HPV Infections (DNA Virus)

Question 1

Cutaneous warts (except mx)

Answer 1

@
Verruca vulgaris (common wart)
Verruca plana (plane wart)

Benign tumours
Infection of keratinocytes with HPV

CLINICAL FEATURES
Common warts
- Firm papules with rough dry horny surface
- Most commonly on backs of hands, fingers +/- knees in children
- But can be anywhere on skin including genital i.e. shaft of penis in adult M
- Koebner-like phenomenon (new warts at sites of trauma)
- Usually asymptomatic
- May be tender on palmar fingers, when fissured, growing beneath nail plate
- Warts on eyelids —> may be complicated by conjunctivitis, keratitis
- DDx hand warts —> epidermal naevus, bowen disease, AK, callus
- HPV 2 +/- 1, 4, 27, 57
- Regression asymptomatic and gradual over weeks, usually without blackening

Periungual warts

• Common warts around the nails esp at nail folds, beneath nail
• Can disturb nail growth
• Nail biting is a risk for spread
• Malignant change rare, but reported in immunosuppression —> usually high risk HPV subtype present i.e. HPV 16

Plantar warts

• Sharply defined rounded lesion with rough keratotic surface surrounded by smooth collar of protective thickened horny ring
• Bleeding points when pared down (tips of elongated dermal papillae)
• Most are beneath pressure points (heel, metatarsal heads)
• May have small satellite lesions around large wart
• Mosaic warts are clustered/group of small warts —> especially persistent
• May be painful (except for mosaic warts which are usually painless)
• Variable duration
• Spontaneous regression may be delayed in adults, hyperhidrosis, orthopaedic defects
• DDx —> punctate keratoderma, corn/callus (amorphous appearance with cemtral keratotic area on dermoscopy vs wart where there are mosaic, papillomatous features +/- pinpoint thrombosed capillaries), lichen planus, acrokeratosis verruciformis of Darier disease (warty papules symmetrically distributed back of the hands)
• HPV 1, 2, 4, 27, 57
• regression occalsionally inflammatory, often results in blackening from thrombosed blood before lesion separates vs drying and gradual separation

Plane warts (flat warts)

• Smooth, flat or slightly elevated
• Usually skin coloured or greyish yellow, may be pigmented
• Round or polygonal in shape
• Face, back of hands, shins
• Linear arrangement in scratch marks
• HPV 3, 10
• Regression usually heralded by inflammation + complete within 1 month —> itch, erythema, swelling, depigmented halos may occur around lesions

CLINICAL VARIANTS
Filiform warts
- Commonly in M
- Face, neck +/- limbs
- Clustered

Digitate warts

• Scalp
• Often in small groups
• Occasionally confused with epidermal naevi

Butcher’s warts

• Hands of Occupational handlers of meat, poultry, fish
• At risk as hands prolonged contact with moist animal flesh
• HPV 2 +/- 7

Epidermoid plantar cysts

• Weight bearing areas of the sole
• HPV 60 +/- 57

Pigmented warts

• Palms and soles of Japanese patients
• Melanosomes increased
• HPV 65, 4, 60

HPV SUBTYPES
Common warts = HPV 2 +/- 1, 4, 27, 57
Plantar warts = HPV 1, 2, 4, 27, 57
Plane warts = HPV 3, 10
Butcher’s warts = HPV 2 +/- 7
Epidermoid plantar cysts = HPV 60 +/- 57
Pigmented warts = HPV 65, 4, 60

PREDISPOSING FACTORS
Direct vs indirect contact
Wart virus particle may need to come into contact with basal keratinocytes —> barrier function impairment i.e. by trauma (mild abrasions, maceration) predisposes to inoculation
- Plantar warts from swimming pool/shower room floors (rough surfaces abrade moistened keratin from wart infected feet —> inoculate into soften skin of others)
- Common hand warts around nails in those that bite their nails, periungual skin, finger sucking —> spread to lips, surrounding skin
- Shaving —> spread infection over beard area
- Hand warts in Occupational meat handlers i.e. fish, meat, poultry (skin injury and prolonged contact with wet flesh, water)

ASSOCIATED DISEASES
Immunosuppression (more common, more persistent)

IX
Clinical
Atypical, subclinical or dysplastic lesioms may need lab confirmation of HPV infection using 4 methods -
- Histo
- IHC or immunocytochemistry using type-common or type-specific antibodies
- DNA in situ hybridisation
- HPV DNA PCR

GENERAL HISTO
Papillomatosis
Acanthosis
Hyperkeratosis
Hypergranulosis
Koilocytosis (cytopathic effect) of upper keratinocytes —> Basophilic flattened or twisted nuclear inclusion bodies within vacuolated cells (HPV viral particles)
Some vacuolated cells have Eosinophilic inclusions (irregular clumped keratohyaline granules)

COMMON & PLANTAR WARTS HISTO
Epidermal hyperplasia
Hyperkeratosis
Areas of parakeratosis esp above papillomatous projections
Thickened granular and spinous layers
Elongated rete ridges bent inwards towards centre of wart
Koilocytes

PLANE WARTS HISTO
Looose lamellar hyperkeratosis
Acanthosis
No papillomatosis
Koilocytes

COURSE/PROGNOSIS
Spontaneous clearance few months to few years, quicker in children than adults
Malignant change reported in context of immunosuppression (rare)

Question 2

Cutaneous warts Mx

Answer 2

Combo Rx often used

GENERAL MEASURES
Gentle reduction of hyperkeratotic epidermis by regular filing/paring down (for comfort)
Cleaning baths after use
Avoid shared towels and baths

PLANTAR WARTS
Cover with adequate plaster strapping
Cover foot with close fitting rubber “verruca socks”
Wear pool-side sandals at w]swimming pools, communal baths and showers

PERIUNGUAL, PERIORAL WARTS
Spread is often due to biting of nails or periungial skin
Use adhesive strapping after application of wart paint (helps to break habit)

FIRST LINE RX - TOPICALS AT HOME

Salicylic acid (keratolytic) for > 3 months —> Reduce thickness +/- stimulate inflammatory response

• Gentle removal of surface keratin with Pumice stone, emery board, foot file (avoid aggressive abrasion —> spread)
• Then accurately apply 12-26% sal acid paint with cocktail stick, sharpened matchstick
• Occlusion with adhesive plaster (promotes maceration amd barrier impairment)
• Adhesive plaster impregnated with 40% sal acid cut to shape, secure with plain adhesive plaster, applied daily
• Cautious use in feet with peripheral neuropathy, impaired circulation i.e. diabetics (risk of ulceration which may not heal)
• lower concentration can be used for plane warts

Glutaraldehyde (virucidal, dries and hardens skin)

• 10-20% in aqueous ethanol
• S/E brown discolouration (not ideal for sites other than plantar warts), ACD, cutaneous necrosis (if too strong)

Formalin (virucidal, dries and hardens skin)

• soaks/compresses 2-3% formalin in water for 15-20 mins daily, protect surrounding skin with WSP (plantar warts)
• Time consuming, difficult to limit to affected skin
• S/E Irritant dermatitis of surrounding skin

Contious Duct Tape Occlusion for up to 2 months

• pain free for children
• combo wih other topicals

5-FU 5% cream (also IL 40mg/ml 5-FU weekly for 4 weeks)

• Applied daily under occlusion for 4 weeks
• S/E onycholysis (if applied periungually), hyperpigmentation, erythema, erosion

Caustics (irritants)

• TCA
• Silver nitrate
• Cantharidin
• Phenol
• Formic acid
• Glycolic acid (plane warts)
• S/E painful reactions

Retinoid

• Topical 0.05% tretinoin cream (plane warts)
• can be effective im imunosuppressed patients

Vit D analogues

SECOND LINE RX - PHYSICAL RX ADMINISTERED BY PHYSICIAN (more time consuming, expensive)

Cryotherapy (cold thermal damage) every 3 weeks

• Pare off thick keratin
• Dry surface before LN2
• Apply LN2 until a 1mm rim of iced tissue (seen as white) develops in normal skim surrounding wart “gentle freeze” comtinuous of pulse between 5-20s depending on size and thickness of wart —> repeat second freeze cycle for plantar warts
• Longer freeze of 25s continuous more likely to leave scarring and damage underlying structures
• Expect swelling within mins, blister +/- haemorrhagic within 2-3 days, resolution by 2-3 weeks
• S/E Pain, damage to tendon, nail matrix, damage to nerves on sides of fingers, depigmentation in dark skin types

Laser

• 595nm PDL (Min 2 Rx)
• 1064nm Nd:YAG
• Ablative 2940nm Er:YAG
• Ablative 10600nm CO2 greater risk of hypertrophic scarring, pain, temporary loss of function, virus in the plume (may be needed for recalcitrant periungual, subungual warts)

Hyperthermia
- Localised heat 44 degree celcius for 30 mins

Surgery

• C&C for filiform warts can be effective
• C&C for painful and resistant warts carry risk of scarring
• Excision to be avoided as scarring inevitable, recurrence of wart in scar frequent

PDT

• METVIX PDT
• METVIX + PDL light source
• limited by pain

THIRD LINE RX - FOR SEVERE AND RECALCITRANT INFX, OR FAILURE OF PRIOR RX

Topical Podophyloin and purified podophyllotoxin (antimitotics) - C/I pregnancy and not licensed in children

• Mainly for anogenital warts, can also be considered in common warts though pemetration into keratinised skin may be poor
• used in caution under prolonged occlusion or combo with salc acid/cantharidin every 2/52 for 10 weeks
• S/E acute pain d/t intense local inflammation

Topical imiquimod 5% cream (immunomodulatory)

• Licensed for genital warts
• Poor penetration for common warts through keratinised surface —> BD for 24 weeks or combo with sal acid
• Butcher’s warts, filiform warts, plane warts may respond
• Occlusion does not affect clearance rates
• Immunosuppression does nit block therapeutic effect
• S/E irritation, discomfort, erosion, vitiligo-like depigmentation

Topical DPCP (immunotherapy)

• Suitable for immunosuppressed
• S/E itching at Rx site, widespread urticaria, secondary eczematisation

Topical SADB squaric acid dibutylester (immunotherapy)
- Better tolerated than DPCP

IL immunotherapy (recalcitrant cases)

• candida antigen —> local hypersensitivity reaction
• MMR vaccine

IL Interferon (experimental)

H2 receptor antagonists

• Oral cimetidine 30-40mg/kg/day 3-4 months (conflicting data of efficacy, may produce slightly netter efficacy im children than adults) +/- levamisole
• Ranitidine 300mg BD

Oral zinc sulphate 10mg/kg/day

Oral retinoid (reduce epidermal proliferation) - Acitretin, isotretinoin 0.5mg/kg/day

• Helpful in extensive and hyperkeratotic warts immunosuppressed patients
• 2 months
• Plane warts most responsive

IL bleomycin (cytotoxic) - C/I pregnancy

• Expect blanching of wart
• Very painful
• Consider LA esp semsitivemsites fimgers, soles
• Expect haemorrhagic eschar 2-3 weeks later, pared down if has not detached spontaneously
• Periungual injections S/E nail loss, nail dystrophy, Raynaud phenomenon
• Other S/E local pigmentation, urticaria, flagellate hyperpigmentation
• Implantation from surface applicatiom usomg sterile lancet/Dermojet may be better tolerated

Cidofovir (nucleoside analogue - damages dividing cells)

• Suitable in immunosuppressed patients
• 3-5mg/kg IV single dose every 1-2 weeks for very severe warts
• IL diluted from 375mg/ml to 15mg/ml injected directly into wart monthly
• Topical 1% cream
• S/E systemic dose nephrotoxicity, metabolic acidosis, bone marrow suppression

Question 3

Anogenital warts

Answer 3

@ condyloma acuminatum

Incidence highest in young adults
M > F

CLINICAL FEATURES
Often asymptomatic
May cause discomfort, discharge, bleeding
Soft, pink, elngated, sometikes filiform and pedunculated
Usually multiple esp on moist surfaces
Growth can be enhanced during pregnancy, presence of other local infections
Large malodorous masses may form on vulvar, perianal skin

Commonest sites (correspond to greatest coital friction)

• frenulum, corona, glans penis (men)
• Posterior fourchette (women)

Non-mucosal sites —> may be flat and pigmented resembling seb Ks

• Penile shaft
• Pubic skin
• Perianal skin
• Groin

HPV SUBTYPES
HPV 6, 11 (low risk subtypes)
+/- HPV 1, 2
HPV 2, 27, 57 (children - cutaneous warts types)

CLINICAL VARIANTS (caused by low risk HPV subtypes 6, 11 to other mucosal sites)
Oral warts
- Common in assoc with HIV
- Presents as leukoplakia, oropharyngeal CA
- HPV 6,11
- HPV 2, 27, 16 (rare)
- HPV 7 (if hx HIV)

Respiratory papillomatosis
- HPV 11 (assoc with malignant transformation)
+/- HPV 6, 16
- Childhood cases from maternal anogenital wart infection (acquired at birth during vaginal delivery)
- Adult cases - either from latent/subclinical childhood infection or sexual transmission
- Rx recurrent debulking of lesions

Conjunctival papillomas

• Low risk mucosal HPV subtypes 6, 11
• Rarely high risk types

Nasal inverting papillomas

• HPV 6, 11, 16, 18, 57
• Rare progression to SCC

DDX
Seb K
Anogenital intraepithelial neoplasia (bowenoid papulosis, IEC)
Development of large protuberamt masses, induration, pain, serousanguinous discharge —> suspect malignant change —> prompt excision or bx, assessment immune status ? Immunosuppressed/HIV
Verrucous CA (Buschke-Lowenstein tumour)
Condyloma lata (secondary syphillis)
Lymphogranuloma venereum
Metastatic Crohns disease (presents woth skin tags on oedematous, indurated background)
Pearly penile papules
Vulval papillomatosis (diffuse velvery/granular appearance in vaginal introitus)

PREDISPOSING FACTORS
Commonest in sites subject to greatest coital friction
Acquired most commonly from sexual contact, but not always transmitted sexually

Genital warts +/- Perianal warts due to local spread of infection or direct contact from anal coitus

CHILDHOOD TRANSMISSION PREDISPOSING FACTORS
Uncommon

Perinatal transmission

• Infection from mother’s genital tract during delivery —> May not manifest as genital warts for years
• laryngeal papilloma

Non-sexual Postnatal Transmission from adult with genital warts

• sharing bath with infected adult
• clinical resemblance of common warts
• Location on fully keratinised skin rather than genital or anal mucosa
• young age of 1-2 years at onset of warts

HISTO
Extreme acanthosis
Papillomatosis
Parakeratosis
Limited koilocytes
Capillaries tortuous
Connective tissue oedematous

MX - PREVENTION
Anti-HPV vaccine against HPV 6, 11, 16, 18

FIRST LINE RX
Topical Purified Podophyllotoxin (from podophyllin) - avoid in pregnancy
- most commonly used
- Self applied by patient at home
- Topical 0.15% cream BD for 3 consecutive days in 1 week for 4 consecutive weeks

Topical Imiquimod

• Self applied by patient at home
• 5% cream 3 x per week for up to 16 weeks OR
• 3.75% cream BD for 2 weeks ON, 2 weeks OFF, then 2 weeks ON
• risk of skin irritation

SECOND LINE RX
Cryotherapy
Electrocautery
Surgery
Laser
Caustics (80-90% TCA)
PDT
Sinecathecins (polyphenol E from green tea) self applied by patient

THIRD LINE RX (severe cases, extensive, giant warts pften in immunosuppressed patients)
Systemic or IL Interferon
- combo/adjuvant with other modalities

COURSE/PROGNOSIS
Duration varies few weeks, many years
Possible recurrence most lil;ey due to latent infection

COMPLICATIONS
Other STDs
High risk HPV —> screening for anogenital intraepithelial neoplasia
Underlying immune deficiency if very florid warts