Human Papillomavirus


Article Author:
Lynette Studer


Article Editor:
Gabriella Cardoza-Favarato


Editors In Chief:
Susan Johnson
Alexandra Caley


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
10/27/2018 12:31:38 PM

Introduction

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

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]

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 the development of cervical cancer.

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 to be 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 which inactivate p53 and pRb proteins respectively; these inactivations lead to dysregulation of the cell cycle and neoplastic transformation of 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 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.

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.

Evaluation

Patients with cutaneous, anogenital, and/or oropharyngeal warts may have them excised and submitted for histopathological examination if there is any question as to 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, which is an assay test performed on cervical cells to evaluate for 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 for 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. The overarching purpose behind many of these treatments is to manually or chemically irritate the area, thereby invoking a host immune response to assist in clearing the infected tissue.[8][9][10]

For the prevention of 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 may 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 of the 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

Deterrence and Patient Education

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

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. For the most part, HPV is sexually acquired, and one of the best ways to decrease the morbidity of this infection is the education of the patient. Both the nurse and the pharmacist are in a prime position to educate patients about safe sex, use of condoms and avoidance of multiple sex partners. Further, women should be encouraged to undergo the Pap smear to screen for cervical dysplasia and presence of HPV. More important, patients should be told that if they have the presence of genital warts, sexual activity should be avoided until the lesions have been treated or have resolved. The pharmacists should also encourage the patients to be vaccinated against HPV. Finally, patients need to be educated that if they have HPV, they should be screened for other sexually transmitted infections.  [13][14][15](Level II)

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 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)


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Human Papillomavirus - Questions

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In an HIV male with anal warts, which subtype of HPV would one suspect?



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Which subtypes of human papillomavirus are most common in an HIV male with anal warts?



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A homosexual male is seen for a routine checkup. He denies any constitutional symptoms. He expresses concern that he has some fleshy nodules around the anus and wants to get rid of them. What is the most likely cause of his anal nodules?



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What is the biggest morbidity of infection with human papillomavirus?



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Which of the following is not a recommended treatment for Human papillomavirus-related verrucous conditions?



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A 27-year-old female presents with koilocytic cells on her Pap smear. She most likely has been infected with which of the following viruses?



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Human papilloma virus (HPV) increases a woman's risk of which of the following disorders?



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Which of the following types of human papillomavirus does not have oncogenic potential?



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Select the human papillomavirus subtypes most often associated with cervical cancer.



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What condition is associated with the cellular changes of koilocytosis?



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What percentage of LGSIL lesions progress to HGSIL?



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Which of the following can be caused by the human papillomavirus?



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What Human papillomavirus subtype is not associated with cervical cancer?



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A 24-year old female has a pap smear showing a precancerous lesion on her cervix. What is the most likely infection that caused this pathology?



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Which of the following genes is affected by the Human papillomavirus (HPV) E6 oncoprotein?



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A 23-year-old woman presents for her first gynecological examination and Pap smear. Which of the following counseling points can you offer to help decrease her risk of developing cervical carcinoma?



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Which statement best describes the Human papillomavirus (HPV)?



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What percentage of women fail to clear the human papilloma virus (HPV) once infected?



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What is the estimated percentage of genital human papillomaviruses DNA in the United States male population?



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A young female has come in for her pap smear. The procedure is done without any problems, and it is discovered that she is infected with human papillomavirus (HPV). Which of the following HPV types are considered to be oncogenic for cervical cancer? Select all that apply.



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A client is seen in the clinic, and testing reveals that she has acquired the human papillomavirus (HPV). This virus is known to cause lesions in which of the following locations? Select all that apply.



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How is Human papillomavirus (HPV) transmitted?



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What can be caused by Human papillomavirus infection?



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Human Papillomavirus - References

References

Bradbury M,Xercavins N,García-Jiménez Á,Pérez-Benavente A,Franco-Camps S,Cabrera S,Sánchez-Iglesias JL,De La Torre J,Díaz-Feijoo B,Gil-Moreno A,Centeno-Mediavilla C, Vaginal Intraepithelial Neoplasia: Clinical Presentation, Management, and Outcomes in Relation to HIV Infection Status. Journal of lower genital tract disease. 2018 Aug 29     [PubMed]
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Soe NN,Ong JJ,Ma X,Fairley CK,Latt PM,Jing J,Cheng F,Zhang L, Should human papillomavirus vaccination target women over age 26, heterosexual men and men who have sex with men? A targeted literature review of cost-effectiveness. Human vaccines     [PubMed]
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Rositch AF,Krakow M, Invited Commentary: Moving From Evidence to Impact for Human Papillomavirus Vaccination-The Critical Role of Translation and Communication in Epidemiology. American journal of epidemiology. 2018 Jun 1     [PubMed]
Arrossi S,Temin S,Garland S,Eckert LO,Bhatla N,Castellsagué X,Alkaff SE,Felder T,Hammouda D,Konno R,Lopes G,Mugisha E,Murillo R,Scarinci IC,Stanley M,Tsu V,Wheeler CM,Adewole IF,de Sanjosé S, Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline. Journal of global oncology. 2017 Oct     [PubMed]
Ouh YT,Lee JK, Proposal for cervical cancer screening in the era of HPV vaccination. Obstetrics     [PubMed]
Cheraghlou S,Torabi SJ,Husain ZA,Otremba MD,Osborn HA,Mehra S,Yarbrough WG,Burtness BA,Judson BL, HPV status in unknown primary head and neck cancer: Prognosis and treatment outcomes. The Laryngoscope. 2018 Aug 27     [PubMed]
Donken R,Ogilvie GS,Bettinger JA,Sadarangani M,Goldman RD, Effect of human papillomavirus vaccination on sexual behaviour among young females. Canadian family physician Medecin de famille canadien. 2018 Jul     [PubMed]

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