PERSPECTIVES & TREATMENT OF HPV Part 2: Cancers, Treatments & Images

Progression from HSIL to Anal Cancer

Indirect calculation
- 1 in 377 HIV-infected MSM per year
- 1 in 4196 HIV-uninfected MSM per year

Anal Cancer

90% associated with hr-HPV, primarily HPV-16
Risk factors:
- Factors associated with HPV acquisition
  - Multiple sexual partners
  - Anal condylomata
  - Anal receptive intercourse
  - Women: history cervical/vulvar/vaginal HSIL/cancer
- Tobacco
- HIV

Anal Cancer Screening, Guidelines

Obtain anal cytology and refer for high-resolution anoscopy if abnormal, analogous to colposcopy
For the general population: None!
HIV-infected patients:
- HIVMA: MSM, women with a history of receptive anal
intercourse, individuals with a history of genital warts¹
- New York State DOH: MSM, women with a history of vulvar or cervical squamous intraepithelial lesion, individuals with a history of anogenital warts²

Anal Cancer Screening, Expert Opinion

HIV-infected men and women
HIV-uninfected MSM
Women with cervical or vulvar HSIL or cancer
Men and women with perianal condylomata
Solid organ transplant recipients
Initiation of screening:
- > 25 years if immunosuppressed, including HIV
- > 40 years if immunocompetent

Anal Cancer and Cervical Cancer

Anatomic commonality:
- Transformation zone
- Region of active squamous metaplasia
- Vulnerable to high-risk HPV
Morphologic similarity
- Precursor lesions
  - HSIL and LSIL
  - CIN vs AIN
- Cancer: Squamous cell carcinoma

American Society of Colorectal Surgeons: Practice Parameters for Anal Squamous Neoplasms

Anal cytological examination may be useful in the detection and follow-up of LGAIN/HGAIN.
Grade of Recommendation:
- Strong recommendation
- Based on low-quality evidence, 1C.

Steele SR et al. Diseases of the Colon & Rectum 2012; 55:7

Screening and Diagnosis

HPV-related lesions of the anogenital tract
Anal Cytology
Digital examination
- Digital anal-rectal examination
- DARE
High resolution anoscopy (HRA)
HRA-directed anal biopsy

HRA – Lugol’s application

After identifying an area of the AnTZ with acetic acid, apply Lugol’s solution with small cotton swabs(not scopettes)
- apply systematically to small areas or individual lesions, while observing through the colposcope
- apply Lugol’s the area of AnTZ under view, then proceed to next area first with AA, then Lugol’s etc. apply small amounts, to avoid staining other areas.
- wipe off excess w/AA

Squamous Cell Abnormalities

Low grade SIL
- HPV effect (koilocytosis, condyloma)
- Mild dysplasia, C/AIN 1
High grade SIL
- Moderate dysplasia, C/AIN 2
- Severe dysplasia/carcinoma-in-situ, C/AIN 3
Squamous cell carcinoma

Conclusions

Anogenital HPV infection is extremely common
Low-grade and high-grade lesions are distinct entities that do not reflect a morphologic continuum
HIV-infected patients are particularly susceptible to HPV-related malignancies; risk persists despite antiretroviral therapy
High resolution anoscopy may decrease risk of anal cancer

DIFFERENTIAL DIAGNOSIS: BENIGN SKIN LESIONS

Seborrheic keratoses – rough-surfaced lesions
Sebaceous glands
Nevi – typically raised and pigmented
Lichen planus
Lichen sclerosus
Psoriasis
Drug eruptions
Vestibular papillae

DIFFERENTIAL DIAGNOSIS OF EGWs

Papular and flat erythematous lesions
- Easily confused with EGWs
Genital papules
- Normal anatomic structures:
  - Pearly penile papules
  - Vestibular papillae
  - Sebaceous glands
- Acquired lesions:
  - Molluscum contagiosum
  - Seborrheic keratoses
  - Lichen planus
  - Skin tags
  - Melanocytic nevi
  - Pseudoverrucous keratoses
  - Condyloma latum
  - Flat, erythematous lesions:
  - Psoriadid
  - Seborrheic dermatitis
  - Circinate balanitis (Reiter’s syndrome)
  - High-grade squamas intaepithelial lesions (Bowen’s didease)
  - Squamous cell carcinoma
  - Bowenoid papulosis

Principles of Treatment

Patient-applied therapies can be first line of treatment for subset of patients.
Many are FDA-approved for LSIL.
Determine utility of patient-applied vs. clinician-applied:
- Extent of disease
- Difficulty distinguishing atypia from HSIL
May be irritating, but less destructive
Induction of interferon response/immune response
Assess ability to self-apply – needs to be used correctly.
Is patient willing to refrain from receptive anal sex?

Podofilox 5% Gel

Useful for treatment of external warts but can cause significant irritation around the anus.
Apply twice daily in a thin film to warts for 3 days then none for 4 days, cycle can repeated for up to 4 courses. If good response can continue additional week(s) until clear.
Patients often experience transient and acceptable erythema, burning and shallow erosions which resolve in about a week.

Imiquimod 5%

Treatment of external warts, particularly in immunocompetent patients.
Postulated to act as an immune response modifier by stimulating local production of
Apply 1 packet to affected area at bedtime 3x weekly (QOD), and rinse off in AM.

15% Sinecatechins

FDA approved since 2006 for treatment of external genital warts.
Botanical topical ointment - purified aqueous extract of green tea leaves (camellia sinensis).
Sinecatechin is active ingredient.

Application

TID (not q8) continually up to 16 weeks.
Scheduled RTC after 8-12 weeks to assess
Approved for immunocompetent; used off-label in HIV seropositive.
In patients refractory to, or with intolerable response to imiquimod or podofilox, or per treatment regimen preference.

5-fluorouracil 5% Cream

Indications: diffuse perianal or intra-anal HSIL, ablation contra-indicated, delay in treatment.
BID for 5 days on /off 9 days. Continue two week cycles for 8-16 weeks.
Apply ¼” (.5ml) with applicator into anus (not rectum).
Additional .5 ml to perianus if involved.
Insert finger (left then right) to assure thorough application to entire anal canal. Wear gloves, wash hands, protect untreated skin with zinc oxide.
Reduce or discontinue for intolerable side effects.
Examine at 8 weeks, continue to 16 if effective with scheduled ablation to follow.

5FU topical cream summary

Most failures d/t inability to insert cream.
Must be able to insert cream correctly.
HSIL seems to respond better than condyloma.
Imiquimod may be superior for condyloma.
Probably effective, safe and good option for high volume disease.
Remains off-label.

IMMUNE-MODULATING METHOD

Spontaneous wart regression thought to be immune mediated
Enhancing immune response appealing therapeutic approach
IFN has variable efficacy against EGWs
Other immune modulators have no proven efficacy (e.g., levamisole, recombinant cytokines)
Imiquimod enhances immune response; induces IFN and other cytokines

SUBLESIONAL INTERFERON THERAPY

Application: 5 MU 3x/wk for 3 wk
Clearance rates: 19%-62% (% of warts cleared)
Advantages
- Transient side effects
- Reversible systemic toxicity
Drawbacks
- Frequent mild-to-moderate flulike symptoms
- Expensive repeat office visits
- Liver enzymes may be elevated; depresses WBC
- Pain, discomfort with injections
- Impractical for extensive disease

ADDITIONAL RESOURCES (Combination Therapy)

"... Aetna considers interferon alfa-N3 (Alferon N) medically necessary for intralesional treatment of refractory or recurring external condylomata acuminata (venereal/genital warts)..."

Aetna Interferons NO: 0404

"... These three groups of IFNs have been used successfully as monotherapy or in combination with traditional modalities to treat anogenital condyloma acuminatum."

Interferons alpha, beta and gamma therapy of anogenital human papillomavirus infections

" ... Conclusion: Interferon is effective as adjuvant treatment in controlling the recurrence of genital HPV."

Interferon as an adjuvant treatment for genital condyloma acuminatum

"... In conclusion we believe that IFN alpha-2a can be used with excellent results as first line treatment in combination with CO2 laser vaporization or/plus 5-FU in patients with C.A. or F.C. or combined condylomata."

Treatment of men with flat (FC) or acuminata (CA) condylomata with interferon alpha-2a

(SYMPTOMS & TESTING)

“Local or systemic treatment with interferon may also decrease the likelihood of recurrence following surgical excision or ablative therapy, but is uncommonly used in clinical practice…”

Condylomata Acuminata (anogenital warts)

ADDITIONAL RESOURCES (AVOIDING REINFECTION)

“We conclude that intralesional injections of alpha-2b interferon following carbon dioxide laser vaporization of recalcitrant ano-genital condylomata substantially reduce the risk of recurrence or reinfection.”

Interferon alpha-2b injections used as an adjuvant therapy to carbon dioxide laser vaporization of recalcitrant ano-genital condylomata acuminata.

[https://www.ncbi.nlm.nih.gov/pubmed/2124244]

“Interferon tends to be a fairly well-tolerated form of therapy. According to different routes of administration, locally-used interferon appears to be much more effective than both systemically-used interferon and placebo in either improving the complete response rate or reducing the recurrence rate for the treatment of genital warts.”

Interferon for the treatment of genital warts: a systematic review.

[https://www.ncbi.nlm.nih.gov/pubmed/19772554]

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