Introduction

Understanding the terminology surrounding the Human Papillomavirus (HPV) is crucial for patients, researchers, and healthcare providers. This glossary provides clear, scientifically accurate definitions for more than 40 essential terms related to HPV virology, pathology, clinical diagnosis, and treatment. From molecular concepts like viral integration to clinical procedures such as colposcopy and LEEP, this resource aims to demystify the language used in HPV research and care.

Human papillomavirus infection (HPV infection) is an infection caused by a DNA virus from the Papillomaviridae family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. Sometimes an HPV infection persists and results in warts or precancerous lesions. Many warts are caused by HPV. These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat.

Nearly all cervical cancer is due to HPV and two strains, HPV16 and HPV18, account for 70% of all cases. HPV16 is responsible for almost 90% of HPV-related cancers of the mouth, throat, or tonsils. Between 60% and 90% of the other cancers listed above are also linked to HPV. HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis.

Over 200 types of HPV have been described. An individual can become infected with more than one type of HPV and the disease is only known to affect humans. More than 40 types may be spread through sexual contact and infect the anus and genitals. Risk factors for persistent infection by sexually transmitted types include early age of first sexual intercourse, multiple sexual partners, smoking and poor immune function.

These types are typically spread by direct skin-to-skin contact, with vaginal and anal sex being the most common methods. HPV infection can spread from a mother to baby during pregnancy. There is limited evidence that HPV can spread indirectly, but some studies suggest it is theoretically possible to spread via contact with contaminated surfaces. HPV is not killed by common hand sanitizers or disinfectants, increasing the possibility of the virus being transferred via non-living infectious agents called fomites.

HPV vaccines can prevent the most common types of infection. Many public health organisations now test directly for HPV. Screening allows for early treatment, which results in better outcomes. Nearly every sexually active individual is infected with HPV at some point in their lives. HPV is the most common sexually transmitted infection (STI), globally. High-risk HPVs cause about 5% of all cancers worldwide and about 37,300 cases of cancer in the United States each year.

Cervical cancer is among the most common cancers worldwide, causing an estimated 604,000 new cases and 342,000 deaths in 2020. About 90% of these new cases and deaths of cervical cancer occurred in low and middle income countries. Roughly 1% of sexually active adults have genital warts. HPV is a group of more than 200 viruses, which are designated by a number for each virus type.

Some HPV types, such as HPV5, may establish infections that persist for the lifetime of the individual, without manifesting any clinical symptoms. HPV types 1 and 2 can cause warts in some infected individuals. HPV types 6 and 11 can cause genital warts and laryngeal papillomatosis. Many HPV types are carcinogenic. About twelve HPV types (including types 16, 18, 31, and 45) are called "high-risk" types (HR-HPV) because persistent infection has been linked to cancer of the oropharynx, larynx, vulva, vagina, cervix, penis, and anus.

These cancers all involve sexually transmitted infection of HPV to the stratified epithelial tissue. HPV type 16 is the strain most likely to cause cancer and is present in about 47% of all cervical cancers, and in many vaginal and vulvar cancers, penile cancers, anal cancers and cancers of the head and neck. The table below lists common signs of HPV infection and the associated types of HPV.

Skin infection ("cutaneous" infection) with HPV is common and can cause noncancerous skin growths called warts (verrucae). Warts are caused by the rapid growth of cells on the outer layer of the skin. While cases of warts have been described since ancient Greece, their viral cause was not known until 1907, when Dr. Giuseppe Ciuffo showed their viral nature by inoculating a wart extract into the skin.

Skin warts are most common in childhood and typically appear and regress spontaneously over weeks to months. Recurrence is common. Types of warts include: Common warts are usually found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Cutaneous HPV types can cause genital warts but are not associated with the development of cancer.

Plantar warts are found on the soles of the feet; they grow inward, generally causing pain when walking. Subungual or periungual warts form under the fingernail (subungual), around the fingernail, or on the cuticle (periungual). They are more difficult to treat than warts in other locations. Flat warts are most commonly found on the arms, face, or forehead. Like common warts, flat warts occur most frequently in children and teens.

In people with normal immune function, flat warts are not associated with the development of cancer. HPV infection of the skin in the genital area is the most common sexually transmitted infection worldwide. Such infections are associated with genital or anal warts (medically known as condylomata acuminata or venereal warts) and these warts can be diagnosed on visual inspection and confirmed by biopsy.

The strains of HPV that can cause genital warts are usually different from those that cause warts on other parts of the body. A wide variety of HPV types can cause genital warts, but types 6 and 11 together account for about 90% of all cases. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months.

People may transmit the virus to others even if they do not display overt symptoms of infection. Most people acquire genital HPV infections at some point in their lives, and about 10% of women are currently infected. In addition to genital warts, infection by HPV types 6 and 11 can cause a rare condition known as recurrent laryngeal papillomatosis, in which warts form on the larynx or other areas of the respiratory tract.

These warts can recur frequently, may interfere with breathing, and in extremely rare cases can progress to cancer. For these reasons, repeated surgery to remove the warts may be advisable. Cervical cancer is among the most common cancers worldwide, causing an estimated 604,000 new cases and 342,000 deaths in 2020. About 90% of these new cases and deaths occurred in low and middle income countries, where screening tests and treatment of early cervical cell changes are not readily available.

In the USA, cervical cancer accounts for 0.7% of new cancer cases. Oral cavity and pharynx cancer accounts for 2.9% of new cancer cases and predominantly affects men. HPV is thought to cause 60% to 70% of oropharyngeal cancers. 37,300 cases of cancer, caused by HPV, occur each year. In some infected individuals, their immune systems may fail to control HPV.

Lingering infection with high-risk HPV types, such as types 16, 18, 31, and 45, can favor the development of cancer. Co-factors such as cigarette smoke can also enhance the risk of HPV-related cancers. HPV is believed to cause cancer by integrating its genome into nuclear DNA. Some of the early genes expressed by HPV, such as E6 and E7, act as oncogenes that promote tumor growth and malignant transformation.

HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number. E6 produces a protein (also called E6) that simultaneously binds to two host cell proteins called p53 and E6-Associated Protein (E6-AP). E6AP is an E3 ubiquitin ligase, an enzyme whose purpose is to tag proteins with a post-translational modification called Ubiquitin. By binding both proteins, E6 induces E6AP to attach a chain of ubiquitin molecules to p53, thereby flagging p53 for proteosomal degradation.

Normally, p53 acts to prevent cell growth and promotes cell death in the presence of DNA damage. p53 also upregulates the p21 protein, which blocks the formation of the cyclin D/Cdk4 complex, thereby preventing the phosphorylation of retinoblastoma protein (RB), and in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor-suppressor protein that arrests the cell cycle and prevents cell growth and survival when DNA damage occurs.

Thus, the degradation of p53, induced by E6, promotes unregulated cell division, cell growth, and cell survival, all characteristics of cancer. It is important to note that although the interaction between E6, E6AP, and p53 was the first to be characterized, several other proteins in the host cell interact with E6, supporting the induction of cancer. Studies have also shown a link between a wide range of HPV types and squamous cell carcinoma of the skin.

In such cases, in vitro studies suggest that the E6 protein of the HPV virus may inhibit apoptosis induced by ultraviolet light. Nearly all cases of cervical cancer are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases. In 2012, twelve HPV types were considered carcinogenic for cervical cancer by the International Agency for Research on Cancer: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59.

One study found that 74% of squamous cell carcinomas and 78% of adenocarcinomas tested positive for HPV types 16 or 18. Persistent HPV infection increases the risk for developing cervical carcinoma. Individuals who have an increased incidence of these types of infection are women with HIV/AIDS, who are at a 22-fold increased risk of cervical cancer. The carcinogenic HPV types in cervical cancer belong to the alphapapillomavirus genus.

They can be grouped further into HPV clades. The two major carcinogenic HPV clades, alphapapillomavirus-9 (A9) and alphapapillomavirus-7 (A7), contain HPV16 and HPV18, respectively. These two HPV clades were shown to have different effects on tumour molecular characteristics and patient prognosis, with clade A7 being associated with more aggressive pathways and an inferior prognosis. In 2020, about 604,000 new cases and 342,000 deaths from cervical cancer occurred worldwide.

Around 90% of these occurred in the developing world. Most HPV infections of the cervix are cleared rapidly by the immune system and do not progress to cervical cancer (see below the Clearance subsection in Virology). Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people who have been infected with HPV for a long time, usually over a decade or more (persistent infection).

Furthermore, both the HPV infection and cervical cancer drive metabolic modifications that may be correlated with the aberrant regulation of enzymes related to metabolic pathways. Non-European (NE) HPV16 variants are significantly more carcinogenic than European (E) HPV16 variants. Initially, cervical cancer is often asymptomatic. Symptoms of more advanced cervical cancer include pain during sex, unusual vaginal bleeding, changes to vaginal discharge, lower back pain, and pelvic pain.

Women and men who have HPV are at increased risk of developing anal cancer. Most cases (90%) are linked HPV infection. The risk for anal cancer is 17 to 31 times higher among HIV-positive individuals who were co-infected with high-risk HPV, and 80 times higher for HIV-positive men who have sex with men.

Human papillomavirus infection (HPV infection) is an infection caused by a DNA virus from the Papillomaviridae family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. Sometimes an HPV infection persists and results in warts or precancerous lesions. Many warts are caused by HPV. These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat. Nearly all cervical cancer is due to HPV and two strains, HPV16 and HPV18, account for 70% of all cases. HPV16 is responsible for almost 90% of HPV-related cancers of the mouth, throat, or tonsils. Between 60% and 90% of the other cancers listed above are also linked to HPV. HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis.

Over 200 types of HPV have been described. An individual can become infected with more than one type of HPV and the disease is only known to affect humans. More than 40 types may be spread through sexual contact and infect the anus and genitals. Risk factors for persistent infection by sexually transmitted types include early age of first sexual intercourse, multiple sexual partners, smoking and poor immune function. These types are typically spread by direct skin-to-skin contact, with vaginal and anal sex being the most common methods. HPV infection can spread from a mother to baby during pregnancy. There is limited evidence that HPV can spread indirectly, but some studies suggest it is theoretically possible to spread via contact with contaminated surfaces. HPV is not killed by common hand sanitizers or disinfectants, increasing the possibility of the virus being transferred via non-living infectious agents called fomites.

HPV vaccines can prevent the most common types of infection. Many public health organisations now test directly for HPV. Screening allows for early treatment, which results in better outcomes. Nearly every sexually active individual is infected with HPV at some point in their lives. HPV is the most common sexually transmitted infection (STI), globally.

High-risk HPVs cause about 5% of all cancers worldwide and about 37,300 cases of cancer in the United States each year. Cervical cancer is among the most common cancers worldwide, causing an estimated 604,000 new cases and 342,000 deaths in 2020. About 90% of these new cases and deaths of cervical cancer occurred in low and middle income countries. Roughly 1% of sexually active adults have genital warts.

HPV is a group of more than 200 viruses, which are designated by a number for each virus type. Some HPV types, such as HPV5, may establish infections that persist for the lifetime of the individual, without manifesting any clinical symptoms. HPV types 1 and 2 can cause warts in some infected individuals. HPV types 6 and 11 can cause genital warts and laryngeal papillomatosis.

Many HPV types are carcinogenic. About twelve HPV types (including types 16, 18, 31, and 45) are called "high-risk" types (HR-HPV) because persistent infection has been linked to cancer of the oropharynx, larynx, vulva, vagina, cervix, penis, and anus. These cancers all involve sexually transmitted infection of HPV to the stratified epithelial tissue. HPV type 16 is the strain most likely to cause cancer and is present in about 47% of all cervical cancers, and in many vaginal and vulvar cancers, penile cancers, anal cancers and cancers of the head and neck.

The table below lists common signs of HPV infection and the associated types of HPV.

Skin infection ("cutaneous" infection) with HPV is common and can cause noncancerous skin growths called warts (verrucae). Warts are caused by the rapid growth of cells on the outer layer of the skin.

While cases of warts have been described since ancient Greece, their viral cause was not known until 1907, when Dr. Giuseppe Ciuffo showed their viral nature by inoculating a wart extract into the skin.

Skin warts are most common in childhood and typically appear and regress spontaneously over weeks to months. Recurrence is common.

Types of warts include:

Common warts are usually found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Cutaneous HPV types can cause genital warts but are not associated with the development of cancer.

Plantar warts are found on the soles of the feet; they grow inward, generally causing pain when walking.

Subungual or periungual warts form under the fingernail (subungual), around the fingernail, or on the cuticle (periungual). They are more difficult to treat than warts in other locations.

Flat warts are most commonly found on the arms, face, or forehead. Like common warts, flat warts occur most frequently in children and teens. In people with normal immune function, flat warts are not associated with the development of cancer.

HPV infection of the skin in the genital area is the most common sexually transmitted infection worldwide. Such infections are associated with genital or anal warts (medically known as condylomata acuminata or venereal warts) and these warts can be diagnosed on visual inspection and confirmed by biopsy.

The strains of HPV that can cause genital warts are usually different from those that cause warts on other parts of the body. A wide variety of HPV types can cause genital warts, but types 6 and 11 together account for about 90% of all cases.

The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. People may transmit the virus to others even if they do not display overt symptoms of infection.

Most people acquire genital HPV infections at some point in their lives, and about 10% of women are currently infected.

In addition to genital warts, infection by HPV types 6 and 11 can cause a rare condition known as recurrent laryngeal papillomatosis, in which warts form on the larynx or other areas of the respiratory tract. These warts can recur frequently, may interfere with breathing, and in extremely rare cases can progress to cancer. For these reasons, repeated surgery to remove the warts may be advisable.

Cervical cancer is among the most common cancers worldwide, causing an estimated 604,000 new cases and 342,000 deaths in 2020. About 90% of these new cases and deaths occurred in low and middle income countries, where screening tests and treatment of early cervical cell changes are not readily available.

In the USA, cervical cancer accounts for 0.7% of new cancer cases. Oral cavity and pharynx cancer accounts for 2.9% of new cancer cases and predominantly affects men. HPV is thought to cause 60% to 70% of oropharyngeal cancers. 37,300 cases of cancer, caused by HPV, occur each year.

In some infected individuals, their immune systems may fail to control HPV. Lingering infection with high-risk HPV types, such as types 16, 18, 31, and 45, can favor the development of cancer.

Co-factors such as cigarette smoke can also enhance the risk of HPV-related cancers.

HPV is believed to cause cancer by integrating its genome into nuclear DNA. Some of the early genes expressed by HPV, such as E6 and E7, act as oncogenes that promote tumor growth and malignant transformation. HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number.

E6 produces a protein (also called E6) that simultaneously binds to two host cell proteins called p53 and E6-Associated Protein (E6-AP). E6AP is an E3 ubiquitin ligase, an enzyme whose purpose is to tag proteins with a post-translational modification called Ubiquitin. By binding both proteins, E6 induces E6AP to attach a chain of ubiquitin molecules to p53, thereby flagging p53 for proteosomal degradation. Normally, p53 acts to prevent cell growth and promotes cell death in the presence of DNA damage. p53 also upregulates the p21 protein, which blocks the formation of the cyclin D/Cdk4 complex, thereby preventing the phosphorylation of retinoblastoma protein (RB), and in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor-suppressor protein that arrests the cell cycle and prevents cell growth and survival when DNA damage occurs. Thus, the degradation of p53, induced by E6, promotes unregulated cell division, cell growth, and cell survival, all characteristics of cancer.

It is important to note that although the interaction between E6, E6AP, and p53 was the first to be characterized, several other proteins in the host cell interact with E6, supporting the induction of cancer.

Studies have also shown a link between a wide range of HPV types and squamous cell carcinoma of the skin. In such cases, in vitro studies suggest that the E6 protein of the HPV virus may inhibit apoptosis induced by ultraviolet light.

Nearly all cases of cervical cancer are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases. In 2012, twelve HPV types were considered carcinogenic for cervical cancer by the International Agency for Research on Cancer: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. One study found that 74% of squamous cell carcinomas and 78% of adenocarcinomas tested positive for HPV types 16 or 18. Persistent HPV infection increases the risk for developing cervical carcinoma. Individuals who have an increased incidence of these types of infection are women with HIV/AIDS, who are at a 22-fold increased risk of cervical cancer.

The carcinogenic HPV types in cervical cancer belong to the alphapapillomavirus genus. They can be grouped further into HPV clades. The two major carcinogenic HPV clades, alphapapillomavirus-9 (A9) and alphapapillomavirus-7 (A7), contain HPV16 and HPV18, respectively. These two HPV clades were shown to have different effects on tumour molecular characteristics and patient prognosis, with clade A7 being associated with more aggressive pathways and an inferior prognosis.

In 2020, about 604,000 new cases and 342,000 deaths from cervical cancer occurred worldwide. Around 90% of these occurred in the developing world.

Most HPV infections of the cervix are cleared rapidly by the immune system and do not progress to cervical cancer (see below the Clearance subsection in Virology). Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people who have been infected with HPV for a long time, usually over a decade or more (persistent infection). Furthermore, both the HPV infection and cervical cancer drive metabolic modifications that may be correlated with the aberrant regulation of enzymes related to metabolic pathways.

Non-European (NE) HPV16 variants are significantly more carcinogenic than European (E) HPV16 variants.

Initially, cervical cancer is often asymptomatic. Symptoms of more advanced cervical cancer include pain during sex, unusual vaginal bleeding, changes to vaginal discharge, lower back pain, and pelvic pain.

Women and men who have HPV are at increased risk of developing anal cancer. Most cases (90%) are linked HPV infection.

The risk for anal cancer is 17 to 31 times higher among HIV-positive individuals who were co-infected with high-risk HPV, and 80 times higher for HIV-positive men who have sex with men.

A literature review of studies and meta-analysis concluded that HPV16 was most carcinogenic, regardless of whether a person is HIV positive or negative, and that detecting the presence of HPV16 should be a priority for anal cancer prevention.

HPV is associated with approximately 50% of penile cancers. In the United States, penile cancer accounts for about 0.5% of all cancer cases in men. HPV16 is the most commonly detected associated type. The risk of penile cancer increases 2- to 3-fold for individuals who are infected with HIV as well as HPV.

Oral infection with high-risk carcinogenic HPV types (most commonly HPV 16) is associated with an increasing number of head and neck cancers. This association is independent of tobacco and alcohol use.

The local percentage varies widely, from 70% in the United States to 4% in Brazil. Engaging in anal or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers.

In the United States, the number of newly diagnosed, HPV-associated head and neck cancers has surpassed that of cervical cancer cases. The rate of such cancers has increased from an estimated 0.8 cases per 100,000 people in 1988 to 4.5 per 100,000 in 2012, and, as of 2021, the rate has continued to increase. Researchers explain these recent data by an increase in oral sex. This type of cancer is more common in men than in women.

The mutational profile of HPV-positive and HPV-negative head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases.

Some evidence links HPV to benign and malignant tumors of the upper respiratory tract. The International Agency for Research on Cancer has found that people with lung cancer were significantly more likely to have several high-risk forms of HPV antibodies compared to those who did not have lung cancer. Researchers looking for HPV among 1,633 lung cancer patients and 2,729 people without the lung disease found that people with lung cancer had more types of HPV than noncancer patients did, and among lung cancer patients, the chances of having eight types of serious HPV were significantly increased. In addition, expression of HPV structural proteins by immunohistochemistry and in vitro studies suggest HPV presence in bronchial cancer and its precursor lesions. Another study detected HPV in the exhaled breath condensate (EBC), bronchial brushing and neoplastic lung tissue of cases, and found a presence of an HPV infection in 16.4% of the subjects affected by nonsmall cell lung cancer, but in none of the controls. The reported average frequencies of HPV in lung cancers were 17% and 15% in Europe and the Americas, respectively, and the mean number of HPV in Asian lung cancer samples was 35.7%, with considerable heterogeneity between certain countries and regions.

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