Continuing Education Activity

The human papillomavirus (HPV) is a non-enveloped, double-stranded, circular DNA virus that is responsible for causing multiple epithelial lesions and cancers. It can manifest as cutaneous and anogenital warts, which depending on the subtype, may progress to carcinoma. This activity reviews the evaluation and management of human papillomavirus infection and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of human papillomavirus infection.
• Review the role of E6 and E7 protein in the pathophysiology of human papillomavirus infection.
• Explain the management of human papillomavirus infection.

Introduction

The Human Papillomavirus (HPV) is the initiating force behind multiple epithelial lesions and cancers, predominantly cutaneous and mucosal surfaces.[1][2][3]

There are more than 100 subtypes of HPV. Individuals with persistent HPV infection and those who have multiple sexual partners are at very high risk for acquiring more HPV subtypes. The current classification of HPV infection is as follows:

• Non-genital (Cutaneous)
• Mucosal or anogenital
• Epidermodysplasia verruciformis (EV)

The clinical lesions may be visibly obvious, but in some cases (latent lesions) may require testing for viral DNA. The majority of HPV infections are latent, and most clinical lesions present as warts rather than a malignancy.

Today, HPV has been implicated as a cause of laryngeal, oral, lung, and anogenital cancer. Subtypes 6 and 11 are low risk and usually present with the formation of condylomata and low-grade precancerous lesions. HPV subtypes 16 and 18 are high risk and are responsible for high-grade intraepithelial lesions that progress to malignancies. It is important to understand that HPV alone does not cause cancer but requires triggers like smoking, folate deficiency, UV light exposure, immunosuppression, and pregnancy.

Etiology

HPV is a non-enveloped, double-stranded, circular DNA virus of the Papillomaviridae family. The virus enters the epithelium through disruption to the skin/mucosa and infects basal stem cells. Its genome contains seven early (E) and two late (L) phase genes required for viral propagation. The viral DNA may remain as an independent episome for a period before integrating into the host’s genome. HPV preferentially integrates at fragile sites in the human DNA where the strand is prone to breakages.[4]

Risk factors:

• Sexual activity, age of first sexual intercourse, and number of sexual partners
• Smoking
• Use of oral contraceptives (more than 5 years)
• Chewing betel nut
• Exposure to radiation and UV light

Epidemiology

HPV subtypes show a predilection for body sites they most commonly infect, and disease manifestations that result from infection may vary. Over 180 subtypes of HPV have been identified. Cutaneous warts of the hands and feet, such as verruca vulgaris or verruca plantaris, are most commonly caused by HPV subtypes 1, 2, 4, 27, or 57. Most anogenital warts, such as condyloma acuminatum, are caused by HPV subtypes 6 or 11 and termed low-risk HPV; these subtypes also are responsible for juvenile and adult recurrent respiratory papillomatosis. Pre-cancerous and cancerous lesions of the cervix, male and female anogenital areas, and oropharyngeal area are most commonly caused by HPV subtypes 16 and 18. However, subtypes 31, 33, 35, 45, 52, and 58 also fall in the high-risk HPV group as they are associated with cervical cancer development.

The HPV subtypes which cause cutaneous verrucae are spread by contact between skin with microscopic or macroscopic epidermal damage and a fomite-harboring HPV. The prototypical location for contracting warts of the feet is a locker room.

Both low-risk and high-risk HPV (sometimes referred to as alpha-papillomaviruses) are considered sexually transmitted but may be spread by other forms of intimate contact. According to the Center for Disease Control and Prevention (CDC), the most recent studies show the prevalence of genital HPV for adults aged 18 to 59 to be approximately 45.2% in men and 39.9% in women.[5][6]

Pathophysiology

E6 and E7 are oncoproteins that inactivate p53 and pRb proteins, respectively; these inactivations lead to dysregulation of the cell cycle and neoplastic transformation of the affected tissue. The virus remains relatively inactive in early infection but keeps the cell from entering a resting (G0) state. As the infected cells grow and mature, E2 regulates the transition from early- to late-phase genes, and the virus increases the production of virions for dispersal. This increase in virion production in HPV-driven lesions typically manifests as hypertrophy of the infected tissue (discrete, thickened lesions, e.g., the common wart) with the potential for atypia and malignant transformation in those lesions infected with high-risk HPV.

Histopathology

The wart histology may reveal hyperkeratosis, papillomatosis, and parakeratosis. The long rete ridges usually point to the wart center, and the capillaries are often thrombosed.

History and Physical

Evaluation and treatment of HPV infection vary by body site and disease manifestation. For a more in-depth examination of each disease entity, please visit those specific topics.

History

• Cutaneous warts (verruca vulgaris, verruca plantaris): Ask about potential infectious contacts and hygiene habits (e.g., "Do you wear shower shoes when showering at the gym?" or "Are the lesions painful and/or prone to bleeding?")

• Anogenital warts (condyloma acuminatum): Providers should ask about:

1. Sexual history/infectious contacts
2. Duration and location of the wart(s)
3. Prior vaccination for HPV (Gardasil, Cervarix)
4. History of wart removal/treatment
5. History of diseases or medications that may cause them to be immunocompromised.

• Pap smears (cervical for females, anal Pap smear for males), HPV testing, and sexually transmitted infections.

• Cervical dysplasia (squamous and glandular): Providers should ask about:

1. Menses/prior Pap smears/HPV testing,
2. Sexually transmitted infections/sexual history/infectious contacts,
3. Prior vaccination for HPV (Gardasil, Cervarix), and
4. Associated symptoms, such as bleeding/spotting outside of menses, pelvic or genital pain, pain/bleeding during intercourse, and/or palpable lesions felt on the cervix.

 Physical Examination

• Cutaneous warts (verruca vulgaris, verruca plantaris): Examine hands and feet thoroughly, including between digits and the underside of the toes.
• Anogenital warts (condyloma acuminatum): Examine the anogenital region. Patients may additionally require a speculum examination of the vaginal walls and/or anus. Men may require an examination of the urethra, depending on signs and symptoms. Depending on the history of sexual practices, an oropharyngeal examination may be prudent.
• Cervical dysplasia (squamous and glandular): Perform a speculum examination of the cervix. Depending on the patient’s age and Pap smear history, an initial or repeat Pap smear may be warranted.

Epidermodysplasia verruciformis is an autosomal recessive trait that increases the susceptibility to specific warts that are not usually observed in the general population. EV is also seen in immunocompromised individuals and those who have undergone transplants. The condition starts in childhood and can affect any part of the body. The warts are flat and often mistaken for tinea versicolor. While warts have weak metastatic potential, they are locally destructive.

Evaluation

Patients with cutaneous, anogenital, and/or oropharyngeal warts may have them excised and submitted for histopathological examination if there is any question about the diagnosis or concern for dysplasia.[6][7]

Screening for cervical dysplasia/malignancy is typically accomplished through speculum examination and Pap smear with concurrent or reflex HPV testing, an assay test performed on cervical cells to evaluate the most common HPV subtypes associated with dysplasia. Treatment protocols stratify patients by age, HPV status, and Pap smear results. Depending on treatment stratification, patients with results concerning intraepithelial squamous or glandular lesions may proceed to colposcopy (a procedure in which the cervix is coated with acetic acid, acetowhite areas are evaluated with a colposcope, and concerning areas are biopsied to examine for histopathologic evidence of dysplasia or malignancy).

Treatment / Management

Individuals with cutaneous warts have numerous treatment options available, including surgical removal, cryotherapy (freezing the infected tissue), irritant or immunomodulating medications, and laser removal. Many of these treatments' overarching purpose is to manually or chemically irritate the area, thereby invoking a host immune response to assist in clearing the infected tissue.[8][9][10]

To prevent lower anogenital tract HPV infection by the most common high-risk and low-risk subtypes, the CDC recommends that boys and girls be vaccinated for HPV starting at ages 11 to 12. It is further recommended that women get vaccinated through the age of 26 and men through the age of 21. 

Anogenital and oropharyngeal warts may be treated similarly to cutaneous warts as long as the patient is immunocompetent. Development of HPV-related carcinoma at these sites may require resection, chemotherapy, and/or radiation.

Cervical HPV-driven lesions may regress without any intervention. Young immunocompetent women with dysplasia are usually monitored at shortened intervals through Pap smears, HPV testing, and colposcopic examination. Persistent cervical dysplasia at any age, or high-grade dysplasia in older women, is treated with cryotherapy, loop electrosurgical excision procedure (LEEP), or cold knife cone (CKC) excision. Both surgical procedures (LEEP, CKC) involve resection of the cervical os and transformation zone. If the patient progresses to malignancy (e.g., squamous cell carcinoma, endocervical adenocarcinoma), further resection, chemotherapy, and/or radiation may be required.[11][12]

For a fuller explanation of the disease entities associated with HPV infection, please visit those topics specifically.

Differential Diagnosis

• Corns & calluses
• Acrochordon
• Condyloma latum
• Keratoacanthoma
• Psoriasis
• Seborrhea
• Chancroid
• Herpes simplex
• Molluscum contagiosum

Prognosis

The prognosis after an HPV infection is good, but recurrences are common. Even though there are many treatments for warts, none works well, and most patients require repeated treatments. The HPV infection can also result in vulvar intraepithelial dysplasia, cervical dysplasia, and cervical cancer. Some women remain at high risk for developing vaginal and anal cancer. The risk of malignant transformation is highest in immunocompromised individuals. Finally, when a patient has been diagnosed with HPV infection, there is a 5-20% risk of having other STDs like gonorrhea and/or chlamydia.

Complications

• Poor cosmesis
• Depression, loss of self-esteem
• Genital warts may cause urethral obstruction.
• Condylomata may form ulcers and become infected.
• Progression to malignancy
• Transmission of HPV to others

Postoperative and Rehabilitation Care

Long term follow up is essential as recurrence of warts is common. In addition, all treatments for warts have side effects that need to be monitored

The sexual partner also needs to be examined for condylomata.

Because of the risk of cancer, DNA testing and screening is required in high-risk patients.

Consultations

• Infectious disease to manage HPV infection in immunocompromised individuals
• ENT to manage oropharyngeal papillomas
• Urologist to manage urethral/penile warts and penile cancer
• Colorectal surgeon to manage the anal disease
• Dermatologist to help manage warts and EV

Deterrence and Patient Education

• Avoid multiple sexual partners.
• Use a condom
• Practice safe sex
• Undergo Pap smear screen

Vaccination

The 9 valent HPV vaccine is available to prevent certain cancerous lesions in males and females. The vaccine covers HPV subtypes 6,11,16,18,31,33,45,52 and 58. The effectiveness of the HPV vaccine has been inferred from several studies. It has been shown to prevent anal cancer, genital warts, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, and anal intraepithelial neoplasia. The vaccine is most effective when administered before initiating sexual activity at ages 9-12.

Pearls and Other Issues

• Boys and girls aged 11-12 should receive the HPV vaccine
• To be effective, the vaccination should be completed by age 13
• Studies show that the vaccine is effective after 2 doses in younger children

Enhancing Healthcare Team Outcomes

HPV is known to cause lesions of the mucous membranes and skin. There are over 100 subtypes of HPV, and some are associated with an increased risk of malignancy. HPV diagnosis and treatment is best done with an interprofessional team.

For the most part, HPV is sexually acquired, and one of the best ways to decrease the morbidity of this infection is the patient's education. Both the nurse and the pharmacist are in a prime position to educate patients about safe sex, the use of condoms, and avoidance of multiple sex partners.

The pharmacist should provide information on the different treatments for warts, their benefits, and adverse effects. The pharmacist should also encourage the patients to be vaccinated against HPV.

 Further, the primary care provider should encourage these women to undergo the Pap smear to screen for cervical dysplasia and the presence of HPV. More importantly, patients should be told that if they have genital warts, sexual activity should be avoided until the lesions have been treated or have resolved.

Finally, patients need to be educated that if they have HPV, they should be screened for other sexually transmitted infections. The sex partner's evaluation is vital if the cycle of spread is to be broken.[13][14][15](Level II) Only through such collaboration between team members will the morbidity of HPV be reduced.

Outcomes

Once HPV is acquired, recurrences are common. However, for most patients with genital warts, there are treatments. In about 60% of cases, genital warts resolve spontaneously. Irrespective of the treatment of genital warts, the risk of cervical cancer is not altered.

The biggest concern with genital warts is the risk of cervical cancer. HPV is also known to be associated with anal and head and neck cancers. Individuals who are immunocompromised are also at risk for developing dysplasia or cancer of the vagina and vulva.

Finally, in at least one-third of patients with HPV, there is the presence of other sexually transmitted infections.[16][1][17](Level II)