Anogenital warts

A brief description of a very common skin condition presenting as warts in the genital area. Affecting both children and adults; Aims of helping dermatologists diagnose common skin conditions. References from reknown dermatology books like Rooks as well as from Journals.Useful for exam preparation for post graduate students, USMLE, MRCP and FCPS, MCPS exams. Cosmetics. Useful for doctors, medical students, gynecologists, and dermatologists.

1. Human Papilloma Virus Anogenital Warts:

2. INTRODUCTION: Anogenital warts are benign proliferative lesions found on the epithelium of any part of the genitalia, anus or perianal area and may also involve the inguinal or pubic regions. They are caused by human papillomavirus (HPV) genotypes 6 and 11 in >95% of cases.

3. Epidemiology: Incidence and prevalence: Slight decrease in the rate of rise of ano ‐genital warts due to the introduction of the HPV vaccine Age: Incidence highest is age group 16-24 years. Sex: Male: female ratio of 1:0.7

4. Pathophysiology : Predisposing factors Genital warts have a high infectivity. The thinner mucosal surface is more susceptible to inoculation of virus than thicker keratinized skin Occur at sites subject to greatest coital friction in both sexes. Acquisition of infection could be by both sexual as well as non sexual (via spread of local infection) means. Incubation Period: Incubation period between contact and diagnosis of genital warts is 3 weeks to 24 months, with a median of 3–10 months. Transmission of ano ‐genital warts in children: Sexual contact Non – Sexual Contact: At the time of delivery: Infection from the mother’s genital tract ican cause childhood ano ‐genital warts presenting up to 2 years of age. Sharing the bath with an infected adult. Features: (a) Absence of other physical evidence of molestation, (b) location of the warts on fully keratinized skin as opposed to genital or anal mucosa, (c) Clinical resemblance to common warts and (d) young age of the child, perhaps up to 1–2 years at the onset of the warts

5. Stratum Corneum : Parakeratotic but not very thick. Stratum Granulosum : Koilocytes limited in distribution and not found in all sections. Stratum Spinosum : Extreme acanthosis The epidermal processes are wide and rounded, with a well‐defined lower border. Dermis: Papillomatosis . The connective tissue is very oedematous Capillaries tortuous and increased. Pathology:

6. Genital wart displaying Papillomatosis Genital wart displaying Parakeratosis :

7. Hypergranulosis : Dilated Blood Vessels

8. Koilocytosis

9. Low‐risk HPVs: HPV‐6 (in about 45–90%) or HPV‐11. HPV‐1 and HPV‐2 may also occur in genital warts. In children: warts are more hyperkeratotic than in adults and may be caused by HPV types associated with cutaneous disease (HPV 2, 27 and 57) as well as HPV‐6 and ‐11. Causative Organisms:

10. Clinical Features: May be asymptomatic, but may cause discomfort, discharge or bleeding. Warts are soft, pink, elongated and sometimes filiform or pedunculated . Growth can be enhanced during pregnancy or in the presence of other local infections.

11. Different clinical types of genital warts: Condyloma acuminata : Large malodorous masses may form on vulvar and perianal skin with a cauliflower appearance Papular warts: Protruberant , non- pedunculated , dome-shaped, or hemispherical masses, about 1-4mm in diameter. Located in fully keratinized epithelium. Macular warts: found on mucosal surfaces, characterized by subtle changes in the colour , a greyish -white colour being most common manifestation. Verruca vulgaris or Keratotic Warts. Sessile Warts. Flat Warts: are slightly raised, may exhibit an undulating wavy surface. Intraepithelial Neoplasia ( Bowenoid Papulosis and Bowen's disease) Giant Condyloma ( Buschke Lowenstein tumor).

12. Low risk mucosal HPV types (6 and 11) responsible for ano ‐genital warts can cause disease at other mucosal surfaces. 1) Oral warts: Usually contain HPV‐6 or ‐11 and rarely HPV‐2, ‐57 or ‐16. Commonly associated with HIV disease when a greater variety of HPV types may be found, including HPV‐7, more usually associated with butchers’ warts. Antiretroviral treatment may lead to worsening of the warts rather than improvement. High‐risk genital HPVs (16 and 18) detected in over 80% of cases of oral leukoplakia , and in about 50% of cases of orophranygeal carcinoma. Clonical Variants:

13. (2) Respiratory Papillomatosis : Most commonly due to HPV‐11, but also associated HPV‐6 and very rarely HPV‐16. Childhood cases due to maternal infection, probably at birth during vaginal delivery. Adult cases may be due to latent or subclinical infection in the laryngeal mucosa or due to sexual transmission. Treatment : recurrent debulking of lesions . Malignant transformation occurs rarely and is most commonly associated with HPV‐11 (3) Conjunctival papillomas : Low‐risk HPV mucosal type is frequently detected in conjunctival papillomas Rare detection of high‐risk types (4) Nasal inverting papillomas (synonym: inverted papilloma, Schneiderian papilloma ) HPV‐6/11, ‐16/18 and ‐57 have been detected in nasal inverting papilloma and in an inverting papilloma of the maxillary sinus . Progression to squamous cell carcinoma is rarely reported.

14. Differential Diagnosis: Seborrhoeic keratosis and ano -genital intraepithelial dysplasia : can produce pigmented warty lesions in the genital area similar to anogenital warts Histological features and immunostaining for HPV and cell cycle associated proteins can help to distinguish the lesions. Verrucous carcinoma ( Buschke–Löwenstein tumour ) is often initially misdiagnosed as genital warts. Condylomata lata : differentiated by other stigmata of syphillis Lymphogranuloma venereum Metastatic Crohn disease involving the vulval or perianal area often presents with skin tags on an oedematous or indurated background. Vulval papillomatosis , with a diffuse velvety or granular appearance in the vaginal introitus , may also cause confusion. Pearly penile papules may cause confusion with the possibility of warts.

15. Complications: Patients with genital warts frequently have other sexually transmitted genital infections. Presence of any type of ano ‐genital wart should raise the possibility of infection with high‐risk HPVs and prompt screening for detecting ano ‐genital intraepithelial neoplasia . Very florid warts should warrant consideration of an underlying immune deficiency. Disease course and prognosis Duration of ano ‐genital warts: a few weeks to many years. Recurrence: in about 25% of cases, the interval varying from 2 months to 23 years. HPV DNA can be demonstrated in clinically and histologically normal skin adjacent to warts and intraepithelial neoplasia , and this latent infection correlates well with recurrence after clinical cure.

16. Management: Prevention: Two types of vaccines are available: Gardasil and Cervarix . 3 doses: I/M; 2 nd dose 2months after 1 st ; 3 rd dose 6 months after 1 st . (1) Gardasil : The quadrivalent vaccine( Gardasil ) protects against HPV types 6, 11, 16 and 18. Contains recombinant virus-like particles from the L1 proteins of HPV-6, 11, 16, and 18. Recommended to be given to females between 9-26years. 2) Cervarix : The bivalent vaccine( Cervarix ) protects against HPV 16, 18 types. Contains L-1 protein of viral capsid . Vaccine has no live virus so do not infect the patient. Given to females between 10-45 years of age. More effective against HPV than Gardasil

17. First line Treatments: 1) Podophyllotoxin : Podophyllotoxin is purified from podophyllin and is the most common treatment used. Applied as a 0.15% cream twice daily for consecutive 3 days in a week for 4 consecutive weeks. Podophyllin and podophyllotoxin are contraindicated in pregnancy. The wart area treated should not exceed 10 cm2, and the total volume of podophyllotoxin should be limited to 0.5 mL per day.

18. 2) Imiquimod : 5% or 3.75% cream. The 5% cream is applied three times per week for up to 16 weeks 3.75% cream applied twice daily for 2 weeks and repeated 2 weeks later seems to be equally effective. The treatment area should be washed with soap and water 6-10 hours after the application Skin irritation is common for both these treatments.

19. Second Line Treatments: Cryotherapy , Electrocautery , Surgery, Photodynamic therapy, Laser and 80–90% trichloroacetic acid. Other home treatments include sinecatechins ( polpyphenol E from green tea), which can also be applied by the patient.

20. Third Line Treatments: Used in cases of extensive or giant warts, often in immunosuppressed patients. Interferon: Interferon administered either systemically or intralesionally , Intralesional IFN‐α or ‐β as monotherapy gives an overall response rate of 36–63% for genital warts, but oral warts may respond slightly better. Interferon has been used as adjuvant therapy, together with surgery, cryotherapy or topical measures. IFN‐β and ‐γ reduce the rate of acquisition of new lesions

21. Introduction: High risk HPV strains are associated with several different dysplastic or malignant conditions. Well established association exists between infection with high‐risk HPVs and the development of cervical carcinoma. HPV associated Intraepithelial and Invasive Neoplasias of Genitalia and Mucosae :

22. General description of disease domain Squamous cell pre‐malignancy and malignancy of the skin, anogenital area, oro ‐pharynx, nasal cavities, larynx, oesophagus , lung and conjunctiva may harbour high risk α or β HPVs.

23. Basic Biology: In ano ‐genital lesions, type 16 is found most commonly and, together with HPV‐18, account for 70–80% of HPV‐positive cervical lesions. In cervical carcinoma cells, the HPV DNA is almost always integrated into the host cell genome, in contrast to its extrachromosomal location in benign and early premalignant lesions

24. Cervical intraepithelial neoplasia and invasive carcinoma Epidemiology: Epidemiologically associated with: sexual activity, including age of first sexual intercourse, multiplicity of partners history of sexually transmitted diseases, in both the female patient and her male partner(s). personal history of overt genital warts and with penile warts or penile intraepithelial neoplasia in the partner.

25. Pathophysiology : HPV is commonly detected in dysplastic cervical lesions and is found in 90–100% of cervical cancers High‐risk HPVs can also be detected by sensitive PCR in 5 and 80%, of cytologically normal cervices. This association is highest in young sexually active women in whom infection may be transient. The finding of a high‐risk HPV type in the cervix increases the likelihood of progression of the disease.

26. Management: Vaccination against HPVs is already showing signs of reducing the incidence of CIN. Cervical carcinomas are best managed in the gynaecology unit.

27. Future Topics to be Discussed: Epidermodysplasia Verruciformis

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