Cutaneous warts
Salient
features
·
HPV
are ubiquitous in humans, causing:
1.
Subclinical
infection.
2.
Wide
variety of benign clinical lesions on skin and mucous membranes.
3.
Cutaneous
and mucosal premalignancies: Squamous cell carcinoma in situ (SCCIS); invasive
SCC.
·
More
than 150 types of HPV have been identified, with some regional specificity.
Low-risk types cause warts; high-risk types are associated with intraepithelial
neoplasia and malignancy.
1.
Cutaneous
HPV infections occur commonly in the general population.
2.
Common
warts: Represent approximately 70% of all cutaneous warts, occurring in up to
20% of all school-age children.
3.
Butcher's
warts: Common in butchers, meat packers, and fish handlers.
4.
Plantar
warts: Common in older children and young adults, accounting for 30% of
cutaneous warts.
5.
Flat
warts: Occur in children and adults, accounting for 4% of cutaneous warts.
6.
Oncogenic
HPV can cause SCCIS and invasive SCC with host defense defects.
·
Epidermodysplasia
verruciformis (EDV).
·
Anogenltal
HPV infections.
·
External
genital wart: Most prevalent sexually transmitted infection.
·
Squamous
Cell Carcinoma. Some HPV types have a major etiologic role in the pathogenesis
of in situ as well as invasive SCC of the anogenital epithelium.
·
During
delivery, maternal genital HPV infection can be transmitted to the neonate,
resulting in a anogenital warts and respiratory papillomatosis after aspiration
of the virus Into the upper respiratory tract.
Introduction
Human papillomaviruses (HPVs) are
DNA viruses that infect stratified squamous epithelia, either keratinizing
(skin) or non‐keratinizing (mucosa), causing cell proliferation. Clinical lesions
induced by HPV and their natural history are largely determined by HPV type,
which are grouped according to their pathologic associations and tissue
specificity, either as cutaneous or mucosal. Mucosal-associated HPV can be
further sub grouped according to their risk of malignant transformation.
The commonest effect of HPV infection is the development of benign papillomas or warts (verrucae). These virus‐induced
tumors are pleomorphic and can affect various sites, principally the skin of
the extremities, genital skin and mucosa, larynx and oral mucosa.
All papillomavirus types have a
tropism for stratified squamous epithelial cells, but they vary in their
specificity for different anatomical sites. HPVs are often categorized as cutaneous
(nongenital) and include genotypes such as HPV-1, -2, -3, and -4, whereas
HPV-6, -11, -16, and -18 predominate in genital and mucosal infections.
The clinical problems encountered
with such infections can be broadly divided into benign lesions such as
cutaneous warts, ano‐genital warts, oral warts and laryngeal warts and pre‐malignant or malignant lesions such as intraepithelial
neoplasia and squamous cell cancers of the ano‐genital
area such as all cervical and most anal cancers, a subset of vaginal,
vulvar, penile and also oropharyngeal cancers;
and
rarely, squamous cell cancer of the digits.
Condylomata acuminata or benign
anogenital warts are typically caused by HPV-6 or -11, which are considered to
be low-risk types.
Persistent infection with high-risk HPV types, predominantly
HPV-16 and -18 are associated with intraepithelial neoplasia and malignancy.
Patients with cellular immunodeficiencies are at higher risk
for persistent HPV infection and progressive disease with an
increased risk of developing anogenital neoplasias.
The three licensed subunit vaccines (bivalent, quadrivalent, and
9-valent) are comprised of empty virus-like particles (VLP); when administered
prophylactically, they are highly efficacious in preventing type-specific
persistent HPV infection and neoplasia.
Basic
biology
The virus infects the basal layer of
the epithelium, probably the stem cells, but viral replication takes place only
in fully differentiated keratinocytes – cells of the upper stratum spinosum and
stratum granulosum.
Subclinical and latent human papillomavirus
infection
Infection
with HPV may be clinical, subclinical, or latent. Clinical lesions are visible
by gross inspection. Subclinical and latent HPV
infections are found mainly in genital skin and mucosa. It has been estimated
that up to 70% of genital HPV infections may be subclinical (i.e. unnoticed by
the patient) but detectable by full clinical examination, histology, cytology
or molecular analysis. In a latent infection, there may be no morphological
changes, but the viral DNA is present in apparently normal skin. As latent
infection is common in genital warts, and so it explains in part the failure of
destructive methods to eradicate warts.
Human papillomavirus (HPV): cutaneous warts
• Certain human HPV types commonly infect keratinized
skin.
• Cutaneous warts are:
1. Discrete
benign epithelial hyperplasia with varying degrees of surface hyperkeratosis.
2. Manifested
as minute papules to large plaques.
• Lesions may become confluent, forming a mosaic.
• The extent of lesions is determined by the immune
status of the host
Definition
Skin warts are benign tumors caused by infection of
keratinocytes with HPV, visible as well‐defined
hyperkeratotic protrusions.
Epidemiology
Warts
are very common, as majority of individuals will have at least one infection
with the virus during the course of a lifetime. Cutaneous warts occur at any
age, but common in school aged children and young adults (between the ages of 5
and 20 years). Warts are transmitted simply by touch; it is not unusual to see
warts on adjacent toes (“kissing lesions”). The majority of warts will regress spontaneously within 1–2
years. After clearance occurs, reinfection with the same HPV type appears to be
uncommon, suggesting that protective type-specific immunity may develop.
Pathogenesis
Human papillomavirus (HPV) Life Cycle
The papillomavirus life cycle is completed only in
fully differentiated squamous epithelia. Productive infection and induction of
hyperproliferation are initiated when the virus enters proliferating basal
epithelial cells. HPV
infects the basal layer of the stratified epithelium through a micro wound.
Upon entry into the cell, the virus transiently amplifies to 50–100 copies per
cell. HPV genomes are maintained at a stable copy number in undifferentiated
basal cells by replicating along with cellular DNA. Upon differentiation, the
productive phase of the life cycle is activated, resulting in late gene
expression and amplification of viral genomes to thousands of copies per cell.
The expression of E6 and E7 allows for cell cycle re-entry upon
differentiation, providing cellular factors for productive replication. E4 and
E5 also contribute to efficient productive replication. Expression of L1 and L2
promotes the encapsidation of newly replicated genomes, resulting in virion
release from the uppermost layers of the epithelium (brown hexagons).
Predisposing factors
Warts are spread by direct skin contact or less often,
through inert objects, such as nail files, scissors and other personal care
items. For infection to occur, the wart virus particle may need to come into
contact with a stem cell in the basal epidermal layer. This layer of cells is
not normally accessible to the virus because of the mechanical barrier provided
by the overlying differentiated cell layers. Therefore, it is likely that
infection requires an abrasion or other trauma to the epithelium to expose the
basal cells to the virus. Thus, impairment of the epithelial barrier functions,
by trauma (including mild abrasions), maceration or both, exposes the basal
cells to the virus so that the virus gets inoculated.
Plantar warts are commonly acquired from swimming pool or
shower room floors, whose rough surfaces abrade moistened keratin and help to
inoculate virus into the softened skin of feet.
Common hand warts may spread widely round the nails in
those who bite their nails or periungual skin.
Shaving may spread wart infection over the beard area.
Occupational handlers of meat, fish and poultry have high
incidences of hand warts, attributed to cutaneous injury and prolonged contact
with wet flesh and water.
The incubation period for common and plantar warts ranges
from weeks to years.
Pathology
The
histopathologic changes induced by HPV infection are variable, reflecting the
myriad clinical presentations and different anatomic sites. In productive HPV
infections, a
common feature in epithelial cells is the presence of large keratinocytes with
an eccentric, pyknotic nucleus surrounded by a perinuclear halo. These cells
are called koilocytotic cells or koilocytes and are characteristic of
HPV-associated papillomas and is a useful feature distinguishing verrucae from
other types of papillomas.
Koilocytotic cells: The HPV cytopathic effect (koilocytosis) is shown in a cervical biopsy specimen (left, H&E staining), a cervical cytology preparation (middle, Pap stain), and a cultured cells (right, H&E staining). Arrows show typical koilocyte features: an acentric, hyperchromatic, moderately enlarged nucleus (white arrow) displaced by a large perinuclear vacuole (green arrow), surrounded by a thickened cytoplasm (black arrow).
Common and plantar warts
These are characterized by hyperplasia of all layers of
the epidermis.
Common
warts are well circumscribed from the surrounding skin and characteristically
have steeply sloping “church
spire” papillomatosis heaped with ortho- and parakeratosis. Parakeratosis is
most commonly observed directly overlying the summits of the papillomatosis and
is often accompanied by small intracorneal hemorrhages. There is also marked
acanthosis and the rete ridges are elongated. In palmoplantar warts, the
lateral edges of the wart bow inward to create a cup-shaped invagination below
the papillomatosis. Koilocytosis is typically observed in the upper stratum spinosum and the
stratum granulosum. In koilocytes and other granular layer cells, there
may be basophilic nuclear inclusion bodies, which are seen ultrastructurally to
be composed of viral particles. As the cells cornify and shed, these viral
particles are released for potential further infection or transmission. The
dermal capillary vessels are prominent and may be thrombosed. These thromboses
correspond to the “black dots” that can be detected on clinical examination,
especially of pared warts. Plantar warts have a more endophytic growth pattern
and a very thick cornified layer.
Flat Warts
The
characteristic features of flat warts include orthokeratosis alternating with
parakeratosis, acanthosis, no papillomatosis, a uniformly thickened granular
layer, and vacuolization of cells in the granular and upper malpighian layers
(termed “bird’s eyes”).
Some patients with flat warts develop
clinically evident inflammation around these warts, which may precede their
spontaneous involution. Characteristic histologic features of regressing flat
warts include parakeratosis, spongiosis, exocytosis of mononuclear cells into
the lower epidermis, and (occasionally) satellite cell necrosis.
Clinical features
Cutaneous HPV types comprise a small group of viruses
that infect the skin and induce common warts (Latin verrucae vulgares; singular verruca vulgaris), palmar and plantar warts (verrucae palmares et plantares), mosaic warts, flat
warts (verrucae planae), and butcher’s warts. In general,
classification of warts is based on morphology, histology, and anatomic
location.
Warts: The primary lesion
Viral warts are tumors initiated by a viral infection of
keratinocytes. The cells proliferate to form a mass but the mass remains
confined to the epidermis. There are no “roots” that penetrate the dermis.
Several types of warts form cylindrical projections. These projections diverge
when the wart grows in thin skin and are clearly seen in digitate warts that
occur on the face. The cylindrical projections are tightly packed together in
common warts on thicker skin. This produces a highly organized uniform mosaic
pattern on the surface. This pattern is
unique to warts and is a useful diagnostic sign. The pattern can be easily seen
with a hand lens. Thrombosed black vessels become trapped in these projections
and are seen as black dots on the surface of some warts. Although warts remain
confined to the epidermis, the growing mass can protrude deeper into the skin
and displace the dermis, giving the impression that it extends into the dermis
or subcutaneous tissue. The undersurface is round and smooth. Warts obscure
normal skin lines; this is an important diagnostic feature. When skin lines are
reestablished, the warts are gone. The rate of spontaneous remission of
cutaneous warts is around 60% in the first 2 years, primarily as result of
localized cellular immune response.
Warts: the primary lesion. Warts form
cylindrical projections. They diverge when the wart grows in thin skin.
Warts: the primary lesion. The
cylindrical projections are partially fused in this larger wart.
Warts: the primary lesion. The
cylindrical projections are tightly packed together, confined by the
surrounding skin. This uniform mosaic surface pattern is unique to warts and is
a useful diagnostic sign. The pattern can be easily seen with a hand lens.
Warts: the primary lesion. Thrombosed
black vessels are trapped in the cylindrical projections. They appear as black
dots when only the surface of the projections can be seen.
A wart has a vascular supply thus, on
paring the wart with a blade, it bleeds once the vasculature is encountered.
Warts: the primary lesion. The
undersurface of a wart. Contrary to popular belief, warts do not have roots.
The undersurface is round and smooth. The wart is confined to the epidermis,
but it expands and displaces the dermis, giving the impression that it extends
into the dermis or subcutaneous tissue.
Common warts
Common warts (verruca vulgaris) hyperkeratotic, clefted surface, with vegetations, exophytic, dome-shaped papules or plaques that is typically associated with HPV-1, -2, -4, -27 or -57. On the surface of the wart, tiny black dots may be visible, representing thrombosed, dilated capillaries. Pairing the hyperkeratotic surface with a #15 surgical blade makes the capillaries more prominent and bleeds and may be used as an aid in diagnosis. Warts do not have dermatoglyphics (fingerprint folds), as opposed to calluses, in which these lines are accentuated. Common warts are usually located on the fingers back of the hands or in other sites prone to trauma such as the knees or elbows, but they may occur anywhere on the skin surface. Autoinoculation by scratching may cause a linear arrangement of warts. Children under 12 years of age are frequently affected. Common warts are usually asymptomatic but may be tender. About 95% will clear spontaneously within 4 years.
Treatment
Topical
salicylic acid preparations, liquid nitrogen, and very light electrocautery are
the best methods of initial therapy. For recalcitrant warts imiquimod cream is
used.
Subungual and Periungual warts
Common warts around the nails are more common in nail biters and may be confluent, involving the proximal and lateral nail folds, and are more resistant to treatment than are warts located in other areas. A wart next to the nail may simply be the tip of the iceberg; much more of the wart may be submerged under the nail which may destroy the nail matrix and bed resulting in partial or complete absence of the nail plate. Periungual warts are often spread by finger chewing (Pseudo Koebner phenomenon), as the wart viruses can easily settle in the epithelial defects. The same is observed in patients who constantly forcefully remove the skin in the paronychial space.
Treatment
The tips of
the fingers and toes are a confined area. Therapeutic measures that cause
inflammation and swelling, such as cryosurgery, may produce considerable pain.
Cryosurgery
Small
periungual warts respond to conservative cryosurgery; warts that extend under
the nail do not respond. The use of aggressive cryosurgery over superficial
nerves on the volar or lateral aspects of the proximal phalanges of the fingers
has caused neuropathy. Permanent nail changes may occur if the nail matrix is
frozen.
Keratolytic preparations
The same
procedures described for treating plantar warts with salicylic acid and lactic
acid paint and salicylic acid plasters are useful for periungual warts.
Blunt dissection
When
conventional measures fail, blunt dissection offers an excellent surgical
alternative. Local anesthesia is induced with 2% lidocaine without epinephrine
around and under small warts. A digital block is required for larger warts.
Hemostasis during the procedure is maintained by firm pressure over the digital
arteries or with a rubber-band tourniquet. The nail should be removed only if
the wart is very large and imbedded. The procedure is exactly the same as that
described for blunt dissection of plantar warts.
Duct tape occlusion
Duct tape
occlusion therapy may be more effective than cryotherapy for common warts. To
completely cover the wart, the tip of the finger is wrapped with duct tape. The
tape remains in place for 6 days, is removed at home, is then reapplied in a
similar manner 12 hours later, and remains in place for an additional 6 days.
This procedure is repeated for up to 2 months.
Plantar warts
These are rough hyperkeratotic endophytic
papules with gently sloping sides and a central depression resembling an
anthill (hence the term myrmecia, meaning
anthill). The soft, pulpy cores are surrounded by a firm, horny ring. If the
surface is gently pared with a scalpel, the abrupt separation between the wart
tissue and the protective horny ring becomes more obvious, as the epithelial
ridges (dermatoglyphics)
of the plantar skin are not continued over the surface of the wart. Return of
dermatoglyphics is a sign of resolution of the wart. If the paring is
continued, small bleeding points, the tips of the elongated thrombsed dermal
papillae, are evident.
Plantar warts frequently occur at points of maximum
pressure, the heel or the metatarsal heads. Individuals may be affected by
single or numerous lesions. A large hyperkeratotic plaque made up of multiple
small coalescing warts is called Mosaic wart. The angular outlines of the
tightly compressed individual warts are seen when the surface is pared. "Kissing"
warts are lesion that occurs on opposing surface of two toes.
Pain is a common symptom. On the soles, these are often painful
from pressure when walking, due to their deep inward growth, but may be absent
and many warts are discovered only on routine inspection. Mosaic warts are
often painless. The number of warts present does not influence the prognosis,
but mosaic warts tend to be especially persistent. Same HPV types causing
common warts also causes majority of plantar warts.
Differential diagnosis
Corns
Corns are a
mechanically induced lesion that forms over or under a weight-bearing surface
or structure. Corns (clavi) over the metatarsal heads are frequently mistaken
for warts. The two entities can be easily distinguished by paring the callus
with a #15 surgical blade. Warts lack skin lines that cross their surface and
have centrally located black dots and punctuate hemorrhage with additional
paring. Examination with a hand lens shows a highly organized mosaic pattern on
the surface. Clavi or corns also lack skin lines crossing the surface, but they
have a hard, painful, well-demarcated, translucent central core. Pain is
greatly relieved when this central core is removed. In corn, pain can be induced
if pressure is applied vertically on the center of the lesion, while in
verrucae pain also appears when pressure is applied sideways at the border of
the lesion.
Black warts
Warts in the
process of undergoing spontaneous resolution, particularly on the plantar
surface, may be painful and turn black and feel soft. They are easily removed
without anesthesia by using a curette. Cell-mediated immunity against
virus-infected keratinocytes may take place in the process of regression of
some warts.
Treatment
Plantar
warts do not require therapy as long as they are painless. Although their
number may increase, it is sometimes best to explain the natural history of the
viral infection and wait for resolution rather than subject the patient to a
long treatment program. Minimal discomfort can be relieved by periodically
removing the callus with a blade or pumice stone.
Painful
warts must be treated. A technique that does not cause scarring should be used;
scars on the soles of the feet may be painful for years.
Debridement
It is very
important to debride the hyperkeratotic tissue over and around plantar warts to
ensure penetration of the medication. This may require seeing the patient every
2 to 3 weeks.
Combination therapy
Multiple
simultaneous techniques are often required to successfully treat plantar warts
and may include the following regimens.
Keratolytic therapy (salicylic acid liquid)
Keratolytic
therapy with salicylic acid (over-the-counter) is conservative initial therapy
for plantar warts. The treatment is non-scarring and relatively effective but
requires persistent application of medication once each day for many weeks.
The wart is paired
with a blade, pumice stone, or sandpaper (emery board). The affected area is
soaked in warm water to hydrate the keratin surface; this facilitates
penetration of the medicine. A drop of solution is applied with the applicator
and allowed to dry. Solution may be added as needed to cover the entire surface
of the wart. Penetration of the acid mixture is enhanced if the treated wart is
covered with a piece of adhesive tape. Inflammation and soreness may follow
tape occlusion, necessitating periodic interruption of treatment; consequently,
the patient may be satisfied with the longer, more comfortable process of
simply applying the solution at bedtime. White, pliable keratin forms in a few
days and should be pared with a blade or worn away with abrasives such as
sandpaper or a pumice stone. Ideally, the white keratin should be removed to
expose pink skin; to accomplish this, an occasional visit to the office may be
necessary.
Keratolytic therapy (40% salicylic acid plasters)
Salicylic
acid plasters are particularly useful in treating mosaic warts that cover a
large area.
The plaster
is cut to the shape of the wart. The backing of the plaster is removed and the
sticky surface is applied to the wart and secured with tape. The plaster is
removed in 24 to 48 hours, the pliable white keratin is reduced in the manner
previously described, and another plaster is applied. The treatment requires
many weeks, but it is effective and less irritating than salicylic acid and
lactic acid liquid. Pain is relieved because a large amount of keratin is
removed during the first few days of treatment.
5-fluorouracil (5-FU)
Application
of 5-FU cream 5% under tape over 12 weeks resulted in an 85% clearance rate.
The average time to cure occurred at 9 weeks of treatment.
Blunt dissection
Blunt
dissection is a surgical alternative that is fast, effective (90% cure rate),
and usually non scarring. It is superior to both electrodesiccation-curettage
and excision because normal tissue is not disturbed.
Imiquimod
The
immunomodulating drug imiquimod is more effective on thicker keratinized
(nongenital) skin when occluded and used in combination with cryotherapy or a
keratolytic agent. It is essential to debride the thick scale before applying
imiquimod. The patient applies the cream daily and covers with tape (for ≥12
hours) to enhance penetration.
Laser
Various
lasers are available for treating resistant warts. The procedure is expensive
and at times painful.
Caustic (trichloroacetic acid)
This technique
is occasionally used to treat warts that have recurred after treatment with
other techniques and is occasionally used as initial therapy. Like keratolytic
therapy, repeated application is required. Home application of acids is too
dangerous; therefore weekly or biweekly visits to the clinician’s office are
required. A number of acids may be used (bichloroacetic acid, trichloroacetic
acid).
Treatment is
as follows: The excess callus is pared. The surrounding area is protected with
petrolatum. The entire lesion is coated with acid, and the acid is worked into
the wart with a sharp toothpick. This procedure is repeated every 7 to 10 days.
Formalin
This may be considered for resistant cases. Surrounding
skin is prone to be affected by an irritant dermatitis. Mosaic warts or other
large involved areas may be treated with daily soaking for 30 minutes in 4%
formalin solution, using soft paraffin as a barrier application to protect more
sensitive skin. The formalin is virucidal, but also dries and hardens the skin.
The firm, fixed tissue is pared before subsequent soaking.
Cryosurgery
Cryosurgery
on the sole may produce a deep, painful blister and interfere with mobility.
Cryotherapy is equally effective when applied with a cotton wool bud or by
means of a spray. A surgical blade is used to debulk the wart before freezing.
Liquid nitrogen is applied until ice-ball formation has spread from the center
to include a margin of 2 mm around each wart. A double or triple freeze-thaw
cycle may be more effective than a single freeze. Treatment is given every 3
weeks for up to 3 months.
Plane warts (flat warts)
Flat warts (verruca plana) are
skin-colored or pinkish to brown, relatively smooth-surfaced, slightly
elevated, flat-topped round or polygonal in shape and vary in size from 1 to 5
mm in diameter, the thickness of the lesion is 1 to 2 mm. Plana warts are
mainly caused by HPV-3 and HPV-10. Children and young adults are primarily
affected. Sun exposure appears to be a risk factor for acquiring flat warts. Typical
sites of involvement are around the mouth, on the forehead, on the backs of the
hands, and on shaved areas such as the beard area in men and the lower legs in
women. In the beard
and on the legs, they spread by inoculation through shaving. They are generally
multiple and are grouped. A useful
finding is the tendency for the warts to Koebnerize, a line of flat warts may
appear as a result of scratching.
Treatment
Flat warts
present a special therapeutic problem. Imiquimod 5% cream applied every day or
every other day may be effective. Freezing of individual lesions with liquid
nitrogen or applying a very light touch with the electrocautery needle may be
performed for patients who are concerned with cosmetic appearance and desire quick
results. Treatment with 5-fluorouracil cream applied once a day for a month may
produce dramatic clearing of flat warts; it is worth the attempt if other
measures fail. Persistent hyperpigmentation may occur following 5-fluorouracil
use. This result may be minimized by applying the cream to individual lesions
with a cotton-tipped applicator. Warts may reappear in skin inflamed by
5-fluorouracil.
A study of
patients with recalcitrant facial plana (age range from 5 to 35 years) reported
that oral isotretinoin 0.5 mg/kg/day prescribed for 2 months resulted in a
complete response in 73% of patients.
Filiform and digitate warts
These growths consist of a few or several fingerlike,
flesh-colored projections emanating from a narrow or broad base and occur mainly
in males. These are most commonly
observed on the face about the mouth, beard, eyes, and ala nasi and neck. Digitate
warts appear in the nostrils in young children from nose picking. Digitate
warts, often in small groups, also occur on the scalp in both sexes, where they
are occasionally confused with epidermal naevi. Shaving spreads the virus over
wide areas of the beard.
Treatment
These are
the easiest warts to treat. Those with a very narrow base do not require
anesthesia. A firm base is created by retracting the skin on either side of the
wart with the index finger and thumb. A curette is then firmly drawn across the
base, removing the wart with one stroke. Bleeding is controlled with gauze
pressure rather than by using Monsel’s solution, which is painful. This
technique is particularly useful for young children who refuse local anesthesia
with a needle. Light electrocautery is an alternative.
Butchers’ warts
Butcher’s warts, which earn their
name from their occurrence of hand warts in occupational handlers of meat,
poultry or fish where the skin is in prolonged contact with moist animal flesh.
They appear as extensive verrucous papules or
cauliflower-like lesions on the dorsal, palmar or periungual aspects of
the hands and fingers, and have a high risk of recurrence even after successful
treatment. These warts are associated with HPV-7. HPV-7 is very rarely found in
warts in the general population (less than 0.3%), and in butchers it is found
only on the hands where there is direct contact with meat.
Disease course and prognosis of warts
In Immunocompetent individuals, cutaneous HPV infections
usually resolve spontaneously, without therapeutic intervention. With host
defense defects, cutaneous HPV infections may be very resistant to all
modalities of therapy. Spontaneous clearance of warts can occur at any time
from a few months to years and it is impossible to offer a reliable prognosis
in the individual patient. Clearance is usually quicker in children than adults.
In primary school‐aged
children, about half will clear within a year. About 65% of warts disappear
spontaneously within 2 years and 95% within 4 years.
Regression of common warts is asymptomatic and occurs
gradually over several weeks, usually without blackening. Regression of plane
warts is usually heralded by inflammation in the lesions, causing itch,
erythema and swelling, such that previously unnoticed warts may become evident.
Depigmented haloes may appear around the lesions. Resolution is usually
complete within a month.
Regression of plantar warts is occasionally clinically
inflammatory, and often culminates in blackening from thrombosed blood before
the lesion separates, but in many cases there is apparent drying and gradual
separation.
Malignant change in periungual warts is extremely rare
but has been reported in immunosuppression. HPV‐16 or other high‐risk genital virus types are
frequently found in such lesions.
Investigations
Clinical diagnosis of warts is often sufficient, but atypical,
subclinical or dysplastic lesions may need laboratory confirmation of HPV
infection. Methods available are as follows:
1. Histology.
2. Immunohistochemistry
or immunocytochemistry using type‐common
or type‐specific antibodies.
3. DNA
in situ hybridization.
4. PCR
for HPV DNA.
Management
There is currently no specific antiviral therapy
available to cure HPV infection. Because of the benign and self-limited nature
of warts, treatments that cause scarring should be avoided. There is no
evidence that aggressive treatment results in a better long-term outcome, and
temporary interruption of therapy is an option. Common warts often regress
spontaneously in children and therefore may not require treatment.
Gentle reduction of the layer of hyperkeratotic epidermis
by regular filing or paring down will usually make the lesion more comfortable.
Advice on simple measures to limit the spread of the
infection will be appreciated. Plantar warts should be covered with adequate
plaster strapping, or the foot with close‐fitting
rubber ‘verruca socks’, or pool‐side
sandals worn at swimming pools or communal baths or showers. The spread of
periungual and perioral warts is often due to biting of nails or periungual
skin, and this practice must be strongly discouraged; the use of adhesive
strapping after the application of a ‘wart paint’ helps to break the habit. In
addition, simple domestic hygiene, such as cleaning of baths after use and
avoidance of shared towels, may be advised.
Treatment often requires physical or immune mediated
destruction of infected epithelial cells. Combination therapies are often used.
Whatever method is used there will be failures and
recurrences. The best clinical guide to cure is the restoration of normal
epidermal texture, including the epidermal ridge pattern where appropriate.
First line
Topical treatments that can be used by the patient at
home can be regarded as first line.
Salicylic acid
The keratolytic effect of salicylic acid helps to reduce
the thickness of warts and may stimulate an inflammatory response. Daily
application of a preparation containing 12–26% salicylic acid, possibly with
additional lactic acid, in a quick‐drying
collodion or acrylate base (1:1:4), if possible with
occlusion and after removing the thickened stratum corneum, for up to 12 weeks, is the treatment
of first choice for common and plantar warts, which results in regression in
two-thirds of patients. Application of petrolatum to the surrounding normal
skin protects against the corrosive effect of the concentrated acid. Weight
pressure causes deep inward growth of plantar warts, and the resulting pain can
be reduced by repeated shaving of the hyperkeratotic surface to a level at
which capillary bleeding occurs. Removal of surface keratin and the remnants of
the previous application by gentle use of a pumice stone, emery board or foot
file are a helpful. However, overenthusiastic abrasion is a common, which may
enhance spread of the virus by inoculation into adjacent skin. It is
conceivable that abrasion of warts may help to stimulate an immune response.
Accurate application of a salicylic acid preparation, avoiding normal skin, may
require a fine applicator such as a sharpened matchstick or a cocktail stick,
and will minimize subsequent local discomfort. After drying, a whitish deposit
remains. Penetration into thick keratin, as on the sole, is enhanced by
adhesive plaster occlusion, which promotes maceration of the keratin layer and
a reduction in barrier function.
Adhesive plaster containing 40% salicylic acid is useful
for plantar warts. It is applied daily, cut to the shape of the wart and held
in place by plain adhesive plaster. Salicylic acid ointment 40% is also
effective.
The regular use of salicylic acid preparations on warts
may need to be continued for at least 3 months and often longer.
The use of salicylic acid on feet with neuropathy or
impaired circulation, as in diabetics, must be cautious due to the risk of
producing ulceration which may not heal.
Topical 5‐fluorouracil
A 5% cream of 5‐fluorouracil
(5‐FU) carefully applied daily
under occlusion for a month can be effective, but hyperpigmentation as well as
erythema and erosion can be limiting side effects and, if used periungually,
may cause onycholysis.
Caustics
Application of TCA 70–90% solution is a commonly utilized
office-applied therapy that results in local tissue destruction. Although
scarring may occur following dermal injury, TCA has the advantage of a complete
lack of systemic toxicity and it can be used during pregnancy.
Retinoic acid
This treatment topically may be tried in plane warts. In
a study of children with plane warts treated with 0.05% tretinoin cream, 85%
cleared their warts. The therapy can be effective in immunosuppressed patients.
Second line
Treatments that are physician administered, more time
consuming or expensive can be classed as second line.
Cryotherapy
Liquid nitrogen produces the coldest freeze and is
commonly used in hospital practice, applied either by a cotton wool bud or from
a cryospray. Both methods seem to be equally effective.
Any thick keratin should be pared off, especially in
plantar warts, and the surface dried before freezing begins. In standard
treatment, the application is continued until a rim of iced tissue (easily seen
as a white discoloration) about 1 mm in width 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. Longer freezing
(over 25 s of continual freeze) is more likely to leave scarring, possibly
damage underlying structures and not improve clearance rates. A gentler or
‘traditional’ freeze involves freezing until the 1 mm rim of frozen skin is
visible and then stopping. This milder method seems to be 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. As well as
damaging cells, cryotherapy may lead to clearance by stimulating the development
of an immune response.
The response to treatment with cryotherapy is comparable
or slightly better than that achieved with salicylic acid. Treatment repeated
every 3 weeks gives a 30–70% cure rate for hand warts after 3 months. More
frequent treatments may improve responses although will induce more pain, and
longer intervals are less effective. If this fails, or when a wart is
particularly painful or deep, or both, as may occur over a bony prominence on
the foot, more prolonged application, typically up to 30 s, perhaps repeated
after thawing, may be used to achieve a greater destructive effect at the cost
of significantly greater blistering and pain. For such treatment, local or even
general anesthesia may be considered. The common practice of dipping cotton
buds for different patients into a common flask containing the liquid nitrogen
may carry a risk of cross‐infection.
The main disadvantage of freezing is pain. This is
unpredictable and surprisingly variable between patients, but in some cases,
especially with longer freezing times, it may be severe and persist for many
hours or even a few days. Oral aspirin and strong topical steroids may help.
Swelling of the treated area and the surrounding skin begins within minutes,
and where tissues are lax as in the periorbital area it may be dramatic. A
blister, sometimes hemorrhagic, may ensue within a day or two. After the usual
short freezing times, the reaction will be likely to have resolved within 2–3
weeks. Scarring is unlikely with freezing times under 30 s. Occasionally,
damage to underlying tissues may result, for example to a tendon or the nail
matrix, and excessive freezing times should be avoided over nerves, for example
on the sides of the fingers. Depigmentation may occur, and can be a significant
cosmetic disadvantage in patients with darkly pigmented skin.
Laser
The pulsed dye laser has been used to treat warts with
cure rates of approximately 32–75%, using a minimum of two treatments. Other
lasers such as the erbium: yttrium aluminium garnet (Er: YAG) and the neodymium:aluminium
garnet (Nd: YAG) can also be used.
The carbon dioxide laser has a greater risk of producing
scarring but has been used to treat a variety of different forms of wart, both
cutaneous and mucosal. It can be effective in eradicating some difficult warts,
such as periungual and subungual warts which have been unresponsive to other
treatments. Clearance of cutaneous warts at 12 months is reported to be 55–70%.
Carbon dioxide laser therapy is well tolerated, but can cause significant
postoperative pain and hypertrophic scarring. Infectious virus can be detected
in the plume during carbon dioxide laser use, so operators mask and air
extraction system are advised.
Laser treatment for other indications has been associated
with the spread of facial warts.
Surgery
Excision is usually to be avoided since scarring is
inevitable and recurrences of the wart in the scar are frequent. However,
curettage can be effective as treatment for filiform warts. Curettage and
cautery/electrocoagulation, usually in combination, may be used for painful or
resistant warts, but carry a risk of scarring.
Third line
Third line treatments are used in severe and recalcitrant
infection and also when first and second line treatments have produced no
effect.
Podophyllin and podophyllotoxin
Podophyllin and purified podophyllotoxin act as
antimitotics. They are used mainly for the treatment of ano‐genital warts but can also
have an effect in cutaneous warts, although penetration into keratinized skin
may be poor.
Podophyllin and podophyllotoxin are contraindicated in
pregnancy and are not licensed for use in children.
Imiquimod
Imiquimod is an imidazoquinoline compound with
immunomodulatory activities that has been approved by the US Food and Drug
Administration (FDA) for the topical treatment of condylomata acuminata.
Imiquimod has been shown to interact with Toll-like receptors 7 and (to a
lesser degree) 8, resulting in activation of cytokine secretion from
monocytes/macrophages (including interferon-α,
interleukin-12 and tumor necrosis factor-α) as
well as stimulation of antigen-presenting dendritic cells.
Therapeutic efficacy of imiquimod 5% cream
has also been described for persistent cutaneous warts,
although poor penetration through the keratinized surface may necessitate twice
daily application for up to 24 weeks. Occlusion
and/or concurrent use of salicylic acid or cryotherapy may increase imiquimod’s
penetration through the stratum corneum, which is especially important in acral
sites. Butchers’ warts, facial filiform warts and plane warts may all
respond. Side effects of imiquimod include application site reactions
(inflammation, erosion) that may require treatment-free periods, with a small
risk of causing vitiligo‐like
depigmentation. Imiquimod therapy is often more costly than other treatment
options.
