Human Papillomavirus Infections

Human papillomaviruses (HPV) are very widespread-to-ubiquitous in humans, causing

subclinical infection or a wide variety of benign clinical lesions on skin and mucous
membranes. They also have a role in the oncogenesis of cutaneous and mucosal
premalignancies [squamous cell carcinoma (SCC) and SCC in situ (SCCIS)] and
malignancies (invasive SCC). More than 150 types of HPV have been identified and are
associated with various clinical lesions and diseases (Table 25-2).

Table 25-2 Correlation of Human Papillomavirus Type with Disease

Disease

Associated HPV Types

Plantar warts

1,* 2, 4, 63

Myrmecia

60

Common warts

1,* 2,* 4, 26, 27, 29, 41, 57, 65, 77

Common warts of meat

handlers

1, 2,* 3, 4, 7,* 10, 28

Flat warts

3,* 10,* 27, 38, 41, 49, 75, 76

Intermediate warts

10,* 26, 28

Epidermodysplasia
verruciformis

2,* 3,* 5,* 8,* 9,* 10,* 12,* 14,* 15,* 17,* 19, 20, 21, 22, 23, 24,
25, 36, 37, 38, 47, 50

Condyloma acuminatum

6,* 11,* 30, 42, 43, 44, 45, 51, 54, 55, 70

Intraepithelial neoplasias
Unspecified

30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 69, 71

Low-grade

6,* 11,* 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, 74

High-grade

6, 11, 16,* 18,* 31, 33, 34, 35, 39, 42, 44, 45, 51, 52, 56, 58,
66,

Bowen's disease

16,* 31, 34

Bowenoid papulosis

16,* 34, 39, 42, 45, 55

Disease

Associated HPV Types

Cervical carcinoma

16,* 18,* 31, 33, 35, 39, 45, 51, 52, 56, 58, 66, 68, 70

Laryngeal papillomas

6,* 11*

Focal epithelial hyperplasia of 13,* 32*

Heck
Conjunctival papillomas

6,* 11,* 16*

Others

6, 11, 16, 30, 33, 36, 37, 38, 41, 48, 60, 72, 73

Most common associations.

High malignant potential.

NOTE: Additional

information on new HPV types can be found on the HPV Sequence Data
Base through the Internet (http://hpv-web.lanl.gov).
SOURCE: From RC

Reichman, in E Braunwald, AS Fauci, DL Kasper, SL Hauser, DL Lango,

JL Jameson (eds): Harrison's Principles of Internal Medicine, 15th ed. New York, McGrawHill, 2001.
Three clinical manifestations of cutaneous HPV infections occur commonly in the general
population: common warts, plantar warts, and flat warts. Common warts represent
approximately 70% of all cutaneous warts, occurring in up to 20% of all school-age children.
Plantar warts are common in older children and young adults, accounting for 30% of
cutaneous warts. Flat warts occur in children and adults, accounting for 4% of cutaneous
warts. Common in butchers, meat packers, and fish handlers are butcher's warts. Oncogenic
HPV can cause SCCIS and invasive SCC in immunocompromised hosts, especially in those
with HIV disease, solid organ transplant recipients, and those with epidermodysplasia
verruciformis (EDV).
The most common presentation of mucosal HPV infection is condyloma acuminatum (genital
wart), which is the most prevalent sexually transmitted disease (see Section 27). 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 anogenital warts or recurrent respiratory papillomatosis (RRP) after
aspiration of the virus into the upper respiratory tract.
Etiology
Papillomaviruses are double-stranded DNA viruses of the papovavirus class which infect
most vertebrate species with exclusive host and tissue specificity. They infect squamous
epithelia of skin and mucous membranes. Clinical lesions induced by HPV and its natural
history are largely determined by HPV type. HPV are normally grouped according to their

pathologic associations and tissue specificityeither cutaneous or mucosal. The 23 mucosalassociated HPV can be further subgrouped according to their risk of malignant
transformation. New types of HPV are defined as possessing <90% homology to known types
in six specified early and late genes.
Human Papillomavirus: Cutaneous Infections

Certain human HPV types commonly infect keratinized skin. Cutaneous warts are a discrete
benign epithelial hyperplasia with varying degrees of surface hyperkeratosis 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.
Synonym: Verruca, myrmecia.
Epidemiology and Etiology
Etiology
See Table 25-2.
Transmission
Skin-to-skin contact. Minor trauma with breaks in stratum corneum facilitates epidermal
infection. Contagion occurs in groupssmall (home) or large (school gymnasium).
Other Factors
Immunocompromise, such as occurs in HIV disease or after iatrogenic immunosuppression
with solid organ transplantation, is associated with an increased incidence of and more
widespread cutaneous warts. Occupational risk associated with meat handling.
Inheritance
EDV: most commonly autosomal recessive.
History
Duration of Lesions
Warts often persist for several years if not treated.
Symptoms
Cosmetic disfigurement. Plantar warts act as a foreign body and can be quite painful during
normal daily activities such as walking if located over pressure points. More aggressive
therapies such as cryosurgery often result in much more pain than that caused by the wart
itself. Bleeding, especially after shaving.

Physical Examination
Skin Lesions
Verruca Vulgaris (Common Warts)
Firm papules, 1 to 10 mm or rarely larger (Fig. 25-9), hyperkeratotic, clefted surface, with
vegetations (Fig. 25-10). Palmar lesions disrupt the normal line of fingerprints. Return of
fingerprints is a sign of resolution of the wart. Characteristic "red or brown dots" (Figs. 25-9
and 25-10) are better seen with hand lens and are pathognomonic, representing thrombosed
capillary loops. Isolated lesion, scattered discrete lesions. Annular at sites of prior therapy.
Occur at sites of trauma: hands, fingers, knees. Butcher's warts: large cauliflower-like lesions
on hands of meat handlers. Filiform warts have relatively small bases, extending out with
elongated cap (Fig. 25-11).

Figure 25-9

Verruca vulgaris: periungual Hyperkeratotic papules located periungually on the dorsum

of a finger. Similar lesions were present on all fingers of both hands. All modalities of
therapy had failed. The warts resolved with microinjections of bleomycin. Note, black and
brown dots.

Figure 25-10

Verruca vulgaris in an immunocompromised individual Large, very thick, fissured,

painful periungual and subungual warts are present on two fingers of a 20-year-old male
treated with immunosuppressive drugs after renal transplantation. Similar lesions were also
present on multiple toes.

Figure 25-11

Filiform warts Multiple, elongated keratotic papules on the face of a child; note the

clustering on the eyelids.

Verruca Plantaris (Plantar Warts)

Early small, shiny, sharply marginated papule (Fig. 25-12) plaque with rough hyperkeratotic
surface, studded with brown-black dots (thrombosed capillaries). As with palmar warts,
normal dermatoglyphics are disrupted. Return of dermatoglyphics is a sign of resolution of
the wart. Warts heal without scarring. Therapies such as cryosurgery and electrosurgery can
result in lifelong scarring at treatment sites. Tenderness may be marked, especially in certain
acute types and in lesions over sites of pressure (metatarsal head). Confluence of many small
warts results in a mosaic wart (Fig. 25-9). "Kissing" lesion may occur on opposing surface of
two toes. Plantar foot, often solitary but may be three to six or more. Pressure points, heads of
metatarsal, heels, toes.

Figure 25-12

Verruca plantaris Confluent, skin-colored, verrucous papules, forming a mosaic, disrupting

the normal dermatoglyphics of the plantar foot. The thrombosed capillaries (brown dots)
differentiate the lesion from a corn (an often painful, translucent, yellowish, keratotic
granule) and a callus (a poorly demarcated, hyperkeratotic plaque with normal
dermatoglyphics at pressure sites). The patient had some degree of immunocompromise
associated with prior non-Hodgkin's lymphoma. Warts nearly resolved with oral acitretin.

Verruca Plana (Flat Warts)

Sharply defined, flat papules (1 to 5 mm); "flat" surface; the thickness of the lesion is 1 to 2
mm (Fig. 25-13). Skin-colored or light brown. Round, oval, polygonal, linear lesions
(inoculation of virus by scratching). Lesions that arise after trauma may have a linear
arrangement. Occur on face, beard area, dorsa of hands, shins.

Figure 25-13

Verruca plana (flat warts) Flat-topped, pink papules with sharp margination and minimal
hyperkeratosis on the dorsa of the hands and fingers.

Epidermodysplasia Verruciformis

Rare condition. Flat-topped papules. Pityriasis versicolor-like lesions, particularly on the

trunk. Color: skin-colored, light brown, pink, hypopigmented. Lesions may be numerous,
large, and confluent. Seborrheic keratosis-like and actinic keratosis-like lesions. SCC, in situ
and invasive. Lesions often become confluent, forming large maplike areas. Linear
arrangement after traumatic inoculation. Distribution: face, dorsa of hands, arms, legs,
anterior trunk. Premalignant and malignant lesions arise most commonly on face.
HIV Disease, Iatrogenic Immunosuppression
HPV-induced warts are common and may be difficult to treat successfully. Some have
atypical histologic features and may progress into SCC.
Differential Diagnosis
Verruca Vulgaris
Molluscum contagiosum, seborrheic keratosis, actinic keratosis, keratoacanthoma, SCCIS,
invasive SCC.
Verruca Plantaris
Callus, corn (keratosis) have no thrombosed capillary loops, exostosis.
Verruca Plana
Syringoma (facial), molluscum contagiosum.
Epidermodysplasia Verruciformis
Pityriasis versicolor, actinic keratoses, seborrheic keratoses, SCC, basal cell carcinoma.
Laboratory Examination
Dermatopathology
Acanthosis, papillomatosis, hyperkeratosis. Characteristic feature is foci of vacuolated cells
(koilocytosis), vertical tiers of parakeratotic cells, foci of clumped keratohyaline granules.
Diagnosis
Usually made on clinical findings. In the immunocompromised host, HIV-induced SCC at
periungual sites or anogenital region should be ruled out by lesional biopsy.
Course and Prognosis
In immunocompetent individuals, cutaneous HPV infections usually resolve spontaneously,
without therapeutic intervention. In immunocompromised individuals, cutaneous HPV
infections may be very resistant to all modalities of therapy. In EDV, disease starts at 5 to 7
years of age; lesions appear progressively, becoming widespread in some. 30 to 50% of

individuals with EDV develop malignant cutaneous lesions on areas of skin exposed to
sunlight.
Management
Goal

Aggressive therapies, which are often quite painful and may be

followed by scarring, are usually to be avoided because the natural
history of cutaneous HPV infections is for spontaneous resolution in
months or a few years. Plantar warts that are painful because of their
location warrant more aggressive therapies.

Patient-initiated
therapy

Minimal cost; no/minimal pain.

For small lesions 1020% salicylic acid and lactic acid in collodion.
For large lesions

40% salicylic acid plaster for 1 week, then application of salicylic acid
lactic acid in collodion.

Imiquimod cream At sites that are not thickly keratinized, apply half-strength 3 times per
week. Persistent warts may require occlusion. Hyperkeratotic lesions on
palms/soles should be debrided frequently; Imiquimod used alternately
with a topical retinoid such as tazarotene topical gel may be effective.
Hyperthermia for Hyperthermia with hot water (113F) immersion for 1/2 to 3/4 h two or
verruca plantaris
three times weekly for 16 treatments is effective in some patients.
Clinician-initiated Costly, painful.
therapy
Cryosurgery

If patients have tried home therapies and liquid nitrogen is available,

light cryosurgery using a cotton-tipped applicator or cryospray, freezing
the wart and 1 to 2 mm of surrounding normal tissue for approximately
30 s, is quite effective. Freezing kills the infected tissue but not HPV.
Cryosurgery is usually repeated about every 4 weeks until the warts
have disappeared. Painful.

Electrosurgery

More effective than cryosurgery, but also associated with a greater

chance of scarring. EMLA cream can be used for anesthesia for flat
warts. Lidocaine injection is usually required for thicker warts,
especially palmar/plantar lesions.

CO2 laser surgery May be effective for recalcitrant warts, but no better than cryosurgery or
electrosurgery in the hands of an experienced clinician.
Surgery

Single, nonplanatar verruca vulgaris:curettage after freon freezing;

surgical excision of cutaneous HPV infections is not indicated in that
these lesions are epidermal infections.