal intraepithelial neoplasia. Clinical trials evaluating efficacy of the quadrivalent vaccine have followed women for more than 5 years and support sustained clinical protection from the vaccine.^43-45 Other studies of long-term results of a monovalent vaccine (HPV-16) precursor also demonstrated sustained clinical efficacy of more than 8 years.^44-46 The impact of the prophylactic vaccines in the prevention of HPV-related oropharyngeal cancers is currently unknown. However, as vaccination programs decrease the overall prevalence of HPV in the general population, it is hoped that the incidence of HPV-related OPSCC cancer will decrease. Thus far, none of the prophylactic vaccine studies in the United States has evaluated oral HPV infection or oral immunity to HPV.^47,48

A randomized study from Central America demonstrated lower HPV-16/18 prevalence 4 years after vaccination with a bivalent vaccine.^47,48 Out of 5840 participants who provided oral specimens during this study, there were 15 prevalent infections in the control group and 1 in the vaccine group.⁴⁷ Although the difference did not reach statistical significance, it suggests that vaccination may afford protection against oral HPV infection.⁴⁷ However, the effect of these vaccines in decreasing the incidence of HPV-related cancers will take decades to fully assess.⁴⁹ These trials may not be able to determine whether HPV vaccines will affect the incidence of head and neck cancers, which typically affect individuals in their 50s and 60, for many years.⁴⁹

Ongoing clinical trials are evaluating the role of HPV-directed therapeutic vaccines. Historically, the control or elimination of a chronic viral infection is T-cell mediated, and therefore, it is believed that an effective immunotherapy for established HPV infection will also require a T-cell-driven response.⁴³ There are a number of different therapeutic vaccines under development. The concept of therapeutic vaccines is to target antigens inside infected cells. The main targeted antigens are the HPV oncogenes E6 and E7, whose expression is necessary for the maintenance of the malignant phenotype.^50,51 A number of therapeutic vaccines evaluated in studies have targeted the E2, E5, E6, and E7 proteins. E6 and E7 are expressed early in the HPV replication cycle and have been identified as strong targets for vaccine because their expression is retained through multiple stages of infection and may increase in expression as the severity of pathology increases.⁵² E1 and E2 also have critical roles in viral DNA replication and are retained through multiple stages of viral infection: therefore, they are also important targets for immune responses.⁴³

Thus far, the majority of these studies have been conducted in patients with advanced cervical cancer, a population that has been shown to have diminished immune function. One such study showed limited clinical benefit in a population of patients with refractory cervical cancer.⁵³ More recent studies have tested the efficacy of vaccines in those with earlier preinvasive disease.⁵⁴ More recent vaccine strategies are based on peptides/proteins, viral vectors, DNA, or dendritic cells.⁵¹

Studies with small HPV-16 E7 peptide fragments linked to a nonspecific helper peptide have been associated with variable clinical responses. A clinical study conducted at the Johns Hopkins Hospital uses an HPV-16-specific therapeutic vaccine, which is designed to enhance the cytotoxic T-cell response to HPV oncoproteins; this vaccine was used as adjuvant therapy.⁵⁵ Other studies are evaluating the efficacy of therapeutic vaccines that fuse E7 to a heat shock protein, thus, eliciting cytolytic response to cells expressing viral proteins.⁵⁶ Promising results have been obtained with HPV-16 E6/E7-derived synthetic long peptide vaccines; thus far, this has been tested in patients with cervical cancer.⁵⁷ A recent phase II study conducted in women with HPV-positive high-grade vulvar intraepithelial neoplasia showed promising results, showing induction of a strong HPV-16-specific immune response and encouraging clinical results,^54,58 reported on a novel vaccine modality comprising synthetic peptides in Freund’s adjuvant in a subcutaneous vaccine. This vaccine in phase I/II studies was shown to be safe and to be highly immunogenic in women with advanced HPV-positive cervical cancer.^54,57

Other immunization strategies under development include the application of naked viral DNA, viral RNA, vector-based systems, or intranasal application of modified HPV protein–expressing bacterial strains.⁵⁹ These strategies may have advantages such as priming of stronger T helper 1 and Cytotoxic T-lymphocytes(CTL) responses and prolonged antigen exposure.⁵⁹

Future Directions

Screening: Gynecological Cancer

There has been a significant reduction in the number of women diagnosed with lower-genital-tract malignancies since the inception of screening program.⁶⁰ With the addition of HPV testing during Pap tests, we have been able to detect the precursors of cervical cancer much sooner and more accurately as compared with the single Pap test alone.⁶¹ This type of testing has high negative predictive values, but the positive predictive values are moderate. With this in mind, novel screening techniques are needed to improve our ability to predict the oncogenic progression and reduce the number of unnecessary surgical excisions, resulting in no significant pathology. Current understanding of the genetic and epigenetic alterations occurring in the earliest steps of the malignant progression of cervix uteri has led to testing for the presence of these abnormalities(ie, P16 expression alterations for earlier diagnosis).⁶² Several studies evaluating the methylation states of TSGs (tumor suppressor genes) have revealed some genes to be hypermethylated in preinvasive lesions. This has led to researchers developing a panel of methylation markers, which may have value in early detection of cancer precursors, increase accuracy in women who are candidates for less-frequent screens, and better predict the oncogenic progression in women infected with oncogenic types of HPV.⁶³

Screening: Oropharyngeal Cancer

There have not been any studies to date validating the screening of the general population for oropharyngeal cancer. However, there are several areas of active research. For instance, the identification of head and neck biomarkers in saliva is a concept being studied, which could facilitate widespread screening programs. One study reported the increased expression of a panel of 7 mRNA and 3 protein markers in patients with oral cavity cancers compared with controls.⁶⁴ This panel has not yet been validated, but work in this area continues.

An alternative to screening directly for oropharyngeal cancer is to screen for the presence of HPV in the oropharynx to identify people at risk of developing cancer. However, there are several factors that make screening for the virus impractical. In a healthy population, the incidence of oral oncogenic HPV infections is low (~1.3%),⁶⁵ and most infections are cleared within 1 year.⁶⁶ Even in a relatively high-risk population, the partners of patients with HPV-positive oropharyngeal cancer, the prevalence of oral HPV-16, the most common type of oncogenic HPV in oropharyngeal cancers, was low (~2.5%), and the virus was cleared within 1 year.⁶⁷ A “Pap test equivalent” was proposed by Fakhry et al⁶⁸ to detect precancerous lesions, which they attempted to correlate with HPV infection. They looked at asymptomatic patients with HIV infections, who are at high risk for oropharyngeal cancer. Screening of these patients from salivary samples and tonsillar crypt brushings showed that cytological abnormalities of the oropharynx (atypical squamous cells of unknown significance) were rare and not associated with the presence of oral HPV-16 infection. Biomarker studies to detect HPV in the blood are also being developed. For example, HPV E6 antibody was found in the prediagnostic blood of 34.8% of patients with oropharyngeal cancer and 0.6% of control patients (odds ratio = 274; 95% confidence interval = 110-681) taken more than 10 years prior to diagnosis.⁶⁶

Therapy: Gynecological Cancer

Targeted therapies are being evaluated in the setting of HPV-associated recurrent gynecological cancer. A recent trial completed by the Gynecologic Oncology Group (GOG240) included 452 patients with pretreated metastatic, recurrent, or persistent cervical cancer enrolled from 2009 to 2012 in the United States and Spain.⁶⁹ There were 4 arms in this trial: patients were randomly assigned to receive either topotecan or cisplatin in combination with paclitaxel and also to have bevacizumab added or not added to the regimen. The bevacizumab was administered at the same time as chemotherapy at a dose of 15 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity occurred. The median overall survival was 17 months for women receiving the combination, compared with 13.3 months for women receiving chemotherapy alone (hazard ratio = 0.71; P = .0035).⁶⁹ Those women receiving bevacizumab lived for a median of 3.7 months longer. The response rate was significantly better with bevacizumab than without it (48% vs 36%; P = .00807), as was progression-free survival (8.2 vs 5.9 months: P = .0002).⁶⁹ This study is the first step toward potentially turning cervical cancer into a chronic disease, allowing time for possible new therapies, because earlier, there were very few choices for treatment in this group of women.

Transcriptional therapy is very promising in the treatment of cancer and being extensively studied. Experimental data are available with evidence in support of the development of drugs that target the epigenome via inhibition of methylation or histone modification, but clinical data are pending. Different from genetic changes, aberrant DNA methylation and histone modifications of neoplastic cells are reversible. This suggests that we could manipulate these alterations pharmacologically. There are some promising epigenome-modifying agents, which are 2 main classes of epigenetic drugs, methylation inhibitors and Histone deacetylase(HDAC) inhibitors; they are currently being evaluated in a clinical trial. Other targeted therapies are in development and look very promising.

The sentinel lymph node (SLN) is the first node where primary tumor afferent lymphatic flow drains; therefore, it is the first node where malignant cells metastasize. This node is identified by injecting a marking dye or radioactive substance intratumorally or peritumorally. If the SLN is negative in terms of metastasis, then nonsentinel nodes are expected to be negative.^70,71,72 A Gynecologic Oncology Group trial validated SLN mapping in vulvar cancer.⁷³ A total of 510 eligible women underwent intraoperative lymphatic mapping, SLN biopsy, and inguinal femoral lymphadenectomy between 1999 and 2008. A total of 445 patients had complete data available for review. In this subset of patients, the SLN was successfully identified in 67/85 (78.8%) patients using blue dye only and in 306/318 (96.2%) using a combination of radiolabeled tracer and blue dye. The validation of SLN mapping in vulvar cancer is significant because through the use of this technique, surgeons can reduce the morbidity associated with vulvar resection and inguinal lymphadenectomy.^71,72,73

As noted previously, the standard surgical treatment for early-stage cervical cancer (IA2-IIA) is radical hysterectomy and complete pelvic lymphadenectomy. The pelvic lymphadenectomy, like other extensive lymph node dissections (such as those performed in the groin in vulvar cancer therapy), can result in lower-extremity edema, lymphocele formation, and nerve damage. Moreover, the rate of complications associated with this procedure increases when postoperative radiotherapy is given. The use SNL mapping can limit the extent of nodal dissection and thereby limit the toxicity surgery (particularly when combined with radiotherapy) with acceptable efficacy.⁷⁴

The use of fertility-sparing procedures in women with early-stage carcinoma of the cervix is another concept that continues to evolve. For many years, women with microinvasive stage IA-1 cervix cancer have been treated with limited surgical procedures such as loop electroexcision or cold knife conizations, which spare fertility. However, women with higher-stage cancer have traditionally been treated with hysterectomy or radiation (both fertility ending procedures). Recently, fertility sparing procedures in selected patients with stage 1A2-1B1 cervical cancer have been explored. In these patients, a concept that is being expanded is the use of radical trachelectomy, with the placement of a permanent upper cervical cerclage and reattachment of the remaining cervix to the vagina. This is a conservative approach that appears to be effective and safe in preserving fertility in selected patients. However, in women who become pregnant after this procedure, there is a higher risk of premature birth.⁷⁵

Therapy: Oropharyngeal Cancer

The paradigm of concurrent chemoradiation with standard-dose radiation has contributed to improvements in survival over the past few decades. However, these treatment paradigms also are associated with increased risk of late swallowing complications and other late functional implications.⁷⁶ Many patients with HPV-associated SCC of the oropharynx are younger, with fewer competing comorbidities and, therefore, more likely to experience long-term survivorship issues from delayed sequelae of current treatment paradigms.

As Chung and Schwartz⁷⁷ point out, it is important that new clinical trials integrate stratification for HPV status such that the various arms of studies are balanced for important prognostic characteristics. HPV-associated SCC of the oropharynx represents a unique disease entity, which provides an opportunity to tailor treatment intensity to improve therapeutic index and minimize long-term morbidity. Future strategies and works in progress for the treatment of HPV-OPSCC are mainly focused on HPV-directed vaccines (see section on HPV vaccines above) and deintensification of radiation/chemotherapy dose. In addition, there are some who question the need to add chemotherapy concurrently with radiation in this population, and clinical trials are likely forthcoming exploring this question. The majority of trials of targeted agents in head and neck cancer are for the unstratified (ie, no identification of HPV status) or HPV-negative population. However, there are a few ongoing trials with targeted agents for the HPV-positive population. In 1 trial, afatinib, an epidermal growth factor receptor (EGFR) inhibitor, is combined with ribavirin, an antiviral agent approved to treat hepatitis C infections, along with carboplatin and paclitaxel for induction therapy.⁷⁸ The Cancer Genome Atlas (TCGA) analysis of head and neck cancers reported that 40% to 50% of HPV-positive tumors harbored alterations in PIK3CA.⁷⁹ Therapies directed against PI3KCA alterations have been developed and are an area of active research for many tumor types and may be tested in HPV-OPSCC in the near future. Most tumors also had very low rates of EGFR alterations, which could affect their response to EGFR-directed therapies such as cetuximab.

As noted above, because of the superior outcomes of patients with HPV-positive oropharyngeal cancer, one of the concepts being explored is the feasibility of treatment deintensification. There are several approaches to testing this concept that are actively being investigated. Ongoing studies are currently triaging patients to standard therapy versus deintensified treatment based on response to induction chemotherapy, in the hopes of reducing the long-term sequelae of treatment without loss of locoregional control.⁷⁷ Moreover, Radiation Therapy Oncology Group completed accrual to Radiation Therapy Oncology Group protocol 1016, which is a phase III study of radiotherapy plus cetuximab versus platinum-based chemoradiotherapy.⁸⁰ In this study, the theme of dose deintensified treatment takes 2 forms. First, the investigators are using lower total doses of chemotherapy than have been customary in the setting of locally advanced disease.^18,34,81 Second, anatomical regions of the head and neck not directly involved with measurable disease and felt to be at low risk of harboring a significant tumor burden are treated to doses of radiation that are lower than those used in the past. As an extension of this concept, future clinical trials are being designed to explore the feasibility of delivering less radiation dose to gross disease with and without chemotherapy and cetuximab.⁸²

Another concept with the aim of deintensifying treatment involves using surgical resection upfront. Transoral surgical techniques such as transoral robotic surgery are being used in the treatment of oropharyngeal cancer. Although these minimally invasive techniques no longer require external incisions or mandibular splitting approaches to gain access, there is little prospective literature examining the role of transoral robotic surgery within the paradigm of multidisciplinary treatment.^83,84 The Eastern Cooperative Group opened a randomized phase II study evaluating upfront transoral surgery followed by risk stratified adjuvant treatment in HPV-positive locally advanced oropharyngeal cancer. Patients with low-risk disease receive no postoperative treatment.⁸⁵ Those with intermediate disease are randomized to either dose-reduced radiation or standard-dose radiation. The rationale behind this concept is that the avoidance of surgery in the low-risk patients and the reduction in radiation in the intermediate-risk patients will lead to lower long-term toxicity, with equivalent cancer-related outcomes.

Conclusion

The field of medicine has been privy to the knowledge that certain viruses are intimately associated with human cancer for decades. The association between anogenital tract malignancies and HPV (particularly cervical cancer) dates back to the 1980s. In that time, our understanding has grown. As a result of robust research and innovation, our screening and treatment programs have improved. The incidence of and death resulting from HPV-related anogenital cancer in the United States has been relatively stable for many years. However, the worldwide disease burden remains high. The biggest global need, at least with respect to cervical cancer, is the improvement of screening programs and access to care. Second, we need to focus on disease prevention. The implementation of large-scale vaccination programs has the potential to significantly decrease the incidence of these diseases.

HPV-associated oropharyngeal cancer is a relatively new phenomenon. Currently, we know that HPV-positive cancer of the oropharynx is a biologically distinct entity from HPV-negative disease, with drastically better treatment response and survival. However, screening for this disease entity is at its infancy and is fraught with challenges. The short-term focus related to HPV-positive oropharyngeal cancer is to improve treatment toxicity by different approaches aimed at treatment deintensification. Subsequent goals should be to validate vaccination programs and develop usable screening techniques. Furthermore, there is the additional challenge of how best to tailor treatment strategies for patients with HPV-negative SCC of the head and neck because it is well documented in the literature that radiation response rates for patients with HPV-negative tumors are extremely low.^18,81 This remains an important topic of current and future investigations.

References

Carbone

De Paoli

Cancers related to viral agents that have a direct role in carcinogenesis: pathological and diagnostic techniques. J Clin Pathol. 2012;65:680-686.

Begum

Cao

Gillison

Zahurak

Westra

WH.

Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res. 2005;11:5694-5699.

Bosch

Castellsagué

Muñoz

Male sexual behavior and human papillomavirus DNA: key risk factors for cervical cancer in Spain. J Natl Cancer Inst. 1996;88:1060-1067.

Boshart

Gissmann

Ikenberg

A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J. 1984;3:1151-1157.

Durst

Gissmann

Ikenberg

zur Hausen

A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci U S A. 1983;80:3812-3815.

Javier

Butel

JS.

The history of tumor virology. Cancer Res. 2008;68:7693-7706.

Psyrri

DiMaio

Human papillomavirus in cervical and head-and-neck cancer. Nat Clin Pract Oncol. 2008;5:24-31.

Howard

Chung

CH.

Biology of human papillomavirus-related oropharyngeal cancer. Semin Radiat Oncol. 2012;22:187-193.

Scheffner

Werness

Huibregtse

The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990;63:1129-1136.

10.

Munger

Howley

PM.

Human papillomavirus immortalization and transformation functions. Virus Res. 2002;89:213-228.

11.

Syrjänen

Väyrynen

Castrén

Morphological and immunohistochemical evidence of human papilloma virus (HPV) involvement in the dysplastic lesions of the uterine cervix. Int J Gynaecol Obstet. 1983;21:261-269.

12.

Jemal

Siegel

Ward

Global cancer statistics. CA Cancer J Clin. 2011;61:69-90.

13.

International Agency for Research on Cancer. Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon, France: World Health Organization, International Agency for Research on Cancer; 2007.

14.

Hording

Daugaard

Junge

Human papillomaviruses and multifocal genital neoplasia. Int J Gynecol Pathol. 1996;15:230-234.

15.

Gillison

Koch

Capone

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92:709-720.

16.

Chaturvedi

Engels

Pfeiffer

Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26:612-619.

17.

Chaturvedi

Engels

Pfeiffer

Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-4301.

18.

Ang

Harris

Wheeler

Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24-35.

19.

Liaw

Hildesheim

Burk

A prospective study of human papillomavirus (HPV) type 16 DNA detection by polymerase chain reaction and its association with acquisition and persistence of other HPV types. J Infect Dis. 2001;183:8-15.

20.

Clifford

Franceschi

Diaz

Munoz

Villa

LL.

Chapter 3: HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine. 2006;24(suppl 3):26-34.

21.

Holowaty

Miller

Rohan

The natural history of dysplasia of the uterine cervix. J Natl Cancer Inst. 1999;91:252-258.

22.

McIndoe

McLean

Jones

Mullins

PR.

The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol. 1984;64:451-458.

23.

Jones

Rowan

Stewart

AW.

Vulvar intraepithelial neoplasia: aspects of the natural history and outcome in 405 women. Obstet Gynecol. 2005;106:1319-1326.

24.

Santoso

Crigger

English

Smoking cessation counseling in women with genital intraepithelial neoplasia. Gynecol Oncol. 2012;125:716-719.

25.

National Cancer Institute. Surveillance, epidemiology, and end results program. Cancer Statistics 2013. http://seer.cancer.gov/statfacts.

26.

Pytynia

Dahlstrom

Sturgis

EM.

Epidemiology of HPV-associated oropharyngeal cancer. Oral Oncol. 2014;50:380-386.

27.

Gillison

Broutian

Pickard

Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693-703.

28.

Chung

Bagheri

D’Souza

Epidemiology of oral human papillomavirus infection. Oral Oncol. 2014;50:364-369.

29.

Mendenhall

Logan

HL.

Human papillomavirus and head and neck cancer. Am J Clin Oncol. 2009;32:535-539.

30.

Hafkamp

Manni

Haesevoets

Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. Int J Cancer. 2008;122:2656-2664.

31.

Goldenberg

Begum

Westra

Cystic lymph node metastasis in patients with head and neck cancer: an HPV-associated phenomenon. Head Neck. 2008;30:898-903.

32.

Gillison

D’Souza

Westra

Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100:407-420.

33.

Joseph

D’Souza

Epidemiology of human papillomavirus-related head and neck cancer. Otolaryngol Clin North Am. 2012;45:739-764.

34.

Adelstein

Adams

An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21:92-98.

35.

Calais

Alfonsi

Bardet

Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91:2081-2086.

36.

Jeremic

Shibamoto

Milicic

Elective ipsilateral neck irradiation of patients with locally advanced maxillary sinus carcinoma. Cancer. 2000;88:2246-2251.

37.

Brizel

Albers

Fisher

Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med. 1998;338:1798-1804.

38.

Fakhry

Westra

Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261-269.

39.

Lin

Wang

D’Souza

Long-term prognosis and risk factors among patients with HPV-associated oropharyngeal squamous cell carcinoma. Cancer. 2013;119:3462-3471.

40.

Villa

Costa

RLR

Petta

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6:271-278.

41.

Harper

Franco

Wheeler

Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364:1757-1765.

42.

GlaxoSmithKline. Immunogenicity of GlaxoSmithKline Biological’s human papilloma virus (HPV) vaccine (580299) versus Merck’s Gardasil in healthy females 18-45 years of age. https://clinicaltrials.gov/ct2/show/NCT00423046. Accessed January 19, 2015.

43.

Morrow

Yan

Sardesai

NY.

Human papillomavirus therapeutic vaccines: targeting viral antigens as immunotherapy for precancerous disease and cancer. Expert Rev Vaccines. 2013;12:271-283.

44.

Romanowski

Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines. Hum Vaccin. 2011;7:161-169.

45.

Romanowski

Schwarz

Ferguson

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccin. 2011;7:1374-1386.

46.

Olsson

Villa

Costa

Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine. 2007;25:4931-4939.

47.

Herrero

Hildesheim

Rodriguez

Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013;8:e68329.

48.

Lang Kuhs

Gonzalez

Struijk

Prevalence of and risk factors for oral human papillomavirus among young women in Costa Rica. J Infect Dis. 2013;208:1643-1652.

49.

D’Souza

Dempsey

The role of HPV in head and neck cancer and review of the HPV vaccine. Prev Med. 2011;53(suppl 1):S5-S11.

50.

Albers

Kaufmann

AM.

Therapeutic human papillomavirus vaccination. Public Health Genomics. 2009;12:331-342.

51.

Albers

Siniković

Banko

Developments in therapeutic human papillomavirus vaccination. Acta Chir Iugosl. 2009;56:29-37.

52.

Jabbar

Fernando

Saunders

Immune responses induced by BCG recombinant for human papillomavirus L1 and E7 proteins. Vaccine. 2000;18:2444-2453.

53.

van Driel

Ressing

Brandt

The current status of therapeutic HPV vaccine. Ann Med. 1996;28:471-477.

54.

Kenter

Welters

Valentijn

Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med. 2009;361:1838-1847.

55.

Hsu

Hung

Cheng

Enhancement of suicidal DNA vaccine potency by linking Mycobacterium tuberculosis heat shock protein 70 to an antigen. Gene Ther. 2001;8:376-383.

56.

Cid-Arregui

Therapeutic vaccines against human papillomavirus and cervical cancer. Open Virol J. 2009;3:67-83.

57.

Welters

Kenter

Piersma

Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res. 2008;14:178-187.

58.

Melief

CJ.

Treatment of established lesions caused by high-risk human papilloma virus using a synthetic vaccine. J Immunother. 2012;35:215-216.

59.

Hellner

Munger

Human papillomaviruses as therapeutic targets in human cancer. J Clin Oncol. 2011;29:1785-1794.

60.

Wang

Sherman

Hildesheim

Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976-2000. Cancer. 2004;100:1035-1044.

61.

Bulkmans

Berkhof

Rozendaal

Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet. 2007;370:1764-1772.

62.

Nieh

Chen

Chu

Is p16(INK4A) expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies. Gynecol Oncol. 2005;97:35-40.

63.

Laird

PW.

The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3:253-266.

64.

Elashoff

Zhou

Reiss

Prevalidation of salivary biomarkers for oral cancer detection. Cancer Epidemiol Biomarkers Prev. 2012;21:664-672.

65.

Kreimer

Alberg

Daniel

The epidemiology of oral HPV infection among a multinational sample of healthy men. Cancer Epidemiol Biomarkers Prev. 2011;20:172-182.

66.

Kreimer

Johansson

Waterboer

Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer. J Clin Oncol. 2013;31:2708-2715.

67.

D’Souza

Kreimer

Viscidi

Oral HPV infection in HPV-positive oropharyngeal cancer cases and their spouses. J Clin Oncol. 2013;31(suppl):CRA6031.

68.

Fakhry

Rosenthal

Clark

Associations between oral HPV16 infection and cytopathology: evaluation of an oropharyngeal “pap-test equivalent” in high-risk populations. Cancer Prev Res (Phila). 2011;4:1378-1384.

69.

Tewari

Sill

Monk

Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group. J Clin Oncol. 2013;31(15, suppl):abstract 3.

70.

Selman

Luesley

Acheson

Khan

Mann

CH.

A systematic review of the accuracy of diagnostic tests for inguinal lymph node status in vulvar cancer. Gynecol Oncol. 2005;99:206-214.

71.

Levenback

Burke

Gershenson

Morris

Malpica

Ross

MI.

Intraoperative lymphatic mapping for vulvar cancer. Obstet Gynecol. 1994;84:163-167.

72.

de Hullu

Hollema

Piers

Sentinel lymph node identification with technetium-99m-labeled nanocolloid in squamous cell cancer of the vulva. J Nucl Med. 1998;39:1381-1385.

73.

Levenback

van der Zee

Rob

Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study. J Clin Oncol. 2012;30:3786-3791.

74.

Lambaudie

Collinet

Narducci

Laparoscopic identification of sentinel lymph nodes in early stage cervical cancer: prospective study using a combination of patent blue dye injection and technetium radiocolloid injection. Gynecol Oncol. 2003;89:84-87.

75.

Boss

van Golde

Beerendonk

Pregnancy after radical trachelectomy: a real option?

Gynecol Oncol. 2005;99(3, suppl 1):S152-S156.

76.

Cmelak

AJ.

Current issues in combined modality therapy in locally advanced head and neck cancer. Crit Rev Oncol Hematol. 2012;84:261-273.

77.

Chung

Schwartz

DL.

Impact of HPV-related head and neck cancer in clinical trials: opportunity to translate scientific insight into personalized care. Otolaryngol Clin North Am. 2012;45:795-806.

78.

Memorial Sloan-Kettering Cancer Center. Induction chemotherapy with afatinib, ribavirin, and weekly carboplatin/paclitaxel for stage IVA/IVB HPV associated squamous cell carcinoma (OPSCC). https://clinicaltrials.gov/ct2/show/NCT01721525. Accessed January 19, 2015.

79.

Walter

Yin

Wilkerson

Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PLoS One. 2013;8:e56823.

80.

Radiation Therapy Oncoloy Group. Radiation therapy with cisplatin or cetuximab in treating patients with oropharyngeal cancer. https://clinicaltrials.gov/ct2/show/NCT01302834. Accessed January 19, 2015.

81.

Rischin

Young

Fisher

Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28:4142-4148.

82.

De-intensification of Radiation and Chemotherapy for Low-Risk HPV-related Oropharyngeal SCC: Follow-up Study. https://clinicaltrials.gov/ct2/show/NCT02281955. Accessed February 10, 2015.

83.

Simon

El-Baba

Albrecht

Holsinger

Plinkert

PK.

Initial experience with transoral robotic surgery using the da Vinci(R) surgical system. HNO. 2011;59:261-265.

84.

Weinstein

O’Malley

Jr Magnuson

Transoral robotic surgery: a multicenter study to assess feasibility, safety, and surgical margins. Laryngoscope. 2012;122:1701-1707.

85.

Eastern Cooperative Group. Transoral surgery followed by low-dose or standard-dose radiation therapy with or without chemotherapy in treating patients with HPV positive stage III-IVA oropharyngeal cancer. https://clinicaltrials.gov/ct2/show/NCT01898494. Accessed January 19, 2015.

The Impact of HPV as an Etiological Factor in Gynecological and Oropharyngeal Cancer

Abstract

Keywords

Background

Human-Associated Viruses and Cancer

HPV and Cancer

HPV Carcinogenesis

Risk Factors and Incidence

HPV and Gynecological Malignancies

Genital HPV Infection and Cancer

Treatment of Preinvasive Disease

Treatment of Invasive Disease

HPV and Head and Neck Cancer

Oral HPV Infection and Cancer

Treatment of OPSCC

HPV Vaccines

Future Directions

Screening: Gynecological Cancer

Screening: Oropharyngeal Cancer

Therapy: Gynecological Cancer

Therapy: Oropharyngeal Cancer

Conclusion

References