Human papillomavirus (HPV) infections are very common, occurring in a worldwide distribution,

affecting all ages and lasting months or years. The majority of individuals will have at least one infection
with the virus during the course of a lifetime, although theseverity and duration of the disease will
depend, to a large extent, on the immune response raised againstthe virus-infected cells.The clinical
disease caused by the virus is also dependent on the viral genotype and the body site. Whereas skin and
mucosal warts are benign and induced by one of several different types according to body site,
premalignancies and invasive cancer of the anogenital area or oropharynx are associated with other, so-
called high-risk, HPV types (Table 167-1).
VIROLOGY
The papillomaviruses form a large group of closely related viruses, defined by their host range. HPVs
only infect humans and, in particular, epithelial keratinocytes. In experimental systems, the virus does
not infect keratinocytes in monolayer tissue culture.Papillomaviruses are DNA viruses with each virus
particle or virion consisting of a nonenveloped icosahedral capsid containing the double-stranded
genetic material as a circular genome (Fig. 167-1). The virus is much smaller, both in particle size and
length of genetic material, than other common viruses that infect skin such as herpes simplex virus and
molluscum contagiosum virus. The genes are all transcribed in one direction from one DNA strand,
leading to the production of 5 to 6 early (E) proteins involved in DNA replication, cell cycle control and
immune evasion; and 2 late (L) proteins, L1 and L2, that form the outer shell or capsid (Fig. 167-2).The
virus is shed from the surface of the skin or mucosa within sloughed, dead keratinocytes. New infection
occurs when the virus particle contacts the basal epidermal keratinocyte, presumed to be via small
microabrasions in the skin or mucosa. Maceration of skin can increase the chance of infection because
of impairment of barrier function. Cell entry depends on an initial adherence of the virion to the cell via
heparin sulphate and α6-integrins,1,2 although the full process of receptor binding leading to
internalization by endocytosis has not yet been clarified. Within a stem cell or transit amplifying cell of
the basal layer, the virus is maintained in low copy number. It is carried to the surface in daughter cells,
producing, as it goes, the early viral proteins. High-volume viral DNA amplification and L1 and L2 protein
production occurs in the upper layers, with formation of completely new virus particles in the granular
layer. The switch to capsid protein production depends on a change in splice site usage in the early
genes.The E6 and E7 proteins are pivotal to the process of viral genome amplification, which also
depends on the E1 and E2 proteins. The viral E1^E4 protein can interact with keratin filaments,
weakening cytoplasmic structure and potentially facilitating virus particle release at the surface.infect
skin such as herpes simplex virus and molluscum contagiosum virus. The genes are all transcribed in one
direction from one DNA strand, leading to the production of 5 to 6 early (E) proteins involved in DNA
replication, cell cycle control and immune evasion; and 2 late (L) proteins, L1 and L2, that form the outer
shell or capsid (Fig. 167-2).The virus is shed from the surface of the skin or mucosa within sloughed,
dead keratinocytes. New infection occurs when the virus particle contacts the basal epidermal
keratinocyte, presumed to be via small microabrasions in the skin or mucosa. Maceration of skin can
increase the chance of infection because of impairment of barrier function. Cell entry depends on an
initial adherence of the virion to the cell via heparin sulphate and α6-integrins,1,2 although the full
process of receptor binding leading to internalization by endocytosis has not yet been clarified. Within a
stem cell or transit amplifying cell of the basal layer, the virus is maintained in low copy number. It is
carried to the surface in daughter cells, producing, as it goes, the early viral proteins. High-volume viral
DNA amplification and L1 and L2 protein production occurs in the upper layers, with formation of
completely new virus particles in the granular layer. The switch to capsid protein production depends on
a change in splice site usage in the early genes. The E6 and E7 proteins are pivotal to the process of viral
genome amplification, which also depends on the E1 and E2 proteins. The viral E1^E4 protein can
interact with keratin filaments, weakening cytoplasmic structure and potentially facilitating virus particle
release at the surface. There are more than 150 HPV types, defined according to the DNA sequence
within the L1 gene.A virus is defined as a distinct type if there is greater than 10% dissimilarity from
other known HPVs in the DNA of this region. The HPVs have been grouped, according to phylogeny, into
five genera: alpha, beta, gamma, mu, and nu (see Table 167-1). HPVs that are not found in malignancies
or premalignancies are termed low-risk types, and those found in invasive or preinvasive disease are
called high-risk types. The high-risk anogenital HPVs fall into the large alpha genus. High-risk genital HPV
types can integrate within the host cell genome, and the maintained expression of their E6 and E7
proteins has oncogenic effects on cell division and cell function. These E6 and E7 proteins affect cell
cycle control and apoptosis via interaction with ubiquitin ligases, telomerase, and several other cellular
pathways.In the process of integration, the E2, E4, L2, and to a lesser extent the L1 regions of the
genome are frequently disrupted. In malignant lesions, late proteins and virus particles are rarely, if ever
found, although episomal (nonintegrated) viral DNA may be maintained in preinvasive disease

EPIDEMIOLOGY

Infection with HPV occurs throughout the world and in all ages. Benign cutaneous warts are most
common in childhood and into the 20s, with 30% to 70% of school-age children having skin warts,7,8 but
anogenital warts, which are usually spread via sexual contact, are most common in early adult life. In
children, anogenital warts should raise consideration of sexual abuse, although HPV types that cause
common warts may often be found in warts of prepubertal children.Squamous cell malignancy,
associated most strongly with the high-risk anogenital HPV types, usually only develops after an
infection has persisted for several years.Spread of infection can be via direct contact, but the virus
particles, released from epithelial surfaces as keratinocytes are shed, can remain present in the
environment for an unknown duration and may later lead to infection in another individual.10 Even
after infection, it can take months before a visible wart appears.After being established, infection can
spread on the surface to adjacent skin.Protection against a new infection is via neutralizing antibodies.
The anti-HPV vaccines, produced as the L1 capsid protein assembled into virus-like particles, lead to a
humoral response against the virus particle. In natural infection, seroconversion also occurs, but in this
situation, anti-HPV antibodies are not effective in the resolution of established infection. Clearance of
the virus from infected tissue is dependent on a cell-mediated immune response, and as yet there is no
available, effective therapeutic vaccine. Most warts in children will clear within 2 years,8 but in a
minority of otherwise well individuals, warts can spread and persist longer.In individuals with long-term
immune compromise, especially those with inherited immunodeficiency and transplant recipients
receiving high-dose immune suppression, warts and malignancy caused by HPVs can be a major
problem. Five years after renal transplant, it is estimated that approximately 90% of patients have
warts13 caused by the HPV types that cause warts in healthy people.14 Many other HPV types, mainly
from the beta papilloma viruses (PVs), can be detected by polymerase chain reaction (PCR) on the skin
(normal or lesional) of transplant recipients.15-17 Using such sensitive methods, these virus types are
also found on the skin and in the hair follicles of healthy individuals.

SKIN HUMAN PAPILLOMAVIRUS INFECTIONS

CUTANEOUS WARTS

CLINICAL FEATURES

Viral warts are initially asymptomatic and often unnoticed but grow to form well-defined, thickened,
hyperkeratotic lesions (Fig. 167-3). These are often unsightly and may cause pain if sited at pressure
points or if they crack and bleed. Walking and use of the hands can be affected according to the site of
the warts (Fig. 167-4). Common sites are the hands and feet, especially at areas of minor trauma, such
as knuckles or around nails (Fig. 167-5). On the dorsal aspects of hands or feet or on the limbs, warts are
exophytic or “cauliflower shaped” (Fig. 167-6), but on soles or palms, they are often relatively flat to the
surface with a more endophytic growth pattern. The term mosaic warts is applied to a group of small
adjacent but relatively flat warts on the sole (Fig. 167-7). Smaller and flatter warts, often on the backs of
the hands or face, may be plane warts (also called verruca plana; see Fig. 167-8). On the face and limbs,
warts can sometimes have a small base and longer, fingerlike projections, a morphological type called
filiform warts (Fig. 167-9).
Warts are most common in children and young adults but can occur at any age.

ETIOLOGY AND PATHOGENESIS

Common warts are caused most frequently by HPV-2/27/57, HPV-4, and HPV-1 (soles and palms) and
less frequently by HPV-7 (called butcher’s warts). Flat warts are usually caused by type 3 or 10 or very
occasionally type 28.Butchers’ warts were originally described in meat workers, whose hands were in
direct contact with wet meat. The finding of HPV-7 is not limited to these warts but has been reported
rarely in hand warts, face warts, and HIV infection.HPV-1 warts are found only on the palms and soles
and may be called myrmecia. They produce higher amounts of new particles compared to other
cutaneous types. Some unusual HPV types, HPV-57 and -60, have been found in epidermoid plantar
cysts of Japanese patients.20

DIAGNOSIS AND HISTOLOGY

Warts can usually be diagnosed clinically without the need for histologic confirmation. Paring the
surface of a wart will reveal capillary loops close to the surface and often causes bleeding. These
capillaries often thrombose and then appear as black dots (see Fig. 167-3).The histology is of acanthosis,
hypergranulosis, and hyperkeratosis of the epidermis. The keratinocytes of the upper granular layer may
show koilocytosis with clear cytoplasm and a dense twisted nucleus (Fig. 167-10). Detection of HPV DNA
by PCR or in situ hybridization will confirm the diagnosis but is not in use for standard clinical care. The
differential diagnoses are listed in Table 167-2.

CLINICAL COURSE, PROGNOSIS, AND MANAGEMENT

Untreated, warts in young people usually clear spontaneously within about 2 years, and only a few
remain at 4 years. In adults, clearance can often be very slow, with warts persisting for years. Large and
widespread warts (Fig. 167-11) are common in immunosuppressed individuals such as transplant
recipients and in children or adults with genetic immunodeficiency (Table 167-3). In these cases, large
areas of skin may be affected as well as mucous membranes, and the condition may be called
generalized verrucosis.Treatment can speed clearance in warts but often fails in immunosuppressed
individuals.There is no virus-specific anti-viral therapy for warts, so available treatments aim to (1)
damage the infected epithelium and debulk the lesions, (2) have some effect on the virus life cycle, or
(3) to stimulate an immune response (Table 167-4). It is possible that most treatments may have more
than one effect. Recent reviews of treatments for warts give more detail of the spectrum and potential
efficacy of the range of treatments used today.The most commonly used treatments for warts are
destructive and include topical applications with salicylic acid and physical treatment with cryotherapy.
For the greatest effect, treatment needs to be repeated and of long duration. It is worth informing
patients that regular treatment for at least 3 months or longer is likely to be required. Even with
assiduous treatment, the clearance rate for most common treatments is 60% to 70% compared with
30% clearing with placebo.Salicylic acid (12%–17% in a paint or up to 50% in plasters or an ointment) is
applied to the wart, which can be rubbed down or pared gently beforehand. Occlusion with an adhesive
dressing after application may improve clearance. Daily treatment is recommended, but as the salicylic
acid gradually destroys and so removes the keratin layer, the wart or more likely surrounding tissue can
become sore, and treatment may need to be reduced in frequency. For this reason, salicylic acid in these
strengths is not recommended for facial or anogenital warts. Cryotherapy (see Chap. 206) with liquid
nitrogen is best used as a double freeze, repeated every 3 weeks for at least 3 months. This is a painful
treatment and often not tolerated to warts around nails, on the soles, or by children.Other treatments
that damage or destroy the infected epithelium include caustics such as silver nitrate, phenol, mono- or
trichloroacetic acid, and surgical approaches with laser or excisional surgery. Plane warts require less
keratolysis, and treatment with other topical applications such as the immune modulator imiquimod can
be effective.Severe proliferative warts may be helped but sometimes only for the duration of the
treatment by treatments that reduce or slow epidermal growth, such as podophyllotoxin or retinoids.In
immune compromise, clearance of warts, either spontaneously or with treatment, is rare and treatment
is usually aimed at measures to reduce wart bulk, maintain function, and avoid pain.
EPIDERMODYSPLASIA VERRUCIFORMIS AND EPIDERMODYSPLASIA VERRUCIFORMIS–LIKE
SYNDROMES

CLINICAL FEATURES

Epidermodysplasia verruciformis (EV) is a rare, heritable skin disorder with a mild underlying primary
immunodeficiency. The signs of EV become apparent in late childhood or adolescence, but in the
absence of a family history, diagnosis may be delayed until a decade or two later. Widespread flaky,
scaly, or flat warty lesions are seen on the face, hands, and forearms and other sun-exposed sites (Fig.
167-12). There is often erythema, hyperpigmentation, or more rarely hypopigmentation of lesions, and
there can be confusion with pityriasis versicolor and plane warts. In early adult life, actinic keratoses,
Bowen disease, and invasive squamous cell carcinoma (SCC) can develop at affected sites (Fig. 167-13).
Metastatic disease can follow. Patients with EV have a mild cell-mediated immune impairment.42 This is
often not obvious on clinical grounds because widespread susceptibility to other infections is not a
feature but can reduce susceptibility to contact allergy. A clinical appearance very similar to EV, called
acquired EV, may be seen after long-term immunocompromise from several causes

ETIOLOGY AND PATHOGENESIS

EV can be inherited, usually with an autosomal recessive pattern. The genes implicated most commonly
are EVER-1 and -2, which produce the transmembrane, zinc-containing proteins TMC6 and TMC8.A large
number of HPV types are associated with EV lesions and the clinically unaffected skin of patients.These
include HPV-3 and -10, the cause of plane warts, as well as the beta PVs, some of which are found in
SCCs and some of which are only found in benign lesions (see Table 167-1). Patients may also have warts
harboring the usual HPV types found in common warts.

DIAGNOSIS AND HISTOLOGY

Diagnosis may be made on a combination of clinical features and family history. Skin biopsy shows mild
acanthosis and hyperkeratosis. In some lesions, there may also be pallor or clearing of the cytoplasm of
the upper spinous layer keratinocytes, called ballooning, with small dense nuclei (so-called clear cells;
see Fig. 167-14). With sensitive HPV detection, the beta PVs are found most commonly.

CLINICAL COURSE, PROGNOSIS, AND TREATMENT

Treatments usually make little lasting difference, but short-term, cosmetic improvement can be
obtained by a number of approaches that remove the hyperkeratosis.42,43 Cryotherapy, topical salicylic
acid, 5-fluorourcil, and imiquimod have all been used with varying results.47,48 Photodynamic therapy
(PDT)49 or an oral retinoid, such as acitretin,50 can produce a useful improvement in lesions.To reduce
the risk of skin cancers, sun protection is important. Regular surveillance for SCC and early treatment of
suspicious lesions may avoid metastatic disease.

SQUAMOUS CELL CARCINOMA AND HUMAN PAPILLOMAVIRUS

Common warts in immunocompetent individuals are not forerunners of skin cancer. However, there are
a very few reports, usually in the setting of immunosuppression, of long-standing periungual warts
progressing into Bowen disease (full-thickness dysplasia) or invasive SCC.51 In such cases, the high-risk
anogenital HPV type, HPV-16, is usually present. Long-standing and slowly enlarging warty areas on the
soles, fingers, or anogenital skin can be a feature of carcinoma cuniculatum or verrucous carcinoma
(Buschke-Löwenstein tumour), in which the HPV types usually associated with anogenital warts, HPV-6
or -11, are occasionally detected.Skin SCCs on sun exposed skin are also found to contain a number of
EV-related beta HPV types, with a higher yield in the cancers of immunosuppressed individuals. These
HPVs are often found in normal skin of both immunocompetent and immunocompromised
individuals,16,18 and the exact role they play in the steps of carcinogenesis is still under debate.

MUCOSAL AND PERI-MUCOSAL HUMAN PAPILLOMAVIRUS INFECTIONS

ANOGENITAL WARTS

CLINICAL FEATURES

Warts can affect the vulva, vagina, cervix, penis, scrotum, perianal skin, and anal canal. They may
present singly but are usually found as multiple, well-defined papules or as flat or filiform lesions and
may grow into larger protuberant lesions (Fig. 167-15). The moist fold beneath an abdominal apron of
an obese patient is another site for these warts.55 On mucosal surfaces, they are often macerated and
appear pale, but on drier skin, they can become more obviously hyperkeratotic and hard. They may be
asymptomatic but can be itchy and uncomfortable and may be traumatized with movement or sexual
activity.

DIAGNOSIS
HPV-6 or -11 are the most common causative agents, but other HPV types are found with PCR analysis.
Anogenital warts produce less virus particles than cutaneous warts. For differential diagnosis, see Table
167-2.
CLINICAL COURSE, PROGNOSIS, AND TREATMENT

Anogenital warts are usually treated with a topical application as first-line therapy.56 Podophyllotoxin or
imiquimod are both self-applied treatments with a 50% to 70% clearance rate.57 Recurrence rates after
imiquimod treatment are slightly less than after podophyllotoxin.Other treatments in use include topical
trichloroacetic acid,59 sinecatechins from green tea,60 and physical therapies with cryotherapy, PDT,
laser, electrocautery, or surgery.
Since the introduction of the quadrivalent anti-HPV vaccine in 2007, there has been a recorded decrease
in presentation of genital warts or prevalence of HPV-6 and -11.61,62

ORAL WARTS

Warts can develop on the lips, in the oral cavity, and in upper respiratory tract and are usually regarded
as a sexually transmitted disease. Because of the moist site, they are usually macerated and can be flat
or cauliflower shaped (Fig. 167-16). The low-risk genital HPV types are the usual cause. Laryngeal warts
(laryngeal papillomatosis) can develop in childhood, probably caused by infection from the mother at
birth, and can affect speech and breathing.Oral warts are common in HIV infection and may worsen,
rather than improve, during antiretroviral therapy.

ANOGENITAL INTRAEPITHELIAL NEOPLASIA AND CANCER

CLINICAL FEATURES
Anogenital intraepithelial neoplasia (AGIN) includes dysplasia of the vulva (vulvar intraepithelial
neoplasia; see Fig. 167-17), vagina (vaginal intraepithelial neoplasia), cervix (cervical intraepithelial
neoplasia), penis (penile intraepithelial neoplasia), perianal skin, and anal canal (anal intraepithelial
neoplasia). The term Bowenoid papulosis has been used to describe the disorder, especially when the
lesions are pigmented and resemble seborrheic keratosis. AGIN may also present with velvety plaques,
white macerated, wartylesions or less distinct erythematous areas.

ETIOLOGY
The high risk HPV types, especially HPV-16, are associated with these disorders. Biopsy is essential for
diagnosis with the histology showing full-thickness epidermal dysplasia, classified as undifferentiated
intraepithelial neoplasia. Differentiated intraepithelial neoplasia occurs in association with chronic
inflammatory genital disease, such as lichen sclerosus, and histologically is a subtler basal dysplasia,
often with acanthosis and hyperkeratosis, and is not associated with HPV infection (see Chap. 64).
CLINICAL COURSE, PROGNOSIS, AND MANAGEMENT
Surgery is the treatment of choice for single lesions if the site is easily operable but may not be best for
multifocal or multicentric disease. Laser or topical immunotherapy with imiquimod offers an alternative
approach.Both the patient and physician need to be aware of the changes that could indicate malignant
change, and these include a persistent area of discomfort, an ulcer, or a frank tumor. It is estimated that
an individual with AGIN has an approximate 5% lifetime risk of developing cancer. Cancer can be the
presenting feature.

ORAL AND OROPHARYNGEAL SQUAMOUS CELL CARCINOMA

Silent infection with high risk HPVs within the mouth or throat can present later in life with
oropharyngealSCC. The traditional association of this malignancy with smoking and alcohol is being
replaced with a stronger association with HPV infection, especially in younger male patients. The
incidence of this malignancy is rising but should be reduced following the introduction of the anti-HPV
vaccine to male patients.