A brief explanation of a very common skin condition called warts. The presentation explains the types, morphology, pathogenesis and treatment of viral warts. Information taken from renowned dermatology books to assist students to prepare for USMLE, MRCP and post graduate MCPS and FCPS exams. Very beneficial for medical students, dermatologists, nurses and doctors.

1. Human Papilloma Virus

2. INTRODUCTION:
 Small 50–55 nm diameter DNA viruses that infect squamous epithelia, whether
keratinized or non-keratinized causing cell proliferation.
 Divided into five genera: α, β, γ, μ and ν papillomaviruses.
 Disease Manifestations include:
(1) Benign lesions: Cutaneous warts,
Ano‐genital warts,
Oral warts
Laryngeal warts
(2) Pre‐malignant or malignant lesions:
Intraepithelial neoplasia
SCC of anogenital area & upper respiratory tract.

3. Basic Biology:
 The virus infects the stem cells of the basal layer and causes cellular
replication in the fully differentiated cells of stratum spinosum and stratum
granulosum.
 Viral DNA is functionally divided:
(I) Early (E) regions; responsible for DNA replication,
Transcriptional regulation
Transformation
(II)Late (L) regions: encode the structural proteins of the
viral capsid.

4. Immunity to HPV:
 The principal mechanism for the rejection of warts is via the cell-mediated
immune system. Especially CD8 T-cells and a Th1 Response.
 In persistent disorders of cell‐mediated immunity, the prevalence and
severity of warts and the incidence of HPV‐related malignancy are
increased

5. Epidemiology:
Incidence and prevalence
 Cutaneous warts occur at any age, but are unusual in infancy and early childhood.
 2–30% of school‐age children and young adults have warts
Age
 Incidence increases during the school years peaking in adolescence and early
adulthood then declines thereafter.
Associated diseases
 Warts are more common and more persistent in conditions of immune compromise.

6. Pathophysiology:
Predisposing factors
 spread by direct or indirect contact.
 For infection to occur, the wart virus particle may need to come into contact with a stem cell in the basal epidermal layer. Thus, trauma or maceration
greatly predisposes to inoculation of the virus,
Plantar warts:
 acquired from swimming pool or shower room floors, whose rough surfaces abrade moistened keratin and help to inoculate virus into the softened
skin.
Common hand warts:
 Spread around the nails in those who bite their nails or periungual skin over habitually sucked fingers in young children, and to the lips and
surrounding skin in both cases.
Shaving:
 may spread wart infection over the beard area.
Occupational handlers of meat, fish and poultry:
 Increased incidence of hand warts, attributed to cutaneous injury and prolonged contact with wet flesh and water.
Incubation Period:
 few weeks and more than a year

7. Iatrogenic Transmission:
 HPV DNA has been detected on instruments used for the examination of women with clinical or
subclinical HPV infection and in the environment of a genito‐urinary medicine clinic.
 Human papillomavirus DNA is found in the smoke plume from warts treated with laser or
electrocautery.
 The practice of dipping cotton wool swabs for a series of patients into the same flask of liquid nitrogen
could transfer herpes simplex virus.

8.  Viral warts show acanthosis and hyperkeratosis, with the
characteristic feature of koilocytosis of upper keratinocytes.
 Koilocytes:
 Are vacuolated cells with a dark flattened or twisted nucleus.
 There are basophilic nuclear inclusion bodies, which are composed of arrays
of viral particles.
 They also have eosinophilic inclusions representing irregular clumped
keratohyaline granules.
Pathology:

9. Histology of viral wart (a) low power, ×40, showing
morphology of wart lesion with papillomatous acanthosis
and hyperkeratosis
Koilocytes in the upper epithelium display a
dark small nucleus with clear cytoplasm
(hematoxylin and eosin stain, original
magnification X100). Courtesy of Sheldon
Mintz, DDS.

10. Histology of Common and plantar warts:
 Hyperplasia of all layers of the epidermis.
 Stratum Corneum: gross hyperkeratosis with areas of parakeratosis, especially above the
papillomatous projections.
 Stratum Granulosum: conspicuously thickened. Foci of koilocytes.
 Startum Spinosum: grossly thickened
 Elongated and flattened rete ridges are bent inwards towards the centre of the wart.
Palmoplantar warts: cytopathic changes are more marked and may be visible in the lower
stratum spinosum.
Plantar warts: have a more endophytic growth pattern and a very thick cornified layer.
Common warts have a morphology similar to genital warts with exophytic growth and a variable
amount of hyperkeratosis.

11. Histology of Plane warts:
 The hyperkeratosis is of a loose lamellar type
 Acanthosis without papillomatosis.
 Vacuolated epidermal cells are more conspicuous and contain numerous
viral particles.

12.  Common warts (excluding plantar warts): HPV‐2, but also to the closely
related types 27, 57 and types 1 and 4.
 Plantar warts: HPV‐1, ‐2, ‐4, ‐27 or ‐57.
 ‘Myrmecia’ form: HPV‐1. They begin as small shiny papules on the
plantar surfaces and progress to deep endophytic, sharply defined, round
lesions with a rough keratotic surface, surrounded by a smooth collar of
calloused skin.
 Mosaic warts: HPV‐2.
 Plane warts: HPV‐3 and ‐10.
 Butcher’s wart: HPV-2 and HPV- 7
 Facial and oral warts in HIV: HPV 7
Causative Organisms:

13. Clinical Features:
Common Warts:
 Morphology: firm papules with a rough horny surface.
 Size: <1 mm to over 1 cm in diameter, and can form large masses.
 Location: backs of the hands and fingers, and, in children on the knees. May form at
sites of trauma.
 Usually symptomless, but may be tender on the palmar aspects of the fingers, when
fissured or when growing beneath the nail plate;
 Warts on the eyelids: associated with conjunctivitis or keratitis.
 Account for only 1 or 2% of warts on or around the genitalia in adults; Usually confined
to the shaft of the penis in males. They often retain their dry hyperkeratotic
morphology compared to the soft acuminate (genital) warts.
 In children, common warts may account for up to two-thirds of ano‐genital warts.

14. Common warts on the dorsal surface of the hand

15. Periungual warts
 Common warts around the nails, especially at the nail folds or
beneath the nail, can disturb nail growth.
 Nail biting may increase the risk of infection at this site.

16. Plantar Warts:
 Initial appearance: a small shining ‘sago‐grain’ papule,
 Gradually develops a sharply defined rounded lesion, with a rough keratotic surface
surrounded by a smooth collar of thickened horn.
 Gentle paring with a scalpel reveals the abrupt separation between the wart tissue
and the protective horny ring. It also shows small bleeding points representing tips of
elongated dermal papillae.
 Epithelial ridges of the plantar skin are not continued over the surface of the wart.
 Location: beneath pressure points, the heel or the metatarsal heads.
 Mosaic warts: presented as a plaque of closely grouped small warts. Usually
painless
 Regression is delayed if hyperhidrosis or orthopaedic defects are present.

17. Mosaic Plantar Warts:

18.  Morphology:
 Smooth, flat or slightly elevated.
 Skin coloured or greyish yellow, but may be pigmented.
 Round or polygonal in shape.
 Size: 1 to 5 mm
 Location: face, and the backs of the hands, shins
 Koebenerization is a characteristic feature.
Plane Warts
Plane warts on the
face
Koebnerization in Plane warts

19. Clinical variants
(A) Filiform and digitate warts
 Filiform warts occur commonly in the male, on the face and neck.
 Digitate warts, often in small groups, also occur on the scalp may be confused with
epidermal naevi.
(B) Huge Hyperkeratotic Warts:
 Are extensive and extremely hyperkeratotic retaining long horny projections.
 Underlying immune compromise may be present.
Filiform wart on the forearm:

20. (C) Butchers’ warts: (HPV-2 & HPV-7)
 Seen in occupational handlers of meat, poultry or fish.
 Location: on hand warts from prolonged contact with moist animal flesh.
 Larger than common warts, and have a high risk of recurrence even after successful
treatment.
(D) Epidermoid plantar cysts: (HPV-60 & HPV-57)
 Epidermoid cysts of weight‐bearing areas of the sole may contain HPV.
(E) Pigmented warts:
 Mainly on the palms and soles in Japanese patients.
 Melanosomes are increased within the lesions,
 Organism: HPV‐65 (64%),
HPV- 4 (23%)
HPV‐60 (13%).

21. Differential Diagnosis:
(A) Hand warts
 Epidermal naevus,
 Bowen disease,
 Actinic keratosis and
 Callus.
(B) Plantar warts
 Corns and calluses,
 Punctate keratoderma of genetic origin: Dermoscopy helps to distinguish a plantar wart from a corn or a
callosity. In warts, the plantar ridges of the epidermis are seen to be pushed apart with dark pinpoints of
thrombosed capillaries. Central keratotic ‘seed’ may be seen in a corn.
(C) Plane warts:
 Lichen planus
 In acrokeratosis verruciformis numerous warty papules are symmetrically distributed on the backs of the
hands.

22. Disease course and prognosis:
 Clearance is usually quicker in children but warts may persist for many
years in adults.
 Regression of common warts: occurs over several weeks, usually
without blackening.
 Regression of plane warts: is heralded by inflammation, itch, erythema
and swelling. Depigmented haloes may appear around the lesions.
Resolution is usually complete within a month.
 Regression of plantar warts: is clinically inflammatory, and culminates
in blackening from thrombosed blood before the lesion separates.
Sometimes it takes the form of apparent drying and gradual separation.
 Malignant change in warts: seen in immunosuppression ,with bowenoid
hyperkeratotic plaques or with genital HPV disease.

23. Investigations:
 Clinical diagnosis of warts is often sufficient.
 Atypical, subclinical or dysplastic lesions may need laboratory
confirmation with:
 Histology.
 Immunohistochemistry using type common or type‐specific antibodies.
 DNA in situ hybridization.
 PCR for HPV DNA.

24. Management:
 Aim of Treatment: restoration of normal epidermal texture including the epidermal ridge pattern.
 Some warts will resolve spontaneously.
General Measures:
 Gentle reduction of the hyperkeratotic epidermis by regular filing or paring down will make the lesion
more comfortable.
 Simple measures to limit the spread of the infection:
(a) Plantar warts: to be covered with adequate plaster strapping, or wearing of
close‐fitting rubber ‘verruca socks’, or pool‐side sandals at swimming pools.
(b) Periungual and perioral warts: Use of adhesive strapping after the application of a
‘wart paint’ helps to break the habit of nail biting.
(c) Cleaning of baths after use and avoidance of shared towels.
 Counseling patient that recurrences is common and compliance to medication is necessary.

25. First Line Treatments:
Can be used by the patient at home.

26. A) Salicylic acid:
 Mechanism of Action: The keratolytic effect helps to reduce the thickness of warts and stimulate an inflammatory response.
 Preparations: 12–26% salicylic acid possibly with additional lactic acid.
 Salicylic acid ointment 40% can also be used for over 3 months.
 Adhesive plaster containing 40% salicylic acid is useful for plantar warts. Applied daily, cut to the shape of the wart and held in
place by plain adhesive plaster
 Method of Use:
 Daily use for 3 months achieved cure rates of 67% for hand warts, 84% for simple plantar warts and 45% for mosaic plantar
warts.
 Removal of surface keratin and the remnants of the previous application by gentle use of a pumice stone, is a helpful
preliminary step.
 Overenthusiastic abrasion may enhance spread of the virus by inoculation into adjacent skin.
 Accurate application may require a fine applicator such as a sharpened matchstick or a cocktail stick. After drying, a whitish
deposit remains.
 Penetration into thick skin on the sole, is enhanced by plain adhesive plaster occlusion, which promotes maceration of the
keratin layer and a reduction in barrier function.
 Caution : when using on feet with neuropathy or impaired circulation, due to the risk of producing ulceration which may not heal.
 Less irritant cream based formulations can used for plane warts.

27. (B) Glutaraldehyde:
 Mechanism of Action: Virucidal agent
 Treated skin dries into the skin without a surface deposit. It can be
scraped off easily.
 Preparations:
10% glutaraldhyde in aqueous ethanol
 20% glutaraldehyde in aqueous solution
 Side Effects:
Allergic contact dermatitis to the glutaraldehyde
Cutaneous necrosis
Imparts a brown color so unsightly on hands

28. (C) Formalin:
 Mechanism of Action: Viriucidal properties
 Preparations:
Soaks or compresses of 2–3% formalin in water for plantar warts.
0.75% Fornmaldehyde gel
 Formalin is about 37% formaldehyde in water.
 Reported cure rate of 80% in children
 Method:
 Area must be soaked in the solution for 15–20 min daily, using soft paraffin as a
barrier application to protect more sensitive skin.
 The treated area dries and hardens the skin, facilitating paring.
 Side Effects:
time consuming and
difficult to limit to affected skin.
Irritant dermatitis in the surrounding skin.

29. (D) Occlusion:
 Continuous duct tape occlusion of common warts for up to 2 months.
 Accompanied with topical therapy to enhance clearance.
(E) Topical 5‐fluorouracil:
 Preparations:
 A 5% cream of 5‐fluorouracil (5‐FU) applied daily under occlusion for a month.
 5% Ointment
 Intraleisonal 5-FU: 40mg/mL weekly for up to 4 weeks (clearance rate in 60% warts)
 Combination of 5% 5-FU with 10% Salicylic acid (Clearance rate in 63% warts)
 Side Effects:
 if used periungually, may cause onycholysis.
 Hyperpigmentation, erythema and erosion

30. (F) Caustics:
 Preparations:
Monochloroacetic acid,
Trichloroacetic acid,
Silver nitrate,
Cantharidin,
Phenol,
Formic acid.
 Side Effects: may cause painful reactions.
 Peeling agents pyruvic acid and glycolic acid useful for plane warts.

31. (G) Retinoic acid:
 Useful in plane warts,
 0.05% tretinoin cream with a clearance rate of 85% of the warts.
 Effective in immunosuppressed patients.
 Side Effects: Irritation
(H) Vitamin D analogues:
 Maxacalcitol alone or in combination with salicylic acid effective in common warts.

32. Second Line Treatments:
Treatments that are physician administered, more time
consuming or expensive

33. (1) Cryotherapy:
 Mechanism of Action: Produces cold thermal damage to the skin and stimulates
an immune response
 Preparations: Dimethyl ether spray,
Carbon dioxide snow and
Liquid nitrogen: produces the coldest freeze, applied either by a cotton wool bud or from a cryospray.
 Procedure:
 (A) The Standard Method
 Thick keratin should be pared off, and the surface dried before freezing begins.
 Application is continued until a 1mm rim of iced tissue develops in the normal skin surrounding the wart.
 The freeze is maintained for 5–30 s depending on the size and site of the wart. This may require a continuous or pulsed
spray for between 5 and 20 s.
 Longer freezing (over 25 s)can cause scarring, damage to underlying structures and not improve clearance rates.
 (B) Gentler or ‘Traditional’ Method:
 Freezing until the 1 mm rim of frozen skin is visible and then stopping.
 Less efficacious in clearance .
 After thawing, a second freeze cycle will improve the cure rate in plantar warts, although the benefit is less marked in hand warts.
Treatment repeated every 3 weeks gives a 30–70% cure rate for hand warts after 3 months

34. Cryotherapy Contd:
 Freeze time of up to 30s for warts that are resistant to treatment, or painful or deep, warts
or over a bony prominence.
 Longer freeze times cause greater blistering and pain. Use local or even general
anaesthesia in such cases.
Side Effects of Cryotherapy:
 Dipping cotton buds for different patients into a common flask containing the liquid
nitrogen may carry a risk of cross‐infection.
 Painful procedure. Oral aspirin and strong topical steroids may help.
 Swelling begins within minutes.
 Blister, sometimes haemorrhagic, may ensue within a day or two.
 Scarring if freezing times > 30 s.
 Damage to underlying tissues: tendons, nail matrix
 Longer freezing times avoided over nerves, for example on the sides of the fingers.
 Depigmentation in darkly pigmented skin.

35. (2) Laser:
 Pulsed dye laser:
 cure rates of approximately 32–75%, using a minimum of two treatments
 Erbium : yttrium aluminium garnet (Er : YAG)
 Neodymium : aluminium garnet (Nd : YAG)
 Carbon dioxide laser:
 Affective for cutaneous, mucosal warts, periungual and subungual warts.
 Well tolerated
 Clearance rate at 12 months is 55–70%
 Significant postoperative pain, hypertrophic scarring and temporary loss of function.
 Infectious virus can be detected in the plume during carbon dioxide laser use. An
operator mask and air extraction system are advised.
 Laser treatment for other indications has been associated with the spread of facial
warts

36. 3) Hyperthermia:
 Localized heat of up to 30 min at 44°C
 Clearance rate of 54% clearance
 Infrared coagulator can be used to treat warts. Cure rate of 70%
4) Surgery:
 Excision can cause scarring and recurrences of the wart in the scar
 May be effective for filiform warts.
 Curettage and cautery/electrocoagulation, for painful or resistant warts, but carry a risk of scarring.
5) Photodynamic therapy:
 Systemic or topical aminolaevulinic acid can be taken up by dividing cells, metabolized to protoporphyrin and then
photoactivated to produce a damaging effect on the cell.
 Clearance rates of 75–90% .
 Can be combined with pulsed dye laser. Clearance rate of 53% of warts.
 The treatment may need to be repeated two or three times
 Side Effect: Pain

37. Third line Treatments:
• Include those that might be considered in situations of severe and recalcitrant infection
• Include those treatments when first and second line treatments have produced no
effect.

38. 1)Podophyllin and podophyllotoxin:
 Mechanism of Action: Act as antimitotics, disrupting the formation of the
spindle on which chromosomes align at mitosis.
 Uses: mainly for ano‐genital warts but can also be used for cutaneous warts,
though penetration into keratinized skin may be poor.
 Preparations: May be combined with salicylic acid or cantharidin to be applied
every 2 weeks for up to 10 weeks.
 Clearance rates: 80–95%,
 Side Effect:
 acute pain
 Intense local inflammation.
 Contraindication:
 Pregnancy
 Children

39. 2) Imiquimod:
 Mechanism of Action: through immunomodulation
 Preparations:
 Imiquimod 5% cream
 Combination with salicylic acid.
 Uses: for genital warts. Can be used for cutaneous warts though poor penetration through the
keratinized surface may necessitate twice daily application for up to 24 weeks.
 Butchers’ warts, facial filiform warts and plane warts may all respond
 Immunosuppression does not appear to block the therapeutic effect.
 Side Effects:
 Irritation,
 Discomfort and
 Erosion
 causing vitiligo‐like depigmentation

40. (3) Topical immunotherapy:
 Dinitrochlorobenzene used to treat cutaneous warts but no longer used due to the potential risk of
carcinogenesis.
 Diphenylcyclopropenone (diphencyprone, DPC) is now used more commonly.
 Cure rates of between 44% and 88% of patients
 Can be used with the immunosuppressed.
 Side Effect:
 Itching
 Dermatitis in other areas or widespread urticaria.
 The use of squaric acid dibutylester as a contact may be equally efficacious and better tolerated.
(4) Intralesional immunotherapy:
 Trials using intralesional Candida antigen to produce a local hypersensitivity reaction can speed wart
resolution in recalcitrant cases
 Immunogens for mumps or tuberculosis and the measles, mumps and rubella (MMR) vaccine have
been used similarly.

41. (5) Interferon:
 Use of interferons in warts is still experimental.
 Used for recalcitrant common and plantar warts being treated with human IFN‐α intralesionally
using a needleless injector.
(6) H2 receptor antagonists:
 Cimetidine:
 High‐dose oral cimetidine (30–40 mg/kg/day for 3–4 months),
 Improvement or complete resolution without recurrence in 2/3rd cases.
 Greater benefit seen in children.
 Combining treatment with levamisole may enhance the effect.
 Ranitidine:
 300mg twice daily.
 Clearance of warts in 49% of patients suffering with common or plane warts

42. (7) Zinc:
 Oral zinc sulphate: (10 mg/kg/day) produces cures rates up to 78–87%
Side effects are common and often lead to discontinuation of therapy.
 Topical, zinc sulphate as a 10% aqueous solution applied three times daily for 4 weeks produced a
cure rate of 86% for plane warts
Zinc oxide 20% may also be used.
(8) Oral retinoids:
 Mechanism of Action: reducing epidermal proliferation, therefore can debulk hyperkeratotic warts.
Although the infection may persist making relapse likely.
 Acitretin and isotretinoin: in cases of extensive and hyperkeratotic warts in immunosuppressed patients.
 Hyperkeratotic warts in otherwise healthy patients can respond to oral retinoid therapy.
 Decreases the pain and disability in the warts and facilitates the use of other treatments.
 Plane warts respond better and may clear with isotretinoin 0.5 mg/kg/day for 2 months or low‐dose
acitretin therapy.

43. (9) Intralesional bleomycin:
 Doses are given in units or in milligrams;
 1 mg contains 1500–2000 U.
 Bleomycin sulphate 0.25–1 mg/mL is injected up to three times to a
maximum total dose of 4 mg.
 or 1000 U/mL to two injections and a maximum total dose of 2000 U.
 Injections are into the wart itself, confirmed by observing blanching in the
lesion,
 The volume per injected lesion: 0.2 to 1.0 mL.
 Injections are very painful and preceding or concurrent local anaesthesia
should be considered for sensitive sites such as the fingers and soles.

44.  A haemorrhagic eschar develops; 2–3 weeks later, it is pared down if it has not
detached spontaneously.
 Cure rates for previously refractory warts: 20 to 100%
 Local complications:
 nail loss and dystrophy following periungual injections,
 Raynaud phenomenon in treated fingers and
 Local pigmentation
 Urticaria
 Flagellate hyperpigmentation, though seen in systemic administration, has been
reported after local injection
 Contraindication:
 potential risk of systemic absorption so intralesional bleomycin in avoided in
pregnancy

45. (10) Cidofovir:
 Mechanism of Acton: By incorporating into replicating DNA, this nucleoside
analogue damages dividing cells.
 Preparations:
 Intravenously (3–5 mg/kg as a single dose given every 1–2 weeks) for very severe
warts.
 Injected intralesionally, diluted from 375 mg/mL to 15 mg/mL and injected monthly or
 Applied as a 1% cream
 Cidofovir can be used in immunosuppression.
 Side effects: mainly seen with systemic administration:
 nephrotoxicity,
 metabolic acidosis and
 bone marrow suppression.
 Local application on mucosal surfaces can produce erosion and pain but generally
well tolerated.

47. Future Topics to be Discussed:
1)Anogenital warts
2)Epidermodysplasia Verruciformis