Human Papillomavirus

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](B3)

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