Viral infections-Human papillomaviruses infection

Major Types of viruses thatMajor Types of viruses that
affect the skin:affect the skin:
 HUMAN PAPILLOMAVIRUSESHUMAN PAPILLOMAVIRUSES
 HUMAN HERPESVIRUSESHUMAN HERPESVIRUSES
 OTHER VIRAL DISEASESOTHER VIRAL DISEASES

HUMAN PAPILLOMAVIRUSESHUMAN PAPILLOMAVIRUSES
 Papovavirus
 dsDNA,
 icosahedral in shape
 Naked (non-enveloped)
 Resistant to drying,
freezing, and solvents
 Human papillomaviruses include at least 200 types200 types that
infect the skin and mucosa
 Most types cause specific typesspecific types of warts and favor
certain anatomic locationscertain anatomic locations
 Infections are described as clinical, subclinical & latent

Viral replication mainly within the granular layer of the epidermis

Classification
 Nongenital warts
 Anogenital warts

Classification
1. Commonwarts (Verruca vulgaris)
2. Filiform warts
3. Butcher's warts
4. Flat warts (Verruca plana)
5. Palmoplantar warts
a) Mosaic warts
b) Myrmecial warts
6. Periungual wart
7. Oral warts
8. Epidermodysplasia verruciformis
9. Focal epithelial hyperplasia
(Heck disease).
10.Verrucous cyst (plantar cysts)

Classification
1. Condylomata acuminata
2.2. Bowenoid papulosisBowenoid papulosis
3.3. Buschke-LBuschke-Lööwenstein tumorwenstein tumor
4.4. Erythroplasia of QueyratErythroplasia of Queyrat

Clinical variant depend on:
1. Anatomic location
2. Morphology
3. Histopathology
4. HPV subtype

In clinical practice, subtyping is generally only performed routinely on
Papanicolaou smears. Subtyping does not usually change management
of cutaneous lesions.

NONGENITAL WARTS
 Mode of TransmissionMode of Transmission: via direct person-to-
person contact or indirect contact with
contaminated surfaces/objects.
 Prevalence:Prevalence: of increase in incidence among school-
aged children 20% in school children but may
arise at any age.
 Sex:Sex: Male-to-female ratio approaches 1:1.
 Incubation period:Incubation period: ranges from 1-6 months
 Latency period:Latency period: of up to 6m-3 years or more.

NONGENITAL WARTS
 Numerous warts or persistent/progressive
warts should prompt consideration of
immunosuppression or defects in cellular
immunity.
 Malignant change in nongenital warts is
rare but has been reported and is termed
verrucous carcinoma.
 A third or more self-regress within one
years.

1. Verruca vulgaris (Common warts)1. Verruca vulgaris (Common warts)
 HPV TYPE:HPV TYPE: most common HPV 22
 RISK FACTORS:RISK FACTORS:
1. Frequent trauma/disruption to the normal epithelial
barrier.
2. Frequent emersion of hands in water.
 SITESSITES: Any site but usually located on the hands
 Spread by autoinnoculation
 Natural history is for spontaneous resolution,
half by 1 year and two thirds by 2 years

 PRESENTATIONPRESENTATION: Present as asymptomatic elevated,
rough, grayish hyperkeratotic, exophytic or dome
shaped papules or plaques range from smaller than 1
mm to larger than 1 cm with punctate black dots
(thrombosed capillaries/pathognomonic) that may
require paring to see.

1. Verruca vulgaris/Histopathology

‘church spire’ papillomatosis

Pap smear with group of normal cervical cells on left andPap smear with group of normal cervical cells on left and
HPV-infected cells showing features typical ofHPV-infected cells showing features typical of
koilocytes: enlarged (x2 or x3) nuclei andkoilocytes: enlarged (x2 or x3) nuclei and
hyperchromasia.hyperchromasia.KOILOCYTES MAY HAVE THE FOLLOWING CELLULAR CHANGES:KOILOCYTES MAY HAVE THE FOLLOWING CELLULAR CHANGES:
1.A clear area around the nucleus, known as a perinuclear halo.
2.Nuclear enlargement (two to three times normal size)
3.A darker than normal staining pattern in nucleus (Hyperchromasia)
4.Irregularity of the nuclear membrane contour
KoilocytosisKoilocytosis
(pathognomonic feature of HPV infection)

1. Orthokeratosis
2. Parakeratosis
3. Hypergranulosis
4. Acanthosis.
5. Koilocytosis
6. ‘Church spire’
papillomatosis
7. Elongated rete ridges that slope inwards (point radially
toward lesion center)
8. Dilated dermal papillary capillaries

1. Verruca vulgaris/DDx
1. Seborrheic keratosis,
2. Actinic keratosis,
3. Cutaneous horn,
4. SCC (especially periungual),
5. Trichilemmoma,
6. Spitz nevus.
7. Lichen Planus
8. Prurigo Nodularis

2. Filiform warts2. Filiform warts

2. Filiform wartsFiliform warts
 long slender growths, usually seen on the
face around the lips, eyelids, or nares /scalp
 Filiform warts may appear similar to
common warts but tend to have prominent
papillomatosis.

2. Filiform warts / Histopathology

3. Butcher's warts3. Butcher's warts
 HPV type 7
 Seen in people who frequently handle raw
meat. Their morphology is similar to
common warts, with a higher prevalence of
hyperproliferative cauliflower-like lesions.
They are seen most commonly on the
hands.

3. Butcher's warts /Histopathology
 Prominent acanthosis, hyperkeratosis, and
papillomatosis.
 Small vacuolized cells with centrally
located shrunken nuclei may be seen in
clusters within the granular layer rete
ridges.

4. Verruca plana (Flat/Plane Warts)4. Verruca plana (Flat/Plane Warts)
 HPV TYPE:HPV TYPE: HPV 3,3, 1010
 SITESSITES: Face, neck, dorsa of hands, shins
and knees
 Children and young adults. Men who shave
and women who shave their legs
 Koebnerization => linear distribution
 Highest rate of spontaneous remission
which usually is heralded by inflammation.

 They are characterized as flat-topped,
slightly elevated flesh-colored papules or
slightly pinkpink or brownbrown that may be smooth
or slightly hyperkeratotic. They range from
1-5 mm or more, and numbers range from a
few to hundreds of lesions that may become
grouped or confluent.
4. Verruca plana (Flat/Plane Warts)

4. Verruca plana /Histopathology
 Resemble common warts but the features
tend to be muted.
 Cells with prominent perinuclear
vacuolization around pyknotic, strongly
basophilic, centrally located nuclei may be
in the granular layer. These may be referred
to as "owl's eye cells."

Histopathology of verruca plana showing the typical cytopathic
effect on keratinocytes called as koilocytes having a perinuclear halo
referred to as "owl-eye appearance”

1. Common warts
2. Small seborrheic keratoses
3. Lichen Planus
4. Lichen Nitidus
5. Molluscum Contagiosum
4. Verruca plana DDx

5. Verruca Palmaris/Plantaris5. Verruca Palmaris/Plantaris
(Palmoplantar warts)(Palmoplantar warts)
 HPV type 11
 usually are found on weight-bearing areas
(pressure points), such as the metatarsal head
and heel.
 Frequently several lesions are seen
 Plantar warts can be painful, and extensive
involvement on the sole of the foot may
impair ambulation.

Deep plantar warts also are termed myrmecia.

 MOSAICMOSAIC WART:WART: plaque of closely grouped warts. When
the surface is pared, the angular outlines of tightly
compressed individual warts are seen, relatively
asymptomatic.
 MYRMECIAL WART:MYRMECIAL WART: sloping sides and a central
depression occurs as deep, often inflamed and tender
papules or plaques. They begin as small shiny papules and
progress to deep endophytic, sharply defined, round lesions
with a rough keratotic surface, surrounded by a smooth
collar of calloused skin; may be confused with callus, (no
black dots)
5. Verruca Palmaris/Plantaris
(Palmoplantar warts)

Verrucae plantaresVerrucae plantares
Photo after the shaving
of the hyperkeratotic
surface

5. Palmoplantar warts
/Histopathology
 Similar to common warts except that most of the
lesion lies deep to the plane of the skin surface.
 BasophilicBasophilic nuclear inclusions and basophilic
parakeratotic cells loaded with virions may be in
the upper layers of the epidermis.
 Endophytic epidermal growth often has the
distinctive feature of polygonal, refractile-
appearing, eosinophiliceosinophilic, cytoplasmic inclusions
composed of keratin filaments, forming ringlike
structures.

5. Palmoplantar warts DDx
1. Corns
2. Punctate palmoplantar keratoderma
3. Arsenical keratoses,
4. SCC
5. Amelanotic melanoma.
6. Plantar cyst

6. Periungual warts6. Periungual warts
 Myrmecia arising around nails. They tend
to be periungual &/or subungual.
 Difficult to Rx
 May lead to permanent nail dystrophy

7. Oral warts7. Oral warts
 Buccal, gingival, and labial mucosae as well
as tongue and hard palate
 Small, soft, mucosal-colored to whitewhite,
slightly elevated papillomatous papules.
 DDx:DDx:
1. Verrucous proliferative leukoplakia,
2. Heck’s disease
3. Early SCC,
4. Bite fibroma.

8. Epidermodysplasia verruciformis8. Epidermodysplasia verruciformis
 A rare inherited disorder or acquired
immunosuppression (e.g. HIV infection)
 Characterized by widespread HPV infection
and cutaneous SCCs
 Most commonly inherited as and AR trait
 HPV-5, HPV-8 and many other “unique” types
 Presents in childhood (inherited form) and
continues throughout life

 Skin lesions include flat, wart-like lesions
of the dorsal hands, extremities, and face
 SCCs develop in 30-60% of pts, most often
on sun exposed areas.
 Actinic background
 DDx:DDx: flat warts or tinea versicolor
 Surgery, radiation is contraindicated
 Strict sun avoidance

Histopathological view: Koiliocytes and moderate dysplasia
Distinctive histopathology with expanded
gray-blue cytoplasm within the keratinocytes
Of the upper stratum spinosum.

9. Focal epithelial hyperplasia9. Focal epithelial hyperplasia
(Heck disease)(Heck disease)
 HPV types 13 and 32
 HPV infection occurring in the oral cavity,
usually on the lower labial mucosa. The
lesions appear as sessile multiple flat-
topped or dome-shaped pink-pink-whitewhite papules.
They usually are 1-5 mm, with some lesions
coalescing into plaques. They are seen most
frequently in children of American Indian
or Inuit descent.

10. Cystic warts (plantar10. Cystic warts (plantar
epidermoid cysts)epidermoid cysts)
 HPV type 60
 A cystic wart appears as a nodule on the sole
usually is smooth with visible rete ridges but may
become hyperkeratotic. If the lesion is incised,
cheesy material may be expressed.
 The etiology of these lesions is uncertain. One
theory is that a cyst forms, originating from the
eccrine duct, and secondary HPV infection occurs.
Another theory is that the epidermis infected with
HPV becomes implanted into the dermis, forming
an epidermal inclusion cyst.

Anogenital Warts (venereal wart,
Condyloma acuminatum)

1. Condylomata Acuminata1. Condylomata Acuminata
 Anogenital infection with HPV.
 Most common sexually transmitted disease.
 If present in children may be acquired through:
1. Vertical transmission perinatally
2. Via the same routes as nongenital warts direct & indirect
contact (digital inoculation or autoinoculation, fomite or
social nonsexual contact).
3. Sexual abuse should be considered if >3 years of age
 May be subclinical (closely linked with cancer especially
of the cervix) or latent
 Numerous genital warts may appear during pregnancy

1. Condylomata Acuminata
 HPV types:HPV types:
o HPV-6, HPV-11 (benign lesions- low risk)
o HPV-16 and HPV-18 (cancer- high risk or
oncogenic type)

1. Condylomata acuminata/CP
 Appear as lobulated papules that are frequently
multifocal range from discrete, sessile, smooth-
surfaced papilloma to large cauliflower-like lesions
skin-coloredskin-colored to pinkpink to brownbrown.
 Intraurethral condylomata may present with terminal
hematuria, altered urinary stream, or urethral bleeding
 They may coalesce to form huge fungating plagues
causing discomfort and irritation.
 The vaginal and anorectal mucosae may be affected.
 Other sexually transmitted disease may be present

1. Condylomata Acuminata/ DDx
1. Seborrheic keratosis
2. Skin tag
3. Molluscum contagiosum
4. Bowenoid papulosis
5. SCC
6. Pearly penile papules
7. Free sebaceous glands
8. Condyloma lata.

2. Bowenoid papulosis2. Bowenoid papulosis
 HPV-16 may behave similar to other
genital warts
 Similar to condylomata acuminata.
 Singly or in multiples
 Primarily in the anogenital region. pinkpink to
red-brownbrown smooth- flat to warty papules or
plaques.
 May progress to invasive SCC

Bowenoid papulosis of
the anus positive for
high-risk HPV in a
homosexual male

2. Bowenoid papulosis/2. Bowenoid papulosis/Histopathology
 Numerous mitoses scattered throughout the
epidermis (which distinguishes it from
condyloma acuminatum) keratinocytes may
show less atypia than in an SCC

3. Buschke-L3. Buschke-Lööwenstein tumorwenstein tumor
(Giant condyloma acuminatum)(Giant condyloma acuminatum)
 HPV-6
 A rare, aggressive wart-like growth that is a
verrucous carcinomaverrucous carcinoma
 Cauliflower-like deeply infiltrating giant
condyloma acuminata fistulas and/or
abscesses may be present.
 Most often occurs on the glans penis or
prepuce of an uncircumcised male
 May invade deeply, and rarely metastases

 Well-demarcated pink to red plaque
 Favors the glabrous skin.
4. Erythroplasia of Queyrat (Intraepithelial4. Erythroplasia of Queyrat (Intraepithelial
neoplasia/Squamous Cell Carcinoma In Situ)neoplasia/Squamous Cell Carcinoma In Situ)

A well demarcated velvety plaque of the
prepuce positive for high-risk HPV

Diagnosis of Verruca
- Primarily on the basis of clinical findings.
A. Laboratory Studies
B. Clinical Procedures
C. Histologic Findings

A.Laboratory Studies
B.Office Procedures
C.Histologic Findings
1) Immunohistochemical
detection of HPV structural
proteins may confirm the
presence of virus in a lesion/
low sensitivity.
2) Viral DNA identification
using Southern blot
hybridization is a more
sensitive and specific
technique used to identify the
specific HPV type present in
tissue. PCR may be used to
amplify viral DNA for testing.

A.Laboratory Studies
B.Office Procedures
C.Histologic Findings
Paring of warts may reveal
minute black dots, which
represent thrombosed
capillaries.

Treatment of Warts
 Aims of therapy are:
1) To remove the wart;
2) Not to produce scarring;
3) To induce lifelong immunity to prevent
recurrence.
 Consider benign neglect
 Depends on the type of wart and the age of the
patient
 Allow 2-3 months of therapy
 Do not abandon any treatment too quickly

Treatment of Warts
 Two basic approaches
 Destruction and/or Induction of local
immune reactions

Management of Warts
 MEDICAL TREATMENT “5”MEDICAL TREATMENT “5”
I. Topical agents
II. Systemic agents
III.Intralesional injections
IV.Photodynamic therapy
V. Alternative treatments

Management of Warts
 SURGICAL TREATMENT “5”SURGICAL TREATMENT “5”
I. Cryotherapy
II. Electrosurgery
III.Lasers.
IV.Curettage
V. Surgical excision

MEDICAL TREATMENTMEDICAL TREATMENT

Management of Warts
I. Topical agents
II. Systemic agents
1. Keratolytics
2.2. TTrichloacetic acid
3.3. TTretinoin
4.4. PodophyllPodophyllin
5.5. PodophyllPodophyllotoxin
6. Imiquimod (Aldara)®
7.7. CChemotherapeutichemotherapeutic
agent/agent/5-fluorouracil
8.8. CCantharidin
9.9. CContact allergens
10.10. CCidofoviridofovir

Management of Warts
I. Topical agents
II. Systemic agents
1. Systemic retinoids
(acitretin and isotretinoin)
2. Cimetidine
3. Intravenous cidofovir

Management of Warts
I. Topical agents
II. Systemic agents
1. Bleomycin
2. Interferon alpha
3. Intralesional
immunotherapy
using injections of
Candida, PPD,
mumps/MMR.

Management of Warts
I. Topical agents
II. Systemic agents
ALA

Management of Warts
I. Topical agents
II. Systemic agents
1. Occlusion/Adhesio-
therapy
2. Heat treatment
3. Hypnotic suggestion
4. Garlic
5.5. Tea tree oilTea tree oil

I.I. Topical agents
1.1. KeratolyticsKeratolytics: Salicylic acid 10-50% is a first-line therapy used
to treat warts / more cost-effective.
2.2. TTrichloroacetic acid (30-80%)richloroacetic acid (30-80%): causes tissue necrosis.
3.3. TTretinoinretinoin is a topical retinoic acid that primarily is used to treat
acne. It has been successful in treating flat warts.
4.4. PodophyllPodophyllin:in: is a cytotoxic compound used more commonly in
the treatment of genital warts more effective in treating warts
on occluded or moist surfaces, such as the mucosa or under the
prepuce. as a crude extract, usually in 25 % in tincture of
benzoin.
5.5. PodophyllPodophyllotoxin 0.5%otoxin 0.5% solution or gel purified podophyllin is
applied by the patient twice a day for 3 consecutive days of
each week in 4- to 6-week treatment cycles.

I.I. Topical agents
1.1. KeratolyticsKeratolytics: Salicylic acid 10-50% is a first-line therapy used
to treat warts / more cost-effective.
2.2. TTrichloroacetic acid (80%)richloroacetic acid (80%): causes tissue necrosis.
3.3. TTretinoinretinoin is a topical retinoic acid that primarily is used to treat
acne. It has been successful in treating flat warts.
4.4. PodophyllPodophyllin:in: is a cytotoxic compound used more commonly in
the treatment of genital warts more effective in treating warts
on occluded or moist surfaces, such as the mucosa or under the
prepuce. as a crude extract, usually in 25 % in tincture of
benzoin.
5.5. PodophyllPodophyllotoxin 0.5%otoxin 0.5% solution or gel purified podophyllin is
applied by the patient twice a day for 3 consecutive days of
each week in 4- to 6-week treatment cycles.

I.I. Topical agents
6.6. Imiquimod (Aldara)®:Imiquimod (Aldara)®: is an immune response modifier
approved for the treatment of genital warts.
7.7. CChemotherapeutic agent 5-Fluorouracilhemotherapeutic agent 5-Fluorouracil. It has been
reported to be effective in treating warts when used under
occlusion daily for up to 1 month.
8.8. CCantharidin:antharidin: is an extract of the blister beetle that causes
epidermal necrosis and blistering.
9.9. CContact sensitizersontact sensitizers e.g. diphencyclopropenone (DCP)
10.10. CCidofoviridofovir is an antiviral agent used for the treatment of
CMV infection in HIV patients. gel applied 1-2 times per
day. This remains an investigational drug for warts

I.I. Topical agents
occlusion daily for up to 1 month esp. bowenoid
papulosis
8.8. CCantharidin:antharidin: is an extract of the blister beetle that causes
epidermal necrosis and blistering.

I.I. Topical agents
occlusion daily for up to 1 month.
8.8. CCantharidin:antharidin: is an extract of the blister beetle
that causes epidermal necrosis and blistering.

II.II. Systemic agents
1.1. RetinoidsRetinoids are synthetic vitamin A analogs. The
limiting side effects include liver function
abnormalities, increased serum lipid levels, and
teratogenicity.
2.2. CimetidineCimetidine is a type-2 histamine receptor antagonist
commonly used to treat peptic ulcer disease. Because
of its immunomodulatory effects at higher doses.
3.3. Intravenous cidofovirIntravenous cidofovir used for the treatment of
extensive, disfiguring, and refractory warts. This
should be used with caution because of the risk of
nephrotoxicity

III. Intralesional injectionsIII. Intralesional injections
1.1. BleomycinBleomycin is a chemotherapeutic agent that
inhibits DNA synthesis in cells and viruses. Cure
rates have ranged from 33-92%.
2. Interferon-alfa is a naturally occurring cytokine
with antiviral, antibacterial, anticancer, and
immunomodulatory effects. Cure rates of 36-
63% have been reported.
3. Intralesional immunotherapy using injections of
Candida, PPD, mumps/MMR.

1. Bleomycin is a chemotherapeutic agent that
2.2. Interferon-alfaInterferon-alfa is a naturally occurring cytokine
3. Intralesional immunotherapy using injections of

1. Bleomycin is a chemotherapeutic agent that
2. Interferon-alfa is a naturally occurring cytokine
3.3. Intralesional immunotherapyIntralesional immunotherapy using injections of

IV.IV. Photodynamic therapy
 5-Aminolevulinic acid
(ALA) is a photosensitizer
that has been successfully
used topically kept under
occlusion for 5h, then
followed by
photoactivationphotoactivation with redred
light-emitting diodes at 2-
to 3-week intervals or
with blueblue light to treat flat
warts

V. Alternative treatmentsV. Alternative treatments
1.1. AdhesiotherapyAdhesiotherapy is performed by applying duct tape to the
wart daily. This method is painless and inexpensive.
2.2. HypnosisHypnosis has been used to treat refractory warts with
prepubertal children more likely to respond than adults.
3.3. HyperthermiaHyperthermia involves immersing the involved surface in
hot water (45ºC) for 30-45 minutes, 2-3 times per week.
4.4. Raw garlic clovesRaw garlic cloves have been demonstrated to have
antiviral activity. This can be rubbed onto the wart
nightly, followed by occlusion.
5.5. Tea tree oilTea tree oil possesses antimicrobial properties and when
applied topically has also been reported as successful

SURGICAL TREATMENTSURGICAL TREATMENT

I. CryosurgeryI. Cryosurgery
 Liquid nitrogen (-196ºC) is the
most effective method of
cryosurgery. Apply liquid nitrogen
using a cotton bud applicator or
cryospray to the recommended 1-2
mm rim of normal skin tissue
around the wart. Repeat every 1-4
weeks for approximately 3 months,
as needed. Warn patients about
pain and possible blistering after
treatment.

II. ElectrosurgeryII. Electrosurgery
 Electrodesiccation and curettageElectrodesiccation and curettage, it is
painful, more likely to scar, and HPV can be
isolated from the plume smoke potentially
infectious
 20% recur
within few
months.

III. LasersIII. Lasers
 This is an expensive treatment, and is reserved only for
large or refractory warts. Multiple treatments may be
required. Local or general anesthesia may be necessary.
1.1. Carbon dioxideCarbon dioxide lasers have successfully treated
resistant warts; however, the procedure can be painful
and leave scarring.
2.2. Pulse dyePulse dye laser targets the blood vessels that feed warts
with decreased risk of scarring
3.3. Nd:YAGNd:YAG laser may be used for deeper, larger warts.

IV. CurettageCurettage
 Avoid using curettage in most
circumstances because of the risks of
koebnerization and recurrence.

V. Surgical excisionV. Surgical excision
 Avoid using surgical excision in most
circumstances because of the risks of
scarring and recurrence.

Prevention
HPV Vaccines
 Two vaccines are available to prevent infection by some
HPV types: Gardasil, and Cervarix. Both protect against
initial infection with HPV types 16 and 18, which cause
most of the HPV associated cancer cases. Gardasil also
protects against HPV types 6 and 11, which cause 90% of
genital warts.

References
 Bolognia Dermatology Essentials.
 Bolognia Dermatology 2nd
ed.
 http://www.dermnetnz.org
 http://en.wikipedia.org
 http://www.ijdvl.com
 http://emedicine.medscape.com

Viral infections-Human papillomaviruses infection

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