Human Papillomavirus Infection

Overview

Human papillomavirus infections can manifest clinically as warts, cancer (especially of the cervix, but also of the oropharynx and the genital areas), and less commonly, recurrent respiratory papillomatosis. Certain genotypes are associated with warts: HPV 6 and HPV 11 cause about 90% of genital warts.  Other genotypes are associated with cervical cancer: HPV 16 and 18 cause 70% of cervical cancer. Transmission occurs via genital contact, close personal contacts, and can also occur during passage of the fetus through an infected birth canal.

 

Warts

Warts are cutaneous lesions that are caused by the Human Papillomavirus(HPV) which invades epithelial cells and cause benign epithelial tumors. There are over 70 types of HPV identified and although some types are associated with specific types of warts, there is some overlap. Warts are most common in children and adolescents and affect between 5-10% of the population. Transmission is usually from skin-to-skin and mucous membrane-to-mucous membrane. The virus can also be transmitted by fomites. The acquisition is related to the amount of virus inoculated, the integrity of the skin, and the patient's cellular immunity. The incubation period may be from weeks to years. 

 

Common Clinical Presentations

  1. Common Warts- most commonly on the fingers, dorsum of the hand, paronychial areas, face, knees and elbows. They are gray or brown and have an irregular roughened keratotic surface.
  2. Plantar Warts - most commonly on the soles and palms. Often flattened because of pressure and may be painful. Sometimes confused with calluses or corns. If you shave the surface, will see black dot which are thrombosed blood vessels which help differentiate them from callous. 
  3. Flat Warts- multiple small flat-topped slightly pigmented lesion most common on the dorsum of the hands and on the face. Often in linear pattern. 
  4. Anogenital Warts-Condyloma acuminata- most commonly on anogenital skin and mucous membranes. May occur by sexual contact but also must consider acquisition from birth canal and auto-inoculation. After 3 years of age, most likely sexually transmitted. Range from slightly pigmented flat lesions to moist pink to brown cauliflower growths. Should be differentiated from skin tags, molluscum, and dermatitis. Are present in 40% of sexually active adolescents. Most commonly types 6 and 11. 
  5. Laryngeal papillomas- children who present with persistent stridor or airway obstruction, should be evaluated for possible laryngeal warts. Vertical transmission from infected mothers and may present months to years after birth.

 

Treatment

The majority of warts will spontaneously resolve without treatment and there will be no scarring. Reasons for removal include cosmetic, pain, and continuous self-inoculation. Most methods of removal are time consuming and painful and if surrounding tissue damage occurs, may lead to scaring. Prior to treatment, paring the lesions with scalpel, by soaking, or occlusive dressing, may improve effectiveness of removing. Recurrence rates are high if the entire wart isn't removed. 

  1. Folk remedies
  2. Keratolytics- response may take months. There are some easy to use "patches" available. Inexpensive. Effective for plantar and common warts. Salicylic acid.
  3. Destructive techniques may lead to scaring and pigmentation changes.
    1. Cryotherapy. Liquid nitrogen can be delivered by the physician in their office. Cause blister formation and may be painful and leave a scar.
    2. Caustic materials like Podophylum
    3. Cantharidin 
    4. Electrocautery and laser therapy. 
    5. Immunotherapy- Interferron has been used. Very expensive.

 

Cervical Cancer

The major risk factor for cervical cancer is sexual activity. However, cigarette smoking and immunosuppression also increases the risk of HPV associated cervical cancer. No correlation between the risk of cervical cancer with genetic biomarkers/HLA genotypes have been found.

In terms of screening, ACOG recommends starting at age 21 and ending at 65-70 if there are no recent abnormal results. Between these two ages, ACOG recommends screening every 1-2 years under 30 years of age and every 2-3 years over 30 years of age (every 3 years if done with HPV).

The prognosis depends on the histological grade of the lesion, with CIN1 having a higher rate of regression compared to CIN3. With excisional or ablative outpatient therapy, there is a 98% risk reduction of developing invasive cancer in eight years. However, treated women remain at increased risk for as long as 20 to 25 years of invasive cancer as compared to the general population.

 

Diagnosis

The diagnosis of precancerous cervical lesions is based on cytology and histology.

  1. CIN 1 is considered a low grade lesion. It refers to mildly atypical cellular changes in the lower third of the epithelium (formerly called mild dysplasia). It is caused by a transient (both low and high risk) HPV infection (koilocytotic atypia). It is not truly precancerous.
  2. CIN 2 is considered a high grade lesion. It refers to moderately atypical cellular changes confined to the basal two-thirds of the epithelium (formerly called moderate dysplasia) with preservation of epithelial maturation. Like with CIN 3, this is more likely to be associated with persistent HPV infection and a higher risk of progression to cervical cancer. CIN 2 lesions will regress following biopsy in nearly 40 percent of women under 20, and the colposcopist may elect to follow a patient with a diagnosis of CIN 2 (but no CIN 3) under some circumstances
  3. CIN 3 is also considered a high grade lesion. It refers to severely atypical cellular changes: full-thickness lesions (formerly called severe dysplasia or carcinoma in situ).
  4. LSIL and HSIL were originally intended to describe cytology, but they may correlate to histologic features. LSIL is equivalent to CIN1 and other abnormalities defined above and HSIL comprises either CIN 2 or 3.

 

Treatment

  1. For CIN1 - Expectant management is recommended- Follow up with HPV testing or repeat cytology/colposcopy at 6 and 12 months. After two negative smears or a negative HPV DNA test, routine screening may be resumed. Ablation or excision is acceptable if CIN 1 persists for more than 24 months or if patient may be lost to follow-up
  2. CIN 2,3 –  Two approaches are possible: Ablation vs. Excision. Both methods are equally effective. The entire transformation zone should be removed.
    • Ablation – cryotherapy or laser ablation. Preferred if patient has no suspected invasive disease and will follow-up.
    • Excision – cold knife or laser conization, or loop electrosurgical excision. Preferred for women past childbearing, or unable to rule out invasive disease.
    • Hysterectomy — Not an initial treatment option. Indications for hysterectomy:
      • Conization specimen margins that are positive for CIN 2,3, especially in the setting of completed childbearing and expected poor compliance with follow-up.
      • Anatomical problems including scarring that compromises reliability of cervical cytology
      • Presence of coexistent gynecologic conditions requiring hysterectomy
      • Patient request and persistent or recurrent CIN 2,3
  3. Pregnancy is a special consideration - Defer follow-up for CIN 1 until at least six weeks postpartum. Defer treatment of CIN 2,3 during pregnancy but monitor with colposcopy (without endocervical curettage).
  4. Adolescence is also a special consideration -  In one study, only 0.4 percent of women under 20 years with CIN 1 or less diagnosed by colposcopy with directed and random biopsies were subsequently diagnosed with CIN 3 or more. For CIN 2, observation with colposcopy and cytology at six-month intervals for up to two years is preferable to excisional or ablative therapy

 

Follow-up

  1. HPV testing and/or cervical cytology at 6 to 12 months or cytology and colposcopy with endocervical curettage at 6 and 12 months
  2. The  CDC recommends HPV vaccination regardless of a history of genital warts, abnormal Papanicolaou test, or positive HPV DNA test, because these conditions are not evidence of prior infection with all vaccine HPV types
  3. For positive margins - Clinical follow-up with cytology and endocervical sampling at four to six months, or repeat excision.
  4. For post-hysterectomy —
    • CIN1 -  women do not need post-hysterectomy vaginal cytology
    • CIN2,3 -  0.9 to 6.8 percent of patients develop VAIN.  ACOG and the ACS recommend screening until three vaginal cytology tests are negative.

 

References

  1. Cohen, Bernard Warts and Children: Can They be Separated. Contemporary Pediatrics Feb 1997
  2. Stulberg D. Hutchinson A. Molloscum Contagiosum and Warts. American Family Physician. March 15 2003
  3. Dasher D, Burkhart C, Morrell D. Immunotherapy for Childhood Warts. Pediatric annals. 2009 Vol 38 Number 7
  4. Culton D, Morrell D, Burkhart C. The Management of Condyloma Acuminata in the Pediatric Population.  Pediatric annals.  2009. Vol 38 Number 7
  5. Cox, JT, Schiffman, M, Solomon, D, ASCUS-LSIL Triage Study (ALTS) Group. Prospective follow-up suggests similar risk of subsequent cervical intraepithelial neoplasia grade 2 or 3 among women with cervical intraepithelial neoplasia grade 1 or negative colposcopy and directed biopsy. Am J Obstet Gynecol 2003; 188:1406.
  6. Holschneider, Christine. “Cervical intraepithelial neoplasia: Management”. Uptodate.
  7. Holschneider, Christine. “Cervical intraepithelial neoplasia: Definition, incidence and pathogenesis”. Up todate.
  8. Holschneider, C; Crum, C. “Cervical cytology: Interpretation of results”. Uptodate.
  9. Holowaty, P, Miller, AB, Rohan, T, To, T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 1999; 91:252.
  10.  Sirovich, B, et. al. “Screening for cervical cancer”. Uptodate.

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