Papillomaviruses are a diverse group of DNA-based viruses that infect the skin and mucous membranes of humans and a variety of animals. Over 100 different human papillomavirus (HPV) types have been identified. Some HPV types may cause condylomas (skin warts) while others may cause a subclinical infection resulting in precancerous lesions. All HPVs are transmitted by skin-to-skin contact. A group of about 30-40 HPVs is typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPVs — types 6, 11, may cause genital warts. However, other HPV types which may infect the genitals do not to cause any noticeable signs of infection.

Persistent infection with a subset of about 13 so-called “high-risk” sexually transmitted HPVs, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 — different from the ones that cause warts — may lead to the development of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), and/or anal intraepithelial neoplasia (AIN). These are precancerous lesions and can progress to invasive cancer. HPV infection is a necessary factor in the development of nearly all cases of cervical cancer.^[1]

The fact that prostitutes have much higher rates of cervical cancer than nuns was a key early observation leading researchers to speculate about a causal link between sexually transmitted HPVs and cervical cancer.^[2]

Human papilloma virus may have different presentations depending on the anatomical region of involvement and the virus type. Mainly it is classified to cutaneous, anogenital and other mucosal surfaces. Currently, 210 different types of HPV have been discovered and the number keeps increasing.^[3][4] Clinical manifestations depend on which HPV type involve which anatomic area.^[5][6]

Human papilloma virus is usually transmitted via the sexual route to the human host.^[7] HPV life cycle is linked to epithelial differentiation and maturation of host keratinocytes, with transcription of specific gene products at every level.^[8][9] The pathogenesis of HPV infection causing cancer is mainly linked to high-risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). E6 and E7 protein products of HPV interact with two important cell cycle regulatory proteins, P53 and Rb proteins of the host cell, causing unchecked cellular replication accumulating mutations leading to cancer.^[10][11][12]

Genital HPV infection is very common, with estimates suggesting that more than 50% of women will become infected with one or more of the sexually transmitted HPV types at some point during adulthood.^[13]

Common risk factors for anogenital HPV infection are number of sex partners, having a new partner, duration of being sexually active, vaginal delivery and multiple deliveries. Close contact is the most potent factor for cutaneous infection.

High-risk HPV types are associated with 70% of cervical cancers in females having persistent infection.^[14] Due to this strong association between HPV and cervical cancer, cervical cancer screening is recommended in all females from age 21. According to the US Preventive Services Task Force (USPSTF), specific screening guidelines for cervical cancer includes screening all females from age 21 to 65 for cervical cancer.^[15][16]

Most infections with HPV are subclinical, asymptomatic and resolves without any complications in immunocompetent individuals. Time to develop symptoms and signs is not well defined but it may take 3 weeks to 3 months for genital warts, several months to years for cellular abnormalities (metaplasia and dysplasia) and years for development of cancers. 90% of infections resolve within 2 years due to host immune response.^[17]Persistent HPV infection is associated with risk factors such as multiple sexual partners, alcohol consumption, immunosuppression, older age, and multiple types of HPV detected previously. Without treatment, persistent infection with low-risk types (low-grade intraepithelial lesions) may resolve spontaneously or persist and proliferate as warty lesions. However, high-risk HPV types (16,18,31,32) may lead to high-grade intraepithelial lesions which ultimately to carcinoma(cervical, anal, vaginal, vulvar, penile and oropharyngeal).^{[18][19][20][14]}Prognosis of HPV infection depends primarily on the type of HPV causing infection.^{[21][22][23][24][25]}

Detailed history about sexual activities and partners must be taken from every patient with anogenital involvement. Symptoms are mostly related to skin irritation and mucosal surface involvement. The hallmark of cutaneous involvement is pruritus however, the majority of the people acquiring HPV are asymptomatic. The clinical manifestation of HPV infection is wart that sometimes might be painful.^[26]

Certain types of sexually transmitted HPVs can cause cervical cancer. Persistent infection with one or more of about a dozen of these “high-risk” HPV types is an important factor in nearly all cases of cervical cancer. The development of HPV-induced cervical cancer is a slow process that generally takes many years. During this development phase, pre-cancerous cells can be detected by annual or semi-annual cervical cytology Papanicolaou screening, colloquially known as “Pap” smear testing. A cervical Pap smear with HPV DNA testing is used to detect cellular abnormalities and the presence of HPV. This allows targeted surgical removal of condylomatous and/or pre-cancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. A recently approved HPV vaccine, Gardasil, that blocks initial infection with several of the most common sexually transmitted HPV types may lead to further decreases in the incidence of HPV-induced cancer.^[27]

There is no definitive medical treatment of HPV infection. However, treatment is mainly aimed to treat warts or precancerous lesions. Two types of medical therapy which may be considered are cytodestructive therapy and immunotherapy. No treatment is considered superior to the other. However, selection of the treatment may depend on the wart size, number of warts, anatomic site of wart, wart morphology, patient preference, cost of treatment, convenience, adverse effects. Medical therapies for human papillomavirus infection include either imiquimod, sinecatechins, or podofilox.^{[28][29][30][31][32][33]} Surgical removal of external genital warts may be an alternative regimen to pharmacologic therapy. Surgical therapies include either tangential scissor excision, tangential shave excision, curettage, laser, or electrosurgery.^[34]

Most people become infected with various cutaneous HPV types during childhood. Papillomaviruses have a sturdy outer protein shell or “capsid” that renders them capable of lingering in the environment for long periods of time. Avoiding contact with contaminated surfaces, such as the floors of communal showers or airport security lines, might reduce the risk of cutaneous HPV infection. Treating common warts soon after they first appear may also reduce the spread of the infection to additional sites.

Genital HPV infections may be distributed widely over genital skin and mucosal surfaces, and transmission can occur even when there are no overt symptoms. Several strategies should be employed to minimize the risk of developing diseases caused by genital HPVs:

Warts as a cutaneous manifestation of HPV infection were first described by Hippocrates. Dr. Harald Zur Hausen (father of HPV virology) in 1975 described the relationship between HPV and cervical cancer.

• Genital warts were first described by Hippocrates (460–377 B.C.). Since those days, the term condyloma (a word of Greek origin) has been used for genital warts meaning “a round swelling around the anus”.^[1]
• In 1891 Infectious nature of common warts was noticed by Payne and Jadassohn.
• In 1943, Parson and Kidd published their milestone study where they showed that oral papillomatosis of rabbits is a viral disease and the oral papillomavirus was distinct from the skin papillomavirus
• In 1956, The concept of koilocytosis in PAP smears and cervical biopsies described by Koss & Durfee.
• EM demonstration of HPV particles in genital warts was shown by Dunn & Ogilvie in 1968 and Almeida et al in 1969.
• In 1975, Zur Hausen German physician presented the hypothesis on HPV as a potential cause of cervical cancer.^[2]
• Nobel prize in medicine went to Dr. Harald Zur Hausen in 2008 regarding his discoveries in HPV relation to cervical cancer.

• 
  Dr. Herald zur Hausen

Human papillomavirus may have different presentations depending on the anatomical region of involvement and the virus type. Mainly it is classified to cutaneous, anogenital and other mucosal surfaces.

Based on tissue involvement, human papillomavirus (HPV) is classified in to 3 main groups:

• Cutaneous
• Anogenital
• Other Mucosal surfaces

Currently, 210 different types of HPV have been discovered and the number keeps increasing.^[1][2] Clinical manifestations depend on which HPV type involve which anatomic area.^[3][4]

Human papilloma virus is usually transmitted via the sexual route to the human host.^[1] HPV life cycle is linked to epithelial differentiation and maturation of host keratinocytes, with transcription of specific gene products at every level.^[2][3] The pathogenesis of HPV infection causing cancer is mainly linked to high risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). E6 and E7 protein products of HPV interact with two important cell cycle regulatory protiens, P53 and Rb proteins of host cell, causing unchecked cellular replication accumulating mutations leading to cancer.^[4][5][6]

• Human papilloma virus is usually transmitted via the sexual route to the human host.^[1]
• Different types of HPV has a predilection for different types of epithelial tissue.^[7]

• HPV life cycle is linked to epithelial differentiation and maturation of host keratinocytes, with transcription of specific gene products at every level.^[2][3][8]
• HPV primarily infects basal cell layer of stratified squamous keratinised epithelium.^[9]
• Following transmission, the HPV uses the microabrasions to enter the basal stem cells via tissue specific heparan sulfate proteoglycans through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV.^[10]
• It than undergoes viral uncoating and viral DNA genome is than transported to nucleus maintaining a low copy number 10-200 viral genomes per cell (episome form).^[11]
• A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium.
• HPV uses host DNA replicative machinery to multiply as it lacks DNA polymerase activity.
• Specific viral genes are transcribed at every level of keratinocyte differention.
• Early proteins: E1, E2, E3, E4, E5, E6 and E7 proteins are synthesized primarily in middle layers, for reactivation of replication process in the differentiated cells.
• Late proteins: L1, L2 proteins are transcribed in the most superficial layers for virion assesmbly, release and reinfection, as they code for capsid proteins.^[12]

The pathogenesis of HPV infection causing cancer is mainly linked to high risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). Following HPV proteins play a significant role in the development of cancers associated with HPV.^[13]

E6 and E7 protein products of HPV interact with two important cell cycle regulatory protiens, P53 and Rb proteins of host cell, causing unchecked cellular replication accumulating mutations leading to cancer.^[4]

• Inhibition of P53

P53 protein is a cellular check point at G0/G1 to S phase of cell cycle and is also responsible for cell apoptosis for unrepaired DNA mutations. E6 protein binds P53 which results in degradation of P53, leaving cell without any check for mutations and unregulated cell.^[5][14]

growth.^{[15][16][17][18][19]}

• Inhibition of Rb protein

Rb protein is negative regulator of cell growth. It binds E2F transcription factor which controls DNA replication and cyclin protein induced entering of cell into S phase of cell cycle. E7 protein binds Rb/E2F, releasing E2F from the inhibitory effect of Rb causing increased cyclin induced entry of cell into S phase of cell cycle, resulting in increased replication rate of cells accumulating mutations.^{[19][20][6][21]}

HPV is a double-stranded DNA, non-enveloped capsid virus. Currently, 210 subtypes of this virus have been recognized. It may cause cutaneous or mucosal lesions. Some types have strong relation to cervical cancer and some types are found in benign skin lesion.

• Human papillomavirus (HPV) is a DNA virus belonging to its own family, papillomaviridae. There are 210 types of HPV and as reflected in its name, species specific for humans. It is a double-stranded DNA, non-enveloped capsid virus that has 7900 base pairs which have 90% homology between the types.
• The base pairs are arranged in a circle which includes the codes for two key proteins known as L1 and L2.
• These two proteins act as the “immunogene” which is required for self-assembly and the infectivity protein, respectively.^[1][2]

• 
  HPV invasion cycle

• Some types of HPV cause local self-limited infections while others can be differentiated by their predilection towards the development of human cancers. For example, HPV 16 and 18 are most frequently associated with cervical cancer.
• HPV 16 accounts for up to 50% of HPV causing cervical and anal cancers worldwide.^[3] In addition to those viruses associated with penile cancer, 70% are of the HPV 16 phenotype and occurs 6 times higher in males with histories of venereal warts or condylomata acuminata.

HPV infection must be differentiated from other diseases that causes warty lesions, pruritis, postcoital spotting or vaginal discharge, vaginal bleeding, painful sexual intercourse, respiratory distress

HPV infection must be differentiated from other diseases that causes warty lesions, pruritis, postcoital spotting or vaginal discharge, vaginal bleeding, painful sexual intercourse, respiratory distress and stridor in infants:^[1][2][3]

• Condylomata lata^[1]
• Molluscum contagiosum
• Seborrheic keratosis
• Lichen planus
• Fibroepithelial polyp, adenoma
• Melanocytic nevus
• Neoplastic lesions
• Pink pearly penile papules
• Vestibular papillae (micropapillomatosis labialis)
• Skin tags (acrochordons)
• Squamous cell carcinoma in situ
• Bowenoid papulosis
• Erythroplasia of Queyrat
• Bowen’s disease of the genitalia
• Benign Cervical Lesions
• Benign Vulvar Lesions
• Head and Neck Cutaneous Squamous Cell Carcinoma

Genital HPV infection is very common, with estimates suggesting that more than 50% of women will become infected with one or more of the sexually transmitted HPV types at some point during adulthood.^[1]

• Widespread in general population
• Incidence of common warts is more than plantar or flat warts

• Anogenital HPV is the most common sexually transmitted infection in the USA ^[2]
• In USA, the prevalence of anogenital HPV infection is estimated to be 79 million with incidence of 14 million new cases each year ^[2]
• Worldwide, 90% of genital warts is caused by the HPV 6 and 11^[3]
• Prevalence of genital warts is 1% in USA as compared to 10% in Scandinavian countries
• In USA, the incidence of genital warts has slightly increased in the year 2013

Genital Warts — Initial Visits to Physicians’ Offices, United States, 1966–2013

†Data from CDC

• In USA, the incidence of HPV associated cancer is 38,793 each year (data 2008-2012)^[4]

Cervical cancer

• Worldwide, the incidence of invasive cervical cancer is 500,000 cases each year.
• Worlwide, 70% of cervical cancer is caused by the HPV 16 and 18^[3]
• In USA, more than 90% of cervical cancer is caused by HPV.^[4]

Oropharyngeal cancer

• Incidence of oropharyngeal cancer associated with HPV is showing an increasing trend in USA^[5][6]
• 70% of oropharyngeal cancers are associated with HPV^[4]

Anal cancer

• In USA, the incidence of anal cancer has increased in the last three decades^[5][7][8][9]
• There is increased incidence among HIV positive individuals and incidence has not shown a decline after the advent of antiretroviral therapy.^[10]

Recurrent respiratory papillomatosis

• Rare with rates of about 2 cases per 100,000 children in the United States^[11]
• Common in children born to females having active genital warts at the time of vaginal delivery

Following demographic factors may affect the incidence and prevalence of HPV infection:

Cutaneous warts

• More common in children aged 12-16 yrs of age^{[12] [13]}
• 10% of children and 3.5% of adults are affected, worldwide

Genital warts

• Incidence of genital HPV infection increases at the age when individuals begin to engage in sexual activity.^[14][15]
• Highest incidence of genital warts is seen in females aged 20-24 yrs and males aged 25-29 yrs of age^[16] (CDC)
• Prevalence of cervical HPV in females may decline after age 30^[17]

HPV associated cancer

• Incidence is more common in younger age group(sexually active)^[18](2196503)^[19][20]

Recurrent respiratory papillomatosis

• Increased incidence is seen in children as compared to adults^[21][22]

Human Papillomavirus — Cervicovaginal Prevalence of Types 6, 11, 16 and 18 Among Women Aged 14–59 Years by Age Group and Time Period, National Health and Nutrition Examination Survey, 2003–2006 and 2007–2010

†Data from CDC

Genital warts

Prevalence per 1000 person-years Among participants in private health plans aged 10–39 years by sex, age group, and year, 2003–2010 is shown in the graph below:

†Data from CDC

HPV associated cancers

• Out of total 38,793 HPV-associated cancers that occur in the United States each year, 23,000 occur among women, and about 15,793 among men^[4]
• Three fold increased prevalence of HPV associated anal and oropharyngeal cancer in men as compared to women.
• Increased incidence of oropharngeal and anal cancer among men who have sex with men (MSM)^{[23][24][25][26][27]}
• Worldwide, the point prevalence of HPV in females is 10%, with highest prevalence among African females^[28]

• There may be increased incidence of high risk HPV infections in African American females as compared to Caucasian^[15][29]

Common risk factors for anogenital HPV infection are number of sex partners, having a new partner, duration of being sexually active, vaginal delivery and multiple deliveries. Close contact is the most potent factor for cutaneous infection.

The most potent risk factor in acquiring HPV skin infection is close contact,^[1] while the most important risk factor for anogenital infection is sexual activity.^[2]

Risk factors responsible for sexual transmission of HPV include:

• Number of sex partners^[3][4]
• Acquisition of new partner^[3]
• Having nonmonogamous sex partner^[5][6]
• Starting sexual activity at young age^[5]
• Vaginal delivery and multiple deliveries^[7]
• Age over 40 for women^[8]
• History of Chlamydia infection^[9]
• Long term OCP use^[10]

Most infections with HPV are subclinical, asymptomatic and resolves without any complications in immunocompetent individuals. Time to develop symptoms and signs is not well defined but it may take 3 weeks to 3 months for genital warts, several months to years for cellular abnormalities (metaplasia and dysplasia) and years for development of cancers. 90% of infections resolve within 2 years due to host immune response.^[1]Persistent HPV infection is associated with risk factors such as multiple sexual partners, alcohol consumption, immunosuppression, older age, and multiple types of HPV detected previously. Without treatment, persistent infection with low-risk types (low-grade intraepithelial lesions) may resolve spontaneously or persist and proliferate as warty lesions. However, high-risk HPV types (16,18,31,32) may lead to high-grade intraepithelial lesions which ultimately to carcinoma(cervical, anal, vaginal, vulvar, penile and oropharyngeal).^[2][3][4][5]Prognosis of HPV infection depends primarily on type of HPV causing infection.^{[6][7][8][9][10]}

Most infections with HPV are subclinical, asymptomatic and resolves without any complications in immunocompetent individuals. Time to develop symptoms and signs is not well defined but it may take 3 weeks to 3 months for genital warts, several months to years for cellular abnormalities (metaplasia and dysplasia) and years for development of cancers. 90% of infections resolve within 2 years due to host immune response.^[1]

Persistent HPV infection is associated with risk factors such as multiple sexual partners, alcohol consumption, immunosuppression, older age, and multiple types of HPV detected previously. Without treatment, persistent infection with low-risk types (low-grade intraepithelial lesions) may resolve spontaneously or persist and proliferate as warty lesions. However, high-risk HPV types (16,18,31,32) may lead to high-grade intraepithelial lesions which ultimately to carcinoma(cervical, anal, vaginal, vulvar, penile and oropharyngeal).^[2][3][4][5]Complications associated with the human papillomavirus infection include:^{[11][12][13][14][15][16][17][18]}genital warts, cervical cancer, vaginal cancer, vulvar cancer, anal cancer, penile cancer, head and neck cancer.

Complications associated with the human papilloma virus infection include:^{[11][12][13][14][15][16][17][18]}

• Genital warts
• Cervical cancer
• Vaginal cancer
• Vulvar cancer
• Anal cancer
• Penile cancer
• Head and neck cancer

Prognosis of HPV infection depends primarily on type of HPV causing infection.^{[6][7][8][9][10][19][20][21][22]}

• Low risk HPV type (1, 2, 4, 6, 11)^[9]
• Immunocompetent^[10]
• Early diagnosis and treatment^[9][19]
• Regular follow-up
• Safe sex behavior

• High risk HPV type(16, 18, 31, 32)^[6][7]
• Immunocompromised^[10]
• Multiple sexual partners^[8][21]
• Repeated infection in past years
• Delay in seeking treatment^[23]
• Lack of follow up and screening^[23]
• Metastatic carcinoma (cervical, anal, vaginal, oropharyngeal)^[8][24]
• Presence of other STDs (HIV, syphilis, chlamydia)^[20][21][22]
• Tobacco and alcohol usage^[8][25][26]