Papillomaviruses

 

Warts

There are over 100 Human papillomavirus types. There is no cross protection.

Transmission- direct contact (including sexual and perinatal transmission)

Recurrence is common after treatment.

Incubation period is between 4 weeks to 8 months.

 

Clinical presentations

Common warts

Affects mainly children.

Rough plaques of skin.

Regress over time

HPV 1 to 5, HPV 7, HPV 10

 

Respiratory papillomatosis

HPV 55, 64

 

Laryngeal papilloma

HPV 6  and 11

 

Anogenital warts

Common between 17-30 years of age

 

Condyloma acuminatum

HPV 6 and HPV 11

Regression- 30 % in 3 months, 75 % in 2 years.

 

Oncogenic

Type 16 and 18 (associated with cervical Ca (nearly 100%))

Type 16 (associated with anal squamous cell carcinoma (70%))

Basal cell ca of the skin (50%)

Laryngeal Ca (25 %)

Esophageal ca (20 %)

 

Investigation

Biopsy

Colposcopy and acetic acid staining for screening of anal intra-epithelial neoplasm

 Specific tests

Biopsy- EM and PCR

Typing- PCR

 

 Management

Management of Warts in children

Self limiting.

Some advocate observation without any intervention. Topical salicylic acid and cimetidine may  be used (cimetidine acts as immunomodulator (enhance Th2 cells)).

 

Warts Pregnant women

Cryotherapy and TCA can be used for small lesion.

Surgical excision may be required for large lesions.  Laser can also be used.

Regression after delivery is common

 

Anogenital warts

Visible area

Keratinized warts- cryotherapy, electrocautery and laser ablations are effective

Non-keratinized warts- podophyllin and podophylotoxin. Imiquimod is also effective.

Large lesions generally require surgical excision.

 

Non- visible area

Cervix- cryotherapy, TCA and large loop excision

Vagina- cryotherapy, TCA, podophylin and surgical excision

Urethral meatus- cryotherapy, electrocautery,  imiquimod

Perianal- podophyllotoxin, cryotherapy, imiquimod, electrocautery

 

Medical treatment for HPV

1. Podophyllin and podophyllotoxin

Preparation- 0.5 % solutions applied twice a day.

Adverse effect- ulceration. These drugs can cause intrauterine death, and they are potentially teratogenic.

 

2. Fluorouracil 5 % cream

Adverse effect- potential teratogenic

 

3. Trichloracetic acid (TCA)

Adverse effect- burning sensation for 10-20 minutes, scarring

Can be considered safe for use in pregnancy as it has only local effect.

 

4. Imiquimod 5 % cream

Stimulate production of Interferon and Tissue Necrosis Factors (TNF).

With Imiquimod the recurrence rate is low but it is expensive.

 

5. Interferon alpha and betha

Can be used as topical and can also be administered to the lesions.

Adverse effect- flu like illness

 

Surgical

1.Curettage

For non-kertinazed

Adverse effect- bleeding

 

2. electrocautery

 

3. surgical excision

adverse effect- bleeding, high recurrence

 

Other modalities

1. Cryotherapy

Liquide nitrogen applies with cotton swab.

Adverse effects- discomfort, blister and ulcer.

 

2. Laser therapy

Carbon dioxide laser therapy.

High recurrence rate.

 

Prevention

Avoidance of communal shower is an ideal measure to prevent infection.

Difficult to decontaminate as it is non-enveloped virus.

Condom may not prevent HPV transmission.

 

 

Papillomavirus and Cervical cancer

Cervical cancer is the second commonest malignancy in women. It is common in patients over the age of 35 years.

It is associated with Human Papillomavirus infections.

Transmission is mainly through sexual intercourse. After infection, spontaneous clearance is common (in over 80 % of HPV infected individuals).

 

Risk factors

Papillomavirus infections (HPV DNA is detected in almost 100 % cervical Ca.)

Other risk factors include

 

Papillomavirus type

Eighteen different serotypes are associated with cervical ca.

 

Intermediate Oncogenic types

31, 33, 35,45,51,52,56

Highly Oncogenic types

16,18,39,58

 

 Over 80 % of cervical ca is caused by type 16 and 18.

 

Mechanism of Cell transformations

HPV viral genome integrates into the cellular DNA and products of some of the viral genome transform the cell into malignant cells. Abnormal cells and carcinoma in situ are seen a few months to several years.

 

Clinical presentation

Where there is no national screening program for cervical ca, patients may present with vaginal bleeding and vaginal discharge. Post-coital bleeding is also common. Later patient may present with urinary problems.

On vaginal examination a mass can be palpated. Blood on examining finger may be observed.

Staging is based on clinical examination.

 

Investigation

Biopsy- Colposcopy

Renal pyelography

Ultrasound

MRI/ CT scan

 

Specific tests

There is serological test.

Screening of patient for Papillomavirus infection can be carried out by PCR. It is more sensitive than the Pap smear screening methods. It can be more useful particularly in patient with borderline result of pap smear. In addition, patient who has abnormal Pap smear would benefit if confirmation test with molecular method is carried out as the negative predictive value is very high.

For invasive carcinoma, surgery, radiotherapy and chemotherapy are used as therapeutic measures. In these patients follow up with molecular method is very essential. It has high predictive value of recurrence after treatment.  Furthermore molecular tests can be used when interpretations of cytology or Colposcopy examination is difficult when inflamed tissues are examined.

 

Management

Cone biopsy

Cryotherapy

Hysterectomy

 

Prevention

Vaccination- A number of clinical trials was conducted on the use of HPV virus like particle (VLPs) as a vaccine. It was protective in almost all subjects involved in the studies. However, in these studies antigens found in only HPV 16 and 18 were used.

 

Screening

The objective is to detect cervical intraepithelial neoplasia (CIN) before leading to cervical cancer.

The majority of CIN 2 and 3 are caused by HPV type 16 and 18.

Pap smear

It is cytology test.

Used to detect pre- malignant conditions- based on presence of mitotic activities and nuclear atypia

It is less sensitive (50-60 %) and has low specificity.

 

Liquid base cytology is more sensitive than conventional cytology

 

Molecular testing

It is very sensitive and has high negative predictive value.

The main advantage is that it may reduce follow up cytology and referral for borderline or mild dyskaryotic  smears. Combined cytology and molecular testing have a negative predictive vale of > 99 %.

 

Type of molecular tests

1. Hybrid Capture 2

It is a signal amplification test. It is less sensitive than PCR and requires high purified DNA. The test can detect HPV types which are associated with cervical cancer, however it does not determine the specific HPV type.

 

2. PCR

Amplify target gene and it is very sensitive. It can be modified to determine viral load and genotype.

DNA sequencing and LiPA (Line probe assay) are used for genotyping

 

Advantage of Combined Pap smear and molecular testing

May increase the sensitivity of screening test

May improve the negative predictive value

May increase the period interval between screening tests

May reduce unnecessary referral and distress to the patients.

Papillomavirus in immunocompromised patients

 

Malignancies induced by Papillomavirus are mostly seen in transformation zone. Both benign and malignant associated HPV have high tendency of persistent infection among immunocompromised patients. Cell mediated immunity is considered to be essential to stop recurrence.

 

Risk factors

·        HIV infected patients

·        Post- transplant patient

·        Patient on immunosuppressive therapy

·        Congenital immunodeficiency 

 

Clinical presentation

In transplant and HIV infected patients wart is common. In immunocompromised patients widely spread warts are commonly observed. In addition warts can reappear after successful treatment.

In HIV infected patients papillomavirus is associated with

 

Invasive cervical cancer is considered to be an AIDS defining illness.

 

Epidermodysplesia verrucformis

It is an autosomal recessive disease trait. Affected individual can develop disseminated flat warts that rarely lead to squamous cell carcinoma after exposure to UV.

 

Investigation

Biopsy

Molecular method is not reliable in non-cervical lesions as the results are not reproducible. Serial and qualitative molecular methods should be evaluated before they are used for clinical purpose.

 

Management

Warts- see management of warts

Surgery

Imiquimod and Cidofovir may be effective to treat cutaneous and vulavar lesions.

HAART may reduce the risk of CIN among HIV positive.

 

Prevention

There is no standard screening method however frequent clinical examination may benefit patients who are immunocompromised.

HIV infected patients particularly involved in receptive intercourse are high risk. Pap smear and colposcopy examination like for cervical intraepithelial lesions may be useful to detect early malignancy.