Human Papillomavirus (HPV) - Etiopathogenesis, Clinical Features, and Treatment

Etiopathogenesis

The Virus

• Early genes (E1, E2, E4, E5, E6, E7) - regulate replication and oncogenesis
• Late genes (L1 and L2) - encode capsid proteins
• Upstream regulatory region (URR)

HPV Types and Associated Lesions

Pathogenesis / Immune Evasion

1. Antigens are not expressed on keratinocyte surfaces until cells migrate above the level of antigen-presenting cells
2. L2 protein reduces and inactivates local Langerhans cells
3. Through E6 and E7, HPV reduces local immune reactants (TLR9, IL-8), muting the local immune response
4. This results in immune tolerance, allowing long-term persistence

Clinical Features

Verruca Vulgaris (Common Warts)

• HPV types: 1, 2, 4, 27, 57, 63
• Most common between ages 5-20; only 15% occur after age 35
• Appear on dorsal hands, fingers, periungual areas
• Rough, hyperkeratotic, gray-brown papules; often coalesce into plaques
• May spread from infected close contacts; public exposures (swimming pools, showers) are risk factors

Verruca Plantaris (Plantar Warts)

• Occur on the plantar surface of the foot
• Endophytic growth pattern - pushed inward by weight bearing
• Painful with pressure; interrupt skin lines (vs. corns which follow skin lines)
• "Mosaic warts" = confluent plantar warts

Verruca Plana (Flat Warts)

• Small (1-5 mm), minimally elevated, flesh-colored or slightly pigmented papules
• Occur on face, dorsal hands, shins
• Linear distribution from autoinoculation (Koebner phenomenon)
• Can be mistaken for lichen planus

Condylomata Acuminata (Genital Warts)

• HPV 6/11 (low-risk types)
• Soft, skin-colored to pink, cauliflower-like papules and plaques on anogenital skin
• In women: vulva, vagina, cervix, perianal area
• In men: penile shaft, glans, scrotum, perianal area
• High-risk types (HPV 16/18) cause cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma

Epidermodysplasia Verruciformis (EV)

• Rare, often inherited, T-cell immunodeficiency
• Widespread flat wart-like and pityriasis versicolor-like lesions
• High malignant potential (SCC) on sun-exposed areas

Features in Immunosuppressed Patients

• Lesions are multiple, coalescent, and extensive (see image below)
• Warts may have atypical morphology
• HPV in HIV patients: >90% of MSM have anal HPV; up to 50% have high-grade AIN; 30-50x increased risk of anal cancer

Treatment of HPV/Warts

Principle

Destructive / Physical Methods

• Cryotherapy (liquid nitrogen): first-line for most warts; repeat every 2-3 weeks; painful
• Salicylic acid (topical): 10-40% preparations applied daily; effective for common and plantar warts; takes months
• Electrosurgery / laser: for refractory or large lesions
• Surgical excision: reserved for large, refractory lesions; risk of scarring

Immunotherapy

• Topical sensitizers (DNCB, squaric acid dibutylester, DPCP): applied topically; sensitize patient, then induce local immune response; 60-80% cure rates; useful for recalcitrant warts
• Intralesional Candida antigen: 0.1 mL injected into 1-3 lesions every 3-4 weeks; up to 80% cure rate; may cause cytokine-mediated systemic reactions (fever, chills, myalgia 6-8 hours post-injection)

Antiproliferative Agents

• Bleomycin (1 U/mL, intralesional): reserved for recalcitrant adult warts; ~90% response with 2 treatments; side effects include local pain, Raynaud's phenomenon of digits, rarely digital necrosis
• 5-FU (topical or intralesional): variable results

Topical Immunomodulators

• Imiquimod: approved for genital warts; significantly less effective than cryotherapy or topical immunotherapy for common/plantar warts; two large RCTs showed no difference from placebo for non-genital warts
• Podophyllotoxin: for genital warts (patient-applied)
• Sinecatechins: green tea extract, approved for external genital warts

For Genital Warts Specifically

• Patient-applied: imiquimod cream (3x/week), podophyllotoxin 0.5% (twice daily x 3 days/week)
• Provider-applied: cryotherapy, trichloroacetic acid (TCA), surgical removal, laser

Vaccination (Prevention)

• 9-valent HPV vaccine (Gardasil-9): covers HPV 6, 11, 16, 18, 31, 33, 45, 52, 58
• Recommended at age 11-12 (up to age 45 in some guidelines)
• Immunogenic and well-tolerated even in HIV-positive individuals
• VLPs from L1 protein are the vaccine antigens

Molluscum Contagiosum - Etiopathogenesis, Clinical Features, and Treatment

Etiopathogenesis

The Virus

• MCV-1: most common worldwide; virtually all infections in young children
• MCV-2: majority of infections (60%) in HIV-infected patients
• No difference in anatomic site of isolation based on type (unlike HSV)

Epidemiology - Three High-Risk Groups

1. Young children (peak age 1-4 years)
2. Sexually active young adults (age 20-29)
3. Immunosuppressed individuals (especially HIV/AIDS)

Immune Evasion Mechanism

• MCV encodes an IL-18-binding protein that blocks the host's Th1 immune response by reducing local IFN-γ production
• MCV also inhibits NF-κB activation (via MC005 protein targeting NEMO-regulated IKK activation), preventing activation of innate immunity
• This allows MCV to persist in the epidermis without triggering a significant inflammatory response until the lesions eventually resolve

Histopathology

• Lesions primarily affect follicular epithelium
• Acanthotic, cup-shaped structure
• Henderson-Paterson bodies (molluscum bodies): large eosinophilic (early) then basophilic (late) cytoplasmic inclusion bodies in prickle cells; the bulk compresses the nucleus to the periphery
• Each lobule empties into a central crater (forming the umbilication)
• Inflammatory changes are slight or absent in uncomplicated lesions; resolving/inflamed lesions show dense lymphocytic and neutrophilic infiltrate

Clinical Features

Typical Presentation

• Small, smooth-surfaced, firm, dome-shaped, pearly papule averaging 3-5 mm in diameter
• Central umbilication (central white core) - pathognomonic feature
• Side-lighting highlights the central opening; light cryotherapy highlights the umbilication
• May range from <1 mm (early) to >1 cm ("giant" cystic lesions)

By Patient Group

• Usually generalized; few to >100 lesions
• Common sites: axillae, inguinal areas, popliteal/antecubital fossae, face
• Genital lesions as part of wider distribution in 10% (isolated genital MC in a child requires consideration of sexual abuse, though it is usually not from sexual contact)
• Children with atopic dermatitis (AD): 4x more likely to have >50 lesions; prolonged course; lesions tend to be confined to dermatitic skin

• Lower abdomen, upper thighs, perineum, penile shaft in men
• Pubic hair removal (shaving, waxing) is a risk factor
• Mucosal involvement is rare

• Lesions favor the face (cheeks, neck, eyelids) and genitalia
• May develop larger (>1 cm), coalescent, verrucous, and widespread lesions
• Present in 10-30% of AIDS patients not receiving ART (virtually always when CD4 <100)
• MCV-2 predominates in this group

Inflammatory Reactions

1. Molluscum dermatitis (40% of children): eczematous eruption surrounding individual lesions; more common in atopic children
2. Inflamed MC (20%): erythema, swelling, sometimes pustulation of individual lesions; often heralds resolution - the "BOTE sign" (Beginning Of The End)
3. Rupture into dermis: intense suppurative reaction resembling abscess or cellulitis
4. Rarely: erythema annulare centrifugum, Gianotti-Crosti type reaction

Diagnosis

• Clinical diagnosis in most cases based on central umbilication
• Confirmation: express the pasty core between two microscope slides, stain with Wright, Giemsa, or Gram stain - shows Henderson-Paterson bodies
• Dermoscopy useful
• DDx: Cryptococcus, Histoplasmosis, Coccidioidomycosis (in immunosuppressed), keratoacanthoma, desmoplastic trichilemmoma, BCC
• Important to differentiate from condyloma acuminata in children

Treatment

Treatment Decision

Physical/Destructive Methods

At-Home Therapies

• Pressing tape against lesion repeatedly, or continuous application of surgical tape daily for 16 weeks
• Topical tretinoin: applied with Q-tip to individual lesions; useful especially for facial lesions

Topical Agents - Limited Evidence

• Imiquimod: NOT recommended - two large RCTs showed no benefit over placebo
• Podophyllotoxin: similarly not effective for MC (failure to respond to these agents should prompt reconsideration of the diagnosis)
• 10% Potassium hydroxide (KOH): some evidence of efficacy
• Oral cimetidine: some immunomodulatory benefit, especially in atopic patients

For Genital MC in Adults

• Cryotherapy or curettage: very effective
• Screen for coexistent STIs; examine sexual partners

For Immunosuppressed/HIV Patients

• Primary treatment: antiretroviral therapy (ART) - results in dramatic resolution (though delayed 6-8 months)
• Topical 1-3% cidofovir or systemic IV cidofovir for refractory cases
• TCA peels (>35%) or daily 5-FU applications to point of erosion for widespread lesions
• Topical tretinoin nightly at highest tolerated concentration - reduces rate of new lesion appearance
• Shaving with blade razors should be discontinued in beard-area MC

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