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A. Epidemiology navigator

  1. DNA virus causes anogenital warts and squamous cell neoplasia
    1. Cervical cancer
    2. Vuvlar cancer
    3. Anal cancer
  2. Over 82 Known HPV Serotypes [1]
    1. Associated with benign lesions: types 6, 11, 40, 42-44, 54, 61, 70, 72, 81, CP6108
    2. Moderate oncogenic potential: types 26, 39, 40, 43, 53, 55, 59, 66, 68
    3. High oncogenic potential: types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82
  3. HPV Infection Rates
    1. At any given time, 10-25% of young women with normal Pap smears have HPV DNA
    2. Over 36-month period, incidence of new HPV detection in young women is ~45% [8]
    3. In normal women, >80% with HPV DNA once are negative for HPV DNA on followup
    4. About 20% of adults become infectd with HPV type 16 during their lifetimes
    5. Prevalence of high cancer risk HPV is 35% amongst age 14-19; 6% age 50-65; 23% overall [13]
    6. Male circumcision associated with reduced risk of penile HPV infection [2]
    7. Male circumcision also associated with reduced risk of cervical cancer in current female partners [2]
    8. Regular condom use associated with about 70% reduction in new HPV infections [6]
  4. HPV Persistence
    1. Persistance of HPV >4-6 months associated with increased risk of abnormal Pap [11]
    2. HPV infection is a 6-10X risk factor for development of LGSIL lesions on Pap [10]
    3. The presence of HIV infection increases risk of persistent HPV DNA
    4. High HPV viral loads in Pap smears is a risk factor for high grade CIN development [8]
    5. The CD4+ count in HIV+ women is inversely related to persistence of HPV DNA
  5. HPV and Human Immunodeficiency Virus (HIV)
    1. Immunodeficiency, particularly HIV, increases risk for persistent viral infection
    2. CD4+ T cell counts <200/µL strongly associated with inability to eradicate HPV
    3. Probability of persistent HPV in HIV with CD4+ count <500/µL is >70% over 1 year
    4. HPV in HIV+ patients increases risk for invasive cervical as well as anal cancers [5,14]
    5. About 1 in 5 HIV+ women develop high grade HPV associated disease over 3 years [23]
    6. HPV testing is recommended in patients with HIV for general screening [7]
  6. Risk Factors for Transmission
    1. Overall, increasing incidence of anogenital warts and HPV infections in US population
    2. Number of sex partners - genital, anal, and oral sex
    3. Inversely related to use of condoms
    4. HIV+ status increases risk of virus shedding and persistence
    5. History of injection (illegal) drug abuse
    6. Socioeconomic status also inversely proportional to risk
    7. Male homosexual contacts are a major risk factor for anal cancer and HPV+ anal lesions

B. HPV and Cancer Screeningnavigator

  1. Benign Tumors
    1. Genital and Nongenital Warts
    2. Raised lesions most common
    3. Flat lesions less common
  2. HPV Infection and Cancer [9]
    1. HPV is associated with >90% of all cervical cancers and their precursors
    2. Also associated with anal and certain types of oropharyngeal cancers
    3. Cervical cancers usually arise from infection of cells in the "transformation zone"
    4. Transformation zones in the cervix, anus, and oropharynx are most susceptible
    5. Transformation zones are areas with transformation between different epithelial types
  3. Dysplastic Lesions and Cervical Cancer [3]
    1. Precursors include high grade intraepithelial lesions and carcinoma in situ
    2. HPV associated pre-malignant and malignant lesions are usually flat
    3. Of cervical cancers, ~55% with type 16, ~16% type 18; types 33,45,31,58,52 in 2-5% [9]
    4. About 95% of squamous cell cervical cancers have high risk serotype HPV DNA [8]
    5. Not all persons with oncogenic serotypes develop cancer, however
    6. Highly oncogenic HPV ~17X more common in early Pap Smears in patients who later developed cervical cancer versus those who did not
    7. In young women, persistance of HPV >4-6 months associated with abnormal Pap [11]
    8. >5 years oral contraceptive use increased risk for cervical cancer 2.8-4X [37]
    9. One or 2 full term pregnancies in HPV+ women associated with 2.3X increased risk of cervical cancer [38]
  4. HPV and Pap Smears
    1. HPV testing is more sensitive (94% versus 55%) and about as specific (94.1% versus
  5. 8%) for CIN 2 or 3 compared to Pap smear [18]
    1. In another study, high risk HPV positivity 20% more sensitive for detecting CIN2 or CIN3 and 5% less specific than Pap smear [4]
    2. HPV testing has positive predictive value of 15% and a negative predictive value of 99% for presence of High Grade SIL on colposcopy
    3. Reflex HPV DNA testing should be considered for any ASCUS or AGUS on Pap [34]
    4. Persistence of high risk serotype HPV (DNA testing) predicts CIN 3 morphology
    5. All women with persistent high risk HPV on second test after 3-6 months should undergo invasive analysis by gynecologist
    6. HPV-positive women with normal or borderline followup cytology should undergo repeat HPV testing in 12 months [4]
    7. HPV testing and visual inspection with acetic acid can replace standard Pap smear [31]
    8. Immediate colposcopy in patients with high risk HPV or abnormal visual inspection results in reduced rates of CIN2/3 after 6-12 months compared with delayed evaluation [31]
    9. Combination of Pap and HPV testing reduces incidence of grade 2 or 3 CIN or cervical cancer detected on subsequent screening examinations [19]
  6. HPV and Other Cancers
    1. HPV (high risk serotypes) is the major cause of Type 1 vulvar cancers [17]
    2. HPV DNA is found in >90% of female and ~70% of male anal carcinomas
    3. HPV may be acquired in the absence of anal intercourse in HIV+ anal cancer or SIL [5]
    4. Types 16 and 18 HPV have also been found in bladder cancers
    5. With sensitive techniques, HPV 16 DNA found in 72% of oropharyngeal cancers OPC) [29]
    6. Type 16 assocatied with >15X risk of OPC, independent of other risks [29]
    7. Increasing numbers of oral sex partners associated with increased HPV and OPC [29]
    8. Most HPV associated cancers occur in "transformation zones" in specific tissues [9]

C. Pathophysiology navigator

  1. Double-stranded DNA viruses
  2. Seven early (E1-E7), two late (L1, L2), and two nucleocapsid (N1, N2) proteins
  3. Usually exists as episome, particularly in association with warts
  4. Integration of HPV into host genome
    1. Nearly 100% of cervical cancers have chromosomally integrated HPV DNA
    2. Integration of HPV at the viral E2 site leads to disruption of E2 function
    3. The E2 protein is known to inhibit the expression of E6 and E7 genes
    4. Disruption of E2 upon integration increases E6 and E7 expression
    5. Type 16 HPV has highest predisposition to integration
    6. The factors responsible for shifting the virus from episome to integration are not clear
  5. The viral E6 and E7 gene products are necessary and sufficient for neoplasia
    1. Viral E6 protein binds to, and increases degradation of, cellular p53 protein
    2. This degradation occurs with E6 complexed to p53 and a cellular protein E6-AP
    3. Inactivation of the p53 protein causes cellular resistance to apoptosis
    4. Viral E7 protein binds to and inactivates cellular Rb protein and other "pocket" proteins
    5. Inactivation of Rb promotes progression through the cell cycle
    6. Transgenic mice expressing E6 and E7 develop diffuse squamous cell neoplasms
    7. About 80% of cervical cancers come from HPV types 16, 18, 31, 33, or 45
    8. Delayed type hypersensitivity to HPV-16 E7 associated with regression of pre-tumors [27]
  6. Viral - Host Interactions
    1. Strong T cell responses, mainly cytotoxic T cells have been associated with eradication
    2. CD4+ T cell counts in HIV+ persons strongly correlate with ability to eradicate HPV
    3. Very likely that Type 1 T helper responses required to eradicate virus
    4. Type 2 T helper responses are associated with viral persistence
    5. Serum antibodies have little relationship to persistence of HPV

D. Diagnosis of HPV Related Lesionsnavigator

  1. Morphology of cervical, vulvar, or anal lesions on Physical Examination
  2. Colposcopic morphology
  3. Cervical Cancer Screening [30]
    1. Papanicolaou (Pap) testing has been standard for screening for cervical cancer
    2. Pap may be replaced by initial HPV testing, or both may be used together [18,19]
    3. HPV screening for cervical cancer is as effective but more expensive than Pap [40]
    4. HPV screening is more sensitive but less specific than Pap [13,36]
    5. Screening for HPV may be as accurate as Pap with long screening intervals [36]
    6. Pap + HPV testing every 2 years until age 65 is cost effective [40]
    7. Pap smear with atypical squamous or glandular cells should be followed by HPV test [41]
  4. Biopsy
    1. Any abnormal or persistent wart should be biopsied
    2. Careful evaluation for early invasive cancers is required
    3. Anal biopsy is required for detection and diagnosis of anal cancer
  5. HPV DNA Detection
    1. HPV DNA testing on Pap Smear and/or biopsy lesions is most sensitive detection method
    2. Both hybrid capture assays and PCR based tests have been developed
    3. Less subject to specimen bias (that is, inadequate specimen) than cytopathology
    4. >80% of HIV negative women will eradicate HPV [35]
    5. Over 50% of high-risk HPV is cleared at 2 years in patients with non-severe dyskaryosis [35]
    6. Persistence of any known oncogenic HPV >4 months >10X increased risk for any SIL [11]
    7. Therefore, DNA detection on a single test provides a high number of false positive results
    8. Specificity of the increased sensitivity second generation assay is 89% [22]
    9. HPV DNA test specificity 94% versus Pap smear; sensitivity of Pap ~78% in this study [22]
    10. HPV testing is more sensitive (94% versus 55%) and about as specific (94.1% versus
  6. 8%) for CIN 2 or 3 compared to Pap smear [20]
    1. HPV DNA testing detects more CIN III on initial screen than control Pap Smear [48]
    2. On subsequent screen, patients initially tested with HPV DNA had lower CIN III rates than those tested with Pap [48]
    3. Therefore, HPV DNA assessment results in earlier detection of CIN III lesions than Pap [48]
    4. Adding HPV testing to screening cytology will detect more high-risk HPV types and potentially increase need for followup [13]
  7. HPV 16 Viral Load
    1. Initial high levels [25] and persistent high levels [26] of HPV type 16 are strong risk factors for the development of cervical carcinoma in situ (CIS)
    2. Therefore, assessing HPV viral loads in Pap smear samples may have prognostic utility
  8. Self-collected vaginal swab detection of HPV DNA [21]
    1. As sensitive for detection of high-grade servical disease as Pap smear
    2. Less specific (17% false positives) than Pap smear (12% false positives)
    3. HPV DNA testing with self-collected swabs may be used if Pap smear not available
    4. HPV18, highly oncogenic, probably does not induce similar cytologic changes as HPV16 [49]
  9. Serology is not very reliable for assessing aggressiveness of lesions
  10. Dysplastic Pathology
    1. Grading System
    2. Disordered Cell Replication
    3. Nuclei Small and Dense, Halos, called Koilocytes
    4. Intraobserver variability is ~50% for cytologic and histologic readings (all pathology) [28]
    5. Most of this variability is found in mildly to moderately abnormal pathology
    6. Variability also likely due to different viral subtypes (such as HPV16 versus 18) [39]

E. Differential Diagnosis of Condyloma Accuminatanavigator

  1. Sexually Transmitted Diseases
    1. Syphilis - broad based, smooth surface, flat topped
    2. Herpes Simplex Virus - vesicular eruptions, red base, ulceration, painful
    3. Molluscum contagiosum - umbilicated yellowish papules with central core
  2. Benign Skin Conditions
    1. Seborrheic keratoses
    2. Melanocytic Nevi
    3. Pearly penile papules - 1-2mm in diameter, usually over proximal edge of glans penis
  3. Neoplasms
    1. Bowenoid papulosis - carcinoma in situ, rough 2-4mm papules, flesh to red-brown color
    2. Malignant Melanoma
    3. Giant Condyloma - Buschke-Lowenstein Tumor, locally invasive malignancy

F. Treatment of Genital Warts [47]navigator

  1. No current therapy has been shown to eradicate virus
    1. Removal of affected areas and careful followup appears to reduce cancer risk
    2. HIV testing is generally recommended in all persons with dysplastic lesions
    3. Agents or surgery >60-70% response rates with 20-30% recurrence
  2. Patient Applied Treatments [49]
    1. Podofilox (generic and Condylox®)
    2. Imiquimod (Aldara®)
    3. Sinecatechins (Veregen®)
  3. Podophyllin or Podofilox (Condylox®) [49]
    1. Toxin with fairly good response rates for genital or perianal warts
    2. Condylox 0.5% gel or solution
    3. Twice daily for 3 days, then 4-day drug-free period = 1 cycle
    4. May repeat for up to 4 cycles
    5. >50% with local pain, burning, inflammation or erosion
  4. Imiquimod (Aldara®) [12]
    1. Imidazoquinoline amine, stimulates production of various lymphokines
    2. 5% cream approved for genital and perianal warts (condyloma acuminata)
    3. Also active in treatment (once weekly x 16 weeks) for vulvar intraepithelial neoplasia (VIN) [50]
    4. Apply for 8-16 weeks, three times weekly, application by patient (up to 16 weeks)
    5. Erythemna, erosion, flaking occur at at site of application
    6. Discontinuation rate 1% due to adverse effects (similar to podophyllins)
  5. Sinecatechins (Veregen®) [49]
    1. Water-extract of green tea leaves; mixture of catechins and other green tea components
    2. Apply 15% ointment tid for up to 16% weeks
    3. Discontinuation rate >5% due to adverse events (similar to podophyllins)
  6. Other Topical Agents
    1. Trichloroacetic acid (TCA)
    2. Topical 5-Fluorouracil (Efudex®)
    3. Thiotepa has been used for urethral lesions
  7. Surgical / Invasive
    1. Laser ablation
    2. Cryotherapy
    3. Surgical Excision - loop diathermy, conization
    4. Electrocauterization
    5. Interferon alpha - efficacious for warts when given as intralesional injection
  8. Treatment of premalignant lesions

G. Treatment of Nongenital Warts [24]navigator

  1. Invasive / Surgical
    1. Cryotherapy
    2. Curetage
    3. Cautery
    4. Paring of warts
    5. Lasar and photodynamic therapy
  2. Topical Agents
    1. Glutaraldehyde
    2. TCA
    3. Topical alpha-lactalbumin-oleic acid
  3. Topical Human alpha-Lactalbumin-Oleic Acid [42]
    1. HAMLET=human alpha-lactalbumin-oleic acid made lethal to tumor cells
    2. Complex of alpha-lactalbumin and oleic acid which kills variety of malignant cells
    3. Highly active (>75% skin papilloma volume reduction) in >95% of patients
    4. Complete lesion resolution after 2 years in 83% of patients
  4. Photodynamic Therapy [24]
    1. Topical 5-aminolevulinic acid followed by red-light irradiation
    2. Effective or non-hypertrophic actinic keratosis and basal cell carcinomas
    3. Also effective for resistant hand and foot warts (50% reduction in size versus placebo)

H. Followup Evaluationsnavigator

  1. Women with genital warts (HPV types16,18, 31, 33, others) are at increased risk for development of cervical dysplasia or frank carcinoma
  2. Patients with only types 6 or 11 HPV are at very low risk for progression to carcinoma
  3. HIV+ patients with HPV do not eradicate HPV and should be followed very carefully
  4. Gynecologic Evaluation
    1. All women with severe cervical dyskaryosis should be evaluated by a gynecologist
    2. All women with mild to moderate cervical dyskaryosis and high risk HPV should undergo a colposcopy and biopsy
    3. All women with persistent moderate or high risk HPV serotypes should be evaluated
  5. Sexual contacts should be examined carefully
  6. Delayed type hypersensitivity to HPV-16 E7 associated with regression of CIN lesions [27]

I. Vaccines for HPVnavigator

  1. Recombinant Quadrivalent Vaccine (Gardasil®) [15,16,32,33,44]
    1. Approved for females 9-26 years old to prevent HPV associated disease
    2. Includes types 6, 11, 16 and 18
    3. Prevents genital wars, precancerous cervical, vaginal, vulvar lesions, cervical cancer
    4. Appears nearly 100% in preventing persistent HPV infection after 3 doses
    5. 98% reduction in serious pre-cancerous (CIN2/3, CIS) cervical lesions after 3 doses [15]
    6. Essentially 100% effective in preventing any anogenital lesions after 3 doses in women [16]
    7. ~97% in preventing new HPV associated vulvar and vaginal lesions (VIN 2/3, ValN2/3) [33]
    8. Composoite of 4 trials in ~10,000 patients showed 99% efficacy in reducing cervical neoplastic lesions in women negative for HPV 16 or 18 at the beginning of the trial [44]
    9. Administered as 3 separate 0.5mL intramuscular injections at 0, 2, 6 months
    10. Need for booster after the standard 3 doses is not yet known
  2. Bivalent HPV-16/18 L1 virus-like particle vaccine [43,45]
    1. ~91% effective in reducing infection with HPV-16 or -18
    2. ~92% effective in reducing HPV associated cytologic abnormalities
    3. in large Phase III study, 90.4% effective in reducing CIN2+ containing HPV16/18 lesions [45]
    4. HPV45 and HPV31 appear to be cross-reactively reduced with this vaccine
    5. No therapeutic benefit of vaccine in women already infected with HPV [46]
    6. No clinically meaningful tolerability issues

References navigator

  1. Munoz N, Bosch FX, de Sanjose S, et al. 2003. NEJM. 348(6):518 abstract
  2. Castellsague X, Bosch FX, Munoz N, et al. 2002. NEJM. 346(15):1105 abstract
  3. Waggoner SE. 2003. Lancet. 361(9376):2217 abstract
  4. Cuzick J, Szarewski A, Cubie H, et al. 2003. Lancet. 362(9399):1871 abstract
  5. Piketty C, Darragh TM, Da Costa M, et al. 2003. Ann Intern Med. 138(6):453 abstract
  6. Winer RL, Hughes JP, Feng Q, et al. 2006. NEJM. 354(25):2645 abstract
  7. Goldie SJ, Freedberg KA, Weinstein MC, et al. 2001. Am J Med. 111(2):140 abstract
  8. Woodman CBJ, Collins S, Winter H, et al. 2001. Lancet. 357(9271):1831 abstract
  9. Schiffman M, Castle PE, Jeronimo J, et al. 2007. Lancet. 370(9590):890 abstract
  10. Mosciecki AB, Hills N, Shiboski S, et al. 2001. JAMA. 285(23):2995 abstract
  11. Schlecht NF, Kulaga S, Robitaille J, et al. 2001. JAMA. 286(24):3106 abstract
  12. Imiquimod. 1997. Med Let. 37(1016):118
  13. Datta SD, Koutsky LA, Ratelle S, et al. 2008. Ann Intern Med. 148(7):493 abstract
  14. Goedert JJ, Cote TR, Virgo P, et al. 1998. Lancet. 351(9119):1833 abstract
  15. FUTURE II STudy Group. 2007. NEJM. 356(19):1915 abstract
  16. Garland SM, Hernandez-Avila M, Wheeler CM, et al. 2007. NEJM. 356(19):1928 abstract
  17. Canavan TP and Cohen D. 2002. Am Fam Phys. 66(7):1269 abstract
  18. Mayrand MH, Duarte-Franco E, Rodrigues I, et al. 2007. NEJM. 357(16):1579 abstract
  19. Naucler P, Ryd W, Tornberg S, et al. 2007. NEJM. 357(16):1589 abstract
  20. Mayrand MH, Duarte-Franco E, Rodrigues I, et al. 2007. NEJM. 357(16):1579 abstract
  21. Wright TC Jr, Denny L, Kuhn L, et al. 2000. JAMA. 283(1):81 abstract
  22. Schiffman M, Herrero R, Hildesheim A, et al. 2000. JAMA. 283(1):87 abstract
  23. Ellerbrock TV, Chiasson MA, Bush TJ, et al. 2000. JAMA. 283(8):1031 abstract
  24. Stender IM, Na R, Fogh H, et al. 2000. Lancet. 355(9208):963 abstract
  25. Josefsson AM, Magnusson PKE, Ylitalo N, et al. 2000. Lancet. 355(9222):2189 abstract
  26. Ylitalo N, Sorensen P, Josefsson AM, et al. 2000. Lancet. 355(9222):2194 abstract
  27. Hopfl R, Heim K, Christensen N, et al. 2000. Lancet. 356(9246):1985 abstract
  28. Stoler MH and Schiffman M. 2001. JAMA. 285(11):1500 abstract
  29. D'Souza G, Kreimer AR, Viscidi R, et al. 2007. NEJM. 356(19):1944 abstract
  30. Sawaya GF, Brown AD, Washington AE, Garber AM. 2001. NEJM. 344(21):1603 abstract
  31. Denny L, Kuhn L, De Souza M, et al. 2005. JAMA. 294(17):2173 abstract
  32. Recombinant HPV Vaccine. 2006. Med Let. 48(1241):65
  33. Joura EA, Leodolter S, Hernandez-Avila M, et al. 2007. Lancet. 369(9574):1693 abstract
  34. Nuovo J, Melnikow J, Howell LP. 2001. Am Fam Phys. 64(5):780 abstract
  35. Nobbenhuis MAE, Helmerhorst TJM, van den Brule AJC, et al. 2001. Lancet. 358(9295):1782 abstract
  36. Kulasingam SL, Hughes JP, Kiviat NB, et al. 2002. JAMA. 288(14):1749 abstract
  37. Moreno V, Bosch FX, Munoz N, et al. 2002. Lancet. 359(9312):1085 abstract
  38. Munoz N, Franceschi S, Bosetti C, et al. 2002. Lancet. 359(9312):1093 abstract
  39. Woodman CBJ, Collins S, Rollason TP, et al. 2003. Lancet. 361(9351):40 abstract
  40. Mandelblatt JS, Lawrence WF, Womack SM, et al. 2002. JAMA. 287(18):2372 abstract
  41. Kim JJ, Wright TC, Goldie SJ. 2002. JAMA. 287(18):2382 abstract
  42. Gustafsson L, Leijonhufvud I, Aronsson A, et al. 2004. NEJM. 350(26):2663 abstract
  43. Harper DM, Franco EL, Wheeler C, et al. 2004. Lancet. 364(9447):1757 abstract
  44. Future II Study Group. 2007. Lancet. 469(9576):1861
  45. Paavonen J, Jenkins D, Bosch FX, et al. 2007. Lancet. 369(9580):2161 abstract
  46. Hildesheim A, Herrero R, Wacholder S, et al. 2007. JAMA. 298(7):743 abstract
  47. Treatment of Warts. 1995. Med Let. 37(964):117
  48. Bulkmans NW, Berkhof J, Rozendaal L, et al. 2007. Lancet. 370(9601):1764 abstract
  49. Sineatechins. 2008. Med Let. 50(1280):15
  50. Van Sters M, van Beurden M, ten Kate FJ, et al. 2008. NEJM. 358(14):1465 abstract