A 22 yr old female presents to her gynecologist complaining of “bumps”. She admits to being sexual active although she states that she only has one partner. Physical exam reveals brown, warty lesions. Labs: presence of kilocytes in the squamous epithelial cells.
Diagnosis of genital warts is made by clinical presentation.
Genital Warts
Genital warts (condyloma acuminata)
Etiology:
Human Papillomavirus (HPV)
It is an nonenveloped viruses with double stranded circular DNA & an icosahedral nucleocapsid 100+ varieties
Most are harmless.
35 are transmitted sexually
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HPV 16,18, 31 and 45 are considered “high risk” Can lead to cervical cancer HPV- 6, 11, 42, 43 and 44 are considered “low risk” Often lead to the development of genital warts Other types cause warts of the skin such as plantar warts is caused by HPV-1 through HPV-4
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Genital warts (condylomata acuminata) are caused primarily by HPV-6 & HPV-11.
Adding Up the Facts
1) HPV is present in the majority of sexually active adults. 2) Presence of HPV does not indicate promiscuity. 3) HPV is asymptomatic and short-lived in most adults. 4) If high-risk HPV persists, it can lead to cervical cancer. 5) Cervical cancer kills 4,000 U.S. women and 200,000
women worldwide a year.
6) HPV vaccine, given at age 11, would eliminate 70% of cervical cancer and save lives.
Epidemiology
20 million people are infected with genital warts with 6.2 million new cases of this disease every year. More than 50% of sexually active adults will acquire HPV in their lifetime. Most infections are transient; persistent infection is a major risk factor for cancer.
In the United States, there are 2.8 million abnormal Pap tests according to annual estimates, as well as 10,520 cases of infection have been identified every year,
500,000 to 1 million cases of genital warts from HPV.
3,900 die of cervical cancer All cancers of cervix is mainly due to chronic infection with HPV It affects 20 million people 80% acquire HPV by the age of 50.
Subclinical Genital HPV Infection: HPV- DNA (types 16, 18 (70%)) has been found in over 93% of the cervical carcinomas
Infection is almost always sexually transmitted
The incubation period is variable and it is often difficult to determine the source of infection. Sex partners usually are infected by the time of the patient's diagnosis They may have no symptoms or signs of infection
The natural history of genital warts is generally benign The types of HPV that usually cause external genital warts are not associated with cancer. Recurrence of genital warts within the first several months after treatment is common and usually indicates recurrence rather than reinfection.
HPV Epidemiology
Reservoir
Transmission
Human
Direct contact, usually sexual
Communicability
Presumed to be high
Mode of transmission : Skin to skin contact from infected individual Normal epithelium covering the cervix has four layers on top of the basement membranes Single Basal cell layer differentiate into Parabasal cell layer, Intermediate layer & Superficial layer. Superficial layer gets sloughed off and replaced by the cells underneath. HPV can only infect the basal cells.
HPV – DNA contains three important components URR – upper regulatory region
ER – early region. These genes codes for infrastructure replication oncogenesis
LR – late region. Produce final capsid layer to make it infective.
Greatest risk of HPV infection coincides with the metaplastic activity which begins at puberty. Cervical cancer rise at Squamocolumnar junction Here the depth of the epithelium is only few cells above the basal cell layers, whereas mature squamous epithelium on cervix or vagina contains more layers hence requires microabrasions through all of these cells.
The virion infects the new basal cell, the outer capsid layer is destroyed by endocytosis. It then passes HPV- DNA into the cell nucleus.
HPV- DNA remains separately from the cellular DNA.
It replicates slowly without leaving the cell nucleus. It can remains like this upto weeks or decades until it is signalled for maturation. Hence it cannot be detected by any method.
It completes its replication as the superficial cells discriminates As the superficial cells are sloughed off the HPV is now capable of infecting new Basal cell.
Throughout this process HPV is detected cytologically & in tissue as CIN (cervical intraepithelial neoplasia)grade 1
HPV attacking the epithelial cells
Humoral immunity may be more important in preventing infection.
Type specific antibody production is seen after 4 mths - 5 years of infection. Cervical cancer precursors CIN 2 & 3 result from the integration of high risk viral DNA with cellular DNA. Resulting in viral or severe dysphlagia, high grade disease CIN2/3 and eventually cancer.
Natural History of HPV Infection
Within 1 Year 1-5 Years Up to Decades
Initial HPV Infection
Persistent Infection
CIN 2/3
Cervical Cancer
CIN 1
Cleared HPV Infection
HPV infection: to the left, healthy cervical tissue; in the middle, the phase in which the virus multiplies, and to the right, the integration of the virus into the DNA of the cells. This is where the virus DNA sets a process of malignant change in motion. The vaccine is directed against these DNA-affected cells.
Pathogenesis of warts: After entering the body via surface abrasions the virus infects cells in the basal layers of the skin or mucosa. Virus replication is slow & is critically dependent upon the differentiation of host cells. Viral antigen & infectious virus are produced only when the cell begin to become squamified and keratinized as they approach the surface. The infected cells are stimulated to divide & after 1-6 months of initial infection, the mass of infected cells protrude from the body surface to form a visible papilloma or wart.
Warts can be:
Filiform with finger-like projections. Flat topped Flat because they grow inwards due to external pressure (plantar warts). A cauliflower-like protuberance (e.g. genital warts) A flat area of dysplasia on the cervix.
Manifestations
Soft, fleshy, cauliflower -like lesions on the skin, genitalia, perineum, and perinal regions. The HPV infected cells of the cervix do not have any recognizable lesion. Only after the addition of dilute acetic acid can one see an "acetowhite" epithelium.
Diagnosis:
For the cauliflower -like lesions, clinical presentation is enough. These must be differentiated from condyloma lata and molluscum contagiosum. Placing dilute acetic acid on the cervix can reveal the acetowhite epithelium. A "PAP" smear should be performed and the pathologist will look for Kilocytosis (A squamous cell, often binucleated, showing a perinuclear halo; characteristic of condyloma acuminatum).
Pap Smear: The Key to Understanding HPV and Cervical Cancer
What is a Pap Smear? • Involves collecting cells from the cervix during pelvic exam - Cells are examined under a microscope • Women begin tests within 3 years of first sexual intercourse or after age 21 Categories of Pap Smear Results 1. Normal (Out of 50 million, 45 million are normal) 2. Atypical (2 million) - Result of general infection, irritation or trauma, or HPV 3. Pre-cancerous or cancerous (1.5 million of each) - Requires follow-up - 90% cure rate with early diagnosis
Therapy: Cryotherapy, surgical excision, laser vaporization, cautery, podophyllin, podophyllotoxin, 5fluorouracil, trichloroacetic acid or interferon for exophytic lesions. Annual pap smears to stage subclinical infections with various treatments depending of the stage of the disease progression . Invasive squamous cell carcinoma usually remains localized or regional for a considerable time; distant metastases occur late. The 5-yr survival rates are 80 to 90% for CIN stage I, 50 to 65% for stage II, 25 to 35% for stage III, and 0 to 15% for stage IV.
Prevention
Avoid contact with lesions.
The likelihood of transmission to future partners and the duration of infectivity after treatment are unknown.
The use of latex condoms has been associated with a lower rate of cervical cancer, an HPV-associated disease.
Human Papillomavirus Vaccine
HPV L1 major capsid protein of the virus is antigen used for immunization L1 protein expressed in yeast cells using recombinant technology L1 proteins self-assemble into virus-like particles (VLP) Noninfectious and nononcogenic
Routine HPV Vaccination
Routine vaccination for females 11-12 years of age is recommended. The vaccination series can be started as young as 9 years of age at the clinician’s discretion “Catch-up” vaccination recommended for females 13 through 26 years of age
HPV Vaccination Schedule
Routine schedule is 0, 2, 6 months
Minimum intervals ◦ 4 weeks between doses 1 and 2 ◦ 12 weeks between doses 2 and 3
Do not restart the series if the schedule is interrupted
Quadrivalent HPV Vaccine:
HPV vaccine is not licensed for use among males
◦ Efficacy data are not available ◦ Off-label use not recommended
Efficacy studies in males is in progress now
Vaccination During Pregnancy Provisional Recommendation
Initiation of the vaccine series should be delayed until after completion of pregnancy
If a woman is found to be pregnant after initiating the vaccination series, remaining doses should be delayed until after the pregnancy
BLISTERS
Etiological Agent: HSV Molluscum contagiosum (MCV) • Symptoms of Herpes painful sores (see image) tingling or burning sensation pain or burning with urination outbreaks, in people with symptoms, usually decrease in frequency over time flu-like symptoms, including fever and/or swollen glands (first outbreak only) Most cases have no symptoms.
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Molluscum contagiosum: In adults, the genital, stomach, buttock, and inner thigh areas are more often affected as intimate contact with another is the typical source of infection. Men are more often affected than women. Adults with defective immune systems (such as with HIV) may have severe, extensive infection.
Practical Exams : Date: 22-09-08 Monday Time: 10.30-12.30